Rare Occurrence of Classical Hodgkin's Disease as a T Cell Lymphoma

Abstract

Recent work identified Hodgkin and Reed-Sternberg (H/RS) cells in classical Hodgkin's disease (cHD) as clonal progeny of mature B cells. Therefore, it is generally assumed that cHD homogenously represents a B cell lymphoma. In a subset of cHD, however, H/RS cells expressing T cell–associated proteins may be candidates for alternative lineage derivation. Single H/RS cells with cytotoxic T cell phenotype were micromanipulated from three cases of cHD and analyzed by single cell polymerase chain reaction for immunoglobulin heavy (IgH) and light chain (IgL) gene rearrangements, T cell receptor (TCR)-β gene rearrangements, and germline configuration of the IgH and TCR-β loci. H/RS cells from two cases of cHD harbored clonal, somatically mutated Ig gene rearrangements, whereas TCR-β loci were in germline configuration. In contrast, H/RS cells from an additional case harbored clonal TCR-β variable/diversity/joining (VDJ) and DJ gene rearrangements, whereas the IgH locus was in germline configuration on both alleles. Thus, in two cases of cHD with H/RS cells expressing cytotoxic T cell molecules, the tumor cells are derived from mature B cells that aberrantly express T cell markers. In a third case, however, H/RS cells were derived from a T cell, demonstrating that cHD can also occur as a T cell lymphoma.

Molecular Single-Cell Analysis of Hodgkin- and Reed-Sternberg Cells Harboring Unmutated Immunoglobulin Variable Region Genes

“…However, three clonal Ig-gene rearrangements, namely a V H 1-, a V 2-, and a V 3-gene rearrangement, were amplified from 81 H/RS cells. Hence, this case represents another example of cHD in which the H/RS cells expressed T lineage markers although derived from a mature B cell (Müschen et al, 2000).…”

“…The first experiment (39 H/RS cells) was omitted from analysis because there was an indication of PCR contamination (see "Materials and Methods"). Derivation from either the B or the T lineage is possible for H/RS cells expressing cytotoxic T-cell markers (Müschen et al, 2000). Micromanipulated H/RS cells were analyzed for Ig and TCR␤ gene rearrangements (Table 1).…”

“…In most cases of cHD, H/RS cells do not express B lineage markers, although in more than 90% of cHD cases, H/RS cells represent the outgrowth of a tumor clone derived from mature antigen-experienced B cells , and derivation of H/RS cells from the T lineage is rare (Müschen et al, 2000). This conclusion is based on the amplification of clonally related immunoglobulin (Ig) gene rearrangements from single micromanipulated H/RS cells in 45 of 46 analyzed cases (Bräuninger et al, 1999a;Irsch et al, 1998;Kanzler et al, 1996aKanzler et al, , 1996bKüppers et al, 1994;Marafioti et al, 1999Marafioti et al, , 2000Müschen et al, 2000;Ohno et al, 1998;Vockerodt et al, 1998). In all informative B-lineage cases (41 in total), the H/RS cells harbored somatically mutated variable (V) region genes, indicating their (post-) germinal center (GC) B-cell origin.…”

“…In all informative B-lineage cases (41 in total), the H/RS cells harbored somatically mutated variable (V) region genes, indicating their (post-) germinal center (GC) B-cell origin. In 12 of 41 cases, the originally productive Ig V diversity (D) joining (J)-gene rearrangements were rendered nonfunctional by the introduction of stop codons, deletions, or destructive promoter mutations generated within the GC (Jox et al, 1999;Kanzler et al, 1996a;Küppers et al, 1994;Marafioti et al, 2000;Müschen et al, 2000). H/RS cells for which B-cell receptor (BCR) function was compromised by destructive somatic mutations are derived from GC B cells as BCRdeficient B cells are eliminated within the GC, and thus prevented from entering the memory compartment .…”

TP53 gene mutations in Hodgkin lymphoma are infrequent and not associated with absence of Epstein-Barr virus

“…Probably these samples were admixed with activated B cells or their RS cell population escaped detection due to somatic mutations in the primer hybridization sites of the IgH gene, which perturbs amplification. Although the occurrence of classical HL as T-cell lymphoma is rare, 28 this cannot be excluded for the case in which no PCR product was obtained. Overall, 74% showed evidence of a monoclonal IgH gene rearrangement (Table IV).…”