Integrated Pathologic, Genomic, and Transcriptomic Analysis of Renal Neuroendocrine Tumors Reveals Neuroendocrine Transcriptional Programs and Associated Gastrointestinal-Type Epithelium in a Subset of Cases.

Renal well-differentiated neuroendocrine tumors (RenNETs) are rare primary renal neoplasms with enigmatic histogenesis. To define the molecular features of RenNETs and clarify their relationship to neuroendocrine tumors (NETs) from other sites, we performed whole-exome DNA sequencing and transcriptomic profiling on six RenNETs. In one case, adjacent non-neuroendocrine cystic epithelium and a regional lymph node metastasis were independently analyzed. RenNETs demonstrated a low-to-intermediate tumor mutational burden and recurrent copy number alterations, including losses involving chromosomes 3, 11, and 18 and gains involving chromosomes 1, 2, 8, and 14, partially overlapping those reported in gastroenteropancreatic NETs, in the absence of alterations in canonical NET-associated driver genes. RNA sequencing revealed marked upregulation of genes involved in neuroendocrine differentiation, peptide processing, and pancreatic beta cell function, accompanied by loss of renal lineage markers, indicating a neuroendocrine transcriptional program distinct from other primary renal neoplasms. RenNETs showed heterogeneous activation of hormone related transcriptional programs, rather than conforming to a discrete EC-cell or L-cell signature. Immunohistochemistry confirmed strong membranous expression of somatostatin receptor 2A (SSTR2A) in all cases, supporting established imaging and therapeutic paradigms used for NETs. Notably, two RenNETs were associated with adjacent CDX2-positive epithelial-lined cysts with intestinal differentiation. In one case, a shared somatic mutation was identified across the epithelial cyst, the adjacent RenNET, and a nodal metastasis, providing genetic evidence of a common clonal origin and implicating gastrointestinal-type epithelium as a potential precursor lesion in a subset of cases. Features supporting teratomatous origin, such as chromosome 12p gains or other germ cell tumor elements, were not identified. Together, these findings demonstrate that RenNETs exhibit convergent transcriptomic and phenotypic neuroendocrine programs, along with partial copy number overlap, with well-differentiated gastroenteropancreatic NETs, and support a model in which RenNETs may arise from developmentally displaced or aberrantly differentiated epithelial precursors with gastrointestinal-type differentiation, although this hypothesis requires validation in larger cohorts.