Introduction
After cardiovascular disease, cancer is the second leading cause of death among transplant recipients.
To adjust the poorer outcomes of cancer, cancer screening strategies is considered for early detection of cancer
Incidence of all cause and site specific cancer after transplantation
The cumulative incidence of solid organ cancer 15 years after transplantation about 10 to 15%. The cumulative incidence of skin cancer is about 60% exceeds that of the general population by 2 to 3 folds.
According to cancer type, there is a great risk in viral related and immune driven cancers such as PTLD, anogenital cancer and kaposi sarcoma.
Breast and prostate cancers aren’t increased in transplant recipients.
Cancer mortality
Once cancer develops, the risk of death is high.
The standard mortality ratio for all cancer are 1.8 to 1.9 times higher compared with matched population.
The risk is the highest among those with melanoma,urogenital and non-Hodgkin lymphoma.
Risk factors for cancer development
Old age
Male sex
Smoking
Prolonged sun exposure
T cell depleting Immunosuppressive agents.
Acute rejection
Sensitization status
Duration of dialysis before transplantation
Mechanisms of cancer development after transplantation
1. Poor immune control of known oncogenic viruses in patients on immunosuppression as in viral associated cancers.
2. The accumulation of mutations especially in skin cancer
Common cancers after transplantation
1. Renal cell carcinoma up to seven fold compared with the general population.
2. Skin cancer
The most common type in kidney transplant recipients and is more aggressive.
3. Post-transplant lymphoproliferative disease
Management of recipients of kidney transplant who have cancer
Immunosuppression Management and treatment in transplant recipients with cancer
Reduction of immunosuppression should be balanced to prevent the risk of rejection and induce cancer regression.
The using of immune checkpoint inhibitors is limited in transplant patients due to increased risk of rejection.
1. Please summarize this article Introduction
Kidney transplantation is the best treatment option for acceptable candidates with kidney failure because it improves the quality of life and overall survival for patients on maintenance dialysis. It is also the most cost-effective treatment strategy for those needing KRT. However, transplantation is not a cure. Which means that recipient needs to continue on life-long immunosuppression. Cancer is a major complication of immunosuppression in kidney transplantation and is the second cause of death after cardiovascular disease. Incidence of All-Cause and Site-Specific Cancer after Transplantation
The cumulative incidence of solid organ cancer ranges between 10% and 15% at around 15 years after transplantation.
For skin cancers it reaches 60% in Europe, Australia, and New Zealand.
In kidney transplant it exceeds that of the general population by approximately two- to three folds after adjustment for age and sex. Cancer Mortality in Recipients of Kidney Transplants
Once cancers develop, the risk of death is high.
Observational data in most Western countries have shown the standard mortality ratios for all cancer types are at least 1.8–1.9 times higher compared with the age- and sex-matched general population. Risk Factors for Cancer Development
There are many reasons for the higher cancer risk after transplantation.
Risk factors shared with general population:
1. Increasing age,
2. Male sex
3. Smoking, and
4. Prolonged sun exposures.
Other risk factors unique to transplantation:
1. Immunosuppression use (T cell–depleting agents).
2. acute rejection.
3. Sensitization status.
4. Duration of dialysis before transplantation.
Mechanisms of Cancer Development after Transplantation
One potential mechanism is through poor immune control of known oncogenic viruses in patients on immunosuppression (e.g Kaposi sarcoma (human herpesvirus 8), PTLD (Epstein– Barr virus [EBV]), and lip and anal cancers (HPV)).
Another mechanism is accumulation of mutations that would otherwise be repaired or recognized by the immune system.
Common Cancers after Transplantation
Although the risk of overall cancer development is high after transplantation, the risks of certain cancer types are much higher than others.
The three most common cancer types:
Renal cell carcinoma
Skin cancer
PTLD Cancer Screening Strategies in Transplant Recipients
High-quality, randomized controlled trials have shown that cancer screening through early detection reduces cancer-specific mortality in the general population.
Despite the lack of trial-based evidence to support routine screening in this high-risk group, routine population-based cancer screening for breast, colorectal, and cervical cancer is recommended and should be aligned to the guidelines as per the general population.
Some guidelines also suggest routine skin checks by dermatologists in recipients of transplants who are at high risk, and abdominal ultrasounds and serum a-fetoprotein levels should be checked every 6 months for those with underlying liver disease and chronic HBV infections.
For patients who are at risk of developing renal cell carcinoma (such as those with a history of acquired cystic disease, those with a family history, those who are heavy smokers, and those who use long-term analgesics), ultrasonographic screening (annually or biennially) of the native kidneys may be considered to detect occult malignancy. Management of Recipients of Kidney Transplants Who Have Cancer Immunosuppression Management and Treatment in Transplant Recipients with Cancer
Management of immunosuppression in recipients of transplants who are living with cancer is complex and challenging. A consensus plan between transplant professionals, oncologists, and allied health professionals is therefore needed. Reduction of immunosuppression needs to be balanced against risk of rejection. No strong evidence to support change to MTOR inhibitor except in case of Kaposi sarcoma and squamous cell carcinoma.
The use of checkpoint inhibitors is limited in recipients of transplants given the potential for rejection with nonspecific immune-system activation. Although checkpointinhibitors are effective in treating melanoma, non–small cell lung cancer, and renal cell carcinoma in the general population, their use in the kidney transplant population requires further investigation and cannot be recommended at this time, outside of a study protocol. Putting Patients’ Perspectives at the Heart of Cancer Management Patient centered approach is needed to take into account patient concern, also multidisciplinary approach is essential. Conclusions
Cancer is the leading cause of morbidity and mortality in patients with kidney transplants. No good evidence to help optimize the immunosuppression to reduce risk from cancer without increasing risk on graft. Also screening protocol to help prevent cancer occurrence and early discovery is extrapolated from general population. Further studies are needed to answer a lot of questions.
After cardiovascular disease, cancer is the second leading cause of death among recipients of transplants in most Western countries.One of the most feared complications associated with immunosuppression after kidney transplantation is cancer .Cancer is also considered as one of the core clinical outcomes by clinicians, patients, and caregivers, and there is now consensus among key stakeholders suggesting cancer should be included as an outcome in all interventional trials of kidney transplantation.
Incidence of All-Cause and Site-Specific Cancer after Transplantation
The cumulative incidence of solid organ cancer ranges between 10% and 15% at around 15 years after transplantation. For skin cancers, the cumulative incidence reaches 60% in Europe, Australia, and New Zealand. The excess overall cancer risk in patients with kidney transplant exceeds that of the general population by approximately two- to three-fold after adjustment for age and sex. The magnitude of the higher risk is also dependent on cancer types, with the greatest risk in viral-related and immunedriven cancers such as post-transplant lymphoproliferative disease (PTLD), anogenital cancer, and Kaposi sarcoma ., Interestingly, certain solid organ cancers such as breast and prostate cancers are not increased in recipients of transplants
Cancer Mortality in Recipients of Kidney Transplant
Once cancers develop, the risk of death is high. Observational data in most Western countries have shown the standard mortality ratios for all cancer types are at least 1.8–1.9 times higher compared with the age- and sex-matched general population. The risk is greatest among those with melanoma, urogenital cancers, and non-Hodgkin lymphoma, with an overall risk of cancer-related death exceeding five to ten times that of those without kidney transplants.
Risk Factors for Cancer Development
There are many reasons for the higher cancer risk after transplantation. Some of these factors, such as increasing age, male sex, smoking, and prolonged sun exposures, are shared by patients in the general population. Other risk factors, including immunosuppression use (T cell–depleting agents), acute rejection , sensitization status , and duration of dialysis before transplantation.The specific types of cancer that develop after transplantation also vary by geographic areas. Observational and registry data from Europe, North America, Australia, and New Zealand indicate the most common cancer types are nonmelanoma skin cancers (NMSCs), PTLD, and lip cancer . In contrast, data from non-Western Asian and Middle Eastern transplant cohorts suggest higher incidences of urothelial transitional cell carcinoma, renal cell carcinoma, and gastrointestinal cancers in their populations.
Mechanisms of Cancer Development after Transplantation
Although the precise mechanisms are unclear, the effects of immunosuppression on dampening the immune system may create a variety of pathways for cancer development. One potential mechanism is through poor immune control of known oncogenic viruses in patients on immunosuppression. For example, increases in viral-associated cancers, such as Kaposi sarcoma (human herpesvirus 8), PTLD (Epstein– Barr virus [EBV]), and lip and anal cancers (HPV) are common in patients with suppressed immune systems . Another mechanism of immunosuppression-related cancer development is through accumulation of mutations that would otherwise be repaired or recognized by the immune system. This mechanism may be predominant in skin cancers.
Common Cancers after Transplantation
Renal Cell Carcinoma–
Compared with the general population, recipients of kidney transplants have a higher risk (up to seven-fold) of renal cell carcinoma.Ninety percent of renal cell carcinomas develop in the native kidneys as opposed to the allograft. Risk factors for development of renal cell carcinomas posttransplantation include male sex , increasing age African descent and longer time on dialysis .
Skin Cancer
Skin Cancer Skin cancer is the most common cancer type in recipients of kidney transplants and is more aggressive than skin cancers occurring in the general population. The most commonly reported skin cancers in recipients of kidney transplants include cutaneous squamous cell carcinoma, basal cell carcinoma, Kaposi sarcoma, and malignant melanoma
.
Post-Transplant Lymphoproliferative Disease
PTLD is a well-recognized complication after kidney transplantation. Although it is a rare disease, it is associated with poor outcomes. In most instances (approximately 90%), PTLD is associated with EBV.Compared with adult recipients of transplants, the risk of developing lymphoproliferative disease in pediatric recipients of transplants is at least 30-times higher than the age- and sex-matched general population.
Human Papillomavirus Vaccination in Recipients of Kidney Transplants
The incidence of HPV-related anogenital cancer is at least ten- to 15-fold higher in recipients of kidney transplants compared with the age- and sex-matched general population.
Management of Recipients of Kidney Transplants Who Have Cancer
Transplant Recipients with Cancer Management of immunosuppression in recipients of transplants who are living with cancer is complex and challenging. A concerted approach between transplant professionals, oncologists, and allied health professionals is therefore needed to ensure optimal care for our patients. Meticulous understanding of the underlying immunologic risk and cancer severity is needed to optimize immunosuppression dose to prevent the risk of acute rejection, while balancing against the need to induce regression of the cancer.For patients with squamous cell carcinoma, there is now trial-based evidence to suggest conversion to an mTOR inhibitor may reduce the risk of cancer in the longer term .However, mTOR-inhibitor use may also be associated with a higher risk of death . Therefore, there are insufficient data to consider mTOR inhibitors as protective against other cancer types apart from squamous cell carcinoma and Kaposi sarcoma
What is the level of evidence provided by this article
Level 5
Renal transplantation is by far considered the best therapeutic option for ESRD compared to maintenance on haemodialysis. However the risk of immunosuppression is associated with the increased incidence of malignancies. Cancer is the second leading cause of death among recipients of transplants in most Western countries after cardiovascular disease.
Some recommended strategies were adopted to decrease cancer risk as human papillomavirus (HPV) vaccination and cancer-screening programs to detect cancers at their earliest stages.
Incidence of All-Cause and Site-Specific Cancer after Transplantation
The cumulative incidence of solid organ cancer ranges between 10% and 15% at around 15 years after transplantation. The cumulative incidence for skin cancers is nearly 60%. The estimated overall cancer risk in patients with kidney transplant exceeds that of the general population by about two- to three-fold after adjustment for age and sex.
The magnitude of the higher risk is also dependent on cancer types, with considerable risk in viral related and immune driven cancers such as post-transplant lymphoproliferative disease (PTLD), anogenital cancer, and Kaposi sarcoma.
Cancer Mortality in Recipients of Kidney Transplants
The risk of death increases once cancers develop. The standard mortality ratios for all cancer types are 1.8–1.9 times higher compared with the age- and sex-matched general population.
The risk is greatest among those with melanoma, urogenital cancers, and non-Hodgkin lymphoma, with an overall risk of cancer-related death exceeding five to ten times that of general population.
Potential differences in the cancer cell biology in recipients of transplants may be attributed to long-term immunosuppression, associated comorbidities, and low uptake of recommended prevention and screening strategies.
Risk Factors for Cancer Development
Higher cancer risk post transplantation could be due to increasing age, male sex, smoking, and prolonged sun exposures. Risk factors as long-term immunosuppression use (T cell–depleting agents), acute rejection, sensitization status, and duration of dialysis prior to transplantation are peculiar to kidney disease and transplant populations.
CKD is linked to higher cancer risk and poor cancer outcomes is a point under studies. Many of these cancers, such as renal cell carcinoma and multiple myeloma, are over-represented in the CKD/ ESRD populations.
Impaired tumor surveillance and immunity to viral or other tumor antigens are probable contributing factors to development of post-transplant malignancy.
For cancer associated with kidney disease and kidney failure, such as kidney and bladder cancer, the overall standardized incidence ratios (SIRs) are 44 and 43, respectively. Women have a much higher risk than men for kidney (SIR, 94.6; [95% CI], 75 to 120) and bladder cancers (SIR, 120; 95% CI, 77 to 134).
Mechanisms of Cancer Development after Transplantation
The effects of immunosuppression on dampening the immune system may establish plenty of pathways for cancer development. Theories highlighted indicate poor immune control of known oncogenic viruses being common as Kaposi sarcoma (human herpes virus 8), PTLD (Epstein Barr virus [EBV]), and lip and anal cancers (HPV) in candidates with suppressed immune systems. Other suggested theory is probable accumulation of mutations that should have been repaired or recognized by the immune system which is out of optimum function. This theory can explain why skin cancers are predominant in such population as immunosuppression impairs the cells’ ability to repair ultraviolet (UV) radiation–induced DNA damage. Moreover immunosuppression can lead to a decrease of xeroderma pigmentosum complementation groups A and G, which are components of nucleotide excision repair.
Tacrolimus is criminated for elevation the level of TGF-b, hence promotes tumor progression and metastasis. Besides calcineurin inhibitors inhibit signaling via calcineurin and NF of activated T cells, which can activate p53, a hallmark of some NMSCs. Cyclosporine potentiates as well direct effects on tumor development and progression via TGF-b or IL-6 overexpression pathways.
Cyclosporine itself inhibits DNA repair consequently accumulates mutations resulting in induction of apoptosis in activated T cells and inhibition of apoptosis in other cells by opening the mitochondrial permeability transition pores.
Regarding the oncogenic role of azathioprine sensitizes the skin to UVA radiation and leads to further accumulation of 6-thioguanine in the DNA associated with a higher risk of NMSCs.
Contrarily Mammalian target of rapamycin (mTOR) inhibitors are believed to have potential antitumor effects by inhibiting cancer growth through cell-cycle arrest and initiation of apoptosis. It can also induce cell death in B-cell lymphoma lines phosphatase and tensin homolog-lacking human tumors, and dendritic cells, possibly through p53 activation and reduction in the cyclin and survivin levels.
Induction therapy with T cell–depleting agents including polyclonal agents, such as anti-thymocyte globulin, and monoclonal agents increases the risks of cancers, such as PTLD and melanoma.
Common Cancers after Transplantation
Renal Cell Carcinoma
Renal transplant recipients have a higher risk reaching to seven-fold of renal cell carcinoma compared to general population. Masses detected in patients post-transplantation on regular ultrasound follow up are typically early, low-grade, small kidney masses about 75%–80% are renal cell carcinoma with the risk of metastasis at presentation being 2%. Interestingly ninety percent of renal cell carcinomas develop in the native kidneys as opposed to the allograft. Renal cell carcinoma in the kidney allograft is rare about 0.1% usually of low-grade T1 lesions; clear cell carcinomas or papillary renal cell carcinomas. They occur mostly in males..
Risk factors suggested include male sex (female hazard ratio [HR], 0.56; 95% CI, 0.47 to 0.66), increasing age (601 years; HR, 6.59; 95% CI, 4.29 to 10.15), African descent (HR, 1.50; 95% CI, 1.24 to 1.80), and longer time on dialysis (31 years; HR, 2.23; 95% CI, 1.58 to 3.13).
Astonishingly it seems risk factors may vary according to disease etiology. It is found that those patients transplanted for kidney failure secondary to glomerular diseases (HR, 1.24; 95% CI, 1.05 to 1.47), hypertensive nephrosclerosis (HR, 1.55; 95% CI, 1.29 to 1.86), and vascular disease (HR, 1.53; 95% CI, 1.15 to 2.03) have the greatest associated risk. On the contrary, patients with renal kidney failure secondary to diabetes (HR, 0.77; 95% CI, 0.62 to 0.94) or autosomal dominant polycystic kidney disease (HR, 0.81; 95% CI, 0.62 to 1.06) have a lower risk of renal cell carcinomas.
Management of De novo renal cell carcinomas differ based on patient factors as age, comorbidities, functional status as well as mass characteristics including size, biopsy specimen findings, growth kinetics.
Treatment policy varied between partial nephrectomy (67%), radical nephrectomy (19%) and percutaneous ablation (12%). Finally it is observed that the overall duration and intensity of immunosuppression rather than components of the drug regimen have greater influence on the expected risk of renal cell carcinoma.
Skin Cancer
Regarding skin cancer in renal transplant recipients; they tend to be more common and even more aggressive than normal population.
Types vary among cutaneous squamous cell carcinoma, basal cell carcinoma, Kaposi sarcoma, and malignant melanoma, with keratinocyte carcinomas comprising 90%–95% of these skin cancers.
The pathogenesis could be due to complex interaction of risk factors including exposure to UV radiation, HPV, pretransplant skin cancer, older age, race, sex (males at greater risk than females) besides the augmenting effect of immunosuppressive medications particularly CNI and azathioprine.
Despite the fact that the incidence of Kaposi sarcoma is rare among general population, yet in recipients of transplants exceeds 100 times that of the general population mainly in Mediterranean, Africa, and Central Europe. Transplant recipients have excess risk of squamous cell carcinoma about 250 times compared to the general population.
Topical fluorouracil and imiquimod cream, photodynamic therapy, surgical excision or electrodesiccation and curettage is the preferred management for patients with actinic keratoses and squamous cell carcinoma in situ being with good outcome. The option of Mohs micrographic surgery after histologic confirmation of negative margins presents the most definitive method of treatment with excellent cure rates of 95%–100% for biopsy sample–proven cutaneous squamous cell carcinoma in SOT recipients.
High risk for Kaposi sarcoma is encountered in patients on CNI regimen. It is thought to be best managed by switching to mTORi is the appropriate choice in this situation. The role of mTORi is believed to restore the proper effector and memory T-cell immune activity against human herpesvirus 8.
The risk of developing malignant melanoma is elevated by 5 to 8 fold in SOT recipients with marked poor outcome in relation to that of general population even up to mortality.
Possible risk factors highlighted involve pretransplant melanoma being the strongest followed by White race and older age above 50 years. Management is primarily by surgical with wide excision along with modification of immunosuppression regimen vary according to the extent of melanoma and transplant function.
Post-Transplant Lymphoproliferative Disease
PTLD is associated with EBV being a common virus affecting most of the people during childhood. Most PTLDs are of B-cell types, only about 5% of patients have the T-cell type. The estimated incidence in the first 10 years post renal transplantation ranges about 1%–2% in adult recipients while only 3% in pediatric recipients.
Pretransplant EBV seronegativity and primary EBV infection are crucial risk factors for early EBV-positive PTLD especially in younger SOT recipients. Interestingly there is a considerable proportion representing 40%–50% of late B-cell PTLDs are EBV-negative lesions. The fact is that the risk of acquiring PTLD in pediatric SOT recipients is at least 30-times higher than the age- and sex-matched general population. The use of use of T cell–depleting agents, belatacept, Ortho Kung T3 (muromonab-CD3) along with high dose tacrolimus synergizes the development of PTLD by four-fold excess.
The reported use of rituximab and chemotherapy (doxorubicin, cyclophosphamide, vincristine, and prednisone) is believed to improve the survival, with 5-year survival up to 60%. Rituximab, positive EBV status and normal lactate dehydrogenase levels contribute to predictors of favourable response.
The problem is when PTLD develops, the associated risk of death becomes very high up to 14 fold higher than recipients without PTLD. Thanks to advances in treatment strategies as the use of rituximab and immunotherapy the risk of death has declined by 62%–68% at 1 year and approximately 41%–48% at 10 years. It is also noted that the risk of is greater in case of bone marrow/reticuloendothelial disease then extranodal and nodal disease comes consequently. Unfortunately, the median time elapsed from diagnosis till to death is expected to be 6 months.
Cancer Screening Strategies in Transplant Recipients
Considering renal transplant recipients, it is worthy to adopt strategies against developing renal cell carcinoma in those with a history of acquired cystic disease, those with a family history, those who are heavy smokers, and those who use long-term analgesics necessarily ultrasonographic screening (annually or biennially) of the native kidneys to be considered to detect occult malignancy.
Human Papillomavirus Vaccination in Recipients of Kidney Transplants
The incidence of HPV-related anogenital cancer is at least 10 to 15 fold higher in recipients of kidney transplants. The development of quadrivalent vaccines used for prevention of cervical intraepithelial neoplasia have reached efficacy up to 99%–100% with the advantage that they are generally safe for SOT population. Further recommendations advise to get vaccinated prior to transplantation.
Management of Recipients of Kidney Transplants Who Have Cancer
Immunosuppression Management and Treatment in Transplant Recipients with Cancer
A multidisciplinary targeted approach involving transplant professionals, oncologists, and allied health professionals is mandatory. Ultimate balance between proper immunosuppression dose to avoid rejection and the need to induce regression of the malignant lesions as well as to prevent disease progression. The first reasonable step is to reduce the burden of immunosuppression for patients with early to moderate stage malignancy to be tailored according to individual patient situation. It is believed to be wise to switch to an mTOR inhibitor may reduce the risk of cancer in the longer term.
Immunotherapy
Recent discovery of immune-checkpoint inhibitors targeting the programmed death-1/programmed death ligand-1 interaction and/or the CD28-CD80/86 axis with cytotoxic T lymphocyte–associated protein-4 Ig has changed the treatment policy of a variety of malignancies through immune system activation against the cancer. In the present time despite they have shown to be effective in treating melanoma, non–small cell lung cancer, and renal cell carcinoma in the general population, yet their use in renal transplant recipients is under clinical trials.
Introduction de novo cancer development is a major complication of organ transplantation.
cancer is the second leading cause of death among recipients of transplants in most Western countries
incidence of cancer in SOT ranges between 10% and 15%, at around 15 years after transplantation.
For skin cancers, the cumulative incidence reaches 60% in Europe, Australia, and New Zealand.
risk in KTRs exceeds that of the general population by approximately two- to three-folds.
greatest risk in viral-related and immune driven cancers such as post-transplant lymphoproliferative disease (PTLD), anogenital cancer, and Kaposi sarcoma.
Cancer Mortality in Recipients of Kidney Transplants
In Western countries mortality ratios for cancer are 1.8–1.9 times higher than general population. greater risk among those with melanoma, urogenital cancers, and non-Hodgkin lymphoma, with an overall risk of cancer-related death is five to ten times that of those without kidney transplants.
Risk Factors for Cancer Development
-General risk factors shared by patients in the general population as increasing age, male sex, smoking, and prolonged sun exposures.
– specific risk factors: including immunosuppression use (T cell–depleting agents), acute rejection episodes, sensitization status, and duration of dialysis, long-term immunosuppression and pretransplant malignancy.
– Cancer develop in recipients of kidney transplants because of impaired tumor surveillance and immunity to viral or other tumor antigens.
– The specific types of cancer that develop after transplantation also vary by geographic area.
– no conclusive evidence to suggest one type of immunosuppression is more oncogenic than others
But it was shown that tacrolimus increases the level of TGF-b and promotes tumor progression and metastasis,
also CNI inhibit signaling via calcineurin and NF of activated T cells, which can activate p53, a hallmark of some NMSCs .
Cyclosporine also has direct effects on tumor development and progression , through TGF-b or IL-6 overexpression pathways , It inhibit DNA repair, causing accumulating mutations, inducing apoptosis in activated T cells, and inhibiting apoptosis in other cells.
-azathioprine also has a well known oncogenic potential, sensitizes the skin to UVA radiation and causes the accumulation of 6-thioguanine in the DNA, leading to a higher risk of NMSCs.
-mTOR inhibitors may have potential antitumor effects by inhibiting cancer growth through cell-cycle arrest and initiation of apoptosis. –
-Induction therapy with T cell–depleting agents such as anti-thymocyte globulin, and monoclonal agents, such as anti-CD52 increases the risks of cancers, such as PTLD and melanoma.
Common Cancers after Transplantation
Although risk of all types of cancers are higher in transplant recipients but still Certain types of tumors are more common after organ transplantation.
The most common tumors types are: renal cell carcinoma (RCC), PTLD, and melanoma and nonmelanoma skin cancers. Renal Cell Carcinoma (RCC) is common in KTRs s with a risk about 7 folds higher than general population.
Due to frequent abdominal imaging, most of kidney tumors detected early, and mostly low-grade, small masses, 80% of these masses are RCC.
90% of RCC occurs in the native kidneys.
Risk factors include male sex, older age, African, and longer dialysis duration.
The cause of kidney failure also affected the risk where patients who had renal failure due to glomerular diseases, hypertensive nephrosclerosis and vascular disease had greater risk than patients with failure due to diabetes and APKD.
Management with radical surgery according to stage ,after radical surgery of RCC the prognosis in transplant recipients is comparable to general population, with 5-year survival rates of 68%–97% . Skin Cancer is commonest malignancy in KTRs more aggressive in the general population.
reported skin cancers that are reported in KTRs include cutaneous squamous cell carcinoma (SSC), basal cell carcinoma (BCC), malignant melanoma and Kaposi sarcoma.
keratinocyte carcinomas represent 90%–95% all skin malignancy.
risk factors include: UV radiation exposure, HPV, skin malignancy before TX, old age, male sex (52).
Kaposi sarcoma has 100 times higher incidence in transplant recipients than general population, it is seen commonly in patients Africa Mediterranean areas and Central Europe.
the risk of SCC is about 250 times more than general population .
For in situ SCC management with topical fluorouracil and imiquimod cream, with the use of photodynamic treatment, and surgical removal and curettage showed good outcomes.
For biopsy proven SCC in recipients, micro-graphic surgery, with negative margins is the most definitive treatment method, cure rates are up to of 95%–100% (52).
, primary radiation for inoperable cases provides local cure rates .
Chemoprophylaxis with retinoids and nicotinamide might be considered for Patients with multiple SCC (more than five) every year, aggressive type of SCC , or early occurrence of SCC ,metastatic might be managed with chemotherapy and/or immunotherapy.
calcineurin inhibitors are associated with increased risk of Kaposi sarcoma, Decreasing the dose of CNI or shifting to an mTOR inhibitor is the cornerstone of treatment with good response and reported regression of the tumor due to restoration of the effector regulatory cells and memory T-cell activity against HHV 8 .
malignant melanoma risk is 5- 8 folds higher in transplant recipients o, with bad prognosis compared to general population, as melanoma has the highest mortality (52).
Presence of melanoma before TX is the most strong risk factor other risk factors includes: White race and older age .
treatment is mainly surgery with adequate margins and immunosuppression adjustment according to the extent of melanoma and graft function.
Post-Transplant Lymphoproliferative Disease (PTLD) Although rare disease but it has poor prognosis.
Mostly occurs in association with EBV.
EBV which infects the B cells and remain latent, reactivation can occur with suppression of T-cell function, and decrease control of T-cell on proliferation of B-cell, finally result in occurrence of PTLD.
Mostly PTLDs arise from B-cells, only 5% may arise from T-cells.
incidence of PTLD is 1%–2% in the first 10 years post-transplantation.
The highest risk is in the 12 months after transplant, decreases till the fifth year.
the risk of developing lymphoproliferative disease in pediatric recipients of transplants is at least 30-times higher than the age- and sex-matched general population
seronegative EBV and primary infection are important risks for early development of EBV-associated PTLD, in contrast, 40%–50% of late B-cell type PTLDs shows EBV-negative lesions .
death among recipients of kidney transplants who have PTLD is .14- fold higher than recipients without PTLD although rituximab has improved survival over the last years.
Treatment of PTLD post transplantation mainly depends on subtype.
mainstay of treatment is immunosuppression reduction. However, the response to immunosuppression reduction varies considerably between individuals.
rituximab and chemotherapy (doxorubicin, cyclophosphamide, vincristine, prednisone) have improved overall survival, with 5-year survival at around 60% .
Rituximab is also generally well tolerated with minimal side effects, and factors that predicted response included positive EBV status and normal lactate dehydrogenase levels.
Cancer Screening Strategies in Transplant Recipients
randomized controlled trials have shown that cancer screening through early detection reduces cancer-specific mortality in the general population, screening program based on programs established for general population could be used as a guide.
Human Papillomavirus in Kidney Transplants Recipients
HPV-related is associated with anogenital and lip cancer with increased risk about 10-15 folds higher in KTRs compared with matched general population.
in randomized clinical trials Quadrivalent vaccines (against 6, 11, 16, and 18 genotypes) and the HPV 9-valent vaccines (against more 5 genotypes 31, 33, 45, 52, and 58) are greatly effective with efficacy of 99%–100% in prevention of cervical neoplasia.
In the transplant population, HPV vaccines are safe. However, seropositivity was detected in 50%–60% of patients, depending on genotypes, higher levels of tacrolimus were detected in non-responders.
HPV vaccination is more effective to be given to women before transplantation and its highly recommended for women after transplantation if not taken before.
Immunosuppression Management and Treatment in Transplant Recipients with Cancer
reduction in the overall immunosuppression for patients with early- to moderate-stage malignancy may be a reasonable first step, patients should be informed about the potential adverse effects, and all strategies should be tailored to the individual’s needs.
-For patients with squamous cell carcinoma, it is suggested to do conversion to an mTOR inhibitor may reduce the risk of cancer in the longer term .
-mTOR-inhibitor use may also be associated with a higher risk of death, and there are insufficient data to consider mTOR inhibitors as protective against other cancer types apart from squamous cell carcinoma and Kaposi sarcoma – the use of checkpoint inhibitors is limited in recipients of transplants given the potential for rejection with nonspecific immune-system activation
Conclusions
-Cancer is the leading cause of morbidity and mortality in patients with kidney transplants.
-optimizing allograft function with immunosuppression are often challenging.
-Currently, the evidence to define the amount of immunosuppression by which a clinician could safely reduce is unknown. More importantly, evidence to support primary prevention and screening programs in recipients of transplants are largely extrapolated from the
This review explains the kidney transplanted patients, idea, education and experience of cancer in the context of kidney transplantation along with the epidemiology and burden of cancer in kidney transplant recipients.
Regarding renal transplant patients, cancer is the second cause of death after cardiovascular causes. Incidence of All-Cause and Site-Specific Cancer after Transplantation:
The cumulative incidence of solid organ cancer ranges between 10% and 15% at around 15 years after transplantation. The excess overall cancer risk in patients with kidney transplant exceeds that of the general population by approximately
two- to three-fold after adjustment for age and sex. The greatest risk in viral-related and immune driven cancers such as post-transplant lymphoproliferative disease (PTLD), anogenital cancer, and Kaposi sarcoma. Interestingly, certain solid organ cancers such as breast and prostate cancers are not increased in transplant recipients.Cancer Mortality in Recipients of Kidney Transplants :
Once cancers develop, the risk of death is high. Observational data in most Western countries have shown the standard mortality ratios for all cancer types are at least 1.8–1.9 times higher compared with the age- and sex-matched general
population. The risk is greatest among those with melanoma, urogenital cancers, and non-Hodgkin lymphoma, with an overall risk of cancer-related death exceeding five
to ten times that of those without kidney transplants.
Risk Factors for Cancer Development :
factors that increase cancer risk include;
increasing age
male sex
smoking
prolonged exposure to sun
use of immunosuppression
acute rejection
sensitization status
dialysis duration before transplantation
some observations suggestion of CKD as risk factor for cancer, and poor outcome like renal cell carcinoma and multiple myeloma. Mechanisms of Cancer Development after Transplantation:
Immunosuppressive drug mechanism is through poor immune control of known oncogenic viruses. For example, increases in viral-associated cancers, such as
Kaposi sarcoma (human herpesvirus 8), PTLD (Epstein– Barr virus [EBV]), and lip and anal cancers (HPV) are common.
Immunosuppression-related cancer development through accumulation of mutations that
would otherwise be repaired or recognized by the immune system. This mechanism may be predominant in skin cancers, where immunosuppression impairs the cells’ ability to
repair ultraviolet (UV) radiation–induced DNA damage.
More specifically, immunosuppression can lead to a decrease of xeroderma pigmentosum complementation groups A and G, which are components of nucleotide
excision repair. Common Cancers after Transplantation:
Renal Cell Carcinoma
Skin Cancer
Post-transplant lymphoproliferative disease Management of Recipients of Kidney Transplants Who Have Cancer:
Optimization of immunosuppression dose
Immunotherapy
Introduction
Cancer is the second-leading cause of mortality for transplant recipients in Western nations and is a feared consequence linked to immune suppression used after kidney transplants. Preventive interventions have been tried in response to the dismal results, including the use of HPV vaccines and cancer-screening techniques. The etiology, diagnosis, prevention, and treatment of cancer following kidney transplantation were the main topics of this review.
incidence of all-cause and site-specific cancer after transplantation
It has been noticed that 15 years following transplantation, the cumulative incidence of solid organ cancer varies from 10-15%. The risk varies depending on the cancer kind and the region where it is most common. Breast and prostate cancers are two solid tumors whose incidence is not raised in transplant recipients.
Cancer Mortality in recipients of kidney transplants
Once cancer has begun to spread, there is a high risk of death. Patients with non-Hodgkin’s lymphoma, melanoma, and urogenital malignancies have a higher death risk. The elevated mortality risk may be brought on by variations in the biology of cancer cells in transplant recipients, the use of long-term immune suppression, related co-morbidities, and decreased adherence to advised preventive and screening measures.
Risk factors for developing malignancy after transplantation
Ageing, male sex, smoking, and prolonged sun exposure are some risk factors for cancer following transplantation. The majority of people have these characteristics. Immune suppression usage, acute rejection, sensitization status, and length of dialysis prior to the transplant are risk factors specific to individuals who have had transplantation. Poor results are linked to having CKD, a proven risk factor for cancer.
Mechanisms of cancer development after transplantation
Immune suppression during maintenance reduces acute and long-term rejection and consequent allograft loss. Another proposed pathway involves individuals receiving immune suppression having inadequate immunological control of recognized carcinogenic viruses. Accumulation of mutations that the immune system would normally correct or detect is one putative mechanism of immune suppression-related cancer growth. There isn’t enough proof right now to say one sort of immune suppression is more likely to cause cancer than another.
Introduction
Cancer is a dreaded complication associated with immune suppression used after kidney transplants, and is the second leading cause of death among transplant recipients in the Western countries. After noting the poor outcomes, preventive measures have been attempted, such as using HPV vaccinations, and cancer-screening strategies. This review focused on the mechanisms, diagnosis, prevention and treatment of cancer after kidney transplantation.
Incidence of all-cause and site-specific cancer after transplantation
It is noted that the cumulative incidence of solid organ cancer ranges from 10-15% at around 15 years after transplantation. The risk is dependent on the type of cancer and the area that it is most prevalent in. some solid cancers, such as breast and prostate are not increased in transplant recipients.
Cancer mortality in recipients of kidney transplants
Once the cancer develops, the risk of death is high. The mortality risk is increased in patients with melanoma, urogenital cancers and non-Hodgkin’s lymphoma. The increased risk of mortality may be due to differences in cancer cell biology in transplant recipients, the use of long-term immune suppression, associated co-morbidities and lower use of recommended prevention and screening strategies.
Risk factors for cancer development
Some of the risk factors for developing cancer after transplantation include increasing age, male sex, smoking and prolonged sun exposure. These factors are shared by the general population. Risk factors specific to patients who have undergone transplantation include immune suppression use, acute rejection, sensitization status and duration of dialysis before the transplantation. Having CKD is known risk factor for cancers, and it is associated with poor outcomes.
Mechanisms of cancer development after transplantation
Maintenance immune suppression decreases acute and chronic rejection, and subsequent allograft loss. Another potential mechanism is through poor immune control of known oncogenic viruses in patients on immune suppression. One potential mechanism of immune suppression-related cancer development is through accumulation of mutations that would otherwise be repaired or recognized by the immune system. Currently, there is no conclusive evidence to suggest one type of immune suppression is more oncogenic than another.
Common cancers after transplantation 1.Renal cell carcinoma
Recipients of kidney transplants have up to a seven fold increased risk of renal cell carcinoma, as compared to the general population.
Most of the renal cell carcinomas (up to 90%) develop in the native kidney, as opposed to the allograft.
The risk factors for developing renal cell carcinomas after transplantation include male sex, increasing age (more than 60 years), African descent, longer time on dialysis prior to transplantation and patients that required transplantation due to glomerular disease, hypertensive nephrosclerosis and vascular disease.
Patients who required kidney transplantation due to diabetes or autosomal polycystic kidney disease have a lower risk of renal cell carcinoma.
The outcome of renal cell carcinomas after radical treatment in transplant population has shown a reduced 5-year survival rates as compared to the general population.
The management of the malignancy should be individualized for optimal results. 2.Skin cancer
It is the most common cancer type in kidney transplant recipients, and it is more aggressive than skin cancers occurring in the general population.
The most commonly reported skin cancers in patients who have undergone kidney transplants include cutaneous squamous cell carcinoma, basal cell carcinoma, Kaposi sarcoma and malignant melanoma.
The risk factors include exposure to UV radiation, HPV, pretransplant skin cancer, older age, male sex and immune suppressive medications (that augment the carcinogenic effects).
Patients treated with calcineurin inhibitors are particularly at a higher risk of developing Kaposi sarcoma.
Amongst all the types of skin cancer, melanoma has the highest mortality rate. 3.PTLD
Although PTLD is a rare disease, it is a known complication after kidney transplants. It is commonly associated with EBV. Some of the risk factors include a younger age at transplantation, male sex, use of T cell-depleting agents, Ortho Kung T3, high dose tacrolimus and negative recipient EBV serology with a positive donor serology. The treatment goal is to cure the disease, and that is achieved by immune suppression reduction. It has a high risk of death once it develops.
Cancer screening strategies in transplant recipients
Studies have shown that cancer screening through early detection reduces cancer-specific mortality in the general population. However, patients with kidney disease and post-kidney transplantation are generally overwhelmed with their diagnosis, and are sometimes reluctant to undergo further testing. Decisions regarding screening must be individualized, and based on clear considerations of the patient’s preferences and values, along with the assessing the potential harms and benefits of the various options.
HPV vaccination in recipients of kidney transplants
The incidence of HPV-related anogenital cancer is at least 15 times higher in patients who have received kidney transplants compared to the general population. Quadrivalent vaccines are highly effective for the prevention of cervical intraepithelial neoplasia. HPV vaccination is indicated in both males and females aged 9 to 25 years in the general population for the prevention of HPV related malignancies. Recent data has shown that it is also effective in women up to the age of 45 years. HPV vaccination is recommended for women before transplantation.
Management of recipients of kidney transplants who have cancers
Immune suppression management and treatment in transplant recipients with cancer
Multidisciplinary management is required for patients with cancer who have undergone kidney transplantation. This is needed to understand the underlying immunologic risk and cancer severity to optimize immunosuppression dosages to prevent the risk of acute rejection, while balancing the need to induce regression of the malignant lesion. However, there is insufficient evidence and therefore, patient care should be individualized.
Immunotherapy
The use on immune-checkpoint inhibitors targeting the programmed death-1/programed death ligand-1 interaction and/or the CD28-CD80/86 axis with cytotoxic T lymphocyte-associated protein-4 Ig has assisted greatly in the treatment of various malignancies. However, their role in kidney transplant patient requires further investigation.
Putting patients’ perspectives at the heart of cancer management
Understanding the personal experiences and requirements of patients will assist health care practitioners to deliver optimum, appropriate and relevant care. A multidisciplinary team will aid in delivering holistic care to the patient. This will also help in addressing the psychosocial, functional and nutritional issues experienced by the patient.
Conclusion
Cancer is the leading cause of morbidity and mortality in patients with kidney transplant. Evidence to address the issues is currently limited. Therefore, it is important to individualize management for the patients for optimal results.
Level of Evidence:
Level V as it is a narrative review
This review highlights the incidence, mechanisms, diagnosis, prevention, and treatment of cancer after kidney transplantation. Cancer is one of the most feared complications associated with immunosuppression after kidney transplantation and is the one of the major leading cause of death among transplant recipients. The higher risks and poorer cancer outcomes have prompted clinicians and policymakers to adopt preventive policies and cancer screening strategies to detect cancers at their advanced stage, incurable disease.
The current review under discussion also outlines risk factors for cancer development, the incidence of all-cause and site-specific cancer after transplantation, and mechanisms of cancer development after transplantation.
After kidney transplantation, the overall risk of developing cancer is higher compared to the general population, with certain cancer types being more prevalent than others. The three most common cancers after transplantation are renal cell carcinoma, skin cancer, and post-transplant lymphoproliferative disease (PTLD).
Renal cell carcinoma is up to seven times more common in kidney transplant recipients compared to the general population. The risk factors include male sex, increasing age, African descent, and longer time on dialysis.
Skin cancer is also one of the most common cancer type in kidney transplant recipients and is more aggressive than in the general population. Risk factors include exposure to UV radiation, HPV, pre-transplant skin cancer, older age, race, and sex, with immunosuppressive medications augmenting the carcinogenic effects. Treatment options for skin cancer include topical treatments, surgical excision, Mohs micrographic surgery, and systemic chemotherapy or immunotherapy for metastatic cases.
PTLD is a rare but serious complication after kidney transplantation, with most cases associated with Epstein-Barr virus (EBV). Risk factors for PTLD include younger age, male sex, T-cell depleting agents, and high-dose tacrolimus. Treatment options for PTLD include reducing immunosuppression and rituximab and chemotherapy for improved overall survival.
Kidney transplant recipients have a higher risk of developing certain cancer types compared to the general population, and early detection and management are critical for improved outcomes.
Cancer screening through early detection has been shown to reduce cancer-specific mortality in the general population. Routine screening in patients with kidney disease and those on dialysis may not be as effective in terms of costs and survival benefits. Despite this, routine population-based cancer screening for breast, colorectal, and cervical cancer is recommended and should be aligned to the guidelines as per the general population.
Management of immunosuppression in recipients of transplants who are living with cancer is complex and challenging, and a concerted approach between transplant professionals, oncologists, and allied health professionals is necessary to ensure optimal care for patients. Patients’ perspectives are essential to guide clinicians and healthcare professionals to deliver relevant and appropriate care. A personalized, rather than a one-size-fits-all approach, is most preferred. Collaborative efforts between healthcare professionals, policy-makers, trialists, and patients are needed to ensure quality evidence is generated to support the long-term care of recipients of transplants.
De Novo Malignancies after Kidney Transplantation
Inspite of the advantages of kidney transplant to the patient with ESRD, it is not a cure and has its own consequences as a result of ch immunosuppression status. cancer should be one of the outcomes of kidney transplant to be assessed.
After cardiovascular disease, cancer is the second leading cause of death among recipients of transplants in most Western countries.
Due to high risk preventive strategies were adopted such as vaccination and cancer-screening strategies, to detect cancers earlier. Incidence of All-Cause and Site-Specific Cancer after Transplantation
The cumulative incidence of solid organ cancer ranges between 10% – 15% at around 15 years after transplantation.
For skin cancers, the cumulative incidence reaches 60% in Europe, Australia, and New Zealand.
kidney transplant has higher risk as compared to general population by approximately 2-3-fold after adjustment for age and sex.
Increasing risk is depending on
1-cancer types
2- viral-related cancers such as PTLD, anogenital cancer, and Kaposi sarcoma. Cancer Mortality in Recipients of Kidney Transplants
standard mortality ratios for all cancer types are at least 1.8–1.9 times higher compared with the age- and sex-matched general population.
Higher risk observed in melanoma, urogenital cancers, and non-Hodgkin lymphoma, with an overall risk of cancer-related death 5-10 times that of those without kidney transplants .
Cancer screening and prevention, effective patient education and heightened awareness are key. Risk Factors for Cancer Development
· Shared with general population
increasing age, male sex, smoking, and prolonged sun exposures.
· Specific to kidney disease and transplant populations
immunosuppression use , acute rejection sensitization status and duration of dialysis before transplantation. Contributing factor to high risk of development of cancer
1. long-term immunosuppression
2. having CKD (irrespective of the CKD stage) is associated with higher cancer risk and poor cancer outcomes
3. impaired tumor surveillance and immunity to viral or other tumor antigens.
4. previously treated pretransplant malignancy
5. geographic areas
A. nonmelanoma skin cancers (NMSCs), PTLD, and lip cancer most common in Europe, North America, Australia, and New Zealand.
B. urothelial transitional cell carcinoma, renal cell carcinoma, and gastrointestinal cancers more common in Middle Eastern transplant cohorts .
6. loss of control of oncogenic viral replication and control in the context of chronic immunosuppression.
Taiwan is an endemic area for chronic hepatitis B virus (HBV) infection in Far East Asia, kidney transplant has liver cancer of 5 fold compared with the sex- and age-matched general population
Mechanisms of Cancer Development after Transplantation
Maintenance immunosuppression dampening the immune system may create a variety of pathways for cancer development.
1- poor immune control of known oncogenic viruses in patients on immunosuppression. This will increases viral-associated cancers, such as Kaposi sarcoma (human herpesvirus 8), PTLD (Epstein– Barr virus [EBV]), and lip and anal cancers (HPV)
2- accumulation of mutations that would otherwise be repaired or recognized by the immune system. mainly in skin cancers,
3- type of immunosuppressant:
a) calcineurin inhibitors associated with hepatocellular carcinoma, human lung adenocarcinoma cells, and renal cell carcinoma .
b) calcineurin inhibitors inhibit signaling via calcineurin and NF of activated T cells, which can activate p53, a hallmark of some NMSCs.
c) Cyclosporine also has direct effects on tumor development and progression, through TGF-b or IL-6 overexpression pathways.
d) cyclosporine is capable of inhibiting DNA repair, thereby accumulating mutations, inducing apoptosis in activated T cells, and inhibiting apoptosis in other cells by opening the mitochondrial permeability transition pores .
e) Azathioprine sensitizes the skin to UVA radiation and causes the accumulation of 6-thioguanine in the DNA, leading to a higher risk of NMSCs .
f) Mammalian target of rapamycin (mTOR) inhibitors, have potential antitumor effects by inhibiting cancer growth through cell-cycle arrest and initiation of apoptosis. This is helpful in small cell lung cancer, sarcoma, neuroblastoma, glioblastoma, osteosarcoma, pancreatic cancer, breast cancer, prostate cancer, leukemia, and B-cell lymphomas.
g) Induction therapy with T cell–depleting agents (including polyclonal agents, such as anti-thymocyte globulin, and monoclonal agents, such as anti-CD52 and, historically, Ortho Kung T3 [muromonab-CD3]) increases the risks of cancers, such as PTLD and melanoma .
h) T cell–depleting agents for acute rejection of the kidney allograft also heighten the risk of cancer development ; Common Cancers after Transplantation
a) renal cell carcinoma (7 fold higher), 90% in native kidney
· factors for development
male sex, increasing age, African descent and longer time on dialysis , kidney failure secondary to glomerular diseases , hypertensive nephrosclerosis and vascular disease
b) skin cancer (squamous cell carcinoma, basal cell carcinoma, Kaposi sarcoma, and malignant
· factors for development
exposure to UV radiation, HPV, pretransplant skin cancer, older age, race, and male sex, immunosuppressive medications (cyclosporine and azathioprine) certain ethnic groups (Mediterranean, Africa, and Central Europe). melanoma, with keratinocyte carcinomas comprising 90%–95% of these skin cancers)
c) PTLD associated with EBV, There also appears to be a bimodal distribution in PTLD incidence, with the risk of PTLD being the highest in the 12 months post-transplant, and it then decreases until the 5th year after transplantation.
· factors for development
Pretransplant EBV sero-negativity ,primary EBV infection, younger recipients of transplants, The use of belatacept,
Cancer Screening Strategies in Transplant Recipients
· early detection reduces cancer-specific mortality in the general population.
· In kidney disease, studies suggesting screening may not be as effective in terms of costs and survival benefits
· routine population-based cancer screening for breast, colorectal, and cervical cancer is recommended.
· routine skin checks by dermatologists in recipients of transplants who are at high risk.
· abdominal ultrasounds and serum a-fetoprotein levels should be checked every 6 months for those with liver disease and chronic HBV infections.
· If at risk of developing renal cell carcinoma (such as those with a history of acquired cystic disease, those with a family history, those who are heavy smokers, and those who use long-term analgesics), ultrasonographic screening (annually or biennially) of the native kidneys may be considered .
· Screening decisions must be made with clear considerations of patients’ preferences and values, incorporating the potential harms and benefits of the various options. Human Papillomavirus Vaccination in Recipients of Kidney Transplants
· The incidence of HPV-related anogenital cancer is at least ten- to 15-fold higher in recipients of kidney transplants compared with the age- and sex-matched general population.
· Quadrivalent vaccines (against genotype 6, 11, 16, and 18).
· the HPV 9-valent vaccines (against five additional genotypes of 31, 33, 45, 52, and 58) are highly effective
· overall efficacy of 99%–100% for the prevention of cervical intraepithelial neoplasia in both males and females aged 9–25 years in the general population for the prevention of HPV-related malignancies. Disadvanytage
· seropositivity was only detected in approximately 50%–60% of patients
· nonresponders depend on 1-genotypes, 2- higher tacrolimus levels Management of Recipients of Kidney Transplants
· A concerted approach between transplant professionals, oncologists, and allied health professionals is therefore needed to ensure optimal care.
· To balance between treatment of cancer and avoid its progression and between acute rejection.
· Reduction of immunosuppression in consultation with the patient.
· squamous cell carcinoma, evidence to suggest conversion to an mTOR inhibitor may reduce the risk of cancer in the longer term Immunotherapy
· The use of immune-checkpoint inhibitors targeting the programmed death-1/programmed death ligand-1 interaction and/or the CD28-CD80/86 axis with cytotoxic T lymphocyte–associated protein-4 Ig has revolutionized the treatment of a variety of malignancies through immunesystem activation against the cancer .
· However, there is risk of rejection
· Although checkpoint inhibitors are effective in treating melanoma, non–small cell lung cancer, and renal cell carcinoma in the general population, their use in the kidney transplant population requires further investigation and cannot be recommended at this time, outside of a study protocol.
· a personalized, rather than a one-size-fits-all, approach is most preferred.
· For patients who have progressed to advanced-stage malignancy, complete immunosuppression withdrawal is a difficult decision for both patients and clinicians.
· a multidisciplinary, integrated approach that involves the transplant and palliative care team is crucial. together with a social worker, dietitian, clinical psychologist, and other allied health workers to address the psychosocial, functional, and nutritional issues experienced by our patients.
Kidney transplantation is the best treatment option for acceptable candidates with kidney failure, but it is not a cure. Patients require life-long immunosuppression to maintain optimal allograft function, and cancer is the second leading cause of death among recipients of transplants. This review focuses on the incidence, mechanisms, diagnosis, prevention, and treatment of cancer after kidney transplantation.
Risk Factors for Cancer Development:
Risk factors for cancer development after transplantation include increased age, male sex, smoking, and prolonged sun exposures, as well as immunosuppression use, acute rejection, sensitization status, and duration of dialysis.
Mechanisms of Cancer Development after Transplantation
Immunosuppression can lead to cancer development through poor immune control of known viruses, UV-induced DNA damage, and accumulation of mutations. Azathioprine has potential antitumor effects by inhibiting cancer growth through cell-cycle arrest and initiation of apoptosis.
Common cancers after transplantation : Renal cell carcinoma :
Risk of cancer-related death in recipients of kidney transplants is higher than the general population, with the majority of kidney masses detected post-transplantation being renal cell carcinoma. Risk factors include male sex, age, African descent, hypertensive nephrosclerosis, vascular disease, and kidney failure secondary toglomerular diseases. De novo renal cell carcinomas should be managed according to urologic guidelines, with 5-year, disease-specific and overall patient survival rates of 68%–97% and 69%–88%. Negative prognostic factors include presence of symptoms, higher Fuhrman grade, absence of transplantation, and advanced-stage disease. Nephron-sparing surgery was safe and an appropriate option with good longterm functional and oncologic outcomes. Overall duration and intensity of immunosuppression influence risk.
Skin Cancer:
Skin cancer is the most common cancer type in recipients of kidney transplants and is more aggressive than skin cancers occurring in the general population. It is caused by a complex interaction of risk factors, including exposure to UV radiation, HPV, pretransplant skin cancer, older age, race, and sex, and immunosuppressive medications. Management options include topical fluorouracil and imiquimod cream, photodynamic therapy, and surgical excision or electrodesiccation and curettage. Primary radiation therapy is the most effective method of treatment for squamous cell carcinoma, with cure rates of 95%–100%. Chemoprophylaxis and systemic chemotherapy are recommended, and patients treated with calcineurin inhibitors are at high risk for Kaposi sarcoma. Adjustment of immunosuppression is individualized to each patient on the basis of the extent of melanoma and transplant function.
Post-Transplant Lymphoproliferative Disease:
PTLD is a rare complication after kidney transplantation that is associated with EBV and is associated with poor outcomes. Most PTLDs are of B-cell types, with approximately 5% of patients having the T-cell type. There is evidence to suggest that the incidence of PTLD has been decreasing in recent years, with an 8% reduction in the risk of developing PTLD from 2000 onward. Pretransplant EBV seronegativity and primary EBV infection are important risk factors for early EBV-positive PTLD, and may explain the higher risk of disease early post-transplant. PTLD is a 30-times higher risk of death among recipients of kidney transplants than the general population, and the mainstay of treatment is immunosuppression reduction.
Prior work reported that rituximab and chemotherapy have improved overall survival, with 5-year survival at around 60%. The risk of death is dependent on site, with those having bone marrow/reticuloendothelial disease having the highest risk.
Cancer Screening Strategies in Transplant Recipients:
Routine population-based cancer screening for breast, colorectal, and cervical cancer is recommended and should be aligned to guidelines as per the general population. Ultrasonographic screening (annually or biennially) of the native kidney may be considered to detect occult malignancy. Screening decisions must be made with clear considerations of patients’ preferences and values, incorporating the potential harms and benefits of the various options.
Human Papillomavirus Vaccination in Recipients of Kidney Transplants:
HPV vaccination is recommended for both males and females aged 9-25 years in the general population for the prevention of HPV-related malignancies, and is also efficacious in women up to 45 years.
Management of Recipients of Kidney Transplants Who Have Cancer:
Immunosuppression management and treatment in transplant recipients with cancer is complex and challenging, and a concerted approach between transplant professionals, oncologists, and allied health professionals is needed to ensure optimal care. Judicious reduction in immunosuppression load for patients with early- to moderate-stage malignancy may be a reasonable first step, and all strategies should be tailored to the individual’s needs.
Immunotherapy:
Immune-checkpoint inhibitors are effective in treating melanoma, non-small cell lung cancer, and renal cell carcinoma, but their use in the kidney transplant population requires further investigation.
Putting Patients’ Perspectives at the Heart of Cancer Management:
Patients with cancer and transplant may experience multiple symptoms, and the burden of self-management in the context of multiple morbidities is immense. Multidisciplinary interventions to alleviate concurrent, multiple symptoms is an example of how a multidisciplinary team could deliver suitable measures. Ongoing dialogues between clinicians and patients, and close attention to the patients’ overall personal needs, are essential to ensure their voices are heard. Complete immunosuppression withdrawal is a difficult decision for both patients and clinicians, and some clinicians may consider stopping either or both the calcineurin inhibitors and antiproliferative agents gradually and rotating to higher-dose corticosteroids to prevent the risk of acute rejection. Conclusion : Cancer is the leading cause of morbidity and mortality in patients with kidney transplants, and a multidisciplinary, integrated approach is needed to manage the high symptom burden.
Abstract
Malignancy is one of significant complication of organ transplantation including renal transplantation.
The risk of malignancy post renal transplantation is high reaching about two to three times higher than the incidence in general population. The prognosis of these malignancy is usually poor especially for melanoma , RCC , PTLD. The screening strategy and treatment in this specific group of patient is still need to be improved .
Introduction
Between the options of renal replacement therapy , renal transplantation is best option as it is cost effective , improve survival and life quality.
In spite of these advantages transplantation patient should be kept on immunosuppressive therapy for ever , which carry a high risk of malignancy and opportunistic infection .
Post -transplant malignancy is the 2nd most common cause of death. Post- transplant patient are high risk and usually carry bad prognosis and to prevent this it is important to implement the preventive measures like vaccination ( HPV) and malignancy screening programs in order to diagnose the cancer early before advancement to untreatable level .
Incidence of All-Cause and Site-Specific Cancer after Transplantation:
The overall incidence of malignancy post renal transplantation is around 10% to 15% at fifteen year post transplant.
According to some country reports, the skin malignancy incidence is around 60% , which is about 2-3 time higher than that of general population.
The degree of high risk is also related to malignancy types with higher is associated with viral and immune related malignancy like post-transplant lymphoproliferative disease (PTLD), anogenital Ca , and Kaposi sarcoma . In contrast , the incidence of some other malignancies like breast and prostate is not increased I post transplantation.
Cancer Mortality in Recipients of Kidney Transplants:
When malignancy is diagnosed , the prognosis is usually poor with high mortality which is about 1.8- 1.9 time the mortality in general population. The high risk of death reported with melanoma, urogenital cancers, and non-Hodgkin lymphoma , is 5 – 10 times higher than in non- transplant patient .
The cause of this high risk of death is not understood , but may be associated with
a- Alteration in cell biology because of immune suppression.
b- Accompanying chronic disease.
c- Under developed screening program.
d- Low patient a awareness about this complication.
Risk Factors for Cancer Development :
Risk factors for post transpalant malignancy include :
A- As with general population
1- Old patients ,
2- Gender – male,
3- Tobacco use
4- Excessive sun exposures .
5- Geographical area may affect the type of malignancy .
B- Specific to transplantation.
1- Potent immunosuppression (depleting agents). Because of altered surveillance and immunity against viruses and tumor cells .
2- acute rejection .
3- sensitization state pre transplant.
4- hemodialysis vintage .
5- Pre transplant malignancy.
Although it is known that the overall immunosuppression state rather than specific immunosuppressive drug is the precipitating factor for malignancy , but there is some experimental evidence to support the role of specific drug in inducing malignancy .
Currently, there is no conclusive evidence to suggest one.
some experimental report that shown that tacrolimus increases the level of TGF-B and therefore enhances tumor promotes tumor progression and metastasis.
More over CNI stop signaling by calcineurin and nuclear factor of activated T lymphocyte, which can
activate p53, a feature of NMSCs.
.Cyclosporine has direct oncogenic role in malignancy effects on tumor occurrence and progression,
by TGF-B or IL-6 overexpression ways .
New reports shows that cyclosporine has ability to prevent DNA repair, which may lead to mutation accumulation, predisposing to active T lymphocyte apoptosis , and preventing apoptosis in other cells by opening the mitochondrial permeability transition pores (37).
Azathioprine has a close association with malignancy , this is because the azathioprine increase the skin sensitivity to UVA light with accumulation of its metabolite in DNA may predispose to NMSCs.
Mammalian target of rapamycin (mTOR) inhibitors, Has anti malignancy properties by inhibiting malignancy cell growth by stopping the cell cycle and enhancement of apoptosis. This anti malignancy property is reported againist many types of malignancy like ( pancreas Ca, breast Ca , prostate Ca and more others ) .
The specific mechanism behind the anti tumor property of mTORI inhibitors are :
A- Cell type–specific c fashion apoptosis induction.
B- P53 activation and reduction in the cyclin and survivin levels .
Depleting agent (r ATG-, Alemtuzmab, OKT3- has been removed from markets ) uses is a risk factor for development of malignancy such as post- transplant lymph proliferative disorders and melanoma . the mechanism of this association is not well understood. But it could be due to an inadequate immune recovery after the use of these agent .
Common Cancers after Transplantation:
Risk of post transpalant malignancy as a general is higher when Compared to general population, but some types of malignancy is much more common than other types.
Renal Cell Carcinoma:
The risk of renal cell carcinoma in post renal transplantation is about seven times higher than general population. Usually it is of renal cell carcinoma ( 78%) and when diagnosed it is in early stage , low grade and small size with metastatic risk at the time of diagnosis of only two percent . 90% is originating from native kidney .
Melanoma is about six fold higher in renal transplanted patient compared to general population with poor prognosis ( highest death rate )
Risk factors for RCC are :
A- Gender- male sex.
B- Old age.
C- Africa origin.
D- Long dialysis vintage .
E- Potency of immune suppression – rather than specific drug .
F- Underlying cause – like glomerular diseases , hypertensive nephropathy and vasculitis .
Note: But the lowest risk for RCC is reported with Diabetic nephropathy and ADPCKD
Treatment options: the treatment should be individualized. 1- Partial nephrectomy . 2- Radical nephrectomy . 3- Percutaneous ablation .
Note : nephron sparing approach is safe and effective .
Skin Cancer:
Types : – keratinocyte carcinomas, squamous cell carcinoma, basal cell carcinoma, Kaposi sarcoma, and malignant melanoma. They are highly aggressive than same malignancy in normal non transplant patient . Kaposi sarcoma has 100 fold higher and squamous cell carcinoma has 250 fold higher than non transplant patient.
Pathogenesis and risk factors : is multifactorial
A- UVR
B- HPV – human papilloma virus ,
C- History of skin malignancy before transplantation.
D- older age.
E- Race ( Mediterranean, Africa, and Central Europe ).
F- Gender (males).
G- Immunosuppression drugs may enhance malignancy occurrence. (mainly cyclosporine and azathioprine)
TREATMENT :
1- Carcinoma in situ :
a. topical “flurouracil and imiquimod cream.
b. photodynamic therapy.
surgical excision or electrodesiccation and curettage.
c. Mohs micrographic surgery, 98% cure
2- Inoperable situations :
a- primary radiation.
b- Chemoprophylaxis – specific indication ( retinoids and nicotinamide ).
3- Metastatic cutaneous squamous cell carcinoma :
3-systemic chemotherapy and/or immunotherapy .
4- If patient on CNI treatment :
Reducing the dose or change to mTORi inhibitor may induce cancer regression by reaugmenting the immunity againist the HHV (The causative virus ).
Risk factors for melanoma development:
A- Pretransplant melanoma.
B- White race .
C- older age (50 years) . treatment of melanoma : A- surgery – full margin removal. B- Manipulation of immunesupresion – according to case.
Post-Transplant Lymphoproliferative Disease:B cell type
It is a rare disease 1%-2% with bimodal pattern ( 1st at 1st year second at 5th year). The studies report a recent decreasing incidence. Ninety five percent are of B cell type , 5% only are of T cell type.
Although it is a rare complication but associated with poor prognosis . ninety percent has association with EBV infection. Which acquired early in life with mild non-specific symptoms , and stay quiescent within B lymphocyte for years. This virus can reassumes activity once there is immune suppression and play important role in PTLD oncogenesis.
Risk factors :
1- Pretransplant EBV seronegativity and primary EBV infection are important risk factors for early EBV-positive PTLD.
2- Pediatric age group. 30 fold higher than general population.
3- Gender – male .
4- depleting agents, OKT , large dose tacrolimus,
5- EBV D +VE / R –VE .
6- co stimulation blocker (belatacept ) .
treatment :
1- The target is complete cure .
2- Immunosuppresion manipulation is important with variable result.
3- rituximab and chemotherapy (doxorubicin, cyclophosphamide, vincristine, prednisone)
this complication is associated with high mortality , patient with PTLD has fourteen times higher risk of death than post- transplant patient without PTLD . The survival rate is about 45% after ten years of transplantation. The worsts prognosis is with bone marrow involvement type then extra nodal then the nodal type.
Cancer Screening Strategies in Transplant Recipients:
Malignancy screening is beneficial in general population because it helps to detect the cancer in its early stage and this will reduce mortality . but the same thing is not applied in malignancy of post renal transplantation as its benefit is not proven.
As there is no specific evidence based recommendation for screening post- transplant patients, usual recomondation for general population is used for screening of breast Ca , colorectal Ca ,and cervical Ca .
Some suggest Dermatologist examination in high risk group for skin cancer . Serum alfa fetoprotein and liver ultrasound image needs to be carried out every 6 month in liver cirrhosis and chronic viral hepatitis patients.
Regular renal ultra sound examination ( annually or biannually ) is needed in patient with high risk of RCC like
A- acquired cystic disease.
B- a family history of renal cancer . C- . excesive smoking D- Chronic analgesics use .
Human Papillomavirus Vaccination in Recipients of Kidney Transplants:
Human papilloma virus is closely related to anogenital cancer . this malignancy is higher ( about 12 times) in post transplantation patient compared to general population . vaccination present to prevent this to prevent this viral infection . This vaccination is very effective ( BY 100%) in prevention cervical intraepithelial neoplasia.
This vaccine now is used for all genders between nine and twenty five year age. This vaccine is safe in transplantation but the response to vaccination is detected in half of vaccinated patients may be due to virus genotype and degree of immunosuppression . therefore it preferred to vaccinate patients before transplantation as it is more efficacious. .
Management of Recipients of Kidney Transplants Who Have Cancer:
Immunosuppression Management and Treatment in Transplant Recipients with Cancer
Immunosuppression manipulation in transplant patient with cancer is not easy .it need multidisciplinary team involving nephrologist and oncologist .
Careful decreasing the immunosuppression state is important point in management of these patient. As this approach may carry a risk of graft rejection , this should be discussed with patient.
Changing the immunosuppressant to mTORI inhibitor is proven to be beneficial to induce malignancy regression in squamous cell carcinoma and Kaposi sarcoma but put the recipient to face the wide side .
Immunotherapy:
The use of checkpoint inhibitors directed to the programmed death-1/programmed death ligand-1 interaction and/or the CD28-CD80/86 axis with cytotoxic T lymphocyte–associated protein-4 Ig
Is a very important step in treatment of malignancy by enhancing immunity against malignant cells.
But its use in transplant patient is limited by high risk of graft rejection for that reason it is not recommended for transplant recipient at this time.
Cancer is one of the most dreaded side effects of immunosuppression following kidney donation.
In most Western nations, cancer is the second most common cause of death among transplant recipients, behind cardiovascular illness.
Clinicians and decision-makers have adopted preventive policies, such as human papillomavirus (HPV) vaccination and cancer-screening strategies, to detect cancers at their earliest possible stage before they progress into advanced-stage, incurable disease, in response to higher risks and poorer cancer outcomes.
Incidence of All-Cause and Site-Specific Cancer after Transplantation
At around 15 years after transplantation ,the incidence of solid organ cancer ranges between 10% and 15%.
The cumulative incidence reaches 60% in Europe, Australia, and New Zealand for skin cancers.
In patients with kidney transplant ,The excess overall cancer risk exceeds that of the general population by approximately two- to three-fold after adjustment for age and sex.
The cancer type is also determine the magnitude of the higher risk , viral-related and immune- driven cancers such as post-transplant lymphoproliferative disease (PTLD), anogenital cancer, and Kaposi sarcoma have the greater risk.
Breast and prostate cancers are not increased in recipients of transplants .
Cancer Mortality in Recipients of Kidney Transplants
The risk of death is high once cancer developed.
The standard mortality ratios for all cancer types are at least 1.8–1.9 times higher compared with the age- and sex-matched general population.
Risk Factors for Cancer Development
Some of these factors are shared by patients in the general population such as increasing age, male sex, smoking, and prolonged sun exposures.
Other risk factors, including immunosuppression use (T cell–depleting agents), acute rejection ,sensitization status ,and duration of dialysis before transplantation ,are specific to those with kidney disease and transplant populations.
having CKD (irrespective of the CKD stage) is associated with higher cancer risk and poor cancer outcomes .
impaired tumor surveillance and immunity to viral or other tumor antigens.
A previously treated pretransplant malignancy .
The geographic areas also affect specific cancer development .
Mechanisms of Cancer Development after Transplantation
The effects of immunosuppression on dampening the immune system may create a variety of pathways for cancer development.
1-poor immune control of known oncogenic viruses in patients on immunosuppression.
2-accumulation of mutations that would otherwise be repaired or recognized by the immune system.
3- Type of immunosuppressant , tacrolimus increases the level of TGF-b and thereby promotes tumor progression and metastasis. Cyclosporine also ,through TGF-b or IL-6 overexpression pathways has direct effects on tumor development and progression .cyclosporine is capable of inhibiting DNA repair, thereby accumulating mutations, inducing apoptosis in activated T cells, and inhibiting apoptosis in other cells by opening the mitochondrial permeability transition pores .
Also Azathioprine sensitizes the skin to UVA radiation and causes the accumulation of 6-thioguanine in the DNA, leading to a higher risk of NMSCs.
On contrary, Mammalian target of rapamycin (mTOR) inhibitors, have potential antitumor effects by inhibiting cancer growth through cell-cycle arrest and initiation of apoptosis.
the risks of cancers such as PTLD and melanoma increases with the use of induction therapy with T cell-depleting agents In addition, T cell–depleting agents used in the treatment of acute rejection of the kidney allograft also heighten the risk of cancer development .
Level of evidence V
This is a narrative review of new onset malignancy after renal transplantation. Renal transplantation remains the best treatment modality for end stage renal disease both due to improvement in quality of life as well as cost effectiveness. However it is not without its drawbacks. The second leading cause of death in transplant recipients is cancer (after cardiovascular disease), but unlike cardiovascular disease a lot still remains unknown about pathogenesis, risk factors and preventive measures for malignancy.
INCIDENCE AND RISK FACTORS:
The incidence of solid organ cancers is 10-15% & >60% for skin cancer in kidney recipients. There is 2-3 fold increase in overall risk of cancer in kidney recipients with 2 times risk of death as compared to general population. Age, male gender, smoking, sun exposure are risk factors for cancers in general population and apply to renal recipients as well. Immunosuppression, viral infections, acute rejections, sensitization status and history of dialysis before transplant are risk factors specific to transplant recipients.
MECHANISMS:
1. Immunosuppression. 2. Oncogenic viruses. 3. Accumulation of mutations. 4. CNI associated activation of p53. 5. Azathioprine associated skin cancers. 6. T-cell depleting agents for induction / rejection. 7. mTOR inhibitors having protective effect against cancers.
COMMON CANCERS:
1. Renal neoplasms: are 7 times more common in post-transplant patients however usually caught at earlier stage due to regular abdominal scans, with < 2% metastasis at presentation. Renal malignancy is almost always in native kidneys with only 0.1% incidence in graft. Surgical treatment leads to comparable survival as for non-transplant patients.
2. Dermatological cancer: Most common cancer in renal transplant recipients. More aggressive than in general population, with risk increased by 250 times for squamous cell carcinoma, 100 times for Kaposi sarcoma, and 5-8 times for melanoma. Risk factors include UV exposure, HPV infection, pre-transplant skin cancer, older age, male gender, and race. Management depends on the diagnosis ranging from topical fluorouracil, imiquimod cream, photodynamic therapy, surgical excision, to chemoprophylaxis with retinoids and nicotinamide in aggressive, multiple or early onset cancers.
3. PTLD: Rare (1-2% in adults and 3% in children in first 10 years post-transplant), but associated with poor outcomes, with death rates 14 times more than non-PTLD kidney transplant recipients. Associated with EBV in 90% cases. 95% are B-cell type lymphoma. Risk factors for adults include pre-transplant EBV seronegativity and primary EBV infection. Risk factors for children include young age, male gender, donor EBV seropositivity with recipient seronegativity, T cell depleting agent use, Belatacept use, and high tacrolimus dose. Treatment involves reduction in immunosuppression and chemotherapy. Risk for death include male gender, increased age at diagnosis, and bone marrow, RES site more than extranodal and nodal disease, with median time to death being 6 months.
SCREENING:
Cancer screening recommendations in transplant recipients are not based on any trial based evidence, but are extrapolated mainly from general population (breast, colorectal, and cervical cancer). Routine skin check for patients with high-risk for skin cancer, regular abdominal ultrasound for patients with liver disease and chronic HBV infection, and regular ultrasound for RCC detection in high-risk patients are recommended.
VACCINATIONS
HPV vaccination has 99-100% efficacy to prevent cervical intraepithelial neoplasm, is safe and generally recommended in women prior to transplant.
MANAGEMENT
Management of transplant recipients developing cancer involve a multidisciplinary approach and includes reduction or alteration in immunosuppression as well as use of immunotherapy (immune checkpoint inhibitors). For early to moderate stage malignancy, judicious immunosuppression reduction is an early step. For squamous cell carcinoma, conversion to mTOR inhibitor is associated with reduced risk of cancer in long-term although with increased risk of death. There is insufficient data to consider mTOR inhibitors as protective except for squamous cell cancer and Kaposi sarcoma. Data for use of immune checkpoint inhibitors in transplant recipients is also limited, hence not recommended.
What is the level of evidence provided by this article?
Q1: cancer development following kidney transplantation is the second cause of death in recipients after
cardiovascular diseases.
preventive strategies such as HPV vaccinations, and screening strategies following immunosuppression
are necessary. There are greater risks of viral and immune-related cancers such as PTLD, anogenital, and
Kaposi sarcoma. However, breast and prostate cancers are not increased. Mortality is high, especially for
melanoma, urogenital cancers, and PTLD. Therefore, patient education is necessary. Risk factors include
immunosuppression, sensitization, and long-term dialysis before TX. Geographic area determines the
specific type of cancer. Impaired immunity to viral or other tumor antigens is the other risk. Chronic
hepatitis B virus infection is a major risk factor for liver cancer. Mechanisms of cancer development by
immunosuppression are through the accumulation of mutation that should be recognized by the
immune system. For instance, UV-induced DNA damage results in skin cancers. Tacrolimus increases
TGF-B and promotes metastasis. CNIs can activate p53 which is a hallmark of NMSC. Azathioprine
sensitizes the skin to UV radiation. On the other hand, mTOR inhibitors have potential anticancer
effects. ATG increases the risk of cancer. Common cancers after TX are renal cell carcinoma, skin cancer,
and PTLD.
HPV vaccination is recommended for women considered for TX.
Management of recipients with cancer includes alteration in immunosuppression or conversion to
mTOR inhibitors and immunotherapy.
Q2: The level of evidence if V
The increase risk of cancer after transplantation is approximately two to three times higher than the age- and sex-matched general population, driven largely by viral- and immune-related cancers.
Once cancers develop, the risk of death is high.
This review focuses on the incidence, mechanisms, diagnosis, prevention, and treatment of cancer after kidney transplantation.
Risk factors:
Old age, male sex, smoking, prolonged sun exposures, immunosuppression use (T cell–depleting agents), acute rejection, sensitization status duration of dialysis before transplantation and different geography area have different risk of particular malignancy.
Viral-associated cancers, such as Kaposi sarcoma (human herpesvirus 8), PTLD (Epstein– Barr virus [EBV]), and lip and anal cancers (HPV) are common in patients with suppressed immune systems.
Immunosuppression mechanism for malignancy:
-Tacrolimus increases the level of TGF-b and thereby promotes tumour progression and metastasis.
-Calcineurin inhibitors inhibit signalling via calcineurin and NF of activated T cells, which can activate p53, a hallmark of some Non Melanotic Skin Cancers.
-Cyclosporine also has direct effects on tumour development and progression, through TGF-b or IL-6 overexpression pathway.
-Azathioprine sensitizes the skin to UVA radiation and causes the accumulation of 6-thioguanine in the DNA, leading to a higher risk of NMSCs.
-T-cell depletion, there is often an incomplete T-cell recovery, which may have a long-term effect on immune homeostasis, leading to an impaired immune system (and subsequent cancer development.
-Mammalian target of rapamycin (mTOR) inhibitors, have potential antitumor effects by inhibiting cancer growth through cell-cycle arrest and initiation of apoptosis.
Renal Cell Carcinoma post-transplant:
-Up to 7 fold increase risk
-90% of renal cell carcinomas develop in the native kidneys, only 0.1% incidence in kidney allograft.
-Risk factors for development of renal cell carcinomas post transplantation include male sex, increasing age, African descent, and longer time on dialysis, with regard to disease aetiology, patients transplanted for kidney failure secondary to glomerular diseases, hypertensive nephrosclerosis, and vascular disease appear to have the greatest associated risk.
-Surgical options include Radical nephrectomy, Partial nephrectomy, Cryotherapy or HIFU. Skin cancer post-transplant:
The most commonly include cutaneous squamous cell carcinoma, basal cell carcinoma, Kaposi sarcoma, and malignant melanoma, with keratinocyte carcinomas comprising 90%–95% of these skin cancers.
Risk factors are exposure to UV radiation, HPV, pretransplant skin cancer, older age, race, and sex (males at greater risk than females), immunosuppressive medications (mainly cyclosporine and azathioprine).
Kaposi sarcoma exceeds 100 times than that of the general populations. Melanoma has the highest mortality.
Management:
In patients with actinic keratoses and squamous cell carcinoma in situ, management options include topical fluorouracil and imiquimod cream, photodynamic therapy, and surgical excision or electrodesiccation and curettage, in inoperable case radiation, chemoprophylaxis in early onset.
Regression of Kaposi sarcoma has been reported after switching from calcineurin inhibitors to sirolimus by restoring effector and memory T-cell immune activity against human herpesvirus.
For melanoma Primary treatment is surgical with wide excision and adequate margins, based on Breslow thickness, as per the National Comprehensive Cancer Network guidelines.
Post-Transplant Lymphoproliferative Disease post transplantation:
Approximately 90%, PTLD is associated with EBV, viruses can reactivate because of depressed T-cell function, with a lack of T-cell control over B-cell proliferation.
PTLDs are of B-cell types, with approximately 5% of patients having the T-cell type.
There is a bimodal distribution in PTLD incidence, with the risk of PTLD being the highest in the 12 months post-transplant, and it then decreases until the fifth year after transplantation.
The risk of death among recipients of kidney transplants who have PTLD is 4- fold higher than recipients without PTLD but it has decreased due to chemotherapy.
Pretransplant EBV seronegative and primary EBV infection are important risk factors for early EBV-positive PTLD.
Belatacept, has also been found to be associated with a higher risk of PTLD, particularly cerebral PTLD in patients who are EBV negative, and when used in higher doses.
Mainstay of treatment is immunosuppression reduction. Prior work reported the use of rituximab and chemotherapy (doxorubicin, cyclophosphamide, vincristine, prednisone) have improved overall survival, with 5-year survival at around 60%.
Prevention:
HPV vaccination is recommended for women before or after transplantation.
There is lack of evidence to support routine screening in this high-risk group, routine population-based cancer screening for breast, colorectal, and cervical cancer is recommended.
Management of Recipients of Kidney Transplants Who Have Cancer:
Multidisciplinary approach
Risk of acute rejection from under-immunosuppression, and cancer resulting from over-immunosuppression is big challenge in management.
Judicious reduction in the overall immunosuppression load for patients with early- to moderate-stage malignancy may be a reasonable first step.
There are insufficient data to consider mTOR inhibitors as protective against other cancer types apart from squamous cell carcinoma and Kaposi sarcoma.
The use of checkpoint inhibitors is limited in recipients of transplants given the potential for rejection with nonspecific immune-system activation.
For patients who have progressed to advanced-stage malignancy, complete immunosuppression withdrawal is a difficult decision for both patients and clinicians.
Long term kidney transplant recipients have clinical complications.. After cardiovascular disease cancer is the second most common cause of death in few western countries apart from infection being the second cause of death in developing countries…. The higher incidence and morbidity from cancers have made clinicians aware about cancer screening programs and HPV vaccination….
The cumulative incidence of solid organ transplantation after transplantation is 10 to 15% after renal transplant at the end of 15 years…. The cumulative incidence of few skin cancers can reach around 60% in few European and Australian countries. Kaposis sarcoma, non Hodgkins lymphoma, non melanoma and melanoma skin cancers are more common in solid organ transplant recipients….Few cancers like breast and prostate are not increased incidence in post transplant recipients…
There is increased risk of mortality of 1.5-2 times after skin cancer in renal transplant patients
There are many reasons for higher incidence of cancer after renal transplantation…some factors like increasing age, male sex, smoking, prolonged sun exposure are common… the longer the duration of CKD itself seems to be a risk factor for de novo malignancy after renal transplantation…RCC and multiple myeloma seem to have an increased incidence in dialysis and CKD patients themselves…Recent studies show increased incidence of all cause mortality in recipients after pre transplant malignancy which may not be related to malignancy recurrence alone…
Geographic variations are also reported in various population groups….Observational date from Europe, North America and Australia indicate that there is increased incidence of Non melanoma skin cancer, PTLD and lip cancer as compared to Asian and middle eastern countries where urothelial cancers and renal cell cancers were more….Taiwan for example is endemic to Hepatitis B and there is increased incidence of liver cancer after renal transplantation…
Maintenance immunosuppression after renal transplant paves the way for other malignancies…One such mechanism is increased incidence of oncogenic viruses after renal transplant like HHV8 – Kaposis sarcoma, EBV – PTLD, Lip and anal cancer – HPV. There is increasing evidence to say that CNI have tumor progression effect….Tacrolimus has shown to increase the levels of TGF beta which promotes tumor progression and metastasis….Activation of p53 takes place as a side effect of calcineurin inhibition which inturn causes NMSC.. Similarly CYC also has been shown to have increased DNA mutations and inhibiting apoptosis in other cells….AZA increases the accumulation of 6 thioguanine sensitizing the skin towards UVA and NMSC…mTOR inhibitors have potent antitumor activities…inhibits cell cycle growth and promotes apoptosis… invitro studies have demonstrated reduced activity of cancer cells incubated with mTOR inhibitors….Studies have consistently demonstrated increased cancer incidence after use of ATG, Anti CD3 agents used for induction agents presumbly due to prolonged T cell suppression causing immune dysregulation….
Renal cell carcinoma: There is increased incidence(7 fold) in post renal transplant patient as compared to general population… due to increased abdominal imaging many cases are detected in the early stages with less spread amenable to surgery…there is increased incidence of RCC in the native kidneys as compared to de novo malignancy after transplant in these patients…the longer duration of dialysis, hypertension, male gender, African descent are associated with increased risk… De novo RCC of transplant kidney should be managed as per standard urological guidelines. Nephron sparing surgery and immunosuppression modulation are the key to prolong the life of the transplant kidney…. The overall outcome after Radical nephrectomy in renal transplant population are comparable to general population…
Skin cancer – most common in renal transplant recipients… SCC is more common as compared to BCC which is reverse in the general population…. Kaposi’s sarcoma and melanoma are also more common… The pathogenesis of skin cancer after renal transplant is related to sun exposure and is more common in sun exposed areas.. Sun exposure is difficult to avoid and it can get reflected even from water and sand…UVB and UVA are both implicated…Sun exposure during the mid day when there is less atmosphere for it to reach the patient has been shown to have highest risk as compared to early morning and late evening sun exposure… CNI and AZA are implicated in the pathogenesis of SCC and BCC…Kaposi sarcoma is more common by 100 times in African, Middle eastern and Mediterranian groups. Kaposis sarcoma have excellent response to reduction in immunosuppression…..Those with in situ cancer of SCC have a very good response to local skin excision and topical applications like Imiquomod and 5FU… Multifocal SCC may have requirement for chemotherapy… Risk of development of Malignant melanoma is highest after renal transplant in those with pre existing melanoma…
Post Transplant lymphoproliferative Disease: incidence is 1-2% after renal transplantation..It is more common in pediatric age group…It is associated with proliferation of EBV infected B cells..EBV is a common viral infection and post transplant scenario the EBV infected memory B cells can get activated in the post renal scenario leading on PTLD….Recent data suggest that the incidence of PTLD is decreasing…..EBV positive PTLD seem to occur in the early stages and is associated with Donor positive EBV status pre transplant and has a good prognosis as compared to late onset EBV negative PTLD…Once PTLD develops the overall risk of death is nearly 14 times more as compared to those without PTLD in renal transplants.. the mainstay is reduction in immunosuppression and chemotherapy with CHOP and Rituximab….
Cancer screening is recommended as per the guidelines for general population itself as there are no major recommendations… frequent skin examination to detect early skin lesion must be taught to the renal transplant patients… for those with chronic liver disease due to Hep B it is associated to screen every bieenially with
USG and AFP….Annual screnning for RCC of native kidneys are recommeded for those with prolonged dialysis duration and acquired cystic disease and smoking
Vaccination of transplant patient with HPV vaccine is recommended to reduce the incidence of anogenital cancer…ideally vaccination should happen before transplant itself…
This review focuses on the incidence, mechanisms, diagnosis, prevention and treatment of cancer after kidney transplantation
Risk factors & mechanisms of cancer development after transplantation:
Increasing age, male, smoking and prolonged sun exposure
Immunesupressive drugs, sensitization status, and duration of dialysis before transplantation, and CKD, HPV, EBV, HBV …etc.
CNI increases the level of TGF-b and thereby promotes tumor progression and metastasis, inhibit signaling via calcineurin and activate p53, a hallmark of some NMSCs.
Azathioprine sensitizes the skin to UVA radiation and causes the accumulation of 6-thioguanine in the DNA, leading to a higher risk of NMSCs.
m-TOR inhibitors, may have potential antitumor effects by inhibiting cancer growth through cell-cycle arrest and initiation of apoptosis.
Common cancers after transplantation:
Renal cell carcinoma: Usually early, low-grade, small kidney masses; of which, 75%–80% are renal cell carcinoma, in the native kidenys, with the risk of metastasis at presentation being 2%. Kidney failure secondary to glomerular diseases, hypertensive nephrosclerosis and vascular disease appear to have the greatest risk. The outcome of renal cell carcinomas after radical treatment in the transplant population is comparable with that of the general population.
Skin Cancer: Cutaneous squamous cell carcinoma, basal cell carcinoma, Kaposi sarcoma, and malignant melanoma, with keratinocyte carcinomas comprising 90%–95% of these skin cancers. UV radiation, HPV, pretransplant skin cancer, older age, race, and male sex are risk factors for skin cancer in transplant recipients. Mohs micrographic surgery, offers the most definitive method of treatment, with cure rates of 95%–100%. Topical fluorouracil and imiquimod cream, photodynamic therapy, are modalities used for treatment. Kaposi sarcoma increased by the use of CNI, this could be overcome by m-TORi use. The prognosis is worse among transplant patients than that for the general age and sex matched population, melanoma has the worst prognosis.
Post-Transplant Lymphoproliferative Disease: PTLD is associated with EBV, and pears a poor prognosis;14 % mortality. PTLDs are of B-cell types, with approximately 5% of patients having the T-cell type. Risk factors are: First year post-transplant and 5 years after transplant, Pretransplant EBV seronegativity/ donor positive and primary EBV infection, particularly in younger recipients of transplants. The mainstay of treatment is immunosuppression reduction, Rituximab and chemotherapy. HPV vaccination is the preventive measure recommended.
Cancer screening strategies in transplant recipients:
High quality, randomized controlled trials have shown that cancer screening through early detection reduces cancer- specific mortality in the general population. Breast cancer: screening mammography once every 2 years for 50-74 years of woman Cervical cancer: annual Pap testing Bowel cancer : sigmoidoscopy every 5 years or colonoscopy every 5-10 years. Skin cancer : monthly self skin examination and 6 to 12 monthly total body skin examination by expert physicians and dermatologists
Management
Immunosuppression managemeny:
Optimization of IS therapy to prevent both rejection and graft loss and manage cancer is the challenge here.
Shift from CNI to mTORi in case of SCC and Kaposi sarcoma helps in treatment but unfortunately was associated with risk of mortality and discontinuation due to its complications.
Immunotherapy
Use of immune therapy targeting cell apoptosis may be beneficial in melanoma, lung and renal cell carcinoma
Conclusion
The study identify patient groups and cancer types, helps in surveillance program, and providing data on counselling pretransplant patients on the risk of malignancy.
2.What is the level of evidence provided by this article
Level V evidence
Cancer is the second most common cause of death in kidney transplant recipients after cardiovascular disease. Risk factors for cancer development are: increasing age, male sex, smoking, prolonged sun exposure, immunosuppression use, actute rejection, sensitization status and duration of dialysis before transplantation. Though types of cancer vary according to geographic region, the common cancer that developed after renal transplantation are Kaposi sarcoma, non- melanoma skin cancer, PTLD, malignant melanoma, RCC and anogenital cancer. Specific virus are associated with some specific cancer e.g. EBV with PTLD, HHV-8 with NMSC, HPV with anogenital cancer, HVB with liver cancer. Risk of death is greatest among those with melanoma, urogenital cancer & PTLD. Among immunosuppresive drugs CNI, AZA, T- cell depleting agents are associated with risk of cancer development & mTOR is associated with regression of cancer. Though Transplant patient are always at increased risk of cancer development, specific guidelines about screening are not not well established, most are derived from guidelines for general population. Though ruduction of immunosuppresion and adding mTOR inhibitiors, ICI are the current treatment option for post transplant cancer patients, a combined work of nephrologist, oncologist, other specialist, psychiatrist are always needed. At the same time, try to give importance the patient preferences & always calculate the risk benefit ratio of prescribed medicine.
1. Summary of the article Basis and introduction:
After cardiovascular disease, cancer is the second leading cause of death among recipients of transplants in most Western countries. The cumulative incidence of solid organ malignancy ranges between 10% and 15% at around 15 years post-transplantation. The prevalence of cancer in post-kidney transplantation is three times more than in the general population. Cancer related mortality also is increased 5-10 folds post-transplant. This, in recent time, has triggered the need for physicians, policymakers, and patients to develop joint decisions on preventive methods to reduce morbidity and mortality from different cancers post-transplant. In this review article, the incidence, mechanisms, diagnosis, prevention, and treatment of cancer after kidney transplantation are elaborated. Risk factors: · Increasing age, male sex, smoking, prolonged sun exposures · Heavy immunosuppression (T cell–depleting agents like Thymoglobulin), treatment of acute rejection, sensitized patients requiring desensitization, and long duration on dialysis (RCC, Multiple myeloma) · Geographical variations differ risk of particular cancers –
Europe, North America, Australia, and New Zealand – skin cancer (NMSCs), PTLD, and lip cancer Asian and Middle East – urothelial transitional cell carcinoma, renal cell carcinoma, and GI cancers Taiwan – 5 folds excess risk of liver cancer · Neoplastic lesions and cancer (treated) prior to transplant · Viral infection associated – Kaposi sarcoma (HHV8, PTLD (EBV), Lip and anal cancers (HPV) are common in immunosuppressed patients
Mechanisms of Cancer development after transplant: · poor immune control of viruses – increase viral-associated cancers Kaposi sarcoma (HHV8), PTLD (EBV), lip and anal cancers (HPV)
· accumulation of mutations (not repaired / recognized by immune system).
– immunosuppression impairs the cells’ ability to repair UV radiation–induced DNA damage. · Immuno-suppression drugs with direct oncogenic potential -Tacrolimus increases TGF-b à tumour progression and metastasis; -inhibits signalling via calcineurin and NF of activated T cells à activate p53 (hallmark of NMSCs) -Cyclosporine has direct effects on tumour development and progression, through TGF-b or IL-6 overexpression pathway. -Azathioprine sensitizes the skin to UVA radiation and causes the accumulation of 6-thioguanine in the DNA, leading to a higher risk of NMSCs. -T-cell depleting drugs cause incomplete T-cell recovery à long-term effect on immune homeostasis and impaired immune system – mTOR inhibitors – have potential antitumor effects by inhibiting cancer growth through cell-cycle arrest and initiation of apoptosis. COMMON CANCERS after TRANSPLANT 1. Kidney cancers (RCC) – Up to 7th fold increase risk -90% are RCC develop in the native kidneys – 80% low grade small tumors – only 0.1% incidence of tumours in kidney allograft. Risk factors – male sex, increasing age, African descent, and longer time on dialysis, -Native kidney disease (etiology) – glomerular diseases, hypertensive nephrosclerosis, and vascular disease are high risk Treatment – Partial nephrectomy in majority (67%) of small tumours; Radical nephrectomy (19%); percutaneous ablation (Cryotherapy and HIFU) 12%. Good prognosis of surgically treated tumours, similar to gen polulation
2. Skin cancers: – Most common cancers post renal transplant and more aggressive than in general population – Squamous cell carcinoma, basal cell carcinoma, Kaposi sarcoma, and malignant melanoma, keratinocyte carcinomas comprise 90%–95% of skin cancers. – Risk factors are UV radiation, HPV, pretransplant skin cancer, older age, white race, and male sex, immunosuppressive medications (CsA and azathioprine). – Kaposi sarcoma common in ethnic groups (Mediterranean, Africa, Central Europe) – 100 times more, than in general populations. Melanoma has the highest mortality. Management of skin cancers – Ø Actinic keratoses, SCC in situ – topical 5FU and imiquimod cream, photodynamic therapy, and surgical excision or electrodesiccation and curettage
Ø Mohs micrographic surgery, with histologic negative margins – 95–100% cure rate Ø Radiation in inoperable cases for local control
Ø Chemoprophylaxis – (Retinoids and Nicotinamide) for SCC advised if multiple recurrences (>5 / year), aggressive or early onset disease
Ø systemic chemotherapy and/or immunotherapy – for metastatic SCC Ø Melanoma – Surgical excision with adequate margins; v Reduction of immune-suppression – Stopping AZT, MMF v Switching CNI àSirolimus: regression of Kaposi sarcoma reported 3.Post-Transplant Lymphoproliferative Disease (PTLD) rare but associated with poor outcome – increase mortality >14times 90% associated with EBV infection of B cells (latent infection) à viral reactivation causes uncontrolled B-cell proliferation (lack of T-cell control) Incidence – 1-2% of adult and 3% of paediatric renal Tx recipients bimodal distribution – highest in first 12 months, then decreases until 5 years post-transplant. Risk factors – Pretransplant EBV sero-negativity primary EBV infection negative recipient EBV serology (with positive donor EBV serology) – x 4 folds
Young age & male sex – paediatric recipients (30-times higher)
T cell–depleting agents (Thymoglobulin), OKT3 (muromonab-CD3), high dose of Tacrolimus and Belatacept (EBV negative Cerebral PTLD) Mainstay of treatment is reduction of immunosuppression. Rituximab and chemotherapy (doxorubicin, cyclophosphamide, vincristine, prednisone) have improved overall survival, with 5-year survival at around 60%. Prevention (Vaccination + Screening): · HPV vaccination is recommended for women before or after transplantation. · Although supportive evidence is lacking, routine population-based cancer screening for breast, colorectal, and cervical cancer is recommended
· 6monthly skin checks by dermatologists for recipients with high risk
· Chronic HBV infections & liver disease – abdominal ultrasound and serum AFP every 6 months · Patients with risk of developing RCC (acquired cystic disease, family history, smokers, long-term analgesics use) – annually / biennially USG of native kidney Managing Kidney Transplant Recipients having Cancer: v Multidisciplinary approach – discussion with patient and family is required
v Understanding immunologic risk versus cancer severity — optimize immunosuppression dose to prevent the risk of rejection, while balancing against the need to induce tumour regression and prevent progression.
v Judicious reduction in immunosuppression load for patients with early- to moderate-stage malignancy may be a reasonable. v There are insufficient data to consider mTOR inhibitors as protective against other cancer types, apart from SCC and Kaposi sarcoma. v Immunotherapy – Immune checkpoint inhibitors can cause rejection due to nonspecific immune-system activation, thus not recommended. v For patients who have progressed to advanced-stage malignancy, complete immunosuppression withdrawal is a difficult decision for both patients and clinicians. 2. What is the level of evidence provided by this article? Level of evidence: Level 5
The excess risk of cancer after transplantation is approximately two to three times higher than the age- and sex-matched general population, driven largely by viral- and immune-related cancers. Once cancers develop, the risk of death is high. This review focuses on the incidence, mechanisms, diagnosis, prevention, and treatment of cancer after kidney transplantation.
Risk factor
Increasing age, male sex, smoking, prolonged sun exposures, immunosuppression use (T cell–depleting agents), acute rejection, sensitization status duration of dialysis before transplantation and different geography area have different risk of particular malignancy.
Viral-associated cancers, such as Kaposi sarcoma (human herpesvirus 8), PTLD (Epstein– Barr virus [EBV]), and lip and anal cancers (HPV) are common in patients with suppressed immune systems.
Immunosuppression mechanism for malignancy
-Tacrolimus increases the level of TGF-b and thereby promotes tumor progression and metastasis.
-Calcineurin inhibitors inhibit signaling via calcineurin and NF of activated T cells, which can activate p53, a hallmark of some NMSCs.
-Cyclosporine also has direct effects on tumor development and progression, through TGF-b or IL-6 overexpression pathway.
-Azathioprine sensitizes the skin to UVA radiation and causes the accumulation of 6-thioguanine in the DNA, leading to a higher risk of NMSCs.
-T-cell depletion, there is often an incomplete T-cell recovery, which may have a long-term effect on immune homeostasis, leading to an impaired immune system (and subsequent cancer development.
-Mammalian target of rapamycin (mTOR) inhibitors, have potential antitumor effects by inhibiting cancer growth through cell-cycle arrest and initiation of apoptosis.
-90% of renal cell carcinomas develop in the native kidneys, only 0.1% incidence in kidney allograft.
-Risk factors for development of renal cell carcinomas post transplantation include male sex, increasing age, African descent, and longer time on dialysis, with regard to disease etiology, patients transplanted for kidney failure secondary to glomerular diseases, hypertensive nephrosclerosis, and vascular disease appear to have the greatest associated risk.
-Surgical options include Radical nephrectomy, Partial nephrectomy, Cryotherapy or HIFU. Skin cancer post-transplant
The most commonly include cutaneous squamous cell carcinoma, basal cell carcinoma, Kaposi sarcoma, and malignant melanoma, with keratinocyte carcinomas comprising 90%–95% of these skin cancers.
Risk factor are-exposure to UV radiation, HPV, pretransplant skin cancer, older age, race, and sex (males at greater risk than females), immunosuppressive medications (mainly cyclosporine and azathioprine). Kaposi sarcoma exceeds 100 times than that of the general populations. Melanoma has the highest mortality. Managment
In patients with actinic keratoses and squamous cell carcinoma in situ, management options include topical fluorouracil and imiquimod cream, photodynamic therapy, and surgical excision or electrodesiccation and curettage, in inoperable case radiation, chemoprophylaxis in early onset.
Regression of Kaposi sarcoma has been reported after switching from calcineurin inhibitors to sirolimus by restoring effector and memory T-cell immune activity against human herpesvirus.
For melanoma Primary treatment is surgical with wide excision and adequate margins, based on Breslow thickness, as per the National Comprehensive Cancer Network guidelines.
Post-Transplant Lymphoproliferative Disease post transplantation
Approximately 90%, PTLD is associated with EBV, viruses can reactivate because of depressed T-cell function, with a lack of T-cell control over B-cell proliferation. PTLDs are of B-cell types, with approximately 5% of patients having the T-cell type.
There is a bimodal distribution in PTLD incidence, with the risk of PTLD being the highest in the 12 months post-transplant, and it then decreases until the fifth year after transplantation. The risk of death among recipients of kidney transplants who have PTLD is 4- fold higher than recipients without PTLD but it has decreased due to chemotherapy.
Pretransplant EBV seronegativity and primary EBV infection are important risk factors for early EBV-positive PTLD.
Belatacept, has also been found to be associated with a higher risk of PTLD, particularly cerebral PTLD in patients who are EBV negative, and when used in higher doses.
Mainstay of treatment is immunosuppression reduction. Prior work reported the use of rituximab and chemotherapy (doxorubicin, cyclophosphamide, vincristine, prednisone) have improved overall survival, with 5-year survival at around 60%.
Prevention
HPV vaccination is recommended for women before or after transplantation. There is lack of evidence to support routine screening in this high-risk group, routine population-based cancer screening for breast, colorectal, and cervical cancer is recommended.
Management of Recipients of Kidney Transplants Who Have Cancer
Multidisciplinary approach
Risk of acute rejection from under-immunosuppression, and cancer resulting from over-immunosuppression is big challenge in management.
Judicious reduction in the overall immunosuppression load for patients with early- to moderate-stage malignancy may be a reasonable first step.
There are insufficient data to consider mTOR inhibitors as protective against other cancer types apart from squamous cell carcinoma and Kaposi sarcoma.
The use of checkpoint inhibitors is limited in recipients of transplants given the potential for rejection with nonspecific immune-system activation.
For patients who have progressed to advanced-stage malignancy, complete immunosuppression withdrawal is a difficult decision for both patients and clinicians.
What is the level of evidence provided by this article? Level of evidence: Level 5
Kidney transplantation still remains the best form of renal replacement therapy for patients with ESRD, but it also comes with unintended complications like developments like cancers after cardiovascular disease. As a result of this negative outcome, there is a need for physicians, policymakers, and patients to develop a preventive method to reduce morbidity and mortality that could come with different cancer.
The cumulative incidence of solid organ malignancy ranges between 10% and 15% at around 15 years post-transplantation. The prevalence of cancer in post-kidney transplantation is three times more than in the general population.
Risk factors for cancer development
Increasing age
male sex
smoking
use of T-cell depleting agent
sensitization
dialysis vintage
Mechanism of cancer development in transplantation
The following mechanism has been postulated as the pathogenesis of cancer development post-kidney transplantation.
poor immune control of known oncogenic viruses in patients on immunosuppression. e.g, EBV, HHV-8
accumulation of mutation that would otherwise be repaired e.g the effect of UV-light B
CNI inhibitor has been postulated to inhibit the repair of DNA
Common cancer after Transplantation
Renal cell cancer
Skin cancer
Post-transplant lymphoproliferative disease
Management of recipients with cancer
Reduction of immunosuppressive drugs
switch to mTOR inhibitors
Use of Immunotherapy
Conclusion
Cancer remains one of the leading causes of morbidity and mortality following successful transplantation as a result of a few risk factors like the type of induction medication use, prolonged use of certain immunosuppressive, and age of the recipients. Asides from some preventive method that appears to be promising, there is yet no standard treatment method or cure for cancer in post-transplant patients. Hence, there is a need for continuous research to fill this knowledge gap.
kidney transplantation is the best treatment for end stage kidney disease, immunosuppressive drugs associated with increased incidence of cancer. ·Malignancy is the second leading cause of death in recipients of transplants in most Western countries, this encouraged transplant specialist to screen for cancer.Incidence of cancer is 10-15 % in solid organ at 15 y post-transplant . Common Cancers after Transplantation Renal Cell Carcinoma Compared with the general population, recipients of kidney transplants have a higher risk (up to seven-fold) Skin Cancer The most common cancer type in recipients of kidney transplants Post-Transplant Lymphoproliferative Disease. Recommendations for cancer screening For breast cancer, screening is recommended every 2 years for patients between 50- 74 years but depends on individual risk assessment in people less than 50 years. Prostate cancer screening is only recommended in patients between 55 and 69 years after explaining the risk and benefits. Pap smear or HPV testing every 3-5 years is recommended starting at 25 years until 74 years for cervical cancer screening. Bowel cancer screening is recommended at 45 years till 75 years with biennial fecal immunohistochemistry and sigmoidoscopy or colonoscopy every 5 years. Lung cancer screening with low dose chest CT is recommended at 55 years till 79 years in heavy smokers only. For skin cancer, monthly self-examination and 6 monthly total body examination by dermatologist is advised. Renal cancer screening is not routinely recommended. Recommendation for liver cancer screening includes ultrasound scanning and 6-monthly alpha-fetoprotein in cirrhotic patients. Post-transplant lymphoproliferative disease is also screened for in EBD seronegative recipient of seropositive organ once at 1 week after transplant, monthly every 1-3 months and every 3/12 till the end of first year post transplant using the nucleic acid testing method. Management of recipient with cancer.
This need multidisciplinary approach between oncologist, transplant physician, and allied health professionals.
Optimization of immunosuppression.
Immunotherapy is not recommended still need further investigation.
In conclusion the recipient are in risk of developing different types of tumors specially skin cancer.
So highly recommended for screening before transplantation and post-transplant surveillance.
Level of evidence V.
This is a narrative review of level 5 evidence Summary of the article Cancer is the second cause of mortality in transplant recipients after the cardiovascular disease . Melanoma, Non-Hodgkin lymphoma and ano-genital cancers carry the highest among the kidney transplant recipients being increased with the following risk factors : · Old age · Males · Smoking · Prolonged sun exposure · HBV infection. · Impaired immunity to viral or tumour antigens · Pre-transplant malignancy · Acute rejection
The most common 3 cancers post-renal transplant are : -PTLD -Renal cell carcinoma -Skin cancer
Proper management of post operative malignancy includes : -Optimization of immunosuppression -Conversion to mTORi especially in patients with kaposi sarcoma and squamous cell carcinoma -Immunotherapy usage is an option but with limited application . -Treatment always starts by proper prevention through cancer screening of breast, cervical, prostate and colon cancer .
Use of immunosuppression in post transplant cases , leads to increased incidence of malignancy which is linked to higher prevalence of viral infection , poor immune surveillance of body.
the pattern of cancer is variable
in Europe and Australia , NZ- skin , PTLD, lip cancer is more common , men> women
in middle east and non -western Asia – Liver , urothelial cancer are common
in Taiwan – liver is common due to HBV infection and women outnumbered the men
mechanism of cancer development
virus linked – HHV-B with kaposi, HPV with anogenital , HBV with liver cancer , EBV with PTLD
accumulation of mutation like skin cancer
CNI can cause tumor
T cell depleting agent increases the risk of cancer
screening for cancer
special protocol for post transplant patient is not recommended based on available evidence
routine population-based cancer screening for breast, colorec-
tal, and cervical cancer is recommended
trials.
HPV vaccination is indicated in both males and females aged 9–25 years in the general pop-ulation for the prevention of HPV-related malignancies.
treatment is mainly to reduce the immunosuppression
shift to MTOR inhibitor
patient centric approach is recommended rather than a generalized approach
Introduction:
• Since cancer is the second most common cause of death in the majority of Western nations, it is a significant outcome following kidney transplantation.
• Compared to the general population of people of the same age and sex, the extra risk of cancer following transplantation is around two to three times greater.
• Viral and immune-related malignancies account for the majority of this excess risk.
• More significantly, this high-risk group lacks access to efficient screening and treatment methods. Cancer Mortality in Recipients of Kidney Transplants
Standard mortality ratios for all cancer types are at least 1.8–1.9 times higher compared with the age- and the sex-matched general population.
The risk is greatest among those with melanoma, urogenital cancers, and non-Hodgkin lymphoma,
The exact reasons for the higher risk of death are unclear but may be due to:
• Long-term immunosuppression.
• Associated co-morbidities.
• Low uptake of recommended prevention and screening strategies. Risk Factors for Cancer Development Shared by patients in the general population
• Increasing age,
• Male sex,
• Smoking,
• Prolonged sun exposures Specific to those with kidney disease and transplant populations
• Immunosuppression use (T cell–depleting agents),
• Acute rejection.
• Sensitization status.
• Duration of dialysis before transplantation. Mechanisms of Cancer Development after Transplantation
• Through inadequate immune regulation of recognized carcinogenic viruses in immunosuppressed individuals. (Cancers linked to viruses, such as Kaposi sarcoma (HH8) and PTLD (EBV),
• As a result of mutations that would typically be corrected or identified by the immune system accumulating. (Most prevalent in the skin) Common Cancers after Transplantation Renal Cell Carcinoma
Compared with the general population, recipients of kidney transplants have a higher risk (up to seven-fold) Skin Cancer
The most common cancer type in recipients of kidney transplants Post-Transplant Lymphoproliferative Disease
In most instances (approximately 90%), PTLD is associated with EBV. Management of Recipients of Kidney Transplants Who Have Cancer Immunosuppression Management and Treatment in Transplant Recipients with Cancer
• It is complex and challenging.
• Need transplant professionals, oncologists, and allied health.
• Aim to optimize immunosuppression dose to prevent the risk of acute rejection, while balancing against the need to induce regression of the malignant lesion and prevent future progression,
• All strategies should be tailored to the individual’s needs. Immunotherapy
• The use of immune-checkpoint inhibitors targeting the programmed death Conclusions
• Cancer is the leading cause of morbidity and mortality in patients with kidney transplants.
• The lifestyle changes and the complex feelings caused by the diagnoses are overwhelming. The priorities of optimizing
• Allograft function with immunosuppression is often challenged and superseded by having a “cure” for cancer and may involve immunosuppression reduction or cessation to reduce the risk of cancer relapse and improve long-term cancer survival.
• Collaborative efforts between healthcare professionals, policymakers, trialists, and patients are needed to ensure quality evidence.
What is the level of evidence provided by this article?
Level V
De Novo Malignancies after Kidney Transplantation Introduction
· Although kidney transplantation is the best treatment for end stage kidney disease, immunosuppressive drugs associated with increased incidence of cancer.
· Malignancy is the second leading cause of death in recipients of transplants in most Western countries, this encouraged transplant specialist to screen for cancer.
· This review about the incidence, mechanisms, diagnosis, prevention, and treatment of cancer after kidney transplantation.
Incidence of All-Cause and Site-Specific Cancer after Transplantation
· Incidence of cancer is 10-15 % in solid organ at 15 y post-transplant
· For skin cancers, the cumulative incidence reaches .60% in Europe, Australia, and New Zealand
· The excess overall cancer risk in patients with kidney transplant exceeds that of the general population by approximately 2-3-fold after adjustment for age and sex
· Breast and prostate cancers are not increased in recipients of transplants
Cancer Mortality in Recipients of Kidney Transplants
· The standard mortality ratios for all cancer types are at least 1.8–1.9 times higher compared with the age- and sex-matched general population
· The risk is greatest among those with melanoma, urogenital cancers, and non-Hodgkin lymphoma, with an overall risk of cancer-related death exceeding 5-10 times that of those without kidney transplants
Risk Factors for Cancer Development
· increasing age, male sex, smoking, and prolonged sun exposures
· immunosuppression use (T cell–depleting agents),
· acute rejection, sensitization status
· duration of dialysis before transplantation
· impaired tumor surveillance and immunity to viral or other tumor antigens.
· renal cell carcinoma and multiple myeloma, are over-represented in the CKD/ kidney-failure populations
Mechanisms of Cancer Development after Transplantation
· poor immune control of known oncogenic viruses in patients on immunosuppression such as Kaposi sarcoma (human herpesvirus 8), PTLD [EBV], and lip and anal cancers (HPV)
· accumulation of mutations that would otherwise be repaired or recognized by the immune system mainly in skin cancers
· tacrolimus may promotes tumor progression and metastasis of hepatocellular carcinoma, human lung adenocarcinoma cells, and renal cell carcinoma
· Cyclosporine also has direct effects on tumor development and progression,
· The potential oncogenic potential of azathioprine is well known and well recognized.
· Azathioprine sensitizes the skin to UVA radiation and causes the accumulation of 6-thioguanine in the DNA, leading to a higher risk of NMSCs
· On the other hand mTOR i may have potential antitumor effects by inhibiting cancer growth through cell-cycle arrest and initiation of apoptosis Common Cancers after Transplantation
Renal Cell Carcinoma
· recipients of kidney transplants have up to 7-fold increased risk of renal cell carcinoma
· 90 % of renal cell carcinomas develop in the native kidneys as opposed to the allograft.
· Risk factors for development of renal cell carcinomas posttransplantation include male sex, increasing age, African descent, and longer time on dialysis
· With regard to disease etiology, patients transplanted for kidney failure secondary to glomerular diseases, hypertensive nephrosclerosis, and vascular disease appear to have the greatest associated risk
· In contrast, patients with kidney failure secondary to diabetes or autosomal dominant polycystic kidney disease have a lower risk of renal cell carcinomas.
Skin Cancer
· Is the commonest cancer in recipients of kidney transplants and is more aggressive than skin cancers occurring in the general population
· The most commonly reported skin cancers in recipients of kidney transplants include cutaneous squamous cell carcinoma, basal cell carcinoma, Kaposi sarcoma, and malignant melanoma, with keratinocyte carcinomas comprising 90%–95% of these skin cancers
· the incidence of Kaposi sarcoma in recipients of transplants exceeds 100 times that of the general population.
· recipients of transplants experience an excess risk of squamous cell carcinoma by approximately 250 times
· Patients treated with CNI are at particularly high risk for Kaposi sarcoma. Decreasing the intensity or switching immunosuppressive agents to an mTOR inhibitor is the cornerstone of treatment.
· Among all skin cancer types, melanoma has the highest mortality
· History of pretransplant melanoma is the strongest risk factor for post-transplant melanoma, followed by White race and older age (>50 years) Post-Transplant Lymphoproliferative Disease
· In most instances (approximately 90%), PTLD is associated with EBV
· The cumulative incidence of PTLD in the first 10 years after kidney transplantation is around 1%–2% in adult recipients and about 3% in pediatric recipients of transplants
· Pretransplant EBV seronegativity and primary EBV infection are important risk factors for early EBV-positive PTLD, particularly in younger recipients of transplants
· Compared with adult recipients of transplants, the risk of developing lymphoproliferative disease in pediatric recipients of transplants is at least 30-times higher than the age- and sex-matched general population
· Apart from younger age at transplantation, male sex, use of T cell–depleting agents, muromonab-CD3, and high dose tacrolimus, negative recipient EBV serology (with positive donor EBV serology) incur a four-fold excess risk of PTLD
· Belatacept associated with a higher risk of PTLD, particularly cerebral PTLD in patients who are EBV negative, and when used in higher doses
· the risk of death among recipients of kidney transplants who have PTLD is .14- fold higher than recipients without PTLD
· Recently survival improved after the use of rituximab and immunotherapy Cancer Screening Strategies in Transplant Recipients
· routine population-based cancer screening for breast, colorectal, and cervical cancer is recommended according to the guidelines as per the general population
· routine skin checks by dermatologists in recipients of transplants who are at high risk,
· abdominal ultrasounds and serum a-fetoprotein levels should be checked every 6 months for those with underlying liver disease and chronic HBV infections
· ultrasonographic screening (annually or biennially) of the native kidneys for patients who are at risk of developing renal cell carcinoma Human Papillomavirus Vaccination in Recipients of Kidney Transplants
· Quadrivalent and the HPV 9-valent vaccines are highly effective and have an overall efficacy of 99%–100% for the prevention of cervical intraepithelial neoplasia in randomized clinical trials.
· HPV vaccination is indicated in both males and females aged 9–25 years in the general population for the prevention of HPV-related malignancies.
· Although HPV vaccination is recommended for women after transplantation, it may be more efficacious to vaccinate before transplantation. Management of Recipients of Kidney Transplants Who Have Cancer Immunosuppression Management and Treatment in Transplant Recipients with Cancer
· judicious reduction in the overall immunosuppression load for patients with early- to moderate-stage malignancy may be a reasonable first step
· For patients with squamous cell carcinoma, there is now trial-based evidence to suggest conversion to an mTOR inhibitor may reduce the risk of cancer in the longer term
Immunotherapy
· The use of immune-checkpoint inhibitors has revolutionized the treatment of a variety of malignancies through immunesystem activation against the cancer
· checkpoint inhibitors are effective in treating melanoma, non–small cell lung cancer, and renal cell carcinoma in the general population but their use in the kidney transplant population requires further investigation
Putting Patients’ Perspectives at the Heart of Cancer Management
· a multidisciplinary team could deliver the suitable measures for patients transitioning between many disciplines of care
· Ongoing dialogues between clinicians and patients, and close attention to the patients’ overall personal needs, are crucial to ensure our patients’ voices are heard Conclusions
· Cancer has high impact on morbidity and mortality in patients with kidney transplants
· To treat cancer you may need to reduce or change immunosuppressive drugs which has risk on graft function
· a multidisciplinary team is needed for prevention, screening and management
Introduction
Cancer is one of the most feared long-term complications of kidney transplantation and a leading cause of death among transplant recipient after cardiovascular disease. This has prompted adoption of strategies for early detection and treatment. Therefore, understanding the pathogenetic mechanism of development of these cancers is imperative for optimal care of patients.
Al- Adra et al. in this review article, discusses the epidemiology of malignancies after kidney transplantation, current screening methods, prevention and treatment.
Epidemiology of post-transplant malignancy
The cumulative incidence of de novo solid organ malignancies at 15 years after transplantation ranges from 10% to 15%. For skin cancers, the cumulative incidence
reaches .60% In Europe, Australia, and New Zealand, the cumulative incidence of skin cancers is about 60%. Generally, kidney transplant recipients have a two – to – three fold higher risk of malignancy compared to age and sex – matched controls in the general population. However, there is no increased risk of breast and prostate cancer post transplantation.
Mortality rate associated with post-transplant malignancies is high. Patients with post-transplant malignancies have approximately, 2 times increased risk of dying when compared with age and sex –matched controls in the general population according to data from most western countries. The highest risk of death was found in those with melanoma, urogenital cancers and non-hodgkin’s lymphomas.
Risk Factors for Cancer Development
Numerous risk factors have been attributed to the increased risk of cancers after transplantation. Risk factors share with the general population includes; male sex, advancing age, smoking history, and prolonged exposure to ultraviolet sun radiation. Other risk factors such as use of lymphocyte-depleting agents, acute rejection, high sensitization and long dialysis vintage are specific for kidney disease and transplant populations.
Mechanisms of Cancer Development after transplantation
Poor immune control of oncogenic viruses, impaired DNA damage repair resulting in accumulation of mutations, skin sensitization by immunosuppressive drugs, inhibition of tumor suppressive genes like p53 and activation of TGF- beta have been adduced as the mechanism of tumorigenesis after transplantation.
Recommendations for cancer screening
For breast cancer, screening is recommended every 2 years for patients between 50- 74 years but depends on individual risk assessment in people less than 50 years. Prostate cancer screening is only recommended in patients between 55 and 69 years after explaining the risk and benefits. Pap smear or HPV testing every 3-5 years is recommended starting at 25 years until 74 years for cervical cancer screening. Bowel cancer screening is recommended at 45 years till 75 years with biennial fecal immunohistochemistry and sigmoidoscopy or colonoscopy every 5 years. Lung cancer screening with low dose chest CT is recommended at 55 years till 79 years in heavy smokers only.
For skin cancer, monthly self-examination and 6 monthly total body examination by dermatologist is advised. Renal cancer screening is not routinely recommended. Recommendation for liver cancer screening includes ultrasound scanning and 6-monthly alpha-fetoprotein in cirrhotic patients. Post-transplant lymphoproliferative disease is also screened for in EBD seronegative recipient of seropositive organ once at 1 week after transplant, monthly every 1-3 months and every 3/12 till the end of first year post transplant using the nucleic acid testing method.
Management of cancers in recipients of kidney transplantation.
This involves a patient-centered, multidisciplinary approach with the reduction or withdrawal of immunosuppressive therapy depending on the stage of malignancy, switching to mTOR inhibitors, use of immune checkpoint inhibitors, local therapies such as imiquimoid with fluorouracil in skin cancers, systemic chemotherapy, radiotherapy and surgery.
Cancer is an important outcome after kidney transplantation because it is the second leading cause of death in most Western countries, once cancer develops, outcomes are generally poor, particularly for those with melanoma, renal cell carcinoma, and post-transplant lymphoproliferative disease,The excess risk of cancer after transplantation is approximately two to three times higher than the age- and sex-matched general population, driven largely by viral- and immune-related cancers.
Risk factor: male,old age,smooker , acute rejection, high immunosuppression, family history,desensitazation.
most common cancer skin cancer, renal cell cancer, PTLD cause by EBV virus.
in this article focuses on support routine screening for malignancy in solid organ transplantation.
2.What is the level of evidence provided by this article.
1.Please summarise this article; Introduction; -Cancer is the second cause of death following CVD in kidney recipients. This led to development of preventive strategies such as HPV vaccination and cancer screening strategies for early defection and treatment of cancer. Incidence; -10 to 15 % for solid organ tumors at 15 years and > 60% for skin cancer, -Overall it is 2 to 3 fold higher than the general population, -The morality is at least 1.5 greater than the general population. Highest are seen with melanoma,urogenital and PTLD. Risk factors; for increased incidence of cancer post-transplant: -Increasing age – Male sex -Smoking -Prolonged sun exposures -Immunosuppression use -Acute rejection -Sensitization status
-Duration of dialysis before transplantation Most common cancers; 1-Renal cell carcinoma; -Risk seven times higher when compared to the general population, -Male, Age over 60 , African descent , Prolonged dialysis time longer than 3 years, -Renal-based disease is also a risk factor: glomerular disease, -Hypertensive nephrosclerosis and vascular disease, Diabetes Mellitus, -Polycystic kidney disease. 2-Skin cancer;
-Skin cancer is the most common cancer type in recipients of kidney transplants and is more aggressive than skin cancers occurring in the general population. -The most commonly reported skin cancers in recipients of kidney transplants include cutaneous squamous cell carcinoma, basal cell carcinoma, Kaposi sarcoma, and malignant melanoma, with keratinocyte carcinomas comprising 90%–95% of these skin cancers. -The pathogenesis of skin carcinoma involves a complex interaction of risk factors, including exposure to UV radiation, HPV, pre transplant skin cancer, older age, race, and sex (males at greater risk than females). Additionally, immunosuppressive medications augment the carcinogenic effects (mainly cyclosporine and azathioprine). 3-PTLD; -It is rare disease, caused by EBV infection and it has bad prognosis. It is mostly Bcell type, the highest risk is in the first year post-transplant, and it then risk declines -Pediatrics are at higher risk; include pediatric transplantation, male , Tcell–depleting agents,Tac high dose, co use of belatacept ,seronegative EBV recipient. -Treatment includes reduction of immunosuppression and rituximab and chemotherapy. -Screening in transplant recipients; -There is insufficient trial-based evidence to support routine screening for solid organ transplantation. -Routine population-based cancer screening for breast, colorectal, and cervical cancer is recommended. -Some guidelines recommend routine checks of transplant recipients by dermatologists. -Recipients with higher risk of kidney cancer, annual or semi-annual USG screening. 2.What is the level of evidence provided by this article; -Level of evidence V
The article “De Novo Malignancies after Kidney Transplantation” by David Al-Adra provides an overview of the incidence and risk factors associated with the development of new (de novo) cancers after kidney transplantation.
The article explains that kidney transplant recipients have an increased risk of developing certain types of cancer due to their use of immunosuppressive medications. The author discusses the most common types of de novo cancers in kidney transplant recipients, including renal cell carcinoma, skin cancer, and PTLD.
The article also explores the risk factors for de novo cancers in kidney transplant recipients, including the type and duration of immunosuppressive therapy, age, male gender, smoking, and prolonged sun exposures, and prior exposure to cancer-causing agents. are shared by patients in the general population. Other risk factors, including immunosuppression use (T cell–depleting agents), acute rejection, sensitization status, and duration of dialysis before transplantation, are specific to those with kidney disease and transplant populations.
The author highlights the importance of regular cancer screening for kidney transplant recipients to detect new cancers at an early stage, when treatment is more likely to be successful.
The priorities of optimizing allograft function with immunosuppression are often challenged and superseded by having a “cure” for the cancer and may involve immunosuppression reduction or cessation to reduce the risk of cancer relapse and improve long-term cancer survival.
In conclusion, the article provides a comprehensive overview of the incidence and risk factors for de novo cancers in kidney transplant recipients, and the importance of regular cancer screening in this population.
The author emphasizes the need for ongoing research to better understand the relationship between immunosuppressive therapy and cancer risk, and to develop strategies to reduce the risk of de novo cancers in kidney transplant recipients.
Summarize the article
Rena replacement therapy is the ultimate treatment of end stage renal disease, and to compare the dialysis vs transplantation, transplantation has many advantages over dialysis especially better quality of life. However, transplantation is not a cure, because recipient require lifelong immunosuppression.
Immunosuppressive drugs has its consequences, and the second most common cause of death is drugs associated cancer post transplantation.
The aim of this article is to focus on the prevention, incidence, diagnosis, and treatment of cancer after transplantation.
Post-transplantation the cumulative risk cancer is around 10 to 15%. If developed cancer the risk of cancer associated risk is as high as 1.8 to 1.9 times of normal population.
In addition, the risk is more with non-Hodgkin lymphoma, melanoma, and urogenital cancer, may exceeds up-to 5-10 times that with those without kidney transplantation.
In some European countries the skin cancers cumulative risk is as high as >60%. This magnitude of higher risk has association with viral infections and immunosuppression medication.
Risk factors for cancer development;
Some of the main risk associated factors are age, male sex, prolonged sun exposure, and smoking.
There is associated increased risk of development of cancer if there was any treated cancer before transplantation, also immunosuppression type, induction medications, any rejection, duration of dialysis like acquired cyst formation and development of renal cell carcinoma, and immunosuppression duration which has very strong association.
Geographical association like European, and North American countries the most common cancers types are non-melanoma skin cancer, PTLD, and lip cancers, while in Asian and middle East registry shows the commonest tumors are urothelial transitional cell carcinoma, RCC, and GI cancers.
The estimated prevalence of liver cancers in Taiwan has increased up-to 9-24% in renal transplant recipients secondary to strong association with HBV antigenemia. This hypothesis is becoming stronger that chronic immunosuppression use can alter and loss of control of oncogenic viral replication. The overall SIR for kidney and bladder cancer is 44and 43, respectively.
Mechanism of cancer development after transplantation;
The mechanism is unclear thoroughly, but experimental studies shows there. Although, the potential causes may be immunosuppression medication that alter the immune system, another one may be the oncogenic viruses.
In skin related cancers the mechanism could be secondary to impaired cell repair.
Immunosuppression decreases components of nucleotide excision repair factors xeroderma pigmentosum complementation group A, G.
By direct stimulation calcineurin inhibitors has direct effect on TGF-B or IL-6 over expression and development and progression of tumor.
Cacineurin inhibitors can also activate NF of the activated T cell, p53.
Capable of inhibiting damaged DNA repair from UV radiation.
Azathioprine increases sensitivity of skin to UV radiation leading to accumulation of 6-thioguanine in the DNA and increases risk of the NMSC.
mTORI.
On the other hand mTORinhibitors ha protective and antitumor effect by different mechanism including inhibiting cell-cycle arrest and cancer growth.
Monoclonal and polyclonal agents used for induction can increases risk of PTLD, melanoma, although mechanism is unknown, however, there is often an incomplete T- cell recovery and long term effect on immune homeostasis.
The most common cancers post-transplantation.
Renal cell carcinoma. Seven fold higher risk compared to general population.
90% of RCC develop in the native kidneys.
Risk factors are male, older age, African descent, and longer time on dialysis.
Cause of renal failure was glomerulonephritis.
Hypertensive nephrosclerosis.
If early diagnosis and radical removal the prognosis is good with 5-years survival is 68- 97% compared to general population respectively.
Overall the immunosuppression intensity and duration influences the risk of renal cell carcinoma. Skin Cancer.
This is the most common and more aggressive tumor post-transplantation compared to general population.
Risk factors are UV radiation, older age, black race, males, in addition immunosuppression medications.
SCC is 250 times more common.
Among all skin cancers melanoma has higher mortality.
Treatment option are microsurgery, if inoperable other options are primary radiation, chemotherapy, if metastatic disease then will be needing systemic chemotherapy and immunotherapy.
Switch calcineurin inhibitors to mTOR inhibitors.
Ø Post-transplant Lymphoproliferative Disease.
It’s comparatively rare tumor post-transplantation but be as much as 90%, and has strong association with EBV infection.
Virus reactivate due to dysfunctional T and B cells and there proliferations.
Mostly B-cell only 5% T-cell type.
Incidence 10 years after transplantation is 1-2%.
There is reduction in incidence of PTLD since 2000 onward.
There is more risk within 12 months after transplantation, and this more on seropositive patients, while, in after 5 years post-transplantation 40-50% proportions are with EBV negative.
This is 30 times higher in pediatric recipient with age-sex matched compared to general population.
One survival rate is 62-68% and 10 years survival is 41-48%.
Survival depends on site and extent of disease.
Otherwise median survival from diagnosis to death is about six months.
Ø Human Papillomavirus vaccine is mandatory, and with overall efficacy of 100% for prevention.
Ø Management of recipient with cancer.
This need multidisciplinary approach between oncologist, transplant physician, and allied health professionals.
Optimization of immunosuppression.
Immunotherapy is not recommended still need further investigation.
In conclusion the recipient are in risk of developing different types of tumors specially skin cancer.
So highly recommended for screening before transplantation and post-transplant surveillance.
After cardiovascular disease, cancer is the second leading cause of death among recipients of transplants in most Western countries
The higher risks and poorer cancer outcomes have prompted clinicians and policy makers to adopt preventive policies, such as human papillomavirus (HPV) vaccination and cancer-screening strategies, to detect cancers at their earliest possible stage before they progress into advancedstage, incurable disease
Incidence of All-Cause and Site-Specific Cancer after Transplantation The cumulative incidence of solid organ cancer ranges between 10% and 15% at around 15 years after transplantation. For skin cancers, the cumulative incidence reaches .60% in Europe, Australia, and New Zealand. The excess overall cancer risk in patients with kidney transplant exceeds that of the general population by approximately two- to three-fold after adjustment for age and sex
Cancer Mortality in Recipients of Kidney Transplants
The exact reasons for the higher risk of death are unclear, but may be due to potential differences in the cancer cell biology in recipients of transplants resulting from long-term immunosuppression, associated comorbidities, and low uptake of recommended prevention and screening strategies
Patients are primarily committed to and preoccupied with their kidney and graft health, and their present health needs. Cancer screening and prevention may impose multiple burdens on patients’ daily lives hence, effective patient education and heightened awareness are key.
Risk Factors for Cancer Development
There are many reasons for the higher cancer risk after transplantation. Some of these factors, such as
-increasing age
-male sex
-smoking
-prolonged sun exposures are shared by patients in the general population.
– immunosuppression use (T cell–depleting agents)
– acute rejection sensitization status and duration of dialysis before transplantation
Mechanisms of Cancer Development after Transplantation
the effects of immunosuppression on dampening the immune system may create a variety of pathways for cancer development. One potential mechanism is through poor immune control of known oncogenic viruses in patients on immunosuppression. For example, increases in viral-associated cancers, such as Kaposi sarcoma (human herpesvirus 8), PTLD (EpsteinBarr virus [EBV]), and lip and anal cancers (HPV) are common in patients with suppressed immune systems Another mechanism of immunosuppression-related cancer development is through accumulation of mutations that would otherwise be repaired or recognized by the immune system.
Common Cancers after Transplantation
1-Renal Cell Carcinoma Compared with the general population, recipients of kidney transplants have a higher risk (up to seven-fold) of renal cell carcinoma
2-Skin Cancer Skin cancer is the most common cancer type in recipients of kidney transplants and is more aggressive than skin cancers occurring in the general population.
3- Post-Transplant Lymphoproliferative Disease
PTLD is a well-recognized complication after kidney transplantation. Although it is a rare disease, it is associated with poor outcomes. In most instances (approximately 90%), PTLD is associated with EBV.
Cancer Screening Strategies in Transplant Recipients
High-quality, randomized controlled trials have shown that cancer screening through early detection reduces cancer-specic mortality in the general population .In patients with kidney disease, some have questioned the benefit of routine screening
Patients with kidney disease and kidney transplants undergo radical changes to their overall health and wellbeing, which could be overwhelming for the patients and their caregivers.
ImmunosuppressionManagementandTreatmentin TransplantRecipientswithCancer
Meticulous understanding of the underlying immunologic risk and cancer severity is needed to optimize immunosuppression dose to prevent the risk of acute rejection, while balancing against the need to induce regression of the malignant lesion and prevent future progression. In the absence of quality evidence, judicious reduction in the overall immunosuppression load for patients with early- to moderate-stage malignancy may be a reasonable first step, and this should be conducted in consultation with the patients, where they are informed about the potential adverse effects, and all strategies should be tailored to the individual’s needs.
Immunotherapy
The use of immune-checkpoint inhibitors targeting the
programmed death-1/programmed death ligand-1 interaction and/or the CD28-CD80/86 axis with cytotoxic T lymphocyte–associated protein-4 Ig has revolutionized the treatment of a variety of malignancies through immunesystem activation against the cancer
Putting Patients’ Perspectives at the Heart of Cancer Management
The use of multimodal interventions to alleviate concurrent, multiple symptoms is an example of where a multidisciplinary team could deliver the suitable measures for patients transitioning between many disciplines of care. Patients living with kidney transplants are often frustrated with the lack of innovative strategies to prevent the risk of acute rejection from under-immunosuppression, and cancer resulting from over-immunosuppression . Therefore, a personalized, rather than a one-size-fits-all, approach is most preferred.
Conclusions
Cancer is the leading cause of morbidity and mortality in
patients with kidney transplants. Having cancer is a devastating event for patients and their families because the lifestyle changes and the complex feelings caused by the diagnoses are overwhelming. The priorities of optimizing allograft function with immunosuppression are often challenged and superseded by having a “cure” for the cancer, and may involve immunosuppression reduction or cessation to reduce the risk of cancer relapse and improve longterm cancer survival.
Summary of De Novo Malignancies after Kidney TransplantationCancer is the most common complication resulting from immunosuppression
Cancer is the cause of death in transplant recipients in western countries.
This review focuses on the incidence, mechanisms, diagnosis prevention, and treatment of cancer after kidney transplantation. Incidence of all causes and site-specific cancer after transplantation:-
The cumulative incidence of solid organ cancer range between 10% and 15% around 15 years after transplantation.
Cancer match in recipients of kidney transplants:-
The standard mortality ratios for all cancer types are at least 1.8-1.9 times higher compared with the age and sex-matched general population. Risk Factors For Cancer Development:-
Risk for post-kidney transplant recipients to develop cancer:-
Immune suppression uses CT cell-depleting agents.
Acute rejection.
Sensitization status.
Duration of dialysis before transplantation.
Long-term immunosuppression.
Having CKD. Mechanism of cancer development after transplantation:-
Immunosuppression made prior to immune control of the known oncogenic virus in post Transplantation patients.
Impaired repair of mutation by the immune system by immunosuppression.
Induction therapy with T cell-depleting agents uncertain mechanism.
The most common cancer after transplantation is renal cell carcinoma skin cancer and PTLD. Renal Cell Carcinoma
90% of renal cell carcinoma develops in the native kidney.
The risk of renal cell carcinoma increase with the intensity and duration of immunosuppression therapy. Skin cancer:-
Is the most common cancer type in recipients of Kidney transplantation.
The pathogenesis of skin carcinoma is a complex interaction of risk factors. Post-Transplant Lymphoproliferative disease:-
It is a rare disease it is associated with poor outcomes.
And associated with EBV infections. Cancer strategies in transplant recipients:-
The same guidelines suggest routine skin cheeks by dermatologists in recipients of transplants.
Abdominal ultrasound.
The alpha-fetoprotein level should be every 6 month Human papilloma vaccination in recipients of Kidney transplants:-
The incidence of HPV-related anogenital cancer is at least ten to 15-fold higher
Recipients of kidney transplants compared with the age and sex-matched general population.
Quadrivalent vaccines (against genotypes 6, 11, 16, and 18).
More recently HPV valent vaccine against five genotypes 31, 45, 52, and 58 are effective 99-100% for the prevention of cervical intraepithelial neoplasia in randomized clinical trials.
HPV vaccination is indicated in both males and female aged 9-25 years. Management of recipients of Kidney transplants who have cancer:-
Immunosuppression management and treatment in transplant recipient with cancer:-
Optimize the immunosuppression dose to prevent the risk of acute rejection while balancing against the need to induce regression of malignant lesion and prevent function progression.
For patients with square cell carcinoma an mTOR inhibitor may reduce the risk of cancer in the longer term.
Immunotherapy use in the kidney transplant population requires for investigation and can not be recommended at this time. Conclusion:-
The amount of immunosuppression a clinician could safely reduce is unknown.
Evidence to support primary prevention and screening programs in recipients of transplant are largely extrapolated from the general population and finding may not necessarily be applicable to transplant populations.
level 5
This review focuses on the incidence, mechanisms, diagnosis, prevention, and treatment of cancer after kidney transplantation Introduction Cancer is the second leading cause of death in most Western countries after renal transplantation. It is excess risk is approximately two to three times higher than the age- and sex-matched general population, driven largely by viral- and immune-related cancers
The higher risks and poorer cancer outcomes have prompted clinicians and policy makers to adopt preventive policies, such as human papillomavirus (HPV) vaccination (7) and cancer-screening strategies. Incidence of All-Cause and Site-Specific Cancer after Transplantation The excess overall cancer risk in patients with kidney transplant exceeds that of the general population by approximately two- to three-fold after adjustment for age and sex.
The magnitude of the higher risk is also dependent on cancer types, with the greatest risk in viral-related and immunedriven cancers such as post-transplant lymphoproliferative disease (PTLD), anogenital cancer, and Kaposi sarcoma Breast and prostate cancers are not increased in recipients of transplants . Cancer Mortality in Recipients of Kidney Transplants Once cancers develop, the risk of death is high. The risk is greatest among those with melanoma, urogenital cancers, and non-Hodgkin lymphoma, with an overall risk of cancer-related death exceeding five to ten times that of those without kidney transplants. Risk Factors for Cancer Development
A. Factors that are shared by patients in the general population
1. Increasing age
2. Male sex
3. Smoking 4. Prolonged sun exposures.
B. Other risk factors:
1. Immunosuppression use (T cell–depleting agents).
2. Acute rejection
3. Sensitization status
4. Duration of dialysis before transplantation
Renal cell carcinoma and multiple myeloma, are over-represented in the CKD/kidney-failure populations.
Cancer may also develop in recipients of kidney transplants because of impaired tumor surveillance and immunity to viral or other tumor antigens. The observed higher cancer risk is further compounded in patients who have had a previously treated pretransplant malignancy.
The specific types of cancer that develop after transplantation also vary by geographic areas. Mechanisms of Cancer Development after Transplantation The effects of immunosuppression on dampening the immune system may create a variety of pathways for cancer development. 1. poor immune control of known oncogenic viruses which can cause an increase in viral-associated cancers (Kaposi sarcoma (human herpesvirus 8), PTLD (Epstein– Barr virus [EBV]), and lip and anal cancers (HPV). 2. Accumulation of mutations (predominant in skin cancers) 3. On a molecular level, several mechanisms have been identified for mTOR inhibitor–mediated tumor inhibition. 4. After T-cell depletion, there is often an incomplete T-cell recovery, which may have a long-term effect on immune homeostasis, leading to an impaired immune system and subsequent cancer development. The three most common cancer types after renal transplantation: 1. Renal Cell Carcinoma: the risk is higher (up to seven-fold). 2. Skin Cancer: is the most common cancer type in recipients of kidney transplants and is more aggressive. The most commonly reported skin cancers in recipients of kidney transplants include cutaneous squamous cell carcinoma, basal cell carcinoma, Kaposi sarcoma, and malignant melanoma, with keratinocyte carcinomas comprising 90%–95% of these skin cancers. Cancer Screening Strategies in Transplant Recipients Routine population-based cancer screening for breast, colorectal, and cervical cancer is recommended and should be aligned to the guidelines as per the general population. Some guidelines also suggest routine skin checks by dermatologists in recipients of transplants who are at high risk Abdominal ultrasounds and serum a-fetoprotein levels should be checked every 6 months for those with underlying liver disease and chronic HBV infections. Patients who are at risk of developing renal cell carcinoma, ultrasonographic screening (annually or biennially) of the native kidneys may be considered to detect occult malignancy Screening decisions must be made with clear considerations of patients’ preferences and values, incorporating the potential harms and benefits of the various options. Human Papillomavirus Vaccination in Recipients of Kidney Transplants HPV vaccination is indicated in both males and females aged 9–25 years in the general population for the prevention of HPV-related malignancies. Some recent data have shown that it is also efficacious in women up to the age of 45 years. In the transplant population, HPV vaccines are generally safe. Management of Recipients of Kidney Transplants Who Have Cancer A concerted approach between transplant professionals, oncologists, and allied health professionals is needed to ensure optimal care for patients. Meticulous understanding of the underlying immunologic risk and cancer severity is needed to optimize immunosuppression dose to prevent the risk of acute rejection, while balancing against the need to induce regression of the malignant lesion and prevent future progression. Conclusions In transplanted patients with cancer, the priorities of optimizing allograft function with immunosuppression are often challenged and superseded by having a “cure” for the cancer, and may involve immunosuppression reduction or cessation to reduce the risk of cancer relapse and improve long term cancer survival. Currently, the evidence to define the amount of immunosuppression by which a clinician could safely reduce is unknown. Evidence to support primary prevention and screening programs in recipients of transplants are largely extrapolated from the general population, and the findings may not necessarily be applicable to the transplant population. Collaborative efforts between health care professionals, policy makers, trialists, and patients are needed to ensure quality evidence.
-This is a narrative review discussing cancer in kidney transplant recipients, including current screening and treatment options along with the disease’s epidemiology and burden. also, considering the patients’ viewpoints on the state of knowledge regarding the best care for kidney transplant recipients who develop cancer. -Post-transplantation malignancy is the second leading cause of death after cardiovascular causes. Renal transplant recipients have a 2-3-fold higher risk of malignancy than the general population. – viral and immunological mechanisms play an important mechanisms in PTLD, anogenital cancer, and Kaposi sarcoma -Transplantation does not raise breast or prostate cancer rates. -Malignancy increases mortality by 2–5 times in comparison to the non-transplant population, with malignant melanoma, PTLD, and RCC having the worst outcomes.
Risk Factors for Cancer Development:
-increasing Age -Long-term exposure to the sun -Use of immunosuppressants -rejection episodes -long duration on dialysis
renal cell carcinoma
Renal transplantation increases the risk of RCC sevenfold. Due to frequent imaging, RCC is typically found early, with an incidence of metastasis of 2% and often low-grade early lesions. Usually in the native kidney (99%). Partial nephrectomy and radical nephrectomy are the options for management, with surveillance rarely used.
skin cancer:
Skin cancer is the most common malignancy post-kidney transplantation. It is more aggressive and more common in transplant recipients than in the general population. Malignant melanoma incidence increases 5–8 times more than it does in the general population. 90% of skin cancers are caused by SCC and BCC. SCC is more common than BCC in kidney transplants (although in the general population, BCC is more common) Both SCC and melanoma have a poor outcome, with malignant melanoma having the highest mortality. management is by decreasing the immunosuppression & switching to mTORi & managing cancer by excision by safety margins if operable.
-90% EBV association and is associated with poor results and a higher mortality rate. T-cell types are present in 5% of PTLD patients, although B-cell types are more common. -Risk factors include male sex, the use of T cell-depleting treatments, muromonab-CD3, high dose tacrolimus, younger age at transplantation, and a negative recipient EBV serology—especially with a positive donor EBV serology. -decrease of immunosuppression and chemotherapy protocols with the use of rituximab are the options for management.
screening:
-table 1
conclusion:
-Cancer is the leading cause of morbidity and mortality in patients with kidney transplants. -Treatment is often challenging and involves reducing or stopping immunosuppression to lower the chance of cancer returning and increase long-term cancer survival. -The majority of the data used to support primary prevention and screening programs in transplant recipients is extrapolated from the general population, therefore, the results may not always be applicable to the transplant population.
Renal transplant recipients are at 2-3 times risk of developing malignancy compared to general population. Malignancy is the second leading cause of death in renal transplant recipients. Cutaneous malignancy is the most common cancer in renal Tx recipients, its risk increases with duration post-transplantation.
The risk of breast and prostatic cancer is the same between renal transplant recipients and general population.
PTLD, anogenital and Kaposi sarcoma are attributed to viral infection and immune disturbance in renal Tx recipients.
Post-transplant malignancy risk factors include:
1-Older age,
2-Male sex,
3-Racial factors (skin cancer is higher in white than black),
4-Smoking,
5-UV rays sun exposure,
6-Vintage on dialysis and
7-Pre-transplant malignancy increases the risk of post Tx cancer.
8-Geographical location is associated with common types of malignancies as follows:
Australia, Europe and North America—à NMSC, PTLD, and lip cancer.
Africa, Central Europe and Mediterranean Sea—à Kaposi Sarcoma.
Korea and middle east——àRCC, GIT cancers.
Taiwan—-à HCC because of HBV prevalence.
9-The cause of native renal failure was associated with different types of cancers:
GN, vascular or HTN causes—–àhigh risk of RCC
DM, ADPCKD———–à Low risk of RCC.
10-Recipients with negative pre-Tx EBV serology is at higher risk to develop PTLD especially if the donor’s EBV serology was positive.
11-Exposure to higher IS especially with ATG (sensitized patients or treatment of rejection episodes)
12-Viral infections are considered as risk factors for specific malignancies as follows:
EBV—àPTLD, HHV-8—-à Kaposi Sarcoma, HPV—-à lip and cancer.
13-Immunosuppressive medications can predispose to malignancy as follows:
CNI—à increases risk skin cancer especially NMSC, and the risk of metastasis.
Azathioprine–à high risk of NMSC.
OKT3, and Belatacept——–à high risk of PTLD.
MMF, and m-TOR inhibitors——-à low risk of malignancy.
This paper discussed few malignancies including RCC, Skin cancer and PTLD.
RENAL CELL CARCINOMA:
Risk of RCC post Renal Tx is 7 times higher than general population.
It happens 99% in the native kidneys; frequent imaging can detect RCC at earlier stages with low risk of metastasis<2%. Treatment outcomes are the same in general population.
SKIN CANCER:
90% are SCC and BCC. Other types of skin cancer include Melanoma and Kaposi sarcoma.
SCC is more common than BCC in renal Tx recipients However, in general population BCC is more common.
Malignant melanomas, KS, and SCC incidence is 8, 100 and 250 times respectively more prevalent in renal Tx recipients compared to general population.
Malignant Melanoma and SCC carry higher poor prognosis. Malignant melanoma carries the highest mortality risk.
1-2% of renal Tx recipients can develop PTLD in the first decade post renal Tx. The peak of occurrence is the first year then slowly decline until fifth year. The most common type is B-cell lymphoma in 95% of cases, and T-cell lymphoma is only in 5%.
Mainly due to activation of EBV. The overall survival is 65%-45% at 1 -10 years respectively. The prognosis is poor in elderly male renal transplant recipient especially with bone marrow, reticulo-endothelial system infiltration and extra-nodal disease.
ANOGENITAL CANCER: Mainly related to HPV, the incidence risk of anogenital cancer in renal transplant recipients is 10-15 times compared to general population.
MALIGNANCY SCREENING AFTER RENAL TRANSPLANTATION: Breast Cancer: Self-examination, Mammogram every 1-2 years for female aged 50-74. Prostate Cancer: Annual PSA for men aged 55-69. Cancer Cervix: HPV vaccination for female aged 9-45 years, better to be given before renal-Tx., women aged 25-74 years need HPV testing every 3-5 years. Colonic Cancer: Fecal occult blood test every 6 months for patients aged 45-75 years, sigmoidoscopy every 5 years or colonoscopy every 5-10 years. Cancer Lung: annual low dose CT chest for patients aged 55-75 years with smoke pack history of 30. Cutaneous Cancer: monthly self-skin- examination and annual skin examination by dermatologist. Renal Cell Carcinoma: 6 monthly USS-KUB for high risk patients. Hepatic Cancer: 6 monthly USS and AFP for those with liver cirrhosis. PTLD: in high risk recipients, EBV test in the first week, then monthly for the first 6 months then every 3 months till the end of first year. Management of post-transplant malignancy: Multidisciplinary approach. Modification of immunosuppression: target level reduction, switch CNI to m-TOR inhibitors. Monitor for rejection. Specific treatment depends on the type of cancer and stage either surgical, chemotherapy, radiotherapy and others.
2. What is the level of evidence provided by this article
Level V.
Introduction;
Kidney transplantation is considered the best modality of RRT but it is associated with much adverse association like infection, cardiovascular events and cancers. Cancer is the second leading cause of mortality after cardiovascular events among recipients of transplantation.
Incidence of All-cause and site-specific cancer after transplantation;
The cumulative risk of solid organ cancers is around 10-15% at 15 years of transplantation. The magnitude of risk is dependent on cancer type with greatest risk associated with viral and immune driven mechanisms cancers like;
· PTLD
· Kaposi sarcoma and
· Anogenital cancers. Cancer mortality in recipients of kidney transplantation;
The standard mortality ratio for all cancers is 1.8 to 1.9 times higher compared to age& sex matched general population. Risk factors for cancer;
· Male sex
· Increasing age
· Smoking
· Sun exposure
· IS(T-cell depleting agents)
· Rejections
· Duration of dialysis prior to transplantation.
Specific types of cancer that develop after transplantation also vary to geographic distributions.
Mechanism;
1. Viral associated like, HHV-8, EBV and HPV.
2. Accumulation of mutation otherwise repaired.
3. CNI and AZA while protective effect of mTOR.
4. Depleting agents.
Common cancers after Transplantation are;
· Renal cell carcinoma
· Skin Cancer
· PTLD
Strategies;
In keeping patient preference and value t develop screening strategies is really challenging and complex task, but supporting patient to have informed preferences and decisions. Following are of potential benefits;
· HPV vaccination
· Immunosuppressant’s management.
· Immunotherapy.
De-Novo-Malignancies-after-Kidney-Transplantation: Introduction: Kidney transplant is the best option for patients with end stage renal disease to improve quality of life and prolong survival rate, but it’s carry high risk of cardiovascular disease and malignancy. Malignancy contribute to increase mortality rate. Risk of malignancy in kidney transplant related to use of immunosuppressive therapy and to viral infection like human papilloma virus or chronic hepatitis due to reduce immunity.
Objective of this study:
To review the incidence, mechanisms, diagnosis, prevention, and treatment of cancer after kidney transplantation.
Incidence:
Incidence of cancer range between 10-15% over 15 years post transplant. Incidence of skin cancer reach to 60% in the most of developed countries.
Over all cancer risk to 2-3 folds in transplant patients in comparison to general population.
Magnitude of cancer incidence depend on type of cancer and type of viral infection and immunosuppressive therapy.
Mortality:
Cancer mortality increase to 1.8-1.9 compare to age and sex.
Risk increase with melanoma and urogenital cancer and non Hodgkin’s lymphoma while non significant with breast and prostatic cancer.
Risk factors of cancer in transplant patients:
Male
Age
Smoking
Prolonged sun exposure
Use of immunosuppressive therapy
Acute rejection
Sensitised patients
Duration of dialysis
Cancer related to Primary disease like renal cell carcinoma and multiple myeloma.
Mechanism of Cancer: One of the most common cause of cancer is suppressed immune system and activation of oncogenic virus like Kaposi sarcoma (human herpesvirus 8), PTLD (Epstein– Barr virus ), and lip and anal cancers (HPV).
Other mechanism related to immunosuppressive agents are impair of immune system and induce skin cancer and lymphoma.
Common Cancers after Transplantation:
Renal cell carcinoma:
It’s account seven times higher in comparison to general population because of increased abdominal imaging, the majority of kidney masses detected in patients post-transplantation are typically early, low-grade, small kidney masses.
Risk more in native kidney
Risk factors for renal cell carcinoma:
Male/ age more than 60years and black, history of hypertension and DM, risk more with primary glomerular disease and renovascular disease and duration of dialysis. However risk of renal cell carcinoma is very low in poly cystic disease.
De novo renal cell carcinomas should be treated according to urology guidelines on basis of staging and patients factors (comorbidites, age and sex and features of kidney failure),
The outcome of renal cell carcinomas after radical treatment in the transplant population is comparable with that of the general population, with 5-year, disease specific and overall patient survival rates of 68%–97% and 69%–88%, respectively.
Renal cell carcinoma in the kidney allograft is rare with incidence less than 0.1%.
Skin cancer:
The most common type of cancer occur in kidney transplant and it’s very aggressive in comparison to general population. Its account 90-95% from cancers in transplant patients.
The most common types are ude cutaneous squamous cell carcinoma, basal cell carcinoma, Kaposi sarcoma, and malignant melanoma, with keratinocyte carcinomas.
Risk factors of skin cancer are:
exposure to UV radiation, HPV, pretransplant skin cancer, older age, race, and sex (male), and immunosuppressive medications.
Kaposi sarcoma is the most common cause of skin cancer in transplant patients.
The incidence of Kaposi sarcoma in recipients of transplants exceeds 100 times that of the general population.
The risk of squamous cell carcinoma by reaching to 250 times in comparison to general population.
In patients with actinic keratoses and squamous cell carcinoma in situ, the management options with good outcomes include topical “uorouracil and imiquimod cream, photodynamic therapy, and surgical excision or electrodesiccation and curettage.
the patients with multiple squamous cell carcinoma carry high risk if local recurrence and need chemotherapy and local radiotherapy.
The retinoids and nicotinamide used as chemoprophylaxis.
Patients treated with calcineurin inhibitors should be shifted to mTOR inhibitors.
The risk of melanoma is high in kidney transplant with high rate of mortality.
Treatment is surgical excision and adjusting immunosuppressive therapy.
Post-Transplant Lymphoproliferative Disease:
It’s rare disease with poor outcome and associated with EBV.
It’s account 1-2% from cancer in transplant patients.
The best treatment is immunosuppressive therapy reduction.
Rituximab used in treatment with good outcome.
Cancer Screening Strategies in Transplant Recipients:
Guidelines recommended for breast, cervical and colorectal cancer screening and some guidelines recommended for skin cancer screening by dermatologist.
Vaccination for HPV related cancer.
Alfa fetoprotein every 6 months for chronic hepatitis B to role out liver cancer.
Human Papillomavirus Vaccination in Recipients of Kidney Transplants:
it’s 15 folds increase risk of cancer .
Management of Recipients of Kidney Transplants:
The use of immune-checkpoint inhibitors is not recommended in transplant patients and needs further evaluation and investigation.
Conclusions: Cancer is the leading cause of death and screening is important in pretransplant malignancy and all patients with risk of malignancy.
De Novo malignancy post renal transplantation is an important topic because its the second leading cause of death after cardiovascular disease and once diagnosed is associated with poor out come , two main causes for malignancy post renal transplantation the 1st is viral infection related and the 2nd is immunosuppression related , so effective screening , vaccination , and proper treatment strategies is very important .
The over all incidence of solid cancer range between 10 – 15 % at around 15 years after transplantation , for skin cancers, the cumulative incidence reaches .60% , then come viral-related and immune driven cancers such as post-transplant lymphoproliferative disease (PTLD), anogenital cancer, and Kaposi sarcoma .
Unfortunately malignancy post renal transplantation associated with high mortality rate could be due to potential differences in the cancer cell biology in recipients of transplants resulting from long-term immunosuppression, associated comorbidities, and low uptake of recommended prevention and screening strategies .
Risk factors for the higher cancer incidence after transplantation.
increasing age,
male sex,
smoking,
prolonged sun exposures,
T cell–depleting agents
acute rejection
sensitization status
duration of dialysis before transplantation
previously treated pretransplant malignancy
geographic areas.
specific viral infection
there is no conclusive evidence to suggest one type of immunosuppression is more oncogenic than others but it’s the overall cumulative effect of immunosuppression but some studies showed that : – tacrolimus increases the level of TGF-b and thereby promotes tumor progression and metastasis . – Cyclosporine also has direct effects on tumor development and progression, through TGF-b or IL-6 overexpression pathways . – Azathioprine sensitizes the skin to UVA radiation and causes the accumulation of 6-thioguanine in the DNA, leading to a higher risk of NMSCs . – Induction therapy with T cell–depleting agents increases the risks of cancers, such as PTLD and melanoma . Specific types of malignancy associated with some viral infection such as Kaposi sarcoma (human herpesvirus 8), PTLD (Epstein–Barr virus [EBV]), and lip and anal cancers (HPV) are common in patients with suppressed immune systems.
Recipients of kidney transplants have a higher risk (up to seven-fold) of RRC more than general population which mainly developed in the native kidneys specially with those were longer time on dialysis.
High risk is mainly associated with ESRD due to glomerular diseases, hypertensive nephrosclerosis, and vascular disease and lower risk with ESRD secondary to diabetes or autosomal dominant polycystic kidney disease.
most cases of RCC treated by partial nephrectomy (67%), radical nephrectomy (19%), and percutaneous ablation.
2- Skin Cancer: The most commonly reported skin cancers cutaneous squamous cell carcinoma, basal cell carcinoma, Kaposi sarcoma, and malignant melanoma, with keratinocyte carcinomas comprising 90%–95% of these skin cancers 3- Post-Transplant Lymphoproliferative Disease
PTLD associated with poor outcomes and higher mortality rate , 90% is associated with EBV.
Most PTLDs are of B-cell types, with 5% of patients having the T-cell type.
Bimodal distribution in incidence, the highest in the 12 months post-KTx, and it then decreases until the 5th year.
Risk is higher in : younger age at transplantation, male sex, use of T cell–depleting agents, muromonab-CD3, and high dose tacrolimus, negative recipient EBV serology particularly in younger recipients. (with positive donor EBV serology).
The mainstay of treatment is immunosuppression reduction, chemotherapy and novel immunotherapy such as Rituximab .
Summary of Recommendations for cancer screening in recipients of kidney transplants
Breast :
For women aged 50–74 years, screening mammography once every 2 years.
For women ,50, the decision to start regular screening should be an individual one
Prostate :
For men aged 55–69 years, screening decisions should be individualized after a conversation with their clinician about the potential benefits and harms.
For men >70 years, the potential benefits may not outweigh the expected harms, and these men should not be routinely screened for prostate cancer
Cervical :
Annual Pap testing or HPV testing every 3–5 years starting at the age of 25 years until 74 years
Bowel
For adults aged 45–75 years, fecal immunochemical testing biennially, sigmoidoscopy every 5 years, or colonoscopy every 5–10 years .
Lung :
For adults aged 55–79 years, annual low-dose computed tomography scans for those who have smoked one pack per day for 30 years or equivalent (two packs per day for 15 years)
Skin:
Monthly self-skin examination and 6- to 12-monthly total body skin examination by expert physicians and dermatologists .
Renal cell :
Routine screening for renal cell carcinoma using US is not recommended for all recipients of transplants, except for high-risk individuals.
Liver :
Routine screening using US, with and without a-fetoprotein, every 6 months in patients with cirrhosis.
PTLD :
Routine monitoring of patients at high risk (donor EBV seropositive/ recipient seronegative) for EBV by NAT. Once in the first week after transplantation, monthly for the first 3–6 months, and every 3 months until the end of the first post-transplant year .
Conclusions :
Cancer is the leading cause of morbidity and mortality in patients with kidney transplants. and support primary prevention and screening programs in recipients of transplants is the most important step .
The cumulative incidence of solid organ cancer ranges between 10% and 15%. Incidence is progressively increasing as time is passing after transplantation
Viral and immune related cance incidence is more ( The standardized incidence ratios is highe for Kaposi sarcoma and PTLD) while breast and prostate cancer SIR is low
Regarding cancer mortality, the SIR of death is higher in non- Hodgkin lymphoma, kidney and thyroid than other type and cancer site
The underlying Mechanisms of Cancer Development after Transplantation: include
– poor immune control of known oncogenic viruses in patients on immunosuppression
– accumulation of mutations that would otherwise be repaired or recognized by the immune system that get compromised by the use of immunosuppression either during induction or maintenance Common cancers post-transplant
recipients of kidney transplants have a 7-fold as compared to general population, 90% RCC develop in native kidney rather than graft.
Risk factors for development of renal cell carcinomas post transplantation include male sex increasing age African descent and longer time on dialysis
De novo renal cell carcinomas should be definitively managed according to urologic guidelines on the basis of risk stratification and staging
The outcome after treatment is comparable to the non-transplant population. . Negative prognostic factors include presence of symptoms at diagnosis, higher Fuhrman grade (.2), absence of transplantation, and advanced-stage disease Skin Cancer
Skin cancer is the most common cancer type in recipients of kidney transplants and is more aggressive than skin cancers occurring in the general population. Commonly,it is keratinocyte carcinoma. Risk factors are exposure to UV radiation, HPV, pretransplant skin cancer, older age, race, and sex (males at greater risk than females). Treatment depending on the staging and visceral involvement. management options include topical fluorouracil and imiquimod cream, photodynamic therapy, and surgical excision or electrodesiccation and curettage. Mohs micrographic surgery, with histologic confirmation of negative margins, offers the most definitive method of treatment in SSC, with cure rates of 95%–100%. Radiotherapy and chemoprophylaxis is effective as well for inoperable and multiple SSC as well. modulation of immunosuppressive is important in the management of Kaposi sarcoma Melanoma has poor prognosis carrying the highest mortality. risk factors are History of pretransplant melanoma, followed by White race and older age (.50 years) treatment is by surgical excision based on Breslow thickness, Post-Transplant Lymphoproliferative Disease
PTLD is a well-recognized complication after kidney transplantation. Although it is a rare disease, it is associated with poor outcomes. In most instances (approximately 90%), PTLD is associated with EBV.
Incidence shows a bimodal distribution in PTLD incidence, with the risk of PTLD being the highest in the 12 months post-transplant, and it then decreases until the fifth year after transplantation.
Risk factors Pretransplant EBV seronegative (negative recipient EBV serology (with positive donor EBV serology), particularly in younger recipients of transplants, and may explain the higher risk of disease early post-transplant. use of T cell–depleting agents, Ortho Kung T3 (muromonab-CD3), and high dose tacrolimus
The treatment goal of PTLD is to cure the disease, and the mainstay of treatment is immunosuppression reduction
Once PTLD developed mortality increase but the current treatment strategies with the use of rituximab and chemotherapy along with management of immunosuppression effectively reduce mortality Cancer screening in transplant patient in breast, colorectal, and cervical cancer be linked with the general population’s screening guidelines. skin” High-risk transplant recipients should receive Monthly self-skin
examination and 6- to 12-monthly total body skin examination by expert physicians and dermatologists· Liver: Those with underlying liver cirrosis and chronic HBV infections must have abdominal ultrasounds and blood a-fetoprotein levels monitored every six months. Renal : for only high risk group, ultrasonographic screening of the native kidneys (annually or biannually) may be considered PTLD: Routine monitoring of patients at high risk (donor EBV seropositive/ recipient seronegative) for EBV by NAT. Once in the first week after transplantation, monthly for the first 3–6 months, and every 3 months until the end of the first post-transplant year Management of Recipients of Kidney Transplants Who Have Cancer Immunosuppression modulation : either reduction of the dose or changing to mTOR according to cancer type keeping into consideration the graft function and avoid acute rejection Immunotherapy The use of immune-checkpoint inhibitors but it carry the risk of immune system activation and rejection Conclusion
The priorities of optimizing allograft function with immunosuppression are often challenged and superseded by having a “cure” for the cancer, and may involve immunosuppression reduction or cessation to reduce the risk of cancer relapse and improve long term cancer survival
The excess risk of cancer after transplantation is approximately two to three times higher than the age- and sex-matched general population, driven largely by viral- and immune-related cancers. Once cancer develops, outcomes are generally poor, particularly for those with melanoma, renal cell carcinoma, and post-transplant lymphoproliferative disease. More importantly, effective screening and treatment strategies are limited in this high-risk population.
One of the most feared complications associated with immunosuppression after kidney transplantation is cancer.
After cardiovascular disease, cancer is the second leading cause of death among recipients of transplants in most Western countries .The higher risks and poorer cancer outcomes have prompted clinicians and policy makers to adopt preventive policies, such as human papillomavirus (HPV) vaccination and cancer-screening strategies, to detect cancers at their earliest possible stage before they progress into advancedstage, incurable disease.
Incidence of All-Cause and Site-Specific Cancer after Transplantation
The cumulative incidence of solid organ cancer ranges between 10% and 15% at around 15 years after transplantation. For skin cancers, the cumulative incidence reaches .60% in Europe, Australia, and New Zealand. The excess overall cancer risk in patients with kidney transplant exceeds that of the general population by approximately two- to three-fold after adjustment for age and sex.
the greatest risk in viral-related and immunedriven cancers such as post-transplant lymphoproliferative disease (PTLD), anogenital cancer, and Kaposi sarcoma .
Interestingly, certain solid organ cancers such as breast and prostate cancers are not increased in recipients of transplants
Cancer Mortality in Recipients of Kidney Transplants
Once cancers develop, the risk of death is high. The exact reasons for the higher risk of death are unclear, but may be due to potential differences in the cancer cell biology in recipients of transplants resulting from long-term immunosuppression, associated comorbidities, and low uptake of recommended prevention and screening strategies.
Patients are primarily committed to and preoccupied with their kidney and graft health, and their present health needs. Cancer screening and prevention may impose multiple burdens on patients’ daily lives ,hence, effective patient education and heightened awareness are key.
Risk Factors for Cancer Development
increasing age
male sex
smoking
prolonged sun exposures
immunosuppression use (T cell–depleting agents)
acute rejection
sensitization status
duration of dialysis before transplantation.
geographic areas
long-term immunosuppression is a major contributor to cancer development after transplantation, there is now convincing observational evidence to suggest that having CKD (irrespective of the CKD stage) is associated with higher cancer risk and poor cancer outcomes
Mechanisms of Cancer Development after Transplantation
there is no conclusive evidence to suggest one type of immunosuppression is more oncogenic than others.
tacrolimus increases the level of TGF-b and thereby promotes tumor progression and metastasis. In addition, calcineurin inhibitors inhibit signaling via calcineurin and NF of activated T cells, which can activate p53, a hallmark of some NMSCs (35). Cyclosporine also has direct effects on tumor development and progression, through TGF-b or IL-6 overexpression pathways.
Azathioprine sensitizes the skin to UVA radiation and causes the accumulation of 6-thioguanine in the DNA, leading to a higher risk of NMSCs .
Mammalian target of rapamycin (mTOR) inhibitors, on the contrary, may have potential antitumor effects by inhibiting cancer growth through cell-cycle arrest and initiation of apoptosis.
Induction therapy with T cell–depleting agents (including polyclonal agents, such as anti-thymocyte globulin, and monoclonal agents, such as anti-CD52 and, historically, Ortho Kung T3 [muromonab-CD3]) increases the risks of cancers, such as PTLD and melanoma.
Common Cancers after Transplantation
renal cell carcinoma, skin cancer, and PTLD
Cancer Screening Strategies in Transplant Recipients
support routine screening in this high-risk group, routine population-based cancer screening for breast, colorectal, and cervical cancer is recommended and should be aligned to the guidelines as per the general population .
Some guidelines also suggest routine skin checks by dermatologists in recipients of transplants who are at high risk, and abdominal ultrasounds and serum a-fetoprotein levels should be checked every 6 months for those with underlying liver disease and chronic HBV infections. For patients who are at risk of developing renal cell carcinoma (such as those with a history of acquired cystic disease, those with a family history, those who are heavy smokers, and those who use long-term analgesics), ultrasonographic screening (annually or biennially) of the native kidneys may be considered to detect occult malignancy.
A shared decision-making process, defined as an approach where clinicians and patients share the best available evidence when faced with the task of making decisions, and where patients are supported to consider options to achieve informed preferences, should be adopted to guide decision making.
Human Papillomavirus Vaccination in Recipients of Kidney Transplants
Quadrivalent vaccines (against genotype 6, 11, 16, and 18) and, more recently, the HPV 9-valent vaccines (against five additional genotypes of 31, 33, 45, 52, and 58) are highly effective and have an overall efficacy of 99%–100% for the prevention of cervical intraepithelial neoplasia in randomized clinical trials. HPV vaccination is indicated in both males and females aged 9–25 years in the general population for the prevention of HPV-related malignancies.
Although HPV vaccination is recommended for women after transplantation, it may be more efficacious to vaccinate before transplantation.
Management of Recipients of Kidney Transplants
Who Have Cancer
Immunosuppression Management and Treatment in Transplant Recipients with Cancer
concerted approach between transplant professionals, oncologists, and allied health professionals is therefore needed to ensure optimal care for our patients.
For patients with squamous cell carcinoma, there is now trial-based evidence to suggest conversion to an mTOR inhibitor may reduce the risk of cancer in the longer term.
Immunotherapy
The use of multimodal interventions to alleviate concurrent, multiple symptoms is an example of where a multidisciplinary team could deliver the suitable measures for patients transitioning between many disciplines of care. Patients living with kidney transplants are often frustrated with the lack of innovative strategies to prevent the risk of acute rejection from under-immunosuppression, and cancer resulting from over-immunosuppression.
multidisciplinary, integrated approach that involves the transplant and palliative care team is crucial. The team should consist of a palliative care physician to assist with the medical aspects of managing the high symptom burden, together with a social worker, dietitian, clinical psychologist, and other allied health workers to address the psychosocial, functional, and nutritional issues experienced by our patients.
More importantly, evidence to support primary prevention and screening programs in recipients of transplants are largely extrapolated from the
general population, and the findings may not necessarily be applicable to the transplant population.
Please summarise this article Introduction
Cancer is the second major cause of death in kidney transplant recipients after CV disease. Preventive policies, such as HPV vaccination and cancer-screening strategies, to detect cancers earlier is recommended The aim of the study: discuss the incidence, mechanisms, diagnosis, prevention, and treatment of cancer after kidney transplantation Incidence
10% and 15% (15 years after transplantation)
>60% in Europe, Australia, and New Zealand (for skin cancer)
Overall cancer risk exceeds that of the general population (approximately two- to three-fold after adjustment for age and sex)
The higher risk is also dependent on type of cancer (viral-related, PTLD, anogenital cancer, and Kaposi sarcoma) Mortality
Mortality is 1.8–1.9 times higher compared with the age- and sex-matched general population
The highest risk is with melanoma, urogenital cancers, and non-Hodgkin lymphoma (the risk of death exceeding five to ten times that of those without kidney transplants) Risk Factors for malignancy post transplantation
1. General: increasing age, male sex, smoking, and prolonged sun exposures
2. Specific: use of immunosuppression, acute rejection, sensitization status, and duration of dialysis before transplantation
3. Pretransplant malignancy
4. CKD (renal cell carcinoma and multiple myeloma)
5. geographic part:
NMSCs, PTLD, and lip cancer (Europe, North America, Australia, and New Zealand)
Urothelial TCC, RCC, and GI cancers (non-Western Asian and Middle East)
Liver cancer (chronic HBV): Taiwan Mechanisms of Cancer Development
Bad immune control of known oncogenic viruses in patients on immunosuppression (Kaposi sarcoma (human herpesvirus 8), PTLD (Epstein– Barr virus [EBV]), and lip and anal cancers (HPV))
Accumulation of mutations (mainly in skin cancers) Common Cancers after Transplantation: Renal Cell Carcinoma (RCC)
Seven-fold higher risk than general population
Usually detected early due to advanced imaging
90 % develop in the native kidneys, rare in kidney allograft and usually low-grade T1 lesions, clear cell carcinomas, or papillary renal cell carcinomas, and occur more commonly in males.
Risk factors: male sex, increasing age (>60), African descent, longer time on dialysis, and cause of kidney failure (high risk in glomerular, hypertensive and vascular causes, lower in diabetes and APKD)
The outcome is the same as in general population after radical treatment
Treatment options are partial nephrectomy, radical nephrectomy, and percutaneous ablation Skin Cancer
It is the most common cancer and more aggressive than in general population. The risk of SCC and Kaposi sarcoma is 250 and 100 times that of the general population.
Cutaneous SCC, BCC, Kaposi sarcoma, and malignant melanoma (keratinocyte carcinomas comprising 90%–95% of these skin cancers)
Risk factors include UV radiation exposture, HPV, pretransplant skin cancer, older age, race, sex (males > females), and immunosuppressive medications
The risk of malignant melanoma is 5-8 folds and is poor prognosis Post-Transplant Lymphoproliferative Disease (PTLD)
Rare (1%–2% 10 years after transplant), poor outcome, and associated with EBV in 90%
The virus acquired during childhood with minimal symptoms (infects B cells and remain dormant)
Most PTLDs are of B-cell types (T-cell type only in 5%)
Bimodal distribution [early in the first year (EBV seronegative pretransplantand primary EBV infection) and late (EBV-negative lesions)]
Immunosuppression reduction is the cornerstone of treatment (rituximab and chemotherapy improve survival with 5-year survival of around 60%)
The risk of death is high (14 fold). The median time from diagnosis to death is 6 months Overall survival 62%–68% at 1 year and 41%–48% at 10 years Cancer screening after kidney transplantation Breast: For women aged 50–74 years, mammography once every 2 years. For women <50 screening is individual Prostate: For men aged 55–69 years, screening individual. For men >70 years, no screen Cervical: Annual Pap testing or HPV testing every 3–5 years starting at the age of 25 years until 74 years Bowel: adults aged 45–75 years, fecal immunochemical testing biennially, sigmoidoscopy every 5 years, or colonoscopy every 5–10 years Lung: adults aged 55–79 years, annual low-dose computed tomography scans for those who have smoked one pack per day for 30 years or equivalent (two packs per day for 15 years) Skin: Monthly self-skin examination and 6- to 12-monthly total body skin examination by expert physicians and dermatologists Renal cell: screening only for high-risk individuals Liver: Routine screening using US, with and without a -fetoprotein, every 6 months in patients with cirrhosis. PTLD: for high risk (donor EBV seropositive/ recipient seronegative) for EBV by NAT. Once in the first week after transplantation, monthly for the first 3–6 months, and every 3 months until the end of the first post-transplant year Human Papilloma virus Vaccination in Recipients of Kidney Transplants
The incidence of HPV-related anogenital cancer is 10 to 15-fold higher in recipients of kidney transplants compared general population
Highly effective (99%–100% for the prevention of cervical intraepithelial neoplasia)
Vaccination is indicated in both males and females aged 9–25 years in the general population
Post transplant, vaccine is safe
It is recommended for women after transplantation but better before transplantation. Management of cancer after transplantation
Needs MDT Immunosuppression Management
Modulation of immunosuppression is challenging and needs MDT
In early- to moderate-stage malignancy the first step is to reduce immunosuppression after consultation with the patient
For patients with SCC and Kaposi sarcoma, conversion to an mTOR inhibitor may reduce the risk of cancer in the longer term Immunotherapy
Promise use of immune-checkpoint inhibitors (risk of rejection with nonspecific immune-system activation)
Effective in treating melanoma, non–small cell lung cancer, and renal cell carcinoma in the general population Conclusions
In patients with kidney transplants, cancer is a main cause of morbidity and mortality
Management is challenging (treatment of cancer and optimize allograft function)
What is the level of evidence provided by this article? Level v (narrative review)
After cardiovascular disease, cancer is the second leading cause of death among recipients of transplants. The higher risks and poorer cancer outcomes have led clinicians and policy makers to adopt preventive policies, such as human papillomavirus (HPV) vaccination and cancer-screening strategies, to detect cancers at their early stages.
Cancer Mortality in Recipients of Kidney Transplants is high. Observational data have shown the standard mortality ratios for all cancer types are at least 1.8–1.9 times higher compared with the age- and sex-matched general population. The risk is greatest among those with melanoma, urogenital cancers, and non-Hodgkin lymphoma, with an overall risk of cancer-related death exceeding five to ten times that of those without kidney transplants.
Risk Factors for Cancer Development
There are many reasons for the higher cancer risk after transplantation. Some of these factors, such as increasing age, male sex, smoking, and prolonged sun exposures, are shared by patients in the general population. Other risk factors, including immunosuppression use (T cell–depleting agents), acute rejection , sensitization status , and duration of dialysis before transplantation , are specific to those with kidney disease and transplant populations.
Mechanisms of Cancer Development after Transplantation
The effects of immunosuppression on dampening the immune system may create a variety of pathways for cancer development. One potential mechanism is through poor immune control of known oncogenic viruses in patients on immunosuppression. For example, increases in viral-associated cancers, such as Kaposi sarcoma (human herpesvirus 8), PTLD (Epstein– Barr virus [EBV]), and lip and anal cancers (HPV) are common in patients with suppressed immune systems. Currently, there is no conclusive evidence to suggest one type of immunosuppression is more oncogenic than others. However, experimental studies in hepatocellular carcinoma, human lung adenocarcinoma cells, and renal cell carcinoma have shown that tacrolimus increases the level of TGF-b and thereby promotes tumor progression and metastasis. Mammalian target of rapamycin (mTOR) inhibitors, on the contrary, may have potential antitumor effects by inhibiting cancer growth through cell-cycle arrest and initiation of apoptosis.
Common Cancers after Transplantation
Although the risk of overall cancer development is high after transplantation, the risks of certain cancer types are much higher than others
Renal Cell Carcinoma Compared with the general population, recipients of kidney transplants have a higher risk (up to seven-fold) renal cell carcinoma . Due to increased abdominal imaging, the majority of kidney masses detected in patients post-transplantation are typically early, low-grade, small kidney masses of which, 75%–80% are renal cell carcinoma, with the risk of metastasis at presentation being ,2%.
Skin Cancer Skin cancer is the most common cancer type in recipients of kidney transplants and is more aggressive than skin cancers occurring in the general population. The most commonly reported skin cancers in recipients of kidney transplants include cutaneous squamous cell carcinoma, basal cell carcinoma, Kaposi sarcoma, and malignant melanoma, with keratinocyte carcinomas comprising 90%–95% of these skin cancers.
Post-Transplant Lymphoproliferative Disease PTLD is a well-recognized complication after kidney transplantation. It is associated with poor outcomes. In most instances (approximately 90%), PTLD is associated with EBV. EBV is a common virus, and most people acquire the virus during childhood. Most present with mild or minimal symptoms, but the virus can infection the B cells and remain dormant in these cells during the latent phase. After transplantation, these viruses can reactivate because of depressed T-cell function, with a lack of T-cell control over B-cell proliferation, and contributes to the development of PTLD.
Cancer Screening Strategies in Transplant Recipients
High-quality, randomized controlled trials have shown that cancer screening through early detection reduces cancer-specific mortality in the general population. Some guidelines suggest routine skin checks by dermatologists in recipients of transplants who are at high risk, and abdominal ultrasounds and serum a-fetoprotein levels should be checked every 6 months for those with underlying liver disease and chronic HBV infections. For patients who are at risk of developing renal cell carcinoma (such as those with a history of acquired cystic disease, those with a family history, those who are heavy smokers, and those who use long-term analgesics), ultrasonographic screening (annually or biennially) of the native kidneys may be considered to detect occult malignancy. Human Papillomavirus Vaccination in Recipients of Kidney Transplants The incidence of HPV-related anogenital cancer is at least ten- to 15-fold higher in recipients of kidney transplants compared with the age- and sex-matched general population. Quadrivalent vaccines (against genotype 6, 11, 16, and 18) and, more recently, the HPV 9-valent vaccines (against five additional genotypes of 31, 33, 45, 52, and 58) are highly effective and have an overall efficacy of 99%–100% for the prevention of cervical intraepithelial neoplasia in randomized control trials.
HPV vaccination is indicated in both males and females aged 9–25 years in the general population for the prevention of HPV-related malignancies. Some recent data have shown that it is also efficacious in women up to the age of 45 years. In the transplant population, HPV vaccines are generally safe.
Management of Recipients of Kidney Transplants Who Have CancerImmunosuppression Management and Treatment in Transplant Recipients with Cancer: For patients with squamous cell carcinoma, there is now trial-based evidence to suggest conversion to an mTOR inhibitor may reduce the risk of cancer in the longer term. However, Tor-inhibitor use may also be associated with a higher risk of death. There are insufficient data to consider mTOR inhibitors as protective against other cancer types apart from squamous cell carcinoma and Kaposi sarcoma.
Incidence of All-Cause and Site-Specific Cancer after Transplantation:
The cumulative incidence of solid organ cancer ranges between 10% and 15% at around 15 years after transplantation. skin cancers cumulative incidence reaches 60% and it exceeds that of the general population by approximately two- to three-fold after adjustment for age and sex. There is greatee risk of viral-related and immunedriven cancers (PTLD, anogenital cancer, and Kaposi sarcoma
Cancer Mortality in Recipients of Kidney Transplants
Western countries mortality ratios for all cancer types are at least 1.8–1.9 times higher compared with the age- and sex-matched general population with greatest risk among those with melanoma, urogenital cancers, and non-Hodgkin lymphoma( overall risk of cancer-related death exceeding five to ten times that of those without kidney transplants). Risk Factors for Cancer Development
Risk factors are the general population factors like increasing age, male sex, smoking, and prolonged sun exposures beside immunosuppression use, acute rejection, sensitization status, and duration of dialysis before transplantation. long-term immunosuppression and having CKD (irrespective of the CKD stage) impaired tumor surveillance and immunity to viral or other tumor antigens.a previously treated pretransplant malignancy. The specific types of cancer that develop after transplantation
In Europe, North America, Australia, and New Zealand indicate the most common cancer types are nonmelanoma skin cancers (NMSCs), PTLD, and lip cancer while in Western Asian and Middle Eastern transplant cohorts the commonest are urothelial transitional cell carcinoma, renal cell carcinoma, and gastrointestinal cancers in their populations. A nationwide population study of 4716 recipients of kidney transplants in Taiwan reported an excess risk of liver cancer and Taiwan is an endemic area for chronic hepatitis B virus infection. Mechanisms of Cancer Development after Transplantation
Maintenance immunosuppression may create a variety of pathways for cancer development:
1. through poor immune control of known oncogenic viruses Kaposi sarcoma (human herpesvirus 8), PTLD (Epstein– Barr virus [EBV]), and lip and anal cancers (HPV)
2. through accumulation of mutations not repaired by the immune system: skin cancers in cells damaged by ultraviolet (UV) radiation–induced DNA damage.
3. decrease of xeroderma pigmentosum complementation groups A and G, which are components of nucleotide excision repair
immunosuppressants effects :
1- tacrolimus increases the level of TGF-b and thereby promotes tumor progression and metastasis of hepatocellular carcinoma, human lung adenocarcinoma cells, and renal cell carcinoma.
2- CNI inhibit signaling via calcineurin and NF of activated T cells, which can activate p53, a hallmark of some NMSCs .
3- Cyclosporine is through TGF-b or IL-6 overexpression pathways and inhibiting DNA repair, thereby accumulating mutations, inducing apoptosis in activated T cells, and inhibiting apoptosis in other cells by opening the mitochondrial permeability transition pores
4- Azathioprine sensitizes the skin to UVA radiation and causes the accumulation of 6-thioguanine in the DNA, leading to a higher risk of NMSCs
5- Mammalian target of rapamycin (mTOR) inhibitors, have antitumor effects by
1- inhibiting cancer growth through cell-cycle arrest and initiation of apoptosis. ( small cell lung cancer, sarcoma, neuroblastoma, glioblastoma, osteosarcoma, pancreatic cancer, breast cancer, prostate cancer, leukemia, and B-cell lymphomas)
2- On a molecular level mTOR inhibitors can induce apoptosis in a cell type–specific fashion.
3- It can also induce cell death in B-cell lymphoma lines, phosphatase and tensin homolog-lacking human tumors, and dendritic cells, possibly through p53 activation and reduction in the cyclin and survivin levels
6- T cell–depleting agents increases the risks of cancers, such as PTLD and melanoma . after T-cell depletion, there is often an incomplete T-cell recovery which may have a long-term effect on immune homeostasis, leading to an impaired immune system and subsequent cancer development. Common Cancers after Transplantation
the three most common cancer types: renal cell carcinoma, skin cancer, and PTLD. Renal Cell Carcinoma
recipients of kidney transplants have seven-fold higher risk of renal cell carcinoma and the majority are early, low-grade, small kidney masses of which, 75%–80% are RCC, with 2% risk of metastasis at presentation. 90% of renal cell carcinomas develop in the native kidneys as opposed to the allograft. Risk factors are male sex, increasing age, African descent and longer time on dialysis, disease etiology (glomerular diseases, hypertensive nephrosclerosis and vascular disease). The outcome of renal cell carcinomas after radical treatment in the transplant population is comparable with that of the general population. Renal cell carcinoma in the kidney allograft is rare, and multicenter data have demonstrated an incidence of 0.1%.
Overall duration and intensity of immunosuppression, rather than individual components of the drug regimen, influence risk of renal cell carcinoma. Skin Cancer
Skin cancer is the most common and is more aggressive than skin cancers occurring in the general population. They include cutaneous squamous cell carcinoma, basal cell carcinoma, Kaposi sarcoma and malignant melanoma.
The risk factors are exposure to UV radiation, HPV, pretransplant skin cancer, older age, race, and sex (males at greater risk than females), immunosuppressive medications ( cyclosporine and azathioprine) certain ethnic groups( Mediterranean, Africa, and Central Europe have more Kaposi).
Compared with the general population, the incidence of Kaposi sarcoma in recipients of transplants exceeds by 100 times , squamous cell carcinoma by 250 times and malignant melanoma is 5-8 folds more. Among all skin cancer types, melanoma has the highest mortality. Risk factors are:History of pretransplant melanoma ,White race and older age (>50 years).
squamous cell carcinoma Management in recipients of transplant:
1- actinic keratoses and squamous cell carcinoma in situ : topical fluorouracil and imiquimod cream, photodynamic therapy, and surgical excision or electrodesiccation and curettage.
2- biopsy sample–proven cutaneous squamous cell carcinoma: Mohs micrographic surgery, with histologic confirmation of negative margins( cure rates of 95%–100%)
3- inoperable cases: primary radiation therapy may achieve local cure rates.
4- chemoprophylaxis : for multiple squamous cell carcinomas (more than five) every year, aggressive squamous cell carcinomas, or early onset of squamous cell carcinomas.These may include retinoids and nicotinamide.
5- metastatic cutaneous squamous cell carcinoma, systemic chemotherapy and/or immunotherapy are recommended. Kaposi sarcoma management
Decreasing the intensity or switching CNI agents to an mTOR inhibitor lead to regression of Kaposi sarcoma by restoring effector and memory T-cell immune activity against human herpesvirus 8 .
Kidney transplantation is the best treatment of ESRD. It is more cost effective with better outcomes as compared to dialysis. Post transplant malignancy is the second most common cause of death after cardiovascular events. The recipients have 2-3 fold higher risk of developing cancers after transplant than general population. The most common cancers are skin cancers followed by solid organ canacers. The cumulative incidence of solid organ cancer ranges between 10% and 15% at 15 years.
The risk also depends on the cancer types. The risk is higher in viral and immune related cancers ,e.g post-transplant lymphoproliferative disease (PTLD), anogenital cancer, and Kaposi sarcoma. Some cancers like breast and prostate are not increased after transplant.
The mortality ratios for all cancer types are at least 1.8–1.9 times higher compared with the age- and sex-matched general population. The risk is greatest among those with melanoma, urogenital cancers, and non-Hodgkin lymphoma.
Risk Factors for cancer development
Increasing age
Male sex
Smoking
Prolonged sun exposures
Immunosuppression use (T cell–depleting agents)
Acute rejection
Sensitization status
Duration of dialysis before transplantation
Type of immune suppression
Induction with ATG increases the risk of PTLD and melanoma
After T-cell depletion, there is often an incomplete T-cell recovery (41), which may have a long-term effect on immune homeostasis, leading to an impaired immune system
MMF and Sirolimus increases the risk of malignancy.
Renal Cell Carcinoma
The risk of 6-7 fold higher and occur mostly in native kidneys. Surgical options include Radical nephrectomy, Partial nephrectomy , Cryotherapy or HIFU.
Skin Cancers
The most common skin cancers in recipients include cutaneous squamous cell carcinoma, basal cell carcinoma, Kaposi sarcoma, and malignant melanoma, with keratinocyte carcinomas comprising 90%–95% .
The common risk factors are exposure to UV radiation, HPV, pretransplant skin cancer, older age, race, and sex. Treatment includes, 5FU, photodynamic therapy and Excision.
PTLD
PTLD is associated with EBV with poor outcomes.
Treatment is reduction of immune suppression, rituximab or chemotherapy
Cancer Screening
There is lack of evidence to support routine screening in this high-risk group, routine population-based cancer screening for breast, colorectal, and cervical cancer is recommended
HPV Vaccination
This is more effective when given before transplant
. Please summarise this article Introduction
-Kidney transplantation is the best treatment option
for acceptable candidates with kidney failure but transplantation is not a cure.
-Patients require life-long immunosuppression to maintain optimal allograft function and the most important complications associated with immunosuppression after kidney transplantation is cancer . Incidence of All-Cause and Site-Specific Cancer after Transplantation
-The cumulative incidence of solid organ cancer ranges between 10% and 15% at around 15 years after transplantation.
– The cumulative incidence of skin cancers reaches 60% in Europe, Australia, and New Zealand.
-The excess overall cancer risk in patients with kidney transplant exceeds that of the general population by approximately two- to three-fold after adjustment for age and sex.
-There is high risk of viral-related and immune driven cancers such as post-transplant lymphoproliferative disease (PTLD), anogenital cancer, and Kaposi sarcoma while breast and prostate cancers are not increased in recipients
of transplants . Cancer Mortality in Recipients of Kidney Transplants
-Once cancers develop, the risk of death is high.
-The risk is greatest among those with melanoma, urogenital cancers, and non-Hodgkin lymphoma, with an overall risk of cancer-related death exceeding 5-10
times that of those without kidney transplants. Risk Factors for Cancer Development
-Some of these factors, such as increasingage, male sex, smoking, and prolonged sun exposures, are shared by patients in the general population.
-Other risk factors,including immunosuppression use (T cell–depleting
agents), acute rejection , sensitization status , duration of dialysis before transplantation , and pretransplant malignancy are specific to those with kidney disease and transplant populations.
-Cancer may develop in recipients of kidney transplants because of impaired tumor surveillance and immunity to viral or other tumor antigens.
-The specific types of cancer that develop after transplantation vary by geographic areas. Observational and registry data from Europe, North America, Australia, and New Zealand indicate the most common cancer types are nonmelanoma skin cancers (NMSCs), PTLD, and lip cancer
-Data from non-Western Asian and Middle Eastern transplant cohorts suggest higher incidences of urothelial transitional cell carcinoma, renal cell carcinoma,
and gastrointestinal cancers in their populations . Mechanisms of Cancer Development after Transplantation
-One potential mechanism is through poor immune control of known oncogenic viruses in patients on immunosuppression.
-Another mechanism of immunosuppression-related cancer development is through accumulation of mutations that would otherwise be repaired or recognized by the immune system.
-Currently, there is no conclusive evidence to suggest one type of immunosuppression is more oncogenic than others. Common Cancers after Transplantation
-The three most common cancer types: renal cell carcinoma, skin cancer,
and PTLD. Renal Cell Carcinoma
-Compared with the general population, recipients of kidney
transplants have a higher risk of renal cell carcinoma .
– 90% of renal cell carcinomas develop in the native kidneys as opposed to the allograft.
-Risk factors for development of renal cell carcinomas posttransplantation include male sex , increasing age , African descent , longer time on dialysis , kidney failure secondary to glomerular diseases , hypertensive nephrosclerosis , and vascular disease .
-The outcome of renal cell carcinomas after radical treatment in the transplant population is comparable with that of the general population.
-Overall duration and intensity of immunosuppression, rather than individual components of the drug regimen, influence risk of renal cell carcinoma.
-The management of these malignancies should be individualized
and use a patient-centered approach to ensure optimal care . Skin Cancer
-Skin cancer is the most common cancer type in recipients of kidney transplants and is more aggressive than skin cancers occurring in the general population.
-The most commonly reported skin cancers include cutaneous squamous cell carcinoma, basal cell carcinoma, Kaposi sarcoma, and malignant melanoma, with keratinocyte carcinomas comprising 90%–95% of these skin cancers .
-Risk factors, including exposure to UV radiation, HPV, pretransplant skin cancer,
older age, race, sex (males at greater risk than females) and immunosuppressive medications mainly cyclosporine and azathioprine.
-Kaposi sarcoma is more commonly in certain ethnic groups, including patients from the Mediterranean, Africa, and Central Europe.
– In patients with actinic keratoses and squamous cell carcinoma in situ, management options with good outcomes include topical fluorouracil and imiquimod cream, photodynamic therapy, and surgical excision or electrodesiccation and curettage.
– In inoperable cases, primary radiation therapy may achieve local cure rates.
-Patients who develop multiple squamous cell carcinomas (more than five) every year, those who have aggressive squamous cell carcinomas, or those with early onset of squamous cell carcinomas can be considered for chemoprophylaxis.
-Chemoprophylaxis may include retinoids and nicotinamide and in metastatic cutaneous squamous cell carcinoma, systemic chemotherapy and/or immunotherapy are recommended .
-Patients treated with calcineurin inhibitors are at particularly high risk for Kaposi sarcoma. Decreasing the intensity or switching immunosuppressive agents to an mTOR inhibitor is the cornerstone of treatment.
-The risk of developing malignant melanoma is elevated by approximately 5-8 fold in recipients of transplants, and these patients have poor outcomes and the highest mortality .
-History of pretransplant melanoma is the strongest risk factor for post-transplant melanoma, followed by White race and older age .
– Primary treatment is surgical with wide excision and adequate margins and adjustment of immunosuppression on the basis of the extent of melanoma and transplant function. Post-Transplant Lymphoproliferative Disease
-It is a rare disease but associated with poor outcomes.
-90% of PTLD is associated with EBV.
-Most PTLDs are of B-cell types, with approximately 5% of patients having
the T-cell type.
– The use of costimulatory blockade, such as belatacept, has been found to be associated with a higher risk of PTLD, particularly cerebral PTLD in patients
who are EBV negative, and when used in higher doses .
-The treatment goal of PTLD is to cure the disease, and the mainstay of treatment is immunosuppression reduction.
– Prior work reported the use of rituximab and chemotherapy (doxorubicin,
cyclophosphamide, vincristine, prednisone) have improved overall survival, with 5-year survival at around 60% .
-Once PTLD develops, the risk of death is high. Cancer Screening Strategies in Transplant Recipients
-Despite the lack of trial-based evidence to support routine screening in this high-risk group, routine population-based cancer screening for breast, colorectal,
and cervical cancer is recommended and should be aligned to the guidelines as per the general population .
-Some guidelines also suggest routine skin checks by dermatologists in recipients of transplants who are at high risk, and abdominal ultrasounds and serum a-fetoprotein levels should be checked every 6 months for those with underlying liver disease and chronic HBV infections.
-For patients who are at risk of developing renal cell carcinoma, ultrasonographic
screening (annually or biennially) of the native kidneys may be considered to detect occult malignancy. Human Papillomavirus Vaccination in Recipients of Kidney Transplants
-The incidence of HPV-related anogenital cancer is at least ten- to 15-fold higher in recipients of kidney transplants compared with the age- and sex-matched general population.
-Quadrivalent vaccines (against genotype 6, 11, 16, and 18) and, more recently, the HPV 9-valent vaccines (against five additional genotypes of 31, 33, 45, 52, and 58) are highly effective and have an overall efficacy of 99%–100% for the prevention of cervical intraepithelial neoplasia in randomized clinical trials. Management of Recipients of Kidney Transplants Who Have Cancer
Immunosuppression Management and Treatment in Transplant Recipients with Cancer:
-A concerted approach between transplant professionals, oncologists, and allied health professionals is therefore needed to ensure optimal care for our patients.
-In the absence of quality evidence, judicious reduction in the overall immunosuppression load for patients with early- to moderate-stage malignancy may be a reasonable first step.
Immunotherapy:
-The use of immune-checkpoint inhibitors has revolutionized the treatment of a variety of malignancies through immune system activation against the cancer. However, their use in the kidney transplant population requires further investigation and cannot be recommended at this time, outside of a study protocol.
Putting Patients’ Perspectives at the Heart of Cancer Management
-A personalized, rather than a one-size-fits-all, approach is most preferred and a multidisciplinary, integrated approach that involves the transplant and palliative
care team is crucial. Conclusions
-The evidence to support primary prevention and screening programs in
recipients of transplants are largely extrapolated from the general population, and the findings may not necessarily be applicable to the transplant population. Collaborative efforts between health care professionals, policy makers, trialists, and patients are needed to ensure quality evidence— in the form of intervention trials, large-care observational studies, and qualitative and health service
research—are generated to support the long-term care of recipients of transplants. What is the level of evidence provided by this article?
Level 5
SUMMARY
This is a review article on de-novo malignancies in kidney transplant recipients. Introduction
Kidney transplantation is the best option for the eligible patient however it is associated with life long use of immunosuppressive therapy. This is associated with complications with the most feared being cancer. Thus cancer is prevalent in the transplant recipients and it is the second cause of death after cardiovascular disease in this population. Most common cancers are skin cancer, viral related and immune driven cancers. Risk factors
Traditional risk factors do play a role in this population and they include increased age, male gender, smoking and prolonged sun exposure.
However other risk factors tend to be specific for the transplant recipients and this include use of immunosuppressive agents, incidence of acute rejection, sensitisation status and duration on dialysis.
Other risk factors tend to be region specific for example a Taiwan study showed a high incidence of liver cancer however there is a high prevalence of chronic HBV infection in Taiwan with transplant recipients having a prevalence of HBV between 9-24%. Immunosuppression and malignancy
Generally immunosuppressive agents are good since they reduce the incidence of rejection and in so doing reduce the incidence of graft loss. However they do dampen the immune system and thus creating pathways for developing malignancy.
One way they do this is by poor immune control of oncogenic virus thus allowing their proliferation and hence increased incidence of viral associated cancer eg Kaposi sarcoma-HHV8, lip and anogenital cancer-HPV, PTLD-EBV.
Another way is by accumulation of mutations which would have otherwise been recognised and repaired by the immune system. This is more so for skin cancers where they inhibit ability to repair DNA damaged by UV radiation. Specific immunosuppressive therapy
Azathioprine associated with high risk of NMSC due to the accumulation of thioguanine in the DNA thus sensitising the skin to UV radiation.
Cyclosporine inhibits DNA repair thus accumulation of mutations which induce apoptosis in activated T cells. It also causes over expression of IL6 and TGF beta.
CNI inhibit signalling via calcineurin in activated T cells leading to activation of P53 which is a hallmark of NMSC.
Tacrolimus in experimental studies have been shown to increase the expression of TGF beta which promotes tumour progression and metastasis.
However it should be noted that there is no enough evidence to show one agent to be more oncogenic than another, it is rather the duration and intensity. Specific cancers
1.Renal cell carcinoma
Kidney transplant recipients have a 7 fold risk. They tend to occur in the native kidneys. The increased risk could be due to traditionally risk factors like gender, ethnicity, increased age, duration on dialysis, intensity and duration of immunosuppression and the primary diagnosis.
However it should be noted that this particular patient population have increased frequency of abdominal imaging this explains why they are routinely caught early and could also explain the high incidence in comparison to other malignancies that are not routinely screened for in this patient population.
2.Skin cancers
They tend to be more aggressive than the general population. The most common is squamous cell carcinoma, however malignant melanoma is associated with the highest mortality. Risk factors include UV exposure, HPV, older age, race, gender, pre-transplant skin cancers and use of immunosuppressive agents.
3.PTLD
It associated with poor outcomes and in 90% of the cases it is associated with EBV. Most people acquire EBV in childhood and it remains latent in B cells, due to decreased T cell function caused by the immunosuppressive agents after transplant, there is unchecked B cell proliferation and thus of the virus. Thus most PTLD are B cells.
Screening
Screening for breast, colorectal and cervical cancers which have a low incidence would be as per the local guidelines. Some guidelines do recommend regular skin checks with a dermatologists and screening for at risk patients groups for example regular abdominal U/S for recipients with chronic HBV. However the decision to screen and the intensity should be made in collaboration with the patients.
Vaccination
The high incidence of anogenital malignancies associated with HPV should advocate vaccination in this patient population more so in the pre-transplant period.
Management
The management should be a balance between avoidance of rejection in the graft and induction of regression in the malignant cell.
Patients not in advanced cancer stage the first line should be reduction in the immunosuppressive agent.
The is limited evidence of use of immunotherapy agents due to risk of rejection.
LEVEL OF EVIDENCE
This is a level 5 they are reporting evidence from other studies.
This review article focuses on post-transplant malignancy, including its incidence, diagnosis, treatment and prevention. Cancer is the second most common cause of death in transplant patient after cardiovascular disease. The most common cancer being non melanoma skin cancer, while the risk of mortality is highest among melanoma, urogenital cancers, and non-Hodgkin lymphoma.
Risk factors for cancer development specific for kidney transplant patients depend on the type and intensity of immunosuppression, episodes of rejection, sensitization status, duration of dialysis prior to transplantation, certain oncogenic virus like EBV, HPV.
Among renal transplant recipients, risk of renal cell carcinoma is seven times that of general population. Ninety percent of renal cell carcinomas develop in the native kidneys, risk factors include male sex, increasing age, African descent, and longer time on dialysis (more than 3 years). RCC is managed as per urological guidelines and the outcome after treatment is comparable to general population.
Skin cancer is the most common post-transplant malignancy and includes squamous cell carcinoma, melanoma, Kaposi sarcoma, basal cell carcinoma. Risk factors include exposure to UV radiation, HPV, pretransplant skin cancer, older age, race, and male sex, type of immunosuppression such as azathioprine and cyclosporin. Management options include topical fluorouracil and imiquimod cream, photodynamic therapy, and surgical excision or electrodesiccation and curettage. PTLD is associated with EBV in 90 % of cases. The incidence of PTLD in the first 10 years after kidney transplantation is 1%–2% in adults, it has a bimodal distribution, with the risk of PTLD being the highest in the 12 months post-transplant, and it then decreases until the fifth year after transplantation. Risk factors include EBV, younger age, males, type of immunosuppression such as T call depleting agents, high dose of tacrolimus and belatacept. Treatment options include reduction of immunosuppression, rituximab and chemotherapy.
Routine screening of breast, cervical and colorectal cancer is recommended in transplant recipients. Some guidelines advocate skin cancer checks by dermatologists. Recipients with underlying liver disease should be screened for HCC by 6 monthly ultrasounds and serum a-fetoprotein levels.
The incidence of HPV-related anogenital cancer is at least ten- to 15 times higher in kidney transplants recipients compared with general population. HPV vaccination is recommended for recipients aged 9-25 years, preferably prior to transplantation.
Review article focuses on the incidence, mechanisms, diagnosis, prevention, and treatment of cancer after kidney transplantation. Written at 2022
Incidence (SIR) and mortality (SMR)
Cancer is the second cause of death among transplants.
All cancer SIRs 2-3 and SMR almost 2.
Incidence for skin cancers >60 SIR. Risk of cancer related death 5-10 times in melanoma, urogenital cancers, and non-Hodgkin lymphoma.
breast and prostate cancers are not increased in recipients of transplants
Risk Factors for Cancer Development· Like general population: increasing age, male sex, smoking, and prolonged sun exposures.
· Kidney tx population specific: immunosuppression use (T cell–depleting agents), acute rejection, sensitization status, and duration of dialysis before transplantation.
· geographic areas: Europe, North America: nonmelanoma skin cancers, PTLD, and lip cancer. Asian and Middle Eastern: urothelial transitional cell carcinoma, renal cell carcinoma, and gastrointestinal cancers.(? aristolochic acid related)
Mechanisms of Cancer Development after Transplantation1. poor immune control of known oncogenic viruses due to immunosuppression:
For example, increases in viral-associated cancers, such as Kaposi sarcoma (human herpesvirus 8), PTLD (Epstein–Barr virus [EBV]), and lip and anal cancers (HPV)
2. immunosuppression-related cancer development is through accumulation of mutations that would otherwise be repaired or recognized by the immune system. Example: skin cancers, where immunosuppression impairs the cells’ ability to UV radiation–induced DNA damage.
3. Type of immunosuppression: (Table attached as pic)
Renal Cell CarcinomaSIR 7 Early detection ¾ early small lesions Due to increased imaging, metastasis <2%. Risk factors: male, age ≥ 60, African descent, dialysis ≥ 3y, Primary renal dse: glomerular diseases, hypertensive nephrosclerosis, and vascular disease greatest associated risk managed according to urologic guidelines. Prognosis: Similar to general population 70-90 % survival after radical surgery Negative prognostic factors include presence of symptoms at diagnosis, higher Fuhrman grade (>2), absence of transplantation, and advanced-stage disease (53–56). Allograft RCC incidence 0.1%. Most are low-grade T1 lesions, clear cell carcinomas, or papillary renal cell carcinomas, and occur more commonly in males. Two third of tumours can be with partial nephrectomy
Skin CancerMost common: squamous cell carcinoma, basal cell carcinoma, Kaposi sarcoma, and malignant melanoma, with keratinocyte carcinomas Risk factors: UV radiation, HPV, pre transplant skin cancer, older age, race, and male sex. Cyclosporine and azathioprine can augment the risk, Geographical Kaposi sarcoma (Mediterranean, Africa, and Central Europe). Management: – See table in the pic
Malignant melanoma SIR 5-8, poorer outcomes and highest mortality. Risk: History of pretransplant melanoma (strongest), White race and older age (>50 years). Primary treatment is surgical with wide excision and adequate margins. Adjustment of immunosuppression is individualized
Post-Transplant Lymphoproliferative Disease
PTLD is associated with EBV in 90 % of cases. EBV natural Hx:Pre-Transplant: Most people acquire the virus during childhood. Most present with mild or minimal symptoms, but the virus can infection the B cells and remain dormant in these cells during the latent phase. After transplantation, these viruses can reactivate because of depressed T-cell function, with a lack of T-cell control over B-cell proliferation, and contributes to the development of PTLD. Most PTLDs are of B-cell types, with approximately 5% of patients having the T-cell type.
The cumulative incidence in the first 10 years after kidney transplantation is around 1%–2%. There also appears to be a bimodal distribution in PTLD incidence, first and 5th year post Tx. Early PTLD common in pre transplant seronegative with primary infection post Tx.
Risk factors: younger age at transplantation, male, use of T cell–depleting agents, Ortho Kung T3 (muromonab-CD3), and high dose tacrolimus, positive to negative, The use of costimulatory blockade, such as belatacept (cerebral PTLD)
Treatment: Rituximab (better outcome with EBV +ve and normal LDH) and chemotherapy (doxorubicin, cyclophosphamide, vincristine, prednisone) have improved overall survival, with 5-year survival at around 60%.
Survival: 1 Y 66 % and 10 Y 44 % worse with bone marrow/reticuloendothelial (can die within 6 months). Worse prognosis with male and increasing age of diagnosis.
Human Papillomavirus Vaccination in Recipients of Kidney Transplants The incidence 10- to 15-fold higher in recipients of kidney transplants. Quadrivalent vaccines (against genotype 6, 11, 16, and 18) and the HPV 9-valent vaccines (against five additional genotypes of 31, 33, 45, 52, and 58) are highly effective in prevention.
HPV vaccination is indicated in both males and females aged 9–25 years in the general population.
Non responders: 50% patients, depending on genotypes, and higher tacrolimus levels
Management of Recipients of Kidney Transplants Who Have Cancer judicious reduction immunosuppression load for patients with early- to moderate-stage malignancy squamous cell carcinoma Kaposi sarcoma: switch to mTOR Immunotherapy: Trials Advanced-stage malignancy, Some clinicians may consider stopping either or both the calcineurin inhibitors and antiproliferative agents gradually and rotate to higher-dose corticosteroids to prevent the anticipated symptoms.
Level of Evidence:
Review article (not systematic review) provide expert opinion based on previous studies which is the lowest in the pyramid
Summery:
This article is about development and outcome of cancer post transplantation .It seems that the developded of cancer post trsnapnat is mainly related to cell and immunology modulation.Malignancies such as melanoma, renal cell carcinoma, and PTLD have bad outcome in comparison with other malignancies.
Risk factors for cancer development form a long list, including increasing age, male sex, smoking, prolonged sun exposure, immunosuppressive therapy, acute rejection episodes, status of sensitization, duration of dialysis prior to transplantation.
Accumulation of mutation is the second cuase of cancer , with Specifically, this can be applied to skin cancers, where immunosuppression can lead to a decrease of xeroderma pigmentosum complementation groups A and G.
In this article also increase of hepatocellualr carcinoma IN patientient on Tacrolimus which increase TGF and P 53 and both of them promoting tumoer growth.
Adding to that PTLD is associated with EBV ,with regression in rate of this cancer due to pretranspkant screening for EBV . in This type of cancer rituximab and reduction of immunosuppression medications is the main corner .
Primary prevention and the screening program is the main corner stone ,
This review begins with a patient’s journey to understand the patient’s knowledge, education, and experience with cancer in the context of transplantation.
The epidemiology and burden of cancer in kidney transplant recipients are discussed, as well as current screening and treatment strategies.
It also examines the current state of knowledge regarding best care for kidney transplant recipients who are also cancer patients.
The Prevalence of All-Cause & Site-Specific Cancer
At around 15 years after transplantation, the cumulative incidence of solid organ cancer ranges between 10% and 15%. In Europe, Australia, and New Zealand, the cumulative incidence of skin cancer is 60%.
Kidney transplant patients have a two- to three-fold increase in overall cancer risk compared to the general population.
The magnitude of the increased risk varies by cancer type, with viral-related and immune-driven cancers carrying the greatest risk. Surprisingly, breast and prostate cancer do not increase in transplant recipients.
Cancer Mortality in Recipients of Kidney Transplants
Cancer has a high mortality rate once it has developed. Observational data from the majority of Western countries show that the standard mortality ratios for all cancer types are at least 1.8-1.9 times higher than in the age- and sex-matched general population.
The risk is highest in those with melanoma, urogenital cancers, and non-Hodgkin lymphoma(5 to 10 times that of those who do not have kidney transplants).
The precise causes of the increased risk of death are unknown. However, it could be due to differences in cancer cell biology as a result of long-term immuno-suppression and associated comorbidities, as well as a failure to put recommended prevention and screening strategies into action.
Patients are most concerned about their kidney and graft health, as well as their current medical needs. Because cancer screening and prevention can have a significant impact on patients’ daily lives, effective patient education and increased awareness are critical.
Risk Factors for Cancer Development
Increasing age
Male sex
Smoking
Prolonged sun exposures
Immunosuppression use (T cell–depleting agents)
Acute rejection
Sensitization status
Duration of dialysis before transplantation
Geographic areas.
Mechanisms of Cancer Development:
One possible mechanism is poor immune control of known oncogenic viruses in immunocompromised patients.
There is an increase in viral-associated cancers in patients with suppressed immune systems, such as:
-Kaposi sarcoma (HHV 8),
-PTLD (EBV), and
-lip and anal cancers (HPV).
The accumulation of mutations that would otherwise be repaired or recognized by the immune system is another mechanism of immunosuppression-related cancer development. This mechanism may be more common in skin cancers, where immunosuppression impairs the ability of cells to repair UV-induced DNA damage.
There is currently no conclusive evidence that one type of immunosuppression is more oncogenic than another. Tacrolimus raises TGF-b levels, promoting tumor progression & metastasis.
CNIs inhibit activated T cell signaling via calcineurin & NF, which can activate p53, a feature of some NMSCs.
Azathioprine increases skin sensitivity to UVA radiation and causes 6-thioguanine accumulation in DNA, increasing the risk of NMSCs.
mTOR inhibitors may have antitumor effects by inhibiting cancer growth via cell-cycle arrest & apoptosis induction.
T cell–depleting agents increase the risks of cancers, such as PTLD & melanoma. Following T-cell depletion, T-cell recovery is frequently incomplete, resulting in a weakened immune system and the development of cancer.
Common Cancers Following Transplantation
The three most common cancer types are:
-renal cell carcinoma,
-skin cancer, and
-PTLD.
Recipients of kidney TX have a higher risk of renal cell carcinoma (up to 7-fold) than the general population.
Male sex, increasing age, African ancestry, and longer dialysis time are all risk factors for the development of renal cell carcinomas after transplantation.
Skin Cancer is the most common cancer type in kidney TX recipients &is more aggressive than skin cancers in the general population. The most common skin cancers are:
-Squamous cell carcinoma,
-basal cell carcinoma,
-Kaposi sarcoma, &
-malignant melanoma.
Pathogenesis:
Interaction of risk factors such as UV exposure, HPV, pre-transplant skin cancer, older age, race, & sex (males > females).
IS drugs increase the carcinogenic effect (mainly cyclosporine & azathioprine).
PTLD
A well-known complication following kidney TX.
Though rare (1-2%), it is associated with poor outcomes.
Associated with EBV in the vast majority of cases.
Most present with mild or minimal symptoms.
The majority of PTLDs are B-cell types, with only 5% being T-cell types.
The prevalence of PTLD has been declining in recent years (Australian and New Zealand Dialysis and Transplant Registry).
Cancer Screening:
Routine population-based screening for breast, colorectal, & cervical cancer is recommended & should follow general population guidelines.
Routine skin checks by dermatologists.
Abdominal US & serum a-fetoprotein levels checked every 6 months for those with underlying liver disease & chronic HBV infections.
Management:
Optimize IS dose to avoid AR while balancing the need to induce malignant lesion regression & prevent future progression.
Patients should be informed about any potential side effects, and all strategies should be tailored to the specific needs of the individual.
Conversion to an mTOR inhibitor may reduce the risk of cancer in the longer term in patients with squamous cell carcinoma.
Immunotherapy with checkpoint inhibitors is effective in treating melanoma, non–small cell lung cancer, & renal cell carcinoma in the general population; however, their use in the KTX recipients is not currently recommended outside of a study protocol.
Collaboration between health care professionals & patients is needed to ensure good evidence-based long-term care.
========================== 2. What is the level of evidence provided by this article Level V
Summaryof the article DE NOVO MALIGNANCIES AFTER KIDNEY TRANSPLANTATION
· Cancer is the second leading cause of death after cardiovascular diseases among recipients of transplants.
· Incidence of All-Cause solid organ cancer ranges between 10% and 15% at around 15 years after transplantation.
· The excess overall cancer risk in patients with kidney transplant exceeds that of the general population by approximately two- to three-fold after adjustment for age and sex.
· An overall risk of cancer-related death exceeding five to ten times that of those without kidney transplants.
· Risk factors for cancer development shared by patients in the general population are: increasing age, male sex, smoking, and prolonged sun exposures. Additional risk factors specifc to those with kidney disease and transplant populations include; immunosuppression use (T cell–depleting agents), acute rejection , sensitization status , and duration of dialysis before transplantation. CKD (irrespective of the CKD stage) is associated with higher cancer risk and poor cancer outcomes.RCC and multiple myeloma, are over-represented in the CKD/ kidney-failure populations.When stratifed by sex, women have a much higher risk than men for kidney and bladder cancers.
Mechanisms of Cancer Development after Transplantation: 1. Poor immune control of known oncogenic viruses in patients on immunosuppression. · Kaposi sarcoma (human herpesvirus 8) · PTLD (Epstein– Barr virus EBV). · Lip and anal cancers (HPV). 2. Accumulation of mutations; this mechanism may be predominant in skin cancers. · immunosuppression impairs the cells’ ability to repair ultraviolet (UV) radiation–induced DNA damage. · immunosuppression can lead to a decrease of xeroderma pigmentosum complementation groups A and G, which are components of nucleotide excision repair. 3. Calcineurin inhibitors inhibit signaling via calcineurin and NF of activated T cells, which can activate p53, a hallmark of some NMSCs. · Tacrolimus increases the level of TGF-b and thereby promotes tumor progression and metastasis. · Cyclosporine is capable of inhibiting DNA repair, thereby accumulating mutations, inducing apoptosis in activated T cells, and inhibiting apoptosis in other cells by opening the mitochondrial permeability transition pores. 4. Azathioprine sensitizes the skin to UVA radiation and causes the accumulation of 6-thioguanine in the DNA, leading to a higher risk of NMSCs. 5. Mammalian target of rapamycin (mTOR) inhibitors may have potential antitumor effects by inhibiting cancer growth through cell-cycle arrest and initiation of apoptosis. 6. Induction therapy with T cell–depleting agents (including polyclonal agents, such as anti-thymocyte globulin, and monoclonal agents, such as anti-CD52 and, historically, Ortho Kung T3 [muromonab-CD3]) increases the risks of cancers, such as PTLD and melanoma. 7. After T-cell depletion, there is often an incomplete T-cell recovery , which may have a long-term effect on immune homeostasis, leading to an impaired immune system and subsequent cancer development.
Common Cancers after Transplantation
The three most common cancer types: renal cell carcinoma, skin cancer, and PTLD. 1. Renal Cell Carcinoma · KTRs have higher risk reaching up to seven-fold of RCC. · 75-80% of early detected small kidney masses are low grade RCC. · 90% of RCC develop in the native kidneys as opposed to the allograft. · Renal cell carcinoma in the kidney allograft is rare, and multicenter data have demonstrated an incidence of 0.1%. Most are low-grade T1 lesions, clear cell carcinomas, or papillary renal cell carcinomas, and occur more commonly in males. · Risk factors for development of RCC post-transplantation include male sex, increasing age, African descent and longer time on dialysis. · The followings appear to have the greatest associated risk; kidney failure secondary to glomerular diseases, hypertensive nephrosclerosis and vascular disease. · DM and autosomal dominant PKD have a lower risk of renal cell carcinomas. · De novo renal cell carcinomas should be definitively managed according to urologic guidelines on the basis of risk stratification and staging. · The outcome of renal cell carcinomas after radical treatment in the transplant population is comparable with that of the general population (with 5-year, disease-specific and overall patient survival rates of 68%–97% and 69%–88%, respectively). · Nephron-sparing surgery was safe and an appropriate option with good long- term functional and oncologic outcomes, evading return to dialysis. · Negative prognostic factors include; presence of symptoms at diagnosis, higher Fuhrman grade , absence of transplantation, and advanced-stage disease.
2. Skin Cancer · Skin cancer is the most common cancer type in recipients of kidney transplants and is more aggressive than skin cancers occurring in the general population. · The most commonly reported skin cancers in recipients of kidney transplants include cutaneous squamous cell carcinoma, basal cell carcinoma, Kaposi sarcoma, and malignant melanoma, with keratinocyte carcinomas comprising 90%–95% of these skin cancers. · Risk factors for skin cancers: exposure to UV radiation, HPV, pretransplant skin cancer, older age, race, and sex (males at greater risk than females). Additionally, immunosuppressive medications augment the carcinogenic effects (mainly cyclosporine and azathioprine). · Kaposi sarcoma is more commonly seen in certain ethnic groups, including patients from the Mediterranean, Africa, and Central Europe. Although Kaposi sarcoma is a rare cancer, the incidence of Kaposi sarcoma in recipients of transplants exceeds 100 times that of the general population. · Recipients of transplants experience an excess risk of squamous cell carcinoma by approximately 250 times. · Management options: a. Decreasing the intensity or switching immunosuppressive agents to an mTOR inhibitor is the cornerstone of treatment. b. Topical fluorouracil and imiquimod cream. c. Photodynamic therapy. d. Surgical excision or electrodesiccation and curettage. e. The cure rate of micrographic surgery is 95%-100%. f. Chemoprophylaxis(retinoids and nicotinamide) for aggressive SCC. g. In patients with metastatic cutaneous squamous cell carcinoma, systemic chemotherapy and/or immunotherapy are recommended. h. Among all skin cancer types, melanoma has the highest mortality. Primary treatment is surgical with wide excision and adequate margins.
3. Post-Transplant Lymphoproliferative Disease · It is rare, but associated with poor outcomes. · In most instances (approximately 90%), PTLD is associated with EBV. · Most PTLDs are of B-cell types, with approximately 5% of patients having the T-cell type. · The cumulative incidence of PTLD in the first 10 years after kidney transplantation is around 1%–2%. · According to recent analysis from ANZDT registry,there appears to be a bimodal distribution in PTLD incidence, with the risk of PTLD being the highest in the 12 months post-transplant, and it then decreases until the fifth year after transplantation. · Risk factors for PTLD: a. Pretransplant EBV seronegativity and primary EBV. b. Apart from younger age at transplantation, male sex, use of T cell–depleting agents, Ortho Kung T3 (muromonab-CD3), and high dose tacrolimus, negative recipient EBV serology (with positive donor EBV serology) incur a four-fold excess risk of PTLD. c. The use of costimulatory blockade has also been found to be associated with a higher risk of PTLD, particularly cerebral PTLD in patients who are EBV negative. · The treatment of PTLD: the goal is to cure and the mainstay is IS reduction. a. Prior work reported the use of rituximab and chemotherapy (doxorubicin, cyclophosphamide, vincristine, prednisone) have improved overall survival, with 5-year survival at around 60%. b. The risk of death among recipients of kidney transplants who have PTLD is 14- fold higher than recipients without PTLD. Rituximab and other novel therapies have shown an improvement in overall survival. · The median time from diagnosis to death is 6 months. · The risk of death appears to be dependent on: a. Site; with those having bone marrow/reticuloendothelial disease experiencing the greatest risk of death followed by extranodal and nodal disease. b. Apart from site, other predictive factors of death included male sex and increasing age of diagnosis.
Cancer Screening Strategies in Transplant Recipients · Routine population-based cancer screening for breast, colorectal, and cervical cancer is recommended and should be aligned to the guidelines as per the general population. · Some guidelines suggest routine skin checks by dermatologists in recipients of transplants who are at high risk. · Abdominal ultrasounds and serum a-fetoprotein levels should be checked every 6 months for those with underlying liver disease and chronic HBV infections. · For those at high risk for RCC, ultrasonographic screening (annually or biennially) of the native kidneys may be considered to detect occult malignancy.
HPV Vaccination in KTRs · The incidence of HPV-related anogenital cancer is at least ten- to 15-fold higher in KTRs. · HPV vaccination is indicated in both males and females aged 9–25 years in the general population for the prevention of HPV-related malignancies. · Although HPV vaccination is recommended for women after transplantation, it may be more efficacious to vaccinate before transplantation.
Management of KTRs Who Have Cancer:
1. Immunosuppression Management and Treatment in KTRs with Cancer: · Reduction of the IS load may be the first step in early to moderate stage of cancer. · Conversion to an mTOR inhibitor may reduce the risk of cancer in the longer term(SCC and Kaposi sarcoma). There are insufficient data to consider mTOR inhibitors as protective against other cancer types apart from squamous cell carcinoma and Kaposi sarcoma. 2. Immunotherapy :Although the use of immune-checkpoint inhibitors are effective in treating melanoma, non–small cell lung cancer, and renal cell carcinoma in the general population, their use in the kidney transplant population requires further investigation and cannot be recommended at this time, outside of a study protocol.
The level of evidence provided by this article
This is a narrative review article with level of evidence grade 5.
De Novo Malignancies after kidney Transplantation Introaduction: Although kidney transplantation is not a cure of kidney failure, itis a best option for kidney failure:
Improve qulaity of life.
Better patient survival than patient been on dialysis.
Cost-effective, than other modalities of KRT.
Unfortionately cancer is on of the outcome of kidney transplantation under effects of immunosuppressants medication, so measures to be taken to reduce the risk of cancer in transplant candidate, including:
vaccination against viral infections e.g (HBV).
Strategies to reduce the cancer risk.
Undestand the underline mechanism of immunosuppressant induce cancer.
Screening strategy and self examination.
Studies on outcomes of kdiney transplantation should include incidence of cancer among transplant patient, as the cancer is the second leading cause of death after cardiac disease. Incidence of All-cause and Site-specific cancer after transplantation:
The cumulative incidence of solid organ cancer is approximately between 10-15% after 15 years after transplantation.
The cumulative incidence of skin cancer is approximately >60% in Europe, Australia and New Zeland.
The overall cancer risk increase risk is 2 to 3 fold higher in transplanted patient compared to matched age and sex group in the general population.
Surprisingly breast and prostate cancer is not at increased risk in transplant patient compared to general matched population.
Cancer Mortality in Recipients of Kidney Transplant:
The score of death is rising with cancer incidence in transplant patient by 1.8 to 1.9% higeher compared to matched group n general population.
Effort should be taken on patient education and awareness of cancer risk and need of screening and self- detection are vital in reduce the risk.
Risk of death is higher (5-10%) among patient with:
Melanoma.
Urogenital cancers.
Non-Hodgkin lymphoma.
Risk Factors of Cancer development:
Old age.
Male sex.
Smoking.
Prolong sun exposure.
Immunosuppressant medications, e.g (ATG).
Acute rejection.
Sensitization condition.
Time been on dialysis before transplantation.
CKD is per say is a risk factor and so; RCC, multiple myeloma, are observed higher in CKD patients.
Reduce cancer screening.
Viral infection.
Pretransplant tumor.
The most common cancers in US, Europe, Australia, and New Zeland:
NMSC non-melanoma skin cancer.
PTLD, post transplant lymphopolifertaive disorder.
Lip cancer.
The most common prevalent skin cancer post tarnsplant in non-Western Asian, Middle East:
Urothelial transitional cell carcinoma.
RCC.
Gastrointestinal cancer.
The variation in the cancer-type incidence may be associated with dietary style in each region. In Taiwan the liver vancer is prevalent in transplant patient, may be related to undeline endemic HBV infection. Immunosuppressants and cancer risk association;
No evidence base that specific type of immunosuppressant is oncogenic over the other type.
Studies show, risk of HCC, Lung adenocarcinoma, RCC, inceased with TAC use, and found that TAC incease the TGF-B which increase tumor progression.
CNI inhibit signaling via calcineurin and NF of activated T cell, which activate p53, a factor of NMSCs.
Cyclosporin inhibit DNA repair, lead to accumulation of mutations, inhibition of apoptosis in the cell except T-cell.
Oncogenic properties of azathioprine, which increase sensitivity of skin to UV light.
Muromonab-CD3 incraese the risk of cancer such as PTLD, and melanoma.
mTORi, in reverse have an anti-tumor effect.
RCC:
7 fold higher risk than general population.
Early detected cancer due to ferquent abdominal imaging, so early, law grade, small kidney masses, for which 75% to 80% are RCC, with low risk of metastesis to < 2%.
90% develop in native kidneys.
Treated based on urological guidelines, and staging, treatment option include: @ partial nephrectomy (67%). @ radical nephrectomy (19%). @ percutaneous ablation (12%).
Outcome of RCC treatment after radical resection is comparable to the general population, with 5- years disease-specific and overall patient survival rate of 68% -97% and 69% – 88% respectively.
Negative prognostic factors; @ Symptoms at duagnosis. @ Higher Fuhrman grade >2 @ abscence of transplantation. @ Advance stage disease.
Management should be individualized.
Skin Cancer:
Most common cancers in kidney recipients.
More agressive than skin camcer in general population.
Most common types: include; ((I)) SCC. ((II)) BCC. ((III))Kaposi sarcoma. ((IV))Malignant Malinoma.
This study focuses on the development and treatment of cancer in kidney transplant patients. Kidney transplant recipients are at a higher risk to cancer in comparison with the general population. The risk can be as high as three fold. The cancers are usually viral and immune related. Malignancies such as melanoma, renal cell carcinoma, and PTLD have bad outcome in comparison with other malignancies.
The exact reason for high risk of kidney transplant recipients is unknown, although this may be in part to the cell biology changes due to long term immunosuppression and associated comorbidities.
Risk factors for cancer development form a long list, including increasing age, male sex, smoking, prolonged sun exposure, immunosuppressive therapy, acute rejection episodes, status of sensitization, duration of dialysis prior to transplantation. Tumor surveillance that has been impaired and impaired immunity to viral or other tumor antigens is a baseline reason for cancer development in recipients. Cause of death, however, may not be due to cancer incidence or recurrence alone.
Another mechanism for cancer development in these patients is accumulation of mutations. These mutations, in normal healthy individuals, would be recognized by the immune system and repaired. Specifically, this can be applied to skin cancers, where immunosuppression can lead to a decrease of xeroderma pigmentosum complementation groups A and G, which are components of nucleotide excision repair.
Other cancers such as hepatocellular cancers may be contributed to b immunosuppressive drugs like Tacrolimus that increase the level of TGF beta, which in turn promotes tumor progression and metastasis. CNIs can activate p53, promoting cancer.
PTLD associated with EBV can occur within the first 10 years following kidney transplant. However, the incidence of this malignancy has been decreasing in the recent years partly due to better screening for pre transplant EBV and prompt treatment. The risk appears to be higher in the first 12 months post transplant, gradually decreasing after the fifth year mark. Treatment would include reduction of immunosuppression, with the use of rituximab and chemotherapy regimen such as cyclophosphamide, vincristine, prednisone and doxorubicin. Risk of death is high with this malignancy.
Due to the fact that immunosuppression is a major cause for the incidence of cancer in these patients, reduction of immunosuppression or even cessation in some cases is practiced. Primary prevention and screening programs for risk may be helpful in the long term outcomes of these patients. Collaboration between the health care team, policy makers, trialists, and patients is required to identify proper practice for long term care of renal transplant recipients.
Level of evidence
This article is a narrative review, and hence the level of evidence would be 5.
3. De Novo Malignancies after Kidney Transplantation
· Summarise the article
Introduction
Kidney transplantation not only improves the patient’s quality of life and overall survival, but is also cost effective. To maintain optimal graft function, patients require long-term immunosuppression which unfortunately, is associated with an increased risk of malignancies. Cancer is the second leading cause of mortality among transplant recipients, with cardiovascular disease taking the lead. Cancer prevention, screening and treatment strategies are key areas that ought to be addressed.
Incidence of cancer after kidney transplantation
The overall cancer risk in kidney transplant recipients is two to three times greater than that of the general population. The risk s greatest in viral-related and immune-driven cancers like PTLD, KS and anogenital cancer. Solid organ cancers like prostate and breast cancers are not increased in transplant recipients. The risk of cancer-related mortality is 1.8 -1.9 times higher compared to that in the general population. The greatest risk is among kidney transplant recipients with melanoma, NHL and urogenital cancers.
Common risk factors for cancer development include: – increasing age, male sex, smoking, prolonged sun exposure, immunosuppression use, acute rejection, sensitization status, hemodialysis vintage, CKD, pretransplant malignancy, dietary supplements e.g. aristolochic acid, HBV infection.
Impaired tumor surveillance, impaired immunity to viral or other tumor antigens, loss of control of oncogenic viral replication also contribute to the increased risk of cancer in kidney transplant recipients.
Mechanisms of cancer development after kidney transplantation
-Poor immune control of oncogenic viruses in patients on immunosuppressive therapy e.g., KS and HHV8, PTLD and EBV, lip and anal cancers and HPV
-Accumulation of mutations that would normally be repaired or recognized by an intact immune system e.g., in skin cancer where the cells’ ability to repair UV radiation-induced DNA damage is impaired by the immunosuppressive therapy
-Immunosuppressive drugs: –
*Tacrolimus – promotes tumor progression and metastasis by increasing TGF-ß levels
CNIs – inhibit signaling and activate p53 a hallmark in some NMSCs
*Cyclosporine – causes overexpression of TGF-ß and IL-6 pathways leading to tumor development and progression; it also inhibits DNA repair hence accumulating mutations and affecting apoptosis
*Azathioprine – sensitises the skin to UVA radiation leading to an increased risk of NMSCs
*Induction therapy e.g., ATG, anti-CD52, muromonab increase the risk of PTLD and melanoma – this could be related to T-cell depletion with incomplete T-cell recovery resulting in a dysregulated immune system and subsequent cancer development
*mTORi – have antitumor effects i.e., they inhibit cancer growth through cell-cycle arrest and inducing apoptosis
Common cancers after kidney transplantation
Renal cell carcinoma (RCC), skin cancer and PTLD are the three most common cancers.
*The risk of RCC is up to 7-fold in kidney transplant recipients compared to the general population. 90% of RCC develop in the native kidney as opposed to the graft kidney. Risk factors for RCC include: – male sex, increasing age, African descent, long hemodialysis vintage, ESKD secondary to glomerular disease, hypertensive nephrosclerosis, vascular disease. Patients with ESKD secondary to diabetes or ADPKD have a lower risk of RCC.
*Skin cancer is the commonest malignancy in kidney transplant recipients and is more aggressive than in the general population. Cutaneous SCC, BCC, KS and malignant melanoma are the most commonly reported skin cancers.
Risk factors include: – advancing age, male sex, race, UV radiation, HPV, pretransplant skin cancer, immunosuppressive therapy (mainly cyclosporine, azathioprine), ethnicity. The risk of SCC in kidney transplant recipients is 250 times greater that of the general population.
Treatment options include topical fluorouracil, imiquimod cream, photodynamic therapy, surgical excision, electrodesiccation and curettage, radiation therapy. CNIs increase the risk for KS and the cornerstone of treatment is decreasing the intensity of immunosuppression or switching to an mTORi. Kidney transplant recipients have a 5 – 8-fold increased risk of developing malignant melanoma, and have poorer outcomes compared to the general population.
Malignant melanoma has the highest mortality among all skin cancers. Risk factors for post-transplant melanoma include pretransplant melanoma, older age, white race. Management entails surgical excision and individualized adjustment of immunosuppression.
*PTLD is rare but is associated with poor outcomes and high mortality. It is commonly associated with EBV with most people acquiring the virus in childhood which is then reactivated in states of immunosuppression. Risk factors for PTLD include younger age at transplantation, male sex, ATG, muromonab-CD3, high dose tacrolimus, EBV D+ and EBV R- status, belatacept. Treatment entails immunosuppression reduction with an aim of curing the disease. Rituximab and chemotherapeutic agents have also been used i.e., doxorubicin, cyclophosphamide, vincristine, prednisone) with improved overall survival.
Cancer screening strategies in transplant recipients
Cancer screening reduces cancer-related mortality. Routine screening for breast, cervical, prostate and colorectal cancer is recommended. Skin checks, abdominal ultrasounds to detect occult malignancies in those at risk e.g., patients with underlying liver disease, chronic HBV infections, increased risk of RCC.
Incidence of HPV-related anogenital cancer is 10 – 15-fold greater in kidney transplant recipients than that in the general population. HPV vaccines are highly effective in the prevention of cervical intraepithelial neoplasia. HPV vaccination may be more efficacious before transplantation.
Management of cancer in kidney transplant recipients
Multidisciplinary approach
Optimization of immunosuppression – reduce risk of rejection and induce tumor regression
Conversion to mTORi – in patients with KS and SCC
Immunotherapy using immune-checkpoint inhibitors – their use in kidney transplant recipients is limited due to the risk of rejection with nonspecific immune-system activation.
Putting patients’ perspectives at the heart of cancer management
Understand the patient’s personal experiences – helps improve patient care
A multidisciplinary and integrated approach in patient management – to address the medical, psychosocial, functional and nutritional issues experienced by patients
Individualized strategies to prevent rejection from underimmunosuppression and development of cancer from overimmunosuppression
Conclusion
Cancer is the second leading cause of morbidity and mortality among kidney transplant recipients. Balancing between managing the malignancy while optimizing graft function with immunosuppression is quite challenging. The extent to which immunosuppressive therapy should be reduced to remains unknown. Cancer prevention and screening strategies are extrapolated from the general population hence may not be applicable in the transplant recipients. There is need to generate quality evidence to support the long-term care of transplant recipients.
· Level of evidence provided by this article
Level V – narrative review
Kidney transplant, although improves quality of life and survival of ESRD patients, is associated with 2-3 times increased risk of cancer which is the second most common of death in transplant recipients. Cumulative incidence of cancer at 15 years post-transplant is 10-15% with >60% incidence of skin cancer in Europe, Australia, and New Zealand. Cancer risk in kidney transplant is highest for Kaposi sarcoma, anogenital cancer and post-transplant lymphoproliferative disease (PTLD). Risk of mortality post-cancer development is 1.8-1.9 times general population, with maximum risk in melanoma (5-10 times), urogenital cancers and non-Hodgkin’s lymphoma (NHL).
Risk factors for cancer development include increased age, male gender, smoking, prolonged sun exposure, T cell depleting agent use, acute rejection, sensitization, and increased dialysis vintage. Cancers commonly seen in Europe, North America, Australia and New Zealand include non-melanoma skin cancers (NMSC), PTLD, and lip cancer while renal cell carcinoma, urothelial transitional cell carcinoma, and gastrointestinal carcinoma is more common in Asian and middle eastern populations. For cancers associated with kidney disease and kidney failure, the SIR for kidney and bladder cancer are very high (44 and 43).
Mechanisms for cancer development after transplantation is mainly related to immunosuppressive state and include:
a) Poor immune control of oncogenic viruses like Human herpes virus-8 (causing Kaposi sarcoma), Ebstein Barr virus – EBV (causing PTLD), Human Papilloma virus – HPV (causing lip and anal cancers).
b) Accumulation of mutations (in skin cancers).
c) Calcineurin inhibitors inhibit calcineurin leading to inhibition of p53 causing NMSC.
d) Tacrolimus increases TGF-beta leading to tumor progression and metastasis in hepatocellular carcinoma, renal cell carcinoma, and lung adenocarcinoma.
e) Cyclosporin inhibits DNA repair leading to tumor progression.
f) Azathioprine sensitizes skin to UVA radiation leading to NMSC.
g) Anti-thymocyte globulin increases PTLD and melanoma.
mTOR inhibitors, on the contrary, have shown antitumor properties by causing cell-cycle arrest and apoptosis.
Common cancers post-transplant include renal cell carcinoma (RCC), skin cancer and PTLD.
a) RCC: 7 times increased risk, with mostly early, low-grade, and small sized masses. Risk factors include male gender, increased age, African ethnicity, increased dialysis vintage, more with glomerular disease, vascular disease, and hypertension with lower risk with diabetic nephropathy and ADPKD. Outcomes post-treatment are comparable to general population. RCC in the graft are rare (0.1%).
b) Skin cancer: Most common cancer in renal transplant recipients. More aggressive than in general population, with risk increased by 250 times for squamous cell carcinoma, 100 times for Kaposi sarcoma, and 5-8 times for melanoma. Risk factors include UV exposure, HPV infection, pre-transplant skin cancer, older age, male gender, and race. Management depends on the diagnosis ranging from topical fluorouracil, imiquimod cream, photodynamic therapy, surgical excision, to chemoprophylaxis with retinoids and nicotinamide in aggressive, multiple or early onset cancers.
c) PTLD: Rare (1-2% in adults and 3% in children in first 10 years post-transplant), but associated with poor outcomes, with death rates 14 times more than non-PTLD kidney transplant recipients. Associated with EBV in 90% cases. 95% are B-cell type lymphoma. Risk factors for adults include pre-transplant EBV seronegativity and primary EBV infection. Risk factors for children include young age, male gender, donor EBV seropositivity with recipient seronegativity, T cell depleting agent use, Belatacept use, and high tacrolimus dose. Treatment involves reduction in immunosuppression and chemotherapy. Risk for death include male gender, increased age at diagnosis, and bone marrow, RES site more than extranodal and nodal disease, with median time to death being 6 months.
Cancer screening recommendations in transplant recipients are not based on any trial based evidence, but are extrapolated mainly from general population (breast, colorectal, and cervical cancer). Routine skin check for patients with high-risk for skin cancer, regular abdominal ultrasound for patients with liver disease and chronic HBV infection, and regular ultrasound for RCC detection in high-risk patients are recommended.
HPV vaccination has 99-100% efficacy to prevent cervical intraepithelial neoplasm, is safe and generally recommended in women prior to transplant.
Management of transplant recipients developing cancer involve a multidisciplinary approach and includes reduction or alteration in immunosuppression as well as use of immunotherapy (immune checkpoint inhibitors). For early to moderate stage malignancy, judicious immunosuppression reduction is an early step. For squamous cell carcinoma, conversion to mTOR inhibitor is associated with reduced risk of cancer in long-term although with increased risk of death. There is insufficient data to consider mTOR inhibitors as protective except for squamous cell cancer and Kaposi sarcoma. Data for use of immune checkpoint inhibitors in transplant recipients is also limited, hence not recommended.
To summarize, a personalized approach is required for prevention, early detection, and treatment of cancer in transplant recipients. It is important to have a multidisciplinary approach while managing such patients. A balancing act is required while reducing immunosuppression, to prevent episodes of rejection and poor graft outcomes.
2. What is the level of evidence provided by this article
summary:
The second most common cause of death after RT after cardiovascular disease. Incidence:
– The cumulative incidence of solid organ cancer ranges between 10% and 15% at around 15 years after transplantation.
– For skin cancers, the cumulative incidence reaches .60% in Europe, Australia, and New Zealand.
– In RT: the risk is 2-3 folds as general population (SIR:2-3)
Cancer-mortality:
– The standard mortality ratios for all cancer types are at least 1.8–1.9 times higher compared with matched general population.
– For melanoma, urogenital cancers, and non-Hodgkin lymphoma, the overall risk of cancer-related death exceeding 5-10 times that of those without kidney transplants.
– The exact reasons for the higher risk of death are unclear, but may be due to:
a- Potential differences in the cancer cell biology in recipients of transplants resulting from long-term immunosuppression.
b- Associated comorbidities.
c- Low uptake of recommended prevention and screening strategies.
Risk factors:
– Increased age.
– Male sex.
– Smoking
– Prolonged sun exposure
– T- cell depleting immunosuppression agent
– Acute rejection, sensitization.
– Prolonged dialysis duration
– Previous treated malignancy. In Europe, Australia, and New Zealand, the most common cancers are NMSC, PTLD and lip cancer. Where in Asia and Middle East, genitourinary and gastrointestinal cancers are more common. In Tiwan, liver cancer is the most common because of the endemic HBV. -Genitourinary cancers are more common among women. Mechanisms of cancer development in transplant patient:
Potential mechanisms are:
1- Poor immune control of known oncogenic viruses in patients on immunosuppression. For example, increases in viral-associated cancers, such as Kaposi sarcoma (human herpesvirus 8), PTLD (Epstein– Barr virus [EBV]), and lip and anal cancers (HPV)
2- Accumulation of mutations that would otherwise be repaired or recognized by the immune system. This mechanism may be predominant in skin cancers, where immunosuppression impairs the cells’ ability to repair ultraviolet (UV) radiation–induced DNA damage. 3- Immunosuppression type:
Currently, there is no conclusive evidence to suggest one type of immunosuppression is more oncogenic than others a- CNI:
– Inhibit signaling via calcineurin and NF of activated T cells, which can activate p53, a hallmark of some NMSCs.
– Over expression of TGF-b or IL-6 — tumour progression.
– Cyclosporine inhibit DNA repair and accumulate mutations.
– Tacrolimus increases the level of TGF-b and thereby promotes tumor progression and metastasis. (experimental studies) b- Azathioprine:
Sensitizes the skin to UVA radiation and causes the accumulation of 6-thioguanine in the DNA, leading to a higher risk of NMSCs. c- M-TOR inhibitors:
Have potential antitumor effects by inhibiting cancer growth through cell-cycle arrest and initiation of apoptosis.
d- T-cell depleting agents, anti-CD52 and muromonab-CD3:
Increase the risk of PTLD and melanoma.
Cancer screening strategy:
– There is no absolute recommended guideline for cancer screening among RT.
– Screening decisions must be made with clear considerations of patients’ preferences and values, incorporating the potential harms and benefits of the various options
– Recommendations for cancer screening: Cancer Recommendations Skin
Monthly self-skin examination and 6- to 12-monthly total body skin
examination by expert physicians and dermatologists RCC
Routine screening by US is not recommended
for all recipients of transplants, except for high-risk individuals PTLD
Screening for high risk for EBV (negative serology and positive donor):
for EBV by NAT. Once in the first week after
transplantation, monthly for the 3–6 months, and every 3 months until the end of the first post-transplant year
Liver cancer
Us and α-fetoprotein / 6 months for those with cirrhosis Breast
For women aged 50–74 years, screening mammography once every
2 years. For women ,50, the decision to start regular screening
should be an individual one Prostate
As non-RT Cervical
Annual Pap testing or HPV testing every 3–5 years starting at the age of
25 years until 74 years Bowel
For adults aged 45–75 years, fecal immunochemical testing biennially,
sigmoidoscopy every 5 years, or colonoscopy every 5–10 years Lung
For adults aged 55–79 years, annual low-dose computed tomography
scans for those who have smoked one pack per day for 30 years or
equivalent. Management of RT with cancer: 1- Immunosuppression management:
– Judicious reduction in the overall immunosuppression load for patients with early- to moderate-stage malignancy may be a reasonable first step.
– There are insufficient data to consider mTOR inhibitors as protective against other cancer types apart from squamous cell carcinoma and Kaposi sarcoma
2- Immunotherapy: such as targeting PD-1 andPD-L1
Not recommended till now because of the unexpected risk of rejection.
Cancer is the second leading cause of mortality in most Western countries, making kidney transplantation outcomes critical. Virus- and immune-related malignancies drive the two- to three-fold increase in cancer risk after transplantation. Melanoma, renal cell carcinoma, and post-transplant lymphoproliferative diseases have dismal outcomes after malignancy. Furthermore, this high-risk population lacks adequate screening and treatment methods. This evaluation begins with a patient’s journey through kidney transplantation and cancer education and experience. Cancer prevalence and screening and treatment strategies in kidney transplant recipients are examined. Mortality/incidence
· 10-15% cumulative incidence.
· 15 years post-transplant, Europe, New Zealand, and Australia report over 60% skin cancer. Skin cancer risk is 15 times higher.
· KS and PTLD are common post-transplant viral and immune-driven cancers. Transplantation does not impact breast or prostatic ca.
· NHL, Melanoma, and Urogenital cancer patients have 5-10 times the risk of the overall population’s mortality rate.
Cancer risks factor
· CKD is a risk factor for poor outcomes irrespective of stage. RCC and malignant melanoma predominate in this cohort.
· KTR malignancies are increased by impaired tumor surveillance and immunity to viral or other tumor antigens.
· Pre-transplant cancers increase risk.
· Aristocholic acid diets in Asia and the Middle East enhance urothelial cancer risk.
· Chronic Hep B increases liver cancer risk in Taiwan.
· Gender: Bladder and kidney cancer are more common in women. Mechanisms of cancer development
· Immunosuppression impairs immunological regulation of oncogenic viruses, increasing Kapoci Sarcoma and PTLD
· Immunosuppression increases DNA damaging mutations and skin Ca risk.
· Tacrolimus enhances TGF beta in HCC, lung, and renal ca, increasing tumor growth and metastasis. CNI suppress T cell calcineurin and NF activation, activating P53 and raising NMSC risk.
· AZA increases UVA sensitivity and NMSC risk.
· Cell cycle stoppage by -MTOR inhibitors suppresses cancer growth.
· After induction, T cell-deleting drugs degrade immune function and increase cancer risk.
Common malignancies post-transplant
RCC
· 90% of kidney diseases occur in the native kidney, not the allograft.
· Sevenfold higher incidence than the overall population.
· Risk factors; male gender, age > 60, African ancestry, duration of HD > 3 years, kidney failure from glomerulonephritis, hypertensive nephrosclerosis, and vascular disease.
· DM and ADPKD are associated with a lower incidence of RCC following transplant.
· Its 5-year prognosis following radical therapy is comparable to that of the general population.
· Unfavorable prognosis variables; symptoms at diagnosis, higher fuhrman grade (>2), lack of transplantation, and advanced stage.
· Nephron-sparing surgery is safe and has favorable oncological results.
Skin Cancer
The most often reported skin cancers are cutaneous squamous cell carcinoma, basal cell carcinoma, Kaposi sarcoma, and malignant melanoma, with keratinocyte carcinomas accounting for 90–95% of these cancers.
PTLD
• 90% attributable to the EBV
• Ten years after transplantation, the cumulative incidence is 1-25 in adults and 3% in children. It reaches its peak in the first year following transplantation, and then begins to drop until the fifth year.
• 30 times greater risk among children than among the general population.
• Additional risks include male sex, the use of T-cell-depleting medicines, and the use of Co stimulatory blocking therapies such as Belatacept.
• Reducing the dosage of immunosuppressive drugs is the mainstay of treatment. Positive results for chemotherapy with Rituximab and Others have been documented (doxorubicin, cyclophosphamide, vincristine, and prednisone). Cancer screening strategies
· It is recommended that population-based cancer screening for breast, colorectal, and cervical cancer be linked with the general population’s guidelines.
· High-risk transplant recipients should receive dermatologist skin examinations.
· Those with underlying liver illness and chronic HBV infections must have abdominal ultrasounds and blood a-fetoprotein levels monitored every six months.
· Ultrasonographic screening of the native kidneys (annually or biannually) may be considered to detect concealed cancer.
Management of cancer in kidney transplant recipients
· Optimal care requires a coordinated effort involving transplant experts, oncologists, and allied health providers.
· Minimization of the total IS load.
· Some clinicians may consider progressively discontinuing either or both CNI and antiproliferative drugs and substituting higher-dose steroids.
· Conversion to a mTOR inhibitor may minimize the cancer risk of SCC and Kaposi sarcoma over the long run.
· Immune-checkpoint inhibitors
Introduction:
Kidney transplantation is the best treatment option for end stage renal disease patients, although transplantation is not cure. Patients require life long immunosuppression and the feared complication of long term immunosuppression is cancer.
Incidence:
The cumulative incidence of solid organ cancer is 10- 15% at around 15 years after transplantation.
Cancer mortality:
The risk is greatest with melanoma, urogenital cancers and non- Hodgkin lymphoma and overall risk of cancer related death is 5 to 10 times higher in kidney transplant recipients.
Risk factors:
Increasing age
Male sex
Smoking
Prolong sun exposure
Immunosuppression use
Sensitization status
Duration of dialysis before transplantation
Geographic area
Mechanism of cancer development:
Poor immune control of known oncogenic viruses in patients on immunosuppression.
Accumulation of mutations that would be otherwise repaired by immune system.
Tacrolimus increases the level of TGF-beta and promotes tumour progression and metastasis.
Ciclosporin inhibits DNA repair, thereby accumulates mutation.
Azathioprine sensitizes skin to UVA radiation
Induction therapy with T cell depleting agents increases risk s of cancers , such as PTLD and melanoma.
Cancer screening:
Breast- For women 50-74 years- mammography every 2 years.
Cervical- annual Pap testing or HPV testing every 3-5 years from age 25 – 74 years.
Bowel- For adults 45-75 years, fecal immunochemical testing biennially, sigmoidoscopy every 5 years, colonoscopy every every 5-10 years.
Skin- monthly self skin examination and 6 to 12 monthly total body skin examination by dermatologists.
PTLD- Routine monitoring of patients at high risk for EBV by NAT. Once in first week, monthly for first 3- 6 months, and every 3 months until the end of first post transplant year.
Immunosuppressive management:
Judicious reduction in the overall immunosuppression load for patients with early to moderate stage malignancy may be fiest step.
Immunotherapy
Conclusion:
Primary prevention and screening programme for recipients is very important for malignancy .
That is an excellent summary and very well structured reply. What is the level of evidence of this study? Please use bold or underline for heading or sub-headings.
De Novo Malignancies after Kidney Transplantation. Introduction.
Kidney transplantation is the best choice for ESKD as it improves the quality of life, but the other face of the story is the long term complications of immunosuppression such as malignancies which is considered the second leading cause of death among recipients of transplants in most Western countries. Incidence of All-Cause and Site-Specific Cancer after Transplantation.
The excess overall cancer risk in patients with kidney transplant exceeds that of the general population by approximately two- to three-fold after adjustment for age and sex, with the greatest risk in viral-related and immune driven cancers such as post-transplant lympho-proliferative disease (PTLD), and Kaposi sarcoma. Cancer Mortality in Recipients of Kidney Transplants.
Mortality ratios for all cancer types are at least 1.8–1.9 times higher compared with the age- and sex-matched general population and The risk is greatest with melanoma, urogenital cancers, and non-Hodgkin lymphoma, with mortality rate five to ten times that of those without kidney transplants. Risk Factors for Cancer Development. General factors: increasing age, male sex, smoking, and prolonged sun exposures. Specific factors: immunosuppression use, acute rejection, sensitization status, and duration of dialysis before transplantation. Mechanisms of Cancer Development after Transplantation.
1-Due to immunosuppressive status increases in viral-associated cancers, such as Kaposi sarcoma (human herpesvirus 8), PTLD (Epstein–Barr virus [EBV]), and lip and anal cancers (HPV) are common in patients with suppressed immune systems.
2-Accumulation of mutations that would otherwise be repaired or recognized by the immune system.
3-Each one of immunosuppression medications has special role in cancer development such as Cyclosporine which has direct effects on tumor development and progression, through TGF-b or IL-6 overexpression pathways and on the contrary, (mTOR) inhibitors may have potential antitumor effects by inhibiting cancer growth through cell-cycle arrest and initiation of apoptosis. Common Cancers after Transplantation. Renal Cell Carcinoma. – Recipients of kidney transplants have a higher risk (up to seven-fold) of RRC more than general population which mainly developed in the native kidneys specially with those were longer time on dialysis.
-High risk is mainly associated with ESRD due to glomerular diseases, hypertensive nephrosclerosis, and vascular disease and lower risk with ESRD secondary to diabetes or autosomal dominant polycystic kidney disease.
– Renal cell carcinoma in the kidney allograft is rare with an incidence of 0.1% and the majority of tumors were treated by partial nephrectomy (67%), radical nephrectomy (19%), and percutaneous ablation. Skin Cancer.
Skin cancer is the most common cancer type in recipients of kidney transplants and is more aggressive than skin cancers occurring in the general population and Kaposi sarcoma in recipients of transplants exceeds 100 times that of the general population.
Risk factors are exposure to UV radiation, HPV, pretransplant skin cancer, older age, race, sex and immunosuppressive medications augment the carcinogenic effects.
Many line of treatment such as topical “uorouracil and imiquimod cream, photodynamic therapy, and surgical excision or electro desiccation and curettage.
Decreasing the intensity or switching immunosuppressive agents to an mTOR inhibitor is the cornerstone of treatment. Post-Transplant Lymphoproliferative Disease.
PTLD is associated with EBV, the risk of PTLD being the highest in the 12 months post-transplant, and it then decreases until the fifth year after transplantation and using of costimulatory blockade, such as
belatacept, has also been found to be associated with a higher risk of PTLD.
The mainstay of treatment is immunosuppression reduction with chemotherapy. Cancer Screening Strategies in Transplant Recipients.
For early detection of malignancy which has good prognosis, such as routine skin checks by dermatologists in recipients of transplants who are at high risk, and abdominal ultrasounds and serum a-fetoprotein levels should be checked every 6 months for those with underlying liver disease and chronic HBV infections.
For patients who are at risk of developing renal cell carcinoma (such as those with a history of acquired cystic disease, those with a family history, those who are heavy smokers, and those who use long-term analgesics), ultrasonographic screening (annually or biennially) of the native kidneys may be considered to detect occult malignancy. Management of Recipients of Kidney Transplants Who Have Cancer. –Immunosuppression Management and Treatment in Transplant Recipients with Cancer.
Still we are in need for consensus guidelines to modulate immunosuppression and to tailor reduction of the medications according to the risk of rejection and the only trial-based evidence to suggest conversion to an mTOR inhibitor may reduce the risk of cancer in the longer term specially with SCC. -Immunotherapy.
Checkpoint inhibitors use in the kidney transplant population requires further investigation and cannot be recommended at this time, outside of a study protocol. Conclusion:
Denovo malignancy post kidney transplant is considered a challenge for diagnosis and treatment and reduction of immunosuppression is the cornerstone but on the contract risk of rejections increasing and so a multidisciplinary, integrated approach that involves the transplant and palliative care team is crucial. Level of evidence: V.
Amongst patients with ESRD,RRT is the most preferred compared to dialysis due yo its long term low cost and good outcomes. Immunosuppressive medications to prevent graft rejection increases risk of malignancy and currently rank 2nd after cardiovascular disease as cause of mortality post transplant. Preventive and appropriate follow up strategies after transplantation need to be incorporated in post transplant care plan to improve outcome.
Incidence and Mortality.
-Cumulative incidence is 10-15%.15 yrs post transplant with skin cancer being reported at more than 60 % in Europe, New Zealand and Australia. The risk of skin ca is x15 that in the general population.
-Viral related and immune driven malignancies like KS & PTLD have a high risk of occurrence post transplant. Breast and prostatic ca are not affected by transplantation process.
-Standard mortality rate is x 1.8-1.9 the general population with greatest risk amongst those with NHL, Melanoma and Urogenital cancer that have more than x5-10 risk that in the general population.
Risk factors for cancer.
-CKD irrespective of stage is a risk factor with poor outcomes. RCC and malignant melanoma are most prevalent in this cohort.
-Impaired tumor surveillance and immunity to viral or other tumor antigens in KTR increases risk of malignancies.
-Pre transplant malignancies increase risk compared to those without.
-Diet i.e aristocholic acid in non western Asia and middle east increase the risk of urothelial carcinoma.
-Chronic Hep B has been associated with increased risk of liver ca in Taiwan.
-Gender -Women have a higher risk for bladder and kidney ca compared to men.
Mechanisms of Cancer development.
-Poor immune control of oncogenic viruses from immunosuppression increases the risk of KS,PTLD,EBP lip and anal cancer.
-Immunosuppression leads to accumulation of unrepaired mutations in DNA damage increasing the risk of skin Ca.
-Tacrolimus increases the level of TGF beta in HCC, lung and renal ca promoting tumor progression and metastases. CNI inhibit calcineurin and NF activation of T cells activating P 53 increasing risk of NMSC
-AZA too has been found to increase sensitivity of skin to UVA with an antecedent increased risk of NMSC
-MTOR inhibitors have anti tumor effects by arrest of cell cycle that inhibits cancer growth.
-T cell deleting agents lead to incomplete T cell recovery with impaired immune system and risk of cancer after use in induction.
Common cancers post transplant.
RCC
-Increased x 7 post KTR compared to the general population.90% occur in the native kidney and not the allograft.
-Risk factors ; Male sex,> 60 years of age, African descent, HD more than 3 years, Kidney failure from GN, hypertensive nephrosclerosis and vascular disease.DM and ADPKD have a decreased risk of RCC post transplant.
-It has a comparable 5yr outcome post radical tx with the general population.
-Negative prognostic factors ;Symptoms at diagnosis, higher fuhrman grade(>2),absence of transplantation and advanced stage.
-Nephron sparing surgery is safe with good oncological outcomes.
Skin Cancer.
-Most common and aggressive in KTR compared to the general population.
-Common types ;Cutaneous SCC,BCC,KS and malignant melanoma.
-Risks ; UV radiation exposure, HPV, pre transplant skin cancer, old age, race and M>Cyclosporine increases risk. KS has more than x100 incidence in KTR compared to the general population while SCC has x250 risk in KTR compared to the general population.
-Treatment for SCC depends on stage and involves; Topical 5FU,imiquimod cream, photodynamic curettage, mohs micrographic surgery and radiotherapy fir inoperable cases. Those with multiple lesions are candidates for systemic chemotherapy. Switching CNI to MTOR inhibitors is key in KS treatment. Melanoma has a high mortality amongst skin cancer patients and pre transplant lesions are a risk factor. Surgical excision with wide margins is the primary treatment..
PTLD.
-90% associated with EBV.
-Cumulative incidence 10 year post KTR is 1-25 in adults and 3% in paeds population. It is highest in first 1 yr post transplant and then decreases until the 5th year.
-x30 times risk in pediatric group compared to the general population.
-Other risks ; male sex, use of T cell depleting agents and use of Co stimulatory blockade agents like Belatacept.
-Main stay treatment is immunosuppressive treatment dose reduction. Chemotherapy with Rituximab and Others( doxorubicin, cyclophosphamide, vincristine and prednisone) have been reported to have good outcomes.
Cancer screening strategies.
-Routine breast, colorectal and cervical ca screening in high risk group as per national guidelines should be done post KTR.
-Routine derm review for high risk patients, Abd US and 6 monthly serum AFP in those with underlying liver disease and chronic hep B infection should be considered.
-Those at risk of RCC should have annually or bi annually abd us of native kidney to detect occult malignancies.
-Pts should be educated on malignancies and a shared decision making approach adopted.
HPV vaccine in KTR
-Quadrivalent vaccines (Against types 6,11,16 and 18) and HPV 9 Valent(Additional 5 types ;31,33,45,52 and 58) are effective with an overall efficacy of 99-100% in prevention of CIN in RCTS done.
-More efficacious pre transplant and indicated in both males and females 9-25 years in general population and women up to the age of 45 yrs.
Management of KTR with Cancer.
–MDT;Oncologist,transpalnt proffesionals and allied health workers shuol d all be involved in optimizing immunosuppressive medications appropriately.
-For SCC and KS ,convert to MTOR inhibitors and monitor.
-Future studies are needed on check point inhibitors before adoption into KTR cohort with malignancies.
-An individualized holistic approach to patients is key in managing cancer in the transplant population.
Kidney transplantation is the best renal modality of treatment for patient with end stage kidney disease ,less cost effective and improve quality of life .
Patients require life-long immunosuppression to maintain optimal allograft function. One of the most feared complications associated with immunosuppression after kidney transplantation is cancer
Incidence of All-Cause and Site-Specific Cancer after transplantation:
The higher risk is dependent on cancer types, with the greatest risk in viral-related and immune driven cancers such as:
· Post-transplant lympho proliferative disease (PTLD),
· Canogenital cancer.
· Kaposi sarcoma
Cancer Mortality in Recipients of Kidney Transplants:
The standard mortality ratios for all cancer types are at least 1.8–1.9 times higher
compared with the age- and sex-matched general population.
The risk is greatest among those with melanoma, urogenital cancers, and non-Hodgkin lymphoma, with an overall risk of cancer-related death exceeding five ve
to ten times that of those without kidney transplants
Risk Factors for Cancer Development:
Ø Increasing age.
Ø Male sex.
Ø Smoking,
Ø Prolonged sun exposures
Ø Immunosuppression use (T cell–depleting agents).
Ø Acute rejection .
Ø Sensitization status
Ø Duration of dialysis before transplantation
The speci!c types of cancer that develop after transplantation also vary by geographic areas. Observational and registry data from Europe, North America, Australia, and New Zealand indicate the most common cancer types are nonmelanoma skin cancers (NMSCs), PTLD, and lip cancer
Data from non-Western Asian and Middle Eastern transplant cohorts suggest higher incidences of urothelial transitional cell carcinoma, renal cell carcinoma,
and gastrointestinal cancers in their populations
Mechanisms of Cancer Development after Transplantation:
Oncogenic viruses in patients on immunosuppression. such as
Ø Kaposi sarcoma (human herpesvirus 8)
Ø PTLD (Epstein– Barr virus [EBV]).
Ø Lip and anal cancers (HPV)
Development is through accumulation of mutations that would otherwise be repaired or recognized by the immune system
Tacrolimus increases the level of TGF-b and thereby promotes tumor
progression and metastasis.
Cyclosporine also has direct effects on tumor development and progression, through TGF-b or IL-6 overexpression pathways
The potential oncogenic potential of A zathioprine is well known and well recognized. A zathioprine sensitizes the skin to UVA radiation and
causes the accumulation of 6-thioguanine in the DNA, leading to a higher risk of NMSC
Mammalian target of rapamycin (mTOR) inhibitors have potential antitumor effects by inhibiting cancer growth through cell-cycle arrest and initiation of apoptosis
Common Cancers after Transplantation:
Renal Cell Carcinoma
Skin Cancer
Post-Transplant Lymphoproliferative Disease
Cancer Screening Strategies in Transplant Recipients
Immunosuppression Management and Treatment in Transplant Recipients with Cancer
Management of immunosuppression in recipients of transplants who are living
with cancer is complex and challenging.
mTOR inhibitor may reduce the risk of cancer in the longer term
Introduction:
One of the most feared complications associated with immunosuppression after kidney transplantation is cancer.
After cardiovascular disease, cancer is the second leading cause of death among recipients of transplants in most Western countries.
Incidence of All-Cause and Site-Specific Cancer after Transplantation:
Incidence of solid organ cancer 10% -15%after 15years.
Viral related malignancy is more, PTLA, kS, anogenital cancer, Cancer Mortality in Recipients of Kidney Transplants:
Risk of cancer-related death exceeding five to ten times that of those without kidney transplants. Risk Factors for Cancer Development: Common:
Age, male sex, smoking, and prolonged sun exposures. Specific risk factors:
Immunosuppression.
Acute rejection
Sensitization status
Duration of dialysis before transplantation.
Having CKD.
Previously treated Pretransplant malignancy.
NMSCs, PTLD, and lip cancer, more in Europe and Australia.
Urothelial transitional cell carcinoma, renal cell carcinoma, and gastrointestinal cancers in Middle Eastern transplant. Mechanisms of Cancer Development after Transplantation:
-Dump immune system, expose to viral infection.
-accumulation of mutation.
-TGF-b or IL-6 overexpression.
Accumulation of 6-thioguanine Common Cancers after Transplantation: Renal Cell Carcinoma:
90 percent in native kidney:
Patients transplanted for kidney failure secondary to glomerular diseases hypertensive nephrosclerosis and vascular disease appear to have the greatest associated risk.
In contrast, patients with kidney failure secondary to diabetes autosomal dominant polycystic kidney disease low risk.
Renal cell carcinoma in the kidney allograft is rare, and multicenter data have demonstrated an incidence of 0.1%. Most are low-grade T1 lesions, clear cell carcinomas, or papillary renal cell carcinomas, and occur more commonly in males. The majority of tumors were treated by partial nephrectomy (67%), radical nephrectomy (19%), and percutaneous ablation (12%). Skin Cancer:
The most commonly reported skin cancers cutaneous squamous cell carcinoma, basal cell carcinoma, Kaposi sarcoma, and malignant melanoma, with keratinocyte carcinomas comprising 90%–95% of these skin cancers. Post-Transplant Lymphoproliferative Disease:
PTLD is associated with EBV. EBV is a common virus.
Pretransplant EBV seronegativity and primary EBV infection are important risk factors for early EBV-positive PTLD, particularly in younger recipients of transplants.
, a significant proportion (approximately 40%–50%) of late B-cell PTLDs involves EBV-negative lesions.
The treatment goal of PTLD is to cure the disease, and the mainstay of treatment is immunosuppression reduction. Prior work reported the use of rituximab and chemotherapy (doxorubicin, cyclophosphamide, vincristine, prednisone) have improved overall survival, with 5-year survival at around 60%. Cancer Screening Strategies in Transplant Recipients
Routine population-based cancer screening for breast, colorectal, and cervical cancer is recommended and should be aligned to the guidelines as per the general population.
Skin checks by dermatologists in recipients of transplants who are at high risk
Abdominal ultrasounds and serum a-fetoprotein levels should be checked every 6 months for those with underlying liver disease and chronic HBV infections.
Ultra sonographic screening (annually or biennially) of the native kidneys may be considered to detect occult malignancy.
Transplant population, HPV vaccines are generally safe. However, seropositivity was only detected in approximately 50%–60%.
Management of Recipients of Kidney Transplants Who Have Cancer Immunosuppression Management and Treatment in Transplant Recipients with Cancer:
WIEGHT BENFIT AGAINST RISK IN COLLABERATION WITH ONCOLOGIST.
Judicious reduction in the overall immunosuppression load for patients with early- to moderate-stage malignancy ma
Consider Mtor therapy in patient with SCC. Putting Patients’ Perspectives at the Heart of Cancer Management:
Personized, rather than a one-size-fits-all, approach is most preferred approach.
A multidisciplinary, integrated approach that involves the transplant and palliative care team is crucial. In case of advance malignancy.
That is an excellent summary and very well structured reply. I like your analysis of level of evidence of this study.
I like when you type, ‘Putting Patients’ Perspectives”.
Introduction:
Kidney transplant recipient require life-long IS to maintain optimal allograft function. Cancer is a complication and one of the core clinical outcome associated with IS after kidney transplantation, and considered the second leading cause of death in this population.
Incidence of All-Cause and Site-Specific Cancer after Transplantation
– Kidney transplant recipient has 2-3 times overall cancer risk compared to matched general population.
– The risk is higher in viral-related and immune driven cancers.
Cancer Mortality in Recipients of Kidney Transplants
– The standard mortality ratios for all cancer types are at least 1.8–1.9 times higher than general population.
– The risk is greatest among those with melanoma, urogenital cancers, and non-Hodgkin lymphoma,
– The overall risk of cancer-related death exceeding 5-10 times that of those without kidney transplants.
Risk Factors for Cancer Development Geveral risks:: increasing age, male sex, smoking, and prolonged sun exposures. Factors specific to KTRs: immunosuppression use (T cell–depleting agents), acute rejection, sensitization status, duration of dialysis before transplantation, having CKD, and having pre-transplant malignancy.
-The specific types of cancer that develop after transplantation also vary by geographic areas.
Mechanisms of Cancer Development after Transplantation
– The effects of IS on dampening the immune system
– Oncogenic viruses; Kaposi sarcoma (HHV 8), PTLD (EBV), and lip and anal cancers (HPV).
– Accumulation of mutations; predominant in skin cancer >>UV radiation–induced DNA damage.
– Currently, there is no conclusive evidence to suggest one type of immunosuppression is more oncogenic than others.
· CNI tacrolimus, cyclosporine; may increases the level of TGF-b and thereby promotes tumor progression.
· Azathioprine; DNA damage.
· mTORi ; may have potential antitumor effects.
· T cell–depleting agents; increases the risks of cancers, such as PTLD and melanoma.
Common Cancers after Transplantation Renal Cell Carcinoma
– KTRs have 7 fold higher risk compared to general population.
– Typically detected early, low-grade, small kidney masses, with the risk of metastasis at presentation being <2%.
– 90 % in native kidneys, rare in allograft.
– Risk is higher in: male sex, increasing age, African descent, longer time on dialysis, and primary disease (glomerular diseases hypertensive, nephrosclerosis and vascular disease).
Skin Cancer
-The most common cancer type in KTRs, and is more aggressive than in the general population.
– cSSC, BSC, Kaposi sarcoma, and malignant melanoma, with keratinocyte carcinomas comprising 90%–95% of these
skin cancers.
– The pathogenesis is complex interaction of risk factors.
– IS medications augment the carcinogenic effects (mainly cyclosporine and azathioprine).
– Compared with the general population the risk of squamous cell carcinoma is 250 times higher in KTRs.
– Patients treated with CNI are at particularly high risk for Kaposi sarcoma.
– Decreasing the intensity or switching to an mTOR inhibitor is the cornerstone of treatment.
– Among all skin cancer types, melanoma has the highest mortality.
Post-Transplant Lymphoproliferative Disease
– It is a rare disease, however; it is associated with poor outcomes and higher mortality rate.
– 90% is associated with EBV.
– Most PTLDs are of B-cell types, with 5% of patients having the T-cell type.
– The cumulative incidence of PTLD in the first 10 years post- KTx is around 1%–2% in adult and 3% in pediatric.
– Bimodal distribution in incidence, the highest in the 12 months post-KTx, and it then decreases until the 5th year.
– Risk is higher in : younger age at transplantation, male sex, use of T cell–depleting agents, muromonab-CD3, and high dose tacrolimus, negative recipient EBV serology particularly in younger recipients. (with positive donor EBV serology).
– The mainstay of treatment is IS reduction, chemotherapy and novel immunotherapy.
Cancer Screening Strategies in Transplant Recipients
-Lack of trial-based evidence to support routine screening in this high-risk group.
– A shared decision-making process with patients should be adopted to guide decision.
– Some guidelines also suggest:
· Routine skin checks by dermatologists in recipients.
· Abdominal US and serum AFP every 6 months of the native kidneys to detect occult malignancy RCC, for recipients with liver disease and chronic HBV.
· Routine screening for breast, colorectal, and cervical cancer aligned to the general population guidelines. HVP Vaccination in Recipients of Kidney Transplants.
– The incidence of HPV-related anogenital cancer is 10-15-fold higher than matched general population.
– Vaccine is highly effective with overall efficacy of 99%–100% for the prevention of cervical intraepithelial neoplasia.
– HPV vaccines are generally safe.
– It is recommended after transplantation, it may be more efficacious to vaccinate before transplantation.
Management of Recipients of Kidney Transplants Who Have Cancer.
– A concerted approach between transplant professionals, oncologists, and allied health professionals is therefore needed to ensure optimal care.
– Judicious reduction in the overall IS load.
– Some clinicians may consider stopping either or both CNI and antiproliferative agents gradually and rotate to higher-dose steroids – Conversion to an mTOR inhibitor may reduce the risk of cancer in the longer term for SCC and Kaposi sarcoma.
– Immune-checkpoint inhibitors
o Skin cancer and other malignancies are common post transplantation.
o It is the 2nd cause of death after cardiovascular causes, with about 2 folds increase in mortality then age and sex matched controls.
o Regular screening and counseling of transplant recipients are important steps for early detection and management of cancer. In addition, vaccination against HPV may protect against skin and cervical cancer.
o Non melanoma skin cancer, PTLD, anogenital cancer, and Kaposi sarcoma are among the most common types of cancer in transplant patients that are related to use of over immunosuppression and associated higher risk of viral infections.
o However, breast, lung, colorectal and prostate carcinomas are not increased in renal transplant recipients.
o Risk factors:
§ General as old age, male gender, smoking and sun exposure.
§ Specific to transplant patients: use of immusosuoression, prolonged duration on dialysis, sensitizing events and rejection.
§ Pretransplant malignancies and precancerous lesions.
o Renal cell carcinoma and multiple myeloma are commonly associated in CKD patients.
o Cancer development in transplant patients is multifactorial and usually related to oncogenic viruses, concomitant immunosuppressive medications and lack of natural immunesurvillance for tumor antigens.
o Regional or geographic variation in most common type of cancer may be related to the associated dietary or habitual risk factors in addition to variation in prevalence of certain oncogenic viruses as HBV.
o Oncogenic viruses as (HPV in cancer skin and cervix, HSV 8 in Kaposi sarcoma, EBV in PTLD, HBV and HCV in hepatocellular carcinoma, and may be BKV in bladder carcinoma)
o Use of immunosuppressive drugs increases the risk of cancer, it is related to cumulative effect with DNA damage rather than specific drug. However, azathioprine is well- known drug associated with skin cancer.
o The use of induction therapy as ATG and treatment of repeated rejection episodes are associated with higher risk of cancer.
o In the contrary, the use of mTORi as sirolimus is protective has been associated with decreased incidence of cancer as it induces apoptosis of malignant cells.
Ø Renal cell carcinoma:
o 7 times higher in renal transplant recipients than general population.
o 90 % in native kidney and 10 % in the allograft.
o Usually discovered early and none metastasis (due to frequent imaging), so mostly low grade clear cell or papillary carcinoma.
o Risk factors are older age, male gender, Africans and longer duration on HD before transplantation, glomerular disease and vasculitis as original kidney disease.
o Diabetic nephropathy and ADPCKD have the least incidence of RCC.
o Treatment according to staging and grading including radical or partial nephrectomy (nephron sparing) or percutaneous ablation.
Ø Skin cancer:
o Most common cancer in renal transplant recipients, more aggressive than in general population.
o It includes SCC, BCC, Kaposi sarcoma and malignant melanoma.
o None melanoma skin cancerrepresents 90 % of skin cancer.
o Melanoma is 8 times higher in renal transplant recipients than general population and it carries the worst prognosis among skin cancer (highest mortality).
o Risk factors include: old age, male gender, sun exposure and use of tacrolimus and azathioprine.
o Treatment according to the stage, 5FU and local excision for CIS and surgical excision and systemic chemo and immunotherapy in invasive and metastasizing ones.
o Shift from CNI to mTORi is the corner stone in ttt of Kaposi sarcoma.
o Ttt of malignant melanoma by surgical excision with adequate margine.
Ø PTLD:
o Rare but well recognized in renal transplant recipients and has poor prognosis.
o Related to EBV infection in 90 % of cases.
o 90 % are B cell type.
o Higher mortality (9 folds) especially in those with marrow and reticuloendothelial system involvement and in male gender and older age.
o Risk factors: younger age at time of transplantation, Male gender, pediatric age group, bimodal peaks at 1 then at 5 years post-transplant, use of induction depleting therapy, use of high doses of belatacept (costimulation blockade) and serostatus of EBV (EBV -R, with EBV +ve donor).
o Treatment: reduction of immunosuppression plus chemotherapy as (steroids, cyclophosphamide and vincristine).
o Rituximab is relatively safe and effective especially in EBV +ve cases with normal LDH levels.
Ø Screening for cancer:
o US and AFP for liver cancer.
o US for those with acquired cystic kidney diseases.
o Annual skin examination by expert dermatologist.
Ø Prevention of cancer:
o Screening and early detection of breast, prostate, lung and colorectal cancer as extrapolated from the general population recommendations.
o HPV vaccination better giver prior to transplantation but is also safe after transplantation.
Ø Management of cancer:
o Optimization of IS therapy to prevent both rejection and graft loss and manage cancer is the challenge here.
o Shift from CNI to mTORi in case of SCC and Kaposi sarcoma helps in treatment but unfortunately was associated with risk of mortality and discontinuation due to its complications.
o Use of immune therapy targeting cell apoptosis may be beneficial in melanoma, lung and renal cell carcinoma
o Multidisciplinary team with patient involvement in his plan of therapy are crucial to personalize treatment plan rather than one-size-fits-all strategy.
o In case of advanced malignancy, complete withdrawal of IS seems difficult and it is better to stop CNI and MMF and shift to larger dose of steroids to guard against symptoms of acute rejection or graft rupture.
o Team should include social worker, dietitian, clinical psychologist for better outcomes.
That is an excellent summary and very well structured reply. I like your analysis of level of evidence of this study. You need not to type everything in bold or capitals when you plan to emphasise a point. That amounts to ‘shouting’. Use bold or underline for only for heading or sub-headings.
Please summarise this article: Introduction: Kidney transplantation is the best treatment option for patients with ESRD, it improves quality of life and overall survival, is more cost effective, the patients received a transplant required to be on immunosuppressive mediacations that may lead to cancers. Malignancies considered the second most common cause of death in organ recipients, this mandates preventive policies and cancer-screening stratigies, eg; HPV vaccination for prevention of anorectal/ cervical cancers.
Incidence of All-Cause and Site-Specific Cancer after Transplantation: The cumulative incidence of solid organ cancer is 10 -15% at 15 years post TX. The risk is 2-3 times higher than that of the general population. The higher risk in viral- related and immune-driven cancers, PTLDs, anogenital, and Kaposi sarcoma. Breast and prostate cancers are not increased among transplant recipients.
Cancer Mortality in Recipients of Kidney Transplants: Mortality is 1,5-1,9 folds higher among transplant recipient, when compared to matched age and sex matched general population. The risk is 5 -10times more among viral-related cancers(PTLD, melanoma, anogenital ca…etc) than age and sex related general population.
Risk Factors for Cancer Development: Increasing age, male, smoking and prolonged sun exposure Immunesupressive drugs, sensitization status, and duration of dialysis before transplantation, and CKD, HPV, EBV, HBV …etc. CNI increases the level of TGF-b and thereby promotes tumor progression and metastasis, inhibit signaling via calcineurin and activate p53, a hallmark of some NMSCs. Azathioprine sensitizes the skin to UVA radiation and causes the accumulation of 6-thioguanine in the DNA, leading to a higher risk of NMSCs. m-TOR inhibitors, may have potential antitumor effects by inhibiting cancer growth through cell-cycle arrest and initiation of apoptosis.
Common Cancers after Transplantation: Renal cell carcinoma: (7 folds) Usually early, low-grade, small kidney masses; of which, 75%–80% are renal cell carcinoma, in the native kidenys, with the risk of metastasis at presentation being 2%. Kidney failure secondary to glomerular diseases, hypertensive nephrosclerosis and vascular disease appear to have the greatest risk. The outcome of renal cell carcinomas after radical treatment in the transplant population is comparable with that of the general population. Skin Cancer: (Most common) Cutaneous squamous cell carcinoma, basal cell carcinoma, Kaposi sarcoma, and malignant melanoma, with keratinocyte carcinomas comprising 90%–95% of these skin cancers. UV radiation, HPV, pretransplant skin cancer, older age, race, and male sex are risk factors for skin cancer in transplant recipients. Mohs micrographic surgery, offers the most definitive method of treatment, with cure rates of 95%–100%. Topical fluorouracil and imiquimod cream, photodynamic therapy, are modalities used for treatment. Kaposi sarcoma increased by the use of CNI, this could be overcome by m-TORi use. The prognosis is worse among transplant patients than that for the general age and sex matched population, melanoma has the worst prognosis. Post-Transplant Lymphoproliferative Disease: PTLD is associated with EBV, and pears a poor prognosis;14 % mortality. PTLDs are of B-cell types, with approximately 5% of patients having the T-cell type. Risk factors are: First year post-transplant and 5 years after transplant, Pretransplant EBV seronegativity/ donor positive and primary EBV infection, particularly in younger recipients of transplants. The mainstay of treatment is immunosuppression reduction, Rituximab and chemotherapy. HPV vaccination is the preventive measure recommended.
Management of Recipients of Kidney Transplants Who Have Cancer: – Immunosuppressive drugs reduction, and use of m-TORi. – Surgical treatment when needed. – Patient education, life style preventive measures.
Conclusion: – The study identify patient groups and cancer types, helps in surveillance program, and providing data on counselling pretransplant patients on the risk of malignancy. – All transplant patients should be screened regularly for NMSC, oral and anal cancers, combined with lifestyle changes prevents sun exposure. What is the level of evidence provided by this article? Level of evidence V.
Summary: · Cancer is the second most important cause of death following cardiovascular disease in kidney recipient. And it is 2 to 3 fold higher than that of general population. Commonly, melanoma, urogenital carcinoma and PTLD are seen. · Risk factors include mainly immune related and viral infection. · More importantly, this high-risk group lacks access to efficient screening and treatment approaches. · This review explore the patient’s knowledge, education, and experience of cancer in the context of transplantation · There is currently no evidence to indicate how much immunosuppression a clinician could safely reduce. · The primary prevention and screening programs for transplant recipients are supported by research that is primarily derived from the general population, and the results may not always be appropriate to the transplant population. Level of evidence: level V
That is a succinct summary. I like your analysis of level of evidence of this study. Suggestion: please use bold or underline for sub-headings when you type the main heading ‘Summary’.
cancer is the leading cause of morbidity and mortality in renal transplant patients as it is the 2nd cause of death in most western countries.
unfortunately, there is an increased risk of cancer of 2-3 times in transplant patients as compared to the general population. this increased risk is mainly due to viral and immune-related cancers.
the outcome is generally poor in renal transplant patients with cancers especially those with melanoma, renal cell carcinoma, and post-transplant lymphoproliferative disorders. additionally, there is an overwhelming lifestyle change and complex feelings experienced by those patients.
the priority of optimizing allograft function with adequate immunosuppression is challenged by managing these cancers as the management rests mainly on the reduction or even cessation of some of the immunosuppressive medicines.
effective screening and treatment strategies are limited in this high-risk population.
currently, the evidence to define the safe amount of immunosuppression reduction is unknown. also, the evidence to support 1ry prevention and screening programs in recipients is extrapolated from that related to the general population which may not apply to transplant recipients.
finally collaborative efforts between healthcare professionals, policymakers, and patients are needed to ensure quality evidence in the form of intervention trials and large-care observational studies to support the long-term care of these patients
What is the level of evidence provided by this article?
That is a succinct summary. I like your analysis of level of evidence of this study. Suggestion: please use bold or underline for sub-headings when you type the main heading ‘Summary’.
III. De Novo Malignancies after Kidney Transplantation
==================================================================
summarise this article
Introduction
Cancer should be included as an outcome in all inter- ventional trials of kidney transplantation, according to experts. Kidney transplantation is the most cost-effective treatment strategy for those need-ning KRT, but it is not a cure for disease.
Cancer is the second-leading cause of death among recipients of kidney transplants in most Western countries (5), with higher risks and poorer outcomes.
It is imperative to understand the mechanistic insights into cancer cell development under the influence of immunosuppression, and devise new treatment strategies for transplant recipients.
Incidence of All-Cause and Site-Specific Cancer after Transplantation
Cancer risk in patients with kidney transplants is three-fold higher than that of the general population, according to a study published in the British Journal of Clinical Oncology.
The cumulative incidence of solid organ cancer ranges between 10% and 15% (6,9–11) in recipients.
Old age, male sex, smoking and prolonged sun exposure are some of the factors that predispose men to skin cancer, lip cancer and uretheral transitional cell cancer.
Post transplant specific cancer can vary according geographical area e.g. NMSC, PTLD and lip cancer are common in Europe, Australia, North America and NZ, but less common in non Western Asian and Middle East countries.
Mechanisms of Cancer Development afterTransplantation
The effects of immunosuppression on dampening the immune system may create a variety of pathways for cancer development.
One potential mechanism is through poor immune control of known oncogenic viruses.
Another is through accumulation of mutations that would otherwise be repaired or recognized by the immune system.
The potential oncogenic potential of azathioprine is well known and well recognized.
Cyclosporine has direct effects on tumor development and progression, through TGF- b or IL-6 overexpression pathways.
It can also activate p53, a hallmark of some NMSCs, leading to an increased risk of developing cancer.
Mammalian target of rapamycin (mTOR) may have potential antitumor effects by inhibiting cancer growth through cell-cycle arrest and initiation of apoptosis.
Growth inhibition of tumor cells has been demonstrated in vitro for cells from tumors, such as small lung, sarcoma, neuroblastoma, glioblastoma and pancreatic cancer.
Induction therapy with T cell–depleting agents, such as antithymocyte globulin and anti-CD52, increases the risk of developing cancer .
Cancer Screening Strategies in Transplant Recipients
Cancer screening through early detection reduces cancer-specific mortality in the general population, but some have questioned the benefits of routine screening in transplant patients.
Some guidelines suggest routine skin checks and abdominal ultrasounds for those at high risk of developing renal cell carcinoma.
A shared decision-making process should be adopted to guide screening decisions for patients with kidney disease and transplants.
Screening decisions must be made with clear considerations of patients’ preferences and values, incorporating the potential harms and benefits of the various options.
Recommendations for cancer screening in recipients of kidney transplants
Breast
For women aged 50–74 years, screening mammography once every 2 years.
For women ,50, the decision to start regular screening should be an individual one
Prostate
For men aged 55–69 years, screening decisions should be individualized after a conversation with their clinician about the potential benefits and harms.
For men 70 years, the potential benefits may not outweigh the expected harms, and these men should not be routinely screened for prostate cancer.
Cervical
Annual Pap testing or HPV testing every 3–5 years starting at the age of 25 years until 74 years
Bowel
For adults aged 45–75 years, fecal immunochemical testing biennially, sigmoidoscopy every 5 years, or colonoscopy every 5–10 years .
Lung
For adults aged 55–79 years, annual low-dose computed tomography scans for those who have smoked one pack per day for 30 years or equivalent (two packs per day for 15 years) .
Skin
Monthly self-skin examination and 6- to 12-monthly total body skin examination by expert physicians and dermatologists .
Renal cell
Routine screening for renal cell carcinoma using US is not recommended for all recipients of transplants, except for high-risk individuals.
Liver
Routine screening using US, with and without a-fetoprotein, every 6 months in patients with cirrhosis.
PTLD
Routine monitoring of patients at high risk (donor EBV seropositive recipient seronegative) for EBV by NAT.
Once in the first week after transplantation, monthly for the first 3–6 months, and every 3 months until the end of the first post-transplant year.
The human papillomavirus (HPV) vaccination
Is indicated for protection against HPV-related malignancies in the general population, and it is also efficacious in women up to the age of 45 years.
In the transplant population, HPV vaccination is generally safe, although it may be more efficacious to vaccinate before or after transplantation.
Management of Recipients of Kidney Transplants Who Have Cancer
In the absence of quality evidence, judicious reduction in the immunosuppression load for patients with early- to-moderate-stage malignancy may be a reasonable first step.
A concerted approach between transplant professionals, oncologists, and allied health professionals is there- fore needed to ensure optimal care for our patients.
MTOR-inhibitor use has been shown to be protective against some types of cancer, such as squamous cell carcinoma and Kaposi sarcoma.
Immunotherapy
The use of immune-checkpoint inhibitors targeting the CD28-CD80/86 axis with cytotoxic T-lymphocyte–associated protein-4 Ig has revolutionized the treatment of a variety of malignancies.
However, the use of checkpoint inhibitors is limited in recipients of transplants given the potential for rejection.
Check point inhibitors are effective in treating melanoma, non–small cell lung cancer, and renal cell carcinoma in the general population, but their use in the kidney transplant population requires further investigation.
Putting Patients’ Perspectives at the Heart of Cancer Management
Patients with cancer and transplant may experience multiple symptoms, and the burden of self-management in the context of multiple morbidities is immense.
Understanding patients’ personal experiences in their journey for the fight of cancer is crucial because it will provide important insights to help clinicians deliver relevant and appropriate care.
A multidisciplinary, integrated approach that involves the transplant and palliative care team is crucial.
Conclusion
Cancer is the leading cause of morbidity and mortality in patients with kidney transplants.
The priorities of optimizing allograft function with immunosuppression are often challenged and superseded by having a “cure” for the cancer.
That is an excellent summary and very well structured reply. I like your analysis of level of evidence of this study. Suggestion: please use bold or underline for sub-headings when you describe mechanism of cancer development after transplant.
-It summarized the incidence, Risk factors, mechanism, diagnosis, prevention, and treatment of cancer after renal transplantation.
Introduction,
-Kidney Transplant is the best treatment option for patients with ESRD, but it associated with many complications (due use immunosuppression) as cancer.
-Post transplantation malignancy is considered the second cause of death after cardiac disease, renal transplant recipients have at 2-3-fold increase in the risk of malignancy compared to general population, -So many polices adopted for prevention and screening for early detection of cancer
-Cumulative incidence risk of of solid organ transplant cancer ~10-15% at 15 years post transplant, but the risk of skin cancer can reach 60%.
-The main causes of post-transplant malignancy is viral and immune which play the main mechanism in PTLD, anogenital cancer, and Kaposi sarcoma. On the other hand, the incidence of breast and prostate cancers are not increased in transplantation
-Mortality increased once malignancy develops, overall mortality is near 2 times the mortality in non-transplant patients with the same malignancy, and the most worse outcome occur with malignant melanoma, PTLD and RCC in which mortality increase 5-10 times.
Risk Factors for Cancer Development,
– Age (increasing age) – Gender (male >female) – Race (skin cancer is far more common in white > black especially malignant melanoma) – Smoking – Prolonged Sun exposure due to exposure to UV radiation
–Geographical location : -NMSC, PTLD, and lip cancer are more common in Australia, Europe and North America -Kaposi Sarcoma is more common in Mediterranean, Africa & Europe – RCC & gastrointestinal cancers higher incidence in Korea and Middle East – liver cancer higher incidence in Taiwan due to high prevalence of hepatitis B
-Previously treated pre-transplant malignancy: Pre-transplant malignancy which is common in CKD patients, for example the presence of pre-transplant malignant melanoma is the strongest risk factor for the development of post- transplant melanoma
–Cause of renal failure, as patients who develop ESRD due to glomerular, vascular aetiology or HTN nephro-sclerosis are at risk of RCC, on the other hand DM and ADPKD as a cause of ESRD are associated with lower risk of RCC
–Longer duration of dialysis before transplantation: – Duration of dialysis prior to transplantation is a risk factor for RCC due to the development of acquired renal cysts
– Pretransplant EBV status, patients with seronegative EBV status are at increasing risk of early PTLD especially if the donor is positive, and this may explain the higher risk of PTLD in children compared to adult Higher Sensitization Status Acute Rejection – Immunosuppression duration and intensity including the use of ATG which is affected by sensitization, acute rejection episodes. -Immunosuppression may cause activation of oncogenic viruses like EBV (PTLD), HHV-8(KS), and HPV (lip and anal cancer) -Immunosuppression may cause accumulation of mutations that should be fixed regularly by immune system (impairment of the ability of cells to repair DNA damage induced by UV radiation in skin cancer)
Type of immunosuppression: Long term immunosuppression -CNI increases the level of TGF-b that may increase the probability of tumor progression and metastasis, also CNI may cause impairment of the ability of cells to repair DNA damage induced by UV radiation leading to skin cancer, moreover they activate p53 which is associated with NMSC development -Azathioprine increases the sensitivity of skin to UV radiation and increase accumulation of 6-thioguanine in the DNA leading to increase in te risk of NMSC mainly -Use of T cell–depleting agents: -ATG on short term may impair T cell function on long-term leading to cancer development -OKT3 / Belatacept were found to increase the risk of PTLD -MMF and sirolimus may decrease the risk of malignancies
Mechanisms of Cancer Development after Transplantation,
A- Poor immune control of oncogenic viruses e.g., HHV8 (KS), EBV (PTLD), HPV(Lip Ca), in patients on immunosuppression, From Poor immune surveillance and accumulation of mutations due to long term immunosuppression B- Immunosuppression-related cancer development is through Accumulation of mutation (which can be recognized and repaired by unsuppressed immune system) as skin cancer.
–CNI, azathioprine, T-cell depleted induction therapy are known to increase risk of cancer, while mTOR-I can reduce this risk.
–Renal cell cancer increased 7-fold in transplant recipients, and its outcome after radical treatment is similar to general population.
–Skin cancer is the commonest cancer in transplant recipients and more aggressive than general population.
–PTLD associated with poor prognosis and 90% of cases associated with EBV infection. Incidence in first 10 years 1-2%( highest in first 12 months).
Cancer Screening In Transplant Recipients,
Renal Cancer : only in high-risk patients (acquired cystic kidney disease, heavy smokers, those with family history and those on long term analgesia), US /6 m-year -Breast cancer screened as in general population, For female aged 50-74 years, mammogram/1-2 years -Prostate cancer: For men aged 55–69 years, PSA annually -Cervical carcinoma: annual Pap test or HPV rest every 3-5 years (age 25 -74 years).
–Gi malignancy : For adults aged 45–75 years, faecal immuno-chemical test / f.occult blood/6 months,
– sigmoidoscopy / 5 years, or colonoscopy every 5–10 years. -Lung cancer: For adults aged 55–79 years with (one pack per day for 30 years or 2 packs per day for 15 years), low-dose computed tomography/year -Skin cancer: monthly self examination & 6-12 months total skin examination by dermatologist -Recipients with higher risk of kidney cancer, annual or semi-annual USG screening -Liver cancer: US every 6 months for patients with liver cirrhosis &.Some guidelines also suggest abdominal ultrasounds and serum a-fetoprotein levels should be checked every 6 months for those with underlying liver disease and chronic HBV infections. -PTLD: Only in high-risk patients (donor EBV seropositive/ recipient seronegative), EBV by NAT once in the first week post transplantation / month for the first 3–6 months, and every 3 months until the end of the first post -transplant year -HPV vaccine recommended for all male and female at age 9-25years in the general population for the prevention of HPV-related malignancies, because the incidence of HPV-related anogenital cancer is at least ten- to 15-fold higher in recipients of kidney transplants compared with the age- and sex-matched general population -In the transplant population HPV vaccines are generally safe.
Common cancers after kidney transplantation, Skin cancers: -Most common cancer type in recipients of kidney transplants -More aggressive than general populations -More prevalent in females. -Squamous cell carcinoma risk greater than 250 times general population -Most reported skin cancers(comprising 90-95% cases) Cutaneous squamous cell carcinoma, Basal cell carcinoma, Kaposi sarcoma, Malignant melanoma(highest mortality with 5-to-8-fold higher risk) Keratinocyte carcinomas -Treatment as per biopsy, stage and recurrence
Post-Transplant Lympho-proliferative Disease – Pre transplant EBV seronegative and primary EBV infection are important risk factors for early EBV-positive PTLD – Common with dormant EBV infection of B cells – Cumulative incidence in first 10 years post-transplant Adult recipients:1-2% Paediatric recipients: 3% – Risk of death is 14 times higher than in recipients without PTLD – Greatest risk of death with bone marrow and reticuloendothelial disease followed by extra nodal and nodal disease – Highest risk in EBV seronegative recipient with EBV seropositive donor – Main stay of treatment is immunosuppression reduction
Renal Cancers: – Up to 7-fold higher risk of RCC – 90% develops in native kidneys – Higher risk with Male sex Increasing age African descent Longer time on dialysis Acquired renal cystic disease
–Patients transplanted for kidney failure 2ry to glomerular diseases ,hypertensive nephrosclerosis ,and vascular disease appear to have the greatest associated risk of renal cell carcinomas .Patients with kidney failure secondary to diabetes or autosomal dominant polycystic kidney disease have a lower risk of renal cell carcinomas. – Treatment, outcome and prognosis is like general population
Potential management options for kidney recipients with cancer include
-Multidisciplinary (transplant and palliative care team) involvement(For patients who have progressed to advanced-stage malignancy, complete immunosuppression withdrawal is a difficult decision for both patients and clinicians).
–Modulation or Switching to mTOR inhibitors, For patients with squamous cell carcinoma & Kaposi sarcoma, there is now trial-based evidence to suggest conversion to an mTOR inhibitor may reduce the risk of cancer in the longer term .
–Shift from CNI to sirolimus may be warranted in some cases especially KS, and some cases of SCC , the rule of switching to m TOR is doubtful in other forms of malignancies, and is associated with increase in the risk of rejection and cardiovascular, infection-related deaths (especially pneumonia) and post-transplant DM
-Immunotherapy, CPI are effective in treating melanoma, non small cell lung cancer, and renal cell carcinoma in the general population, their use in the kidney transplant population requires further investigation and cannot be recommended currently, outside of a study protocol. -Patient Shared decision making
– Local treatment .In skin cancer such as topical fluorouracil , imiquimod cream, photodynamic therapy, surgical excision or electrodesiccation and curettage, radiation therapy .Surgical excision of visceral tumour as indicated
– Systemic treatment .Chemoprophylaxis in aggressive SCC or recurrent SCC occurring > 5 times per year, Includes retinoids (acitretin) and nicotinamide. .Chemotherapy in metastatic disease, PTLD (doxorubicin, cyclophosphamide, vincristine, prednisone) .Rituximab in PTLD .Immunotherapy needs further evaluation to assess safety to use in transplant recipients
What is the level of evidence provided by this article?
Level 5(V) => Narrative Review
Expert opinion without explicit critical appraisal, or based on physiology, bench research or “first principles”
Incidence of Solid Organ Cancer after Transplantation;
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The cumulative incidence of solid organ cancer ranges between 10% and 15% (6,9–11) at around 15 years after transplantation.
Cancer Mortality in Recipients of Kidney Transplants;
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The overall risk of cancer-related death exceeding five to ten times that of those without kidney transplants .The risk is greatest among those with melanoma, urogenital cancers, and non-Hodgkin lymphoma.
Risk Factors for Cancer Development;
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Some of these factors, such as increasing age, male sex, smoking, and prolonged sun exposures, are shared by patients in the general population. Other risk factors, including immunosuppression use (T cell–depleting agents), acute rejection , sensitization status , and duration of dialysis before transplantation , are specific to those with kidney disease and transplant populations.
Mechanisms of Cancer Development after Transplantation;
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1-Poor immune control of known oncogenic viruses in patients on immunosuppression.
2- Immunosuppression-related cancer development is through accumulation of mutations that would otherwise be repaired or recognized by the immune system.
Common Cancers after Transplantation;
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1-Renal Cell Carcinoma;
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Compared with the general population, recipients of kidney transplants have a higher risk (up to seven-fold) of renal cell carcinoma . Ninety percent of renal cell carcinomas develop in the native kidneys as opposed to the allograft . are typically early, low-grade, small kidney masses ; of which, 75%–80% are renal cell carcinoma, with the risk of metastasis at presentation being less than 2% .
Risk factors for development of renal cell carcinomas post-transplantation include ;
1-Male sex. 2- Increasing age .3-African descent . 4-Longer time on dialysis .
Patients transplanted for kidney failure secondary to glomerular diseases ,hypertensive nephrosclerosis ,and vascular disease appear to have the greatest associated risk of renal cell carcinomas .Patients with kidney failure secondary to diabetes or autosomal dominant polycystic kidney disease have a lower risk of renal cell carcinomas.
2-Skin Cancer;
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Skin cancer is the most common cancer type in recipients of kidney transplants and is more aggressive than skin cancers occurring in the general population.
The most commonly reported skin cancers in recipients of kidney transplants include cutaneous squamous cell carcinoma, basal cell carcinoma, Kaposi sarcoma, and malignant melanoma, with keratinocyte carcinomas comprising 90%–95% of these
skin cancers .
The pathogenesis of skin carcinoma involves a complex interaction of risk factors, including exposure to UV radiation, HPV, pre transplant skin cancer, older age, race, and sex (males at greater risk than females). Additionally, immunosuppressive medications augment the carcinogenic effects (mainly cyclosporine and azathio- prine) .
Pre transplant EBV seronegativity and primary EBV infection are important risk factors for early EBV-positive PTLD, particularly in younger recipients of transplants, and may explain the higher risk of disease early post-transplant. In contrast, a significant proportion (approximately 40%–50%) of late B-cell PTLDs involves EBV-negative lesions .
Apart from younger age at transplantation, male sex, use of T cell–depleting agents, Ortho Kung T3 (muromonab-CD3), and high dose tacrolimus, negative recipient EBV serology (with positive donor EBV serology) incur a four-fold excess risk of PTLD, after accounting for potential confounding factors .The use of costimulatory blockade, such as belatacept, has also been found to be associated with a higher risk of PTLD, particularly cerebral PTLD in patients who are EBV negative, and when used in higher doses .
The treatment goal of PTLD is to cure the disease, and the mainstay of treatment is immunosuppression reduction. Prior work reported the use of rituximab and chemotherapy (doxorubicin, cyclophosphamide, vincristine, prednisone) have improved overall survival, with 5-year survival at around 60% .
Cancer Screening Strategies in Transplant Recipients;
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1- Routine population-based cancer screening for breast, colorectal, and cervical cancer is recommended and should be aligned to the guidelines as per the general population .
2-Some guidelines suggest routine skin checks by dermatologists in recipients of transplants who are at high risk.
3- Some guidelines also suggest abdominal ultrasounds and serum a-fetoprotein levels should be checked every 6 months for those with underlying liver disease and chronic HBV infections.
4-For patients who are at risk of developing renal cell carcinoma (such as those with a history of acquired cystic disease, those with a family history, those who are heavy smokers, and those who use long-term analgesics), ultrasonographic screening (annually or biennially) of the native kidneys may be considered to detect occult malignancy .
Human Papillomavirus Vaccination in Recipients of Kidney Transplants;
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The incidence of HPV-related anogenital cancer is at least ten- to 15-fold higher in recipients of kidney transplantscompared with the age- and sex-matched general population . HPV vaccination is indicated in both males and females aged 9–25 years in the general population for the prevention of HPV-related malignancies. In the transplant population HPV vaccines are generally safe.
Management of Recipients of Kidney Transplants Who Have Cancer;
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1-Immunosuppression Management and Treatment in Transplant Recipients with Cancer;
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A- Judicious reduction in the overall immunosuppression load for patients with early- to moderate-stage malignancy may be a reasonable first step .
B- For patients with squamous cell carcinoma, there is now trial-based evidence to suggest conversion to an mTOR inhibitor may reduce the risk of cancer in the longer term .
2- Immunotherapy;
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Checkpoint inhibitors are effective in treating melanoma, non–small cell lung cancer, and renal cell carcinoma in the general population, their use in the kidney transplant population requires further investigation and cannot be recommended at this time, outside of a study protocol.
3- Putting Patients’ Perspectives at the Heart of Cancer Management;
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For patients who have progressed to advanced-stage malignancy, complete immunosuppression withdrawal is a difficult decision for both patients and clinicians. Therefore, a multidisciplinary, integrated approach that involves the transplant and palliative care team is crucial. The team should consist of a palliative care physician to assist with the medical aspects of managing the high symptom burden, together with a social worker, dietitian, clinical psychologist, and other allied health workers to address the psychosocial, functional, and nutritional issues experienced by our patients.
What is the level of evidence provided by this article;
Level V
That is an excellent summary and very well structured reply. I like your analysis of level of evidence of this study. Please use bold or underline for heading or sub-headings.
Cancer is the second-leading cause of death after kidney transplantation.
This paper highlights the incidence, mechanism, diagnosis, prevention, and treatment of cancer after renal transplantation.
Incidence of cancer after solid organ transplantation
Overall risk 2 to 3 times higher than age and sex matched general population.
Cumulative incidence of solid organ cancers at 15 years: 10% to 15%.
Greatest risk of virus-related and immune driven cancer such as post-transplant lympho-proliferative disease(PTLD), anogenital, and Kaposi’s sarcoma.
Cancer mortality in kidney transplant recipients:
Mortality of all cancers is 1.8 to 1.9 times higher than age and sex matched population.
Greatest risk of mortality in those with melanoma, urogenital cancers, and non-Hodgkin lymphoma (5 to 10 times higher in those with kidney transplants compared to general population)
Risk factors for cancer development specific to solid organ transplantation include:
Use of T cell–depleting agents
Acute rejection
Higher sensitization status
Longer duration of dialysis before transplantation
Long term immunosuppression
Previously treated pre-transplant malignancy
Geographic variation of cancer after solid organ transplantation:
Europe, North America, Southeast Asia (ANZ): most common cancers are nonmelanoma skin cancers (NMSCs), PTLD, and lip cancer
Non-Western Asian and Middle East: higher incidences of urothelial transitional cell carcinoma, renal cell carcinoma, and gastrointestinal cancers.
Potential mechanisms of cancer post-transplant:
Poor immune surveillance and accumulation of mutations due to long term immunosuppression
Specific risks of immunosuppressive drugs that promote cancer pathways:
Tacrolimus and cyclosporine: TGF-b overexpression
Cyclosporine: inhibiting DNA repair, inducing apoptosis in activated T cells, and inhibiting apoptosis in other cells
Azathioprine: sensitization of skin to UVA radiation, leading to NMSC
Common cancers after kidney transplantation:
Skin cancers:
a. Commonest
b. More aggressive than general populations
c. More prevalent in females.
d. Squamous cell carcinoma risk greater than 250 times general population
e. Most commonly reported skin cancers(comprising 90-95% cases)
cutaneous squamous cell carcinoma,
basal cell carcinoma,
Kaposi sarcoma,
malignant melanoma(highest mortality with 5 to 8 fold higher risk)
keratinocyte carcinomas
f. Treatment as per biopsy, stage and recurrence
Post-Transplant Lymphoproliferative Disease
a. Associated with dormant EBV infection of B cells
b. Cumulative incidence in first 10 years post-transplant
Adult recipients:1-2%
Paediatric recipients: 3%
c. Risk of death is 14 times higher than in recipients without PTLD
d.Greatest risk of death with bone marrow and reticuloendothelial disease followed by extra nodal and nodal disease
e. Highest risk in EBV seronegative recipient with EBV seropositive donor
f. Main stay of treatment is immunosuppression reduction
Renal Cancers:
a. Up to 7 fold higher risk of RCC
b. 90% develops in native kidneys
c. Higher risk with
Male sex
Increasing age
African descent
Longer time on dialysis
Acquired renal cystic disease
d. Treatment, outcome and prognosis is similar to general population
Strategies for cancer screening in transplant recipients:
There is insufficient trial-based evidence to support routine screening for solid organ transplantation.
Routine population-based cancer screening for breast, colorectal, and cervical cancer is recommended.
Some guidelines recommend routine checks of transplant recipients by dermatologists
Recipients with higher risk of kidney cancer, annual or semi-annual USG screening
Potential management options for kidney recipients with cancer include:
Multidisciplinary team involvement
Switching to mTOR inhibitors
Use of immunotherapy
Patient Shared decision making
What is the level of evidence provided by this article?
That is an excellent summary. I like your analysis of level of evidence of this study. Yes, MDT approach and Patient Shared Decision Making to individualise the patient care is needed.
Renal transplantation is the best treatment option for patients with ESRD, but it associated with many complications (due use immunosuppression) as cancer. Post transplant malignancy is the second cause of mortality among trans plant recipients, so many polices adopted for prevention and screening for early detection of cancer.
Cumulative risk of of cancer ~10-15% at 15 years post transplant, but the risk of skin cancer can reach 60% in Europe..
Some malignancies closely related to viral infections as PTLD. anogenital and kaposi cancer.
Mortality risk of all types of cancer after diagnosis ~1.8-1.9 times higher than general population, and the highest risk of mortality occur in melanoma, urogenital cancer and NHL (5-10 times higher than person without transplantation).
Risk factors of malignancy development:
Shared with general population: old age, male sex, smoking and prolonged sun exposure.
Specific to renal disease and transplantation: immunosuppression use, acute rejection, sensitization status, and dialysis vintage.
Post transplant specific cancer can vary according geographical area e.g. NMSC, PTLD and lip cancer are common in Europe, Australia, North America and NZ, while uretheral transitional cell cancer, renal cell cancer & GI cancer are common in non Western Asian and Middle East countries.
Mechanisms of post transplant malignancy:
poor immune control of oncogenic viruses e.g. HHV8 (kaposi sarcoma), EBV (PTLD), HPV(lip cancer).
accumulation of mutation (which can be recognized and repaired by unsuppressed immune system) as skin cancer.
CNI, azathioprine, T-cell depleted induction therapy are known to increase risk of cancer, while mTOR-I can reduce this risk.
Renal cell cancer increased 7 fold in transplant recipients, and its outcome after radical treatment is similar to general population.
Skin cancer is the commonest cancer in transplant recipients and more aggressive than general population.
PTLD associated with poor prognosis and 90% of cases associated with EBV infection.Incidence in first 10 years 1-2%( highest in first 12 months).
Screening recommendations:
Breast and prostate cancer screened as in general population.
Cervical carcinoma: annual Pap test or HPV rest every 3-5 years (age 25-74 years).
Gi malignancy: biannual fecal immunochemical test, or sigmoidoscopy every 5years.
Lung cancer: low dose CT scan at age 55-79 years for smokers.
Skin cancer: monthly self examination & 6-12 months total skin examination by dermatologist
Renal cell cancer screened by US for high risk patients.
Liver cancer: US every 6 months for patients with liver cirrhosis.
PTLD: for high risk patient screening start at first week post transplantation, monthly in first 3-6 months, every 3months in first year post transplant.
HPV vaccine recommended for all male and female at age 9-25years.
Management of post transplant malignancy:
immunosuppression modification: reduce the dose in early and moderate stage of cancer is beneficial, and switch to mTOR-I in skin cancer and kaposi sarcoma.
Immunotherapy: checkpoint inhibitors found to be beneficial in treatment of malignancy in general population but it is not recommended in transplant recipients.
So personalized rather than one size fit all approach is preferred
1- Summary Introduction
Cancer is the worst complication of immunosuppression after renal transplantation ,it is the second cause of death in renal recipients in Western countries.
Therefor prevention is important as HPV vaccine and cancer screening. Cancer incidence post transplant
Cumulative incidence of cancer skin is >60% in Europe , New Zealand and Australia.
Cancer risk is 2-3 times in transplant recipients compared to general population with highest risk with PTLD, anogenital cancer, and Kaposi sarcoma and lowest risk of cancer breast and prostate. Cancer Mortality of Kidney Transplants recipients
Death risk is high after cancer develops which is 1.8-1.9 times in transplant recipients compared to general population with highest risk with melanoma, urogenital cancers, and non-Hodgkin lymphoma.
The high death risk in transplant recipients could be due to altered cancer cell biology with long term immunosuppressive use and low compliance of preventive and screening measures. Cancer risk factors
Include old age, male gender, smoking, and prolonged sun exposures, sensitisation, immunosuppressives used, dialysis duration , CKD ,pretransplant malignancy and acute rejection.
Renal cell carcinoma and multiple myeloma are common in CKD .
NMSCs, PTLD, and lip cancer are more common post transplant cancers in Europe, North America, Australia, and New Zealand.
Urothelial transitional cell carcinoma, renal cell carcinoma ,and gastrointestinal cancers are more common in Asia and Middle East.
A study in Taiwan showed increased risk of liver cancer of 5fold compared with the general population due to being endemic for HBV infection.
Women have more risk of kidney and bladder cancer than men. Cancer mechanism after transplantation
The Immunosuppressive effect on the immune system can open the door for cancer development by many ways as through
· oncogenic viruses as Kaposi sarcoma (human herpesvirus 8), PTLD [EBV], and lip and anal cancers (HPV).
· Mutation accumulation as in skin cancer
· In a study in hepatocellular carcinoma, human lung adenocarcinoma cells, and renal cell carcinoma, Tac increased cancer progression and metastasis ,CNI and Azathioprine promoted NMSC , Cyclosporine as well was implicated in cancer development in different ways
· mTORI has antitumor effect
· PTLD and melanoma risk increases with Induction therapy as T cell depleting agents by impairing immune system. Common cancers after transplantation Renal cell carcinoma
Renal transplant recipients have 7 fold risk of renal cell carcinoma compared to general population but likely most cases are detected early ,90% of cases develop from native kidneys ,rarely develop from graft.
Risk factors involve older age ,male gender , long dialysis duration,Africans ,renal failure caused by glomerular lesions , vascular etiology , hypertensive nephrosclerosis .
Renal cell carcinoma prognosis is comparable in transplant recipients to general population within 5 years . Skin cancer
It is the most common cancer for renal transplant recipients involving squamous cell carcinoma, basal cell carcinoma, Kaposi sarcoma, and malignant melanoma, with keratinocyte carcinomas and has an aggressive behaviour in transplant recipients compared to general population.
Risk factors are exposure to UV radiation, HPV, pretransplant skin cancer, older age, race, and male gender.
Actinic keratoses and squamous cell carcinoma in situ, can be treated with topical fluorouracil and imiquimod cream, photodynamic therapy, and surgical excision or electrodesiccation and curettage.
Mohs micrographic surgery can be a definite treatment for squamous cell carcinoma, primary radiotherapy for inoperable cases ,chemoprophylaxis for aggressive squamous cell carcinoma.
CNI therapy increases the risk of Kaposi sarcoma ,and switching to m TORI is the main therapy .
Melanoma has highest mortality , previous melanoma history ,white race and old age are the risks. PTLD
It is rare disease, caused by EBV infection and it has bad prognosis.
It is mostly Bell type, the highest risk is in the first year post-transplant, and it then risk declines , pediatrics are at higher risk
Risk factors include pediatric transplantation, male , T
cell–depleting agents, Tac high dose, co use of belatacept ,seronegative EBV recipient.
Treatment includes reduction of immunosuppression and rituximab and chemotherapy. Screening of cancer in transplant recipients
Early screening can decrease mortality, routine cancer screening was queationable in kidney disease cases.
Meanwhile breast, colorectal, and cervical cancer screening is recommended as in general population.
As well as routine skin screening for high risk patients and abdominal US , alpha fetoprotein/6 months for CLD cases and renal cell carcinoma screening for high risk cases. HPV vaccine for renal transplant recipients
Quadrivalent vaccines and the HPV 9-valent vaccines are efficient in preventing CIN Management of cancer in renal transplant recipients Immunosuppressive therapy
Multidisciplinary team to decide for decreasing immunosuppression risking the graft versus cancer severity.
Shifting to m TORI reduces can risk for squamous cell carcinoma and Kaposi sarcoma meanwhile mTORI can increase death risk. Immunotherapy
Inhibitors targeting the programmed death-1/programmed death ligand-1 interaction and/or the CD28-CD80/86 axis with cytotoxic T lymphocyte–associated protein-4 Ig stimulates immune system against cancer.
It is efficient in treatment of melanoma, non–small cell lung cancer, and renal cell carcinoma in the general population, but needs further evaluation in renal transplant recipients Cancer management and perspective of the patient
A multidisciplinary management including the transplant and palliative care team is mandatory to individualize policy and balance rejection risk versus cancer risk. Conclusion
Maximizing allograft function with immunosuppression is challenging and added cancer renders it more difficult .
More research is needed in transplant recipients as prevention and screening protocol for cancer are taken from general population recommendations which may not suite transplant recipients.
That is an excellent summary. I like your analysis of level of evidence of this study. Yes, MDT approach to individualise the immunosuppresion is needed.
Narrative review study (Level of Evidence 5) on neoplasms in patients after kidney transplantation.
After cardiovascular disease, neoplasms are the leading cause of death and graft loss in most Western countries. Risk factors for this worse outcome are the absence of preventive policies, lack of vaccinations against HPV, lack of protocols for screening strategies for neoplasms for early diagnosis and to prevent the disease from spreading.
Although breast and prostate cancer does not have important statistical data in this population, oncogenic viruses such as HPV, EBV, BKV, HV8, HBV, and HCV increase the risk of neoplasia after transplantation. Another theory is that the use of specific immunosuppressants may increase the risk of neoplasia. Non-melanoma skin cancer should be actively evaluated by both the patient and the care team. Risk factors such as age, gender, smoking history, prolonged sun exposure, use of calcineurin inhibitors, acute rejection, previous sensitivity and time on dialysis should be evaluated and their risks calculated to be discussed with the patient. Another risk factor to consider is pre-transplant cancer.
Immunosuppression may favor the reactivation of oncogenic viruses or cause accumulated lesions due to DNA mutation, the latter favoring non-melanoma skin neoplasms. Calcineurin inhibitors act on immune axes that increase the production of tumor necrosis factors, facilitating growth and metastases. Azathioprim increases the risk for DNA damage and mutations. There are no data on anti-lymphocyte drugs such as Muronomab, thymoglobulin and alemtuzumab, but mTor-inhibiting medications may have an antineoplastic effect and interfere favorably to prevent or even reverse these neoplasms.
Most common cancers
1. Renal cell carcinoma
Risk seven times higher when compared to the general population, male, age over 60 HR 6.59; African descent HR 1.5; prolonged dialysis time longer than 3 years HR 2.23. Renal-based disease is also a risk factor: glomerular disease HR 1.24; hypertensive nephrosclerosis HR 1.55 and vascular disease HR 1.53; or protective: diabetes mellitus HR 0.77; polycystic kidney disease HR 0.81.
2. Non-melanoma skin cancer
Undoubtedly the most common, being more closely related to squamous cell carcinoma. Treatments with local chemotherapy (5 fluororacil or imiquimod), phototherapy, retinoic acid, nicotinamide or surgical excision. Systemic chemotherapy or immunotherapy is performed when there is associated systemic disease. The adjustment of immunosuppressants must be individualized depending on the risk factors and the cancer involved.
3. PTLD
Negative pre-transplant serology or acute post-transplant infection are the main risk factors. Early age, used immunosuppression, anti-lymphocyte induction are additional risk factors. Most of the time, the disease is caused by Bm lymphocytes, which is why rituximab (anti-CD20) is the drug of choice to control the disease.
Screening for these neoplasms in this patient profile is debatable due to the lack of specific clinical protocols for transplanted patients or those using immunosuppressive medications. The decision ends up being together with the patient assessing their risk factors and environmental exposure. Undoubtedly, HPV vaccination is highly recommended and should preferably be given before transplantation. Care to prevent sun exposure is also crucial. Immunotherapy is questionable and further studies are needed to define its role.
That is an excellent summary. I like your analysis of level of evidence of this study. Suggestion: please use bold or underline for sub-headings when you describe differnt cancers under the main heading ‘Most common Cancers’.
-Kidney transplantation increases the quality of life and survival rates for maintenance dialysis patients. It’s also KRT’s most cost-effective therapy.
Allograft function requires lifelong immunosuppression.
-Cancer is a major risk of immunosuppression following kidney donation. Clinicians, patients, and caregivers also consider cancer a primary clinical outcome, and key stakeholders now agree that kidney transplantation interventional studies should include cancer as an outcome.
-At 15 years following transplantation, solid organ cancer incidence is 10% to 15%. Europe, Australia, and New Zealand have 0.60% skin cancer incidence. After age and sex adjustments, kidney transplant patients had a two- to three-fold higher cancer risk than the general population.
-Most Western nations have observed that all cancer mortality rates are at least 1.8–1.9 times higher than the age- and sex-matched general population. Melanoma, urogenital, and non-Hodgkin lymphoma patients had a five to ten-fold higher risk of cancer-related mortality than those without kidney transplants.
-Transplantation raises cancer risk for numerous reasons. These characteristics include age, male sex, smoking, and extended sun exposure.
Immunosuppression (T cell–depleting drugs), acute rejection, sensitization status, and dialysis length before transplantation are renal disease and transplant-specific risk factors.
-Even though long-term immunosuppression is a major cause of cancer after a transplant, there is now strong evidence that CKD, at any stage, is linked to a higher risk of cancer and a worse outcome for cancer patients.
-Induction treatment with T cell–depleting drugs, such as anti-thymocyte globulin and anti-CD52 increases the risk of malignancies such PTLD and melanoma.
-Immunosuppression does not seem to be more oncogenic than others. However, experimental investigations in hepatocellular carcinoma, human lung adenocarcinoma cells, and renal cell carcinoma have indicated that tacrolimus enhances TGF-b and promotes tumor development and metastasis.
-mTOR inhibitors may limit cancer development by arresting cell cycles and initiating apoptosis. Tumor growth has been inhibited.
-Checkpoint inhibitors may cause nonspecific immune-system activation and rejection in transplant patients, limiting their usage.
-A sensible decrease in the total immunosuppressive burden for patients with early- to moderate-stage malignancy may be a good first step. Patients should be informed of the possible side effects, and all measures should be customized to their requirements.
That is an excellent summary and very well structured reply. I like your analysis of level of evidence of this study. Please use bold or underline for heading or sub-headings.
The aim of this review article is to address the incidence, prevalence, screening, diagnosis, and treatment of post-transplant malignancy Introduction
Kidney transplantation remained the best option for patients with ESKD it’s associated with better quality of life and survival however still patient need Long-life immunosuppression therapy with increased risks of malignancies, post-transplantation cancer is the second leading cause of death following CVD, and the prevalence 2-3times higher than the general population and some viral and immunological risk like PTLD and EBV infection, PV8 and Kaposi sarcoma
The mortality increased by 1.8-1.9 times in the transplant population compared to the age and sex-matched general population, especially for melanoma skin cancers, PTLD (NK Large cell lymphoma ) , RCC, anogenital tumors risk of death is even higher 5-10times those without transplantation
Solid organ cancers like breast and prostate are similar to the general population Factors that increased the risk of tumors after transplantation include
Old age, Sex more in males, smoking history, and prolonged sun exposure is considered shared risk factors to the general population but in kidney transplant patient there are additional specific risk factors including the duration of CKD and dialysis, immunosuppression type like t cell depleting agents, history of sensitization, the acute rejection rate. As per data registries there is also geographical variation in the incidence and type of tumors in western &Australis more no-melanoma skin cancers compared to Asian and middle east have a higher rate of urethral and colorectal malignancies, while in endemic areas of chronic HBV infection like Vietnam, they reported a higher incidence of liver cancers The mechanism for cancer after transplantation
1. the effects of immunosuppression drugs on reducing the immune system may generate a diversity of pathways for cancer development via poor immune control of known oncogenic viruses in patients on immunosuppression and associated with an increased rate of viral-associated cancers, such as Kaposi sarcoma (human herpesvirus 8), PTLD (Epstein–Barr virus [EBV]), and lip and anal cancers (HPV) are common in patients with suppressed immune systems.
2. In the case of skin cancer immunosuppression can lead to a decrease of xeroderma pigmentosum complementation groups A and G, which are components of nucleotide excision repair.
3.Type of Immunosuppression therapy, based on limited evidence from few studies supports that CNI, including tacrolimus and Cyclosporin, is associated with a risk of nonmelanoma skin cancers Cyclosporine also has direct effects on tumor development and progression, through TGF-b or IL-6 overexpression pathways
4. Azathioprine sensitizes the skin to UVA radiation and causes the accumulation of 6-thioguanine in the DNA, leading to a higher risk of NMSCs
5. M Tor inhibitors like sirolimus and everolimus have a protective effect by inhibiting the tumor cells’ growth through cell-cycle arrest and initiation of apoptosis.
The most common types of cancers after renal transplantation based on evidence from epidemiology and registry studies include skin cancer like squamous cell carcinoma, basal cell carcinoma, Kaposi sarcoma, and melanoma skin cancer, and usually, aggressive course compared to the general population due to interaction of many risk factors like exposure to UV radiation, HPV, pretransplant skin cancer, older age, race, and sex (males at greater risk than females).
Kaposi sarcoma is rare skin cancer in the general population but kidney transplantation is 100 times high rate due to Cyclosporine use and is more found in central Europe, Africa, and the Mediterranean region, however, the main treatment is stopped cyclosporine and shifted to m TOR inhibitors like everolimus or sirolimus
That is an excellent summary and very well structured reply. I like your analysis of level of evidence of this study. Suggestion: please use bold or underline for sub-headings when you describe mechanism of cancer development after transplant.
Introduction; Cancer is the second cause of death following CVD in kidney recipient. This led to development of preventive strategies such as HPV vaccination and cancer screening strategies for early defection and treatment of cancer.
Incidence; 10 to 15 % for solid organ tumors at 15 years and > 60% for skin cancer. Overall it is 2 to 3 fold higher than the general population. The morality is at least 1.5 greater than the general population. Highest are seen with melanoma,urogenital and PTLD.
Mechanism / risk factors; are immune-suppression, acute rejection, sensitization status, duration of dialysis before transplantation, poor immune-surveillance, viral infections,and pre-transplant malignancy.
Common cancer after Transplantation;
Renal Cell Carcinoma;
-Risk is 7-folds greater than the general population(male,age>60, HD > 3 yrs, GN,HTN)
-Mostly in native kidneys
-Treatments are partial nephrectomy, radical nephrectomy, and per-cutaneous ablation
2.Skin Cancer;
-Most common type of cancer in kidney recipients and with aggressive behavior.
-Risk factors are UV radiation, HPV, pretransplant skin cancer, white race, male
-Squamous cell carcinoma is 250 times higher than the general population
-Melanoma has the greatest mortality
-Treatment options are;FLU, photo-dynamic therapy, surgical excision and curettage
3.PTLD;
-90% of cases are associated with EBV
-Bimodal distribution,the first year of transplantation and then after 5 years
-Risk factors are;young, male,lympho-depletion, Belatacept, EBV -ve,
-Treatment; Reduction of immune-suppression, rituximab, or chemotherapy
Cancer Screening in Recipients; this is a debatable issue but a decision can be made through education and discussions with the patient (= shared decision- making process)
HPV vaccination; the vaccine is more effective when given before transplantation
Management of Cancer in the Recipients;
1.Careful reduction of immune-suppression after discussion with the patient
2.mTORi in cases of squamous cell carcinoma and Kaposi sarcoma
3.Check-point inhibitors; may increase risk of rejection, more evidence is needed
The incidence of de novo malignancy post-transplant is higher than general population because of immunosuppression medications , and the incidence of specific malignancy differ from solid organ to another as documented by British registry in Britain.
In heart, liver and kidney post-transplant, the incidence of overall malignancy with the exclusion of non-melanoma skin cancer NMSC is 2- fold increase than general population (SIR 2.5, 2.2, 2.4) and more than 3-fold increase in lung and combined heart and lung transplant recipient (SIR 3.6).
SIR is standardized incidence ratio, which is the relation between number of observed cases and number of expected cases.
SIR of NMSC post kidney and cardiothoracic transplant is 16, this is 3 fold increase than post liver transplant.
The incidence of cancer may be under-estimated because of removal or ablation of the skin lesions without biopsy and histological examination.
Also the incidence depends on registration which differs from country to country and it is affected by many factors.
Journal 3
Renal transplantation is the best management for end stage renal disease ESRD, and it is cost effective solution than dialysis with its different modalities.
Renal transplantation is not a curative management of ESRD, so, after transplantation there will be risk of side effects and complications related to immunosuppressive medications and state of the patients, as cardiovascular complications are the first leading cause of death in transplant patients, the second cause of death post-transplant is cancer , once developed, leads to very poor outcome.
Counselling of the patient pre-transplant and screening for cancer is very important, also early detection and diagnosis of cancer is necessary for early management and avoid morbidity and mortality, also introduction of human papilloma virus vaccination is very important against cancer cervix.
Risk of cancer in solid organ transplant recipient increased by the time post-transplant, it is 2-3 fold increase in its incidence than general population, it may be immune related or viral related like PTLD, skin cancer, Kaposi sarcoma.
The cause of high mortality of cancer in transplant patients is due to potential differences in the cancer cell biology in recipients of transplants resulting from long-term immunosuppression, associated comorbidities.
Risk factors for increased incidence of cancer post-transplant:
1- increasing age
2- male sex
3- smoking
4- prolonged sun exposures
5- immunosuppression use
6- acute rejection
7- sensitization status
8- duration of dialysis before transplantation
Type of commonest cancer post-transplant depends on geographic area like endemic viral infection in one area …etc.
In Europe, North America, Australia, and New Zealand, there is increased incidence of NMSCs, PTLD, lip cancer.
In non-Western Asian and Middle Eastern, there is increased incidence of urothelial transitional cell carcinoma, renal cell carcinoma, and gastrointestinal cancers.
In Taiwan, there is increased risk of liver cancer five-fold compared with the sex- and age-matched general population, Taiwan is an endemic area for chronic hepatitis B virus.
As regard immunosuppressive medications and its role:
1- Tacrolimus increases the level of TGF-b, which promotes tumor progression and metastasis.
2- Calcineurin inhibitors inhibit signaling via calcineurin and NF of activated T cells, which can activate p53, a hallmark of some NMSCs.
3- Cyclosporine also has direct effects on tumor development and progression, through TGF-b or IL-6 overexpression pathways.
4- Cyclosporine is capable of inhibiting DNA repair, thereby accumulating mutations, inducing apoptosis in activated T cells, and inhibiting apoptosis in other cells by opening the mitochondrial permeability transition pores.
5- Oncogenic potential of azathioprine is well known and well recognized. Azathioprine sensitizes the skin to UVA radiation and causes the accumulation of 6-thioguanine in the DNA, leading to a higher risk of NMSCs.
6- Mammalian target of rapamycin (mTOR) inhibitors, on the contrary, may have potential antitumor effects by inhibiting cancer growth through cell-cycle arrest and initiation of apoptosis.
7- Induction therapy with T cell–depleting agents (including polyclonal agents, such as anti-thymocyte globulin, and monoclonal agents, such as anti-CD52 and, historically, Ortho Kung T3 [muromonab-CD3]) increases the risks of cancers, such as PTLD and melanoma.
RCC renal cell carcinoma:
1- It is 7 fold increased in transplant recipient, may be due to increase frequency of abdominal imaging.
2- It developed in native kidney not in allograft.
3- Male sex, old age, long duration on dialysis
4- Etiology of renal disease; glomerular, vascular, hypertensive nephrosclerosis have increased incidence of RCC than in diabetic etiology or APKD
5- The outcome of renal cell carcinomas after radical treatment in the transplant population is comparable with that of the general population, with 5-year, disease-specific and overall patient survival rates of 68%–97% and 69%–88%, respectively.
6- RCC is rare in allograft and of low grade
Skin cancer:
1- Skin cancer is the most common cancer in renal transplant recipient, may be due to interplay between predisposing factors like exposure to UVA and B with the state of immunosuppression, male sex , old age.
2- It can be cutaneous squamous cell carcinoma, basal cell carcinoma, Kaposi sarcoma, and malignant melanoma, with keratinocyte carcinomas comprising 90%–95% of these skin cancers.
3- Incidence of Kaposi sarcoma in renal allograft recipient is 100 times higher than general population.
4- Risk of squamous cell carcinoma is 250 times more than general population.
5- Kaposi sarcoma is related to use of CNI and regress after shifting to sirolimus
6- Risk of malignant melanoma in renal transplant recipients is 8 times than general population.
7- Melanoma is of high mortality, and pre transplant melanoma, and white race are risk factors for post-transplant melanoma.
PTLD
1- Post-transplant lymphoproliferative disease is rare disease but it is common to occur post renal transplant, it is caused by EBV infection which happens in the childhood or any time with mild to no symptoms , it infects B cells and remains dormant in it in the latent phase, after transplantation as immunity decreased and T cell function decreased and became out of control B cells , this virus will be reactivated and leads to PTLD.
2- Most PTLD are B cell 95%, and 5% are T cell.
3- Pre transplant seronegative and EBV primary infection are important risk factors.
4- High incidence at 1 year then decreased toward fifth year post transplant
5- Compared with adult recipients of transplants, the risk of developing lymphoproliferative disease in pediatric recipients of transplants is at least 30-times higher than the age- and sex-matched general population. Apart from younger age at transplantation, male sex, use of T cell–depleting agents, Ortho Kung T3 (muromonab-CD3), and high dose tacrolimus, negative recipient EBV serology (with positive donor EBV serology) incur a four-fold excess risk of PTLD, after accounting for potential confounding factors . The use of costimulatory blockade, such as belatacept, has also been found to be associated with a higher risk of PTLD, particularly cerebral PTLD in patients who are EBV negative, and when used in higher doses.
6- Management of PTLD is immunosuppression reduction.
7- Once developed, mortality is high.
8- Rituximab can be used in treatment.
Screening of cancer pretransplant with introduction of HPV vaccination is important, also counselling of the patient and relatives especially old age and male sex patients , and considering other risk factors for cancer.
Management of the patient with cancer should be individualized based on the general condition of the patient, staging of the cancer.
So balance between risk of rejection and risk of fulminant metastases should be done and individualized with handling of immunosuppression doses.
That is an excellent summary and very well structured reply. I like your analysis of level of evidence of this study. Please use bold or underline for heading or sub-headings.
Post transplantation malignancy is considered the second cause of death after cardiac disease, renal transplant recipients have at 2-3 fold increase in the risk of malignancy compared to general population, the incidence of solid malignancy and skin cancer is around 10% and 15% and 60% at 15 years after transplantation.
The main cause of post-transplant malignancy is viral and immune which play the main mechanism in PTLD, anogenital cancer, and Kaposi sarcoma. On the other hand, the incidence of breast and prostate cancers are not increased in transplantation
Mortality increased once malignancy develops, overall mortality is near 2 times the mortality in non-transplant patients with the same malignancy, and the most worse outcome occur with malignant melanoma, PTLD and RCC in which mortality increase 5-10 times.
Risk factors for post-transplant malignancy
1- Age (increasing age)
2- Gender (male are affected more)
3– Race (skin cancer is far more common in white than black especially malignant melanoma)
4- Smoking
5- Sun exposure due to exposure to UV radiation
6– Geographical location :
NMSC, PTLD, and lip cancer are more common in austuralia, europe and North America
KS is more common in Mediterranean, Africa, and Central Europe
Korea and middle east have higher incidence of RCC and gastrointestinal cancers,
Taiwan has higher incidence of liver cancer due to high prevalence of hepatitis B
7- Pretransplant malignancy which is common in CKD patients, for example the presence of pretransplant malignant melanoma is the strongest risk factor for the development of post-transplant melanoma
8- The cause of renal failure, as patients who develop ESRD due to glomerular, vascular etiology or HTN nephrosclerosis are at risk of RCC, on the other hand DM and ADPKD as a cause of ESRD are associated with lower risk of RCC
9- Duration of dialysis prior to transplantation is a risk factor for RCC due to the development of acquired renal cysts
10- Pretranplant EBV status, patients with seronegative EBV status are at increasing risk of early PTLD especially if the donor is positive, and this may explain the higher risk of PTLD in children compared to adult
11– Immunosuppression duration and intensity including the use of ATG which is affected by sensitization, acute rejection episodes.
Immunosuppression may cause activation of oncogenic viruses like EBV (PTLD), HHV-8(KS), and HPV (lip and anal cancer)
Immunosuppression may cause accumulation of mutations that should be fixed regularly by immune system (impairment of the ability of cells to repair DNA damage induced by UV radiation in skin cancer)
12- Type of immunosuppression:
CNI increases the level of TGF-b that may increase the probability of tumer progression and metastasis, also CNI may cause impairment of the ability of cells to repair DNA damage induced by UV radiation leading to skin cancer, moreover they activate p53 which is associated with NMSC development
Azathioprine increases the sensitivity of skin to UV radiation and increase accumulation of 6-thioguanine in the DNA leading to increase in te risk of NMSC mainly
Use of short term ATG may impair T cell function on long term leading to cancer development
Use of OKT3 and Belatacept were found to increase the risk of PTLD
MMF and sirolimus may decrease the risk of malignancies
Renal cell carcinoma
Renal transplantation increase the risk of RCC 7 folds
Usually in the native kidney (99%), tumers in the transplant keincy is usually low grade clear cell or papillary carcinoma
RCC is usually detected early due to frequent imaging, with low risk of metastasis < 2%
Treatment is the same as in non transplant patients and includes partial nephrectomy, radical nephrectomy and survilance, with comparable outcome in patients undergoing radical nephrectomy
Skin cancer
Cutaneous malignancy is the most common malignancy encountered in renal transplantation, and are more aggressive and more frequent in renal transplant recipients when compared to general population, for example incidence of KS and SCC is 100 and 250 times more common in transplant recipient compared to general population, respectively. On the other hand, the incidence of malignant melanoma increases 5-8 folds compared to general population.
90% of cutaneous malignancies are due to SCC and BCC, other include melanoma and Kaposi sarcoma
In renal transplantation SCC occur more commonly than BCC (although in general population BCC is more common)
SCC and melanoma have poor prognosis with the highest mortality observed with malignant melanoma
Post-Transplant Lymphoproliferative Disease
Rare, occurring in 1-2% of renal transplant recipients in the first 10 years after transplantation and it is highest in the first year post transplantation the decreasing until fifth year.
Around 90% occur due to activation of EBV viruses acquired in childhood
Around 95% of cases are B cell type, T cell lymphoma accounts for 5%
Overall survival is 65% at 1 year ,and 45% at 10 years.
Time from diagnosis to death is around 6 months
Elderly male are more prone to death from the disease
Positive EBV status and normal LDH levels predict response to treatment
Patient with BM and RES infiltration has the worst prognosis, followed by extranodal then nodal disease
Anogenital cancer
Renal transplant recipients are at 10-15 times increase in the risk of developing anogenital cancer related to HPV
Screening of malignancy after transplantation
Breast cancer: For female aged 50-74 years, mammogram/1-2 years
Prostate cancer: For men aged 55–69 years, PSA annually
Cervical cancer : for female aged 25-74 years, HPV testing /3–5 years, vaccination in male and female aged 9-25 years, can be given in female up to 45 years, better to be given before transplantation
Cancer colon: For adults aged 45–75 years, occult blood/6 months, sigmoidoscopy / 5 years, or colonoscopy every 5–10 years.
Lung cancer : For adults aged 55–79 years with smoke pack history of 30 (one pack per day for 30 years or 2 packs per day for 15 years), low-dose computed tomography/year
Skin cancer : self-skin examination monthly and total skin examination by dermatologist /6-12 months
RCC : only in high risk patients (acquired cystic kidney disease, heavy smokers, those with family history and those on long term analgesia), US /6 m-year
Liver cancer : in patients with liver cirrhosis, US and AFP /6 months
PTLD only in high risk patietns (donor EBV seropositive/ recipient seronegative), EBV by NAT once in the first week posttransplantation, /month for the first 3–6 months, and every 3 months until the end of the first post-transplant year
Management of post tranaplant malignancy (challenging and needs multidisplinary team)
A- Modulation of immunosuppression
Including either reduction of immunosuppression or conversion of CNI to sirolimus
Benefit should be weighed against risk of rejection
Reduction of immunosuppression is indicated in most of the cases of organ malignancy (mild to moderate), in skin cancer reduction of immunosuppression is indicated only in metastatic, aggressive or recurrent skin cancer
In aggressive non skin cancer, complete withdrawal of antimetabolite and/or CNI may be done, keeping high dose steroid to prevent occurrence of symptoms related to acute rejection
Shift from CNI to sirolimus may be warranted in some cases especially KS, and some cases of SCC , the rule of switching to m TOR is doubtful in other forms of malignancies, and is associated with increase in the risk of rejection and cardiovascular, infection-related deaths (especially pneumonia) and post-transplant DM
B- Local treatment
In skin cancer such as topical fluorouracil , imiquimod cream, photodynamic therapy, surgical excision or electrodesiccation and curettage, radiation therapy
Surgical excision of visceral tumor as indicated
C- Systemic treatment
Chemoprophylaxis in aggressive SCC or recurrent SCC occuring > 5 times per year, Includes retinoids (acitretin) and nicotinamide.
Chemotherapy in metastatic disease, PTLD (doxorubicin, cyclophosphamide, vincristine, prednisone)
Rituximab in PTLD
Immunotherapy needs further evaluation to asses safty to use in transplant recipients
Introduction
After cardiovascular disease, cancer is the second leading cause of death among transplant recipients.
To adjust the poorer outcomes of cancer, cancer screening strategies is considered for early detection of cancer
Incidence of all cause and site specific cancer after transplantation
The cumulative incidence of solid organ cancer 15 years after transplantation about 10 to 15%. The cumulative incidence of skin cancer is about 60% exceeds that of the general population by 2 to 3 folds.
According to cancer type, there is a great risk in viral related and immune driven cancers such as PTLD, anogenital cancer and kaposi sarcoma.
Breast and prostate cancers aren’t increased in transplant recipients.
Cancer mortality
Once cancer develops, the risk of death is high.
The standard mortality ratio for all cancer are 1.8 to 1.9 times higher compared with matched population.
The risk is the highest among those with melanoma,urogenital and non-Hodgkin lymphoma.
Risk factors for cancer development
Old age
Male sex
Smoking
Prolonged sun exposure
T cell depleting Immunosuppressive agents.
Acute rejection
Sensitization status
Duration of dialysis before transplantation
Mechanisms of cancer development after transplantation
1. Poor immune control of known oncogenic viruses in patients on immunosuppression as in viral associated cancers.
2. The accumulation of mutations especially in skin cancer
Common cancers after transplantation
1. Renal cell carcinoma up to seven fold compared with the general population.
2. Skin cancer
The most common type in kidney transplant recipients and is more aggressive.
3. Post-transplant lymphoproliferative disease
Management of recipients of kidney transplant who have cancer
Immunosuppression Management and treatment in transplant recipients with cancer
Reduction of immunosuppression should be balanced to prevent the risk of rejection and induce cancer regression.
The using of immune checkpoint inhibitors is limited in transplant patients due to increased risk of rejection.
Level 5
1. Please summarize this article
Introduction
Kidney transplantation is the best treatment option for acceptable candidates with kidney failure because it improves the quality of life and overall survival for patients on maintenance dialysis. It is also the most cost-effective treatment strategy for those needing KRT. However, transplantation is not a cure. Which means that recipient needs to continue on life-long immunosuppression. Cancer is a major complication of immunosuppression in kidney transplantation and is the second cause of death after cardiovascular disease.
Incidence of All-Cause and Site-Specific Cancer after Transplantation
The cumulative incidence of solid organ cancer ranges between 10% and 15% at around 15 years after transplantation.
For skin cancers it reaches 60% in Europe, Australia, and New Zealand.
In kidney transplant it exceeds that of the general population by approximately two- to three folds after adjustment for age and sex.
Cancer Mortality in Recipients of Kidney Transplants
Once cancers develop, the risk of death is high.
Observational data in most Western countries have shown the standard mortality ratios for all cancer types are at least 1.8–1.9 times higher compared with the age- and sex-matched general population.
Risk Factors for Cancer Development
There are many reasons for the higher cancer risk after transplantation.
Risk factors shared with general population:
1. Increasing age,
2. Male sex
3. Smoking, and
4. Prolonged sun exposures.
Other risk factors unique to transplantation:
1. Immunosuppression use (T cell–depleting agents).
2. acute rejection.
3. Sensitization status.
4. Duration of dialysis before transplantation.
Mechanisms of Cancer Development after Transplantation
One potential mechanism is through poor immune control of known oncogenic viruses in patients on immunosuppression (e.g Kaposi sarcoma (human herpesvirus 8), PTLD (Epstein– Barr virus [EBV]), and lip and anal cancers (HPV)).
Another mechanism is accumulation of mutations that would otherwise be repaired or recognized by the immune system.
Common Cancers after Transplantation
Although the risk of overall cancer development is high after transplantation, the risks of certain cancer types are much higher than others.
The three most common cancer types:
Renal cell carcinoma
Skin cancer
PTLD
Cancer Screening Strategies in Transplant Recipients
High-quality, randomized controlled trials have shown that cancer screening through early detection reduces cancer-specific mortality in the general population.
Despite the lack of trial-based evidence to support routine screening in this high-risk group, routine population-based cancer screening for breast, colorectal, and cervical cancer is recommended and should be aligned to the guidelines as per the general population.
Some guidelines also suggest routine skin checks by dermatologists in recipients of transplants who are at high risk, and abdominal ultrasounds and serum a-fetoprotein levels should be checked every 6 months for those with underlying liver disease and chronic HBV infections.
For patients who are at risk of developing renal cell carcinoma (such as those with a history of acquired cystic disease, those with a family history, those who are heavy smokers, and those who use long-term analgesics), ultrasonographic screening (annually or biennially) of the native kidneys may be considered to detect occult malignancy.
Management of Recipients of Kidney Transplants Who Have Cancer
Immunosuppression Management and Treatment in Transplant Recipients with Cancer
Management of immunosuppression in recipients of transplants who are living with cancer is complex and challenging. A consensus plan between transplant professionals, oncologists, and allied health professionals is therefore needed.
Reduction of immunosuppression needs to be balanced against risk of rejection. No strong evidence to support change to MTOR inhibitor except in case of Kaposi sarcoma and squamous cell carcinoma.
The use of checkpoint inhibitors is limited in recipients of transplants given the potential for rejection with nonspecific immune-system activation. Although checkpoint inhibitors are effective in treating melanoma, non–small cell lung cancer, and renal cell carcinoma in the general population, their use in the kidney transplant population requires further investigation and cannot be recommended at this time, outside of a study protocol.
Putting Patients’ Perspectives at the Heart of Cancer Management
Patient centered approach is needed to take into account patient concern, also multidisciplinary approach is essential.
Conclusions
Cancer is the leading cause of morbidity and mortality in patients with kidney transplants.
No good evidence to help optimize the immunosuppression to reduce risk from cancer without increasing risk on graft. Also screening protocol to help prevent cancer occurrence and early discovery is extrapolated from general population. Further studies are needed to answer a lot of questions.
What is the level of evidence:
level V
Introduction
After cardiovascular disease, cancer is the second leading cause of death among recipients of transplants in most Western countries.One of the most feared complications associated with immunosuppression after kidney transplantation is cancer .Cancer is also considered as one of the core clinical outcomes by clinicians, patients, and caregivers, and there is now consensus among key stakeholders suggesting cancer should be included as an outcome in all interventional trials of kidney transplantation.
Incidence of All-Cause and Site-Specific Cancer after Transplantation
The cumulative incidence of solid organ cancer ranges between 10% and 15% at around 15 years after transplantation. For skin cancers, the cumulative incidence reaches 60% in Europe, Australia, and New Zealand. The excess overall cancer risk in patients with kidney transplant exceeds that of the general population by approximately two- to three-fold after adjustment for age and sex. The magnitude of the higher risk is also dependent on cancer types, with the greatest risk in viral-related and immunedriven cancers such as post-transplant lymphoproliferative disease (PTLD), anogenital cancer, and Kaposi sarcoma ., Interestingly, certain solid organ cancers such as breast and prostate cancers are not increased in recipients of transplants
Cancer Mortality in Recipients of Kidney Transplant
Once cancers develop, the risk of death is high. Observational data in most Western countries have shown the standard mortality ratios for all cancer types are at least 1.8–1.9 times higher compared with the age- and sex-matched general population. The risk is greatest among those with melanoma, urogenital cancers, and non-Hodgkin lymphoma, with an overall risk of cancer-related death exceeding five to ten times that of those without kidney transplants.
Risk Factors for Cancer Development
There are many reasons for the higher cancer risk after transplantation. Some of these factors, such as increasing age, male sex, smoking, and prolonged sun exposures, are shared by patients in the general population. Other risk factors, including immunosuppression use (T cell–depleting agents), acute rejection , sensitization status , and duration of dialysis before transplantation.The specific types of cancer that develop after transplantation also vary by geographic areas. Observational and registry data from Europe, North America, Australia, and New Zealand indicate the most common cancer types are nonmelanoma skin cancers (NMSCs), PTLD, and lip cancer . In contrast, data from non-Western Asian and Middle Eastern transplant cohorts suggest higher incidences of urothelial transitional cell carcinoma, renal cell carcinoma, and gastrointestinal cancers in their populations.
Mechanisms of Cancer Development after Transplantation
Although the precise mechanisms are unclear, the effects of immunosuppression on dampening the immune system may create a variety of pathways for cancer development. One potential mechanism is through poor immune control of known oncogenic viruses in patients on immunosuppression. For example, increases in viral-associated cancers, such as Kaposi sarcoma (human herpesvirus 8), PTLD (Epstein– Barr virus [EBV]), and lip and anal cancers (HPV) are common in patients with suppressed immune systems . Another mechanism of immunosuppression-related cancer development is through accumulation of mutations that would otherwise be repaired or recognized by the immune system. This mechanism may be predominant in skin cancers.
Common Cancers after Transplantation
Renal Cell Carcinoma–
Compared with the general population, recipients of kidney transplants have a higher risk (up to seven-fold) of renal cell carcinoma.Ninety percent of renal cell carcinomas develop in the native kidneys as opposed to the allograft. Risk factors for development of renal cell carcinomas posttransplantation include male sex , increasing age African descent and longer time on dialysis .
Skin Cancer
Skin Cancer Skin cancer is the most common cancer type in recipients of kidney transplants and is more aggressive than skin cancers occurring in the general population. The most commonly reported skin cancers in recipients of kidney transplants include cutaneous squamous cell carcinoma, basal cell carcinoma, Kaposi sarcoma, and malignant melanoma
.
Post-Transplant Lymphoproliferative Disease
PTLD is a well-recognized complication after kidney transplantation. Although it is a rare disease, it is associated with poor outcomes. In most instances (approximately 90%), PTLD is associated with EBV.Compared with adult recipients of transplants, the risk of developing lymphoproliferative disease in pediatric recipients of transplants is at least 30-times higher than the age- and sex-matched general population.
Human Papillomavirus Vaccination in Recipients of Kidney Transplants
The incidence of HPV-related anogenital cancer is at least ten- to 15-fold higher in recipients of kidney transplants compared with the age- and sex-matched general population.
Management of Recipients of Kidney Transplants Who Have Cancer
Transplant Recipients with Cancer Management of immunosuppression in recipients of transplants who are living with cancer is complex and challenging. A concerted approach between transplant professionals, oncologists, and allied health professionals is therefore needed to ensure optimal care for our patients. Meticulous understanding of the underlying immunologic risk and cancer severity is needed to optimize immunosuppression dose to prevent the risk of acute rejection, while balancing against the need to induce regression of the cancer.For patients with squamous cell carcinoma, there is now trial-based evidence to suggest conversion to an mTOR inhibitor may reduce the risk of cancer in the longer term .However, mTOR-inhibitor use may also be associated with a higher risk of death . Therefore, there are insufficient data to consider mTOR inhibitors as protective against other cancer types apart from squamous cell carcinoma and Kaposi sarcoma
What is the level of evidence provided by this article
Level 5
Introduction
Renal transplantation is by far considered the best therapeutic option for ESRD compared to maintenance on haemodialysis. However the risk of immunosuppression is associated with the increased incidence of malignancies. Cancer is the second leading cause of death among recipients of transplants in most Western countries after cardiovascular disease.
Some recommended strategies were adopted to decrease cancer risk as human papillomavirus (HPV) vaccination and cancer-screening programs to detect cancers at their earliest stages.
Incidence of All-Cause and Site-Specific Cancer after Transplantation
The cumulative incidence of solid organ cancer ranges between 10% and 15% at around 15 years after transplantation. The cumulative incidence for skin cancers is nearly 60%. The estimated overall cancer risk in patients with kidney transplant exceeds that of the general population by about two- to three-fold after adjustment for age and sex.
The magnitude of the higher risk is also dependent on cancer types, with considerable risk in viral related and immune driven cancers such as post-transplant lymphoproliferative disease (PTLD), anogenital cancer, and Kaposi sarcoma.
Cancer Mortality in Recipients of Kidney Transplants
The risk of death increases once cancers develop. The standard mortality ratios for all cancer types are 1.8–1.9 times higher compared with the age- and sex-matched general population.
The risk is greatest among those with melanoma, urogenital cancers, and non-Hodgkin lymphoma, with an overall risk of cancer-related death exceeding five to ten times that of general population.
Potential differences in the cancer cell biology in recipients of transplants may be attributed to long-term immunosuppression, associated comorbidities, and low uptake of recommended prevention and screening strategies.
Risk Factors for Cancer Development
Higher cancer risk post transplantation could be due to increasing age, male sex, smoking, and prolonged sun exposures. Risk factors as long-term immunosuppression use (T cell–depleting agents), acute rejection, sensitization status, and duration of dialysis prior to transplantation are peculiar to kidney disease and transplant populations.
CKD is linked to higher cancer risk and poor cancer outcomes is a point under studies. Many of these cancers, such as renal cell carcinoma and multiple myeloma, are over-represented in the CKD/ ESRD populations.
Impaired tumor surveillance and immunity to viral or other tumor antigens are probable contributing factors to development of post-transplant malignancy.
For cancer associated with kidney disease and kidney failure, such as kidney and bladder cancer, the overall standardized incidence ratios (SIRs) are 44 and 43, respectively. Women have a much higher risk than men for kidney (SIR, 94.6; [95% CI], 75 to 120) and bladder cancers (SIR, 120; 95% CI, 77 to 134).
Mechanisms of Cancer Development after Transplantation
The effects of immunosuppression on dampening the immune system may establish plenty of pathways for cancer development. Theories highlighted indicate poor immune control of known oncogenic viruses being common as Kaposi sarcoma (human herpes virus 8), PTLD (Epstein Barr virus [EBV]), and lip and anal cancers (HPV) in candidates with suppressed immune systems. Other suggested theory is probable accumulation of mutations that should have been repaired or recognized by the immune system which is out of optimum function. This theory can explain why skin cancers are predominant in such population as immunosuppression impairs the cells’ ability to repair ultraviolet (UV) radiation–induced DNA damage. Moreover immunosuppression can lead to a decrease of xeroderma pigmentosum complementation groups A and G, which are components of nucleotide excision repair.
Tacrolimus is criminated for elevation the level of TGF-b, hence promotes tumor progression and metastasis. Besides calcineurin inhibitors inhibit signaling via calcineurin and NF of activated T cells, which can activate p53, a hallmark of some NMSCs. Cyclosporine potentiates as well direct effects on tumor development and progression via TGF-b or IL-6 overexpression pathways.
Cyclosporine itself inhibits DNA repair consequently accumulates mutations resulting in induction of apoptosis in activated T cells and inhibition of apoptosis in other cells by opening the mitochondrial permeability transition pores.
Regarding the oncogenic role of azathioprine sensitizes the skin to UVA radiation and leads to further accumulation of 6-thioguanine in the DNA associated with a higher risk of NMSCs.
Contrarily Mammalian target of rapamycin (mTOR) inhibitors are believed to have potential antitumor effects by inhibiting cancer growth through cell-cycle arrest and initiation of apoptosis. It can also induce cell death in B-cell lymphoma lines phosphatase and tensin homolog-lacking human tumors, and dendritic cells, possibly through p53 activation and reduction in the cyclin and survivin levels.
Induction therapy with T cell–depleting agents including polyclonal agents, such as anti-thymocyte globulin, and monoclonal agents increases the risks of cancers, such as PTLD and melanoma.
Common Cancers after Transplantation
Renal Cell Carcinoma
Renal transplant recipients have a higher risk reaching to seven-fold of renal cell carcinoma compared to general population. Masses detected in patients post-transplantation on regular ultrasound follow up are typically early, low-grade, small kidney masses about 75%–80% are renal cell carcinoma with the risk of metastasis at presentation being 2%. Interestingly ninety percent of renal cell carcinomas develop in the native kidneys as opposed to the allograft. Renal cell carcinoma in the kidney allograft is rare about 0.1% usually of low-grade T1 lesions; clear cell carcinomas or papillary renal cell carcinomas. They occur mostly in males..
Risk factors suggested include male sex (female hazard ratio [HR], 0.56; 95% CI, 0.47 to 0.66), increasing age (601 years; HR, 6.59; 95% CI, 4.29 to 10.15), African descent (HR, 1.50; 95% CI, 1.24 to 1.80), and longer time on dialysis (31 years; HR, 2.23; 95% CI, 1.58 to 3.13).
Astonishingly it seems risk factors may vary according to disease etiology. It is found that those patients transplanted for kidney failure secondary to glomerular diseases (HR, 1.24; 95% CI, 1.05 to 1.47), hypertensive nephrosclerosis (HR, 1.55; 95% CI, 1.29 to 1.86), and vascular disease (HR, 1.53; 95% CI, 1.15 to 2.03) have the greatest associated risk. On the contrary, patients with renal kidney failure secondary to diabetes (HR, 0.77; 95% CI, 0.62 to 0.94) or autosomal dominant polycystic kidney disease (HR, 0.81; 95% CI, 0.62 to 1.06) have a lower risk of renal cell carcinomas.
Management of De novo renal cell carcinomas differ based on patient factors as age, comorbidities, functional status as well as mass characteristics including size, biopsy specimen findings, growth kinetics.
Treatment policy varied between partial nephrectomy (67%), radical nephrectomy (19%) and percutaneous ablation (12%). Finally it is observed that the overall duration and intensity of immunosuppression rather than components of the drug regimen have greater influence on the expected risk of renal cell carcinoma.
Skin Cancer
Regarding skin cancer in renal transplant recipients; they tend to be more common and even more aggressive than normal population.
Types vary among cutaneous squamous cell carcinoma, basal cell carcinoma, Kaposi sarcoma, and malignant melanoma, with keratinocyte carcinomas comprising 90%–95% of these skin cancers.
The pathogenesis could be due to complex interaction of risk factors including exposure to UV radiation, HPV, pretransplant skin cancer, older age, race, sex (males at greater risk than females) besides the augmenting effect of immunosuppressive medications particularly CNI and azathioprine.
Despite the fact that the incidence of Kaposi sarcoma is rare among general population, yet in recipients of transplants exceeds 100 times that of the general population mainly in Mediterranean, Africa, and Central Europe. Transplant recipients have excess risk of squamous cell carcinoma about 250 times compared to the general population.
Topical fluorouracil and imiquimod cream, photodynamic therapy, surgical excision or electrodesiccation and curettage is the preferred management for patients with actinic keratoses and squamous cell carcinoma in situ being with good outcome. The option of Mohs micrographic surgery after histologic confirmation of negative margins presents the most definitive method of treatment with excellent cure rates of 95%–100% for biopsy sample–proven cutaneous squamous cell carcinoma in SOT recipients.
High risk for Kaposi sarcoma is encountered in patients on CNI regimen. It is thought to be best managed by switching to mTORi is the appropriate choice in this situation. The role of mTORi is believed to restore the proper effector and memory T-cell immune activity against human herpesvirus 8.
The risk of developing malignant melanoma is elevated by 5 to 8 fold in SOT recipients with marked poor outcome in relation to that of general population even up to mortality.
Possible risk factors highlighted involve pretransplant melanoma being the strongest followed by White race and older age above 50 years. Management is primarily by surgical with wide excision along with modification of immunosuppression regimen vary according to the extent of melanoma and transplant function.
Post-Transplant Lymphoproliferative Disease
PTLD is associated with EBV being a common virus affecting most of the people during childhood. Most PTLDs are of B-cell types, only about 5% of patients have the T-cell type. The estimated incidence in the first 10 years post renal transplantation ranges about 1%–2% in adult recipients while only 3% in pediatric recipients.
Pretransplant EBV seronegativity and primary EBV infection are crucial risk factors for early EBV-positive PTLD especially in younger SOT recipients. Interestingly there is a considerable proportion representing 40%–50% of late B-cell PTLDs are EBV-negative lesions. The fact is that the risk of acquiring PTLD in pediatric SOT recipients is at least 30-times higher than the age- and sex-matched general population. The use of use of T cell–depleting agents, belatacept, Ortho Kung T3 (muromonab-CD3) along with high dose tacrolimus synergizes the development of PTLD by four-fold excess.
The reported use of rituximab and chemotherapy (doxorubicin, cyclophosphamide, vincristine, and prednisone) is believed to improve the survival, with 5-year survival up to 60%. Rituximab, positive EBV status and normal lactate dehydrogenase levels contribute to predictors of favourable response.
The problem is when PTLD develops, the associated risk of death becomes very high up to 14 fold higher than recipients without PTLD. Thanks to advances in treatment strategies as the use of rituximab and immunotherapy the risk of death has declined by 62%–68% at 1 year and approximately 41%–48% at 10 years. It is also noted that the risk of is greater in case of bone marrow/reticuloendothelial disease then extranodal and nodal disease comes consequently. Unfortunately, the median time elapsed from diagnosis till to death is expected to be 6 months.
Cancer Screening Strategies in Transplant Recipients
Considering renal transplant recipients, it is worthy to adopt strategies against developing renal cell carcinoma in those with a history of acquired cystic disease, those with a family history, those who are heavy smokers, and those who use long-term analgesics necessarily ultrasonographic screening (annually or biennially) of the native kidneys to be considered to detect occult malignancy.
Human Papillomavirus Vaccination in Recipients of Kidney Transplants
The incidence of HPV-related anogenital cancer is at least 10 to 15 fold higher in recipients of kidney transplants. The development of quadrivalent vaccines used for prevention of cervical intraepithelial neoplasia have reached efficacy up to 99%–100% with the advantage that they are generally safe for SOT population. Further recommendations advise to get vaccinated prior to transplantation.
Management of Recipients of Kidney Transplants Who Have Cancer
Immunosuppression Management and Treatment in Transplant Recipients with Cancer
A multidisciplinary targeted approach involving transplant professionals, oncologists, and allied health professionals is mandatory. Ultimate balance between proper immunosuppression dose to avoid rejection and the need to induce regression of the malignant lesions as well as to prevent disease progression. The first reasonable step is to reduce the burden of immunosuppression for patients with early to moderate stage malignancy to be tailored according to individual patient situation. It is believed to be wise to switch to an mTOR inhibitor may reduce the risk of cancer in the longer term.
Immunotherapy
Recent discovery of immune-checkpoint inhibitors targeting the programmed death-1/programmed death ligand-1 interaction and/or the CD28-CD80/86 axis with cytotoxic T lymphocyte–associated protein-4 Ig has changed the treatment policy of a variety of malignancies through immune system activation against the cancer. In the present time despite they have shown to be effective in treating melanoma, non–small cell lung cancer, and renal cell carcinoma in the general population, yet their use in renal transplant recipients is under clinical trials.
The level of evidence is Level v.
Introduction
de novo cancer development is a major complication of organ transplantation.
cancer is the second leading cause of death among recipients of transplants in most Western countries
incidence of cancer in SOT ranges between 10% and 15%, at around 15 years after transplantation.
For skin cancers, the cumulative incidence reaches 60% in Europe, Australia, and New Zealand.
risk in KTRs exceeds that of the general population by approximately two- to three-folds.
greatest risk in viral-related and immune driven cancers such as post-transplant lymphoproliferative disease (PTLD), anogenital cancer, and Kaposi sarcoma.
Cancer Mortality in Recipients of Kidney Transplants
In Western countries mortality ratios for cancer are 1.8–1.9 times higher than general population. greater risk among those with melanoma, urogenital cancers, and non-Hodgkin lymphoma, with an overall risk of cancer-related death is five to ten times that of those without kidney transplants.
Risk Factors for Cancer Development
-General risk factors shared by patients in the general population as increasing age, male sex, smoking, and prolonged sun exposures.
– specific risk factors: including immunosuppression use (T cell–depleting agents), acute rejection episodes, sensitization status, and duration of dialysis, long-term immunosuppression and pretransplant malignancy.
– Cancer develop in recipients of kidney transplants because of impaired tumor surveillance and immunity to viral or other tumor antigens.
– The specific types of cancer that develop after transplantation also vary by geographic area.
– no conclusive evidence to suggest one type of immunosuppression is more oncogenic than others
But it was shown that tacrolimus increases the level of TGF-b and promotes tumor progression and metastasis,
also CNI inhibit signaling via calcineurin and NF of activated T cells, which can activate p53, a hallmark of some NMSCs .
Cyclosporine also has direct effects on tumor development and progression , through TGF-b or IL-6 overexpression pathways , It inhibit DNA repair, causing accumulating mutations, inducing apoptosis in activated T cells, and inhibiting apoptosis in other cells.
-azathioprine also has a well known oncogenic potential, sensitizes the skin to UVA radiation and causes the accumulation of 6-thioguanine in the DNA, leading to a higher risk of NMSCs.
-mTOR inhibitors may have potential antitumor effects by inhibiting cancer growth through cell-cycle arrest and initiation of apoptosis. –
-Induction therapy with T cell–depleting agents such as anti-thymocyte globulin, and monoclonal agents, such as anti-CD52 increases the risks of cancers, such as PTLD and melanoma.
Common Cancers after Transplantation
Although risk of all types of cancers are higher in transplant recipients but still Certain types of tumors are more common after organ transplantation.
The most common tumors types are: renal cell carcinoma (RCC), PTLD, and melanoma and nonmelanoma skin cancers.
Renal Cell Carcinoma (RCC) is common in KTRs s with a risk about 7 folds higher than general population.
Due to frequent abdominal imaging, most of kidney tumors detected early, and mostly low-grade, small masses, 80% of these masses are RCC.
90% of RCC occurs in the native kidneys.
Risk factors include male sex, older age, African, and longer dialysis duration.
The cause of kidney failure also affected the risk where patients who had renal failure due to glomerular diseases, hypertensive nephrosclerosis and vascular disease had greater risk than patients with failure due to diabetes and APKD.
Management with radical surgery according to stage ,after radical surgery of RCC the prognosis in transplant recipients is comparable to general population, with 5-year survival rates of 68%–97% .
Skin Cancer is commonest malignancy in KTRs more aggressive in the general population.
reported skin cancers that are reported in KTRs include cutaneous squamous cell carcinoma (SSC), basal cell carcinoma (BCC), malignant melanoma and Kaposi sarcoma.
keratinocyte carcinomas represent 90%–95% all skin malignancy.
risk factors include: UV radiation exposure, HPV, skin malignancy before TX, old age, male sex (52).
Kaposi sarcoma has 100 times higher incidence in transplant recipients than general population, it is seen commonly in patients Africa Mediterranean areas and Central Europe.
the risk of SCC is about 250 times more than general population .
For in situ SCC management with topical fluorouracil and imiquimod cream, with the use of photodynamic treatment, and surgical removal and curettage showed good outcomes.
For biopsy proven SCC in recipients, micro-graphic surgery, with negative margins is the most definitive treatment method, cure rates are up to of 95%–100% (52).
, primary radiation for inoperable cases provides local cure rates .
Chemoprophylaxis with retinoids and nicotinamide might be considered for Patients with multiple SCC (more than five) every year, aggressive type of SCC , or early occurrence of SCC ,metastatic might be managed with chemotherapy and/or immunotherapy.
calcineurin inhibitors are associated with increased risk of Kaposi sarcoma, Decreasing the dose of CNI or shifting to an mTOR inhibitor is the cornerstone of treatment with good response and reported regression of the tumor due to restoration of the effector regulatory cells and memory T-cell activity against HHV 8 .
malignant melanoma risk is 5- 8 folds higher in transplant recipients o, with bad prognosis compared to general population, as melanoma has the highest mortality (52).
Presence of melanoma before TX is the most strong risk factor other risk factors includes: White race and older age .
treatment is mainly surgery with adequate margins and immunosuppression adjustment according to the extent of melanoma and graft function.
Post-Transplant Lymphoproliferative Disease (PTLD) Although rare disease but it has poor prognosis.
Mostly occurs in association with EBV.
EBV which infects the B cells and remain latent, reactivation can occur with suppression of T-cell function, and decrease control of T-cell on proliferation of B-cell, finally result in occurrence of PTLD.
Mostly PTLDs arise from B-cells, only 5% may arise from T-cells.
incidence of PTLD is 1%–2% in the first 10 years post-transplantation.
The highest risk is in the 12 months after transplant, decreases till the fifth year.
the risk of developing lymphoproliferative disease in pediatric recipients of transplants is at least 30-times higher than the age- and sex-matched general population
seronegative EBV and primary infection are important risks for early development of EBV-associated PTLD, in contrast, 40%–50% of late B-cell type PTLDs shows EBV-negative lesions .
death among recipients of kidney transplants who have PTLD is .14- fold higher than recipients without PTLD although rituximab has improved survival over the last years.
Treatment of PTLD post transplantation mainly depends on subtype.
mainstay of treatment is immunosuppression reduction. However, the response to immunosuppression reduction varies considerably between individuals.
rituximab and chemotherapy (doxorubicin, cyclophosphamide, vincristine, prednisone) have improved overall survival, with 5-year survival at around 60% .
Rituximab is also generally well tolerated with minimal side effects, and factors that predicted response included positive EBV status and normal lactate dehydrogenase levels.
Cancer Screening Strategies in Transplant Recipients
randomized controlled trials have shown that cancer screening through early detection reduces cancer-specific mortality in the general population, screening program based on programs established for general population could be used as a guide.
Human Papillomavirus in Kidney Transplants Recipients
HPV-related is associated with anogenital and lip cancer with increased risk about 10-15 folds higher in KTRs compared with matched general population.
in randomized clinical trials Quadrivalent vaccines (against 6, 11, 16, and 18 genotypes) and the HPV 9-valent vaccines (against more 5 genotypes 31, 33, 45, 52, and 58) are greatly effective with efficacy of 99%–100% in prevention of cervical neoplasia.
In the transplant population, HPV vaccines are safe. However, seropositivity was detected in 50%–60% of patients, depending on genotypes, higher levels of tacrolimus were detected in non-responders.
HPV vaccination is more effective to be given to women before transplantation and its highly recommended for women after transplantation if not taken before.
Immunosuppression Management and Treatment in Transplant Recipients with Cancer
reduction in the overall immunosuppression for patients with early- to moderate-stage malignancy may be a reasonable first step, patients should be informed about the potential adverse effects, and all strategies should be tailored to the individual’s needs.
-For patients with squamous cell carcinoma, it is suggested to do conversion to an mTOR inhibitor may reduce the risk of cancer in the longer term .
-mTOR-inhibitor use may also be associated with a higher risk of death, and there are insufficient data to consider mTOR inhibitors as protective against other cancer types apart from squamous cell carcinoma and Kaposi sarcoma
– the use of checkpoint inhibitors is limited in recipients of transplants given the potential for rejection with nonspecific immune-system activation
Conclusions
-Cancer is the leading cause of morbidity and mortality in patients with kidney transplants.
-optimizing allograft function with immunosuppression are often challenging.
-Currently, the evidence to define the amount of immunosuppression by which a clinician could safely reduce is unknown. More importantly, evidence to support primary prevention and screening programs in recipients of transplants are largely extrapolated from the
This review explains the kidney transplanted patients, idea, education and experience of cancer in the context of kidney transplantation along with the epidemiology and burden of cancer in kidney transplant recipients.
Regarding renal transplant patients, cancer is the second cause of death after cardiovascular causes.
Incidence of All-Cause and Site-Specific Cancer after Transplantation:
The cumulative incidence of solid organ cancer ranges between 10% and 15% at around 15 years after transplantation. The excess overall cancer risk in patients with kidney transplant exceeds that of the general population by approximately
two- to three-fold after adjustment for age and sex. The greatest risk in viral-related and immune driven cancers such as post-transplant lymphoproliferative disease (PTLD), anogenital cancer, and Kaposi sarcoma. Interestingly, certain solid organ cancers such as breast and prostate cancers are not increased in transplant recipients.Cancer Mortality in Recipients of Kidney Transplants :
Once cancers develop, the risk of death is high. Observational data in most Western countries have shown the standard mortality ratios for all cancer types are at least 1.8–1.9 times higher compared with the age- and sex-matched general
population. The risk is greatest among those with melanoma, urogenital cancers, and non-Hodgkin lymphoma, with an overall risk of cancer-related death exceeding five
to ten times that of those without kidney transplants.
Risk Factors for Cancer Development :
factors that increase cancer risk include;
increasing age
male sex
smoking
prolonged exposure to sun
use of immunosuppression
acute rejection
sensitization status
dialysis duration before transplantation
some observations suggestion of CKD as risk factor for cancer, and poor outcome like renal cell carcinoma and multiple myeloma.
Mechanisms of Cancer Development after Transplantation:
Immunosuppressive drug mechanism is through poor immune control of known oncogenic viruses. For example, increases in viral-associated cancers, such as
Kaposi sarcoma (human herpesvirus 8), PTLD (Epstein– Barr virus [EBV]), and lip and anal cancers (HPV) are common.
Immunosuppression-related cancer development through accumulation of mutations that
would otherwise be repaired or recognized by the immune system. This mechanism may be predominant in skin cancers, where immunosuppression impairs the cells’ ability to
repair ultraviolet (UV) radiation–induced DNA damage.
More specifically, immunosuppression can lead to a decrease of xeroderma pigmentosum complementation groups A and G, which are components of nucleotide
excision repair.
Common Cancers after Transplantation:
Renal Cell Carcinoma
Skin Cancer
Post-transplant lymphoproliferative disease
Management of Recipients of Kidney Transplants Who Have Cancer:
Optimization of immunosuppression dose
Immunotherapy
Introduction
Cancer is the second-leading cause of mortality for transplant recipients in Western nations and is a feared consequence linked to immune suppression used after kidney transplants. Preventive interventions have been tried in response to the dismal results, including the use of HPV vaccines and cancer-screening techniques. The etiology, diagnosis, prevention, and treatment of cancer following kidney transplantation were the main topics of this review.
incidence of all-cause and site-specific cancer after transplantation
It has been noticed that 15 years following transplantation, the cumulative incidence of solid organ cancer varies from 10-15%. The risk varies depending on the cancer kind and the region where it is most common. Breast and prostate cancers are two solid tumors whose incidence is not raised in transplant recipients.
Cancer Mortality in recipients of kidney transplants
Once cancer has begun to spread, there is a high risk of death. Patients with non-Hodgkin’s lymphoma, melanoma, and urogenital malignancies have a higher death risk. The elevated mortality risk may be brought on by variations in the biology of cancer cells in transplant recipients, the use of long-term immune suppression, related co-morbidities, and decreased adherence to advised preventive and screening measures.
Risk factors for developing malignancy after transplantation
Ageing, male sex, smoking, and prolonged sun exposure are some risk factors for cancer following transplantation. The majority of people have these characteristics. Immune suppression usage, acute rejection, sensitization status, and length of dialysis prior to the transplant are risk factors specific to individuals who have had transplantation. Poor results are linked to having CKD, a proven risk factor for cancer.
Mechanisms of cancer development after transplantation
Immune suppression during maintenance reduces acute and long-term rejection and consequent allograft loss. Another proposed pathway involves individuals receiving immune suppression having inadequate immunological control of recognized carcinogenic viruses. Accumulation of mutations that the immune system would normally correct or detect is one putative mechanism of immune suppression-related cancer growth. There isn’t enough proof right now to say one sort of immune suppression is more likely to cause cancer than another.
Introduction
Cancer is a dreaded complication associated with immune suppression used after kidney transplants, and is the second leading cause of death among transplant recipients in the Western countries. After noting the poor outcomes, preventive measures have been attempted, such as using HPV vaccinations, and cancer-screening strategies. This review focused on the mechanisms, diagnosis, prevention and treatment of cancer after kidney transplantation.
Incidence of all-cause and site-specific cancer after transplantation
It is noted that the cumulative incidence of solid organ cancer ranges from 10-15% at around 15 years after transplantation. The risk is dependent on the type of cancer and the area that it is most prevalent in. some solid cancers, such as breast and prostate are not increased in transplant recipients.
Cancer mortality in recipients of kidney transplants
Once the cancer develops, the risk of death is high. The mortality risk is increased in patients with melanoma, urogenital cancers and non-Hodgkin’s lymphoma. The increased risk of mortality may be due to differences in cancer cell biology in transplant recipients, the use of long-term immune suppression, associated co-morbidities and lower use of recommended prevention and screening strategies.
Risk factors for cancer development
Some of the risk factors for developing cancer after transplantation include increasing age, male sex, smoking and prolonged sun exposure. These factors are shared by the general population. Risk factors specific to patients who have undergone transplantation include immune suppression use, acute rejection, sensitization status and duration of dialysis before the transplantation. Having CKD is known risk factor for cancers, and it is associated with poor outcomes.
Mechanisms of cancer development after transplantation
Maintenance immune suppression decreases acute and chronic rejection, and subsequent allograft loss. Another potential mechanism is through poor immune control of known oncogenic viruses in patients on immune suppression. One potential mechanism of immune suppression-related cancer development is through accumulation of mutations that would otherwise be repaired or recognized by the immune system. Currently, there is no conclusive evidence to suggest one type of immune suppression is more oncogenic than another.
Common cancers after transplantation
1.Renal cell carcinoma
Recipients of kidney transplants have up to a seven fold increased risk of renal cell carcinoma, as compared to the general population.
Most of the renal cell carcinomas (up to 90%) develop in the native kidney, as opposed to the allograft.
The risk factors for developing renal cell carcinomas after transplantation include male sex, increasing age (more than 60 years), African descent, longer time on dialysis prior to transplantation and patients that required transplantation due to glomerular disease, hypertensive nephrosclerosis and vascular disease.
Patients who required kidney transplantation due to diabetes or autosomal polycystic kidney disease have a lower risk of renal cell carcinoma.
The outcome of renal cell carcinomas after radical treatment in transplant population has shown a reduced 5-year survival rates as compared to the general population.
The management of the malignancy should be individualized for optimal results.
2.Skin cancer
It is the most common cancer type in kidney transplant recipients, and it is more aggressive than skin cancers occurring in the general population.
The most commonly reported skin cancers in patients who have undergone kidney transplants include cutaneous squamous cell carcinoma, basal cell carcinoma, Kaposi sarcoma and malignant melanoma.
The risk factors include exposure to UV radiation, HPV, pretransplant skin cancer, older age, male sex and immune suppressive medications (that augment the carcinogenic effects).
Patients treated with calcineurin inhibitors are particularly at a higher risk of developing Kaposi sarcoma.
Amongst all the types of skin cancer, melanoma has the highest mortality rate.
3.PTLD
Although PTLD is a rare disease, it is a known complication after kidney transplants. It is commonly associated with EBV. Some of the risk factors include a younger age at transplantation, male sex, use of T cell-depleting agents, Ortho Kung T3, high dose tacrolimus and negative recipient EBV serology with a positive donor serology. The treatment goal is to cure the disease, and that is achieved by immune suppression reduction. It has a high risk of death once it develops.
Cancer screening strategies in transplant recipients
Studies have shown that cancer screening through early detection reduces cancer-specific mortality in the general population. However, patients with kidney disease and post-kidney transplantation are generally overwhelmed with their diagnosis, and are sometimes reluctant to undergo further testing. Decisions regarding screening must be individualized, and based on clear considerations of the patient’s preferences and values, along with the assessing the potential harms and benefits of the various options.
HPV vaccination in recipients of kidney transplants
The incidence of HPV-related anogenital cancer is at least 15 times higher in patients who have received kidney transplants compared to the general population. Quadrivalent vaccines are highly effective for the prevention of cervical intraepithelial neoplasia. HPV vaccination is indicated in both males and females aged 9 to 25 years in the general population for the prevention of HPV related malignancies. Recent data has shown that it is also effective in women up to the age of 45 years. HPV vaccination is recommended for women before transplantation.
Management of recipients of kidney transplants who have cancers
Immune suppression management and treatment in transplant recipients with cancer
Multidisciplinary management is required for patients with cancer who have undergone kidney transplantation. This is needed to understand the underlying immunologic risk and cancer severity to optimize immunosuppression dosages to prevent the risk of acute rejection, while balancing the need to induce regression of the malignant lesion. However, there is insufficient evidence and therefore, patient care should be individualized.
Immunotherapy
The use on immune-checkpoint inhibitors targeting the programmed death-1/programed death ligand-1 interaction and/or the CD28-CD80/86 axis with cytotoxic T lymphocyte-associated protein-4 Ig has assisted greatly in the treatment of various malignancies. However, their role in kidney transplant patient requires further investigation.
Putting patients’ perspectives at the heart of cancer management
Understanding the personal experiences and requirements of patients will assist health care practitioners to deliver optimum, appropriate and relevant care. A multidisciplinary team will aid in delivering holistic care to the patient. This will also help in addressing the psychosocial, functional and nutritional issues experienced by the patient.
Conclusion
Cancer is the leading cause of morbidity and mortality in patients with kidney transplant. Evidence to address the issues is currently limited. Therefore, it is important to individualize management for the patients for optimal results.
Level of Evidence:
Level V as it is a narrative review
This review highlights the incidence, mechanisms, diagnosis, prevention, and treatment of cancer after kidney transplantation.
Cancer is one of the most feared complications associated with immunosuppression after kidney transplantation and is the one of the major leading cause of death among transplant recipients. The higher risks and poorer cancer outcomes have prompted clinicians and policymakers to adopt preventive policies and cancer screening strategies to detect cancers at their advanced stage, incurable disease.
The current review under discussion also outlines risk factors for cancer development, the incidence of all-cause and site-specific cancer after transplantation, and mechanisms of cancer development after transplantation.
After kidney transplantation, the overall risk of developing cancer is higher compared to the general population, with certain cancer types being more prevalent than others. The three most common cancers after transplantation are renal cell carcinoma, skin cancer, and post-transplant lymphoproliferative disease (PTLD).
Renal cell carcinoma is up to seven times more common in kidney transplant recipients compared to the general population. The risk factors include male sex, increasing age, African descent, and longer time on dialysis.
Skin cancer is also one of the most common cancer type in kidney transplant recipients and is more aggressive than in the general population. Risk factors include exposure to UV radiation, HPV, pre-transplant skin cancer, older age, race, and sex, with immunosuppressive medications augmenting the carcinogenic effects. Treatment options for skin cancer include topical treatments, surgical excision, Mohs micrographic surgery, and systemic chemotherapy or immunotherapy for metastatic cases.
PTLD is a rare but serious complication after kidney transplantation, with most cases associated with Epstein-Barr virus (EBV). Risk factors for PTLD include younger age, male sex, T-cell depleting agents, and high-dose tacrolimus. Treatment options for PTLD include reducing immunosuppression and rituximab and chemotherapy for improved overall survival.
Kidney transplant recipients have a higher risk of developing certain cancer types compared to the general population, and early detection and management are critical for improved outcomes.
Cancer screening through early detection has been shown to reduce cancer-specific mortality in the general population. Routine screening in patients with kidney disease and those on dialysis may not be as effective in terms of costs and survival benefits. Despite this, routine population-based cancer screening for breast, colorectal, and cervical cancer is recommended and should be aligned to the guidelines as per the general population.
Management of immunosuppression in recipients of transplants who are living with cancer is complex and challenging, and a concerted approach between transplant professionals, oncologists, and allied health professionals is necessary to ensure optimal care for patients. Patients’ perspectives are essential to guide clinicians and healthcare professionals to deliver relevant and appropriate care. A personalized, rather than a one-size-fits-all approach, is most preferred. Collaborative efforts between healthcare professionals, policy-makers, trialists, and patients are needed to ensure quality evidence is generated to support the long-term care of recipients of transplants.
Level 4
level of evidence V
De Novo Malignancies after Kidney Transplantation
Inspite of the advantages of kidney transplant to the patient with ESRD, it is not a cure and has its own consequences as a result of ch immunosuppression status. cancer should be one of the outcomes of kidney transplant to be assessed.
After cardiovascular disease, cancer is the second leading cause of death among recipients of transplants in most Western countries.
Due to high risk preventive strategies were adopted such as vaccination and cancer-screening strategies, to detect cancers earlier.
Incidence of All-Cause and Site-Specific Cancer after Transplantation
The cumulative incidence of solid organ cancer ranges between 10% – 15% at around 15 years after transplantation.
For skin cancers, the cumulative incidence reaches 60% in Europe, Australia, and New Zealand.
kidney transplant has higher risk as compared to general population by approximately 2-3-fold after adjustment for age and sex.
Increasing risk is depending on
1-cancer types
2- viral-related cancers such as PTLD, anogenital cancer, and Kaposi sarcoma.
Cancer Mortality in Recipients of Kidney Transplants
standard mortality ratios for all cancer types are at least 1.8–1.9 times higher compared with the age- and sex-matched general population.
Higher risk observed in melanoma, urogenital cancers, and non-Hodgkin lymphoma, with an overall risk of cancer-related death 5-10 times that of those without kidney transplants .
Cancer screening and prevention, effective patient education and heightened awareness are key.
Risk Factors for Cancer Development
· Shared with general population
increasing age, male sex, smoking, and prolonged sun exposures.
· Specific to kidney disease and transplant populations
immunosuppression use , acute rejection sensitization status and duration of dialysis before transplantation.
Contributing factor to high risk of development of cancer
1. long-term immunosuppression
2. having CKD (irrespective of the CKD stage) is associated with higher cancer risk and poor cancer outcomes
3. impaired tumor surveillance and immunity to viral or other tumor antigens.
4. previously treated pretransplant malignancy
5. geographic areas
A. nonmelanoma skin cancers (NMSCs), PTLD, and lip cancer most common in Europe, North America, Australia, and New Zealand.
B. urothelial transitional cell carcinoma, renal cell carcinoma, and gastrointestinal cancers more common in Middle Eastern transplant cohorts .
6. loss of control of oncogenic viral replication and control in the context of chronic immunosuppression.
Taiwan is an endemic area for chronic hepatitis B virus (HBV) infection in Far East Asia, kidney transplant has liver cancer of 5 fold compared with the sex- and age-matched general population
Mechanisms of Cancer Development after Transplantation
Maintenance immunosuppression dampening the immune system may create a variety of pathways for cancer development.
1- poor immune control of known oncogenic viruses in patients on immunosuppression. This will increases viral-associated cancers, such as Kaposi sarcoma (human herpesvirus 8), PTLD (Epstein– Barr virus [EBV]), and lip and anal cancers (HPV)
2- accumulation of mutations that would otherwise be repaired or recognized by the immune system. mainly in skin cancers,
3- type of immunosuppressant:
a) calcineurin inhibitors associated with hepatocellular carcinoma, human lung adenocarcinoma cells, and renal cell carcinoma .
b) calcineurin inhibitors inhibit signaling via calcineurin and NF of activated T cells, which can activate p53, a hallmark of some NMSCs.
c) Cyclosporine also has direct effects on tumor development and progression, through TGF-b or IL-6 overexpression pathways.
d) cyclosporine is capable of inhibiting DNA repair, thereby accumulating mutations, inducing apoptosis in activated T cells, and inhibiting apoptosis in other cells by opening the mitochondrial permeability transition pores .
e) Azathioprine sensitizes the skin to UVA radiation and causes the accumulation of 6-thioguanine in the DNA, leading to a higher risk of NMSCs .
f) Mammalian target of rapamycin (mTOR) inhibitors, have potential antitumor effects by inhibiting cancer growth through cell-cycle arrest and initiation of apoptosis. This is helpful in small cell lung cancer, sarcoma, neuroblastoma, glioblastoma, osteosarcoma, pancreatic cancer, breast cancer, prostate cancer, leukemia, and B-cell lymphomas.
g) Induction therapy with T cell–depleting agents (including polyclonal agents, such as anti-thymocyte globulin, and monoclonal agents, such as anti-CD52 and, historically, Ortho Kung T3 [muromonab-CD3]) increases the risks of cancers, such as PTLD and melanoma .
h) T cell–depleting agents for acute rejection of the kidney allograft also heighten the risk of cancer development ;
Common Cancers after Transplantation
a) renal cell carcinoma (7 fold higher), 90% in native kidney
· factors for development
male sex, increasing age, African descent and longer time on dialysis , kidney failure secondary to glomerular diseases , hypertensive nephrosclerosis and vascular disease
b) skin cancer (squamous cell carcinoma, basal cell carcinoma, Kaposi sarcoma, and malignant
· factors for development
exposure to UV radiation, HPV, pretransplant skin cancer, older age, race, and male sex, immunosuppressive medications (cyclosporine and azathioprine) certain ethnic groups (Mediterranean, Africa, and Central Europe). melanoma, with keratinocyte carcinomas comprising 90%–95% of these skin cancers)
c) PTLD associated with EBV, There also appears to be a bimodal distribution in PTLD incidence, with the risk of PTLD being the highest in the 12 months post-transplant, and it then decreases until the 5th year after transplantation.
· factors for development
Pretransplant EBV sero-negativity ,primary EBV infection, younger recipients of transplants, The use of belatacept,
Cancer Screening Strategies in Transplant Recipients
· early detection reduces cancer-specific mortality in the general population.
· In kidney disease, studies suggesting screening may not be as effective in terms of costs and survival benefits
· routine population-based cancer screening for breast, colorectal, and cervical cancer is recommended.
· routine skin checks by dermatologists in recipients of transplants who are at high risk.
· abdominal ultrasounds and serum a-fetoprotein levels should be checked every 6 months for those with liver disease and chronic HBV infections.
· If at risk of developing renal cell carcinoma (such as those with a history of acquired cystic disease, those with a family history, those who are heavy smokers, and those who use long-term analgesics), ultrasonographic screening (annually or biennially) of the native kidneys may be considered .
· Screening decisions must be made with clear considerations of patients’ preferences and values, incorporating the potential harms and benefits of the various options.
Human Papillomavirus Vaccination in Recipients of Kidney Transplants
· The incidence of HPV-related anogenital cancer is at least ten- to 15-fold higher in recipients of kidney transplants compared with the age- and sex-matched general population.
· Quadrivalent vaccines (against genotype 6, 11, 16, and 18).
· the HPV 9-valent vaccines (against five additional genotypes of 31, 33, 45, 52, and 58) are highly effective
· overall efficacy of 99%–100% for the prevention of cervical intraepithelial neoplasia in both males and females aged 9–25 years in the general population for the prevention of HPV-related malignancies.
Disadvanytage
· seropositivity was only detected in approximately 50%–60% of patients
· nonresponders depend on 1-genotypes, 2- higher tacrolimus levels
Management of Recipients of Kidney Transplants
· A concerted approach between transplant professionals, oncologists, and allied health professionals is therefore needed to ensure optimal care.
· To balance between treatment of cancer and avoid its progression and between acute rejection.
· Reduction of immunosuppression in consultation with the patient.
· squamous cell carcinoma, evidence to suggest conversion to an mTOR inhibitor may reduce the risk of cancer in the longer term
Immunotherapy
· The use of immune-checkpoint inhibitors targeting the programmed death-1/programmed death ligand-1 interaction and/or the CD28-CD80/86 axis with cytotoxic T lymphocyte–associated protein-4 Ig has revolutionized the treatment of a variety of malignancies through immunesystem activation against the cancer .
· However, there is risk of rejection
· Although checkpoint inhibitors are effective in treating melanoma, non–small cell lung cancer, and renal cell carcinoma in the general population, their use in the kidney transplant population requires further investigation and cannot be recommended at this time, outside of a study protocol.
· a personalized, rather than a one-size-fits-all, approach is most preferred.
· For patients who have progressed to advanced-stage malignancy, complete immunosuppression withdrawal is a difficult decision for both patients and clinicians.
· a multidisciplinary, integrated approach that involves the transplant and palliative care team is crucial. together with a social worker, dietitian, clinical psychologist, and other allied health workers to address the psychosocial, functional, and nutritional issues experienced by our patients.
level of evidence V
Introduction :
Kidney transplantation is the best treatment option for acceptable candidates with kidney failure, but it is not a cure. Patients require life-long immunosuppression to maintain optimal allograft function, and cancer is the second leading cause of death among recipients of transplants. This review focuses on the incidence, mechanisms, diagnosis, prevention, and treatment of cancer after kidney transplantation.
Risk Factors for Cancer Development:
Risk factors for cancer development after transplantation include increased age, male sex, smoking, and prolonged sun exposures, as well as immunosuppression use, acute rejection, sensitization status, and duration of dialysis.
Mechanisms of Cancer Development after Transplantation
Immunosuppression can lead to cancer development through poor immune control of known viruses, UV-induced DNA damage, and accumulation of mutations. Azathioprine has potential antitumor effects by inhibiting cancer growth through cell-cycle arrest and initiation of apoptosis.
Common cancers after transplantation :
Renal cell carcinoma :
Risk of cancer-related death in recipients of kidney transplants is higher than the general population, with the majority of kidney masses detected post-transplantation being renal cell carcinoma. Risk factors include male sex, age, African descent, hypertensive nephrosclerosis, vascular disease, and kidney failure secondary toglomerular diseases. De novo renal cell carcinomas should be managed according to urologic guidelines, with 5-year, disease-specific and overall patient survival rates of 68%–97% and 69%–88%. Negative prognostic factors include presence of symptoms, higher Fuhrman grade, absence of transplantation, and advanced-stage disease. Nephron-sparing surgery was safe and an appropriate option with good longterm functional and oncologic outcomes. Overall duration and intensity of immunosuppression influence risk.
Skin Cancer:
Skin cancer is the most common cancer type in recipients of kidney transplants and is more aggressive than skin cancers occurring in the general population. It is caused by a complex interaction of risk factors, including exposure to UV radiation, HPV, pretransplant skin cancer, older age, race, and sex, and immunosuppressive medications. Management options include topical fluorouracil and imiquimod cream, photodynamic therapy, and surgical excision or electrodesiccation and curettage. Primary radiation therapy is the most effective method of treatment for squamous cell carcinoma, with cure rates of 95%–100%. Chemoprophylaxis and systemic chemotherapy are recommended, and patients treated with calcineurin inhibitors are at high risk for Kaposi sarcoma. Adjustment of immunosuppression is individualized to each patient on the basis of the extent of melanoma and transplant function.
Post-Transplant Lymphoproliferative Disease:
PTLD is a rare complication after kidney transplantation that is associated with EBV and is associated with poor outcomes. Most PTLDs are of B-cell types, with approximately 5% of patients having the T-cell type. There is evidence to suggest that the incidence of PTLD has been decreasing in recent years, with an 8% reduction in the risk of developing PTLD from 2000 onward. Pretransplant EBV seronegativity and primary EBV infection are important risk factors for early EBV-positive PTLD, and may explain the higher risk of disease early post-transplant. PTLD is a 30-times higher risk of death among recipients of kidney transplants than the general population, and the mainstay of treatment is immunosuppression reduction.
Prior work reported that rituximab and chemotherapy have improved overall survival, with 5-year survival at around 60%. The risk of death is dependent on site, with those having bone marrow/reticuloendothelial disease having the highest risk.
Cancer Screening Strategies in Transplant Recipients:
Routine population-based cancer screening for breast, colorectal, and cervical cancer is recommended and should be aligned to guidelines as per the general population. Ultrasonographic screening (annually or biennially) of the native kidney may be considered to detect occult malignancy. Screening decisions must be made with clear considerations of patients’ preferences and values, incorporating the potential harms and benefits of the various options.
Human Papillomavirus Vaccination in Recipients of Kidney Transplants:
HPV vaccination is recommended for both males and females aged 9-25 years in the general population for the prevention of HPV-related malignancies, and is also efficacious in women up to 45 years.
Management of Recipients of Kidney Transplants Who Have Cancer:
Immunosuppression management and treatment in transplant recipients with cancer is complex and challenging, and a concerted approach between transplant professionals, oncologists, and allied health professionals is needed to ensure optimal care. Judicious reduction in immunosuppression load for patients with early- to moderate-stage malignancy may be a reasonable first step, and all strategies should be tailored to the individual’s needs.
Immunotherapy:
Immune-checkpoint inhibitors are effective in treating melanoma, non-small cell lung cancer, and renal cell carcinoma, but their use in the kidney transplant population requires further investigation.
Putting Patients’ Perspectives at the Heart of Cancer Management:
Patients with cancer and transplant may experience multiple symptoms, and the burden of self-management in the context of multiple morbidities is immense. Multidisciplinary interventions to alleviate concurrent, multiple symptoms is an example of how a multidisciplinary team could deliver suitable measures. Ongoing dialogues between clinicians and patients, and close attention to the patients’ overall personal needs, are essential to ensure their voices are heard. Complete immunosuppression withdrawal is a difficult decision for both patients and clinicians, and some clinicians may consider stopping either or both the calcineurin inhibitors and antiproliferative agents gradually and rotating to higher-dose corticosteroids to prevent the risk of acute rejection.
Conclusion :
Cancer is the leading cause of morbidity and mortality in patients with kidney transplants, and a multidisciplinary, integrated approach is needed to manage the high symptom burden.
Abstract
Malignancy is one of significant complication of organ transplantation including renal transplantation.
The risk of malignancy post renal transplantation is high reaching about two to three times higher than the incidence in general population. The prognosis of these malignancy is usually poor especially for melanoma , RCC , PTLD. The screening strategy and treatment in this specific group of patient is still need to be improved .
Introduction
Between the options of renal replacement therapy , renal transplantation is best option as it is cost effective , improve survival and life quality.
In spite of these advantages transplantation patient should be kept on immunosuppressive therapy for ever , which carry a high risk of malignancy and opportunistic infection .
Post -transplant malignancy is the 2nd most common cause of death. Post- transplant patient are high risk and usually carry bad prognosis and to prevent this it is important to implement the preventive measures like vaccination ( HPV) and malignancy screening programs in order to diagnose the cancer early before advancement to untreatable level .
Incidence of All-Cause and Site-Specific Cancer after Transplantation:
The overall incidence of malignancy post renal transplantation is around 10% to 15% at fifteen year post transplant.
According to some country reports, the skin malignancy incidence is around 60% , which is about 2-3 time higher than that of general population.
The degree of high risk is also related to malignancy types with higher is associated with viral and immune related malignancy like post-transplant lymphoproliferative disease (PTLD), anogenital Ca , and Kaposi sarcoma . In contrast , the incidence of some other malignancies like breast and prostate is not increased I post transplantation.
Cancer Mortality in Recipients of Kidney Transplants:
When malignancy is diagnosed , the prognosis is usually poor with high mortality which is about 1.8- 1.9 time the mortality in general population. The high risk of death reported with melanoma, urogenital cancers, and non-Hodgkin lymphoma , is 5 – 10 times higher than in non- transplant patient .
The cause of this high risk of death is not understood , but may be associated with
a- Alteration in cell biology because of immune suppression.
b- Accompanying chronic disease.
c- Under developed screening program.
d- Low patient a awareness about this complication.
Risk Factors for Cancer Development :
Risk factors for post transpalant malignancy include :
A- As with general population
1- Old patients ,
2- Gender – male,
3- Tobacco use
4- Excessive sun exposures .
5- Geographical area may affect the type of malignancy .
B- Specific to transplantation.
1- Potent immunosuppression (depleting agents). Because of altered surveillance and immunity against viruses and tumor cells .
2- acute rejection .
3- sensitization state pre transplant.
4- hemodialysis vintage .
5- Pre transplant malignancy.
Although it is known that the overall immunosuppression state rather than specific immunosuppressive drug is the precipitating factor for malignancy , but there is some experimental evidence to support the role of specific drug in inducing malignancy .
Currently, there is no conclusive evidence to suggest one.
some experimental report that shown that tacrolimus increases the level of TGF-B and therefore enhances tumor promotes tumor progression and metastasis.
More over CNI stop signaling by calcineurin and nuclear factor of activated T lymphocyte, which can
activate p53, a feature of NMSCs.
.Cyclosporine has direct oncogenic role in malignancy effects on tumor occurrence and progression,
by TGF-B or IL-6 overexpression ways .
New reports shows that cyclosporine has ability to prevent DNA repair, which may lead to mutation accumulation, predisposing to active T lymphocyte apoptosis , and preventing apoptosis
in other cells by opening the mitochondrial permeability transition pores (37).
Azathioprine has a close association with malignancy , this is because the azathioprine increase the skin sensitivity to UVA light with accumulation of its metabolite in DNA may predispose to NMSCs.
Mammalian target of rapamycin (mTOR) inhibitors, Has anti malignancy properties by inhibiting malignancy cell growth by stopping the cell cycle and enhancement of apoptosis. This anti malignancy property is reported againist many types of malignancy like ( pancreas Ca, breast Ca , prostate Ca and more others ) .
The specific mechanism behind the anti tumor property of mTORI inhibitors are :
A- Cell type–specific c fashion apoptosis induction.
B- P53 activation and reduction in the cyclin and survivin levels .
Depleting agent (r ATG-, Alemtuzmab, OKT3- has been removed from markets ) uses is a risk factor for development of malignancy such as post- transplant lymph proliferative disorders and melanoma . the mechanism of this association is not well understood. But it could be due to an inadequate immune recovery after the use of these agent .
Common Cancers after Transplantation:
Risk of post transpalant malignancy as a general is higher when Compared to general population, but some types of malignancy is much more common than other types.
Renal Cell Carcinoma:
The risk of renal cell carcinoma in post renal transplantation is about seven times higher than general population. Usually it is of renal cell carcinoma ( 78%) and when diagnosed it is in early stage , low grade and small size with metastatic risk at the time of diagnosis of only two percent . 90% is originating from native kidney .
Melanoma is about six fold higher in renal transplanted patient compared to general population with poor prognosis ( highest death rate )
Risk factors for RCC are :
A- Gender- male sex.
B- Old age.
C- Africa origin.
D- Long dialysis vintage .
E- Potency of immune suppression – rather than specific drug .
F- Underlying cause – like glomerular diseases , hypertensive nephropathy and vasculitis .
Note: But the lowest risk for RCC is reported with Diabetic nephropathy and ADPCKD
Treatment options: the treatment should be individualized.
1- Partial nephrectomy .
2- Radical nephrectomy .
3- Percutaneous ablation .
Note : nephron sparing approach is safe and effective .
Skin Cancer:
Types : – keratinocyte carcinomas, squamous cell carcinoma, basal cell carcinoma, Kaposi sarcoma, and malignant melanoma. They are highly aggressive than same malignancy in normal non transplant patient . Kaposi sarcoma has 100 fold higher and squamous cell carcinoma has 250 fold higher than non transplant patient.
Pathogenesis and risk factors : is multifactorial
A- UVR
B- HPV – human papilloma virus ,
C- History of skin malignancy before transplantation.
D- older age.
E- Race ( Mediterranean, Africa, and Central Europe ).
F- Gender (males).
G- Immunosuppression drugs may enhance malignancy occurrence. (mainly cyclosporine and azathioprine)
TREATMENT :
1- Carcinoma in situ :
a. topical “flurouracil and imiquimod cream.
b. photodynamic therapy.
surgical excision or electrodesiccation and curettage.
c. Mohs micrographic surgery, 98% cure
2- Inoperable situations :
a- primary radiation.
b- Chemoprophylaxis – specific indication ( retinoids and nicotinamide ).
3- Metastatic cutaneous squamous cell carcinoma :
3-systemic chemotherapy and/or immunotherapy .
4- If patient on CNI treatment :
Reducing the dose or change to mTORi inhibitor may induce cancer regression by reaugmenting the immunity againist the HHV (The causative virus ).
Risk factors for melanoma development:
A- Pretransplant melanoma.
B- White race .
C- older age (50 years) .
treatment of melanoma :
A- surgery – full margin removal.
B- Manipulation of immunesupresion – according to case.
Post-Transplant Lymphoproliferative Disease:B cell type
It is a rare disease 1%-2% with bimodal pattern ( 1st at 1st year second at 5th year). The studies report a recent decreasing incidence. Ninety five percent are of B cell type , 5% only are of T cell type.
Although it is a rare complication but associated with poor prognosis . ninety percent has association with EBV infection. Which acquired early in life with mild non-specific symptoms , and stay quiescent within B lymphocyte for years. This virus can reassumes activity once there is immune suppression and play important role in PTLD oncogenesis.
Risk factors :
1- Pretransplant EBV seronegativity and primary EBV infection are important risk factors for early EBV-positive PTLD.
2- Pediatric age group. 30 fold higher than general population.
3- Gender – male .
4- depleting agents, OKT , large dose tacrolimus,
5- EBV D +VE / R –VE .
6- co stimulation blocker (belatacept ) .
treatment :
1- The target is complete cure .
2- Immunosuppresion manipulation is important with variable result.
3- rituximab and chemotherapy (doxorubicin, cyclophosphamide, vincristine, prednisone)
this complication is associated with high mortality , patient with PTLD has fourteen times higher risk of death than post- transplant patient without PTLD . The survival rate is about 45% after ten years of transplantation. The worsts prognosis is with bone marrow involvement type then extra nodal then the nodal type.
Cancer Screening Strategies in Transplant Recipients:
Malignancy screening is beneficial in general population because it helps to detect the cancer in its early stage and this will reduce mortality . but the same thing is not applied in malignancy of post renal transplantation as its benefit is not proven.
As there is no specific evidence based recommendation for screening post- transplant patients, usual recomondation for general population is used for screening of breast Ca , colorectal Ca ,and cervical Ca .
Some suggest Dermatologist examination in high risk group for skin cancer . Serum alfa fetoprotein and liver ultrasound image needs to be carried out every 6 month in liver cirrhosis and chronic viral hepatitis patients.
Regular renal ultra sound examination ( annually or biannually ) is needed in patient with high risk of RCC like
A- acquired cystic disease.
B- a family history of renal cancer .
C- . excesive smoking
D- Chronic analgesics use .
Human Papillomavirus Vaccination in Recipients of Kidney Transplants:
Human papilloma virus is closely related to anogenital cancer . this malignancy is higher ( about 12 times) in post transplantation patient compared to general population . vaccination present to prevent this to prevent this viral infection . This vaccination is very effective ( BY 100%) in prevention cervical intraepithelial neoplasia.
This vaccine now is used for all genders between nine and twenty five year age. This vaccine is safe in transplantation but the response to vaccination is detected in half of vaccinated patients may be due to virus genotype and degree of immunosuppression . therefore it preferred to vaccinate patients before transplantation as it is more efficacious. .
Management of Recipients of Kidney Transplants Who Have Cancer:
Immunosuppression Management and Treatment in Transplant Recipients with Cancer
Immunosuppression manipulation in transplant patient with cancer is not easy .it need multidisciplinary team involving nephrologist and oncologist .
Careful decreasing the immunosuppression state is important point in management of these patient. As this approach may carry a risk of graft rejection , this should be discussed with patient.
Changing the immunosuppressant to mTORI inhibitor is proven to be beneficial to induce malignancy regression in squamous cell carcinoma and Kaposi sarcoma but put the recipient to face the wide side .
Immunotherapy:
The use of checkpoint inhibitors directed to the programmed death-1/programmed death ligand-1 interaction and/or the CD28-CD80/86 axis with cytotoxic T lymphocyte–associated protein-4 Ig
Is a very important step in treatment of malignancy by enhancing immunity against malignant cells.
But its use in transplant patient is limited by high risk of graft rejection for that reason it is not recommended for transplant recipient at this time.
level of evidence 5 .
De Novo Malignancies after Kidney Transplantation
Cancer is one of the most dreaded side effects of immunosuppression following kidney donation.
In most Western nations, cancer is the second most common cause of death among transplant recipients, behind cardiovascular illness.
Clinicians and decision-makers have adopted preventive policies, such as human papillomavirus (HPV) vaccination and cancer-screening strategies, to detect cancers at their earliest possible stage before they progress into advanced-stage, incurable disease, in response to higher risks and poorer cancer outcomes.
Incidence of All-Cause and Site-Specific Cancer after Transplantation
At around 15 years after transplantation ,the incidence of solid organ cancer ranges between 10% and 15%.
The cumulative incidence reaches 60% in Europe, Australia, and New Zealand for skin cancers.
In patients with kidney transplant ,The excess overall cancer risk exceeds that of the general population by approximately two- to three-fold after adjustment for age and sex.
The cancer type is also determine the magnitude of the higher risk , viral-related and immune- driven cancers such as post-transplant lymphoproliferative disease (PTLD), anogenital cancer, and Kaposi sarcoma have the greater risk.
Breast and prostate cancers are not increased in recipients of transplants .
Cancer Mortality in Recipients of Kidney Transplants
The risk of death is high once cancer developed.
The standard mortality ratios for all cancer types are at least 1.8–1.9 times higher compared with the age- and sex-matched general population.
Risk Factors for Cancer Development
Some of these factors are shared by patients in the general population such as increasing age, male sex, smoking, and prolonged sun exposures.
Other risk factors, including immunosuppression use (T cell–depleting agents), acute rejection ,sensitization status ,and duration of dialysis before transplantation ,are specific to those with kidney disease and transplant populations.
having CKD (irrespective of the CKD stage) is associated with higher cancer risk and poor cancer outcomes .
impaired tumor surveillance and immunity to viral or other tumor antigens.
A previously treated pretransplant malignancy .
The geographic areas also affect specific cancer development .
Mechanisms of Cancer Development after Transplantation
The effects of immunosuppression on dampening the immune system may create a variety of pathways for cancer development.
1-poor immune control of known oncogenic viruses in patients on immunosuppression.
2-accumulation of mutations that would otherwise be repaired or recognized by the immune system.
3- Type of immunosuppressant , tacrolimus increases the level of TGF-b and thereby promotes tumor progression and metastasis. Cyclosporine also ,through TGF-b or IL-6 overexpression pathways has direct effects on tumor development and progression .cyclosporine is capable of inhibiting DNA repair, thereby accumulating mutations, inducing apoptosis in activated T cells, and inhibiting apoptosis in other cells by opening the mitochondrial permeability transition pores .
Also Azathioprine sensitizes the skin to UVA radiation and causes the accumulation of 6-thioguanine in the DNA, leading to a higher risk of NMSCs.
On contrary, Mammalian target of rapamycin (mTOR) inhibitors, have potential antitumor effects by inhibiting cancer growth through cell-cycle arrest and initiation of apoptosis.
the risks of cancers such as PTLD and melanoma increases with the use of induction therapy with T cell-depleting agents In addition, T cell–depleting agents used in the treatment of acute rejection of the kidney allograft also heighten the risk of cancer development .
Level of evidence V
Please summarize this article
INTRODUCTION:
This is a narrative review of new onset malignancy after renal transplantation. Renal transplantation remains the best treatment modality for end stage renal disease both due to improvement in quality of life as well as cost effectiveness. However it is not without its drawbacks. The second leading cause of death in transplant recipients is cancer (after cardiovascular disease), but unlike cardiovascular disease a lot still remains unknown about pathogenesis, risk factors and preventive measures for malignancy.
INCIDENCE AND RISK FACTORS:
The incidence of solid organ cancers is 10-15% & >60% for skin cancer in kidney recipients. There is 2-3 fold increase in overall risk of cancer in kidney recipients with 2 times risk of death as compared to general population. Age, male gender, smoking, sun exposure are risk factors for cancers in general population and apply to renal recipients as well. Immunosuppression, viral infections, acute rejections, sensitization status and history of dialysis before transplant are risk factors specific to transplant recipients.
MECHANISMS:
1. Immunosuppression. 2. Oncogenic viruses. 3. Accumulation of mutations. 4. CNI associated activation of p53. 5. Azathioprine associated skin cancers. 6. T-cell depleting agents for induction / rejection. 7. mTOR inhibitors having protective effect against cancers.
COMMON CANCERS:
1. Renal neoplasms: are 7 times more common in post-transplant patients however usually caught at earlier stage due to regular abdominal scans, with < 2% metastasis at presentation. Renal malignancy is almost always in native kidneys with only 0.1% incidence in graft. Surgical treatment leads to comparable survival as for non-transplant patients.
2. Dermatological cancer: Most common cancer in renal transplant recipients. More aggressive than in general population, with risk increased by 250 times for squamous cell carcinoma, 100 times for Kaposi sarcoma, and 5-8 times for melanoma. Risk factors include UV exposure, HPV infection, pre-transplant skin cancer, older age, male gender, and race. Management depends on the diagnosis ranging from topical fluorouracil, imiquimod cream, photodynamic therapy, surgical excision, to chemoprophylaxis with retinoids and nicotinamide in aggressive, multiple or early onset cancers.
3. PTLD: Rare (1-2% in adults and 3% in children in first 10 years post-transplant), but associated with poor outcomes, with death rates 14 times more than non-PTLD kidney transplant recipients. Associated with EBV in 90% cases. 95% are B-cell type lymphoma. Risk factors for adults include pre-transplant EBV seronegativity and primary EBV infection. Risk factors for children include young age, male gender, donor EBV seropositivity with recipient seronegativity, T cell depleting agent use, Belatacept use, and high tacrolimus dose. Treatment involves reduction in immunosuppression and chemotherapy. Risk for death include male gender, increased age at diagnosis, and bone marrow, RES site more than extranodal and nodal disease, with median time to death being 6 months.
SCREENING:
Cancer screening recommendations in transplant recipients are not based on any trial based evidence, but are extrapolated mainly from general population (breast, colorectal, and cervical cancer). Routine skin check for patients with high-risk for skin cancer, regular abdominal ultrasound for patients with liver disease and chronic HBV infection, and regular ultrasound for RCC detection in high-risk patients are recommended.
VACCINATIONS
HPV vaccination has 99-100% efficacy to prevent cervical intraepithelial neoplasm, is safe and generally recommended in women prior to transplant.
MANAGEMENT
Management of transplant recipients developing cancer involve a multidisciplinary approach and includes reduction or alteration in immunosuppression as well as use of immunotherapy (immune checkpoint inhibitors). For early to moderate stage malignancy, judicious immunosuppression reduction is an early step. For squamous cell carcinoma, conversion to mTOR inhibitor is associated with reduced risk of cancer in long-term although with increased risk of death. There is insufficient data to consider mTOR inhibitors as protective except for squamous cell cancer and Kaposi sarcoma. Data for use of immune checkpoint inhibitors in transplant recipients is also limited, hence not recommended.
What is the level of evidence provided by this article?
Narrative review at level V of evidence.
Q1: cancer development following kidney transplantation is the second cause of death in recipients after
cardiovascular diseases.
preventive strategies such as HPV vaccinations, and screening strategies following immunosuppression
are necessary. There are greater risks of viral and immune-related cancers such as PTLD, anogenital, and
Kaposi sarcoma. However, breast and prostate cancers are not increased. Mortality is high, especially for
melanoma, urogenital cancers, and PTLD. Therefore, patient education is necessary. Risk factors include
immunosuppression, sensitization, and long-term dialysis before TX. Geographic area determines the
specific type of cancer. Impaired immunity to viral or other tumor antigens is the other risk. Chronic
hepatitis B virus infection is a major risk factor for liver cancer. Mechanisms of cancer development by
immunosuppression are through the accumulation of mutation that should be recognized by the
immune system. For instance, UV-induced DNA damage results in skin cancers. Tacrolimus increases
TGF-B and promotes metastasis. CNIs can activate p53 which is a hallmark of NMSC. Azathioprine
sensitizes the skin to UV radiation. On the other hand, mTOR inhibitors have potential anticancer
effects. ATG increases the risk of cancer. Common cancers after TX are renal cell carcinoma, skin cancer,
and PTLD.
HPV vaccination is recommended for women considered for TX.
Management of recipients with cancer includes alteration in immunosuppression or conversion to
mTOR inhibitors and immunotherapy.
Q2: The level of evidence if V
Summary of this article:
The increase risk of cancer after transplantation is approximately two to three times higher than the age- and sex-matched general population, driven largely by viral- and immune-related cancers.
Once cancers develop, the risk of death is high.
This review focuses on the incidence, mechanisms, diagnosis, prevention, and treatment of cancer after kidney transplantation.
Risk factors:
Old age, male sex, smoking, prolonged sun exposures, immunosuppression use (T cell–depleting agents), acute rejection, sensitization status duration of dialysis before transplantation and different geography area have different risk of particular malignancy.
Viral-associated cancers, such as Kaposi sarcoma (human herpesvirus 8), PTLD (Epstein– Barr virus [EBV]), and lip and anal cancers (HPV) are common in patients with suppressed immune systems.
Immunosuppression mechanism for malignancy:
-Tacrolimus increases the level of TGF-b and thereby promotes tumour progression and metastasis.
-Calcineurin inhibitors inhibit signalling via calcineurin and NF of activated T cells, which can activate p53, a hallmark of some Non Melanotic Skin Cancers.
-Cyclosporine also has direct effects on tumour development and progression, through TGF-b or IL-6 overexpression pathway.
-Azathioprine sensitizes the skin to UVA radiation and causes the accumulation of 6-thioguanine in the DNA, leading to a higher risk of NMSCs.
-T-cell depletion, there is often an incomplete T-cell recovery, which may have a long-term effect on immune homeostasis, leading to an impaired immune system (and subsequent cancer development.
-Mammalian target of rapamycin (mTOR) inhibitors, have potential antitumor effects by inhibiting cancer growth through cell-cycle arrest and initiation of apoptosis.
Renal Cell Carcinoma post-transplant:
-Up to 7 fold increase risk
-90% of renal cell carcinomas develop in the native kidneys, only 0.1% incidence in kidney allograft.
-Risk factors for development of renal cell carcinomas post transplantation include male sex, increasing age, African descent, and longer time on dialysis, with regard to disease aetiology, patients transplanted for kidney failure secondary to glomerular diseases, hypertensive nephrosclerosis, and vascular disease appear to have the greatest associated risk.
-Surgical options include Radical nephrectomy, Partial nephrectomy, Cryotherapy or HIFU.
Skin cancer post-transplant:
The most commonly include cutaneous squamous cell carcinoma, basal cell carcinoma, Kaposi sarcoma, and malignant melanoma, with keratinocyte carcinomas comprising 90%–95% of these skin cancers.
Risk factors are exposure to UV radiation, HPV, pretransplant skin cancer, older age, race, and sex (males at greater risk than females), immunosuppressive medications (mainly cyclosporine and azathioprine).
Kaposi sarcoma exceeds 100 times than that of the general populations. Melanoma has the highest mortality.
Management:
In patients with actinic keratoses and squamous cell carcinoma in situ, management options include topical fluorouracil and imiquimod cream, photodynamic therapy, and surgical excision or electrodesiccation and curettage, in inoperable case radiation, chemoprophylaxis in early onset.
Regression of Kaposi sarcoma has been reported after switching from calcineurin inhibitors to sirolimus by restoring effector and memory T-cell immune activity against human herpesvirus.
For melanoma Primary treatment is surgical with wide excision and adequate margins, based on Breslow thickness, as per the National Comprehensive Cancer Network guidelines.
Post-Transplant Lymphoproliferative Disease post transplantation:
Approximately 90%, PTLD is associated with EBV, viruses can reactivate because of depressed T-cell function, with a lack of T-cell control over B-cell proliferation.
PTLDs are of B-cell types, with approximately 5% of patients having the T-cell type.
There is a bimodal distribution in PTLD incidence, with the risk of PTLD being the highest in the 12 months post-transplant, and it then decreases until the fifth year after transplantation.
The risk of death among recipients of kidney transplants who have PTLD is 4- fold higher than recipients without PTLD but it has decreased due to chemotherapy.
Pretransplant EBV seronegative and primary EBV infection are important risk factors for early EBV-positive PTLD.
Belatacept, has also been found to be associated with a higher risk of PTLD, particularly cerebral PTLD in patients who are EBV negative, and when used in higher doses.
Mainstay of treatment is immunosuppression reduction. Prior work reported the use of rituximab and chemotherapy (doxorubicin, cyclophosphamide, vincristine, prednisone) have improved overall survival, with 5-year survival at around 60%.
Prevention:
HPV vaccination is recommended for women before or after transplantation.
There is lack of evidence to support routine screening in this high-risk group, routine population-based cancer screening for breast, colorectal, and cervical cancer is recommended.
Management of Recipients of Kidney Transplants Who Have Cancer:
Multidisciplinary approach
Risk of acute rejection from under-immunosuppression, and cancer resulting from over-immunosuppression is big challenge in management.
Judicious reduction in the overall immunosuppression load for patients with early- to moderate-stage malignancy may be a reasonable first step.
There are insufficient data to consider mTOR inhibitors as protective against other cancer types apart from squamous cell carcinoma and Kaposi sarcoma.
The use of checkpoint inhibitors is limited in recipients of transplants given the potential for rejection with nonspecific immune-system activation.
For patients who have progressed to advanced-stage malignancy, complete immunosuppression withdrawal is a difficult decision for both patients and clinicians.
Level of evidence provided by this article:
Level of evidence is V
Long term kidney transplant recipients have clinical complications.. After cardiovascular disease cancer is the second most common cause of death in few western countries apart from infection being the second cause of death in developing countries…. The higher incidence and morbidity from cancers have made clinicians aware about cancer screening programs and HPV vaccination….
The cumulative incidence of solid organ transplantation after transplantation is 10 to 15% after renal transplant at the end of 15 years…. The cumulative incidence of few skin cancers can reach around 60% in few European and Australian countries. Kaposis sarcoma, non Hodgkins lymphoma, non melanoma and melanoma skin cancers are more common in solid organ transplant recipients….Few cancers like breast and prostate are not increased incidence in post transplant recipients…
There is increased risk of mortality of 1.5-2 times after skin cancer in renal transplant patients
There are many reasons for higher incidence of cancer after renal transplantation…some factors like increasing age, male sex, smoking, prolonged sun exposure are common… the longer the duration of CKD itself seems to be a risk factor for de novo malignancy after renal transplantation…RCC and multiple myeloma seem to have an increased incidence in dialysis and CKD patients themselves…Recent studies show increased incidence of all cause mortality in recipients after pre transplant malignancy which may not be related to malignancy recurrence alone…
Geographic variations are also reported in various population groups….Observational date from Europe, North America and Australia indicate that there is increased incidence of Non melanoma skin cancer, PTLD and lip cancer as compared to Asian and middle eastern countries where urothelial cancers and renal cell cancers were more….Taiwan for example is endemic to Hepatitis B and there is increased incidence of liver cancer after renal transplantation…
Maintenance immunosuppression after renal transplant paves the way for other malignancies…One such mechanism is increased incidence of oncogenic viruses after renal transplant like HHV8 – Kaposis sarcoma, EBV – PTLD, Lip and anal cancer – HPV. There is increasing evidence to say that CNI have tumor progression effect….Tacrolimus has shown to increase the levels of TGF beta which promotes tumor progression and metastasis….Activation of p53 takes place as a side effect of calcineurin inhibition which inturn causes NMSC.. Similarly CYC also has been shown to have increased DNA mutations and inhibiting apoptosis in other cells….AZA increases the accumulation of 6 thioguanine sensitizing the skin towards UVA and NMSC…mTOR inhibitors have potent antitumor activities…inhibits cell cycle growth and promotes apoptosis… invitro studies have demonstrated reduced activity of cancer cells incubated with mTOR inhibitors….Studies have consistently demonstrated increased cancer incidence after use of ATG, Anti CD3 agents used for induction agents presumbly due to prolonged T cell suppression causing immune dysregulation….
Cancer screening is recommended as per the guidelines for general population itself as there are no major recommendations… frequent skin examination to detect early skin lesion must be taught to the renal transplant patients… for those with chronic liver disease due to Hep B it is associated to screen every bieenially with
USG and AFP….Annual screnning for RCC of native kidneys are recommeded for those with prolonged dialysis duration and acquired cystic disease and smoking
Vaccination of transplant patient with HPV vaccine is recommended to reduce the incidence of anogenital cancer…ideally vaccination should happen before transplant itself…
Level of evidence 5
This review focuses on the incidence, mechanisms, diagnosis, prevention and treatment of cancer after kidney transplantation
Risk factors & mechanisms of cancer development after transplantation:
Increasing age, male, smoking and prolonged sun exposure
Immunesupressive drugs, sensitization status, and duration of dialysis before transplantation, and CKD, HPV, EBV, HBV …etc.
CNI increases the level of TGF-b and thereby promotes tumor progression and metastasis, inhibit signaling via calcineurin and activate p53, a hallmark of some NMSCs.
Azathioprine sensitizes the skin to UVA radiation and causes the accumulation of 6-thioguanine in the DNA, leading to a higher risk of NMSCs.
m-TOR inhibitors, may have potential antitumor effects by inhibiting cancer growth through cell-cycle arrest and initiation of apoptosis.
Common cancers after transplantation:
Renal cell carcinoma:
Usually early, low-grade, small kidney masses; of which, 75%–80% are renal cell carcinoma, in the native kidenys, with the risk of metastasis at presentation being 2%.
Kidney failure secondary to glomerular diseases, hypertensive nephrosclerosis and vascular disease appear to have the greatest risk.
The outcome of renal cell carcinomas after radical treatment in the transplant population is comparable with that of the general population.
Skin Cancer:
Cutaneous squamous cell carcinoma, basal cell carcinoma, Kaposi sarcoma, and malignant melanoma, with keratinocyte carcinomas comprising 90%–95% of these skin cancers.
UV radiation, HPV, pretransplant skin cancer, older age, race, and male sex are risk factors for skin cancer in transplant recipients.
Mohs micrographic surgery, offers the most definitive method of treatment, with cure rates of 95%–100%.
Topical fluorouracil and imiquimod cream, photodynamic therapy, are modalities used for treatment.
Kaposi sarcoma increased by the use of CNI, this could be overcome by m-TORi use.
The prognosis is worse among transplant patients than that for the general age and sex matched population, melanoma has the worst prognosis.
Post-Transplant Lymphoproliferative Disease:
PTLD is associated with EBV, and pears a poor prognosis;14 % mortality.
PTLDs are of B-cell types, with approximately 5% of patients having the T-cell type.
Risk factors are: First year post-transplant and 5 years after transplant, Pretransplant EBV seronegativity/ donor positive and primary EBV infection, particularly in younger recipients of transplants.
The mainstay of treatment is immunosuppression reduction, Rituximab and chemotherapy.
HPV vaccination is the preventive measure recommended.
Cancer screening strategies in transplant recipients:
High quality, randomized controlled trials have shown that cancer screening through early detection reduces cancer- specific mortality in the general population.
Breast cancer: screening mammography once every 2 years for 50-74 years of woman
Cervical cancer: annual Pap testing
Bowel cancer : sigmoidoscopy every 5 years or colonoscopy every 5-10 years.
Skin cancer : monthly self skin examination and 6 to 12 monthly total body skin examination by expert physicians and dermatologists
Management
Immunosuppression managemeny:
Optimization of IS therapy to prevent both rejection and graft loss and manage cancer is the challenge here.
Shift from CNI to mTORi in case of SCC and Kaposi sarcoma helps in treatment but unfortunately was associated with risk of mortality and discontinuation due to its complications.
Immunotherapy
Use of immune therapy targeting cell apoptosis may be beneficial in melanoma, lung and renal cell carcinoma
Conclusion
The study identify patient groups and cancer types, helps in surveillance program, and providing data on counselling pretransplant patients on the risk of malignancy.
2.What is the level of evidence provided by this article
Level V evidence
Cancer is the second most common cause of death in kidney transplant recipients after cardiovascular disease. Risk factors for cancer development are: increasing age, male sex, smoking, prolonged sun exposure, immunosuppression use, actute rejection, sensitization status and duration of dialysis before transplantation. Though types of cancer vary according to geographic region, the common cancer that developed after renal transplantation are Kaposi sarcoma, non- melanoma skin cancer, PTLD, malignant melanoma, RCC and anogenital cancer. Specific virus are associated with some specific cancer e.g. EBV with PTLD, HHV-8 with NMSC, HPV with anogenital cancer, HVB with liver cancer. Risk of death is greatest among those with melanoma, urogenital cancer & PTLD. Among immunosuppresive drugs CNI, AZA, T- cell depleting agents are associated with risk of cancer development & mTOR is associated with regression of cancer. Though Transplant patient are always at increased risk of cancer development, specific guidelines about screening are not not well established, most are derived from guidelines for general population. Though ruduction of immunosuppresion and adding mTOR inhibitiors, ICI are the current treatment option for post transplant cancer patients, a combined work of nephrologist, oncologist, other specialist, psychiatrist are always needed. At the same time, try to give importance the patient preferences & always calculate the risk benefit ratio of prescribed medicine.
1. Summary of the article
Basis and introduction:
After cardiovascular disease, cancer is the second leading cause of death among recipients of transplants in most Western countries.
The cumulative incidence of solid organ malignancy ranges between 10% and 15% at around 15 years post-transplantation. The prevalence of cancer in post-kidney transplantation is three times more than in the general population.
Cancer related mortality also is increased 5-10 folds post-transplant.
This, in recent time, has triggered the need for physicians, policymakers, and patients to develop joint decisions on preventive methods to reduce morbidity and mortality from different cancers post-transplant.
In this review article, the incidence, mechanisms, diagnosis, prevention, and treatment of cancer after kidney transplantation are elaborated.
Risk factors:
· Increasing age, male sex, smoking, prolonged sun exposures
· Heavy immunosuppression (T cell–depleting agents like Thymoglobulin), treatment of acute rejection, sensitized patients requiring desensitization, and long duration on dialysis (RCC, Multiple myeloma)
· Geographical variations differ risk of particular cancers –
Europe, North America, Australia, and New Zealand – skin cancer (NMSCs), PTLD, and lip cancer
Asian and Middle East – urothelial transitional cell carcinoma, renal cell carcinoma, and GI cancers
Taiwan – 5 folds excess risk of liver cancer
· Neoplastic lesions and cancer (treated) prior to transplant
· Viral infection associated – Kaposi sarcoma (HHV8, PTLD (EBV), Lip and anal cancers (HPV) are common in immunosuppressed patients
Mechanisms of Cancer development after transplant:
· poor immune control of viruses – increase viral-associated cancers Kaposi sarcoma (HHV8), PTLD (EBV), lip and anal cancers (HPV)
· accumulation of mutations (not repaired / recognized by immune system).
– immunosuppression impairs the cells’ ability to repair UV radiation–induced DNA damage.
· Immuno-suppression drugs with direct oncogenic potential
-Tacrolimus increases TGF-b à tumour progression and metastasis;
-inhibits signalling via calcineurin and NF of activated T cells à activate p53 (hallmark of NMSCs)
-Cyclosporine has direct effects on tumour development and progression, through TGF-b or IL-6 overexpression pathway.
-Azathioprine sensitizes the skin to UVA radiation and causes the accumulation of 6-thioguanine in the DNA, leading to a higher risk of NMSCs.
-T-cell depleting drugs cause incomplete T-cell recovery à long-term effect on immune homeostasis and impaired immune system
– mTOR inhibitors – have potential antitumor effects by inhibiting cancer growth through cell-cycle arrest and initiation of apoptosis.
COMMON CANCERS after TRANSPLANT
1. Kidney cancers (RCC)
– Up to 7th fold increase risk
-90% are RCC develop in the native kidneys – 80% low grade small tumors
– only 0.1% incidence of tumours in kidney allograft.
Risk factors
– male sex, increasing age, African descent, and longer time on dialysis,
-Native kidney disease (etiology) – glomerular diseases, hypertensive nephrosclerosis, and vascular disease are high risk
Treatment – Partial nephrectomy in majority (67%) of small tumours; Radical nephrectomy (19%); percutaneous ablation (Cryotherapy and HIFU) 12%.
Good prognosis of surgically treated tumours, similar to gen polulation
2. Skin cancers:
– Most common cancers post renal transplant and more aggressive than in general population
– Squamous cell carcinoma, basal cell carcinoma, Kaposi sarcoma, and malignant melanoma, keratinocyte carcinomas comprise 90%–95% of skin cancers.
– Risk factors are UV radiation, HPV, pretransplant skin cancer, older age, white race, and male sex, immunosuppressive medications (CsA and azathioprine).
– Kaposi sarcoma common in ethnic groups (Mediterranean, Africa, Central Europe) – 100 times more, than in general populations. Melanoma has the highest mortality.
Management of skin cancers –
Ø Actinic keratoses, SCC in situ – topical 5FU and imiquimod cream, photodynamic therapy, and surgical excision or electrodesiccation and curettage
Ø Mohs micrographic surgery, with histologic negative margins – 95–100% cure rate
Ø Radiation in inoperable cases for local control
Ø Chemoprophylaxis – (Retinoids and Nicotinamide) for SCC advised if multiple recurrences (>5 / year), aggressive or early onset disease
Ø systemic chemotherapy and/or immunotherapy – for metastatic SCC
Ø Melanoma – Surgical excision with adequate margins;
v Reduction of immune-suppression – Stopping AZT, MMF
v Switching CNI àSirolimus: regression of Kaposi sarcoma reported
3.Post-Transplant Lymphoproliferative Disease (PTLD)
rare but associated with poor outcome – increase mortality >14times
90% associated with EBV infection of B cells (latent infection) à viral reactivation causes uncontrolled B-cell proliferation (lack of T-cell control)
Incidence – 1-2% of adult and 3% of paediatric renal Tx recipients
bimodal distribution – highest in first 12 months, then decreases until 5 years post-transplant.
Risk factors –
Pretransplant EBV sero-negativity
primary EBV infection
negative recipient EBV serology (with positive donor EBV serology) – x 4 folds
Young age & male sex – paediatric recipients (30-times higher)
T cell–depleting agents (Thymoglobulin), OKT3 (muromonab-CD3), high dose of Tacrolimus and Belatacept (EBV negative Cerebral PTLD)
Mainstay of treatment is reduction of immunosuppression.
Rituximab and chemotherapy (doxorubicin, cyclophosphamide, vincristine, prednisone) have improved overall survival, with 5-year survival at around 60%.
Prevention (Vaccination + Screening):
· HPV vaccination is recommended for women before or after transplantation.
· Although supportive evidence is lacking, routine population-based cancer screening for breast, colorectal, and cervical cancer is recommended
· 6monthly skin checks by dermatologists for recipients with high risk
· Chronic HBV infections & liver disease – abdominal ultrasound and serum AFP every 6 months
· Patients with risk of developing RCC (acquired cystic disease, family history, smokers, long-term analgesics use) – annually / biennially USG of native kidney
Managing Kidney Transplant Recipients having Cancer:
v Multidisciplinary approach – discussion with patient and family is required
v Understanding immunologic risk versus cancer severity — optimize immunosuppression dose to prevent the risk of rejection, while balancing against the need to induce tumour regression and prevent progression.
v Judicious reduction in immunosuppression load for patients with early- to moderate-stage malignancy may be a reasonable.
v There are insufficient data to consider mTOR inhibitors as protective against other cancer types, apart from SCC and Kaposi sarcoma.
v Immunotherapy – Immune checkpoint inhibitors can cause rejection due to nonspecific immune-system activation, thus not recommended.
v For patients who have progressed to advanced-stage malignancy, complete immunosuppression withdrawal is a difficult decision for both patients and clinicians.
2. What is the level of evidence provided by this article?
Level of evidence: Level 5
Please summarise this article
The excess risk of cancer after transplantation is approximately two to three times higher than the age- and sex-matched general population, driven largely by viral- and immune-related cancers. Once cancers develop, the risk of death is high. This review focuses on the incidence, mechanisms, diagnosis, prevention, and treatment of cancer after kidney transplantation.
Risk factor
Increasing age, male sex, smoking, prolonged sun exposures, immunosuppression use (T cell–depleting agents), acute rejection, sensitization status duration of dialysis before transplantation and different geography area have different risk of particular malignancy.
Viral-associated cancers, such as Kaposi sarcoma (human herpesvirus 8), PTLD (Epstein– Barr virus [EBV]), and lip and anal cancers (HPV) are common in patients with suppressed immune systems.
Immunosuppression mechanism for malignancy
-Tacrolimus increases the level of TGF-b and thereby promotes tumor progression and metastasis.
-Calcineurin inhibitors inhibit signaling via calcineurin and NF of activated T cells, which can activate p53, a hallmark of some NMSCs.
-Cyclosporine also has direct effects on tumor development and progression, through TGF-b or IL-6 overexpression pathway.
-Azathioprine sensitizes the skin to UVA radiation and causes the accumulation of 6-thioguanine in the DNA, leading to a higher risk of NMSCs.
-T-cell depletion, there is often an incomplete T-cell recovery, which may have a long-term effect on immune homeostasis, leading to an impaired immune system (and subsequent cancer development.
-Mammalian target of rapamycin (mTOR) inhibitors, have potential antitumor effects by inhibiting cancer growth through cell-cycle arrest and initiation of apoptosis.
Renal Cell Carcinoma post-transplant
-Upto 7th fold increase risk
-90% of renal cell carcinomas develop in the native kidneys, only 0.1% incidence in kidney allograft.
-Risk factors for development of renal cell carcinomas post transplantation include male sex, increasing age, African descent, and longer time on dialysis, with regard to disease etiology, patients transplanted for kidney failure secondary to glomerular diseases, hypertensive nephrosclerosis, and vascular disease appear to have the greatest associated risk.
-Surgical options include Radical nephrectomy, Partial nephrectomy, Cryotherapy or HIFU.
Skin cancer post-transplant
The most commonly include cutaneous squamous cell carcinoma, basal cell carcinoma, Kaposi sarcoma, and malignant melanoma, with keratinocyte carcinomas comprising 90%–95% of these skin cancers.
Risk factor are-exposure to UV radiation, HPV, pretransplant skin cancer, older age, race, and sex (males at greater risk than females), immunosuppressive medications (mainly cyclosporine and azathioprine). Kaposi sarcoma exceeds 100 times than that of the general populations. Melanoma has the highest mortality.
Managment
In patients with actinic keratoses and squamous cell carcinoma in situ, management options include topical fluorouracil and imiquimod cream, photodynamic therapy, and surgical excision or electrodesiccation and curettage, in inoperable case radiation, chemoprophylaxis in early onset.
Regression of Kaposi sarcoma has been reported after switching from calcineurin inhibitors to sirolimus by restoring effector and memory T-cell immune activity against human herpesvirus.
For melanoma Primary treatment is surgical with wide excision and adequate margins, based on Breslow thickness, as per the National Comprehensive Cancer Network guidelines.
Post-Transplant Lymphoproliferative Disease post transplantation
Approximately 90%, PTLD is associated with EBV, viruses can reactivate because of depressed T-cell function, with a lack of T-cell control over B-cell proliferation. PTLDs are of B-cell types, with approximately 5% of patients having the T-cell type.
There is a bimodal distribution in PTLD incidence, with the risk of PTLD being the highest in the 12 months post-transplant, and it then decreases until the fifth year after transplantation. The risk of death among recipients of kidney transplants who have PTLD is 4- fold higher than recipients without PTLD but it has decreased due to chemotherapy.
Pretransplant EBV seronegativity and primary EBV infection are important risk factors for early EBV-positive PTLD.
Belatacept, has also been found to be associated with a higher risk of PTLD, particularly cerebral PTLD in patients who are EBV negative, and when used in higher doses.
Mainstay of treatment is immunosuppression reduction. Prior work reported the use of rituximab and chemotherapy (doxorubicin, cyclophosphamide, vincristine, prednisone) have improved overall survival, with 5-year survival at around 60%.
Prevention
HPV vaccination is recommended for women before or after transplantation.
There is lack of evidence to support routine screening in this high-risk group, routine population-based cancer screening for breast, colorectal, and cervical cancer is recommended.
Management of Recipients of Kidney Transplants Who Have Cancer
Multidisciplinary approach
Risk of acute rejection from under-immunosuppression, and cancer resulting from over-immunosuppression is big challenge in management.
Judicious reduction in the overall immunosuppression load for patients with early- to moderate-stage malignancy may be a reasonable first step.
There are insufficient data to consider mTOR inhibitors as protective against other cancer types apart from squamous cell carcinoma and Kaposi sarcoma.
The use of checkpoint inhibitors is limited in recipients of transplants given the potential for rejection with nonspecific immune-system activation.
For patients who have progressed to advanced-stage malignancy, complete immunosuppression withdrawal is a difficult decision for both patients and clinicians.
What is the level of evidence provided by this article?
Level of evidence: Level 5
SUMMARY
Introduction
Kidney transplantation still remains the best form of renal replacement therapy for patients with ESRD, but it also comes with unintended complications like developments like cancers after cardiovascular disease. As a result of this negative outcome, there is a need for physicians, policymakers, and patients to develop a preventive method to reduce morbidity and mortality that could come with different cancer.
The cumulative incidence of solid organ malignancy ranges between 10% and 15% at around 15 years post-transplantation. The prevalence of cancer in post-kidney transplantation is three times more than in the general population.
Risk factors for cancer development
Mechanism of cancer development in transplantation
The following mechanism has been postulated as the pathogenesis of cancer development post-kidney transplantation.
Common cancer after Transplantation
Management of recipients with cancer
Conclusion
Cancer remains one of the leading causes of morbidity and mortality following successful transplantation as a result of a few risk factors like the type of induction medication use, prolonged use of certain immunosuppressive, and age of the recipients. Asides from some preventive method that appears to be promising, there is yet no standard treatment method or cure for cancer in post-transplant patients. Hence, there is a need for continuous research to fill this knowledge gap.
Level of evidence is 5
kidney transplantation is the best treatment for end stage kidney disease, immunosuppressive drugs associated with increased incidence of cancer.
·Malignancy is the second leading cause of death in recipients of transplants in most Western countries, this encouraged transplant specialist to screen for cancer.Incidence of cancer is 10-15 % in solid organ at 15 y post-transplant . Common Cancers after Transplantation
Renal Cell Carcinoma
Compared with the general population, recipients of kidney transplants have a higher risk (up to seven-fold)
Skin Cancer
The most common cancer type in recipients of kidney transplants
Post-Transplant Lymphoproliferative Disease. Recommendations for cancer screening
For breast cancer, screening is recommended every 2 years for patients between 50- 74 years but depends on individual risk assessment in people less than 50 years. Prostate cancer screening is only recommended in patients between 55 and 69 years after explaining the risk and benefits. Pap smear or HPV testing every 3-5 years is recommended starting at 25 years until 74 years for cervical cancer screening. Bowel cancer screening is recommended at 45 years till 75 years with biennial fecal immunohistochemistry and sigmoidoscopy or colonoscopy every 5 years. Lung cancer screening with low dose chest CT is recommended at 55 years till 79 years in heavy smokers only.
For skin cancer, monthly self-examination and 6 monthly total body examination by dermatologist is advised. Renal cancer screening is not routinely recommended. Recommendation for liver cancer screening includes ultrasound scanning and 6-monthly alpha-fetoprotein in cirrhotic patients. Post-transplant lymphoproliferative disease is also screened for in EBD seronegative recipient of seropositive organ once at 1 week after transplant, monthly every 1-3 months and every 3/12 till the end of first year post transplant using the nucleic acid testing method. Management of recipient with cancer.
This need multidisciplinary approach between oncologist, transplant physician, and allied health professionals.
Optimization of immunosuppression.
Immunotherapy is not recommended still need further investigation.
In conclusion the recipient are in risk of developing different types of tumors specially skin cancer.
So highly recommended for screening before transplantation and post-transplant surveillance.
Level of evidence V.
This is a narrative review of level 5 evidence
Summary of the article
Cancer is the second cause of mortality in transplant recipients after the cardiovascular disease .
Melanoma, Non-Hodgkin lymphoma and ano-genital cancers carry the highest among the kidney transplant recipients being increased with the following risk factors :
· Old age
· Males
· Smoking
· Prolonged sun exposure
· HBV infection.
· Impaired immunity to viral or tumour antigens
· Pre-transplant malignancy
· Acute rejection
The most common 3 cancers post-renal transplant are :
-PTLD
-Renal cell carcinoma
-Skin cancer
Proper management of post operative malignancy includes :
-Optimization of immunosuppression
-Conversion to mTORi especially in patients with kaposi sarcoma and squamous cell carcinoma
-Immunotherapy usage is an option but with limited application .
-Treatment always starts by proper prevention through cancer screening of breast, cervical, prostate and colon cancer .
Use of immunosuppression in post transplant cases , leads to increased incidence of malignancy which is linked to higher prevalence of viral infection , poor immune surveillance of body.
the pattern of cancer is variable
in Europe and Australia , NZ- skin , PTLD, lip cancer is more common , men> women
in middle east and non -western Asia – Liver , urothelial cancer are common
in Taiwan – liver is common due to HBV infection and women outnumbered the men
mechanism of cancer development
virus linked – HHV-B with kaposi, HPV with anogenital , HBV with liver cancer , EBV with PTLD
accumulation of mutation like skin cancer
CNI can cause tumor
T cell depleting agent increases the risk of cancer
screening for cancer
special protocol for post transplant patient is not recommended based on available evidence
routine population-based cancer screening for breast, colorec-
tal, and cervical cancer is recommended
trials.
HPV vaccination is indicated in both males and females aged 9–25 years in the general pop-ulation for the prevention of HPV-related malignancies.
treatment is mainly to reduce the immunosuppression
shift to MTOR inhibitor
patient centric approach is recommended rather than a generalized approach
level of evidence
level 1
observational study
1- Please summarise this article
Introduction:
• Since cancer is the second most common cause of death in the majority of Western nations, it is a significant outcome following kidney transplantation.
• Compared to the general population of people of the same age and sex, the extra risk of cancer following transplantation is around two to three times greater.
• Viral and immune-related malignancies account for the majority of this excess risk.
• More significantly, this high-risk group lacks access to efficient screening and treatment methods.
Cancer Mortality in Recipients of Kidney Transplants
Standard mortality ratios for all cancer types are at least 1.8–1.9 times higher compared with the age- and the sex-matched general population.
The risk is greatest among those with melanoma, urogenital cancers, and non-Hodgkin lymphoma,
The exact reasons for the higher risk of death are unclear but may be due to:
• Long-term immunosuppression.
• Associated co-morbidities.
• Low uptake of recommended prevention and screening strategies.
Risk Factors for Cancer Development
Shared by patients in the general population
• Increasing age,
• Male sex,
• Smoking,
• Prolonged sun exposures
Specific to those with kidney disease and transplant populations
• Immunosuppression use (T cell–depleting agents),
• Acute rejection.
• Sensitization status.
• Duration of dialysis before transplantation.
Mechanisms of Cancer Development after Transplantation
• Through inadequate immune regulation of recognized carcinogenic viruses in immunosuppressed individuals. (Cancers linked to viruses, such as Kaposi sarcoma (HH8) and PTLD (EBV),
• As a result of mutations that would typically be corrected or identified by the immune system accumulating. (Most prevalent in the skin)
Common Cancers after Transplantation
Renal Cell Carcinoma
Compared with the general population, recipients of kidney transplants have a higher risk (up to seven-fold)
Skin Cancer
The most common cancer type in recipients of kidney transplants
Post-Transplant Lymphoproliferative Disease
In most instances (approximately 90%), PTLD is associated with EBV.
Management of Recipients of Kidney Transplants Who Have Cancer
Immunosuppression Management and Treatment in Transplant Recipients with Cancer
• It is complex and challenging.
• Need transplant professionals, oncologists, and allied health.
• Aim to optimize immunosuppression dose to prevent the risk of acute rejection, while balancing against the need to induce regression of the malignant lesion and prevent future progression,
• All strategies should be tailored to the individual’s needs.
Immunotherapy
• The use of immune-checkpoint inhibitors targeting the programmed death
Conclusions
• Cancer is the leading cause of morbidity and mortality in patients with kidney transplants.
• The lifestyle changes and the complex feelings caused by the diagnoses are overwhelming. The priorities of optimizing
• Allograft function with immunosuppression is often challenged and superseded by having a “cure” for cancer and may involve immunosuppression reduction or cessation to reduce the risk of cancer relapse and improve long-term cancer survival.
• Collaborative efforts between healthcare professionals, policymakers, trialists, and patients are needed to ensure quality evidence.
What is the level of evidence provided by this article?
Level V
De Novo Malignancies after Kidney Transplantation
Introduction
· Although kidney transplantation is the best treatment for end stage kidney disease, immunosuppressive drugs associated with increased incidence of cancer.
· Malignancy is the second leading cause of death in recipients of transplants in most Western countries, this encouraged transplant specialist to screen for cancer.
· This review about the incidence, mechanisms, diagnosis, prevention, and treatment of cancer after kidney transplantation.
Incidence of All-Cause and Site-Specific Cancer after Transplantation
· Incidence of cancer is 10-15 % in solid organ at 15 y post-transplant
· For skin cancers, the cumulative incidence reaches .60% in Europe, Australia, and New Zealand
· The excess overall cancer risk in patients with kidney transplant exceeds that of the general population by approximately 2-3-fold after adjustment for age and sex
· Breast and prostate cancers are not increased in recipients of transplants
Cancer Mortality in Recipients of Kidney Transplants
· The standard mortality ratios for all cancer types are at least 1.8–1.9 times higher compared with the age- and sex-matched general population
· The risk is greatest among those with melanoma, urogenital cancers, and non-Hodgkin lymphoma, with an overall risk of cancer-related death exceeding 5-10 times that of those without kidney transplants
Risk Factors for Cancer Development
· increasing age, male sex, smoking, and prolonged sun exposures
· immunosuppression use (T cell–depleting agents),
· acute rejection, sensitization status
· duration of dialysis before transplantation
· impaired tumor surveillance and immunity to viral or other tumor antigens.
· renal cell carcinoma and multiple myeloma, are over-represented in the CKD/ kidney-failure populations
Mechanisms of Cancer Development after Transplantation
· poor immune control of known oncogenic viruses in patients on immunosuppression such as Kaposi sarcoma (human herpesvirus 8), PTLD [EBV], and lip and anal cancers (HPV)
· accumulation of mutations that would otherwise be repaired or recognized by the immune system mainly in skin cancers
· tacrolimus may promotes tumor progression and metastasis of hepatocellular carcinoma, human lung adenocarcinoma cells, and renal cell carcinoma
· Cyclosporine also has direct effects on tumor development and progression,
· The potential oncogenic potential of azathioprine is well known and well recognized.
· Azathioprine sensitizes the skin to UVA radiation and causes the accumulation of 6-thioguanine in the DNA, leading to a higher risk of NMSCs
· On the other hand mTOR i may have potential antitumor effects by inhibiting cancer growth through cell-cycle arrest and initiation of apoptosis
Common Cancers after Transplantation
Renal Cell Carcinoma
· recipients of kidney transplants have up to 7-fold increased risk of renal cell carcinoma
· 90 % of renal cell carcinomas develop in the native kidneys as opposed to the allograft.
· Risk factors for development of renal cell carcinomas posttransplantation include male sex, increasing age, African descent, and longer time on dialysis
· With regard to disease etiology, patients transplanted for kidney failure secondary to glomerular diseases, hypertensive nephrosclerosis, and vascular disease appear to have the greatest associated risk
· In contrast, patients with kidney failure secondary to diabetes or autosomal dominant polycystic kidney disease have a lower risk of renal cell carcinomas.
Skin Cancer
· Is the commonest cancer in recipients of kidney transplants and is more aggressive than skin cancers occurring in the general population
· The most commonly reported skin cancers in recipients of kidney transplants include cutaneous squamous cell carcinoma, basal cell carcinoma, Kaposi sarcoma, and malignant melanoma, with keratinocyte carcinomas comprising 90%–95% of these skin cancers
· the incidence of Kaposi sarcoma in recipients of transplants exceeds 100 times that of the general population.
· recipients of transplants experience an excess risk of squamous cell carcinoma by approximately 250 times
· Patients treated with CNI are at particularly high risk for Kaposi sarcoma. Decreasing the intensity or switching immunosuppressive agents to an mTOR inhibitor is the cornerstone of treatment.
· Among all skin cancer types, melanoma has the highest mortality
· History of pretransplant melanoma is the strongest risk factor for post-transplant melanoma, followed by White race and older age (>50 years)
Post-Transplant Lymphoproliferative Disease
· In most instances (approximately 90%), PTLD is associated with EBV
· The cumulative incidence of PTLD in the first 10 years after kidney transplantation is around 1%–2% in adult recipients and about 3% in pediatric recipients of transplants
· Pretransplant EBV seronegativity and primary EBV infection are important risk factors for early EBV-positive PTLD, particularly in younger recipients of transplants
· Compared with adult recipients of transplants, the risk of developing lymphoproliferative disease in pediatric recipients of transplants is at least 30-times higher than the age- and sex-matched general population
· Apart from younger age at transplantation, male sex, use of T cell–depleting agents, muromonab-CD3, and high dose tacrolimus, negative recipient EBV serology (with positive donor EBV serology) incur a four-fold excess risk of PTLD
· Belatacept associated with a higher risk of PTLD, particularly cerebral PTLD in patients who are EBV negative, and when used in higher doses
· the risk of death among recipients of kidney transplants who have PTLD is .14- fold higher than recipients without PTLD
· Recently survival improved after the use of rituximab and immunotherapy
Cancer Screening Strategies in Transplant Recipients
· routine population-based cancer screening for breast, colorectal, and cervical cancer is recommended according to the guidelines as per the general population
· routine skin checks by dermatologists in recipients of transplants who are at high risk,
· abdominal ultrasounds and serum a-fetoprotein levels should be checked every 6 months for those with underlying liver disease and chronic HBV infections
· ultrasonographic screening (annually or biennially) of the native kidneys for patients who are at risk of developing renal cell carcinoma
Human Papillomavirus Vaccination in Recipients of Kidney Transplants
· Quadrivalent and the HPV 9-valent vaccines are highly effective and have an overall efficacy of 99%–100% for the prevention of cervical intraepithelial neoplasia in randomized clinical trials.
· HPV vaccination is indicated in both males and females aged 9–25 years in the general population for the prevention of HPV-related malignancies.
· Although HPV vaccination is recommended for women after transplantation, it may be more efficacious to vaccinate before transplantation.
Management of Recipients of Kidney Transplants Who Have Cancer
Immunosuppression Management and Treatment in Transplant Recipients with Cancer
· judicious reduction in the overall immunosuppression load for patients with early- to moderate-stage malignancy may be a reasonable first step
· For patients with squamous cell carcinoma, there is now trial-based evidence to suggest conversion to an mTOR inhibitor may reduce the risk of cancer in the longer term
Immunotherapy
· The use of immune-checkpoint inhibitors has revolutionized the treatment of a variety of malignancies through immunesystem activation against the cancer
· checkpoint inhibitors are effective in treating melanoma, non–small cell lung cancer, and renal cell carcinoma in the general population but their use in the kidney transplant population requires further investigation
Putting Patients’ Perspectives at the Heart of Cancer Management
· a multidisciplinary team could deliver the suitable measures for patients transitioning between many disciplines of care
· Ongoing dialogues between clinicians and patients, and close attention to the patients’ overall personal needs, are crucial to ensure our patients’ voices are heard
Conclusions
· Cancer has high impact on morbidity and mortality in patients with kidney transplants
· To treat cancer you may need to reduce or change immunosuppressive drugs which has risk on graft function
· a multidisciplinary team is needed for prevention, screening and management
This is a Narrative review with evidence 5
Introduction
Cancer is one of the most feared long-term complications of kidney transplantation and a leading cause of death among transplant recipient after cardiovascular disease. This has prompted adoption of strategies for early detection and treatment. Therefore, understanding the pathogenetic mechanism of development of these cancers is imperative for optimal care of patients.
Al- Adra et al. in this review article, discusses the epidemiology of malignancies after kidney transplantation, current screening methods, prevention and treatment.
Epidemiology of post-transplant malignancy
The cumulative incidence of de novo solid organ malignancies at 15 years after transplantation ranges from 10% to 15%. For skin cancers, the cumulative incidence
reaches .60% In Europe, Australia, and New Zealand, the cumulative incidence of skin cancers is about 60%. Generally, kidney transplant recipients have a two – to – three fold higher risk of malignancy compared to age and sex – matched controls in the general population. However, there is no increased risk of breast and prostate cancer post transplantation.
Mortality rate associated with post-transplant malignancies is high. Patients with post-transplant malignancies have approximately, 2 times increased risk of dying when compared with age and sex –matched controls in the general population according to data from most western countries. The highest risk of death was found in those with melanoma, urogenital cancers and non-hodgkin’s lymphomas.
Risk Factors for Cancer Development
Numerous risk factors have been attributed to the increased risk of cancers after transplantation. Risk factors share with the general population includes; male sex, advancing age, smoking history, and prolonged exposure to ultraviolet sun radiation. Other risk factors such as use of lymphocyte-depleting agents, acute rejection, high sensitization and long dialysis vintage are specific for kidney disease and transplant populations.
Mechanisms of Cancer Development after transplantation
Poor immune control of oncogenic viruses, impaired DNA damage repair resulting in accumulation of mutations, skin sensitization by immunosuppressive drugs, inhibition of tumor suppressive genes like p53 and activation of TGF- beta have been adduced as the mechanism of tumorigenesis after transplantation.
Recommendations for cancer screening
For breast cancer, screening is recommended every 2 years for patients between 50- 74 years but depends on individual risk assessment in people less than 50 years. Prostate cancer screening is only recommended in patients between 55 and 69 years after explaining the risk and benefits. Pap smear or HPV testing every 3-5 years is recommended starting at 25 years until 74 years for cervical cancer screening. Bowel cancer screening is recommended at 45 years till 75 years with biennial fecal immunohistochemistry and sigmoidoscopy or colonoscopy every 5 years. Lung cancer screening with low dose chest CT is recommended at 55 years till 79 years in heavy smokers only.
For skin cancer, monthly self-examination and 6 monthly total body examination by dermatologist is advised. Renal cancer screening is not routinely recommended. Recommendation for liver cancer screening includes ultrasound scanning and 6-monthly alpha-fetoprotein in cirrhotic patients. Post-transplant lymphoproliferative disease is also screened for in EBD seronegative recipient of seropositive organ once at 1 week after transplant, monthly every 1-3 months and every 3/12 till the end of first year post transplant using the nucleic acid testing method.
Management of cancers in recipients of kidney transplantation.
This involves a patient-centered, multidisciplinary approach with the reduction or withdrawal of immunosuppressive therapy depending on the stage of malignancy, switching to mTOR inhibitors, use of immune checkpoint inhibitors, local therapies such as imiquimoid with fluorouracil in skin cancers, systemic chemotherapy, radiotherapy and surgery.
Level of evidence
Level V
Cancer is an important outcome after kidney transplantation because it is the second leading cause of death in most Western countries, once cancer develops, outcomes are generally poor, particularly for those with melanoma, renal cell carcinoma, and post-transplant lymphoproliferative disease,The excess risk of cancer after transplantation is approximately two to three times higher than the age- and sex-matched general population, driven largely by viral- and immune-related cancers.
Risk factor: male,old age,smooker , acute rejection, high immunosuppression, family history,desensitazation.
most common cancer skin cancer, renal cell cancer, PTLD cause by EBV virus.
in this article focuses on support routine screening for malignancy in solid organ transplantation.
2.What is the level of evidence provided by this article.
Level of evidence V.
De Novo Malignancies after Kidney Transplantation
1.Please summarise this article;
Introduction;
-Cancer is the second cause of death following CVD in kidney recipients. This led to development of preventive strategies such as HPV vaccination and cancer screening strategies for early defection and treatment of cancer.
Incidence;
-10 to 15 % for solid organ tumors at 15 years and > 60% for skin cancer,
-Overall it is 2 to 3 fold higher than the general population,
-The morality is at least 1.5 greater than the general population. Highest are seen with melanoma,urogenital and PTLD.
Risk factors;
for increased incidence of cancer post-transplant:
-Increasing age – Male sex -Smoking -Prolonged sun exposures
-Immunosuppression use -Acute rejection -Sensitization status
-Duration of dialysis before transplantation
Most common cancers;
1-Renal cell carcinoma;
-Risk seven times higher when compared to the general population,
-Male, Age over 60 , African descent , Prolonged dialysis time longer than 3 years,
-Renal-based disease is also a risk factor: glomerular disease,
-Hypertensive nephrosclerosis and vascular disease, Diabetes Mellitus,
-Polycystic kidney disease.
2-Skin cancer;
-Skin cancer is the most common cancer type in recipients of kidney transplants and is more aggressive than skin cancers occurring in the general population.
-The most commonly reported skin cancers in recipients of kidney transplants include cutaneous squamous cell carcinoma, basal cell carcinoma, Kaposi sarcoma, and malignant melanoma, with keratinocyte carcinomas comprising 90%–95% of these skin cancers.
-The pathogenesis of skin carcinoma involves a complex interaction of risk factors, including exposure to UV radiation, HPV, pre transplant skin cancer, older age, race, and sex (males at greater risk than females). Additionally, immunosuppressive medications augment the carcinogenic effects (mainly cyclosporine and azathioprine).
3-PTLD;
-It is rare disease, caused by EBV infection and it has bad prognosis.
It is mostly Bcell type, the highest risk is in the first year post-transplant, and it then risk declines
-Pediatrics are at higher risk; include pediatric transplantation, male , Tcell–depleting agents,Tac high dose, co use of belatacept ,seronegative EBV recipient.
-Treatment includes reduction of immunosuppression and rituximab and chemotherapy.
-Screening in transplant recipients;
-There is insufficient trial-based evidence to support routine screening for solid organ transplantation.
-Routine population-based cancer screening for breast, colorectal, and cervical cancer is recommended.
-Some guidelines recommend routine checks of transplant recipients by dermatologists.
-Recipients with higher risk of kidney cancer, annual or semi-annual USG screening.
2.What is the level of evidence provided by this article;
-Level of evidence V
This is a review article
The article “De Novo Malignancies after Kidney Transplantation” by David Al-Adra provides an overview of the incidence and risk factors associated with the development of new (de novo) cancers after kidney transplantation.
The article explains that kidney transplant recipients have an increased risk of developing certain types of cancer due to their use of immunosuppressive medications. The author discusses the most common types of de novo cancers in kidney transplant recipients, including renal cell carcinoma, skin cancer, and PTLD.
The article also explores the risk factors for de novo cancers in kidney transplant recipients, including the type and duration of immunosuppressive therapy, age, male gender, smoking, and prolonged sun exposures, and prior exposure to cancer-causing agents. are shared by patients in the general population. Other risk factors, including immunosuppression use (T cell–depleting agents), acute rejection, sensitization status, and duration of dialysis before transplantation, are specific to those with kidney disease and transplant populations.
The author highlights the importance of regular cancer screening for kidney transplant recipients to detect new cancers at an early stage, when treatment is more likely to be successful.
The priorities of optimizing allograft function with immunosuppression are often challenged and superseded by having a “cure” for the cancer and may involve immunosuppression reduction or cessation to reduce the risk of cancer relapse and improve long-term cancer survival.
In conclusion, the article provides a comprehensive overview of the incidence and risk factors for de novo cancers in kidney transplant recipients, and the importance of regular cancer screening in this population.
The author emphasizes the need for ongoing research to better understand the relationship between immunosuppressive therapy and cancer risk, and to develop strategies to reduce the risk of de novo cancers in kidney transplant recipients.
Summarize the article
Rena replacement therapy is the ultimate treatment of end stage renal disease, and to compare the dialysis vs transplantation, transplantation has many advantages over dialysis especially better quality of life. However, transplantation is not a cure, because recipient require lifelong immunosuppression.
Immunosuppressive drugs has its consequences, and the second most common cause of death is drugs associated cancer post transplantation.
The aim of this article is to focus on the prevention, incidence, diagnosis, and treatment of cancer after transplantation.
Post-transplantation the cumulative risk cancer is around 10 to 15%. If developed cancer the risk of cancer associated risk is as high as 1.8 to 1.9 times of normal population.
In addition, the risk is more with non-Hodgkin lymphoma, melanoma, and urogenital cancer, may exceeds up-to 5-10 times that with those without kidney transplantation.
In some European countries the skin cancers cumulative risk is as high as >60%. This magnitude of higher risk has association with viral infections and immunosuppression medication.
Risk factors for cancer development;
Some of the main risk associated factors are age, male sex, prolonged sun exposure, and smoking.
There is associated increased risk of development of cancer if there was any treated cancer before transplantation, also immunosuppression type, induction medications, any rejection, duration of dialysis like acquired cyst formation and development of renal cell carcinoma, and immunosuppression duration which has very strong association.
Geographical association like European, and North American countries the most common cancers types are non-melanoma skin cancer, PTLD, and lip cancers, while in Asian and middle East registry shows the commonest tumors are urothelial transitional cell carcinoma, RCC, and GI cancers.
The estimated prevalence of liver cancers in Taiwan has increased up-to 9-24% in renal transplant recipients secondary to strong association with HBV antigenemia. This hypothesis is becoming stronger that chronic immunosuppression use can alter and loss of control of oncogenic viral replication. The overall SIR for kidney and bladder cancer is 44and 43, respectively.
Mechanism of cancer development after transplantation;
The mechanism is unclear thoroughly, but experimental studies shows there. Although, the potential causes may be immunosuppression medication that alter the immune system, another one may be the oncogenic viruses.
In skin related cancers the mechanism could be secondary to impaired cell repair.
Immunosuppression decreases components of nucleotide excision repair factors xeroderma pigmentosum complementation group A, G.
By direct stimulation calcineurin inhibitors has direct effect on TGF-B or IL-6 over expression and development and progression of tumor.
Cacineurin inhibitors can also activate NF of the activated T cell, p53.
Capable of inhibiting damaged DNA repair from UV radiation.
Azathioprine increases sensitivity of skin to UV radiation leading to accumulation of 6-thioguanine in the DNA and increases risk of the NMSC.
mTORI.
On the other hand mTORinhibitors ha protective and antitumor effect by different mechanism including inhibiting cell-cycle arrest and cancer growth.
Monoclonal and polyclonal agents used for induction can increases risk of PTLD, melanoma, although mechanism is unknown, however, there is often an incomplete T- cell recovery and long term effect on immune homeostasis.
The most common cancers post-transplantation.
Renal cell carcinoma. Seven fold higher risk compared to general population.
90% of RCC develop in the native kidneys.
Risk factors are male, older age, African descent, and longer time on dialysis.
Cause of renal failure was glomerulonephritis.
Hypertensive nephrosclerosis.
If early diagnosis and radical removal the prognosis is good with 5-years survival is 68- 97% compared to general population respectively.
Overall the immunosuppression intensity and duration influences the risk of renal cell carcinoma.
Skin Cancer.
This is the most common and more aggressive tumor post-transplantation compared to general population.
Risk factors are UV radiation, older age, black race, males, in addition immunosuppression medications.
SCC is 250 times more common.
Among all skin cancers melanoma has higher mortality.
Treatment option are microsurgery, if inoperable other options are primary radiation, chemotherapy, if metastatic disease then will be needing systemic chemotherapy and immunotherapy.
Switch calcineurin inhibitors to mTOR inhibitors.
Ø Post-transplant Lymphoproliferative Disease.
It’s comparatively rare tumor post-transplantation but be as much as 90%, and has strong association with EBV infection.
Virus reactivate due to dysfunctional T and B cells and there proliferations.
Mostly B-cell only 5% T-cell type.
Incidence 10 years after transplantation is 1-2%.
There is reduction in incidence of PTLD since 2000 onward.
There is more risk within 12 months after transplantation, and this more on seropositive patients, while, in after 5 years post-transplantation 40-50% proportions are with EBV negative.
This is 30 times higher in pediatric recipient with age-sex matched compared to general population.
One survival rate is 62-68% and 10 years survival is 41-48%.
Survival depends on site and extent of disease.
Otherwise median survival from diagnosis to death is about six months.
Ø Human Papillomavirus vaccine is mandatory, and with overall efficacy of 100% for prevention.
Ø Management of recipient with cancer.
This need multidisciplinary approach between oncologist, transplant physician, and allied health professionals.
Optimization of immunosuppression.
Immunotherapy is not recommended still need further investigation.
In conclusion the recipient are in risk of developing different types of tumors specially skin cancer.
So highly recommended for screening before transplantation and post-transplant surveillance.
Level of evidence V.
After cardiovascular disease, cancer is the second leading cause of death among recipients of transplants in most Western countries
The higher risks and poorer cancer outcomes have prompted clinicians and policy makers to adopt preventive policies, such as human papillomavirus (HPV) vaccination and cancer-screening strategies, to detect cancers at their earliest possible stage before they progress into advancedstage, incurable disease
Incidence of All-Cause and Site-Specific Cancer after Transplantation The cumulative incidence of solid organ cancer ranges between 10% and 15% at around 15 years after transplantation. For skin cancers, the cumulative incidence reaches .60% in Europe, Australia, and New Zealand. The excess overall cancer risk in patients with kidney transplant exceeds that of the general population by approximately two- to three-fold after adjustment for age and sex
Cancer Mortality in Recipients of Kidney Transplants
The exact reasons for the higher risk of death are unclear, but may be due to potential differences in the cancer cell biology in recipients of transplants resulting from long-term immunosuppression, associated comorbidities, and low uptake of recommended prevention and screening strategies
Patients are primarily committed to and preoccupied with their kidney and graft health, and their present health needs. Cancer screening and prevention may impose multiple burdens on patients’ daily lives hence, effective patient education and heightened awareness are key.
Risk Factors for Cancer Development
There are many reasons for the higher cancer risk after transplantation. Some of these factors, such as
-increasing age
-male sex
-smoking
-prolonged sun exposures are shared by patients in the general population.
– immunosuppression use (T cell–depleting agents)
– acute rejection sensitization status and duration of dialysis before transplantation
Mechanisms of Cancer Development after Transplantation
the effects of immunosuppression on dampening the immune system may create a variety of pathways for cancer development. One potential mechanism is through poor immune control of known oncogenic viruses in patients on immunosuppression. For example, increases in viral-associated cancers, such as Kaposi sarcoma (human herpesvirus 8), PTLD (EpsteinBarr virus [EBV]), and lip and anal cancers (HPV) are common in patients with suppressed immune systems Another mechanism of immunosuppression-related cancer development is through accumulation of mutations that would otherwise be repaired or recognized by the immune system.
Common Cancers after Transplantation
1-Renal Cell Carcinoma Compared with the general population, recipients of kidney transplants have a higher risk (up to seven-fold) of renal cell carcinoma
2-Skin Cancer Skin cancer is the most common cancer type in recipients of kidney transplants and is more aggressive than skin cancers occurring in the general population.
3- Post-Transplant Lymphoproliferative Disease
PTLD is a well-recognized complication after kidney transplantation. Although it is a rare disease, it is associated with poor outcomes. In most instances (approximately 90%), PTLD is associated with EBV.
Cancer Screening Strategies in Transplant Recipients
High-quality, randomized controlled trials have shown that cancer screening through early detection reduces cancer-specic mortality in the general population .In patients with kidney disease, some have questioned the benefit of routine screening
Patients with kidney disease and kidney transplants undergo radical changes to their overall health and wellbeing, which could be overwhelming for the patients and their caregivers.
ImmunosuppressionManagementandTreatmentin TransplantRecipientswithCancer
Meticulous understanding of the underlying immunologic risk and cancer severity is needed to optimize immunosuppression dose to prevent the risk of acute rejection, while balancing against the need to induce regression of the malignant lesion and prevent future progression. In the absence of quality evidence, judicious reduction in the overall immunosuppression load for patients with early- to moderate-stage malignancy may be a reasonable first step, and this should be conducted in consultation with the patients, where they are informed about the potential adverse effects, and all strategies should be tailored to the individual’s needs.
Immunotherapy
The use of immune-checkpoint inhibitors targeting the
programmed death-1/programmed death ligand-1 interaction and/or the CD28-CD80/86 axis with cytotoxic T lymphocyte–associated protein-4 Ig has revolutionized the treatment of a variety of malignancies through immunesystem activation against the cancer
Putting Patients’ Perspectives at the Heart of Cancer Management
The use of multimodal interventions to alleviate concurrent, multiple symptoms is an example of where a multidisciplinary team could deliver the suitable measures for patients transitioning between many disciplines of care. Patients living with kidney transplants are often frustrated with the lack of innovative strategies to prevent the risk of acute rejection from under-immunosuppression, and cancer resulting from over-immunosuppression . Therefore, a personalized, rather than a one-size-fits-all, approach is most preferred.
Conclusions
Cancer is the leading cause of morbidity and mortality in
patients with kidney transplants. Having cancer is a devastating event for patients and their families because the lifestyle changes and the complex feelings caused by the diagnoses are overwhelming. The priorities of optimizing allograft function with immunosuppression are often challenged and superseded by having a “cure” for the cancer, and may involve immunosuppression reduction or cessation to reduce the risk of cancer relapse and improve longterm cancer survival.
level 5
Summary of De Novo Malignancies after Kidney TransplantationCancer is the most common complication resulting from immunosuppression
Cancer is the cause of death in transplant recipients in western countries.
This review focuses on the incidence, mechanisms, diagnosis prevention, and treatment of cancer after kidney transplantation.
Incidence of all causes and site-specific cancer after transplantation:-
The cumulative incidence of solid organ cancer range between 10% and 15% around 15 years after transplantation.
Cancer match in recipients of kidney transplants:-
The standard mortality ratios for all cancer types are at least 1.8-1.9 times higher compared with the age and sex-matched general population.
Risk Factors For Cancer Development:-
Risk for post-kidney transplant recipients to develop cancer:-
Immune suppression uses CT cell-depleting agents.
Acute rejection.
Sensitization status.
Duration of dialysis before transplantation.
Long-term immunosuppression.
Having CKD.
Mechanism of cancer development after transplantation:-
Immunosuppression made prior to immune control of the known oncogenic virus in post Transplantation patients.
Impaired repair of mutation by the immune system by immunosuppression.
Induction therapy with T cell-depleting agents uncertain mechanism.
The most common cancer after transplantation is renal cell carcinoma skin cancer and PTLD.
Renal Cell Carcinoma
90% of renal cell carcinoma develops in the native kidney.
The risk of renal cell carcinoma increase with the intensity and duration of immunosuppression therapy.
Skin cancer:-
Is the most common cancer type in recipients of Kidney transplantation.
The pathogenesis of skin carcinoma is a complex interaction of risk factors.
Post-Transplant Lymphoproliferative disease:-
It is a rare disease it is associated with poor outcomes.
And associated with EBV infections.
Cancer strategies in transplant recipients:-
The same guidelines suggest routine skin cheeks by dermatologists in recipients of transplants.
Abdominal ultrasound.
The alpha-fetoprotein level should be every 6 month
Human papilloma vaccination in recipients of Kidney transplants:-
The incidence of HPV-related anogenital cancer is at least ten to 15-fold higher
Recipients of kidney transplants compared with the age and sex-matched general population.
Quadrivalent vaccines (against genotypes 6, 11, 16, and 18).
More recently HPV valent vaccine against five genotypes 31, 45, 52, and 58 are effective 99-100% for the prevention of cervical intraepithelial neoplasia in randomized clinical trials.
HPV vaccination is indicated in both males and female aged 9-25 years.
Management of recipients of Kidney transplants who have cancer:-
Immunosuppression management and treatment in transplant recipient with cancer:-
Optimize the immunosuppression dose to prevent the risk of acute rejection while balancing against the need to induce regression of malignant lesion and prevent function progression.
For patients with square cell carcinoma an mTOR inhibitor may reduce the risk of cancer in the longer term.
Immunotherapy use in the kidney transplant population requires for investigation and can not be recommended at this time.
Conclusion:-
The amount of immunosuppression a clinician could safely reduce is unknown.
Evidence to support primary prevention and screening programs in recipients of transplant are largely extrapolated from the general population and finding may not necessarily be applicable to transplant populations.
level 5
This review focuses on the incidence, mechanisms, diagnosis, prevention, and treatment of cancer after kidney transplantation
Introduction
Cancer is the second leading cause of death in most Western countries after renal transplantation. It is excess risk is approximately two to three times higher than the age- and sex-matched general population, driven largely by viral- and immune-related cancers
The higher risks and poorer cancer outcomes have prompted clinicians and
policy makers to adopt preventive policies, such as human papillomavirus (HPV) vaccination (7) and cancer-screening strategies.
Incidence of All-Cause and Site-Specific Cancer after Transplantation
The excess overall cancer risk in patients with kidney transplant exceeds that of the general population by approximately two- to three-fold after adjustment for age and sex.
The magnitude of the higher risk is also dependent on cancer types, with the greatest risk in viral-related and immunedriven cancers such as post-transplant lymphoproliferative disease (PTLD), anogenital cancer, and Kaposi sarcoma
Breast and prostate cancers are not increased in recipients
of transplants .
Cancer Mortality in Recipients of Kidney Transplants
Once cancers develop, the risk of death is high. The risk is greatest among those with melanoma, urogenital cancers, and non-Hodgkin lymphoma, with an overall risk of cancer-related death exceeding five to ten times that of those without kidney transplants.
Risk Factors for Cancer Development
A. Factors that are shared by patients in the general population
1. Increasing age
2. Male sex
3. Smoking
4. Prolonged sun exposures.
B. Other risk factors:
1. Immunosuppression use (T cell–depleting agents).
2. Acute rejection
3. Sensitization status
4. Duration of dialysis before transplantation
Renal cell carcinoma and multiple myeloma, are over-represented in the CKD/kidney-failure populations.
Cancer may also develop in recipients of kidney transplants because of impaired tumor surveillance and immunity to viral or other tumor antigens.
The observed higher cancer risk is further compounded in patients who have had a previously treated pretransplant malignancy.
The specific types of cancer that develop after transplantation also vary by geographic areas.
Mechanisms of Cancer Development after Transplantation
The effects of immunosuppression on dampening the immune system may create a variety of pathways for cancer development.
1. poor immune control of known oncogenic viruses which can cause an increase in viral-associated cancers (Kaposi sarcoma (human herpesvirus 8), PTLD (Epstein– Barr virus [EBV]), and lip and anal cancers (HPV).
2. Accumulation of mutations (predominant in skin cancers)
3. On a molecular level, several mechanisms have been identified for mTOR
inhibitor–mediated tumor inhibition.
4. After T-cell depletion, there is often an incomplete T-cell recovery, which may have a long-term effect on immune homeostasis, leading to an impaired immune system and subsequent cancer development.
The three most common cancer types after renal transplantation:
1. Renal Cell Carcinoma: the risk is higher (up to seven-fold).
2. Skin Cancer: is the most common cancer type in recipients of kidney transplants and is more aggressive. The most commonly reported skin cancers in recipients of kidney transplants include cutaneous squamous cell carcinoma, basal cell carcinoma, Kaposi sarcoma, and malignant melanoma, with keratinocyte carcinomas comprising 90%–95% of these
skin cancers.
Cancer Screening Strategies in Transplant Recipients
Routine population-based cancer screening for breast, colorectal, and cervical cancer is recommended and should be aligned to the guidelines as per the general population.
Some guidelines also suggest routine skin checks by dermatologists in recipients of transplants who are at high risk
Abdominal ultrasounds and serum a-fetoprotein levels should be checked every 6 months for those with underlying liver disease and chronic HBV infections.
Patients who are at risk of developing renal cell carcinoma, ultrasonographic screening (annually or biennially) of the native kidneys may be considered to detect occult malignancy
Screening decisions must be made with clear considerations of patients’ preferences and values, incorporating the potential harms and benefits of the various options.
Human Papillomavirus Vaccination in Recipients of Kidney Transplants
HPV vaccination is indicated in both males and females aged 9–25 years in the general population for the prevention of HPV-related malignancies.
Some recent data have shown that it is also efficacious in
women up to the age of 45 years. In the transplant population, HPV vaccines are generally safe.
Management of Recipients of Kidney Transplants Who Have Cancer
A concerted approach between transplant professionals, oncologists, and allied health professionals is needed to ensure optimal care for patients.
Meticulous understanding of the underlying immunologic risk and cancer severity is needed to optimize immunosuppression dose to prevent the risk of acute rejection, while balancing against the need to induce regression of the malignant lesion and prevent future progression.
Conclusions
In transplanted patients with cancer, the priorities of optimizing allograft function with immunosuppression are often challenged and superseded by having a “cure” for the cancer, and may involve immunosuppression reduction or cessation to reduce the risk of cancer relapse and improve long term cancer survival.
Currently, the evidence to define the amount of immunosuppression by which a clinician could safely reduce is unknown.
Evidence to support primary prevention and screening programs in recipients of transplants are largely extrapolated from the general population, and the findings may not necessarily be applicable to the transplant population.
Collaborative efforts between health care professionals, policy makers, trialists, and patients are needed to ensure quality evidence.
◇ Level of Evidence: V
-This is a narrative review discussing cancer in kidney transplant recipients, including current screening and treatment options along with the disease’s epidemiology and burden.
also, considering the patients’ viewpoints on the state of knowledge regarding the best care for kidney transplant recipients who develop cancer.
-Post-transplantation malignancy is the second leading cause of death after cardiovascular causes. Renal transplant recipients have a 2-3-fold higher risk of malignancy than the general population.
– viral and immunological mechanisms play an important mechanisms in PTLD, anogenital cancer, and Kaposi sarcoma
-Transplantation does not raise breast or prostate cancer rates.
-Malignancy increases mortality by 2–5 times in comparison to the non-transplant population, with malignant melanoma, PTLD, and RCC having the worst outcomes.
-increasing Age
-Long-term exposure to the sun
-Use of immunosuppressants
-rejection episodes
-long duration on dialysis
Renal transplantation increases the risk of RCC sevenfold.
Due to frequent imaging, RCC is typically found early, with an incidence of metastasis of 2% and often low-grade early lesions.
Usually in the native kidney (99%).
Partial nephrectomy and radical nephrectomy are the options for management, with surveillance rarely used.
Skin cancer is the most common malignancy post-kidney transplantation.
It is more aggressive and more common in transplant recipients than in the general population.
Malignant melanoma incidence increases 5–8 times more than it does in the general population.
90% of skin cancers are caused by SCC and BCC.
SCC is more common than BCC in kidney transplants (although in the general population, BCC is more common)
Both SCC and melanoma have a poor outcome, with malignant melanoma having the highest mortality.
management is by decreasing the immunosuppression & switching to mTORi & managing cancer by excision by safety margins if operable.
-90% EBV association and is associated with poor results and a higher mortality rate.
T-cell types are present in 5% of PTLD patients, although B-cell types are more common.
-Risk factors include male sex, the use of T cell-depleting treatments, muromonab-CD3, high dose tacrolimus, younger age at transplantation, and a negative recipient EBV serology—especially with a positive donor EBV serology.
-decrease of immunosuppression and chemotherapy protocols with the use of rituximab are the options for management.
-table 1
-Cancer is the leading cause of morbidity and mortality in
patients with kidney transplants.
-Treatment is often challenging and involves reducing or stopping immunosuppression to lower the chance of cancer returning and increase long-term cancer survival.
-The majority of the data used to support primary prevention and screening programs in transplant recipients is extrapolated from the general population, therefore, the results may not always be applicable to the transplant population.
-level 5, a narrative review
table 1
1. Please summarize this article
Renal transplant recipients are at 2-3 times risk of developing malignancy compared to general population. Malignancy is the second leading cause of death in renal transplant recipients. Cutaneous malignancy is the most common cancer in renal Tx recipients, its risk increases with duration post-transplantation.
The risk of breast and prostatic cancer is the same between renal transplant recipients and general population.
PTLD, anogenital and Kaposi sarcoma are attributed to viral infection and immune disturbance in renal Tx recipients.
Post-transplant malignancy risk factors include:
1-Older age,
2-Male sex,
3-Racial factors (skin cancer is higher in white than black),
4-Smoking,
5-UV rays sun exposure,
6-Vintage on dialysis and
7-Pre-transplant malignancy increases the risk of post Tx cancer.
8-Geographical location is associated with common types of malignancies as follows:
Australia, Europe and North America—à NMSC, PTLD, and lip cancer.
Africa, Central Europe and Mediterranean Sea—à Kaposi Sarcoma.
Korea and middle east——àRCC, GIT cancers.
Taiwan—-à HCC because of HBV prevalence.
9-The cause of native renal failure was associated with different types of cancers:
GN, vascular or HTN causes—–àhigh risk of RCC
DM, ADPCKD———–à Low risk of RCC.
10-Recipients with negative pre-Tx EBV serology is at higher risk to develop PTLD especially if the donor’s EBV serology was positive.
11-Exposure to higher IS especially with ATG (sensitized patients or treatment of rejection episodes)
12-Viral infections are considered as risk factors for specific malignancies as follows:
EBV—àPTLD, HHV-8—-à Kaposi Sarcoma, HPV—-à lip and cancer.
13-Immunosuppressive medications can predispose to malignancy as follows:
CNI—à increases risk skin cancer especially NMSC, and the risk of metastasis.
Azathioprine–à high risk of NMSC.
OKT3, and Belatacept——–à high risk of PTLD.
MMF, and m-TOR inhibitors——-à low risk of malignancy.
This paper discussed few malignancies including RCC, Skin cancer and PTLD.
RENAL CELL CARCINOMA:
Risk of RCC post Renal Tx is 7 times higher than general population.
It happens 99% in the native kidneys; frequent imaging can detect RCC at earlier stages with low risk of metastasis<2%. Treatment outcomes are the same in general population.
SKIN CANCER:
90% are SCC and BCC. Other types of skin cancer include Melanoma and Kaposi sarcoma.
SCC is more common than BCC in renal Tx recipients However, in general population BCC is more common.
Malignant melanomas, KS, and SCC incidence is 8, 100 and 250 times respectively more prevalent in renal Tx recipients compared to general population.
Malignant Melanoma and SCC carry higher poor prognosis. Malignant melanoma carries the highest mortality risk.
POST-TRANSPLANT LYMPHOPROLIFERATIVE DISEASE (PTLD):
1-2% of renal Tx recipients can develop PTLD in the first decade post renal Tx. The peak of occurrence is the first year then slowly decline until fifth year. The most common type is B-cell lymphoma in 95% of cases, and T-cell lymphoma is only in 5%.
Mainly due to activation of EBV. The overall survival is 65%-45% at 1 -10 years respectively. The prognosis is poor in elderly male renal transplant recipient especially with bone marrow, reticulo-endothelial system infiltration and extra-nodal disease.
ANOGENITAL CANCER:
Mainly related to HPV, the incidence risk of anogenital cancer in renal transplant recipients is 10-15 times compared to general population.
MALIGNANCY SCREENING AFTER RENAL TRANSPLANTATION:
Breast Cancer: Self-examination, Mammogram every 1-2 years for female aged 50-74.
Prostate Cancer: Annual PSA for men aged 55-69.
Cancer Cervix: HPV vaccination for female aged 9-45 years, better to be given before renal-Tx., women aged 25-74 years need HPV testing every 3-5 years.
Colonic Cancer: Fecal occult blood test every 6 months for patients aged 45-75 years, sigmoidoscopy every 5 years or colonoscopy every 5-10 years.
Cancer Lung: annual low dose CT chest for patients aged 55-75 years with smoke pack history of 30.
Cutaneous Cancer: monthly self-skin- examination and annual skin examination by dermatologist.
Renal Cell Carcinoma: 6 monthly USS-KUB for high risk patients.
Hepatic Cancer: 6 monthly USS and AFP for those with liver cirrhosis.
PTLD: in high risk recipients, EBV test in the first week, then monthly for the first 6 months then every 3 months till the end of first year.
Management of post-transplant malignancy:
Multidisciplinary approach.
Modification of immunosuppression: target level reduction, switch CNI to m-TOR inhibitors.
Monitor for rejection.
Specific treatment depends on the type of cancer and stage either surgical, chemotherapy, radiotherapy and others.
2. What is the level of evidence provided by this article
Level V.
Introduction;
Kidney transplantation is considered the best modality of RRT but it is associated with much adverse association like infection, cardiovascular events and cancers. Cancer is the second leading cause of mortality after cardiovascular events among recipients of transplantation.
Incidence of All-cause and site-specific cancer after transplantation;
The cumulative risk of solid organ cancers is around 10-15% at 15 years of transplantation. The magnitude of risk is dependent on cancer type with greatest risk associated with viral and immune driven mechanisms cancers like;
· PTLD
· Kaposi sarcoma and
· Anogenital cancers.
Cancer mortality in recipients of kidney transplantation;
The standard mortality ratio for all cancers is 1.8 to 1.9 times higher compared to age& sex matched general population.
Risk factors for cancer;
· Male sex
· Increasing age
· Smoking
· Sun exposure
· IS(T-cell depleting agents)
· Rejections
· Duration of dialysis prior to transplantation.
Specific types of cancer that develop after transplantation also vary to geographic distributions.
Mechanism;
1. Viral associated like, HHV-8, EBV and HPV.
2. Accumulation of mutation otherwise repaired.
3. CNI and AZA while protective effect of mTOR.
4. Depleting agents.
Common cancers after Transplantation are;
· Renal cell carcinoma
· Skin Cancer
· PTLD
Strategies;
In keeping patient preference and value t develop screening strategies is really challenging and complex task, but supporting patient to have informed preferences and decisions. Following are of potential benefits;
· HPV vaccination
· Immunosuppressant’s management.
· Immunotherapy.
Level of evidence v
De-Novo-Malignancies-after-Kidney-Transplantation:
Introduction:
Kidney transplant is the best option for patients with end stage renal disease to improve quality of life and prolong survival rate, but it’s carry high risk of cardiovascular disease and malignancy.
Malignancy contribute to increase mortality rate.
Risk of malignancy in kidney transplant related to use of immunosuppressive therapy and to viral infection like human papilloma virus or chronic hepatitis due to reduce immunity.
Objective of this study:
To review the incidence, mechanisms, diagnosis, prevention, and treatment of cancer after kidney transplantation.
Incidence:
Incidence of cancer range between 10-15% over 15 years post transplant. Incidence of skin cancer reach to 60% in the most of developed countries.
Over all cancer risk to 2-3 folds in transplant patients in comparison to general population.
Magnitude of cancer incidence depend on type of cancer and type of viral infection and immunosuppressive therapy.
Mortality:
Cancer mortality increase to 1.8-1.9 compare to age and sex.
Risk increase with melanoma and urogenital cancer and non Hodgkin’s lymphoma while non significant with breast and prostatic cancer.
Risk factors of cancer in transplant patients:
Mechanism of Cancer:
One of the most common cause of cancer is suppressed immune system and activation of oncogenic virus like Kaposi sarcoma (human herpesvirus 8), PTLD (Epstein– Barr virus ), and lip and anal cancers (HPV).
Other mechanism related to immunosuppressive agents are impair of immune system and induce skin cancer and lymphoma.
Common Cancers after Transplantation:
Renal cell carcinoma:
It’s account seven times higher in comparison to general population because of increased abdominal imaging, the majority of kidney masses detected in patients post-transplantation are typically early, low-grade, small kidney masses.
Risk more in native kidney
Male/ age more than 60years and black, history of hypertension and DM, risk more with primary glomerular disease and renovascular disease and duration of dialysis. However risk of renal cell carcinoma is very low in poly cystic disease.
De novo renal cell carcinomas should be treated according to urology guidelines on basis of staging and patients factors (comorbidites, age and sex and features of kidney failure),
The outcome of renal cell carcinomas after radical treatment in the transplant population is comparable with that of the general population, with 5-year, disease specific and overall patient survival rates of 68%–97% and 69%–88%, respectively.
Renal cell carcinoma in the kidney allograft is rare with incidence less than 0.1%.
Skin cancer:
The most common type of cancer occur in kidney transplant and it’s very aggressive in comparison to general population. Its account 90-95% from cancers in transplant patients.
The most common types are ude cutaneous squamous cell carcinoma, basal cell carcinoma, Kaposi sarcoma, and malignant melanoma, with keratinocyte carcinomas.
Risk factors of skin cancer are:
exposure to UV radiation, HPV, pretransplant skin cancer, older age, race, and sex (male), and immunosuppressive medications.
Kaposi sarcoma is the most common cause of skin cancer in transplant patients.
The incidence of Kaposi sarcoma in recipients of transplants exceeds 100 times that of the general population.
The risk of squamous cell carcinoma by reaching to 250 times in comparison to general population.
In patients with actinic keratoses and squamous cell carcinoma in situ, the management options with good outcomes include topical “uorouracil and imiquimod cream, photodynamic therapy, and surgical excision or electrodesiccation and curettage.
the patients with multiple squamous cell carcinoma carry high risk if local recurrence and need chemotherapy and local radiotherapy.
The retinoids and nicotinamide used as chemoprophylaxis.
Patients treated with calcineurin inhibitors should be shifted to mTOR inhibitors.
The risk of melanoma is high in kidney transplant with high rate of mortality.
Treatment is surgical excision and adjusting immunosuppressive therapy.
Post-Transplant Lymphoproliferative Disease:
It’s rare disease with poor outcome and associated with EBV.
It’s account 1-2% from cancer in transplant patients.
The best treatment is immunosuppressive therapy reduction.
Rituximab used in treatment with good outcome.
Cancer Screening Strategies in Transplant Recipients:
Guidelines recommended for breast, cervical and colorectal cancer screening and some guidelines recommended for skin cancer screening by dermatologist.
Vaccination for HPV related cancer.
Alfa fetoprotein every 6 months for chronic hepatitis B to role out liver cancer.
Human Papillomavirus Vaccination in Recipients of Kidney Transplants:
it’s 15 folds increase risk of cancer .
Management of Recipients of Kidney Transplants:
The use of immune-checkpoint inhibitors is not recommended in transplant patients and needs further evaluation and investigation.
Conclusions:
Cancer is the leading cause of death and screening is important in pretransplant malignancy and all patients with risk of malignancy.
Level V
De Novo malignancy post renal transplantation is an important topic because its the second leading cause of death after cardiovascular disease and once diagnosed is associated with poor out come , two main causes for malignancy post renal transplantation the 1st is viral infection related and the 2nd is immunosuppression related , so effective screening , vaccination , and proper treatment strategies is very important .
The over all incidence of solid cancer range between 10 – 15 % at around 15 years after transplantation , for skin cancers, the cumulative incidence reaches .60% , then come viral-related and immune driven cancers such as post-transplant lymphoproliferative disease (PTLD), anogenital cancer, and Kaposi sarcoma .
Unfortunately malignancy post renal transplantation associated with high mortality rate could be due to potential differences in the cancer cell biology in recipients of transplants resulting from long-term immunosuppression, associated comorbidities, and low uptake of recommended prevention and screening strategies .
Risk factors for the higher cancer incidence after transplantation.
there is no conclusive evidence to suggest one type of immunosuppression is more oncogenic than others but it’s the overall cumulative effect of immunosuppression
but some studies showed that :
– tacrolimus increases the level of TGF-b and thereby promotes tumor progression and metastasis .
– Cyclosporine also has direct effects on tumor development and progression, through TGF-b or IL-6 overexpression pathways .
– Azathioprine sensitizes the skin to UVA radiation and causes the accumulation of 6-thioguanine in the DNA, leading to a higher risk of NMSCs .
– Induction therapy with T cell–depleting agents increases the risks of cancers, such as PTLD and melanoma .
Specific types of malignancy associated with some viral infection such as Kaposi sarcoma (human herpesvirus 8), PTLD (Epstein–Barr virus [EBV]), and lip and anal cancers (HPV) are common in patients with suppressed immune systems.
2- Level of evidence :V
Common Cancers after Transplantation.
1- Renal Cell Carcinoma.
2- Skin Cancer:
The most commonly reported skin cancers cutaneous squamous cell carcinoma, basal cell carcinoma, Kaposi sarcoma, and malignant melanoma, with keratinocyte carcinomas comprising 90%–95% of these skin cancers
3- Post-Transplant Lymphoproliferative Disease
Summary of Recommendations for cancer screening in recipients of kidney transplants
Breast :
Prostate :
Cervical :
Bowel
Lung :
Skin:
Renal cell :
Liver :
PTLD :
Conclusions :
Cancer is the leading cause of morbidity and mortality in patients with kidney transplants. and support primary prevention and screening programs in recipients of transplants is the most important step .
Summary
The cumulative incidence of solid organ cancer ranges between 10% and 15%. Incidence is progressively increasing as time is passing after transplantation
Viral and immune related cance incidence is more ( The standardized incidence ratios is highe for Kaposi sarcoma and PTLD) while breast and prostate cancer SIR is low
Regarding cancer mortality, the SIR of death is higher in non- Hodgkin lymphoma, kidney and thyroid than other type and cancer site
The underlying Mechanisms of Cancer Development after Transplantation: include
– poor immune control of known oncogenic viruses in patients on immunosuppression
– accumulation of mutations that would otherwise be repaired or recognized by the immune system that get compromised by the use of immunosuppression either during induction or maintenance
Common cancers post-transplant
recipients of kidney transplants have a 7-fold as compared to general population, 90% RCC develop in native kidney rather than graft.
Risk factors for development of renal cell carcinomas post transplantation include male sex increasing age African descent and longer time on dialysis
De novo renal cell carcinomas should be definitively managed according to urologic guidelines on the basis of risk stratification and staging
The outcome after treatment is comparable to the non-transplant population. . Negative prognostic factors include presence of symptoms at diagnosis, higher Fuhrman grade (.2), absence of transplantation, and advanced-stage disease
Skin Cancer
Skin cancer is the most common cancer type in recipients of kidney transplants and is more aggressive than skin cancers occurring in the general population. Commonly,it is keratinocyte carcinoma.
Risk factors are exposure to UV radiation, HPV, pretransplant skin cancer, older age, race, and sex (males at greater risk than females).
Treatment depending on the staging and visceral involvement. management options include topical fluorouracil and imiquimod cream, photodynamic therapy, and surgical excision or electrodesiccation and curettage. Mohs micrographic surgery, with histologic confirmation of negative margins, offers the most definitive method of treatment in SSC, with cure rates of 95%–100%. Radiotherapy and chemoprophylaxis is effective as well for inoperable and multiple SSC as well. modulation of immunosuppressive is important in the management of Kaposi sarcoma
Melanoma has poor prognosis carrying the highest mortality. risk factors are History of pretransplant melanoma, followed by White race and older age (.50 years) treatment is by surgical excision based on Breslow thickness,
Post-Transplant Lymphoproliferative Disease
PTLD is a well-recognized complication after kidney transplantation. Although it is a rare disease, it is associated with poor outcomes. In most instances (approximately 90%), PTLD is associated with EBV.
Incidence shows a bimodal distribution in PTLD incidence, with the risk of PTLD being the highest in the 12 months post-transplant, and it then decreases until the fifth year after transplantation.
Risk factors Pretransplant EBV seronegative (negative recipient EBV serology (with positive donor EBV serology), particularly in younger recipients of transplants, and may explain the higher risk of disease early post-transplant. use of T cell–depleting agents, Ortho Kung T3 (muromonab-CD3), and high dose tacrolimus
The treatment goal of PTLD is to cure the disease, and the mainstay of treatment is immunosuppression reduction
Once PTLD developed mortality increase but the current treatment strategies with the use of rituximab and chemotherapy along with management of immunosuppression effectively reduce mortality
Cancer screening in transplant patient
in breast, colorectal, and cervical cancer be linked with the general population’s screening guidelines.
skin” High-risk transplant recipients should receive Monthly self-skin
examination and 6- to 12-monthly total body skin examination by expert physicians and dermatologists·
Liver: Those with underlying liver cirrosis and chronic HBV infections must have abdominal ultrasounds and blood a-fetoprotein levels monitored every six months.
Renal : for only high risk group, ultrasonographic screening of the native kidneys (annually or biannually) may be considered
PTLD: Routine monitoring of patients at high risk (donor EBV seropositive/ recipient seronegative) for EBV by NAT. Once in the first week after transplantation, monthly for the first 3–6 months, and every 3 months until the end of the first post-transplant year
Management of Recipients of Kidney Transplants Who Have Cancer
Immunosuppression modulation : either reduction of the dose or changing to mTOR according to cancer type keeping into consideration the graft function and avoid acute rejection
Immunotherapy The use of immune-checkpoint inhibitors but it carry the risk of immune system activation and rejection
Conclusion
The priorities of optimizing allograft function with immunosuppression are often challenged and superseded by having a “cure” for the cancer, and may involve immunosuppression reduction or cessation to reduce the risk of cancer relapse and improve long term cancer survival
Level of evidence :V
The excess risk of cancer after transplantation is approximately two to three times higher than the age- and sex-matched general population, driven largely by viral- and immune-related cancers. Once cancer develops, outcomes are generally poor, particularly for those with melanoma, renal cell carcinoma, and post-transplant lymphoproliferative disease. More importantly, effective screening and treatment strategies are limited in this high-risk population.
One of the most feared complications associated with immunosuppression after kidney transplantation is cancer.
After cardiovascular disease, cancer is the second leading cause of death among recipients of transplants in most Western countries .The higher risks and poorer cancer outcomes have prompted clinicians and policy makers to adopt preventive policies, such as human papillomavirus (HPV) vaccination and cancer-screening strategies, to detect cancers at their earliest possible stage before they progress into advancedstage, incurable disease.
Incidence of All-Cause and Site-Specific Cancer after Transplantation
The cumulative incidence of solid organ cancer ranges between 10% and 15% at around 15 years after transplantation. For skin cancers, the cumulative incidence reaches .60% in Europe, Australia, and New Zealand. The excess overall cancer risk in patients with kidney transplant exceeds that of the general population by approximately two- to three-fold after adjustment for age and sex.
the greatest risk in viral-related and immunedriven cancers such as post-transplant lymphoproliferative disease (PTLD), anogenital cancer, and Kaposi sarcoma .
Interestingly, certain solid organ cancers such as breast and prostate cancers are not increased in recipients of transplants
Cancer Mortality in Recipients of Kidney Transplants
Once cancers develop, the risk of death is high. The exact reasons for the higher risk of death are unclear, but may be due to potential differences in the cancer cell biology in recipients of transplants resulting from long-term immunosuppression, associated comorbidities, and low uptake of recommended prevention and screening strategies.
Patients are primarily committed to and preoccupied with their kidney and graft health, and their present health needs. Cancer screening and prevention may impose multiple burdens on patients’ daily lives ,hence, effective patient education and heightened awareness are key.
Risk Factors for Cancer Development
long-term immunosuppression is a major contributor to cancer development after transplantation, there is now convincing observational evidence to suggest that having CKD (irrespective of the CKD stage) is associated with higher cancer risk and poor cancer outcomes
Mechanisms of Cancer Development after Transplantation
there is no conclusive evidence to suggest one type of immunosuppression is more oncogenic than others.
tacrolimus increases the level of TGF-b and thereby promotes tumor progression and metastasis. In addition, calcineurin inhibitors inhibit signaling via calcineurin and NF of activated T cells, which can activate p53, a hallmark of some NMSCs (35). Cyclosporine also has direct effects on tumor development and progression, through TGF-b or IL-6 overexpression pathways.
Azathioprine sensitizes the skin to UVA radiation and causes the accumulation of 6-thioguanine in the DNA, leading to a higher risk of NMSCs .
Mammalian target of rapamycin (mTOR) inhibitors, on the contrary, may have potential antitumor effects by inhibiting cancer growth through cell-cycle arrest and initiation of apoptosis.
Induction therapy with T cell–depleting agents (including polyclonal agents, such as anti-thymocyte globulin, and monoclonal agents, such as anti-CD52 and, historically, Ortho Kung T3 [muromonab-CD3]) increases the risks of cancers, such as PTLD and melanoma.
Common Cancers after Transplantation
renal cell carcinoma, skin cancer, and PTLD
Cancer Screening Strategies in Transplant Recipients
support routine screening in this high-risk group, routine population-based cancer screening for breast, colorectal, and cervical cancer is recommended and should be aligned to the guidelines as per the general population .
Some guidelines also suggest routine skin checks by dermatologists in recipients of transplants who are at high risk, and abdominal ultrasounds and serum a-fetoprotein levels should be checked every 6 months for those with underlying liver disease and chronic HBV infections. For patients who are at risk of developing renal cell carcinoma (such as those with a history of acquired cystic disease, those with a family history, those who are heavy smokers, and those who use long-term analgesics), ultrasonographic screening (annually or biennially) of the native kidneys may be considered to detect occult malignancy.
A shared decision-making process, defined as an approach where clinicians and patients share the best available evidence when faced with the task of making decisions, and where patients are supported to consider options to achieve informed preferences, should be adopted to guide decision making.
Human Papillomavirus Vaccination in Recipients of Kidney Transplants
Quadrivalent vaccines (against genotype 6, 11, 16, and 18) and, more recently, the HPV 9-valent vaccines (against five additional genotypes of 31, 33, 45, 52, and 58) are highly effective and have an overall efficacy of 99%–100% for the prevention of cervical intraepithelial neoplasia in randomized clinical trials. HPV vaccination is indicated in both males and females aged 9–25 years in the general population for the prevention of HPV-related malignancies.
Although HPV vaccination is recommended for women after transplantation, it may be more efficacious to vaccinate before transplantation.
Management of Recipients of Kidney Transplants
Who Have Cancer
Immunosuppression Management and Treatment in Transplant Recipients with Cancer
concerted approach between transplant professionals, oncologists, and allied health professionals is therefore needed to ensure optimal care for our patients.
For patients with squamous cell carcinoma, there is now trial-based evidence to suggest conversion to an mTOR inhibitor may reduce the risk of cancer in the longer term.
Immunotherapy
The use of multimodal interventions to alleviate concurrent, multiple symptoms is an example of where a multidisciplinary team could deliver the suitable measures for patients transitioning between many disciplines of care. Patients living with kidney transplants are often frustrated with the lack of innovative strategies to prevent the risk of acute rejection from under-immunosuppression, and cancer resulting from over-immunosuppression.
multidisciplinary, integrated approach that involves the transplant and palliative care team is crucial. The team should consist of a palliative care physician to assist with the medical aspects of managing the high symptom burden, together with a social worker, dietitian, clinical psychologist, and other allied health workers to address the psychosocial, functional, and nutritional issues experienced by our patients.
More importantly, evidence to support primary prevention and screening programs in recipients of transplants are largely extrapolated from the
general population, and the findings may not necessarily be applicable to the transplant population.
level of evidence V
Please summarise this article
Introduction
Cancer is the second major cause of death in kidney transplant recipients after CV disease. Preventive policies, such as HPV vaccination and cancer-screening strategies, to detect cancers earlier is recommended
The aim of the study: discuss the incidence, mechanisms, diagnosis, prevention, and treatment of cancer after kidney transplantation
Incidence
10% and 15% (15 years after transplantation)
>60% in Europe, Australia, and New Zealand (for skin cancer)
Overall cancer risk exceeds that of the general population (approximately two- to three-fold after adjustment for age and sex)
The higher risk is also dependent on type of cancer (viral-related, PTLD, anogenital cancer, and Kaposi sarcoma)
Mortality
Mortality is 1.8–1.9 times higher compared with the age- and sex-matched general population
The highest risk is with melanoma, urogenital cancers, and non-Hodgkin lymphoma (the risk of death exceeding five to ten times that of those without kidney transplants)
Risk Factors for malignancy post transplantation
1. General: increasing age, male sex, smoking, and prolonged sun exposures
2. Specific: use of immunosuppression, acute rejection, sensitization status, and duration of dialysis before transplantation
3. Pretransplant malignancy
4. CKD (renal cell carcinoma and multiple myeloma)
5. geographic part:
NMSCs, PTLD, and lip cancer (Europe, North America, Australia, and New Zealand)
Urothelial TCC, RCC, and GI cancers (non-Western Asian and Middle East)
Liver cancer (chronic HBV): Taiwan
Mechanisms of Cancer Development
Bad immune control of known oncogenic viruses in patients on immunosuppression (Kaposi sarcoma (human herpesvirus 8), PTLD (Epstein– Barr virus [EBV]), and lip and anal cancers (HPV))
Accumulation of mutations (mainly in skin cancers)
Common Cancers after Transplantation:
Renal Cell Carcinoma (RCC)
Seven-fold higher risk than general population
Usually detected early due to advanced imaging
90 % develop in the native kidneys, rare in kidney allograft and usually low-grade T1 lesions, clear cell carcinomas, or papillary renal cell carcinomas, and occur more commonly in males.
Risk factors: male sex, increasing age (>60), African descent, longer time on dialysis, and cause of kidney failure (high risk in glomerular, hypertensive and vascular causes, lower in diabetes and APKD)
The outcome is the same as in general population after radical treatment
Treatment options are partial nephrectomy, radical nephrectomy, and percutaneous ablation
Skin Cancer
It is the most common cancer and more aggressive than in general population. The risk of SCC and Kaposi sarcoma is 250 and 100 times that of the general population.
Cutaneous SCC, BCC, Kaposi sarcoma, and malignant melanoma (keratinocyte carcinomas comprising 90%–95% of these skin cancers)
Risk factors include UV radiation exposture, HPV, pretransplant skin cancer, older age, race, sex (males > females), and immunosuppressive medications
The risk of malignant melanoma is 5-8 folds and is poor prognosis
Post-Transplant Lymphoproliferative Disease (PTLD)
Rare (1%–2% 10 years after transplant), poor outcome, and associated with EBV in 90%
The virus acquired during childhood with minimal symptoms (infects B cells and remain dormant)
Most PTLDs are of B-cell types (T-cell type only in 5%)
Bimodal distribution [early in the first year (EBV seronegative pretransplantand primary EBV infection) and late (EBV-negative lesions)]
Immunosuppression reduction is the cornerstone of treatment (rituximab and chemotherapy improve survival with 5-year survival of around 60%)
The risk of death is high (14 fold). The median time from diagnosis to death is 6 months Overall survival 62%–68% at 1 year and 41%–48% at 10 years
Cancer screening after kidney transplantation
Breast: For women aged 50–74 years, mammography once every 2 years. For women <50 screening is individual
Prostate: For men aged 55–69 years, screening individual. For men >70 years, no screen
Cervical: Annual Pap testing or HPV testing every 3–5 years starting at the age of 25 years until 74 years
Bowel: adults aged 45–75 years, fecal immunochemical testing biennially, sigmoidoscopy every 5 years, or colonoscopy every 5–10 years
Lung: adults aged 55–79 years, annual low-dose computed tomography scans for those who have smoked one pack per day for 30 years or equivalent (two packs per day for 15 years)
Skin: Monthly self-skin examination and 6- to 12-monthly total body skin examination by expert physicians and dermatologists
Renal cell: screening only for high-risk individuals
Liver: Routine screening using US, with and without a -fetoprotein, every 6 months in patients with cirrhosis.
PTLD: for high risk (donor EBV seropositive/ recipient seronegative) for EBV by NAT. Once in the first week after transplantation, monthly for the first 3–6 months, and every 3 months until the end of the first post-transplant year
Human Papilloma virus Vaccination in Recipients of Kidney Transplants
The incidence of HPV-related anogenital cancer is 10 to 15-fold higher in recipients of kidney transplants compared general population
Highly effective (99%–100% for the prevention of cervical intraepithelial neoplasia)
Vaccination is indicated in both males and females aged 9–25 years in the general population
Post transplant, vaccine is safe
It is recommended for women after transplantation but better before transplantation.
Management of cancer after transplantation
Needs MDT
Immunosuppression Management
Modulation of immunosuppression is challenging and needs MDT
In early- to moderate-stage malignancy the first step is to reduce immunosuppression after consultation with the patient
For patients with SCC and Kaposi sarcoma, conversion to an mTOR inhibitor may reduce the risk of cancer in the longer term
Immunotherapy
Promise use of immune-checkpoint inhibitors (risk of rejection with nonspecific immune-system activation)
Effective in treating melanoma, non–small cell lung cancer, and renal cell carcinoma in the general population
Conclusions
In patients with kidney transplants, cancer is a main cause of morbidity and mortality
Management is challenging (treatment of cancer and optimize allograft function)
What is the level of evidence provided by this article?
Level v (narrative review)
De Novo Malignancies after Kidney Transplantation
Introduction:
After cardiovascular disease, cancer is the second leading cause of death among recipients of transplants. The higher risks and poorer cancer outcomes have led clinicians and policy makers to adopt preventive policies, such as human papillomavirus (HPV) vaccination and cancer-screening strategies, to detect cancers at their early stages.
Cancer Mortality in Recipients of Kidney Transplants is high. Observational data have shown the standard mortality ratios for all cancer types are at least 1.8–1.9 times higher compared with the age- and sex-matched general population. The risk is greatest among those with melanoma, urogenital cancers, and non-Hodgkin lymphoma, with an overall risk of cancer-related death exceeding five to ten times that of those without kidney transplants.
Risk Factors for Cancer Development
There are many reasons for the higher cancer risk after transplantation. Some of these factors, such as increasing age, male sex, smoking, and prolonged sun exposures, are shared by patients in the general population. Other risk factors, including immunosuppression use (T cell–depleting agents), acute rejection , sensitization status , and duration of dialysis before transplantation , are specific to those with kidney disease and transplant populations.
Mechanisms of Cancer Development after Transplantation
The effects of immunosuppression on dampening the immune system may create a variety of pathways for cancer development. One potential mechanism is through poor immune control of known oncogenic viruses in patients on immunosuppression. For example, increases in viral-associated cancers, such as Kaposi sarcoma (human herpesvirus 8), PTLD (Epstein– Barr virus [EBV]), and lip and anal cancers (HPV) are common in patients with suppressed immune systems. Currently, there is no conclusive evidence to suggest one type of immunosuppression is more oncogenic than others. However, experimental studies in hepatocellular carcinoma, human lung adenocarcinoma cells, and renal cell carcinoma have shown that tacrolimus increases the level of TGF-b and thereby promotes tumor progression and metastasis. Mammalian target of rapamycin (mTOR) inhibitors, on the contrary, may have potential antitumor effects by inhibiting cancer growth through cell-cycle arrest and initiation of apoptosis.
Common Cancers after Transplantation
Although the risk of overall cancer development is high after transplantation, the risks of certain cancer types are much higher than others
Renal Cell Carcinoma Compared with the general population, recipients of kidney transplants have a higher risk (up to seven-fold) renal cell carcinoma . Due to increased abdominal imaging, the majority of kidney masses detected in patients post-transplantation are typically early, low-grade, small kidney masses of which, 75%–80% are renal cell carcinoma, with the risk of metastasis at presentation being ,2%.
Skin Cancer Skin cancer is the most common cancer type in recipients of kidney transplants and is more aggressive than skin cancers occurring in the general population. The most commonly reported skin cancers in recipients of kidney transplants include cutaneous squamous cell carcinoma, basal cell carcinoma, Kaposi sarcoma, and malignant melanoma, with keratinocyte carcinomas comprising 90%–95% of these skin cancers.
Post-Transplant Lymphoproliferative Disease PTLD is a well-recognized complication after kidney transplantation. It is associated with poor outcomes. In most instances (approximately 90%), PTLD is associated with EBV. EBV is a common virus, and most people acquire the virus during childhood. Most present with mild or minimal symptoms, but the virus can infection the B cells and remain dormant in these cells during the latent phase. After transplantation, these viruses can reactivate because of depressed T-cell function, with a lack of T-cell control over B-cell proliferation, and contributes to the development of PTLD.
Cancer Screening Strategies in Transplant Recipients
High-quality, randomized controlled trials have shown that cancer screening through early detection reduces cancer-specific mortality in the general population. Some guidelines suggest routine skin checks by dermatologists in recipients of transplants who are at high risk, and abdominal ultrasounds and serum a-fetoprotein levels should be checked every 6 months for those with underlying liver disease and chronic HBV infections. For patients who are at risk of developing renal cell carcinoma (such as those with a history of acquired cystic disease, those with a family history, those who are heavy smokers, and those who use long-term analgesics), ultrasonographic screening (annually or biennially) of the native kidneys may be considered to detect occult malignancy. Human Papillomavirus Vaccination in Recipients of Kidney Transplants The incidence of HPV-related anogenital cancer is at least ten- to 15-fold higher in recipients of kidney transplants compared with the age- and sex-matched general population. Quadrivalent vaccines (against genotype 6, 11, 16, and 18) and, more recently, the HPV 9-valent vaccines (against five additional genotypes of 31, 33, 45, 52, and 58) are highly effective and have an overall efficacy of 99%–100% for the prevention of cervical intraepithelial neoplasia in randomized control trials.
HPV vaccination is indicated in both males and females aged 9–25 years in the general population for the prevention of HPV-related malignancies. Some recent data have shown that it is also efficacious in women up to the age of 45 years. In the transplant population, HPV vaccines are generally safe.
Management of Recipients of Kidney Transplants Who Have Cancer Immunosuppression Management and Treatment in Transplant Recipients with Cancer: For patients with squamous cell carcinoma, there is now trial-based evidence to suggest conversion to an mTOR inhibitor may reduce the risk of cancer in the longer term. However, Tor-inhibitor use may also be associated with a higher risk of death. There are insufficient data to consider mTOR inhibitors as protective against other cancer types apart from squamous cell carcinoma and Kaposi sarcoma.
Immunotherapy
Level of evidence :V
Incidence of All-Cause and Site-Specific Cancer after Transplantation:
The cumulative incidence of solid organ cancer ranges between 10% and 15% at around 15 years after transplantation. skin cancers cumulative incidence reaches 60% and it exceeds that of the general population by approximately two- to three-fold after adjustment for age and sex. There is greatee risk of viral-related and immunedriven cancers (PTLD, anogenital cancer, and Kaposi sarcoma
Cancer Mortality in Recipients of Kidney Transplants
Western countries mortality ratios for all cancer types are at least 1.8–1.9 times higher compared with the age- and sex-matched general population with greatest risk among those with melanoma, urogenital cancers, and non-Hodgkin lymphoma( overall risk of cancer-related death exceeding five to ten times that of those without kidney transplants).
Risk Factors for Cancer Development
Risk factors are the general population factors like increasing age, male sex, smoking, and prolonged sun exposures beside immunosuppression use, acute rejection, sensitization status, and duration of dialysis before transplantation. long-term immunosuppression and having CKD (irrespective of the CKD stage) impaired tumor surveillance and immunity to viral or other tumor antigens.a previously treated pretransplant malignancy.
The specific types of cancer that develop after transplantation
In Europe, North America, Australia, and New Zealand indicate the most common cancer types are nonmelanoma skin cancers (NMSCs), PTLD, and lip cancer while in Western Asian and Middle Eastern transplant cohorts the commonest are urothelial transitional cell carcinoma, renal cell carcinoma, and gastrointestinal cancers in their populations. A nationwide population study of 4716 recipients of kidney transplants in Taiwan reported an excess risk of liver cancer and Taiwan is an endemic area for chronic hepatitis B virus infection.
Mechanisms of Cancer Development after Transplantation
Maintenance immunosuppression may create a variety of pathways for cancer development:
1. through poor immune control of known oncogenic viruses Kaposi sarcoma (human herpesvirus 8), PTLD (Epstein– Barr virus [EBV]), and lip and anal cancers (HPV)
2. through accumulation of mutations not repaired by the immune system: skin cancers in cells damaged by ultraviolet (UV) radiation–induced DNA damage.
3. decrease of xeroderma pigmentosum complementation groups A and G, which are components of nucleotide excision repair
immunosuppressants effects :
1- tacrolimus increases the level of TGF-b and thereby promotes tumor progression and metastasis of hepatocellular carcinoma, human lung adenocarcinoma cells, and renal cell carcinoma.
2- CNI inhibit signaling via calcineurin and NF of activated T cells, which can activate p53, a hallmark of some NMSCs .
3- Cyclosporine is through TGF-b or IL-6 overexpression pathways and inhibiting DNA repair, thereby accumulating mutations, inducing apoptosis in activated T cells, and inhibiting apoptosis in other cells by opening the mitochondrial permeability transition pores
4- Azathioprine sensitizes the skin to UVA radiation and causes the accumulation of 6-thioguanine in the DNA, leading to a higher risk of NMSCs
5- Mammalian target of rapamycin (mTOR) inhibitors, have antitumor effects by
1- inhibiting cancer growth through cell-cycle arrest and initiation of apoptosis. ( small cell lung cancer, sarcoma, neuroblastoma, glioblastoma, osteosarcoma, pancreatic cancer, breast cancer, prostate cancer, leukemia, and B-cell lymphomas)
2- On a molecular level mTOR inhibitors can induce apoptosis in a cell type–specific fashion.
3- It can also induce cell death in B-cell lymphoma lines, phosphatase and tensin homolog-lacking human tumors, and dendritic cells, possibly through p53 activation and reduction in the cyclin and survivin levels
6- T cell–depleting agents increases the risks of cancers, such as PTLD and melanoma . after T-cell depletion, there is often an incomplete T-cell recovery which may have a long-term effect on immune homeostasis, leading to an impaired immune system and subsequent cancer development.
Common Cancers after Transplantation
the three most common cancer types: renal cell carcinoma, skin cancer, and PTLD.
Renal Cell Carcinoma
recipients of kidney transplants have seven-fold higher risk of renal cell carcinoma and the majority are early, low-grade, small kidney masses of which, 75%–80% are RCC, with 2% risk of metastasis at presentation. 90% of renal cell carcinomas develop in the native kidneys as opposed to the allograft. Risk factors are male sex, increasing age, African descent and longer time on dialysis, disease etiology (glomerular diseases, hypertensive nephrosclerosis and vascular disease). The outcome of renal cell carcinomas after radical treatment in the transplant population is comparable with that of the general population. Renal cell carcinoma in the kidney allograft is rare, and multicenter data have demonstrated an incidence of 0.1%.
Overall duration and intensity of immunosuppression, rather than individual components of the drug regimen, influence risk of renal cell carcinoma.
Skin Cancer
Skin cancer is the most common and is more aggressive than skin cancers occurring in the general population. They include cutaneous squamous cell carcinoma, basal cell carcinoma, Kaposi sarcoma and malignant melanoma.
The risk factors are exposure to UV radiation, HPV, pretransplant skin cancer, older age, race, and sex (males at greater risk than females), immunosuppressive medications ( cyclosporine and azathioprine) certain ethnic groups( Mediterranean, Africa, and Central Europe have more Kaposi).
Compared with the general population, the incidence of Kaposi sarcoma in recipients of transplants exceeds by 100 times , squamous cell carcinoma by 250 times and malignant melanoma is 5-8 folds more. Among all skin cancer types, melanoma has the highest mortality. Risk factors are:History of pretransplant melanoma ,White race and older age (>50 years).
squamous cell carcinoma Management in recipients of transplant:
1- actinic keratoses and squamous cell carcinoma in situ : topical fluorouracil and imiquimod cream, photodynamic therapy, and surgical excision or electrodesiccation and curettage.
2- biopsy sample–proven cutaneous squamous cell carcinoma: Mohs micrographic surgery, with histologic confirmation of negative margins( cure rates of 95%–100%)
3- inoperable cases: primary radiation therapy may achieve local cure rates.
4- chemoprophylaxis : for multiple squamous cell carcinomas (more than five) every year, aggressive squamous cell carcinomas, or early onset of squamous cell carcinomas.These may include retinoids and nicotinamide.
5- metastatic cutaneous squamous cell carcinoma, systemic chemotherapy and/or immunotherapy are recommended.
Kaposi sarcoma management
Decreasing the intensity or switching CNI agents to an mTOR inhibitor lead to regression of Kaposi sarcoma by restoring effector and memory T-cell immune activity against human herpesvirus 8 .
level of evidence is 5
Kidney transplantation is the best treatment of ESRD. It is more cost effective with better outcomes as compared to dialysis. Post transplant malignancy is the second most common cause of death after cardiovascular events. The recipients have 2-3 fold higher risk of developing cancers after transplant than general population. The most common cancers are skin cancers followed by solid organ canacers. The cumulative incidence of solid organ cancer ranges between 10% and 15% at 15 years.
The risk also depends on the cancer types. The risk is higher in viral and immune related cancers ,e.g post-transplant lymphoproliferative disease (PTLD), anogenital cancer, and Kaposi sarcoma. Some cancers like breast and prostate are not increased after transplant.
The mortality ratios for all cancer types are at least 1.8–1.9 times higher compared with the age- and sex-matched general population. The risk is greatest among those with melanoma, urogenital cancers, and non-Hodgkin lymphoma.
Risk Factors for cancer development
Increasing age
Male sex
Smoking
Prolonged sun exposures
Immunosuppression use (T cell–depleting agents)
Acute rejection
Sensitization status
Duration of dialysis before transplantation
Type of immune suppression
Induction with ATG increases the risk of PTLD and melanoma
After T-cell depletion, there is often an incomplete T-cell recovery (41), which may have a long-term effect on immune homeostasis, leading to an impaired immune system
MMF and Sirolimus increases the risk of malignancy.
Renal Cell Carcinoma
The risk of 6-7 fold higher and occur mostly in native kidneys. Surgical options include Radical nephrectomy, Partial nephrectomy , Cryotherapy or HIFU.
Skin Cancers
The most common skin cancers in recipients include cutaneous squamous cell carcinoma, basal cell carcinoma, Kaposi sarcoma, and malignant melanoma, with keratinocyte carcinomas comprising 90%–95% .
The common risk factors are exposure to UV radiation, HPV, pretransplant skin cancer, older age, race, and sex. Treatment includes, 5FU, photodynamic therapy and Excision.
PTLD
PTLD is associated with EBV with poor outcomes.
Treatment is reduction of immune suppression, rituximab or chemotherapy
Cancer Screening
There is lack of evidence to support routine screening in this high-risk group, routine population-based cancer screening for breast, colorectal, and cervical cancer is recommended
HPV Vaccination
This is more effective when given before transplant
Level of evidence V
. Please summarise this article
Introduction
-Kidney transplantation is the best treatment option
for acceptable candidates with kidney failure but transplantation is not a cure.
-Patients require life-long immunosuppression to maintain optimal allograft function and the most important complications associated with immunosuppression after kidney transplantation is cancer .
Incidence of All-Cause and Site-Specific Cancer after Transplantation
-The cumulative incidence of solid organ cancer ranges between 10% and 15% at around 15 years after transplantation.
– The cumulative incidence of skin cancers reaches 60% in Europe, Australia, and New Zealand.
-The excess overall cancer risk in patients with kidney transplant exceeds that of the general population by approximately two- to three-fold after adjustment for age and sex.
-There is high risk of viral-related and immune driven cancers such as post-transplant lymphoproliferative disease (PTLD), anogenital cancer, and Kaposi sarcoma while breast and prostate cancers are not increased in recipients
of transplants .
Cancer Mortality in Recipients of Kidney Transplants
-Once cancers develop, the risk of death is high.
-The risk is greatest among those with melanoma, urogenital cancers, and non-Hodgkin lymphoma, with an overall risk of cancer-related death exceeding 5-10
times that of those without kidney transplants.
Risk Factors for Cancer Development
-Some of these factors, such as increasingage, male sex, smoking, and prolonged sun exposures, are shared by patients in the general population.
-Other risk factors,including immunosuppression use (T cell–depleting
agents), acute rejection , sensitization status , duration of dialysis before transplantation , and pretransplant malignancy are specific to those with kidney disease and transplant populations.
-Cancer may develop in recipients of kidney transplants because of impaired tumor surveillance and immunity to viral or other tumor antigens.
-The specific types of cancer that develop after transplantation vary by geographic areas. Observational and registry data from Europe, North America, Australia, and New Zealand indicate the most common cancer types are nonmelanoma skin cancers (NMSCs), PTLD, and lip cancer
-Data from non-Western Asian and Middle Eastern transplant cohorts suggest higher incidences of urothelial transitional cell carcinoma, renal cell carcinoma,
and gastrointestinal cancers in their populations .
Mechanisms of Cancer Development after Transplantation
-One potential mechanism is through poor immune control of known oncogenic viruses in patients on immunosuppression.
-Another mechanism of immunosuppression-related cancer development is through accumulation of mutations that would otherwise be repaired or recognized by the immune system.
-Currently, there is no conclusive evidence to suggest one type of immunosuppression is more oncogenic than others.
Common Cancers after Transplantation
-The three most common cancer types: renal cell carcinoma, skin cancer,
and PTLD.
Renal Cell Carcinoma
-Compared with the general population, recipients of kidney
transplants have a higher risk of renal cell carcinoma .
– 90% of renal cell carcinomas develop in the native kidneys as opposed to the allograft.
-Risk factors for development of renal cell carcinomas posttransplantation include male sex , increasing age , African descent , longer time on dialysis , kidney failure secondary to glomerular diseases , hypertensive nephrosclerosis , and vascular disease .
-The outcome of renal cell carcinomas after radical treatment in the transplant population is comparable with that of the general population.
-Overall duration and intensity of immunosuppression, rather than individual components of the drug regimen, influence risk of renal cell carcinoma.
-The management of these malignancies should be individualized
and use a patient-centered approach to ensure optimal care .
Skin Cancer
-Skin cancer is the most common cancer type in recipients of kidney transplants and is more aggressive than skin cancers occurring in the general population.
-The most commonly reported skin cancers include cutaneous squamous cell carcinoma, basal cell carcinoma, Kaposi sarcoma, and malignant melanoma, with keratinocyte carcinomas comprising 90%–95% of these skin cancers .
-Risk factors, including exposure to UV radiation, HPV, pretransplant skin cancer,
older age, race, sex (males at greater risk than females) and immunosuppressive medications mainly cyclosporine and azathioprine.
-Kaposi sarcoma is more commonly in certain ethnic groups, including patients from the Mediterranean, Africa, and Central Europe.
– In patients with actinic keratoses and squamous cell carcinoma in situ, management options with good outcomes include topical fluorouracil and imiquimod cream, photodynamic therapy, and surgical excision or electrodesiccation and curettage.
– In inoperable cases, primary radiation therapy may achieve local cure rates.
-Patients who develop multiple squamous cell carcinomas (more than five) every year, those who have aggressive squamous cell carcinomas, or those with early onset of squamous cell carcinomas can be considered for chemoprophylaxis.
-Chemoprophylaxis may include retinoids and nicotinamide and in metastatic cutaneous squamous cell carcinoma, systemic chemotherapy and/or immunotherapy are recommended .
-Patients treated with calcineurin inhibitors are at particularly high risk for Kaposi sarcoma. Decreasing the intensity or switching immunosuppressive agents to an mTOR inhibitor is the cornerstone of treatment.
-The risk of developing malignant melanoma is elevated by approximately 5-8 fold in recipients of transplants, and these patients have poor outcomes and the highest mortality .
-History of pretransplant melanoma is the strongest risk factor for post-transplant melanoma, followed by White race and older age .
– Primary treatment is surgical with wide excision and adequate margins and adjustment of immunosuppression on the basis of the extent of melanoma and transplant function.
Post-Transplant Lymphoproliferative Disease
-It is a rare disease but associated with poor outcomes.
-90% of PTLD is associated with EBV.
-Most PTLDs are of B-cell types, with approximately 5% of patients having
the T-cell type.
– The use of costimulatory blockade, such as belatacept, has been found to be associated with a higher risk of PTLD, particularly cerebral PTLD in patients
who are EBV negative, and when used in higher doses .
-The treatment goal of PTLD is to cure the disease, and the mainstay of treatment is immunosuppression reduction.
– Prior work reported the use of rituximab and chemotherapy (doxorubicin,
cyclophosphamide, vincristine, prednisone) have improved overall survival, with 5-year survival at around 60% .
-Once PTLD develops, the risk of death is high.
Cancer Screening Strategies in Transplant Recipients
-Despite the lack of trial-based evidence to support routine screening in this high-risk group, routine population-based cancer screening for breast, colorectal,
and cervical cancer is recommended and should be aligned to the guidelines as per the general population .
-Some guidelines also suggest routine skin checks by dermatologists in recipients of transplants who are at high risk, and abdominal ultrasounds and serum a-fetoprotein levels should be checked every 6 months for those with underlying liver disease and chronic HBV infections.
-For patients who are at risk of developing renal cell carcinoma, ultrasonographic
screening (annually or biennially) of the native kidneys may be considered to detect occult malignancy.
Human Papillomavirus Vaccination in Recipients of Kidney Transplants
-The incidence of HPV-related anogenital cancer is at least ten- to 15-fold higher in recipients of kidney transplants compared with the age- and sex-matched general population.
-Quadrivalent vaccines (against genotype 6, 11, 16, and 18) and, more recently, the HPV 9-valent vaccines (against five additional genotypes of 31, 33, 45, 52, and 58) are highly effective and have an overall efficacy of 99%–100% for the prevention of cervical intraepithelial neoplasia in randomized clinical trials.
Management of Recipients of Kidney Transplants Who Have Cancer
Immunosuppression Management and Treatment in Transplant Recipients with Cancer:
-A concerted approach between transplant professionals, oncologists, and allied health professionals is therefore needed to ensure optimal care for our patients.
-In the absence of quality evidence, judicious reduction in the overall immunosuppression load for patients with early- to moderate-stage malignancy may be a reasonable first step.
Immunotherapy:
-The use of immune-checkpoint inhibitors has revolutionized the treatment of a variety of malignancies through immune system activation against the cancer. However, their use in the kidney transplant population requires further investigation and cannot be recommended at this time, outside of a study protocol.
Putting Patients’ Perspectives at the Heart of Cancer Management
-A personalized, rather than a one-size-fits-all, approach is most preferred and a multidisciplinary, integrated approach that involves the transplant and palliative
care team is crucial.
Conclusions
-The evidence to support primary prevention and screening programs in
recipients of transplants are largely extrapolated from the general population, and the findings may not necessarily be applicable to the transplant population. Collaborative efforts between health care professionals, policy makers, trialists, and patients are needed to ensure quality evidence— in the form of intervention trials, large-care observational studies, and qualitative and health service
research—are generated to support the long-term care of recipients of transplants.
What is the level of evidence provided by this article?
Level 5
SUMMARY
This is a review article on de-novo malignancies in kidney transplant recipients.
Introduction
Kidney transplantation is the best option for the eligible patient however it is associated with life long use of immunosuppressive therapy. This is associated with complications with the most feared being cancer. Thus cancer is prevalent in the transplant recipients and it is the second cause of death after cardiovascular disease in this population. Most common cancers are skin cancer, viral related and immune driven cancers.
Risk factors
Traditional risk factors do play a role in this population and they include increased age, male gender, smoking and prolonged sun exposure.
However other risk factors tend to be specific for the transplant recipients and this include use of immunosuppressive agents, incidence of acute rejection, sensitisation status and duration on dialysis.
Other risk factors tend to be region specific for example a Taiwan study showed a high incidence of liver cancer however there is a high prevalence of chronic HBV infection in Taiwan with transplant recipients having a prevalence of HBV between 9-24%.
Immunosuppression and malignancy
Generally immunosuppressive agents are good since they reduce the incidence of rejection and in so doing reduce the incidence of graft loss. However they do dampen the immune system and thus creating pathways for developing malignancy.
One way they do this is by poor immune control of oncogenic virus thus allowing their proliferation and hence increased incidence of viral associated cancer eg Kaposi sarcoma-HHV8, lip and anogenital cancer-HPV, PTLD-EBV.
Another way is by accumulation of mutations which would have otherwise been recognised and repaired by the immune system. This is more so for skin cancers where they inhibit ability to repair DNA damaged by UV radiation.
Specific immunosuppressive therapy
Azathioprine associated with high risk of NMSC due to the accumulation of thioguanine in the DNA thus sensitising the skin to UV radiation.
Cyclosporine inhibits DNA repair thus accumulation of mutations which induce apoptosis in activated T cells. It also causes over expression of IL6 and TGF beta.
CNI inhibit signalling via calcineurin in activated T cells leading to activation of P53 which is a hallmark of NMSC.
Tacrolimus in experimental studies have been shown to increase the expression of TGF beta which promotes tumour progression and metastasis.
However it should be noted that there is no enough evidence to show one agent to be more oncogenic than another, it is rather the duration and intensity.
Specific cancers
1.Renal cell carcinoma
Kidney transplant recipients have a 7 fold risk. They tend to occur in the native kidneys. The increased risk could be due to traditionally risk factors like gender, ethnicity, increased age, duration on dialysis, intensity and duration of immunosuppression and the primary diagnosis.
However it should be noted that this particular patient population have increased frequency of abdominal imaging this explains why they are routinely caught early and could also explain the high incidence in comparison to other malignancies that are not routinely screened for in this patient population.
2.Skin cancers
They tend to be more aggressive than the general population. The most common is squamous cell carcinoma, however malignant melanoma is associated with the highest mortality. Risk factors include UV exposure, HPV, older age, race, gender, pre-transplant skin cancers and use of immunosuppressive agents.
3.PTLD
It associated with poor outcomes and in 90% of the cases it is associated with EBV. Most people acquire EBV in childhood and it remains latent in B cells, due to decreased T cell function caused by the immunosuppressive agents after transplant, there is unchecked B cell proliferation and thus of the virus. Thus most PTLD are B cells.
Screening
Screening for breast, colorectal and cervical cancers which have a low incidence would be as per the local guidelines. Some guidelines do recommend regular skin checks with a dermatologists and screening for at risk patients groups for example regular abdominal U/S for recipients with chronic HBV. However the decision to screen and the intensity should be made in collaboration with the patients.
Vaccination
The high incidence of anogenital malignancies associated with HPV should advocate vaccination in this patient population more so in the pre-transplant period.
Management
The management should be a balance between avoidance of rejection in the graft and induction of regression in the malignant cell.
Patients not in advanced cancer stage the first line should be reduction in the immunosuppressive agent.
The is limited evidence of use of immunotherapy agents due to risk of rejection.
LEVEL OF EVIDENCE
This is a level 5 they are reporting evidence from other studies.
This review article focuses on post-transplant malignancy, including its incidence, diagnosis, treatment and prevention. Cancer is the second most common cause of death in transplant patient after cardiovascular disease. The most common cancer being non melanoma skin cancer, while the risk of mortality is highest among melanoma, urogenital cancers, and non-Hodgkin lymphoma.
Risk factors for cancer development specific for kidney transplant patients depend on the type and intensity of immunosuppression, episodes of rejection, sensitization status, duration of dialysis prior to transplantation, certain oncogenic virus like EBV, HPV.
Among renal transplant recipients, risk of renal cell carcinoma is seven times that of general population. Ninety percent of renal cell carcinomas develop in the native kidneys, risk factors include male sex, increasing age, African descent, and longer time on dialysis (more than 3 years). RCC is managed as per urological guidelines and the outcome after treatment is comparable to general population.
Skin cancer is the most common post-transplant malignancy and includes squamous cell carcinoma, melanoma, Kaposi sarcoma, basal cell carcinoma. Risk factors include exposure to UV radiation, HPV, pretransplant skin cancer, older age, race, and male sex, type of immunosuppression such as azathioprine and cyclosporin. Management options include topical fluorouracil and imiquimod cream, photodynamic therapy, and surgical excision or electrodesiccation and curettage.
PTLD is associated with EBV in 90 % of cases. The incidence of PTLD in the first 10 years after kidney transplantation is 1%–2% in adults, it has a bimodal distribution, with the risk of PTLD being the highest in the 12 months post-transplant, and it then decreases until the fifth year after transplantation. Risk factors include EBV, younger age, males, type of immunosuppression such as T call depleting agents, high dose of tacrolimus and belatacept. Treatment options include reduction of immunosuppression, rituximab and chemotherapy.
Routine screening of breast, cervical and colorectal cancer is recommended in transplant recipients. Some guidelines advocate skin cancer checks by dermatologists. Recipients with underlying liver disease should be screened for HCC by 6 monthly ultrasounds and serum a-fetoprotein levels.
The incidence of HPV-related anogenital cancer is at least ten- to 15 times higher in kidney transplants recipients compared with general population. HPV vaccination is recommended for recipients aged 9-25 years, preferably prior to transplantation.
Level of evidence: Level 5
Please use bold or underline for heading or sub-headings.
I like your analysis of level of evidence, limitations and strengths of this study
Please use bold or underline for heading or sub-headings.
I like your analysis of level of evidence of this study.
Review article focuses on the incidence, mechanisms, diagnosis, prevention, and treatment of cancer after kidney transplantation. Written at 2022
Incidence (SIR) and mortality (SMR)
Cancer is the second cause of death among transplants.
All cancer SIRs 2-3 and SMR almost 2.
Incidence for skin cancers >60 SIR. Risk of cancer related death 5-10 times in melanoma, urogenital cancers, and non-Hodgkin lymphoma.
breast and prostate cancers are not increased in recipients of transplants
Risk Factors for Cancer Development· Like general population: increasing age, male sex, smoking, and prolonged sun exposures.
· Kidney tx population specific: immunosuppression use (T cell–depleting agents), acute rejection, sensitization status, and duration of dialysis before transplantation.
· geographic areas: Europe, North America: nonmelanoma skin cancers, PTLD, and lip cancer. Asian and Middle Eastern: urothelial transitional cell carcinoma, renal cell carcinoma, and gastrointestinal cancers.(? aristolochic acid related)
Mechanisms of Cancer Development after Transplantation1. poor immune control of known oncogenic viruses due to immunosuppression:
For example, increases in viral-associated cancers, such as Kaposi sarcoma (human herpesvirus 8), PTLD (Epstein–Barr virus [EBV]), and lip and anal cancers (HPV)
2. immunosuppression-related cancer development is through accumulation of mutations that would otherwise be repaired or recognized by the immune system. Example: skin cancers, where immunosuppression impairs the cells’ ability to UV radiation–induced DNA damage.
3. Type of immunosuppression: (Table attached as pic)
Renal Cell CarcinomaSIR 7
Early detection ¾ early small lesions Due to increased imaging, metastasis <2%.
Risk factors: male, age ≥ 60, African descent, dialysis ≥ 3y, Primary renal dse: glomerular diseases, hypertensive nephrosclerosis, and vascular disease greatest associated risk
managed according to urologic guidelines.
Prognosis: Similar to general population 70-90 % survival after radical surgery
Negative prognostic factors include presence of symptoms at diagnosis, higher Fuhrman grade (>2), absence of transplantation, and advanced-stage disease (53–56).
Allograft RCC incidence 0.1%. Most are low-grade T1 lesions, clear cell carcinomas, or papillary renal cell carcinomas, and occur more commonly in males. Two third of tumours can be with partial nephrectomy
Skin CancerMost common: squamous cell carcinoma, basal cell carcinoma, Kaposi sarcoma, and malignant melanoma, with keratinocyte carcinomas
Risk factors: UV radiation, HPV, pre transplant skin cancer, older age, race, and male sex. Cyclosporine and azathioprine can augment the risk, Geographical Kaposi sarcoma (Mediterranean, Africa, and Central Europe).
Management: – See table in the pic
Malignant melanoma SIR 5-8, poorer outcomes and highest mortality. Risk: History of pretransplant melanoma (strongest), White race and older age (>50 years). Primary treatment is surgical with wide excision and adequate margins. Adjustment of immunosuppression is individualized
Post-Transplant Lymphoproliferative Disease
PTLD is associated with EBV in 90 % of cases.
EBV natural Hx: Pre-Transplant: Most people acquire the virus during childhood. Most present with mild or minimal symptoms, but the virus can infection the B cells and remain dormant in these cells during the latent phase. After transplantation, these viruses can reactivate because of depressed T-cell function, with a lack of T-cell control over B-cell proliferation, and contributes to the development of PTLD. Most PTLDs are of B-cell types, with approximately 5% of patients having the T-cell type.
The cumulative incidence in the first 10 years after kidney transplantation is around 1%–2%. There also appears to be a bimodal distribution in PTLD incidence, first and 5th year post Tx. Early PTLD common in pre transplant seronegative with primary infection post Tx.
Risk factors: younger age at transplantation, male, use of T cell–depleting agents, Ortho Kung T3 (muromonab-CD3), and high dose tacrolimus, positive to negative, The use of costimulatory blockade, such as belatacept (cerebral PTLD)
Treatment: Rituximab (better outcome with EBV +ve and normal LDH) and chemotherapy (doxorubicin, cyclophosphamide, vincristine, prednisone) have improved overall survival, with 5-year survival at around 60%.
Survival: 1 Y 66 % and 10 Y 44 % worse with bone marrow/reticuloendothelial (can die within 6 months). Worse prognosis with male and increasing age of diagnosis.
Human Papillomavirus Vaccination in Recipients of Kidney Transplants
The incidence 10- to 15-fold higher in recipients of kidney transplants. Quadrivalent vaccines (against genotype 6, 11, 16, and 18) and the HPV 9-valent vaccines (against five additional genotypes of 31, 33, 45, 52, and 58) are highly effective in prevention.
HPV vaccination is indicated in both males and females aged 9–25 years in the general population.
Non responders: 50% patients, depending on genotypes, and higher tacrolimus levels
Management of Recipients of Kidney Transplants Who Have Cancer
judicious reduction immunosuppression load for patients with early- to moderate-stage malignancy
squamous cell carcinoma Kaposi sarcoma: switch to mTOR
Immunotherapy: Trials
Advanced-stage malignancy, Some clinicians may consider stopping either or both the calcineurin inhibitors and antiproliferative agents gradually and rotate to higher-dose corticosteroids to prevent the anticipated symptoms.
Level of Evidence:
Review article (not systematic review) provide expert opinion based on previous studies which is the lowest in the pyramid
Second table for types of immunosuppression and their mechanism in cancer
That is a good summary.. Please type headings and sub-headings in bold or in underline.
Ajay
Summery:
This article is about development and outcome of cancer post transplantation .It seems that the developded of cancer post trsnapnat is mainly related to cell and immunology modulation.Malignancies such as melanoma, renal cell carcinoma, and PTLD have bad outcome in comparison with other malignancies.
Risk factors for cancer development form a long list, including increasing age, male sex, smoking, prolonged sun exposure, immunosuppressive therapy, acute rejection episodes, status of sensitization, duration of dialysis prior to transplantation.
Accumulation of mutation is the second cuase of cancer , with Specifically, this can be applied to skin cancers, where immunosuppression can lead to a decrease of xeroderma pigmentosum complementation groups A and G.
In this article also increase of hepatocellualr carcinoma IN patientient on Tacrolimus which increase TGF and P 53 and both of them promoting tumoer growth.
Adding to that PTLD is associated with EBV ,with regression in rate of this cancer due to pretranspkant screening for EBV . in This type of cancer rituximab and reduction of immunosuppression medications is the main corner .
Primary prevention and the screening program is the main corner stone ,
this is annaritive writing level v
That is a good summary.. Please type headings and sub-headings in bold or in underline.
Ajay
1. Please summarise this article
The Prevalence of All-Cause & Site-Specific Cancer
Cancer Mortality in Recipients of Kidney Transplants
Risk Factors for Cancer Development
Mechanisms of Cancer Development:
Common Cancers Following Transplantation
Pathogenesis:
PTLD
Cancer Screening:
Management:
==========================
2. What is the level of evidence provided by this article
Level V
That is an excellent summary and very well structured reply.
I like your analysis of level of evidence of this study.
Summary of the article
DE NOVO MALIGNANCIES AFTER KIDNEY TRANSPLANTATION
· Cancer is the second leading cause of death after cardiovascular diseases among recipients of transplants.
· Incidence of All-Cause solid organ cancer ranges between 10% and 15% at around 15 years after transplantation.
· The excess overall cancer risk in patients with kidney transplant exceeds that of the general population by approximately two- to three-fold after adjustment for age and sex.
· An overall risk of cancer-related death exceeding five to ten times that of those without kidney transplants.
· Risk factors for cancer development shared by patients in the general population are: increasing age, male sex, smoking, and prolonged sun exposures. Additional risk factors specifc to those with kidney disease and transplant populations include; immunosuppression use (T cell–depleting agents), acute rejection , sensitization status , and duration of dialysis before transplantation. CKD (irrespective of the CKD stage) is associated with higher cancer risk and poor cancer outcomes.RCC and multiple myeloma, are over-represented in the CKD/ kidney-failure populations. When stratifed by sex, women have a much higher risk than men for kidney and bladder cancers.
Mechanisms of Cancer Development after Transplantation:
1. Poor immune control of known oncogenic viruses in patients on immunosuppression.
· Kaposi sarcoma (human herpesvirus 8)
· PTLD (Epstein– Barr virus EBV).
· Lip and anal cancers (HPV).
2. Accumulation of mutations; this mechanism may be predominant in skin cancers.
· immunosuppression impairs the cells’ ability to repair ultraviolet (UV) radiation–induced DNA damage.
· immunosuppression can lead to a decrease of xeroderma pigmentosum complementation groups A and G, which are components of nucleotide excision repair.
3. Calcineurin inhibitors inhibit signaling via calcineurin and NF of activated T cells, which can activate p53, a hallmark of some NMSCs.
· Tacrolimus increases the level of TGF-b and thereby promotes tumor progression and metastasis.
· Cyclosporine is capable of inhibiting DNA repair, thereby accumulating mutations, inducing apoptosis in activated T cells, and inhibiting apoptosis in other cells by opening the mitochondrial permeability transition pores.
4. Azathioprine sensitizes the skin to UVA radiation and causes the accumulation of 6-thioguanine in the DNA, leading to a higher risk of NMSCs.
5. Mammalian target of rapamycin (mTOR) inhibitors may have potential antitumor effects by inhibiting cancer growth through cell-cycle arrest and initiation of apoptosis.
6. Induction therapy with T cell–depleting agents (including polyclonal agents, such as anti-thymocyte globulin, and monoclonal agents, such as anti-CD52 and, historically, Ortho Kung T3 [muromonab-CD3]) increases the risks of cancers, such as PTLD and melanoma.
7. After T-cell depletion, there is often an incomplete T-cell recovery , which may have a long-term effect on immune homeostasis, leading to an impaired immune system and subsequent cancer development.
Common Cancers after Transplantation
The three most common cancer types: renal cell carcinoma, skin cancer, and PTLD.
1. Renal Cell Carcinoma
· KTRs have higher risk reaching up to seven-fold of RCC.
· 75-80% of early detected small kidney masses are low grade RCC.
· 90% of RCC develop in the native kidneys as opposed to the allograft.
· Renal cell carcinoma in the kidney allograft is rare, and multicenter data have demonstrated an incidence of 0.1%. Most are low-grade T1 lesions, clear cell carcinomas, or papillary renal cell carcinomas, and occur more commonly in males.
· Risk factors for development of RCC post-transplantation include male sex, increasing age, African descent and longer time on dialysis.
· The followings appear to have the greatest associated risk; kidney failure secondary to glomerular diseases, hypertensive nephrosclerosis and vascular disease.
· DM and autosomal dominant PKD have a lower risk of renal cell carcinomas.
· De novo renal cell carcinomas should be definitively managed according to urologic guidelines on the basis of risk stratification and staging.
· The outcome of renal cell carcinomas after radical treatment in the transplant population is comparable with that of the general population (with 5-year, disease-specific and overall patient survival rates of 68%–97% and 69%–88%, respectively).
· Nephron-sparing surgery was safe and an appropriate option with good long- term functional and oncologic outcomes, evading return to dialysis.
· Negative prognostic factors include; presence of symptoms at diagnosis, higher Fuhrman grade , absence of transplantation, and advanced-stage disease.
2. Skin Cancer
· Skin cancer is the most common cancer type in recipients of kidney transplants and is more aggressive than skin cancers occurring in the general population.
· The most commonly reported skin cancers in recipients of kidney transplants include cutaneous squamous cell carcinoma, basal cell carcinoma, Kaposi sarcoma, and malignant melanoma, with keratinocyte carcinomas comprising 90%–95% of these skin cancers.
· Risk factors for skin cancers: exposure to UV radiation, HPV, pretransplant skin cancer, older age, race, and sex (males at greater risk than females). Additionally, immunosuppressive medications augment the carcinogenic effects (mainly cyclosporine and azathioprine).
· Kaposi sarcoma is more commonly seen in certain ethnic groups, including patients from the Mediterranean, Africa, and Central Europe. Although Kaposi sarcoma is a rare cancer, the incidence of Kaposi sarcoma in recipients of transplants exceeds 100 times that of the general population.
· Recipients of transplants experience an excess risk of squamous cell carcinoma by approximately 250 times.
· Management options:
a. Decreasing the intensity or switching immunosuppressive agents to an mTOR inhibitor is the cornerstone of treatment.
b. Topical fluorouracil and imiquimod cream.
c. Photodynamic therapy.
d. Surgical excision or electrodesiccation and curettage.
e. The cure rate of micrographic surgery is 95%-100%.
f. Chemoprophylaxis(retinoids and nicotinamide) for aggressive SCC.
g. In patients with metastatic cutaneous squamous cell carcinoma, systemic chemotherapy and/or immunotherapy are recommended.
h. Among all skin cancer types, melanoma has the highest mortality. Primary treatment is surgical with wide excision and adequate margins.
3. Post-Transplant Lymphoproliferative Disease
· It is rare, but associated with poor outcomes.
· In most instances (approximately 90%), PTLD is associated with EBV.
· Most PTLDs are of B-cell types, with approximately 5% of patients having the T-cell type.
· The cumulative incidence of PTLD in the first 10 years after kidney transplantation is around 1%–2%.
· According to recent analysis from ANZDT registry,there appears to be a bimodal distribution in PTLD incidence, with the risk of PTLD being the highest in the 12 months post-transplant, and it then decreases until the fifth year after transplantation.
· Risk factors for PTLD:
a. Pretransplant EBV seronegativity and primary EBV.
b. Apart from younger age at transplantation, male sex, use of T cell–depleting agents, Ortho Kung T3 (muromonab-CD3), and high dose tacrolimus, negative recipient EBV serology (with positive donor EBV serology) incur a four-fold excess risk of PTLD.
c. The use of costimulatory blockade has also been found to be associated with a higher risk of PTLD, particularly cerebral PTLD in patients who are EBV negative.
· The treatment of PTLD: the goal is to cure and the mainstay is IS reduction.
a. Prior work reported the use of rituximab and chemotherapy (doxorubicin, cyclophosphamide, vincristine, prednisone) have improved overall survival, with 5-year survival at around 60%.
b. The risk of death among recipients of kidney transplants who have PTLD is 14- fold higher than recipients without PTLD. Rituximab and other novel therapies have shown an improvement in overall survival.
· The median time from diagnosis to death is 6 months.
· The risk of death appears to be dependent on:
a. Site; with those having bone marrow/reticuloendothelial disease experiencing the greatest risk of death followed by extranodal and nodal disease.
b. Apart from site, other predictive factors of death included male sex and increasing age of diagnosis.
Cancer Screening Strategies in Transplant Recipients
· Routine population-based cancer screening for breast, colorectal, and cervical cancer is recommended and should be aligned to the guidelines as per the general population.
· Some guidelines suggest routine skin checks by dermatologists in recipients of transplants who are at high risk.
· Abdominal ultrasounds and serum a-fetoprotein levels should be checked every 6 months for those with underlying liver disease and chronic HBV infections.
· For those at high risk for RCC, ultrasonographic screening (annually or biennially) of the native kidneys may be considered to detect occult malignancy.
HPV Vaccination in KTRs
· The incidence of HPV-related anogenital cancer is at least ten- to 15-fold higher in KTRs.
· HPV vaccination is indicated in both males and females aged 9–25 years in the general population for the prevention of HPV-related malignancies.
· Although HPV vaccination is recommended for women after transplantation, it may be more efficacious to vaccinate before transplantation.
Management of KTRs Who Have Cancer:
1. Immunosuppression Management and Treatment in KTRs with Cancer:
· Reduction of the IS load may be the first step in early to moderate stage of cancer.
· Conversion to an mTOR inhibitor may reduce the risk of cancer in the longer term(SCC and Kaposi sarcoma). There are insufficient data to consider mTOR inhibitors as protective against other cancer types apart from squamous cell carcinoma and Kaposi sarcoma.
2. Immunotherapy :Although the use of immune-checkpoint inhibitors are effective in treating melanoma, non–small cell lung cancer, and renal cell carcinoma in the general population, their use in the kidney transplant population requires further investigation and cannot be recommended at this time, outside of a study protocol.
The level of evidence provided by this article
This is a narrative review article with level of evidence grade 5.
De Novo Malignancies after kidney Transplantation
Introaduction:
Although kidney transplantation is not a cure of kidney failure, itis a best option for kidney failure:
Unfortionately cancer is on of the outcome of kidney transplantation under effects of immunosuppressants medication, so measures to be taken to reduce the risk of cancer in transplant candidate, including:
Studies on outcomes of kdiney transplantation should include incidence of cancer among transplant patient, as the cancer is the second leading cause of death after cardiac disease.
Incidence of All-cause and Site-specific cancer after transplantation:
Cancer Mortality in Recipients of Kidney Transplant:
Risk Factors of Cancer development:
The most common cancers in US, Europe, Australia, and New Zeland:
The most common prevalent skin cancer post tarnsplant in non-Western Asian, Middle East:
The variation in the cancer-type incidence may be associated with dietary style in each region.
In Taiwan the liver vancer is prevalent in transplant patient, may be related to undeline endemic HBV infection.
Immunosuppressants and cancer risk association;
RCC:
Skin Cancer:
PTLD, Post Transplant Lymphoproliferative Disorder:
HPV Vaccination:
Conclusion:
Level of evidence:
Article review ((IV))
Why level 4?
Summary
This study focuses on the development and treatment of cancer in kidney transplant patients. Kidney transplant recipients are at a higher risk to cancer in comparison with the general population. The risk can be as high as three fold. The cancers are usually viral and immune related. Malignancies such as melanoma, renal cell carcinoma, and PTLD have bad outcome in comparison with other malignancies.
The exact reason for high risk of kidney transplant recipients is unknown, although this may be in part to the cell biology changes due to long term immunosuppression and associated comorbidities.
Risk factors for cancer development form a long list, including increasing age, male sex, smoking, prolonged sun exposure, immunosuppressive therapy, acute rejection episodes, status of sensitization, duration of dialysis prior to transplantation. Tumor surveillance that has been impaired and impaired immunity to viral or other tumor antigens is a baseline reason for cancer development in recipients. Cause of death, however, may not be due to cancer incidence or recurrence alone.
Another mechanism for cancer development in these patients is accumulation of mutations. These mutations, in normal healthy individuals, would be recognized by the immune system and repaired. Specifically, this can be applied to skin cancers, where immunosuppression can lead to a decrease of xeroderma pigmentosum complementation groups A and G, which are components of nucleotide excision repair.
Other cancers such as hepatocellular cancers may be contributed to b immunosuppressive drugs like Tacrolimus that increase the level of TGF beta, which in turn promotes tumor progression and metastasis. CNIs can activate p53, promoting cancer.
PTLD associated with EBV can occur within the first 10 years following kidney transplant. However, the incidence of this malignancy has been decreasing in the recent years partly due to better screening for pre transplant EBV and prompt treatment. The risk appears to be higher in the first 12 months post transplant, gradually decreasing after the fifth year mark. Treatment would include reduction of immunosuppression, with the use of rituximab and chemotherapy regimen such as cyclophosphamide, vincristine, prednisone and doxorubicin. Risk of death is high with this malignancy.
Due to the fact that immunosuppression is a major cause for the incidence of cancer in these patients, reduction of immunosuppression or even cessation in some cases is practiced. Primary prevention and screening programs for risk may be helpful in the long term outcomes of these patients. Collaboration between the health care team, policy makers, trialists, and patients is required to identify proper practice for long term care of renal transplant recipients.
Level of evidence
This article is a narrative review, and hence the level of evidence would be 5.
That is an excellent summary and very well structured reply.
I like your analysis of level of evidence of this study.
3. De Novo Malignancies after Kidney Transplantation
· Summarise the article
Introduction
Kidney transplantation not only improves the patient’s quality of life and overall survival, but is also cost effective. To maintain optimal graft function, patients require long-term immunosuppression which unfortunately, is associated with an increased risk of malignancies. Cancer is the second leading cause of mortality among transplant recipients, with cardiovascular disease taking the lead. Cancer prevention, screening and treatment strategies are key areas that ought to be addressed.
Incidence of cancer after kidney transplantation
The overall cancer risk in kidney transplant recipients is two to three times greater than that of the general population. The risk s greatest in viral-related and immune-driven cancers like PTLD, KS and anogenital cancer. Solid organ cancers like prostate and breast cancers are not increased in transplant recipients. The risk of cancer-related mortality is 1.8 -1.9 times higher compared to that in the general population. The greatest risk is among kidney transplant recipients with melanoma, NHL and urogenital cancers.
Common risk factors for cancer development include: – increasing age, male sex, smoking, prolonged sun exposure, immunosuppression use, acute rejection, sensitization status, hemodialysis vintage, CKD, pretransplant malignancy, dietary supplements e.g. aristolochic acid, HBV infection.
Impaired tumor surveillance, impaired immunity to viral or other tumor antigens, loss of control of oncogenic viral replication also contribute to the increased risk of cancer in kidney transplant recipients.
Mechanisms of cancer development after kidney transplantation
-Poor immune control of oncogenic viruses in patients on immunosuppressive therapy e.g., KS and HHV8, PTLD and EBV, lip and anal cancers and HPV
-Accumulation of mutations that would normally be repaired or recognized by an intact immune system e.g., in skin cancer where the cells’ ability to repair UV radiation-induced DNA damage is impaired by the immunosuppressive therapy
-Immunosuppressive drugs: –
*Tacrolimus – promotes tumor progression and metastasis by increasing TGF-ß levels
CNIs – inhibit signaling and activate p53 a hallmark in some NMSCs
*Cyclosporine – causes overexpression of TGF-ß and IL-6 pathways leading to tumor development and progression; it also inhibits DNA repair hence accumulating mutations and affecting apoptosis
*Azathioprine – sensitises the skin to UVA radiation leading to an increased risk of NMSCs
*Induction therapy e.g., ATG, anti-CD52, muromonab increase the risk of PTLD and melanoma – this could be related to T-cell depletion with incomplete T-cell recovery resulting in a dysregulated immune system and subsequent cancer development
*mTORi – have antitumor effects i.e., they inhibit cancer growth through cell-cycle arrest and inducing apoptosis
Common cancers after kidney transplantation
Renal cell carcinoma (RCC), skin cancer and PTLD are the three most common cancers.
*The risk of RCC is up to 7-fold in kidney transplant recipients compared to the general population. 90% of RCC develop in the native kidney as opposed to the graft kidney. Risk factors for RCC include: – male sex, increasing age, African descent, long hemodialysis vintage, ESKD secondary to glomerular disease, hypertensive nephrosclerosis, vascular disease. Patients with ESKD secondary to diabetes or ADPKD have a lower risk of RCC.
*Skin cancer is the commonest malignancy in kidney transplant recipients and is more aggressive than in the general population. Cutaneous SCC, BCC, KS and malignant melanoma are the most commonly reported skin cancers.
Risk factors include: – advancing age, male sex, race, UV radiation, HPV, pretransplant skin cancer, immunosuppressive therapy (mainly cyclosporine, azathioprine), ethnicity. The risk of SCC in kidney transplant recipients is 250 times greater that of the general population.
Treatment options include topical fluorouracil, imiquimod cream, photodynamic therapy, surgical excision, electrodesiccation and curettage, radiation therapy. CNIs increase the risk for KS and the cornerstone of treatment is decreasing the intensity of immunosuppression or switching to an mTORi. Kidney transplant recipients have a 5 – 8-fold increased risk of developing malignant melanoma, and have poorer outcomes compared to the general population.
Malignant melanoma has the highest mortality among all skin cancers. Risk factors for post-transplant melanoma include pretransplant melanoma, older age, white race. Management entails surgical excision and individualized adjustment of immunosuppression.
*PTLD is rare but is associated with poor outcomes and high mortality. It is commonly associated with EBV with most people acquiring the virus in childhood which is then reactivated in states of immunosuppression. Risk factors for PTLD include younger age at transplantation, male sex, ATG, muromonab-CD3, high dose tacrolimus, EBV D+ and EBV R- status, belatacept. Treatment entails immunosuppression reduction with an aim of curing the disease. Rituximab and chemotherapeutic agents have also been used i.e., doxorubicin, cyclophosphamide, vincristine, prednisone) with improved overall survival.
Cancer screening strategies in transplant recipients
Cancer screening reduces cancer-related mortality. Routine screening for breast, cervical, prostate and colorectal cancer is recommended. Skin checks, abdominal ultrasounds to detect occult malignancies in those at risk e.g., patients with underlying liver disease, chronic HBV infections, increased risk of RCC.
Incidence of HPV-related anogenital cancer is 10 – 15-fold greater in kidney transplant recipients than that in the general population. HPV vaccines are highly effective in the prevention of cervical intraepithelial neoplasia. HPV vaccination may be more efficacious before transplantation.
Management of cancer in kidney transplant recipients
Multidisciplinary approach
Optimization of immunosuppression – reduce risk of rejection and induce tumor regression
Conversion to mTORi – in patients with KS and SCC
Immunotherapy using immune-checkpoint inhibitors – their use in kidney transplant recipients is limited due to the risk of rejection with nonspecific immune-system activation.
Putting patients’ perspectives at the heart of cancer management
Understand the patient’s personal experiences – helps improve patient care
A multidisciplinary and integrated approach in patient management – to address the medical, psychosocial, functional and nutritional issues experienced by patients
Individualized strategies to prevent rejection from underimmunosuppression and development of cancer from overimmunosuppression
Conclusion
Cancer is the second leading cause of morbidity and mortality among kidney transplant recipients. Balancing between managing the malignancy while optimizing graft function with immunosuppression is quite challenging. The extent to which immunosuppressive therapy should be reduced to remains unknown. Cancer prevention and screening strategies are extrapolated from the general population hence may not be applicable in the transplant recipients. There is need to generate quality evidence to support the long-term care of transplant recipients.
· Level of evidence provided by this article
Level V – narrative review
That is an excellent summary and very well structured reply.
I like your analysis of level of evidence of this study.
1. Please summarise this article
Kidney transplant, although improves quality of life and survival of ESRD patients, is associated with 2-3 times increased risk of cancer which is the second most common of death in transplant recipients. Cumulative incidence of cancer at 15 years post-transplant is 10-15% with >60% incidence of skin cancer in Europe, Australia, and New Zealand. Cancer risk in kidney transplant is highest for Kaposi sarcoma, anogenital cancer and post-transplant lymphoproliferative disease (PTLD). Risk of mortality post-cancer development is 1.8-1.9 times general population, with maximum risk in melanoma (5-10 times), urogenital cancers and non-Hodgkin’s lymphoma (NHL).
Risk factors for cancer development include increased age, male gender, smoking, prolonged sun exposure, T cell depleting agent use, acute rejection, sensitization, and increased dialysis vintage. Cancers commonly seen in Europe, North America, Australia and New Zealand include non-melanoma skin cancers (NMSC), PTLD, and lip cancer while renal cell carcinoma, urothelial transitional cell carcinoma, and gastrointestinal carcinoma is more common in Asian and middle eastern populations. For cancers associated with kidney disease and kidney failure, the SIR for kidney and bladder cancer are very high (44 and 43).
Mechanisms for cancer development after transplantation is mainly related to immunosuppressive state and include:
a) Poor immune control of oncogenic viruses like Human herpes virus-8 (causing Kaposi sarcoma), Ebstein Barr virus – EBV (causing PTLD), Human Papilloma virus – HPV (causing lip and anal cancers).
b) Accumulation of mutations (in skin cancers).
c) Calcineurin inhibitors inhibit calcineurin leading to inhibition of p53 causing NMSC.
d) Tacrolimus increases TGF-beta leading to tumor progression and metastasis in hepatocellular carcinoma, renal cell carcinoma, and lung adenocarcinoma.
e) Cyclosporin inhibits DNA repair leading to tumor progression.
f) Azathioprine sensitizes skin to UVA radiation leading to NMSC.
g) Anti-thymocyte globulin increases PTLD and melanoma.
mTOR inhibitors, on the contrary, have shown antitumor properties by causing cell-cycle arrest and apoptosis.
Common cancers post-transplant include renal cell carcinoma (RCC), skin cancer and PTLD.
a) RCC: 7 times increased risk, with mostly early, low-grade, and small sized masses. Risk factors include male gender, increased age, African ethnicity, increased dialysis vintage, more with glomerular disease, vascular disease, and hypertension with lower risk with diabetic nephropathy and ADPKD. Outcomes post-treatment are comparable to general population. RCC in the graft are rare (0.1%).
b) Skin cancer: Most common cancer in renal transplant recipients. More aggressive than in general population, with risk increased by 250 times for squamous cell carcinoma, 100 times for Kaposi sarcoma, and 5-8 times for melanoma. Risk factors include UV exposure, HPV infection, pre-transplant skin cancer, older age, male gender, and race. Management depends on the diagnosis ranging from topical fluorouracil, imiquimod cream, photodynamic therapy, surgical excision, to chemoprophylaxis with retinoids and nicotinamide in aggressive, multiple or early onset cancers.
c) PTLD: Rare (1-2% in adults and 3% in children in first 10 years post-transplant), but associated with poor outcomes, with death rates 14 times more than non-PTLD kidney transplant recipients. Associated with EBV in 90% cases. 95% are B-cell type lymphoma. Risk factors for adults include pre-transplant EBV seronegativity and primary EBV infection. Risk factors for children include young age, male gender, donor EBV seropositivity with recipient seronegativity, T cell depleting agent use, Belatacept use, and high tacrolimus dose. Treatment involves reduction in immunosuppression and chemotherapy. Risk for death include male gender, increased age at diagnosis, and bone marrow, RES site more than extranodal and nodal disease, with median time to death being 6 months.
Cancer screening recommendations in transplant recipients are not based on any trial based evidence, but are extrapolated mainly from general population (breast, colorectal, and cervical cancer). Routine skin check for patients with high-risk for skin cancer, regular abdominal ultrasound for patients with liver disease and chronic HBV infection, and regular ultrasound for RCC detection in high-risk patients are recommended.
HPV vaccination has 99-100% efficacy to prevent cervical intraepithelial neoplasm, is safe and generally recommended in women prior to transplant.
Management of transplant recipients developing cancer involve a multidisciplinary approach and includes reduction or alteration in immunosuppression as well as use of immunotherapy (immune checkpoint inhibitors). For early to moderate stage malignancy, judicious immunosuppression reduction is an early step. For squamous cell carcinoma, conversion to mTOR inhibitor is associated with reduced risk of cancer in long-term although with increased risk of death. There is insufficient data to consider mTOR inhibitors as protective except for squamous cell cancer and Kaposi sarcoma. Data for use of immune checkpoint inhibitors in transplant recipients is also limited, hence not recommended.
To summarize, a personalized approach is required for prevention, early detection, and treatment of cancer in transplant recipients. It is important to have a multidisciplinary approach while managing such patients. A balancing act is required while reducing immunosuppression, to prevent episodes of rejection and poor graft outcomes.
2. What is the level of evidence provided by this article
Level of evidence: Level 5 – Narrative review
That is an excellent summary and very well structured reply.
I like your analysis of level of evidence of this study.
summary:
The second most common cause of death after RT after cardiovascular disease.
Incidence:
– The cumulative incidence of solid organ cancer ranges between 10% and 15% at around 15 years after transplantation.
– For skin cancers, the cumulative incidence reaches .60% in Europe, Australia, and New Zealand.
– In RT: the risk is 2-3 folds as general population (SIR:2-3)
Cancer-mortality:
– The standard mortality ratios for all cancer types are at least 1.8–1.9 times higher compared with matched general population.
– For melanoma, urogenital cancers, and non-Hodgkin lymphoma, the overall risk of cancer-related death exceeding 5-10 times that of those without kidney transplants.
– The exact reasons for the higher risk of death are unclear, but may be due to:
a- Potential differences in the cancer cell biology in recipients of transplants resulting from long-term immunosuppression.
b- Associated comorbidities.
c- Low uptake of recommended prevention and screening strategies.
Risk factors:
– Increased age.
– Male sex.
– Smoking
– Prolonged sun exposure
– T- cell depleting immunosuppression agent
– Acute rejection, sensitization.
– Prolonged dialysis duration
– Previous treated malignancy.
In Europe, Australia, and New Zealand, the most common cancers are NMSC, PTLD and lip cancer. Where in Asia and Middle East, genitourinary and gastrointestinal cancers are more common. In Tiwan, liver cancer is the most common because of the endemic HBV.
-Genitourinary cancers are more common among women.
Mechanisms of cancer development in transplant patient:
Potential mechanisms are:
1- Poor immune control of known oncogenic viruses in patients on immunosuppression. For example, increases in viral-associated cancers, such as Kaposi sarcoma (human herpesvirus 8), PTLD (Epstein– Barr virus [EBV]), and lip and anal cancers (HPV)
2- Accumulation of mutations that would otherwise be repaired or recognized by the immune system. This mechanism may be predominant in skin cancers, where immunosuppression impairs the cells’ ability to repair ultraviolet (UV) radiation–induced DNA damage.
3- Immunosuppression type:
Currently, there is no conclusive evidence to suggest one type of immunosuppression is more oncogenic than others
a- CNI:
– Inhibit signaling via calcineurin and NF of activated T cells, which can activate p53, a hallmark of some NMSCs.
– Over expression of TGF-b or IL-6 — tumour progression.
– Cyclosporine inhibit DNA repair and accumulate mutations.
– Tacrolimus increases the level of TGF-b and thereby promotes tumor progression and metastasis. (experimental studies)
b- Azathioprine:
Sensitizes the skin to UVA radiation and causes the accumulation of 6-thioguanine in the DNA, leading to a higher risk of NMSCs.
c- M-TOR inhibitors:
Have potential antitumor effects by inhibiting cancer growth through cell-cycle arrest and initiation of apoptosis.
d- T-cell depleting agents, anti-CD52 and muromonab-CD3:
Increase the risk of PTLD and melanoma.
Cancer screening strategy:
– There is no absolute recommended guideline for cancer screening among RT.
– Screening decisions must be made with clear considerations of patients’ preferences and values, incorporating the potential harms and benefits of the various options
– Recommendations for cancer screening:
Cancer
Recommendations
Skin
Monthly self-skin examination and 6- to 12-monthly total body skin
examination by expert physicians and dermatologists
RCC
Routine screening by US is not recommended
for all recipients of transplants, except for high-risk individuals
PTLD
Screening for high risk for EBV (negative serology and positive donor):
for EBV by NAT. Once in the first week after
transplantation, monthly for the 3–6 months, and every 3 months until the end of the first post-transplant year
Liver cancer
Us and α-fetoprotein / 6 months for those with cirrhosis
Breast
For women aged 50–74 years, screening mammography once every
2 years. For women ,50, the decision to start regular screening
should be an individual one
Prostate
As non-RT
Cervical
Annual Pap testing or HPV testing every 3–5 years starting at the age of
25 years until 74 years
Bowel
For adults aged 45–75 years, fecal immunochemical testing biennially,
sigmoidoscopy every 5 years, or colonoscopy every 5–10 years
Lung
For adults aged 55–79 years, annual low-dose computed tomography
scans for those who have smoked one pack per day for 30 years or
equivalent.
Management of RT with cancer:
1- Immunosuppression management:
– Judicious reduction in the overall immunosuppression load for patients with early- to moderate-stage malignancy may be a reasonable first step.
– There are insufficient data to consider mTOR inhibitors as protective against other cancer types apart from squamous cell carcinoma and Kaposi sarcoma
2- Immunotherapy: such as targeting PD-1 andPD-L1
Not recommended till now because of the unexpected risk of rejection.
That is an excellent summary and very well structured reply.
I like your analysis of level of evidence of this study.
Cancer is the second leading cause of mortality in most Western countries, making kidney transplantation outcomes critical. Virus- and immune-related malignancies drive the two- to three-fold increase in cancer risk after transplantation. Melanoma, renal cell carcinoma, and post-transplant lymphoproliferative diseases have dismal outcomes after malignancy. Furthermore, this high-risk population lacks adequate screening and treatment methods. This evaluation begins with a patient’s journey through kidney transplantation and cancer education and experience. Cancer prevalence and screening and treatment strategies in kidney transplant recipients are examined.
Mortality/incidence
· 10-15% cumulative incidence.
· 15 years post-transplant, Europe, New Zealand, and Australia report over 60% skin cancer. Skin cancer risk is 15 times higher.
· KS and PTLD are common post-transplant viral and immune-driven cancers. Transplantation does not impact breast or prostatic ca.
· NHL, Melanoma, and Urogenital cancer patients have 5-10 times the risk of the overall population’s mortality rate.
Cancer risks factor
· CKD is a risk factor for poor outcomes irrespective of stage. RCC and malignant melanoma predominate in this cohort.
· KTR malignancies are increased by impaired tumor surveillance and immunity to viral or other tumor antigens.
· Pre-transplant cancers increase risk.
· Aristocholic acid diets in Asia and the Middle East enhance urothelial cancer risk.
· Chronic Hep B increases liver cancer risk in Taiwan.
· Gender: Bladder and kidney cancer are more common in women.
Mechanisms of cancer development
· Immunosuppression impairs immunological regulation of oncogenic viruses, increasing Kapoci Sarcoma and PTLD
· Immunosuppression increases DNA damaging mutations and skin Ca risk.
· Tacrolimus enhances TGF beta in HCC, lung, and renal ca, increasing tumor growth and metastasis. CNI suppress T cell calcineurin and NF activation, activating P53 and raising NMSC risk.
· AZA increases UVA sensitivity and NMSC risk.
· Cell cycle stoppage by -MTOR inhibitors suppresses cancer growth.
· After induction, T cell-deleting drugs degrade immune function and increase cancer risk.
Common malignancies post-transplant
RCC
· 90% of kidney diseases occur in the native kidney, not the allograft.
· Sevenfold higher incidence than the overall population.
· Risk factors; male gender, age > 60, African ancestry, duration of HD > 3 years, kidney failure from glomerulonephritis, hypertensive nephrosclerosis, and vascular disease.
· DM and ADPKD are associated with a lower incidence of RCC following transplant.
· Its 5-year prognosis following radical therapy is comparable to that of the general population.
· Unfavorable prognosis variables; symptoms at diagnosis, higher fuhrman grade (>2), lack of transplantation, and advanced stage.
· Nephron-sparing surgery is safe and has favorable oncological results.
Skin Cancer
The most often reported skin cancers are cutaneous squamous cell carcinoma, basal cell carcinoma, Kaposi sarcoma, and malignant melanoma, with keratinocyte carcinomas accounting for 90–95% of these cancers.
PTLD
• 90% attributable to the EBV
• Ten years after transplantation, the cumulative incidence is 1-25 in adults and 3% in children. It reaches its peak in the first year following transplantation, and then begins to drop until the fifth year.
• 30 times greater risk among children than among the general population.
• Additional risks include male sex, the use of T-cell-depleting medicines, and the use of Co stimulatory blocking therapies such as Belatacept.
• Reducing the dosage of immunosuppressive drugs is the mainstay of treatment. Positive results for chemotherapy with Rituximab and Others have been documented (doxorubicin, cyclophosphamide, vincristine, and prednisone).
Cancer screening strategies
· It is recommended that population-based cancer screening for breast, colorectal, and cervical cancer be linked with the general population’s guidelines.
· High-risk transplant recipients should receive dermatologist skin examinations.
· Those with underlying liver illness and chronic HBV infections must have abdominal ultrasounds and blood a-fetoprotein levels monitored every six months.
· Ultrasonographic screening of the native kidneys (annually or biannually) may be considered to detect concealed cancer.
Management of cancer in kidney transplant recipients
· Optimal care requires a coordinated effort involving transplant experts, oncologists, and allied health providers.
· Minimization of the total IS load.
· Some clinicians may consider progressively discontinuing either or both CNI and antiproliferative drugs and substituting higher-dose steroids.
· Conversion to a mTOR inhibitor may minimize the cancer risk of SCC and Kaposi sarcoma over the long run.
· Immune-checkpoint inhibitors
Level of evidence: V
That is an excellent summary and very well structured reply.
I like your analysis of level of evidence of this study.
Introduction:
Kidney transplantation is the best treatment option for end stage renal disease patients, although transplantation is not cure. Patients require life long immunosuppression and the feared complication of long term immunosuppression is cancer.
Incidence:
The cumulative incidence of solid organ cancer is 10- 15% at around 15 years after transplantation.
Cancer mortality:
The risk is greatest with melanoma, urogenital cancers and non- Hodgkin lymphoma and overall risk of cancer related death is 5 to 10 times higher in kidney transplant recipients.
Risk factors:
Increasing age
Male sex
Smoking
Prolong sun exposure
Immunosuppression use
Sensitization status
Duration of dialysis before transplantation
Geographic area
Mechanism of cancer development:
Poor immune control of known oncogenic viruses in patients on immunosuppression.
Accumulation of mutations that would be otherwise repaired by immune system.
Tacrolimus increases the level of TGF-beta and promotes tumour progression and metastasis.
Ciclosporin inhibits DNA repair, thereby accumulates mutation.
Azathioprine sensitizes skin to UVA radiation
Induction therapy with T cell depleting agents increases risk s of cancers , such as PTLD and melanoma.
Cancer screening:
Breast- For women 50-74 years- mammography every 2 years.
Cervical- annual Pap testing or HPV testing every 3-5 years from age 25 – 74 years.
Bowel- For adults 45-75 years, fecal immunochemical testing biennially, sigmoidoscopy every 5 years, colonoscopy every every 5-10 years.
Skin- monthly self skin examination and 6 to 12 monthly total body skin examination by dermatologists.
PTLD- Routine monitoring of patients at high risk for EBV by NAT. Once in first week, monthly for first 3- 6 months, and every 3 months until the end of first post transplant year.
Immunosuppressive management:
Judicious reduction in the overall immunosuppression load for patients with early to moderate stage malignancy may be fiest step.
Immunotherapy
Conclusion:
Primary prevention and screening programme for recipients is very important for malignancy .
That is an excellent summary and very well structured reply.
What is the level of evidence of this study?
Please use bold or underline for heading or sub-headings.
De Novo Malignancies after Kidney Transplantation.
Introduction.
Kidney transplantation is the best choice for ESKD as it improves the quality of life, but the other face of the story is the long term complications of immunosuppression such as malignancies which is considered the second leading cause of death among recipients of transplants in most Western countries.
Incidence of All-Cause and Site-Specific Cancer after Transplantation.
The excess overall cancer risk in patients with kidney transplant exceeds that of the general population by approximately two- to three-fold after adjustment for age and sex, with the greatest risk in viral-related and immune driven cancers such as post-transplant lympho-proliferative disease (PTLD), and Kaposi sarcoma.
Cancer Mortality in Recipients of Kidney Transplants.
Mortality ratios for all cancer types are at least 1.8–1.9 times higher compared with the age- and sex-matched general population and The risk is greatest with melanoma, urogenital cancers, and non-Hodgkin lymphoma, with mortality rate five to ten times that of those without kidney transplants.
Risk Factors for Cancer Development.
General factors: increasing age, male sex, smoking, and prolonged sun exposures.
Specific factors: immunosuppression use, acute rejection, sensitization status, and duration of dialysis before transplantation.
Mechanisms of Cancer Development after Transplantation.
1-Due to immunosuppressive status increases in viral-associated cancers, such as Kaposi sarcoma (human herpesvirus 8), PTLD (Epstein–Barr virus [EBV]), and lip and anal cancers (HPV) are common in patients with suppressed immune systems.
2-Accumulation of mutations that would otherwise be repaired or recognized by the immune system.
3-Each one of immunosuppression medications has special role in cancer development such as Cyclosporine which has direct effects on tumor development and progression, through TGF-b or IL-6 overexpression pathways and on the contrary, (mTOR) inhibitors may have potential antitumor effects by inhibiting cancer growth through cell-cycle arrest and initiation of apoptosis.
Common Cancers after Transplantation.
Renal Cell Carcinoma.
– Recipients of kidney transplants have a higher risk (up to seven-fold) of RRC more than general population which mainly developed in the native kidneys specially with those were longer time on dialysis.
-High risk is mainly associated with ESRD due to glomerular diseases, hypertensive nephrosclerosis, and vascular disease and lower risk with ESRD secondary to diabetes or autosomal dominant polycystic kidney disease.
– Renal cell carcinoma in the kidney allograft is rare with an incidence of 0.1% and the majority of tumors were treated by partial nephrectomy (67%), radical nephrectomy (19%), and percutaneous ablation.
Skin Cancer.
Skin cancer is the most common cancer type in recipients of kidney transplants and is more aggressive than skin cancers occurring in the general population and Kaposi sarcoma in recipients of transplants exceeds 100 times that of the general population.
Risk factors are exposure to UV radiation, HPV, pretransplant skin cancer, older age, race, sex and immunosuppressive medications augment the carcinogenic effects.
Many line of treatment such as topical “uorouracil and imiquimod cream, photodynamic therapy, and surgical excision or electro desiccation and curettage.
Decreasing the intensity or switching immunosuppressive agents to an mTOR inhibitor is the cornerstone of treatment.
Post-Transplant Lymphoproliferative Disease.
PTLD is associated with EBV, the risk of PTLD being the highest in the 12 months post-transplant, and it then decreases until the fifth year after transplantation and using of costimulatory blockade, such as
belatacept, has also been found to be associated with a higher risk of PTLD.
The mainstay of treatment is immunosuppression reduction with chemotherapy.
Cancer Screening Strategies in Transplant Recipients.
For early detection of malignancy which has good prognosis, such as routine skin checks by dermatologists in recipients of transplants who are at high risk, and abdominal ultrasounds and serum a-fetoprotein levels should be checked every 6 months for those with underlying liver disease and chronic HBV infections.
For patients who are at risk of developing renal cell carcinoma (such as those with a history of acquired cystic disease, those with a family history, those who are heavy smokers, and those who use long-term analgesics), ultrasonographic screening (annually or biennially) of the native kidneys may be considered to detect occult malignancy.
Management of Recipients of Kidney Transplants Who Have Cancer.
– Immunosuppression Management and Treatment in Transplant Recipients with Cancer.
Still we are in need for consensus guidelines to modulate immunosuppression and to tailor reduction of the medications according to the risk of rejection and the only trial-based evidence to suggest conversion to an mTOR inhibitor may reduce the risk of cancer in the longer term specially with SCC.
-Immunotherapy.
Checkpoint inhibitors use in the kidney transplant population requires further investigation and cannot be recommended at this time, outside of a study protocol.
Conclusion:
Denovo malignancy post kidney transplant is considered a challenge for diagnosis and treatment and reduction of immunosuppression is the cornerstone but on the contract risk of rejections increasing and so a multidisciplinary, integrated approach that involves the transplant and palliative care team is crucial.
Level of evidence: V.
That is an excellent summary and very well structured reply.
I like your analysis of level of evidence of this study.
1.SUMMARISE ARTICLE.
Introduction.
Amongst patients with ESRD,RRT is the most preferred compared to dialysis due yo its long term low cost and good outcomes. Immunosuppressive medications to prevent graft rejection increases risk of malignancy and currently rank 2nd after cardiovascular disease as cause of mortality post transplant. Preventive and appropriate follow up strategies after transplantation need to be incorporated in post transplant care plan to improve outcome.
Incidence and Mortality.
-Cumulative incidence is 10-15%.15 yrs post transplant with skin cancer being reported at more than 60 % in Europe, New Zealand and Australia. The risk of skin ca is x15 that in the general population.
-Viral related and immune driven malignancies like KS & PTLD have a high risk of occurrence post transplant. Breast and prostatic ca are not affected by transplantation process.
-Standard mortality rate is x 1.8-1.9 the general population with greatest risk amongst those with NHL, Melanoma and Urogenital cancer that have more than x5-10 risk that in the general population.
Risk factors for cancer.
-CKD irrespective of stage is a risk factor with poor outcomes. RCC and malignant melanoma are most prevalent in this cohort.
-Impaired tumor surveillance and immunity to viral or other tumor antigens in KTR increases risk of malignancies.
-Pre transplant malignancies increase risk compared to those without.
-Diet i.e aristocholic acid in non western Asia and middle east increase the risk of urothelial carcinoma.
-Chronic Hep B has been associated with increased risk of liver ca in Taiwan.
-Gender -Women have a higher risk for bladder and kidney ca compared to men.
Mechanisms of Cancer development.
-Poor immune control of oncogenic viruses from immunosuppression increases the risk of KS,PTLD,EBP lip and anal cancer.
-Immunosuppression leads to accumulation of unrepaired mutations in DNA damage increasing the risk of skin Ca.
-Tacrolimus increases the level of TGF beta in HCC, lung and renal ca promoting tumor progression and metastases. CNI inhibit calcineurin and NF activation of T cells activating P 53 increasing risk of NMSC
-AZA too has been found to increase sensitivity of skin to UVA with an antecedent increased risk of NMSC
-MTOR inhibitors have anti tumor effects by arrest of cell cycle that inhibits cancer growth.
-T cell deleting agents lead to incomplete T cell recovery with impaired immune system and risk of cancer after use in induction.
Common cancers post transplant.
RCC
-Increased x 7 post KTR compared to the general population.90% occur in the native kidney and not the allograft.
-Risk factors ; Male sex,> 60 years of age, African descent, HD more than 3 years, Kidney failure from GN, hypertensive nephrosclerosis and vascular disease.DM and ADPKD have a decreased risk of RCC post transplant.
-It has a comparable 5yr outcome post radical tx with the general population.
-Negative prognostic factors ;Symptoms at diagnosis, higher fuhrman grade(>2),absence of transplantation and advanced stage.
-Nephron sparing surgery is safe with good oncological outcomes.
Skin Cancer.
-Most common and aggressive in KTR compared to the general population.
-Common types ;Cutaneous SCC,BCC,KS and malignant melanoma.
-Risks ; UV radiation exposure, HPV, pre transplant skin cancer, old age, race and M>Cyclosporine increases risk. KS has more than x100 incidence in KTR compared to the general population while SCC has x250 risk in KTR compared to the general population.
-Treatment for SCC depends on stage and involves; Topical 5FU,imiquimod cream, photodynamic curettage, mohs micrographic surgery and radiotherapy fir inoperable cases. Those with multiple lesions are candidates for systemic chemotherapy. Switching CNI to MTOR inhibitors is key in KS treatment. Melanoma has a high mortality amongst skin cancer patients and pre transplant lesions are a risk factor. Surgical excision with wide margins is the primary treatment..
PTLD.
-90% associated with EBV.
-Cumulative incidence 10 year post KTR is 1-25 in adults and 3% in paeds population. It is highest in first 1 yr post transplant and then decreases until the 5th year.
-x30 times risk in pediatric group compared to the general population.
-Other risks ; male sex, use of T cell depleting agents and use of Co stimulatory blockade agents like Belatacept.
-Main stay treatment is immunosuppressive treatment dose reduction. Chemotherapy with Rituximab and Others( doxorubicin, cyclophosphamide, vincristine and prednisone) have been reported to have good outcomes.
Cancer screening strategies.
-Routine breast, colorectal and cervical ca screening in high risk group as per national guidelines should be done post KTR.
-Routine derm review for high risk patients, Abd US and 6 monthly serum AFP in those with underlying liver disease and chronic hep B infection should be considered.
-Those at risk of RCC should have annually or bi annually abd us of native kidney to detect occult malignancies.
-Pts should be educated on malignancies and a shared decision making approach adopted.
HPV vaccine in KTR
-Quadrivalent vaccines (Against types 6,11,16 and 18) and HPV 9 Valent(Additional 5 types ;31,33,45,52 and 58) are effective with an overall efficacy of 99-100% in prevention of CIN in RCTS done.
-More efficacious pre transplant and indicated in both males and females 9-25 years in general population and women up to the age of 45 yrs.
Management of KTR with Cancer.
–MDT;Oncologist,transpalnt proffesionals and allied health workers shuol d all be involved in optimizing immunosuppressive medications appropriately.
-For SCC and KS ,convert to MTOR inhibitors and monitor.
-Future studies are needed on check point inhibitors before adoption into KTR cohort with malignancies.
-An individualized holistic approach to patients is key in managing cancer in the transplant population.
2.LEVEL OF EVIDENCE.
V – A Narration.
Introduction:
Kidney transplantation is the best renal modality of treatment for patient with end stage kidney disease ,less cost effective and improve quality of life .
Patients require life-long immunosuppression to maintain optimal allograft function. One of the most feared complications associated with immunosuppression after kidney transplantation is cancer
Incidence of All-Cause and Site-Specific Cancer after transplantation:
The higher risk is dependent on cancer types, with the greatest risk in viral-related and immune driven cancers such as:
· Post-transplant lympho proliferative disease (PTLD),
· Canogenital cancer.
· Kaposi sarcoma
Cancer Mortality in Recipients of Kidney Transplants:
The standard mortality ratios for all cancer types are at least 1.8–1.9 times higher
compared with the age- and sex-matched general population.
The risk is greatest among those with melanoma, urogenital cancers, and non-Hodgkin lymphoma, with an overall risk of cancer-related death exceeding five ve
to ten times that of those without kidney transplants
Risk Factors for Cancer Development:
Ø Increasing age.
Ø Male sex.
Ø Smoking,
Ø Prolonged sun exposures
Ø Immunosuppression use (T cell–depleting agents).
Ø Acute rejection .
Ø Sensitization status
Ø Duration of dialysis before transplantation
The speci!c types of cancer that develop after transplantation also vary by geographic areas. Observational and registry data from Europe, North America, Australia, and New Zealand indicate the most common cancer types are nonmelanoma skin cancers (NMSCs), PTLD, and lip cancer
Data from non-Western Asian and Middle Eastern transplant cohorts suggest higher incidences of urothelial transitional cell carcinoma, renal cell carcinoma,
and gastrointestinal cancers in their populations
Mechanisms of Cancer Development after Transplantation:
Oncogenic viruses in patients on immunosuppression. such as
Ø Kaposi sarcoma (human herpesvirus 8)
Ø PTLD (Epstein– Barr virus [EBV]).
Ø Lip and anal cancers (HPV)
Development is through accumulation of mutations that would otherwise be repaired or recognized by the immune system
Tacrolimus increases the level of TGF-b and thereby promotes tumor
progression and metastasis.
Cyclosporine also has direct effects on tumor development and progression, through TGF-b or IL-6 overexpression pathways
The potential oncogenic potential of A zathioprine is well known and well recognized. A zathioprine sensitizes the skin to UVA radiation and
causes the accumulation of 6-thioguanine in the DNA, leading to a higher risk of NMSC
Mammalian target of rapamycin (mTOR) inhibitors have potential antitumor effects by inhibiting cancer growth through cell-cycle arrest and initiation of apoptosis
Common Cancers after Transplantation:
Renal Cell Carcinoma
Skin Cancer
Post-Transplant Lymphoproliferative Disease
Cancer Screening Strategies in Transplant Recipients
Immunosuppression Management and Treatment in Transplant Recipients with Cancer
Management of immunosuppression in recipients of transplants who are living
with cancer is complex and challenging.
mTOR inhibitor may reduce the risk of cancer in the longer term
LEVEL 5
That is an excellent summary and very well structured reply.
I like your analysis of level of evidence of this study.
Introduction:
One of the most feared complications associated with immunosuppression after kidney transplantation is cancer.
After cardiovascular disease, cancer is the second leading cause of death among recipients of transplants in most Western countries.
Incidence of All-Cause and Site-Specific Cancer after Transplantation:
Incidence of solid organ cancer 10% -15%after 15years.
Viral related malignancy is more, PTLA, kS, anogenital cancer,
Cancer Mortality in Recipients of Kidney Transplants:
Risk of cancer-related death exceeding five to ten times that of those without kidney transplants.
Risk Factors for Cancer Development:
Common:
Age, male sex, smoking, and prolonged sun exposures.
Specific risk factors:
Immunosuppression.
Acute rejection
Sensitization status
Duration of dialysis before transplantation.
Having CKD.
Previously treated Pretransplant malignancy.
NMSCs, PTLD, and lip cancer, more in Europe and Australia.
Urothelial transitional cell carcinoma, renal cell carcinoma, and gastrointestinal cancers in Middle Eastern transplant.
Mechanisms of Cancer Development after Transplantation:
-Dump immune system, expose to viral infection.
-accumulation of mutation.
-TGF-b or IL-6 overexpression.
Accumulation of 6-thioguanine
Common Cancers after Transplantation:
Renal Cell Carcinoma:
90 percent in native kidney:
Patients transplanted for kidney failure secondary to glomerular diseases hypertensive nephrosclerosis and vascular disease appear to have the greatest associated risk.
In contrast, patients with kidney failure secondary to diabetes autosomal dominant polycystic kidney disease low risk.
Renal cell carcinoma in the kidney allograft is rare, and multicenter data have demonstrated an incidence of 0.1%. Most are low-grade T1 lesions, clear cell carcinomas, or papillary renal cell carcinomas, and occur more commonly in males. The majority of tumors were treated by partial nephrectomy (67%), radical nephrectomy (19%), and percutaneous ablation (12%).
Skin Cancer:
The most commonly reported skin cancers cutaneous squamous cell carcinoma, basal cell carcinoma, Kaposi sarcoma, and malignant melanoma, with keratinocyte carcinomas comprising 90%–95% of these skin cancers.
Post-Transplant Lymphoproliferative Disease:
PTLD is associated with EBV. EBV is a common virus.
Pretransplant EBV seronegativity and primary EBV infection are important risk factors for early EBV-positive PTLD, particularly in younger recipients of transplants.
, a significant proportion (approximately 40%–50%) of late B-cell PTLDs involves EBV-negative lesions.
The treatment goal of PTLD is to cure the disease, and the mainstay of treatment is immunosuppression reduction. Prior work reported the use of rituximab and chemotherapy (doxorubicin, cyclophosphamide, vincristine, prednisone) have improved overall survival, with 5-year survival at around 60%.
Cancer Screening Strategies in Transplant Recipients
Routine population-based cancer screening for breast, colorectal, and cervical cancer is recommended and should be aligned to the guidelines as per the general population.
Skin checks by dermatologists in recipients of transplants who are at high risk
Abdominal ultrasounds and serum a-fetoprotein levels should be checked every 6 months for those with underlying liver disease and chronic HBV infections.
Ultra sonographic screening (annually or biennially) of the native kidneys may be considered to detect occult malignancy.
Transplant population, HPV vaccines are generally safe. However, seropositivity was only detected in approximately 50%–60%.
Management of Recipients of Kidney Transplants Who Have Cancer Immunosuppression Management and Treatment in Transplant Recipients with Cancer:
WIEGHT BENFIT AGAINST RISK IN COLLABERATION WITH ONCOLOGIST.
Judicious reduction in the overall immunosuppression load for patients with early- to moderate-stage malignancy ma
Consider Mtor therapy in patient with SCC.
Putting Patients’ Perspectives at the Heart of Cancer Management:
Personized, rather than a one-size-fits-all, approach is most preferred approach.
A multidisciplinary, integrated approach that involves the transplant and palliative care team is crucial. In case of advance malignancy.
Level of evidence V.
That is an excellent summary and very well structured reply.
I like your analysis of level of evidence of this study.
I like when you type, ‘Putting Patients’ Perspectives”.
Introduction:
Kidney transplant recipient require life-long IS to maintain optimal allograft function. Cancer is a complication and one of the core clinical outcome associated with IS after kidney transplantation, and considered the second leading cause of death in this population.
Incidence of All-Cause and Site-Specific Cancer after Transplantation
– Kidney transplant recipient has 2-3 times overall cancer risk compared to matched general population.
– The risk is higher in viral-related and immune driven cancers.
Cancer Mortality in Recipients of Kidney Transplants
– The standard mortality ratios for all cancer types are at least 1.8–1.9 times higher than general population.
– The risk is greatest among those with melanoma, urogenital cancers, and non-Hodgkin lymphoma,
– The overall risk of cancer-related death exceeding 5-10 times that of those without kidney transplants.
Risk Factors for Cancer Development
Geveral risks:: increasing age, male sex, smoking, and prolonged sun exposures.
Factors specific to KTRs: immunosuppression use (T cell–depleting agents), acute rejection, sensitization status, duration of dialysis before transplantation, having CKD, and having pre-transplant malignancy.
-The specific types of cancer that develop after transplantation also vary by geographic areas.
Mechanisms of Cancer Development after Transplantation
– The effects of IS on dampening the immune system
– Oncogenic viruses; Kaposi sarcoma (HHV 8), PTLD (EBV), and lip and anal cancers (HPV).
– Accumulation of mutations; predominant in skin cancer >>UV radiation–induced DNA damage.
– Currently, there is no conclusive evidence to suggest one type of immunosuppression is more oncogenic than others.
· CNI tacrolimus, cyclosporine; may increases the level of TGF-b and thereby promotes tumor progression.
· Azathioprine; DNA damage.
· mTORi ; may have potential antitumor effects.
· T cell–depleting agents; increases the risks of cancers, such as PTLD and melanoma.
Common Cancers after Transplantation
Renal Cell Carcinoma
– KTRs have 7 fold higher risk compared to general population.
– Typically detected early, low-grade, small kidney masses, with the risk of metastasis at presentation being <2%.
– 90 % in native kidneys, rare in allograft.
– Risk is higher in: male sex, increasing age, African descent, longer time on dialysis, and primary disease (glomerular diseases hypertensive, nephrosclerosis and vascular disease).
Skin Cancer
-The most common cancer type in KTRs, and is more aggressive than in the general population.
– cSSC, BSC, Kaposi sarcoma, and malignant melanoma, with keratinocyte carcinomas comprising 90%–95% of these
skin cancers.
– The pathogenesis is complex interaction of risk factors.
– IS medications augment the carcinogenic effects (mainly cyclosporine and azathioprine).
– Compared with the general population the risk of squamous cell carcinoma is 250 times higher in KTRs.
– Patients treated with CNI are at particularly high risk for Kaposi sarcoma.
– Decreasing the intensity or switching to an mTOR inhibitor is the cornerstone of treatment.
– Among all skin cancer types, melanoma has the highest mortality.
Post-Transplant Lymphoproliferative Disease
– It is a rare disease, however; it is associated with poor outcomes and higher mortality rate.
– 90% is associated with EBV.
– Most PTLDs are of B-cell types, with 5% of patients having the T-cell type.
– The cumulative incidence of PTLD in the first 10 years post- KTx is around 1%–2% in adult and 3% in pediatric.
– Bimodal distribution in incidence, the highest in the 12 months post-KTx, and it then decreases until the 5th year.
– Risk is higher in : younger age at transplantation, male sex, use of T cell–depleting agents, muromonab-CD3, and high dose tacrolimus, negative recipient EBV serology particularly in younger recipients. (with positive donor EBV serology).
– The mainstay of treatment is IS reduction, chemotherapy and novel immunotherapy.
Cancer Screening Strategies in Transplant Recipients
-Lack of trial-based evidence to support routine screening in this high-risk group.
– A shared decision-making process with patients should be adopted to guide decision.
– Some guidelines also suggest:
· Routine skin checks by dermatologists in recipients.
· Abdominal US and serum AFP every 6 months of the native kidneys to detect occult malignancy RCC, for recipients with liver disease and chronic HBV.
· Routine screening for breast, colorectal, and cervical cancer aligned to the general population guidelines.
HVP Vaccination in Recipients of Kidney Transplants.
– The incidence of HPV-related anogenital cancer is 10-15-fold higher than matched general population.
– Vaccine is highly effective with overall efficacy of 99%–100% for the prevention of cervical intraepithelial neoplasia.
– HPV vaccines are generally safe.
– It is recommended after transplantation, it may be more efficacious to vaccinate before transplantation.
Management of Recipients of Kidney Transplants Who Have Cancer.
– A concerted approach between transplant professionals, oncologists, and allied health professionals is therefore needed to ensure optimal care.
– Judicious reduction in the overall IS load.
– Some clinicians may consider stopping either or both CNI and antiproliferative agents gradually and rotate to higher-dose steroids
– Conversion to an mTOR inhibitor may reduce the risk of cancer in the longer term for SCC and Kaposi sarcoma.
– Immune-checkpoint inhibitors
Level of evidence: 5 narrative review.
That is an excellent summary and very well structured reply.
I like your analysis of level of evidence of this study.
· Summary
o Skin cancer and other malignancies are common post transplantation.
o It is the 2nd cause of death after cardiovascular causes, with about 2 folds increase in mortality then age and sex matched controls.
o Regular screening and counseling of transplant recipients are important steps for early detection and management of cancer. In addition, vaccination against HPV may protect against skin and cervical cancer.
o Non melanoma skin cancer, PTLD, anogenital cancer, and Kaposi sarcoma are among the most common types of cancer in transplant patients that are related to use of over immunosuppression and associated higher risk of viral infections.
o However, breast, lung, colorectal and prostate carcinomas are not increased in renal transplant recipients.
o Risk factors:
§ General as old age, male gender, smoking and sun exposure.
§ Specific to transplant patients: use of immusosuoression, prolonged duration on dialysis, sensitizing events and rejection.
§ Pretransplant malignancies and precancerous lesions.
o Renal cell carcinoma and multiple myeloma are commonly associated in CKD patients.
o Cancer development in transplant patients is multifactorial and usually related to oncogenic viruses, concomitant immunosuppressive medications and lack of natural immunesurvillance for tumor antigens.
o Regional or geographic variation in most common type of cancer may be related to the associated dietary or habitual risk factors in addition to variation in prevalence of certain oncogenic viruses as HBV.
o Oncogenic viruses as (HPV in cancer skin and cervix, HSV 8 in Kaposi sarcoma, EBV in PTLD, HBV and HCV in hepatocellular carcinoma, and may be BKV in bladder carcinoma)
o Use of immunosuppressive drugs increases the risk of cancer, it is related to cumulative effect with DNA damage rather than specific drug. However, azathioprine is well- known drug associated with skin cancer.
o The use of induction therapy as ATG and treatment of repeated rejection episodes are associated with higher risk of cancer.
o In the contrary, the use of mTORi as sirolimus is protective has been associated with decreased incidence of cancer as it induces apoptosis of malignant cells.
Ø Renal cell carcinoma:
o 7 times higher in renal transplant recipients than general population.
o 90 % in native kidney and 10 % in the allograft.
o Usually discovered early and none metastasis (due to frequent imaging), so mostly low grade clear cell or papillary carcinoma.
o Risk factors are older age, male gender, Africans and longer duration on HD before transplantation, glomerular disease and vasculitis as original kidney disease.
o Diabetic nephropathy and ADPCKD have the least incidence of RCC.
o Treatment according to staging and grading including radical or partial nephrectomy (nephron sparing) or percutaneous ablation.
Ø Skin cancer:
o Most common cancer in renal transplant recipients, more aggressive than in general population.
o It includes SCC, BCC, Kaposi sarcoma and malignant melanoma.
o None melanoma skin cancer represents 90 % of skin cancer.
o Melanoma is 8 times higher in renal transplant recipients than general population and it carries the worst prognosis among skin cancer (highest mortality).
o Risk factors include: old age, male gender, sun exposure and use of tacrolimus and azathioprine.
o Treatment according to the stage, 5FU and local excision for CIS and surgical excision and systemic chemo and immunotherapy in invasive and metastasizing ones.
o Shift from CNI to mTORi is the corner stone in ttt of Kaposi sarcoma.
o Ttt of malignant melanoma by surgical excision with adequate margine.
Ø PTLD:
o Rare but well recognized in renal transplant recipients and has poor prognosis.
o Related to EBV infection in 90 % of cases.
o 90 % are B cell type.
o Higher mortality (9 folds) especially in those with marrow and reticuloendothelial system involvement and in male gender and older age.
o Risk factors: younger age at time of transplantation, Male gender, pediatric age group, bimodal peaks at 1 then at 5 years post-transplant, use of induction depleting therapy, use of high doses of belatacept (costimulation blockade) and serostatus of EBV (EBV -R, with EBV +ve donor).
o Treatment: reduction of immunosuppression plus chemotherapy as (steroids, cyclophosphamide and vincristine).
o Rituximab is relatively safe and effective especially in EBV +ve cases with normal LDH levels.
Ø Screening for cancer:
o US and AFP for liver cancer.
o US for those with acquired cystic kidney diseases.
o Annual skin examination by expert dermatologist.
Ø Prevention of cancer:
o Screening and early detection of breast, prostate, lung and colorectal cancer as extrapolated from the general population recommendations.
o HPV vaccination better giver prior to transplantation but is also safe after transplantation.
Ø Management of cancer:
o Optimization of IS therapy to prevent both rejection and graft loss and manage cancer is the challenge here.
o Shift from CNI to mTORi in case of SCC and Kaposi sarcoma helps in treatment but unfortunately was associated with risk of mortality and discontinuation due to its complications.
o Use of immune therapy targeting cell apoptosis may be beneficial in melanoma, lung and renal cell carcinoma
o Multidisciplinary team with patient involvement in his plan of therapy are crucial to personalize treatment plan rather than one-size-fits-all strategy.
o In case of advanced malignancy, complete withdrawal of IS seems difficult and it is better to stop CNI and MMF and shift to larger dose of steroids to guard against symptoms of acute rejection or graft rupture.
o Team should include social worker, dietitian, clinical psychologist for better outcomes.
· Level of evidence: V (narrative review).
That is an excellent summary and very well structured reply.
I like your analysis of level of evidence of this study.
You need not to type everything in bold or capitals when you plan to emphasise a point. That amounts to ‘shouting’.
Use bold or underline for only for heading or sub-headings.
Please summarise this article:
Introduction:
Kidney transplantation is the best treatment option for patients with ESRD, it improves quality of life and overall survival, is more cost effective, the patients received a transplant required to be on immunosuppressive mediacations that may lead to cancers.
Malignancies considered the second most common cause of death in organ recipients, this mandates preventive policies and cancer-screening stratigies, eg; HPV vaccination for prevention of anorectal/ cervical cancers.
Incidence of All-Cause and Site-Specific Cancer after Transplantation:
The cumulative incidence of solid organ cancer is 10 -15% at 15 years post TX.
The risk is 2-3 times higher than that of the general population.
The higher risk in viral- related and immune-driven cancers, PTLDs, anogenital, and Kaposi sarcoma.
Breast and prostate cancers are not increased among transplant recipients.
Cancer Mortality in Recipients of Kidney Transplants:
Mortality is 1,5-1,9 folds higher among transplant recipient, when compared to matched age and sex matched general population.
The risk is 5 -10times more among viral-related cancers(PTLD, melanoma, anogenital ca…etc) than age and sex related general population.
Risk Factors for Cancer Development:
Increasing age, male, smoking and prolonged sun exposure
Immunesupressive drugs, sensitization status, and duration of dialysis before transplantation, and CKD, HPV, EBV, HBV …etc.
CNI increases the level of TGF-b and thereby promotes tumor progression and metastasis, inhibit signaling via calcineurin and activate p53, a hallmark of some NMSCs.
Azathioprine sensitizes the skin to UVA radiation and causes the accumulation of 6-thioguanine in the DNA, leading to a higher risk of NMSCs.
m-TOR inhibitors, may have potential antitumor effects by inhibiting cancer growth through cell-cycle arrest and initiation of apoptosis.
Common Cancers after Transplantation:
Renal cell carcinoma: (7 folds)
Usually early, low-grade, small kidney masses; of which, 75%–80% are renal cell carcinoma, in the native kidenys, with the risk of metastasis at presentation being 2%.
Kidney failure secondary to glomerular diseases, hypertensive nephrosclerosis and vascular disease appear to have the greatest risk.
The outcome of renal cell carcinomas after radical treatment in the transplant population is comparable with that of the general population.
Skin Cancer: (Most common)
Cutaneous squamous cell carcinoma, basal cell carcinoma, Kaposi sarcoma, and malignant melanoma, with keratinocyte carcinomas comprising 90%–95% of these skin cancers.
UV radiation, HPV, pretransplant skin cancer, older age, race, and male sex are risk factors for skin cancer in transplant recipients.
Mohs micrographic surgery, offers the most definitive method of treatment, with cure rates of 95%–100%.
Topical fluorouracil and imiquimod cream, photodynamic therapy, are modalities used for treatment.
Kaposi sarcoma increased by the use of CNI, this could be overcome by m-TORi use.
The prognosis is worse among transplant patients than that for the general age and sex matched population, melanoma has the worst prognosis.
Post-Transplant Lymphoproliferative Disease:
PTLD is associated with EBV, and pears a poor prognosis;14 % mortality.
PTLDs are of B-cell types, with approximately 5% of patients having the T-cell type.
Risk factors are: First year post-transplant and 5 years after transplant, Pretransplant EBV seronegativity/ donor positive and primary EBV infection, particularly in younger recipients of transplants.
The mainstay of treatment is immunosuppression reduction, Rituximab and chemotherapy.
HPV vaccination is the preventive measure recommended.
Management of Recipients of Kidney Transplants Who Have Cancer:
– Immunosuppressive drugs reduction, and use of m-TORi.
– Surgical treatment when needed.
– Patient education, life style preventive measures.
Conclusion:
– The study identify patient groups and cancer types, helps in surveillance program, and providing data on counselling pretransplant patients on the risk of malignancy.
– All transplant patients should be screened regularly for NMSC, oral and anal cancers, combined with lifestyle changes prevents sun exposure.
What is the level of evidence provided by this article?
Level of evidence V.
That is a succinct summary.
But I could not understand when you types, ‘Surgical treatment when needed”.
Summary:
· Cancer is the second most important cause of death following cardiovascular disease in kidney recipient. And it is 2 to 3 fold higher than that of general population. Commonly, melanoma, urogenital carcinoma and PTLD are seen.
· Risk factors include mainly immune related and viral infection.
· More importantly, this high-risk group lacks access to efficient screening and treatment approaches.
· This review explore the patient’s knowledge, education, and experience of cancer in the context of transplantation
· There is currently no evidence to indicate how much immunosuppression a clinician could safely reduce.
· The primary prevention and screening programs for transplant recipients are supported by research that is primarily derived from the general population, and the results may not always be appropriate to the transplant population.
Level of evidence: level V
That is a succinct summary.
I like your analysis of level of evidence of this study.
Suggestion: please use bold or underline for sub-headings when you type the main heading ‘Summary’.
Please summarise this article :
What is the level of evidence provided by this article?
That is a succinct summary.
I like your analysis of level of evidence of this study.
Suggestion: please use bold or underline for sub-headings when you type the main heading ‘Summary’.
III. De Novo Malignancies after Kidney Transplantation
==================================================================
summarise this article
Introduction
· ===============================================================
Incidence of All-Cause and Site-Specific Cancer after Transplantation
========================================================
Cancer Mortality in Recipients of Kidney Transplants
===================================================================
Risk Factors for Cancer Development
===================================================================
Mechanisms of Cancer Development afterTransplantation
=================================================================
Common Cancers after Transplantation
====================================================================
Cancer Screening Strategies in Transplant Recipients
Recommendations for cancer screening in recipients of kidney transplants
Breast
Prostate
Cervical
Bowel
Lung
Skin
Renal cell
Liver
PTLD
The human papillomavirus (HPV) vaccination
Management of Recipients of Kidney Transplants
Who Have Cancer
Immunotherapy
Putting Patients’ Perspectives at the Heart of Cancer Management
Conclusion
====================================================================
The level of evidence provided by this article(5)
That is an excellent summary and very well structured reply.
I like your analysis of level of evidence of this study.
Suggestion: please use bold or underline for sub-headings when you describe mechanism of cancer development after transplant.
Yes
Thanks verey much Prof.Sharma ,for these necessary tips and instructions
In Summary For The Most Clinical Article,
-It summarized the incidence, Risk factors, mechanism,
diagnosis, prevention, and treatment of cancer after renal
transplantation.
Introduction,
-Kidney Transplant is the best treatment option for patients with ESRD, but it associated with many complications (due use immunosuppression) as cancer.
-Post transplantation malignancy is considered the second cause of death after cardiac disease, renal transplant recipients have at 2-3-fold increase in the risk of malignancy compared to general population,
-So many polices adopted for prevention and screening for early detection of cancer
-Cumulative incidence risk of of solid organ transplant cancer ~10-15% at 15 years post transplant, but the risk of skin cancer can reach 60%.
-The main causes of post-transplant malignancy is viral and immune which play the main mechanism in PTLD, anogenital cancer, and Kaposi sarcoma. On the other hand, the incidence of breast and prostate cancers are not increased in transplantation
-Mortality increased once malignancy develops, overall mortality is near 2 times the mortality in non-transplant patients with the same malignancy, and the most worse outcome occur with malignant melanoma, PTLD and RCC in which mortality increase 5-10 times.
Risk Factors for Cancer Development,
– Age (increasing age)
– Gender (male >female)
– Race (skin cancer is far more common in white > black especially malignant melanoma)
– Smoking
– Prolonged Sun exposure due to exposure to UV radiation
–Geographical location :
-NMSC, PTLD, and lip cancer are more common in Australia,
Europe and North America
-Kaposi Sarcoma is more common in Mediterranean, Africa &
Europe
– RCC & gastrointestinal cancers higher incidence in Korea and Middle East
– liver cancer higher incidence in Taiwan due to high prevalence
of hepatitis B
-Previously treated pre-transplant malignancy:
Pre-transplant malignancy which is common in CKD patients, for example the presence of pre-transplant malignant melanoma is the strongest risk factor for the development of post- transplant melanoma
–Cause of renal failure, as patients who develop ESRD due to glomerular, vascular aetiology or HTN nephro-sclerosis are at risk of RCC, on the other hand DM and ADPKD as a cause of ESRD are associated with lower risk of RCC
–Longer duration of dialysis before transplantation:
– Duration of dialysis prior to transplantation is a risk factor for RCC due to the development of acquired renal cysts
– Pretransplant EBV status, patients with seronegative EBV status are at increasing risk of early PTLD especially if the donor is positive, and this may explain the higher risk of PTLD in children compared to adult
Higher Sensitization Status
Acute Rejection
– Immunosuppression duration and intensity including the use of ATG which is affected by sensitization, acute rejection episodes.
-Immunosuppression may cause activation of oncogenic viruses like EBV (PTLD), HHV-8(KS), and HPV (lip and anal cancer)
-Immunosuppression may cause accumulation of mutations that should be fixed regularly by immune system (impairment of the ability of cells to repair DNA damage induced by UV radiation in skin cancer)
Type of immunosuppression:
Long term immunosuppression
-CNI increases the level of TGF-b that may increase the probability of tumor progression and metastasis, also CNI may cause impairment of the ability of cells to repair DNA damage induced by UV radiation leading to skin cancer, moreover they activate p53 which is associated with NMSC development
-Azathioprine increases the sensitivity of skin to UV radiation and increase accumulation of 6-thioguanine in the DNA leading to increase in te risk of NMSC mainly
-Use of T cell–depleting agents:
-ATG on short term may impair T cell function on long-term leading to cancer development
-OKT3 / Belatacept were found to increase the risk of PTLD
-MMF and sirolimus may decrease the risk of malignancies
Mechanisms of Cancer Development after Transplantation,
A- Poor immune control of oncogenic viruses e.g., HHV8 (KS), EBV (PTLD),
HPV(Lip Ca), in patients on immunosuppression, From Poor immune surveillance and accumulation of mutations due to long term immunosuppression
B- Immunosuppression-related cancer development is through Accumulation of
mutation (which can be recognized and repaired by
unsuppressed immune system) as skin cancer.
–CNI, azathioprine, T-cell depleted induction therapy are known to
increase risk of cancer, while mTOR-I can reduce this risk.
–Renal cell cancer increased 7-fold in transplant recipients, and its outcome
after radical treatment is similar to general population.
–Skin cancer is the commonest cancer in transplant recipients and more
aggressive than general population.
–PTLD associated with poor prognosis and 90% of cases associated with EBV
infection. Incidence in first 10 years 1-2%( highest in first 12 months).
Cancer Screening In Transplant Recipients,
Renal Cancer : only in high-risk patients (acquired cystic kidney disease, heavy smokers, those with family history
and those on long term analgesia), US /6 m-year
-Breast cancer screened as in general population, For female aged 50-74 years, mammogram/1-2 years
-Prostate cancer: For men aged 55–69 years, PSA annually
-Cervical carcinoma: annual Pap test or HPV rest every 3-5 years (age 25
-74 years).
–Gi malignancy : For adults aged 45–75 years, faecal immuno-chemical test / f.occult blood/6 months,
– sigmoidoscopy / 5 years, or colonoscopy every 5–10 years.
-Lung cancer: For adults aged 55–79 years with (one pack per day for 30 years or 2 packs per day for 15 years),
low-dose computed tomography/year
-Skin cancer: monthly self examination & 6-12 months total skin examination by dermatologist
-Recipients with higher risk of kidney cancer, annual or semi-annual USG screening
-Liver cancer: US every 6 months for patients with liver cirrhosis &.Some guidelines also suggest abdominal
ultrasounds and serum a-fetoprotein levels should be checked every 6 months for those with underlying liver
disease and chronic HBV infections.
-PTLD: Only in high-risk patients (donor EBV seropositive/ recipient seronegative), EBV by NAT once in the first
week post transplantation / month for the first 3–6 months, and every 3 months until the end of the first post
-transplant year
-HPV vaccine recommended for all male and female at age 9-25years in the general population for the
prevention of HPV-related malignancies, because the incidence of HPV-related anogenital cancer is at least ten-
to 15-fold higher in recipients of kidney transplants compared with the age- and sex-matched general population
-In the transplant population HPV vaccines are generally safe.
Common cancers after kidney transplantation,
Skin cancers:
-Most common cancer type in recipients of kidney transplants
-More aggressive than general populations
-More prevalent in females.
-Squamous cell carcinoma risk greater than 250 times general population
-Most reported skin cancers(comprising 90-95% cases)
Cutaneous squamous cell carcinoma,
Basal cell carcinoma,
Kaposi sarcoma,
Malignant melanoma(highest mortality with 5-to-8-fold higher risk)
Keratinocyte carcinomas
-Treatment as per biopsy, stage and recurrence
Post-Transplant Lympho-proliferative Disease
– Pre transplant EBV seronegative and primary EBV infection are important risk
factors for early EBV-positive PTLD
– Common with dormant EBV infection of B cells
– Cumulative incidence in first 10 years post-transplant
Adult recipients:1-2%
Paediatric recipients: 3%
– Risk of death is 14 times higher than in recipients without PTLD
– Greatest risk of death with bone marrow and reticuloendothelial disease followed by extra nodal and nodal disease
– Highest risk in EBV seronegative recipient with EBV seropositive donor
– Main stay of treatment is immunosuppression reduction
Renal Cancers:
– Up to 7-fold higher risk of RCC
– 90% develops in native kidneys
– Higher risk with
Male sex
Increasing age
African descent
Longer time on dialysis
Acquired renal cystic disease
–Patients transplanted for kidney failure 2ry to glomerular diseases ,hypertensive nephrosclerosis ,and vascular
disease appear to have the greatest associated risk of renal cell carcinomas .Patients with kidney failure
secondary to diabetes or autosomal dominant polycystic kidney disease have a lower risk of renal cell carcinomas.
– Treatment, outcome and prognosis is like general population
Potential management options for kidney recipients with cancer include
-Multidisciplinary (transplant and palliative care team) involvement(For patients who have progressed to advanced-stage malignancy, complete immunosuppression withdrawal is a difficult decision for both patients and clinicians).
–Modulation or Switching to mTOR inhibitors, For patients with squamous cell carcinoma & Kaposi sarcoma, there is now trial-based evidence to suggest conversion to an mTOR inhibitor may reduce the risk of cancer in the longer term .
–Shift from CNI to sirolimus may be warranted in some cases especially KS, and some cases of SCC , the rule of switching to m TOR is doubtful in other forms of malignancies, and is associated with increase in the risk of rejection and cardiovascular, infection-related deaths (especially pneumonia) and post-transplant DM
-Immunotherapy, CPI are effective in treating melanoma, non
small cell lung cancer, and renal cell carcinoma in the general
population, their use in the kidney transplant population
requires further investigation and cannot be recommended
currently, outside of a study protocol.
-Patient Shared decision making
– Local treatment
.In skin cancer such as topical fluorouracil , imiquimod cream,
photodynamic therapy, surgical excision or electrodesiccation
and curettage, radiation therapy
.Surgical excision of visceral tumour as indicated
– Systemic treatment
.Chemoprophylaxis in aggressive SCC or recurrent SCC occurring >
5 times per year, Includes retinoids (acitretin) and nicotinamide.
.Chemotherapy in metastatic disease, PTLD (doxorubicin,
cyclophosphamide, vincristine, prednisone)
.Rituximab in PTLD
.Immunotherapy needs further evaluation to assess safety to use in transplant recipients
What is the level of evidence provided by this article?
Level 5(V) => Narrative Review
Expert opinion without explicit critical appraisal, or based on physiology, bench research or “first principles”
That is an excellent summary and very well structured reply.
I like your analysis of level of evidence of this study.
Incidence of Solid Organ Cancer after Transplantation;
—————————————————————————————————-
The cumulative incidence of solid organ cancer ranges between 10% and 15% (6,9–11) at around 15 years after transplantation.
Cancer Mortality in Recipients of Kidney Transplants;
——————————————————————————————–
The overall risk of cancer-related death exceeding five to ten times that of those without kidney transplants .The risk is greatest among those with melanoma, urogenital cancers, and non-Hodgkin lymphoma.
Risk Factors for Cancer Development;
——————————————————————————
Some of these factors, such as increasing age, male sex, smoking, and prolonged sun exposures, are shared by patients in the general population. Other risk factors, including immunosuppression use (T cell–depleting agents), acute rejection , sensitization status , and duration of dialysis before transplantation , are specific to those with kidney disease and transplant populations.
Mechanisms of Cancer Development after Transplantation;
—————————————————————————————-
1-Poor immune control of known oncogenic viruses in patients on immunosuppression.
2- Immunosuppression-related cancer development is through accumulation of mutations that would otherwise be repaired or recognized by the immune system.
Common Cancers after Transplantation;
———————————————————————-
1-Renal Cell Carcinoma;
———————————
———————————-
Compared with the general population, recipients of kidney transplants have a higher risk (up to seven-fold) of renal cell carcinoma . Ninety percent of renal cell carcinomas develop in the native kidneys as opposed to the allograft . are typically early, low-grade, small kidney masses ; of which, 75%–80% are renal cell carcinoma, with the risk of metastasis at presentation being less than 2% .
Risk factors for development of renal cell carcinomas post-transplantation include ;
1-Male sex. 2- Increasing age .3-African descent . 4-Longer time on dialysis .
Patients transplanted for kidney failure secondary to glomerular diseases ,hypertensive nephrosclerosis ,and vascular disease appear to have the greatest associated risk of renal cell carcinomas .Patients with kidney failure secondary to diabetes or autosomal dominant polycystic kidney disease have a lower risk of renal cell carcinomas.
2-Skin Cancer;
———————–
————————
Skin cancer is the most common cancer type in recipients of kidney transplants and is more aggressive than skin cancers occurring in the general population.
The most commonly reported skin cancers in recipients of kidney transplants include cutaneous squamous cell carcinoma, basal cell carcinoma, Kaposi sarcoma, and malignant melanoma, with keratinocyte carcinomas comprising 90%–95% of these
skin cancers .
The pathogenesis of skin carcinoma involves a complex interaction of risk factors, including exposure to UV radiation, HPV, pre transplant skin cancer, older age, race, and sex (males at greater risk than females). Additionally, immunosuppressive medications augment the carcinogenic effects (mainly cyclosporine and azathio- prine) .
3- Post-Transplant Lymphoproliferative Disease;
————————————————————-
————————————————————
Pre transplant EBV seronegativity and primary EBV infection are important risk factors for early EBV-positive PTLD, particularly in younger recipients of transplants, and may explain the higher risk of disease early post-transplant. In contrast, a significant proportion (approximately 40%–50%) of late B-cell PTLDs involves EBV-negative lesions .
Apart from younger age at transplantation, male sex, use of T cell–depleting agents, Ortho Kung T3 (muromonab-CD3), and high dose tacrolimus, negative recipient EBV serology (with positive donor EBV serology) incur a four-fold excess risk of PTLD, after accounting for potential confounding factors .The use of costimulatory blockade, such as belatacept, has also been found to be associated with a higher risk of PTLD, particularly cerebral PTLD in patients who are EBV negative, and when used in higher doses .
The treatment goal of PTLD is to cure the disease, and the mainstay of treatment is immunosuppression reduction. Prior work reported the use of rituximab and chemotherapy (doxorubicin, cyclophosphamide, vincristine, prednisone) have improved overall survival, with 5-year survival at around 60% .
Cancer Screening Strategies in Transplant Recipients;
————————————————————————————-
1- Routine population-based cancer screening for breast, colorectal, and cervical cancer is recommended and should be aligned to the guidelines as per the general population .
2-Some guidelines suggest routine skin checks by dermatologists in recipients of transplants who are at high risk.
3- Some guidelines also suggest abdominal ultrasounds and serum a-fetoprotein levels should be checked every 6 months for those with underlying liver disease and chronic HBV infections.
4-For patients who are at risk of developing renal cell carcinoma (such as those with a history of acquired cystic disease, those with a family history, those who are heavy smokers, and those who use long-term analgesics), ultrasonographic screening (annually or biennially) of the native kidneys may be considered to detect occult malignancy .
Human Papillomavirus Vaccination in Recipients of Kidney Transplants;
————————————————————————————————-
The incidence of HPV-related anogenital cancer is at least ten- to 15-fold higher in recipients of kidney transplantscompared with the age- and sex-matched general population . HPV vaccination is indicated in both males and females aged 9–25 years in the general population for the prevention of HPV-related malignancies. In the transplant population HPV vaccines are generally safe.
Management of Recipients of Kidney Transplants Who Have Cancer;
—————————————————————————————————–
1-Immunosuppression Management and Treatment in Transplant Recipients with Cancer;
—————————————————-
A- Judicious reduction in the overall immunosuppression load for patients with early- to moderate-stage malignancy may be a reasonable first step .
B- For patients with squamous cell carcinoma, there is now trial-based evidence to suggest conversion to an mTOR inhibitor may reduce the risk of cancer in the longer term .
2- Immunotherapy;
—————————
Checkpoint inhibitors are effective in treating melanoma, non–small cell lung cancer, and renal cell carcinoma in the general population, their use in the kidney transplant population requires further investigation and cannot be recommended at this time, outside of a study protocol.
3- Putting Patients’ Perspectives at the Heart of Cancer Management;
——————————–
For patients who have progressed to advanced-stage malignancy, complete immunosuppression withdrawal is a difficult decision for both patients and clinicians. Therefore, a multidisciplinary, integrated approach that involves the transplant and palliative care team is crucial. The team should consist of a palliative care physician to assist with the medical aspects of managing the high symptom burden, together with a social worker, dietitian, clinical psychologist, and other allied health workers to address the psychosocial, functional, and nutritional issues experienced by our patients.
What is the level of evidence provided by this article;
Level V
That is an excellent summary and very well structured reply.
I like your analysis of level of evidence of this study.
Please use bold or underline for heading or sub-headings.
Please summarise this article
Cancer is the second-leading cause of death after kidney transplantation.
This paper highlights the incidence, mechanism, diagnosis, prevention, and treatment of cancer after renal transplantation.
Incidence of cancer after solid organ transplantation
Cancer mortality in kidney transplant recipients:
Risk factors for cancer development specific to solid organ transplantation include:
Geographic variation of cancer after solid organ transplantation:
Potential mechanisms of cancer post-transplant:
Poor immune surveillance and accumulation of mutations due to long term immunosuppression
Specific risks of immunosuppressive drugs that promote cancer pathways:
Common cancers after kidney transplantation:
Skin cancers:
a. Commonest
b. More aggressive than general populations
c. More prevalent in females.
d. Squamous cell carcinoma risk greater than 250 times general population
e. Most commonly reported skin cancers(comprising 90-95% cases)
f. Treatment as per biopsy, stage and recurrence
Post-Transplant Lymphoproliferative Disease
a. Associated with dormant EBV infection of B cells
b. Cumulative incidence in first 10 years post-transplant
c. Risk of death is 14 times higher than in recipients without PTLD
d.Greatest risk of death with bone marrow and reticuloendothelial disease followed by extra nodal and nodal disease
e. Highest risk in EBV seronegative recipient with EBV seropositive donor
f. Main stay of treatment is immunosuppression reduction
Renal Cancers:
a. Up to 7 fold higher risk of RCC
b. 90% develops in native kidneys
c. Higher risk with
d. Treatment, outcome and prognosis is similar to general population
Strategies for cancer screening in transplant recipients:
Potential management options for kidney recipients with cancer include:
What is the level of evidence provided by this article?
Narrative Review: Level 5
That is an excellent summary.
I like your analysis of level of evidence of this study.
Yes, MDT approach and Patient Shared Decision Making to individualise the patient care is needed.
Risk factors of malignancy development:
Mechanisms of post transplant malignancy:
Screening recommendations:
Management of post transplant malignancy:
Level of evidence is 4
Why level 4?
Narrative review, case series or case report and expert opinion are included level 4 of evidence
1- Summary
Introduction
Cancer is the worst complication of immunosuppression after renal transplantation ,it is the second cause of death in renal recipients in Western countries.
Therefor prevention is important as HPV vaccine and cancer screening.
Cancer incidence post transplant
Cumulative incidence of cancer skin is >60% in Europe , New Zealand and Australia.
Cancer risk is 2-3 times in transplant recipients compared to general population with highest risk with PTLD, anogenital cancer, and Kaposi sarcoma and lowest risk of cancer breast and prostate.
Cancer Mortality of Kidney Transplants recipients
Death risk is high after cancer develops which is 1.8-1.9 times in transplant recipients compared to general population with highest risk with melanoma, urogenital cancers, and non-Hodgkin lymphoma.
The high death risk in transplant recipients could be due to altered cancer cell biology with long term immunosuppressive use and low compliance of preventive and screening measures.
Cancer risk factors
Include old age, male gender, smoking, and prolonged sun exposures, sensitisation, immunosuppressives used, dialysis duration , CKD ,pretransplant malignancy and acute rejection.
Renal cell carcinoma and multiple myeloma are common in CKD .
NMSCs, PTLD, and lip cancer are more common post transplant cancers in Europe, North America, Australia, and New Zealand.
Urothelial transitional cell carcinoma, renal cell carcinoma ,and gastrointestinal cancers are more common in Asia and Middle East.
A study in Taiwan showed increased risk of liver cancer of 5fold compared with the general population due to being endemic for HBV infection.
Women have more risk of kidney and bladder cancer than men.
Cancer mechanism after transplantation
The Immunosuppressive effect on the immune system can open the door for cancer development by many ways as through
· oncogenic viruses as Kaposi sarcoma (human herpesvirus 8), PTLD [EBV], and lip and anal cancers (HPV).
· Mutation accumulation as in skin cancer
· In a study in hepatocellular carcinoma, human lung adenocarcinoma cells, and renal cell carcinoma, Tac increased cancer progression and metastasis ,CNI and Azathioprine promoted NMSC , Cyclosporine as well was implicated in cancer development in different ways
· mTORI has antitumor effect
· PTLD and melanoma risk increases with Induction therapy as T cell depleting agents by impairing immune system.
Common cancers after transplantation
Renal cell carcinoma
Renal transplant recipients have 7 fold risk of renal cell carcinoma compared to general population but likely most cases are detected early ,90% of cases develop from native kidneys ,rarely develop from graft.
Risk factors involve older age ,male gender , long dialysis duration,Africans ,renal failure caused by glomerular lesions , vascular etiology , hypertensive nephrosclerosis .
Renal cell carcinoma prognosis is comparable in transplant recipients to general population within 5 years .
Skin cancer
It is the most common cancer for renal transplant recipients involving squamous cell carcinoma, basal cell carcinoma, Kaposi sarcoma, and malignant melanoma, with keratinocyte carcinomas and has an aggressive behaviour in transplant recipients compared to general population.
Risk factors are exposure to UV radiation, HPV, pretransplant skin cancer, older age, race, and male gender.
Actinic keratoses and squamous cell carcinoma in situ, can be treated with topical fluorouracil and imiquimod cream, photodynamic therapy, and surgical excision or electrodesiccation and curettage.
Mohs micrographic surgery can be a definite treatment for squamous cell carcinoma, primary radiotherapy for inoperable cases ,chemoprophylaxis for aggressive squamous cell carcinoma.
CNI therapy increases the risk of Kaposi sarcoma ,and switching to m TORI is the main therapy .
Melanoma has highest mortality , previous melanoma history ,white race and old age are the risks.
PTLD
It is rare disease, caused by EBV infection and it has bad prognosis.
It is mostly Bell type, the highest risk is in the first year post-transplant, and it then risk declines , pediatrics are at higher risk
Risk factors include pediatric transplantation, male , T
cell–depleting agents, Tac high dose, co use of belatacept ,seronegative EBV recipient.
Treatment includes reduction of immunosuppression and rituximab and chemotherapy.
Screening of cancer in transplant recipients
Early screening can decrease mortality, routine cancer screening was queationable in kidney disease cases.
Meanwhile breast, colorectal, and cervical cancer screening is recommended as in general population.
As well as routine skin screening for high risk patients and abdominal US , alpha fetoprotein/6 months for CLD cases and renal cell carcinoma screening for high risk cases.
HPV vaccine for renal transplant recipients
Quadrivalent vaccines and the HPV 9-valent vaccines are efficient in preventing CIN
Management of cancer in renal transplant recipients
Immunosuppressive therapy
Multidisciplinary team to decide for decreasing immunosuppression risking the graft versus cancer severity.
Shifting to m TORI reduces can risk for squamous cell carcinoma and Kaposi sarcoma meanwhile mTORI can increase death risk.
Immunotherapy
Inhibitors targeting the programmed death-1/programmed death ligand-1 interaction and/or the CD28-CD80/86 axis with cytotoxic T lymphocyte–associated protein-4 Ig stimulates immune system against cancer.
It is efficient in treatment of melanoma, non–small cell lung cancer, and renal cell carcinoma in the general population, but needs further evaluation in renal transplant recipients
Cancer management and perspective of the patient
A multidisciplinary management including the transplant and palliative care team is mandatory to individualize policy and balance rejection risk versus cancer risk.
Conclusion
Maximizing allograft function with immunosuppression is challenging and added cancer renders it more difficult .
More research is needed in transplant recipients as prevention and screening protocol for cancer are taken from general population recommendations which may not suite transplant recipients.
2- Level of evidence is V
That is an excellent summary.
I like your analysis of level of evidence of this study.
Yes, MDT approach to individualise the immunosuppresion is needed.
Narrative review study (Level of Evidence 5) on neoplasms in patients after kidney transplantation.
After cardiovascular disease, neoplasms are the leading cause of death and graft loss in most Western countries. Risk factors for this worse outcome are the absence of preventive policies, lack of vaccinations against HPV, lack of protocols for screening strategies for neoplasms for early diagnosis and to prevent the disease from spreading.
Although breast and prostate cancer does not have important statistical data in this population, oncogenic viruses such as HPV, EBV, BKV, HV8, HBV, and HCV increase the risk of neoplasia after transplantation. Another theory is that the use of specific immunosuppressants may increase the risk of neoplasia. Non-melanoma skin cancer should be actively evaluated by both the patient and the care team. Risk factors such as age, gender, smoking history, prolonged sun exposure, use of calcineurin inhibitors, acute rejection, previous sensitivity and time on dialysis should be evaluated and their risks calculated to be discussed with the patient. Another risk factor to consider is pre-transplant cancer.
Immunosuppression may favor the reactivation of oncogenic viruses or cause accumulated lesions due to DNA mutation, the latter favoring non-melanoma skin neoplasms. Calcineurin inhibitors act on immune axes that increase the production of tumor necrosis factors, facilitating growth and metastases. Azathioprim increases the risk for DNA damage and mutations. There are no data on anti-lymphocyte drugs such as Muronomab, thymoglobulin and alemtuzumab, but mTor-inhibiting medications may have an antineoplastic effect and interfere favorably to prevent or even reverse these neoplasms.
Most common cancers
1. Renal cell carcinoma
Risk seven times higher when compared to the general population, male, age over 60 HR 6.59; African descent HR 1.5; prolonged dialysis time longer than 3 years HR 2.23. Renal-based disease is also a risk factor: glomerular disease HR 1.24; hypertensive nephrosclerosis HR 1.55 and vascular disease HR 1.53; or protective: diabetes mellitus HR 0.77; polycystic kidney disease HR 0.81.
2. Non-melanoma skin cancer
Undoubtedly the most common, being more closely related to squamous cell carcinoma. Treatments with local chemotherapy (5 fluororacil or imiquimod), phototherapy, retinoic acid, nicotinamide or surgical excision. Systemic chemotherapy or immunotherapy is performed when there is associated systemic disease. The adjustment of immunosuppressants must be individualized depending on the risk factors and the cancer involved.
3. PTLD
Negative pre-transplant serology or acute post-transplant infection are the main risk factors. Early age, used immunosuppression, anti-lymphocyte induction are additional risk factors. Most of the time, the disease is caused by Bm lymphocytes, which is why rituximab (anti-CD20) is the drug of choice to control the disease.
Screening for these neoplasms in this patient profile is debatable due to the lack of specific clinical protocols for transplanted patients or those using immunosuppressive medications. The decision ends up being together with the patient assessing their risk factors and environmental exposure. Undoubtedly, HPV vaccination is highly recommended and should preferably be given before transplantation. Care to prevent sun exposure is also crucial. Immunotherapy is questionable and further studies are needed to define its role.
That is an excellent summary.
I like your analysis of level of evidence of this study.
Suggestion: please use bold or underline for sub-headings when you describe differnt cancers under the main heading ‘Most common Cancers’.
-Kidney transplantation increases the quality of life and survival rates for maintenance dialysis patients. It’s also KRT’s most cost-effective therapy.
Allograft function requires lifelong immunosuppression.
-Cancer is a major risk of immunosuppression following kidney donation. Clinicians, patients, and caregivers also consider cancer a primary clinical outcome, and key stakeholders now agree that kidney transplantation interventional studies should include cancer as an outcome.
-At 15 years following transplantation, solid organ cancer incidence is 10% to 15%. Europe, Australia, and New Zealand have 0.60% skin cancer incidence. After age and sex adjustments, kidney transplant patients had a two- to three-fold higher cancer risk than the general population.
-Most Western nations have observed that all cancer mortality rates are at least 1.8–1.9 times higher than the age- and sex-matched general population. Melanoma, urogenital, and non-Hodgkin lymphoma patients had a five to ten-fold higher risk of cancer-related mortality than those without kidney transplants.
-Transplantation raises cancer risk for numerous reasons. These characteristics include age, male sex, smoking, and extended sun exposure.
Immunosuppression (T cell–depleting drugs), acute rejection, sensitization status, and dialysis length before transplantation are renal disease and transplant-specific risk factors.
-Even though long-term immunosuppression is a major cause of cancer after a transplant, there is now strong evidence that CKD, at any stage, is linked to a higher risk of cancer and a worse outcome for cancer patients.
-Induction treatment with T cell–depleting drugs, such as anti-thymocyte globulin and anti-CD52 increases the risk of malignancies such PTLD and melanoma.
-Immunosuppression does not seem to be more oncogenic than others. However, experimental investigations in hepatocellular carcinoma, human lung adenocarcinoma cells, and renal cell carcinoma have indicated that tacrolimus enhances TGF-b and promotes tumor development and metastasis.
-mTOR inhibitors may limit cancer development by arresting cell cycles and initiating apoptosis. Tumor growth has been inhibited.
-Checkpoint inhibitors may cause nonspecific immune-system activation and rejection in transplant patients, limiting their usage.
-A sensible decrease in the total immunosuppressive burden for patients with early- to moderate-stage malignancy may be a good first step. Patients should be informed of the possible side effects, and all measures should be customized to their requirements.
Level of evidence 5, narrative review
That is an excellent summary and very well structured reply.
I like your analysis of level of evidence of this study.
Please use bold or underline for heading or sub-headings.
The aim of this review article is to address the incidence, prevalence, screening, diagnosis, and treatment of post-transplant malignancy
Introduction
Kidney transplantation remained the best option for patients with ESKD it’s associated with better quality of life and survival however still patient need Long-life immunosuppression therapy with increased risks of malignancies, post-transplantation cancer is the second leading cause of death following CVD, and the prevalence 2-3times higher than the general population and some viral and immunological risk like PTLD and EBV infection, PV8 and Kaposi sarcoma
The mortality increased by 1.8-1.9 times in the transplant population compared to the age and sex-matched general population, especially for melanoma skin cancers, PTLD (NK Large cell lymphoma ) , RCC, anogenital tumors risk of death is even higher 5-10times those without transplantation
Solid organ cancers like breast and prostate are similar to the general population
Factors that increased the risk of tumors after transplantation include
Old age, Sex more in males, smoking history, and prolonged sun exposure is considered shared risk factors to the general population but in kidney transplant patient there are additional specific risk factors including the duration of CKD and dialysis, immunosuppression type like t cell depleting agents, history of sensitization, the acute rejection rate. As per data registries there is also geographical variation in the incidence and type of tumors in western &Australis more no-melanoma skin cancers compared to Asian and middle east have a higher rate of urethral and colorectal malignancies, while in endemic areas of chronic HBV infection like Vietnam, they reported a higher incidence of liver cancers
The mechanism for cancer after transplantation
1. the effects of immunosuppression drugs on reducing the immune system may generate a diversity of pathways for cancer development via poor immune control of known oncogenic viruses in patients on immunosuppression and associated with an increased rate of viral-associated cancers, such as Kaposi sarcoma (human herpesvirus 8), PTLD (Epstein–Barr virus [EBV]), and lip and anal cancers (HPV) are common in patients with suppressed immune systems.
2. In the case of skin cancer immunosuppression can lead to a decrease of xeroderma pigmentosum complementation groups A and G, which are components of nucleotide excision repair.
3.Type of Immunosuppression therapy, based on limited evidence from few studies supports that CNI, including tacrolimus and Cyclosporin, is associated with a risk of nonmelanoma skin cancers Cyclosporine also has direct effects on tumor development and progression, through TGF-b or IL-6 overexpression pathways
4. Azathioprine sensitizes the skin to UVA radiation and causes the accumulation of 6-thioguanine in the DNA, leading to a higher risk of NMSCs
5. M Tor inhibitors like sirolimus and everolimus have a protective effect by inhibiting the tumor cells’ growth through cell-cycle arrest and initiation of apoptosis.
The most common types of cancers after renal transplantation based on evidence from epidemiology and registry studies include skin cancer like squamous cell carcinoma, basal cell carcinoma, Kaposi sarcoma, and melanoma skin cancer, and usually, aggressive course compared to the general population due to interaction of many risk factors like exposure to UV radiation, HPV, pretransplant skin cancer, older age, race, and sex (males at greater risk than females).
Kaposi sarcoma is rare skin cancer in the general population but kidney transplantation is 100 times high rate due to Cyclosporine use and is more found in central Europe, Africa, and the Mediterranean region, however, the main treatment is stopped cyclosporine and shifted to m TOR inhibitors like everolimus or sirolimus
Review article level 5, narrative review
That is an excellent summary and very well structured reply.
I like your analysis of level of evidence of this study.
Suggestion: please use bold or underline for sub-headings when you describe mechanism of cancer development after transplant.
-Risk is 7-folds greater than the general population(male,age>60, HD > 3 yrs, GN,HTN)
-Mostly in native kidneys
-Treatments are partial nephrectomy, radical nephrectomy, and per-cutaneous ablation
2.Skin Cancer;
-Most common type of cancer in kidney recipients and with aggressive behavior.
-Risk factors are UV radiation, HPV, pretransplant skin cancer, white race, male
-Squamous cell carcinoma is 250 times higher than the general population
-Melanoma has the greatest mortality
-Treatment options are;FLU, photo-dynamic therapy, surgical excision and curettage
3.PTLD;
-90% of cases are associated with EBV
-Bimodal distribution,the first year of transplantation and then after 5 years
-Risk factors are;young, male,lympho-depletion, Belatacept, EBV -ve,
-Treatment; Reduction of immune-suppression, rituximab, or chemotherapy
1.Careful reduction of immune-suppression after discussion with the patient
2.mTORi in cases of squamous cell carcinoma and Kaposi sarcoma
3.Check-point inhibitors; may increase risk of rejection, more evidence is needed
That is an excellent summary and very well structured reply.
I like your analysis of level of evidence of this study.
The incidence of de novo malignancy post-transplant is higher than general population because of immunosuppression medications , and the incidence of specific malignancy differ from solid organ to another as documented by British registry in Britain.
In heart, liver and kidney post-transplant, the incidence of overall malignancy with the exclusion of non-melanoma skin cancer NMSC is 2- fold increase than general population (SIR 2.5, 2.2, 2.4) and more than 3-fold increase in lung and combined heart and lung transplant recipient (SIR 3.6).
SIR is standardized incidence ratio, which is the relation between number of observed cases and number of expected cases.
SIR of NMSC post kidney and cardiothoracic transplant is 16, this is 3 fold increase than post liver transplant.
The incidence of cancer may be under-estimated because of removal or ablation of the skin lesions without biopsy and histological examination.
Also the incidence depends on registration which differs from country to country and it is affected by many factors.
Journal 3
Renal transplantation is the best management for end stage renal disease ESRD, and it is cost effective solution than dialysis with its different modalities.
Renal transplantation is not a curative management of ESRD, so, after transplantation there will be risk of side effects and complications related to immunosuppressive medications and state of the patients, as cardiovascular complications are the first leading cause of death in transplant patients, the second cause of death post-transplant is cancer , once developed, leads to very poor outcome.
Counselling of the patient pre-transplant and screening for cancer is very important, also early detection and diagnosis of cancer is necessary for early management and avoid morbidity and mortality, also introduction of human papilloma virus vaccination is very important against cancer cervix.
Risk of cancer in solid organ transplant recipient increased by the time post-transplant, it is 2-3 fold increase in its incidence than general population, it may be immune related or viral related like PTLD, skin cancer, Kaposi sarcoma.
The cause of high mortality of cancer in transplant patients is due to potential differences in the cancer cell biology in recipients of transplants resulting from long-term immunosuppression, associated comorbidities.
Risk factors for increased incidence of cancer post-transplant:
1- increasing age
2- male sex
3- smoking
4- prolonged sun exposures
5- immunosuppression use
6- acute rejection
7- sensitization status
8- duration of dialysis before transplantation
Type of commonest cancer post-transplant depends on geographic area like endemic viral infection in one area …etc.
In Europe, North America, Australia, and New Zealand, there is increased incidence of NMSCs, PTLD, lip cancer.
In non-Western Asian and Middle Eastern, there is increased incidence of urothelial transitional cell carcinoma, renal cell carcinoma, and gastrointestinal cancers.
In Taiwan, there is increased risk of liver cancer five-fold compared with the sex- and age-matched general population, Taiwan is an endemic area for chronic hepatitis B virus.
As regard immunosuppressive medications and its role:
1- Tacrolimus increases the level of TGF-b, which promotes tumor progression and metastasis.
2- Calcineurin inhibitors inhibit signaling via calcineurin and NF of activated T cells, which can activate p53, a hallmark of some NMSCs.
3- Cyclosporine also has direct effects on tumor development and progression, through TGF-b or IL-6 overexpression pathways.
4- Cyclosporine is capable of inhibiting DNA repair, thereby accumulating mutations, inducing apoptosis in activated T cells, and inhibiting apoptosis in other cells by opening the mitochondrial permeability transition pores.
5- Oncogenic potential of azathioprine is well known and well recognized. Azathioprine sensitizes the skin to UVA radiation and causes the accumulation of 6-thioguanine in the DNA, leading to a higher risk of NMSCs.
6- Mammalian target of rapamycin (mTOR) inhibitors, on the contrary, may have potential antitumor effects by inhibiting cancer growth through cell-cycle arrest and initiation of apoptosis.
7- Induction therapy with T cell–depleting agents (including polyclonal agents, such as anti-thymocyte globulin, and monoclonal agents, such as anti-CD52 and, historically, Ortho Kung T3 [muromonab-CD3]) increases the risks of cancers, such as PTLD and melanoma.
RCC renal cell carcinoma:
1- It is 7 fold increased in transplant recipient, may be due to increase frequency of abdominal imaging.
2- It developed in native kidney not in allograft.
3- Male sex, old age, long duration on dialysis
4- Etiology of renal disease; glomerular, vascular, hypertensive nephrosclerosis have increased incidence of RCC than in diabetic etiology or APKD
5- The outcome of renal cell carcinomas after radical treatment in the transplant population is comparable with that of the general population, with 5-year, disease-specific and overall patient survival rates of 68%–97% and 69%–88%, respectively.
6- RCC is rare in allograft and of low grade
Skin cancer:
1- Skin cancer is the most common cancer in renal transplant recipient, may be due to interplay between predisposing factors like exposure to UVA and B with the state of immunosuppression, male sex , old age.
2- It can be cutaneous squamous cell carcinoma, basal cell carcinoma, Kaposi sarcoma, and malignant melanoma, with keratinocyte carcinomas comprising 90%–95% of these skin cancers.
3- Incidence of Kaposi sarcoma in renal allograft recipient is 100 times higher than general population.
4- Risk of squamous cell carcinoma is 250 times more than general population.
5- Kaposi sarcoma is related to use of CNI and regress after shifting to sirolimus
6- Risk of malignant melanoma in renal transplant recipients is 8 times than general population.
7- Melanoma is of high mortality, and pre transplant melanoma, and white race are risk factors for post-transplant melanoma.
PTLD
1- Post-transplant lymphoproliferative disease is rare disease but it is common to occur post renal transplant, it is caused by EBV infection which happens in the childhood or any time with mild to no symptoms , it infects B cells and remains dormant in it in the latent phase, after transplantation as immunity decreased and T cell function decreased and became out of control B cells , this virus will be reactivated and leads to PTLD.
2- Most PTLD are B cell 95%, and 5% are T cell.
3- Pre transplant seronegative and EBV primary infection are important risk factors.
4- High incidence at 1 year then decreased toward fifth year post transplant
5- Compared with adult recipients of transplants, the risk of developing lymphoproliferative disease in pediatric recipients of transplants is at least 30-times higher than the age- and sex-matched general population. Apart from younger age at transplantation, male sex, use of T cell–depleting agents, Ortho Kung T3 (muromonab-CD3), and high dose tacrolimus, negative recipient EBV serology (with positive donor EBV serology) incur a four-fold excess risk of PTLD, after accounting for potential confounding factors . The use of costimulatory blockade, such as belatacept, has also been found to be associated with a higher risk of PTLD, particularly cerebral PTLD in patients who are EBV negative, and when used in higher doses.
6- Management of PTLD is immunosuppression reduction.
7- Once developed, mortality is high.
8- Rituximab can be used in treatment.
Screening of cancer pretransplant with introduction of HPV vaccination is important, also counselling of the patient and relatives especially old age and male sex patients , and considering other risk factors for cancer.
Management of the patient with cancer should be individualized based on the general condition of the patient, staging of the cancer.
So balance between risk of rejection and risk of fulminant metastases should be done and individualized with handling of immunosuppression doses.
level of evidence 5
That is an excellent summary and very well structured reply.
I like your analysis of level of evidence of this study.
Please use bold or underline for heading or sub-headings.
Post transplantation malignancy is considered the second cause of death after cardiac disease, renal transplant recipients have at 2-3 fold increase in the risk of malignancy compared to general population, the incidence of solid malignancy and skin cancer is around 10% and 15% and 60% at 15 years after transplantation.
The main cause of post-transplant malignancy is viral and immune which play the main mechanism in PTLD, anogenital cancer, and Kaposi sarcoma. On the other hand, the incidence of breast and prostate cancers are not increased in transplantation
Mortality increased once malignancy develops, overall mortality is near 2 times the mortality in non-transplant patients with the same malignancy, and the most worse outcome occur with malignant melanoma, PTLD and RCC in which mortality increase 5-10 times.
Risk factors for post-transplant malignancy
1- Age (increasing age)
2- Gender (male are affected more)
3– Race (skin cancer is far more common in white than black especially malignant melanoma)
4- Smoking
5- Sun exposure due to exposure to UV radiation
6– Geographical location :
7- Pretransplant malignancy which is common in CKD patients, for example the presence of pretransplant malignant melanoma is the strongest risk factor for the development of post-transplant melanoma
8- The cause of renal failure, as patients who develop ESRD due to glomerular, vascular etiology or HTN nephrosclerosis are at risk of RCC, on the other hand DM and ADPKD as a cause of ESRD are associated with lower risk of RCC
9- Duration of dialysis prior to transplantation is a risk factor for RCC due to the development of acquired renal cysts
10- Pretranplant EBV status, patients with seronegative EBV status are at increasing risk of early PTLD especially if the donor is positive, and this may explain the higher risk of PTLD in children compared to adult
11– Immunosuppression duration and intensity including the use of ATG which is affected by sensitization, acute rejection episodes.
12- Type of immunosuppression:
Renal cell carcinoma
Skin cancer
Post-Transplant Lymphoproliferative Disease
Anogenital cancer
Screening of malignancy after transplantation
Management of post tranaplant malignancy (challenging and needs multidisplinary team)
A- Modulation of immunosuppression
B- Local treatment
C- Systemic treatment
Level of evidence
That is an excellent summary and very well structured reply.
I like your analysis of level of evidence of this study.