Gamma heavy chain disease (gHCD) is defined by an abnormally truncated IgG heavy chain monoclonal protein that lacks associated light chains and is secreted by a small B-cell neoplasm with plasmacytic differentiation.21 Clinically, gHCD is associated with a female predominance and a high incidence of concurrent autoimmune conditions. As in the past, the 2008 WHO classification designates gHCD as a variant of lymphoplasmacytic lymphoma (LPL),3 although it also states that gHCD is sufficiently distinctive to be considered a separate entity.4
In a recent study of the histopathological findings in 13 cases of gHCD,5 we showed that gHCD is heterogeneous with some cases being morphologically typical of splenic marginal zone lymphoma (SMZL) or extranodal marginal zone (MALT) lymphoma, while other cases consist of a polymorphous B-cell neoplasm with predominantly small lymphocytes, plasmacytic differentiation, and variable numbers of admixed histiocytes and large transformed cells (Figure 1).6 This latter group of cases technically meets the 2008 WHO definition of LPL, which is largely a diagnosis of exclusion, even though they are not typical of classic nodal LPL which is characterized by preservation of sinuses and a relatively monomorphic small lymphoplasmacytic infiltrate.873 These histopathological differences suggested that gHCD and typical LPL may, in fact, represent unrelated disorders.
In recent landmark studies, the MYD88 L265P mutation, which results in increased signaling through the NF-κB pathway, was identified in more than 90% of Waldenstrom’s macroglobulinemia (WM), i.e. LPL with an IgM paraprotein.149 This mutation has also been reported in diffuse large B-cell lymphoma, at least some cases of IgG or IgA positive LPL, and approximately 50% of IgM MGUS, but is present in only a small minority of other small B-cell neoplasms. The MYD88 L265P mutation, therefore, represents a diagnostically useful marker to assist in distinguishing LPL from other small B-cell neoplasms that may show plasmacytic differentiation.149 To further assess the potential relationship between gHCD and LPL, we analyzed a series of 11 gHCD cases involving lymph nodes, bone marrow or extramedullary tissues, and 10 cases of IgM positive, bone marrow-based LPL/WM for the MYD88 L265P mutation.
PCR was performed using 20 ng DNA extracted from bone marrow aspirate, peripheral blood, or formalin-fixed, paraffin embedded tissues using the qBiomarker Somatic Mutation Assay for MYD88_85940 (Qiagen, Valencia, CA, USA) on the LightCycler 480 (Roche, Indianapolis, IN, USA). This assay employs two separate real-time reactions: one specific for the MYD88 L265P mutation, and one that targets a reference, non-mutated portion of the MYD88 gene. A crossing point (CT) value is calculated for the mutant and reference MYD88 reactions, and a ΔCT is computed (ΔCT= CTmutant − CTreference). Analysis of 120 normal peripheral blood samples identified a cut off of ΔCT less than 10 for interpretation as positive for the MYD88 L265P mutation. Serial dilutions of the MYD88 L265P mutant cell line OCI-LY-10 demonstrated a limit of detection of 0.5% mutant alleles (1% heterozygous tumor cells).
The clinical and pathological findings of the 11 cases of gHCD are shown in Table 1. Ten of these patients have been previously reported.155 Remarkably, each of the 11 cases of gHCD was negative for the MYD88 L265P mutation. In contrast, 9 of the 10 cases of LPL/WM were positive for the mutation. The single LPL/WM case negative for the mutation was a peripheral blood sample. Because PCR in this study was performed without prior B-cell purification, the neoplastic cells in this peripheral blood sample may have been below the limit of detection of this assay.
These findings show that gHCD lacks the MYD88 L265P mutation that is characteristic of the vast majority of cases of LPL. Because this study utilized an allele-specific assay that targeted only the L265P mutation, the possibility of other MYD88 mutations cannot be ruled out. Additional studies will be required to determine whether other recurrent abnormalities may be found in gHCD that may contribute to lymphomagenesis. In conjunction with our prior observation that gHCD is histologically diverse and rarely, if ever, resembles typical nodal cases of LPL, these results argue strongly that gHCD should no longer be considered a variant of LPL. Similarly, Randen et al. have recently shown that primary cold agglutinin-associated lymphoproliferative disease lacks the MYD88 L265P mutation and shows other features distinct from LPL.6 Together, these reports help further refine LPL as a diagnostic category.
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