An 83-year-old woman with fatigue and weight loss was found to have cold agglutinin disease. She had a remote history of diffuse large B-cell lymphoma treated with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy. Clinically, she had no predisposing infections and no lymphadenopathy or splenomegaly.

Her hemoglobin was 71 g/L, leukocyte count 10.5 × 10⁹/L, and platelet count 195 × 10⁹/L. There was evidence of hemolysis (elevated LDH [lactate dehydrogenase], indirect bilirubin, and reticulocytes), and a direct antiglobulin test was positive for C3 coating the red cells. Cold agglutinins were present with a titer of 1:1024 at 4°C. The peripheral smear showed red cell agglutinates (see arrows) and an infrequent atypical lymphocyte (panel A). Serum protein electrophoresis with immunofixation demonstrated a monoclonal IgM level of 3.6 g/L. The computed tomography (CT) of the thorax, abdomen, and pelvis showed no evidence of an underlying lymphoproliferative disorder. She was treated with chlorambucil followed by rituximab with a good response to the latter.

Five months later she developed severe hypotension and abdominal pain. Ultrasonography suggested cholecystitis that required an urgent cholecystectomy. Peripheral blood smear showed agglutinated red cells (panel B) and a population of large monomorphic lymphocytes. Flow cytometry of the blood revealed a monoclonal B-cell population expressing CD19/CD5, CD20, FMC7, and κ light chains. Pathology of the gallbladder showed diffuse infiltration of the wall with large lymphoid cells of similar immunophenotype in keeping with diffuse large B-cell lymphoma that relapsed.

Cold agglutinins can be associated with a viral or mycoplasma infection but should raise the suspicion of an associated malignancy. The blood films provided a clue to the presence of the relapsed lymphoma responsible for this patient's cold agglutinins.