Abstract
Human papillomavirus (HPV)-related head and neck carcinoma (HNC) represents an important subgroup of head and neck cancer that is characterized by a consistent microscopic appearance and a favorable prognosis. A growing experience with HPV testing, however, has uncovered variants that deviate from the prototypic HPV-HNC with respect to morphology. While these HPV-HNCs may deviate morphologically from the prototype, they do not appear to stray far from the favorable clinical outcome assigned to HPV-positive status. In effect, HPV positivity trumps traditional prognostic features predicated on morphology such as tumor grade and histologic subtype when it comes to predicting clinical behavior. For the diagnostic pathologist, the pedestrian task of tumor grading and subtyping would seem to be of little prognostic or therapeutic relevance when it comes to HPV-HNC. Recognition and documentation of neuroendocrine differentiation is a most notable exception. Forms of HPV-HNC have now been reported that morphologically resemble small cell carcinoma (SCC) and large cell neuroendocrine carcinoma (LCNEC) of other sites, and that immunohistochemically exhibit neuroendocrine differentiation. Despite the presence of HPV, these SCCs and LCNECs share the same aggressive clinical behavior of their counterparts in the lung and other sites where the high grade neuroendocrine phenotype is associated with early distant spread and poor overall survival. Consequently, the high grade neuroendocrine phenotype should be regarded as an aggressive form of HPV-HNC where tumor morphology displaces HPV positivity as the most important prognostic feature.