Identification and Surveillance of Unusual Primary Site Using Human Papillomavirus‐Specific Cell‐Free Tumor DNA

The increasing incidence of head and neck squamous cell carcinoma (HNSCC) is associated with the rising prevalence of human papillomavirus (HPV)-associated disease.1 HPV-associated HNSCC represents a distinct clinical entity with a favorable prognosis compared to non-HPV-associated HNSCC.1 Current clinical guidelines recommend imaging within 6 months after treatment and office-based physical exams from that point at specified intervals. However, surveillance in this population can be demanding as providers balance clinical guidelines and patient anxieties. An intermediate surveillance mechanism is desired. There has been increasing clinical utility with circulating cell-free tumor DNA (ctDNA) as a diagnostic and surveillance tool for HPV-associated HNSCC.2 A commercially available blood test known as tumor tissue-modified viral (TTMV)-HPV DNA (NavDx; Naveris Inc) testing has shown promise in this regard.2 In this report, we highlight the diagnostic utility of NavDx in an unusual case of a patient with HPV-associated HNSCC of unknown origin with the emergence of a unique primary site. Such advancements present a promising avenue for early detection of HPV-associated HNSCC, revolutionizing the way this disease is managed.3 A 74-year-old female never-smoker presented with 3-week history of a nontender left neck mass. Review of systems was otherwise negative. Physical exam and nasal endoscopy did not reveal any abnormalities. Computed tomography (CT) soft tissue neck showed a solitary cystic left level IIA node; the upper aerodigestive tract was otherwise normal. She was referred to otolaryngology for fine needle aspiration (FNA) which showed squamous cell carcinoma (SCC). Primary tumor site remained unknown following pretreatment whole body positron emission tomography (PET)-CT scan. After review in multidisciplinary head and neck tumor board, she underwent left selective neck dissection (levels II-IV) as well as left palatine and lingual tonsillar resection. Pathology revealed a p16-positive 1.4 cm left level I node without extracapsular extension; confirmatory HPV in-situ hybridization was positive. An additional 33 nodes, as well as the palatine and lingual tonsil specimens, were negative for carcinoma. Patient then underwent surveillance with NavDx. NavDx score was 5 (positive) 5-months postoperatively and 3 (indeterminant) 8-months postoperatively. Then, at 15-months postoperatively, the NavDx score increased to 61, and at 16-months postoperatively, it increased to 571. (Figure 1). This prompted further evaluation to determine primary site. Repeat CT soft tissue neck showed subtle soft tissue thickening along the anterior superior left nasal cavity with cortical thinning, erosion of nasal bone, and mucosal thickening toward the cribriform plate (Figure 2). On nasal endoscopy, the left inferior turbinate was found to be hyperplastic without overt evidence of surface mass. Biopsy revealed HPV-associated SCC, confirming primary site emergence in the left nasal cavity. Patient subsequently underwent endoscopic resection. The tumor was more extensive than suggested by imaging and involved the left septal mucosa extending to the cribriform plate, nasal floor, lateral nasal wall, and the anterior ethmoid cavity. Surgical removal involved a total septectomy, left nasal degloving, left medial maxillectomy via Denker's approach, bilateral endoscopic sinus surgery, modified Lothrop frontal drill out, and repair of cribriform defect using nasal septal flap. She recovered well and underwent 6-weeks of adjuvant radiation therapy with decline of NavDx to 20. Approximately 2-months following radiation, she had enlargement of a left level IB node (9-12 mm), level V, and multiple right-sided neck nodes. Repeat NavDx decreased to 11, however, this remained a positive score. Posttreatment PET scan revealed hypermetabolic left levels IB, V, and right levels I to IV nodes concerning for metastasis. FNA of the left IB node showed atypical squamous cells suspicious for malignancy. Patient underwent bilateral neck dissection with 1 positive node out of the 59 nodes removed in left level IB. This report describes the novel application of TTMV-HPV DNA monitoring with circulating ctDNA in the context of HPV-related sinonasal SCC. The oropharynx is the primary site of interest for the majority of HPV-related unknown primaries of the head and neck,4 however nonoropharyngeal HNSCC may be HPV-associated as well. This is the first documented case using ctDNA for the management of nonoropharyngeal primary site in the head and neck, including a previous report which used TTMV-HPV DNA to monitor anal SCC.5 There is growing interest in utilizing ctDNA for surveillance of HPV-related HNSCC, with potential application pending further research. Therefore, future studies should establish the efficacy of ctDNA in non-oropharyngeal SCC because early detection and intervention translates to lower resource utilization and more favorable patient outcomes. Russell A. Whitehead, drafted, edited, approved the final manuscript and takes full responsibility for its content; Peter Papagiannopoulos, drafted, edited, approved the final manuscript and takes full responsibility for its content; Nikhil Joshi, drafted, edited, approved the final manuscript and takes full responsibility for its content; Mihir K. Bhayani, drafted, edited, approved the final manuscript and takes full responsibility for its content. None. 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