Evolving beyond the "unknown primary": Investigating histopathology after diagnostic transoral robotic surgery for microscopic HPV-associated oropharyngeal carcinoma.

Abstract

6092 Background: Squamous cell carcinoma metastatic to the head and neck arising from an unknown primary tumor (hnSCCUP) is a common presentation for HPV-associated oropharyngeal carcinoma. Previously, with traditional approaches, rates of primary site identification for hnSCCUP were low. Using diagnostic transoral robotic surgery (TORS), primary tumors are now routinely found. In this report, we evaluate the histopathology and oncologic outcomes of these tumors. Methods: A retrospective review was conducted on 100 patients referred to Stanford University for hnSCCUP evaluation between October 2013 and April 2022. A final cohort of 80 patients who remained classified as hnSCCUP after comprehensive multidisciplinary review was analyzed. Surgical excision followed a standardized protocol targeting oropharyngeal subsites, and specimens were meticulously analyzed by three H&N pathologists. Results: The primary site was identified in 66 of 80 patients (83%), with a mean tumor size of 6 mm (range: 2–20 mm). Among the identified tumors, 97% were staged as T1, and 71% measured ≤1 cm, confirming their predominantly microscopic nature. The most common tumor locations were the palatine tonsil (26%), lateral tongue base (24%), glossopharyngeal sulcus (21%), and midline tongue base (18%). Histologically, most tumors exhibited a pushing pattern embedded within lymphoid stroma, while 29% demonstrated a pagetoid growth pattern, spreading in a ribbon-like distribution along the superficial lymphoepithelium. Following diagnostic TORS, 23 patients (29%) underwent further surgery, including 10 with surgery alone and 13 with adjuvant therapy. Radiation alone was administered to 15 patients (19%), while 42 patients (53%) underwent chemoradiation. At a median follow-up of 38 months (range: 12–101 months), 77 patients (97%) were alive with no locoregional tumor recurrence. Two patients (2.5%) developed distant metastases, with one death, and one patient (1.2%) experienced persistent regional disease after chemoradiation. Functional swallowing outcomes declined temporarily across all treatment groups. At six months, patients who underwent surgery alone had the least decline in Functional Oral Intake Scale (FOIS) scores, while those receiving chemoradiation experienced the greatest impact. By one year, all patients showed significant recovery, with no long-term feeding tube dependence. Conclusions: With a systematic surgical technique for p16+ oropharyngeal carcinoma, diagnostic TORS has revealed a unique pattern of small-volume, often microscopic primary tumors often initially mistaken as hnSCCUP. In many cases, it seems the unknown primary represents a T1-microscopic tumor measuring < 1 cm in maximum diameter with a prominent pattern of submucosal spread.