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 metasta-tic 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 pro vide 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 FDG-SPECT 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 This has led to the use of EBV assays for diagnostic purposes in patients having metastatic squamous cell carcinoma to the cervical lymph nodes for which the primary site is unknown, but suspected to be the nasopharynx.10'12 Fu10 suggests that for patients with poorly differentiated or undifferentiated metastatic carcinomas, the identification of the EBV genome in the cervical metastasis of a patient also having elevated IgA antiviral capsid antigen is strongly suggestive of a nasopharyngeal primary. However, it has been shown that the presence of EBV genomic DNA in metastatic lymph nodes alone is predictive of the presence of nasopharyngeal carcinoma.13 Testing a metastatic node for EBV DNA or obtaining EBV immunoglobulin titers is a reasonable approach that should be considered for any case of metastatic poorly differentiated or undifferentiated carcinoma of cervical lymph nodes, particularly if upper deep cervical or posterior cervical nodes are involved.
The usual and preferred manner of diagnosis for a cervical mass with a nonrevealing history and physical examination is FNAB. This can be done relatively early in the diagnostic evaluation of such cases, even at the initial visit, if a complete history and examination are normal. The diagnostic accuracy and ability to yield a diagnosis for this test are high. If a single attempt fails to provide diagnostic information, it should be repeated, or a core needle biopsy should be considered.
Only after a repeated needle biopsy fails to establish a diagnosis should an open biopsy procedure be contemplated. Open biopsy is also often necessary for cases in which FNAB shows a probable lymphoma or an epithelial malignancy of uncertain type. If open biopsy is done, frozen section examination should be performed to determine whether the biopsied tissue should be processed for a lymphoma evaluation or for an infectious disease etiology.
In the past, the usual approach to open biopsy of a suspicious neck mass by head and neck oncologists involved the performance of an immediate complete neck dissection if the biopsy confirmed a metastatic squamous cell carcinoma. Failing to do a neck dissection or being unprepared to perform this operation at the time of an open biopsy showed metastatic carcinoma was regarded as very poor and risky patient management. Some recent studies, however, suggest that if an open biopsy of a metastatic squamous cell carcinoma is subsequently followed by adequate treatment with either radiotherapy or surgery, but not necessarily immediate neck dissection, the outcome is not compromised.14'15 One study reported a 5-year disease-specific survival of 95% among patients whose treatment included excisional biopsy.16 Nevertheless, open biopsy remains the least preferred way to establish a diagnosis in a patient with metastatic carcinoma presenting with a cervical mass.
The remaining part ofthe diagnostic evaluation that is generally regarded as indispensable for a patient presenting with a metastatic carcinoma from an occult primary is the endoscopic examination under anesthesia. This usually includes careful palpation of the oral cavity and oropharynx, with particular attention given to the base of tongue and palatine tonsils, as well as direct laryngoscopy, pharyngoscopy, esophagoscopy, and bron-choscopy. Any abnormal or suspicious areas should be biopsied. The yield of primary site identification for panendoscopy after an unrevealing history and physical examination is 24 to 44%.3
Of a more controversial nature is the value of random biopsies taken from head and neck mucosal sites when the endoscopic examination is normal. One approach is to biopsy the sites where the occult primary is statistically most likely to be located.9 These would be the nasopharynx, the base of tongue, the ipsilateral palatine tonsil, and the ipsilateral pyriform sinus. Another approach is to select biopsy sites on the basis of the location of the involved lymph nodes.9 The rationale for this approach is that head and neck cancer will metastasize in a relatively predictable fashion to the cervical lymph nodes and that the location of an occult primary lesion can be inferred by the location of the nodal metastasis. Finally, biopsy sites can be selected on the basis of suspicious areas identified on CT or MRI scans. In addition to random biopsies, bronchial washings have been recommended.12
The value of routine ipsilateral tonsillectomy to identify the source of a metastatic squamous cell carcinoma has been debated.3,9 One small retrospective review concluded that ipsi-lateral tonsillectomy was the only reliable screening technique to rule out an occult tonsil carcinoma.17 This conclusion was made on the basis of a case series; no comparison was made to other methods of detection, such as palpation under anesthesia or tonsil biopsy. By contrast, a larger review by Mendenhall et al.3 concluded that the diagnostic value of routine ipsilateral tonsillectomy was uncertain.
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