Severe post‐transplant lymphoproliferative disorder after living donor liver transplantation

Post‐transplant lymphoproliferative disorder (PTLD) is a well‐known complication after transplantation. A living donor liver transplantation was performed on a 31‐year‐old man for fulminant hepatitis. He again developed liver dysfunction after 7 months. He was diagnosed as having acute cellular rejection and the steroid pulse therapy introduced resulted in little improvement. He gradually developed a high fever and right axillary lymphadenopathy appeared. Chest computed tomography (CT) was performed revealing small lung nodules and axillary lymphadenopathy. Because his serological status for Epstein–Barr virus was positive, PTLD was highly suspected and immunosuppression treatment was withdrawn with little improvement. One week later, he developed tachycardia. Chest CT was re‐performed revealing an infiltration to the left cardiac chamber. For diagnosis, axillary lymph node biopsy was performed and during the procedure, he developed ventricular tachycardia (VT). Immunohistological staining revealed PTLD of T lymphocytes, and chemotherapy was introduced on the same day he developed VT. After two cycles of tetrahydropyranyl, adriamycin, cyclophosphamide, vincristine, prednisolone and etoposide treatment, he completely recovered. This is a first case report of severe PTLD with VT, and our case implies the feasibility of chemotherapy after the appearance of dissemination symptoms.     

Subacute immune response to primary EBV infection leading to post‐transplant lymphoproliferative disease in a renal transplant patient

A 23‐year‐old man sero‐negative for Epstein–Barr virus (EBV) developed recurrent sore throats 3 and 6 months after a renal transplant from an EBV sero‐positive donor. Tonsillar biopsy at 9 months post‐transplant showed post‐transplant lymphoproliferative disease (PTLD) caused by EBV. Following reduction of immunosuppressive treatment, he developed further signs and symptoms, and serological evidence of infectious mononucleosis followed by resolution of lymphadenopathy. This case emphasizes the difficulty in interpreting EBV serology in immunosuppressed patients and the importance of pre‐transplant EBV serology.     

Epstein–Barr virus‐associated pneumonia in patients with post‐transplant lymphoproliferative disease after hematopoietic stem cell transplantation

Q.‐F. Liu, Z.‐P. Fan, X.‐D. Luo, J. Sun, Y. Zhang, Y.‐Q. Ding. Epstein–Barr virus‐associated pneumonia in patients with post‐transplant lymphoproliferative disease after hematopoietic stem cell transplantation.
Transpl Infect Dis 2010: 12: 284–291. All rights reserved. Abstract: Epstein–Barr virus (EBV) reactivation or infection after hematopoietic stem cell transplantation (HSCT) most often induces post‐transplant lymphoproliferative disease (PTLD), but it also may be associated with clinical symptoms such as pneumonia. Our aim was to investigate and describe the clinical manifestations of PTLD and PTLD accompanied by EBV‐associated pneumonia in 323 patients after HSCT. PTLD within extravisceral lymphoid tissue was identified in 7 cases (5 with CD20⁺ diffuse large B‐cell lymphoma, 1 with CD20⁺ polymorphic B‐cell hyperplasia, and 1 with CD3⁺CD45RO⁺ peripheral T‐cell lymphoma unspecified). Six of the patients with PTLD were EBV positive. Three patients had EBV‐associated pneumonia, and chest computed tomography revealed multifocal patchy and diffuse ground‐glass attenuation in both lungs. EBV‐DNA was positive in bronchoalveolar lavage (BAL) fluid, which contained mainly CD3⁺ T cells but no CD19⁺ or CD20⁺ B cells. Lung biopsy showed interstitial intra‐alveolar infiltrates of mainly CD3⁺ T cells and some CD68⁺ macrophages without CD19⁺ and CD20⁺ B cells. The patients with PTLD accompanied by EBV‐associated pneumonia developed hyperpyrexia and dyspnea, which progressed rapidly, and eventually all died within 2 weeks of the onset of PTLD. EBV‐associated PTLD accompanied by EBV‐associated pneumonia after HSCT is rare. Cytology of BAL fluid and lung biopsy may help establish the diagnosis.     

Epstein–Barr virus (EBV) genotypes among human immunodeficiency virus (HIV)‐related B‐cell Lymphomas and B‐cell post‐transplant lymphoproliferative disorders (B‐PTLD) – late‐onset lymphomas,especially in the HIV setting,are associated with type‐B‐EBV

We investigated 26 B‐cell post‐transplant lymphoproliferative disorders (B‐PTLD) and 15 human immunodeficiency virus‐related aggressive B‐cell lymphomas (HIV‐BCL) from England that were associated with Epstein–Barr virus (EBV) for the polymorphic sequences of the EBV‐encoded nuclear antigen 3C (EBNA3C) gene to distinguish the two different EBV strains. Type‐A‐EBV was identified in 92% of B‐PTLDS and in 53% of HIV‐BCL (P = 0.003). Among HIV‐BCL, patients associated with type‐B‐EBV had been HIV positive for significantly longer when compared to those associated with type‐A (P = 0.037) although there were no correlations with ethnicity, CD4 cell counts or plasma HIV viral load.     

Mutational landscape of B‐cell post‐transplant lymphoproliferative disorders

It is currently unclear whether post‐transplant diffuse large B‐cell lymphomas (PT‐DLBCL) display a similar genomic landscape as DLBCL in immunocompetent patients (IC‐DLBCL). We investigated 50 post‐transplant lymphoproliferative disorders (PTLDs) including 37 PT‐DLBCL samples for somatic mutations frequently observed in IC‐DLBCL. Targeted Next Generation Sequencing (NGS) using the Ion Torrent platform and a customized panel of 68 genes was performed on genomic DNA. Non‐tumoural tissue was sequenced to exclude germline variants in cases where available. A control cohort of 76 IC‐DLBCL was available for comparative analyses. In comparison to IC‐DLBCLs, PT‐DLBCL showed more frequent mutations of TP53 (P = 0·004), and absence of ATM and B2M mutations (P = 0·004 and P = 0·016, respectively). In comparison to IC‐DLBCLs, Epstein–Barr virus (EBV)⁺ PT‐DLBCL had fewer mutated genes (P = 0·007) and particularly fewer mutations in nuclear factor‐κB pathway‐related genes (P = 0·044). TP53 mutations were more frequent in EBV^‐ PT‐DLBCL as compared to IC‐DLBCL (P = 0·001). Germinal centre B cell (GCB) subtype of PT‐DLBCL had fewer mutations and mutated genes than GCB‐IC‐DLBCLs (P = 0·048 and 0·04 respectively). Polymorphic PTLD displayed fewer mutations as compared to PT‐DLBCL (P = 0·001). PT‐DLBCL differs from IC‐DLBCL with respect to mutations in genes related to DNA damage control and immune‐surveillance, and EBV association is likely to have a bearing on the mutational pattern.     

Hashimoto's encephalopathy after interferon therapy for hepatitis C virus in adult liver transplant recipient accompanied by post‐transplant lymphoproliferative disorder related to Epstein–Barr virus infection

T. Hori, F. Oike, K. Hata, M. Nishikiori, Y. Ogura, K. Ogawa, Y. Takada, H. Egawa, J.H. Nguyen, S. Uemoto. Hashimoto's encephalopathy after interferon therapy for hepatitis C virus in adult liver transplant recipient accompanied by post‐transplant lymphoproliferative disorder related to Epstein–Barr virus infection
Transpl Infect Dis 2010: 12: 347–352. All rights reserved Abstract: A 55‐year‐old woman underwent living‐donor liver transplantation (LDLT). She had no history of autoimmune diseases. Spleen was preserved. Steroids were withdrawn at 3 months after LDLT. Epstein–Barr virus (EBV) infection occurred at 3.5 years after LDLT. Recurrent hepatitis C virus infection was confirmed at 4.5 years after LDLT, and pegylated interferon was introduced. Diagnosis of EBV‐positive post‐transplant lymphoproliferative disorder (PTLD) was made at 4.8 years after LDLT, and tacrolimus (Tac) was stopped completely. Then, unconsciousness, convulsion, and cervical stiffness appeared suddenly. Electroencephalography, cerebrospinal fluid analysis, and image studies revealed normal or only nonspecific findings. The patient was in a state of exhaustion; therefore, steroid pulse therapy (SPT) was attempted. Surprisingly, her general condition, including consciousness disturbance, was improved markedly, and Hashimoto's encephalopathy (HE) was suspected, based on this reaction to SPT. Elevations of anti‐thyroglobulin antibody and anti‐thyroid peroxidase antibody were confirmed. After withdrawal of Tac, and treatment with acyclovir and steroids, EBV‐positive PTLD and HE improved, although they recurred at 5.1 years after LDLT. SPT improved only neurological symptoms. Molecular‐targeted therapy was given for recurrent PTLD, based on analysis of sampling specimens. This therapy was effective, but tumor lysis syndrome occurred, and the patient died at 5.3 years after LDLT.     

Isolated cerebral manifestation of Epstein–Barr virus‐associated post‐transplant lymphoproliferative disorder after allogeneic hematopoietic stem cell transplantation: a case of clinical and diagnostic challenges

N.A. Kittan, F. Beier, K. Kurz, H.H. Niller, L. Egger, W. Jilg, R. Andreesen, E. Holler, G.C. Hildebrandt. Isolated cerebral manifestation of Epstein–Barr virus‐associated post‐transplant lymphoproliferative disorder after allogeneic hematopoietic stem cell transplantation: a case of clinical and diagnostic challenges.
Transpl Infect Dis 2011: 13: 524–530. All rights reserved Abstract: We present the case of a 49‐year‐old male patient with Epstein–Barr virus (EBV)‐associated post‐transplant lymphoproliferative disorder (PTLD) limited to the brain that occurred 6 months after allogeneic hematopoietic stem cell transplantation (HSCT). Clinical symptoms included mental confusion, ataxia, and diplopia. Magnetic resonance imaging (MRI) revealed cerebellar and periventricular lesions consistent with an inflammatory process. Cerebrospinal fluid (CSF) analysis, but not peripheral blood, was positive for EBV‐DNA, but no malignant cells were found. Brain biopsy was not feasible because of low platelet counts. As we considered a diagnosis of either EBV‐associated encephalitis or PTLD, the patient was treated with rituximab combined with antiviral therapy. However, the cerebral lesions progressed and follow‐up CSF testing revealed immunoglobulin H clonality as evidence of a malignant process. Subsequent treatment attempts included 2 donor lymphocyte infusions (DLI). Despite treatment, the patient died from autopsy‐proven PTLD within 8 weeks of the onset of symptoms. This case demonstrates the clinical and diagnostic challenges of primary cerebral PTLD in a patient following allogeneic HSCT.     

Post‐transplant lymphoproliferative disorder of the adrenal gland after allogeneic hematopoietic stem cell transplantation: report of two cases and literature review

Post‐transplant lymphoproliferative disorder (PTLD) is one of the life‐threatening complications after hematopoietic stem cell transplantation (HSCT) and solid organ transplantation (SOT), and it is associated almost exclusively with Epstein–Barr virus (EBV). We herein report 2 cases of EBV‐associated PTLD after allogeneic HSCT localized in the adrenal gland. Both patients developed adrenal tumor within 3 months after HSCT and were successfully treated with rituximab or tapering immunosuppressive agents. Both remained alive without recurrence. A literature review revealed 12 reported cases of PTLD involving the adrenal gland, but the adrenal gland was involved as one of the lesions of advanced‐stage PTLD after SOT. To the best of our knowledge, this is the first report to show cases of isolated EBV‐associated adrenal PTLD after HSCT. PTLD should be recognized as one of the causes of isolated adrenal tumor after HSCT.     

Epstein‐Barr virus associated post‐transplant lymphoproliferative disorder mimicking acute graft versus host disease

We present a case series of 3 patients to highlight the fact that PTLD post‐transplant can mimic GVHD, and should be part of the differential diagnosis for diarrhea post allo‐HCT. Awareness of this presentation has important therapeutic implications, as increased immune suppression for the management of GVHD, can worsen clinical features of PTLD. Diagnostic imaging and tissue biopsies should be undertaken early in post‐transplant patients presenting with diarrhea or hepatic abnormalities, especially with atypical presentations like fever, and EBV PCR monitoring can expedite clinical decision‐making in such complicated scenarios while awaiting results of gut biopsies.     

Management of post‐transplant lymphoproliferative disorders

The post‐transplant lymphoproliferative disorders (PTLDs) are a heterogeneous group of neoplasms that are one of the most serious complications of bone marrow and solid organ transplants. Because these disorders are rare, there are no randomized trials from which to derive optimal treatment. Management can be challenging and must balance the goal of PTLD eradication with the risks of graft rejection, graft‐versus‐host disease, further delays in immune reconstitution and life‐threatening infections, among others. This paper will provide a comprehensive review of PTLD following solid organ transplant and haematopoietic stem cell transplant with a focus on management. Included is a discussion of novel agents that are being studied in clinical trials and, when combined or sequenced with conventional therapy, have the potential to improve outcomes.     

Epstein–Barr virus‐associated smooth muscle tumors in a composite tissue allograft and a pediatric liver transplant recipient

Epstein–Barr virus (EBV) is known to establish latent infections in B‐lymphocytes that can cause lymphoproliferative disorders particularly in immunocompromised patients. More recently, the development of rare EBV‐associated smooth muscle tumors has been reported in transplant recipients. We herein describe 2 new cases of EBV‐associated post‐transplant smooth muscle tumors (EBV‐PTSMT), including the first in a facial composite tissue graft recipient. Among the striking features shared by these 2 patients were their young ages, the fact that they were naïve for EBV before the transplantation, that they developed a post‐transplant lymphoproliferative disorder before the diagnosis of EBV‐PTSMT, and that they responded favorably to reduction of immunosuppression. Radiological and histologic features of EBV‐PTSMT are shown. Finally, pathophysiology and therapeutic management of EBV‐PTSMT are discussed based on a comprehensive review of the literature.     

Epstein–Barr virus encephalitis in a renal transplant recipient manifesting as hemorrhagic,ring‐enhancing mass lesions

Epstein–Barr virus (EBV) encephalitis has been infrequently described in immunocompromised patients. Here, we report a unique case of biopsy‐proven EBV encephalitis in a renal transplant recipient presenting with altered mental status, prominent visual disturbances, and hemorrhagic, ring‐enhancing mass lesions on magnetic resonance imaging. The patient was successfully treated with a prolonged course of antivirals. This case illustrates the difficulty in interpretation of cerebrospinal fluid EBV polymerase chain reaction assay, given the lack of specificity in immunocompromised patients.     

Risk factors and clinical outcomes of pediatric liver transplant recipients with post‐transplant lymphoproliferative disease in a multi‐ethnic Asian cohort

Background

We aimed to evaluate clinical characteristics, risk factors, and disease outcomes for liver transplant recipients (LTR) with post‐transplant lymphoproliferative disease (PTLD) at our center.

Methods

Retrospective review of data of all pediatric LTR (1991‐2015) was conducted.

Results

The overall incidence of PTLD was 16.4% (18/110), the majority (13/18) were early lesions, while 3/18 were polymorphic/monomorphic PTLD. The risk factors significant on univariate analysis were as follows: mean age (years) at transplant (1.66 vs 4.76, P = .006); age <2 years at transplant (odds ratio [OR] 3.53 [95% confidence interval [CI]: 1.16‐10.73], P = .026); cytomegalovirus (CMV) primary infection (OR 11.39 [95% CI: 3.44‐37.7], P < .001); recipient CMV seronegativity (OR 7.50 [95% CI: 2.02‐27.78], P = .003); presence of CMV end‐organ disease (OR 4.00 [95% CI: 1.22‐13.16], P = .022); Chinese ethnicity; and higher mean duration of intravenous ganciclovir prophylaxis. In multivariate analysis, CMV primary infection (OR 5.22 [95% CI: 1.25‐21.87], P = .024), CMV seronegativity (OR 5.91 [95% CI: 1.13‐30.90, P = .035]), and having acute cellular rejections (ACR) prior to PTLD (OR 5.53 [95% CI: 1.43‐21.48, P = .013]) were significant risk factors for PTLD, with the latter two factors having a synergistic effect in increasing PTLD risk in a stratified analysis. The final multivariate model in predicting the risk of PTLD, utilizing CMV primary infection, recipient CMV seronegativity, and ACR before PTLD as predictive variables, was statistically significant (likelihood ratio chi square statistic = 25.18, P < .0001 with df = 3).

Conclusions

We report a unique clinicopathologic and risk factor profile in our cohort—early lesion PTLD accounts for the majority and the incidence of monomorphic PTLD remains low. In addition, we show a synergism between CMV naivety and ACR on PTLD risk, a higher prevalence of gastrointestinal manifestations, and a lack of significant association with Epstein‐Barr virus seronegativity.     

Two rare cases of Epstein–Barr virus‐associated lymphoproliferative disorders in inflammatory bowel disease patients on thiopurines and other immunosuppressive medications

The setting of chronic immunosuppression in inflammatory bowel disease (IBD) may promote the proliferation of Epstein–Barr virus‐positive neoplastic clones. We report two rare cases of Epstein–Barr virus‐associated lymphoproliferative disorder in IBD patients: one resembled lymphomatoid granulomatosis, and the other was a lymphoma resembling Hodgkin lymphoma. There are currently no guidelines for the prevention of lymphoproliferative disorder in IBD patients on immunosuppressive therapy.     

Long‐term remission in an adult heart transplant recipient with advanced Burkitt’s lymphoma post‐transplant lymphoproliferative disorder after anthracycline‐free chemotherapy: A case report and literature review

Incidence of Burkitt's lymphoma post‐transplant lymphoproliferative disorder (BL‐PTLD) in solid organ transplant (SOT) recipients in 1.4%‐1.6% with unknown cure rate. We report a case of Epstein‐Barr virus (EBV) positive, late‐onset BL‐PTLD in a 24‐year‐old EBV donor positive/recipient negative female. This is the first reported case of advanced BL‐PTLD post‐heart transplant in an adult. This is also the first reported case of treatment of advanced BL‐PTLD in a heart transplant recipient with a combined chemotherapy regimen without anthracyclines to avoid cardiotoxicity. The patient received 6 cycles of R‐COEP (rituximab with cyclophosphamide, vincristine, etoposide, prednisone) over 6 months and subsequently 3 cycles of high‐dose methotrexate (MTX) over 3 months for CNS prophylaxis. She remains without evidence of disease at 19 months post‐treatment. This case demonstrates that an anthracycline‐free regimen can be the therapy option for patients with BL‐PTLD after heart transplantation.     

Treatment and outcomes of post-transplant lymphoproliferative disease: a single institution study

Post-transplant lymphoproliferative disorders (PTLD) complicate up to 10% of solid organ transplants. This retrospective study was conducted to review the PTLD experience among 2,300 recipients of solid organ or allogeneic bone marrow transplants from a single institution. Twenty-seven cases of PTLD were identified, leading to an overall incidence of 1.2%. Polymorphic B cell hyperplasia/lymphoma was the most common type. The median time to development of PTLD was 8.4 months. Ten patients had localized (stage I or II) disease, and 12 patients presented with B symptoms. Nine patients each were treated with systemic chemotherapy or surgical resection as part of the initial therapy. After a median follow-up duration of 2.6 years, the median survival has not been reached. There were no late relapses of PTLD, and 17 patients remain alive. Age, sex, organ source, LDH, stage, presence of extranodal disease, or presentation with B symptoms did not influence overall survival when examined by Cox proportional hazard model. Thirteen patients retained their graft function throughout PTLD treatment. This study confirms the ability to treat a significant proportion of PTLD patients with chemotherapy or surgical resection (depending on presentation), without sacrificing graft function in those receiving chemotherapy.