Renal Pelvis Squamous Cell Carcinoma Arising in the Setting of Long-Standing Nephrolithiasis: Clinicopathologic and Molecular Insights.

Squamous cell carcinoma (SCC) of the renal pelvis is an exceptionally rare and aggressive malignancy, commonly associated with long-standing nephrolithiasis and chronic inflammation. We report 2 renal pelvis SCCs arising in the setting of decades-long renal stone disease, highlighting clinicopathologic features, immunophenotype, and molecular alterations. Both tumors showed extensive squamous metaplasia, moderately differentiated SCC with comedo-type necrosis, aggressive local invasion, and poor clinical outcome. Immunohistochemically, tumors demonstrated diffuse p63/p40/keratin 5/6 expression, aberrant p53 patterns, p16 negativity, and strikingly high PD-L1 expression (CPS 85 and 72.5). Molecular analysis revealed TP53 alterations in both tumors and a TERT promoter mutation (C228T) in one tumor, which was associated with early distant metastases. These findings support the concept that renal pelvis SCC represents a biologically distinct, inflammation-driven carcinoma with adverse prognosis, limited response to conventional therapy, and potential relevance of immune checkpoint inhibition.