Posttransplant lymphoproliferative disorders in lung transplant patients: the Cleveland Clinic experience.

PTLD is a well-recognized complication of organ transplantation. Large series of heart, renal, and liver transplants have been examined for the incidence and behavior of PTLD. However, reports of the incidence and characteristics of PTLDs in lung transplant (LTx) patients are few. We report our experience with PTLDs in a large series of LTx recipients at a single institution and compare them to other solid organ transplant recipient PTLDs seen at our institution. Twenty-eight patients were found to have PTLD, of whom 8 were lung transplant recipients. We evaluated nine PTLD specimens from these 8 patients for their histology, immunophenotype (CD20, CD3, EBV-LMP1), EBER status by in situ hybridization, and clinical features. The incidence of PTLD was 3.3% (8/244 patients). The time to development of PTLD, after transplant, was short (median time, 7 mo). All were of B-cell lineage. Overall, EBV was demonstrated in 77.7% (7 of 9 specimens) of PTLDs. All specimens tested for clonality were found to be monoclonal. Five patients died, with a median time to death of only 4.6 months. PTLDs in LTx patients are EBV-associated B-cell, predominantly monoclonal lymphoid lesions similar to other solid organ transplant PTLDs. Compared with other solid organ transplant recipients with PTLD at our institution, PTLDs in LTx patients have a propensity to involve the transplanted organ (P =.001, Fisher's exact test), occur earlier after transplant (P =.003, Wilcoxon test), and have a shorter survival (P =.002, log rank test). Reasons for this may include the relatively higher level of immunosuppression required in these patients and limited options in decreasing it. Although the incidence is low, careful early monitoring of lung transplantation patients is warranted because of the poor prognosis of patients developing this complication.     

The clinical spectrum, pathology, and clonal analysis of Epstein-Barr virus-associated lymphoproliferative disorders in heart-lung transplant recipients

This study presents the clinical and laboratory observations on posttransplant lymphoproliferative disorders (PTLDs) occurring in 5 of 53 heart-lung transplantation recipients. Cervical lymph nodes, tonsils, lungs, and gastrointestinal tract were the common sites of involvement by PTLDs. The histopathologic findings showed a spectrum of lymphoid and immunoblastic proliferation ranging from diffuse hyperplasia to malignant lymphoma, immunoblastic or large cell type. All cases were associated with a primary Epstein-Barr virus infection, and viral DNA was demonstrated within the lesional tissue in three cases. Immunohistochemical and immunoglobulin gene rearrangement studies revealed a B-cell proliferation that was monoclonal in three cases and polyclonal in two cases. Compared with PTLDs arising in other organ transplant recipients, this series is remarkable for a high incidence of PTLDs (9.4%), a short interval to tumor diagnosis (2.2 months, mean), involvement of the primary allograft in three cases (60%), and the frequent development of bronchiolitis obliterans. Possible reasons for this distinct clinicopathologic profile are discussed.     

Posttransplant lymphoproliferative disorders: A fine-needle aspiration biopsy study

Fine-needle aspiration biopsy (FNAB) has been used with high sensitivity and specificity in the diagnosis of both Hodgkin's and non-Hodgkin's lymphoma. However, studies of FNAB of posttransplant lymphoproliferative disorders (PTLDs) are rare. The clinical course of 593 allograft recipients (cardiac, 288; renal, 250; lung, 50; and heart/lung, 5) was reviewed. Twenty-six patients developed PTLD with an overall incidence of 4.4%. Of these patients, 12 underwent FNAB. Their age ranged from 33–67 yr (mean, 55 yr). The interval between transplantation and FNAB ranged between 2–14 mo (average, 8.4 mo). The lungs were the most common site aspirated (7 cases), followed by lymph nodes (3 cases) and other extranodal sites (2 cases, liver and paraspinal mass). The cytologic features of these aspirates could be classified into two categories: a polymorphous smear composed of a spectrum of mature and immature lymphocytes with scattered plasma cells and histiocytes; and a monotonous population of large lymphoid cells consistent with malignant lymphoma, large-cell type. Surgical biopsies were available in 10 (83.3%) cases and confirmed the FNAB diagnosis. In summary, FNAB appears to be a highly sensitive and specific diagnostic tool in patients with PTLD. Diagn. Cytopathol. 16:392–395, 1997. © 1997 Wiley-Liss, Inc.     

Detection of Epstein-Barr virus DNA in sera from transplant recipients with lymphoproliferative disorders

Early diagnosis of Epstein-Barr Virus (EBV)-associated posttransplant lymphoproliferative disease (PTLD) is important because many patients respond to reduction in immunosuppression, especially if PTLD is detected at an early stage. Previous studies have found elevated EBV DNA levels in blood from patients with PTLD, but these assays required isolation of cellular blood fractions and quantitation. We evaluated the presence of cell-free EBV DNA in serum from solid-organ transplant recipients as a marker for PTLD. Five of 6 transplant recipients with histopathologically documented PTLD had EBV DNA detected in serum at the time of diagnosis (sensitivity = 83%), compared with 0 of 16 matched transplant recipients without PTLD (specificity = 100%) (P < 0.001 [Fisher's exact test]). Furthermore, EBV DNA was detected in serum 8 and 52 months prior to the diagnosis of PTLD in two of three patients for whom stored sera were analyzed. Detection of EBV DNA in serum appears to be a useful marker for the early detection of PTLD in solid-organ transplant recipients. Further studies to define the role of such assays in evaluating solid-organ transplant patients at risk for PTLD are warranted.     

Cytomegalovirus pneumonitis in heart-lung transplant recipients: histopathology and clinicopathologic considerations

Three cases of cytomegalovirus (CMV) pneumonitis in heart-lung transplant recipients are presented, and the clinical course and autopsy findings described. The patients survived transplantation for 15, 6, and 2 months, respectively. Cytomegalovirus pneumonitis was diagnosed between 5 and 12 weeks postoperatively, and was still detectable in two of the patients at postmortem examination. In one patient, at autopsy there was no further evidence of CMV pneumonitis 3 months after its onset. Instead we found widespread obliterative bronchiolitis (OB) and signs of acute pulmonary rejection. Early-stage OB was present together with CMV pneumonitis in the patient who had survived transplantation for 2 months. The cause of death in the remaining patient was a bacterial superinfection of the chronic CMV pneumonitis still present more than 1 year after its first manifestation. There were no signs of OB. The marked differences in the clinical course and histologic presentation of CMV pneumonitis in heart-lung transplant recipients and its high, but not uniform, association with OB emphasize the complex interrelations between viral infections and pulmonary rejection.     

Molecular characterization of post‐transplant lymphoproliferative disorders of donor origin occurring in liver transplant recipients

Post‐transplant lymphoproliferative disorders (PTLDs) represent a frequent complication of solid organ transplantation. Although most PTLDs arise from recipient lymphoid cells, a considerable fraction of cases may arise from donor B‐cells. In an attempt to clarify the histogenesis and pathogenesis of PTLDs derived from donor B‐cells, monoclonal PTLDs occurring in liver transplant recipients were chosen as a model to compare donor (D‐PTLDs) versus recipient PTLDs (R‐PTLDs). The tumour panel included nine D‐PTLDs and six R‐PTLDs. D‐PTLDs were early‐onset, EBV‐infected lymphoproliferations classified as polymorphic PTLD (P‐PTLD; n = 7) or diffuse large B‐cell lymphoma (DLBCL; n = 2) with tumour localization confined to the hepatic hilum. All R‐PTLDs were late‐onset DLBCLs and showed extrahepatic localization. A BCL‐6^?/MUM1⁺/CD138^+/? phenotype, consistent with a post‐germinal centre (GC) stage of pre‐terminal B‐cell differentiation, was observed in all D‐PTLDs and in 2/6 R‐PTLDs, whereas a BCL6⁺/MUM1^?/CD138^? profile, reminiscent of GC B‐cells, was detected in 4/6 R‐PTLDs. The presence of somatic IGHV hypermutation was observed in 6/9 D‐PTLDs and in 4/6 R‐PTLDs, suggesting derivation from antigen‐experienced B‐cells. IGHV4‐39 was the IGHV gene most frequently encountered, being rearranged in 3/9 D‐PTLDs. Among IGHV‐mutated PTLDs, a mutational profile suggesting antigen stimulation and/or selection was observed in 4/6 D‐s and in 2/4 R‐PTLDs. The presence of ongoing IGHV mutations was detected in 2/4 D‐PTLDs. Aberrant SHM was detected in 10/15 (66.7%) PTLDs, including 6/9 D‐PTLDs and 4/6 R‐PTLDs. Our findings suggest that (i) D‐PTLDs show a clinical presentation distinct from R‐PTLDs; (ii) immunophenotypic and genetic features of D‐PTLDs are consistent with mature, GC‐experienced B‐cells; (iii) transformed donor‐derived B‐cells may experience antigen‐driven stimulation and selection, and may acquire genetic lesions during neoplastic expansion in the recipient environment; and (iv) EBV infection and expression of viral oncoproteins may be relevant in the pathogenesis of D‐PTLDs. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Interactions between bronchoalveolar lymphocytes and macrophages in heart-lung transplant recipients

Bronchoalveolar lavages (BAL) were obtained from heart-lung transplant patients. Following transplantation, the number of lymphocytes and macrophages are considerably increased. BAL lymphocytes frequently exhibit donor specific secondary allogeneic proliferation measured in primed lymphocyte testing (PLT) assays. We report our findings regarding a persistence of donor derived macrophages and lymphocytes in BAL during the posttransplant period. The presence of donor specific macrophages causes a proliferative response of alloreactive BAL lymphocytes from the recipient. This "Bronchoalveolar Macrophage Lymphocyte Reaction," or "BMLR," may represent a unique aspect of in vivo interactions associated with lung allograft responses. Comparative studies showed considerably lower PLT responsiveness of peripheral blood lymphocytes than that of BAL lymphocytes. These studies suggest that functional assays on BAL cells may be useful in monitoring lung transplant rejection and other immunological phenomena that affect pulmonary function of heart-lung transplant patients.     

Post-transplantation lymphoproliferative disorders arising in solid organ transplant recipients are usually of recipient origin.

Recent clinical, pathological, and molecular studies have increased our understanding of posttransplantation lymphoproliferative disorders (PT-LPDs). Studies have shown that the majority of PT-LPDs arising in bone marrow transplant recipients are of donor origin; however, the source (host or donor) of the lymphoid cells that make up PT-LPDs arising in solid organ transplant recipients has not been systemically investigated. In this study, 18 PT-LPDs occurring in 16 organ transplant recipients (13 heart, 2 kidney, 1 lung), 9 donor tissues (for 10 recipients), and 14 uninvolved recipient tissues (from 12 patients) were examined employing restriction fragment length polymorphism analysis to determine their host or donor origin. The PstI-digested DNAs were analyzed by Southern blot hybridization using two highly informative polymorphic probes that map to chromosome 21 (CRI-PAT-pL427-4) and chromosome 7 (CRI-PAT-pS194). All solid organ PT-LPDs with corresponding uninvolved recipient DNA showed identical hybridization patterns; none of the PT-LPDs exhibited a hybridization pattern that matched donor DNA. These findings suggest that the vast majority of PT-LPDs arising in solid organ transplant recipients, in contrast to those arising in bone marrow transplant recipients, are of recipient origin.     

The two forms of bronchiolitis obliterans in heart-lung transplant recipients.

Bronchiolitis obliterans has emerged as the major long-term complication of heart-lung transplantation. We reviewed the histologic findings in lungs obtained from 11 patients who had received a combined heart-lung transplant at The Johns Hopkins Hospital. Ten lungs were obtained at autopsy, and one was obtained from a patient who was retransplanted because of severe bronchiolitis obliterans. Bronchiolitis obliterans was identified in seven of these 11 lungs. Three of the seven lungs with bronchiolitis obliterans were from patients who had received their transplants more than 6 months previously; the bronchiolitis obliterans in these patients was characterized by a relatively acellular concentric fibrosing process that was limited to the terminal bronchioles. The bronchiolitis obliterans in these three patients was felt to be secondary to chronic lung allograft rejection. Four of the seven patients with bronchiolitis obliterans had received their transplants less than 6 months previously; the bronchiolitis obliterans in these patients was focal and cellular. It extended into the distal alveolar spaces and, in several cases, was associated with aspirated material and foreign body-type giant cells. All four of these patients had concurrent infections, aspiration, or large airway obstruction, which were felt to be responsible for the development of bronchiolitis obliterans. Bronchiolitis obliterans in lung allograft recipients may have a variety of etiologies, and the etiology of this process in a particular case can often be deduced by the morphologic appearance of this lesion.     

Low incidence of Epstein-Barr virus-associated posttransplantation lymphoproliferative disorders in 272 unrelated-donor umbilical cord blood transplant recipients.

Umbilical cord blood (UCB) is being increasingly used for transplantation, but the ability of neonatal T cells to regulate Epstein-Barr virus (EBV)-associated lymphoproliferation is unknown. Because UCB transplantation (UCBT) is associated with a relatively low infused dose of donor T cells, frequent donor-recipient HLA disparity, and use of antithymocyte globulin during conditioning, we hypothesized that the risk of EBV-associated posttransplantation lymphoproliferative disorders (EVB-PTLD) after UCBT may be increased. To investigate the incidence of EBV-PTLD after UCBT, we analyzed 272 unrelated-donor UCBTs performed from August 1993 to December 1999 at Duke University Medical Center and the University of Minnesota. Five cases of EBV-PTLD were identified, with a cumulative incidence of 2% (95% confidence interval, 0.3%-3.7%) at 2 years. EBV-PTLD affected UCB recipients aged 1 to 49 years (median, 8 years), with 4 patients undergoing transplantation for leukemia and 1 for immunodeficiency. Patients received UCB grafts that were HLA matched (n = 1) or mismatched at 1 (n = 1) or 2 (n = 3) HLA loci. Diagnoses occurred at 4 to 14 months (median, 6 months) after UCBT, with 4 of 5 patients having preceding grade II to IV acute graft-versus-host disease and 1 being diagnosed at autopsy. Treatment of 4 patients consisted of withdrawal of immunosuppressive treatment and administration of rituximab, with 2 of 4 patients responding. Thus, the incidence of EBV-PTLD after unrelated-donor UCBT appears similar to that observed after transplantation using unrelated bone marrow (BM) and compares favorably with unrelated-donor T-cell-depleted BM transplantation. Because adoptive immunotherapy with donor lymphocytes is not an available option for recipients of unrelated-donor UCBT, new therapeutic strategies are needed, and rituximab appears promising.     

Psychological symptom levels and their correlates in lung and heart-lung transplant recipients

This study examined depression, anxiety, and anger-hostility symptom levels, as well as overall quality of life, in a cohort of 50 lung and heart-lung transplant recipients. Only the subjects' mean anxiety symptoms were substantially elevated over normative levels. However, nearly half of the sample showed clinically significant distress in one or more of the three symptom areas. Pretransplant psychiatric history, educational level, posttransplant caregiver support, and health concerns were the most important independent correlates of the recipients' psychological outcome. Low sense of mastery and poorer physical functional status also showed some evidence of association with mental health.     

Lymphoproliferative disorders in Oxford renal transplant recipients

BACKGROUND: Increased cancer incidence, particularly lymphoproliferative disease, is a complication of immunosuppression in organ transplantation. Non-Hodgkin's lymphomas (NHLs) occur frequently during the first year after transplantation, more so in North America than in Europe. METHODS: This study audited and correlated the demographic, clinical, pathological, and outcome features of post-transplant lymphoproliferative disorders (PTLDs) in a large centre in Oxford, and assessed whether the time of onset fitted more with the European or North American pattern. RESULTS: There were 1383 renal transplants in the study period and 27 patients developed lymphoma: 26 NHLs and one Hodgkin's disease (1.95%). Four of the patients never received cyclosporin. The mean time of diagnosis after transplant was 46 months. Most tumours (21/27) presented extranodally. Management included reduction of immunosuppression, surgical excision, antiviral treatment, radiotherapy, and chemotherapy. Three patients presented in the first post-transplant year-0.34% of cyclosporin managed patients-similar to the North American incidence, although the incidence of extranodal late PTLDs was also high (mean onset, 36 months v 15 months international mean). Post-transplant lymphomas were the most common malignancy associated with death in transplant patients. CONCLUSIONS: PTLDs occurred in 2% of renal transplant patients, presenting both in the first year in association with cyclosporin use, as in North America, but also in subsequent years, giving an overall presentation time later than the international mean. The disease usually presented extranodally, accounting for the wide range of symptoms and signs. Despite awareness and active management, the disease contributed to death in more that 50% of patients with PTLDs.     

EBV-associated B- and T-cell posttransplant lymphoproliferative disorders following primary EBV infection in a kidney transplant recipient

Posttransplant lymphoproliferative disorders (PTLDs) usually are of B-cell lineage and associated with Epstein-Barr virus (EBV). PTLDs of T-cell lineage are much less common and infrequently associated with EBV. We report a rare case of a girl in whom B-cell and T-cell PTLDs developed following 2 EBV-negative kidney transplants. Within 2 years of the second transplantation, the originally EBV-negative patient developed both an EBV-associated clonal B-cell PTLD involving lymph nodes and an EBV-positive T-cell PTLD involving bone marrow and liver. These proliferations occurred concurrently with evidence of primary EBV infection and high plasma viral load. The patient eventually died of multiorgan failure 5 years after the initial transplant (3 years after the second transplant). To our knowledge, only 4 cases of both B-cell and T-cell PTLDs have been reported. Only 2 cases have been proven to be monoclonal and EBV-associated, as in this case, the first following kidney transplantation.     

Cyclosporine-associated organic mental disorders in liver transplant recipients

The cases presented here, along with a preliminary body of clinical literature, suggest that, in conjunction with other factors, cyclosporine has an etiologic role in the production of a variety of organic mental disorders, including delirium, generalized anxiety disorder, hallucinosis, and organic mood disorder-depressed. The cases in this report were chosen in part because they illustrate definable organic syndromes. Other transplant recipients may experience less severe or isolated symptoms, such as sleep-wake reversal, insomnia, anxiety, lethargy, or mild confusional states that do meet full criteria for organic mental syndrome but that appear to be related to cyclosporine. Persecutory delusions may also occur in both floridly delirious patients and in patients with only minimal disorientation. Mental state aberrations most commonly begin within 2 weeks of treatment with cyclosporine, and, frequently, most acute symptoms resolve within a few weeks of onset. However, in more severely delirious patients or in patients with medical courses complicated by other problems, symptoms may continue longer. In particular, difficulties with memory and with the acquisition of new information may persist for several weeks. Less commonly, mental syndromes may also occur following longer periods of treatment with cyclosporine. Individual vulnerability appears to vary widely, and many patients demonstrate mental complications at cyclosporine levels that are in the moderate therapeutic range for immunosuppression. In addition, patients who have recently been started on cyclosporine and who demonstrate high therapeutic, rapidly rising, or toxic serum levels may be at greatest risk. Other risk factors may include intravenous administration, hypomagnesemia, hypocholesterolemia, and concurrent methylprednisolone bolus.(ABSTRACT TRUNCATED AT 250 WORDS)     

High levels of Epstein-Barr virus DNA in blood of solid-organ transplant recipients and their value in predicting posttransplant lymphoproliferative disorders

Epstein-Barr virus (EBV) DNA was quantitated in peripheral blood mononuclear cells (PBMC) from 25 healthy subjects, 105 asymptomatic solid-organ transplant (SOT) recipients, and 15 SOT recipients with symptomatic EBV infections by using a newly developed quantitative-PCR technique. Patients with symptomatic EBV infections had significantly higher (P < 0.001) median EBV DNA levels than asymptomatic SOT recipients and immunocompetent individuals. In SOT recipients, the positive predictive value of EBV DNA levels of >1, 000 genome equivalents (GE)/0.5 microg of total PBMC DNA was 64.7% for symptomatic EBV infection, while the negative predictive value was 96.1%. In 19 of 32 (59.3%) asymptomatic SOT recipients, EBV DNA levels were consistently below 1,000 GE for as long as 18 months, while 10 of 32 (31.2%) patients had 1,000 to 5,000 EBV GE at least once during follow-up. In a minority of patients (3 of 32; 9.3%), >/=5,000 GE could be detected at least once during follow-up. Reduction of immunosuppressive treatment decreased EBV DNA levels by >/=1 log(10) unit in patients with symptomatic EBV infections. Quantification of EBV DNA is valuable for the diagnosis and monitoring of symptomatic EBV infections in SOT recipients.     

Mantle cell lymphoma arising within primary nodal marginal zone lymphoma: a unique presentation of two uncommon B-cell lymphoproliferative disorders

Mantle cell lymphoma and primary nodal marginal zone lymphoma are uncommon tumors thought to arise within discrete anatomic compartments of the B-cell follicle. We report an unusual composite lymphoma comprised of these two neoplasms within an isolated lymph node in a 72-year-old woman. Strikingly, both tumors were completely confined to the respective microanatomic sites of their proposed nonneoplastic lymphoid counterparts, in keeping with early detection of these lesions. The tumors were distinguished by a combination of morphologic, phenotypic, and cytogenetic findings, and the presence of dual, unrelated neoplasms was confirmed by molecular diagnostic studies. After local radiation treatment, there was no recurrence or evidence of systemic disease over more than 2 years. These findings underscore the unique characteristics of these B-cell tumors and support the notion that early in disease development both neoplasms are confined to the distinct anatomic compartments of their postulated normal B-cell counterparts.     

B-Cell crossmatching and kidney allograft outcome in 9031 United States transplant recipients

The predictive power of a positive B-cell crossmatch remains controversial due to the presence of cofactors, such as sensitization and human leukocyte antigen (HLA) mismatch levels. UNOS OPTN/Scientific Registry data were analyzed on 9031 cadaveric kidney graft recipients who were B-cell crossmatched during 1994 and 1995 for graft outcome. This 2-year time period was chosen so that most US transplant recipients in this study would have had a similar regimen of immunosuppression consisting of prednisone, Sandimmune, and azathioprine The two patient groups that were analyzed were B-pos (n = 336) and B-neg (n = 8,695). All T-cell crossmatches were negative. Data analyzed included donor-recipient demographics, sensitization levels, B-cell crossmatch techniques, histocompatibility mismatching, graft rejection incidence, early graft loss, cause of graft failure, and statistical analyses (univariate and multivariate) in primary and repeat graft recipients. Significant factors in both crossmatch groups included pretransplant transfusions, peak and most recent class I PRA levels, a previous kidney graft, histocompatibility mismatching at HLA-A plus -B, urine in first 24 h, and rejection incidence between discharge and 6 months post-transplantation. Class II antibody specificities and panel reactive antibody (PRA) levels were not available from the UNOS database. Fifty-seven percent of 15,896 (1994-1995) transplant recipients (n 9031) were B-cell crossmatched, and 336 of 9031 recipients (3.7%) were transplanted with a B-pos crossmatch. Sixteen percent of B-pos recipients experienced early graft loss (< 6 months) compared with 11% of B-neg recipients (p < 0.001). Both primary and repeat grafts with B-pos crossmatches experienced an increase in rejection incidence (p = 0.023) and early graft loss (p < 0.001). In the sensitized (PRA > 10%) recipient subset (n = 2,789), both primary (n = 93) and regraft (n = 52) recipients with B-pos crossmatches had a higher incidence of early graft loss at 3 months, p < 0.001 and p = 0.016, respectively. HLA-DR mismatch levels in both patient groups were not different (p = 0.109). There was a 68% increase in the odds of 3-month graft loss in B-pos versus B-neg recipients (multivariate logistic regression analysis p = 0.054, 95% confidence interval 0.99-2.85). In conclusion, a B-pos crossmatch in primary and regraft recipients, including a sensitized subset, is predictive of inferior kidney graft outcome.     

Hepatosplenic gamma-delta T-cell lymphoma as a late-onset posttransplant lymphoproliferative disorder in renal transplant recipients

We report 2 cases of renal transplant recipients in whom hepatosplenic gamma-delta T-cell lymphoma (gamma-delta HSTCL) developed 5 and 10 years after transplantation. Both patients had marked hepatosplenomegaly, B symptoms (weight loss, fever, and night sweats), and abnormal peripheral blood findings, including anemia in both, thrombocytopenia and leukoerythroblastic changes in 1, and leukocytosis in the other. Markedly atypical lymphoid infiltrate of intermediate to large cells was observed in the spleen, liver, and bone marrow. The malignant cells showed typical immunophenotype of gamma-delta T cells (CD2+, CD3+, CD4-, CD8-, CD7+, gamma-delta T-cell receptor-positive, and alpha-beta T-cell receptor-negative) with clonal T-cell receptor gene rearrangement and were of the V-delta-1 subset. In addition, the cells contained a cytolytic granule-associated protein, TIA-1, and Fas ligand, indicating cytotoxic T-cell differentiation. The malignant T cells in both cases were of host tissue origin. Both cases were negative for Epstein-Barr virus genome using Southern blot analysis. The patients did not respond to reduction of immunosuppression. Despite initial response to chemotherapy, both patients died within 6 months of diagnosis. Our findings indicate that gamma-delta HSTCL can occur as a late complication in transplant recipients.     

Quantitative Epstein-Barr virus (EBV) serology in lung transplant recipients with primary EBV infection and/or post-transplant lymphoproliferative disease

The Epstein-Barr virus (EBV)-specific antibody response was studied in lung transplant patients to assess their value in the diagnosis and prognosis of post-transplant lymphoproliferative disease. Recently developed synthetic peptides representing Epstein-Barr nuclear antigen-1 (EBNA-1), diffuse early antigen (EA(D)), and virus capsid antigen (VCA) were studied in a semiquantitative enzyme-linked immunosorbent assay (ELISA) to study antibody patterns in 12 seronegative lung transplant patients, of whom four developed a post-transplant lymphoproliferative disease, and seven seropositive lung transplant patients, all of whom developed a post-transplant lymphoproliferative disease. Immunoblot technique was used as a control. All 12 EBV-seronegative patients had a very limited antibody response that was restricted mainly to VCA antibodies. EA(D) antibodies became detectable in only two patients. Antibody response never preceded clinical diagnosis of post-transplant lymphoproliferative disease in the four EBV-seronegative patients who developed post-transplant lymphoproliferative disease. In the seven seropositive lung transplant patients with post-transplant lymphoproliferative disease, we found a rise in antibody titer in only two patients. Immunoblot analysis confirmed the serological results. In conclusion, EBV-specific antibody patterns after lung transplantation are highly restricted and variable and of limited value for the diagnosis or prognosis of post-transplant lymphoproliferative disease.