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Postoperative radiotherapy (PORT) is routinely recommended for patients with head and neck squamous cell carcinoma (HNSCC) based on pathologic risk factors (pRFs) such as perineural invasion (PNI). Patients with PNI as the sole pRF after resection of HNSCC are uncommon and their prognosis is less clear. The aim of this study is to assess the role of PNI as a sole risk factor in patients with otherwise pathologically low-risk HNSCC.  Methods  Patients with HNSCC of the oral cavity, pharynx, or larynx treated with primary surgical resection from 2013 to 2018 were identified from an institutional cancer registry. Those with pRFs (pathologic T3-4 disease, lymphovascular space invasion [LVSI], multiple positive lymph nodes, close [within 2 mm] or positive margins, extranodal extension [ENE], or recurrent disease) were excluded, yielding an otherwise pathologically low-risk cohort with or without incidental, pathologic PNI. Locoregional control (LRC), overall survival (OS) and disease-specific survival (DSS) were estimated and compared between PNI groups and by adjuvant therapy.  Results  A total of 1,058 patients were identified as having undergone surgical resection. Exclusion of patients with other pRFs, those with unknown PNI, and oral cavity patients with depth of invasion > 10 mm yielded a study cohort of 85 patients. Eight patients (10% of study group, <1% of all patients) had PNI as the sole pRF, none of which had clinical signs or symptoms of perineural tumor spread. The remaining 77 were negative for PNI and thus pathologically low risk. Patients with PNI were more likely to have oral cavity cancer, to be younger, and to have received PORT than those without PNI; no patient received concurrent chemotherapy. At a median follow-up of 46.4 months, two- and five-year LRC rates were 81.4% and 78.5%, respectively. No differences were noted between PNI-positive and PNI-negative groups (p=0.73) or PORT v. no-PORT groups (p=0.39). While the utility of PORT is not possible to assess given limited sample size, four patients with PNI who did not receive PORT did not experience locoregional failure. Seventeen patients overall experienced locoregional failure and 14 were ultimately salvaged. Five-year OS and DSS were 77.4% and 90.8%, respectively.  Conclusion  Patients with pathologically low-risk HNSCC after surgical resection experience high rates of LRC. In this large institutional cohort, PNI as the sole pRF was exceedingly rare, and the benefit of adjuvant therapies is difficult to assess. Within this limitation, PORT remains the standard of care for patients with PNI to reduce the risk of locoregional failure. Further collaborative studies are required to adequately assess the prognostic impact of PNI alone in resected HNSCC.

Perineural Invasion As the Sole Pathologic Risk Factor After Surgical Resection for Head and Neck Squamous Cell Carcinoma