An Unusual Posttransplant T-cell Lymphoma After Liver Transplantation: A Case Report

Posttransplantation lymphoproliferative disorders (PTLDs) encompass a spectrum of heterogeneous entities ranging from benign lymphocytic proliferations to high-grade malignant lymphomas. The majority of PTLDs are associated with reactivation of Epstein-Barr virus (EBV), which induces B-cell proliferation and occurs in the setting of severe immune suppression after solid organ or bone marrow transplantation. T-cell/natural killer cell PTLDs are relatively rare, constituting ～15% of all cases. T-cell PTLDs are usually aggressive, and outcomes are poor. This article describes an unusual case of T-cell PTLD with a favorable outcome. The patient is a 57-year-old man who underwent a liver transplantation due to hepatitis C cirrhosis. He developed graft-versus-host disease with skin and gastrointestinal involvement and generalized lymphadenopathy 4 months after transplantation. Histologic sections of an excised axillary lymph node showed atypical medium and larger T-lymphocytes that were positive for CD3, CD5, CD43, and CD8 but were negative for B-cell antigens, CD56, and in situ hybridization for EBV-encoded RNA. Polymerase chain reaction analysis revealed monoclonal T-cell receptor gamma chain gene rearrangement. A diagnosis of high-grade T-cell PTLD was made. The patient was treated with 4 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone and is currently in remission, 4 years after therapy. The rapid presentation of an EBV-negative T-cell PTLD with a nonaggressive course and complete response to treatment is an unusual presentation of posttransplantation T-cell lymphoma, which is usually associated with a high mortality rate.     

Large Granular Lymphocytic Leukemia Presenting Late After Solid Organ Transplantation: A Case Series of Four Patients and Review of the Literature

Post-transplantation lymphoproliferative disorder (PTLD) is a significant complication of solid organ transplantation. Most PTLD is of the B-cell subtype, although T-cell subtype PTLD uncommonly occurs. T-cell PTLDs are usually aggressive neoplasms and shorten patient and allograft survivals significantly. We present a single-center case series of 4 patients who developed T-cell large granular lymphocytic (LGL) leukemia, a rare T-cell PTLD characterized by large granular lymphocytes that have characteristic azurophilic granules and a highly variable clinical course.     

Plasmacytoma-like posttransplant lymphoproliferative disorder following orthotopic liver transplantation: a case report

Posttransplant lymphoproliferative disorders (PTLDs) are among the most serious and potentially fatal complications of both stem-cell and solid-organ transplantation. Most monomorphic PTLDs are of B-cell origin and frequently associated with Epstein-Barr virus (EBV) infection in the setting of pharmacological immunosuppression posttransplantation. The majority of monomorphic PTLDs commonly resemble diffuse large B-cell or Burkitt's lymphoma; plasmacytoma-like PTLDs are very rare. We report a case of plasmacytoma-like PTLD arising in the allograft in a 66-year-old male diagnosed 2 months following an orthotopic liver transplant for alcohol-related end-stage liver disease. The liver biopsy revealed marked infiltration of atypical plasma cells with lambda light chain restriction and positivity for EBV by in situ hybridization confirming the diagnosis. Also noted was a remarkable increase of tissue eosinophils. Reduction of immunosuppression led to improvement in his clinical condition, and also resolution of the hepatic lesions and abdominal lymphadenopathy noted on imaging studies. While a few cases of plasmacytoma-like PTLDs have been described in literature, to our knowledge, this is the first reported case of early onset plasmacytoma-like PTLD in a liver transplant recipient occurring in the allograft with associated lymphadenopathy having distinct histopathologic features including tissue eosinophilia. Timely recognition of such an entity is critical in order to initiate early and appropriate intervention.     

T-cell posttransplant lymphoproliferative disorder occurring in a pediatric solid-organ transplant patient

Posttransplantation lymphoproliferative disorder (PTLD) is a serious complication seen in transplant patients as a consequence of immunosuppressant therapy. Most cases are of B-cell origin and are commonly associated with Epstein-Barr virus (EBV) infection. T-cell PTLDs are rare and only 13 pediatric T-cell PTLDs with clinicopathologic correlation have been reported previously. We present the histologic, immunophenotypic, and molecular features of a monomorphic PTLD (T-cell lymphoma) identified in a pediatric patient following orthotopic liver transplantation. The lymphoma was identified in the ileum, rectum, and mesenteric lymph nodes. In situ hybridization revealed numerous EBER-1-positive tumor cells. A current review of the literature is also discussed. Of the 14 cases of pediatric T-cell PTLD reported in the literature, only 3 (21.4%) are described as being EBV positive. Most of the reported PTLDs are monoclonal, with 9 of 11 cases (82%) showing a clonal T-cell population by gene rearrangement studies. T-cell PTLD cases appear to have a poor prognosis (11 of 14 patients died of the disease), although patients with involvement of specific anatomic sites may have a better outcome.     

Anaplastic large cell lymphoma associated with Epstein-Barr virus following cardiac transplant

Posttransplantation lymphoproliferative disorders (PTLDs) eventually occur in approximately 5% of all organ transplant recipients. Most of cases are B-cell proliferations associated with the Epstein-Barr virus (EBV). T-cell PTLDs are relatively rare, although some estimate that up to 14% of posttransplantation malignant lymphomas are T-cell lymphomas even though only a few of these cases are described in the literature. A literature review found only 77 cases of T-cell PTLD, including 1 case following cardiac transplant, 15 cases associated with EBV, and only 1 case of anaplastic large cell lymphoma (ALCL). This single ALCL case followed a liver transplant, was of the T-cell phenotype, and was EBV negative. In this report, we describe a 14-year-old male who developed an EBV-positive, T-cell PTLD of the ALCL subtype after a period of 14 years following cardiac transplant. Immunohistochemical staining established the T-cell origin of the neoplasm with strong expression of CD45, CD3, CD43, and CD2 and also showed expression of CD30 consistent with the histologic features that suggested ALCL. EBER in situ hybridization detected the presence of the EBV. Polymerase chain reaction analysis for T-cell receptor-gamma gene rearrangements confirmed the T-cell lineage of this lymphoma. To our knowledge, this is the first reported case of an EBV-positive T cell lymphoma of the anaplastic large cell subtype following organ transplant.     

Successful treatment with rituximab of lymphoproliferative disorder in a child after cardiac transplantation

Post-transplantation lymphoproliferative disorders (PTLDs) are life-threatening complications. We report the case of a 7-year-old girl in whom a lymphoproliferative disorder developed more than 2 years after cardiac transplantation. The patient was taking ganciclovir for Epstein-Barr virus hepatitis at the time the PTLD occurred. Rituximab, an anti-CD20 monoclonal antibody, given in the presence of reduced immunosuppression therapy, resulted in a complete response of the PTLD. The Epstein-Barr viral load in the peripheral blood, which was extremely high at diagnosis, dropped promptly and remained below the detection threshold 11 months after completion of therapy. We observed complete depletion of B lymphocytes until 7 months after rituximab therapy, which was associated with an important decrease in immunoglobulin levels.     

Indications and results of chemotherapy in children with posttransplant lymphoproliferative disease after liver transplantation

Among 39 posttransplant lymphoproliferative diseases (PTLD) in a cohort of 450 pediatric liver transplant recipients, 3 had a malignant lymphoma, unresponsive to arrest of immunosuppression and to gancyclovir, interferon, and anti-interleukin 6 antibodies. Lymphoma appeared 20, 46, and 96 months posttransplantation and 16, 43, and 90 months after primary Epstein-Barr virus infection. In one case, the patient had histological progression from plasmacytic hyperplasia PTLD, concomitant with symptomatic primary infection, to Burkitt-like lymphoma 43 months later. These three patients received five courses of chemotherapy, after a cyclophosphamide, doxorubicin, vincristine, and prednisone regimen for Burkitt-like or LH 89 scheme for Hodgkin-like PTLDs. Chemotherapy was well tolerated, and all three were free of disease and without immunosuppression 19, 14, and 4 months after chemotherapy. In Burkitt-like or Hodgkin-like PTLDs, immunomodulatory or antiviral drugs were inefficient. Chemotherapy is indicated and can be safely and successfully used. Long-term arrest of immunosuppression seems feasible without graft rejection.     

Posttransplant lymphoproliferative disorder in a kidney-pancreas transplanted recipient: simultaneous development of clonal lymphoid B-cell proliferation of host and donor origin

Posttransplant lymphoproliferative disorders (PTLDs) are lymphoid proliferations or lymphomas that develop as a consequence of immunosuppression after solid organ or bone marrow transplantation and are mostly associated with an Epstein-Barr virus infection. The morphologic categories include different types of benign and malignant lymphoid proliferations. The majority of PTLDs is of B-cell origin with clonal rearrangements of the immunoglobulin genes. The PTLDs in solid organ transplants are reported to be either of host or of donor origin. Donor-related PTLDs frequently involve the allograft. We report a case of a 52-year-old woman recipient who developed simultaneously PTLDs in several organs 5 month after receiving a sex-mismatched renal and pancreas allograft. Immunosuppression regimen comprised antithymocyte globulin, tacrolimus, mycophenolate mofetil, and steroids. Pathologic features appeared as polymorphic PTLDs in the renal allograft, liver, and central nervous system (CNS). Molecular genetic studies revealed different clonal immunoglobulin heavy chain gene rearrangements in all 3 organs as determined by polymerase chain reaction (PCR). Epstein-Barr virus were detected by nested PCR and in situ hybridization in all 3 tumors. The PTLDs in liver and CNS were of host origin whereas the allograft kidney PTLD was found to originate from the male donor as shown by the simultaneous detection of female and male sex chromosomes by PCR and fluorescence in situ hybridization. The recipient died in consequence of the CNS involvement, after intracerebral hemorrhage with uncal and tonsillar herniation.     

Epstein-Barr virus-negative post-transplant lymphoproliferative disorders: a distinct entity?

Post-transplant lymphoproliferative disorders (PTLDs) are usually but not invariably associated with Epstein-Barr virus (EBV). The reported incidence, however, of EBV-negative PTLDs varies widely, and it is uncertain whether they should be considered analogous to EBV-positive PTLDs and whether they have any distinctive features. Therefore, the EBV status of 133 PTLDs from 80 patients was determined using EBV-encoded small ribonucleic acid (EBER) in situ hybridization stains with or without Southern blot EBV terminal repeat analysis. The morphologic, immunophenotypic, genotypic, and clinical features of the EBV-negative PTLDs were reviewed, and selected features were compared with EBV-positive cases. Twenty-one percent of patients had at least one EBV-negative PTLD (14% of biopsies). The initial EBV-negative PTLDs occurred a median of 50 months post-transplantation compared with 10 months for EBV-positive cases. Although only 2% of PTLDs from before 1991 were EBV negative, 23% of subsequent PTLDs were EBV negative (p <0.001). Of the EBV-negative PTLDs, 67% were of monomorphic type (M-PTLD) compared with 42% of EBV-positive cases (p <0.05). The other EBV-negative PTLDs were of infectious mononucleosis-like, plasma cell-rich (n = 2), small B-cell lymphoid neoplasm, large granular lymphocyte disorder (n = 4) and polymorphic (P) types. B-cell clonality was established in 14 specimens and T-cell clonality was established in three (two patients). None of the remaining specimens were studied with Southern blot analysis and some had no ancillary studies. Rearrangement of c-MYC was identified in two M-PTLDs with small noncleaved-like features, and rearrangement of BCL-2 was found in one large noncleaved-like M-PTLD. Ten patients were alive at 3 to 63 months (only three patients received chemotherapy). Seven patients, all with M-PTLDs, are dead at 0.3 to 6 months. Therefore, EBV-negative PTLDs have distinct features, but some do respond to decreased immunosuppression, similar to EBV-positive cases, suggesting that EBV positivity should not be an absolute criterion for the diagnosis of a PTLD.     

EBV Positive Primary Cutaneous CD30+ Large T-Cell Lymphoma in a Heart Transplanted Patient: Case Report

Most post-transplant lymphoproliferative disorders (PTLDs) are of B-cell origin, whereas T-cell lymphomas rarely occur. We detail the clinicopathological features of the first case of Epstein-Barr virus (EBV)-associated primary cutaneous CD30+ anaplastic large cell lymphoma (ALCL) in the setting of heart transplant. A 71-year-old patient, 111 months after transplant, presented with multiple cutaneous lesions on the left thigh; histological and immunohistochemical examinations led to diagnosis of T-cell CD30+ ALCL. In situ hybridization demonstrated the presence of EBV-positive tumour cells. The patient received radiotherapy, but he relapsed at the same cutaneous site with loco-regional nodal spread. Chemotherapy was administered resulting in complete remission; four years later the patient is alive and well. Our findings indicate that primary cutaneous EBV+ CD30+ ALCLs should be included within the T-cell PTLDs spectrum; further studies are required to confirm whether they may be also considered, in transplantation settings, a distinct lymphoma subset with relatively favourable outcome.     

Spleen-Restricted Posttransplant Lymphoproliferative Disorder in the First Year After Kidney Transplant – A Case Report

Posttransplant lymphoproliferative disorders (PTLDs) are a feared complication after transplant. They are mostly of B cell origin and are frequently Epstein-Barr virus (EBV)–positive, particularly in early onset PTLD. Later on, non-B and EBV-negative PTLD are increasingly reported. EBV seronegative receptors (particularly when paired with an EBV seropositive donor) together with the net degree of immunosuppression—a concept often difficult to quantify—are the most consistently described risk factors for the development of PTLD. Conversely, its association with a particular immunosuppressive agent or other virus, namely cytomegalovirus (CMV) infection or disease, has been inconsistently reported. We present a challenging case where an EBV negative monomorphic peripheric T-cell lymphoma was diagnosed in the first year after kidney transplant in a patient with a recent history of CMV disease from a resistant strain.     

Long-term survival after post-transplant lymphoproliferative disease in children

Post-transplant lymphoproliferative disease (PTLD) is a well-known complication of immunosuppressive therapy. We present a series of 19 children who developed PTLD, following renal transplantation in 11 and liver transplantation in 8. The mean time between transplantation and the onset of PTLD was 19.5 months. Two patients had T-cell PTLD and died despite intensive chemotherapy. B-cell PTLD was observed in 17 patients and was associated with proven Epstein-Barr virus infection in 9. Despite immediate reduction of immunosuppressive therapy, only 8 of these 17 patients were alive at a 5.6-year mean follow-up. None of these patients had recurrence of PTLD when immunosuppression was resumed.     

Posttransplant lymphoproliferative disorder following nonmyeloablative allogeneic stem cell transplantation

Posttransplantation lymphoproliferative disorder (PTLD) is a well-recognized complication of conventional bone marrow/stem cell and solid organ transplantation. However, not much is known about PTLD following the more recently introduced nonmyeloablative allogeneic stem cell transplantation (NMST). This study reports the findings from two cases of PTLD following NMST and compares them to the one previously reported case. The donor origin of the PTLD was determined using short tandem repeat analysis, and B- and T-cell clonalities were evaluated by polymerase chain reaction. Two cases of PTLD evolved in a total of 70 patients who have undergone NMST at our institution from 1999 to 2003. Both patients received conditioning with Fludarabine/Cytoxan/Campath 1H (alemtuzumab, anti-CD52 antibody) and T-cell-depleted donor cells with Campath-1H. Both PTLDs were EBV positive (by immunohistochemistry and in situ hybridization) with diffuse large B-cell lymphoma morphology. Our findings indicate the incidence of PTLD following NMST is 3% (2 of 70 patients from our institution and 1 of 30 from the previously reported case). All three PTLDs arose 6 to 7 months after NMST and were rapidly fatal. The pathology of the PTLD in all cases was donor origin, EBV positive, diffuse large B-cell lymphoma.     

Anti-CD20 monoclonal antibody treatment of Epstein-Barr virus-induced intrahepatic lymphoproliferative disorder following liver transplantation

Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disorders (PTLDs) are a common cause of death in transplant patients. Their incidence following liver transplantation is reported to be between 0.5% and 4%. Despite various therapeutic approaches, there is still no consensus on a treatment strategy. The treatment of transplant recipients with monoclonal antibodies directed against B-cell antigens is a new, therapeutic approach with which, however, little clinical experience has so far been gained. Two patients developed intrahepatic PTLD 7 and 15 months, respectively, after transplantation. In one case, this was diagnosed as polymorphic PTLD, in the other as monomorphic, monoclonal PTLD. After having their immunosuppression terminated, 4 weeks after establishment of the diagnosis, both patients were treated with anti-CD20 antibodies (rituximab) at a dose of 375 mg/m(2) on days 1, 8, 15 and 22. Treatment with rituximab was tolerated well by both patients. One of the patients in whom cholestasis parameters remained high underwent re-transplantation. In one of the cases, the histological work-up confirmed necrosis of 90% of the tumour cells, and complete remission in the other. Both patients died of secondary complications 10 weeks and 10 months, respectively, after the diagnosis of PTLD. We can conclude that treatment of PTLD with Rituximab led to remission in both of our patients. Nevertheless, progression of cholestasis persisted, and both patients ultimately died of complications unrelated to PTLD.     

Successful treatment of posttransplant lymphoproliferative disease with prolonged rituximab treatment in intestinal transplant recipients

BACKGROUND: Posttransplant Epstein-Barr virus-associated B-cell lymphoproliferative disease (PTLD) has a higher incidence after intestinal transplantation than after transplantation of other solid organs and is associated with a high mortality. A new anti-CD20 monoclonal antibody, rituximab, has shown efficiency in the treatment of B-cell lymphoma, including PTLD, but its use has not yet been reported in intestinal transplant recipients. METHODS: We retrospectively reviewed five patients who were diagnosed with PTLD from March 1999 to August 2001, after intestinal transplantation. These patients were primarily managed with rituximab, associated with reduction or interruption of immunosuppression and antiviral therapy with ganciclovir and cytomegalovirus immune globulin. Rituximab was administered at weekly doses of 375 mg/m until full remission was ascertained, and the interval between doses was then increased. No patient received chemotherapy. RESULTS: One patient had nonmalignant lymphoproliferation, and four had malignant PTLD, as assessed by histopathology and monoclonality of the tumor. Two pediatric patients had severe generalized disease. All patients had received OKT3 as treatment of rejection before developing PTLD. All tumors showed proliferation of CD20 cells and were positive for Epstein-Barr virus by in situ hybridization. All patients responded to rituximab therapy and have achieved full remission with a follow-up of 3 to 30 (median, 8) months. CONCLUSION: Prolonged rituximab treatment, in association with reduction of immunosuppression and antiviral therapy, is highly efficient as part of the first-line treatment of CD20 B-cell PTLD after intestinal transplantation.     

Long-Term Complete Remission of Multiple Extranodal Natural Killer/T-cell–Type Posttransplant Lymphoproliferative Disorder After Surgical Resection: A Case Report

Background

Posttransplant lymphoproliferative disorder (PTLD) is a life-threatening complication of organ transplantation that results from immunosuppression therapy. Most cases of PTLD derive from the B-cell lineage. T-cell PTLD, particularly natural killer (NK)/T-cell PTLD, is quite rare; only a few cases have been described.

Case Report

A 42-year-old woman received a living-related renal allograft from her father. Sixteen years after transplantation, the patient presented with a 1-week history of low-grade fever and epigastralgia. Computed tomography revealed intestinal masses and a right upper lung lobe mass. Gallium scintigraphy showed uptake in the abdominal mass. Epstein-Barr virus–related antibody was not detected in the patient's serum sample. We performed extirpation of the jejunum and ileum tumors. The pathologic findings showed that these 2 tumors were NK/T-cell lymphoma. After the operation, the lung mass rapidly enlarged, and right upper lobectomy was performed. The right upper lung lobe tumor showed the same histopathologic findings as the small bowel tumor. The final histologic diagnosis was established as multiple extranodal NK/T cell type PTLD of the small bowel and right upper lung lobe.

Conclusions

After reduction of the immunosuppressive agent, no recurrence of PTLD has been observed for the past 9 years.     

Posttransplant lymphoproliferative disorder after umbilical cord blood transplantation in children

Reported are 7 cases of posttransplant lymphoproliferative disorder (PTLD) arising in children who received umbilical cord blood transplantation (UCBT). There were 4 females and 3 males with a median age of 3 years (range, 1-16 years). All 7 patients received UCBT, including 1 patient who received multiple units and 1 transplanted under nonmyeloablative condition. The time interval from UCBT to PTLD averaged 4 months (range, 2 weeks to 9 months). Patients typically presented with high-stage disease with visceral organ involvement. Histology of the PTLDs showed monomorphic morphology in 5 cases and polymorphic morphology in the remaining 2 cases. Bone marrow biopsies were performed in 3 cases and were negative for PTLD. Epstein-Barr virus (EBV) was detected in the PTLD in all 7 patients by in situ hybridization. Evidence of past EBV infection was found in the recipients, but the EBV genome was not detected in the donor cord blood samples, suggesting that donor cord blood was not the source of EBV infection. The origin of the PTLD was investigated in 5 cases. PTLD was of host origin in 2 patients who failed engraftment and of donor origin in the remaining 3 patients who had complete engraftment. Four of 5 patients with monomorphic PTLD failed to demonstrate significant responses to rituximab and/or reduction of immunosuppression and died within 1 month after diagnosis. The remaining 2 patients with polymorphic PTLD showed complete response to therapy. One patient was alive 35 months after transplant, and the other patient died of infection 6 months after transplant. It is concluded that PTLD arising after UCBT in children occurs early after transplant and represents a serious EBV-related complication. PTLD may be of donor or recipient origin depending on engraftment status. Both monomorphic and polymorphic histology may be seen, and monomorphic histology appears to predict an unfavorable prognosis.     

Mucosa-associated lymphoid tissue-type lymphomas occurring in post-transplantation patients

Post-transplantation lymphoproliferative disorders (PTLDs) are usually Epstein-Barr virus (EBV)-associated B-cell lymphoproliferative disorders that vary in their morphologic spectrum. Extranodal marginal zone lymphomas of the mucosa-associated lymphoid tissue-type (MALT-type) have not been considered to be part of this spectrum. The authors encountered five such cases recently. The clinical, histopathologic, and immunophenotypic features are reported. There were three men and two women with a mean age of 51.2 years (range, 48-63 years). Two patients were cardiac transplant recipients, two patients were liver transplant recipients, and the remaining patient was a renal transplant patient. Sites of lymphoma were the stomach in three patients and the parotid gland in two patients. Mean time to the lymphoma was 84 months after transplantation. All patients had morphologic features of low-grade extranodal marginal zone lymphomas of the MALT-type, and Helicobacter pylori was present in all three gastric cases. All patients exhibited the B-cell immunophenotype and were negative for EBV by in situ hybridization. These lymphomas were treated with a variety of modalities, including reduction of immunosuppression, antibiotics, surgical resection, radiation therapy, and chemotherapy. At last follow-up, one patient had developed signet ring adenocarcinoma at 27 months but had no evidence of PTLD, one patient relapsed at 17 months but is alive with stable disease at 24 months, and the remaining patients were alive without disease at 11, 12, and 14 months. Extranodal low-grade MALT-type lymphomas can occur in the post-transplantation setting and generally develop years after transplant. As seen in immunocompetent patients, EBV appears to play no role in the pathogenesis of these lymphomas. These lymphomas appear to have more in common with MALT-type lymphomas in nonimmunocompromised patients than conventional PTLDs, although they occur in "at-risk" patients due to their immunosuppressive therapy. These lymphomas do not appear to be clinically aggressive. Recognition of MALT-type lymphomas in the post-transplantation setting as an indolent disease avoids unnecessary treatment.     

Treatment of post-transplant lymphoproliferative disorder with monoclonal CD20 antibody (rituximab) after heart transplantation.

Post-transplant lymphoproliferative disorder (PTLD) is a frequent and often fatal complication of organ transplantation. It most often results from an Epstein-Barr virus (EBV)-transformed B-cell clone, which expresses B-cell surface markers such as CD20. We describe a case of a heart transplant recipient who EBV seroconverted post-transplant and subsequently developed subcutaneous and lymphatic B-cell lymphoma, successfully treated with CD20 antibody (rituximab). The patient has been in remission during 10 months of clinical follow-up.