Neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms that originate from neuroendocrine cells and can arise in various organs, most commonly the gastrointestinal tract, lungs, and pancreas [1]. Although the overall incidence of NETs has been rising globally, primary renal neuroendocrine tumors (RenNETs) remain exceedingly rare, accounting for less than 1 % of all renal neoplasms [2]. Fewer than 200 cases have been reported in the literature, most as isolated case reports or small series, leaving their clinical behavior and molecular underpinnings poorly understood [3], [4], [5].

RenNETs present significant diagnostic challenges. Histologically, they often mimic well-differentiated NET of other anatomic sites, exhibiting trabecular or solid growth patterns and characteristic neuroendocrine cytologic features [3]. However, their distinction from metastatic NETs to the kidney, as well as from non-neuroendocrine renal tumors with overlapping morphology, requires careful clinicopathologic correlation. Immunohistochemical panels aid in diagnosis, but variability in marker expression and limited standardization further complicate interpretation [3].

The molecular pathogenesis of RenNETs is largely unknown [1], [2], [3], [4], [5]. Unlike pancreatic or pulmonary NETs—which frequently harbor mutations in MEN1, DAXX, or ATRX—RenNETs lack a well-defined genetic profile [1]. Preliminary evidence suggests that they may exhibit unique alterations, such as TP53 or APC mutations, or changes in DNA repair pathways [6], [7]. Comprehensive genomic studies are lacking.

In this multi-institutional study, we present the clinicopathologic, immunophenotypic, and molecular features of seven primary RenNETs. Through integrated morphologic characterization and next-generation sequencing (NGS) analysis, we aim to refine the diagnostic criteria for these rare neoplasms and delineate their distinct molecular landscape in comparison with both renal cell carcinoma and NETs arising from extra-renal sites.