Primary central nervous system lymphomas. Immunophenotypic, virologic, and cytogenetic findings of three patients without immune defects.

BACKGROUND: Primary central nervous system (PCNS) lymphoma is a relatively rare disease, but an increasing incidence is reported. The Epstein-Barr virus (EBV), which is often found in lymphomas of immunocompromised patients, has been implicated in the development of lymphomas. Many cytogenetic analyses of nodal B cell lymphomas have been performed, but few studies on PCNS lymphomas have been reported. METHODS: The detection of EBV genome using the polymerase chain reaction (PCR) method and cytogenetic studies were performed, in addition to histopathologic and immunophenotypic approaches in biopsied tissue from three patients with PCNS lymphoma. Immunosuppressive states and exposure to mutagens were not clear in all patients. RESULTS: Histopathologic examination disclosed a diffuse type of malignant lymphoma in all patients. Immunophenotypic studies revealed B cell phenotype in all patients, two of whom showed positive reaction for CD5. The PCR method revealed no involvement of EBV genome in tumors in any patients. The cytogenetic study showed clonal chromosome abnormalities in all patients, and abnormalities of chromosome 1 (1q21), 6 (-6, 6q15 and 6q21), 7 (-7 and 7p15), and 14 (14q24 and 14q32) were prominent. The t(6;14)(q15;q32) observed in Patient 1 is the first case to be reported in human de novo lymphoma. CONCLUSIONS: These findings indicate that the causative role of EBV in PCNS lymphoma without immune defects is not clear. The cytogenetic findings were similar to those observed in nodal B-cell lymphoma, suggesting that the origin of PCNS lymphoma cells does not differ from nodal B cell lymphoma cells cytogenetically.

Frequent detection of human herpesvirus-6 sequences by polymerase chain reaction in paraffin-embedded lymph nodes from patients with angioimmunoblastic lymphadenopathy and angioimmunoblastic lymphadenopathy-like lymphoma.

In search of a possible involvement of viral agents in angioimmunoblastic lymphadenopathy with dysproteinaemia (AILD) and AILD-like lymphoma (AILD-L), we studied the presence of human herpesvirus-6 (HHV-6) in the lymph node biopsies of 12 cases by polymerase chain reaction (PCR). Given the rarity of this lymphoproliferative disorder, we investigated archival specimens, consisting of formalin-fixed and paraffin-embedded tissues, obtained from patients with a clinical and histologic diagnosis of AILD and AILD-L. HHV-6 sequences were detected in the lymph node biopsies of 7 out of the 12 AILD and AILD-L cases examined. HHV-6 sequences were identified also in the involved liver and spleen tissues of one patient and in the PBMCs of two patients, all carrying viral sequences in the affected lymph nodes. We also used PCR to characterize the HHV-6 genomes, showing that two different viral strains are represented in the pathologic tissues. This study provides evidence of the presence of HHV-6 specific sequences in an unexpectedly high proportion of our series of AILD and AILD-L cases, suggesting a possible involvement of this lymphotropic virus in the pathogenesis of at least some cases of the disease.

Incidence of Epstein-Barr virus in AIDS-related lymphoma specimens.

We used the polymerase chain reaction, in situ hybridization, and immunohistochemical stains against latent membrane protein, CD23, and Epstein-Barr viral nuclear antigens 1 and 2 to identify Epstein-Barr virus (EBV) in fixed and unfixed (cryopreserved) AIDS-related lymphoma (ARL) specimens. The study included 17 cases of large-cell (immunoblastic) lymphoma, 11 cases of small non-cleaved cell lymphoma, and two cases of Hodgkin's disease. The EBV DNA was more frequently detected by polymerase chain reaction in cryopreserved specimens (94%) than in fixed specimens (17%). Significantly, the immunohistochemical and in situ hybridization studies detected evidence of EBV in only a small (< 10%) subset of the cells in 27 of 30 ARL specimens. We conclude that tissue fixation reduced the ability to detect EBV in ARL by polymerase chain reaction and that EBV was detectable in only a minority of cells in most ARL tissues.

Heterogeneous Epstein-Barr virus infection patterns in peripheral T-cell lymphoma of angioimmunoblastic lymphadenopathy type.

In this study, 32 cases of T-cell lymphoma of angioimmunoblastic lymphadenopathy type (AILD-TCL) were investigated for their association with Epstein-Barr virus (EBV). For this purpose, three different approaches were applied: polymerase chain reaction (PCR) for the presence of EBV-DNA, in situ hybridization (ISH) for EBV-encoded small nuclear RNAs (EBER), and immunohistology for EBV-encoded latent membrane protein (LMP). PCR and EBER-ISH produced almost identical results, showing that all but one case of AILD-TCL contained EBV genomes. Three distinctive patterns of EBV infection were observed after immunophenotypical characterization of EBER-positive cells: (1) in 26% of the cases, B and T cells were infected, the majority of which were B cells of immunoblastic morphology located in the remnants of lymphoid follicles; (2) in 42% of the cases, the vast majority of infected cells were neoplastic T cells diffusely distributed in the lymph nodes, but infected B cells were also present; and (3) in 32% of the cases, there were only a few infected small lymphoid cells. Detectable LMP was frequent in cases exhibiting patterns 1 and 2. These findings suggest that in AILD-TCL patients, B cells and especially T cells are highly susceptible to a persistent EBV infection, which often leads to a growth advantage of the infected cells. Thus EBV, in conjunction with genetic abnormalities and selective defects of the immune system, might be involved in the pathogenesis of AILD-TCL.

Primary B cell lymphoma of the rectum in a patient coinfected with HIV-1 and HTLV-I.

This report describes a clinical case of a large cell, immunoblastic plasmacytoid malignant B-cell lymphoma of the rectum in an AIDS patient coinfected with HTLV-I. The malignant cells showed clonal genetic rearrangement of the HC (JH) and LCK genes. Infection by EBV was demonstrated serologically and with slot blots using genomic DNA of the cancer cells. Southern blot analysis with DNA extracted from the lymphoma cells were negative for HTLV-I. The patient received seven cycles of VACO-B which induced complete but transient clinical remission of the tumor. The final outcome of the patient is unknown.

Tumorigenicity of EBV-carrying lymphoblastoid cell lines (LCLs): distinctive grading in SCID mice.

The in vitro and in vivo growth of lymphoblastoid cell lines (LCLs), Burkitt lymphomas (BLs) and PBL-derived immunoblastomas in SCID mice was studied in parallel. Most, but not all, of the LCLs tested were tumorigenic in SCID mice. Long-term culturing in vitro was not a necessary prerequisite for tumorigenicity. There was a good correlation between in vivo and in vitro growth. Three major classes of cells could be distinguished on the basis of their growth properties.

Epstein-Barr virus-associated peripheral T-cell lymphoma of activated CD8 phenotype.

Two childhood cases are reported of peripheral T-cell lymphoma; the neoplastic cells expressed activated CD8 (T8) phenotype and contained Epstein-Barr viral (EBV) DNA. Both patients had an aggressive and rapid clinical course despite chemotherapy. Elevated titers of antibodies to EBV-viral capsid antigen (greater than 640) and early antigen (greater than 10) were found in both patients. Histology revealed pleomorphic immunoblastic lymphoma with extensive necrosis in one case and an angioimmunoblastic lymphadenopathy-like pattern containing Reed-Sternberg-like giant cells in the other. Southern blot hybridization studies showed clonal rearrangement of the T-cell-receptor beta gene in both cases, and a cytogenetic study on one case revealed clonal structure abnormality involving chromosomes 1, 6, 7, 10, and 19. Analysis of the tumor DNA showed a high copy number of EBV genome per cell compared with that of Raji and Marmoset B 95.8 lines; the study for human T-cell leukemia virus type I was negative. The EBV genome was found by in situ hybridization in the tumor nuclei in both cases. In addition to Burkitt's lymphoma, T-cell lymphoma of the helper phenotype, and Hodgkin's disease, EBV can contribute to the development of CD8-positive aggressive T-cell lymphoma.