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Management of the unknown primary in patients with metastatic cancer of the head and neck.


The evaluation of the patient with metastatic cervical lymph node squamous cell carcinoma and an unknown primary tumor frequently involves the use of guided biopsies as a diagnostic tool. This study was performed to assess the effectiveness of these biopsies. Using a retrospective chart review, we identified 25 patients who had undergone a total of 100 guided biopsies to evaluate an unknown primary malignancy of the head and neck. We found that 99 of the 100 biopsies were negative for malignancy. Although guided biopsies were obviously not helpful in these cases, we believe this might be attributable to the fact that the method of performing them is inconsistent among surgeons. Therefore, we present an algorithm for the management of the unknown primary head and neck malignancy, including recommendations regarding the use of guided biopsies.


When an adult has a unilateral neck mass, it often represents a head and neck malignancy. [1] Approximately 5.5% of patients with metastatic disease in cervical lymph nodes fail to have a primary tumor site identified, despite extensive evaluation. [2] These patients are considered to have an "unknown primary."

During the evaluation of a metastatic neck mass, the search for the primary tumor should include a careful examination of the oral cavity, nasopharynx, hypopharynx, larynx, thyroid, salivary glands, and skin of the head and neck region. Evaluation might also include radiologic studies of the paranasal sinuses, chest, and esophagus, and possibly even the thyroid. When examination of these areas yields no finding, the surgeon should consider direct endoscopic examination of the nasopharynx, larynx, hypopharynx, esophagus, and bronchial tree. [3]

In patients with metastatic cancer in cervical lymph nodes, the areas most likely to reveal a primary tumor are, in order of decreasing likelihood, the tonsils, nasopharynx, tongue, extrinsic larynx, floor of the mouth, pharyngeal wall, and palate. [4] When an endoscopic examination of these areas fails to reveal a gross malignancy, guided biopsy of the likely primary sites has been recommended. [3,5-7]

A guided biopsy was defined in this study as a biopsy taken in the absence of gross malignancy from an area known to have a high probability of containing the primary tumor. We reviewed the charts of patients with a diagnosis of unknown primary squamous cell carcinoma of the head and neck to evaluate the efficacy of guided biopsy in locating the primary tumor.

Materials and methods

We identified 25 patients who had undergone a guided biopsy between 1988 and 1995 as part of the evaluation of cervical malignancy with an unknown primary. Their ages ranged from 43 to 93 years, and 14 (56%) were men. The records reviewed were from three hospitals associated with the State University of New York at Buffalo consortium. We reviewed these charts to determine the site of each biopsy, its pathology, and the number of participating surgeons.

According to the records, some of these biopsies were taken from a "suspicious area of erythema." Although these biopsies were directed by the finding of erythema, there was no evidence that any gross malignancy was present. Nevertheless, we included these cases in our study.


The 25 patients had undergone a total of 100 biopsies, which were performed by nine different surgeons. The biopsied sites included the hypopharynx (43 biopsies), oropharynx (24), nasopharynx (15), glottis (9), and supraglottis (9).

Only one of the 100 biopsies was positive for malignancy. Sixteen of the specimens revealed either mild dysplasia or mild to marked epithelial hyperplasia. One specimen revealed a possible invasive squamous cell carcinoma in the base of the tongue, but further evaluation excluded this site as the location of the primary malignancy; later, the primary site was found to be a tonsil.

Records of long-term patient management were not available to track the progress of most of these patients. Therefore, we had no usable information on the eventual identification of the site of the primary tumor.


The diagnostic evaluation of the adult who has a neck mass is a challenge. The probability of malignancy is high in these patients. Patients often see their ultimate surgeon after having already undergone fine-needle aspiration or even an open biopsy of the neck mass. When squamous cell carcinoma exists in a neck node and no primary tumor has been identified, an exhaustive search is warranted.

Previous studies have directed our attention to those areas that are most likely to harbor the primary tumor. Martin and Morfit studied a series of 152 patients who initially were found to have a cervical malignancy. [4] These patients eventually had their primary head or neck tumor identified on subsequent examinations (table). As a result of Martin and Morfit's findings, as well as those of other researchers, it is now recommended that the search for a primary tumor be directed to, in order of decreasing likelihood, the tonsils, nasopharynx, tongue, and extrinsic larynx. [4,7] Lesions in these sites accounted for 78% of the primary lesions that surfaced in Martin and Morfit' s 1944 study, which is still one of the largest documented series of patients with unknown primary head and neck cancers. It is generally accepted that biopsy of these areas should be performed during direct endoscopic examination, even in the absence of a gross tumor.

In our study, mucosal abnormalities--specifically, dysplasia or hyperplasia--were found in 16 of the 100 specimens. Because no malignancies were found in these 16 specimens, the mucosal changes can be explained by the "condemned mucosa theory." [8-10] This theory suggests that smoking results in epithelial dysplasia throughout the upper aerodigestive tract. The dysplastic mucosa is condemned to develop multiple malignancies in the future. The dysplastic mucosa identified in our patients might have simply represented premalignant lesions.

Only one of the 100 biopsies taken in this series was successful in detecting the unknown primary malignancy. Therefore, biopsy was useful in only one of the 25 patients. The positive biopsy was taken from the supraglottic region (false fold).

Our data suggest that the practice of performing a guided biopsy in the absence of a gross malignancy is not beneficial. However, there at least have been anecdotal reports of success that must be acknowledged. One limitation of our study is the fact that we evaluated only 25 patients, a figure that only begins to approach a statistically valid sample. Therefore, we must wait for large new studies to provide a useful assessment of the practice.

Another confounding element of our study is that the manner in which the various surgeons performed these biopsies was far from uniform. If we ever hope to be able to perform a critical review of the usefulness of this technique, we will need a systematic method of assembling data, and in order to generate valid data, surgeons must begin performing the procedure in a consistent manner, With this in mind, we present an algorithm for the evaluation of an unknown primary head and neck malignancy, including our recommendations on how to best perform a guided biopsy (figure).

Proposed evaluation

What follow are our recommendations for evaluating a patient with squamous cell carcinoma in a lymph node of the neck:

History. The importance of a thorough history was emphasized by Martin and Morfit in their landmark report in 1944. [4] In their study, 30% of all patients who initially were found to have a neck mass had symptoms from their primary tumor that were identified only by thorough questioning by the examining physician.

Specific factors in a patient's history can help the physician find the primary tumor. A history of malignancy, especially if it was in the upper aerodigestive tract, is an important clue. Recent epistaxis, nasal obstruction, chronic sinusitis, rhinorrhea, or otalgia suggests a nasal, paranasal sinus, or nasopharyngeal source. Pharyngeal pain, dysphagia, or dysarthria implies an oral or oropharyngeal site. Otalgia and dysphagia might accompany a hypopharyngeal or laryngeal primary. Hoarseness, a change in voice quality, or shortness of breath might signal hypopharyngeal, laryngeal, or tracheobronchial lesions. Pruritus of the scalp, ears (including the external auditory canals), or facial skin has been associated with a cutaneous primary. A history of skin lesions, including those that have been previously treated, should also be elicited. It is not unusual for a metastatic cutaneous malignancy to masquerade as an unknown primary after the primary has been excised.

Physical examination. A detailed, systematic physical examination will often reveal a primary malignancy. A thorough head and neck examination includes a visual inspection of all the skin of the scalp, neck, face, and ears (pinna and external auditory canals). Squamous cell carcinoma of the external auditory canal is often mistaken for chronic otitis media for many months before it is detected. Other areas to assess include the nasal cavity, nasopharynx, oral cavity, oropharynx, hypopharynx, and larynx.

Examination of the nasal cavity can be performed with anterior rhinoscopy. If adequate visualization is not achieved, nasal endoscopy can be utilized. Application of a topical decongestant to the area will improve visualization during this examination.

Assessment of the nasopharyax, oropharyax, hypopharynx, and larynx can all be achieved with an indirect mirror examination. Recognize, however, that a thorough examination might not be possible with the mirror, even for experienced head and neck surgeons. In such situations, flexible fiberoptic nasopharyngolaryngoscopy is essential. Within the nasopharynx, the fossa of Rosenm[[ddot{u}]ller should be visualized bilaterally to look for asymmetry. Areas of concern in the hypopharynx include the piriform sinuses, vallecula, pharyngeal walls, and esophageal inlet. In the larynx, attention should be directed to both surfaces of the epiglottis, aryepiglottic folds, and arytenoids. Examination of the false and true vocal folds, including an assessment of vocal fold mobility, is essential. It must be stressed that a mirror examination is not sufficient when all of these areas cannot be inspected. Flexible fiberoptic examination dramatically improves visualization of the nasopharyngeal, hypopharyngeal, and laryngeal s tructures, and it should be performed without hesitation when needed.

Examination of the oral cavity and pharynx should include both visual inspection and palpation. Visualization of these areas is usually readily achieved. Primary malignancies in the tonsils, buccal mucosa, and the tongue (including the base of the tongue) are often submucosal and might not be apparent until palpated. Performing palpation as part of the routine examination of these areas is essential.

Toluidine blue staining. When a thorough examination has not detected a primary tumor, additional evaluation is required. Staining with toluidine blue dye might provide a clue to the primary site.

Toluidine blue dye is an acidophilic metachromatic dye of the thiazine group. It selectively stains acidic tissue components. As such, it readily stains DNA and RNA. [11] Anaplastic and dysplastic cells often contain more nucleic acids than do normal tissues, so they would be expected to take up the stain more readily. [12] Moreover, malignant epithelial intracellular canals can be wider than normal, which facilitates the penetration of the dye. [13] The dye will direct your attention to any suspicious area.

Toluidine blue dye will also stain some forms of nondysplastic tissue, such as areas of inflammation. The administration of an acetic acid rinse after application of the dye should decrease the dye's uptake in nonmalignant tissues and thus lower the false-positive rate. If there is any doubt about the positivity of a stained area, a prudent plan is to repeat the stain in 2 weeks, and perform a biopsy if it again shows signs of positivity [14] One recent study suggests that the sensitivity of toluidine blue dye is 100% for assessing perceivable malignant lesions and 79.5% for detecting dysplasias. [15] The same study reported that the dye's specificity was 62%.

Given the high sensitivity of this test and the ease of its application, its use is warranted in the search for an unknown primary tumor. It can be performed either in the office setting or during panendoscopy.

Examination under anesthesia. If all the previously described examination efforts have failed to detect the primary tumor, examination under anesthesia is warranted. There are multiple parts to this examination. The entire head and neck examination can be conducted much more thoroughly under anesthesia. It should begin with a nasopharyngeal examination. This can be done with a mirror while the palate is being retracted, or it can be done with a nasal endoscope. The laryngoscope can be used to assess the hypopharynx and larynx. Bronchoscopy and esophagoscopy should follow. If no tumor is found, palpation should be performed. Palpation is especially useful in examining the base of the tongue and the tonsils, because submucosal tumors are often found in these areas.

Guided biopsies. Once all examination options have been exhausted, strong consideration must be given to performing a guided biopsy at the sites where unknown primary tumors are most likely to be found. Biopsies have been categorized as random, blind, and guided. [1,3-7,16] The term guided (or directed) is appropriate because it conveys the fact that the choice of biopsy site is guided by the probability that the tumor will be found in that location. Random biopsies are not appropriate, because they are performed without a specific plan; biopsies should be performed systematically. Blind biopsies are also unwise; the surgeon should not biopsy any area that cannot be visualized. The findings of our study are evidence of just how literal the term random biopsy is; in the 25 patients we studied, no two patients had the same biopsy pattern.

We need a uniform method of performing guided biopsies. Some authors suggest that the tonsil biopsy should include a complete ipsilateral tonsillectomy rather than a superficial tonsil biopsy to avoid missing submucosal lesions. [17,18] There are two main criticisms of an ipsilateral tonsillectomy. First, the initial metastasis from a tonsil cancer might be to the contralateral neck. In such a case, the ipsilateral tonsillectomy would fail to detect the primary tumor. Second, symmetry cannot be assessed in evaluating the remaining tonsil during future surveillance examinations. Therefore, we recommend a bilateral tonsillectomy as the tonsillar biopsy of choice when searching for an unknown primary head and neck malignancy.

We also recommend that biopsies of the nasopharynx, tongue, and extrinsic larynx be taken from both sides because bilateral metastases are common from any tumor that approaches the midline. Lesions in these areas all have the potential for bilateral spread.

Additional investigations. Finally, it must be recognized that despite a thorough evaluation, a primary tumor can still elude detection. Before ending the search, the surgeon should order a chest x-ray and possibly even computed tomography of the chest if they haven't already been obtained, because a primary lung malignancy can spread to the cervical lymph nodes. Likewise, any evidence of chronic sinusitis warrants a radiographic examination of the sinuses to rule out a malignancy there. Computed tomography of the sinuses is preferred because plain x-rays often miss small tumors.

A chest x-ray and barium swallow study might be an acceptable alternative to bronchoscopy and esophagoscopy. However, if any uncertainty exists in the interpretation of these tests, endoscopy will be necessary to confirm or rule out the possibilities. Therefore, if a barium x-ray is to be used, it should be performed before any endoscopic examination so that the patient is not subjected to the possibility of two courses of general anesthesia.

Post-treatment followup. When an exhaustive search has failed to find the primary tumor, treatment should begin. The specifics of the treatment protocols are not the focus of this article. Let it suffice to say that treatment should be determined on an individual basis according to the extent of disease. Radiation therapy to the likely primary sites and to the neck is the cornerstone of treatment. Radiation can control lymph node disease in nodes that are smaller than 2.5 cm. [19] For larger nodes, dissection should be considered.

Even after treatment, the search is not over. Approximately 30% of unknown primary tumors surface over time. Therefore, monthly examinations are warranted during the first 12 to 18 months after treatment, and at 2-to 3-month intervals thereafter for 5 years. After 5 years, lifelong followup care is recommended every 6 months.


The authors thank Dr. George Simpson, Dr. David Terris, and Dr. R. James Koch for their assistance in the completion of this project.

From the Department of Otolaryngology--Head and Neck Surgery, the State University of New York at Buffalo.


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(3.) McGuirt WF. The unknown primary in metastatic head and neck cancer, a clinical approach. N C Med J 1978; 39:299-300.

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(5.) Coker DD, Casterline PF, Chambers RG, Jaques DA. Metastases to lymph nodes of the head and neck from an unknown primary site. Am J Surg 1977; 134:517-22.

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(9.) Lore JM. An Atlas of Head and Neck Surgery. 3rd ed. Philadelphia: W.B. Saunders, 1988.

(10.) Marchetta FC, Sako K, Camp F. Multiple malignancies in patients with head and neck cancer. Am J Surg 1965; 110:537-41.

(11.) Epstein JB, Scully C, Spinelli J. Toluidine blue and Lugol's iodine application in the assessment of oral malignant disease and lesions at risk of malignancy. J Oral Pathol Med 1992; 21:160-3.

(12.) Caspersson T, Santesson L. Studies on protein metabolism in the cells of epithelial tumors. Acta Radiol 1942; 46:17-8.

(13.) Richart RM. A clinical test for the in vivo delineation of dysplasia and carcinoma in situ. Am J Obstet Gynecol 1963; 86:703-12.

(14.) Mashberg A, Samit A. Early diagnosis of asymptomatic oral and oropharyngeal squamous cancers. CA Cancer J Clin 1995; 45:328-51.

(15.) Warnakulasuriya KA, Johnson NW. Sensitivity and specificity of OraScan(r) toluidine blue mouthrinse in the detection of oral cancer and precancer. J Oral Pathol Med 1996; 25:97-103.

(16.) McGuirt WF. Differential diagnosis of neck masses. In: Cummings CW, Schuller DE, eds. Otolaryngology-Head and Neck Surgery. Vol. 2, 2nd ed. St. Louis: Mosby-Year Book, 1993.

(17.) Righi PD, Sofferman RA. Screening unilateral tonsillectomy in the unknown primary. Laryngoscope 1995; 105:548-50.

(18.) Thawley SE, O'Leary M. Malignant neoplasms of the oropharynx. In: Cummings CW, Schuller DE, eds. Otolaryngology-Head and Neck Surgery. Vol. 2, 2nd ed. St. Louis: Mosby-Year Book, 1993.

(19.) Mendenhall WM, Million RR, Bova FJ. Analysis of time-dose factors in clinically positive neck nodes treated with irradiation alone in squamous cell carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 1984; 10:639-43.
 Primary site as eventually identified on followup
 examination in 152 patients who initially presented
 with cervical malignancy and an unknown primary (as
 presented by Martin and Morfit in 1944 [4])
Site No. cases Pct.
Tonsil 35 23
Nasopharynx 33 22
Tongue 29 19
Extrinsic larynx 22 14
Floor of the mouth 10 7
Pharynx 9 6
Thyroid 7 5
Palate 4 3
Paranasal sinuses 1 0.6
Gums 1 0.6
Intrinsic larynx 1 0.6
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Author:Belles, William
Publication:Ear, Nose and Throat Journal
Geographic Code:1USA
Date:Apr 1, 2000
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