19.1 Epidemiology

Oral cancer comprises 3 to 4% of all cancers and 3 to 4% of all cancer deaths globally. ¹ Carcinomas arising from the buccal mucosa are a subsite of oral cavity cancers that show marked geographic differences in incidence and presentation. Cancer of the buccal mucosa is relatively uncommon in North America and Western Europe, accounting for only 6% of all oral cavity cancers and 0.2% of all cancers in the United States in 2018. ¹ However, the incidence of oral cancer is significantly higher in the Indian subcontinent and southern Asia, where oral cancer is the most common cancer, comprising more than 30% of all cancer cases, with the buccal mucosa the most common site for oral cavity cancer. ^{2 – 4} In India, buccal carcinoma is the most common cancer in men and the third most common cancer in women.

Squamous cell cancer comprises 95% of buccal cancers, with the remainder of buccal tumors arising from minor salivary glands. ⁵ There is a male predominance for this disease, with a male-to-female ratio of 3 to 4:1 in most large series. ^{4 , 6 – 11} While it has been suggested that the incidence in females is greater in North American compared to Asian populations, contemporary data demonstrate a male predominance in the West that is similar to that reported in Asian countries. ^{1 , 2 , 12 – 14} Buccal cancer most commonly presents in patients in the sixth or seventh decade of life; however, large series from India and Taiwan demonstrate a younger age at diagnosis, which likely reflects differences in tobacco product use, the primary etiologic agent. ^{3 , 6 , 11}

Tobacco use has been documented in more than 70% of patients, regardless of geographic origin, and the combined use of alcohol with tobacco has a well-known synergistic effect in the development of mucosal cancers in North America. ^{4 , 8 , 13} In Asia, hand-rolled tobacco products called bidis and betel quid, a combination of tobacco leaves and betel nut, are popular masticatory products that are associated with the development of buccal carcinoma. ^{6 , 7 , 14} In India, betel nut users have an incidence of buccal carcinoma about eight times greater than the general population, and immigrants from India to Western countries have a higher rate of buccal cancer than the host population. ² Betel nut is a paste made primarily of the fruit of the areca palm, which is mixed with tobacco, powdered lime, and a number of other irritants and chewed. ¹⁵ It is said that the use of betel nut can induce a mild state of euphoria. Over 90% of Indian patients with buccal carcinoma have a history of betel nut use. Patients who use these products present with buccal mucosal carcinoma at a much younger age, usually younger than 50 years of age. These malignancies are most frequently located on the occlusal line or the lower gingivobuccal sulcus, which is the site where the betel nut bolus is placed. Reverse smoking, a popular habit in Asia, also induces keratosis in addition to the carcinogenic risks associated with smoking. As is often seen in the development and progression of malignancy, inflammation plays a very significant role. The agents that are mixed together with the tobacco cause a significant inflammatory response in the mucosa and submucosa, which then leads to a dense fibrosis and keratosis of the usually soft pliable tissues of the cheek. This can lead to the development of oral submucosal fibrosis as well as leukoplakia and other precancerous changes. ¹⁶

Oral submucosal fibrosis has been associated with the development of buccal cancer. This condition is characterized by fibroelastic changes resulting in mucosal atrophy and the development of fibrotic bands that lead to scarring and trismus. Oral submucosal fibrosis is associated with tobacco and betel nut use, and appears to have a genetic predisposition, occurring more commonly in young Indian men. ^{17 , 18} Overall, the risk of malignant transformation in oral submucosal fibrosis is 8%, and oral submucosal fibrosis is associated with a 19-fold increase in the risk of oral cancer, with cancer arising in this setting more invasive and with a greater risk of metastases. ⁵

Several precancerous oral lesions have been associated with the development of buccal squamous cell cancer. ⁵ Leukoplakia, which is often found on the buccal mucosa prior to a diagnosis of invasive squamous cell carcinoma, is a clinical term defined as a white patch or plaque that cannot be characterized clinically or pathologically as any other disease. ¹⁹ This lesion is usually associated with smoking and alcohol use. The prevalence of leukoplakia worldwide is between 2 and 3%. Dysplastic changes are seen in only 2 to 5% of patients. The overall rate of malignant transformation for leukoplakia is 3.5%; however, proliferative verrucous leukoplakia is reported to have a malignant transformation rate of 61% and is associated with multiple contiguous or noncontiguous areas of the oral cavity with verrucous features on biopsy. ^{5 , 19} Erythroplakia, which has the appearance of a velvety, bright red painless area or patch, is commonly associated with dysplasia and carcinoma in situ, with malignant transformation occurring in more than 50% of cases. ⁵

Patients with oral lichen planus or oral lichenoid lesions involving the buccal mucosa have an increased risk for developing buccal cancer. Lichen planus and oral lichenoid lesions are common, immunologically mediated diseases of the oral mucosa, characterized by reticular white patches in atrophic mucosa that may have erosive or ulcerated areas and are associated with a malignant transformation rate of 1 to 3%, with an increased risk for the erosive subtype. ^{20 , 21} These lesions usually arise in middle-aged white females with histology characterized by lymphocytic infiltration, but there is no gender predisposition for malignant transformation, with males and females affected equally. ²¹ The risk of buccal cancer is increased in patients with lichenoid changes who use tobacco or alcohol. Verrucous carcinoma is a well-differentiated variant of buccal squamous cell carcinoma with a wartlike, verrucous appearance. These tumors may arise from preexisting oral lichenoid lesions and proliferative verrucous leukoplakia and may represent a continuum of these diseases, with a history of these precursor lesions in one-third of patients. ²²

19.2 Clinical Presentation

Patients with buccal carcinoma uncommonly present with pain or bleeding from the primary site in the early stages of the disease. The origins of the disease are often insidious unless there is concurrent infection or bleeding associated with a mucosal ulceration, and symptoms are generally not present until the tumor is at an advanced stage. The clinical presentation is often associated with a nonhealing mucosal ulceration, fullness or swelling of the cheek, trismus that can restrict the patient’s normal daily functions of eating and speaking, or a mass in the submental or submandibular area, which is often indicative of nodal metastasis (▶ Fig. 18.7a). These clinical presenting signs indicate more advanced stage disease. Multiple areas of leukoplakia and other mucosal and submucosal changes may be associated with the inflammatory insult of topical irritants such as tobacco, alcohol, betel nut may be detected on routine dental evaluation and are usually asymptomatic. Risk factors for malignant transformation include presence of dysplasia, duration of the leukoplakia, and a size greater than 2 cm in a nonsmoker. Erythroplakia is associated with dysplasia and carcinoma in situ in more than 50% of cases. ⁵ Dysplasia is classified by degree from mild, moderate, severe, and finally carcinoma in situ, with many pathologists considering severe dysplasia and carcinoma in situ to be equivalent. Biopsies of these areas are indicated and are necessary to adequately plan the primary resection.

The incidence of early primary site disease varies widely, with the incidence of patients presenting with primary tumors = 4 cm ranging from 18 to 91% in the literature. ^{3 – 5 , 8 , 10 , 12 , 15 , 23 – 26} However, the incidence of advanced primary site disease is higher in underdeveloped countries. In the largest series to date of 665 patients with buccal cancer treated at Tata Memorial Hospital in India, the primary tumor size was greater than 4 cm in 82% of cases. ⁸ Advanced tumor presentations are felt to be related to socioeconomic reasons with lack of access to care, as well as the relative lack of symptoms compared to other oral cancer sites in early stages of disease. Tumor thickness, rather than size, appears to be of greater importance for buccal cancer and increases the risk of early disease spread and local recurrence. ^{9 , 12 , 27} The buccal space has limited anatomic barriers to tumor spread, and thus even early-stage disease may involve the buccinator muscle in more than a third of cases and lead to trismus. ⁴ Careful examination, including bimanual palpation and imaging, is required to adequately assess the extent of local disease.

Trismus is an uncommon presenting symptom that usually indicates advanced primary site disease. Trismus may result from pain from the primary ulcerative lesion, infiltration of the underlying buccinator muscle, or indicate involvement of the pterygoid muscles due to the proximity of the buccal mucosa to the retromolar trigone and mandible. While early-stage disease may result in trismus from pain, the likelihood of trismus increases with primary tumor stage, and skin and bone involvement is present in 41 to 67% of patients presenting with large primary tumors. ^{25 , 26} It is very important to evaluate the overlying facial skin and the possible need for full-thickness resection (▶ Fig. 19.1b). The skin and subcutaneous tissue should be easily mobile over the mass. Erosion into the overlying skin with ulceration or fixation is a sign of very advanced disease. Dimpling of the skin, or “peau d’orange,” is caused by cutaneous lymphatic edema causing swelling. The epidermis is fixed to the dermis, limiting the ability to swell and causing the classic dimpling effect. Failure to adequately evaluate the depth of invasion and proximity to the dermis will lead to early local recurrence in the skin and inability to clear disease. Facial paralysis is a sign of deep infiltration through the buccinator muscle, extending beyond the buccal space, and is associated with very advanced disease.

At the time of initial diagnosis, nearly 50% of patients will present with cervical metastasis. ^{8 , 26} The incidence of nodal involvement increases with increasing primary tumor stage, and is present in less than 10% of tumors = 2 cm in size, and in approximately 50% in tumors greater than 4 cm. ⁴ The exception is verrucous carcinoma, which has a markedly lower incidence of cervical metastasis, reported at 2% in the largest series to date. ²⁸ In general, patients who present with cervical metastasis, more posterior tumors of the buccal mucosa, ulcerated lesions, large tumors, and more poorly differentiated squamous cell carcinoma have a poorer prognosis even with multimodality therapy. ^{4 , 8 , 24}

19.3 Diagnosis and Evaluation

The evaluation of the patient with buccal cancer begins with a careful history and complete head and neck examination, followed by biopsy of the primary site. Particular attention should be paid to not only the extent of mucosal involvement, but also the depth of the tumor, in light of the propensity of buccal carcinoma to demonstrate deep infiltration because of a lack of barriers in the buccal space to tumor infiltration. The importance of depth of invasion rather than tumor diameter alone has recently been recognized as a prognostic variable in the eighth edition of the American Joint Committee on Cancer (AJCC) Tumor Staging Manual as a significant predictor of outcome in oral cancer with advanced depth an indicator of more aggressive disease ²⁹ (Chapter 5). The buccal space is involved in 70% of buccal carcinoma on imaging. ³⁰ Attention should also be paid to involvement of the skin as well as facial nerve function. Dimpling of the skin, or “peau d’orange,” can be difficult to differentiate from direct tumor infiltration and should be taken into account when assessing the extent of the tumor. Tumors may approach or cross the midline of the face, with an increased risk of contralateral nodal involvement. ²⁶

The National Comprehensive Cancer Network (NCCN) guidelines for oral cavity cancer workup and staging recommend obtaining imaging studies using CT scan with contrast and/or MRI with contrast of primary site and neck as particularly important for staging and planning therapy. ³¹ CT provides better evaluation of osseous involvement but provides less soft-tissue?detail than MRI and is more susceptible to dental artifact (▶ Fig. 19.1). Given the proximity of the buccal mucosa to the dentition, MRI is preferred when dental artifact is present. ^{32 , 33} Imaging is particularly important in evaluation of the extent of buccal carcinoma, which has a propensity for both superficial and deep spread of adjacent structures. Radiologic demonstration of tumor infiltration and spread has been reported in 59% of cases, with involvement of other subsites of the oral cavity in 73%, involvement of the buccal space in 70%, infiltration of the masticatory muscles in 58%, and skin involvement in 39% of cases. ³⁰ Fluorodeoxyglucose positron emission tomography (FDG PET) is a functional, rather than an anatomic, imaging study and has inferior resolution to anatomic imaging in evaluating the primary site and neck. In patients with stage III to IV disease, up to 20% of patients may have distant metastases at presentation. ¹¹ FDG PET may alter management through detection of distant disease but is not indicated for staging the clinically N0 neck. ^{31 , 33}

The status of regional lymph nodes has prognostic significance and has been reported in numerous studies to be the most significant predictor of survival and recurrence in buccal cancer. ^{11 , 14} A greater incidence of clinically positive nodes is reported in studies from non-Western countries than in Western countries, primarily because of a greater incidence of advanced T stage at presentation. ¹⁴ Shah ³⁴ described the prevalence of nodal metastases as 34% in patients with clinically N0 disease and 76% in patients with clinical N + disease, with the majority of metastatic nodes located in levels I to III. The proximity of the buccal mucosa to facial nodes increases the likelihood of occult level I nodal disease, with level I most commonly involved in clinically N0 patients. ³⁵ In clinically N0 patients, levels IV and V are involved less than 5% of the time. This observation is the basis for elective supraomohyoid neck dissection for this oral subsite in N0 patients, which removes neck levels I to III.

Extranodal extension (ENE) has long been recognized as an adverse pathologic feature in regional nodal metastases and was incorporated into nodal staging as a prognostic variable in the eighth edition of the AJCC ²⁹ (Chapter 5). Pathologic ENE is defined as metastatic disease that breaches the capsule of the lymph node, with extension into the adjacent soft tissue. Clinically apparent ENE is defined as overt evidence of extension such as invasion of skin, infiltration of muscle, fixation to adjacent structures, or dysfunction of adjacent cranial nerves, the brachial plexus, or phrenic nerve. Radiologic findings of indistinct nodal margins or irregular nodal capsular enhancement may suggest ENE, but alone are not sufficient because of lack of specificity and sensitivity in detecting early ENE and overestimating ENE in cases of brisk stromal inflammation. Clear infiltration of adjacent fat or muscle is the strongest imaging features supporting ENE. ³⁶

Speech and swallowing evaluations are recommended by the NCCN guidelines for “at-risk” patients. ³¹ In patients with buccal cancer, trismus following treatment is a significant concern, as is dysphagia when radiation therapy is employed in treatment, and pretreatment evaluation as well as ongoing swallow therapy and support should be part of the multidisciplinary care of the buccal cancer patient. One group has reported that 53% of patients present with trismus at the time of diagnosis, which then increased to 87% postsurgery. ³⁷