Papillary renal neoplasm with reverse polarity: A clinicopathological and molecular genetic characterization of 16 cases with expanding the morphologic spectrum and further support for a novel entity.

Papillary renal neoplasm with reverse polarity (PRNRP) is a recently described, rare renal tumor that differs clinically, morphologically, and molecularly from papillary renal cell carcinoma (RCC). To further characterize the pathological spectrum of this rare tumor, in this study, we retrospectively identified 16 cases of PRNRP from three institutions to comprehensively investigate the clinicopathological and molecular genetic features, using immunohistochemistry (IHC), fluorescence hybridization (FISH), and targeted next-generation sequencing (NGS). The patients included nine men and seven women, with age ranging from 47 to 80 years (median = 67.5 years, mean = 65 years). The tumor size ranged from 0.4 to 9.5 cm in the greatest dimension (median = 1.8 cm, mean = 2.6 cm). Most tumors (12/16) were incidentally identified by imaging studies. By AJCC stage, 15 were categorized as pT1 and 1 was pT2. Follow-up showed no recurrences, metastases, or disease-related deaths in all the 16 patients. Grossly, 14 cases demonstrated at least a partially cystic appearance. Microscopically, all PRNRPs except 1 (case 13) were composed predominantly of thin, branching papillary architecture covered by a single layer of cuboidal cells with finely granular cytoplasm, and low-grade nuclei typically located toward the apical surface away from the basement. Case 13 consisted mostly of solid, densely packed tubules with only a minor papillary component (5%). Other commonly seen histological features included hyalinized or edematous papillae (n = 11), lymphocyte aggregation in fibrovascular cores (n = 10), mast cell infiltration (n = 8), and intralesional hemorrhage (n = 7). Uncommonly seen histological features included lymphoid cuff (n = 4), hemosiderin deposition (n = 5), foci of clear cell change (n = 4), intracytoplasmic vacuoles (n = 4), eosinophilic hobnail cells (n = 2), and infarct-type necrosis (n = 1). Two PRNRPs were concurrent with ipsilateral clear cell papillary RCC and clear cell RCC, respectively. By IHC, the tumors were consistently positive for GATA3, CK7, and PAX8. Fourteen out of 16 tumors showed a basolateral-membranous E-cadherin expression pattern, and 12/16 cases were positive for 34βE12.The expression of AMACR, CD10, and vimentin was either absent or only weak and focal. By targeted NGS, 13/14 evaluated PRNRPs harbored missense mutations involving c.35G>T resulting in p.G12V (7/13), c.35G>A resulting in p.G12D (4/13), and c.34G>T resulting in p.G12C (2/13). By FISH, 1/15 had gains of chromosomes 7 and 17, and 2/8 male cases had deletion of chromosomes Y. In conclusion, our study confirms that PRNRP is an indolent renal cell neoplasm with unique morphology, consistent immunohistochemical profile, and recurrent mutation. Our study expands the morphologic spectrum of PRNRP and provides further evidence supporting it as a novel entity.