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1. A 36-year-old man with a right renal transplant from his brother presented with loss of weight, night sweats, and night fever associated with deep pelvic discomfort. He has excellent kidney function. Currently, he is on Tacrolimus-based dual immunosuppression. His CT pelvis is shown below:
- What is your differential diagnosis?
- Briefly outline his management
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Differential diagnosis
May be lymphadenopathy ( PTLD)
Granulomatous infection as TB
Outline the management
1. Investigations CBC,LFT,KFT,LDH,uric acid
2.metastic workup CT abdomen , CT chest , lumber puncture for CNS involvement
3. Biopsy from the lesion , PET scan for staging
After diagnosis
Reduction of immunosuppression
Rituximab
Chemotherapy
Radiotherapy
Adoptive immunotherapy
* PTLD can present as a localized or disseminated disease. Malaise, fatigue, fever, and a mononucleosis-like picture are some presenting features of PTLD. B-symptoms of fever, night sweats, and weight loss, as well as lymphadenopathy, are also frequent manifestations. PTLD develops rapidly and may cause compressive symptoms near the tumor site. Patients who are high-risk (EBV IgG Donor+/Recipient-) are generally noted to be at risk for developing PTLD of the transplanted graft causing a decline in organ function. It may be the only presenting symptom. The high index of suspicion for PTLD is necessary given highly variable presentation also rising EBV PCR in post-transplant recipient raises the possibility of PTLD.
*Differential diagnosis
Given the highly variable presentation of PTLD differential diagnosis should broadly be considered depending upon the patient’s clinical presentation. Rejection of allograft organ (in the case of graft involvement), opportunistic infections, and common infectious etiology should be considered in the differential diagnosis.
*Management:
Besides a detailed history and physical examination of patients whom PTLD is considered, the investigations include:
Complete blood cell count (CBC) to evaluate unexplained anemia, thrombocytopenia or leukopenia
Comprehensive chemistry panel
Lactate dehydrogenase (LDH) to evaluate for tumor lysis syndrome.
Urine analysis for Monoclonal protein, hyperuricemia
EBV Status of recipient and donor
Epstein-Barr virus (EBV) testes: EBV IgM, EBV IgG, EBV viral load (PCR). Also, serial EBV quantitative PCR measurement (that is rising) is more important and valuable than single positive EBV quantitative PCR. Negative EBV PCR does not exclude the possibility of PTLD.
Radiological studies include computed tomography (CT), magnetic resonance imaging (MRI), and positive positron emission tomography (PET) scanning to evaluate spread.
Lumbar puncture with cerebral spinal fluid (CSF) analysis (EBV PCR in CSF fluid) in patients with PTLD with CNS involvement
Histopathologic examination of the tumor can only determine the definitive diagnosis
Treatment strategies for PTLD are different from the management of lymphoproliferative disorders in immunocompetent patients. The mainstay of the management strategy includes the reduction of immunosuppression, surgical excision of the localized lesion, radiation therapy, rituximab monotherapy, immunochemotherapy, chemotherapy, stem-cell transplantation, and immunotherapy
Reduction of Immunosuppression
The initial management of PTLD is to reduce immunosuppression to restore cellular immunity without compromising allograft function. Reduction of the immunosuppression strategy should include at least 50% reduction calcineurin inhibitors (cyclosporine or tacrolimus) and discontinuation of antimetabolic agents such as azathioprine or mycophenolate mofetil (MMF).
Rituximab
Rituximab is a monoclonal anti-CD20 antibody. It is a standard of care in patients that do not respond adequately to reduced Immunosuppression. Rituximab can be administered as a single agent after the reduction of immunosuppression medications or in combination with chemotherapy (concurrently or sequentially). In the PTLD-1 study, the complete treatment response rate was around 25% after standard induction plus four courses of rituximab every 21 days. The primary side effects of rituximab include infusion reactions and increased risk of infections due to neutropenia. Also increased risk of hepatitis B reactivation in patients with positive hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (anti-HBc) should be kept in mind.
Chemoimmunotherapy
Chemotherapy is indicated in patients who have not had an adequate response to reduced immunosuppression and rituximab. It is usually administered in combination with rituximab for patients with CD20+ PTLD. R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) is commonly used in chemotherapy regimen for most patients with PTLD.
Radiation Therapy
Radiation therapy is used for patients with localized disease and those with central nervous system (CNS) involvement either alone or in combination.
Adoptive Immunotherapy
Adoptive Immunotherapy uses EBV-specific cytotoxic T lymphocytes (EBV-CTLs) or donor lymphocyte infusion (DLI) to induce a robust EBV-specific cellular immune response in patients with EBV-associated PTLD. However, adoptive immunotherapy is associated with a high risk of developing acute and chronic graft-versus-host disease (GVHD).
Samant H, Vaitla P, Kothadia JP. Post Transplant Lymphoproliferative Disorders. [Updated 2023 Feb 12]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK513249/
Differential Diagnosis:
PTLD
granulomatous infection:TB
Malignancy :metastasis
work up:
history ,examination and investigations
like LDH ,Uric acid ,cbc,
imaging CT CAP, EBV and other serology
PET Scan
Histopathology is the golden standard in diagnosis with immunophenityping and immune cytogenetics
Types:
Monomorphic ,Polymorphic , classic Hodgkin lymphoma like PTLD
Treatment :Rituximab specially in early lesions ,monomorphic and polymorphic in cells carry CD20.
Chemitherapy in some cases
Reduction of immunotherapy
may switch to m-TOR inhibitor like sirolimus
Lymphadenopathy is common in 30% of PTLD cases
PTLD negative EBV can happen with other viruses like HSV HHV 8 and CMV
PTLD ,The majority of the cases of PTLD are associated with Epstein-Barr virus (EBV) and occur within the first posttransplant year.
Other viruses like HSV8
Treatment / Management
Reduction of Immunosuppression
Rituximab
Chemoimmunotherapy
Radiation Therapy
Adoptive Immunotherapy
https://www.ncbi.nlm.nih.gov/books/NBK513249/#:~:text=PTLD%20is%20a%20proliferative%20B-cell%20disorder%20that%20is,EBV-negative%20PTLD%20occurs%20in%20approximately%2023%25%20of%20patients.
This CT shows enlarged lymph nodes; differential diagnosis is PTLD, other bacterial infections as 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.
cases of PTLD may offer proper response to rituximab.
Present ct picture shows a lesion in left iliac fossa,probably enlarged lyph node.
Differential diagnosis
PTLD
various opportunistic infections such as disseminated mycobacterial or fungal infections.
Disseminated bacterial infections
EVALUATION
An accurate diagnosis of PTLD requires a high index of suspicion, since the disorder may present subtly and/or extranodally . The diagnosis of PTLD should be suspected in a patient who has undergone allogeneic transplantation presenting with B symptoms (fever, weight loss, night sweats), unexplained hematologic or biochemical abnormalities, and/or signs or symptoms attributable to the infiltration of extralymphatic tissues. PTLD may also cause symptoms similar to those seen with organ rejection or similar to side effects from immunosuppressive medications.
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 of sufficient size to ensure full characterization of the lesion. Biopsy tissue should be reviewed by an expert hematopathologist and evaluated by morphology, immunophenotype, the presence or absence of EBV, cytogenetics, and antigen receptor gene rearrangement studies
Initial management is largely dependent 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 .
Lymphadenopathy is common in PTLD patients and it seen in 38 % .
Several hypotheses have been postulated that CMV or another viral infection as HSV virus can also cause PTLD .
Fedaey Abbas, Mohsen El Kossi, Ihab Sakr Shaheen, Ajay Sharma, and Ahmed Halawa.
Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches.World J Transplant. 2020 Feb 28; 10(2): 29–46.
What is your differential diagnosis?
The CT shows pelvic calcific soft tissue mass likely pelvic lymphadenopathy Differentials could be infectious or malignancy
1– Infectious cause : infectious Mononucleosis (IMN), disseminated TB, abscess
2- Malignancy : PTLD , metastatic lymph node
Briefly outline his management
Diagnosis:
· Detailed history about the EBV serology status of the Donor and the recipient, the time after transplantation .Besides, CMV serology (could be a a risk for PTLD in EBV negative) and HHV8.
· Blood tests including FBC, LDH, uric acid, CA level LFT. Virology for HIV, hepatitis, CMV and EBV
· Imaging: CT chest, abdomen, and pelvis and PET scan to confirm the diagnosis and for staging. Imaging of the brain and LP to exclude CNS involvement
· The gold standard for diagnosis is excision biopsy with histo-pathologic examination (according to the World Health Organization 2017, 4 types: Monomorphic PTLD, Polymorphic PTLD, Early lesions, Classical Hodgkin lymphoma). A bone marrow may be required to check the extent of the disease.
Treatment:
· MDT approach involving onco-hematology
· Reduce Immunosuppression by 25%: Stop antimetabolites, Reduce the dose of CNIs, aiming 50% reduction in trough level. Keep prednisolone at a dose of 7.5 to 10 mg. In extensive disease stop all immunosuppression except steroids. This helps the T lymphocytes to overcome the unbalanced B cell proliferation. Assess the response after 2-4 weeks. If no complete remission is achieved , move to Rituximab. It is important to Monitor allograft function for rejection.
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
2. Zimmermann H, Babel N, Dierickx D, et al.. Immunosuppression is associated with clinical features and relapse risk of B cell post-transplant lymphoproliferative disorder: a retrospective analysis based on the prospective, international, multicenter PTLD-1 trials. Transplantation 2018; 102:1914–1923.
1- Differential diagnosis include:
lymphomatous mass
Colonic cancer
Tuberculous mass
2- full investigations are needed:
CBC with peripheral blood picture
Blood chemistry
Lower GI endoscopy
Mass biopsy
Transplanted Patient on tacrolimus based immunosuppression; presented with good graft function and night fever ,night sweat
CT pelvis showed pelvic mass
DIFFERENTIAL DIAGNOSIS:
PTLD
TB.
Cancer colon
Abscess
Management approach:
-Detailed history with full clinical examination including lymph nodes examination.
-History about recent contract with cases of TB or other viral infection.
– pre transplant history of EBV in both donor and recipient.
-EBV PCR.
-CBC ,CRP, ESR – to evaluate for leukopenia.
-tacrolimus trough level.
-urine and sputum testing for TB.
-uric acid, ca ,phosphate and LDH to detect tumor lysis syndrome
-viral screening especially opportunistic infections as CMV,HHV8,HIV
-CT Abdomen and chest to detect other masses of lymph nodes
-biopsy CT guided with pathological diagnosis
If malignancy was diagnosed
Full body Imaging and PET scan should be done.
-nephrology , urology and oncology consultants should be involved
This case most probably EBV relate PTLD
(PTLD) represent a heterogeneous group of lymphoid and plasmacytic proliferative diseases, occurring as a result of immunosuppressive therapy in patients who have received solid organ or bone marrow transplantation .
The disease can occur in a wide range of locations, which may be limited to nodal disease or disseminated to involve a variety of extranodal sites including the bone marrow, central nervous system, gastrointestinal system and the transplanted allograft.
It Is one of the most common cancers in kidney transplant recipients. Moreover, presence of PTLD can reduce the patient and allograft survival.
Epstein-Barr virus (EBV) is a significant risk factor for the development of PTLD. However, a substantial portion of PTLD cases is not associated with EBV.
The EBV-negative PTLD cases tend to occur late when compared with those EBV-positive cases . It is still not known whether EBV-negative PTLD may actually represent another disease entity which requires more aggressive treatment
-Treatment
No specific antiviral medications for EBV .the main treatment is reduction of immunosuppressive medication by 50% with monitoring of graft function.
-changing tacrolimus to mTORi might improve malignancy although MMF it has a proven effect only in Kaposi sarcoma.
But many studies has documented the protective effect of mTORi in malignancy.
Will other studies mention that the carcinogenic effect is mainly related to the dose of immunosuppression.
-stop MMF
– Management of PTLD according to type.
– Radiotherapy can be used for localized diseases .
– Surgery for mass removal and for complications as ureteric obstruction
-Rituximab can be given as a single alone or in combination with chemotherapy .
Chi Yuen Cheung, Maggie Kam Man Ma, Ka FoonChau. Posttransplantlymphoproliferative qdisorders in kidney transplant recipients: a retrospective cohort analysis over two decades in Hong Kong.Oncotarget. 2017 Nov 14; 8(57): 96903–96912. Published online 2017 Jun 30.
The image suggests a tumor in the region that could be lymph node. In this situation I would think of two lines of possibility:
1 – Malignancy
– PTLD
2 – Infectious disease
– Tuberculosis
– fungus
We could perform a more accurate exam such as a pelvic MRI
Once the possibility of PTLD was considered, viral research would be necessary, since more than 80% of cases are related to oncoviruses, mainly EBV:
– EBV PCR
– CMV PCR
I would request an opinion from the surgery to perform exploratory videolaparoscopy for biopsy for histopatologic study + culture (BK and fungus)
What is your differential diagnosis?
Based on the symptoms present and infection observed in CT pelvis, the differential diagnosis is of PTLD, lymphoma
Briefly outline his management
Management includes to the investigation of the detailed history via CT contrast or PET guided biopsy, tissue typing for EBV, HHV 8 in the tissues.
Next step is reducing or stopping the immunosuppression
Switching the immunosuppression to sirolimus or mTOR inhibitors
Chemotherapy in case of Hodgkin lymphoma and R-CHOP treatment in case of NHL. Radiotherapy is recommended depending the severity of the disease.
Q1: This patient presented with B syndromes and pelvic lymphadenopathy.
So the differential diagnosis will be two categories: first one chronic infection such as extra pulmonary TB and second one malignancies especially PTLD.
Q2: He needs a comprehensive history about induction therapy pre-transplantation infections dose and level of tacrolimus (low or high dose) EBV serology status before transplantation, physical exam for lymphadenopathy in other sites and external involvement especially central nervous system.
Lab test such as EVB and CMV viral load, TB, NAT, PCR, CBC, ESR, LDH, AST, ALT, Uric acid, Ca, P, CXR, chest and abdominal CT scan, brain MRI, PET-scan, lymph node biopsy if possible Bone marrow and CSF study if indicated.
Treatment depends on diagnosis (if-PTLD) staging and extension to other organs is necessary.
Immunosuppression reduction by reduction of CNI dose and stopping-MMF or other antimetabolites switch to m TOR inhibitors.
If unresponsive: Use IV Rituximab 375mg/m2 for four weeks
For more advance cases:
Chemotherapy with CHOP and adoptive immunotherapy may be the other options
In resistant cases with graft involvement, transplant nephrectomy may be considered.
· What is your differential diagnosis?
36 Y old male, LR renal TX recipient, presented with weight loss, night sweats and night fever and deep pelvic discomfort. Normal graft function.
CT pelvis shows: enlarged irregular left iliac mass that could be a lymph node.
DD:
1- Malignancy: PTLD, lymphomas
2- Infections: TB.
Tissue biopsy is very important.
· Briefly outline his management:
1- Tissue biopsy and histo-pathological examination:
2- History and examination:
pre-TX EBV D/R status, CMV serology D/R status, TB status, full immune-suppression history.
Full clinical examination
3- Routine investigations and CT-chest, abdomen +/- PET CT.
4- MDT discussion with oncologist, infectious disease, surgical team and nephrologist.
5- The most probable diagnosis is PTLD, if it is confirmed so, the following options of treatment include:
A- Reduction of immunosuppression.
B- Switch Tacrolimus to m-TOR inhibitors.
C- Rituximab alone or Rituximab with other chemotherapy depending on type and stage of PTLD.
D- Monitor graft function after reduction of immunosuppression.
E- Adoptive immunotherapy is under trial.
Thank you all for this excellent answer.
How often does PTLD present with lymphadenopathy?
Around 30%-45%.
You mentioned EBV as a causative agent in the majority of PTLD, what are other viruses that could be associated with PTLD?
Other viruses that can predispose to PTLD include CMV, HHV-8, HCV and HTLV-1.
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.
*CT pelvis show Lt iliac fossa mass,in post kidney transplant patient with fever and wt loss the differential diagnosis is between malignancy (PTLD with lymphadenopathy or chronic infections like TB with abscess
* workup include blood test for viral infections like CMV and EBV, screening for TB and tissue biopsy to rich the exact diagnosis
Differential diagnosis
This is differential of pelvic mass in patient immune compromised it looks like lymph node enlargement which may be primary malignancy or metastatic.(PTLD)
Other differential infections like tuberculosis or EB virus or fungal infections .
Other lymphoma.
Management
Detail history about the onset of disease , and duration of fever ,full examination for other lymph nodes,chest,abdominal and skin.
Consulted for haemato-oncologist.
Investigations
CBC..RFT..LFT..VIRAL SCREEN(HBV.HCV.HIV.EBV.HSV8)
Ct abdomen,chest and PET scan.
Tissue biopsy.
TREATMENT
After stablish the diagnosis we treat PTLD as
1.50% reducing in tacrolimus dose,or shifted to sirolimus(mtor)
2.stop anti metabolites like mmf.
3.rituximab +or –chemotherapy.
Rituximab (Rituxan, Mabthera), a chimeric monoclonal antibody to the CD20 antigen on the surface of B-cell lymphocytes, has been used increasingly in the treatment of PTLD.
Chemotherapy and also radiotherapy.
references
1.Young L, Alfieri C, Hennessy K et al. Expression of Epstein-Barr virus transformation-associated genes in tissues of patients with EBV lymphoproliferative disease. N Engl J Med 1989; 321: 1080– . 2 Yang J, Tao Q, Flinn IW et al. Characterization of Epstein-Barr virus-infected B cells in patients with posttransplantation lymphoproliferative disease: Disappearance after rituximab therapy does not predict clinical response. Blood 2000; 96: 4055– 4063.
36-year-old man with Related renal transplant (duration unknown) now presented with pelvic discomfort and B- symptoms. Renal functions stable and on Tac based dual immunosuppressive regime. CT Pelvis shows a left pelvic mass.
What is your differential diagnosis?
· Post-transplant lymphoproliferative disorder
· Disseminated Tuberculosis
· Fungal Infections
Briefly outline his management:
· History: Duration of transplant, duration of symptoms, amount of weight loss, GI symptoms, pulmonary signs and symptoms, CNS related symptoms, dosage of immunosuppressive agents and specifically Tacrolimus trough levels.
· Examination: Lymph nodes, hepatosplenomegaly, oral cavity, CNS, cardiac and respiratory examination.
· Blood work: Complete blood count, Routine biochemistry including calcium & urate levels, LDH levels, EBV PCR, IGRA for Tuberculosis, Fungal markers and cultures, viral serology for Hepatitis B & C as well as HIV.
· Urine examination for monoclonal proteins
· Imaging: Contrast enhanced CT Chest Abdomen & pelvis. Contrast MRI brain + CSF studies in case of neurological symptoms.
· Tissue Diagnosis: Biopsy for histopathology & immunophenotyping
· Management:
a. Involve multidisciplinary team including oncologist, hematologist, transplant physician and radiologist.
b. Reduce immunosuppression by decreasing Tac by 50% and stopping antimetabolite. This allows risk of rejection which must be closely monitored.
c. Rituximab depending on histopathological class of disease.
d. Chemotherapy and radiotherapy in coordination with MDT.
e. Monitoring response to therapy. Disease activity, EBV viral load and renal functions.
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-.
Post-transplant lymphoproliferative disorder (PTLD) constitutes a heterogeneous group of lymphoproliferative disorders increasing in medication-induced immunocompromised transplant recipients, including both solid organ transplantation (SOT) and allogeneic hematopoietic transplantation (HSCT).1 Although not required for diagnosis of PTLD, Epstein–Barr virus (EBV) plays a major role in the pathogenesis of a substantial proportion of cases. However, more recent reports show up to 50% of SOT-related cases are not associated with EBV.2
Established risk factors for PTLD development include EBV serological status at time of transplantation, type of transplant, and the type and intensity of immunosuppressive medication.1 In addition, there is growing interest in other potential contributing factors such as the role of the human leukocyte antigen system and of non-EBV viruses. Similar to other lymphomas, the gold standard for diagnosis is excision biopsy with histopathologic examination and categorization according to the World Health Organization 2017 classification.3 Despite their heterogeneity, about 85% of the PTLD cases are classified as CD20-positive diffuse large B-cell lymphomas (DLBCL). More in depth genetic-molecular research has increased our knowledge on pathogenesis of both EBV+ and EBV− PTLD.1,2
Management of PTLD
References
1. Dierickx D, Habermann TM. Post-transplantation lymphoproliferative disorders in adults. N Engl J Med 2018; 378:549–562.
Dharnidharka VR, Webster AC, Martinez OM, et al.. Post-transplant lymphoproliferative disorders. Nat Rev Dis Primers 2016; 2:15088.This is an excellent review covering in depth all important issues on PTLD, written by authors with extensive clinical and/or research experience in he field.
3. Swerdlow SH, Weber SA, Chadburn A. Swerdlow SH, Campo E, Harris NL, et al.. Post-transplant lymphoproliferative disorders. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues 4th ed.Lyon, France: IARC Press; 2017. 453–462.
4. Dierickx D, Tousseyn T, Gheysens O. How I treat postttransplant lymphoproliferative disorders. Blood 2015; 126:2274–2283.
5. Parker A, Bowles K, Bradley JA, et al.. Management of post-transplant lymphoproliferative disorder in solid organ transplant recipients—BCSH and BTS guidelines. Br J Haematol 2010; 149:693–705.
6. Zimmermann H, Babel N, Dierickx D, et al.. Immunosuppression is associated with clinical features and relapse risk of B cell posttransplant lymphoproliferative disorder: a retrospective analysis based on the prospective, international, multicenter PTLD-1 trials. Transplantation 2018; 102:1914–1923.
Symptoms of Weight loss, fever, and night sweat with dual immunosuppression so the DD will be PTLD as the CT pelvis shows lymphadenopathy or infection including extrapulmonary TB.
I’ll take history about the time after transplantation and the EBV serology status of both the Donor and the recipient, also CMV serology can be a risk for PTLD in EBV negative, HHV8, and any past history IGRA test, and TB NAT PCR.
Physical examination for lymphadenopathy, CNS involvement, PTLD mainly extra nodal but still can be nodal distribution in up to 38%, EBV negative recipient from EBV positive donor can be the most important risk factor for PTLD in addition to the cumulative dose and duration of immunosuppression.
Investigations include FBC and LDH, LFT, staging CT including chest, abdomen, and pelvis plus PET scan for staging and to confirm the diagnosis need tissue biopsy with histopathological in including IHC staining and subtypes
We always need MDT approach with onco haematology team along with transplant nephrologist and histopathologist if tissue biopsy confirmed PTLD and according to the staging will be direct the treatment and by principle.
Reduction of immunosuppression is one of the key factors for the treatment including 50% reduction of the CNI and modification of MMF to Mtor inhibitors , Rituximab alone or in combination with chemotherapy based on the type and stage of the PTLD.
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.kidney transplantion handbook 6th edition.
Soft tissue mass mostly enlarged inguinal LN with solid organ transplant mostly PTLD.
DD
Infection (TB, fungal infection)
Autoimmune
NHL
Management
looking for lymphadenopathy and associated comorbidities.
CT with contrast and PET for disease staging.
Tissue biopsy& identification of EBV DNA in tissue.
EBV viral load
Labs: CBC, KFT, bone profile, LFT,LDH, uric acid, HIV, CMV and Hepatitis B
BM aspiration and biopsy in case of cytopenia.
Gadolinium enhanced MRI +/- CSF for cytology, flowcytometry and EBV PCR to check for CNS involvement.
Cardiac evaluation before treatment with anthracycline.
Treatment of PTLD
Reduction of immunosuppression to enhance immuno-surveillance is the first step in treatment.
Monitoring of graft function and patient counselling regarding risk or rejection.
Follow up of response to treatment.
Treatment based on the PTLD subtype:
Early cases: immunosuppression reduction within 2-5 weeks can lead to response in 80% of cases, Rituximab can be used in refractory cases if PTLD is CD 50 +ve despite immunosuppression reduction.
Polymorphic PTLD: immunosuppression reduction in addition to Rituximab if CD 50 +ve. If CD 50-ve or high-volume disease associated with good performance status, chemotherapy(CHOP) can be used.
Monomorphic PTLD: reduction of immunosuppression in addition to Rituximab with or without chemotherapy, Rituximab can be used for mild disease or when chemotherapy is not tolerated.
Adoptive therapy in case of resistant disease
Radiotherapy is indicated in localized disease/ CNS affection.
Surgical approach is limited to localized or complicated disease.
GCSF if indicated, PCP prophylaxis and fungal prophylaxis
Counselling regarding impact of treatment on fertility, with possible need for sperm preservation
Depending on the degree of immunosupression and intensity and compromization of t-cell function the risk of PTLD increases. It is more prevelant in the first year paralle to intesnity of immunosuppression. The serologic status is a key, with the risk of developing PTLD more in EBV seronegative recepents of seropoistive donors. Mostly extranodal.
We need to decrease the immunosuppression. As this is important, we have to differntiate sypmptoms from rejection as treatment is opposite. Here we have lumph node suggesting PTLD. so treatment mainly by reduction of immunosuprresison. radyotherapy, chemotherapy and Rituximab. Rituximab is usally incorporated but the exact effect in PTLDis not well documented
https://www.uptodate.com/contents/treatment-and-prevention-of-post-transplant-lymphoproliferative-disorders?search=post-transplant%20lymphoproliferative%20disorders%20management&source=search_result&selectedTitle=1~102&usage_type=default&display_rank=1#H22
need MDT approach with oncohematologyy team along with transplant nephrologist andhistopathologistt if tissue biopsy confirmed PTLD and according to the staging will be direct the treatment and by principle , reduction of IS is one of the key factors for the treatment including 50% reduction of the CNI and modification of MMF to Mto inhibitors , rituximab alone or in combination with chemotherapy based on the type and stage of the PTLD.
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.kidny transplantion handbook 6th edition.
There is irregular soft tissue mass or lyphadenopathy for which my differential diagnosis are-
a) PTLD
b) Lymphoma
c) Tuberculosis
d) Other malignancy
Detail history and physical examination to find out lymphadenopathy in another site, anaemia, organomegaly, lung consolidation/ effusion, neurological features.
Investigations:
-CBC, ESR, CRP
– S.LDH, Uric acid
– Ultrasonography of whole abdomen
– CXR P/A view
– LFT
– EBV, CMV serology
– 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) Follow up for recurrence, graft function
The CT pelvis shows irregular outline of the iliac lymph nodes in a kidney transplant patient on immunosuppressive medications…There is history of fever, weight loss and night sweats which can have various differential diagnosis
Infections such as Tuberculosis are the most common causes in endemic countries like India and a FNAC or lymph node biopsy is needed to establish the diagnosis…Other causes of lymphadenopathy include fungal infections, brucellosis, Lymphoma and metastatic carcinoma from pelvic organs or any other solid organ metastasis should be kept in mind….
Last but not the least, I would like to keep in mind PTLD which require high degree of suspicion
Management of this patient includes investigations and treatment….
I would like to the date of transplant, induction agent used, history of any rejections and steroid top up medicines..I would like to know if the EBV status of the donor if available and recipient pre transplant EBV status…
Routine labs like CBC, Kidney function test, LDH, Electrolytes, EBV serology, Incisional biopsy of the lesion, Whole body PET Scan is indicated to detect the spread of the disease… I would involve hematologist, oncologist and take their opinions also..
Treatment will be reduction of immunosuppression…CNI should be reducded by 50%…MMF/AZA should be stopped and maintained on low dose steroids…. If the reduction in the immunosuppression fails to achieve the desired results, patient needs chemotherapy including CHOP (cyclophosphomide, doxorubicin, vincristine, prednisolone) in adult B cell PTLD. ..
Rituximab plus CHOP therapy is recommended with reduction in immunosuppression if there is aggressive lymphoma.. Radiotherapy maybe offered with concurrent immunosuppresion…
In general EBV positive PTLD has a better prognosis as compared to EB V negative PTLD….
Professor questions
1. How often does PTLD present with lymphadenopathy?
PTLD is mostly extranodal.
Lymphadenopaghy presents in about 38%.ymphadenopathy less than 10%
2. what are other viruses that could be associated with PTLD?
HHV8, HCV
This CT image is showing right pelvic soft tissue mass likely pelvic lymphadenopathy , in the setting of his renal transplantation and chronic immunosuppression use in addition to his presentation of loss of weight, night sweats, and night fever so our differentials could be infectious or malignancy
1- Infectious cause : infectious Mononucleosis (IMN), disseminated TB, abscess and invasive fungal infection
2- Malignancy : PTLD , metastatic lymph node
1- the first step is to do a physical exam and testing, which usually includes blood and radiology tests.
If you have abdominal complaints, you may have an endoscopy or colonoscopy performed.
2- Our initial management is largely dependent upon the type of PTLD:
References :
1) Up to date : Treatment and prevention of post-transplant lymphoproliferative disorders
2) https://www.cincinnatichildrens.org/health/p/post-transplant-lymphoproliferative- disorder
3) 2.Professor Ahmed Halawa lectures.
36 years patient post Kidney transplant
– graft function excellent, on TAC MMF (probably steroid withdrawal regime)
Duration post transplant ?? – not mentioned
Presentation – Fever. night sweat, weight loss with left Pelvic lymph nodal mass on CT
Differential Diagnosis:
Management:
Detail history:
duration post transplant
Induction agent (ATG) used ?
GI symptoms / loose stool / Rectal bleed / Loss of appetite
Cough / Breathing difficulty / hemoptysis /
Genital lesion / scrotal mass
Urinary symptoms (voiding problems , dysuria, frequency, hematuria, pus discharge) – GUTb / UTI
any other swelling in Groin / axilla – lymph node mass
H/o HIV – if yes, details of drugs used
History of prior cancer or recurrent infections
Thorough Clinical Examination –
vitals – respiration rate, O2 saturation by pulse oxymeter – (CMV)
axilla and groin nodes
limb skin lesion / scrotal mass / genital lesion
pelvic / abdominal tenderness
Lab tests –
Complete blood count with peripheral film, ESR – look for cytopenia, immature WBC
LFT, Uric acid, Calcium, LDH
Urine ME, proteinuria
serology for HIV, HBV, HCV; CD4 count (if HIV positive)
EBV viral load (early onset PTLD associated with increased viremia)
CMV PCR – viral load
Tacrolimus and MMF drug level
Sputum for AFB 9if available)
Tuberculin skin test
Review the detail CT films and report – for any other mass
if not available – to get CE CT Chest, Abdomen and pelvis with oral and IV contrast
(Oral + IV hydration)
Biopsy from any superficial Lymph node mass // CT guided Biopsy from Pelvic mass
– complete IHC for cancer panel (including CD20, CD50)
Treatment :
monitoring pattern of fever and to give symptomatic treatment
Most probably dealing with Early onset PTLD
1.To Involve multidisciplinary team including hematologist and oncologists, psychologist
To discuss with patient party regarding diagnosis (PTLD/ Cancer/ Infection) and treatment plan, modification of immunosupression and risk of rejection.
2.first line of Tt – modification of immunosupression
To stop MMF / AZT
Reduce Tacrolimus dose (minimum trough level); can change to Cyclosporin
Restart Prednisone
3.If No response in 3-4 weeks –
can change CNI to Sirolimus – but increased risk of rejection and proteinuria need intense monitoring
and Inj Retuximab Inj (375Mg/M2 BSA) with pre-medications — weekly x 3
(Retuxi monotherapy also responds well in CD20+ lesion)
4.If no response – to add Chemotherapy (CHOP regimen) with GSF
Cotrimoxazole for PJP x 6months
associated CMV – treatment with Valgancyclovir
5.If lesion still persists – local Radiation
to keep on intense surveillance for recurrence, rejection and other problems
additional Questions
How often does PTLD present with lymphadenopathy?
about 10%
You mentioned EBV as a causative agent in the majority of PTLD, what are other viruses that could be associated with PTLD?
CMV
HHV8
HCV
CT SCAN SHOWS LEFT ILIAC LYMPH NODAL MASS
PATIENT HAS SYSTEMIC SYMPTOMS
CONSIDERING THE PROFILW NODAL PTLD CAN BE CONSIDERED AS DIFFFERENTIAL DIAGNOSIS ALONG WITH LYMPHOMA
VIRUSES ASSOCOATED
EBV – VERY COMMON’
CMV
HHV
MANAGEMENT
REDUCTION OF IS
ASSESS THE SYMPTIMS AND NODAL MASS REDUCTION
RETUXIMAB 375 MG/M SQ – 4 WEEKLY DOSES
SEQUENTIAL TEHRAPY – CHEMO AFTER RETUXIMAB
ADAPTIVE IMMUNOTHERAPY
IN GENERLA HAVING SYSTEMIC SYMPTOMS IS POOR PROGNOSTIC SIGN ALONG WITH MULTI ORGAN INVOLVEMENT , CNS INVOLVEMENT
Our patient is a young 36 years old renal transplant recipient who presented with night fever , night sweats , loss of weight and deep pelvic pain ;
The CT pelvis shows enlarged inguinal lymph nodes with heterogeneous borders
The Differential diagnosis is ;
-PTLD
-Metastatic solid malignancy
-Infections ( TB adenitis on top)
Management:
-Thorough history of the onset , course and duration of symptoms , if they are recurrent or not and pattern of fever .
-History of induction – what was the inducting agent if any
-History of malignancies or recurrent infections
-Full examination – LN examination
-Full labs and chemistry
-Biopsy CT guided or from another easier site
-Drug levels
-Virology screening ; CMV , EBV
-Pan CTs – PET Scan
-Multidisciplinary team plan including haematologist and oncologists
-Stop MMF or Aza ; Minimise the CNIs to 50% , reintroduction of steroids accordingly
-Shifting to mTori is of undemonstrated evidence
– Mabthera can be used in some cases of PTLD ; CD50+ve
-CHOP regimen
References:
1-Prof.Ahmed Halawa’s lecture
2-Gunawansa N, Rathore R, Sharma A & Halawa A. (2019) PostTransplant Lymphoproliferative Disorder: A Clinical Perspective. J Renal Transplant Sci, 2(2): 109-117
This post-transplant patient with systemic B symptoms is suggestive of PLTD or infection. But CT is keeping with left iliac lymph nodes PLTD.
Work-up
· Measurement of EBV viral load as the majority of patients with EBV-positive PTLD will have a more marked elevation in the EBV viral load.
· Diagnosis and classification requires a tissue biopsy, preferably an excisional biopsy of sufficient size to ensure full characterization of the lesion
· Blood cultures should be taken to rule out disseminated bacterial, mycobacterial, and fungal infections;
Management
1) Reduce Immunosuppression (RI):
· The mainstay of primary PTLD management. RI can reverse 20%-80% of patients with PTLD
· This includes a 50% reduction of (CNI), either tacrolimus and cyclosporine doses in addition to withdrawal of the antimetabolites (azathioprine or MMF)
· With the exception of glucocorticoids, withdrawal of all immunosuppressive medications in critically ill cases should be considered
· Compared to EBV-positive disease, the EBV negative cases are less responsive to RI
· a complete lack of response to RI has been observed in old aged patients (> 50 years), bulky lesions (> 7 cm), as well as in advanced stages of the disease (Ann Arbor stage III/IV)
2) Rituximab therapy
· approved as a standard therapeutic agent in PTLD for three types of the WHO classification: (1) Nondestructive PTLD, (2) Polymorphic PTLD, and (3) Monomorphic diffuse large B-cell lymphoma-like PTLD not responding to RI.
· The overall response to Rtx monotherapy (375 mg/m2 body-surface area, weekly for 4 wk, single agent) in addition to RI, approached 44%-79% with a complete remission has been observed in 20%-55% of cases
3) Chemotherapy
· Indications: 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
· In all CD20+ve subtypes (75% or more), Rtx should be included.
· Safety and efficacy of Rtx (375 mg/square meter/week/4 wk), followed by CHOP regimen every 3 wk and G-CSF support have been elucidated in the PTLD-1 trial
4) Radiation therapy
· For patients with localized disease and those with central nervous system involvement, involved-field radiation therapy, alone or in combination, may be beneficial
5) Adoptive immunotherapy
· Infusion of donor lymphocytes to manage PTLD in HSCT patients that is primarily originating from donor cells.
· Due to the risk of GVHD and the availability of other treatment modalities, the use of adoptive immunotherapy should be reserved for patients with EBV-associated PTLD that persists following initial therapy
1- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093305/#:~:text=Post%2Dtransplantation%20lymphoproliferative,and%20Ahmed%20Halawa
2- https://www.uptodate.com/contents/treatment-and-prevention-of-post-transplant-lymphoproliferativedisorders?search=ptld%20diagnosis&topicRef=83230&source=see_link#H13166231:~:text=Treatment%20and%20prevention%20of%20post%2Dtransplant%20lymphoproliferative%20disorders
PTLD,renal cell carcinoma, Kaposi sarcoma, Left pelvic mass.
Work up:
history, General examination.
investigation: because PTLD highly suspension send EBV PCR as most cause PTLD, CBC, RENAL FUNCTION, uric acid, LDH,LFT,calcium .chest x-ray, abdominal and pelvic CT scan.
Treatment:
Reduction or discontinuation of immunosuppressive therapy, particularly antilymphocyte antibody, cyclosporine, tacrolimus and MMF is recommended.
prednisone is increased to 10 to 15 mg daily to prevent allograft rejection.
Sirolimus has a strong antiproliferative effect on PTLD-derived B-cell lines,24 but whether sirolimus may limit B-cell lymphoma growth while simultaneously providing immunosuppression to prevent graft rejection awaits studies.
Acyclovir or ganciclovir therapy and reduction in immunosuppression are beneficial and
may be curative in benign polyclonal B-cell proliferation.
The role of antiviral therapy in B-cell monoclonal malignant transformation is less well defined; 50% to 90% mortality has been reported despite antiviral therapy.
Surgical resection with or without adjunctive local irradiation has been suggested for
localized disease.
Local irradiation has been advocated as the treatment of choice for PTLD involving the central nervous system.
In lesions unable to do surgery or more aggressive monoclonal types of PTLD, chemotherapy has been used with favorable results compared with reduction in immunosuppression alone.
The most frequently used regimens are CHOP (cyclophosphamide,
doxorubicin [Adriamycin], vincristine, and prednisone).
Monitoring allograft function for rejection.
Early experiences with rituximab (two to six weekly doses of 375 mg/m2) in patients with PTLD (in conjunction with reduction in immunosuppression) have shown promising results, Complete remission rates of 30% to 60% have been reported.
Reference:
1.Beatty PR, Krams SM, Esquivel CO, et al. Effect of cyclosporine and
tacrolimus on the growth of Esptein-Barr virus–transformed B-cell lines.
Transplantation. 1998;65:1248-1255.
2. Nepomuceno RR, Balatoni CE, Natkunam Y, et al. Rapamycin inhibits
the interleukin 10 transduction pathway and the growth of Epstein-Barr
virus B cell lymphomas. Cancer Res. 2003;63:4472-4480.
What is your differential diagnosis?
The finding of the irregular intrapelvic lesions is highly suggestive of:
1. Neoplastic disease, where PTLD, Kaposi’s sarcoma, lymphoma.
2. Infectious diseases like Tuberculosis, invasive fungal disease, Bacillary angiomatosis, and brucellosis.
3. Autoimmune diseases such as Sarcoidosis and Chronic Granulomatous Disease
Briefly outline his management
There is a need to perform a biopsy for a more accurate diagnosis, in addition to markers for the diagnosis of infectious diseases.
A CT-guided biopsy would be the most appropriate method. In addition to collecting cultures and histopathological findings, the possibility of expanding the investigation with immunohistochemistry increases sensitivity and specificity.
Left pelvic mass/left iliac lymph node enlargement.
DD-
Malignancy-PTLD, Lymphoma, Kaposi sarcoma, malignacies related to solid organ transplant.
Infection-mycobacterium tuberculosis, CMV,brucellosis, HHV-8, HIV
Workup:
PTLD needed a High Index of Suspicion
Complete history and through examination.
Clinical feature- as mentioned in scenario.
Investigations:
Blood-for complete blood counts (cytopenia), Uric Acid, Calcium, LDH, LFT
Viral Screening-EBV igg igm, pcr
Radiologic -CECT chest, abdomen and pelvis
Imaging guided biopsy from the pelvic mass
Management:
MDT meeting with oncologist
1st Line reduction of immunosuppression
CNI reduction by 50%, along with withdrawal of the antimetabolites and maintain steroids.
In critically ill cases should consider withdrawal of all immunosuppressive medications except Steroids.
Switch to mTORi
Monitoring allograft function for rejection.
Assess disease response assessment early (at 2–4 weeks) by CT.
In those that fail to respond; can consider sequential therapy Rituximab +/- chemotherapy RCHOP used in addition to Reduction of immunosupression.
Rituximab therapy:
CD20 +ve B-cell PTLD approached 75% of TR.
The overall response to RTx monotherapy approached 44%-79%.
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)
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.
References:
Lecture video:Prof. Ahmed Halawa lecture, Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches
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
Sprangers B, Riella LV, Dierickx D. Posttransplant Lymphoproliferative Disorder Following Kidney Transplantation: A Review. Am J
My DD for :
Post renal transplant presented with loss of weight, night sweats, and night fever associated with deep pelvic discomfort => CT showed left irregular soft tissue mass likely left iliac lymphadenopathy Or mass in left inguinal region for differential diagnosis:
1- Malignancy => PTLD , solid organ tumour
2- TB
3- Fungal
4- Other opportunistic infections
5- Metastatic disease
Risk factors of PTLD:
1. Degree of immunosuppression (cumulative and T cell depletion)
2. Seronegative recipient and seropositive donor
3. Recipient age (<10 years, elderly >60 years)
4. Time since the transplant (first year)
5. Ethnicity (Caucasian)
6. Type of organ transplant (herart, heart-lung and intestine)
7. Pre-transplant malignancy
Workup:
1- In General, A diagnosis Of PTLD Requires A High Index Of Suspicion.
2- The Diagnosis Of PTLD Should Be Suspected In A Patient Who Has Allogeneic
Transplantation With Lymphadenopathy, Constitutional Symptoms (Fever, Weight
Loss, Night Sweats),
3- History And Physical Exam.
4- 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)
5- Viral Screening- HIV,CMV,EBV,HBV,HCV, HHV-8 (High EBV viral load also supports
the diagnosis), Fungal culture, cryptococcal antigen, Septic Screen.
6- Radiologic Pan-CT evidence of a mass or positive positron emission
tomography (PET) scanning(PET-CT scan )(possibly indicating metabolically
active areas)=> utilized for staging .
( If CNS- involvement suspected: consider brain/ orbit and sinuses CT or MRI
with CSF analysis)
7- For accurate Diagnosis and classification require an excisional tissue
biopsy(tissue size adequacy ), CT guided biopsy of the lymph node
8- Bone marrow biopsy may be indicated especially in the setting of cytopenia.
9- Echo to rule out endocarditis
10 – Endoscopy/colonoscopy => in negative cases(Stool for occult blood screen)
Management:
If PTLD Biopsy Proven=> Haemato-Oncologists opinion for management ?
1- 1st Line RI :
– 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 ttt Pearls :
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.
Prevention :
•Since the development of PTLD is related to the degree of immunosuppression and infection with Epstein-Barr virus (EBV) and cytomegalovirus (CMV), prevention largely depends upon limiting patient exposure to aggressive immunosuppressive regimens, rapid withdrawal and or tapering and anti-viral prophylaxis.
Prognostic factors for treatment response:
Poor performance status
EBV-negative tumor
Graft involvement
Monomorphic histology
Older age
CNS or bone marrow involvement.
Raised LDH
Hypoalbuminaemia.
Extra-nodal site involvement.
CD-20 positivity
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.
•UpToDate
I appreciate your summary. 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.
DD:
1- PTLD
2- solid organ malignancy
3- T.B
management:
1-a detailed history of specific symptoms
2-examination for lymphadenopathy or other findings
3-baseline investigations: CBC, LFTs, coagulation profile, LDH, CXR, echocardiography, and serology for HBV, HCV, EBV, and CMV; PCR for EBV and CMV.
4-CT guided biopsy
5-Hematology involvement for diagnosis, staging by histopathology, pan CT or PET CT, and options for management
6-reduction of immunosuppression:
a- hold MMF
b-reduce dose of tacrolimus by 50 % (target trough level 2-4) or shift to mTOR
c-assessment of response within 2 weeks by LDH level, size of the mass, symptoms in addition to graft function.
7-rituximab: 375 mg/m2 every week for 4 weeks
8-chemotherapy: in generalized disease or poor response to the above measures (CHOP regimen)
9-radiotherapy can be used for localized disease
10-adoptive immunotherapy:
>in refractory or relapsed EBV-associated PTLD.
>donor lymphocyte infusion or specific EBV cytotoxic lymphocytes.
I note that. Can you upload some evidence please
I note that. Can you upload some evidence please
Differential diagnosis:
pelvic mass for DD most likely LN given the location. Pelvic lymphadenopathy for DD.
Malignant: primary or secondary (mets)
Reactive: drugs, infection, autoimmune
Infiltrative: sarcoidosis, TB
Will need full assessment, blood tests, CT scan/PET CT and tissue sampling
Management: If proven PTLD, will need staging and MDT management approach, EBV status
Thank you
What is your differential diagnosis?
-Most likely PTLD
-Infectious causes like TB
Briefly outline his management
–Detail history and clinical examination include; date of transplant, organ
type and immunosuppresion regimen.
–Investigations:
-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.
-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).
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.
I note that.
Differential Diagnosis:
Management:
References:
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66(1):7–30. 2. Evens AM, David KA, Helenowski I, Nelson B, Kaufman D, Kircher SM, et al. Multicenter analysis of 80 solid organ transplantation recipients with post-transplantation lymphoproliferative disease: outcomes and prognostic factors in the modern era. J Clin Oncol. 2010;28(6):1038–46. 3. Mumtaz K, Faisal N, Marquez M, Healey A, Lilly LB, Renner EL. Posttransplant lymphoproliferative disorder in liver transplant recipients: characteristics, management, and outcome from a single-centre experience with >1000 liver transplantations. Can J Gastroenterol Hepatol. 2015;29(8):417–22. 4. Caillard S, Porcher R, Provot F, Dantal J, Choquet S, Durrbach A, et al. Post-transplantation lymphoproliferative disorder after kidney transplantation: report of a nationwide French registry and the development of a new prognostic score. J Clin Oncol. 2013;31(10):1302–9. 5. Knight JS, Tsodikov A, Cibrik DM, Ross CW, Kaminski MS, Blayney DW. Lymphoma after solid organ transplantation: risk, response to therapy, and survival at a transplantation center. J Clin Oncol. 2009;27 (20):3354–62. 6. Caillard S, Cellot E, Dantal J, Thaunat O, Provot F, Janbon B, et al. A French cohort study of kidney retransplantation after post-transplant lymphoproliferative disorders. Clin J Am Soc Nephrol. 2017;12(10):1663–70.
I like your structured and precise reply.
What is your differential diagnosis?
The CT showed irregular outline of iliac LN ( irregular mass)
in kidney transplant patient on immunosuppression drugs with fever and weight loss most probably due to
Briefly outline his management
Diagnosis by history and physical examination first hx of date of transplant, immune suppression regimen and organ type.
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.
Treatment
I like your structured and precise reply. Can you upload some evidence please.
What is your differential diagnosis?
viruses involved in PTLD
Briefly outline his management
Detailed history regarding onset of illness and any differentiating point in order to exclude other DDs need to be done
Treatment plan
Three principals of treatment: viz
Treatment options:
REFERENCES:
I like your structured and precise reply supported by evidence.
The differentials are
PTLD,
CMV invasive disease,
Other GI malignancies,
Lymphoma,
Other hematological malignancies with metastasis.
The management plan is,
Through history,
Thorough examination,
EBV infection history, antibodies,
baseline like CBC, CULTUTE, STOOL DR AND CULTURE, GENEXPERT, PERIPHERAL SMEAR, EBV PCR, LDH, URIC ACID, KOH FOR FUNGAL INFECTION, CT with contrast, CHEST ABDOMEN and PELVIS, and biopsy of the lesion for histopathological confirmation and diagnosis.
There should be multidisciplinary team for diagnosis and treatment, including Transplant physician, surgeon, hematologist, oncologist and interventional radiologist/gastroenterologist for biopsy.
Reduction of immunosuppression after confirmation.
Switch CsA to mTORi.
Hold antimetabolite, but close monitoring of allograft function.
May need immunomodulation/ chemotherapy, like cyclophosphamide, doxorubicin, vincristine and prednisolone follow by Rituximab.
If not responding then adaptive therapy for EBV cytotoxic cell derived before therapy to reinfuse as a donor derived infusion.
If no response radiotherapy.
If the primary has shrunken then can consider for surgical removal.
References;
1.https://www.wjgnet.com/2220-3230/abstract/v10/i2/29.htm
2.Professor Ahmed Halawa lectures.
3.https://www.uptodate.com/contents/treatment-and-prevention-of-post-transplant-lymphoproliferative-disorders?search=ptld%20treatment&source=search_result&selectedTitle=1~78&usage_type=default&display_rank=1
Why surgical removal of primary lesion of PTLD if that has shrunken?
I like your structured and precise reply. Can you upload some evidence please. As much I love Prof Halawa, my academic brother, a lecture can not be used as a reference in a scientific writing.
Typing in bold or in capitals is difficult to read and is akin to shouting.
Noted sit.
Usually any tumor that is extended initially need chemo and radiotherapy accordingly to decrease size then can be removed better.
What is your differential diagnosis?
—————————————————————
1-Malignancy ;
a-PTLD
b-Lymphoma
c-Kaposi sarcoma
d-Colon cancer
2-Infections;
HIV ,CMV ,Leishmaniasis ,infectious mononucleosis .
3-Granulomatus diseases ;
a-Tuberculosis
b-Sarcoidosis
Briefly outline his management;
———————————————————
1-Multidisciplinary approach to care;
The cases should be discussed at a haemato-oncology MDT meeting with experience in PTLD management, with input from the organ transplant physicians .
2-Diagnosis and staging ;
1-Obtain tissue biopsy.
2-CT scan and PET if its available .
3-Bone marrow biopsy is indicated and some selected patients it may not be clinically needed or appropriate .
3-Pre treatment evaluation ;
1-Details history and examination;
Should include; date of transplant, organ type and immunosuppresion regimen .
2-Basic blood test ;
1-full blood count, Electrolytes, Renal function, Glucose, Liver enzymes, Urate, Lactate dehydrogenase (LDH).
2-Virology: HIV type 1 & 2, Hepatitis B and C and EBV serology, CMV/EBV DNA titres
3-Graft unction ;
Should be assessed by the transplant physician .
4-Cardiac assessment ;
Echocardiography where appropriate and potentially when cardiotoxic agents are being used .
5-Fertility-preserving treatments;
Such as sperm cryopreservation for male and referral to a fertility specialist in female patients, should be considered for eligible patients .
Treatment of PTLD ;
1-Reduction of immunosuppression ;
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-Rituximab +/- chemotherapy ;
1-Rtx has been approved as a standard therapeutic agent in PTLD for three types of the WHO classification: (1) Nondestructive PTLD, (2) Polymorphic PTLD, and (3) Monomorphic diffuse large B-cell lymphoma-like PTLD not responding to RI.
2-Safety and efficacy of Rtx (375 mg/square meter/week/4 wk), followed by CHOP regimen every 3 wk and G-CSF support have been elucidated in the PTLD-1 trial .
Adoptive immunotherapy;
1-Expanded EBV-specific CTLs have been an effective therapeutic option in autologous (recipient-derived PTLD) as well as in donor-derived PTLD.
2-A variety of recent approaches has been admitted as new therapeutic options for PTLD with no need to decrease the immunosuppressive load e.g.,
A-adoptive transfer of “pamidronate-expanded Vγ9Vδ2 T cells”.
B-Tac-resistant, engineered CTLs .
Reference ;
1-Prof Halawa lecture – PTLD ز
2- Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches Fedaey Abbas, Mohsen El Kossi, Ihab Sakr Shaheen, Ajay Sharma, Ahmed Halawa .
2-Front-line management of post-transplantation lymphoproliferative disorder in adult solid organ recipient patients — A British Society for Haematology Guideline.
I like your structured and precise reply. Can you upload some evidence please. As much I love Prof Halawa, my academic brother, a lecture can not be used as a reference in a scientific writing.
Typing in bold or in capitals is difficult to read and is akin to shouting.
Differential diagnosis:
CT scan of pelvis showing a lobulated mass in the left iliac fossa; possibly enlarged lymph node.
So, this could be
· PTLD
· Tubercular lymphadenopathy
· Deep fungal infection
Management:
According to the confirmed diagnosis. And with this setting this is possibly a case of PTLD.
· Reduction of immune suppression is the key to restore patient’s immunity.
· Rituximab (anti-CD20 monoclonal antibody) can be given when the lymphoid tissues show CD20-positive cells, which are more common.
· The use of mTOR inhibitor; sirolimus and everolimus may be used though there is no strong recommendations.
· Chemotherapy with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) and its modifications remains an effective treatment.
· Radiotherapy is the best available therapeutic modality in established CNS-PTLD.
· Adoptive immunotherapy is a novel approach.
References?
Differential diagnosis:
· PTLD.
· Infection causing lymphadenopathy: like infectious Mononucleosis (IMN), TB, leishmaniasis, brucellosis and fungal infection.
Management plan
A. Diagnosis and staging
1. Relevant clinical information; date of transplant, immune suppression regimen and organ type.
2. CBC, KFT, LFT, LDH and blood sugar.
3. Virology: HIV 1 &2, HBV &HCV, EBV serology, CMV/EBV DNA titres.
4. Bone marrow biopsy may be clinically indicated in this case to look for the extent of disease.
5. Excision biopsy samples to enable accurate PTLD sub-classification.
6. Staging should be recorded using the Ann Arbor classification or the Lugano classification following Positron Emission Tomography–Computed Tomography (PET-CT).
7. MRI or CT imaging of the brain, orbits and sinuses is recommended for patients with suspected central nervous system (CNS) or craniofacial disease.
8. Diagnostic lumbar puncture for cerebrospinal fluid (CSF) analysis, including cytology and flow cytometry, is recommended for patients with suspected CNS involvement.
B. management
1. A management plan should be agreed by a core multidisciplinary team (MDT) which should include transplant physicians, haemato-oncologists, haematopathologists, radiation-oncologists and radiologists.
2. Reduction of immunosuppression
· In this case I will consider reduction of immunosuppression by 25-50% as it is extensive disease.
· I will consider stopping AZA/MMF and maintain prednisolone at 7.5/10 mg/day.
· Response should be assessed within 2–4 weeks, If a complete remission (CR) is obtained, then no other therapy may be required.
3. RTX +/- chemotherapy:
Failure of RIS to be followed by sequential treatment with rituximab and subsequently by CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) chemotherapy in adult B-cell PTLD(1).
4. 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).
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.
Thank you, well done
This is a calcified lymph node in the left iliac fossa.
Differential diagnoses include:
1-PTLD
2-Local pelvic infection
3-Tuberculosis
The diagnostic workup of PTLD includes:
1-Positron emission tomography (PET)
2-Computed tomography (CT)
3-Directed biopsy (bone marrow or lymph node (in this case0) to make a histo-
pathologic diagnosis,
These investigations, beside general investigations like CBC, LDH renal and liver function and inflammatory markers like CRP, ESR. EBV viral load.
If diagnosis is confirmed, then looking for extent of the disease by imaging chest, and abdomen is needed.
Treatment of Established PTLD
The treatment of PTLD is dependent on the morphologic subtype.
1-Some subtypes can be treated with reduction of immunosuppression) RIS alone.
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
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.
Thank you, well done
Are these new agents you described in a trial?
We do you use at your workplace (ask the haematologist) and get back to us
A 36-year-old man with a right renal transplant from his brother presented with loss of weight, night sweats, and night fever associated with deep pelvic discomfort. He has excellent kidney function. Currently, he is on Tacrolimus-based dual immunosuppression. His CT pelvis was suggestive of adenopathy.
What is your differential diagnosis?
– Post-transplant lymphoproliferative disease (PTLD)
– Lymphoma
– Tuberculosis (extrapulmonary)
Briefly outline his management (1-4)
– Detailed history and physical examination – the clinical signs and symptoms are non-specific and highly variable hence we require a high index of suspicion for early diagnosis and timely treatment i.e., assess for risk factors e.g., EBV pre-transplant status (donor EBV seropositive/ recipient EBV seronegative), current immunosuppressive regimen, duration of immunosuppression, time since transplant
– Management requires a multidisciplinary team to provide better care and improve patient’s outcome. Oncologists, hematologists, radiation specialists, surgeons, nurses, primary care-givers
– We need to weigh the benefit of immunosuppression (decreasing risk of graft rejection while increasing risk of complications e.g., PTLD, infections)
– Investigations –
· Laboratory –
o complete blood count, ESR – to evaluate for leukopenia, anaemia, thrombocytopenia
o kidney function test, bone chemistry, urine analysis
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, biopsy (US or CT guided) – to determine the definitive diagnosis
o CSF analysis – in patients with CNS involvement
o BMA analysis, flow cytometry
o SPEP and UPEP
· Imaging – Chest CT scan, CT Abdomen, Brain MRI (if there is CNS involvement), PET scan to evaluate spread, bilateral lower limb doppler ultrasound to rule out DVT
· OGD, Colonoscopy – rule out GI pathology/ involvement
– definitive diagnosis of PTLD is based on histopathological analysis
– WHO classification of PTLD includes 4 categories i.e., Monomorphic PTLD, Polymorphic PTLD, Early lesions, Classical Hodgkin lymphoma
– Treatment – the mainstay of management includes: –
o Reduction of immunosuppression – at least 50% reduction of CNI dose and discontinuation of antimetabolite agents like mycophenolic analogues, azathioprine – this is the initial management of PTLD and it aims at restoring cellular immunity without compromising graft function
o Surgical excision of the localized lesion
o Radiation therapy – in patients with localized disease and those with CNS involvement
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)
o Immunochemotherapy – in patients with inadequate response to reduced immunosuppression and rituximab, the commonly used chemotherapy regimen is R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone)
o Stem-cell transplantation
o Adoptive immunotherapy – aims at inducing a robust EBV-specific cellular response using EBV-specific cytotoxic T lymphocytes (EBV-CTLs) or donor lymphocyte infusion (DLI), unfortunately it is associated with a high risk of developing acute and chronic GVHD (graft-versus-host disease)
– Prognosis – has improved with the immunosuppressive strategies and introduction of rituximab ± CHOP
– Re-transplantation after PTLD treatment is possible in patients who develop graft dysfunction but it is best done at least 1year after treatment for PTLD
References
1. Samant H, Vaitla P, Kothadia JP. Post Transplant Lymphoproliferative Disorders. StatPearls. Treasure Island FL: © 2022, StatPearls Publishing LLC.; 2022.
2. Elserwy NA, Lotfy EE, Fouda MA, Mahmoud MI, Donia AF, Mashaly ME, et al. Postrenal transplant malignancy: Incidence, risk factors, and prognosis. Saudi journal of kidney diseases and transplantation : an official publication of the Saudi Center for Organ Transplantation, Saudi Arabia. 2017 May-Jun;28(3):579-88. PubMed PMID: 28540896. Epub 2017/05/26. eng.
3. Morton M, Coupes B, Roberts SA, Johnson SL, Klapper PE, Vallely PJ, et al. Epstein-Barr virus infection in adult renal transplant recipients. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2014 Jul;14(7):1619-29. PubMed PMID: 24815922. Epub 2014/05/13. eng.
4. Trusson R, Serre JE, Szwarc I, Brunot V, Garrigue V, Delmas S, et al. Treatment Response and Outcomes in Post-transplantation Lymphoproliferative Disease vs Lymphoma in Immunocompetent Patients. Transplantation proceedings. 2016 Jul-Aug;48(6):1927-33. PubMed PMID: 27569924. Epub 2016/08/30. eng.
Thank you, well done
What is your differential diagnosis?
The mass could be:
1- PTLD
2- Malignant tumour.
Briefly outline his management:
Histology is mandatory; accordingly, therapy can be decided.
If this is proven to be PTLD:
• Management of (PTLD) remains challenging without a standardized therapeutic approach that can be applied to all patients.
• A multidisciplinary approach, involving transplant physicians, histopathologists and haemato-oncologists is essential.
• The choice of therapy ideally attempts to balance the risk of life-threatening disease with the risk of allograft rejection and treatment-related morbidity.
• Treatment decisions are made based on histological subtype, grade, stage and site of the tumour as well as an assessment of the patient’s clinical state, including transplanted (and other) organ function, and capacity to tolerate therapy.
For EBV-associated PTLD, the cornerstone of initial management is a stepwise reduction in immune suppression with the aim that EBV-specific immunity will be restored/developed to reverse the lymphoproliferative process. There are no standard approaches for reducing immunosuppression. However, considerable approach is the following:
ü First, stop the anti-proliferative agent (azathioprine/MMF)
ü Then aim to ↓CNI dose by 25%- 50% over 2–4 weeks
ü Continue steroids (or ↑ if AR a concern)
ü Consider replacing CNI with sirolimus.
• 30–50% patients will respond to ↓IS alone, Expect response in 2 – 4 weeks.
• Response can be assessed by serial LDH measurement, repeat imaging, and measure EBV-specific CTL (if the test is available)
• ↓ IS subjects allograft to rejection in <10%. Patients warrants close monitoring.
(EBPG Expert Group on Renal Transplantation (2002), Parker. et al, 2010; Paya, et al, 1999)
Antiviral agents: no proven role in PTLD Rx.
Rituximab: next therapeutic step,
• Indicated in diffuse EBV+, low risk PTLD CD20 disease resistant to ↓ IS
• Remission in 50–60% of patients.
• Relapse of PTLD is not uncommon, moreover, disease response to rituximab monotherapy is slower than chemotherapy, making it less effective therapeutic option for aggressive/ fulminant PTLD (intermediate and high risk groups)(Choquet et al, 2006; Parker et al, 2010).
Clinical low risk is defined as none of the following risk factors: age <60 years, raised LDH, performance status ECOG* grade 2-4.
Chemotherapy
• Required in patients with polymorphic disease who do not respond to the previous treatments and for advanced and T cell PTLD.
• Most regimes used are anthracycline based: CHOP (cyclophosphamide, doxorubicin, vincristine & prednisolone).
• Remission in 60–70% of patients
• Rituximab followed by CHOP chemotherapy (as per international multi-center, prospective, phase II trial) is safe and effective treatment for adult SOT patients with PTLD.
• Patients received 4 weekly courses of rituximab followed by CHOP.
• Alfa interferon: no prospective clinical trials, many reports of its success are anecdotal.
• intravenous gamma globulin (IVIG, CytoGam): has limited value, commonly used as adjunctive therapy in PTLD. As per BCSH & BTS guidelines; treatment with Interferon or intravenous immunoglobulin is not recommended out with a clinical trial (Parker et al, 2010).
• Surgical excision of the lesion/ localized radiation therapy: Useful in patients with localized disease (Tsai et al, 2001, Parker et al, 2010).
• T-cell immunotherapy: Donor EBV-specific cytotoxic T lymphocytes administered to HSCT recipients with PTLD. it was successful in phase RCT though with limited number of cases in SOT (Haque et al, 2007).
Thank you, well done
What is your differential diagnosis?
The mass could be:
1- PTLD
2-Infections such as Tuberculosis, abscess due to bacterial, viral or fungal causes
3-Sarcoidosis
4-Malignacies other than PTLD-Lymphomas, Non-Hodgkin Lymphoma, Solid organ Tumour,
Briefly outline his management
Investigation:
High index suspicion for PTLD pots renal transplant
Proceed with CT chest, abdomen and pelvis
For CT guided biopsy for WHO classification of PTLD- morphology and clonality determines the prognosis factors: Monoclonal has the worse prognosis whereas Early and EBV positive PTLD responds well with treatment
Treatment:
Antiviral – may have role in prophylaxis in EBV positive, but no evidence in effective treatment
Reduction of IS:
To stop either MPA or CNI, change to mTORi
to maintain lower drug level rather than the duration and close monitoring of rejection
Surgery/ Radiotherapy
For localised disease
diagnostic biopsy
indicated for life threating conditions : perforation, obstruction and bleeding
Rituximab
Most PTLD express CD 20
but poor response to: Fulminate/advanced disease, EBV-negative PTLD, late onset tumour, CNS involvement
Chemotherapy
R-CHOP, CYC and pred, ACVPB- overall responce rate -74%
role of Sequential therapy for high risk and poor response patients
Adoptive Immunotherapy
EBV specific cytotoxic T lymphocytes or Donor lymphocyte infusion
references
Prof Ahmed Halawa lecture
Thank you, well done
You mentioned most of the PTLD is CD 20 positive, can you give us a percentage?
This iliac mass mostly a PTLD lesion
– neoplastic like PTLD, lymphoma
– infecteous like abscess, bacterial or viral , CMV,HHV-8, HIV, TB or fungal infection.
Thorough history and physical examination
Investigations include baseline tests like : CBC,blood film ,ESR, CRP,RFT , LFT, serum Ca ,serum p, serum Uris acid serum k , LDH , Qauntiferon TB test, virology screen by serology and PCR for EBV , Hepatitis B and C, HIV, CMV.
CT-guided Lymph node biopsy (excitional or fine needle aspiration) or BMA for confirming PTLD, with histopathological assessment.
CT or PET scan for head ,chest ,abdomen and pelvis for staging and determine the metastasis .
high index of suspicion is required , After confirming the diagnosis we start treatment by RI to about 50% and withhold antimetabolites like MMF or azathioprine or Swech Tom-TOR inhibitors although it’s use is debatable and need more studies to ascertain its use . Then follow up after 2-4 weeks if no response then we move to the next step : if CD20+ve PTLD we use RETUXIMAB vial in 4 doses alone Or in combination with chemotherapy like CHOP . If all these drugs not effective, we try adoptive therapy , EBV – specific cytotoxic T-cells .
Radiology and surgical treatment for local lesions .
Antiviral and ANtiTB also used.
Reference:
Fedaey Abbas, Mohsen El Kossi, Ihab Sakr Shaheen, Ajay Sharma, Ahmed Halawa
Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches. World J Transplant 2020 February 28; 10(2): 29-46
Thank you, well done
A 36-year-old man with a right renal transplant from his brother presented with loss of weight, night sweats, and night fever associated with deep pelvic discomfort. He has excellent kidney function. Currently, he is on Tacrolimus-based dual immunosuppression. His CT pelvis is shown below:
· What is your differential diagnosis?
1. PTLD
2. opportunistic Infections
· Bacteria such as disseminated mycobacterial
· Fungal such as actinomycosis
3. Other malignancies in the adjacent area such as ca urinary bladder/ ca colon.
· Briefly outline his management
Patient will be fully evaluated with the following tests and procedure:
Investigations
· FBC
· Uric acid
· LDH
· blood cultures
· sputum evaluated for acid fast bacilli, Pneumocystis carinii (jirovecii) pneumonia, and fungal infections.
· Estimation of the viral load via PCR of peripheral blood EBV DNA
· serum and urine protein electrophoresis
· CT/PET which helps in staging as well
· A tissue biopsy, preferably an excisional biopsy, with review by an expert hematopathologist, is required to ensure an accurate diagnosis.
Once the diagnosis is confirmed accordingly the management will be initiated, infections will be treated accordingly , if it is confirmed PTLD then
· Reduction of calcineurin inhibitors (Tacrolimus by 50%)
· If on steroid of MMF to stop them
· We can initiate treatment with MTOR inhibitors
It is recommenced by British Society for Haematology to assess the Response (at 2–4 weeks) in those patients following RIS alone so that further treatment can be initiated in those that fail to respond
Rituximab monotherapy is recommended for patients with CD20-positive PTLD who fail to respond adequately to RIS as initial therapy . Four further three-weekly cycles of rituximab are recommended in patients who obtain CR. If did not respond then Four cycles of R-CHOP-21 immunochemotherapy are recommended in patients who fail to obtain CR.
In addition radiotherapy can be offered if it is localized along with reduction in immunosuppression.
If all fails adoptive immunotherapy can be tried .
References:
Front-line management of post-transplantation lymphoproliferative disorder in adult solid organ recipient patients — A British Society for Haematology Guideline. Nimish Shah,1 Toby A. Eyre,2 David Tucker,3 Shireen Kassam,4 Jasvir Parmar,5 Carrie Featherstone,6 Peter Andrews,7 Elham Asgari,8 Sridhar Chaganti,9 Tobias F. Menne,10 Christopher P. Fox,11 Stephen Pettit,5 Abid Suddle,4 Kristian M. Bowles1,12 on behalf of the Haemato-Oncology Task Force of the British Society for Haematology and the British Transplantation Society. British Journal of Haematology, 2021, 193, 727–740
Thank you, well done Dr Amna
What is this protocol you mentioned called?
SWOG protocol S9239
Nodal diseaes in PTLD is around 10% of the case ,it is uncommon .
The virus that were implicated as arisk factoores for PTLD is CMV,HHV8
HCV is another factors increased the risk of PTLD.
PTLD can present with different presentation according to the type and subtype of PTLD.
CNS and cardioc lymphoma were fvery difficult to daignose and treat as well .
PTLD reqiuered high index of suspesious clinically ,and then need to check LDH level as first thing .
PTLD and maintaining the functioning graf is the challenging ,so the treatment depends of reducing the IS medications and in the same time starting the treatment either with Rituximab or other chemotherapy accoring to the type and staging of the PTLD.
Referrens
Prof HAlawa lecture
1-DIFFERENTIAL DIAGNOSIS;
-PTLDS; EBV-positive disease / EBV-negative disease;.
-post-transplantation primary effusion lymphoma may be associated with human herpes virus 8 (HHV-8) infection;.
-Various opportunistic infections, such as disseminated mycobacterial or fungal infections.
– Pneumocystis carinii (jirovecii) pneumonia, and fungal infections
2-DIAGNOSIS;
-An accurate diagnosis of PTLD requires a high index of suspicion.
-Radiologic evidence of a mass, or elevated serum markers (such as increased lactate dehydrogenase [LDH] levels) are suggestive of PTLD;
-Positive positron emission tomography (PET) scanning also favors the diagnosis.
-A tissue biopsy, preferably an excisional biopsy, with review by an expert hematopathologist, is required to ensure an accurate diagnosis.
-Pure lymphadenopathy in PTLD is seen in less than 10%.
-PTLD can present with nodal lesions in 38% cases.
-Diagnosis of central nervous system or cardiac lymphoma is particularly difficult.
3-TREATMENT;
Choice of treatment ;.
-Management of PTLD has varied significantly according to the PTLD subtype and the type of transplant, as well as from institution to institution.
-The main options for initial treatment are reduction of immunosuppression (RIS),
-Immunotherapy with the CD20 monoclonal antibody rituximab,
-chemotherapy,
-radiation therapy, or a combination of these.
-Other treatments, such as adoptive immunotherapy with EBV-specific cytotoxic T cells, are generally reserved for persistent disease despite initial therapy,
-The two main goals of therapy are eradication of the PTLD and preservation of graft function. Not uncommonly, these goals conflict and one must take precedence. As an example, reduction of immunosuppression is commonly employed for PTLD eradication, but increases the risk of graft rejection and/or graft-versus-host disease. Reduction of immunosuppression may be preferred when alternative organ support is available (eg, renal or renal/pancreas transplant). In contrast, there will be cases in which worsening graft function in vital organs (eg, heart transplant) necessitates continued immunosuppression and dictates the need for alternative therapies.
4-References;
–European best practice guidelines for renal transplantation. Nephrol Dial Transplant 2002.
-UP TO DATE.
Do you think CT findings are suggestive of Pneumocystis carinii (jirovecii) pneumonia as you mentioned?
Thank you my prof; for your valuable and helpful guidance’
it is less likely by CT findings
Pneumocystis jirovecii pneumonia is one of the most common pulmonary infections in patients with AIDS. The chest radiograph is deceptively normal in about 10 percent of symptomatic patients, but subtle abnormalities can be seen on HRCT.
The primary change is diffuse or patchy ground-glass opacification, occasionally forming a “crazy paving” pattern. Consolidative changes, nodules, and thickening of interlobular septa are rarely seen.
Thank you, this is a very short answer that does not addressing the management Dr Rihab
– Differential diagnosis
· Neoplastic as PLTD which is the most probable diagnosis ,Lymphoma
· Infectious as Pyelonephritis ie either viralCMV, HSV ,or bacterial as Tuberculosis or Fungal as aspergillosis
– Imaging features are nonspecific , therefore knowing a more detailed history of the patient’s and recipient’s risk factors and the exact transplantation time along with detecting the variations in vascular anatomy, surgical technique applied, all can direct to more specific diagnostic workup and definitive management.
For this case
§ Full basic labs are needed including CBC with differential ,KFT ,LFT ,inflammatory markers ,LDH , serum uric acid , serum calcium , monoclonal protein in serum or urine ,
§ virology screening particularly EBV viral load
§ CT chest abdomen will be needed with this pelvic CT
§ lymph node CT guided biopsy is needed for histopathological evaluation.
PTLD diagnosis requires high suspicion index,
IF virology is positive specific antiviral therapy would be given or if EBV positive PTLD then RI ,need to be initiated so that Tac can be reduced to 50% with tracing drug level or shifted to mTOR and steroids with monitoring of graft function
Rituximab monotherapy then if the case deteriorated RCHOP cycles can be given along with GCSF and PJP prophylaxis
If the previous therapy failed adoptive therapy can be tried
Surgery and radio therapy for localised disease
Reference
-Sugi et al. Imaging of Renal Transplant Com-plications throughout the Life of the Allograft:
Comprehensive Multimodality Review.RSNA 2019:39(5).
-Prof .Halaw’s lecture.
IF virology is positive specific antiviral therapy would be given or if EBV positive PTLD then RI ,need to be initiated so that Tac can be reduced to 50% with tracing drug level or shifted to mTOR and steroids with monitoring of graft function.
What antiviral treatment you refer to?
Can substantiate your answer about mTORi role in PTLD treatment? The role is very controversial.
– Antiviral therapy :refractory EBV-associated PTLD have been treated with concurrent arginine butyrate and ganciclovir.Foscarnet and cidofovir are active in EBV-associated lymphoproliferations and directly inhibit DNA-polymerase without prior intracellular phosphorylization. This is also responsible for the higher rate of toxicity.
Reference
Zimmermann H, Trappe RU. Therapeutic options in post-transplant lymphoproliferative disorders. Ther Adv Hematol. 2011;2(6):393-407.
-Reference for mTORI role in PTLD Kamińska D etal .Post-transplant lymphoproliferative disorder in adult renal transplant recipients: case series and review of literature Centr Eur J Immunol 2020; 45 (4): 498-506
The diagnosis of PTLD is very suspect in this clinical scenario.
Differential diagnosis includes:
– Most certainly PTLD.
– Infectious disease in particular opportunistic infection, disseminated mycobacterial or fungal infections.
-Other hematological disease or metastatic disease
The management in this instance consists of:
a- A thorough history and physical examination: Pay close attention to the existence of palpable lymph nodes or those that are surgically more accessible, so that tissue biopsy is planned
b- Initial laboratory evaluation, which includes a complete blood count, liver enzymes, and serologies in particular donor: recipient’s EBV antibody positivity
c- Tissue diagnosis: Although isolated lymph node involvement is uncommon, a biopsy of the pelvic tumor will confirm the diagnosis.
d- If the biopsy results in PTLD, staging should be carried out using a CT scan of the neck, chest, abdomen, and pelvis, to determine the extent of malignancy and possible metastasis.
e- After confirmation of PTLD, appropriate approach should be commenced.
Initial treatment for PTLD consists of immunosuppression reduction. As tacrolimus use increases the risk of PTLD, the Tacrolimus dosage should be decreased by 50%. The antimetabolite can be discontinued sequentially or concurrently with tacrolimus. Response to immunosuppression reduction can be evaluated over 2-4 weeks for remission of symptoms, decline in LDH levels, and reduction in pelvic mass size on CT imaging. 20-80% of individuals may experience PTLD reversal in cases of early lesion, low-stage, or non-bulky illness.
Rituximab is administered as a second-line treatment in cases of poor response to initial step.
Most certainly PTLD. (Do you think without tissue diagnosis you are most certain?) Fortunately you followed your answer with After confirmation of PTLD which means that you are not almost certain!!!!
DIFFERENTIAL DIAGNOSIS.
PTLD
Granulomatous dx like- TB, Sarcoidosis.
Other malignancies post transplant -Lymphoma, KS, Ca colon.
Other infections ; Abscess, CMV, HIV, Infectious mononucleosis, leishmaniasis etc
MANAGEMENT.
-MDT approach involving the ID, Oncology and Nephrology teams.
-I would then take a good hx including a pre transplant hx and do a physical exam to check out other organ involvement.
-An initial workup will entail; FHG + BMA to assess any hematological involvement, Assessment of tumor lysis syndrome ; serum calcium, uric acid, phosphate and potassium levels, Assessment of EBV status; PCR + Viral load ,Assess other risk factors ; Serostatus of the patient, Evaluate other differential diagnosis; Urine LAM,TB Quantiferon ,Mantoux test, Evaluate for other organ involvement + staging ; A thoraco- abd ct scan, LP to evaluate for CNS involvement if there are any neurological deficits on examination. Finally a biopsy to establish the histological diagnosis and WHO classification.
-Treatment will involve;
1.Adjustment of immunosuppressive medication to lowest possible trough levels.
2.Switch to MTOR inhibitors – This has conflicting data but preliminary data show it to be beneficial with even reduced incidences of PTLD, More studies are needed before it is adopted in clinical practice.
3.Reduction of Immunosuppressive doses, This could involve reduction of CNI initially by 25-50%,mantain the steroids and withhold the antimetabolite while monitoring graft function .This approach has been found to be less effective in EBV negative patients.
4.If CD 20+ve ,Rituximab us has good outcomes, While for CD20 -ve, R-CHOP preferred in terms of chemotherapy
5.Radiotherapy can be used for localized diseases and any other extra-nodal involvement of disease. Surgery can be used for those with complicated disease e.g IO emanating from gut involvement.
A trial with novel approaches like donor derived infusion of specific cytotoxic T cells can be used if the above does not yield good outcomes.
We don’t have much supportive data of good outcomes with use of antivirals in PTLD.
REFERENCES;
Prof Halawa lecture – PTLD.
Uptodate – PTLD.
Fidaeh A et al ;PTLD;Current concepts and future therapeutic approaches.World Journal of Transplantation.2020-28;10(2);29-46
Well done
What is the difference between PTLD and lymphoma in your differential?
As pertains to above differentials, PTLD refers to pts who developed the disease post transplant after immunosuppressive medications, varied categories according to WHO 2017 classification while lymphoma refers to Pts who had the disease pre transplant, were treated and declared well controlled disease and had a transplant after the appropriate wait period.
1- DD diagnosis:
there is left iliac enhancing mass encasing iliac vessels (lymph node mass)
mostly PTLD
Others: TB, infection (abscess)
2- Management:
1- Excisional biopsy or needle biopsy
2- Staging by: CT-scan chest, abdomen and pelvis or PET-CT scan if availabe
3- Other investigations: full labs, viral assesment ( HIV, HBV, HCV, EBV and CMV)
-start 4 weekly doses of rituximab (375 mg/m2 IV)
-re-evaluate by imaging:
-if responded: give 4 three-weekly ritximab doses
-if no response or disease progressed—– start chemotherapy CHOP (4 cycles)
3- supportive therapy with GCSF and PJP prophylaxis (during chemotherapy)
4- radiotherapy Together with RIS is considered if there is no other lesion.
It would be of interest to expand more on the EBV role in PTLD with emphasis on the difference between EBV+ve and EBV-ve disease
· For EBV-positive, the development of PTLD can be attributed to immunosuppressive-induced decline in the T-cell immunesurveillance. Leading to unlimited B-cell transformation and the evolution of lymphoma.
· Pathogenesis of PTLD in EBV-negative patients is less evident. Several hypotheses have been postulated e.g., CMV or another viral infection, prolonged immunosuppression, allograft-driven persistent antigenic triggering, hit-and-run hypothesis i.e., EBV commences the pathogenic process leading to the development of PTLD and then vanishes.
· EBV infection could be currently seen in almost all transplant patients with nondestructive PTLD, in > 90% of patients with polymorphic PTLD and Hodgkin’s lymphoma–like PTLD, and in only 50% of monomorphic PTLD
EBV is responsible for >70% of PTLD and the onset is earlier than EBV -ve PTLD,
A 36-year man with LRRT having loss of weight, night sweats, and fever and CT scan Abdomen showing large pelvic lymph nodes but having good graft function and on dual immunosuppression .All these findings suggest following possibilities:
PTLD
lymphoma
Tuberculosis
Fungal infection.
Management :First thing will be to investigate the patient and confirm the diagnosis. After taking detailed history and examination, baseline investigations including complete blood picture to look for pancytopenia or raised TLC for infection ,renal function test, Liver function test, serum calcium ,LDH ,blood culture ,hepatitis Band C ,PCR for EBV DNA ,Quantiferon Tb Gold test followed by CT scan 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 of lymphoma confirmed.
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 and close monitoring of graft function as chances of rejection high. If no response and the diagnosis is PTLD or lymphoma, then Rituximab followed by chemotherapy (CHOP).Radiotherapy in some cases may help. 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. If disseminated Tuberculosis or fungal infection then ATT or antifungal therapy along with reduction of 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
Thank you, Batool
Please write in bullet points
You mentioned lymphoma in your DD, please explain more.
PTLD presents with lymphadenopathy in only around 30% of cases
it can be caused also by CMV and HHV 8
References
Thank you, Well done.
Thank you, Well done.
Do you think that the imaging is adequate or we need to have more imaging?
Differential Diagnosis
generalized non specific symptoms with long standing history of immunosuppression due to transplantation makes the following DD
lymphadenopathy is rare in PTLD occurring in <10% of cases. But usually have all the constitutional symptoms of weight loss, fever, night sweats etc
management Pan
after taking detail history and physical examination will need extensive investigation as following
CBC, ESR,CRP including special smear
LDH, uric Acid, calcium,
Blood and urine Cultures
CXR, CT chest, abdomen, pelvis
CT guided biopsy
CMV and EBV viral loads
monoclonal protein in serum and urine
Treatment
if PTLD is the histopathological diagnosis then
reduction in tacrolimus dose and continuation of steroids
with monitoring of kidney functions (watching for rejection)
addition of mTOR inhibitors instead of CNI
if B cell PTLD with CD20+ is the case then Rituximab 375mg/m2 weekly 4 doses should be given in addition of above measures
if response is poor to above therapy due to wide spread disease or EBV negative case would need chemotherapy i.e. CHOP therapy with above therapy and even complete withdrawal of immunosuppression therapy may sometime be required
with stoppage of IS patient can loose the transplant and after cure with aggressive therapy and waiting for at least one year after complete remission can be re transplanted
and ideally with a better match to keep the patient on minimal IS doses, and avoidance of ATG
refrenes
Thank you, Well done.
This picture shows an enlarged left iliac LN for differential diagnosis
the underlying cause may be infection or malignancy.
Definitive diagnosis will need pathological-based tissue diagnosis
according to history and presentation, PTLD is most likely the diagnosis
If this is a case of PTLD biopsy-based diagnosis management will be done by a multidisciplinary team including surgery, nephrology, and oncology
pan CT or PET CT is needed for staging and virology screening including EBV, CMV, and HSV.
According to histopathology including CD20 receptor positive staining, metastasis, and underlying cause management plan will be considered including
-Surgical removal
-Rituximab with or without chemotherapy
-Antiviral treatment
-Immunosuppression modifications should be weighted benefits vs risks, especially since the evidence of benefits of shifting from CNI to MTOR is still controversial and this conversion may expose the patient to rejection
after full plan made by the multidisciplinary team should be discussed with the patient and should be explained everything very clearly as again the evidence is weak
Thank you, Ramy
Please expand on your answer.
What do you mean by antiviral treatment? is it effective?
What agent would you use as an antiviral?
Prophylactic treatment (both gancyclovir and cyclovir were used)
A matched case controlled study showed that for every 30 days of acyclovir use the odds ratio for developing PTLD was 0.83, and for every 30 days of ganciclovir use, the odds ratio for developing PTLD was 0.62 (1)
single-arm prospective study for evaluation of the effectiveness of both the prophylactic use of antiviral agents and the early detection of primary EBV infection with polymerase chain reaction (PCR) followed by antiviral therapy and lowering of the immunosuppressive regimen was evaluated in 40 children receiving a liver allograft [2].
the agent was decided based on risk to develop PTLD as follows:
•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 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 with PCR positive.
Patients who developed PTLD was treated with the intravenous ganciclovir and the withdrawal of tacrolimus. At a mean follow-up of approximately 260 days:
•Among 18 high-risk children, there were no cases of PTLD and one case of EBV infection (which resolved).
•Among 22 low-risk patients, two cases of PTLD occurred, both of which resolved after gancyclovir treatment and tacrolimus was stopped; there was one case of EBV increase, which also resolved.
-PTLD incidence was only 5% with this regimen compares to the incidence of 10% previously reported from this same center.
Still number of patients is very low and more RCT are needed
References
1-What is your differential diagnosis?
CT SHOW SOFT TISSUE STRUCTURE LEFT SIDE OF PELVIS MOST LIKELY LYMPHOMA WITH AIR INSIDE THE LESION
SUSPECTED LYMPHNODES OR SMALL BOWEL LYMPHOMA
Differential diagnosis
VIRAL INFECTIONS EBV infectious mononucleosis (IM)-CMV -HIV
BACTERIAL TB -Brucellosis
Malaria
MALIGNANACY Leukemia-LYMPHOMA
B cell lymphomas, T cell lymphomas, Hodgkin lymphoma,
metastasis from nasopharyngeal carcinoma, and gastric carcinomas
2-Briefly outline his management
INVESTIGATIONS
CBC
RFT
CT -X RAY CHEST
CONSECTIUVE SPUTUM GRAM STAIN 3 DAYS AFB
PERIPHERIAL BLOOD SMEAR
BIOPSY
SEPTIC SCREEN (CRP -LDH-FERRTIN
BLOOD -URINE -STOOL -SPUTUM CULTURES
Measurement of EBV viral load
the following abnormal laboratory studies may be seen in patients with PTLD:
Unexplained anemia, thrombocytopenia, or leukopenia
Elevated level of serum lactate dehydrogenase (LDH)
Hypercalcemia
Hyperuricemia
Monoclonal protein in the serum or urine
******TREATMENT
Supportive care − The mainstay of treatment for patients with infectious mononucleosis and other manifestations of primary EBV disease is supportive care.
CONTIUE
Tacrolimus-based dual immunosuppression (TACROLIUMS +STEROIDS ) IN CASE OF MILD INFECTION IF PATIENT HAS SEVER INFECTION HOLD TACROLIUMS AND CONTIUE STERIODS HIGH DOSE Chemoimmunotherapy — Chemotherapy is usually administered in conjunction with rituximab for patients with CD20+ PTLD. Patients whose tumors do not express CD20 are not candidates for rituximab therapy and are treated with chemotherapy alone.
We suggest R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) for most patients with PTLD; we offer CHOP (without rituximab) to those patients whose PTLD does not express CD20. Other chemotherapy regimens used for non-Hodgkin lymphoma may be appropriate in select cases
Thank you, Well done. We need CT abdomen and pelvis as well.
The above CT image of the pelvic of post-kidney transplant shows an echogenic mass around the right pelvis area compressing on pelvic muscle
Differential diagnosis
Based on the above non-specific clinical symptoms and signs:
The use of Tacrolimus base immunosuppression
Although lymphadenopathy is seen in < 10% of PTLD but based on the epidemiology of being the second most common solid organ malignancy after skin cancer, it stands to be a substantial differential in this case. Also, over 80-90% of the population are carriers of EBV infection which have been shown to contribute greatly to PTLD
Management of PTLD
Investigations
a) Blood tests
b) Imagine tests
c) Tissue
Treatments Options
A)
If there is no response to the above treatment option as it has been seen in those above 50 years, bulky lesions, (>7cm), and the advanced stages of the disease.
B)
Poor response to the use of Rituximab has been seen in; PTLD with CNS involvement, EBV-negative PTLD, advanced/fulminant disease, and late-onset tumour
C)
Rituximab + CHOP given over 3 weeks for 4 cycles plus G-CSF
PJP prophylaxis
D)
However, if kidney rejection occurred following RI, the patient will be planned for another transplantation by observing the following steps:
References
Thank you, Well done.
Do you think that the imaging is adequate or we need to have more imaging?
Thank you prof Halawa for the response,
Further imaging like enhanced CT scan of the abdominopelvic for possible spread of the disease and also PET scan will be of great value for disease activity.
Soft tissue mass likely enlarged inguinal LN, in setting of solid organ transplant likely to represent PTLD
Differential Diagnosis
Localized or systemic infection (TB, fungal infection)
Co-incidental NHL
Workup
History and examination look for lymphadenopathy, assess comorbidities and performance status
Contrast enhanced CT TAP for disease staging, PET to measure disease activity.
Histological confirmation, preferably excisional biopsy, identification of EBV DNA in tissue.
EBV viral load
MDT with transplant physician, haemato- oncology and pathologist.
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
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.
Monitoring response ( constitutional symptoms, LDH and size on imaging)
Further treatment depends on the PTLD subtype:
Early PTLD: Reduction of immunosuppression alone result in response in 80% within 2 to 5 weeks, Rituximab can be considered in persistent disease despite IS reduction if PTLD is CD 50 +ve.
Polymorphic PTLD: Reduction of immunosuppression plus Rituximab if CD 50 +ve. Chemotherapy (CHOP) if CD 50-ve or high-volume disease with good performance status
Monomorphic PTLD: IS reduction plus Rituximab either alone or with chemotherapy, Rituximab alone for minimal disease or those who will not tolerate chemotherapy.
Adoptive therapy (EBV specific cytotoxic T cells) for resistant disease
Radiotherapy can be considered if localized disease/ CNS involvement
Limited rule for surgery ( limited to localised disease, complication: obstruction, perforation)
GCSF, PCP prophylaxis +/- fungal prophylaxis
Counselling about the effect of treatment on fertility, refer to fertility clinic for sperm preservation
Thank you for the excellent answer
👉 The present case has generalized non specific constitutional manifestations (fever, wt loss and excess sweating ) in addition to enalrged iliac lymph nodes, in the context of immunosupression so the differential will be:
_ malignancy as PTLD.
_ infections like TB.
_ metastasis from any primary tumor as cancse colon.
👉 the plan of management:
_ through history and clinical examination for any enalged lymph nodes
_ The golden standard to confirm the diagnosis is tissue biopsy (CT guided from enlarged suspicious lymph nodes).
_ Evaluation of the extent of the disease by CT chest, abdomen and pelvis.
_ Screening of caustive viral infection is so crucial in diagnosis and management by EBV and CMV PCR. (No role for serology here as most of transplant recipients in adults will have postive serology).
_ other lab investigations as CBC (for cytopenias) , elevated serum calcium, uric acid and LDH.
👉 After confirmed diagnosis:
_ The 1st step to reduce immunosupression (mostly stop MMF, reduce dose of CNI by 50% and guide it by trough level or shift to sirolimus).
Restart steroids to compensate for stoppage of antimetabolite and follow up graft function and DSA (for fear of rejection).
_ if not responding (disappearance of constitutional symptoms, involution of mass and decrease LDH level), proceed to use of rituximab.
_ in resistant cases, use of sequential chemotherapy (CHOP) with steroids, cyclophosphamide, duxorobcin and vincristine will be indicated.
_ New immunoadoptive therapy (donor lymphocyte infusion and EBV spefic T lymphocytes ) are indicated only in resistant /refractory or recurrent cases and those who are EBV postive (with high viral load).
_ Retransplantation in graft failure and loss only after 1 year from complete remission and with trial to minimization of immunosupression as avoidance of ATG and minimization of tacrolimus dose (through better choice of well matched donor).
Reference:
Prof Halawa lecture.
Thank you, Well done.
Thank you for mentioning metastasis from other sources
Differntial diagnosis:
1- PTLD involving Iliac Lymph node.
2- Cancer colon with metastasis to iliac LN
3- TB
Management plan :
1- Confirm the diagnosis with LN biopsy
2- Assesse the extent of the lesion via pan CT and MRI imaging of head ,neck, chest and pelvi- abdomen
3- Modify IS used with decreasing the dose of MMF and swith from Tac to m Tor and follow up,if no improvement consider Rituximab .For refractory cases chemotherapy as CHOP protocoland radiotherapy for localized tumers.
Ref:
1- Dr Ahmed Halawa lecture :post transplantation lymphoproliferative disorders.
2- 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.
Thank you, Well done.
Welcome sir
The index patient is a transplant recipient with excellent graft function, and on Tacrolimus-based dual immunosuppression. He presents with history of loss of weight, night sweats, and fever with deep pelvic discomfort.
His CT pelvis shows a mass in left inguinal region.
The differential diagnosis in such a clinical setting is either:
a) A malignancy: solid organ tumor, or post-transplant lymphoproliferative disorder (PTLD)
b) An infection: like tuberculosis.
The management in this scenario includes:
a) Detailed history and physical examination: especially look for presence of palpable lymph nodes (which, if present, can be biopsied easily for a tissue diagnosis).
b) Baseline laboratory work-up including full blood count, liver enzymes, 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 pelvic mass will confirm the diagnosis (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).
i. Reduction of immunosuppression (RIS): The Tacrolimus dose should be reduced by 50% (1,2). The antimetabolite should be stopped. 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 pelvis mass 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).
ii. 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).
iii. If complete remission is achieved with rituximab, then 4 cycles of rituximab every 3 weeks should be given.
iv. 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.
v. 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).
vi. Radiotherapy: can be offered concurrent to RIS in localised disease.
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
Thank you, Well done.
KTR on tacrolimus- based IS therapy with non-specific constitutional symptoms. CT showed irregular soft tissue mass likely represent enlarged LN.
Differential diagnosis:
In the setting of SOT high index of suspicion for PTLD diagnosis as it may present with non-specific symptoms.
– PTLD most likely.
– Infections disease; any opportunistic infections; disseminated mycobacterial or fungal infections.
– Metastatic disease.
Work up:
-Relevant clinical information; the date of transplant, IS regimen ( doses and level) and organ type.
-Comprehensive pre-treatment evaluation:
-For accurate diagnosis a tissue biopsy is recommended and preferred excisional biopsy.
– Pan-CT to inform the treatment decisions and to act as a baseline for the assessment of response.
– If PET-CT scan 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.
Management:
-The management will be guided by the biopsy result, histopathological subtype, the staging of disease, general patient condition and graft function.
-MDT should include transplant physicians, haemato-oncologists, haemato-pathologists, radiation-oncologists and radiologists.
If PTLD confirmed:
Reduction of IS
– It is the mainstay of therapy to restore immune surveillance.
– 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 glucocorticoids.
– In critically ill cases should consider withdrawal of all IS medications except glucocorticoids.
– 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: care G-CSF and PJP prophylactic
Adoptive immunotherapy
-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.
Prognostic factors for treatment response and OS:
– Poor performance status
– EBV-negative tumor
– Graft involvement
– Monomorphic histology
– Older age
– CNS or bone marrow involvement.
– Raised LDH
– Hypoalbuminaemia.
– Extra-nodal site involvement.
– CD-20 positivity
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.
Thank you, Well done.
Thank you all for this excellent answer.
1-it is rare in the form of Hodgkin lymphoma
2-HSV-8
Welcome prof;
I note that, Dr Ben. Can you upload some evidence please.
PTLD can present with nodal lesions in 38% cases.
Other viruses associated with PTLD include: CMV, HHV-8 (1,2)
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) Kapelushnik J, Ariad S, Benharroch D, Landau D, Moser A, Delsol G, Brousset P. Post renal transplantation human herpesvirus 8-associated lymphoproliferative disorder and Kaposi’s sarcoma. Br J Haematol. 2001 May;113(2):425-8. doi: 10.1046/j.1365-2141.2001.02740.x. PMID: 11380409.
Yes, Dr Amit.
Pure nodal disease occurs only in 10 %.
Other viruses associated with increase risk of PTLD:
CMV, specially CMV mismatch ( D+ve/R -ve).
HHV8 is associated with primary effusion lymphoma
HCV was initially thought to be associated, however retrospective multicentre US study in 2007 showed no increased risk
Around 30%
_ peripheral lymphadenopathy is present only in 10 % of cases. However, CNS and graft involvement each is present in 30 % of cases
– other viruses as CMV (however, mild increase in risk due to wide scale use of chemoprophylaxis) .
_HHV8 is associated with effusion lymphoma
_HCV is associated with increased risk of PTLD in liver transplant recipients.
I note that. Can you upload some evidence please
1) Pure lymphadenopathy in PTLD is seen in less than 10%
2) Apart from the EBV association with PTLD, other viruses are
I note that. Can you upload some evidence please
thank you prof Ajay the response
Reference
I note that. Can you upload some evidence please
-PTLD present with lymphadenopathy in 10 % and reach 38 % in pediatric population.
-Other viruses includes; HHV-8, CMV
I note that. Can you upload some evidence please
lymphadenopathy might be common and detected in 38% of patients diagnosed with PTLD.
Other viruses were detected in the context of PTLD and might have been having a crucial role in the propagation of the disease, those viruses include CMV and Human herpes virus 6{ HHV 6}
references:
1}Dharnidharka VR. Comprehensive review of post-organ transplant hematologic cancers. Am J Transplant. 2018 Mar. 18 (3):537-549.
2}Liu M, Husain S, Famure O, Li Y, Kim SJ. Incidence, Risk Factors, Clinical Management, and Outcomes of Posttransplant Lymphoproliferative Disorder in Kidney Transplant Recipients. Prog Transplant. 2019 Jun. 29 (2):185-193.
Yes, Dr Jebur
It presents with lymphadenopathy in less than 10%
Other causes ; HHV – 8(Primary effusion lymphoma),CMV(Esp in D+/R-)
I note that. Can you upload some evidence please
1- Isolated lymphadenopathy is uncommon and occurs in up to 10% of cases
2- Other viruses that are attributed to the development of PTLD include HCV, CMV, HHV-8
I note that. Can you upload some evidence please
1-pure lymphadenopathy presents in less than 10% of the cases
2-HHV8 ,CMV,HCV
reference
Prof Halawa lecture
I note that. Can you upload some evidence please. As much I love Prof Halawa, my academic brother, a lecture can not be used as a reference in a scientific writing.
Marie E etal .Posttransplant Lymphoproliferative Disorder in Children: A 360-degree Perspective.RadioGraphics 2020; 40:241–265
I note that. Can you upload some evidence please
Thaks alot Prof.Halawa
1-Most PTLD cases are B cell (5–10 % T/NK cell or Hodgkin lymphoma)
===================================================================
2- Other virus as CMV ,HHV8
Reference
I note that.
It’s the most common site occur in around 38%
CMV/ HSV-8
1- In classical Hodgkin lymphoma
2- other Viral infections:
I note that. Can you upload some evidence please
1. Epidemiology, clinical manifestations, and diagnosis of post-transplant lymphoproliferative disorders – UpToDate
2. Buda A, Caforio A, Calabrese F, Fagiuoli S, Pevere S, Livi U, et al. Lymphoproliferative disorders in heart transplant recipients: role of hepatitis C virus (HCV) and Epstein-Barr virus (EBV) infection. Transplant Int. 2000;13(Suppl 1):S402–S405.
3. Manez R, Breinig MC, Linden P, Wilson J, Torre-Cisneros J, Kusne S, et al. Posttransplant lymphoproliferative disease in primary Epstein-Barr virus infection after liver transplantation: the role of cytomegalovirus disease. J Infect Dis. 1997;176(6):1462–1467.
4. Al-Mansour Z, Nelson BP, Evens AM. Post-transplant lymphoproliferative disease (PTLD): risk factors, diagnosis, and current treatment strategies. Curr Hematol Malig Rep. 2013 Sep;8(3):173-83. doi: 10.1007/s11899-013-0162-5. PMID: 23737188; PMCID: PMC4831913.
1.Lymphadenopathy is often absent (1)
2.Other viruses (2-4)
· CMV mistmatch is associated with a seven-fold increase in PTLD
· HCV and
· HHV-8
References
1. Dotti G, Fiocchi R, Motta T, Mammana C, Gotti E, Riva S, et al. Lymphomas occurring late after solid-organ transplantation: influence of treatment on the clinical outcome. Transplantation. 2002 Oct 27;74(8):1095-102. PubMed PMID: 12438953. Epub 2002/11/20. eng.
2. Buda A, Caforio A, Calabrese F, Fagiuoli S, Pevere S, Livi U, et al. Lymphoproliferative disorders in heart transplant recipients: role of hepatitis C virus (HCV) and Epstein-Barr virus (EBV) infection. Transplant international : official journal of the European Society for Organ Transplantation. 2000;13 Suppl 1:S402-5. PubMed PMID: 11112042. Epub 2000/12/09. eng.
3. Mañez R, Breinig MC, Linden P, Wilson J, Torre-Cisneros J, Kusne S, et al. Posttransplant lymphoproliferative disease in primary Epstein-Barr virus infection after liver transplantation: the role of cytomegalovirus disease. The Journal of infectious diseases. 1997 Dec;176(6):1462-7. PubMed PMID: 9395355. Epub 1997/12/12. eng.
4. Tsao L, Hsi ED. The clinicopathologic spectrum of posttransplantation lymphoproliferative disorders. Archives of pathology & laboratory medicine. 2007 Aug;131(8):1209-18. PubMed PMID: 17683183. Epub 2007/08/09. eng.
I note that.
1/nodal involvement in PTLD is up to 38%.
2/ other incriminated viruses in the pathogenesis of PTLD beside EBV are; HHV-8 and CMV
I note that. Can you upload some evidence please
1. How often does PTLD present with lymphadenopathy?
In the majority of cases, PTLD is extranodal.
Lymphadenopaghy presents in about 38% However, pure lymphadenopathy less than 10%
2. what are other viruses that could be associated with PTLD?
HHV8, HCV , CMV
I note that. Can you upload some evidence please
1- PTLD can be 10-30 as lymphadenopathy.
2-other viruses such as CMV, HHV8.
I note that. Can you upload some evidence please.
It is rare,around 10%,Other causes include HHV8 and CMV
1.ans- less than 10%
2.ans- HHV-8
1- lymphadenopathy is not common in PTLD 38%
2- other viruses causing PTLD: CMV or HHV-8
PTLD can present with nodal lesions in less than 50% of cases.
Other viruses associated with PTLD are CMV, HHV-8
References:
1.UpToDate
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. Kapelushnik J, Ariad S, Benharroch D, Landau D, Moser A, Delsol G, Brousset P. Post renal transplantation human herpesvirus 8-associated lymphoproliferative disorder and Kaposi’s sarcoma. Br J Haematol. 2001 May;113(2):425-8. doi: 10.1046/j.1365-2141.2001.02740.x. PMID: 11380409.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093305/#:~:text=Post%2Dtransplantation%20lymphoproliferative%20disorders%3A%20Current%20concepts%20and%20future%20therapeutic%20approaches
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9740763/#:~:text=Recent%20Advances%20in%20Adult%20Post%2DTransplant%20Lymphoproliferative%20Disorder
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9740763/#:~:text=Recent%20Advances%20in%20Adult%20Post%2DTransplant%20Lymphoproliferative%20Disorder
Pure lymphadenopathy present only on around 10 %
May be due to other viruses such as HHV-8 or other chronic antigenic stimulation
CMV also can also cause PTLD
Thanks prof. Halawa
1. 30-40% cases PTLD present with lymphadenopathy
2. HHV-8, CMV
1-PTLD is present with lymphadenopathy in 30% of cases.
2- other viruses are: CMV and HHV-8.
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. Kapelushnik, J., Ariad, S., Benharroch, D., Landau, D., Moser, A., Delsol, G., & Brousset, P. (2001). Post renal transplantation human herpesvirus 8-associated lymphoproliferative disorder and Kaposi’s sarcoma. British Journal of Haematology, 113(2). https://doi.org/10.1046/j.1365-2141.2001.02740.x
Around 30%
Other virus causes are :
CMV
EBV
HCV
What is your differential diagnosis?
Imaging shows left iliac lymph node enlargement
· PTLD
· Infectious diseases (tuberculosis, other opportunistic infections)
· Kaposi sarcoma
· Malignancies related to transplant
Risk factors of PTLD:
1. Degree of immunosuppression (cumulative and T cell depletion)
2. Seronegative recipient and seropositive donor
3. Recipient age (<10 years, elderly >60 years)
4. Time since the transplant (first year)
5. Ethnicity (Caucasian)
6. Type of organ transplant (herart, heart-lung and intestine)
7. Pre-transplant malignancy
Briefly outline his management
High index of suspicion
History, physical examination (peripheral lymphadenopathy) 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): lymph node biobsy
Staging of disease by CT chest, abdomen and pelvis
MRI or CT of the brain, orbits and sinuses (CNS or craniofacial disease)
Positron emission tomography (PET) in specific instances
Bone marrow aspiration or lumbar puncture to evaluate CSF including cytology and flow cytometry (CNS-PTLD)
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: when conventional therapies fail
Others: surgery and radiotherapy
References
1. Akar Özkan E, Özdemir BH, Ayva EŞ, Gerçeker F, Boyvat F, Haberal M. Spectrum of histopathologic diagnosis of lymph node biopsies after liver and kidney transplant. Exp Clin Transplant. 2015 Apr;13 Suppl 1:177-82. PMID: 25894150.
2. NCC guidelines version 2.2015 post=transplant lymphoproliferative disorders.
3. Front-line management of post-transplantation lymphoproliferative disorder in adult solid organ recipient patients — A British Society for Haematology Guideline.
Thank you for this excellent answer
Ø Differential diagnosis :
ü Malignancy :
1-PTLD (EBV associated PTLD)
2 Lymphoma
ü Infections:
1- Mycobacterial TB
2- CMV
Ø Investigation suspected PTLD :
· EBV serology
· Immunoglobulin and T and B cell subsets
· US looking for lymphadenopathy and US look for transplant organ
· 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 Detailed history and examination
ü Multi disciplinary team .
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 measure by US or chest x ray
§ Follow up CT done after 4 weeks
§ If clinical and radio logical reproces occur follow the pt till achieved complete remission.
v Categories of PTLD :
Early lesion:
Polymorphic PTLD
Monomorphic PTLD
B cell neoplasm
Tcell neoplasm
Classical Hodgkin lymphoma type PTLD .
REFERENCES :
Hand book of kidney tx donvitch
Prof Halawa lecture
Thank you. What do you mean by whole-body CT?
CT brain ,chest ,abdomen
Differential diagnosis
PTLD
Disseminated Tb
Solid organ malignancy-?colonic cancer
Lymphoma
Management
Workups
First thorough history and physical exam.
Baseline lab works that include a complete blood count, serum uric acid levels, serum calcium levels,LDH levels, LFT
To rule out the differentials: TB screening
Diagnosis
Confirmation- biopsy of the lesion
Staging
CT abdomen and pelvis and chest
Treatment
Should have a multi-disciplinary approach
First line- reduction of the tacrolimus dose by 50% with close monitoring of graft function to detect early rejection. Dose reduction can induce remission in 20-80% of patients. Early response should be within 2-4 weeks.
If no response addition of rituximab should be considered. 4 weekly doses with an addition 4 doses of Rituximab have a complete remission rate ranging 34-60%. Indicated in PTLD class 1-3 unresponsive to reduced immunosuppression.
Chemotherapy is indicated in PTLD unresponsive to rituximab and reduced immunosuppression. Patients with CD20 + PTLD should have chemotherapy plus rituximab. Chemotherapeutic regimens include CHOP/ABVD.
There is a role of adaptive immunotherapy where donor lymphocytes are infused to induce an EBV specific cellular immune response.
References
Prof Halawa lecture
Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches
Thank you for this excellent answer
In the current scenario of renal transplant on immunosuppression with B symptoms including significant loss of wight, night fever and night sweat with complaint of deep pelvic discomfort.
These symptoms and signs raise suspicion for post transplant lymphoproliferative diseases. The image shows a pelvic mass which most probably a lymph node enlargement.
DD including disseminated mycobacterial or fungal infections.
Management of the index case:
Diagnosis:
1-Basically, accurate diagnosis of PTLD requires a high index of suspicion. The diagnosis of PTLD should be suspected in a patient who has allogeneic transplantation with adenopathy, B symptoms (fever, weight loss, night sweats), unexplained hematologic or biochemical abnormalities(increased lactate dehydrogenase LDH levels).
2-Radiologic evidence of a mass or positive positron emission tomography (PET) scanning (possibly indicating metabolically active areas).
3-A rising EBV viral load also supports the diagnosis. Diagnosis and classification require a tissue biopsy, preferably an excisional biopsy of sufficient size.
Prevention:
Since the development of PTLD is related to the degree of immunosuppression and infection with Epstein-Barr virus (EBV) and cytomegalovirus (CMV), prevention largely depends upon limiting patient exposure to aggressive immunosuppressive regimens, rapid withdrawal and or tapering and anti-viral prophylaxis.
Treatment:
Early lesions: suggested reduction of immunosuppression.
Polymorphic PTLD :patients with polymorphic PTLD that expresses CD20 (CD20+ PTLD),suggested use of rituximab in addition to reduction of immunosuppression, as tolerated.
Monomorphic PTLD :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 R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) with or without radiation therapy according to protocols used for classic Hodgkin lymphoma.
Thank you for this excellent answer
What is your differential diagnosis?
This CT image is showing likely pelvic lymphadenopathy. As the patient is post transplant and currently on Tacrolimus based triple immune suppression and systemic symptoms, it raises the concern for PTLD. However other differential diagnosis should be considered and ruled out.
These will include
Infections like, tuberculosis, fungal infections, EBV infections, Brucellosis.
Testicular pathology
Lower limb pathologies
Briefly outline his management
The patient will require investigations including,
Blood CP/ESR, Liver functions, LDH, Alpha fetoproteins, LDH , B HCG. EBV PCR, TB Gold test , Test for fungal infections etc
He will also require full imaging like CT Chest , abdomen and pelvis with contrast.
Lymph node biopsy and PET CT in needed.
The case has to be discussed in MDT and Consultation with infectious disease and oncology team is mandatory.
For PTLD the following approach should be adopted-
-Reduction of immune suppression
-in low risk patients Rituximab can be used if lymphoid tissue shows CD 20 positivity
-In aggressive cases systemic chemotherapy should be given.
Rituximab/ CHOP therapy
Adaptive immune therapy
Infusion of donor lymphocytes, to achieve adoptive immunotherapy, has been shown to manage PTLD in HSCT patients that is primarily originating from donor cells.
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.
Well done.
Differential diagnosis: The differential diagnosis of this symptoms in immune-compromised
patient is broad: the CT showed left iliac lymphadenopathy for differential diagnosis
1.Infections: e.g streptoccocal infection, infectious mononeuclosis, brucellosis
2.Malignancy: e.g PTLD, Kapsi sarcoma, hepatoma,and other malignancies e.g.GIT
3.Metabolic: e.g.,PTDM
Management: is multi-disciplinary and it depends on the underlying diagnosis
Investigations: further evaluations may include
Treatment: This will largely depend on the cause but reasonable approach at this point
while awaiting the results would be;
Source: Medscape
Prof Halawa lecture
Thankyou Ben your DD is vast but only considering infection as a cause of lymphadenopathy which is acceptable but missing malignancy in an immuno compromised SOT patient. You can start from here.
Thank you prof
Yes , malignancy is the second most important differential diagnosis
Malignancy: e.g PTLD, Kapsi sarcoma, hepatoma,and other malignancies e.g.GIT
What is your differential diagnosis?
Briefly outline his management
Setting definitive diagnosis
Management of post-transplant malignancy (challenging and needs multidisplinary team)
A- Modulation of immunosuppression
B- Treatment of the malignancy itself according to the type
C- Surveillance
Treatment of CMV colitis
A- Reduction of immunosuppression
B- Antiviral therapy which is indicated in the following:
C- Surgical treatment
D- Prevention of recurrence
REFERANCES
1- Durand CM, Marr KA, Arnold CA, et al. Detection of cytomegalovirus DNA in plasma as an adjunct diagnostic for gastrointestinal tract disease in kidney and liver transplant recipients. Clin Infect Dis 2013; 57:1550.
2- Uptodate
If there is no thickening of the colon detected and just there is iliac lymph node enlargement , diagnosis my be made by LN biopsy
If you revise the symptoms there is no mention of any colonic symptoms given this sizable lymph node which along side with his systemic manifestations could be your starting point. Although surprises can happen so the biopsy findings will be conclusive.
Differential Diagnosis
36 year old kidney transplant
Fever
weight loss
Night sweats
with a soft tissue pelvic mass possibly a lymph node
1.Tuberculous Lymphadenitis in our population
2.PTLD
PTLD is more common during first year of transplant however duration of transplant is not mentioned.
MANAGEMENT
First step in management is confirmation of diagnosis
Detail history and complete examination is needed to find out any other accessible node or visceromegaly.
Complete blood work which should include LDH
CALCIUM
URIC ACID
HIV
ESR
TB GOLD
EBV VIRAL LOAD
Lymph node biopsy is mandatory which will give definitive diagnosis
Further management will be done jointly with oncology team on board
CT CHEST , Abdomen , Pelvis would be needed along with bone marrow and May be a PET .
Definitive treatment will depend upon extent of disease
RITUXIMAB
CHOP
RITUXIMAB FOLLOWED BY CHOP
ADOPTIVE IMMUNOTHERAPY
This patient would require a multidisciplinary approach of management
Well done.
Differential diagnosis;.
Above patient with renal transplant on immunosuppression like tacrolimus, having weight loss, night sweats and fever with deep pelvic discomfort, CT scan shows mass or lymph node in pelvic;
1. PTLD
2. Disseminated T.B
3. Fungal infection.
4. Metastatic disease.
5. Opportunistic infection
General evaluation
Patient should be free of all active and untreated infection and should be properly evaluated especially all viral infection like EBV, HCV,MCV,HBSAG, HIV ETC
There is high index of suspicious require for accurate PTLD diagnosis as it may present with subtly or extranodally.
PTLD is associated with degree of immunosuppresion drug and infection with EBV, CMV. To prevent these need to take care of drugs level withdraw or tapering of drug of switch to other agent and antiviral prophylaxis especially for CMV.
Laboratory evaluation;
CBC, Renal function. Liver function, LDH,
Calcium, albumin, HIV, CMV PCR, EBV PCR
Radiology evaluation;
CT chest, abdomen, and pelvic
As this patient already have CT pelvic that show LN so it’s better to go for diagnostic biopsy. For tissue diagnosis.
Treatment;
Depends upon type of PTLD and type of organ transplant it may varies according to risk factors also depends upon institution to insinuation. The main arms are;
Reduction in immunosuppression.
Immune therapy with RITUXIMAB
Chemotherapy
Radiation
Combination of chemo and radio therapy
References;
Kasiske BL, Vazquez MA, Harmon WE, et al. Recommendations for the outpatient surveillance of renal transplant recipients. American Society of Transplantation. J Am Soc Nephrol 2000; 11 Suppl 15:S1.
Straathof KC, Savoldo B, Heslop HE, Rooney CM. Immunotherapy for post-transplant lymphoproliferative disease. Br J Haematol 2002; 118:728.
European best practice guidelines for renal transplantation. Nephrol Dial Transplant 2002; 17 (Suppl 4):1.
Allen U, Hébert D, Moore D, et al. Epstein-Barr virus-related post-transplant lymphoproliferative disease in solid organ transplant recipients, 1988-97: a Canadian multi-centre experience. Pediatr Transplant 2001; 5:198.
Add adoptive therapy to your list.
A 36-year-old man with a right renal transplant from his brother presented with loss of weight, night sweats, and night fever associated with deep pelvic discomfort. He has excellent kidney function. Currently, he is on Tacrolimus-based dual immunosuppression.
What is your differential diagnosis?
CT shown Lt large pelvic lymphoid tissue which may be due to
1-Disseminated mycobacterial or fungal infections.
2-Maignancy (PTLD, NHL, metastatic from any primary lesion).
Briefly outline his management.
1-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 (1).
2-Radilogical evidence of mass or organ infiltration.
3-A rising Epstein-Barr virus (EBV) viral load also supports the diagnosis.
4- An excisional biopsy is considered the gold standard of diagnosis and it’s important for classifications.
Treatment plan:
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, ect ).
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.
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 posttransplant 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.
What is your differential diagnosis?
Briefly outline his management :
1- Reduction of immunosuppression as changing Tacrolimus to Sirolimus.
2- Chemotherapy for NHL.
3- Anti-tuberculous ttt for TB.
4- Systemic antifungals for histoplasmosis ….
Can the biopsy finding and immune hystochemistry, and CT scanhelp decide the line of treatment and fate of the graft.
yes. specific ttt as chemotherapy combinations may be needed if it was lymphoma with reduction or even stop of immunosuppression then the patient can revert back to hemodialysis
This is a kidney transplant recipient on a CNI based regimen with good graft function and has developed constitutional symptoms of either a malignancy or an infection with deep pelvic discomfort
The arrow is possibly depicting an enlarged lymph node. The differential diagnosis here would include:
He will need to be evaluated further:
Depending on the results:
If is a malignancy – it would be recommended to reduce his CNI and possible switch to an MTOR inhibitor although mTOR inhibitors have bee found to be useful mainly in KS.
Depending on the type of malignancy, the patient will require chemotherapy. The oncology team will also need to be involved.
If it is an infection, he will need treatment for the specific infection and reduction of the immunosuppression
Thankyou but how can CMV cause such a single lymph node with this size.
What are the predisposing factors for this PTLD.
How can a CT scan help in decision making.
Thank you Prof
For this particular patient, the predisposing risk factor is the use of CNI
We have not been told of his ethnicity (Caucasians are more predisposed to PTLD), years post transplant, and his EBV status pretransplant
A CT scan can pick up other lymph nodes, involvement of the liver or spleen or the graft kidney
PTLD affecting the GIT, LN
TB mass
Abscess
appendicular mass
Diagnostics:
A core needle biopsy (CT-guided) or an excisional biopsy may be done after an exploration of the lesion.
-Full blood count, Electrolytes, Renal function, Glucose, Liver enzymes, Urate, Lactate dehydrogenase (LDH)
HIV type 1 and 2, Hepatitis B and C, EBV serology, CMV/EBV DNA titers
-date of transplant, and immunosuppression regimen Every patient needs an evaluation of how the transplanted organ is working, which should be led by the transplant doctor.
At the time of diagnosis, all patients should have a staging CT scan of their neck, chest, abdomen, and pelvis. This will help doctors decide how to treat them and give a starting point for measuring how well they are doing. Where available, a PET-CT scan should be utilized for staging over a CT scan
PTLD management:
PTLD-experienced hemato-oncology MDTs should discuss organ transplants with all patients.
Hematopathologists should analyze all diagnostic material.
Immunosuppression should be lowered in all transplant patients by getting rid of 30–50% of CNIs and DC antiproliferative drugs. Monitor graft function.
“Early disease response assessment (at 2–4 weeks) is recommended for patients getting only RIS so that those who don’t respond can get more treatment.”
Therapies:
CD20-positive PTLD patients who fail RIS should get rituximab monotherapy.
Patients who achieve CR or complete metabolic remission (CMR)
Rituximab patients should receive four additional three-weekly treatments after four cycles of the standard weekly dosage.
Patients who fail to achieve CR or CMR or progress throughout four rounds of R-CHOP-21 immunochemotherapy should get four further treatments.
Patients with clinically severe lymphoma and major organ damage should get RIS with rituximab and anthracycline (usually R-CHOP-21) as soon as possible after their diagnosis.
Involved-field radiotherapy may be possible for standard PTLD histological subtypes.
Reference ;
Front-line management of the post-transplantation lymphoproliferative disorder in adult solid organ recipient patients — A British Society for Haematology Guideline
Good comprehensive plan with decision taking.
This is the left iliac fossa.!
What is your differential diagnosis?
The CT showed an enlarged left pelvic lymphnode in a kidney transplanted patient maintained on tacrolimus based dual immunosuppression.
Differential diagnosis:
– Past transplant lymphoproliferative disease (PTLD).
– Infectious – bacterial, fungal, viral ….etc.
– Vasculitis.
Briefly outline his 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 or surgical LN excisional biopsy.
Serum T.protein , albumin , LDH, calcium and uric acid.
Kidney function, liver function and urinalysis.
Treatment:
First is to stop one of the immunosuppressive medications used MMF, CNI and reduce the other, or swithing to m-TOR inhibitor.
Based on the biopsy histopathology result and extent of involvement – to be discussed with hemato-oncologist.
Rituximab could be the only treatment required.
Radiotherapy is another treatment option.
R-CHOP/ABVD can be a treatment option base on the pathology result.
Adoptive immunotherapy may be usefull but might increase the risk of rejection.
However; PTLD’s carry a poor prognosis with 50% mortality.
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) 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.
(3) Al-Mansour Z, Nelson BP, Evens AM. Post-transplant lymphoproliferative disease (PTLD): risk factors, diagnosis, and current treatment strategies. Curr Hematol Malig Rep. 2013 Sep;8(3):173-83. doi: 10.1007/s11899-013-0162-5. PMID: 23737188; PMCID: PMC4831913.
(4) 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.
How can vasculitis give such a CT picture
otherwise the information you gave is fine but how does it influence your plan choice.
some vasculitis could present with lymphadenopathies and granulomas
Diagnosis and Differential Diagnosis:
PTLD affecting left iliac lymph nodes.
Lymphoma (NHL)
Systemic TB
Management:
Detailed history and physical examination.
Investigations:
1. CT guided biopsy
2. Peripheral smear, Blood culture and sensitivity
3. LDH
4. Serum Uric acid, Calcium
5. CT chest Abdomen
6. EBV-PCR
Reduction of immunosuppression.
Stop CNI, Reduce MMF
Switch to mTOR Inhibitors
Rituximab
CHOP therapy
This is short , how can it help make a decision for the fate of the graft.!
DDx
– Posttransplant lymphoproliferative disease
– Systemic infection ( Tb )
– NHL
How to manage
Diagnosis and staging
– History talking and physical examination
– Calcium uric acid and LDH ESR CRP
– EBV viral load
– Immunophenotyping
– CT abdomen with contrast
– Ct -PET for other body site affection
– Tissue biopsy(Stage and grade of disease • EBV positivity (determined by immunohistochemistry)• Expression of the B cell surface antigen CD20
– Bone marrow aspiration and trephine
Treatment
In Early disease B cell hyperplasia: stop MMF/azathioprine reduce dose of CNI over 2 weeks guided by trough level with close follow up for graft function
In poly morphic disease : reduction of IS and monitor both the response and graft function if no response if it is CD 20+ poly morphic disease give rituximab if CD-ve polymorphic disease CHOP +-rituximab
In monomorphic disease: chemotherapy +-rituximab
Surgical treatment for localized disease or emergency situation: intestinal involvement by perforation
Ref
OSH Renal Transplantation;2011 p.355-365
Thankyou it is EBV PCR not immunhistochemistry .
CT shows irregular left sided soft tissue mass partially attached to kidney , most likely
PTLD.
Differential diagnosis:
PTLD.
Teratoma.
IBD , Crohns disease.
Reactive inflammatory infiltrate.
NHL.
T.B.
Rejection.
EBV systemic infections.
Diagnosis:
CT biopsy for soft tissue.
BM aspiration and biopsy.
The NCCN guideline for PTLD, which is integrated into the larger B-cell lymphoma
guideline, provides the following algorithm to diagnose the disorder with steps
categorized as either “essential” or “useful under certain circumstances.(1).
Essential steps include the following:
without cell surface marker analysis by flow cytometry
AST guidelines recommend the following for the diagnosis of PTLD
Treatment :
According to the NCCN guidelines, treatment depends on the PTLD subtype
Reduction in immunosuppression (RI) is the initial treatment in nearly all cases.
A
treatment options vary according to the World Health Organization (WHO) classification.
Non-destructive lesions
Monomorphic PTLD (B-cell type)
RI if possible, with or without one of the following:
Polymorphic PTLD
For patients with localized disease, RI if possible plus one of the following:
For patients with systemic disease, RI if possible plus one of the following:
References:
1-Guideline] National Comprehensive Cancer Network. NCCN Clinical Practice
Guidelines in Oncology: B-Cell Lymphomas. NCCN. Available
at https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf. Version 5.2022 —
July 12, 2022; Accessed: October 8, 2022.
Exellent to complete mention Adoptive therapy.
How can rejection give this CT image.
Thank Prof.
Adoptive immunotherapy with in vitro–generated donor or third-party EBV-
specific T lymphocytes based on cytotoxic T lymphocytes (CTLs).
How can rejection give this CT image
sorry idont think with this nodal PTLD.
D.D:
PTLD
lymphoma
systemic infection either bacterial or fungal
management :
1- blood culture and sensitivity
2-CT chest and abdomen
3-CBC for pancytopenia
4- uric acid and calcium
5- LDH
6-EBV PCR
7-image guided biopsy for histopathological diagnosis
8- if PTLD or lymphoma 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
references : the lecture of prof. Ahmed Halawa
Well done
Differential diagnosis?
Management :
Depending of type of PTLD;
Adoptive immunotherapy may be considered.
Reference; Robert S Negrin Topic 7335 Version 31.0 UpToDate 2023
Thankyou
Whatis the prognostic value that would direct the treatment plan of the following:
extent of lymphadenopathy
EBV pcr load.
Monomorphic or pleomorphic histology
Polymorphic, EBV positivity, lesser node involvement and early response to treatment
·What is your differential diagnosis?
Posttransplantation lymphoproliferative disease (PTLD): Unenhanced CT image of the left common iliac bifurcation reveals a soft tissue-density mass (arrow) that is consistent with PTLD.
Differential diagnoses include: Hodgkin’s, Burkitt’s, and T-cell lymphomas.
////////////////////////////
·Briefly outline his management
-No efficacy in monotherapy
-Only in EBV+ve cases
file:///C:/Users/TOSHIBA/AppData/Local/Temp/msohtmlclip1/01/clip_image002.jpg
References
1. Vrachliotis et al. CT Findings in Posttransplantation Lymphoproliferative Disorder of Renal Transplants. AJR:175, July 2000
2. Daan Dierickx,Thomas Tousseyn, and Olivier Gheysens. How I treat post-transplant lympho-proliferative disorders. BLOOD, 12 NOVEMBER 2015 x VOLUME 126, NUMBER 20
Thankyou but where is the figure (below)!!
History
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What is your differential diagnosis?
Diagnosis and evaluation
People with immunodeficiency are more likely to develop lymphoproliferative disorders, such as: –
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Briefly outline his management
The first-line treatment strategy is still immunosuppression reduction (RIS) or total discontinuation.
-Systemic Chemothrapy
Adoptive immunotherapy
Prophylactic
Prognosis
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Reference
THhankyou Mahmoud this is Exellent.
Thanks alot for you Prof.Dawlat Belal
A CT image showing a mass in the left iliac fossa marked by an arrow (possibly enlarged lymph nodes)
Any unexplained lymphadenopathy in the setting of organ transplantation showed be investigated to exclude PTLD. However, other possible causes should be considered, like underlying infection (systemic or localized left lower limb infection).
His systemic manifestations may occur with disseminated mycobacterial or fungal infections, which is another rare but serious differential diagnosis.
The management discussed below is based upon confirmation of the diagnosis of PTLD.
However, if the other investigations (including a tissue biopsy) show another pathology, then the treatment will be based on the latest guidelines for treating 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
Any information about Adoptive therapy if feasible.
Thanks, Prof. Dawlat,
Adoptive immunotherapy, as anticipated from the name, is the adoption of the standard immune surveillance of T-lymphocytes against PTLD cells by using EBV-specific cytotoxic T lymphocytes or using donor lymphocyte infusion in the setting of PTLD post-hematopoietic cell transplantation (1).
The major complication of adoptive immunotherapy is acute and chronic graft-versus-host disease (GVHD) (1).
Reference:
1) Robert S Negrin and Daniel C Brennan. Treatment and prevention of post-transplant lymphoproliferative disorders. © 2023 UpToDate (accessed on 30 January 2023).