A Case of Epstein-Barr Virus-Negative Post-transplant Lymphoproliferative Disorder in a Solid Organ Transplant Recipient With Untreated Chronic Hepatitis C.

Post-transplant lymphoproliferative disorder (PTLD) is one of the most common malignancies affecting solid organ transplant recipients. The disease is frequently associated with Epstein-Barr virus (EBV) infection (70% of cases) and cases are often delineated by EBV positivity status. The oncogenesis of EBV-positive PTLD is well-described in the literature; however, the etiology of the EBV-negative subtype is poorly understood. This report describes a case of EBV-negative PTLD developing in a combined kidney-pancreas transplant recipient with an incidental finding of untreated chronic hepatitis C virus (HCV). Our experience suggests an association between HCV and EBV-negative PTLD. Additional well-designed studies are needed to further investigate this association.

Posttransplant lymphoproliferative disorder in a heart transplant recipient: a case report.

Malignancy in heart transplant recipients is a grave complication. Post-transplant lymphoproliferative disorder (PTLD) is the second most common tumour in adults and commonest in children. The incidence varies with the transplanted organ from 1 to 2% following kidney transplantation to as high as 10% following thoracic organ transplantation due to different immunosuppression intensity. PTLD include a wide spectrum of diseases ranging from benign proliferation of lymphoid tissue to frank malignancy with aggressive behaviour (lymphoma). Epstein-Barr virus (EBV) infection and prolonged immunosuppressant therapy are implicated in the pathogenesis of PTLD. The incidence of PTLD varies from 2.6% at 1 year to 28% at 10 years post-transplant. Seronegativity for EBV in recipients with seropositive donors increases the risk of PTLD in recipients. The majority of early-onset PTLDs (85%) are of B-cell origin and associated with EBV. Timely and accurate diagnosis with histological examination of lymphoid tissue is essential for early intervention. Reduction of immunosuppressive therapy (IST) and rituximab usually are effective in remission of PTLD. In resistant cases, chemotherapy is given with or without rituximab. Adoptive T-cell transfer represents a promising therapeutic approach. Early PTLD respond well to lowering immunosuppression and has a favourable prognosis compared to late PTLD. Five-year survival is 30% for high-grade lymphomas. The prognosis of EBV-negative lymphomas is worse. One out of 40 heart transplant recipients followed up in our centre developed PTLD. He was treated to remission and we describe this case here.

Clinical Utility of 18Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography (18F-FDG PET/CT) in Multivisceral Transplant Patients.

Multivisceral transplant (MVTx) refers to a composite graft from a cadaveric donor, which often includes the liver, the pancreaticoduodenal complex, and small intestine transplanted en bloc. It remains rare and is performed in specialist centres. Post-transplant complications are reported at a higher rate in multivisceral transplants because of the high levels of immunosuppression used to prevent rejection of the highly immunogenic intestine. In this study, we analyzed the clinical utility of 28 18F-FDG PET/CT scans in 20 multivisceral transplant recipients in whom previous non-functional imaging was deemed clinically inconclusive. The results were compared with histopathological and clinical follow-up data. In our study, the accuracy of 18F-FDG PET/CT was determined as 66.7%, where a final diagnosis was confirmed clinically or via pathology. Of the 28 scans, 24 scans (85.7%) directly affected patient management, of which 9 were related to starting of new treatments and 6 resulted in an ongoing treatment or planned surgery being stopped. This study demonstrates that 18F-FDG PET/CT is a promising technique in identifying life-threatening pathologies in this complex group of patients. It would appear that 18F-FDG PET/CT has a good level of accuracy, including for those MVTx patients suffering from infection, post-transplant lymphoproliferative disease, and malignancy.

Post-transplant lymphoproliferative disorder risk and outcomes in renal transplant patients treated with belatacept immunosuppression.

Introduction: Post-transplant lymphoproliferative disorder (PTLD) is a rare but life-threatening malignancy that arises in the setting of immunosuppression (IS) after solid organ transplant. IS regimens containing belatacept have been associated with an increased risk of PTLD in Epstein-Barr virus (EBV)-seronegative renal transplant recipients, and the use of belatacept is contraindicated in this population. However, the impact of belatacept-based regimens on PTLD risk and outcomes in EBV-seropositive renal transplant recipients is less well characterized. Methods: A case-control study was conducted to investigate how combinatorial IS regimens impact the risk of PTLD and survival outcomes in renal transplant recipients at a large transplant center between 2010 and 2019. In total, 17 cases of PTLD were identified and matched 1:2 to controls without PTLD by age, sex, and transplanted organ(s). We compared baseline clinical characteristics, examined changes in IS regimen, viral loads, and renal function over time, and evaluated time-to-event analyses, including graft rejection and survival. Results: Cases of PTLD largely resembled matched controls in terms of baseline characteristics, although expected differences in EBV serostatus trended toward significance (42.9% of PTLD cases were donor-positive/recipient-negative vs. 8.3% controls, p = 0.063). PTLD cases were not more likely to have received belatacept than controls. Belatacept was not associated with graft rejection or failure, re-transplant, hospitalization, or decreased survival. Conclusions: Belatacept was not associated with an increased risk of PTLD, and was not associated with decreased survival in either PTLD cases or in the entire cohort. Our case-control study supports the concept that belatacept remains a safe and effective option for IS in EBV-seropositive renal transplant patients.

Stereotactic Radiotherapy for Recurrent Post-Transplant Primary Central Nervous System Lymphoma.

Post-transplant primary central nervous system lymphoma (PCNSL) is a rare complication of solid organ transplantation. The optimal therapy for post-transplant PCNSL is not well established and generally includes reduction of immunosuppression and chemotherapy. Progression after front-line chemotherapy is common, and whole-brain radiotherapy (WBRT) is a standard salvage treatment as there is a concern that localized treatment fields would not prevent out-of-field recurrences. However, WBRT is associated with neurotoxicity and morbidity in these patients with inherently poor prognoses. Here, we report a patient with local recurrence of post-transplant PCNSL who was treated with fractionated stereotactic radiotherapy (SRT). He had no clinical toxicity from treatment and maintained pre-treatment neurocognition and performance status. Local control was achieved for 20 months following SRT, at which point he developed an in-field recurrence. He restarted lymphoma therapy but died one month later from fungal pneumonia. For central nervous system (CNS) lymphoma, further data are needed to optimize tumor control and toxicity outcomes and identify patients in whom localized radiotherapy fields may be beneficial, avoiding the potential toxicity of WBRT.

Neurolymphomatosis of the median nerve, optic nerve, L4 spinal nerve root and cauda equina in patients with B-cell malignancies: a case series.

BACKGROUND: Neurolymphomatosis is rare. Neoplastic lymphocytes are seen to invade nerves (cranial or peripheral), nerve roots or other related structures in patients with hematological malignancy. It is a separate entity from central nervous system lymphoma. Neurolymphomatosis has most commonly been described in association with B-cell non-Hodgkin lymphoma. Neurolymphomatosis in the context of Burkitt lymphoma and the post-renal transplant setting has not been described before. CASE REPORTS: We report for the first time in the Arabian Gulf countries and nearby Arab states four cases of neurolymphomatosis (one Asian, and the other 3 are from Arabic nationals) occurring between 2012 and 2017 involving the median nerve, optic nerve, nerve root and cauda equina in patients with Burkitt lymphoma, Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia and diffuse large B-cell lymphoma. CONCLUSIONS: Neurolymphomatosis is rare and can be difficult to diagnose by biopsy but reliably confirmed by a combined imaging approach. Prior treatment with high-dose dexamethasone might suppress 18F-fluorodeoxyglucose (FDG) activity and decrease the sensitivity of positron emission tomography/computed tomography (PET/CT). The prognosis is generally poor but using high-dose methotrexate as well as high-dose chemotherapy and autologous stem cell transplantation may be an effective way to treat neurolymphomatosis.

Post-renal transplant malignancies: Opportunities for prevention and early screening.

GOAL OF THE REVIEW: While transplant recipients are aware of increased malignancy risk, there is little consensus on the preventative measures. The goal of this review is to bring available preventative measures to light and prompt more research to be done with ultimate goal of developing an individualized prevention plan for each patient based on risk factors and available screening tools. INTRODUCTION: Transplant surgery offers patients with end-stage renal disease a longer life expectancy with help of immunosuppressive therapies. Nonetheless, life-long immunosuppression comes at a cost of post-renal transplant malignancies, which have become the leading cause of morbidity in this patient group. DISCUSSION: Post-renal transplant cancers can develop through either de novo, by donor-related transmission, or recurrence of recipient's pre-transplant cancer. While immunosuppressive therapy is considered to be the leading cause, weakened immunosurveillance of neoplastic cells and inadequate immune response against oncogenic viruses also plays an important role. The most common cancers seen in renal transplant patients are skin cancers and post-transplant lymphoproliferative disorder (PTLD). Risk factors for skin cancers have are ultraviolet light, human papilloma virus infection, and use of cyclosporin and azathioprine. Numerous viral infections have been associated with transplant-related malignancies post-transplant. CONCLUSION: While lowering of immunosuppressive therapy remains the treatment of choice, it may lead to graft failure. Given some of the presented malignancies have modifiable risk factors and options for screening, clinical outcomes can be improved. Limiting skin exposure, dermatologic screening, and prophylactic retinoids can help lower the incidence rate of skin malignancy. Endoscopic screening for renal transplant patients can help identify gastric adenocarcinoma early and improve survival rates. Some of the post-transplant malignancies have been responsive to anti-viral treatment.

Immunodeficiency-Related Lymphoid Proliferations: New Insights With Relevance to Practice.

PURPOSE OF REVIEW: Our understanding of risk factors and mechanisms underlying immunosuppression-related lymphoproliferative disorders continues to evolve. An increasing number of patients are living with altered immune status due to HIV, solid organ or hematopoietic stem cell transplant, treatment of autoimmune disease, or advanced age. This review covers advances in understanding, emerging trends, and revisions to diagnostic guidelines. RECENT FINDINGS: The tumor microenvironment, including interactions between the host immune system and tumor cells, is of increasing interest in the setting of immunosuppression. While some forms of lymphoproliferative disease are associated with unique risk factors, common mechanisms are also emerging. Indolent forms, such as Epstein-Barr virus positive mucocutaneous ulcer, are important to recognize. As methods to modulate the immune system evolve, more data are needed to understand and minimize lymphoproliferative disease risk. A better understanding of individual risk factors and common mechanisms underlying immunosuppression-related lymphoproliferations will ultimately enable improved prevention and treatment of these disorders.

Early Onset Post-transplant Lymphoproliferative Disorder Presenting with Diarrhea Post-orthotopic Liver Transplant Treated Successfully with Single Rituximab Agent.

Post-transplant lymphoproliferative disorder (PTLD) is a rare complication seen in hematologic stem cell (HSC) and solid organ transplantation that results from immune suppressant medications needed to prevent allograft rejection. Epstein-Barr virus (EBV) has been implicated in a majority of these cases, specifically with B-cell-predominant lymphomas. We present a 57-year-old female who underwent an orthotopic liver transplant and presented with diarrhea and weight loss. At the time of transplantation, the patient's quantitative EBV titers were negative; however, repeat titers during her admission were positive. Infectious etiologies for diarrhea were negative so a colonoscopy was pursued which revealed large ulcerated areas and biopsies consistent with monomorphic, diffuse large B-cell lymphoma, plus EBV. Imaging revealed multiple areas below the diaphragm of lymphadenopathy. The patient was started on rituximab and antivirals, and immune suppressive medications were decreased with a resolution of her symptoms. PTLD after any transplantation can be difficult to diagnose, given the wide range of presenting symptoms. Identifying patients who are at high risk for developing PTLD may lead to a more timely diagnosis to initiate treatment and decrease mortality risk.

Post-transplant Lymphoproliferative Disorder Presented in a Form of Primary Effusion Lymphoma with t (8; 14).

Post-transplant lymphoproliferative disorders (PTLD) are emergent complications of organ transplantation occurring in 2% to 10% of transplanted patients. Epstein-Barr virus (EBV) infections are considered the most important factors for the development of these heterogeneous disorders. Primary effusion lymphoma (PEL) is a lymphoproliferative disorder predominantly described in patients with advanced AIDS and it is almost universally associated with human herpesvirus 8 (HHV8). In rare case, PEL also occurs in HHV8-negative patient, in the setting of hepatitis B and C virus infection. However, all these cases showed pan B-cell markers to be positive. Here, we report a case of PTLD presented as HHV8-negative and HIV-negative primary effusion lymphoma lacking near all lymphoid markers except PAX5 on immunohistochemistry, which created a diagnostic challenge. The diagnosis requires multiple approaches including molecular and genetic tests.

Diagnosis and differential diagnosis of hepatic graft versus host disease (GVHD).

Graft versus host disease (GVHD) is a common complication following allogeneic hematopoietic cell transplantation (HCT) that typically manifests as injury to the skin, gastrointestinal mucosa, and liver. In some cases, hepatic GVHD may be histologically indistinguishable from other disorders such as infection and drug-induced liver injury (DILI). Additionally, clinical signs and symptoms are frequently confounded by the superimposed effects of pretransplant chemoradiotherapy, immunotherapy (IT) (targeted to the underlying malignancy), GVHD prophylaxis, and infection. Thus, careful attention to and correlation with clinical findings, laboratory values, and histologic features is essential for diagnosis. This review, aimed at the practicing pathologist, will discuss current clinical and histologic criteria for GVHD, the approach to diagnosis of hepatic GVHD, and features helpful for distinguishing it from other entities in the differential diagnosis.

Role of Epstein-Barr virus status and immunophenotypic studies in the evaluation of exfoliative cytology specimens from patients with post-transplant lymphoproliferative disorders.

BACKGROUND: Post-transplant lymphoproliferative disorders (PTLDs) are well characterized in tissue sections, but their evaluation in exfoliative cytology specimens is limited. This study reports a 25-year experience with PTLDs in exfoliative cytology specimens. METHODS: All solid organ or allogeneic stem cell transplant recipients with PTLDs and exfoliative cytology specimens from 1987 to 2011 were identified. The cytomorphology, Epstein-Barr virus (EBV) status, flow cytometry, immunohistochemistry, and molecular studies were reviewed from all exfoliative cytology specimens previously diagnosed as atypical lymphoid proliferations or PTLDs. RESULTS: A total of 55 patients (age range, 1-72 years) with PTLDs had 434 exfoliative cytology specimens. Thirty-six of the 55 patients (65%) had 54 specimens with abnormal lymphoid proliferations (12% of the specimens), and 26 of these patients had 37 specimens available for review (15 cerebrospinal fluid specimens, 12 peritoneal fluid specimens, 9 pleural fluid specimens, and 1 bronchoalveolar lavage fluid specimen). Thirty percent of the reviewed cytology specimens were diagnostic of PTLDs, including 8 cases of monomorphic post-transplant lymphoproliferative disorder (M-PTLD) with abnormal B/T-cell populations identified with flow cytometry/immunohistochemistry and 3 EBV-positive specimens with a differential diagnosis of polymorphic PTLD versus M-PTLD. All cases diagnostic of a PTLD had 1 to 3 ancillary studies performed. Forty percent of the cytology specimens (15 of 37) were suspicious for a PTLD, but ancillary studies were performed for only a third of them, and they did not support a definitive diagnosis of a PTLD. Thirty percent of the cytology specimens (11 of 37) appeared reactive, but they lacked sufficient ancillary studies to exclude a PTLD. CONCLUSIONS: Atypical lymphoid proliferations are common in exfoliative cytology specimens from patients with PTLDs, and they require ancillary studies at least including immunophenotyping and EBV evaluations for a definitive diagnosis. Cancer Cytopathol 2016;124:425-35. © 2016 American Cancer Society.

Successful treatment of intraocular post-transplant lymphoproliferative disorder with intravenous rituximab.

We reported a rare case of intraocular post-transplant lymphoproliferative disorder (PTLD) arising in a 3-year-old liver transplant recipient who had a prior history of systemic PTLD. The first PTLD entered remission after treatment with intravenous rituximab and withdrawal of immunosuppressants. One year after remission, she presented with granulomatous uveitis and iris nodules in the right eye. Iris biopsy confirmed recurrence of intraocular PTLD, which resolved completely after a second course of intravenous rituximab.

Asymptomatic post-transplant lymphoproliferative disorder diagnosed at one year protocol renal allograft biopsy.

Post-transplant lymphoproliferative disorder (PTLD) is a neoplastic complication with a potentially fatal outcome that develops as a consequence of immunosuppression, and is mainly associated with Epstein-Barr virus (EBV) infection. A 70-year-old woman underwent a live unrelated, ABO-incompatible renal transplant for end-stage renal disease. One year after transplantation, protocol biopsy revealed pathological changes indicative of the histological subtype of 'early lesions of PTLD' according to the World Health Organization classification, while the patient showed no clinical signs or symptoms. The patient was finally diagnosed with EBV-positive PTLD by in situ hybridization for EBER (EBV-encoded RNA), and was successfully treated based on the reduction of immunosuppression. Protocol biopsy within the first post-transplant year is the only diagnostic measure to detect asymptomatic early PTLD, which allows for early intervention and leads to better outcomes.

Detection of Epstein-Barr virus (EBV) in human lymphoma tissue by a novel microbial detection array.

BACKGROUND: Infectious agents are estimated to play a causative role in approximately 20% of cancers worldwide. Viruses, notably the Epstein-Barr virus (EBV), are associated with 10-15% of B-cell lymphomas and are found at a higher frequency in immunosuppressed patients. In this study, we screened human lymphoma tissues using a novel Lawrence Livermore Microbial Detection Array (LLMDA), a comprehensive detection system that contains probes for all sequenced viruses and bacteria. This technology has been applied to identify pathogen-associated diseases. RESULTS: We evaluated samples from 58 cases with various lymphoid tissue disorders using LLMDA. These included 30 B-cell lymphomas (9 indolent and 21 aggressive type), 2 T-cell lymphomas and 2 NK/T cell lymphomas, 4 plasmacytomas as well as 8 specimens of benign lymphoid tissue. Five of 21 high-grade B-cell lymphomas were positive for Epstein-Barr virus-encoded small RNA (EBER+), while all the indolent B-cell lymphomas were EBER-. Similarly, both NK/T cell lymphomas were EBER+, and the benign tissues were EBER-. We also screened 10 cases of post-transplant lymphoproliferative disorder (PTLD). Five of these cases (4 B-cell lymphomas and 1 NK/T cell lymphoma) were EBER+, and the remaining five cases were EBER-. CONCLUSIONS: We have confirmed the reliability of the LLMDA methods by detecting EBV in EBV-positive lymphomas while observing no false-positive results in EBV-negative lymphomas. The LLMDA technique provides a sensitive and alternative method for identifying known viral pathogen associated with tumors and may prove useful for future clinical identification of novel cancer-associated viral pathogens.

Early gene expression changes by Epstein-Barr virus infection of B-cells indicate CDKs and survivin as therapeutic targets for post-transplant lymphoproliferative diseases.

Lymphoproliferative diseases (LPDs) associated with Epstein-Barr virus (EBV) infection cause significant morbidity and mortality in bone marrow and solid organ transplant recipients. To gain insight into LPD pathogenesis and to identify potential effective therapeutic approaches, we investigated early molecular events leading to B-cell transformation by gene expression profiling of EBV-infected B-cells from tonsils by Affymetrix microarray 72 hr postinfection when the B-cells hyperproliferation phase starts. Cell cycle and apoptosis were the most significantly affected pathways and enriched gene sets. In particular, we found significantly increased expression of cyclin-dependent kinase (CDK)1 and CCNB1 (cyclin B1) and of one of their downstream targets BIRC5 (survivin). Importantly, the strong upregulation of the antiapoptotic protein survivin was confirmed in lymphoblastoid cell lines (LCLs) and 71% of EBV-positive post-transplant EBV-LPD lesions scored positive for survivin. The validity of early transforming events for the identification of therapeutic targets for EBV-LPD was confirmed by the marked antiproliferative effect of the CDK inhibitor flavopiridol on LCLs and by the strong induction of apoptosis by survivin inhibition with YM155 or terameprocol. Our results suggest that targeting of CDKs and/or survivin in post-transplant EBV-LPD by specific inhibitors might be an important approach to control and eliminate EBV-transformed B-cells that should be further considered.

Clinical Manifestations of Posttransplantation Lymphoproliferative Disorder (PTLD) after Liver Transplantation / 감염과화학요법

BACKGROUND: Post-transplantation lymphoproliferative disorder (PTLD) after liver transplantation is a rare but potentially fatal disease. Clinical manifestations and prevalence of PTLD after liver transplantation in Korea have not been investigated thoroughly. MATERIALS AND METHODS: A retrospective chart review was done for 284 liver transplant recipients at Samsung Medical Center, Seoul, Korea during the period from 1996 to 2003. RESULTS: The incidence of PTLD after liver transplantation was 3.9% (11/284). PTLDs were more prevalent in children (9/55, 16.4%) than in adults (2/237, 0.9%; P<0.01). Among the PTLD patients, four cases were male (36.3%) and seven were female (63.7%). Median time from the transplantation to PTLD diagnosis was 9 months. The type of PTLD was as follows:early lesion (6 cases, 54.5%), polymorphic PTLD (3 cases, 27.3%), and B cell lymphoma (2 cases, 18.2%). PTLDs were more prevalent in the patients with cyclosporine use (OR 13.28, 95% CI:1.29-136.31, P=0.03), acute rejection (OR 5.63, 95% CI:1.03-30.62, P=0.04), and negative serology for EBV VCA IgG (OR 19.15, 95% CI:1.99-183.98, P=0.01) by multivariate logistic regression. Three patients (27.3%) died of B cell lymphoma (2 cases) and polymorphic PTLD (1 case). The remaining patients were improved with reduction of immunosuppression and treatment with acyclovir. CONCLUSION: The incidence of PTLD was high in children. The risk factors of PTLD were negative serology for EBV VCA IgG, history of acute rejection, and cyclosporine use. Considering the poor prognosis of PTLD, effective strategies for prevention and early diagnosis for early treatment should be emphasized.

Clinical Manifestations of Posttransplantation Lymphoproliferative Disorder (PTLD) after Liver Transplantation / 감염과화학요법

BACKGROUND: Post-transplantation lymphoproliferative disorder (PTLD) after liver transplantation is a rare but potentially fatal disease. Clinical manifestations and prevalence of PTLD after liver transplantation in Korea have not been investigated thoroughly. MATERIALS AND METHODS: A retrospective chart review was done for 284 liver transplant recipients at Samsung Medical Center, Seoul, Korea during the period from 1996 to 2003. RESULTS: The incidence of PTLD after liver transplantation was 3.9% (11/284). PTLDs were more prevalent in children (9/55, 16.4%) than in adults (2/237, 0.9%; P<0.01). Among the PTLD patients, four cases were male (36.3%) and seven were female (63.7%). Median time from the transplantation to PTLD diagnosis was 9 months. The type of PTLD was as follows:early lesion (6 cases, 54.5%), polymorphic PTLD (3 cases, 27.3%), and B cell lymphoma (2 cases, 18.2%). PTLDs were more prevalent in the patients with cyclosporine use (OR 13.28, 95% CI:1.29-136.31, P=0.03), acute rejection (OR 5.63, 95% CI:1.03-30.62, P=0.04), and negative serology for EBV VCA IgG (OR 19.15, 95% CI:1.99-183.98, P=0.01) by multivariate logistic regression. Three patients (27.3%) died of B cell lymphoma (2 cases) and polymorphic PTLD (1 case). The remaining patients were improved with reduction of immunosuppression and treatment with acyclovir. CONCLUSION: The incidence of PTLD was high in children. The risk factors of PTLD were negative serology for EBV VCA IgG, history of acute rejection, and cyclosporine use. Considering the poor prognosis of PTLD, effective strategies for prevention and early diagnosis for early treatment should be emphasized.