Papillary renal neoplasm with reverse polarity: a novel entity for the next WHO classification? a clinical-pathological and molecular study of 15 cases, compared to eosinophilic/oncocytic papillary renal cell carcinoma

: Papillary renal neoplasm with reverse polarity (PRNRP) is a recently recognized renal tumor characterized by papillary architecture lined by a single layer of low-grade eosinophilic cells with apically located nuclei. In the latest WHO classification, they are not recognized as a distinct entity but rather as a morphological pattern of papillary renal cell carcinoma. To date, limited studies have compared PRNRP with eosinophilic/oncocytic papillary renal cell carcinoma (E/OPRCC), which they are not infrequently confused with, although a few previous comparisons with classic papillary renal cell carcinoma have already identified several distinguishing features. A comparative analysis of 15 of PRNRPs and 16 of E/OPRCC cases was conducted, evaluating their histopathological, immunophenotypic, interphase cytogenetic, and molecular profiles. PRNRPs demonstrated distinctive morphological features, including consistent apical nuclear positioning, absence of foamy macrophages in the papillary cores (p = 0.0001), and a lower nucleolar grade compared to E/OPRCCs (p = < 0.0001). Immunohistochemically, PRNRPs exhibited strong and uniform GATA3 expression and were negative for vimentin, CD10, and CD13, in contrast to E/OPRCCs. Cytogenetically, PRNRPs lacked trisomies of chromosomes 7 and 17, which were present in ~ 40% of E/OPRCCs (p = 0.0262). Notably, all PRNRP cases harbored KRAS mutations, absent in E/OPRCCs (p < 0.0001). Our findings support the classification of PRNRP as a distinct renal tumor entity, separated from both classic papillary renal cell carcinoma and its eosinophilic/oncocytic morphological variant.