1 Epidemiology of Oral Cavity Cancer
Oral cavity cancer is one of the most common cancers worldwide. The leading risk factors include the use of tobacco, alcohol, and betel quid, which is predominantly used in Asia. Fortunately, the overall incidence and survival in the United States have improved with the decrease in tobacco use. Recommended treatment generally includes definitive surgery, with adjuvant therapy in indicated cases. The most important prognostic factor is the presence of nodal metastasis, and overall survival decreases dramatically as overall stage increases. Therefore, early detection of premalignant or malignant lesions could lead to improved survival. Resection and reconstruction of oral cavity malignancies are uniquely challenging, as they require consideration of both structure and function and can lead to significant posttreatment changes in quality of life. This chapter will provide an overview of the epidemiology, risk factors, clinical presentation, anatomy, and treatment considerations of this complex disease.
Oral cavity cancer is among the most common cancers worldwide and is often associated with significant patient morbidity and poor survival. Patients may have advanced disease at presentation and therefore require treatment with surgery, radiation therapy, and chemotherapy. While surgical advances over the last 40 years have resulted in better functional outcomes, oncologic outcomes for oral cavity cancer are largely unchanged. 1 Over the last several decades, there has been an increased understanding of etiologic factors associated with oral cancer that extends beyond traditional carcinogenic factors. Investigators have focused on the impact of diet and dental health as potential etiologic factors and have explored the increasing incidence of oral cavity cancer among younger patients. In this chapter, we review the epidemiology of oral cavity cancer, with an emphasis on highlighting established and emerging risk factors associated with this disease. A complete understanding of oral cancer epidemiology is essential towards targeting interventions and improving primary and secondary prevention for oral cavity cancer.
Squamous cell carcinomas constitute more than 90% of all oral cavity cancer and will be the focus of this chapter. However, other malignant tumors can arise from the epithelium, connective tissue, minor salivary glands, lymphoid tissue, and melanocytes. Minor salivary gland carcinomas represent less than 5% of the oral cavity cancers. Most arise in the hard palate (60%), lips (25%), and buccal mucosa (15%). Mucoepidermoid carcinoma is the most common type (54%), followed by low-grade adenocarcinoma (17%), and adenoid cystic carcinoma (15%). Other tumors are mucosal melanomas, osteosarcoma of the mandible or maxilla, and odontogenic tumors such as ameloblastoma. 2
1.2.2 Incidence/Burden of Disease
Oral cavity squamous cell carcinoma (OCSCC) is one of the most common head and neck cancers, accounting for approximately 30% of all cases. In the United States, from 2000 to 2010, the incidence of oral cavity cancer was 4.3 per 100,000. Globally, the age-standardized rate was 2.7 per 100,000 with substantial differences by region, race, and sex. In general, rates of oral cavity cancer are higher in southern Asian counties with Papua New Guinea, Maldives, Sri Lanka, and Pakistan with the highest rates. 3
Race and Gender Distribution
In the United States, from 2000 to 2010, the incidence of OCSCC was much higher among non-Hispanic white males (6.4 per 100,000 population, age-standardized to the 2000 population) compared to non-Hispanic black males (4.2 per 100,000 population). This racial difference is also reflected in females (3.4 per 100,000 population), where non-Hispanic white women have higher rates than non-Hispanic black women (2.1 per 100,000 population). Hispanic males (3.4 per 100,000) also have higher rates compared to Hispanic women (2.1 per 100,000 population). 4
Even globally, the incidence of oral cavity is consistently greater among men than among women. The male:female rate is 2:1 overall, and it is the highest for central and eastern Europe (5:2) and lowest for northern Africa, western Asia, and Oceania (1:4). 3
Recently, there has been a dramatic increase in the incidence of oral tongue squamous cell carcinoma of young females, and to a lesser extent young males. 5 , 6 Studies of the prognosis of this subgroup are mixed with no clear consensus. 7 – 9 The genomic profile of older smokers with tongue cancer is shown to be the same as younger nonsmokers. 10 This subgroup was determined with epidemiologic methods, and since these tumors are not human papillomavirus (HPV) associated or smoking and alcohol related, the etiology remains uncertain. 11
Survival for OCSCC has improved over the past decade. 4 In the Surveillance, Epidemiology, and End Results (SEER) Program, the 5-year overall survival is 57.1%. 12 There are some differences by race, with non-Hispanic blacks having the lowest 5-year survival at 42.7%, and non-Hispanic whites with a 58.0% 5-year survival. However, there is tremendous heterogeneity by stage. As stage increases, 5-year survival decreases dramatically. Five-year survival by stage I is 78.1%, stage II is 60.3%, stage III is 48.7%, stage IVA is 33.2%, stage IVB is 23.8%; and stage IVC is 12.3%. 12
1.2.4 Risk Factors
Tobacco is the leading risk factor for OCSCC, accounting for over a quarter of OCSCC cases. 13 , 14 However, the association between OCSCC and tobacco is smaller than when compared to other subsites of head and neck cancer. 15 – 17 Previous epidemiologic studies have demonstrated that cigarette smokers have almost three times the risk of OCSCC when compared with noncigarette smokers. 18 Even low-frequency smokers (one to two cigarettes a day) have a 50% increased risk of OCSCC. 19
Duration of smoking also plays an important role in OCSCC. A study found that at a low level of consumption (= 15 cigarettes per day), smoking more cigarettes per day for a shorter duration was more deleterious than smoking fewer cigarettes per day for a longer duration. 20 However, this relationship changes for heavier smokers (> 15 cigarettes per day). Among heavy smokers, smoking more cigarettes per day for a shorter duration was less deleterious than fewer cigarettes per day for a longer duration. The excess risk of OCSCC due to tobacco virtually disappears 20 years after smoking cessation and independently of the quantity previously consumed. 20
Studies evaluating smokeless tobacco and OCSCC have been inconsistent. The relationship is complex due to the concurrent use of cigarettes or other fillers such as betel leaves, areca nuts, quicklime, condiments, spices, or sweeteners depending on the region. Animal models of smokeless tobacco have been largely negative. However, in the United States, smokeless tobacco (non-cigarette-smoking) users have demonstrated an approximately twofold increase in the risk of OCSCC. 21 Ultimately, the International Agency for Research on Cancer has concluded that there is sufficient evidence of carcinogenicity in smokeless tobacco. 22
Although not as strongly correlated as tobacco use, high alcohol consumption is also a major risk factor for OCSCC. Alcohol accounts for an 18% increased risk of OCSCC. 15 The risk increases with daily consumption, duration of consumption, and lifetime cumulative consumption. 23 , 24 Heavy beer and liquor drinkers (30 + drinks per week) were about five times more likely than nondrinkers to develop OCSCC. 25 Heavy wine drinking was associated with an increased risk of OCSCC (odds ratio [OR] = 3.2), but there was an attenuated association most likely attributed to differences in socioeconomic status. 25
Interaction between Tobacco and Alcohol Use
Smoking and alcohol consumption have a synergistic interaction that results in an exponentially increased risk in OCSCC and other head and neck cancers. Among never drinkers, heavy smokers had almost 13 times the risk of OCSCC compared with never smokers/never drinkers. However, among those who consume over two alcoholic beverages a day, heavy smokers had almost 31 times the risk of OCSCC compared with never smokers. 26 This same study suggests that 23.5% of OCSCC are attributed to both alcohol and cigarette smoking. 26 , 27
Betel quid contains betel leaf, areca nut, and slaked lime, and it may contain tobacco. It is used by 600 million people worldwide, predominantly in Asia. 28 Betel quid has been classified as an oral carcinogen in humans by the International Agency for Research on Cancer, with evidence for a dose-response relationship (i.e., risk increases in a step-wise fashion with increased exposure). 28 In Asian studies, betel quid chewing appeared to be a stronger risk factor for cancer than either smoking or alcohol consumption. 29 In a recent review, betel quid without tobacco was associated with a sevenfold increase in the risk of OCSCC and a 15-fold increased risk when betel was combined with tobacco. 30
The most consistent finding between diet and OCSCC risk is the association between consumption of fruit and vegetables with decreased risk. 31 In a large prospective cohort study, high consumption of fruits and vegetables was associated with a decreased risk of OCSCC (OR = 0.6; 95% confidence interval [CI]: 0.4-0.9) when compared with low consumption of fruit and vegetables. 31 Since fruits and vegetables do not have a high source of protein or fat, carbohydrates, fiber, and vitamins and minerals likely contribute to this association. Other types of food have been studied less frequently and with inconsistent results. In a meta-analysis, high consumption of processed meat (i.e., meat preserved by smoking, curing, salting, or by addition of chemical preservatives) was associated with an increased risk (OR = 1.91; 95% CI: 1.19-3.06) of OCSCC. However, total meat (white and red meat) consumption was not significantly associated with OCSCC. 32
To further strengthen the association between diet and OCSCC, studies have suggested a link between combined dietary indexes and OCSCC. In a case-control study, OCSCC was associated with a “western” diet, or a diet with high consumption of fried foods, fat, and processed meats. 33 In the same study, more pro-inflammatory diets were also associated with an increased risk. 34
The association between tea and OCSCC is inconsistent and depends largely on the temperature of tea and location. Maté—an herbal tea commonly consumed in South America—was associated with an increased risk of oral cavity (and oropharynx) cancer. 35 , 36 Yet, a meta-analysis found a decreased risk of OCSCC with overall tea consumption. When the meta-analysis considered type of tea, green tea was significantly associated with decreased risk of OCSCC, while black tea was not associated. However, most of the green tea studies were in Asian countries, making them less generalizable. 37
Similarly, coffee consumption is likely also associated with a decreased risk of OCSCC. A pooled analysis found an inverse relationship between OCSCC and coffee consumption (OR: 0.5; 95% CI: 0.3-0.7 for coffee drinkers of more than four cups of coffee per day vs. nondrinkers). 38 This association was also reflected in a French case-control study. 39 In a meta-analysis, coffee was associated with a decreased risk of OCSCC and pharyngeal cancer. 40
Oral Human Papillomavirus Infection
Although HPV infection has been linked definitively to oropharyngeal cancer, its role in OCSCC etiology is controversial. In a meta-analysis that included 5,478 cases worldwide, HPV deoxyribonucleic acid (DNA) was found in 24.5%. 41 Another study of 1,264 cases found 7.4% of OCSCC tumors had HPV DNA. 42 Both studies demonstrate large heterogeneity by region and sex, potentially leading to the difference in prevalence. To date, there is no clear molecular evidence that OCSCC is driven by HPV infection. Unlike oropharyngeal cancer, there does not appear to be a survival advantage for HPV-positive OCSCC. 43 – 47 Additionally, for OCSCC as a whole, no significant relationship was observed between high-risk sexual behaviors and the risk of cancer. 48
Various measures of oral health, such as the number of missing teeth, number of dental checkups, and tooth mobility, have been associated with OCSCC. 49 – 52 Although these results could be confounded by low socioeconomic status and education level as well as the consumption of tobacco and alcohol, poor oral and dental health is a significant risk factor for OCSCC. In a pooled analysis, having the worst oral hygiene score was associated with three times greater risk of OCSCC when compared to having an optimal oral hygiene score. 50
1.3 Clinical Presentation
Patients with oral cavity lesions (benign, premalignant, or malignant) often present initially to a primary care provider or dentist. Due to the wide variety of presentations and pathology in oral cavity lesions, they are often ambiguous and referred to an otolaryngologist or head and neck surgeon in order to rule out malignancy.
1.3.1 Benign Lesions
There are a variety of anatomic variants occurring in the oral cavity that can be confused with pathologic findings, including dental tori, Fordyce granules, and geographic tongue. Dental tori are bony outgrowths most commonly arising from the lingual surface of the mandible or the hard palate. They can be caused or exacerbated by trauma and generally do not require removal. Fordyce granules are small, papular sebaceous glands found in clusters, usually on labial or buccal mucosa. Again, these lesions are safe to leave alone. Geographic tongue, or benign migratory glossitis, presents with erythematous patches that migrate over the surface of the tongue. It is present in 3% of Americans and can often be confused with more concerning lesions such as leukoplakia. 53 Another lesion that sometimes causes concern among primary care providers or dentists is the iatrogenic dental amalgam tattoo. These lesions are found in approximately 1% of the U.S. adult population and can be mistaken for a nonbenign lesion. An amalgam tattoo presents most commonly as a dark-colored macule on mucosa adjacent to a restored tooth. 54
Multiple categories of systemic illness can present with oral manifestations, including immunologic disorders (e.g., lupus, scleroderma, inflammatory bowel disease, human immunodeficiency virus [HIV]/acquired immunodeficiency syndrome [AIDS]), vitamin deficiencies (e.g., vitamin B12 deficiency), colonization or infection (e.g., candidiasis, herpes simplex virus), hematologic disorders (e.g., hereditary hemorrhagic telangiectasia), and endocrinopathies (e.g., hypothyroidism).
1.3.2 Premalignant Lesions
Premalignant oral cavity lesions can resemble benign lesions, but differ in that they have a risk of malignant transformation. Recognition and early detection are important in the prevention of OCSCC. Risk factors of both premalignant and malignant lesion development are similar and are discussed in the “epidemiology” section of this chapter. The most common premalignant oral cavity lesions are leukoplakia, erythroplakia, oral submucous fibrosis, and lichen planus. 55 Leukoplakia is a painless, white plaque determined by diagnosis of exclusion. Histologically, these lesions are comprised of hyperkeratosis with alteration in epithelial thickness. The risk of malignant transformation associated with leukoplakia is as high as 18% within 5 years. 56 Erythroplakia is overall less common, but it has a greater than 90% chance of transforming into a dysplastic or malignant lesion. 57 It presents as a red, flat macule with a velvety appearance. Oral submucous fibrosis is primarily found in southeast Asian countries where chewing betel quid is more common. It appears as a fibrotic, blanching oral mucosal lesion that can later lead to significant trismus. The risk of malignant transformation is 7.6% within 10 years. 58 Oral lichen planus (OLP) is characterized by inflammation of the stratified squamous epithelium, possibly from autoimmune activation of CD8 + T cells. There are six types of OLP, the most common of which is the reticular pattern. This subtype presents as asymptomatic, often bilateral, and symmetric “fine white striae.” 55 A 2010 review reported a risk of malignant transformation of up to 10%. 59
1.3.3 Malignant Lesions
Malignant oral cavity lesions can be variable in appearance, presenting signs and symptoms, and location. Nonhealing ulcers, mucosal irregularities, and exophytic masses are common presentations of oral cavity malignancies (▶ Fig. 1.1, ▶ Fig. 1.2, ▶ Fig. 1.3). A complete history and physical examination is essential, with a focus on assessing risk factors and a complete head and neck examination. Symptoms can range from severe pain to hypoesthesia or anesthesia due to adjacent sensory nerve invasion. Trismus and bleeding are signs potentially concerning for malignant pterygoid invasion and tumor necrosis, respectively. A firm neck mass in a patient with an oral cavity lesion should increase suspicion for malignancy.
1.4 Diagnosis and Evaluation
1.4.1 Physical Examination
The first step on initial presentation is a comprehensive history and physical examination. A physical examination of the oral cavity should include visualization and palpation of all oral cavity subsites (oral tongue, floor or mouth, alveolar ridge, hard palate, buccal mucosa, retromolar trigone). The dentition should be evaluated, and dentures should be removed for better visualization. A full cranial nerve examination is a necessary component, with emphasis on tongue mobility (cranial nerve XII) and sensation in the distribution of the inferior alveolar and mental nerves (cranial nerve V). The complete examination should also include either an indirect mirror or a direct fiberoptic view of the oropharynx and larynx. Understanding the extent or invasiveness of the tumor is essential when planning therapy, and clinicians should assess the potential for invasion into the deep muscles of the tongue, floor or mouth, mandibular or maxillary bone, or pterygoid musculature.
Imaging is a critical tool in assessing tumor invasion of soft tissue and muscle, bone, or neural structures, as well as to evaluate for regional or distant metastases. The National Comprehensive Cancer Network (NCCN) recommends a computed tomography (CT) scan and/or a magnetic resonance imaging (MRI) with chest imaging as indicated and to consider a positron emission tomography (PET/CT) for advanced-stage disease. A CT scan with contrast is generally the mode of imaging performed during initial evaluation. It is very useful in assessing tumor mucosal and bony extent, is relatively cost-effective, and often readily available. An MRI is a useful adjunct in tumors with concern for perineural spread. PET alone has been shown to be more sensitive and specific than other imaging modalities in detecting primary and locally recurrent head and neck cancers. 60 PET/CT has the added benefit of improved localization and correlation with anatomic findings, and it can be useful in the detection of unknown or synchronous primaries or in diagnosing distant metastases. PET/CT has been shown to be extremely useful in the staging and management of advanced head and neck cancer, and its use continues to become more prevalent. 61