Squamous Cell Carcinoma of the Head and Neck with Unknown Primary: Trends and Outcomes from a Hospital-based Registry

Background: Squamous cell carcinoma of unknown primary of the head and neck region is a known entity described mainly by retrospective reports. We searched a hospital-based registry to better describe the changing incidence, and to assess diagnostic and treatment strategies.

Methods: The National Comprehensive Cancer Database was queried for head and neck cancers from oropharynx, tonsil, tongue, larynx, hypopharynx primary sites with a designation of clinical T0, representing an unknown primary. Kaplan Meier, Cox multivariate models, and propensity matched cohorts were used to assess significant factors for overall survival.

Results: There were 964 cases that met the criteria, and 468 cases with known treatments, staging, and survival data. The incidence increased over time, with the highest rates supported in the last 5 years. In patients who underwent HPV testing, 72% were positive. Patients with AJCC 7 clinical N2c or N3 disease had significantly worse outcomes despite the majority receiving neck dissection, radiation, and chemotherapy. Local surgery, compared to incisional or excisional biopsy, had the highest diagnostic yield of finding a primary tumor. In multivariate models, no combination of surgical approach, radiation, or systemic therapy was significantly associated with improved survival. This remained true in 1:1 propensity matched cohorts for age, comorbidities, and clinical nodal burden. In a subset of cN1 patients, combined chemoradiation therapy after excisional biopsy or local surgery was associated with (not statistically significant) improved survival compared to radiation alone (P=0.054).

Conclusions: The incidence of unknown primary head and neck carcinoma is increasing, and current cases have a high proportion of HPV positivity. HPV positivity predicts strongly for a tonsil primary. Local surgery was associated with the highest diagnostic yield. Clinical nodal burden strongly predicts for overall outcome, and type of treatment facility is an important driver of survival. A subset of cN1 patients may benefit from the addition of chemotherapy to radiation.