Gamma heavy-chain disease: defining the spectrum of associated lymphoproliferative disorders through analysis of 13 cases

Abstract

Gamma heavy-chain disease (gHCD) is defined as a lymphoplasmacytic neoplasm that produces an abnormally truncated immunoglobulin gamma heavy-chain protein that lacks associated light chains. There is scant information in the literature regarding the morphologic findings in this rare disorder, but cases have often been reported to resemble lymphoplasmacytic lymphoma (LPL). To clarify the spectrum of lymphoproliferative disorders that may be associated with gHCD, this study reports the clinical, morphologic, and phenotypic findings in 13 cases of gHCD involving lymph nodes (n=7), spleen (n=2), bone marrow (n=8), or other extranodal tissue biopsies (n=3). Clinically, patients showed a female predominance (85%) with frequent occurrence of autoimmune disease (69%). Histologically, 8 cases (61%) contained a morphologically similar neoplasm of small lymphocytes, plasmacytoid lymphocytes, and plasma cells that was difficult to classify with certainty, whereas the remaining 5 cases (39%) showed the typical features of one of several other well-defined entities in the 2008 WHO classification. This report demonstrates that gHCD is associated with a variety of underlying lymphoproliferative disorders but most often shows features that overlap with cases previously reported as "vaguely nodular, polymorphous" LPL. These findings also provide practical guidance for the routine evaluation of small B-cell neoplasms with plasmacytic differentiation that could represent a heavy-chain disease and give suggestions for an improved approach to the WHO classification of gHCD.

FIGURE 1

This group I case (case 8) shows an interfollicular and diffuse infiltrate of small lymphocytes, plasmacytoid cells, and plasma cells (A, H&E; B, H&E). By immunohistochemistry, numerous IgG-positive cells (C) that lack kappa and lambda light-chain expression (D) are seen.

FIGURE 2

A, This group I case (case 10) displays splenomegaly with a red pulp and white pulp infiltrate of small lymphocytes, plasmacytoid cells, and plasma cells. White pulp nodules suggestive of SMZL were not identified (H&E). B, In this group I case (case 9), a submandibular salivary gland mass contained a diffuse and interfollicular infiltrate of small lymphocytes, plasmacytoid cells, and plasma cells. Overt monocytoid morphology and lymphoepithelial lesions typical of salivary MALT lymphomas were not identified (H&E).

FIGURE 3

A–C, This group II case (case 5) shows white pulp that is expanded (A, H&E) by nodules with dark cores of small lymphocytes and paler outer zones of marginal-zone cells and plasma cells (B, H&E). The pale rims of marginal-zone cells and plasma cells are positive for IgG (C) and lack detectable kappa and lambda staining by immunohistochemistry or in situ hybridization (not shown). D–F, In this group II case (case 11) a thyroid specimen shows colonized germinal centers surrounded by an interfollicular infiltrate of small lymphocytes and plasma cells (D, H&E; E, H&E). An IgG stain highlights lymphoepithelial lesions (F).

FIGURE 4

A, A bone marrow core biopsy from a group I case (case 4) shows an aggregate of predominantly small lymphocytes (H&E). B, An IgG immunostain highlights positive cells within the aggregates that appeared to lack kappa or lambda light chains (not shown).