Metastatic disease in cervical lymph nodes may be the initial manifestation of cancer. Most of these patients will have an apparent primary at presentation. However despite the most exhaustive search, approximately 5 to 10% of these tumors remain undetected at the primary site.1–3

Each year, an estimated 40,000 patients with a new unknown primary tumor present in the United States.⁴ Most (>85%) are adenocarcinomas. In the head and neck, approximately 60% of such occult primaries represent squamous cell carcinoma. Thirty percent are adenocarcinomas and the remainder are tumors originating in the thyroid gland, melanoma of the skin and mucosa, and poorly differentiated carcinoma.

If the metastases are from a squamous cell carcinoma, the primary is found in the head and neck region in the majority of cases.¹ Metastatic adenocarcinoma most often originates in a primary tumor below the clavicles, such as in the lung, the gastrointestinal (GI) tract, the genito-urinary (GU) tract, breast, and pancreas. However, a small number of these adenocarcinomas may originate in the head and neck from the salivary glands, paranasal sinuses, and the nasal cavity.

Metastases to the cervical lymph nodes as an initial presenting event from tumors below the clavicles are quite uncommon, representing only approximately 4% of such cases. Only 1.5% of lung tumors, for example, will present in such a manner.¹

Lymph nodes in zone 2 of the neck are the most common sites of metastases from an unknown primary, representing approximately 60 to 70% of cases. A significant proportion of supraclavicular lymph nodes represent metastatic adenocarcinoma and the majority of these tumors originate below the clavicles. Of known primary lesions metastatic to supraclavicular lymph nodes, approximately 20% only originate in the head and neck.

Several aspects of the assessment and management of patients with occult primary tumors have generated controversy and debate over the years. These issues include (1) the role of radiologic studies in identifying the primary lesion and assessment of cervical adenopathy; (2) the possible adverse effects of early open neck biopsy; (3) the value of tonsillectomy in identifying the primary lesion; (4) the question of branchiogenic carcinoma as a possible diagnosis; (5) the role of surgery, radiation, and chemotherapy in the management of these patients; (6) the advantages and disadvantages of treating the likely mucosal sites of the primary lesion; and (7) the value of random or directed biopsies at time of endoscopy.

The successful treatment of the metastatic neck disease and prevention of the primary tumor growth are the keys to patient survival. The management of a patient with an unknown primary carcinoma with metastatic disease in the neck remains a challenge to the head and neck surgeon and others including radiation therapists and oncologists involved in the management of these patients. However with appropriate evaluation and treatment, many of these patients have an excellent prognosis. Those patients with squamous cell carcinoma most of whom likely have primaries in the head and neck, can expect a favorable response to treatment especially if the nodal disease is limited. By contrast, patients with adenocarcinoma, most of which originate below the clavicles, generally have a very poor prognosis.

Evaluation of Patient

It is important that every effort be made to locate the primary tumor. If found, the primary can be adequately and appropriately treated and the patient’s prognosis therefore better assessed. In addition, locating the primary lesion may avoid extensive mucosal radiation and therefore avoid the often severe adverse effects of wide-field mucosal irradiation. These adverse effects include severe xerostomia, dental caries, laryngeal edema, osteoradionecrosis of the mandible, laryngeal chondritis, persistent pain, dysphagia due to submucosal fibrosis of the pharynx, hypothyroidism, hypopituitarism, and aspiration.^5–8

Most patients with head and neck cancer have squamous cell carcinoma arising from mucosal surfaces of the head and neck. Most of these patients are more than 40 years of age with a 4 or 5 to 1 male/female ratio. The vast majority of these patients relate a history of tobacco use, usually cigarette smoking, and many have a history of alcohol abuse. A patient presenting with a mass in the neck that is nontender and enlarging and who matches the above profile, should be regarded as having cancer until proven otherwise. An orderly stepwise approach should be taken in evaluating these patients. Most physicians treating these patients agree that open biopsy of the neck mass should be delayed until later stages of evaluation.

A careful history may elicit symptoms of pain in the oral cavity, the oropharynx, or hypopharyngeal areas, possibly with referred otalgia. Symptoms of hoarseness, dysphagia, odynophagia, or hemoptosis, or the awareness of a mass or ulcer in the oral cavity or the oropharynx, may alert the physician to the possible site of a primary tumor. One should inquire about symptoms such as weight loss, fever or night sweats, abdominal pain, melena, diarrhea, and hematuria. The patient should be questioned about history of thyroid or skin cancer or other tumors, including tumors below the clavicles (i.e., in the GI tract, lung, or GU tract). For example, renal cell carcinoma may metastasize to the head and neck 10 to 15 years or more after the initial diagnosis.

A detailed examination of the head and neck should follow. The number and location of lymph nodes in the neck are then assessed. Contralateral neck disease should not be overlooked. The site of lymph node involvement may suggest the location of the primary tumor.8, 9

Primary Cancer Sites Based on Neck Node Location

The primary cancer sites based on neck node location are as follows:

Level 1. submandibular/submental: lips, buccal mucosa, anterior nasal cavity, soft tissues of the cheek, oral cavity

Level 2. upper jugular: oral cavity, oropharynx, nasopharynx, supraglottic larynx, hypopharynx

Level 3. mid jugular: larynx, hypopharynx, thyroid Level 4. lower jugular: larynx, thyroid, esophagus, lung, upper GI tract

Level 5. posterior triangle of neck: nasopharynx, thyroid, cervical esophagus

When assessing cervical adenopathy, one should also note the size of the lymph nodes, mobility or possible fixation of these lymph nodes to the skull base, prevertebral muscles, or carotid artery. The neck is staged according to the American Joint Committee on Cancer Clinical Nodal Staging Guidelines (1988).

The skin of the head and neck including the scalp should be assessed, as squamous cell carcinoma or melanoma may metasta-size to cervical lymph nodes. The major salivary glands should also be examined. A cranial nerve examination is undertaken.

The oral cavity and the oropharynx are next examined. The patient is requested to remove dentures if these are present. Particular attention is paid to the posterior floor of the mouth and the adjacent tongue and tonsillar fossae as tumors in these areas can be easily missed on a cursory examination. Palpation of the oral cavity and oropharynx should be included in the assessment as some tumors are often palpable before being readily visualized. The ears are evaluated for the possible presence of a middle ear effusion which may be an early finding in cancer of the nasopharynx.

Flexible fiberoptic evaluation of the nasal cavities, the nasopharynx, larynx, and hypopharynx is the next step in the patient’s evaluation. Indirect laryngoscopy and nasopharyngoscopy remain a valuable technique for examination but many physicians simply find the fiberoptic instruments permit a more thorough and detailed evaluation in most patients. The nasal mucosa is prepared by spraying with a topical anesthetic/ vasoconstrictor mix. The nasal mucosa is then carefully evaluated, followed by evaluation of the nasopharynx.

The fiberoptic instrument is now advanced and the hypopharynx and larynx examined. The mobility of the vocal cords should be assessed and during phonation, the depths of the pyriform sinuses and the postcricoid regions may be visualized. The subglottis may be seen during this part of the examination. The tongue base and vallecula should be evaluated and again during phonation, the deeper region of the vallecula including the lingual surface of the epiglottis are usually well seen. The majority of the mucosal surfaces of the larynx, the hypopharynx, and tongue base can thus be thoroughly evaluated. Note should be made of areas of mucosal leukoplakia, erythroplasia, asymmetry, or friability with easy bleeding, as these areas may harbor neoplastic change. Pooling of secretions in the pyriform sinus may also be a clue to the presence of a tumor in the hypopharynx.

In many patients, the primary carcinoma will be identified following such a thorough examination in an office setting. However, if a primary lesion remains undetected at this point, the patient should undergo a further orderly evaluation to include fine needle aspiration of the neck mass, imaging studies, and endoscopy under anesthesia. An open biopsy of the neck mass is best avoided until the rest of the evaluation has been completed.

A recommendation for delaying an open biopsy of the neck mass has been axiomatic in head and neck surgery for many years. McGuirt and McCabe¹⁰ demonstrated an increased incidence of wound necrosis, regional recurrence, and distant metastatic disease in patients who had a nodal biopsy before a full diagnosis and definitive treatment with neck dissection. Other investigators have shared this concern.^{3, 11} However, a subsequent study by Robbins and others, did not corroborate these findings.^12–18 Robbins et al.¹² concluded that an open biopsy does not signify a poor prognosis provided adequate therapy is subsequently given. Mack et al.¹³ concluded, based on their data and on a review of the pertinent literature, that excisional biopsy of a solitary neck node does not have a detrimental effect on neck control or distant metastatic rate as long as the next step in treatment includes radiation therapy. Ellis et al.¹⁴ concluded that the potential adverse effect of violating the neck before definitive treatment cannot be demonstrated if radiation therapy is the next step in the patient’s management. McGuirt’s results might be explained by the fact that open biopsy may spread cancer cells into tissues not removed by classic radical neck dissection, but these cells are often sterilized by adequate doses of radiotherapy. However, as many of these patients with neck masses will be diagnosed as having squamous cell carcinoma, an ongoing search for the primary should be undertaken before open biopsy, so that both the primary and neck can receive definitive treatment. It is recommended that an open biopsy take place at the conclusion of the full evaluation.

A fine-needle aspiration biopsy (FNAB) of the neck mass may now be undertaken. A 22-gauge needle and 10 cc syringe are used to obtain the aspirate. Several passes with the needle through different portions of the neck node should be accomplished in order to obtain an adequate sample. If an adequate sample is obtained, and if squamous cell carcinoma is present in the lymph node, there is an approximately 95 to 98% chance of establishing this diagnosis correctly.⁷ If such a diagnosis is established, the search for the primary tumor should proceed with imaging studies, and endoscopy of the upper aerodigestive tract under anesthesia. The fine-needle aspirate may establish the presence of other malignancies, such as thyroid carcinoma, lymphoma, or adenocarcinoma, in which case the search may be directed to the appropriate regions. Fine-needle aspiration may often establish the histologic diagnosis at this stage. There is no evidence that fine-needle aspiration causes tumor seeding of the needle tract, an increased rate of metastases, or other adverse effects.

If the fine-needle aspirate demonstrates squamous cell carcinoma, the nasopharynx is one possible site of the primary tumor. There is a strong association between carcinoma of the nasopharynx and the Epstein-Barr virus (EBV). High titers of the EBV may be detected in patients with nasopharyngeal carcinoma on serologic testing. The presence of EBV genomes may be detected in cells from the neck aspirate using the polymerase chain reaction (PCR).19 These findings may point to the nasopharynx as the possible site of the primary.

Imaging Studies

There are physicians who believe that radiologic studies of these patients have a minor role to play in the evaluation.^{20, 21} However, most believe that radiologic evaluation should be undertaken and may yield valuable information.^{22, 23} The purpose of pursuing radiologic evaluation is twofold: (1) to assess the extent of nodal disease in the ipsilateral neck and the possible presence of disease in the contralateral neck. Lymph nodes in the retropharyngeal area and the paratrachial region may also be assessed as these are often difficult to detect on clinical examination, (2) possible detection of the primary tumor. Radiologic studies should precede endoscopy and mucosal biopsies. Such studies undertaken after biopsy may be more difficult to interpret because of edema and inflammation at the biopsy sites. Before endoscopy, these studies may alert the physician to mucosal abnormalities that may harbor the primary tumor.

Computed tomography (CT) scanning is the recommended study for evaluation of nodal disease in the neck.^{24, 25} This modality will assist in delineating the presence of single versus multiple lymph nodes, the presence of contralateral lymph nodes, and the possible extranodal extension of disease. Tumor involvement of the carotid artery, the skull base, and the prevertebral musculature may also be detected. Mancuso and others^24–26 have defined the criteria for the diagnosis of tumor-bearing lymph nodes and also for the possible extranodal extension of disease. The CT criteria for suspecting metastatic disease in lymph nodes includes the following: (1) diameter of the lymph node 7 15 mm, (2) grouping of three or more 8- to 15-mm lymph nodes, (3) central decreased density of a lymph node, and (4) poorly defined mass in a lymph node-bearing area.

The CT criteria for possible extranodal extension of disease include (1) ill-defined margins around abnormal lymph nodes, (2) edema or thickening of adjacent fat and muscle, (3) loss of facial planes between a mass and adjacent structures such as the carotid sheath.

Magnetic resonance imaging (MRI) scans may also play a valuable role in assessing neck disease and possible location of the primary tumor.^{24, 25} However, MRI scans have been shown to be less accurate than CT scans in demonstrating the presence of central necrosis in metastatic lymph nodes and in detecting the presence of extracapsular spread of disease. MRI appears to be superior to CT in detecting more subtle mucosal changes possibly due to neoplastic change. The consensus of opinion favors CT over MRI in evaluating these patients and, certainly, CT has been proved more cost effective. In a study by Menden-hall et al.²² CT and/or MRI correctly identified the primary site in 50% of patients evaluated who had no suggestive findings on physical examination.

The involvement of the carotid artery system by tumor can be quite difficult to ascertain. Van den Brekel et al.²⁴

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