Unknown primary head and neck squamous cell carcinoma: Molecular identification of the site of origin

Unknown primary head and neck squamous cell carcinoma (HNSCC) presents as a cervical lymph node metastasis without identification of the primary tumor , despite thorough diagnostic work-up that includes physical examination, c omputed tomography, esophagoscopy, laryngoscopy, bronchoscopy, and multiple surveillance biopsies. We investigated whether the site of origin of the p rimary tumor could be localized in the upper aerodigestive tract mucosa by detection of genetic alterations identical to those found in metastatic les ions. Methods: Microsatellite analysis was performed on metastatic tumors o btained from 18 patients with unknown primary HNSCC. Histologically benign surveillance biopsy specimens were also analyzed, Patients were followed up to 13 years with continuing surveillance for primary mucosal tumors, Most patients were treated with neck dissection followed by radiation therapy to the affected neck and ipsilateral Waldeyer's ring. Results: In 10 (55%) of the 18 patients, at least one histopathologically benign mucosal biopsy sp ecimen from defined anatomic sites (i.e., most likely sites for an occult p rimary tumor) demonstrated a pattern of genetic alterations identical to th at present in cervical lymph node metastases. One patient harboring genetic alterations in the base of the tongue and two patients harboring genetic a lterations in a tonsillar fossa subsequently developed HNSCC in the identic al or adjacent mucosal region; all three of the primary head and neck mucos al tumors that eventually appeared between 1 and 13 years later in these pa tients had genetic changes identical to those in the benign mucosal biopsy specimens and in the metastatic lymph nodes. Conclusions: These data suppor t the hypothesis that histopathologically benign mucosa of the upper aerodi gestive tract may harbor foci of clonal, preneoplastic cells that are genet ically related to metastatic HNSCC and that such mucosal sites are the site s of origin of unknown primary HNSCC, Microsatellite analysis may represent a clinically useful tool for determining such sites.