Renal Tumorigenesis via RAS/RAF/MAPK Pathway Alterations Beyond Papillary Renal Neoplasm With Reverse Polarity.

RAS/RAF/MAPK signaling pathway is one of the best-defined cancer signaling pathways but its role in renal tumorigenesis is unknown outside of papillary renal neoplasm with reverse polarity (PRNRP), which harbors recurrent KRAS alteration. In 383 renal tumors with NGS performed at the University of Chicago and 406 tumors from the available TCGA PRCC/chromophobe RCC data sets, 6 and 9 renal tumors with RAS/RAF/MAPK pathway alteration were identified, respectively. KRAS was the most common gene to be altered (11/15) but alterations in BRAF (2/15), RAF1 (1/15), and NRAS (1/15) were also present. On the basis of morphology, the tumors were separated into 3 groups: classic PRNRPs (group 1), predominantly tubulocystic (group 2), and papillary with high-grade features (group 3). Although morphologically different, groups 1 and 2 shared many similarities in having (1) low-grade appearing eosinophilic tumor cells, (2) identical IHC profile (GATA3+/CK7+/CD117-/Vimentin-), (3) isolated KRAS alteration with no copy number variations, and (4) no proven metastatic potential. Group 3 showed predominantly papillary architecture composed of tumor cells with clear-to-eosinophilic cytoplasm and high-grade cytologic features. Unlike Group 1/2, 57% (4/7) of group 3 tumors showed additional gene alterations on top of RAS/RAF/MAPK pathway alteration and all group 3 tumors (7/7) showed significant copy number variations. On follow-up, 2 of the 7 (2/7) group 3 tumors have metastasized. One tumor with NRAS alteration showed unique morphology unlike any other tumors, composed of mixed tubulocystic and solid architecture with eosinophilic tumor cells. This tumor also showed significant copy number variations. The tumor was staged as pT4N1, displaying metastatic potential. This study shows that renal tumors with RAS/RAF/MAPK pathway alteration are heterogeneous morphologically, immunohistochemically, and molecularly. Although rare, recognition of this novel mechanism in renal tumorigenesis may be clinically important, as there are FDA-approved therapies that can target the RAS/RAF/MAPK pathway hyperactivation.