Primary Cold Agglutinin Associated Lymphoproliferative Disease: A B-Cell Lymphoma Of The Bone Marrow Distinct From Lymphoplasmacytic Lymphoma

Primary chronic cold agglutinin disease (CAD) is a rare hemolytic disease caused by the production of cold agglutinin antibodies that bind to erythrocyte I/i blood group antigens at low temperatures. The binding is mediated by monoclonal IGHV4-34-encoded cold agglutinins. CAD is a disease of older individuals with a median age of 76 years and accounts for about 15 % of all cases of autoimmune hemolytic anemia. The estimated incidence of CAD is 1-4/10⁶ worldwide. The aim of this study is to better characterize the underlying lymphoproliferative disorder in CAD patients by review of bone marrow histology, immunophenotypic and genetic analysis. The bone marrow trephine biopsies of 54 patients with CAD showed circumscribed intraparenchymatous nodules with small monotonous monoclonal B-cells (median infiltration: 10% of marrow cells) with a CD20+, IgM^s+, IgD^s+, CD27+, CD5-/+, CD11c-/+, CD23-, CD38- immunophenotype. Neither plasmacytoid cytological features nor expression of plasma cell differentiation-associated transcription factors IRF4, BLIMP1 and XBP1 were expressed. However, a limited number of mature monoclonal IgM+, IgD- plasma cells were present outside the lymphoid nodules and were diffusely scattered throughout the marrow. Thus, the bone marrow in CAD shows a characteristic lymphoid infiltration pattern that is different from lymphoplasmacytic lymphoma that typically shows an admixture of lymphoid cells, plasmacytoid cells and plasmacells and that, not infrequently, shows a peritrabecular localisation. Of interest, the MYD88 L265P mutation, typical of lymphoplasmacytic lymphoma, was not detected (17/17 cases, sensitivity 3 %). Somatically mutated monoclonal IGHV4-34 gene rearrangement was demonstrated in eight patients with frozen samples (mean sequence homology 95.4%). Unexpectedly, no mutations of BCL6 intron 1 were demonstrated, except in one patient. BCL6 intron 1 mutations usually accompany immunoglobulin gene mutations in B lymphocytes that have matured in the germinal center. In conclusion, the histological, immunophenotypic and genetic properties of CAD are proof that CAD is a lymphoproliferative disease that is distinct from lymphoplasmacytic lymphoma with which it has previously been confounded. The disease likely originates from B lymphocytes that have not matured in the germinal center.