Disclaimer: The information contained within the Grand Rounds Archive is intended for use by doctors and other health care professionals. These documents were prepared by resident physicians for presentation and discussion at a conference held at Baylor College of Medicine in Houston, Texas. No guarantees are made with respect to accuracy or timeliness of this material. This material should not be used as a basis for treatment decisions, and is not a substitute for professional consultation and/or peer-reviewed medical literature. Evaluation and Management of Cervical Metastases of Occult Origin Historically, the diagnosis of cervical nodal metastases from an unknown primary site was not uncommon and carried a poor prognosis. However, with current diagnostic techniques, this diagnosis now accounts for only 5% of all cancers of the head and neck in which the cervical nodes are involved. In addition, by employing various combinations of surgery and radiotherapy, the 5-year survival rate has been reported to be as high as 86%, depending on the extent of disease, the histology, and whether the metastases in fact originated from a head and neck source. A patient is considered to have an unknown primary when there is histologic evidence of malignancy in the neck without an apparent site of origin of the metastasis. This diagnosis can only be made after a thorough physical examination and radiographic evaluation have been performed, focusing on those regions of the body that are most likely to harbor the occult primary. Excluded from this diagnosis are patients in whom a primary becomes evident during or shortly after therapy and those who have a metastasis that is histologically related to a previous primary tumor. In addition, patients with lymphoma or thyroid cancers are not included. The majority of patients with cervical metastases of occult origin have squamous cell carcinoma, accounting for 60% to 85% of cases. The next most common histologic diagnosis is adenocarcinoma, occurring in 13% to 22%. Undifferentiated carcinomas and melanoma account for the remainder, at approximately 10% and 8%. Very rarely, other occult malignant neoplasms metastasize to the neck, such as sarcomas and germ cell tumors. Regardless of the possible origin of the primary, certain elements should be included in the evaluation. A complete history and physical is mandatory in every patient. Fine needle aspiration (FNA) should then be performed to confirm the histology. Excisional biopsies should be avoided if possible because of the theoretical potential for seeding tumor within the neck and for increasing the rate of distant metastases. If an open biopsy is necessary, it should be performed through an incision that will not compromise a subsequent neck dissection. A chest radiograph is also mandatory, and some recommend a sinus series. A CT of the neck is helpful for both detecting the possible primary site and for assessing the extent of the cervical disease. Depending on these results, additional studies such as panendoscopy under anesthesia, bone scans, and CT's of the chest, abdomen and pelvis may be undertaken as indicated. Metastatic squamous cell carcinoma: The evaluation for metastatic squamous cell carcinoma has been well established. After the diagnosis is confirmed by FNA, a comprehensive search for the primary tumor should be undertaken. More than 80% of all occult primary tumors with cervical metastases ultimately arise above the clavicles. If a complete head and neck examination and chest X-ray are not revealing, a CT scan of the neck should be obtained. In addition to defining the extent of the cervical disease, a CT scan can help detect the potential primary source in 60% of cases. Next, panendoscopy with palpation under general anesthesia should be performed. Any abnormality, no matter how slight, should be biopsied. Random, directed biopsies of the nasopharynx, tonsils, pyriform sinuses, and base of tongue should then be taken. Some advocate complete adenoidectomy and ipsilateral tonsillectomy if any significant amount of lymphoid tissue is present. An aggressive nasopharyngeal biopsy should always be performed in patients with disease in the posterior cervical triangle or in those at risk, such as patients of Chinese descent. Bronchoscopy with washings and esophagoscopy are also advocated, although the yield is quite low in the absence of mucosal or other suggestive abnormalities. A CT scan of the chest is recommended in the presence of an abnormality on chest X-ray, if the metastatic disease is located in the supraclavicular region, and if all the above tests are negative. Endoscopy should also be performed at frequent intervals during therapy to detect those rare cases in whom a primary appears. When the primary does later manifest itself, the most common area above the clavicles has been reported to be the pyrifom sinus, followed by the tonsils, base of tongue, and nasopharynx. Below the clavicles, the lung is by far the most common site of primary appearance. Two controversies surround the treatment of metastatic squamous cell carcinoma of unkown origin. The first concerns the management of the neck disease: should it be treated with neck dissection alone, radiation alone, or combination therapy. The second issue is whether to limit treatment to the neck or to prophylactically irradiate the mucosal surfaces that could potentially harbor the primary, such as the nasopharynx, oropharynx, and hypopharynx. Some argue that the incidence of developing a primary after treatment is somewhat less if these regions are irradiated. These questions are difficult to answer because there have been no randomized clinical trials. However, if one compares the recent literature regarding these issues, several observations can be made, which can be used to help select the treatment modality. First, lymph node stage is highly correlated with outcome in all studies. Five-year survival in patients with N1 disease treated surgically has been reported to be as high as 86%. Second, extracapsular tumor extension is inversely related to survival and is more commonly present in those with more advanced disease. Also, involvement of multiple levels of lymph nodes is associated with a significantly worse prognosis. These last two points support the use of adjuvant radiotherapy to help control the disease in the neck. Patients with supraclavicular metastases have an exceptionally poor prognosis, which may be related to the fact that these usually represent only one of many areas of widespread metastases from a primary originating below the clavicles. Patients who develop recurrent disease in the neck or eventually manifest their primary tumor have the worst prognoses, since the tumor itself is the most frequent cause of death. Last, distant metastatic disease is a significant cause of mortality. Specifically with regard to the issue of giving prophylactic mucosal irradiation, the literature is somewhat contradictory. Development of a primary tumor within 5 years of treatment has been reported to occur in as many as 29% of patients, and again, is associated with a very poor prognosis. Some retrospective studies have reported lower incidences when the entire pharyngeal axis was irradiated This argues for irradiation of all mucosal surfaces. However, proponents of a more limited role of radiotherapy present three arguments. One is that compared to treatment of the neck alone, mucosal irradiation adds additional morbidity to the therapy. The second is that the rate of later primary manifestation may be related to the thoroughness and aggressiveness of the initial investigation rather than to the treatment modality. It is therefore difficult to compare studies regarding the treatment of unknown primaries because the completeness of the initial evaluations may differ. The third point argues that if one examines the literature closely and compares equivalent data, it appears that the rate of primary development is roughly the same regardless of the treatment modality. In summary, for patients with stage N1 neck disease, control of disease can be accomplished in 90% of patients with either surgery or radiation alone; combined therapy is not necessary. Postoperative radiation for neck disease should be considered in patients with a single positive node larger than 3 cm, multiple positive nodes, extranodal tumor extension, or previous excisional biopsy. Both sides of the neck should be irradiated, since a patient with unilateral neck disease is at risk for developing disease in the contralateral neck, especially those patients with more advanced disease. If radiotherapy to improve the control of neck disease is indicated by one of these factors, then the potential mucosal primary sites should be irradiated as well. Radiation to the neck alone should never be performed, since it may compromise future radiotherapeutic options should a primary later develop. Metastastic adenocarcinoma: Patients with metastatic adenocarcinoma typically have nodes in the lower echelons of the neck, usually on the left side. The evaluation differs from that of squamous cell carcinoma because cervical metastases in adenocarcinoma are usually just one manifestation of widespread metastatic disease. Once a complete head and neck examination does not reveal a primary source, a limited, directed metastatic workup should be performed. A diligent search for the most common primary sources should be undertaken, which include breast, prostate, ovary, and stomach. During the evaluation, one should should bear in mind that the prognosis for metastatic adenocarcinoma is extremely poor, and the likelihood of finding the primary is low. Therefore, extensive, unproductive testing should be avoided. The most important aspect of the evaluation is a thorough physical examination that includes the breast, prostate, rectum, and pelvis. A CXR is required, and a mammogram is mandatory in women, as is a prostate specific antigen level in men. A CT of the chest, abdomen and pelvis may then be warranted, especially to help locate other metastatic disease. Any subsequent tests, such as radiographic or endoscopic studies of the gastrointestinal and genitourinary tracts, should be performed only if indicated by the above findings. Histologic studies such as immunoperoxidase staining and electron microscopy, can also help determine the site of origin. As far as treatment is concerned, various combinations of surgery, radiotherapy, and chemotherapy have been employed, all with equally poor results. There is some controversy regarding how aggressively the neck disease should be treated, given the short term survival. However, patients who have metastatic nodes confined to the upper neck, without other evidence of metastatic disease, do tend to have longer survivals. Metastases in the upper neck suggest a head and neck primary, which may be less aggressive than adenocarcinomas originating from other regions of the body. Therefore, in patients with only localized neck disease and no other metastases, a neck dissection with or without radiotherapy can be considered. If a single, additional body site is involved, treatment of the neck plus local radiotherapy to the other site can be employed. If more extensive metastases are present, cisplatin-based chemotherapy may be tried. It is always important, though, to balance the benefits and morbidity of treatment with the patient's expected survival. Case Presentations A 62-year-old white male with a long history of tobacco and alcohol use noticed a small, painless mass in his left neck two months prior to presentation. He had no hoarseness, dysphagia, or throat pain, and he denied having weight loss, fever, or other constitutional symptoms. He was treated with several courses of antibiotics, without response. The mass continued to enlarge, and he was referred to the Ben Taub General Hospital Otolaryngology Clinic for further evaluation. During the intervening time, he had developed mild dysphagia, which was attributed to compression by the enlarging neck mass. On physical examination, he was found to have a 3cm x 5cm hard, fixed mass in the mid and lower left jugular regions. No other adenopathy was palpated, and no visible or palpable mucosal lesions were detected after a thorough head and neck examination. A plain chest radiograph showed only changes consistent with chronic obstructive pulmonary disease. A CT scan of the neck revealed the presence of a large soft tissue mass that invaded the left sternocleidomastoid muscle and extended from the mid jugular to the supraclavicular region. No additional abnormalities were identified. A fine needle aspirate of the mass was then obtained, and the diagnosis of metastatic poorly differentiated carcinoma, with squamous features, was made. The patient was subsequently taken to the operating room, where he underwent panendoscopy with random biopsies of the nasopharynx, pyriform sinuses, and base of tongue. Bilateral tonsillectomies were also performed. The results of these biopsies were negative, and CT examinations of the chest, abdomen, and pelvis also revealed no abnormalities. Before additional studies were undertaken, a second fine needle aspirate of the neck mass was obtained. A definitive diagnosis of metastatic squamous cell carcinoma was subsequently made. A left radical neck dissection was performed, and a 4cm x 5cm node that invaded the sternocleidomastoid muscle was found. The final pathology confirmed the presence of metastatic squamous cell carcinoma. Extracapsular tumor extension was present, and one inferior jugular lymph node was also positive for malignancy. Because of the patient's large size, it was necessary to refer for postoperative radiotherapy. 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