Squamous cell carcinoma metastatic to neck from an unknown primary: The potential impact of modern pathologic evaluation on perceived incidence of human papillomavirus-positive oropharyngeal carcinoma prior to 1970

Objectives/Hypothesis: From the 1950s through the 1960s, an unknown number of oropharyngeal squamous cell carcinomas (SCCs) presented with metastases to cervical lymph nodes from an unknown primary (SCCUP) and were not recognized as oropharyngeal in origin. At present, pathologic evaluation of SCCUP for human papillomavirus (HPV) improves discovery of occult oropharyngeal SCC and may partially explain increased incidence of HPV-positive oropharyngeal SCC. Study Design: Retrospective cohort study. Methods: A retrospective study of 13 cases of SCCUP diagnosed from 1956 to 1969 was performed. The probability of these cases of metastatic SCC to originate from the oropharynx was assessed by characterizing their morphology ( keratinizing vs. nonkeratinizing) and HPV status by in situ hybridization and p16 immunostaining. Results: Two cases of nonkeratinizing SCC positive for HPV by in situ hybridization and p16 immunohistochemistry were identified. These cases were most likely of oropharyngeal origin. Conclusions: These two cases can be added to the other 15 cases of HPV- positive primary oropharyngeal SCC identified in our department from 1956 to 1969. When determining the incidence of HPV- positive oropharyngeal SCC before the 1970s, a correction factor of about _13% ( 2/ 15) accounting for modern pathologic workup of SCCUP during the last couple of decades may be appropriate.