Undifferentiated and dedifferentiated head and neck carcinomas

Undifferentiated carcinomas arising at salivary gland and head and neck mucosal sites may originate either de novo or through a process of dedifferentiation of a differentiated carcinoma. While in the latter group the diagnosis is largely dependent on the identification of the differentiated component or recognition of a specific genotype, the classification of undifferentiated carcinomas that lack a differentiated component is mainly based on the identification of specific genetic drivers, like for example the NUTM1 fusions in NUT carcinoma. A further category is represented by virus associated carcinomas (mainly HPV and EBV), that frequently displays an undifferentiated morphology. Overall, these tumors often represent a diagnostic challenge, especially in small biopsies. This review summarizes and discuss the diagnostic approach to the main head and neck carcinoma types that frequently or occasionally display an undifferentiated appearance, with a focus on salivary gland, oropharyngeal, nasopharyngeal and sinonasal subsites.