Histologic Identification of Human Papillomavirus (HPV)-Related Squamous Cell Carcinoma in Cervical Lymph Nodes: A Reliable Predictor of the Site of an Occult Head and Neck Primary Carcinoma

Abstract

Patients with head and neck squamous cell carcinoma (SCC) often present with cervical lymph node metastasis. Occasionally the primary tumor site remains unknown even after thorough investigation. Management of such cases is problematic and may result in over-treatment and consequent increased morbidity. High risk HPV has been advocated recently as an important etiologic factor for a subset of head and neck SCC. These are believed to have a special predilection for the oropharyngeal tonsils and are characterized by nonkeratinizing basaloid morphology, and a strong reactivity to p16 immunostain. Identifying HPV-related SCC in the lymph nodes may thus provide a means for localizing the primary tumor site. Ninety-three cases of SCC metastatic to the neck from known primary tumors were classified morphologically into conventional keratinizing SCC (KSCC) and non-keratinizing SCC (NKCa). In situ hybridization (ISH) for high risk HPV as well as immunostaining for p16 were performed on all metastsatic and primary tumors. Of the 93 cases of metastatic carcinomas 32 were oropharyngeal, 35 oral, and 26 arose in the laryx/hypopharynx. Twenty-three cases were found to be HPV+ by ISH, of which 22/23 had oropharyngeal origin (P < 0.0001), with 95.7% sensitivity and 85.7% specificity. Twenty-one of these HPV+ oropharyngeal tumors were NKCa (P < 0.0001). The remaining case showed overlapping NKCa/KSCC hybrid morphology. All NKCa were HPV+ and stained diffusely and strongly with p16 antibodies. We have demonstrated that HPV status of the lymph node metastasis can be assessed not only by ISH and p16 immunoreactivity but also histomorphologically. In addition, a positive microscopic identification of HPV-related carcinoma is a reliable predictor of oropharyngeal origin.