title: 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.
authors.affiliation: uranden@ous-hf.no.
authors.forename: Ulla
authors.initials: U
authors.lastname: Randen
authors.forename: Gunhild
authors.initials: G
authors.lastname: Trøen
authors.forename: Anne
authors.initials: A
authors.lastname: Tierens
authors.forename: Chloé
authors.initials: C
authors.lastname: Steen
authors.forename: Abdirashid
authors.initials: A
authors.lastname: Warsame
authors.forename: Klaus
authors.initials: K
authors.lastname: Beiske
authors.forename: Geir E
authors.initials: GE
authors.lastname: Tjønnfjord
authors.forename: Sigbjørn
authors.initials: S
authors.lastname: Berentsen
authors.forename: Jan
authors.initials: J
authors.lastname: Delabie
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001706:Biopsy; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D003450:Cryoglobulins / Q000276:immunology / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics; D003937:Diagnosis, Differential; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D016130:Immunophenotyping; D016393:Lymphoma, B-Cell / Q000175:diagnosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008232:Lymphoproliferative Disorders / Q000175:diagnosis* / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics; D051560:Proto-Oncogene Proteins c-bcl-6; D013154:Spleen / Q000378:metabolism / Q000473:pathology; D008258:Waldenstrom Macroglobulinemia / Q000175:diagnosis
chemical_list: C084103:BCL6 protein, human; D003450:Cryoglobulins; D004268:DNA-Binding Proteins; D007143:Immunoglobulin Heavy Chains; D053594:Myeloid Differentiation Factor 88; D051560:Proto-Oncogene Proteins c-bcl-6; C029443:cold agglutinins