Clinicopathological features of primary cold agglutinin disease in the Japanese population: Heterogeneous characteristics and diagnostic challenges.

Cold agglutinin disease (CAD) is an autoimmune hemolytic anemia triggered by exposure to cold. Primary CAD, defined as CAD not associated with malignant neoplasms or infections, has recently been recognized as a monoclonal B-cell lymphoproliferative disorder in the fifth edition of the World Health Organization Classification of Tumors: Hematolymphoid Tumors. This study aimed to clarify the clinicopathologic spectrum of primary CAD in a Japanese cohort through comprehensive clinicopathologic and molecular analyses. Twenty-one patients were clinically diagnosed with CAD, of whom eight were classified as having cold agglutinin syndrome (CAS) due to underlying conditions such as infections or neoplasms. The remaining 13 patients underwent detailed histologic and molecular evaluation and were stratified into three groups: Group 1, four patients with clinicopathologic features consistent with primary CAD; Group 2, six patients showing overlapping features with other indolent B-cell lymphomas; and Group 3, three patients in whom tumor cells were scarcely detectable histologically. Based on integrated clinicopathologic and molecular findings, nine patients (69%) were ultimately classified as having primary CAD, including all Group 1 patients, four from Group 2, and one from Group 3. These findings highlight the diagnostic challenges of primary CAD, even after exclusion of CAS-associated underlying conditions by standard clinical evaluation, and demonstrate that primary CAD encompasses a heterogeneous clinicopathologic spectrum. Our results suggest that further refinement of the current diagnostic criteria for primary CAD may be warranted.