Expanding the Molecular Spectrum of Papillary Renal Neoplasm With Reverse Polarity: A Report of Two Cases and a Literature Review.

Papillary renal neoplasm with reverse polarity (PRNRP) is a rare renal tumor with distinct histomorphologic features and a strong association with KRAS exon 2 mutations, typically at codon 12. We report two cases that expand the molecular spectrum of this entity. The first tumor, a 3.5 cm mass in a 51-year-old female, harbored the classic KRAS codon 12 mutation (p.G12V), whereas the second, a 2.0 cm mass in a 77-year-old female, exhibited a KRAS p.Q61K mutation, rarely reported in PRNRP. Both tumors showed characteristic histology (tubulopapillary architecture, eosinophilic cytoplasm, apical nuclear polarity) and immunoprofile (GATA3+, CK7+, SDHB-retained, FH-retained). Next-generation sequencing using a 505-gene cancer panel also detected additional alterations in FLT3, POLD1, KMT2C, and WHSC1, the significance of which remains uncertain currently but may emerge with more molecular data from additional PRNRP cases. These findings underscore the value of integrated histopathologic and molecular evaluation, highlight KRAS Q61K as a rare variant, and provide a foundation for future genomic studies in this tumor type.