Nasal Tuft Cell Markers Are Predictive of Overall Survival in Sinonasal Neuroendocrine and Sinonasal Undifferentiated Carcinomas

ABSTRACT Background Sinonasal neuroendocrine carcinoma (SNEC) and sinonasal undifferentiated carcinoma (SNUC) are rare aggressive malignancies with no established prognostic markers. Because features of POU2F3+ small cell lung carcinomas have been identified in both tumors, we evaluated immunostaining for POU2F3, a tuft cell transcription factor, and KIT, a tuft‐progenitor marker, to determine whether SNECs/SNUCs exhibit a tuft cell lineage. Methods We retrospectively studied patients with rare sinonasal malignancies treated between 2010 and 2025 at the University of Pennsylvania. Archived specimens underwent immunohistochemistry for KIT, POU2F3, SOX9, TRPM5, ASCL1, and IDH2 R172 mutations. Clinical, radiological, and treatment data were collected. Associations with overall survival (OS) and disease‐free survival (DFS) were evaluated using Kaplan–Meier and Cox regression analyses. Results KIT was expressed in 90.2% of SNECs ( N = 11) and 54.6% of SNUCs ( N = 11), with the KIT + POU2F3 + phenotype in 72.7% and 18.2%, respectively. KIT/POU2F3 expression correlated with SOX9 and TRPM5, and KIT/POU2F3 phenotypes correlated with IDH2 R172 mutation status ( p = 0.015). KIT + POU2F3 + tumors had significantly improved OS ( p = 0.004) and DFS ( p = 0.001). Univariable analysis showed that lack of double positive KIT/POU2F3 phenotype predicted decreased OS (HR: 12.24; 95% CI: 2.29–226.78; p = 0.001) and DFS ( p < 0.001). In multivariable analyses, this association persisted for OS in models including histologic subtype or IDH2 mutation status. Conclusions Results indicate that a subgroup of SNECs and SNUCs expresses a tuft cell‐associated marker profile. KIT + POU2F3 + SNECS and SNUCs have markedly improved OS and DFS suggesting these markers have diagnostic, prognostic and potentially therapeutic utility.