Renal Neuroendocrine Tumors Show GI-Type Precursor Epithelium and Distinct Neuroendocrine Transcriptional Programs

Primary renal well-differentiated neuroendocrine tumors (RenNETs) are exceedingly rare and their origin remains largely unknown. Unlike more common neuroendocrine tumors (NETs) found in the gastroenteropancreatic system, the molecular characteristics and relationship of RenNETs to other NETs are poorly defined. This lack of understanding poses challenges for accurate diagnosis, classification, and the application of established therapeutic paradigms. Defining the unique molecular signatures of RenNETs is crucial to distinguish them from other renal neoplasms and to guide targeted treatment strategies, particularly given the success of somatostatin receptor (SSTR)-targeted therapies in other NETs.

Researchers performed comprehensive molecular profiling on six RenNETs to characterize their genomic and transcriptomic landscape. The study utilized whole-exome DNA sequencing and transcriptomic profiling on all tumor samples. In one specific case, adjacent non-neuroendocrine cystic epithelium and a regional lymph node metastasis were also independently analyzed using the same methods. RNA sequencing was employed to assess gene expression patterns, and immunohistochemistry was used to confirm protein expression, specifically for somatostatin receptor 2A (SSTR2A) and CDX2 markers, across all cases to validate transcriptional findings and investigate potential precursor lesions.

RenNETs exhibited a low-to-intermediate tumor mutational burden and recurrent copy number alterations, including losses on chromosomes 3, 11, and 18, and gains on chromosomes 1, 2, 8, and 14. These alterations partially overlap with those reported in gastroenteropancreatic NETs, but notably, canonical NET-associated driver genes were absent. RNA sequencing revealed a marked upregulation of genes involved in neuroendocrine differentiation, peptide processing, and pancreatic beta cell function, alongside a loss of renal lineage markers, indicating a distinct neuroendocrine transcriptional program. RenNETs showed heterogeneous activation of hormone-related transcriptional programs, not conforming to discrete EC-cell or L-cell signatures. Immunohistochemistry confirmed strong membranous expression of SSTR2A in all cases.

Notably, two RenNETs were associated with adjacent CDX2-positive epithelial-lined cysts demonstrating intestinal differentiation. In one of these cases, 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.