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. Management of Cervical Metastasis in
Squamous Cell Carcinoma of The Oral Tongue Squamous cell carcinoma of the oral tongue is the second most common site for oral cavity cancer behind the lip. Each year there are approximately 6,000 of these diagnoses made and about 2,000 deaths. Five-year survival for early stage disease is around 70%-80% and for advanced stage lesions is 2%, 40% or 50% five-year survival. Thirty percent of patients, who have an oral cavity primary including the oral tongue, will develop a second head and neck primary at some time. Cervical metastases are really important in this disease and diminish survival by at least 30%. The most common cause of death is not distant disease but rather local regional failure. The highest incidence of squamous cell carcinomas of the oral cavity is in the Pacific Rim, but the second highest incidence is actually in Western Europe. In the Pacific Rim there are about 40 cases per 100,000 and in Western Europe, there are 20 cases per 100,000. For the United States, we are somewhere in the middle - at around 12 cases per 100,000. Interestingly, the rest of Europe is actually pretty high as well, with Southern Europe and Eastern Europe being among the top 10 sites for the highest incidences. The Surveillance-Epidemiology-End Results Program, of the National Cancer Institute collects and publishes cancer incidence and survival data. It covers essentially 14% of the population by working with local tumor boards and collecting data on a population basis level. A continuing project of the NCI SEER maps trends in cancer survival and mortality of patients changing demographics. Recent SEER data shows that the incidence over the last three decades has continued to rise. There is a steady but sure trend here of increasing incidence of cancer among patients under 40 years of age. It is a disease that is striking younger patients. After this and other studies, different investigators have actually looked at the patterns of disease and the course of the disease in patients under 40 years of age, and have found across the board, that the disease is more aggressive. So, it has a unique subset of disease that has been changing in the last several years. Also, in another SEER-related project, in Connecticut, there was a striking increase in the number of women that are effected by this disease. In 1935, the incidence of male to female squamous cell of the oral tongue was about 10 to 1 and as late as 1985, it had lowered to 3 to 1. So, this is an ironic new quality between the sexes in an era of increased cigarette use and marketing among women. So, while the disease continues to increase in incidence and has the disturbing propensity to strike newer population groups including younger patients and women, there is little change in the treatment options that are available to patients. These consist mainly of refinements of pre-existing and time-honored modalities of treatment. The therapeutic options for this disease really must be made with careful consideration not only of what is available, but also the patient's age, lifestyle, occupation and willingness to participate in therapeutic regimen. Typically surgery and radiotherapy are used as the primary modalities. In managing this disease, staging and the TNM presentation is critical in the assessment and treatment. Just to go the TNM staging briefly, T1 and T2 lesions are essentially under 4 cm, no greater; local or regional spread are staged T3 to T4. Stage 1 and 2 diseases are essentially tumors of less than 4 cm in diameter and without cervical metastasis. In stage 3 and 4 disease candidates, the treatment of this disease is really best managed with combined modality, typically surgery followed with postoperative radiation, and this is widely accepted. Multiple studies have demonstrated an improved local regional control rate as well as disease-free survival in patients, who are treated this way compared to single modalities of therapy. Yet, despite this combined effort, prognosis remains grim for this type of cancer and can be as low as 20%-40%. Some studies will say survival is as high as 50%, but those are with small numbers of patients. Iit is very different for the earlier stage lesions. Perhaps there is no other site in the head and neck that is so capricious in respect to the clinical course than that of the squamous cell lesion of the oral tongue. Seemingly small insignificant lesions, even when treated, possess an incalculably large predilection to recur locally and to metastasize regionally. This aggressive behavior of T1 and T2 carcinomas of the mobile tongue is reflected in relatively lower rates when compared to the same staged disease in other sub-sites of the head and neck. Consequently, management of the disease has engendered a great deal of controversy in literature, both with regard to management of the primary and with regard to management of the neck. For management of the primary, the options are surgery and radiotherapy. There is evidence for T1 and some T2 lesions that radiotherapy is an adequate modality for treating lesions less than 4 cm. However, surgical extirpation is primarily preferred for a variety of reasons, as recently reviewed by Fein and colleagues in 1994. In this article they discussed the evolution toward surgical management of early squamous cell lesions. The advantages of surgery are not only that you can obtain staging and prognostic data but also that you can preserve options for further treatment if a second head and neck primary does develop. We have already discussed that there is the highest rate of second primary in the oral cavity; so, surgery leaves those options open for the patient and for this reason it has grown in popularity. For early stage disease, T1 and T2 lesions, treatment failure and regional recurrence occurs with an alarming frequency incommensurate with the size of the primary. Regardless of the treatment, either surgical or radiotherapeutic, regional failure in the lymphatics is seen with a great deal of frequency. Reviewing studies published over the last 20 or 30 years shows an occult cervical metastasis rate of anywhere from 23% to 45%. This has been seen in studies again and again, in different centers around the world and in our country, both with small and large numbers of patients. The propensity of these small lesions that cause silent, undetectable regional metastasis confounded generations of head and neck surgeons and has been a source of lively debate in the literature. So, when trying to decide about management of these patients, we should realize that the goal is really to avoid unnecessary treatment of the neck without compromising survival, given this high rate of cervical metastasis. So, your choices are essentially: to electively treat the N0 neck with either radiotherapy or surgery, or to watchfully wait and follow these patients closely with serial exams. As a single modality, surgery or radiotherapy is really effective for eradicating occult cervical metastasis, and the treatment option is really best decided according to the patient's preference, and their lifestyle and age. These survival and local control rates over the last 20 years have been shown to be an effective modality in treatment of the neck. Northrop in 1972, at M.D. Anderson showed an 82% local regional control rate with radiotherapy but a 56% survival rate. Mendenhall showed a 74% local regional control rate but no survival data was given. Decroy Security Institute showed for T1 lesions an 86% control rate, and for T2 , a 78% rate. M.D. Anderson, ten years later, showed essentially the same local regional control rate, but again no survival data was presented for radiotherapy controlling cervical metastasis. But, often glossectomy and selective neck dissection, including levels 1-4, has been the procedure of choice, during the last several years, refinements have been made on this procedure in order to improve on what was typically called the supraomohyoid neck dissection. These changes have been based on careful analysis of the patterns of nodal spread, both in large epidemiological studies conducted in large centers, and in careful assessment of the risks of proceeding with a supraomohyoid neck dissection versus a modified radical or radical neck dissection. But, it was Rouviere in 1938 that first began this careful look at the patterns of nodal metastasis, and detailed anatomical studies first showed that rather than occurring in a haphazard fashion, the sites of metastasis at certain levels in the neck could be predicted based on the size of the primary. Then, Fisch and Sigel in 1964, followed up on these studies and demonstrated with contrast dye lymphography the same pattern of spread. Briefly, to go over how lesions from the tongue metastasize, the more anterior the lesion is, the higher chance that you may have a lower chain in the jugulodigastric area metastasis, and at the more posterior end of the tongue, may drain into level 3 or even level 2, although it seems that through this vast sort of tree of lymph channels, regardless of the site, you could have metastasis at any of these levels. So, studies at M.D. Anderson with Dr. Fidler and Dr. Myers clarify the risks of metastasis and try to identify where you are most likely to have a metastasis. Based on that data, you can make a better guess at where the metastasis will be and provide a better operation, decreasing the morbidity and mortality. As expected, levels 1 and 2 in the submaxillary and upper jugular nodes have the highest rate of metastasis, but there is a small but sizable metastasis lower down in the chain and even rarely in the posterior chain as well. What are the results for neck dissection and for management of cervical metastasis in squamous cell of the oral tongue? Studies from Memorial, Sloane, M.D. Anderson and Florida showed local regional control rates anywhere from 80% to 90% and survival rates still low compared to other T1 and T2 lesions, but a little bit better than the numbers we saw for radiotherapy. Those range from 63% to 82%. One interesting study, that I wanted to bring to your attention, was published last year. It was a prospective multi-center trial that did show that supraomohyoid neck dissection was as effective in local regional control and survival and at controlling cervical metastasis as is the more extensive modified radical. Local regional control rates were the same, actually as little bit better, in the supraomohyoid as well as survival. There was not a statistically significant difference between these two groups. Although the risk for regional recurrence is significant for early stage disease in squamous cell carcinoma of the oral tongue, elective treatment of the neck is justified. We know that up to 40% of those patients will have occult disease but that leaves another 60% that are not going to have disease. Is it fair to subject them to the morbidity and potential mortality of treatment? You have to weigh the risks and benefit, and we are all familiar with the disadvantages of either modality, radiotherapy or the neck dissection. But, is the risk of not proceeding with elective treatment worse than doing nothing at all? During the last three decades, other studies have consistently shown that if you do not treat the primary lesion and do not treat the neck, if there is a regional recurrence, the salvage rate for cure and 5-year survival is much lower, and those rates are as low as 22% and as high as 40%. These rates of survival are actually very similar to the advanced staged lesions that we saw earlier, stages 3 and 4 disease. Spiro showed this in a large study in 1971, and also at the University of Pittsburg and here in Houston, similar results have been seen. So, based on this data, most would advocate the elective treatment in the N0 neck for squamous cell carcinoma of the oral tongue, because it may improve survival. Surgery seems to offer slightly better overall rates of cure; however, there is a risk of increased potential for morbidity and mortality. But with surgery we are going to obtain histological and prognostic data that may be helpful in further managing these patients and preventing regional recurrence. In patients with significant co-morbidities or advanced age, radiotherapy may still be a preferable option. To really answer this question, randomized prospective blind and clinical studies are needed, using a variety of outcome measurements, to assess the morbidity of neck dissection and radiotherapy, and a close evaluation needs to be performed. A large multicenter trial study is now underway with the American College of Surgeons. But, controversies do remain with this, particularly if the patient at high risk for metastasis could be identified, and primary resection and elective treatment of the neck could be justified. Right now our ability to predict those patients with positive lymph nodes either through clinical or pathological data remains limited. Let's go over some of those options: Imaging modalities either ultrasound, CT or magnetic resonance imaging. The new modality is PET scan and histologic criteria that can be obtained at the time of surgery in neck dissection. Ultrasound was looked at in 1987 by Dr. Feinmesser and also again in 1991 by Dr. Van den Brekel. In numerous studies, surgeon's clinical exam preoperatively has been as accurate as ultrasound, or very close to it, in assessing the presence of cervical metastasis. But, a new study in 1999, showed that with ultrasound-guided FNA you might be able to catch potential cervical metastasis if you do elect to watchfully wait and manage this disease. This is a pilot study and only had a 2-year follow-up, but it did show a decreased rate of local recurrence and an increased salvage rate of at least 48 months. So, this is an interesting option in the management of these patients. Although it is labor intensive, it does seem to show some promise. Does CT do any better? Radiographic criteria for a suspicious node have not really changed since the advent of this imaging modality. A suspicious node is any node from essentially 1cm to 1.5cm in size. Unfortunately, due to volume averaging in the computed tomography algorithm, there is really not resolution for images 3 mm or less, and so small regions of tumor growth, micronecrosis may be missed. So, with CT, again, there are conflicting reports of sensitivity. Physical exam may be as reliable as CT of the neck. However, of course, the CT scan is useful in providing other information or if there is a known nodal metastasis. High T2 signal intensity setting in the MRI may provide a more sensitive technique for evaluation of central necrosis, but further investigation is needed here. The PET scan also is a promising new modality but it is costly and not widely available. Dr. Manolidis recently completely a review at the University of California at Davis looking at this modality, both in occult and recurrent cervical metastasis. Are there other criteria that we could use - specifically, histological criteria? There are three that merit attention: perineural invasion, degree of differentiation of the primary tumor, and the depth of invasion of the primary. Two studies have shown that perineural invasion may well be a predictor for either early or late cervical metastasis. At the University of Pittsburgh in 1998, 142 patients were reviewed from all sites in the head and neck, and perineural invasion was, indeed, associated with a high rate of nodal metastasis, 73% versus 46%. Perineural invasion was also actually correlated with a higher rate of local recurrence as well. Dr. Byers at M.D. Anderson, in a smaller series, did not find a statistically significant trend for perineural invasion, but the trend was suggested. Does the degree of tumor differentiation provide any prognostic data in the incidence of regional metastasis? Mendelson first looked at this in 1976, and found that there may be a difference between grade I and II lesions versus less-differentiated and moderately-differentiated lesions. However, subsequent studies have shown the inherent subjectively of interpretation, and observer bias may limit the accuracy and usefulness of these criteria. Depth of invasion has been shown in two other studies to be related to the risk of cervical metastasis, but the degree of invasion has still not been worked out. Spiro, in 1996, showed that depth of invasion greater than 2 mm would be associated with increased rate of cervical metastasis; but Byers, in 1998, found that lesions greater than 4 mm were predictors for increased cervical metastasis. So, in summary, there is at present no really reliable means to accurately detect or to predict cervical metastasis. Imaging studies have a limited value. The PET scanner may be more reliable but is not readily available at this time in numerous centers. Histologic criteria may be more subjective and not as useful, and, in addition, would require intraoperative or postoperative prospective and would not provide important information at the time of the first biopsy when the patient is seen in clinic. At the same time that we are seeing an increase in this disease and realizing the limitations for the assessment for occult cervical metastasis, there have been some new developments in the molecular biology of metastasis that may provide an answer to this question. Our greater understanding of the molecular biology has increased our ability to predict the malignant potential of individual human cancers. Molecular markers in the primary tumor may serve as indicators of metastasis. So, goals of potential future studies would be to identify these markers, which correlate with cervical metastasis, specifically in squamous cell carcinoma of the oral tongue; and, at the same time, to try to determine whether expression of these metastasis- related genes in surgical specimens can predict the eventual development of metastasis. One hypothesis might be to evaluate angiogenesis, a popular and much talked about phase of metastasis. It may serve, based on early pilot studies, as an important process in the malignant progression of squamous cell carcinoma of the head and neck, and in particular the oral tongue. There may be molecular determinates of angiogenesis present within the primary tumor that would give us information about not only occult cervical metastasis but also eventually a relapse of disease, failure control and also ultimately survival data. What would be those potential molecular markers? Vascular endothelial growth factor would be one, a fibroblastic growth factor. Basic fibroblastic growth factor has been shown in other tumors to be an indicator of metastasis, specifically in its role in angiogenesis. An interleukin-8 may also foster the development in the local environment of angiogenesis and may be an important step overall, in metastasis. But at the same time that there may be positive regulatory mediators promoting angiogenesis, the lack of negative regulators such as interferon beta may also be important in the assessment of molecular markers. This is a disease on the rise - striking younger patients, striking more women. The rate of occult cervical metastasis has really not changed and is quite high, ranging from 25% to 43%. Given the poor rates of salvage, elective treatment of the N0 neck may improve survival in the treatment of this disease. For the future, molecular viral markers as well as improvements on imaging may be able to predict metastasis more accurately. Case Presentation A 61-year-old white gentleman presented with 3-month history of oral pain and change in speech. The patient had initially visited his dentist and was referred to the VAMC Otolaryngology-Head and Neck Surgery clinic. The patient was without significant comorbid disease, but did have a significant ethanol consumption history and a 50 pack per year history of cigarette use. Physical exam revealed a 2.5cm x 1.5 cm ulcerative lesion on the right anterior lateral tongue, but no palpable cervical lymphadenopathy. Remainder of head and neck examination was unremarkable. Biopsy was performed in the clinic and returned as moderately differentiated squamous cell carcinoma (SCC). Computed tomography of the neck demonstrated a single 1cm non-necrotic lymph node at the right upper jugulodigastric chain. Metastatic evaluation, including chest roentgenogram and blood chemistry studies, were negative. The patient underwent a right partial glossectomy with selective neck dissection, including levels I-IV. The primary tumor was a moderately differentiated squamous cell carcinoma (SCC) without evidence of perineural or lymphovascular invasion. Examination of the neck dissection revealed 19 nodes; three lymph nodes at level II showed microscopic focus of SCC. Post-operative radiotherapy of 50 Gy was administered over 5 weeks to the cervical lymphatics. Follow-up: At a recent clinic visit, 28 months since surgery, the patient was without evidence of recurrent disease. Bibliography Bailet JW, Abemayor E, Jabour BA, Hawkins RA, Ho C, Ward PH. Positron emission tomography: A new, precise imagingmodality for detection of primary head and neck tumors and assessment of cervical adenopathy. Laryngoscope 1992;102:281-288. Beenken SW, Krontiras H, Maddox WA, Peters GE, Soong S, Urist MM. 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