Importance The presence of human papillomavirus (HPV) in unknown primary squamous cell carcinoma (UPSCC) of the head and neck at initial presentation focuses the investigation for the primary tumor on the oropharynx. The trends, frequency, and detection rate of UPSCCs have not been evaluated in the context of HPV tumor status. OBJECTIVES To determine the frequency of UPSCC over time and to evaluate the proportion of HPV-positive UPSCCs. DESIGN, SETTING, AND PARTICIPANTS Retrospective, single-institutional case series of patients diagnosed with UPSCC and evaluated at the Johns Hopkins Hospital from January 1, 2005, to June 1, 2014. Human papillomavirus tumor status was determined by p16 immunohistochemical analysis and/or high-risk HPV DNA by in situ hybridization as clinically available. MAIN OUTCOMES AND MEASURES Number and clinical characteristics of UPSCC cases over time. RESULTS Eighty-four UPSCC cases were eligible for analysis. The mean age of the patients was 57.3 years (range 29-80 years), and 88.1%(n = 74) were male. The frequency of UPSCC increased significantly over time (P for trend =.01) and was significantly higher during later calendar periods (14 cases during 2005-2008 vs 39 cases during 2012-2014, P =.03). A total of 69 cases (90.7%) with available HPV tumor status were HPV-positive. The patients with HPV-positive UPSCC were significantly more likely to be male (91% vs 42.9%, P =.005) and younger (56.1 vs 67.7 years, P =.002) than the HPV-negative patients with UPSCC. The overall primary tumor site detection rate was 59.3%(n = 48). There was a nonsignificant increase in the detection rate from calendar periods 2005-2008 to 2012-2014 (50.0%vs 64.9%, P =.38). Since transoral robotic surgery was adopted in the diagnostic evaluation of UPSCC in 2011, a nonsignificant increase in the detection of primary tumors was observed (53.8% vs 64.3%, P =.34). CONCLUSIONS AND RELEVANCE The frequency of UPSCC has increased significantly in recent calendar periods, and most cases are HPV-positive. As expected, patients with HPV-positive UPSCC tend to be male and younger.
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