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General Considerations
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The oral cavity is bounded anteriorly by the vermilion border of the lip, superiorly by the hard-soft palate junction, laterally by the tonsillar pillars, and inferiorly by the circumvallate papillae of the tongue. Cancer of the oral cavity is classified by subsite: lip, oral tongue (anterior two thirds), buccal mucosa, floor of mouth, hard palate, upper and lower gingiva (alveolar ridges), and retromolar trigone. There is an estimated annual incidence of 23,110 new oral cavity cancers in the United States with approximately 5370 deaths per year. Men are affected 2–4 times more often than women for all racial and ethnic groups. The incidence of oral cancer increases with age, with median age at diagnosis of 62, although there is a trend of increasing incidence of tongue cancer among young people.
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Tobacco use (both chewing and smoking), alcohol, and betel nut chewing are well-established causes of oral cavity cancer, and their carcinogenic effects are often synergistic. Other etiologic factors include poor oral hygiene and immunosuppression. The majority (90%) of cases of lip cancer are related to chronic sun exposure.
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The oropharynx is posterior to the oral cavity and is bounded by the soft palate superiorly and hyoid inferiorly. Oropharyngeal subsites include the base of tongue (posterior third), palatine tonsil, soft palate, and posterior pharyngeal wall. These lesions are often silent in early stages and, consequently, frequently present at advanced stage. Cancer of the oropharynx occurs in an estimated 7570 patients in the United States each year, resulting in approximately 1340 deaths. Males are afflicted 3–5 times more frequently than females. Oropharyngeal cancer is frequently related to tobacco and alcohol use, although 30–50% of cases may be related to human papilloma virus (especially HPV-16), particularly in tonsil cancer.
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Staging for both lip and oral cavity cancer is determined according to the 2010 American Joint Committee on Cancer (AJCC) TNM (tumor, node, metastasis) staging system (Table 23–1). AJCC staging for oropharyngeal cancer is shown in Table 23–2.
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The oral cavity and the oropharynx are lined by squamous epithelium. Therefore, the most common cancer arising from these regions is squamous cell carcinoma (SCC). Non-SCC histologies account for less than 10% of malignant lesions of the oral cavity. Minor salivary glands found throughout the oral cavity and oropharynx can give rise to adenocarcinoma, adenoid cystic carcinoma, mucoepidermoid carcinoma, and polymorphous low-grade carcinoma. Lymphoma is the second most common tumor of the tonsillar fossa. Other malignant tumors include sarcoma and mucosal melanoma.
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Cancers of the oral cavity are often heralded by precancerous lesions. Leukoplakia and erythroplakia are white and red areas, respectively, which are abnormal but not necessarily neoplastic. These lesions may be entirely benign, precancerous, or frankly invasive, although this can only be determined after biopsy with histologic evaluation. Precancerous lesions range from dysplasia to carcinoma in situ and describe abnormal-appearing cells that have not invaded normal underlying epithelial tissues. Dysplasia is classified as mild, moderate, or severe according to its tendency to progress to cancer. Dysplasia, in mild forms, can regress if the carcinogenic agent is removed. Leukoplakia is usually a benign condition that is unlikely to progress into cancer (5%). Erythroplakia is more likely to be malignant at the time of the initial biopsy (51%).
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The incidence of lymph node involvement from cancers of the oral cavity is related to the depth of invasion, site, size, and histologic grade of the primary tumor. Tumors of thickness greater than 1.5–2 mm are more likely to present with nodal metastases. Cancers of the oral tongue and floor of mouth have a higher incidence of nodal metastases than do cancers of the lip, hard palate, and buccal mucosa. Cancers of the lip most commonly involve the lower lip and rarely proceed to lymphatic spread (<10%). In the case of nodal spread from lip cancer, it is typically the submental and submandibular nodes (level I) that are involved. Lateral tongue, floor of mouth, and buccal cancers drain to the ipsilateral submandibular nodal basin as well as to the upper (level II) and middle (level III) jugulodigastric nodes. Midline tumors may drain bilaterally.
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Oropharyngeal tumors are frequently associated with nodal metastases at the time of diagnosis. The extensive lymphatics in this region drain primarily to the jugulodigastric basin (levels II to IV). It is important to note, however, that the retropharyngeal and parapharyngeal nodes are also at risk with oropharyngeal cancers.
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Lung, liver, and bone are common metastatic sites for SCC of the oral cavity and oropharynx.
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Tobacco use, especially when combined with heavy alcohol intake, which has a multiplicative effect, accounts for 80% of oral cavity and oropharynx cancers in the United States. Stopping the use of tobacco products and decreasing alcohol intake can greatly reduce the risk of oral cancer and improve treatment outcomes. Cancer of the lip can be avoided by limiting sun exposure through the use of sunscreen or a wide-brimmed hat. Pipe smokers are particularly prone to cancer of the lower lip, and cessation of pipe smoking reduces this risk significantly. There is evidence that isotretinoin, a synthetic retinoid, may help prevent malignant progression of leukoplakia.
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Benign and malignant lesions of the oral cavity and oropharynx present in a wide variety of forms. Although the oral cavity is a visually and palpably accessible site, the symptoms associated with malignant lesions are often vague or painless. They most commonly present with nonhealing ulcer, bleeding, pain, or ill-fitting denture. Locally advanced lesions may present with dysarthria, dysphagia, neck mass, and/or referred otalgia due to cranial nerve involvement.
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Malignant lesions of the oropharynx are often asymptomatic until they reach a locally advanced stage. The most frequent complaints at presentation include vague discomfort, irritation and/or neck mass, although presenting symptoms vary by subsite. For example, the base of tongue has few pain fibers and consequently patients often present with an asymptomatic neck mass. Other possible symptoms include foreign body sensation in the throat, referred otalgia, dysphagia and/or dysarthria. Tonsillar lesions commonly present with pain, odynophagia, dysphagia, trismus and/or ipsilateral referred otalgia.
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A standard laboratory evaluation should include a complete blood cell count and blood chemistry profile, including liver and renal function tests. HPV testing of biopsy specimens can be considered in patients with oropharyngeal tumors, especially in patients with tonsillar lesions with no history of smoking.
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A computed tomography (CT) scan, magnetic resonance imaging (MRI), or both types of imaging of the head and neck should be performed to evaluate the primary lesion and lymph node metastases. An MRI is preferred for the evaluation of soft tissue or base of skull involvement; a CT scan is better to evaluate cortical bone involvement. A chest X-ray should be performed to rule out metastases. Positron emission tomography (PET), especially when combined with CT (PET-CT), is increasingly used to assess the extent of primary tumor invasion, evaluate for regional and distant metastases, and detect synchronous second primary tumors.
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Special Tests and Examinations
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All lesions should first be evaluated by a complete history and head and neck examination, followed by flexible fiberoptic endoscopy as needed. Additional tests that may be performed include (1) examination under anesthesia, including palpation, direct laryngoscopy, and biopsy; (2) tumor mapping with toluidine blue dye and acetic acid, (3) a preradiation dental evaluation and audiology exam, and (4) Panorex films of the mandible to rule out mandibular invasion.
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Differential Diagnosis
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When evaluating a patient with any of the above symptoms, the differential diagnosis for a malignant lesion should also include bacterial or viral infection, trauma, leukoplakia or erythroplakia, eosinophilic granuloma, fibroma, giant cell tumor, pyogenic granuloma, papilloma, and verruciform xanthoma.
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Squamous cell cancers of the oral cavity are primarily treated surgically, while those of the oropharynx are primarily treated with definitive radiotherapy (RT). In general, early-stage lesions are treated by surgery or radiation alone, whereas locally advanced disease necessitates a multimodal approach: surgery and postoperative radiotherapy (PORT) ± chemotherapy in the oral cavity and definitive RT with concurrent chemotherapy in the oropharynx.
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Surgery remains the primary treatment for cancers of the oral cavity due to the surgically accessible nature of the oral cavity, as well as the satisfactory functional outcomes that can be achieved. Moreover, treatment of oral cavity cancers with definitive radiation is made challenging by the mobility of structures within the oral cavity, the surrounding maxillodental structures that interfere with ionizing radiation. Tumors of the oral cavity also have a tendency toward well-differentiated histology that renders them relatively radioresistant.
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For early-stage lesions, surgery can be performed through a transoral approach and closed primarily or with a split thickness skin graft with excellent functional outcome. More extensive lesions necessitate a larger surgical approach, often via mandibulotomy and requiring regional flap or free tissue transfer coverage, although minimally invasive (transoral laser and transoral robotic) techniques are increasingly being used. For locally advanced lesions deemed unresectable, definitive chemoradiotherapy is the treatment of choice.
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PORT is recommended for resected patients with a high risk of locoregional recurrence. High risk is defined by close/positive margins or extracapsular lymph node extension. Additional factors involved in risk-stratification include advanced T-stage, perineural or lymphovascular invasion, level IV nodal involvement and multiple positive lymph nodes. In the postoperative setting, a dose of 6000–6300 cGy is delivered to the tumor bed and areas of nodal involvement without remaining gross disease. Areas at high risk for recurrence, especially those with micro- or macroscopically positive margins, can be boosted to 6600–7000 cGy. Regions at risk for micrometastases but without pathologic or radiologic evidence of involvement, including the low neck and supraclavicular fossa, are treated with a prophylactic dose of 5000–5400 cGy. A pooled analysis of two randomized trials showed that the addition of concurrent cisplatin to PORT improves locoregional control and disease-free survival in patients with positive margins and extracapsular nodal extension; one of these studies also showed an improvement in overall survival.
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Primary RT is the preferred treatment for most squamous cell cancers of the oropharynx. In early stage lesions, RT and surgery can both provide high rates of local control, but RT is associated with better functional outcomes. Locally advanced disease is most often treated with definitive RT and concurrent chemotherapy. Several randomized trials, as well as a recent meta-analysis, have provided evidence that the addition of concurrent platinum-based chemotherapy to definitive RT offers a survival advantage in locally advanced disease.
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Radiation has traditionally been delivered to the head and neck through conventional external beam radiation therapy (EBRT), brachytherapy (the implantation of temporary radioactive sources within the tumor; Figure 23–1), or a combination of these two modalities. Current external beam modalities involve three-dimensional dose delivery using 3D conformal radiation therapy (3DCRT) or intensity-modulated radiation therapy (IMRT). IMRT is a sophisticated technique that modulates the intensity of the radiation dose delivered within each field, permitting optimal coverage of tumor regions while sparing the surrounding normal tissue (Figure 23–2). Consequently, when compared to previous RT techniques, IMRT has been shown to reduce the incidence and severity of late toxicities (ie, xerostomia), in addition to allowing for improved locoregional control in many cases.
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Definitive RT involves higher doses than postoperative treatment due to the presence of gross disease. Because of its ability to minimize toxicity to surrounding normal tissue, IMRT has enabled the delivery of higher doses to target volumes than was possible with previous RT techniques. Areas of known gross or macroscopic disease require doses of 7000 cGy. Nodal areas at high risk receive 6000–6600 cGy, and those at low risk receive 5000–5400 cGy.
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Surgery is the preferred modality for primary treatment of the lip. Small tumors can be treated with primary excision with excellent functional and cosmetic results. Primary excision is also preferred for T3 or T4 lesions, often requiring a reconstructive flap from the uninvolved opposing lip (eg, Abbe–Estlander technique) to maintain cosmesis and function. Postoperative RT (PORT) +/− chemotherapy is indicated in resected patients with high-risk features.
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For T1 or T2 lesions, the incidence of lymph node metastasis is less than 10%. Due to the low incidence of regional metastasis, the regional lymph nodes are not usually treated for early-stage cancers of the lip. Locally advanced disease and high-grade lesions warrant neck dissection +/− PORT/chemotherapy.
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For early T1 and T2 tumors that are deemed surgically resectable without significant functional morbidity, transoral partial glossectomy is the treatment of choice for management of the primary lesion. Advanced T3 and T4 disease with deep muscle invasion is often associated with lymph node metastases and is typically treated with transmandibular or transcervical total glossectomy. Depending on the extent of disease, ipsilateral or bilateral neck dissection is indicated at the time of primary resection. PORT +/− chemotherapy is indicated in patients with high-risk features.
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Definitive RT for oral tongue lesions is reserved for patients with unresectable tumors or other contraindications to surgery.
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Small T1 or T2 tumors are highly curable, with transoral resection being the preferred modality. Larger infiltrative T3 or T4 lesions are best treated by radical surgery—often a composite resection incorporating the tongue, extrinsic musculature, and mandibular bone.
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Early metastasis to the regional lymph nodes is common for carcinomas of the floor of mouth. Selective nodal dissection is warranted for T1 or T2 lesions with thickness >4 mm. Ipsilateral comprehensive neck dissection is indicated for advanced lesions, while bilateral neck dissections are warranted for lesions approaching the midline.
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As with other sites of the head and neck, PORT +/− chemotherapy is indicated for high-risk features.
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Primary RT (EBRT +/− brachytherapy) is reserved for patients with unresectable tumors or other contraindications to surgery. Lesions in close proximity to the mandible should not be treated with brachytherapy owing to the risk of osteonecrosis.
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Smaller lesions may be treated with transoral excision alone with good local control, while larger lesions may require a cheek flap approach. T3 and T4 lesions with deep muscle invasion are usually treated with radical surgery, involving resection of the skin of the external cheek or bone of the adjacent maxilla or mandible.
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For small lesions with clinically negative nodes, the neck can be observed, although an elective supraomohyoid (levels I–III) neck dissection is often recommended. Ipsilateral +/− contralateral neck dissection is indicated in T3 and T4 disease. For both the primary region and the neck, PORT +/− chemotherapy is indicated for high-risk features.
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Primary RT is reserved for selected T2 lesions as well as those approaching the commissure so as to maximize cosmetic and functional outcome. In these cases, radiation can be delivered via external beam or brachytherapy, depending on the clinical situation.
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Alveolar Ridge and Retromolar Trigone
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As with other smaller lesions of the oral cavity, T1 lesions with minimal cortical invasion may be treated with primary transoral excision. Although lesions without periosteal invasion may be resected subperiosteally with preservation of the mandible, marginal mandibulectomy is indicated for tumors invading the periosteum, and bony involvement necessitates segmental mandibulectomy.
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Depending on the presence of nodal involvement, either supraomohyoid or comprehensive neck dissection is indicated.
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PORT +/− chemotherapy is indicated for high-risk features.
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Small lesions without periosteal involvement can be excised by transoral wide local excision, while periosteal or bony involvement requires an infrastructure maxillectomy followed by prosthetic rehabilitation. Advanced lesions require radical surgery with total palatectomy.
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Elective treatment of the neck is often omitted due to the low rate of nodal metastases in early stage disease. If the primary disease extends beyond the hard palate, a supraomohyoid neck dissection is indicated.
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PORT +/− chemotherapy is indicated for high-risk features.
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Definitive RT, with or without chemotherapy, is the treatment of choice for most base of tongue tumors. Although comparable locoregional control can be achieved with surgery, RT is associated with better functional outcomes.
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Early stage disease is usually treated with definitive RT consisting of either EBRT alone (preferably IMRT) or EBRT plus a brachytherapy boost. In the latter technique, a lower dose of EBRT is followed by a brachytherapy boost to the primary tumor, and a neck dissection is usually performed. Both techniques have proven track records with local control rates approaching, and in some cases exceeding 90%.
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Chemoradiotherapy is the treatment of choice for locally advanced disease. Many series, both retrospective and prospective, have shown excellent locoregional control with acceptable acute and late toxicity in patients treated with IMRT or 3DCRT plus concurrent chemotherapy.
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Tonsil, Soft Palate, and Pharyngeal Wall
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As in the base of tongue, definitive RT with or without chemotherapy is the treatment of choice for tumors of the tonsil and soft palate.
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Early stage disease may be treated with definitive RT alone. Lateralized early stage tumors of the tonsil may be treated with ipsilateral radiation fields to minimize irradiation to the contralateral side. Selected patients with small, well-localized lesions may be treated with function-preserving surgery and elective neck dissection.
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Definitive radiation with concurrent chemotherapy is the optimal treatment for locally advanced lesions. Many series have shown locoregional control rates of greater than 90% for patients treated with IMRT. Moreover, the improved dose conformality afforded by IMRT has resulted in reduced late adverse effects.
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Tonsillar lesions are frequently associated with HPV infection. Patients with HPV positive tonsillar tumors have been shown to have superior treatment outcomes.
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Surgical Complications
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The complications of surgery include infection; hemorrhage; weight loss; facial swelling; difficulty with speech, phonation, and swallowing; and loss of speech or swallowing capability. The rate of surgical complications, including fistula formation and wound breakdown, is increased in irradiated tissue.
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Radiation-Related Complications
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The complications of radiation are divided into acute and chronic toxicities. Acute toxicities include fatigue, weight loss, mucositis, dysguesia, odynophagia, skin desquamation, and laryngeal edema. Chronic toxicities include dysphagia, xerostomia, trismus, hypothyroidism, hearing loss, and skin and soft tissue fibrosis/atrophy. Rare, but severe, late complications of radiation include osteoradionecrosis and carotid artery rupture. With the advent of IMRT, the rate of xerostomia has significantly decreased, resulting in improvement in patient quality of life.
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The Surveillance, Epidemiology and End Results (SEER) Cancer Statistics review for the years 1999 to 2005 reports 5-year relative survival of oropharynx and oral cavity cancer of 62.5%. Local control and survival rates vary by individual subsite and are inversely related to degree of nodal involvement, tumor size and the presence of distant metastases. There is considerable evidence that survival is higher in patients with HPV-positive oropharyngeal tumors. Recent reports of oropharyngeal cancer treated with IMRT and concurrent chemotherapy have noted 3-year locoregional control rates ranging from 87% to 93%. Locoregional control rates for oral cavity cancer are lower; recent reports of patients treated with surgery and postoperative IMRT have noted 2-year locoregional control rates ranging from 78% to 82%.
Bernier J, Cooper JS, Pajak TF et al. Defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501).
Head and Neck 2005;27:843
[PubMed: 16161069]
.
de Arruda FF, Puri D, Zhung J et al. Intensity-modulated radiation therapy for the treatment of oropharyngeal carcinoma: the Memorial Sloan-Kettering Cancer Center experience.
Int J Radiat Oncol Biol Phys 2006;64:363
[PubMed: 15925451]
.
Denis F, Garaud P, Bardet E et al. Final results of the 94–01 French Head and Neck Oncology and Radiotherapy Group randomized trial comparing radiotherapy alone with concomitant radiochemotherapy in advanced-stage oropharynx carcinoma.
J Clin Oncol 2004;22:69
[PubMed: 14657228]
.
Eisbruch A, Harris J, Gardner AS et al. Multi-institutional trial of accelerated hypofractionated intensity-modulated radiation therapy for early-stage oropharyngeal cancer (RTOG 00-22).
Int J Radiat Oncol Biol Phys 2009 [Article in Press]
[PubMed: 19540060]
.
Pignon JP, le Maître A, Maillard E, Bourhis J; MACH-NC Collaborative Group. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomized trials and 17,346 patients.
Radiother Oncol 2009;92:4
[PubMed: 19540060]
.
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The Cancer Group Institute (Background epidemiological information on oral cavity and oropharyngeal cancers): http://www.cancergroup.com
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The National Cancer Institute (Treatment and prevention of oral cavity and oropharyngeal cancers): http://www.cancer.gov
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(Surveillance Epidemiology and End Results – database of US cancer statistics): http://www.seer.cancer.gov/
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Web MD Corporation (A review of lip and oral cavity cancer, presenting symptoms, staging, and treatment): http://www.webmd.lycos.com
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The American Cancer Society (Overview of benign and malignant lesions of the oral cavity and oropharynx): http://www.cancer.org