When patients present with metastatic tumor in a neck node and no primary site can be identified after appropriate investigation, they are considered to have an “occult” or unknown primary cancer. This is an uncommon disease, accounting for about 5% of patients presenting to referral centers. Head and neck cancer of unknown primary site is a highly curable disease (with surprising survival in view of presentation with nodal metastases). After appropriate evaluation and treatment, most patients experience low morbidity and many will be cured. The primary tumor becomes apparent on follow-up only in a few cases. Patients and oncologists are often concerned when the primary cancer cannot be found. This concern may lead to intensive, fruitless, and costly diagnostic maneuvers.

 Most patients older than 40 years who present with a neck mass prove to have metastatic cancer. The source of the lymphadenopathy is almost always discovered in the course of a complete H&N examination, which should be performed on all patients with neck masses before other studies are initiated. Antecedent history of malignancy, as well as prior excision, destruction, or regression of cutaneous lesions, should be considered during office evaluation.

When patients present with a neck mass, fine-needle aspiration (FNA) should be the first study undertaken. Needle aspiration generally guides management and treatment planning.Open biopsy should be avoided because it may alter or interfere with subsequent treatment. When a needle biopsy demonstrates squamous cell carcinoma, adenocarcinoma, or anaplastic epithelial cancer and no primary site has been found, additional studies are needed. Nasopharyngolaryngoscopy, chest x-ray, and either CT scan with contrast or MRI with gadolinium should be performed. A PET scan is optional. Other imaging studies have very low yield and should not be undertaken. If the FNA proves nondiagnostic, then open biopsy may be needed. Open biopsy should not be performed unless the patient is prepared for definitive surgical management of the malignancy documented in the operating room. This may entail a formal neck dissection. Therefore, an open biopsy of an undiagnosed neck mass should not be undertaken lightly, and patients should be thoroughly apprised of the potential sequelae. When the imaging studies and thorough office examination (including examination of the nasopharynx, oropharynx, larynx, and hypopharynx) do not revel a primary tumor, then an examination under anesthesia should be performed. Mucosal sites should be inspected and examined. Appropriate endoscopies with directed biopsies of likely primary sites are recommended, but they seldom disclose a primary cancer. Many primary cancers are identified after tonsillectomy. However, the clinical significance of such tumors is uncertain. When patients have been treated without tonsillectomy, only a few develop a clinically significant primary tumor.

Comprehensive neck dissection (including level I through level V) is recommended for all patients with squamous cell carcinoma and adenocarcinoma. If the metastatic adenocarcinoma presents high in the neck, parotidectomy may be included with the neck dissection. There are irreducible differences of opinion amongst NCCN member institutions regarding the management of patients with poorly differentiated or nonkeratinizing squamous cell, anaplastic cancer of unknown primary site, or other uncommon histologies. Some believe such patients should be managed with neck dissection, whereas others believe primary RT (category 3) or even chemoradiation (category 3) should be used. If an N1 node was excised in an open biopsy, if there was extracapsular tumor spread, or if the patient presented with N2 or N3 disease, then all NCCN institutions use elective radiation to the neck although some would radiate the neck only (category 3), whereas most institutions would also radiate the likely occult primary sites based on the level of nodes involved . Additional treatment of possible mucosal primary sites is controversial and the source of considerable disagreement. There is little evidence to support a survival benefit from radiation to possible primary sites, and the morbidity of extensive mucosal radiation is not to be ignored.