Correlation of lymphocytic infiltration and degree of pleomorphism with tumor mutation burden in high-grade urothelial carcinoma.

Histopathological features and genomic biomarkers are integral to the management of patients with high-grade urothelial carcinoma (HGUC). Morphological features are often reflective of underlying genomic alterations. In this study, we investigate the correlation between tumor mutation burden (TMB) and specific histopathological features in HGUC to identify surrogate markers for TMB when molecular testing may not be available. We hypothesized that increased nuclear pleomorphism and intense lymphocytic infiltration might correlate with higher TMB, aiding treatment decisions. In this retrospective study, 119 cases with TMB analysis by Next Generation Sequencing (NGS) were evaluated for cytological and nuclear pleomorphism, lymphocytic infiltration, and histological subtypes. Pleomorphism and lymphocytic infiltrate were classified into binary categories (mild versus marked) for improved reproducibility. TMB ≥10 mutations/Mb was defined as high TMB. Both marked pleomorphism and marked lymphocytic infiltration were associated with higher TMB (10.3 vs 7.2 muts/Mb, p = 0.027 and 12.4 vs. 8.9 muts/Mb, p = 0.005 respectively). Micropapillary, squamous, and sarcomatoid subtypes demonstrated higher median TMB, although the differences did not reach statistical significance. In summary, our findings suggest that marked nuclear pleomorphism and lymphocytic infiltrate are associated with higher TMB, indicating their potential as surrogate markers for immunotherapy response.