HHS Public Access: Cancer of The Oral Cavity
HHS Public Access: Cancer of The Oral Cavity
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                                 Surg Oncol Clin N Am. Author manuscript; available in PMC 2016 September 10.
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                    Keywords
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oral cavity cancer; oral cancer; squamous cell carcinoma; head and neck cancer
                    INTRODUCTION
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                                       Cancer of the oral cavity is one of the most common malignancies, especially in
                                                                                                           2
                                       developing countries, but also in the developed world . Squamous cell carcinoma (SCC) is
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                                       the most common histology and the main etiological factors are tobacco and alcohol use .
                                       Although early diagnosis is relatively easy, presentation with advanced disease is not
                                       uncommon. The standard of care is primary surgical resection with or without postoperative
                                       adjuvant therapy. Improvements in surgical techniques combined with the routine use of
                                       postoperative radiation or chemoradiation therapy have resulted in improved survival
                                                                             4
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                                       statistics over the past decade . Successful treatment of patients with oral cancer is
                                       predicated on multidisciplinary treatment strategies to maximize oncologic control and
                                       minimize impact of therapy on form and function.
                    Corresponding Author: Dr. Snehal G. Patel, Head and Neck Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New
                    York, NY 10065. Telephone: 212-639-3412, patels1@mskcc.org.
                    The Authors have nothing to disclose.
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                    Montero and Patel                                                                                                   Page 2
                                        (Figure 2). In the European Union there are an estimated 66,650 new cases each year. The
                                        American Cancer Society estimates that there will be 42,440 new cancers of the oral cavity
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                                                                                                      6
                                        and pharynx in the U.S. causing 8,390 deaths in 2014 . Tobacco smoking and alcohol are
                                                                                                                 3, 7
                                        the main etiological factors in SCC of the oral cavity (SCCOC)   . Other habits such as
                                        betel nut and tobacco chewing have been implicated in the Asian population.
                                                           3, 12, 13
                                        oropharyngeal SCC            . However, alcohol is linked to an increased risk of cancer even in
                                                     14                                             15                        16
                                        non-smokers . Other factors such as poor oral hygiene , wood dust exposure , dietary
                                                    17                                           18, 19
                                        deficiencies , red meat and salted meat consumption              have been reported as etiologic
                                        factors. The herpes simplex virus (HSV) has been suspected but has not been implicated in
                                                                   20
                                        the etiology of SCCOC . Despite the emerging evidence supporting the role of the human
                                        papilloma virus (HPV) in the etiology of oropharyngeal cancer, it has not been conclusively
                                                             21
                                        linked to SCCOC . Host factors such as immune system alterations in transplant
                                                 22, 23                                    24
                                        patients        and HIV-infected patients with AIDS , and genetic conditions like xeroderma
                                        pigmentosum, Fanconi anemia and ataxia telangiectasia are associated with an increased
                                                                                  25–28
                                        incidence of head and neck cancer                 .
                                                                                                                 th
                                        Oral cancer is more common in men and usually occurs after the 5 decade of life. About
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                                        1.5% will have another synchronous primary in the oral cavity or the aero-digestive tract
                                                                        29
                                        (larynx, esophagus or lung)          . Metachronous tumors develop in 10% to 40% in the first
                                                                                          30, 31
                                        decade after treatment of the index primary          and therefore regular post-therapy
                                        surveillance and lifestyle alteration are important strategies for secondary prevention.
                       PATHOLOGY
                                        Squamous cell carcinomas (SCC) constitute more than 90% of all oral cancer. Other
                                        malignant tumors can arise from the epithelium, connective tissue, minor salivary
                                        glands, lymphoid tissue, and melanocytes or metastasis from a distant tumor.
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                                        A variety of premalignant lesions have been associated with development of SCC . The
                                        more common premalignant lesions including leukoplakia, erythroplakia, oral lichen planus,
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                                        and oral submucous fibrosis have varying potential for malignant transformation . The
                                        WHO (2005) classifies premalignant lesions according to degree of dysplasia into mild,
                                        moderate, severe, and carcinoma in situ.
                                        Leukoplakia is a clinical term defined as a “white patch or plaque that cannot be characterized
                                                                                              34
                                        clinically or pathologically as any other disease” . This lesion is usually associated with
                                        smoking and alcohol use. The prevalence of leukoplakia worldwide is about 2%. Dysplastic
                                        changes are seen in only 2–5% of patients. The annual rate of malignant
                                        Surg Oncol Clin N Am. Author manuscript; available in PMC 2016 September 10.
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                                        transformation for leukoplakia is 1%. Risk factors for malignant transformation include
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                                        presence of dysplasia, female gender, long duration of leukoplakia, location on the tongue or
                                        floor of mouth, leukoplakia in non-smokers, size greater than 2cm, and non-homogeneous
                                        type. In addition to lifestyle alteration to avoid tobacco and alcohol use, excision constitutes
                                        the only definitive modality for accurate diagnosis and treatment.
                                        Non-squamous cell carcinomas of the oral cavity are uncommon. Minor salivary gland
                                        carcinomas represent less than 5% of the oral cavity cancers. They frequently arise on the
                                                                                                         35
                                        hard palate (60%), lips (25%) and buccal mucosa (15%) . Mucoepidermoid carcinoma is
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                                        the most common type (54%), followed by low-grade adenocarcinoma (17%), and
                                                                              49,50
                                        adenoid cystic carcinoma (15%)                .
                                        Mucosal melanomas are rare but usually present as locally aggressive tumors, mainly of
                                        the hard palate and gingiva. Bony tumors including osteosarcoma of the mandible or
                                        maxilla and odontogenic tumors such as ameloblastoma can present within the oral cavity
                                        and may be mistaken for a mucosal lesion if there is surface ulceration.
                                        of the extent of the disease, the third dimension of tumor, the presence of bone invasion, or
                                        skin breakdown. Appropriate documentation with drawings and photographic records of the
                                        tumor are useful in staging, decision-making and further follow up.
                                        The clinical TNM stage should be recorded at first encounter and modified as evaluation
                                        progresses. The initial workup consists of diagnosis by biopsy. Accessible lesions may be
                                        adequately biopsied in the clinic using punch forceps, core needle or fine-needle aspiration.
                                        Some patients will require examination under general anesthesia (EUA) in order to access
                                        posteriorly located lesions, or to complete a physical exam limited by pain and trismus.
                                        Radiographic imaging is crucial for evaluation of the relation of the tumor to adjacent bone and
                                        for assessing regional lymph nodes. CT scan is the study of choice for evaluation of bone and
                                        neck nodes, especially early cortical involvement and extracapsular nodal spread. MRI provides
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                                        complementary information about soft tissue extent and perineural invasion and is also helpful
                                        for evaluating the extent of medullary bone involvement because adult marrow is normally
                                        replaced by fat. Most patients with oral cancer are not at risk for distant metastases and
                                        therefore the role of PET scan in initial assessment is debatable. However, a preoperative PET
                                        scan may be useful as a baseline if adjuvant treatment is anticipated and a PET scan will be used
                                        for radiation therapy planning (though this is undertaken differently from a “diagnostic” PET
                                        scan). Patients with locally advanced tumors require appropriate
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                                        The TNM system is the most widely accepted prognostic system due to its relatively
                                        simple design and user-friendliness. The clinical staging of the oral cavity tumors consists
                                        of primary tumor characteristics, the neck, and assessment for distant metastases (Table 1).
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                                        This information allows TNM stage grouping for the tumor (Table 2)                     . The basic
                                        elements in staging of the primary site are the tumor size and invasion of deep structures.
                                        Advanced disease is defined by invasion of structures such as medullary bone, deep muscle
                                        of the tongue, maxillary sinus, and skin for T4a disease, or masticator space, pterygoid
                                        plates, or skull base and/or encasement of the internal carotid artery for T4b disease.
                                        Lymphatic spread into the neck generally occurs in a step-wise, orderly and predictable
                                        fashion. The lymph node echelons of the neck are described using the terminology
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                                        standardized by the American Head and Neck Society Guidelines                       (Figure 3).
                                        Knowledge of the patterns of nodal metastasis has practical implications in the design of
                                        neck dissection for patients with oral cancer. The patient with a clinically negative neck is at
                                                                                      38
                                        highest risk of metastasis to levels I–III . Skip metastases to level IV do occur, especially
                                        in cancer of the anterior tongue. Metastases to level V are extremely rare (1%) even in
                                        patients with clinically positive neck. Oral tongue tumors have the greatest propensity of all
                                        oral cancers for metastasis to the neck, and tumor thickness (Figure 4) is a major predictor
                                                                       39
                                        of risk of nodal metastasis       .
                       TREATMENT
                                        Surgical resection is the treatment of choice for SCCOC. Surgical resection allows accurate
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                                        pathologic staging, with information about the status of margins, tumor spread and
                                        histopathologic characteristics which can then be used to inform subsequent management
                                        based upon assessment of risk versus benefit. Adjuvant radiotherapy ± chemotherapy is
                                        used for specific indications in locoregionally advanced tumors. A multidisciplinary team is
                                        absolutely essential to ensure a favorable outcome. Multiple factors are taken into account in
                                        selecting treatment for an individual patient. The risk of treatment-related complications
                                        should be assessed based on physiological age, comorbid conditions (e.g. cardiopulmonary
                                        status), lifestyle (smoking or alcohol), surgical resectability, and patient expectations.
                       Surgical Management
                                        A detailed description of surgical technique for management of oral cavity cancers is
                                        beyond the scope of this publication and the reader is referred to specialized texts for this
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                                        information . Broad principles of surgical management will be discussed and these include
                                        access to the oral cavity, management of the mandible, management of neck nodes, and
                                        reconstruction of oral cavity surgical defects.
                                        Surgical access—The transoral approach is usually used for premalignant lesions and
                                        small, superficial tumors of the anterior floor of mouth, alveolus and tongue. A more
                                        invasive approach becomes necessary for posteriorly located tumors or if there are
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                    Montero and Patel                                                                                                    Page 5
                                        limitations due to trismus or inadequate surgical exposure (Figure 5). The lip-splitting
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                                        Early cortical invasion of the mandible is difficult to assess with plain radiography, or
                                        orthopantomograms but CT scans are more sensitive. On a practical basis, tumors that are
                                        in close juxtaposition to the mandibular cortex will require consideration for marginal
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                                        Management of the neck—Sixty percent of patients with early stage oral cancer will present
                                        with a clinically negative neck (cN0). Approximately 20–30% will have microscopically evident
                                        nodal metastasis on histologic examination after elective neck dissection (END). The risk of
                                                                                                   44, 45
                                        nodal metastasis is related to several factors (Table 4)      . Cervical lymph node metastasis is
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                                        the single most important prognostic factor in oral cancer: survival chances are reduced by 50%
                                                                                                                            46, 47
                                        when compared to those with similar primary tumors without neck metastases            . SCC of the
                                        oral tongue and the floor of the mouth are more likely to metastasize to the neck, and these
                                        patients should be offered END, even for early stage tumors, if they are thicker than about
                                              48
                                        4mm        . The hard palate and the upper gum have a relatively lower rate of occult nodal
                                                                                      49
                                        metastasis and END may not be indicated            .
                                        Sentinel node biopsy is an alternative to END for staging the cN0 neck in early stage (T1–2)
                                                                                                                       50
                                        SCCOC. The technique was first reported in 2001 by Shoaib et al and has been analyzed
                                        in several single institutional studies as well as two prospective multicenter trials, one in
                                                 51, 52                             53
                                        Europe         and the other in the US . The procedure is technically challenging and
                                        successful identification of sentinel nodes and detecting occult metastasis depends on
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                                        expertise and experience. Therefore, it should be undertaken only in centers with the
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                                        necessary proficiency and the appropriate volume of cases                .
                                        In patients with clinically or radiographically involved neck nodes, a therapeutic comprehensive
                                        neck dissection is indicated (Table 5). It involves dissection of levels I to V. The need to
                                        sacrifice other structures such as the spinal accessory nerve, sternocleidomastoid muscle, or
                                        internal jugular vein depends on the location of the metastasis and its characteristics. The most
                                        common type of comprehensive neck dissection
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                    Montero and Patel                                                                                                     Page 6
                                        is the modified radical neck dissection, MRND Type 1. Radical neck dissection is
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                                        rarely performed unless there is direct infiltration of the relevant structures by gross
                                        extranodal extension of disease (Table 5).
                                        In a patient with a clinically negative neck, the risk of occult metastasis is mainly to levels
                                        I through III. Potential compromise of levels IV and V is very rare. For these reasons, a
                                        supraomohyoid neck dissection (SOHND)(Table 5) is usually adequate to stage the cN0
                                        neck. In patients with primary oral tongue SCCOC dissection of level IV may be indicated
                                        due to the possibility of skip metastasis. For patient with positive nodes on END, neck
                                                                                55
                                        recurrence is observed in 10–24%             . Appropriately selected patients benefit from
                                                                            56, 57
                                        postoperative radiation therapy               . For cN0 patients who are proven pathologically N 0,
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                                        failure rates of less than 10% have been reported             .
                                        the ultimate goal of treatment and is achieved by choosing the appropriate reconstructive
                                        procedure. Surgical defects after resection of early stage tumors can usually be reconstructed
                                        with primary closure or the use of skin graft or skin substitutes. Reconstruction of larger and
                                        more complex defects that result from resection of advanced tumors requires participation from
                                                                                                                                           59,
                                        an expert reconstructive surgeon. Microvascular free tissue transfer is the technique of choice
                                        60
                                             . For example, in patients with soft tissue defects of the oral tongue, floor of mouth and
                                        retromolar trigone, the free radial forearm flap results in excellent functional results (Figure 6).
                                        In addition to soft tissue cover, free flaps are also a reliable source for bone reconstruction. The
                                        fibula free flap is currently the workhorse in reconstruction of defects following segmental
                                        mandibulectomy (Figure 6). Other composite microvascular flaps include the radial forearm
                                        osteocutaneous flap, iliac crest and scapula free flaps. Several studies have demonstrated the
                                                                                                                               61
                                        reliability and low morbidity of microvascular free flap reconstruction techniques        . The ability
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                                        reliably to reconstruct large surgical defects has contributed to improved oncologic outcomes in
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                                        patients with locally advanced cancers by enabling more complete resections . Pedicled
                                        myocutaneous flaps such as the pectoralis major, latissimus dorsi or trapezius flaps are reliable
                                        alternatives if surgical expertise is not available or if the patient is not a good candidate for
                                        microvascular reconstruction.
                       Adjuvant treatment
                                        Adjuvant postoperative treatment is indicated in patients with high risk of locoregional
                                        recurrence. This includes patients with large primary tumors (pT3 or pT4), bulky nodal
                                        disease (pN2 or pN3), metastases to nodal levels IV or V, positive surgical margins,
                                        lymphovascular invasion, perineural invasion, and extracapsular spread. External beam
                                        radiation therapy has been the traditional modality for postoperative adjuvant treatment
                                                                                                            63, 64
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                                        and doses of 66–70 Gy result in good locoregional control       . Two clinical trials have
                                        shown that administration of cisplatin chemotherapy concurrently with postoperative
                                        radiotherapy improves locoregional control and survival (versus radiotherapy alone) in
                                        head and neck cancer patients with extracapsular spread and /or positive surgical
                                                  65, 66
                                        margins        . However, concurrent chemoradiation can result in significant morbidity
                                        and is best used at centers where appropriate expertise and infrastructure is available.
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                    Montero and Patel                                                                                            Page 7
                       OUTCOMES OF TREATMENT
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                                        The results of treatment of SCCOC in recently published major series are shown in Table 6.
                                        The overall 5-year survival in a recently analyzed cohort of patients at Memorial Sloan-
                                        Kettering Cancer Center is 63%. This represents a significant improvement compared to
                                        historical cohorts (Figure 7) and may be related to wider use of microvascular free flaps
                                        with enhanced ability to resect large tumors and reconstruct large and complex defects,
                                        more aggressive regional therapy including increasing use of elective selective neck
                                        dissections, and the use of postoperative adjuvant therapy.
                                        Approximately a third of patients treated for SCCOC relapse, and locoregional recurrence is
                                        the most common pattern of failure. The clinical stage at presentation is an important
                                        predictor of survival (Figure 8) but the most powerful predictor of outcome is the presence
                                        of metastatic lymph nodes (Figure 9). Other clinical signs of locally advanced disease and
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                                        poor prognosis include trismus, which indicates invasion of the pterygoid, temporalis or
                                        masseter muscle; reduced tongue mobility, which indicates invasion of the extrinsic
                                        musculature of the tongue or the hypoglossal nerve; and skin invasion with dermal
                                        lymphatic infiltration. Significant histopathologic predictors of outcome include depth of
                                        invasion of the primary tumor, positive margins of surgical resection, perineural invasion
                                        and major extracapsular nodal extension.
                       Follow up
                                        Oral cancer patients have a high risk of locoregional recurrence and developing subsequent
                                                                                                                67
                                        new primary cancers, but the risk of distant recurrence is low . The possibility of a second
                                        head and neck primary is about 4–7% a year and comprehensive clinical examination and a
                                                                                                      68
                                        high suspicion are the cornerstones of early diagnosis . Control of lifestyle-related risk
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                                        factors, such as tobacco and alcohol consumption, is a priority in these patients because of
                                                                                                           69
                                        the higher risk of treatment failure and second primaries . Unfortunately, there is no
                                        effective chemoprevention and close follow up remains the most important tool in secondary
                                                     70
                                        prevention . Baseline imaging studies are often obtained about 3–6 months following
                                        completion of treatment and then as needed based on clinical suspicion. Chest imaging is not
                                        routinely needed but may be beneficial in patients with a significant smoking history. Other
                                        ancillary measures include speech and swallowing rehabilitation as indicated, monitoring of
                                        thyroid stimulating hormone levels if the neck been treated with radiation therapy, and
                                        regular dental evaluation.
                       CONCLUSION
                                        Treatment results for patients with oral cancer have improved considerably over the last
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                    Montero and Patel                                                                                                     Page 8
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                                                                                     Key Points
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                                        Figure 1.
                                        Anatomic sites of the oral cavity
                                        From Shah JP, Patel SG, Singh B, et al. Jatin Shah's head and neck surgery and oncology.
                                        4th ed. Philadelphia, PA: Elsevier/Mosby; 2012, 232–244 with permisison.
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                    Montero and Patel                                                                                      Page 14
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                                        Figure 2.
                                        Incidence of oral cavity cancer among both sexes expressed by level of Age-
                                        standardized rate (ASR) in countries of the world (From GLOBOCAN 2012
                                        International Agency for Research on Cancer (http://globocan.iarc.fr/Pages/Map.aspx.))
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                    Figure 3.
                    Cervical lymph node level classification
                    From Shah JP, Patel SG, Singh B, et al. Jatin Shah's head and neck surgery and oncology.
                    4th ed. Philadelphia, PA: Elsevier/Mosby; 2012, 232–244, with permisison.
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                    Surg Oncol Clin N Am. Author manuscript; available in PMC 2016 September 10.
                    Montero and Patel                                                                                                Page 16
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                                        Figure 4.
                                        Incidence of lymph node metastasis and survival stratified by the thickness of the primary
                                        tumor. (From Shah JP, Patel SG, Singh B, et al. Jatin Shah's head and neck surgery and
                                        oncology. 4th ed. Philadelphia, PA: Elsevier/Mosby; 2012, 232–244, with permisison.)
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                    Montero and Patel                                                                                         Page 17
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                                        Figure 5.
                                        Various surgical approaches. A, Peroral. B, Mandibulotomy. C, Lower cheek flap. D,
                                        Visor flap. E, Upper cheek flap. (From Shah JP, Patel SG, Singh B, et al. Jatin Shah's head
                                        and neck surgery and oncology. 4th ed. Philadelphia, PA: Elsevier/Mosby; 2012, 232–244,
                                        with permisison.)
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                                                                                                   Montero and Patel   Page 18
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                    Figure 6.
                    Fibular (left) and radial forearm (right) free flaps are two of the most common flaps used in
                    oral cavity reconstruction after major resections.
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                    Figure 7.
                    Outcomes of treatment of SCCOC in three cohorts treated during different time periods
                    at Memorial Sloan-Kettering Cancer Center (1960–2005). Courtesy of Memorial Sloan-
                    Kettering database, New York, NY.
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                                        Figure 8.
                                        Clinical stage at presentation is an important predictor of outcome. Courtesy of Memorial
                                        Sloan-Kettering database, New York, NY.
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                    Montero and Patel                                                                                       Page 21
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                                        Figure 9.
                                        Impact of clinically palpable lymph node metastasis on disease-specific survival in SCCOC.
                                        Courtesy of Memorial Sloan-Kettering database, New York, NY.
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                    Montero and Patel                                                                                                                         Page 22
Table 1
                     T — Primary tumor
                     TX                          Primary tumor cannot be assessed
                     T0                          No evidence of primary tumor
                     Tis                         Carcinoma in situ
                     T1                          Tumor 2 cm or less in greatest dimension
                     T2                          Tumor more than 2 cm but not more than 4 cm in greatest dimension
                     T3                          Tumor more than 4 cm in greatest dimension
                     T4a (lip)                   Tumor invades through cortical bone, inferior alveolar nerve, floor of mouth, or skin (chin or nose)
                     T4a (oral cavity)           Tumor invades through cortical bone, into deep/extrinsic muscle of tongue (genioglossus, hyoglossus, palatoglossus,
                                                 and styloglossus), maxillary sinus, or skin of face
                     T4b (lip and oral cavity)   Tumor invades masticator space, pterygoid plates, or skull base; or encases internal carotid artery
                     Note: Superficial erosion alone of bone/tooth socket by gingival primary is not sufficient to classify a as T4.
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                     M0                          No distant metastasis
                     M1                          Distant metastasis
                       From, Edge SB, Byrd DR, Compton CC, eds. AJCC Cancer Staging Manual. 7th ed. New York, NY.: Springer, 2010; 33, with permission.
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Table 2
                     Stage    T        N           M
                     0        Tis      N0          M0
   Manus
     cript
T1 N1 M0
                     I        T1       N0          M0
                     II       T2       N0          M0
                     III      T3       N0          M0
                              T2       N1          M0
                              T3       N1          M0
                     IVA      T4a      N0          M0
                              T4a      N1          M0
   Autho
                              T1       N2          M0
                              T3       N2          M0
       r
                              T2       N2          M0
   Manuscrip
                              T4a      N2          M0
           t
                     IVB      Any T    N3          M0
                              T4b      Any N       M0
                     IVC      Any T    Any N       M1
                    From, Edge SB, Byrd DR, Compton CC, eds. AJCC Cancer Staging Manual. 7th ed. New York, NY.: Springer, 2010; 33, with permission.
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                    Montero and Patel                                                                                                                    Page 24
Table 3
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Table 4
                          •               Tumor Size
                          •               Histologic Grade
                          •               Depth of Invasion
                          •               Perineural Invasion
                          •               Vascular Invasion
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Table 5
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Table 6
Outcomes in patients treated for squamous carcinoma of the oral cavity in major series around the world.
                                                    Listl et al
N
                                                                     77
                                                    Rogers et al              UK        2008      541                     56.0%                              74.0%                -              -       -            -
.Am
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