THE STATUS OF BCL-6, CD138/SYNDECAN-1, LMP-1 AND BCL-2 IDENTIFIES DISTINCT CATEGORIES OF AIDS-RELATED PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA: PATHOGENETIC AND HISTOGENETIC IMPLICATIONS.

Abstract

89 Background: Primary central nervous system lymphoma (PCNSL) is a major cause of morbidity and mortality among HIV-infected individuals. AIDS-related PCNSL (AIDS-PCNSL) derive from B-cells, display an aggressive clinical behavior, and are histologically classified as diffuse large cell lymphoma. The precise histogenetic derivation of AIDS-PCNSL, as well as their molecular pathogenesis, are poorly understood. This study aimed at clarifying the histogenesis and pathogenesis of AIDS-PCNSL by defining the genotypic and/or phenotypic profile of cancer-related genes and of other biologic markers harboring pathogenetic and histogenetic implications for B-cell neoplasia. Methods: Twenty-six AIDS-PCNSL formed the basis of this study. For comparison. 23 AIDS-unrelated PCNSL were also investigated. All PCNSL were monoclonal B-cell expansions. PCNSL were investigated for protein expression of the BCL-6 and BCL-2 proto-oncogenes, the CD138/syndecan-1 antigen, the hMSH2 DNA mismatch repair enzyme, and the EBV-encoded LMP-1 antigen. These markers bear histogenetic relevance throughout the B-cell lineage, since expression of BCL-6 and hMSH2 cluster with germinal center (GC) B-cells, whereas expression of CD138/syndecan-1 associates specifically with late stages of B-cell differentiation. Molecular investigations of PCNSL included infection by EBV, rearrangements of BCL-2, BCL-6, and c-MYC proto-oncogenes, as well as analysis of mutations of BCL-6 5′ noncoding regions, which denote B-cell transition through the GC. Results: Expression of the BCL-6 protein was detected in 56.2 % AIDS-PCNSL. Expression of BCL-6 was mutually exclusive with expression of LMP-1, of CD138/syndecan-1 and, with few exceptions, of BCL-2, BCL-6+/LMP-1−/BCL-2− AIDS-PCNSL generally displayed a large noncleaved cell morphology, whereas cases expressing the BCL-6−/LMP-1+/BCL-2+ phenotype displayed features consistent with large cell immunoblastic plasmacytoid lymphoma. All AIDS-PCNSL expressed the hMSH2 protein. The most frequent proto-oncogene alteration of AIDS-PCNSL was represented by mutations of BCL-6 5′ regions, occurring in 42 % of cases. Conversely, all AIDS-PCNSL tested were devoid of gross rearrangements of BCL-6, BCL-2, or c-MYC. Infection by EBV occurred in all AIDS-PCNSL. Conclusions: The implications of these data are threefold. First, AIDS-PCNSL are heterogeneous and may be distinguished into two major phenotypic categories, i.e. BCL-6+/syndecan-1−/LMP-1−/BCL-2− and BCL-6−/syndecan-1+/LMP-1+/BCL-2+. Second, the combination of positive BCL-6 expression, hMSH2 expression and frequent BCL-6 5′ mutation suggests that a substantial fraction of AIDS-PCNSL derive from GC B-cells. Finally, BCL-6 mutations represent the most frequent proto-oncogene lesion of AIDS-PCNSL and may provide a molecular inarker for disease monitoring.