Sinonasal low-grade non-intestinal type adenocarcinomas with clear cell features: Clinicopathological and molecular analysis of 6 cases highlighting molecular heterogeneity and identification of a novel ETV6::YEATS4 fusion

Document Type

Article

Department

Pathology and Laboratory Medicine

Abstract

Non-intestinal type sinonasal adenocarcinomas (non-ITACs) are rare entities with a wide range of histologic appearances. In this study we characterize the clinico-pathologic, immunohistochemical and molecular features of six cases of sinonasal adenocarcinoma with clear cell morphology, identified retrospectively in our files and occurring in 2 females and 4 males, with mean age of 62.6 years. Immunohistochemical and molecular studies including RNA sequencing, were performed. All cases showed a proliferation of epithelioid clear cells with slight to moderate atypia, arranged in variable patterns. Two cases had the typical histologic appearance and immunohistochemical profile of sinonasal renal cell-like adenocarcinoma, being formed of follicular structures and solid nests containing eosinophilic colloid-like material, with diffuse positivity for SOX10, carbonic anhydrase IX (CAIX), S100, and cytokeratin 7. One further case had a similar histologic appearance but lacked positivity for CAIX and S100. A previously unreported ETV6::YEATS4 rearrangement was detected by RNA sequencing in this case. Two adenocarcinomas showed mixed tubulo-papillary and acinar architecture with clear cell foci, including areas reminiscent of renal cell-like adenocarcinoma. Finally, one case had a tubulo-cystic appearance with clear cells and a surface component presenting ciliated, papillary and squamoid areas. This adenocarcinoma presented a MAP2K1 p.Gln56Pro; c.167 A > C mutation. Immunohistochemically, all cases were strongly positive for pancytokeratin and cytokeratin 7, SOX10 was positive in all cases tested (5/5), whereas S100 was positive in 4/6 cases and DOG1 in 1/3 cases. Notably, basal/myoepithelial markers and renal cell carcinoma markers, including CD10, PAX8 and RCC, were negative in all cases. Sinonasal adenocarcinomas with clear cell features are a heterogenous group of neoplasms in the spectrum of low-grade non-ITAC that must be differentiated from primary salivary-type sinonasal adenocarcinomas and from metastatic carcinomas. The differential diagnosis requires the support of an immunohistochemical panel, as well as molecular testing in selected cases.

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Publication (Name of Journal)

Virchows Archiv

DOI

10.1007/s00428-026-04579-y

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