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Neck nodal metastases from unknown primary: case series
D. Tamiolakis, T.S. Chimona, E. Proimos, G. Georgiou, G. Perogamvrakis, C.E. Papadakis (Chirurgia, 103 (3): 335-339)

Introduction
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. When an adult has a unilateral neck mass, it often represents a head and neck malignancy (1). Approxima-tely 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).

Case series
Case 1
A 65-year-old man presented in the out patient department of our hospital, with a firm, painless mass on the left side of his neck. He had first noted it approximately 3 months before presentation. Fine needle aspiration of the mass yielded a poorly differentiated carcinoma, with neuroendocrine features as shown by immunocytochemical analysis of the cell block preparations with the employement of chromogranin and neuron specific enolase (NSE) (fig. 1, 2, 3). His clinical examination was normal. C/T imaging of the neck showed the known level V malignant lymph node, and also malignant lymph nodes in all levels and at both sides of the neck but no mass of malignancy. The patient then underwent excision biopsy of the mass which established metastatic infiltration of the node from a neuroendocrine neoplasm. For staging the disease the patient underwent C/T imaging of the head, skull base, and chest which was positive for multifocal disease in the brain and negative for disease other than the known neck abnormality. Direct laryngoscopy, bronchoscopy, and eso-phagoscopy showed no primary malignancy. Guided biopsies from the Waldeyer ring and larynx failed to reveal the primary malignancy site. The patient received palliative combined radiation therapy and chemotherapy and is on monthly follow up three months after the end of the treatment with no evidence of further spread of the disease.

Figure 1
Figure 2
Figure 3

Case 2
A 49-year-old female presented with swollen lymph nodes in her left neck. She felt well without any active systemic or localizing symptoms. She had quit smoking 6 years previously, with a 15 pack-year history. She was on no regular medications and had no allergies.
On physical examination, there were multiple palpable firm nodes measuring 1-2 cm in the lower left cervical and medial left supraclavicular areas. The remainder of her physical examination was negative.
Complete Blood Count test (CBC), chemistry panel, and chest x-ray were negative. Fine needle aspiration was no diagnostic. A biopsy of the left lower cervical nodes revealed poorly differentiated carcinoma (fig. 4).Immunohistochemical results were controversial. Further workup included a computerized tomography (CT) scan of the brain, skull base, chest, and abdomen, which confirmed the left supraclavicular adenopathy and also showed adenopathy in the upper mediastinum (Levels V,VI,VII). Ear, nose, and throat evaluation revealed no evident primary lesion on fiberoptic endoscopy. Breast magnetic resonance imaging (MRI) showed no suspicious lesions. Upper and lower endoscopies of the gastrointestinal (GI) tract were negative. Direct laryngoscopy, bronchoscopy, and esophagoscopy showed no evidence for a primary site of disease. Guided biopsies from the naso-pharynx, tonsils, tongue base, epiglottis failed to reveal the primary malignancy site. The patient was treated with radiation therapy and chemotherapy with a six months up today control of the disease. She is still on follow up monthly.
Case 3
A 61-year-old man presented with a large right-sided level II cervical lymph node. He underwent a fine needle aspiration biopsy and a needle core biopsy that disclosed a poorly differentiated malignant deposit not otherwise specified on cytological grounds (fig. 5). Immunocytochemical and immunohistochemical analysis were unsuccesful due to artifacts introduced by tissue processing. Clinical examination and CT revealed no obvious primary mucosal lesion. Excisional biopsy and guided biopsies from the Waldeyer ring and larynx failed to reveal the primary malignancy site. Panendoscopy, failed to reveal any abnormality of the mucosa and palpation, of the tonsils and tongue base for submucosal masses was negative as well. The patient received radiation therapy to the right neck and Waldeyer ring. Six months later he was referred to the emergencies with acute epigastralgia and hemorrhagic anal discharge. He underwent surgery and serial frozen section biopsies from the small intestine demonstrated a poorly differentiated malignancy (fig. 6). Conven-tional histology with Hematoxylene-eosin stain and immunohistochemical analysis with the employement of CYTOKERATINS, LCA, CEA, EMA, PLAP, VIMENTIN, S-100, and HMB45 the diagnosis of malignant melanoma was established, and the patient was reffered to the oncology department.

Figure 4
Figure 5
Figure 6

Discussion
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. Weir studied a series of 144 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. As a result of Weir 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 Weir 1995 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. Mucosal abnormalities--specifically, dysplasia or hyperplasia-may be found.These 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 most acceptable theories that explain the unknown primary neck node metastasis are that the neck mass is the only site of the carcinoma, that no primary tumor ever existed, that disease developed in an epithelial rest or branchiogenic cyst, and that spontaneous regression of the primary tumor occurs after metastatic disease has become established.
To evaluate patient with squamous cell carcinoma in a lymph node of the neck, we concentrate on the following: 1) History. 2) 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. 3) 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 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. 4) Examination under anesthesia. If all the previously described examination efforts have failed to detect the primary tumor, examination under anesthesia is warranted. It should begin with a nasopharyngeal examination. 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. 5) 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. 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). 6) Additional investigations. Finally, it must be recognized that despite a thorough evaluation, a primary tumor can still escape 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. 7) Post-treatment followup. When an exhaustive search has failed to find the primary tumor, treatment should begin. 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 2.5cm (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.

References
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16. McGuirt, W.F. - Differential diagnosis of neck masses. În “Otolaryngology-Head and Neck Surgery“, vol. 2, 2nd ed., sub redactia Cummings CW, Schuller DE, St. Louis: Mosby-Year Book, 1993.
17. Righi, P.D., Sofferman, R.A. - Screening unilateral tonsillectomy in the unknown primary. Laryngoscope, 1995, 105:548.
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