Clinical and pathological features of posttransplant lymphoproliferative disorders: influence on survival and response to treatment.

PURPOSE: To review the clinical and pathological characteristics of patients with posttransplant lymphoproliferative disorders (PTLD) occurring after solid organ transplantation and determine the influence of these characteristics on response to treatment and survival. PATIENTS AND METHODS: Retrospective review of 32 patients. RESULTS: Overall five-year survival was 59%. Forty-five percent of patients diagnosed within the first year after transplant had advanced disease. Characteristics that were associated with poorer survival were diagnosis within the first year posttransplant, monoclonal tumors and presentation with an infectious mononucleosis-like syndrome. Six of eight patients treated with surgery are alive and disease-free. CONCLUSION: Patients with PTLD can achieve long-term survival. Surgery can play an important role in selected patients. Characteristics that may be associated with poorer survival are diagnosis within the first year after transplant, presence of a monoclonal tumor or an infectious mononucleosis-like presentation.

Comparison of lymphoid neoplasm classification. A blinded study between a community and an academic setting.

The revised European-American classification of lymphoid neoplasms has been reported as reproducible among expert pathologists and feasible in a community setting. We evaluated the reproducibility of lymphoid neoplasm diagnoses between a community and an academic center. We subtyped 188 lymphoid neoplasms using revised European-American classification criteria. Clinical findings, histologic or cytologic preparations, paraffin-section immunostains, and flow cytometry data were reviewed as appropriate. Diagnoses were compared only after completion of the study. Lymphoma subtype was concordant for 167 (88.8%) of 188 cases. Discordant cases included 15 B-cell, 2 T-cell, and 4 Hodgkin lymphomas. For B-cell neoplasms, discordance was most often due to classifying diffuse large cell lymphoma as another aggressive subtype of lymphoma (n = 6), marginal zone lymphoma as another subtype (n = 4), or follicle center lymphoma grade II as grade III (n = 3). For Hodgkin disease, discordance was most often due to classifying nodular sclerosis as mixed cellularity type (n = 3). Comparison of community and academic center diagnoses demonstrated high concordance for most revised European-American classification subtypes. Some sources of discordance have been addressed in the new World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues.

Molecular epidemiology of EBNA-1 substrains of Epstein-Barr virus in posttransplant lymphoproliferative disorders which have infrequent p53 mutations.

Posttransplant lymphoproliferative disorders (PTLDs), which are highly associated with Epstein-Barr virus infection, have a low frequency of molecular genetic abnormalities. Recently it has been suggested certain EBV substrains may be associated with specific lymphoma subtypes. The goals of our study were two fold: 1) to determine the prevalence of EBNA-1 substrains and prognostic utility in PTLD and 2) to determine the incidence of p53 gene mutations and p53 protein overexpression in 32 EBV-positive PTLD cases. Tumor DNA was sequenced to identify EBNA-1 substrains at codon 487 and p53 gene mutations in exons 5-8. The PTLD samples contained the following EBNA-1 substrains: P-thr in 17/32 (53%), P-ala in 11/32 (34%), and V-leu in 4/32 (13%). More heterogeneity within major subtypes was seen in the PTLD cases than in the referral group. A second group of 25 referral (non-PTLD) samples including infectious mononucleosis (6) and sequential EBV positive virology samples (19) contained P-thr in 17/25 (68%); P-ala in 2/25 (8%); and V-leu in 6/25 (24%). In the 29 B-cell PTLD the time to presentation was an average of 13.3 months in the P-ala group, 16.6 months in the P-thr group, and 40.6 months in the V-leu group: (p>0.05). There was no difference in survival in patients (median overall--60 months) between the three different substrains of EBNA-1 (Log rank test, p=0.39). One of 31 (4.1%) cases (a diffuse large cell B-cell) had a p53 mutation. Seven of 31 (23%) cases (all B-cell), including the p53 mutated case, had over-expression of p53 protein. We conclude EBNA-1 substrains vary in PTLD and suggest the pattern reflects the geographical incidence of substrains in the region. We also conclude p53 mutations are not a significant molecular genetic abnormality in PTLD.

Epstein-Barr virus-associated lymphoproliferative disorder after autologous bone marrow transplantation: report of two cases.

Epstein-Barr virus-associated lymphoproliferative disorders have been frequently reported as a complication of solid organ and allogeneic bone marrow transplantation. Their occurrence is rare after autologous bone marrow transplantation (BMT) with only five published reports in the literature. We report two cases of post-transplant lymphoproliferative disorder occurring after autologous BMT for Hodgkin's disease and non-Hodgkin's lymphoma. Post-transplant lymphoproliferative disorders can occur after autologous BMT and should be included in the differential diagnosis of patients with persistent fever, adenopathy or pulmonary infiltrates.

Origin of the Hodgkin/Reed-Sternberg cells in chronic lymphocytic leukemia with "Hodgkin's transformation".

A lymphoma with the characteristic features of Hodgkin's disease (HD) occasionally develops in patients with B-cell chronic lymphocytic leukemia (CLL), and has been called Richter's syndrome with HD features. In such cases, large tumor cells have the morphological and immunophenotypic features of classical Hodgkin and Reed-Sternberg (H-RS) cells. However, it is not known whether the H-RS cells arise from transformation of the underlying CLL cells or from a different pathological process. We report herein a study of the clonal relationship between the CLL cells and the H-RS cells in three cases of Richter's syndrome with HD features by using a single cell assay. We isolated single CLL cells and H-RS cells from immunostained tissue sections by micromanipulation. The immunoglobulin heavy chain gene (IgH) complementarity determining region (CDR) III of each cell was amplified by the polymerase chain reaction (PCR). The products were then compared by gel electrophoresis and nucleotide sequencing. The IgH CDRIII sequences from the H-RS cells were identical to those from the CLL cells in two cases. In one case, the clonal relationship between the two types of cells could not be determined because PCR products could not be obtained from any of the H-RS cells. This study shows that the H-RS cells and the CLL cells belong to the same clonal population in some cases of Richter's syndrome with HD features. Furthermore, our findings indicate that mature B cells can undergo transformation to cells with the features of H-RS cells, in association with a cellular background typical of HD. This study also supports recent findings suggesting that the H-RS cells in classical HD are derived from transformed B cells.

Multicentric angiofollicular lymph node hyperplasia in children: a clinicopathologic study of eight patients.

Multicentric angiofollicular lymph node hyperplasia (MAFH) is an idiopathic systemic disorder that has been reported only rarely in children. Therefore, we reviewed the clinical and pathologic features of eight patients listed in the Angiofollicular Lymph Node Hyperplasia Registry at our institution. The ages of the patients ranged from two to 17 years (median, 10 yr), and the male-to-female ratio was 1:3. The patients presented with constitutional symptoms, multifocal lymphadenopathy, hepatomegaly, and/or splenomegaly. The laboratory findings included peripheral blood cytopenias, polyclonal hypergammaglobulinemia, and renal and hepatic dysfunction. Histologically, we observed the plasma cell variant of MAFH in five patients (62.5%) and the hyaline-vascular variant in three (37.5%). Immunohistochemical stains revealed a polyclonal plasma cell population in all cases. Two of six specimens were positive for Epstein-Barr virus by RNA in situ hybridization. A clonal immunoglobulin heavy gene rearrangement was identified in one of the five specimens studied, but this had no apparent impact on the clinical course of the disease. None of the four specimens analyzed for the presence of Kaposi's sarcoma-associated herpesvirus was positive. Most patients were stable or free of disease after treatment, which included corticosteroids in six of the eight patients. We concluded that the clinical and pathologic features of MAFH in children are similar to those of adults, but MAFH seems to have a more favorable clinical course, i.e., low morbidity and mortality, in children.

Molecular epidemiology of deletions and mutations of the latent membrane protein 1 oncogene of the Epstein-Barr virus in posttransplant lymphoproliferative disorders.

Latent membrane protein 1 (LMP1) is a protooncogene of the Epstein-Barr virus (EBV) that is expressed in most EBV-positive posttransplant lymphoproliferative disorders (PTLD). Small deletions in the carboxy-terminal domain of LMP1 have been recently described in Hodgkin's disease, nasopharyngeal carcinoma, and non-Hodgkin's lymphoma. We characterized the deletions and point mutations of LMP1 in 32 PTLD and 8 reactive lymphoid cases found to contain EBV by one or more methods, including LMP1 immunohistochemistry, EBV-encoded RNA in situ hybridization, LMP1 DNA amplification, or Southern blot analysis. Our goal was to study the relationship of LMP1 deletions and mutations with the PTLD morphology, clonality, EBV strain subtype, and survival of patients. We found a 30-bp deletion (Del-LMP1) in 13 of 32 (41%) PTLD cases and a similar incidence of Del-LMP1 and point mutations in 3 of 8 (38%) reactive EBV cases (rho = 0.87). The presence of the Del-LMP1 in the PTLD cases was not highly associated with a high-grade morphology or clonal immunoglobulin gene rearrangements compared with the wild-type LMP1. We found that 100% of B-strain isolates, compared with 30% of A-strain isolates, harbored the Del-LMP1. There was no significant difference in the survival of PTLD patients with or without Del-LMP1 (rho = 0.83). We conclude that the incidence of Del-LMP1 in PTLD may be reflective of the incidence of this EBV substrain in the regional population and that the Del-LMP1 sequence has no prognostic significance in PTLD.

Hodgkin's disease following solid organ transplantation.

BACKGROUND: The incidence of second malignancies is markedly increased following transplantation of solid organs. However, the development of Hodgkin's disease has been described relatively infrequently in this setting, and there is little clinical information on these patients and few details on management. PATIENTS AND METHODS: We have reviewed the pathologic specimens and clinical history of four patients who developed Hodgkin's disease following transplantation of solid organs. RESULTS: Hodgkin's disease appeared 26-68 months following transplantation of the kidney (2 cases), liver, and heart. Three cases demonstrated evidence of Epstein-Barr virus (EBV) in Reed-Sternberg cells. One case appears to have arisen after a previous EBV-driven polymorphous lymphoproliferation. Hodgkin's disease was localized in three cases and disseminated in one. All patients achieved remission with standard therapy and continue in remission between 9 and 61 months after therapy. Graft function was preserved in all patients. CONCLUSION: Hodgkin's disease occurring in the post-transplantation period should probably be treated like Hodgkin's disease in non-immunosuppressed patients. Prolonged disease-free survival is possible and function of the transplanted organ can be preserved.

Molecular evidence links lymphomatous polyposis of the gastrointestinal tract with mantle cell lymphoma.

Lymphomatous polyposis (LP) is a subtype of non-Hodgkin's lymphoma manifested by numerous polyps affecting long segments of the gastrointestinal tract. The malignant cells of LP often share morphological and immunophenotypic similarity with cells of nodal-based mantle cell lymphoma. Recent genetic studies have shown that mantle cell lymphomas frequently possess a characteristic translocation of the JH/bcl-1 loci. In this study, polymerase chain reaction (PCR) and Southern blot analysis were used to show the presence of JH/bcl-1 translocation in a typical case of LP of the gastrointestinal tract. This provides strong molecular evidence for a biologic link between LP and mantle cell lymphoma. The findings also imply that detection of this translocation may be useful in the diagnosis of morphologically equivocal gastrointestinal biopsy specimens.

Multiple lymphomatous polyposis of the gut. A case with unusually widespread distribution.

Multiple lymphomatous polyposis (MLP) is a term used to describe malignant lymphomas of the gastrointestinal tract that manifest as polyposis. The cell population of MLP is identical to that in "mantle cell lymphoma." In most instances, relatively small segments of small and large intestine are affected. We report a case of MLP in which involvement was unusually widespread. A 56-year-old man, with abdominal pain and weight loss, proved to have a large mass at the ileocecal valve as well as multiple polyps of the stomach and small and large intestine. MLP is distinctive both grossly and microscopically. Clinically, it may be confused with epithelial polyps, and histologically it must be distinguished from benign lymphoid proliferations as well as other types of lymphoma. The latter distinction is important because of the relatively poor prognosis (median survival of < 3 years).

Epstein-Barr virus DNA is abundant and monoclonal in the Reed-Sternberg cells of Hodgkin's disease: association with mixed cellularity subtype and Hispanic American ethnicity.

One hundred twenty-five cases of Hodgkin's disease from the United States (79), Mexico City (31), and Costa Rica (15) were analyzed for the presence of Epstein-Barr virus (EBV) by in situ hybridization to EBER1 transcripts. EBV was more frequently detected in the Reed-Sternberg (RS) cells of mixed cellularity Hodgkin's disease (37 of 48 [77%]) compared with the nodular sclerosis subtype (19 of 71 [27%], P < .001). The presence of EBV was also associated with Hispanic ethnicity (P < .001). In a multivariate analysis, patient age, gender, and geographic location were less predictive of EBV positivity than were mixed cellularity histology (odds ratio = 8.3) and Hispanic ethnicity (odds ratio = 4.3). Southern blot analysis of EBV terminal repeat fragments using the Xho1a probe showed that the viral DNA was monoclonal in 17 of 17 cases having EBER1-positive RS cells. By comparison, EBV DNA was not detected by Southern analysis in 20 cases lacking EBER1 in RS cells, even when occasional background lymphocytes expressed EBER1. Because clonal viral DNA was so readily detected in EBER1-positive cases, the EBV genome is probably amplified at least 50-fold in the infected RS cells. Monoclonality of EBV DNA implies that the RS cells were infected before malignant transformation.

Spontaneously generated non-Hodgkin's lymphoma in twenty-seven simian T-cell leukemia virus type 1 antibody-positive baboons (Papio species).

Simian T-cell leukemia virus type 1 (STLV-1), a type C retrovirus associated with leukemia/lymphoma in Old World monkeys, is closely related to human T-cell leukemia virus type 1, the etiologic agent of adult T-cell leukemia/lymphoma in humans. In a colony of 3200 baboons, the prevalence of antibodies to STLV-1 is more than 40%. Seropositivity is more frequent in female baboons than in males and increases with age. Of 27 STLV-1 antibody-positive baboons with non-Hodgkin's lymphoma, 20 were females and 7 were males, ranging in age from 3 to 21 years (mean, 13 years). Non-Hodgkin's lymphoma was not found in STLV-1 antibody-negative baboons. Clinical signs and laboratory findings were variable but generally included lethargy, low body weights, anemia, dyspnea, lymphadenopathy, hepatosplenomegaly, pneumonia, nodular skin lesions, and leukemia with or without multilobulated lymphocytes in peripheral blood. Radiography revealed pulmonary infiltrates consistent with pneumonia in 17 of the baboons. Serum chemical values were normal except for hypercalcemia in one baboon. Lymphocytosis was found in 18 of the baboons, with leukemia diagnosed in 11. At necropsy, variable enlargement of lymph nodes and other lymphopoietic tissue was usually found. Pale tan to white space-occupying foci typical of proliferative lymphoid tissue were often found in various organs, including lungs, spleens, livers, skin, and hearts. The lungs in 14 baboons had thickened pleuras, congestion,edema, and large tan to brown areas of consolidation.(ABSTRACT TRUNCATED AT 250 WORDS)