| 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. New Biomarkers of Squamous Cell Carcinoma of the Oral Tongue This morning’s Grand Rounds is a little bit of a change of pace. We’re going to shift gears from something that has been always traditionally very clinical at grand rounds to something more basic science. Cancer of the tongue is unfortunately something that can behave much more aggressively than what can be initially perceived. So, in this morning’s talk I’d like to just briefly go over basic anatomy, the standard tumor staging, the current thinking on management for tumor cancers, what we currently know and what we currently use as clinical markers to help us gauge the clinical prognosis of our patients. Current molecular markers that we have known to us, although not in use clinically, but what we know to be involved in the management or the behavior of cancer and then just briefly highlight a couple new ones that might play a role in the development of tumor carcinogenesis of tongue cancer. So some of the basics, this came out of the cancer statistics presented by Greenlee in this paper in 2000. Head and neck cancer accounts for three to five percent of all tumors. Cancers of the oral cavity account for 30% of all head and neck cancers. In 2000 there were approximately 30,000 new cases of oral cavity carcinoma with 7,800 deaths. Of these, there were 6,900 new cases of cancer of the tongue making it one of the more common oral cavity lesions and 1,700 deaths. Some basic anatomy which we all know is familiar to us. The tongue is a striated muscle which is covered with stratified squamous epithelium and the oral tongue basically comprises the anterior two-thirds of the tongue. The blood supply of the tongue is supplied by the bilateral lingual arteries. The venous drainage is by the dorsal lingual veins and the superficial ranine vein. The common nodal pattern drainage is thought to be that the tip drains to the anterior submental nodes, usually to the ipsilateral side and that the remaining anterior two-thirds then drains to the submandibular and jugular omohyoid area. The posterior one-third then drains to the lower jugular omohyoid area. This is the classic TNM staging which is all well known to us. Just a couple of things to emphasize. T1 is tumors less than two cm in dimension. T2 is two to four. T3 is greater than four and T4 is thought to invade surrounding structures although it is important to recognize that what these surrounding structures can be vague because it does include the deep tongue musculature; and obviously the nodal stage and the metastatic involvement. Just to reemphasize here. The nodal status is currently the single most important clinical prognostic indicator for survival. While the five-year survival of patients with T1 and T2 disease in the absence of nodal disease can be as high as 70 to 80%, and 50 to 60% in patients with T3 and T4 disease in the absence of nodal disease, the five-year survival drops by half in the presence of nodal disease to 25 to 30%. So what do we currently know and what do we currently not argue about or there is not much debate about. Most people agree that surgical excision is the goal or mainstay of therapy. For smaller lesions, T1 and T2 disease, single modality treatment is usually favored and usually it’s surgical excision. While radiotherapy has been shown to have equal survival results, because the long-term treatment required for radiotherapy, and morbidities associated with radiotherapy for these small lesions, most people agree that surgical therapy is the better way to go for these small lesions. With larger lesions, T3 and T4 disease, combined therapy is usually recommended, both surgical and radiotherapy. No one argues that in the presence of neck disease, neck dissection is recommended and adjunct radiotherapy is always recommended. With respect to the primary, you radiate the primary site when there is close surgical margins, evidence of perineural invasion or large tumor size. Radiotherapy to the neck is done for any evidence of extracapsular spread or multiple positive nodes. These are sort of the basic concepts that we use currently for the treatment of these tongue cancers that isn’t really debated today. Shaw, in 1990, did a retrospective review of 501 patients undergoing radical neck dissection. He then looked at these patients to ascertain the nodal patterns of spread based on who had an elective neck dissection with clinically negative disease and who had a therapeutic neck dissection. Of the patients who had an elective neck dissection the bulk of the nodal disease was as we stated in the initial diagram, in the submandibular area, the upper jugular chain, with 10% going down into Level IV and only 2% going into the posterior triangle. In patients who ended up requiring a therapeutic neck dissection for positive neck disease at the time of presentation, these patients also had high nodal disease in the upper jugular chain but it’s important to recognize as high as 20% had disease. In 1993 in Davidson’s review of 666 patients who had radical neck dissection for oral squamous cell carcinoma and only 1% of those patients had metastatic disease to Level V. So the question is, what to do about the negative neck? The management options can include serial examination with very close follow-up, surgery or radiotherapy. It is important to realize to occult nodal metastases however, is seen in at least 30% of patients with T1 and T2 disease and clinically negative neck. So although, you may have a patient with a seemingly small disease, or seemingly small primary, it is important to realize that at least 30% of these have clinically undetectable neck disease and the most common site of failure is in the ipsilateral neck and then as I stated earlier, it is important to recognize that nodal status is the most important clinical prognosticator and once neck disease does occur, their survival status is only half. So classically, what do we use to base our thinking in terms of decision for an elective neck dissection. These are some of the historical papers and studies that were done on presence of occult metastases in oral tongue lesions and the recommendations that came out of these based on that. Mendelsohn first presented this in 1976 as one of the first presenters in 1976 and he noted 18% of these patients with clinically negative necks had nodal disease and it went as high as 35% in Johnson’s review of 1980. Based on these findings, retrospective reviews, most people recommended an elective prophylactic neck dissection given the high rate of occult spread. So lets basically go over what are the studies that we have, what is the data that we know regarding that has formed our decision making to do elective versus therapeutic neck dissections in these patients. There are very few randomized prospective trials regarding this. There were two that I could find. One came out of 1980, Vandenbrook et al did a prospective randomized trial of 75 patients with squamous cell carcinoma of the oral cavity, and of these, he divided them into two groups. 39 patients underwent an elective neck dissection and 36 patients underwent very close follow-up with subsequent neck dissection with the development of neck disease. The point of this article was that in both groups, there was only about 50% who, in both the elective neck dissection and in the number of patients who went on to develop neck disease, who had nodal involvement. However, the important thing to recognize is that of these patients, the 50% who underwent elective neck dissection, only 13% were noted to have extracapsular spread which is still fairly high in the number of patients who are theoretically clinically negative neck. Of these patients, the 47% who went on to develop nodal involvement and then underwent a therapeutic neck dissection, they had a much higher percentage of patients, 25% who had extracapsular spread. This trial however, did fail to find a significant statistical significance between the two overall survival curves but they did, as I emphasized, note that delayed therapy does result in higher percentage of extracapsular spread and therefore, a higher percentage of patients with poor survival. And this is another one of the big studies that came out. This one came out of Memorial Sloan-Kettering and was in 1993 based on 500 patients. This was a retrospective review and they looked at 295 patients who had clinically negative neck disease and of those patients, 192 underwent an elective neck dissection and then they looked at these patients who presented with an initial N 0 neck and were followed closely and looked at who required a subsequent neck dissection and then they looked lastly at 206 patients who presented with small N 1 disease. 79 of these 209 had N 1 disease and these underwent an immediate therapeutic neck dissection. Of these patients, it is interesting to note that patients who underwent an immediate neck dissection and patients who underwent an elective neck dissection had a 15 and 16% failure rate of recurrence of the neck where patients who were followed along and waited for a neck dissection until they developed neck disease, they had a 26% failure rate in the neck. So, the thought based on this is that patients who undergo a salvage neck dissection are thought to have higher failure rates secondary to increased extracapsular spread at the time of presentation. In another look out of 1985 by Byers, he looked at 967 cases from 1970 and 1980. He noted that in the pathologically negative neck, patients who underwent an elective neck dissection and had confirmed pathologically negative necks, the failure rate was less than 10%. However, in the 30% of patients who did undergo an elective neck dissection but were noted to have pathologically occult metastatic disease, the failure rate was higher in 25%, and this of course went even higher depending on the number of positive nodes that were found in the presence of extracapsular spread and it was noted that when postoperative radiotherapy was added, the failure rates again dropped back down to less than 15%. So I think today most people don’t argue or question that an elective neck dissection is advocated for tumors of the tongue, particularly for T 2 and higher, given the high rate of occult metastatic spread and as I stated earlier, for T1 and T2 lesions, the five-year survival approximately 80 to 90% when treated by radiotherapy or by surgery. However, for later stage disease, Stage III and IV patients, the survival rates are only about 50 to 30% respectively. And again, these are the results that came out of Memorial Sloan-Kettering, out of Dr. Shah’s group and he noted again five-year survival rates for small tumors can approximate 90%. So what do we currently know about the behavior of these tongue cancers and what can we use to help us in our decision-making. With our patient earlier today this is a classic example of something that can be seemingly benign or be seemingly small and easily treatable can actually turn out to be something very aggressive. What do we have available to us to help us in our decision making or at least help identify the patients who might be at higher risk? In terms of demographic factors, we know for sure that previous studies show that male gender, older age, evidence of high smoking or excessive alcohol use have been associated with poorer prognosis. Carcinoma spread outside of the tongue, large tumor size and as I mentioned, spread to the neck, are all clinical factors that are associated with a high evidence of poorer prognosis. There are a couple other histological factors that we use or that we have available. There is a malignancy scoring system that can be done based on the degree of dysplasia, the degree of mitoses within the tumors, low tumor angiogenesis, the surrounding inflammatory response or leukocytosis around the tumors, evidence of elevated apoptotic levels or over expression of P53. These are some of the current histological markers or factors that we currently know or have been able to show are associated with a poorer prognosis. So, let’s look a little closer at some of these markers. Depth of invasion is one that we commonly use clinically. Sparrow first started in ’86 by looking at tumor depth - tumors less than 2mm, tumors 2-8mm and tumors greater than 8 mm. If you look at their risk of occult spread based on these findings, tumors greater than 8 were at a significantly higher risk of neck disease and even tumors that were 2-8 mm had at least a 25% evidence of nodal spread. These were then confirmed by some later studies. The only other prospective randomized trial that I was able to find in squamous cell carcinoma of the tongue include the study that came out of ’89, out of India, which was prospective randomized trial of 70 patients with T1 or T2 negative neck disease and while they did not find a significant difference with patients who had an elective neck dissection versus patients who had follow-up with a subsequent neck dissection, they did note that patients who had tumors with greater than 4 mm of depth were associated with an increased likelihood of nodal disease and poorer survival. These findings were also noted and mentioned by Byers in 1998. He noted that patients with T1 tumors, less than 4 mm in depth and were well differentiated had less than a 14% chance of occult positive disease. However, patients who had greater than 4 mm were at a much higher risk for going onto to progress neck disease. What are some of the other clinical markers that we use in addition to tumor thickness? Brown also looked at this based on patient archives tissue samples and he noted that tumor thickness, tumor stage, presence of perineural invasion were all associated with poor prognosis. Gaspard also confirmed this by mentioning that perineural invasion is also associated with a poorer outcome. Close, in 1987, brought up the point that perhaps rather than the presence of perineural invasion, it is more the presence of intravascular or angiovessel invasion was involved with a poorer outcome. So, looking at and trying to understand the development of cancer is sort of recognizing that this begins at the molecular level and that it is based on this whole multi-step carcinogenesis idea or model in squamous cell carcinomas of both the head and neck as well as in other sites. The thinking is this is a multi-step process where a series of genetic events eventually leads to unregulated cell growth, tumor cell immortalization and progression toinvasive cancer. So, we start here at this end of the spectrum with normal epithelium and then progression of continued insults, whether genetic, inherent genetic errors or environmental exposures and toxins and these are some of the key loss sites that have been known and documented with poor head and neck tumors. The loss of 9P, the loss of 3P, 17P as an example, activation of telomerase. What is telomerase? T-telomeres are at the end of the chromosome. They tend to shorten in length as the cells get older or closer to senescence. Telomerase is an enzyme that is known to lengthen T-telomeres by adding the DNA using an RNA template. So what happens? Malignant cells are often thought to exhibit dysregulation of the T-telomere and have over activation of the telomerase such that the T-telomere length does not shorten as you would normally see in a senescent cell but in fact, continues to be abnormally long and is thought to lead to continued cell proliferation immortalization of the cell cycle and it has been shown that elevated tolomerase activity can be as high as 35% of patients with oral cancers. The important thing is that this activity has been detectable or detected in some of the oral rinses of cancer patients when compared to oral washes of non-cancer patients. It makes a good potential diagnostic marker. Other markers in activation of P16, P53 which we will go into in a little bit, Cyclin D1 and these are all thought to occur at different sites, either, you know, early on in the cancer process versus being later event in the development of carcinogenesis. So what is P53? We have all heard about P53 and we all know that it is something bad but what’s hard is for the clinician to remember what that all means. P53 functions in response to genotoxic damage and permits the G1 arrest, the growth first cycle arrest, to allow time for the cell to undergo any DNA repair. It is sort of a checkpoint control. In normal cells it is a very short-lived protein but it can accumulate in cells with any DNA damage or in cells undergoing different sorts of stressors and it is when, at that point, decides what to do. In the severely damaged cell it sort of directs the cell to go into apoptosis and programs cell death. In a minor damaged cell or something that it thinks is repairable it undergoes cell cycle arrest, halts the cell growth, permits repair of these enzymes before progression of the cell. And what can activate or inactivate P53? Environmental exposures, external DNA damage, carcinogens as well as oncogenes and upstream regulators such as Semic and Ras. Located on 17P it has been noted to be the most commonly mutated gene among all cancers and among head and neck cancers it is thought to be abnormally mutated in about 45% of invasive tumors. So what is the correlation with head and neck cancer? Well in 1994, Leavy published a study looking at mutant P53 and tongue squamous cell carcinoma and the definite role for this has been questionable. He reported no significant correlation between aberrant P53 and progression to nodal spread. However, in 1996, Unal in his series of 70 patients with tongue cancers, noted a significant correlation with aberrant P53 and large primary size, presence of nodal disease and advanced tumor stage. So, while the definitive prognostic value of P53 is not exactly clear and it remains to be seen and examined further, it is clear that it is involved in the carcinogenesis process. The most popular study that came regarding P53 in head and neck cancer came out of Sidransky’s lab in 1995. They examined both P53 status and the histological margin status of 30 patients with respective head and neck squamous cell carcinomas. Of the 30 patients, five patients had histologically positive margins so they were taken out of the study but of the patients with histologically negative margins, he then went on to do molecular assessment of P53 using PCR analysis and he noted that 13 of these had positive margins by P53 mutation or positive P53 mutations within the margins and 12 of these had negative. Of the 12 who had negative P53 mutations, none went on to develop recurrent disease; however, of the 13 who did have positive margins, five went on to develop recurrent disease, eight did not. So, the importance of this is to sort of highlight that cancer is in fact, a molecular disease and that the progression to development of cancer or recurrence can begin at the molecular level and may be better detected at the molecular level than what we can normally see at the histologic level. Other key players that are involved in the development of head and neck cancer that I think are important to be aware of and may become future potential markers is Cyclin D1. Cyclin D1 is involved in the G1 to S phase transition and it’s actual function is to phosphorylate and inactivate the RB pathway, the retinoblastoma pathway. Now, retinoblastoma is a well-known tumor suppressor gene and so the over activation of Cyclin D1 is thought to inactivate the tumor suppressor activity of retinoblastoma. And it is one of the few known proto-oncogenes that has been implicated or involved in head and neck cancer. Located at 11q and its over expression has been documented in at least 43% of patients with head and neck cancer. Working on the flip side of Cyclin D1 is P16 which activates, which acts to inhibit the Cyclin D1 activity. The inactivation of P16 has been reported by both point mutation, chromosomal deletion and promoter methylation this gene. And the loss of the P16 expression has been reported in up to 80% of head and neck cancers. It is the most commonly injured or deleted region in head and neck cancers. And therefore, also one of the earliest detectable events. And so, it is thought to be one of the earlier events in this multi-step process and it has been found to be deleted in even 20% of benign mucoplakias in the oral cavity. What does it do? It is located at 9P and inhibits the Cyclin D cyclin dependent kinase complex and it is a potential early marker in the development of cancer. bviously the field of tumor biology in head and neck cancer is well beyond the scope of this talk, but there are some other key cell signal regulators that are involved in the development of head and neck cancer. Some of the big ones are integrins, different growth factors which can activate either the Ras pathway which is involved in hyperproliferation, the PI3 kinase and the AKT pathway which is involved in the activation or inactivation of apoptosis, death receptors which activate the apoptotic pathway using via the caspaces and then as well as a whole host of other intracellular signalers. There are also a whole host of the angiogenic factors that are thought to be involved in angiogenesis and in the development of head and neck cancer. It was sort of my impression that the jury is out on whether or not this plays an important role in particular to tongue tumors. One of the reasons or thinking behind this is the tongue in and of itself is a very vascular host so whether or not the addition or the development of further angiogenesis or increased microvessel counts in things like that are really correlative with long-term prognosis or aggressive behavior of the cancers has sort of been debatable and in 1996, Spitzer looked at 75 patients who had T1 disease and he looked at microvessel counts within these tumors and he noted that increased microvessel counts were associated with lymph node metastases. Now, how well these microvessel counts were and how accurate that is as an assessment is sort of debatable as well but, by contrast, in 1994, Leeds did a retrospective review of 57 patients with small T1, T2 tumors and he noted no significant correlation between angiogenesis, high microvessel counts and tumor potentials for lymph node spread. There are a whole host of angiogenic factors, growth factors and so forth that can be involved in the development of cancer and how much of a role this plays in the long-term prognosis of patients is yet to be seen. So what are a couple of new ones? Well, this is one of the potential new hot markers. Fhit is fragile histidine triad and it is located at 3P14. What is it? It is the most fragile site in the human genome, one of the most commonly deleted sites or injured sites in head and neck, in the progression of head and neck cancer. So is this one of those just randomly fragile sites that randomly gets knocked off every time the patient goes on to develop cancer or is this actually involved in the development of tumorogenesis is what remains to be seen with future studies. What does it do? It exhibits an adenosine four phosphate or a three phosphate hydrolase activity. It’s been found to be deleted in multiple tumor types including the digestive tract, breast, lung and head and neck cancer. There have been multiple studies looking at head and neck cancer cell lines and primary tumor sites and have shown it to be deleted or injured in at least 68% of patients. The alterations and whether or not it actually is a tumor suppressor gene is what has been sort of debatable because it doesn’t follow the classic loss of heterozygosity to hit apophysis that Nudsen originally came up with. The different mechanisms have been known to occur at both the genomic, RNA as well as the protein level by both homozygous exon deletions which would be your classic two-hit hypothesis but it has also been found to have insertions at the intronic sequences, aberrant transcripts at the RNA level, loss of protein expression in them, the newest topic is whether or not there is epigenetic modification with hypermethalation at the promoter region. So what does it do? I have basically said before it’s an AP3A or an AP4A hydrolase but the thinking is it’s not actually this hydrolytic activity that’s involved in the tumor suppression, but in fact, the formation of this complex that serves in cell cycle signaling and activates the apoptotic and tumor suppressive pathway. It has been shown that low levels of AP3A is associated with apoptosis and so the maintenance of these low levels is what helps drive this pathway. In the absence of this complex and elevated levels of AP3A accumulate in the cell and the cells have been shown to have sustained cell proliferation and unregulated cell growth which is thought to occur as we know in head and neck cancer. So what is some of the other evidence to suggest that the tumor suppressor function of Fhit in particularly head and neck cancer? The transfection of Fhit has been performed using adenovector viruses in head and neck cell life as well as in non small-cell cell life, non small-cell lung cancer cell life. And this has been shown that if you reintroduce Fhit into the Fhit negative cell, it induces apoptosis and cell growth. As I stated before, the tumor suppressor function of Fhit tends to be independent of its hydrolytic activity and it’s the formation of this complex that is actually involved in the cell-signaling pathway. So what’s another one of that’s a potentially hot marker for the future? P10 which is also known as the phosphatase tensin homologue which is deleted on chromosome 10. It is also a very common site that’s injured in head and neck cancers in the multi-step processes. It is located on 10Q 23.3 and it encodes a dual specific protein and lipid phosphatase. What does it do, where is it involved and what is the significance? Well, it’s involved in the PI3 kinase pathway and it inhibits this pathway or it activates this pathway which inhibits the AKT pathway. Well, what’s the AKT pathway? Its one of the key pathways involved in the development of caspace 9 and phosdependent apoptosis. And so its one of the key regulators in determining both cell proliferation and survival versus the development and progression onto the apoptotic pathway. Germ-line mutations or inherited mutations of P10, have been noted in what’s known as Cowdin syndrome. Its associated with multiple benign hamartomas, malignant breast carcinomas and malignant thyroid neoplasms. Somatic mutations of P10 have been found in multiple neoplasms including glioblastoma, melanoma, prostate carcinoma and endometrial carcinoma. So what is the significance for head and neck cancer and is it involved in head and neck cancer? Well, Shou in 1998 looked at 19 tissue samples from patients with head and neck squamous cell carcinoma and he identified loss of heterozygosity in six of these 15 tumors at that site. And of these a definitive mutation of P10 was noted in three of the specimens suggesting that P10 may in fact, be a player in the development of head and neck carcinoma. Henderson, et all, out of Clayman’s lab in 1998 at Anderson however, looked at both cell lines and tissue, primary tissue samples from patients with head and neck carcinoma and he noted no significant deletions or mutations of P10 so is it involved or is it not involved, that is what remains to be seen with further studies. So, just to highlight. Both Fitt and P10 are potential tumor suppressor genes that may play a prominent role in the development of head and neck cancer. These are sort of two new tumor suppressor markers that can add to our current body of knowledge of markers that are involved in the development of head and neck cancer. What’s the significance? Well, that’s where the whole new field of translational research making the connection from the basic science lab into the clinician’s office is becoming an exciting new field today. It can be used for both its prognostic value. The development of important new markers can help, hopefully help us identify in the future which patients will go on to present with more aggressive behavior, something like our initial patient who had what was well differentiated and no evidence of lymphatic or angiogenic invasion may have had some sort of genetic causes that we may have been able to detect and help us aid in our therapeutic management right off initially. What else can it be used as? Perhaps it can be used as a diagnostic marker for patients who have leukoplakia. In sort of targeting which patients are at higher risk for going onto develop disease or as a predictor for recurrent disease, patients who have already been treated with cancer, have been radiated and now present to your office with ulcerative lesion. Well, is this ulcerative lesion related to radiotherapy, radiation induced changes or is this in fact, an early recurrence? And you, often as the clinician, can biopsy these things and send them over to the pathologist and they can’t, it is very difficult for them to even tell whether or not this is related to radiation induced change or in fact, is a new malignancy. So, perhaps these can be used as new markers for recurrence and then the other potential future avenue is as a direct therapeutic target for gene therapy and so forth. So just to summarize, I just wanted to emphasize again that the natural behavior of squamous cell carcinoma of the tongue can be much more aggressive than it may appear initially and the current management principles include single modality therapy for Stage I and Stage II disease and combined therapies for Stage III and Stage IV disease. Most people today advocate elective neck dissection or super omohyoid neck dissection for patients with the N 0 neck, particularly for patients with T2 and greater disease. And many are even advocating for T1 and greater. And then, just to end, that the development of new prognostic markers may help us in identifying these patients who have more aggressive behavior and help us and permit the tailoring of their therapy Case presentation: DR is a 73-year-old woman who presented with a one-year history of a painful mass of the left lateral tongue. She had no previous smoking or alcohol history. This had previously been biopsied by outside physicians and diagnosed as hyperkeratosis, without evidence of obvious malignancy. On examination, she was noted to have an approximately 1.5 cm ulcerative lesion in the left lateral anterior 1/3 of the tongue, which was exquisitely tender to touch without significant surrounding induration. Given the persistence of pain, she was taken to the operating room for a definitive excisional biopsy. A 1.2-cm x 1.1-cm x 0.1-cm mass was excised, and the ulcerated lesion was a maximum 0.3 cm from the surface. The final pathology was consistent with a well-differentiated T1 N0 squamous cell carcinoma with no evidence of vascular or lymphatic invasion. Given these findings, we had an extensive discussion with her regarding her treatment options. These options included close follow-up, elective neck dissection or radiotherapy. She elected to continue with close follow-up. Post-operatively she did very well, without evidence of recurrence until approximately 11 months after her initial surgery. At this time, she presented with a slowly enlarging right level 4 neck mass. A fine needle aspirate of this was consistent with metastatic SCC. A thorough work-up failed to reveal a second primary. She subsequently went to the OR for a right modified radical neck dissection. The final pathology was consistent with multiple involved nodes along the inferior right jugular chain with extracapsular spread. She has just completed post-operative radiotherapy and is recovering without further evidence of recurrent disease. Bibliograhpy:: Al-Rajhi N, Khafaga Y, El-Husseiny J, Saleem M, Mourad W, Al-Otieschan A, et al. Early stage carcinoma of oral tongue: prognostic factors for local control and survival. Oral Oncology 2000;36:508-514. Beenken SW, Krontiras H, Maddox WA, Peters GE, Soong S-J, Urist MM. 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