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.