Origin of cystic squamous cell carcinoma metastases in head and neck lymph nodes: Addition of EBV testing improves diagnostic accuracy.

Most cases of cystic squamous cell carcinoma (SCC) metastases in the upper neck are associated with an oropharyngeal primary, namely human papillomavirus (HPV)-associated SCC arising in the palatine or lingual tonsil. A retrospective study was performed on 22 patients who presented with cystic head and neck SCC metastases. The purpose of the study was to find out whether histological characteristics, p16 protein expression, HPV and Epstein-Barr virus (EBV) status could be useful in predicting the localization of the primary tumor. The primary site was identified in 20 of 22 patients and included the oropharynx in 14 patients (63.6%), the nasopharynx in 3 patients (13.6%), the lungs in 2 cases (9%), and the skin of the auricle in one case (4.5%). No primary was found in two patients (9%). Sixteen of 17 cases (94.1%) originating in Waldayer's ring (oropharynx and nasopharynx), and both cases with an unknown primary showed morphology of non-keratinizing SCC or non-keratinizing SCC with maturation. All tumors with oropharyngeal primary and both cases with unknown primary showed diffuse p16 staining and presence of HPV DNA. All three cystic metastases of nasopharyngeal carcinoma were EBV-positive and p16/HPV-negative. In contrast, cutaneous and pulmonary metastases showed morphology of a well differentiated keratinizing SCC and poorly differentiated keratinizing SCC, respectively, and were HPV/EBV-negative. We confirmed that cystic SCC lymph node metastases of the head and neck region are strongly associated with the occult primary localized in the oropharynx. The oropharyngeal origin should always be corroborated by p16 immunohistochemistry and HPV-specific testing because SCC arising in other sites, such as nasopharynx, skin or lungs may manifest with cystic neck metastases as well. Addition of EBV testing in p16/HPV-negative cases can disclose the nasopharyngeal origin of the cystic neck metastases in a subset of cases.