Cancer in the head and neck region commonly manifests in an otherwise asymptomatic patient as metastatic disease to the cervical lymph nodes. In most cases, a complete history and physical examination are sufficient to ascertain the primary site of origin of the metastatic disease. The primary lesion is found to be in the head and neck region at least 70% of the time.1, 2 Occasionally, however, the primary lesion responsible for the cervical metastasis is found to have originated at a site remote from the head and neck, and therefore, metastatic neck disease often represents a distant metastasis from this primary site.

Among those patients with head and neck cancer presenting with cervical lymph node metastases, a primary lesion may sometimes fail to be identified despite a thorough diagnostic evaluation. This is reported to occur in approximately 5% of all patients presenting with cervical lymph node metastases, and the term occult primary or unknown primary has been commonly used to describe this clinical situation.¹ The diagnosis of metastatic cancer to the neck from an occult primary requires histologic or cytologic evidence of malignancy in a cervical lymph node as well as the failure to identify the primary site of origin after a systematic, comprehensive search. Thyroid cancers and lymphomas are excluded from this definition. Traditionally, this search has implied a complete history, a thorough physical examination of the upper aerodigestive tract, and multiple endoscopic examinations (direct laryngoscopy, esophagoscopy, bronchoscopy, nasopharyngoscopy) under anesthesia, usually with random or directed biopsies.

There are several controversial issues regarding both the assessment and the treatment of patients with cervical metastases from an unknown primary site. In the realm of assessment, controversy arises over which of the diagnostic studies should be routinely done in order to find the primary site. Imaging studies such as computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), and 2-[fluorine-18]-2-deoxy- D -glucose single photon emission computed tomography (FDG-SPECT) for surveillance of potential primary sites are central to any assessment controversy.³ In addition, the role of serologic Epstein-Barr viral (EBV) tests or EBV genomic DNA assays in patients with cervical lymph node metastases from an occult primary is also uncertain.⁴ Furthermore, the routine use of random aerodigestive tract biopsies and routine ipsilateral tonsillectomy in the diagnostic workup has been recommended by some and rejected by others.^{3, 5}

New technology that has been found to be useful in the assessment of head and neck cancer patients has not always generated controversy. Rigid and flexible endoscopes, generally regarded as indispensable for conducting a thorough examination of the pharynx and larynx today, have been an obvious improvement over the traditional indirect examination methods, particularly for the nasopharynx.

As with most head and neck cancer patients in general, both radiotherapy and surgery have important roles for patients having metastatic cervical disease with an occult primary. Some disagreement exists about whether single-modality treatment, particularly surgery, should be used for earlier-stage disease. The routine practice of irradiating potential primary mucosal sites has also been challenged. Finally, a role for chemotherapy in this group of patients has been suggested.

Discussion

HISTOPATHOLOGIC DIAGNOSIS

The histopathologic type of metastatic cervical lymphadenopathy for which a primary cannot be identified is squamous cell carcinoma in about 80% of the cases.² The remainder are adenocarcinomas, melanomas, undifferentiated carcinomas, and small cell carcinomas.⁶ The diagnosis can usually be reliably established in most cases with a fine-needle aspiration biopsy (FNAB), particularly with metastatic squamous cell carcinoma. Certain instances in which the aspiration biopsy is indeterminate or suggestive of lymphoma require an open cervical lymph node biopsy.

The histopathology of the metastasis provides information that can aid in the search for a primary site and that is used for appropriate management decisions. Adenocarcinoma in low cervical lymph nodes only is strongly suggestive of an infra-clavicular primary lesion. In such cases, further exhaustive evaluation of the upper aerodigestive tract is not warranted. The diagnostic evaluation would shift to focus on the organs being the most likely sources of the metastasis. The potential primary sites in decreasing order of frequency for an infraclavicular adenocarcinoma are lung, gastrointestinal tract, breast, pancreas, prostate, and ovary. Adenocarcinoma from an infraclavicular site manifesting as cervical adenopathy represents distant metastatic disease and, as might be expected, has a very poor prognosis.⁷ By contrast, metastatic adenocarcinomas presenting in the upper neck often arise from salivary tissue in the major or minor salivary glands. Metastatic differentiated or medullary thyroid carcinoma must be considered for adenocarcinoma metastatic to cervical lymph nodes in any location. Immunohistochemical stains specific for these malignancies are useful in establishing a diagnosis. Obviously, histopathologic findings consistent with melanoma require a systematic evaluation of all cutaneous sites, as well as a thorough aerodigestive tract examination to rule out a rare mucosal primary. Finally, small cell or undifferentiated carcinoma may elude detection if evaluation of the salivary glands and paranasal sinuses is omitted from the routine evaluation of the aerodigestive tract and the potential infraclavicular sites.

Cancer manifesting as cervical lymphadenopathy will be discovered in the upper aerodigestive tract in about 70% of cases.1 Obviously, the evaluation for the primary should initially focus on this region until other diagnostic information suggests the primary is elsewhere. Specific historic information should be gathered for every patient who has an undiagnosed neck mass suspected to be malignant. Features such as absence of tenderness and progressive enlargement, particularly in a patient with a history of tobacco use or excessive alcohol use, are associated with a higher probability of malignancy. Further questioning about hoarseness, dysphagia, odynophagia, epistaxis, or nasal obstruction may help identify a head and neck primary site. A history of prior malignancy, including skin cancer of the head and neck or removal of pigmented lesions, should be noted. A history of prior head and neck radiation exposure should be elicited. A system review should investigate any gastrointestinal, pulmonary, or constitutional symptoms that may allude to the primary site.

The evaluation continues with a physical examination that focuses on the head and neck region. This examination should always include palpation of the oral cavity and oropharynx as well as direct endoscopic examination of the nasopharynx, larynx, and hypopharynx. Any area found to be unusual or abnormal should be biopsied.

The location in the neck of a mass confirmed to be a metastatic cervical node can guide the evaluation, as certain nodal groups will primarily drain specific areas in the head and neck. Obviously, this information is only useful when the cervical disease is very localized or solitary. Adenopathy in the submental region often corresponds to a primary lesion of the nose, the lips, or the anterior nasal cavity. Submandibular adenopathy is usually secondary to a primary site in the oral cavity, whereas intraparotid nodal enlargement is common for lip, nasal vestibule, face, and scalp cancers.⁸ Upper and middle posterior cervical metastases usually originate from nasopharyngeal carcinomas. A supraclavicular metastasis will usually arise from an infraclavicular primary site, although thyroid cancer or cervical esophageal cancer is sometimes manifested in this manner.

Various diagnostic imaging studies are available, any one of which may, in some instances, provide useful information about the extent of the cancer. In every case, the chest radiograph should be obtained to assess for either primary or metastatic disease of the lungs. In some cases, patients having advanced neck disease should have a CT scan or an MRI to help gauge the extent of the metastatic neck disease in order to provide the most effective treatment. Also, these studies may be used to evaluate for distant metastases in cases of advanced cervical disease.

The routine use of CT or MRI for the purpose of attempting to identify a primary site responsible for the cervical metastasis, however, is controversial.⁹ Some consider the routine use of either of these studies as unnecessary; others regard them as indispensable. Many of those who favor these imaging studies on a routine basis consider MRI or CT as potentially able to identify an occult primary site, as well as to identify suspicious areas needing careful endoscopic examination and biopsy. A recent retrospective study attempted to ascertain the role of these studies in the context of the evaluation of the occult primary tumor with cervical metastases.³ These investigators found that either CT or MRI correctly identified the primary site in 50% of patients who had no abnormal findings on physical examination. Whether one or the other of these two studies is better able to identify a primary lesion was not addressed in this study and has not yet been determined. However, for cases in which nasopharyngeal carcinoma is suspected to be the primary site, it has been suggested that because early lesions can be seen more readily on MRI, it is the preferred imaging study for this site.¹⁰

When MRI or CT is used to assist with the identification of an occult primary site, the images should evaluate the paranasal sinuses and salivary gland regions for abnormalities that are indicative of a source of the metastasis. This is particularly important for adenocarcinoma that has metastasized to upper cervical lymph nodes.

Recently, the FDG-SPECT or PET scan has been found a useful diagnostic imaging study for differentiating malignancy from normal tissue. This property has led to studies investigating its role in detecting the primary site producing metastatic cancer to the cervical lymph nodes. One study using FDGSPECT as a diagnostic tool to identify a primary site in patients with metastatic squamous cell carcinoma to the cervical lymph nodes from an unknown primary demonstrated a positive scan in 20 of 24 patients. Of the 20 patients with the positive scans, only 7 had a primary cancer site found, and only 1 of those 7 were otherwise without findings suggestive of the primary.³ In four patients with a negative scan, two were found to have tumor. It was concluded that the value of this study for the purpose of discovering an occult primary lesion is very modest. At this time, the routine use of this study in patients with cervical metastases from an occult primary cannot be justified, and its role remains undefined.

A close association of the EBV and nasopharyngeal carcinoma has resulted in the widespread use of EBV antibody titers as post-treatment markers for cancer at this site.¹¹

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