Objective:

To compare insulinoma-associated protein 1 (INSM1) with traditional neuroendocrine markers in mixed renal pelvic UC/SmCC and explore clinicopathological correlates of outcome.

Approach:

• Statistical Analysis: Statistical analysis included comparisons of paired marker positivity using the McNemar test, paired quantitative differences assessed with the Wilcoxon signed-rank test, and overall survival modeled using Kaplan–Meier estimation and Cox proportional hazards regression.

Key Findings:

• INSM1 showed the highest sensitivity for the SmCC compartment (96.3%) compared to synaptophysin (59.3%), chromogranin A (18.5%), and CD56 (85.2%).
• INSM1 was significantly more sensitive than synaptophysin (P < 0.01) and chromogranin A (P < 0.001).
• CK7 and GATA3 were exclusively retained in the UC compartment.
• The median Ki-67 index was significantly higher in SmCC than UC (76% vs 24%; P < 0.001).
• Advanced pT stage, nodal metastasis, predominant SmCC burden, and higher INSM1 H-score were adversely associated with overall survival.

Interpretation:

INSM1 is a sensitive and compartment-specific marker for identifying the SmCC component, performing better than traditional neuroendocrine markers in this cohort.

Limitations:

• The study is based on a small cohort of 27 patients, which may limit the generalizability of the findings.
• Further validation in larger multi-institutional cohorts is needed.

Conclusion:

INSM1 aids in delineating the urothelial and neuroendocrine lineages within mixed tumors, warranting further investigation into its prognostic relevance.