A morphology-driven proof-of-concept study linking interphase nuclear abnormalities to dicentric-mediated genomic...

Genomic instability is a major driver of clinical heterogeneity and treatment resistance in B-cell malignancies. In chronic lymphocytic leukemia (CLL) complex karyotype (CK) and disruption of the TP53 pathway are key markers of poor prognosis. Here we investigated whether interphase nuclear abnormalities - nucleoplasmic bridges (NPB) and nuclear buds (NBUD) - visible on routine blood smears could serve as cytological surrogates of dicentric chromosomes and structural genomic instability. We analyzed 29 patients with indolent B-cell malignancies: CLL (n = 15) and splenic marginal zone lymphoma (SMZL) (n = 14) enriched for dicentric chromosomes. A semi-quantitative Cytological Instability Score (CIS; 0-3) was developed from the systematic evaluation of 200 lymphoid cells per smear, incorporating NPB ≥ 2%, NBUD ≥ 10%, and multinucleated pleomorphic forms. Genomic instability was measured cytogenetically as the Charge of Genomic Instability (CGI). NPB frequency correlated with CGI (Spearman rho = 0.89, p < 0.0001), while NBUD correlated with the total number of chromosomal aberrations (rho = 0.85, p < 0.0001). Increasing CIS categories were associated with progressively complex cytogenetic architectures. Within this dicentric-enriched pilot cohort, cases displaying the highest CIS values generally corresponded to the most rearranged karyotypic patterns. These findings support the concept that specific interphase nuclear morphologies observable on routine cytology may reflect ongoing breakage-fusion-bridge cycles and underlying structural genomic instability; the CIS could be regarded as an exploratory morphology-based framework for assessing cytological manifestations of genomic instability in B-cell malignancies. Larger validation studies including broader cytogenetic profiles will be required to determine its reproducibility and potential clinical utility.