The pathogenesis of nodular lymphocyte–predominant Hodgkin lymphoma (NLPHL) and its relationship to other lymphomas are largely unknown. This is partly because of the technical challenge of analyzing its rare neoplastic lymphocytic and histiocytic (L&H) cells, which are dispersed in an abundant nonneoplastic cellular microenvironment. We performed a genome-wide expression study of microdissected L&H lymphoma cells in comparison to normal and other malignant B cells that indicated a relationship of L&H cells to and/or that they originate from germinal center B cells at the transition to memory B cells. L&H cells show a surprisingly high similarity to the tumor cells of T cell–rich B cell lymphoma and classical Hodgkin lymphoma, a partial loss of their B cell phenotype, and deregulation of many apoptosis regulators and putative oncogenes. Importantly, L&H cells are characterized by constitutive nuclear factor κB activity and aberrant extracellular signal-regulated kinase signaling. Thus, these findings shed new light on the nature of L&H cells, reveal several novel pathogenetic mechanisms in NLPHL, and may help in differential diagnosis and lead to novel therapeutic strategies.

IntroductionHodgkin lymphoma (HL), one of the most frequent lymphomas, is composed of 2 entities: classical HL (cHL), accounting for ϳ 95% of cases, and the rare nodular lymphocyte predominant HL (nLPHL). 1 Tumor cells are named LP cells in nLPHL and Hodgkin and Reed-Sternberg (HRS) cells in cHL. Based on differences in the histologic picture and composition of the microenvironment, cHL is subtyped into nodular sclerosis (NS), mixed cellularity (MC), lymphocyte-rich (LR), and lymphocytedepleted (LD) cHL. 1 HL is very unusual as the tumor cells often account for Ͻ 1% of the cellular population in affected lymph nodes. In cHL, the majority of cells consists of T and B cells, macrophages, and other cell types. The rarity of HRS cells and the existence of only few cHL-derived cell lines have hampered their molecular analysis. Nevertheless, studies of microdissected HRS cells demonstrated that they derive from germinal center (GC) or post-GC B cells because they carry somatically mutated immunoglobulin (Ig) V genes. 2 Destructive IgV gene mutations in a fraction of cases suggest a derivation of HRS cells from GC B cells that acquired such mutations and normally would undergo apoptosis. 3,4 In ϳ 40% of cHL, HRS cells are latently infected by Epstein-Barr virus (EBV), and EBV is likely capable to rescue preapoptotic GC B cells from apoptosis. 5 There is intensive discussion about the relationship between cHL and B-cell non-HL (B-NHL). In particular, cHL shares with primary mediastinal B-cell lymphoma (PMBL) several genetic, immunophenotypic, and biologic characteristics, and the NS-cHL subtype often has also a similar clinical presentation. [6][7][8] Furthermore, gene expression profiling studies showed that part of the signature distinguishing PMBL from diffuse large B-cell lymphomas (DLBCLs) is detected also in cHL cell lines. 9,10 However, the histopathologic picture of these neoplasms is typically quite different. Moreover, additional biologic/diagnostic "gray zones" at the interface between cHL and other B-cell lymphomas, such as nLPHL, T cell/histiocyterich B-cell lymphoma (TCRBL) and DLBCL have been described. 1,8,11,12 We previously performed genome-wide expression studies on cHL cell lines compared with B-NHL and normal B cells, thereby identifying genes aberrantly expressed by HRS cells and uncovering a dramatic loss of the B-cell transcriptional program in cHL. 13,14 However, isolated HRS cells cultured in suspension might not faithfully portray the gene expression program of primary HRS cells in the lymph node microenvironment. Whole-tissue RNA analysis was valuable in characterizing the cHL microenvironment but not the HRS cells. [15][16][17] We recently established an approach to perform genome-wide expression profiling of cells laser-microdissected from frozen biopsies and initially characterized the tumor cells of nLPHL and anaplastic large cell lymphoma. 18 Methods Normal and neoplastic B-cell samplesThe isolation of naive (N) and memory (M) B cells from peripheral blood of 5 healthy adult donors, and...