Histopathological and Molecular Diagnostic Insights into Head and Neck NUT Carcinoma Prognosis: A Systematic Review

Introduction: Nuclear protein in testis (NUT) carcinoma is a rare but aggressive malignancy. This review of the literature aims to investigate histopathological features and targeted diagnostic testing of NUT carcinoma in the head and neck region, as well as the prognostic impact of IHC markers and tumor-specific fusion genes.

Methods: A review of 3042 articles was conducted, and a total of 70 studies highlighting patients with head and neck NUT carcinoma were included in the analysis. Patient demographics and clinical outcomes, histopathological features, and information regarding IHC staining, next generation sequencing (NGS), and fluorescence in-situ hybridization (FISH) results were collected. Predictors of survival were evaluated with Cox regression and Kaplan- Meier (KM) analyses.

Results: A total of 104 cases of head and neck NUT carcinoma were identified. Of the 90 cases with documented histopathology, the most common feature was abrupt keratinization (47.1%), followed by prominent nucleoli (40.4%), scant cytoplasm (31.7%), zones of necrosis (30.8%), and vesicular chromatin (24%). The rate of misdiagnosis on initial histological examination was 64.8%. NUT-antibody was tested in 79 patients and stained positive in 98.7% of cases, with a falsely negative result in only a single case. Other common IHC positive markers were p63 (50%), p40 (29.3%), Ki-67 (18.3%), and p16 (17.1%), none of which were found to impact survival. FISH was performed in 59.6% of cases, while NGS was performed in 39.4% of cases. When one or more of these tests were conducted, there was an 84% success rate in identifying the tumor-specific mutation. The most commonly identified mutation was BRD4-NUTM1 (48.1%), which was found to be a significantly negative predictor of survival (OR=6.21, p=0.01, KM p=0.004).

Conclusions: The histopathological features highlighted in this study are indicative of a rapidly growing and highly aggressive carcinoma. In such cases, NUT IHC staining should be considered. If staining is positive, identifying the type of mutation with NGS or FISH is clinically relevant and may influence discussion of prognosis.