HPV‐associated neuroendocrine carcinomas of the head and neck in FNA biopsies: Clinicopathologic features of a rare entity

Background The majority of human papillomavirus (HPV)–associated oropharyngeal carcinomas are squamous cell carcinomas; however, there are rare reports of HPV–associated neuroendocrine carcinomas (HPV‐NECs) in the upper aerodigestive tract. The aim of this study was to characterize the diagnostic features of fine‐needle aspiration (FNA) cases of head and neck HPV‐NEC. Methods Cytology cases of HPV‐NEC were identified over a 3‐year period from 2 institutions. Clinical, cytomorphologic, and ancillary test results were evaluated. Results Five FNA cases of HPV‐NEC were identified from 4 patients with cervical lymph node metastases with primaries in the oropharynx (n = 2), nasopharynx (n = 1), and larynx (n = 1). Three cases showed mixed small cell and large cell neuroendocrine morphologies; 1 case was a small cell carcinoma, and the last case appeared as a large cell neuroendocrine carcinoma. All tumors were strongly positive for synaptophysin and p16 and negative for p63/p40. Two cases tested for INSM1 showed diffuse nuclear staining. HPV was confirmed by in situ hybridization in 4 cases, and HPV‐18 was detected by polymerase chain reaction in the fifth case. Retinoblastoma (Rb) staining was moderate to weak (5/5), and p53 was weakly positive (5/5). Conclusions Head and neck HPV‐NEC is a rare, aggressive entity that can show mixed small and large cell features and p16 upregulation; p53 and Rb are variable with limited diagnostic utility. Because p16 positivity can be nonspecific, confirmatory HPV testing is required and may be helpful in determining the primary site for neuroendocrine carcinoma of an unknown primary. The accurate diagnosis of HPV‐NEC is also important because of its worse prognosis in comparison with HPV‐associated squamous cell carcinoma. HPV‐associated neuroendocrine carcinoma is an aggressive neoplasm that frequently shows mixed features of small cell carcinoma and large cell neuroendocrine carcinoma, and may pose diagnostic challenges in cytologic samples. Tumors show p16 overexpression, which may be nonspecific in the differential diagnosis; thus, confirmatory testing for high‐risk human papillomavirus is helpful, HPV especially for tumors presenting as cervical lymph node metastases with an unknown primary.