ArticleEJHaem2026
Cold Agglutinin Disease-Like Genetic Signatures in Lymphoplasmacytic Lymphoma-Like Cases Challenge the WHO Fifth Edition Classification.
Article in EJHaem, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Background: The fifth edition of the World Health Organization (WHO) classification defines cold agglutinin disease (CAD) as a clonal B-cell lymphoproliferative disorder occurring in the absence of overt lymphoma, whereas cases associated with lymphoma are classified as cold agglutinin syndrome (CAS). However, whether this distinction fully reflects the biological spectrum of cold agglutinin-associated disorders remains uncertain. Methods: We performed a comprehensive pathological review, immunoglobulin gene analysis and whole-exome sequencing in eight patients with clinically well-characterised CAD or CAS. Results: Five cases showed pathological findings typical of CAD, whereas two cases demonstrated lymphoma-like bone marrow infiltrates resembling lymphoplasmacytic lymphoma (LPL). Nevertheless, no CD5-positive or CD10-positive clonal B-cell population suggestive of a specific lymphoma subtype was identified by flow cytometry. Six patients showed highly restricted Conclusion: These findings demonstrate that CAD-like genetic signatures can be present even in cases with lymphoma-like morphology that would currently be classified as CAS under the WHO criteria. Our results highlight a clinically relevant genotype-phenotype discordance and support the integration of molecular hallmarks into diagnostic algorithms to better reflect the biological spectrum of cold agglutinin-associated disorders.
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