VH Gene Analysis of Primary Cutaneous B-Cell Lymphomas: Evidence for Ongoing Somatic Hypermutation and Isotype Switching

Abstract

Primary cutaneous B-cell lymphomas are B-cell non-Hodgkin’s lymphomas that arise in the skin. The major subtypes discerned are follicle center cell lymphomas, immunocytomas (marginal zone B-cell lymphomas), and large B-cell lymphomas of the leg. In this study, we analyzed the variable heavy chain (VH) genes of 7 of these lymphomas, ie, 4 follicle center cell lymphomas (diffuse large-cell lymphomas) and 3 immunocytomas. We show that all these lymphomas carry heavily mutated VH genes, with no obvious bias in VH gene usage. The low ratios of replacement versus silent mutations observed in the framework regions of 5 of the 7 lymphomas suggest that the structure of the B-cell antigen receptor was preserved, as in normal B cells that are selected for antibody expression. Moreover, evidence for ongoing mutation was obtained in 3 immunocytomas and in one lymphoma of large-cell type. In addition, in 1 immunocytoma, both IgG- and IgA-expressing clones were found, indicative of isotype switching. Our data provide insight into the biology of primary cutaneous B-cell lymphomas and may be of significance for their classification.

Primary cutaneous marginal zone lymphoma with subclinical cutaneous involvement and biclonality

“…Ongoing somatic hypermutation is a feature of MALT lymphoma and at least heavy chain isotype switching has been shown in cutaneous B-cell lymphoma and lymphoplasmacytic lymphoma. 34,35 In conclusion, our report illustrates the existence of a peculiar form of PCMZL exhibiting at least two different clones that initially presented with papules and later involved clinically normal and minimally erythematous skin. Therefore, in a patient with PCZML, biopsies of evanescent erythematous patches and even normal skin should be considered during staging and clinical follow-up.…”

Primary cutaneous B-cell lymphoma is associated with somatically hypermutated immunoglobulin variable genes and frequent use of VH1-69 and VH4-59 segments

“…Analyses of IgV genes in PCBCL have so far been limited to a restricted number of patients. [20][21][22][23] All reports, each based on the analysis of seven or eight cases, identify generally hypermutated IgV heavychain (IgVH) genes, suggesting the derivation of the tumour population from follicular or postfollicular antigen-experienced B cells as for most extranodal B-cell lymphoma.…”

Analysis of immunoglobulin VH genes in CD10‐positive diffuse large B‐cell lymphoma

“…Ongoing mutation, indicated by intraclonal heterogeneity, has been observed in primary DLBCL of nodal and extranodal sites (cutaneous tissue, testis), with somatic mutation present in all cases. 18,24,25 Some cases lacked intraclonal diversity 18 while others demonstrated ongoing mutation. 24,25 We observed significant ongoing mutation in three cases of CD10-positive DLBCL arising in the intestine and subcutis.…”

“…[18][19][20][21][22] Some cases of DLBCL have, however, been observed with an ongoing mutation or a low degree of somatic mutation, indicating that in these cases the VH gene rearrangement in DLBCL cells is not homogeneous. [23][24][25] For CD10-positive DLBCL, it is currently unclear whether the tumor is derived from germinal center or postgerminal center B cells. Detection of ongoing mutation suggests that, in this fraction of cases, the tumors arose from germinal center B cells.…”