THE MOLECULAR AND PHENOTYPIC PROFILE OF PRIMARY CENTRAL-NERVOUS-SYSTEM LYMPHOMA IDENTIFIES DISTINCT CATEGORIES OF THE DISEASE AND IS CONSISTENT WITH HISTOGENETIC DERIVATION FROM GERMINAL CENTER-RELATED B-CELLS

Primary central nervous system lymphoma (PCNSL) is a major cause of mo rbidity and mortality among human immunodeficiency virus (HIV)-infecte d individuals. The precise histogenetic derivation and the molecular p athogenesis of PCNSL is poorly understood. In an attempt to clarify th e histogenesis and pathogenesis of these lymphomas, 49 PCNSL (26 acqui red immunodeficiency syndrome [AIDS]related and 23 AIDS-unrelated) wer e analyzed for multiple biologic markers, which are known to bear hist ogenetic and pathogenetic significance for mature B-cell neoplasms. PC NSL associated frequently (50.0%) with mutations of BCL-6 5' noncoding regions, which are regarded as a marker of B-cell transition through the germinal center (GC), Expression of BCL-6 protein, which is restri cted to GC B cells throughout physiologic B-cell maturation, was detec ted in 100% AIDS-unrelated PCNSL and in 56.2% AIDS-related cases, Nota bly, among AIDS-related PCNSL, expression of BCL-6 was mutually exclus ive with expression of Epstein-Barr virus (EBV)-encoded latent membran e protein (LMP)-1 and, with few exceptions, also of BCL-2. All but one PCNSL expressed hMSH2, which among mature B cells selectively stains GC B cells. These data suggest that PCNSL may be frequently related to GC B cells and may be segregated into two major biologic categories b ased on the expression pattern of BCL-6, LMP-1, and BCL-2. BCL-6(+)/LM P-1(-)/BCL-2(-) PCNSL occur both in the presence and in the absence of HIV infection and consistently display a large noncleaved cell morpho logy. Conversely, BCL-6(-)/LMP-1(+)/BCL-2(+) PCNSL are restricted to H IV-infected hosts and are represented by lymphomas with immunoblastic features. These data are relevant for the pathogenesis and histogenesi s of PCNSL and may be helpful to segregate distinct biologic and progn ostic categories of these lymphomas, (C) 1998 by The American Society of Hematology.