Evolving Beyond the "Unknown Primary": Transoral Surgery facilitates routine identification of a T1-microscopic p16+ Oropharyngeal SCC

Presentation: AHNS43
Topic: Oropharynx / HPV Related Disease
Type: Oral
Date: Thursday, April 28, 2022
Session: 11:15 AM – 12:00 PM Oropharynx HPV
Authors: F. Christopher Holsinger, Professor Head and Neck Surgery1; Michael C Topf, Assistant Professor OHNS2; Ryan K Orosco, Assistant Professor OHNS3; Andrew C Birkland, Assistant Professor OHNS4; Nikita Bedi, Clinical Research Coordinator1; A. Dimitrios Colevas, Professor Medical Oncology1; Beth M Beadle, Professor Radiation Oncology1
Institution(s): 1Stanford University; 2Vanderbilt University; 3University of California at San Diego; 4University of California at Davis


Squamous cell carcinoma metastatic to the neck arising from an unknown primary tumor (hnSCCUP) is a common presentation for human papillomavirus-mediated oropharyngeal squamous cell carcinoma. Prior to transoral endoscopic H&N surgery (eHNS; either TLM and TORS), rates of identification for hnSCCUP were dismal. Now, with transoral endoscopic surgery, small microscopic T1 p16+ SCC are routinely found. Their manifestation clinically appeared to evade detection with any kind of imaging and traditional endoscopy and may represent a “new” clinical entity: T1-micro-p16+ oropharyngeal carcinoma (OPC).


First, to describe the clinical features and oncologic outcomes of patients with T1-micro-p16+ oropharyngeal carcinoma (OPC).

Design: Retrospective chart review from 2013-2021.

Setting: Academic medical center.

Participants: All patients diagnosed with hnSCCUP who underwent diagnostic TORS to identify the primary site were included. Patients were excluded if they had prior history of head and neck cancer or had obvious lesion detected during operative direct laryngoscopy, PET-CT, or MRI.

Main Outcomes and Measures: Identification rate of the occult primary tumor; clinical and pathologic features of T1-micro-OPC

Results: Seventy-five patients with hnSCCUP met inclusion criteria of which 72 (96%) were had p16+ IHC staining; three patients had equivocal IHC but were found to have HPV DNA on in-situ hybridization. The primary site was identified in 67 (89.3%) diagnostic TORS operations with a mean (SD) primary tumor size of 8 mm. Most patients (60%) had classic presentation confined to a single subsite, but 40% of these patients had multifocal, low-volume submucosal disease tracking across multiple subsite. Two patients had disease spanning the entire disease oropharynx from tonsillar tissue, demonstrating histologically a remarkable disease pattern – heretofore not appreciated. Definitive treatment included surgery alone for 7 patients, surgery with adjuvant therapy in 14 patients, and radiotherapy with or without chemotherapy in 54 patients. At last follow-up, 74 patients were alive with no locoregional tumor recurrence and a single patient who died from distant metastatic disease.

Conclusions and Relevance: Transoral eHNS is a useful intraoperative adjunct to facilitate identification of the primary site in patients with SCCUP. Moreover, surgical staging has revealed a unique pattern of submucosal disease, with an average size of 8mm, that is multifocal in nearly 40% of hnSCCUP. These findings suggest that surgery has mostly eliminated the concept of the unknown primary revealing instead a T1-microscopic p16+ OPC.