# Clinicopathological spectrum of non-sinonasal intestinal-type adenocarcinomas of the head and neck: Systematic review of case reports, case series, and cross-sectional studies

## TL;DR

This study reviews rare non-sinonasal intestinal-type adenocarcinomas in the head and neck, highlighting their aggressive nature and distinct features compared to similar cancers in the sinonasal region.

## Contribution

The study systematically characterizes the clinicopathological and molecular profile of non-sinonasal ITACs, revealing distinct features compared to sinonasal ITACs.

## Key findings

- Non-sinonasal ITACs commonly occur in the oral cavity, especially the mobile tongue, and are more prevalent in males.
- These tumors show distinct immunohistochemical and molecular profiles, including mutations in MLL3, TP53, and upregulation of EMT-related genes.
- They are aggressive, with high rates of metastasis and disease-specific mortality, necessitating improved diagnostic and treatment approaches.

## Abstract

Intestinal-type adenocarcinomas (ITACs) most often arise in the sinonasal tract, typically associated with occupational exposures, but they rarely occur in other head and neck sites. When present in extra-sinonasal regions, their clinicopathological and molecular characteristics remain poorly understood. This systematic review aimed to clarify the clinicopathological, immunohistochemical, and molecular features of non-sinonasal intestinal-type adenocarcinomas (ITACs) of the head and neck.

This review was conducted according to PRISMA 2020 guidelines and registered in PROSPERO (CRD42022309841). Two reviewers independently screened, extracted data, and assessed risk of bias using the Joanna Briggs Institute tools. Sources included PubMed/MEDLINE, Scopus, Embase, Web of Science, Google Scholar, and OpenGrey. A comprehensive search identified 1,376 records. After applying eligibility criteria, 26 studies comprising 37 cases were included. Data on clinical, histological, immunophenotypic, molecular, and prognostic features were analyzed.

Most patients were male (73%), with a mean age of 57.9 years. The oral cavity, particularly the mobile tongue (51.4%), was the most commonly affected site. Histologically, colonic (59.5%) and mucinous (56.8%) architectures were the most frequent microscopic patterns presented. Immunohistochemistry frequently showed positivity for CK7, CK20, and CDX2, while SATB2, MUC1, and MUC5AC had variable expression. Mismatch repair proteins were intact in all cases. Molecular findings included mutations in MLL3, TP53, EGFR, and AKT1, and upregulation of PAX1, MUC5B, and EMT-related genes, suggesting a distinct profile from sinonasal ITACs. Surgical resection, often with adjuvant therapy, was the main treatment. Tumors were aggressive, with metastases being present in 35.1% and disease-specific mortality in 24.3%.

Non-sinonasal ITACs are rare, aggressive malignancies requiring accurate diagnosis and further molecular investigation to improve management and outcomes.