Patients diagnosed with cold agglutinin disease (CAD) should always rule out lymphoma as a possible differential or coexistent diagnosis, according to a case report recently published in the International Journal of Laboratory Hematology.

The study describes a 64-year-old male with a history of diffuse large B-cell lymphoma (DLBCL) that had compromised testis, treated with chemotherapy and radical orchiectomy 5 years ago. He presented with episodes of headache and generalized weakness. He had no other relevant past medical history described.

Upon evaluation, blood work revealed anemia with hemoglobin of 7.2 g/dL, hematocrit 20.3%, and red blood cell count of 2.27 x 10^12/L, with normal mean corpuscular volume and mean corpuscular hemoglobin concentration. White blood cell and platelet counts were normal.

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Given these results, the healthcare team ordered a bone marrow smear through aspiration that reported hypercellularity with an increment in hemophagocytic cells and erythroid hyperplasia. Further studies reported reticulocytes above the normal values (1.87%), low haptoglobin at 20 mg/dL, elevated total bilirubin and urobilinogen, and positive direct and indirect Coombs tests.

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Upon such findings, the patient underwent a CAD screening, resulting in a positive with a titer of >1:128, hence establishing the diagnosis of cold agglutinin-mediated autoimmune hemolytic anemia. The patient then evolved satisfactorily until 1 year later when an enlarged cervical lymph node appeared. The biopsy detected a recurrent DLBCL.

Large immature tumor cells matched the findings of the peripheral blood smear done a year earlier. The healthcare providers analyzed the immunophenotype of bone marrow and plasma blood cells and the karyotype of the bone marrow sample. Moreover, red blood cell agglutination remained similar to previous findings, yielding a diagnosis of both lymphoma and CAD.

“DLBCL is the most common non-Hodgkin’s lymphoma and extranodal involvement is relatively common; cases of [bone marrow] involvement with CAD are quite rare and no case of [peripheral blood] invasion with CAD have been reported”, the authors explained.

Regardless, symptoms and paraclinical findings may overlap among both entities and lead to a missed diagnosis. In this case, the possibility of the B-cell lymphoma existing since the first evaluation remains, presuming a delayed onset of treatment.

“Because of these findings, the differential diagnosis of patients with CAD should include DLBCL, considering the possibility of [bone marrow] or even [peripheral blood] involvement,” the authors concluded.


Chang S. Bone marrow and peripheral blood involvement of relapsed diffuse large B‐cell lymphoma after prior cold agglutinin disease. Int J Lab Hematol. Published online May 15, 2022. doi:10.1111/ijlh.13860