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2. A 51-year-old man with a history of right renal transplant presented with right-sided flank pain, chills, and fever. CT was performed in search of the source of infection.
- What is your differential diagnosis?
- Please outline your management
- Are any other tests required?
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CT showing lesions in kidney, liver and spleen
Differential diagnosis
PTLD
HCC
RCC
Disseminated TB
Management
Full investigations FBC, LFT, KFT, LDH ,uric acid
Viral serology EBV, CMV,HBV,HCV
Tumor markers
Biopsy
PET scan for staging
Management of PTLD
Reduction of immunosuppression
Chemotherapy
Radiotherapy
Adoptive therapy
The differential diagnoses in this case are:
PTLD with metastasis
HCC or Liver metastasis
RCC
Infection
Management plan:
Proper history and physical examination patients may have lymphadenopathy or splenomegally or hepatomegaly tonsillar exam if airway symptoms and to the abdominal exam in patients with GI symptoms
CBC, RFT and electrolytes,UA, LDH, LFT and liver enzymes, Tumor marker,
Virology screening(PCR, serology), Biopsy, CT scan, US, TB screening
Management
A multidisciplinary approach to management of PTLD is essential and requires consideration of histological subtype, staging, renal function, proximity to transplant, degree of immunosuppression, modalities of therapy and overall health of recipient.
The goal of treatment for EBV + PTLD is two-fold: (a) eradication of proliferating B cells and (b) recovery of T-cell mediated EBV specific immune response to provide protection from recurrences.
When possible, initial approach includes RIS with reported responses in retrospective reviews ranging from 43 to 63% of patients diagnosed with PTLD.
Modifying immunosuppression to mTOR inhibitors instead of calcineurin inhibitors may aid in early treatment of PTLD.
Patients with significant symptoms from advanced stage disease or fulminant PTLD are not candidates for RIS alone.
Rituximab as monotherapy or in combination with chemotherapy is considered standard of care for most CD20+ EBV + PTLD non-responsive to RIS
In patients who fail RIS and/or rituximab, chemotherapy or adoptive immunotherapy are necessary Chemotherapy for EBV + PTLD is an acceptable first line therapy in fulminant or advanced stage monomorphic PTLD, classical Hodgkin lymphoma-like histologic subtypes, as well as salvage therapy after failed RIS and rituximab.
Diagnosis and management of post-transplant lymphoproliferative disease following solid organ transplantation in children, adolescents, and young adults
Author links open overlay panelJeremy Rubinstein a b 1, Keri Toner c d 1, Thomas Gross e, Birte Wistinghausen c d
Differential diagnosis
PTLD
RCC
HCC
All of above with metastasis
Renal abscess
TB
Management
●Lab tests
CBC- CRP- ESR- PRO CAL- CREA – LFT
LDH- UA
TB TEST
ALPHA FETO PROTEIN
BS – BM
EBV PCR
HCV HBV TEST
●PET- CT
●And the gold standard for diagnosis is biopsy and histology study
●first of all we will reduce immunosuppression drugs
In the case of not responding: Rituximab is the best choice of treatment
Then if not responding CHOP 21 recommended
We need surgical consultation – in addition to the consultation of the hematologist and oncologist
DD
RCC
PTLD
TB
HCC
work up:
history
examination
investigations:
chemistery cbc serology For EBV CMV HCV ,runout markers
imaging CT CAP
PET SCAN
Treatment:
According to the diagnosis
RCC:Nephrectomy and chemotherapy
PTLD:rituximab
TB:Anti tuberculous drugs
PTLD
RCC
HCC
Other infections
The lesion shown in this CT could be PTLD, renal cell carcinoma, hepatocellular carcinomas, metastatic lesions, or infection by TB.
Management involves biopsy from the lesion, metastatic work up, reduction of immunosuppression with better switching to mTORi. Multidisciplinary team would be of great importance.
If the lesion was proved to be PTLD, rituximab may pose a good option with better prognosis.
Cases with TB respond to antituberculous medication with attention to drug level of immunosuppressive agents.
Other labs preclude Alfa feto proteins, complete blood count , liver functions, viral serologies and metastatic work up.
What is your differential diagnosis?
· A CT with contrast showing lesions in the liver, spleen, kidney
· DD:
Are any other tests required?
Please outline your management.
If PTLD is diagnosed by Biopsy:
· MDT approach
· The staging will guide the management plan.
· In limited disease, reduction of immunosuppression (withdraw anti-metabolites and reduce CNIs by 50% while maintain the patient on steroids. In critically ill patients withdraw all immunosuppression except steroids) aiming for complete remission (assess response within 2-4 weeks).This is the main stay that will reverse from 20-80% of PTLD patients. However, EBV negative cases are less responsive.
· If not complete remission or partial remission, start Rituximab monotherapy ( response to monotherapy treatment approached 44%-79%)
· If no complete remission start cycles of R-CHOP-21.
· In extensive disease, immunosuppression reduction and R-CHOP-21.
· Radiotherapy for limited disease.
· Antiviral therapy are not strongly recommended.
· Adoptive immunotherapy is considered in patients with refractory or relapsed EBV-positive PTLD.
If Renal cell carcinoma is diagnosed :
· Treatment is the same as in non-transplant patient.
· Treatment includes partial nephrectomy or radical nephrectomy followed by initiation of RRT and withdrawal of immunosuppression.
If the diagnosis is HCC : GIT must be involved as part of the MDT
References:
1. Abbas F, El Kossi M, Shaheen IS, Sharma A, Halawa A. Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches. World J Transplant. 2020 Feb 28;10(2):29-46.
2. Shah N et al. Haemato-Oncology Task Force of the British Society for Haematology and the British Transplantation Society. Front-line management of post-transplantation lymphoproliferative disorder in adult solid organ recipient patients – A British Society for Hematology Guideline. Br J Haematol. 2021 May;193(4):727-740.
Ct picture on left side showing a mass involving kidney. CT picture on right side showing Metastasis to liver and spleen.
What is your differential diagnosis?
PTLD Involving renal graft with Metastasis to liver and Spleen
RCC with Metastasis to liver and Spleen
Since RCC rarely metastatise to Spleen ,it is most likely PTLD involving Renal graft.
Managment-
Diagnsosis-Radiologic evidence of a mass or the presence of elevated serum markers (such as increased lactate dehydrogenase [LDH] levels) is suggestive of PTLD, with positive positron emission tomography (PET) scanning (possibly indicating metabolically active areas) also favoring the diagnosis . A rising Epstein-Barr virus (EBV) viral load also supports the diagnosis. Diagnosis and classification requires a tissue biopsy, preferably an excisional biopsy
Reduction of immunosuppression is 1st step in the treatment.Further managment dependeds upon the type of PTLD:
Early lesions – For most patients with early lesions, reduction of immunosuppression alone rather than in combination with other therapies .Other agents are generally reserved for those patients with residual disease despite reduced immunosuppression .
Polymorphic PTLD – For most patients with polymorphic PTLD that expresses CD20 (CD20+ PTLD), rituximab in addition to reduction of immunosuppression is used.
Monomorphic PTLD – For patients with monomorphic CD20+ PTLD, we suggest the use of rituximab either alone or in combination with chemotherapy in addition to reduction of immunosuppression Single agent rituximab may be considered for patients who have minimal symptoms and for those who are not candidates for initial chemotherapy. All other patients with CD20+ PTLD are offered rituximab plus combination chemotherapy, administered concurrently or sequentially. Patients whose tumors do not express CD20 are not candidates for rituximab therapy and are treated with combination chemotherapy plus reduction of immunosuppression.
Classic Hodgkin lymphoma-like PTLD – Classic Hodgkin lymphoma-like PTLD is the least common form of PTLD and there is a paucity of data regarding management. For most patients with classic Hodgkin lymphoma-like PTLD management with chemotherapy with or without radiation therapy according to protocols used for classic Hodgkin lymphoma .
Are any other tests required?
Full blood count, Electrolytes, Renal function, Glucose, Liver enzymes, Urate, Lactate dehydrogenase (LDH) Virology: HIV type 1 & 2, Hepatitis B and C and EBV serology, CMV/EBV DNA titres. Echocardiography where appropriate .All patients should have a staging CT- scan of neck, chest, abdomen and pelvis .
Among solid organ transplant recipients, PTLD involving the allograft may have pathologic features that morphologically resemble those seen with graft rejection. Since the treatment options for rejection and PTLD are markedly different, additional studies must be performed to differentiate the two possibilities. Particularly informative studies include immunophenotyping for B and T cell antigens, including kappa and lambda light chains, polymerase chain reaction studies for antigen receptor gene rearrangements, in situ hybridization for Epstein-Barr virus (EBV)-encoded small nuclear RNAs (EBERs), and serum and urine protein electrophoresis. Imaging studies should include the graft, abdomen, pelvis, and any other clinically relevant areas
renal transplant
right-sided flank pain, chills, and fever.
CT was performed in search of the source of infection.
● What is your differential diagnosis?
PTLD
HCC
Metastatic tumor
RCC
Lymphoma
Infectious disease as tuberculosis
● Please outline your management
☆ MDT for the diagnosis and treatment that team must include
Haematologist
Oncologist
Radiologist
Surgeon
☆ First treatment is to reduce the immunotherapy
☆ If RI is not enough we can start Rituximab and in case of no response we can use R- CHOP-21
☆ Radiotherapy in specific cases
● Are any other tests required?
☆ CBC, liver tests, electrolytes, glucose, UA, LDH, renal function tests
☆ Viral serology as PCR (HCV, EBV, CMV, HBV)
☆ Liver biopsy
☆ Bone marrow biopsy
☆ CT scan for head , neck , chest , and ☆ ☆ pelvis as staging CT
☆ Pet scan
DD :
PTLP disorder.
Malignancy such as RCC.
Infectious causes :
CMV.
EBV .
Tuberculosis.
Infestigation:
Detailed history with viral screen .
Biopsy.
This could be malignancy or infection
51-year-old man with a history of right renal transplant presented with right-sided flank pain, chills, and fever.
CT Abd. shows solid lesion in the graft with other smaller lesions in the liver, spleen:
differential diagnosis includes:
– PTLD with metastasis
– renal cell carcinoma with metastasis.
-HCC with metastasis.
-Infections with multiple abscess which might be TB but still the lesion in the CT appears as solid not cystic.
So, it is mostly malignancy with metastasis
Management approach:
– full History and Physical Examination to detect source of infection if present -Lab Investigations:
Kidney function, liver function
CBC, Uric acid, Ca, phosphorus.
LDH Levels.
AFP
PCR for CMV, EBV, HHV-8, HBV, HCV, HIV.
-PET scan
-CT guided biopsy of the lesion in kidney or liver.
-Treatment If the diagnosis of EBV positive PTLD was confirmed by biopsy.
No specific antiviral treatment the main but mainly reduction of Immunosuppression:
EBV negative PTLD usually occurs late and are less responsive to IS reduction.
Treatment includes
-Reduction of CNI by 50% stop MMF.
-Also switching CNI to mTORi all are effective in treatment of PTLD
-Monitoring allograft function for fear rejection episodes.
-management of PTLD if not responding to reduction of IS according to type
-Polymorphic type and early type PTLD usually show good response to immunosuppression reduction and rituximab monotherapy,
-B-cell PTLD usually responsive to Rtx
-In case of monomorphic type, PTLD requires concurrent or sequential chemotherapy.
-Other rare PTLD subtypes, it is recommended to follow guidelines for neonatal lymphoma.
-surgical resection or radiotherapy may be also used as adjuvant treatment According to the degree of malignancy.
-Nonchemotherapy methods as adoptive T cell therapy is promising and must be further studied
Adoptive immunotherapy
– expansion of T lymphocytes, that is able to attack specifically malignant cells Should be considered in patients with refractory and non responding EBV-positive PTLD but the risk of rejection is high.
-If the biopsy showed RCC with metastasis
Management of RCC
Treatment is the same according to guidelines with surgery either partial or radical nephrectomy with chemotherapy for distant metastasis.
reference
Bairu Shen,Zhuofei Cen,1Minghua Tan et al.Current Status of Malignant Tumors after Organ Transplantation.BioMed Research International Volume 2022, Article ID 5852451, 12 pages.
V. Hevia, V. Gómez, V. Díez Nicolás et al., “Development of urologic de novo malignancies after renal transplantation,” Transplantation Proceedings, vol. 46, no. 1, pp. 170–175, 2014.
Image suggested diseases with implants/dissemination.
1 – Malignancy
– PTLD
– Carcinoma
2 – Infectious disease
– Tuberculosis
– fungus
– endocarditis
1 – We could perform a more accurate exam such as a pelvic MRI
2 – Once the possibility of PTLD and carcinoma was considered, viral research would be necessary, since more than 80% of cases are related to oncoviruses,:
– EBV PCR and CMV PCR
– Hepatitis B and C
3 – To rule out endocarditis – I would perform transesophageal ECO + collection of paired blood cultures.
4 – I would request an opinion from the surgery to perform exploratory videolaparoscopy for biopsy histopatologic study + culture (BK and fungus)
Possibility of less specific tests such as alpha-fetoprotein and CEA, but which could be important in the monitoring of treatment in case of carcinoma
What is your differential diagnosis?
The differential diagnosis is of PTLD or renal cell carcinoma
Please outline your management
Reducing the immunosuppression or changing them to sirolimus or mTOR inhibitors
Are any other tests required?
Complete Blood panel tests and Whole-body PET scan to see the spread of the infection
Biopsy for histopathology and immunophenotyping
Q1: CT scan shows a large mass lesion in the graft with liver and spleen involvement.
Differential diagnosis may include:
1- PTLD with widespread involvement
2- Renal cell carcinoma →metastatic
3- Infectious source such as: TB, graft abscess and fungal infections.
In order to identify etiology, we need more work up such as comprehensive history and physical exam.
Lab test: CBC-diff, ESR, BUN, Cr, Ca, P, LDH, Uric acid, AST, ALT
Viral load for: CMV, EBV, HIV, HBV, HCV, HHV-8 sepsis work up for bacterial and fungal infections
Excisional biopsy of the mass and pathologic evaluation.
Imaging like chest, abdomen, pelvic, head and neck CT scan, PET scan are necessary for staging.
Q2: If PTLD diagnosis is established:
1-Reduce immunosuppression: CNIs by 50% and stop antimetabolites
2- Switching to m TOR inhibitors
3-Ritoximab and CHOP chemotherapy
4-Follow up graft function and response
5-Inresistant cases adoptive immunotherapy or radiotherapy may be considered.
Q3- IHC may be informative in biopsy specimens.
Other viral screening for HBV, HCV and CMV and tumor markers are useful, too.
References:
1.Abbas, F., Kossi, M. el, Shaheen, I. S., Sharma, A., & Halawa, A. (2020). Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches. World Journal of Transplantation, 10(2). https://doi.org/10.5500/wjt.v10.i2.29
2. Shah, N., Eyre, T. A., Tucker, D., Kassam, S., Parmar, J., Featherstone, C., Andrews, P., Asgari, E., Chaganti, S., Menne, T. F., Fox, C. P., Pettit, S., Suddle, A., & Bowles, K. M. (2021). Front-line management of post-transplantation lymphoproliferative disorder in adult solid organ recipient patients — A British Society for Haematology Guideline. In British Journal of Haematology (Vol. 193, Issue 4). https://doi.org/10.1111/bjh.17421
What is your differential diagnosis?
immunosuppressed persons after renal transplant with this CT findings may be :
-PTLD
-RCC
-TB
-Fungal infection
Please outline your management
full history
full examination
labs: CBC, CRP, ESR, RFT, LFT, virology including B,C, HIV, EBV , CMV
Radiology : MRI
biopsy
reduction in immunosuppressive medications and shift to sirolimus,
Rituximab +/- chemotherapy
· What is your differential diagnosis?
51 y old male, RTX recipient, presented with right flank pain with fever and rigors.
CT showed: mass in transplanted kidney and lesions in the liver and spleen.
DD includes:
1-malignancy of unknown primary source with metastasis.
2-PTLD.
3-Transplant graft abscess with septic emboli, this is unlikely because the patient would be severely septic.
· Please outline your management:
Management plan includes:
a- Detailed history and examination, EBV , CMV, HBV, HSV, HCV and HIV serology status of D/R.
b- Routine bloods and investigations: FBC, CRP, U&ES, pan-cultures including urine and blood culture, LFT, LDH, CXR, ECHO.
c- More imaging including CT chest, neck and spine looking for more lesions in lung, PET-CT to be considered as well.
d- Histopathological tissue diagnosis
e- If PTLD is confirmed the next management will include:
1- MDT discussion with oncologist, infectious disease, surgical team and nephrologist.
2- Reduction of immunosuppression.
3- Switch Tacrolimus to m-TOR inhibitors.
4- Rituximab alone (if CD-20 positive PTLD) or Rituximab with other chemotherapy depending on type and stage of PTLD.
5- Monitor graft function after reduction of immunosuppression.
6- Adoptive immunotherapy is under trial especially in EBV positive PTLD.
7- Graft nephrectomy might be required in resistant cases, it usually associated with poor outcome especially in presence of metastasis.
References:
1-Heil, D.S.; Luskin, M.R.; Stadtmauer, E.A.; Schuster, S.J.; Tsai, D.E.; Reshef, R. EBV-negative post-transplant lymphoproliferative disorder: Clinical characteristics, response to therapy, and survival. J. Clin. Oncol. 2013, 31, 8578.
2-Kidney transplantation Handbook.
3-Abbas F, El Kossi M, Shaheen IS, Sharma A, Halawa A. Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches. World J Transplant. 2020 Feb 28;10(2):29-46. doi: 10.5500/wjt.v10.i2.29. PMID: 32226769; PMCID: PMC7093305.
Differential diagnosis:
*CT show large heterogeneous mass involved the transplanted kidney with the history of fever and chills this may be:
*we need to do CBC,ESR,LFT,RFT,urine culture ,(CMV and EBV PCR) ,PCR for TB and ultrasound guide biopsy
*Treatment includes antibiotics covering and chemotherapy like rituxmab if it confirmed it is PTLD
What is your differential diagnosis?
This man who is post kidney transplant on immune suppressive drugs presented with this findings on CT most probably is
1.PTLD
2.renal cell carcinoma with mets to liver and spleen.(denovo or native)
3.dissaminated tuberculosis.
4.dissaminated fungal infections.
Please outline your management
Good history and examination
Consulted the haemato-oncologist.
Investigations (cbc..RFT..LFT..ESR..PCR forTB..viral screen(HBV,HCV,HIV,EB VIRUS .CMV pcr))
CT chest and abdomen.
If patient critically ill we stop all immune suppressive except steroids.
If stable decrease the dose of tacrolimus to 50% or shifted to sirolimus.
Stop anti metabolites ..
Ritoimab + or – chemotherapy.
Are any other tests required?
EBV PCR
· Complete Blood count (Anemia, thrombocytopenia, leukopenia)
· LDH, Calcium, urate levels
· Alfa Fetoprotein
· Hepatitis B and C serology and PCR
· Tissue diagnosis – Histopathology and immunophenotyping
REFERENCES:
1. Abbas F, El Kossi M, Shaheen IS, Sharma A, Halawa A. Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches. World J Transplant. 2020 Feb 28;10(2):29-46. doi: 10.5500/wjt.v10.i2.29. PMID: 32226769; PMCID: PMC7093305.
2. Samant H, Vaitla P, Kothadia JP. Post Transplant Lymphoproliferative Disorders. [Updated 2023 Feb 12]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-.
51 year male renal transplant recipient now having right flank pain, chills and fever. CT abdomen showing large exophytic renal mass as well as hepatic and splenic lesions.
What is your differential diagnosis?
1. PTLD
2. RCC with metastases
3. HCC with metastases
Please outline your management.
· Involve multidisciplinary team including oncologist, hematologist, transplant physician and radiologist.
· Reduce immunosuppression by decreasing Tac by 50% and stopping antimetabolite. This allows risk of rejection which must be closely monitored.
· Rituximab depending on histopathological class of disease.
· Chemotherapy and radiotherapy in coordination with MDT.
· Nephron sparing surgery
· Monitoring response to therapy. Disease activity, EBV viral load and renal functions.
Are any other tests required?
· EBV PCR
· Complete Blood count (Anemia, thrombocytopenia, leukopenia)
· LDH, Calcium, urate levels
· Alfa Fetoprotein
· Hepatitis B and C serology and PCR
· Tissue diagnosis – Histopathology and immunophenotyping
REFERENCES:
1. Abbas F, El Kossi M, Shaheen IS, Sharma A, Halawa A. Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches. World J Transplant. 2020 Feb 28;10(2):29-46. doi: 10.5500/wjt.v10.i2.29. PMID: 32226769; PMCID: PMC7093305.
2. Samant H, Vaitla P, Kothadia JP. Post Transplant Lymphoproliferative Disorders. [Updated 2023 Feb 12]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-.
What is your differential diagnosis?
CT Scan shows right renal mass with lesions affecting the liver and spleen. On top of my differential diagnosis is PTLD then RCC with metastasis. Other DDx will include HCC and infectious causes such as disseminated TB and fungal infections.
Please outline your management
My management will start as usual with detailed history and physical examination. We need to start with simple lab tests such as FBC, KFT, LFT, coagulation profile, LDH and alpha fetoprotein. Viral serology for CMV, EBV, HBV, HCV and HHV-8.
Tissue biopsy (Percutaneous true cut biopsy) is needed for definitive diagnosis, then management can be directed after the mentioned work-up and after discussion at MDT meeting. If malignancy diagnosed then staging CT scan / PET will be needed.
If the biopsy showed PTLD, then the management will depend on the stage and grade and involvement of other organs. Treatment starts with reduction of the immunosuppression for early lesion but keeping eyes open for graft function. We should reduce CNI, stop AZT/MMF and start Sirolimus. If failed to induce remission and in low risk patient we can consider Rituximab. Next option is to consider chemotherapy (CHOP) and last option will be graft nephrectomy. For this case scenario and due to involvement of liver and spleen, our patient will need to be managed by chemotherapy and with involvement of oncology.
DD:
-PTLD in addition to hepatic involvement
-HCC with metastasis
Management:
Lab work up:
Treatment: based on FNA result:
In case of PTLD :
This depends on tumour stage& subtype.
. Immunosuppression reduction with monitoring for graft rejection.
. Riuximab in monmorphic or polymorphic PTLD which t express CD20
. Rituximab + CHOP for localized or systemic disease with positive CD20.
.Radiotherapy for classic HL -like PTLD
.Adoptive immunotherapy in resistant cases.
Any other test:
.PET scan for detection of metastatic lesions.
Differential diagnosis :
Most likely diagnosis is graft PTLD with hepatic and splenic involvement.
Management:
Detailed history, physical examination and evaluation of performance status
There must be high index of suspicion
Tissue diagnosis (Histological confirmation, preferably excisional biopsy, peripheral node if any)
MDT meeting with haemato- oncology, pathologist, radiologist and transplant surgeons.
Reduction of immunosuppression
25%-%50 reduction of CNI and antimetabolites, maintain on steroids
Counselling patients about risk of extension of disease and rejection/ graft loss
Further treatment depends on extent of disease, type of PTLD, comorbidities and CD20 positivity.
Rituximab if CD20+ ,+/- chemotherapy (CHOP regimen)
Graft Nephrectomy might be considered given significant tumour volume
Adoptive therapy (EBV specific cytotoxic T cells) for resistant disease in EBV +ve disease disease
Fungal prophylaxis
PCP Prophylaxis
Other tests required:
We need more tests for prognostic issue
Identification of EBV DNA in tissue.
Contrast enhanced CT chest and pelvis and PET.
EBV viral load
Hepatitis B, tuberculosis (gama interferon, sputum) and fungal screen, tumor marker alfa fetoprotein, CEA
Laboratory studies: FBC, U+ES, bone profile, LFT, Albumin, LDH, uric acid, HIV and CMV
Echo if history of cardiac dysfunction/ prior to treatment with anthracycline
Reference:
Uptodate
Prof. Ahmed Halawa lecture, post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches.
This seems to be RCC, I can see intact liver son the right picture but with hypodens lesions. Hypodens lesions are also seen in spleen. I can see the atrophic kidney on lift picture . I guess I tis RCC with metastasis. differentiation is easy with evaluation of all slices of CT. Tumor markers (AFP) will be high in Liver originated HCC.
DDx includes lyphoma so LDH and beta 2 microglobulin may point to that
Management depend on the diagnosis. If it is metatsatic we may aply paliative surgery because of pain followed by chemotherapy. Consult with oncologist.
There is large heterogenous mass involving the right kidney. Also there is hypodense lesion in liver and spleen. So my diferrential diagnosis are-
a) Renal cell carcinoma with metastasis
b) PTLD
c) Lymphoma
d) Hepatocellular carcinoma with metastasis
e) Disseminated infection ( TB, fungal infection)
Detail history and physical examination to find out anorexia, weight losd, lymphadenopathy, anaemia, organomegaly, lung consolidation/ effusion, neurological features.
Investigations:
– CBC, ESR, CRP
– S.LDH, Uric acid
– Ultrasonography of whole abdomen
– CXR P/A view
– LFT, Renal function test
– EBV, CMV serology
– CT guided FNAC. of lesion
– Biopsy of lymph node
– CT abdomen, chest
– MRI of brain
– Bone marrow study
– CSF study
Treatment:
According to diagnosis, staging & other organ involvement.
For PTLD
a) Reduction of immunosuppression(RIS)
-Stop either CNI or anti metabolite and reduce the other.
– Change to sirolimus/ mTOR i
If remission watch & wait
b) If failed RIS 4 weekly 375 mg/ m2 rituximab I/V- good response for low risk patient.
c) If poor response with rituximab then chemotherapy (4 cycle CHOP)
d) If conventional trial fail adaptive immunotherapy.
e) Graft nephrectomy
e) Follow up for recurrence, graft function
Yes, mentioned above
51 year old man with history of renal transplantation presented with flank pain , chills and fever , abdominal CT showed multiple lesion in the transplanted kidney , liver and spleen so our differential diagnosis could be :
1- PTLD
2- Malignancy ( could be primary RCC or HCC with metastasis or the primary lesion could be some where other than renal or liver )
3- Infectious causes such as : disseminated tuberculosis , disseminated fungal infection
1- Detailed history : Duration of transplantation , type of induction therapy , maintenance immunosuppression, viral status of both donor and recipient ( CMV and EBV ) , history of night sweats , weight loss , similar episodes
2 – Full physical examination
3- Routine labs : CBC looking for anemia , leucopenia or thrombocytopenia
CRP : looking for infection
KFT , LFT ,
Uric acid , LDH ( PTLD )
Viral screening ( PCR for both EBV , CMV )
Blood and urine culture
Hepatitis B , C
Tumor marker ( especially alfa feto protein for HCC )
For definite diagnosis we need Biopsy for histological and staging
We should do PET scan looking for other organ or lymph node involvement
Management depend on the diagnosis
1- If infection managed with aspiration and appropriate antibiotics or anti fungal medication
2- If its malignancy , according to the type and staging of tumer , but more imrontant step is to reduce immunosupressiona and chane CNI to mTOR inhibitor
3- Mange viral infection EBV or CMV if presents
4- for PTLP is largely dependent upon the type of PTLD:
Reference :
1) up to date
2) Prof. Ahmed Halawa lecture, post-transplantation lymphoproliferative disorders
CT showing homogeneous Mass in the renal graft with lesions in the liver and spleen.
D/D:
1. PTLD of Renal Allograft with multisystem involvement –
Febrile illness, large mass in graft kidney, small lesions in liver and spleen – PLTD is more likely, as it is the second common malignancy in recipients after solid organ transplant, especially after intense immunosuppression, ATG induction. PTLD in renal transplant recipients were much more likely to have renal lymphoma (14.2%); 20-25% have infiltrative lesions in the allograft, leading to graft dysfunction; more than half of PTLD presents with extra-nodal masses.
2. De Novo RCC of Allograft kidney with Liver & splenic Mets – many RCC in earlier time (before routine USG screening) used to be diagnosed while work up for febrile illness.
3. Native Kidney RCC with Mets in Liver, spleen, Allograft kidney – Rt Flank pain, fever, chill
4. Disseminated tuberculosis
5. Disseminated fungal infection
6. Secondary deposits from Unknown primary
7. Metastatic HCC
Management:
Detail history – Duration of transplant, immunosuppression regimen and dose, Induction drug
Complete Blood count, ESR, PBF, RFT, LFT, RBS, Uric acid, LDH, Cal
Viral assays: EBV & CMV DNA PCR – viral load; HIV, HCV, HBV serology
Tac & MMF trough level
Review detail report and films of the CT scan – get whole body PET-CT or CT Brain (CNS involvement 30%), CT Neck to Pelvis — staging, baseline lesions for response monitoring.
USG / CT guided needle biopsy from graft kidney lesion – histopathology diagnosis; subtype (polymorphic / monomorphic), complete IHC tumour panel including CD20, CD52
Treatment
Tumour Board meeting (transplant team, haemato-oncology team, psychiatry) – discuss treatment plan, pros and cons with patient party
severe form of PTLD with multiorgan / systemic involvement shall require aggressive treatment with Rituximab + sequential chemotherapy.
1. Reduction of immunosuppression:
stopping AZT/MMF;
Reduce CNI to minimum dose (minimum acceptable C0 level).
Change CNI to Sirolimus
2. Sequential Rituximab + CHOP-21 regimen chemotherapy to be started immediately
· 4 cycles of R-CHOP-21 immuno-chemotherapy are recommended in patients who fail to obtain CR or CMR (with Deauville ≤ 3) after four cycles of weekly standard-dose rituximab or who clinically progress during these four cycles
· Rituximab plus anthracycline-based therapy (typically R-CHOP-21) is recommended with RIS for patients at any time following diagnosis with clinically aggressive lymphoma with critical organ compromise
PET-CT should be considered for interim and end-of-treatment response assessment where available
· Supportive treatment with GCSF, multivitamin, PJP prophylaxis with Cotrimoxazole, antifungal prophylaxis
Over all response rate – 70-88%
3. Radiotherapy to kidney tumour
Involved-field radiotherapy may be offered for selected patients with PTLD in line with standard protocols for specific histological subtypes (2C).
In localised disease, radiotherapy may be offered concurrently with RIS
4.Graft Nephrectomy – for residual tumour or non-responders
5. Novel therapeutic approach – Adoptive immunotherapy with EBV-specific cytotoxic T-lymphocyte (CTL) is another potential option, in EBV-positive PTLD whilst avoiding the risk of graft rejection.
The above given scenario is a post transplant patient with 51 years old who presented with right sided flank pain and chills with fever…..Imaging CT scan of the abdomen shows renal mass like lesion near the transplant kidney, splenic and liver lesions…
In the background of renal transplant and the immunosuppressed state of the patient I would think of PTLD, Renal carcinoma, Hepatoma with metastasis…Acute pyelonephritis of the transplant kidney with metastatic abscess, rarely infective endocarditis with systemic embolization can present with multifocal lesions in the abdominal organs due to septic emboli… Mycotic aneurysm of the transplant kidney artery with disseminated fungal sepsis and septic vasculitis picture can present like this…Disseminated TB also present like this
there is a mass like lesion in the renal allograft area with small lesions elsewhere and this means it could be PTLD…PTLD is the second most common malignancy in recipients after solid organ transplants especially after intense immunosuppression…PTLD of the renal allograft are more common than other sites… 20% have infiltrative lesions in the renal allograft….lymphadenopathy is rare in PTLD
Management:
I would need a detailed history on the duration of the post transplant period… I would need the history of donor, induction agent used, history of any rejections if any, dose of immunosuppressive used, history of EBV status of donor and recipient pre transplant
I would get a basic workup done including CBC, Blood culture, Urine culture, procalcitonin, Liver function test, alpha fetoprotein, PET CT scan, EBV serology
PET CT scan will give better tissue evidence of spread of disease, primary HCC if any, Lymphadenopathy to rule out tuberculosis, miliary TB if any….PET scan may not pick up infective endocarditis…..
Patient needs an FNAC/Needle biopsy of the graft lesion for diagnosis to be established….Immunohistochemistry panel in the biopsy lesion is needed for complete diagnosis and prognosis…
I would keep the patient on broad spectrum antibiotics till the arrival of the diagnosis
The key line of management after treatment diagnosis of PTLD is reduction in the immunosuppression…MMF/AZA should be stopped. .CNI should be reduced to 50% with a possible addition of sirolimus. .Low dose steroids should be continued…
Treatment: I would prefer Rituximab + CHOP 21 regimen along with reduction of immunosuppression for the PTLD as this clinically seems aggressive form of PTLD …guidelines recommend adding rituximab at any stage depending on the severity of the PTLD…Supportive treatment include GMCSF, PCP prophylaxsis with cotrimoxazole..Overall response rate is 75% with mean survival rate of 42 months…
Radiotherapy of the involved tumour region maybe applied…
Adoptive immunotherapy with EBV specific cytotoxic lymphocytes is an other potential option in EBV positive PTLD
What is your differential diagnosis?
Outline of management:
Investigation(s):
Treatment:Depend on FNAC report.
If PTLD then :
Treatment of PTLD- This is determined by tumour stage, tumour subtype and associated toxicity
Any other test:
1. PTLD of Renal Allograft with multisystem involvement –
Febrile illness, large mass in graft kidney, small lesions in liver and spleen – PLTD is more likely, as it is the second common malignancy in recipients after solid organ transplant, especially after intense immunosuppression, ATG induction. PTLD in renal transplant recipients were much more likely to have renal lymphoma (14.2%); 20-25% have infiltrative lesions in the allograft, leading to graft dysfunction; more than half of PTLD presents with extra-nodal masses.
2. De Novo RCC of Allograft kidney with Liver & splenic Mets – many RCC in earlier time (before routine USG screening) used to be diagnosed while work up for febrile illness.
3. Native Kidney RCC with Mets in Liver, spleen, Allograft kidney – Rt Flank pain, fever, chill
4. Disseminated tuberculosis
5. Disseminated fungal infection
6. Secondary deposits from Unknown primary
7. Metastatic HCC
Please outline your management
Management:
Detail history – Duration of transplant, immunosuppression regimen and dose, Induction drug
Complete Blood count, ESR, PBF, RFT, LFT, RBS, Uric acid, LDH, Cal
Viral assays: EBV & CMV DNA PCR – viral load; HIV, HCV, HBV serology
Tac & MMF trough level
Review detail report and films of the CT scan – get whole body PET-CT or CT Brain (CNS involvement 30%), CT Neck to Pelvis — staging, baseline lesions for response monitoring.
USG / CT guided needle biopsy from graft kidney lesion – histopathology diagnosis; subtype (polymorphic / monomorphic), complete IHC tumour panel including CD20, CD52
Treatment
Tumour Board meeting (transplant team, haemato-oncology team, psychiatry) – discuss treatment plan, pros and cons with patient party
severe form of PTLD with multiorgan / systemic involvement shall require aggressive treatment with Rituximab + sequential chemotherapy.
1. Reduction of immunosuppression:
stopping AZT/MMF;
Reduce CNI to minimum dose (minimum acceptable C0 level).
Change CNI to Sirolimus
2. Sequential Rituximab + CHOP-21 regimen chemotherapy to be started immediately
· Rituximab plus anthracycline-based therapy (typically R-CHOP-21) is recommended with RIS for patients at any time following diagnosis with clinically aggressive lymphoma with critical organ compromise
PET-CT should be considered for interim and end-of-treatment response assessment where available
· Supportive treatment with GCSF, multivitamin, PJP prophylaxis with Cotrimoxazole, antifungal prophylaxis
Over all response rate – 74% with median survival 42months
3. Radiotherapy to kidney tumour
Involved-field radiotherapy may be offered for selected patients with PTLD in line with standard protocols for specific histological subtypes (2C).
In localised disease, radiotherapy may be offered concurrently with RIS
4.Graft Nephrectomy – for residual tumour or non-responders
5. Novel therapeutic approach – Adoptive immunotherapy with EBV-specific cytotoxic T-lymphocyte (CTL) is another potential option, in EBV-positive PTLD whilst avoiding the risk of graft rejection.
Any Other tests required :
al ready outlined
EBV DNA in tissue
PET CT or Brain + neck to pelvis CT
CMV, HCV
2D Echo in patients with prior Anthracyclin chemotherapy
FINDINGS -CT SCAN SHOWS SOLID LESION IN GRAFT , LIVER AND SPLEEN
DIFF. DIAGNOSIS
PTLD- POOR PROGNOSTIC VARIETY DUE TO MULTI ORGAN LESION
RENAL TUMOR WITH METASTASIS
INFECTIVE LESION LIKE ABSCESS
SECONDARIES WITH UNKNOWN PRIMARY
BIOPSY WILL SHOW IF IT IS PTLD WHICH IS MORE LIKELY OR OTHERWISE
B CELL LYMPHOBLASTIC LESION IS SEEN
LABS-
APART FORM CBC , CREATININE , LDH , EBV VIRAL LOAD AND IMAGING AS PER ORGAN INVOLVEMENT
STRATEGY
REDUCTION OF IS, WHICH IS NOT MENTIONED IN THIS CASE
AVOID CNI
RETUXIMAB 4 WEEKS
SEQUENTIAL CHOP AS CHEMOTHERAPY IS ADVISABLE IN HIGH RISK CASE LIKE THIS
ADAPTIVE IMMUNOTHERAPY LIKE EBV-CTL CAN BE CONSIDERED
What is your differential diagnosis
PTLD
Metastatic RCC
Metastatic HCC
Disseminated tuberculosis
Disseminated fungal infection
Most likely is graft PTLD with hepatic and splenic involvement
Please outline your management
High index of suspicion
History, physical examination and evaluation of performance status
Tissue diagnosis (Histological confirmation, preferably excisional biopsy, peripheral node if any)
Multidisciplinary team meeting with haemato- oncology, pathologist, radiologist and transplant surgeons.
Reduction of immunosuppression
25%-%50 reduction of CNI and antimetabolites, maintain on steroid.
Counselling patients about risk of extension of disease and rejection/ graft loss
Further treatment depends on extent of disease, type of PTLD, comorbidities and CD20 positivity.
Rituximab if CD20+ ,+/- chemotherapy (CHOP)
Nephrectomy might be considered given significant tumour volume
Adoptive therapy (EBV specific cytotoxic T cells) for resistant disease in EBV +ve disease disease.
PCP prophylaxis
Fungal prophylaxis
Are any other tests required?
Yes,
Identification of EBV DNA in tissue.
Contrast enhanced CT chest and pelvis and PET.
EBV viral load
Hepatitis B, tuberculosis (gama interferon, sputum) and fungal screen, tumor marker alfa fetoprotein, CEA
Laboratory studies; FBC, U+ES, bone profile, LFT, Albumin, LDH, uric acid, HIV and CMV
Echo if history of cardiac dysfunction/ prior to treatment with anthracycline
Reference
Prof. Ahmed Halawa lecture, post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches.
Uptodate
PTLD, abscess, renal cell carcinoma, metastatic, hematoma.
good history, physical examination, investigation (RFT, LFT, CBC,Electrolytes,Virology, EBV PCR, CMV PCR, CT- scan of neck, chest and abdomen.
Reduction of immune suppression, stop MMF and AZA, reduction of CNI up to 55% increase steroid.
· Good hydration.
· Broad spectrum antibiotics.
. Anti pyretic.
in the EBV negative cases poor prognosis.
– In critically ill cases should consider withdrawal of all IS medications except
Steroids.
– Switch to mTORi(Sirolimus).
– Monitoring allograft function for rejection.
– Rituximab +/- chemotherapy RCHOP.
Rituximab therapy:
– CD20 +ve B-cell PTLD approache 75% response.
PET scan, CT abdomen, chest and pelvic,EBV PCR.
Reference:
Prof. Ahmed Halawa lecture, post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches.
https://www.uptodate.com/contents/epidemiology-clinical-manifestations-and-diagnosis-of-post-transplant-lymphoproliferative-disorders?
CT showed a mass in the renal graft with small lesions in the liver and spleen.
PLTD is highly suspected as it is the second cause of malignancy in recipients after solid organ transplant
Risk factors for PLTD EBV-negative cases, high intensity of immunosuppressive drugs, ATG as induction therapy
Among patients who developed PTLD, renal transplant recipients were much more likely to have renal lymphoma (14.2 versus 0.7 percent in heart transplant recipients)
More than half of PTLD presents with extra-nodal masses and 20 to 25 percent may have infiltrative lesions in the allograft, and Involvement of the allograft can lead to allograft dysfunction (renal failure)
Baseline investigations
· Full blood count, Electrolytes, Renal function, Glucose, Liver enzymes, Urate, LDH
· Virology: HIV type 1 & 2, Hepatitis B and C and EBV serology, CMV/EBV DNA titres
· Fertility-preserving treatments, such as sperm cryopreservation for male
· Details about date of transplant, organ type and immunosuppresion regimen
· a staging CT- scan of neck, chest, abdomen and pelvis at diagnosis to inform the treatment decisions and to act as a baseline for the assessment of response
· a core needle biopsy for histopathology subtypes and staging.
Management
· After histology result the case should be discussed at a haemato-oncology MDT meeting with experience in PTLD management, with input from the organ transplant physicians
· Reduction of immunosuppression:
1- by stopping azathioprine and MMF and reduction of CNIs by 30–50% whilst maintaining or reducing corticosteroids, is recommended in all patients whenever possible, under the guidance of the transplant physician with surveillance of graft function
2- Early disease response assessment (at 2–4 weeks) is recommended in those patients following RIS alone so that further treatment can be initiated in those that fail to respond
· Rituximab +/− chemotherapy
1- Rituximab monotherapy is recommended for patients with CD20-positive PTLD who fail to respond adequately to RIS as initial therapy
2- Four further three-weekly cycles of rituximab are recommended in patients who obtain CR or complete metabolic remission (CMR) (with Deauville ≤ 3) after four cycles of weekly standard-dose rituximab
3- Four cycles of R-CHOP-21 immunochemotherapy are recommended in patients who fail to obtain CR or CMR (with Deauville ≤ 3) after four cycles of weekly standard-dose rituximab or who clinically progress during these four cycles
4- Rituximab plus anthracycline-based therapy (typically R-CHOP-21) is recommended with RIS for patients at any time following diagnosis with clinically aggressive lymphoma with critical organ compromise
5- Formal assessment of cardiac and renal function should be undertaken in all patients with SOT or in patients where renal or cardiac impairment is suspected.
6- PET-CT should be considered for interim and end-of-treatment response assessment where available
· Radiotherapy
– Involved-field radiotherapy may be offered for selected patients with PTLD in line with standard protocols for specific histological subtypes (2C).
– In localised disease, radiotherapy may be offered concurrently with RIS
Adoptive immunotherapy
· EBV-specific cytotoxic T-lymphocyte (CTL) immunotherapy potentially offers another approach in the treatment of EBV-positive PTLD whilst avoiding the risk of graft rejection.
· Treatment of PTLD with EBV-specific CTLs should be considered where available with R/R EBV-positive PTLD
1) https://onlinelibrary.wiley.com/doi/full/10.1111/bjh.17421#:~:text=Front%2Dline%20management%20of%20post%2Dtransplantation%20lymphoproliferative%20disorder%20in%20adult%20solid%20organ%20recipient%20patients%20%E2%80%94%20A%20British%20Society%20for%20Haematology%20Guideline
2) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9740763/#:~:text=Recent%20Advances%20in%20Adult%20Post%2DTransplant%20Lymphoproliferative%20Disorder
3) https://www.uptodate.com/contents/epidemiology-clinical-manifestations-and-diagnosis-of-post-transplant-lymphoproliferative-disorders?search=PLTD%20of%20the%20graft&source=search_result&selectedTitle=3~150&usage_type=default&display_rank=3#:~:text=Epidemiology%2C%20clinical%20manifestations%2C%20and%20diagnosis%20of%20post%2Dtransplant%20lymphoproliferative
4) https://www.ncbi.nlm.nih.gov/books/NBK513249/#article-27564.s7:~:text=Search%20this%20book-,Post%20Transplant%20Lymphoproliferative%20Disorders,-Hrishikesh%20Samant%3B
DDX,:
Management:
-basic investigations
basic imaging
the treatment depending on the cause/dignosis
any other test?
Differential diagnosis
History – Onset of symptoms, flank swelling, hematuria, weight loss, night sweats, immunosuppressive medications/duration, treatment of rejection etc.
Examination – Palor, cachexia, flank mass, temperature, lymph nodes, organomegaly
Investigations
Diagnosis – Presence of lymphoid infiltration and distortion of tissue architecture, presence of EBV infection and, presence of oligoclonal or polyclonal lymphoid cell population as evidence by light chain expression is diagnostic of EBV positive PTLD.
Treatment of PTLD- This is determined by tumour stage, tumour subtype and associated toxicity
Reference
Robert SN et al. Treatment and prevention of post-transplant lymphoproliferative disease. In: Nelson JC, Arnold SF, ed. Up-to-Date [database on the internet] Waltham(MA): UptoDate; 2022[cited 7 February 2023]. Available from; http;//www.uptodate.com
Differential diagnosis
1. Infectious – Tuberculosis, liver abscess, invasive fungal infection, bacillary angiomatosis, kidney abscess
2. Neoplastic – hepatocellular carcinoma, PTLD, lymphoma, renal cell carcinoma
Investigation
1. Serologies and screening for infectious diseases (HIV, HTLV, viral hepatitis, HHV 5, 6 8, CMV, EBV, IGRA TB)
2. General exams
3. Tomography-guided biopsy for cultures and immunohistochemistry
Treatment
Depending on the findings of the investigation tests. As there is a clinical picture of an infectious condition (chills, high fever, and image compatible with an abscess), the initiation of antimicrobials with the need for coverage for MRSA would be imperative. The combination of Tazocin with Linezolid or the use of Ceftaroline (fifth-generation cephalosporin with coverage for MRSA) can be used depending on the local microbiological profile. If there is AFB or Ziehl Neelsen culture positivity, the RHZE regimen should be started.
Galactomannan, urinary antigen, or culture showing spores or hyphae would proceed with antifungal therapy (depending on the type of structure exposed on the slide). Aspergillosis and Mucormycosis with good response to Isavuconazole, endemic fungi generally respond well to Itraconazole or Amphotericin B lipid formulations.
Lymphomas tend to respond with R CHOP regimen or alternatives depending on immunohistochemistry,
PTLD can be treated with rituximab combined or not with COP.
My differential for the patient will be:
Investigation(s):
Management should be according to the diagnosis:
If PTLD:
Reduction of Immunosuppression:
Rituximab therapy:
Adoptive immunotherapy
Radiotherapy:
Other diagnoses will be discussed with relevant discipline regarding further management in MDT.
References:
Post Transplant with right-sided flank pain, chills, and fever, with CT Abd. shows lesions in the liver, spleen, kidney => So My DD:
1- PTLD with widespread organ affection
2- HCC with metastasis
3- RCC with metastasis(exophytic )
4- Infections: TB, fungal infection ,renal abscess
Workups:
1- In General, A diagnosis Of PTLD Requires A High Index Of Suspicion.
2- Details History And Physical Exam.
3- Investigations: CBC (cytopenia), Sr. Uric Acid Levels, Serum Calcium Levels, LDH Levels, LFT, TB, Brucellosis Screening, B HCG
(Unexplained hematologic or biochemical abnormalities(increase LDH levels)
4- Viral Screening- HIV,CMV,EBV,HBV,HCV, HHV-8 (High EBV viral load also supports
the diagnosis), Fungal culture, cryptococcal antigen, Septic Screen.
5- For accurate Diagnosis and classification require an excision tissue
biopsy(tissue size adequacy ), CT guided biopsy of kidney or liver mass
Management:
If PTLD Biopsy Proven=> MDT (Transplant + Haemato-Oncologists + surgical opinion for management ?
1- Reduction of Immunosuppression:
– It is the mainstay of therapy
– the EBV negative cases are less responsive.
– RI can reverse 20% – 80% of patients with PTLD.
– RI includes: CNI reduction by 50% , along with withdrawal of the
antimetabolites and maintain Steroids.
– In critically ill cases should consider withdrawal of all IS medications except
Steroids.
– Switch to mTORi ( conflicting data)
– Monitoring allograft function for rejection.
– Assess disease response assessment early (at 2–4 weeks) by CT.
– If PR achieved or in those that fail to respond; can consider sequential therapy Rituximab +/- chemotherapy RCHOP- 21 used in addition to RI.
Rituximab therapy:
– CD20 +ve B-cell PTLD approached 75% of TR.
– The overall response to RTx monotherapy approached 44%-79%.
Chemotherapy R-CHOP- 21
– Indications include: Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma and other uncommon lymphomas, and B-cell PTLD unresponsive to Rtx and RI.
– RTx should be included in all CD-20 +ve cells.
Supportive care:
– G-CSF and PJP prophylactic
Adoptive immunotherapy
– Infusion of donor lymphocytes, to achieve adoptive immunotherapy, has been shown to manage PTLD in HSCT patients that is primarily
originating from donor cells.
– Robust EBV-specific immune response is induced by EBV-specific cytotoxic lymphocytes(CTLs)
– The major risk is GVHD development.
– Should be considered in patients with refractory/ relapsed EBV-positive PTLD
Radiotherapy:
– may be considered for localized disease, some extra-nodal sites, such as the orbit, isolated CNS relapse and MALT.
Antivirals, IVIG and interferon-alpha treatment:
Data are limited and is not recommended outside clinical trials.
Summary:
Early lesions: => Recommend RI.
Polymorphic PTLD :
If patients expresses CD20 (CD20+ PTLD),suggested use of rituximab in
addition to reduction of immunosuppression, as tolerated.
Monomorphic PTLD :
If patients with monomorphic CD20+ PTLD, suggested use of rituximab either alone or in
combination with chemotherapy in addition to reduction of immunosuppression.
Classic Hodgkin lymphoma-like PTLD:
Management with chemotherapy RCHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) with or without radiation therapy according to protocols used for classic Hodgkin lymphoma.
Management of RCC
Treatment is the same as in non-transplant patients and includes partial nephrectomy, radical nephrectomy with subsequent initiation of RRT and withdrawal of immunosuppression with comparable outcome ( in patients undergoing radical nephrectomy)
Are any other tests required?
•After the Definitive Diagnosis is by Tissue biopsy which require Excision or needle biopsy, if feasible to confirm diagnosis.( CT guided biopsy from kidney mass or Liver )=> for definitive diagnosis, Histopathology .
•Tumor marker to help DD=> Serum alpha fetoprotein (AFP) , CEA,CA19-9
•Viral Screen: HHV-8, hepatitis C and CMV.
•PET-CT of neck, chest, abdomen and pelvis=> strongly sensitive for diagnosis and staging.
References:
Abbas F, El Kossi M, Shaheen IS, Sharma A, Halawa A. Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches. World J Transplant. 2020 Feb 28;10(2):29-46.
Shah N, Eyre TA, Tucker D, Kassam S, Parmar J, Featherstone C, Andrews P, Asgari E, Chaganti S, Menne TF, Fox CP, Pettit S, Suddle A, Bowles KM; Haemato-Oncology Task Force of the British Society for Haematology and the British Transplantation Society. Front-line management of post-transplantation lymphoproliferative disorder in adult solid organ recipient patients – A British Society for Haematology Guideline. Br J Haematol. 2021 May;193(4):727-740. doi: 10.1111/bjh.17421. Epub 2021 Apr 20. PMID: 33877688.
Gunawansa N, Rathore R, Sharma A & Halawa A. (2019) PostTransplant Lymphoproliferative Disorder: A Clinical Perspective. J Renal Transplant Sci, 2(2): 109-117
Prof. Ahmed Halawa lecture, Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches
Sprangers B, Riella LV, Dierickx D. Posttransplant Lymphoproliferative Disorder Following Kidney Transplantation: A Review. Am J Kidney Dis. 2021 Aug;78(2):272-281. doi: 10.1053/j.ajkd.2021.01.015. Epub 2021 Mar 25. PMID: 33774079.
Nimish Shah,Toby A. Eyre et al. Front-line management of post-transplantation
lymphoproliferative disorder in adult solid organ recipient patients — A British Society for Haematology Guideline. 13652141, 2021, 4
Caillard S, Dharnidharka V, Agodoa L, Bohen E, Abbott K. Posttransplant lymphoproliferative disorders after renal transplantation in the United States in era of modern immunosuppression. Transplantation. 2005 Nov 15;80(9):1233-43. PubMed PMID: 16314791. Epub 2005/11/30. eng.
Sprangers B, Riella LV, Dierickx D. Posttransplant Lymphoproliferative Disorder Following Kidney Transplantation: A Review. American journal of kidney diseases : the official journal of the National Kidney Foundation. 2021 Aug;78(2):272-81. PubMed PMID: 33774079. Epub 2021/03/29. eng.
UpToDate
I like your superbly structured analysis and approach as you have used headings and sub-headings to make it easy to read. I appreciate the evidence to support your arguments.
what is your D/D?
it could be hepatocellular malignancy
PTLD
native kidney malignancy with mets to the liver
outline your management plan:
after full physical examination looking for other findings such as lymph nodes or sother signs of liver diseases such as ascites
further investigations required to confirm the diagnosis.
basic tests such as
CBC
uric acid
LDH
liver function test
EBV
alpha-fetoprotein
PET scan
either excision biopsy if possible of needle biopsy of the liver.
management plan will be according to the exact diagnosis , if PTLD then it will be staged and treatment will start by reduction of IM, by reducing CNI by 50%, stopping antimetabolites, wait 2-4 wks to monitor response, if not better then either rituximab or rituximab -CHOP will be recommended.
other tests required.
biopsy and CT-PET for staging
I like your analysis and approach. Please use headings and sub-headings to make it easy to read. Can you upload some evidence please.
. Differentials are;
Renal cell carcinoma,
PTLD,
Renal abscess,
Other infections, like tuberculosis, pyelonephritis, xanthogranulomatous pyelonephritis
Metastatic carcinoma,
Lymphoma,
Management ;
. This need multidisciplinary approach and opinion which would include transplant physician, surgeon, infectious disease specialist, oncologist, and hematologist.
. Baseline investigation,
. Procalcitonin, CRP, D DIMERs.
. Imaging like CXR, Ultrasound abdomen and pelvis, CT chest, abdomen and pelvis,
. Viral serology and antibodies for EBV, HIV, HPV, HCV, HBV.
. Tumor markers for HCC, CEA, PSA, AFP.
. Genexpert, blood and urine culture,
. PET scan. That is not available in every center.
. CT guided excision biopsy therapeutic and diagnostic confirmation, if the whole team agrees for any primary tumor.
. The treatment depends on diagnosis at all,
. If PTLD treatment will depends on morphological diagnosis, stage, EBV associated not associated.
. Immunosuppression modification.
. Immunomodilator ,
. Small molecule targeting B-cell receptors,
. EBV specific cytotoxic T-cell,
. Antibiotic according to ID specialist,
Surgical removal and staging.
Reffrences:
1.https://www.researchgate.net/publication/350394547_Posttransplant_Lymphoproliferative_Disorder_Following_Kidney_Transplantation_A_Review
2.https://leoriella.com/posttransplant-lymphoproliferative-disorder-following-kidney-transplantation-a-review.
3.https://www.uptodate.com/contents/clinical-manifestations-and-treatment-of-epstein-barr-virus-infection?search=lymphoproliferative%20disorder%20adult&source=search_result&selectedTitle=6~150&usage_type=default&display_rank=6.
What is your differential diagnosis?
This image shows lesion in liver. With the background of kidney transplantation and history, the most probable diagnosis is
Please outline your management
Are any other tests required?
I note that. Can you upload some evidence please.
DD:
1- PTLD with metastasis
2- HCC with metastasis
3-T. B & disseminated infection with abscess formation
management:
I note that. Can you upload some evidence please.
PTLD
HCC
Infection ( liver abscess )
History and examination
lab evaluation CBC, ESR, LFT, RFT, Calcium and uric acid level, serology of HIV, HCV, HbsAg, CMV, EBV TB,
CT abdomen and pelvis
PET scan for staging
Reduction of immunosuppressive therapy to half and consider chemotherapy and radiotherapy after discussion with haematologist and oncologist and transplant physician
tumour markers like alpha fetoprotein
I note that. Can you upload some evidence please.
What is your differential diagnosis?
Graft mass with deposits in the liver and spleen for DD
Are any other tests required?
Please outline your management
1- RI
2- Check response in 2-4 weeks
a) if remission achieved, W&W
b) if not achieved then start Rituximab and monitor
c) if getting worse or no improvement then CHOP-21
I note that. Can you upload some evidence please.
What is your differential diagnosis?
-PTLD
-Hepatocellular carcinoma with metastasis.
Are any other tests required?
-alpha fetoprotein will be high in HCC.
-Liver biopsy.
-Full blood count,RFT and Electrolytes, Glucose, Liver enzymes, Urate, LDH.
-Virology: HIV type 1 & 2, Hepatitis B and C and EBV serology, CMV/EBV DNA titres.
-Bone marrow biopsy .
-A staging CT- scan of neck, chest, abdomen and pelvis at diagnosis to inform the treatment decisions and to act as a baseline for the assessment of response
Where available, PET-CT scan should be utilised for staging over CT scan.
Please outline your management
– If he PTLD :He should be discussed at a haemato-oncology MDT meeting with experience in PTLD management, with input from the organ transplant physicians .
– All diagnostic material should be reviewed by a haematopathologist
-Reduction in immunosuppression by stopping azathioprine and MMF and reduction of CNIs by 30–50% whilst maintaining or reducing corticosteroids, and monitor graft function.
– Early disease response assessment (at 2–4 weeks) is recommended so
that further treatment can be initiated if fail to respond (Rituximab +/_chemotherapy).
-If the diagnosis HCC , GIT must be involved in MDT.
Reference:
Nimish Shah,Toby A. Eyre et al. Front-line management of post-transplantation
lymphoproliferative disorder in adult solid organ recipient patients — A British Society for Haematology Guideline. 13652141, 2021, 4.
That is a good summary and an interesting analysis. Ajay
What is your differential diagnosis?
Most probably malignancy
chronic infection
Abscess
Please outline your management
A management plan should be agreed by a core multidisciplinary team (MDT) which should include transplant physicians, haemato-oncologists, haematopathologists, radiation-oncologists and radiologists.
All cases should be discussed at a haemato-oncology MDT meeting with experience in PTLD management, with input from the organ transplant physicians.
Diagnosis by history and physical examination first hx of date of transplant, immune suppression regimen and organ type.
Treatment
Are any other tests required?
Tumor markers such as AFP ,CEA,CA19-9
reference
Front-line management of post-transplantation lymphoproliferative disorder in adult solid organ recipient patients — A British Society for Haematology Guideline
Prof Ahmed Halawa lecture PTLD
I like your analysis and approach. Please type headings and sub-headings in bold or in underline. As much I love Prof Halawa, my academic brother, a mention of his lecture is not good enough as a reference in a scientific writing.
Ajay
Differential diagnosis:
Outline management:
Another test:
References:
Hanto DW, Frizzera G, Gajl-Peczalska KJ, Simmons RL. Epstein-Barr virus, immunodeficiency, and B-cell proliferation, Transplantation, 1985, vol. 39 (pg. 461-72)
2Nalesnik MA, Jaffe R, Starzl TE, et al. The pathology of posttransplant lymphoproliferative disorders occurring in the setting of cyclosporine A-prednisone immunosuppression, Am J Pathol, 1988, vol. 133 (pg. 173-92)
Mizuno S, Hayasaki A, Ito T, Fujii T, Iizawa Y, Kato H, Murata Y, Tanemura A, Kuriyama N, Azumi Y, Kishiwada M, Usui M, Sakurai H, Isaji S. De Novo Malignancy Following Adult-to-Adult Living Donor Liver Transplantation Focusing on Posttransplantation Lymphoproliferative Disorder. Transplant Proc. 2018 Nov;50(9):2699-2704. [PubMed]
2.
Dharnidharka VR. Comprehensive review of post-organ transplant hematologic cancers. Am J Transplant. 2018 Mar;18(3):537-549. [PubMed]
3.
Elserwy NA, Lotfy EE, Fouda MA, Mahmoud MI, Donia AF, Mashaly ME, Abbas MH, Abuelmagd MM, Abouelenein RK, Ismail MI, Bakr MA. Postrenal transplant malignancy: Incidence, risk factors, and prognosis. Saudi J Kidney Dis Transpl. 2017 May-Jun;28(3):579-588. [PubMed]
I like your analysis and approach.
Ajay
Differential diagnosis:
Outline management:
Another test:
References:
Hanto DW, Frizzera G, Gajl-Peczalska KJ, Simmons RL. Epstein-Barr virus, immunodeficiency, and B-cell proliferation, Transplantation, 1985, vol. 39 (pg. 461-72)
2Nalesnik MA, Jaffe R, Starzl TE, et al. The pathology of posttransplant lymphoproliferative disorders occurring in the setting of cyclosporine A-prednisone immunosuppression, Am J Pathol, 1988, vol. 133 (pg. 173-92)
Mizuno S, Hayasaki A, Ito T, Fujii T, Iizawa Y, Kato H, Murata Y, Tanemura A, Kuriyama N, Azumi Y, Kishiwada M, Usui M, Sakurai H, Isaji S. De Novo Malignancy Following Adult-to-Adult Living Donor Liver Transplantation Focusing on Posttransplantation Lymphoproliferative Disorder. Transplant Proc. 2018 Nov;50(9):2699-2704. [PubMed]
2.
Dharnidharka VR. Comprehensive review of post-organ transplant hematologic cancers. Am J Transplant. 2018 Mar;18(3):537-549. [PubMed]
3.
Elserwy NA, Lotfy EE, Fouda MA, Mahmoud MI, Donia AF, Mashaly ME, Abbas MH, Abuelmagd MM, Abouelenein RK, Ismail MI, Bakr MA. Postrenal transplant malignancy: Incidence, risk factors, and prognosis. Saudi J Kidney Dis Transpl. 2017 May-Jun;28(3):579-588. [PubMed]
Dear All
Any place for tumour markers to differentiate between HCC from PTLD?
Thanks alot for you Prof.Halawa
Zhou L, Liu J, Luo F. Serum tumor markers for detection of hepatocellular carcinoma. World J Gastroenterol. 2006;12(8):1175-1181. doi:10.3748/wjg.v12.i8.1175
Tumor markers for HCC -AFP,Glypican 3,GGT 2,alpha 1 fucosidase,TGF beta 1
Presence of the above point more toward HCC than PTLD.
REF;
Zhou et al – Serum tumor markers for detection of HCC
-Markers for HCC are : AFP, Glypican 3,GGT 2,alpha 1 fucosidase, TGF- beta 1
serum alpha fetoprotein AFP
Any place for tumor markers to differentiate between HCC from PTLD? (1)
– The most widely used tumor marker for diagnosis of HCC is serum AFP. Normal range is 10-20 ng/mL, a level greater than 400 is regarded as diagnostic.
– AFP-L3 and DCP are superior to AFP in differentiating HCC from nonmalignant hepatopathy and detecting small HCC.
– Other tumor markers have also been found to be more accurate than AFP i.e., human cervical cancer oncogene and human telomerase reverse transcriptase mRNA.
– AFP mRNA correlates with metastases and recurrence of HCC. It also acts as a prognostic marker.
– Tumor markers that are supplementary to AFP include TGF-beta 1, GGT II, glypican-3, alpha-1-fucosidase, tumor-specific growth factor.
References
1. Zhou L, Liu J, Luo F. Serum tumor markers for detection of hepatocellular carcinoma. World journal of gastroenterology. 2006 Feb 28;12(8):1175-81. PubMed PMID: 16534867. Pubmed Central PMCID: PMC4124425. Epub 2006/03/15. eng.
What is your differential diagnosis?
1-The history of fever , chills and flank pain raises the possibility of infection ;Pyelonephritis or abscess
2-The provided Ct scan showed renal graft with an exophytic mass ,liver and splenic lesion .This radiological finding raised the possibility of either infection with septic embolization or malignancy (PTLD ,RCC .KS or other metastatic diseases ) .
Please outline your management;
———————————————————–
1- Multidisciplinary approach to care;
This case should evaluated and treated at MDT ( Transplant Physician and haemato-oncolgist ).
2-Diagnosis ;
1-Basic blood test ;
Full blood count, Septic screening , Electrolytes, Renal function, Glucose, Liver enzymes, Urate, Lactate dehydrogenase (LDH) .
.
2-If infectious cause are excluded ,then workup for malignancy should be performed as;
1-Obtain tissue biopsy.
2-CT scan and PET if its available .
3-The treatment ;
1-Reduction of immunosuppression ;
Generally reduction of immunosuppression should be consider in either infection or malignancy ;
a-50% reduction of calcineurin inhibitors .
b- Withdrawal of the antimetabolites such as azathioprine or mycophenolate mofetil (MMF) .
c-With the exception of glucocorticoids, withdrawal of all immunosuppressive medications in critically ill cases should be considered.
2-Anti microbial therapy should be started as soon as possible in the setting of infection .
3-In the case o PTLD ;
1-Rituximab +/- chemotherapy ;
2-Adoptive immunotherapy;
Are any other tests required?
————————————————-
Virology: HIV type 1 & 2, Hepatitis B and C and EBV serology, CMV/EBV DNA titres.
Reference ;
—————————————
1-Prof Halawa lecture – PTLD
2- Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches Fedaey Abbas, Mohsen El Kossi, Ihab Sakr Shaheen, Ajay Sharma, Ahmed Halawa .
How would you confirm PTLD?
How would you differentiate PTLD from a primary tumour of the liver?
Do we need a histological diagnosis?
Differential diagnosis:
· PTLD
· Metastatic malignancy
· Infections: Disseminated Tuberculosis, Deep fungal infection, Renal abscess.
Management:
General:
· Reduction of immune suppression, stop MMF/ AZA, reduction of CNI upto 50%.
· Maintenance of hydration.
· Broad spectrum antibiotics.
. Anti pyretic
Specific:
· According to confirmed diagnosis.
Further investigation:
· Tissue diagnosis, biopsy and histopathology.
· PET-CT
· Viral screening
Thank you Eusha
Any place for tumour markers in the diagnosis of this case?
Please write the references
Histopathology can guide, even use of tumor markers according to biopsy finding helps more.
Reference: UpToDate
Differential diagnosis
· Renal abscess with distant micro-embolization.
· RCC with distant metastasis.
· PTLD.
· Lymphoma.
Management plan(1)
a) other required tests
· Full blood count, KFT, LFT, blood sugar, LDH.
· Virology: HIV 1 &2, HBV &HCV, EBV serology, HHV8, CMV/EBV DNA titres.
· Tissue diagnosis: excisional LN biopsy if any, or CT-guided aspiration or tissue sampling for histopathological examination and accurate diagnosis and sub-classification if neoplastic lesion is confirmed.
· BM aspirate may help in the setting of PTLD to identify any extent of the disease.
b) Management
· A management plan should be agreed by a core multidisciplinary team (MDT) which should include transplant physicians, haemato-oncologists, haematopathologists, microbiologist, radiation-oncologists and radiologists.
· Supportive therapy; adequate hydration and antibiotics if needed.
· Reduction of immunosuppression; to reduce the dose of CNIs by 25-50% and to stop AZA/MMF.
· Further specific therapy depends on the final diagnosis(PTLD, RCC or infection).
References
1. Shah N, Eyre TA, Tucker D, Kassam S, Parmar J, Featherstone C, Andrews P, Asgari E, Chaganti S, Menne TF, Fox CP, Pettit S, Suddle A, Bowles KM; Haemato-Oncology Task Force of the British Society for Haematology and the British Transplantation Society. Front-line management of post-transplantation lymphoproliferative disorder in adult solid organ recipient patients – A British Society for Haematology Guideline. Br J Haematol. 2021 May;193(4):727-740. doi: 10.1111/bjh.17421. Epub 2021 Apr 20. PMID: 33877688.
How would you confirm PTLD?
How would you differentiate PTLD from a primary tumour of the liver?
Do we need a histological diagnosis?
PTLD in renal allograft with mets to liver and spleen.
Primary HCC with mets to spleen and renal allograft.
The diagnostic workup includes:
1-Positron emission tomography (PET)
3-Directed biopsy to make a histo-pathologic diagnosis.
These investigations, beside general investigations like CBC, LDH renal and liver function and inflammatory markers like CRP, EBV viral load.
Treatment of Established PTLD
The treatment of PTLD is dependent on the morphologic subtype.
1-Reduction of immunosuppression) RIS.
Current recommendations include reducing CNI dose (targeting 50% reduction of trough levels), discontinuing antimetabolites, and continuing steroids if possible.
2-Other subtypes require additional aggressive immunochemotherapy, radiation therapy, surgery, or a combination of that.
For CD20- positive PTLD, in particular diffuse large B cell lymphoma, RIS followed by rituximab has become the standard of care, mainly based on results of the prospective
phase 2 multicenter PTLD-1 trial initiated to assess efficacy and toxicity of sequential treatment with rituximab and CHOP chemotherapy.
New Treatment Options
Promising new treatment options have been observed in case reports and very small case series, caution is warranted to maintain balance between tumor control and risk of rejection.
These include:
1. Brentuximab Vedotin
2. Small molecules targeting B cell receptor.
3. Checkpoint Inhibition and Chimeric Antigen Receptor T Cell
4. EBV-Specific Cytotoxic T Cells
PET Scan
Hepatis B and C viral screening as risk factors for HCC.
Reference:
Posttransplant Lymphoproliferative Disorder Following Kidney Transplantation: A Review Ben Sprangers, Leonardo V. Riella, and Daan Dierickx Am J Kidney Dis. 78(2):272-281.March 25, 2021.
How would you confirm PTLD?
How would you differentiate PTLD from a primary tumour of the liver?
PTLD is confirmed by direct biopsy from the lesion/lymph node.
HCC is diagnosed by triphasic CT scan plus high alpha-fetoprotein.
2. A 51-year-old man with a history of right renal transplant presented with right-sided flank pain, chills, and fever. CT was performed in search of the source of infection.
What is your differential diagnosis? lesions in the kidney, spleen and liver on CT scan
– Post Transplant Lymphoproliferative Disease (PTLD)
– Renal cell carcinoma (RCC)
– Hepatocellular carcinoma (HCC)
– Infections e.g., Tuberculosis (TB)
– Metastatic disease ?Primary
Please outline your management (1-3)
– Detailed history and physical examination – any weight loss, lymphadenopathy, jaundice, pallor, hepatosplenomegaly
– Management requires a multidisciplinary team i.e., oncologists, radiation specialists, surgeons
to provide better care and improve patient’s outcome.
– Definitive diagnosis is based on histopathological analysis – CT / US guided biopsy of the renal mass
– Treatment – the mainstay of management includes: –
o Reduction of immunosuppression – maintain corticosteroids; discontinuation of antimetabolite agents like mycophenolic analogues, azathioprine; at least 50% reduction of CNI dose; or switching from CNI to an mTORi
o Rituximab monotherapy – if patient dose not respond to reduced immunosuppression, can be given as a single agent following reduction in immunosuppression or in combination with chemotherapy (concurrently or sequentially) i.e., R-CHOP
Are any other tests required?
· Laboratory –
o complete blood count – to evaluate for leukocytosis, anaemia, thrombocytopenia
o ESR, CRP, Procalcitonin, blood culture
o Peripheral blood film
o kidney function test, bone chemistry, urine analysis, urine culture
o liver function test
o uric acid, LDH – to evaluate for tumor lysis syndrome
o Sputum gene xpert, urine LAM – to screen for TB
o CEA, AFP
o viral screen (EBV, HIV, CMV, hepatitis B and C)
o coagulation profile, renal mass biopsy (US or CT guided) – to determine the definitive diagnosis
o CSF analysis – in patients with CNS involvement
· Imaging – PET scan to evaluate spread
References
1. Caillard S, Dharnidharka V, Agodoa L, Bohen E, Abbott K. Posttransplant lymphoproliferative disorders after renal transplantation in the United States in era of modern immunosuppression. Transplantation. 2005 Nov 15;80(9):1233-43. PubMed PMID: 16314791. Epub 2005/11/30. eng.
2. Kamińska D, Krajewska M, Mazanowska O, Poznański P, Boratyńska M, Klinger M. Post-transplant lymphoproliferative disorder in adult renal transplant recipients: case series and review of literature. Central-European journal of immunology. 2020;45(4):498-506. PubMed PMID: 33658896. Pubmed Central PMCID: PMC7882407. Epub 2020/01/01. eng.
3. Sprangers B, Riella LV, Dierickx D. Posttransplant Lymphoproliferative Disorder Following Kidney Transplantation: A Review. American journal of kidney diseases : the official journal of the National Kidney Foundation. 2021 Aug;78(2):272-81. PubMed PMID: 33774079. Epub 2021/03/29. eng.
Thanks, Dr Kibe
How would you confirm PTLD?
How would you differentiate PTLD from a primary tumour of the liver?
How would you confirm PTLD? (1)
PTLD can only be confirmed by histologic confirmation of tumor tissue.
How would you differentiate PTLD from a primary tumour of the liver?
Liver lesions >1cm or AFP >20ng/mL raise the clinical suspicion of HCC. For such patients, a multiphasic CT scan or MRI can be used as initial diagnostic test. Liver biopsy can be considered when the imaging results are equivocal or in patients who do not have cirrhosis (2).
References
1. Al-Mansour Z, Nelson BP, Evens AM. Post-transplant lymphoproliferative disease (PTLD): risk factors, diagnosis, and current treatment strategies. Current hematologic malignancy reports. 2013 Sep;8(3):173-83. PubMed PMID: 23737188. Pubmed Central PMCID: PMC4831913. Epub 2013/06/06. eng.
2. Lee YT, Wang JJ, Zhu Y, Agopian VG, Tseng HR, Yang JD. Diagnostic Criteria and LI-RADS for Hepatocellular Carcinoma. Clinical liver disease. 2021 Jun;17(6):409-13. PubMed PMID: 34386205. Pubmed Central PMCID: PMC8340355. Epub 2021/08/14. eng.
There’s an enhancing mass in the liver and in the renal allograft. It could be a PTLD, or malignancy with metastasis.
A tissue biopsy is mandatory to confirm the diagnosis and to outline further therapy.
1- DD:
There is a renal allograft enhancing mass and two small masses in liver and splenn
1- PTLD (most probably)
2-RCC with metastasis
3-Metastasis from unknown primary
II- Outline of Management:
a– Diagnnosis:
c- Treatment outline:
1– Reduction of immunotherapy: stop azathiprine and MMF, reduce CNI to 50% and maintain steroid.
2– interim assessment by CT-scan
if responded — for close follow up
if no response:
a- and biopsy confirmed CD+ve PTLD, monomorphic B cell lymphoma, or polymorphic lesion:
Rituximab 4 weekly IV doses and re evaluate:
if respond — give additional 4 3-weekly doses
if not or progression occur: 4 cycles of chemotherapy (CHOP21)
b- if Burkitt’s lymphoma, T cell lymphoma or Hodgkin lymphoma:
give rituximab followed by CHOP
with supportive medications: G-CSF and PJP prophylaxis
3– graft nephrectomy for non-functioning graft
III-other tests:
labs: kidney function, viral evaluation (EBV PCR, other viruses)
staging: CT +PET-CT
Biopsy:
How would you confirm PTLD?
How would you differentiate PTLD from a primary tumour of the liver?
Thank you for mentioning PET-CT
1- PTLD is confirmed by histopathological examination of biopsy from the renal lesion
2- clinically:
The hepatic lesion is small which is unlikely to metastasis in the transplant kidney.
markers for HCC can exclude it like AFP, GCT2, TGF-beta1 and alpha 1 fucosidas
◦ What is your differential diagnosis?
There is lesion in the renal graft,liver and spleen. The DDx include either:
Primary renal malignancy with metastasis to liver and spleen or hepatocellular carcinoma with metastasis to the graft and spleen .
PTLD
Infection (less likely).
◦ Please outline your management
◦ Are any other tests required?
Detailed history and examination especially for any LN enlargement
Investigation include CBC and film, ESR ,RFT,LFT,LDH,serum electrolytes,virology screen for hepatitis B&C CMV ,EBV ,HIV .
Tissue biopsy from the kidney or liver for histopathological study , if it reveal PTLD so CT or PET scan for neck,chest,abdomen and pelvis for staging and metastasis.
If the confirmed diagnosis is PTLD the treatment steps include the following:
RI of CNIs to 50%
Withdrawal of antimetabolite
Use of m-TORi
FU RFT for early detection of acute rejection.
If no response then try RTx if EBV +ve PTLD for 4 doses. If the lesion regress continue
4 cycles every 3 weeks.
If no response then try chemotherapy with CHOP cycle for4 cycles if no response we will give adoptive therapy .
Radiotherapy or surgical removal of localized lesions
Antiviral for positive tests for viruses.
How would you confirm PTLD?
How would you differentiate PTLD from a primary tumour of the liver?
Do we need a histological diagnosis?
-PTLD can be confirmed by histopathological study of tissue involved.
-by imaging like CT scan , tumor markers like AFP.
-liver biopsy may be need if the results of the above modality inconclusive.
Differential diagnosis
CT abdomen with clinical scenario is suggestive of
Management :
CT scan and EBV DNA PCR for montering.
How would you confirm PTLD?
How would you differentiate PTLD from a primary tumour of the liver?
Do we need a histological diagnosis?
This patient presented with fever and chills a long with THis CT finding which showed multiple organ infiltarate with multiple lesion including kidney,liver and spleen.
Infections ; TB, Abscess, Pyelonephritis, Fungal
Malignancies ; PTLD, Lymphoma, RCC, KS, Metastatic disease of unknown primary.
Such case need to be discussed in MDT ,along with IR as this case will need tissue biopsy to diagnose and treat accordingly .
will send general and rutine genela investigations which include CBC,LDH,CMP,
need to send full blood cultuer and send tissue cultuer as well
This patient need full virolohy include HCV,HBV,CMV,SEND FOR EBV as well
he will need panCT to look for other organ involvment and staging purpose as well .
If case of PTLD confirmed we need to reduce the IS medication and keep him on the lowest possible acceptable trough level ,in mean time we need to have histological typeing if it is CD 20 + or no and accordingly we may proceed either withrituximab or other chemotherapy protocol .
Switching CNIs to MTOR inhibitors might also lead to tumor regression or minimize recurrence of the same.
References
UPTODATE
How would you confirm PTLD?
How would you differentiate PTLD from a primary tumour of the liver?
Do we need a histological diagnosis?
DIFFERENTIAL DIAGNOSIS.
Multiple lesions in spleen, kidney and liver associated with fever and chills post transplant;
Infections ; TB, Abscess, Pyelonephritis, Fungal
Malignancies ; PTLD, Lymphoma, RCC, KS, Metastatic disease of unknown primary.
MGT & ADDITIONAL TESTS.
This will need an MDT approach involving an ID specialist, an oncologist, an IR specialist and the nephrologist.
The patient will be admitted in the high dependency unit and stabilized before we start work up and the appropriate management.
We would then investigate;
FHG,ESR,CRP,PCT, Blood & Urine cultures – To assess infection and start a broad spectrum antibiotic awaiting the culture results, An IR specialist would be looped in to drain the abscess or get a sample for histology /culture from one of the lesions for diagnostic purposes and to guide management.
LFTS,LDH to asses hepatic spread and possibility of a lymphoproliferative disorder.
Hep B &Hep c markers ,HIV,CMV PCR,EBV PCR – To assess other viral infections possible in transplant patients that could either present in a similar fashion, their incidence is increased by immunosuppressive medications or increase our risk of malignancy post transplant.
A thoraco – abd CT scan, Head Ct scan – to assess other organ involvement and possibly stage if it is a malignancy.
Investigate for TB considering it is a possibility post transplant and an important ddx in our set up – Histology/culture- gene-xpert, Mantoux tests, Urine LAM in HIV +ve, TB gold interferon.
MGT;
Depending on fluid status we would start on iv fluids and monitor the fluid status to avoid going into shock and initiate ionotropic support when needed.
We would start on broad spectrum antibiotics pending the culture results and avoid nephrotoxic antibiotics.
For TB we would start anti TBS and renal or hepatic dose depending on our LFTS & uecs. We would be mindful of drug interactions and appropriately adjust either our CNI or get TB regimens with less drug interactions.
In sepsis, we will withdraw CNI and Antimetabolites and use stress doses of steroids until infection is cleared.
For PTLD, histological diagnosis will guide our treatment, those with CD20 +VE will benefit from Rituximab, the other variants will have either rituximab monotherapy, R CHOP or benefit from adoptive immunotherapy with cytotoxic T cells. Considering the multiple lesions in multiple organs, we would not have a role for surgery or DXT.
Switching CNIs to MTOR inhibitors might also lead to tumor regression or minimize recurrence of the same.
Other supportive measures; Nutritional review, PPI for gastritis, DVT prophylaxis, Counselling, Management of anemia – Leuko-reduced transfusion in emergencies.
REFERENCES.
Prof Halawa lecture on PTLD.
Uptodate – PTLD
Hrishikesh et al ,PTLD.Stat pearl publishers 2022 Jan.
Adam J et al,Cancer risk followingorgan transplantation;a nationwide cohort study in sweden.Br J cancer 2003;89;1221
A tissue diagnosis will clearly help you to choose the line of management.
Absolutely. Thanks Prof.
-This is a post transplant patient with fever ,chills and right flank pain
His CT reveals right renal graft large mass with hepatic and splenic lesions
Therefore Differential diagnosis
PTLD
Lymphoma
Malignancy wither RCC or metastasising tumor
Renal abcess with disseminating infection
-Management
MDT team need to be involved ,consisting of hemato-oncologist ,radiologist and the transplantation team.
Full assessment including
Treatment include
· RI plan by 50% reduction of CNI and withdrawal of the antimetabolites as MMF
, mTOR can be introduced and glucocorticoids can be continued
Cautious monitoring of the patient and the graft function followed by restaging if the patient respnded to RI but if the case deteriorated un delayed chemotherapy have to be initiated
EBV negative are less responsive to RI as well as bulky lesions
· Rituximab therapy for the 3 PTLD types classified by WHO (375 mg/m2 body-surface area, weekly for 4 wk) and adding 4 more doses can increase possibility of CR ,risk stratification will be needed to assess the response.
· If CR was not achieved then Rituximab course has to be followed by CHOP regimen every 3 wk and G-CSF with proper supportive care
· Adoptive therapy by using EBV-specific cytotoxic lymphocytes (CTLs) or Expanded EBV-specific cytotoxic lymphocytes for recipient-derived PTLD) as well as in donor-derived PTLD
· surgical intervention if needed through nephrectomy of the graft
· antiviral therapy , antibiotic ,antifungal therapy as needed.
– Other tests required
Full basic labs and inflammatory markers and KFT, pancultures,
EBV viral load and CMV as well as virology screening
CT guided biopsy as assessible, Bone marrow aspirate and trephine
PET CT,
monitoring chemotherapy trough levels.
Reference
Abbas F, El Kossi M, Shaheen IS, Sharma A, Halawa A. Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches. World J Transplant. 2020;10(2):29-46.
Very good but the biopsy should be in the early tests not the (other) ones.
Differential diagnosis:
Ø PTLD affecting renal graft
Ø Renal cell carcinoma
Ø Metastasis
Ø Infectious causes :
TB, fungal infection ,renal abscess.
Management :
o Admission
o Detailed history and examination looks for skin change hyper or hypo pigmented area ,lymph node enlargement .
o Intravenous antibiotics
o Anti pyretic .
o Maintenance intravenous fluid
Investigations:
Full blood count ,RBG. CRP and ESR
Renal function test
Prograf level
Liver function test .
TB screen
Blood culture ,urine culture ,
Ø Investigation suspected PTLD :
· EBV serology
· Immunoglobulin and T and B cell subsets
· US looking for lymphadenopathy and· Biopsy of the most accessible site
Ø Investigation at diagnosis of PTLD:
· Uric acid /LDH
· Chest x ray
· Whole body CT
· MRI for the brain if any neurological sign
Bone marrow aspirate and trephine for morphology ,immunophenotyping and cytogenectics
· Lumbar puncture in case of Tcell lymphoma
Ø Treatment :
ü Reduction of immunosuppressive medications
Reduced CNI ,leave steroid un changed , stop MMF and azathioprin
ü If patient has progressive disease start rituximab (anti CD 20 ).,cytotoxic Tcell and or chemotherapy
ü Complete or partial surgical resection as well as radiotherapy have been used with reduction of medication
Ø Clinical assessment of remission :
§ The aim is complete remission
§ The clinical response assessed weekly by checking for fever ,lymphadenopathy, respiratory symptom s ,tonsil enlargement ,organomegaly and size of any mass should be measuer by US or chest xray
§ Follow up CT done after 4 weeks
§ If clinical and radiological respoce occur follow the pt till achieved complete remission.
v Categories of PTLD :
Ø Early lesion:
Ø Polymorphic PTLD
Ø Monomorphic PTLD
Ø B cell neoplasm
Ø Tcell neoplasm
Ø Classical Hodgkin lymphoma type PTLD .
References :
1-Engels EA, Pfeiffer RM, Fraumeni JF Jr, et al. Spectrum of cancer risk among US solid organ transplant recipients. JAMA 2011;306:1891–1901
2-Hosseini-Moghaddam SM, Alhomayeed B, Soliman N, et al. Primary Epstein–Barr virus infection, seroconversion, and posttransplant lymphoproliferative disorder in seronegative renal allograft recipients: a prospective cohort study. Transpl Infect Dis 2016;18:423–430
Is there a reason and use to assess CD20 positive or negative B cells.
The patient in this clinical scenario has a history of fever, chills, and right-sided flank pain which raises the suspicion of infectious process or malignancy.
Provided CT abdomen and pelvis imaging shows:
1) A renal graft with an exophytic mass
2) Hepatic and splenic lesions.
In such a clinical context, PTLD with metastasis is highly suspected however we should keep in mind other differential diagnosis such as metastatic hepatocellular carcinoma or disseminated infection with abscess spreading to the liver and spleen.
A multidisciplinary strategy involving transplant physicians, hemato-oncologists, hemato-pathologists, radiologists, and radiation oncologists would be utilized for treatment.
Are any other tests required?
patient should be investigated for underlying viral illness including HHV-8, hepatitis C and CMV.
Exellent
The index patient is a transplant recipient with history of fever, chills, and right-sided flank pain.
His CT abdomen shows:
a) An exophytic mas in the renal graft
b) Lesions in liver and spleen.
The differential diagnosis in such a clinical setting is either:
a) A primary renal malignancy with hepatic and splenic metastasis
b) Post-transplant lymphoproliferative disorder (PTLD)
c) Hepatocellular carcinoma with metastasis
d) Renal abscess with spread in liver and spleen: unlikely as such a patient will be having other features of septicemia
The management in this scenario includes:
a) Detailed physical examination: especially look for presence of palpable lymph nodes.
b) Baseline laboratory work-up including full blood count, LFT, virology (HIV, Hepatitis B and C and EBV serology, CMV/EBV DNA titres), LDH, chest x-ray, 2D ECHO (1).
c) Tissue diagnosis: A biopsy of the renal mass as well as the hepatic lesion (1).
d) If the biopsy reveals PTLD, then staging using a CT neck, chest, abdomen and pelvis (or PET-CT, if available) should be done (1).
e) Treatment: It would involve a multidisciplinary approach with involvement of transplant physicians, hemato-oncologists, hemato-pathologists, radiologists, and radiation oncologists (1).
a. Reduction of immunosuppression (RIS): The Tacrolimus dose should be reduced by 50% (1,2). The antimetabolite should be stopped. Steroids can be continued. Response to RIS can be monitored over 2-4 weeks with respect to resolution of symptoms, fall in LDH levels, and reduction in size of renal/hepatic/splenic lesions on CT imaging (3). In case of early lesion, low-stage or non-bulky disease, 20-80% of patients may show reversal of PTLD with RIS alone (2).
b. If there is poor response to RIS, second-line of treatment in form of Rituximab (375 mg/m2 IV per week for 4 weeks) should be given in patients with CD20-positive PTLD (1).
c. If complete remission is achieved with rituximab, then 4 cycles of rituximab every 3 weeks should be given.
d. If complete remission not achieved post-rituximab, then patient should be given chemotherapy (CHOP – doxorubicin, cyclophosphamide, vincristine, and prednisolone) every 3 weeks for 4 cycles.
e. Adoptive immunotherapy using donor lymphocyte infusion (DLI) or EBV-specific cytotoxic lymphocytes (CTL) are useful in EBV positive PTLD which are refractory to treatment (1,2).
f. Surgical resection: Graft nephrectomy might be required in refractory cases, although in disseminated PTLD, graft nephrectomy is not associated with better outcomes (4)
Risk of rejection, which is upto 5%, with RIS needs to be kept in mind (5).
The tests required in this scenario include
a) Baseline laboratory work-up including full blood count, LFT, virology (HIV, Hepatitis B and C and EBV serology, CMV/EBV DNA titres), LDH, chest x-ray, 2D ECHO (1).
b) Tissue diagnosis: A biopsy of the renal mass as well as the hepatic lesion (1).
c) If the biopsy reveals PTLD, then staging using a CT neck, chest, abdomen and pelvis (or PET-CT, if available) should be done (1).
References:
1. Shah N, Eyre TA, Tucker D, Kassam S, Parmar J, Featherstone C, Andrews P, Asgari E, Chaganti S, Menne TF, Fox CP, Pettit S, Suddle A, Bowles KM; Haemato-Oncology Task Force of the British Society for Haematology and the British Transplantation Society. Front-line management of post-transplantation lymphoproliferative disorder in adult solid organ recipient patients – A British Society for Haematology Guideline. Br J Haematol. 2021 May;193(4):727-740. doi: 10.1111/bjh.17421. Epub 2021 Apr 20. PMID: 33877688.
2. Abbas F, El Kossi M, Shaheen IS, Sharma A, Halawa A. Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches. World J Transplant. 2020 Feb 28;10(2):29-46. doi: 10.5500/wjt.v10.i2.29. PMID: 32226769; PMCID: PMC7093305.
3. Gunawansa N, Rathore R, Sharma A & Halawa A. (2019) PostTransplant Lymphoproliferative Disorder: A Clinical Perspective. J Renal Transplant Sci, 2(2): 109-117
4. Gholipour-Shoiili A, Gholipour-Shoiili H, Taheri S. An approach to finding indications and contraindications for nephrectomy in post-transplant renal graft lymphomas: PTLD.Int survey. Hematol Oncol Stem Cell Ther. 2011;4(4):167-72. doi: 10.5144/1658-3876.2011.167. PMID: 22198192.
5. Sprangers B, Riella LV, Dierickx D. Posttransplant Lymphoproliferative Disorder Following Kidney Transplantation: A Review. Am J Kidney Dis. 2021 Aug;78(2):272-281. doi: 10.1053/j.ajkd.2021.01.015. Epub 2021 Mar 25. PMID: 33774079.
Exellent.
A 51-year male with Renal transplant ,having history of right flank pain, chills, and fever and CT scan Abdomen showing mass in the renal allograft with focal lesions in liver and spleen .Differentials include:
PTLD
HCC with mets
RCC with mets.
Are any other tests required? Diagnosis can be made by taking detailed history and then examination followed by detailed investigations including complete blood picture to look for pancytopenia,renal function test, Liver function test, serum calcium ,LDH ,blood culture ,Hepatitis B and C , PCR for EBV ,CMV, and HHV-8,Quantiferon Tb Gold test ,Tumor markers like alpa fetoprotein, CEA ,CA 19-9,followed by CT scan Neck, Chest, Abdomen and pelvis and then tissue biopsy and bone marrow for histopathological diagnosis. CT scan will also help to stage the disease once diagnosis confirmed.
Management :Multidisciplinary team should be involved including hematologist, pathologist, oncologist, transplant physician, and interventional radiologist. Reduction of immunosuppression i.e., withhold anti-metabolite and reduction of CNIs to 30-50% and replace mTORi like sirolimus as it has anti-tumor effect but proteinuria should be ruled out and close monitoring of graft function as chances of rejection high. If no response and the diagnosis is PTLD, then Rituximab followed by chemotherapy (CHOP).Radiotherapy in some cases may help(localized disease, extra-nodal sites, such as the orbit, isolated CNS relapse). If all treatment fails then adoptive therapy in the form of EBV specific cytotoxic T-cells (EBV-Tc) by either donor derived infusions (DDI) or stored , donor lymphocyte infusion. Surgical treatment in the form of allograft nephrectomy will be helpful only in localized involvement and graft failure, however, in the above case, as dissemination so not indicated. If RCC with mets-then partial nephrectomy, radical nephrectomy(as for non-transplant case) and stopping all immunosuppression and placing the patient on maintenance hemodialysis. In case of HCC with mets, palliative therapy with or without chemotherapy depending on stage and withholding all immunosuppression.
REFERENCES:
1-Abbas F, El Kossi M, Shaheen IS, Sharma A, Halawa A. Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches. World J Transplant. 2020;10(2):29-46
2-Lecture of Prof. Ahmed Halawa
Well done
Enhanced ct showed a focal lesion in the right kidney, liver, and spleen
the underlying cause may be malignancy(1ry from liver, kidney or metastatic from any other organ) or disseminated infection.
Histopathological diagnosis is a must followed by PETCT or pan CT for staging are needed.
After the histopathological diagnosis multidisciplinary team approach showed be arranged to decide the further plans for the patient including
-Reduction or shifting of immunosuppression from CNI to MTOR
-Surgical removal of the tumor
-Antiviral treatment in case of EBV and CMV-related malignancies
-Rutiximab for CD 20 positive PTLD
-Chemotherapy.
-Radiotherapy.
tumor marker like alpha-fetoprotein, virology screening including HCV, CMV, EBV, and HHV
Good but which tumor are you going to remove.
Surgery in such case has limited role I think and can be used if there is pressure related organ dysfunction.
These two images showed a mass in the kidney transplant, liver, and spleen
differential diagnosis
MDT team approach includes nephrologist, oncologist, and hematologist
lab includes CBC,PBF,LFT,KFT,LHD,s.calcium, uric acid
virology screening: EBV, CMV, HHV-8and HCV
for definite diagnosis biopsy guided CT scan
septic screening blood culture and screening for T.B
CT for chest and pelvis
management
after confirming diagnosis reduction or discontinuing the TAC.
shift TAC to mTOR.
discontinue antimetabolite
if CD20-positive PTLD treats by rituximab as monotherapy. or combined with CHOP
if CD20-negative treats by CHOP.
surgical intervention if there is a complication such as obstruction or bleeding
septic screening includes blood culture urine culture and screening for T.B
ECHO to role infective endocarditis which can shower septic emboli
References
1-harnidharka VR. Comprehensive review of post-organ transplant hematologic cancers. Am J Transplant. 2018;18:537–549. [PubMed] [Google Scholar]
2. Medscape. Post-transplant Lymphoproliferative Disease. Available from: URL: https://emedicine.medscape.com/article/431364-overview#showall. [Google Scholar]
Very good but dont forget the PET scan.
What is your differential diagnosis?
post transplant constitutional symptoms having fever loin pain and chills with ct cscan showing infiltrative process involving Tx graft with infiltration in Liver and spleen.DD would be
PTLD
HCC
RCC
metastatic disease
severe infection like TB, nocardia, CMV, EBV, Fugal etc
Please outline your management
after taking complete and detail history and examination will need extensive investigation like
CBC,ESR,CRP,LDH,uric acid, calcium, special smear, RFTs, LFTs,
CXR, CT CAP (chest, abd, pelvis)
alfa feto proteain, HBS,HCV,EBV,CMV PCRs
tissue diagnosis (histopathology of lesion),
Are any other tests required?
EBV status and type of lymphoma either B or T cell, along with CD20+ status
Treatment
if PTLD is confirmed then would need
reduction in IS like reducing or withdrawal of tacrolimus
switching over to mTOR instead of CNI
addition of Rituximab in CD20+case\
in non responder, CHOP therapy with liaison of oncologist and complete withdrawal
of IS
Graft nephrectomy usually indicated in limited localized disease. However, the index
case has disseminated PTLD but if graft severely affected allograft nephrectomy
can be considered.
Adoptive immunotherapy; Specific EBV- Cytotoxic T- cell in refractory/ relapsed
EBV-positive PTLD
ref
Thankyou do not forget PET scan for extent of disease .
You mentioned graft nephrectomy in advanced disease can you elaborate more :
with full withdrawal of IS with expected a violent rejection.
or just reduction of IS.
Sir if graft involvement is there then graft nephrectomy would be warranted but otherwise reduction in IS would be sufficient.
The above two CTs of the abdomen reviewed multiple mass lesions involving the right kidney, liver, and spleen with the largest involving the kidney.
Differential diagnosis
A multidisciplinary approach will be deployed in managing this patient and this will include, an oncologist, surgeon, transplant physician, and radiologist
Outline management
Investigations
Treatments
Other tests required are:
References
Well done.
1-What is your differential diagnosis?
CT SHOW
TRANSPLANTED KIDNEY (LESION HYPODENSE -PERIPHERIAL CALCIFICATION)-SPLEEN HYPODENSE FOCAL LESION
-LIVER HYPODENSE FOCAL LESION
-METASTASIS TO LIVER AND SPLEEN )
D.D
Benign kidney tumors
Oncocytoma
Angiomyolipoma
Metanephric adenoma
Metastatic disease
Renal abscess or focal pyelonephritis
RENAL CELL CARCINOMA WITH METASTASIS
PYELONEPHRITIS
LYMPHOMA
(PTLD) the most serious and potentially fatal complications of transplantation. While the majority appears to be related to the presence of Epstein-Barr virus (EBV)
types of PTLD in transplant recipients:
Early lesion (ie, plasmacytic hyperplasia and infectious mononucleosis-like PTLD) –
no evidence to suggest malignant transformation.
Polymorphic PTLD polyclonal or monoclonal lymphoid infiltrates that demonstrate evidence of malignant transformation but do not meet all of the criteria for one of the B cell or T/NK cell lymphomas recognized in immunocompetent patients.
Monomorphic PTLD monoclonal lymphoid proliferations that meet the criteria for one of the B cell or T/NK cell lymphomas recognized in immunocompetent patients.
2-Please outline your management
*****Prevention of PTLD *********
Tapering immunosuppressive therapy
Antiviral prophylaxis ganciclovir not routinely given as prophylaxis
High-risk patients (eg, donor EBV-positive, recipient EBV-negative) were administered a minimum of 100 days of intravenous ganciclovir (6 to 10 mg/kg per day).
Low-risk patients (eg, donor EBV-negative, recipient EBV-positive or -negative; donor and recipient EBV-positive) received intravenous ganciclovir only during the period of hospitalization followed by oral acyclovir (40 mg/kg per day).
Target tacrolimus levels were lowered to 2 to 5 ng/mL in patients in whom a rising viral copy number was detected by PCR performed once per month.
TREATMENT
Early lesions reduction of immunosuppression alone rather than in combination with other therapies.
Polymorphic PTLD th rituximab in addition to reduction of immunosuppression
Monomorphic PTLD –rituximab, either alone or in combination with chemotherapy in addition to reduction of immunosuppression,rituximab plus combination chemotherapy (eg, CHOP), administered concurrently or sequentially.
prevention of PTLD largely relies upon limiting patient exposure to aggressive immunosuppressive regimens, aggressive withdrawal and tapering of agents required for graft acceptance, and anti-viral prophylaxis.
Patients whose tumors do not express CD20 are not candidates for rituximab therapy and are treated with combination chemotherapy plus reduction of immunosuppression.
Surgery is reserved for patients with complications such as perforation or obstruction.
3-Are any other tests required?
Initial evaluation of kidney mass
Obtain high-quality, multiphase, cross-sectional abdominal imaging to optimally characterize/stage the kidney mass
.Obtain CMP, CBC, and UA.
If malignancy is suspected, metastatic evaluation should include chest imaging
Assign CKD stage based on GFR and degree of proteinuria.
SEPTIC SCREEN (URINE -BLOOD CULTURES -CRP -ESR -LDH )
REFERENCES UPTODATE
Fine extensive review but:
need to rearrange your DD.
thankyou for mentioning to use Rituximab in only CD20 positive cases.
The above two CTs of the abdomen reviewed multiple mass lesions involving the right kidney, liver, and spleen with the largest involving the kidney.
Differential diagnosis
A 51-year-old man with a history of right renal transplant presented with right-sided flank pain, chills, and fever. CT was performed in search of the source of infection.
What is your differential diagnosis?
Our patient is complaining of B symptoms such as fever, chills with flank pain and signs of infiltration of extra lymphatic tissues.(1)
CT scan on left hand side shown heterogeneous infiltration of the graft and right sided CT picture shown Liver and splenic infiltration.
Differential diagnosis:
1-PTLD which counts about 1-2% of kidney transplantation.
2-Secondires from other primary tumors.
3-Chrnoic disseminated infection such as TB and others.
Please outline your management.
Again we should keep in mind that there is no strong evidence about the effective treatment of PTLD.
1-MDT should be concluded (interventional radiologist, Oncologist, surgeon, transplant nephrologist and transplant surgeon, etc. ).
2-Tapering immunosuppressive therapy.
To decrease tacrolimus trough level is important and may limit the development of this disorder and can reverse 20%-80% (2).
3-Rituximab and Rituximab followed by CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone).
4-Chemotherapy and adoptive immunotherapy are other lines of management (3).
5- If biopsy shown infection so the corner stone is to reduce IS and treatment the source of infection.
Are any other tests required?
We should have a high index of suspicion with abnormal laboratory results such as unexplained anemia, thrombocytopenia, or leukopenia.
●Elevated level of serum lactate dehydrogenase (LDH).
●Hypercalcemia.
●Hyperuricemia.
●Monoclonal protein in the serum or urine.
● EBV,CMV, HCV, HHV 8 .
●Excisional biopsy for pathological assessment.
●CT for staging .
●Exclude all source of infections.
References:
1-Epidemiology, clinical manifestations, and diagnosis of post-transplant lymphoproliferative disorders, UP TO DATE 2022.
2-Tsai DE, Hardy CL, Tomaszewski JE, et al. Reduction in immunosuppression as initial therapy for post-transplant lymphoproliferative disorder: analysis of prognostic variables and long-term follow-up of 42 adult patients. Transplantation. 2001;71(8):1076-1088. doi:10.1097/00007890-200104270-00012.
3-Abbas F, El Kossi M, Shaheen IS, Sharma A, Halawa A. Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches. World J Transplant. 2020;10(2):29-46. doi:10.5500/wjt.v10.i2.29.
Well done but please note infection in this scenario will be pyemic abscesses with a very different clinical presentation.
Differential Diagnosis
In the setting of renal transplant, the likely causes is graft PTLD with hepatosplenic involvement
Metastatic RCC or HCC
Disseminated infection (TB, fungal infection)
Further Test:
Histological confirmation, preferably excisional biopsy, peripheral node if any, identification of EBV DNA in tissue.
Contrast enhanced CT chest and pelvis and PET to measure disease activity.
EBV viral load
TB and fungal screen
Laboratory studies; FBC, U+ES, bone profile, LFT, Albumin, LDH, uric acid, HIV, CMV and Hepatitis B
If Cytopenia, for BM aspiration and biopsy
If suspicion of CNS involvement for gadolinium enhanced MRI +/- CSF for cytology, flowcytometry and EBV PCR
Echo if history of cardiac dysfunction/ prior to treatment with anthracycline
Treatment
MDT with transplant physician, haemato- oncology, pathologist and transplant surgeons.
If PTLD confirmed, Reduction of immunosuppression to restore immuno-surveillance is the mainstay and first step in treatment, (the optimal regime is unknown, 25%-%50 reduction of CNI and antimetabolites, maintain on steroid, mTORI role is controversial)
Carful monitoring of graft function and counselling patients about risk or rejection/ graft loss if in case of extensive disease needing complete withdrawal of IS
Monitor response to treatment (reduction of size on imaging, LDH)
Further treatment depends on extent of disease, type of PTLD, performance status, comorbidities and CD20 positivity.
Rituximab if CD20+ +/- chemotherapy (CHOP)
Nephrectomy might be considered given significant tumour volume
Adoptive therapy (EBV specific cytotoxic T cells) for resistant disease in EBV +ve disease disease.
GCSF, PCP prophylaxis +/- fungal prophylaxis
Well done.
👉The provided CT images illustrate alarge heterogenous mass in the right renal pelvis in addition to involvement of liver and spleen by hypodense nodules which is highly suggestive of:
1_ PTLD of the graft with heptosplenic involvement
2_ metastatic renal cell carcinoma.
3_ pyemic abscesses (however, it the lowest possibilty as the patient mostly will be toxic and very bad general condition unlike the indolent course of malignancy which is more matching the current scenario).
👉 the plan of magement will depends on the final diagnosis.
_ tissue biopsy will confirm the definitive diagnosis.
_Assessment of other tissue involvement by CT head and neck, chest and pelvis will be required.
_ labs as CBC for cytopenias, serum CA, uric acid and LDH.
_ Search for causative virus (EBV and CMV PCR) as EBV postive cases will respond to rituximab and reduction if immunosupression.
.👉 Treatment options;
_ Reduction of immunosupression by stoppage of MMF , reduction of TAC dose according to the trough level, resuming of steroids to guard against rejection.
_ close monitoring of graft function by serum creatinine , urine analysis and DSA.
_ Ritiximab 375 mg/m2 /dose either alone or followed with chemotherapy as CHOP (steroids, cyclophosphamide, vincristine )
_ Graft nephrectomy may be indicated in case of graft failure ..however, it will not be curative alone as the disease is not localized (heptosplenic involvement can be seen in the provided CT images).
_ for refractory cases to the above- mentioned conventional therapy, adoptive immunotherapy as DLI and EBVSTs will be beneficial in EBV postive cases.
Well done ,HCC with metastasis is another possibility.
Differntial diagnosis
1- PTLD:the highest probability due to history of transplantation .
2- RCC with hepatic and splenic metastasis
3- HCC with metastasis
4- Infectoius causes as TB
Management Plan
I- Investigations
– CBC : anemia,lekopenia and thrombocytopenia
– LDH
– Electroltyes specialy S. Ca and uric acid
– Urine and protient electrophoresis
Radiology
– CT ( head ,neck and chest ) to evaluate for remote metastasis and lymphadenopathy.
Treatment :
1- Decrease the dose of MMF , switch from tacrolimus to m TOR inhibitors .
2- If noresponse consider Rituximab as 4 weekly dosesof 375 mg /m2 if responded rebeat for an other 4 doses if no response consider chemotherapy (CHOP protocol).
3- Radiotherapy for localized tumer.
Further investigations
– CBC : anemia,lekopenia and thrombocytopenia
– LDH
– Electroltyes specialy S. Ca and uric acid
– Urine and protient electrophoresis .
– EBV DNA viral load
– Monitoring of graft function and consider protocol biopsy for early detection of graft rejection.
Radiology
– CT ( head ,neck and chest ) to evaluate for remote metastasis and lymphadenopathy.
– CT guided biopsy fromkidney mass.
Ref
1- Dr Ahmed Halawa lecture :post transplantation lymphoproliferative disorders.
Well done.
Contract-enhanced CT showed large heterogenous mass at the area of right renal pelvic.
Cross- section of liver and spleen showed 2 small well defined hypo-dense lesions.
Differential diagnosis:
– PTLD most likely.
– Metastatic disease; RCC with metastasis or HCC with metastasis.
– Opportunistic infection. Fungal, disseminated TB.
In the setting of SOT PTLD is the second common malignancy after skin cancer. Keeping a low threshold for diagnosing this condition is mandatory as if left untreated lead high morbidity and mortality.
Other types of cancer is less common than PTLD. However, the risk is higher compared to immunocompetent individuals.
Management:
– Establish a diagnosis and to assess the extend to this disease.
– For accurate diagnosis a tissue biopsy is mandatory and preferred to be excisional biopsy.
– The index case likely has a disseminated PTLD involving allograft, liver and spleen. Excluding lesions in the chest, brain, BM is recommended.
– The management will be guided by:
– The biopsy result.
– Histopathological subtype.
– The staging of disease
– General patient condition.
– Graft function.
– Managing these case is always challenging and MDT is highly recommended, should include transplant physicians, haemato-oncologists, haemato-pathologists, radiation-oncologists, radiologists, infectious disease specialist and the surgeon.
Once PTLD confirmed the management will be:
A- Reduction of IS to restore immune surveillance.
– Reduce CNI reduction by 50%, along with withdrawal of the antimetabolites and maintain glucocorticoids.
– Consideration to switch to mTORi
– In critically ill cases should consider withdrawal of all IS medications except glucocorticoids.
Monitor:
– Monitoring allograft function for rejection.
– Assess disease response assessment early (at 2–4 weeks) by CT.
– Viral load.
2-If patient faild to response or PR achieved can consider; RTx as monotherapy or sequential therapy RTx +/- chemotherapy RCHOP- 21 used in addition to RI.
3-consider care G-CSF and PJP prophylactic.
4-Radiotherapy: may be considered for localized disease, some extra-nodal sites, such as the orbit, isolated CNS relapse and MALT
5-Surgical; Graft nephrectomy usually indicated in limited localized disease. However, the index case has disseminated PTLD but if graft severely affected allograft nephrectomy can be considered.
6-Adoptive immunotherapy; Specific EBV- Cytotoxic T- cell in refractory/ relapsed EBV-positive PTLD
7-Antivirals, IVIG and interferon-alpha treatment: Data are limited and is not recommended outside clinical trials.
Other Test Required:
– Review the clinical information; the date of transplant, IS regimen ( doses and level) and organ type.
– Comprehensive pre-treatment evaluation:
– Patient already had baseline CT. However; we need to rule out chest and brain involvement.
– If PET-CT scan available, better to be utilized for staging over CT scan.
– If CNS- involvement suspected: consider brain/ orbit and sinuses CT or MRI with CSF analysis.
– Bone marrow biopsy may be indicated especially in the setting of cytopenia.
References:
– Front-line management of post-transplantation lymphoproliferative disorder in adult solid organ recipient patients — A British Society for Haematology Guideline.
– Abbas F, El Kossi M, Shaheen IS, Sharma A, Halawa A. Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches. World J Transplant. 2020 Feb 28;10(2):29-46. doi: 10.5500/wjt.v10.i2.29. PMID: 32226769; PMCID: PMC7093305.
– UpToDate.
Exellent but please exclude Interferon – alpha specially in a TX case.
What is your differential diagnosis?
– The possibility of PTLD is high and depends on high index of suspicion in renal transplant recipient as it is second common malignancy post renal transplant, and here there is a mass in the renal allograft, and there is a small nodule suspicious in the liver and spleen.
– RCC With Liver and Spleen Mets
– HCC With Metastasis
Please outline your management
1-Complete History & Examination
2-Further investigations
3- Monitor for Graft Rejection.
4- Image guided biopsy for histopathological diagnosis
-IF PTLD IS confirmed
-Reduction of Immunosuppresion Meds (Adjustment low Troughs)
-Stop CNI, Reduce MMF
-Switch to mTOR Inhibitors -Some studies have shown successful PTLD regression with sirolimus, others have shown higher incidence of PTLD with its use.
-Rituximab is an anti-CD-20 monoclonal antibody with efficacy against CD-20 positive PTLD. It has been postulated to cause destruction of malignant cells by several mechanisms
-CHOP therapy
-Adoptive immunotherapy : indicated for patient who showed relapse after R- COP21 or other modalities
Surgical treatment;.for localized disease or emergency situation: intestinal involvement by perforation
Are any other tests required
1-Haematology
-CBC
-ESR
-BLOOD FILM
2-Biochemistry
-RENAL PROFILE
-LIVER PROFILE
-LDH
-BONE PROFILE
-CRP
-PROCALCITONIN
3-Serology
-Virology (HCV-HBV-HIV)
-EBV PCR
4-Additional Labs;.
-UPEP &SPEP& immunofixation, kappa, lambda, B2 microglobulins
5-Radiology
-PAN CT SCAN
-CT guided Tissue BX
-PET CT SCAN
References
-up to date
-Dr. Ahmed Halawa lecture
– Post-Transplant Lymphoproliferative Disorder: A Clinical Perspective Nalaka Gunawansa1,2 , Roshni Rathore2,3, Ajay Sharma2,4 and Ahmed Halawa2,5*may 2019
Thankyou but try to priorities your further tests by putting biopsy first.
Thanks so much
noted prof.
Differential diagnosis.
In case of fever and chills the differential diagnosis in kidney transplant patient along with CT scan report that shows dense lesion in right kidney and multiple lesion in liver and spleen the differential could be;
Malignancy; PTLD, HCC, RCC
Infection; pyelonephritis, TB, Nocardia,
Metastatic disease
Treatment
Tissue biopsy of the lesion to confirm the diagnosis.
Switch CNI to MTOR and with draw of metabolite
Rituximab for CD20 positive patients
Chemotherapy regime like CHOP etc
Radiotherapy
Further test. CT chest.
Hematology; CBC for cytopanias, calcium, uric acid, serum LDH, Albumin, LFT, Alpha Fetoprotein, ESR.
Radiology. CTchest.
Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches. Fedaey Abbas, Mohsen El Kossi, Ihab Sakr Shaheen, Ajay Sharma, Ahmed Halawa
Thankyou.
What is your differential diagnosis?
Post transplant symptoms of flank pain, chills, and fever and CT imaging showed renal mass, the most likely diagnosis is allograft PTLD. Other differential is RCC
Please outline your management
High index of suspicion
History, physical examination and evaluation of performance status
Laboratory assessment: CBC with differential and a metabolic panel (albumin, electrolytes, RFT,), LDH, serum uric acid, serum ca, and monoclonal protein in the serum or urine
Definitive diagnosis is by biopsy and histopathology (EBV-DNA)
CT chest, abdomen and pelvis
MD approach with a team including transplant clinicians, surgeons, radiologists, histopathologists and oncologists
Reduction of immunosuppression: stop azathioprine and MMF and reduce CNIs by 30–50% and maintain or reduce corticosteroid with close monitoring of allograft rejection. Assess response in 2- 4 weeks (resolution symptoms, drop in LDH levels and tumor size reduction on imaging). Conversion to m-TOR inhibitor (conflicting evidence)
Rituximab: if poor response within 2-4 weeks. Response is 50-60% in CD-20 positive PTLD. Most often combined with systemic chemotherapy
Systemic chemotherapy (CHOP): for disseminated PTLD. Used a lone or in combination with rituximab. One year survival rate is >65%
Adoptive immunotherapy
Others: surgery and radiotherapy
Graft PTLD has a good outcome (Graft nephrectomy with reduction of immunosuppression may be required)
Are any other tests required?
CT of neck, thorax, abdomen and pelvis
MRI or CT of the brain, orbits and sinuses (CNS or craniofacial disease)
Positron emission tomography (PET) in specific cases
Bone marrow aspiration or lumbar puncture to evaluate CSF including cytology and flow cytometry (CNS-PTLD)
References
1. NCC guidelines version 2.2015 post=transplant lymphoproliferative disorders.
2. Front-line management of post-transplantation lymphoproliferative disorder in adult solid organ recipient patients — A British Society for Haematology Guideline.
3. Gunawansa N, Rathore R, Sharma A & Halawa A. (2019) Post-Transplant Lymphoproliferative Disorder: A Clinical Perspective. J Renal Transplant Sci, 2(2): 109-117.
Well done.
A lumber puncture will be needed if there is suspition of CNS lesion not as a routine.
Thank you Prof.
Yes, when there is suspition
Differential diagnosis
PTLD
Metastatic RCC
Metastatic HCC
Renal abscess.
Management
After confirmation of the diagnosis with a biopsy.
First line for PTLD will be to reduce the CNI and withdrawal of antimetabolites.
Rituximab can be added in CD20 positive and those who fail to respond to reduced immunosuppression.
Chemotherapeutic agents can be used in high risk patients
Additional tests.
Complete blood count looking for anaemia/thrombocytopenia/leucopenia
uric acid levels
LDH levels
Serum calcium levels
Imaging of the chest- CT chest
Biopsy of the lesion
UECS to determine graft function
LFT
PET scan
CRP, ESR,PCT
Alpa fetoprotein
References
Prof Halawa lecture
Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches. Fedaey Abbas, Mohsen El Kossi, Ihab Sakr Shaheen, Ajay Sharma, Ahmed Halawa
Thank you for this excellent answer, do you think that it is an abscess?
Try to look for more references Caroline
Thank you prof.
A renal abscess will be highly unlikely you expect to find a well dermactaed hypoechoic lesion. That is why I put down in my differential list.
Noted prof will work on more references.
-What is your differential diagnosis?
The differential diagnosis in of fever & chills in transplant patient is wide. The CT scan hypo-dense irregular lesion in the right kidney graft. These lesions also affected the liver and spleen. The differentials are:
–Please outline your management ?
Management is MDT and largely dependent on the histology finding:
-Are any other tests required?
Source: Medscape, Prof Halawa, Handbook of kidney transplantaion by Gabriel M. Danovitch 6 edition
Thankyou.
wlcm prof
This 51 year old patient ,post transplant has systemic symptoms. The first axial image is showing the graft in right illiac fossa with solid looking lesion in lower pole. The other image is showing hypodense lesions in liver and spleen.
Possibilities include:
· Renal cell carcinoma with liver and splenic mets
· PTLD
· Hepatocellular carcinoma with splenic and renal METS
The patient will need further investigation including.
Blood CP and ESR. Liver functions. LDH. alpha fetoproteins. EBV load, Calcium, Uric acid,.
Assessment for any lymphanopathy- if nodes are palpable , then a biopsy will be needed
CT chest, abdomen and pelvis
If no obvious nodes are palpable then renal biopsy is mandatory.
The histology has to be discussed in cancer MDT. Opinion from oncologist and Haematologist is required.
As regards considerable graft mass, I will discuss with patient and MDT. He may require graft nephrectomy
For PTLD the approach will be-
· Reduction of immune suppression
· Anti CD 20 in low risk group
· For high risk , chemotherapy like CHOP regimen
· mTORi and adoptive immunotherapy
Well done.
· What is your differential diagnosis?
CT demonstrates a solid, irregular mass attached to right kidney with hypoattenuating
mass in the liver and spleen.
D D:
PTLD.
RCC.
HCC.
Hamartoma.
Inflammatory pseudo tumor.
Abscess.
T.B.
· Please outline your management.
Reduction of immunosuppression (RIS) remains the cornerstone for Epstein-Barr virus
(EBV)–driven B-cell PTLD, independent of histology.
Rituximab: patient not respond to RIS.
Can be given as monotherapy or in combination with chemotherapy, concurrently or
sequentially (1).
NCCN guidelines recommend CHOP, given sequentially or concurrently with rituximab,
as chemo immunotherapy for monomorphic PTLD (B-cell type) and polymorphic PTLD
patient with fulminant or disease progression or relapse
For T cell–type monomorphic PTLD, the NCCN recommends brentuximab vedotin plus
CHP
(Cyclophosphamide, doxorubicin, prednisone) for CD30+ cases.
Adoptive immunotherapy with cytotoxic T lymphocytes (CTLs).
Are any other tests required?
CT guided biopsy: diagnosis of PTLD can only be made by histologic confirmation of
tumor tissue.
Bone marrow aspirate and biopsy.
PCR for trend of EBV viral load in the peripheral blood.
In situ hybridization BV-encoded RNA (Epstein-Barr early region [EBER]-1) probe.
Molecular genetic markers of antigen-receptor genes to assess clonality.
Immunophenotyping to determine lineage and therapy dependent markers (i.e., CD20)
CT or MRI or PET CT scan of the neck, chest, abdomen, pelvis, and head, looking for
evidence of any abnormal nodal or extranodal masses.
References:
1- Hrishikesh Samant; Pradeep Vaitla; Jiten P. Kothadia.Post Transplant
Lymphoproliferative Disorders. StatPearls Publishing; 2022 Jan-.
2- Ralf Trappe, Stephan Oertel, Veronique Leblond, Peter Mollee, Monica Sender, Petra
Reinke, Ruth Neuhaus et al. Sequential treatment with rituximab followed by CHOP
chemotherapy in adult B-cell post-transplant lymphoproliferative disorder (PTLD): the
prospective international multicenter phase 2 PTLD-1 trial. Lancet Oncology 2012.
Well done.
CT scan showed area of lower pole enlargement with non homogenous texture represent multiple radiolucent zones with radiolucency around renal capsule. Similarly, radiolucent areas are prominent in liver and spleen.
Differential diagnosis:
Acute pyelonephritis with multiple septic foci.
Acute rejection.
Thromboembolic disease.
Management :
for blood culture.
urine culture.
CBC and CRP.
Renal function test.
kidney biopsy:
Sometimes its inconclusive as invasion by neutrophils of interstitium and tubules is common phenomenon in both pyelonephritis and acute rejection.
Antibiotic has to be commenced and adjusted according to culture and sensitivity of urine and blood.
Micro RNA (miRNA) was investigated as a potential finding to differentiate between both.
Reference:
1- Acute Pyelonephritis in Renal Allografts–A New Role for MicroRNAs?.Steve Oghumu et al.Transplantation. 2014 Mar 15; 97(5): 559–568.
How can acute rejection give this radiological picture.
The picture is multiple lesions in the kidney,liver and spleen, multiple pyemic abceses is a posibility but then the patient will be moribund. However consider PTLD with a less drastic coarse.
What is your differential diagnosis?
Post-transplant lymphoproliferative disorders (PTLD)
Renal cell carcinoma
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.
Are any other tests required?
Briefly outline his management
Management of PTLD (challenging and needs multidisplinary team)
A- Modulation of immunosuppression
B- Specific treatment
Protocol
Management of RCC
References
Also CT chest and brain is required for complete assessment
Exellent.
DDx
– Posttransplant lymphoproliferative disease invoving the kidney , liver and spleen
– HCC with mtastasis
– Systemic infection ( Tb , HIV)
– NHL
How to manage
Diagnosis and staging
– History talking and physical examination especially serology of EPV of the donor and recipient date of transplant, organ type and immunosuppresion regimen
– Calcium uric acid and LDH ESR CRP
– EBV viral load
– Hepatitis B and C serology
– echocardiography especially if chemotherapy will be used
– Immunophenotyping
– CT abdomen with contrast
– Ct -PET for other body site affection
– Tissue biopsy(Stage and grade of disease Expression of the B cell surface antigen CD20
– Bone marrow aspiration and trephine
Treatment : MDT according to the staging
Reduction of IS should be considered in conjunction with other thera-pies, in patients who have risk factors which include clinically aggressive PTLD Ann Arbor stage≥III, elevated LDH and more than one extra-nodal site
Ct Pet if available at the end of the treatment course to assess remission
Surgical treatment for localized disease or emergency situation: intestinal involvement by perforation
Adoptive immunotherapy : indicated for patient who showed relapse after R- COP21 or other modalities
Ref
Luskin MR, Heil DS, Tan KS, Choi S, et al.The Impact of EBV status on characteristics and outcomes of posttrans-plantation lymphoproliferative disorder.Am J Transplant. 2015;15(10):2665–73
Luskin MR, Heil DS, Tan KS, Choi S, Stadtmauer EA, Schuster SJ, et al.The Impact of EBV status on characteristics and outcomes of posttrans-plantation lymphoproliferative disorder.Am J Transplant. 2015;15(10):2665–73
Well done.
Differential Diagnosis
PTLD
Low attenuation leisons in liver and spleen
? Diffuse PTLD
Metastatic disease,? Primary
Infection,? Fungal
MANAGEMENT
First step is to ascertain the diagnosis
I would prefer to go for a kidney biopsy after discussing with radialogist.
If it is diffuse PTLD then a multidisciplinary approach would be needed , again a staging process would be needed as mentioned in previous case and treatment decided accordingly which would revolve around
stopping CNI
decreasing MMF
Rituximab
CHOP
Adoptive immunotherapy
I would consider graft Nephrectomy if renal function is markedly deranged after oncologists consent
Nephrectomy if the lesion is only in the kidney is an option alongside with lymphoma treatment but the situation here shows multiple organ affection. As a nephrologist your role is to decide the fate of the graft in this situation.
A contrast-enhanced CT scan shows that there is a mass with different intensities of enhancement in the area of the renal pelvis (white arrows).
DD: widespread PTLD
Cancer with Mets: HCC
abscess with multiple location ex: Nocardia infection, TB
After the lesion has been looked at, a diagnostic biopsy can be either an excisional biopsy or a CT-guided core needle biopsy.
-Full blood count, electrolytes, renal function, glucose, liver enzymes, urate, lactate dehydrogenase (LDH), HIV types 1 and 2, hepatitis B and C, EBV serology, and CMV/EBV DNA titers. -Full blood count, electrolytes, renal function, glucose, liver enzymes, urate, and lactate dehydrogenase (LDH). Gold TB test and blood culture for bacteria, fungi, and tuberculosis
-Transplantation date and immunosuppressive regimen Every patient needs to know how well the transplanted organ is working, and the doctor who did the transplant should tell them how to do this.
Reference ;
Front-line management of the post-transplantation lymphoproliferative disorder in adult solid organ recipient patients — A British Society for Haematology Guideline
This case shows lesions in the liver
spleen
kidney
so all your investigation are needed and tissue diagnosis in such a patient to rule out
PTLD with widespread organ affection.
Or aHCC with metastasis.
What is your differential diagnosis?
Please outline your management :
Are any other tests required?
Thank you for this reply. Do you think that CT pelvis and chest are required?
I think so. it may reveal other organ involvement due to metastases or the diffuse pattern of PTLD
This patient has a lower pole heterogenous mass in the allograft kidney with hypodense lesions in the liver and spleen which could be possible metastasis.
The differential diagnosis would be:
Management
The patient will need further evaluation to get the diagnosis
He will need to have a biopsy of the renal mass
A PET CT scan
Once the biopsy confirms the diagnosis of malignancy, he will need to be managed by a multidisciplinary team including the oncologist
He will need to have his immunosuppression reduced and will require rituximab with or without systemic chemotherapy
Further Tests
How about metastatic HCC.?
What is your differential diagnosis?
The CT showed an allograft mass with two lesions one in the liver and other in the spleen.
Differential diagnosis:
– Past transplant lymphoproliferative disease (PTLD).
– Infectious – bacterial, fungal, viral ….etc.
– Metastatic tumor.
– Vasculitis.
Please outline your management:
Full physical examination: vital signs, lymphnodes examination, abdominal examination for organomegaly (spleen, liver).
Review of medical files – looking for EBV serology reported (D+/R-) would be associated with increased risk of EBV associated PTLD.
Laboratory:
Complete blood count- pancytopenia, anemia, thrombocytopenia or leukopenia, eosinophilic count.
Erythrocyte sedimentation rate, CRP, and bllod and urine culture.
Blood film- abnormal lymphocytes, plasma cells ..etc
Chest X-ray, gamma quantiferon test for TB.
Review of the CT – chest, abdomen and pelvis. If other nodes or organ involvement.
Consider CT guided biopsy is a must in such case
Serum T.protein , albumin , LDH, calcium and uric acid.
Kidney function, liver function and urinalysis.
Treatment:
As most of the allograft localized PTLD are in EBV R-/D+, and pears a good prognosis the prognosis becomes worse with distant metastasis such in our case, most of these PTLD’s are polymorphic and polyclonal in histological evaluation. The treatment includes:
– Stop one of the immunosuppressive medications used MMF, CNI and reduce the other, or switching to m-TOR inhibitor.
– Rituximab could be the only treatment required.
– Radiotherapy is another treatment option, with Rituximab.
– R-CHOP/ABVD can be a treatment option base on the pathology result and consultation with hematoncologist.
The overall prognosis in graft localized PTLD is relatively good with >70% survival this decreases to almost 43% with other localization.
Are any other tests required?
EBV viral serology, plasma and urine electrophoresis and immunofixation, kappa, lambda, B2 microglobulins., hepatitis profile and CMV PCR.
References:
(1) Láinez Ramos-Bossini AJ, Moyano Portillo Á, Ruiz Carazo E. Plasmacytoma-like post-transplantation lymphoproliferative disorder in renal allograft. Med Clin (Barc). 2020 Oct 9;155(7):323-324. English, Spanish. doi: 10.1016/j.medcli.2019.06.012. Epub 2019 Aug 22. PMID: 31447086.Allen UD, Preiksaitis JK; AST Infectious Diseases Community of Practice. Post-transplant lymphoproliferative disorders, Epstein-Barr virus infection, and disease in solid organ transplantation: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13652. doi: 10.1111/ctr.13652. Epub 2019 Jul 23. PMID: 31230381.
(2) Kojima Y, Takahara S, Kokado Y, Kakiya R, Yasuda J, Mori H. Post-transplant lymphoproliferative disorder presenting as a large tumor of the renal allograft. J Urol. 2001 May;165(5):1618-9. PMID: 11342932.Abbas F, El Kossi M, Shaheen IS, Sharma A, Halawa A. Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches. World J Transplant. 2020 Feb 28;10(2):29-46. doi: 10.5500/wjt.v10.i2.29. PMID: 32226769; PMCID: PMC7093305.
(3) Khedmat H, Taheri S. Characteristics and prognosis of post-transplant lymphoproliferative disorders within renal allograft: Report from the PTLD.Int. Survey. Ann Transplant. 2010 Jul-Sep;15(3):80-6. PMID: 20877272.
Thank you fine mention of conditions to affect the decision.
Vasculitis!!!!
What is your differential diagnosis?
A heterogeneously enhancing mass is visible on a contrast-enhanced CT scan in the area of the renal pelvis (white arrows).
Contrast-enhanced CT images of the liver and spleen reveal multiple regions of poor attenuation (black arrows).
In the view of the given scenario, these features are highly suggestive of PTLD.
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Please outline your management
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Are any other tests required?
References
Daan Dierickx,Thomas Tousseyn, and Olivier Gheysens. How I treat post-transplant lympho-proliferative disorders. BLOOD, 12 NOVEMBER 2015 x VOLUME 126, NUMBER 20
Is there a difference in your plan whether it is a limited PTLD or widespread as this case alongside with MDT.
A more intensive regimen, including CNS prophylaxis, is required in widespread disease, rather than sequential immunochemotherapy with rituximab followed by CHOP.
History
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What is your differential diagnosis?
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Please outline your management
The first-line treatment strategy is still immunosuppression reduction (RIS) or total discontinuation.
-Systemic Chemothrapy
Adoptive immunotherapy
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Are any other tests required?
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Reference
An extensive fine report.
But after ruling out other possibilities as metastatic HCC, what would be your plan in this advanced case along with MDT.
Thanks alot for you Prof.Dawlat Belal
-In EBV-seronegative patients with an increasing EBV load have
immunosuppressive medication reduced.
American Journal of Transplantation 2009; 9 (Suppl 3): S44–S58
Diagnosis:
PTLD affecting renal allograft, liver, and spleen.
Management:
Detailed history and physical examination.
Investigations:
1. CT guided biopsy
2. Peripheral smear
3. LDH
4. Serum Uric acid, Calcium
5. CT Head, neck, chest, abdomen.
6. EBV-PCR
Reduction of immunosuppression.
Monitor for rejection.
Stop CNI, Reduce MMF
Switch to mTOR Inhibitors
Rituximab
CHOP therapy
Adaptive immunotherapy
Tissue diagnosis is a must (biopsy).
the possibility of PTLD is high and depends on high index of suspicion in renal transplant recipient as it is second common malignancy post renal transplant, and here there is a mass in the renal allograft, and there is a small nodule suspicious in the liver and spleen.
management :
1- blood culture and sensitivity to exclude associated infection
2-CT chest
3-CBC for pancytopenia
4- uric acid and calcium
5- LDH
6-EBV PCR
7-image guided biopsy for histopathological diagnosis
8- if PTLD confirmed, holding of CNI (tacrolimus ) or MMF is recommended with reduction of others
9-introduce sirolimus as it has antitumor effect for keeping good graft function
10-monitore for rejection
11-rituximab
12-rituximab followed by chemotherapy
13-surgery for acute surgical complications
14-radiotherapy in rare cases
15-adoptive therapy in cases of failed conventional treatment in the form of donor lymphocyte infusion
of course , hematological consultation is mandatory in the management of PTLD.
references : the lecture of prof. Ahmed Halawa
Well done
It could be the other way round ie.aHCC with metastasis then a biopsy is mandatory and MDT.
The pictures showed a CT scan with oral contrast images. The image on the left showed the transplanted kidney in the right pelvic space with a large mass outlined by the white arrows. The other pictures showed small masses marked by black arrows (one in the liver and another one in the spleen).
These findings suggest a malignant tumour affecting the kidney allograft with metastasis to the liver and spleen (High suspicion of PTLD due to the higher incidence in transplant recipients compared to other primary kidney neoplasm and the involvement of other lymphoid tissue like spleen and liver).
I will recommend complete laboratory evaluation and pan CT screening (CT head, Neck and chest). Additionally, I will pay attention to findings suggestive of the PTLD like:
· Unexplained anaemia, thrombocytopenia, or leukopenia
· An elevated level of serum lactate dehydrogenase (LDH)
· Hypercalcemia
· Hyperuricemia
· Monoclonal protein in the serum or urine.
· Epstein-Barr virus (EBV) PCR in the peripheral blood
· Lymph node excisional biopsy in case of any detectable lymphadenopathy.
The management discussed below is based upon confirmation of the diagnosis of PTLD. However, if the tissue biopsy shows another tumour, then the treatment will be based on the latest guidelines concerning the underlying pathology.
1- The most effective line of therapy is the restoration of the patient’s immunity (1). Therefore, reducing immune suppression will be the first step (up to the complete discontinuation of immune suppression in selected cases) (1).
2- Rituximab (anti-CD20 monoclonal antibody) can be given when the lymphoid tissues show CD20-positive cells and in low-risk patients (1).
3- In high-risk patients or aggressive PTLD, the recommendation is to use cytotoxic chemotherapy with the reduction of immune suppression (with or without Rituximab) (1).
4- The use of mammalian target of rapamycin inhibitors (mTOR; sirolimus and everolimus) has not been incorporated in solid guideline recommendations. However, some experts have suggested its use due to their proven antineoplastic properties (1).
References:
1) Danovitch GM. Handbook of Kidney Transplantation. Sixth Edition, Wolters Kluwer, eISBN 9781496388841, 2017.
Well done a comprehensive answer.
In this case if confirmed PTLD what would be a MDT approach to a wide spread situation?
Would the graft be a priority?
Thanks, Prof. Dawlat,
Regarding the MDT approach in this specific case scenario, we will need the expert opinion of a haematologist (or oncologist) regarding the possible chemotherapy protocols. Additionally, I will discuss with the transplant surgeon regarding the feasibility of kidney allograft nephrectomy (due to the considerable tumour mass in the allograft and the opportunity to stop all immune suppressive drugs after allograft nephrectomy)
In this case scenario, saving the patient’s life will have priority over preserving the allograft.