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Immunoglobulin Gene Sequence Analysis In Chronic Lymphocytic Leukemia: From Patient Material To Sequence Interpretation
Published on: November 26, 2018
Cold Agglutinin Disease-Like Genetic Signatures in Lymphoplasmacytic Lymphoma-Like Cases Challenge the WHO Fifth
Yuki Sato1, Daisuke Koyama1, Shoki Yamada2
1Department of Hematology Fukushima Medical University Fukushima Japan.
Ejhaem
|June 19, 2026
Summary
Cold agglutinin disease (CAD) and cold agglutinin syndrome (CAS) may share genetic signatures, even when morphology differs. Molecular analysis is crucial for accurate diagnosis and understanding the full spectrum of these B-cell disorders.
Area of Science:
- Hematology
- Oncology
- Genetics
Background:
- The World Health Organization (WHO) classification distinguishes cold agglutinin disease (CAD) from cold agglutinin syndrome (CAS) based on the presence or absence of overt lymphoma.
- Uncertainty exists regarding whether this classification fully captures the biological spectrum of cold agglutinin-associated disorders.
- Distinguishing between CAD and CAS is critical for appropriate patient management and understanding disease pathogenesis.
Purpose of the Study:
- To investigate the clinicopathological and molecular features of patients diagnosed with CAD or CAS.
- To determine if distinct genetic profiles exist between CAD and CAS, or if there is overlap.
- To evaluate the utility of molecular diagnostics in refining the classification of cold agglutinin-associated disorders.
Main Methods:
- Comprehensive pathological review of bone marrow biopsies from eight patients with CAD or CAS.
- Immunoglobulin gene analysis and whole-exome sequencing to identify genetic mutations and B-cell clonality.
- Flow cytometry to assess for specific B-cell populations suggestive of lymphoma subtypes.
Main Results:
- Two cases exhibited lymphoma-like bone marrow infiltrates but lacked typical lymphoma markers and genetic hallmarks.
- These morphologically lymphoma-like cases shared immunogenetic and mutational features characteristic of CAD, including restricted IGHV4-34 usage and KMT2D/CARD11 mutations.
- No pathogenic MYD88 L265P or CXCR4 mutations, common in certain lymphomas, were detected.
Conclusions:
- A genotype-phenotype discordance exists, where CAD-like genetic signatures can be found in cases with lymphoma-like morphology (currently classified as CAS).
- The findings support the integration of molecular data into diagnostic algorithms for cold agglutinin-associated disorders.
- This approach may better reflect the biological continuum and improve classification accuracy.
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