Biphasic (squamoid) papillary renal cell carcinoma: a distinct molecular and morphologic subtype within the PRCC spectrum.

Biphasic (squamoid) papillary renal cell carcinoma (BPRCC) is a recently recognized and rare variant of renal cell carcinoma, defined by biphasic morphology and distinct immunophenotypic features. Previously considered a subtype of classic papillary RCC, its clinicopathologic and molecular characteristics remain underexplored. We analyzed ten BPRCC cases for histologic, immunophenotypic, molecular, and clinical features. The cohort included seven men and three women (median age = 48 years), with tumors measuring 25-45 mm, all staged as pT1. No disease progression or cancer-related deaths were observed over a median follow-up of 55 months. Histologically, all tumors showed biphasic architecture with variable proportions of large eosinophilic squamoid and smaller basophilic cells. One tumor demonstrated focal rhabdoid-like features. Immunostains were diffusely positive for PAX8, CK7, AMACR, and Claudin4. The two cell populations showed differential expression of Cyclin D1, AMACR, HMWCK (K903), E-cadherin, and Ki-67. All tumors were negative for GATA3, p63, and CAIX (focal in 2 cases), and showed intact p53, RB1, and mismatch repair proteins. FISH confirmed trisomy 7 and 17 in all tumors. Targeted NGS revealed MET amplification (2 cases), MET mutation (1 case), NOTCH1 mutations (9 cases), and alterations in MAP2K2, FGFR4, DDR pathway genes (e.g., PMS2, CDK12R44W, RAD51C/D), and chromatin remodeling genes (EZH2, ARID1A). These findings support BPRCC as a distinct subtype of papillary RCC with consistent biphasic morphology, immunophenotypic divergence, and a unique molecular profile enriched for NOTCH, MAPK, and DDR pathway alterations.