Low-Grade Nasopharyngeal Papillary Adenocarcinoma: Toward a Better Molecular, Epigenetic, and Clinicopathological Understanding With Ontological Perspective.

This study reports 6 cases of low-grade nasopharyngeal papillary adenocarcinoma (LGNPPA) reviewed by the REFCOR network, integrating clinicopathological, genetic, and epigenetic analyses to refine our understanding of its histogenesis and biological behavior. Our 6 cases were located in the nasopharynx. Histologically, 5 cases had a frank papillary architecture, whereas 1 case showed a mixed papillary and tubular architecture. Papillary and tubular structures were covered by a single layer of epithelium of nonciliated cuboidal or columnar neoplastic cells. Squamous differentiation foci were present in 2 cases. Neither desmoplastic stroma, vascular invasion, nor perineural invasion was seen. All cases expressed TTF1. Neither local recurrence nor metastasis occurred in any of our cases, nor in the literature when only TTF1-positive cases are considered. At the molecular level, in the 3 cases that underwent CGH array and RNA sequencing, we did not find significant molecular anomalies. Our 3 LGNPPAs with DNA methylation analysis were closely grouped on the UMAP with posterior pituitary tumors. Furthermore, comparison of LGNPPA and low-grade non-ITAC sinonasal adenocarcinoma transcriptomes highlighted CNS-related genes as significantly upregulated in LGNPPAs. In conclusion, our transcriptomic and epigenetic data suggest a putative link to a shared progenitor with pituicyte-derived tumors. Our clinicopathological findings are consistent with the literature, highlighting a very indolent behavior.