So It’s Squamous: What’s Next? Ancillary Testing to Better Classify Head and Neck Tumors with Squamous Differentiation

Squamous differentiation in head and neck tumors is so common that we sometimes don’t think about the diversity of lesions that can show it and how to tease them apart. Accurate molecular subclassification of squamous tumors now directly informs patient diagnosis, prognosis, and treatment. Viral-associated carcinomas remain the largest and most clinically important type. Human papillomavirus (HPV)–associated oropharyngeal squamous cell carcinoma (SCC) and Epstein–Barr virus (EBV)–associated nasopharyngeal carcinoma are defined by distinct oncogenic mechanisms, morphologic features, and clinical behavior, with routine use of p16 and EBER in situ hybridization now standard practice. Testing for viral association also aids in the work-up of metastatic squamous carcinoma of unknown primary. Translocation-associated carcinomas, once considered a non-sequitur, are now recognized as clinically distinct entities in head and neck pathology. DEK::AFF2 fusion nonkeratinizing SCC is typically a papillary sinonasal tumor with deceptively bland morphology while NUT carcinoma represents the opposite extreme, presenting as an aggressive, often midline, poorly differentiated carcinoma, a small subset of which can even be cytokeratin negative. Both can be diagnosed by fluorescence in situ hybridization (FISH) or by fusion specific immunohistochemistry. Finally, hyalinizing clear cell carcinoma (HCCC) is a bland, nested oral cavity and pharyngeal submucosal tumor with squamous immunophenotype and illustrates how EWSR1 fusions blur the boundaries between squamous and salivary neoplasms, with ancillary FISH sometimes needed to confirm the diagnosis. Viral and targeted molecular testing are critical to classification of these tumors. "So it's squamous" is no longer the end of the work up—it is the beginning of a more refined classification.