Primary cold agglutinin-associated lymphoproliferative disease: a B-cell lymphoma of the bone marrow distinct from lymphoplasmacytic lymphoma

Abstract

Primary chronic cold agglutinin disease is a rare hemolytic disease mediated by monoclonal IGHV4-34-encoded cold agglutinins with a predominant specificity for the blood group antigen I. Bone marrow from 54 patients was studied to type the underlying lymphoproliferative disorder better. Bone marrow biopsies showed circumscribed intra-parenchymatous nodules with small monotonous monoclonal B cells in 40/54 patients (median infiltration: 10% of marrow cells) with a CD20(+), IgMs(+), IgDs(+), CD27(+), CD5(-/+), CD11c(-), CD23(-), CD38(-) immunophenotype. Neither plasmacytoid cytological features nor expression of plasma cell differentiation-associated transcription factors MUM1, XBP1 and BLIMP1 were noted in these B cells. However, a limited number of mature monoclonal IgM(+), IgD(-) plasma cells were present outside the lymphoid nodules and were diffusely scattered throughout the marrow. Of interest, the MYD88 L265P mutation, typical of lymphoplasmacytic lymphoma, was not detected (17/17 cases). Somatically mutated monoclonal IGHV4-34 gene rearrangement was demonstrated in eight patients with frozen samples (mean sequence homology 95.4%). However, mutations of BCL6 intron 1 were not demonstrated, except in one patient, suggesting that the lymphoma cells had not matured in the germinal center. In conclusion, cold agglutinin-associated lymphoproliferative disease displays homogeneous histological and immunophenotypic features. The absence of plasmacytoid cells, the presence of plasma cells predominantly outside the nodular lymphoid infiltrates, IGHV4-34 restriction and absence of MYD88 L265P mutation strongly suggest that cold agglutinin-associated lymphoproliferative disease is a distinct entity that is different from lymphoplasmacytic lymphoma.

Figure 1.

The figure illustrates the bone marrow histology in CAD-associated lymphoproliferative disease. A bone marrow trephine biopsy showing intraparenchymatous nodular lymphoid lesions (panels (A) and (B), H&E-staining, 40X and 200X, respectively). Immunoperoxidase staining for CD20 highlights intraparenchymatous nodular B-cell infiltration (panel (C), 200X). Mast cells are not usually discerned around the nodular lymphoid lesions [panel (D) Giemsa-staining, 200X]. High magnification shows small lymphoid cells with rounded nuclei without prominent nucleoli [panels (E) and (F), H&E staining, 400X and Giemsa staining, 600X, respectively]. Scarce plasma cells surround the lymphoid nodules but are also found diffusely within the parenchyma [panel (G), anti-CD138 peroxidase staining, 100X]. The lymphoid cells express membranous IgM and plasma cells express cytoplasmic IgM [panel (H), anti-IgM peroxidase staining, 400X].

Figure 2.

The spleen of patient 4 has a normal red pulp and a rather hypoplastic white pulp [panel (A), H&E-staining, 40x]. Staining for CD20 highlights the white pulp B lymphocytes. Few B lymphocytes are seen in the red pulp [panel (B), anti-CD20 immunoperoxidase staining, 100X]. Immunoperoxidase staining for IgK [panel (C), 100X] and for IgL [panel (D), 100X] does not show an obvious immunoglobulin light chain restriction in B lymphocytes or plasma cells.

Figure 3.

The figure illustrates the immunophenotypic findings in CAD-associated lymphoproliferative disease. The lymphoid nodules consist mainly of B lymphocytes [panel (A), anti-CD20 immunoperoxidase staining, 100X] and a moderate amount of T lymphocytes [panel (B), anti-CD3 immunoperoxidase staining, 100X]. Plasma cells are mainly found in the periphery of the nodular infiltrate and the parenchyma and express IgM and IgK [panels (C–E), anti-IgM, anti-IgK and anti-IgL immunoperoxidase staining, respectively, 100X]. Lymphoid cells within the nodular lesions do not express MUM1, but do variably express nuclear BCL10 and strongly express PAX5 [panels (F–H), immunoperoxidase staining, 400X]. T lymphocytes in the lymphoid nodules are mainly CD4 helper cells whereas few CD8 cytotoxic cells are seen [panels (I–J), immunoperoxidase staining for CD4 and CD8, respectively, 100X].