52 Cancer Prevention and Oral Preneoplasia
Currently, the efforts to reduce and treat oral leukoplakia have not resulted in any cancer prevention treatments for dysplastic leukoplakia or field carcinogenesis. A large number of National Institutes of Health funded research projects and clinical trials has not resulted in a “tamoxifen equivalent” for head and neck preneoplasia or tobacco-induce field carcinogenesis. There are currently 24 clinical trials listed for “oral leukoplakia” in the U.S National Library of Medicine (clinicaltrials.gov). As precision medicine develops, the authors have a strong hope that studies of the tumor milieu in the pathophysiology of leukoplakia (genomics, etc.) will reveal dysregulated metabolic pathways and biomarkers in precancerous squamous cells and milieu cells that become intervention targets.
52.1 Oral Preneoplasia Background
Oral leukoplakias and related lesions occur in approximately 1% of the adult population worldwide. This translates into approximately 2.8 million patients in the United States who harbor these lesions. Oral leukoplakia was originally described in 1877 by Schwimmer, who described and illustrated a lesion on the tongue of an individual. 1 However, there is a wide range of oral lesions and conditions that are associated with the subsequent development of cancer. Oral leukoplakias can anatomically occur anywhere in the mouth, including the inner aspect of the lip contiguous with the buccal mucosa, the lateral aspect of the tongue and the floor of the mouth, the tongue dorsum, and the soft and hard palates. They can occur in the endolarynx as well, but are infrequently observed in the pharynx or hypopharynx.
Oral lesions vary in terms of their likelihood to develop into cancer based on their anatomic site, but the tongue and the floor of the mouth are considered especially high risk sites. Certain lesions, such as those that occur in a socket from a tooth extraction or where the upper and lower teeth meet in the buccal mucosa, pose no significant risk of developing into oral cancer. Dentures and related prosthetic devices can commonly rest at aspects of the upper and lower gingiva and are associated with hyperkeratosis at sites of contact. As a category, these areas are called friction ridges, and the associated lesion is called a friction ridge keratosis. Linea alba is the term commonly used to describe a friction ridge in the buccal mucosa that occurs at the junction of the upper and lower teeth. In aggregate, these types of keratoses are almost always benign. However, these regions can harbor dysplasia if they are associated with chewing tobacco placement or direct inhalational contact of tobacco, so it is not safe to assume these locations are benign until a careful history is obtained.
There are several options to consider for a patient that presents with oral cavity leukoplakia. If the anatomic region and the lesion have been under professional observation for a long period of time, one can immediately perform an incisional biopsy of the lesion, which is a gold standard for diagnosis. There are no biomarkers or special stains that one would normally need to request outside of standard histopathology. However, if a lesion is discovered at the time of a visit or documentation of prior presence of a lesion is unclear, one would recommend reducing or eliminating potential risk factors with re-examination of the oral cavity again in 6 weeks. This a standard recommendation for such patients. When biopsies are performed, they are preserved in formalin and sent for routine histopathology. At our institution, we orient biopsied lesion tissue by laying them flat, mucosal side up, on chromatography filter paper for a few moments. The filter paper with the lesion is then placed in 10% formalin. We do this for all incisional biopsies, many of which are taken with 3-6 mm Baker punches to avoid any crush or tissue folding artifact. This allows high fidelity biopsies for pathologic evaluation for diagnosis, clinical trials, and tissue procurement purposes.
52.2 Risk Factors
The most important risk factors for head and neck squamous cell carcinoma (HNSCC) are smoking and alcohol consumption. 2 These factors are associated with 75% of head and neck cancers and their effects are synergistic. 2 Both combustible and smokeless forms of tobacco have been linked to head and neck cancer, and their use is variable based on geographic location. Cigarettes and cigars are the most commonly used combustible tobacco products, while chewing tobacco, betel quid, and snuff are the most commonly used smokeless tobacco products.
The odds ratio (OR) of developing HNSCC in tobacco users compared to those who have never used tobacco is approximately 2.13. 3 While cessation does lower the risk, it is unclear whether the risk returns to that of a person who has never used tobacco. 4 Some data suggest that the risk returns to that of a person who has never used tobacco after about 20 years of cessation. 5
Hashibe et al have extensively studied the association between carcinogenesis in the head and neck, and tobacco and alcohol use in humans. 3 At least 75% of HNSCC in Europe, the United States, and other industrialized nations are attributable to the combinations of alcohol and tobacco. 3 However, the respective contributions of each risk factor can be difficult to understand as they are strongly associated with each other. In this study, Hashibe et al attempted to understand the independent associations of tobacco and alcohol with HNSCC. 3 They performed a pooled analysis to investigate the extent to which head and neck cancer was associated with cigarette smoking in never drinkers and with alcohol consumption among never smokers. Data was pooled from 15 case control studies to include 10,244 head and neck cancer case subjects and 15,227 control subjects. 1,072 case subjects and 5,775 control subjects had never smoked tobacco, while 1,598 case subjects and 4,051 control subjects had never consumed alcohol. Among never drinkers, cigarette smoking was associated with an increased risk of HNSCC (OR for ever smoking versus never smoking was = 2.13, 95% CI = 1.52 to 2.98). 3 In addition, they demonstrated a clear dose-response relationship for the frequency, duration, and number of pack-years of cigarette smoking. 3 Approximately 24% (95% CI = 16 to 31) of head and neck cancer cases among nondrinkers in this study would have been prevented if these individuals had never smoked cigarettes. 3
Recently, Wyss et al studied the association between cancer and several tobacco products. 6 For combustible products, they found increased risks of HNSCC for cigarettes (OR = 3.46, 95% CI = 3.24–3.70), cigars (OR = 2.54, 1.93–3.34), and pipes (OR = 2.08, 1.55–2.81). 6 In regards to smokeless tobacco, the use of snuff was shown to be associated with HNSCC (OR = 1.71, 1.08-2.70), particularly for oral cavity cancers (OR = 3.01, 1.63-5.55). 7 Chewing tobacco was weakly associated with HNSCC among patients who had never smoked (OR = 1.20, 0.81-1.77). 7 However, when restricted to oral cavity cancers, chewing tobacco had a stronger association (OR = 1.81, 1.04-3.17). 7 Furthermore, while human papillomavirus (HPV)-induced HNSCC is rising in incidence, a 2013 analysis of over 100,000 subjects showed 66% of HNSCC diagnoses were tobacco and alcohol related. 8 Thus, tobacco remains a prominent cause of HNSCC.
Alcohol was first recognized as a convincing risk factor for head and neck cancer by the International Agency for Research on Cancer in 1988. Since then, many studies have been published that support this statement. A recent meta-analysis investigated 572 studies, including 486,538 cancer cases. 9 This study indicated that the relative risks for heavy drinkers compared with nondrinkers and occasional drinkers were 5.13 (95% CI, 4.31-6.10) for oral and pharyngeal cancer and 2.65 (95% CI, 2.19-3.19) for laryngeal cancer. 9 A dose-risk relationship was observed between light, moderate, and heavy drinking among the cancer subsites.
The synergistic effect of tobacco and alcohol is supported by analysis of pooled data from 17 European and American studies. 10 The population attributable risk was 72%, which included 4% for alcohol alone, 33% for tobacco alone, and 35% for both alcohol and tobacco. The ORs of developing HNSCC are 2.37 (1.66-3.39) for tobacco users who are nondrinkers, 1.06 (0.88-1.28) for alcohol users who have never used tobacco, and 5.73 (3.62-9.06) for those who use both. 10 This effect was more than multiplicative. Similar steep rises in the risk of HNSCC among alcohol and tobacco users, especially those using high amounts of each product, have been demonstrated by Dal Maso et al. 11
To date, over 70 known carcinogens have been described in cigarette smoke. 12 Of the many toxic and carcinogenic substances resulting from tobacco exposure, tobacco-specific nitrosamines (TSNAs) and polycyclic aromatic hydrocarbons (PAHs) have been most heavily studied with regard to exposure and carcinogenicity. TSNAs are found in tobacco and tobacco smoke and are formed during the curing and processing of tobacco. They exist in both combustible and smokeless forms of tobacco. Of the TSNAs, N’-nitrosonornicotine (NNN) carries the highest risk for development of head and neck cancer. In rats, NNN reproducibly induces head and neck tumors. Subcutaneous or gavage administration of NNN to rats produces nasal tumors predominantly. 13 However, when administered in drinking water or a liquid diet, NNN exposure results in oral, esophageal, and nasal tumors. 13 PAHs represent a diverse group of carcinogenic compounds that share a similar structure of multiple benzene rings. Several PAHs have also demonstrated carcinogenicity in animal models. 14 The most well-studied constituents in this group include benzo[a]pyrene (BaP) and 1-hydroxypyrene (1-HOP). 4 When given orally, PAHs result in tongue and esophageal cancers and tumors of the upper respiratory tract, including in the nose, larynx, and trachea. When given by inhalation, tumors are found in the upper digestive tract including the pharynx, esophagus, and forestomach. 4
While the above animal studies clearly implicate tobacco and alcohol in the carcinogenicity of HNSCC, not all people who use tobacco products will develop HNSCC. There are complex mechanisms of genetic predisposition, carcinogen metabolism and excretion, immunologic competency, and genetic alterations that put some tobacco users on the path to developing cancer. However, others are able to exit this pathway by excreting the carcinogens or repairing DNA damage, for example. 15
The exact mechanisms for alcohol-related carcinogenesis are not fully understood. However, several carcinogenic effects of ethanol and its major metabolite, acetaldehyde, have been identified. 16 Acetaldehyde disrupts DNA synthesis and repair. 16 Additionally, ethanol is oxidized to acetaldehyde in the oral cavity by microbes. Thus, the concentration of acetaldehyde in saliva is 10- to 100-fold higher than in the blood, increasing the level of carcinogen contact to the oral mucosa. 16 Ethanol is associated with aberrations in several tumor suppressor and oncogene pathways. 16 Ethanol also acts as a solvent for several other carcinogens introduced by tobacco smoking, diet, and chemicals into cells. This is one mechanism by which alcohol and tobacco are thought to act synergistically in head and neck cancer carcinogenesis.
52.4 Other Etiologic Risk Factors for Oral Cavity Carcinoma
It is well established that oral lichen planus has an associated risk of conversion to oral cavity carcinoma about 4% of the time. This 4% risk is realized more frequently in patients who have persistent lesions or who have more severe lesions with dysplasia coexisting in their lesions. 17 In our practice, we regularly screen for and vigorously treat oral lichen planus. Erosive oral lichen planus is the more severe form of the disease. We generally employ various topical agents, including steroid containing mouthwashes, steroid containing creams, antihistamines, and at times, the transplant rejection drug tacrolimus.
Proliferative verrucous leukoplakia is a condition that occurs along the gingiva of the teeth. This is a rare condition of the mouth and frequently converts to gingival malignancies. Affected patients are treated aggressively with topical steroids. Once these lesions convert to malignancy, patients must undergo surgical resections, including cortical mandibulectomy. Despite surgical resection, these lesions can aggressively recur. 18
Submucous fibrosis is another precancerous condition; it seems to be more common in East Asia as a consequence of betel nut chewing. There is often an associated difficulty with trismus that may require surgical intervention for oral rehabilitation. 19