Expression and prognostic significance of INSM1 compared with traditional neuroendocrine markers in mixed urothelial and small-cell carcinoma of the renal pelvis.

Background: Mixed urothelial carcinoma (UC) and small-cell carcinoma (SmCC) of the renal pelvis is a rare but clinically consequential malignancy in which recognition of the neuroendocrine component directly influences diagnosis and treatment. We compared insulinoma-associated protein 1 (INSM1) with traditional neuroendocrine markers and explored clinicopathological correlates of outcome in a retrospective cohort of mixed renal pelvic UC/SmCC. Methods: Twenty-seven consecutive patients with histologically confirmed mixed renal pelvic UC/SmCC were identified from the institutional pathology archive during a prespecified consecutive 5-year accrual window (January 2019 to December 2023). Paired SmCC and urothelial compartments were evaluated separately on 4-μm formalin-fixed paraffin-embedded sections for INSM1, synaptophysin, chromogranin A, CD56, CK7, GATA3, Ki-67, and p53, using a modified H-score (0-300). Paired marker positivity was compared with the McNemar test, paired quantitative differences with the Wilcoxon signed-rank test, and overall survival was modeled with Kaplan-Meier estimation and Cox proportional hazards regression. Results: INSM1 showed the highest sensitivity for the SmCC compartment, with nuclear positivity in 26 of 27 cases (96.3%; 95% CI, 81.0-99.9%), compared with synaptophysin 59.3%, chromogranin A 18.5%, and CD56 85.2%; all paired UC components were INSM1-negative. INSM1 was significantly more sensitive than synaptophysin (P < 0.01) and chromogranin A (P < 0.001), whereas CD56 did not differ significantly from INSM1 (P = 0.375). CK7 and GATA3 were retained exclusively in the UC compartment, and the median Ki-67 index was markedly higher in SmCC than UC (76% vs 24%; P < 0.001). On univariable Cox analysis, advanced pT stage, nodal metastasis, predominant SmCC burden, and higher INSM1 H-score were adversely associated with overall survival, whereas adjuvant chemotherapy was associated with reduced mortality risk. Conclusions: INSM1 is a sensitive and compartment-specific marker for identification of the SmCC component and showed higher sensitivity than synaptophysin and chromogranin A in this cohort, while performing similarly to CD56. Combined with CK7 and GATA3, INSM1 helps delineate the urothelial and neuroendocrine lineages within a single biphasic tumor. Larger multi-institutional cohorts with molecular profiling are needed to validate these exploratory findings and to clarify whether quantitative INSM1 expression carries prognostic relevance.