To explore the clinicopathological characteristics of sinonasal high-grade non-intestinal type adenocarcinoma (non-ITAC) and to investigate its diagnosis, differential diagnosis, histological origin, therapy, and prognosis.

Histomorphological, immunohistochemical, and in situ hybridization studies were performed on two rare cases of sinonasal high-grade non-ITAC, and the relevant literature was reviewed.

One male and one female patient, aged 50 and 60 years, respectively, were admitted to the hospital for several months due to repeated nasal bleeding. CT indicated that the right and left nasal cavity were occupied, respectively. Microscopically, the tumor cells showed obvious atypia, apoptosis, and pathological mitosis. These cells were mainly arranged in a trabecula and ribbon structure with necrosis, forming primitive glandular cavity in the focal area and migrating to the surface epithelium. Immunohistochemistry showed that pan-cytokeratins were widely expressed in tumor cells, and CK7 and CK18 were positively expressed to varying degrees, while CDX2, CK20, Mucin2, Villin, chromogranin A, synaptophysin, NSE, P63, CK5/6, androgen receptor, gross cystic disease fluid protein-15, HMB45, MelanA, S-100, thyroid transcription factor-1, NapsinA, and Vimentin had negative expression. Ki-67 proliferation index was 70%-90%. In situ hybridization showed EBER negativity.

Sinonasal high-grade non-ITAC is an extremely rare malignant tumor. In addition to surgery and chemoradiotherapy, it lacks effective treatment and has a poor prognosis, so an accurate diagnosis is required. Due to its high histomorphological heterogeneity and the lack of relevant molecular biology research, a differential and exclusive diagnosis is often required to be performed by immunohistochemistry.