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. Squamous Cell Carcinoma:
Management of Cervical Lymph Node
Metastasis with an Unknown Primary From a historical perspective, Dr. Hayes Martin is one of the great leaders in head and neck surgery and first to draw attention to this entity. In a classic paper with Morfit in 1944, the two reviewed 218 carcinomas presenting as cervical adenopathy and identified the most likely sites for the primary to be found. They found the incidence of unknown primary at that time to be 25%. Dr. Martin also encouraged the use of FNA, which he was one of the first to popularize and perform as part of a basic diagnostic algorithm that remains relevant today. Speculation about why primary tumors may remain unknown has produced many theories. The incidence of unknown primaries decreased by 20% over the past 50 years as diagnostic capabilities improved and the assumption is that unknown primaries exist in the upper airway or digestive tract, but remain subclinical. Difficult-to-examine anatomic sites such as the tonsillar crypts, the nasopharynx, piriform sinus and base of the tongue may hide primaries. Martin and Morfit in 1944 suggested that the meager nerve supply and the unaffected function with small or moderate growths may contribute to lack of detection in this area. Infraclavicular sites such as lung and esophagus may also be missed. In the past, the theory of branchiogenic carcinomas was thought to be an etiology for these tumors, that the tumor could arise in branchial cleft cyst remnants, but this idea has gone out of favor. It was recently discussed in a 1994 paper looking at squamous cell carcinomas presenting as neck masses which had cystic histologic features, and, of this series, six of nine primaries were discovered in the tonsils and one in the base of tongue. Two remained occult. The conclusion was that squamous cell carcinoma discovered in cystic metastases suggested pharyngeal or lingual tonsil primary and provides no evidence for the existence of branchiogenic carcinoma. Another unlikely explanation is spontaneous regression of the primary with possible persistence of metastases due to heterogeneity. Most sources agree that, unlike melanoma, there is no evidence for spontaneously regressing squamous cell carcinomas. After treatment, whereas some primaries are later discovered, radiotherapy may eliminate others and this is another explanation. An unknown primary implies that a complete head and neck history and physical has been done, that panendoscopy has been done, imaging with CT or MRI and chest x-ray and negative directed biopsies. Most typically, patients will initially present with a painless unilateral neck mass of weeks' to months' duration. The male to female ratio is approximately 6:1 and the average age is 60 years with a significant history of alcohol and tobacco use typically. Regardless of whether the patient initially presents to the specialist undiagnosed or after biopsy, a complete history and physical should be done by the treating otolaryngologist. A history of sun exposure is important as skin and scalp may hide the primary and, in particular, the scalp exam is very important. In oropharynx, tonsillar asymmetry should be noted, visibly or to palpation, and the digital examination at the base of tongue is very important. Additionally, rigid nasopharyngoscopy, flexible nasopharyngoscopy, laryngoscopy with modified Valsava to distend the hypopharynx and piriform sinus is important in examining the area. In the neck examination, measurement of extent, fixation to skin or surrounding structures, and cranial nerve weakness should be noted. The neck examination both stages the disease and helps to direct the search for a primary. The location of lymphadenopathy suggests possible primaries given an understanding of the pattern of lymphatic drainage in the neck. There is a superficial system and a deep system. Starting with the superficial system, the submental nodes receive drainage from the skin of the chin, the mid portion of the lower lip, the tip of the tongue, the anterior oral cavity and the nasal vestibule. The submandibular nodes receive drainage from the submental area, the lower nasal cavity, the upper lip, the lower lateral lip, the anterior oral cavity and the skin of the mid face. The submandibular nodes drain into the superior deep jugular chain. The remaining superficial nodes include facial, preauricular, postauricular, superficial cervical along the external jugular chain and the occipital nodes draining the scalp. The occipital nodes drain into the deep lymphatics of the spinal accessory chain whereas the remaining cervical nodes drain into the superior deep cervical chain. The superior deep jugular nodes include the jugular digastric nodes, which receive primary drainage from the soft palate, tonsils, tonsillar pillars, posterior oral tongue, base of tongue, piriform sinus, and supraglottic larynx as well as secondary drainage from retropharyngeal, spinal accessory, parotid, superficial cervical and submandibular nodes. The middle deep jugular nodes, including the jugulo-omohyoid node, receive primary drainage from the supraglottic larynx, the inferior aspect of the piriform sinus and the posterior cricoid area. The inferior deep jugular nodes receive primary drainage from the thyroid, trachea, cervical esophagus and secondary drainage from the superior and middle chains and upper spinal accessory. The pretracheal nodes receive drainage from the inferior aspect of the larynx, hypopharynx, cervical esophagus, upper trachea and thyroid, and drain into inferior deep jugular and mediastinal nodes. Spinal accessory nodes are located along the spinal accessory nerve and receive drainage from the occipital nodes as well as the nasopharyngeal nodes and retropharyngeal and parapharyngeal node areas. The transverse cervical nodes connect the spinal accessory chain and the internal jugular chain. The anterior scalene or Virchow's nodes and supraclavicular nodes receive drainage from the thoracic duct on the left and the lymphatic duct on the right. Nodal disease presenting in these areas is more often associated with an infraclavicular and, sometimes, subdiaphragmatic primary. In squamous cell carcinoma of unknown primary, the jugulodigastric or upper jugular nodes are most frequently involved. In a 1998 study by Colletier et al summarizing the M.D. Anderson experience, the distribution of nodes in 136 patients by level of involvement, 102 patients with a single level of involvement, 55 were located in the upper jugular nodes. Of 34 patients with multiple levels of disease, 22 had upper jugular involvement in the jugulodigastric area. Involvement of Level II nodes should direct your attention to the Waldeyer ring in the posterior oropharynx. It is important to review the staging system of lymph node metastases. This has changed since several of the earlier studies of unknown primaries were done. Just to review, an "X" refers to the situation where nodes have already been removed, the "disturbed met" as Dr. Goepfert puts it. N1 is a single ipsilateral node less than 3 cm. N2 is a single node greater than 3 cm, but not more than 6 cm. N2b - multiple ipsilateral nodes, none more than 6 cm, and then N2c refers to metastases in bilateral contralateral lymph nodes, none greater than 6 cm. N3 correlates with a lymph node greater than 6 cm. Most cervical squamous cell carcinomas with an unknown primary present as more advanced disease, N2 and N3 nodal status. Now, we will move to diagnostic tests. Ideally the initial diagnosis of squamous cell carcinoma is made by an FNA. FNA is preferred over open biopsy as it is rapid, outpatient and, more importantly, does not limit the options for treatment of the neck. However, in the event that an FNA is inconclusive or suspicious, an excisional biopsy must be done. Often patients are referred after an excisional biopsy has already been performed, and I will address this and how it affects the work-up and treatment later. Histology can be important as the lymphatic pattern of cervical metastases in directing the search for a primary. Undifferentiated, poorly differentiated, and lymphoepithelial patterns can suggest tonsil, nasopharynx, and base of tongue lesions. Cystic histology can suggest tonsil, base of tongue and pharyngeal wall lesions in this order. A well-differentiated histology, especially associated with superficial cervical nodes and along the external jugular chain, can suggest a skin primary. Moving to imaging studies, a chest x-ray is essential to rule out a pulmonary primary. CT and MRI of the neck are an important part of the diagnostic work-up then the H&P does not find a primary. This study should ideally be done before panendoscopy, both to direct biopsies and so that post-biopsy edema does not compromise the specificity of the study. It is useful in locating submucosal lesions and delineating a pattern of adenopathy can suggest a primary such as retropharyngeal adenopathy, which can raise the suspicion for nasopharyngeal primary. FDG CT scanning is an experimental imaging technique of increasing interest in prospective studies identifying primaries as well as early recurrences. Head and neck neoplasms have an increased glycolic rate and this tracer 2 fluorine-18 fluoro-2-deoxy-D-glucose is a positron emitter and a glucose analog, so its uptake parallels the glycolic rate of metabolically active cells. It is increased in infection and inflammation as well as neoplasm. In a preliminary study 17 patients with metastatic cervical adenopathy, not specifically squamous cell carcinoma and unknown primary, were evaluated with FDG CT scanning and this correlated with the CT and MRI results. Two lung carcinomas were identified with CT scanning and nine of the 15 remaining patients had a single suspicious focus where biopsy revealed eight as primary squamous carcinomas in seven patients, and CT and MRI recognized only five of these eight biopsy proven sites seen by the FDG CT scanning. Dr. Manolides in the 1998 study also demonstrated the ability of FDG CT scanning to find occult primaries, although that was not the main emphasis of that particular paper. The term "panendoscopy" is used somewhat loosely in the literature, but usually refers to examination of the nasopharynx, oral cavity and oropharynx, hypopharynx, larynx, esophagus, and sometimes the tracheobronchial tree. Direct laryngoscopy and rigid cervical esophagoscopy are generally standard, but the need for bronchoscopy and full esophagoscopy or barium swallow should be individualized as needed in assessment of a metastatic node in the supraclavicular area, lower jugular chain or tracheoesophageal groove and possibly in the assessment of upper or middle jugular metastases. All abnormal appearing mucosal surfaces or palpable masses should be biopsied at the time of panendoscopy. Classically, random biopsies are taken from normal appearing mucosa in these areas with the greatest likelihood of harboring an occult primary. Classically these areas are the nasopharynx, the tonsil, the base of tongue, and the piriform sinus. A small study from Hopkins revealed a 17% yield of finding a primary from random biopsies in these areas. Tonsillectomy continues to be a controversial issue in the work-up. There is no consensus regarding whether the tonsils should be randomly biopsied and tonsillectomy done only if there is irregularity, size discrepancy or palpable mass or if routine ipsilateral or bilateral tonsillectomy should be done. In a good study from Dr. McQuone done in 1998, she makes an argument for routine bilateral tonsillectomy in the work-up of an unknown primary. Thirty-seven patients presented to Johns Hopkins' Department of Otolaryngology and were taken to the OR for direct laryngoscopy and directed biopsies with a diagnosis of squamous cell carcinoma, metastatic to the neck, from an unknown primary. Tonsillectomies were done in 23 of these 37 patients, and 9 of the 23, or 39%, were positive for squamous cell carcinoma. None of their non-tonsillar biopsies, however, in the nasopharynx, base of tongue and piriform sinus were positive for cancer. Two of the focal tonsil biopsies were positive, but both of these particular cases also had tonsillar asymmetry, which was appreciated on palpation. One patient with a negative tonsillar biopsy had a tonsillectomy specimen positive for squamous cell carcinoma. Whereas the surface epithelium appears normal and showed no evidence of neoplastic changes, the tonsillar crypt harbored an invasive carcinoma. This case demonstrates the problem of sampling error with a directed biopsy. Our other arguments for performing tonsillectomy rather than biopsies are Righi in 1995, who makes an argument for ipsilateral tonsillectomy as he found nine of 16 patients with an unknown primary demonstrated an occult squamous cell carcinoma in the ipsilateral tonsil diagnosed only sigh the pathologic examination as a whole. The argument for bilateral tonsillectomy is that it eliminates the sampling errors from random biopsy. It does not excessively increase the morbidity of a unilateral tonsillectomy. It creates an anatomic symmetry that is important in follow-up and there are the rare cases of bilateral foci of squamous cell carcinoma on both tonsils. M.D. Anderson has encountered these patients as well. There was one case in this study of bilateral foci of squamous cell carcinoma. In the early 1980s, there was interest in the anti-Epstein-Barr virus antibodies that can provide additional evidence for a nasopharyngeal primary; however, this is not as useful clinically as the histology. Location of the adenopathy will direct attention to the nasopharynx as a likely site for the primary although these cases done in 1983 by Neil showed a very significant association. Although I have just discussed the ideal sequence of a head and neck examination: FNA and panendoscopy should be performed prior to surgery, and that excisional biopsy, if it is necessary, should be done by the treating otolaryngologist, it is still quite frequent that patients present as referred, after an open biopsy has been done. The H&P and panendoscopy should be repeated, and biopsies redone in this circumstance. Patients with an indeterminate or suspicious FNA must have an open biopsy. In this situation, the patient should be prepared preoperatively, and consented for a neck dissection as well, given the contingency of finding a metastatic carcinoma. It is appropriate to complete a neck dissection in this setting, which both stages the cancer and may also provide definitive treatment. I will move on to treatment. There is some general agreement in many studies, with some notable exceptions, that guiding principles for treatment are; 1) that the most important prognostic factor is the N-stage extent of the disease, and 2) that extracapsular spread is associated with a worst prognosis and relapse of disease, and most sources recommend more aggressive therapy for patients with advanced nodal disease and/or extracapsular invasion. Beyond this, controversies in treatment include whether excisional biopsy plus radiation is acceptable. Is single-modality therapy effective compared with multiple-modality? Is it necessary to irradiate both the neck and potential primary sites versus the neck alone? And, is it necessary to irradiate both sides of the neck or only the side of the presenting disease? Additionally, what is the role of chemotherapy? N disease is seen at presentation in 17%-29% of the cases, and, for these patients, a single-modality therapy may be an option with some important caveats. Acceptable courses include neck dissection alone, neck dissection plus radiation, or radiation alone. The recent review of the M.D. Anderson experience between the years of 1968 and 1992 outlines the treatment algorithm based on their results. N1 or small mobile N2 disease can be definitively treated with neck dissection, a modified radical neck dissection or radical neck dissection; however, there are very few patients that actually present this way, and they make the exception that if there is connective tissue invasion or extracapsular spread, multiple involved nodes or a suspicion of residual microscopic disease of the neck without clinical detectable tumor, postoperative radiotherapy is added. Following these guidelines, only two of 27 relapses were in the N1 group compared with seven of 64 or 11% in the N2, and 3 of 14 or 21% in the N3 group. Weir et al in 1995 looked at radiotherapy alone in the N1 group and reported a control rate of 67%; however, some of the patients in this study (and these patients were not identified by nodal class) received less than an acceptable minimal radiation dose. Wang et al in 1990 found that there was no statistically significant difference in survival between surgery alone and radiotherapy alone groups, but it is not clear how many of these had N1 disease, and patients with residual disease after therapy are omitted from this study. NX classification includes patients with early stage neck disease, referred after a diagnostic excisional biopsy and with no evidence of residual nodal disease. Although a complete neck dissection was traditionally recommended for better staging and treatment, review of patients receiving only excisional biopsy and radiation have shown this to be an effective and acceptable treatment. Colletier et al reports zero of 39 patients status post- excisional biopsy with a nodal relapse, and Weir et al similarly found an 88% control rate for 63 patients given radiation alone after excisional node biopsy of a single node. It is recommended that N2 and N3 or Stage 4 disease should receive multiple-modality therapy. Modified radical or radical neck dissection, depending on extensive disease, is indicated in most cases. Radiation therapy may be given either preoperatively or postoperatively, but the current preference is for postoperative radiation so that the disease extent can be defined at surgery. Chemotherapy has been advocated in conjunction with radiation in inoperable disease or with distant metastases. A study by De Braud in 1989 advocated combining radiation and chemotherapy in advanced disease. He claims 81% response in the chemoradiation group compared with only 28%, which is very low, with no evidence of disease with surgery and radiation. His control group, however, included 16 of 25 patients with advanced disease treated with radiation alone and without surgery, which would not currently be the standard of care. Most recent trials using chemotherapy and radiation in squamous cell carcinoma with known primaries has had other positive results; however, these studies are in patients with known primaries and with a worse prognosis in general, so we may not be able to apply these results to the unknown primary where the prognosis is better. While the technological aspects of radiotherapy administration are beyond the scope of this talk, I will discuss the dose and some important issues of debate. Fifty gray in 25 fractions is accepted as adequate to control subclinical disease in surgically untampered lymphatics; however, it is a higher dose of 63-68 gray in an operated neck is recommended, because of disrupted lymphatics thought to contain residual disease as well as a patient with extracapsular spread. Inclusion of all possible mucosal primary sites with its consequent mucositis and xerostomia is still an issue of controversy. Weir et al in 1995 looked at radiotherapy to nodes and potential primary sites versus radiotherapy to the involved regions alone, and found that the 5-year survival difference was not statistically significant, but there is a trend favoring treatment of both areas. Based on the M.D. Anderson experience, Carlson recommended radiotherapy to the neck and naso-oral hypopharynx except when there is a strong suggestion that the nasopharynx is a primary site in which case the hypopharynx may be spared. In a similar argument, Harrison's head and neck cancer text recommends that the nasopharynx may be omitted when disease is limited to the lower nodes. With the issue of whether to treat neck ipsilateral to disease or to treat both sides of the neck, the M.D. Anderson, as well as other sources, also favors treating bilateral or both sides of the neck. Analysis of the cases from M.D. Anderson from 1948 to 1980 show most treatment failures happened in patients receiving radiation to the neck as their only therapy, and occurred in patients treated only to the ipsilateral side of the neck. These patients had a 46% recurrence versus a 14% recurrence when both sides of the neck were included. The overall 5-year survival remains at approximately 50%. In the M.D. Anderson series, the 2-, 5-, and 10-year actuarial disease-specific survival rates were 82%, 74%, and 68% respectively while the overall survival rates were 75%, 60%, and 41% respectively. End-stage has been shown in several series to be significantly associated with disease- specific survival. Patients with multiple nodes had a 5-year disease-specific survival rate of 58% compared with 85% of patients with a solitary node. Extracapsular spread is already introduced as another major influence on prognosis. The M.D. Anderson data found that the 5-year disease-specific survival is reduced from 74% to 58% with the presence of extracapsular spread. It also predicts recurrence, which, in turn, also signifies worse disease-specific survival. Finally, the influence on prognosis of a late development of a primary is often debated in the literature. Martin suggests that tumors appearing within 5-years be considered the primary tumor; however, primaries are reported to develop at a rate of approximately 5% per year in head and neck cancer patients, and it is difficult to conclude without some molecular evidence that the new tumor is the primary of the treated cancer and not a second primary. Some authors have found that a late primary has no influence on prognosis whereas others have found that it adversely influences it. Treatment with surgery alone has been associated with a more frequent development of the late primary. In summary, although it is more infrequent now with better diagnosis, approximately 5% of squamous cell carcinoma presents as neck metastases of unknown primary. Thorough history and physical, FNA, then CT, MRI and possibly PET scanning should all be done prior to panendoscopy. Panendoscopy with directed biopsies should be done in the nasopharynx, base of tongue, piriform sinus, and I would recommend bilateral tonsillectomy based on the evidence I reviewed. End-stage and presence of extracapsular spread predicts prognosis and in early disease, neck dissection with or without radiation depending on the individual situation is the recommended treatment, whereas neck dissection, and multi-modality therapy is important in a more advanced disease with surgery, radiation and chemotherapy or possibly radiation and chemotherapy in N2 or N3 disease that is inoperable. The patient is a 50-year-old white male pilot, an infrequent cigar smoker for 2 years, who presents to the Methodist Hospital with a 15-month history of a left neck mass. He initially noticed the neck mass in association with a URI. It improved with treatment, then increased in size again with another episode of drainage and congestion. CT scan done prior to referral revealed a 3 cm x 5 cm x 5 cm lobulated left parapharyngeal space mass suggestive of lymph nodes. Smaller nodes were seen in both jugular chains. MRI also done before referral showed similar findings. The patient denies hypertensive disease, coronary artery disease or diabetes mellitus. He had no known drug allergies. He has smoked cigars for 2 years, and occasionally uses alcohol. On physical examination, his tympanic membranes were clear, with no inflammation or fluid. The nose was patent, with no polyps or lesions. Examination of the OC/OP was clear, with good tongue and palate mobility, with a slight asymmetry with fullness of the left tonsil and parapharyngeal space compared to the right. HP/L was clear with good vocal fold mobility. The facial nerve was intact, with moderately large adenopathy of the left upper jugular chain, which was nonpulsatile. FNA and repeat FNA done at Methodist were inconclusive. The patient was taken to the OR for excisional biopsy. The mass was encountered in the jugulodigastric region and was grossly 6 cm, encapsulated, without evidence of extracapsular spread. The spinal accessory nerve grooved its lateral aspect. With frozen section diagnosis of malignant neoplasm, a MRND was done with removal of levels I-V. Next a direct laryngoscopy was done with biopsy of the left tonsil, right piriform sinus, and left tongue base. Postoperatively, nasopharyngeal exam showed slight asymmetry but no ulcers, masses, or lesions. 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Radiation treatment of cervical lymph node metastases from an unknown primary: an analysis of outcome by treatment volume and other prognostic factors. Radiother Oncol 1995;35:206-211 Grand Rounds Archive | Department Home page BCM Public | BCM Intranet | Privacy Notices | Contact BCM | BCM Site Map | ©2001-2006 Baylor College of Medicine
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