Lymphocyte predominance Hodgkin disease is characterized by recurrent genomic imbalances

Abstract

IntroductionHodgkin disease (HD), one of the most common malignant lymphomas in the western world, was first described by Thomas Hodgkin in 1832. The characteristic morphologic feature of HD is the cellular composition of the tumor tissue containing a small number (approximately 0.1% to 1%) of neoplastic ReedSternberg (RS) cells and a major population of nonneoplastic lymphocytes, histiocytes, neutrophils, fibroblasts, eosinophils, and plasma cells. On the basis of tumor cell morphology, immunophenotype, and the composition of the cellular background, 2 separate biologic entities, namely, lymphocyte predominance Hodgkin disease (LPHD) (or nodular paragranuloma) and classical HD have been recognized in the Revised European-American Lymphoma (REAL) classification. 1 LPHD accounts for 5% of all HD cases. Typically, patients are 25-to 45-year-old men and usually present at an early clinical stage. More than 90% of patients with LPHD have a complete response to therapy, although recurrences frequently occur. In LPHD, a particular variant of RS cells, the "popcorn" or lymphocytic and histiocytic (L&H) cells, is found. In contrast to RS cells of classical HD, "popcorn" cells lack the expression of CD30 and CD15 but express CD45 and CD20. The expression of these markers and presence of nodular structures closely resembling lymphoid B follicles have suggested that "popcorn" cells represent neoplastic germinal center B cells. [2][3][4] Because of the very low frequency of RS and "popcorn" cells in the tumor tissue and the lack of suitable methods for their purification and analysis, clonality and lineage derivation of neoplastic cells in HD have remained uncertain until recently. As soon as single-cell polymerase chain reaction (PCR)-based methods had been developed, clonal Ig rearrangement and consistent occurrence of somatic mutations within the variableregions of Ig genes amplified from isolated RS and "popcorn" cells have been demonstrated in the majority of analyzed cases. These findings indicated a clonal germinal-center (GC) or post-GC B-cell origin of LPHD as well as of classical HD. [5][6][7][8][9][10][11] On the other hand, polyclonal Ig rearrangements found in some HD cases 12-14 led to the hypothesis of a sequential poly-/oligo-/monoclonal origin of HD, a matter that is still under discussion. [15][16] Despite recent progress in HD research, genetic and molecular data are only scarcely available. There are intrinsic technical problems in obtaining metaphase chromosomes in HD (low number of RS cells, low proliferation index, infiltration of reactive cells), and therefore no more than 200 HD cases with [19][20][21] and by comparative genomic hybridization (CGH), 22,23 so far no specific cytogenetic marker(s) could be identified. Single RScell PCR analysis of CMYC, BCL2, and BCL1 suggested that these non-Hodgkin lymphoma (NHL)-specific genes are not involved in the pathogenesis of HD. 24,25 Even less is known about genetic and molecular aberrations in the LP subtype of HD. To the best of our knowledge, only 9 LP...

Follicle center lymphoma is associated with significantly elevated levels of BCL-6 expression among lymphoma subtypes, independent of chromosome 3q27 rearrangements

“…The gene is rearranged in about 30% of diffuse large B cell lymphoma (DLBCL) and in 8 to 15% of follicle center lymphomas (FCL), [9][10][11] but also less frequently in other lymphoma subtypes including nodal and extra-nodal marginal zone lymphoma (MZL), 12,13 or lymphocyte predominant Hodgkin's disease (HD). 14 Immunoglobulin gene (Ig) loci are the most frequently involved partners, 15 but several other non-Ig gene partners have also been characterized, including the small G protein TTF (4p11), 16 the B cell transcriptional coactivator BOB1 (11q23), 17 the Ikaros gene (7p12), 18 or the splicing factor SRP20 (6p21). 19 In almost all cases, breakpoints are located in the 5Ј extremity of the first intron and the rearrangement conducts to substitute BCL-6 regulatory regions with those of the partner, keeping the coding region intact in all cases.…”

Conventional cytogenetics of nodular lymphocyte-predominant Hodgkin's lymphoma

“…To date, for the same reasons the cytogenetic characterization of NLPHL remains partial, limited to some CGH data, 4 to a partial analysis using interphase FISH with probes exploring genes usually involved in B-cell lymphoma 3 and to conventional cytogenetics data from a few number of patients with NLPHL or transformed lymphoma, reported together with extensive FISH and molecular analysis. 6 Our study, where the only significant imbalances involved chromosomes 1, 4, 7, 9 and 13, does not confirm the results obtained using CGH by Franke.…”

“…Cytogenetic characteristics of NLPHL have been rarely reported, and were mainly obtained using molecular cytogenetic methods like fluorescent in situ hybridization (FISH) or comparative genomic hybridization (CGH). 3,4 Between 1979 and 2004, 22 patients referred to the Centre Henri Becquerel had a diagnosis of NLPHL. A single lymph node biopsy was used for morphologic, immunologic, molecular and cytogenetic studies, including molecular cytogenetics.…”

Shades of gray between large B-cell lymphomas and Hodgkin lymphomas: differential diagnosis and biological implications

“…25 CGH from microdissected CD20 þ malignant cells showed recurrent genomic imbalances (average 10.8 per case), involving all chromosomes including 1, 2q, 3, 4q, 5q, 6, 8q, 11q, 12q and X, and loss of chromosome 17, in 36.8-68.4% of the cases. 29 Gains of 2q, 4q, 5q, 6 and 11q are uncommon in NHL. There were frequent gains of chromosome 6q, a region often deleted in NHL.…”

“…29,33 Both have rearranged, mutated IGH genes with ongoing mutations. Partial gain of 4q, a rare change in lymphoma, is frequent in both.…”