Oropharyngeal Cancer

Although largely preventable in developed countries, oral and pharyngeal cancers are more common than Hodgkin’s disease and cancers of the brain, liver, stomach, thyroid, ovary or cervix.1,2 An estimated 29,370 new cases of oral cavity and pharyngeal cancers were diagnosed in 2005 alone, with an estimated mortality rate of 7,320 in the United States.1

Oral cancer includes cancer of the lip, tongue, salivary glands, gum, floor of the mouth, oropharynx, nasopharynx, hypopharynx, pharynx, and buccal area.3 Although it accounts for a mere 2.2 percent of all U.S. cancer cases annually, only 54 percent of patients survive 5 years past diagnosis.2 This statistic has not changed within the past 25 years, and mortality rates for this group of tumors exceed those for cancer of the prostate, breast, bladder, colon, cervix, uterus and larynx.4

Prognosis for survival improves tremendously if tumors are diagnosed in earlier stages. At the time of initial diagnosis, patients with localized tumors have a 5-year survival rate of 81 percent compared to those with regional spread (43 percent) and those with distant metastases (22 percent).5 Unfortunately, only 35 percent of patients with oral cancer are diagnosed at an early stage.6 More than 50 percent of patients have metastases on initial presentation to their primary care provider or dentist.5 Moreover, about 15 percent of patients newly diagnosed with oral cancer have another aerodigestive tract neoplasm in the larynx, esophagus or lung.7

Of the risk factors associated with oral cancer, the two most common are also the two most preventable: tobacco and alcohol use (Table 1). These habits tend to act synergistically to increase the risk for malignancy.2 Oral cancer prevalence is greater among black men than white men, developing more often in the male gender, regardless of race.3,6 In addition to incidence and occurrence increasing with age, life expectancy decreases by 16.5 years at the time of diagnosis. 2

In 1999, an estimated 45.7 million adults (23.1% [95% CI=+0.6]) were former smokers; 25.8 million were men and 19.9 million were women. Former smokers constituted 49.5% (95% CI=+1.0) of persons who had ever smoked >100 cigarettes. 8 However, increasing numbers of adult men, especially between ages 18 and 24 and those with college degrees, now smoke cigars – raising the risk of death from laryngeal, oral and esophageal cancers four to 10 times.9 With the use of smokless tobacco also increasing, the incidence of cancer of the cheek and gums may increase nearly 50-fold among long-term snuff users over the next 10 years.10

Molecular Basis of Oral Cancer
A combination of genetic and environmental factors is believed to be involved in causing oral cancer. 11 Similar to other neoplastic diseases, this aggressive epithelial malignancy is the end result of a multi-step process involving the mutation of cell regulatory genes, i.e., oncogenes, tumor suppressor genes (TSGs) and growth factors. 11

Alterations of several TSGs are believed to be associated with oral cancer: Rb, p16, p53 and doc-1. 12 Inactivation of p53 occurs in 50 percent of oral cancers and is the most frequently observed mutation in most human malignancies.12 The majority of p53 mutations are detected in smokers, and the frequency of genetic changes increases with concurrent alcohol use.13

Other genetic abnormalities may be involved in the course of oral cancer. Genes may influence the effects of viruses (i.e., human papillomavirus) or certain behaviors (i.e., addictions to nicotine or ethanol) might play a role in oral cancer development.12 Two studies found that genetic polymorphisms in the GSTP1 and GSTT1 enzymes (involved in carcinogen detoxification) affected the amount of tobacco carcinogens internalized by smokers.12,13

Risk Overview
To complicate matters, oral cancer may arise in people who do not have any risk factors, whereas others with multiple risk factors never develop malignancy.2 This discrepancy in susceptibility results from an intricate combination of factors involving the environment, genetic alterations and individual behavior.2

Tobacco
In the United States, 90 percent of people with oropharyngeal cancer use tobacco products.4,9,10 Although tobacco smoke contains numerous carcinogens that directly contact the oral mucosa, tobacco tar possesses the most damaging elements.4 Smoking indirectly increases a person’s susceptibility to malignancy by depressing the immune system.14 Secondhand smoke contains four chemicals defined as human carcinogens, as well as 10 others classified by the Environmental Protection Agency as probable carcinogens.15

Tobacco-related cancer risk increases significantly with the frequency and duration of smoking, especially with high-tar and non-filtered cigarettes.16 The highest risk, however, is associated with a smoking history of greater than 20 pack-years (a pack year is defined as the number of packs per day times the number of smoking years).2,16 Smokers increase their risk of developing oral cancer by 2-18 times compared to nonsmokers.2

Recent studies suggest that even greater risk is related to cigars and pipes.9 Smokeless tobacco contains 28 known carcinogens and raises the risk for buccal, gingival and inner lip cancer 50-fold.10 The nicotine in chewing tobacco is absorbed 2-3 times faster than cigarettes and remains in the bloodstream longer. Most frightening is that the quantity of nicotine in 8-10 dips of smokeless tobacco is equivalent to smoking 30-40 cigarettes a day.10

Alcohol
Since only a minority of smokers develop oral cancer despite chronic exposure to tobacco smoke carcinogens, other factors have been explored as co-contributors to malignancy.17 One such agent is alcohol, which seems to exert its greatest damage on the oral, rather than pharyngeal, mucosa.17 Seventy-five to 80 percent of all patients diagnosed with oral cancer frequently drink alcohol, and this type of malignancy occurs six times more often in drinkers than non-drinkers.2 In addition, alcohol alone causes more than 50 percent of oral carcinomas and plays a significant role in the risk to people who have never smoked.17

Total consumption and duration are more important than the type of alcoholic beverage consumed. More than two drinks per day increases cancer risk 2-3 times that of abstainers. Combined with tobacco, alcohol acts synergistically to increase the risk of aerodigestive tract malignancy by 75 percent, with heavy-drinking smokers facing an increased risk 5-16 times that of abstainers. The increased risk to non-drinking smokers is only 2-4 times that of abstainers.18

Alcoholic beverages tend to contain some impurities and contaminants related to fermentation, distillation and maturation that may have carcinogenic potential. In addition, alcohol metabolism produces carcinogenic substances: acetaldehyde, N-nitrosodiethylamine or polyaromatic hydrocarbons (PAH).19 Alcohol may likewise cause mucosal injury while acting as a solvent, allowing other carcinogens (such as hydrocarbons and nitrosamines in cigarette smoke) to easily penetrate the epithelial mucosa.18,19 This is especially detrimental to the most dependent structures within the oral cavity (i.e., the anterior floor of the mouth and base of tongue) and areas that tend to pool food because they may undergo prolonged exposure to dissolved and concentrated carcinogens.20

Alcohol further exacerbates tobacco’s effects by increasing the frequency of p53 mutations and raising the risk of SPT development.21 Additionally, molecular epidemiologists have discovered that a definite increase in oral cancer risk occurs in people who possess a particular variation in a gene that regulates the speed at which the body metabolizes alcohol into alcohol dehydrogenase (a potential carcinogen).22 Alcoholic beverages also act to reduce intestinal absorption of nutrients leading to nutritional deficiencies and immunocompromise. 2

Viral Agents
Several studies suggest that human papillomavirus (HPV) may play a role in oral carcinogenesis. HPV-13 and HPV-32 have been identified in oral lesions only. HPV-16 is the most common culprit in both oral and genital malignancies.23 Nearly 30-40 percent of oral cancer biopsies have HPV DNA.23

HPV most likely acts synergistically with tobacco and alcohol, although one study identified HPV as the only presumable oncogenic risk factor in 50 percent of non-smoking subjects who developed an oral malignancy.24 Also, HPV might instigate uncontrolled cell growth through the action of HPV-16 E6 or HPV-18 E6, which are viral oncoproteins that bind to – and inactivate – p53.21,23

Nutrition and Diet
High intakes of certain food products increase the risk of oral carcinogenesis: eggs, red meat, salted or cured meats, pork, sausage, animal fats, butter, processed foods, additives and preservatives.25,26 Additionally, frequent consumption of saturated fats, cholesterol and starches results in a diet lacking micronutrients, which can lead to decreased production of antioxidants and, consequently, an increased accumulation of free radicals.25 26

Tobacco smoke acts as a pro-oxidant. This can be especially harmful in heavy smokers with poor diets, who require more antioxidants than nonsmokers. Alcoholics tend to be nutritionally deficient, since alcohol serves as their primary energy source, providing empty calories that replace other nutrient-rich sources.2,26

A 50 percent reduction in cancer risk occurs with the addition of a daily serving of fruits and vegetables.26 The most consistent dietary finding across many cultures is the protective effect afforded by high consumption of fruit against the carcinogenic effect of overindulgence of alcohol.4 Foods that decrease the risk of oral malignancy include milk, fish, fruit (especially citrus) and vegetables (especially dark green or yellow and carrots).2,26,27

Micronutrients that confer an anti-neoplastic effect include beta-carotene, retinol, vitamin C (especially in women), vitamin B6, folate, niacin and potassium. 2,26,27 Minimal efficacy has been demonstrated with multivitamin use in patients at risk for secondary cancer development.28 While highly speculated, no research has linked oral cancer to charcoal grilling or consumption of hot, spicy or pickled foods.20

Ultraviolet Light
Cancer of the lip is not a common clinical finding; however, the incidence is directly related to ultraviolet light exposure. 2 Of these, more than 30 percent have outdoor occupations resulting in prolonged sun exposure.29 The lower lip is predominantly affected, since it receives a greater amount of sunlight.29

Race
African-Americans tend to exhibit higher morbidity and mortality from oropharyngeal malignancies than Caucasians.4,20 Only 19 percent of African-Americans are diagnosed at an early stage, when the disease is more amenable to treatment, compared with 38 percent of Caucasians.2,20 Furthermore, the African-American mortality rate is twice that of Caucasians, with a lower 10-year survival rate.2,20

These discrepancies are believed to result from differences in exposure and sensitivity to risk factors. For example, while African-Americans have a similar alcohol consumption rates to Caucasians, African-Americans tend to drink more heavily for longer periods of time than Caucasians do.30 In addition, African-Americans who develop oral cancer utilize the healthcare system less often than Caucasians.20

Gender
Although the risk of oral cancer has always been higher for men, this gap is narrowing. More women smoke today than in past decades, and women comprise a greater proportion of the aging population.31 Oral cancers account for 3 percent of all malignancies in men versus 2 percent in females.4

Whereas no significant interaction between alcohol and gender has been noted, tobacco use is responsible for more than 90 percent of all oral tumors in men and 60 percent of oral tumors in women.31 In addition, with the incidence of mouth and tongue neoplasms rising, especially in young men, it is not surprising that the majority (90 percent) of oral cancer deaths are among men.4,10

Biological explanations proposed to account for this variation in susceptibility to tobacco carcinogens include: differences in nicotine metabolism between genders, menstrual-related nutritional deficiencies during the reproductive years, or increasing estrogen levels.31

Age
On average, oral cancer is diagnosed by the age of 64.4 However, about 50 percent of patients are younger than 60 when diagnosed. Recently, increasing numbers of these cancers have been detected in young adults, most likely due to the use of marijuana and chewing tobacco.32

Heredity
The relationship between heredity and oral cancer is not clear-cut. No specific gene has been identified as a hereditary basis for other forms of oropharyngeal carcinoma.33 However, it is possible that genetic alterations in specific enzymes (i.e., GSTP1, GSTT1) caused by smoking may influence oral malignancy risk.16 Likewise, a hereditary component might serve as a catalyst for certain high-risk behaviors (i.e., tobacco or alcohol abuse).33

Screening
Screening is essential for early detection of carcinomas. In fact, of all existing cancer therapies, early detection has had the greatest effect on survival rates.2 However, it appears that providers are lax in providing routine oral cancer screenings, especially for people at risk, since most oral lesions are moderately advanced with regional or distant spread on initial diagnosis.6,34

Assessing the oral cavity by visual exam is a quick and simple process, taking no longer than 5 minutes and resulting in little to no discomfort. Oral screenings may aid in decreasing the incidence of invasive cancer, subsequently decreasing mortality and lowering treatment costs, since smaller lesions are easier to treat and have a better prognosis.34 By focusing on high-risk sites where more than 90 percent of oral carcinoma occurs (i.e., the floor of the mouth, ventrolateral tongue and soft palate complex), the efficacy of this assessment technique increases.34,35

Clinical Manifestations
The highest percentage of oral cavity cancer occurs at areas in direct contact with carcinogens (i.e., alcohol, tobacco) for prolonged time periods. Fortunately, most sites susceptible to oral squamous cell carcinoma (SCCA) are easily inspected.

Diagnostic delays are not uncommon, however, because the majority of oral carcinomas are asymptomatic and mimic benign conditions.34,35 Often, SCCA of the oral epithelial mucosa only becomes clinically evident after disease has spread regionally and the patient’s immune system is weakened. 36 Moreover, it has been documented that patients tend to delay physical exam for up to 3 months after noticing a lesion, whereas one-third of health care providers contribute to late diagnoses by inappropriately prescribing antibiotics or adjusting dentures.34

Warning Signs, Symptoms
The most common presenting symptom of oral cancer is a sore in the mouth that will not heal (Table 2).2,3 Other red flags might include: pain, bleeding, ulceration, a lump or thickening in the cheek or otalgia.2,3

The patient may notice a white or red patch on the gums, tongue, tonsil or buccal mucosa, a lump in the neck, difficulty chewing or moving the jaw or tongue, swelling in the jaw causing dentures to hurt or fit poorly, loose teeth, or jaw pain.2,6

Signs and symptoms of more advanced disease include dysphagia, lingual numbness, hoarseness and unintentional weight loss.2,3,37

Premalignant Conditions
In a healthy person, the oral mucosa and tongue appear pink, smooth and moist. Observation of mucosal changes such as leukoplakia, erythroplakia, erythroleukoplakia or chronic candidiasis should raise suspicion of potential carcinoma.38

Although difficult to distinguish from asymptomatic conditions, malignancy becomes a possible differential when discomfort or other symptoms do not resolve within 2 weeks after discontinuation of all oral irritants (i.e., tobacco, alcohol or poorly fitting dentures).38

Leukoplakic lesions appear as yellow-white or gray-white patches that commonly are elevated with a rough, leather-like surface and well-defined borders.38 They are most often noticed on the inner lips, lower gingiva and buccal mucosa, with only about 5 percent becoming malignant.2,38

On the other hand, erythroplakia is often indicative of early SCCA.39 These lesions present as red, velvety, inflammatory plaques with irregular borders. They may occur in the floor of the mouth (most common site in men), retromolar trigone, tongue, palate and mandibular mucosa (most common site in women).39 Nearly 51 percent of erythroplakic lesions are malignant.39

A much greater risk of dysplasia and malignancy occurs with erythroleukoplakia. These appear as white lesions with bright red patches. Though quite rare, 60 percent of early asymptomatic SCCAs have this appearance.40

Chronic oral candidiasis should alert any examiner inspecting the oral cavity, since Candida infection of a leukoplakic lesion increases the potential for malignant transformation.41,42 Differentiated from leukoplakia only by biopsy, Candida appears as tough, adherent white patches, usually on the tongue, palate and buccal mucosa. When scraped off, they reveal erythema. 41,42 Described by patients as “dry” or “hot,” Candida often results in a secondary infection related to immunosupression or prolonged antibiotic use. 41,42

Oral Cavity Examination
During the health history, determine whether the patient is experiencing any of the warning signs or symptoms and risk factors characteristic of oral cancer. Has the patient observed any differences in color, texture or sensation in his lips, mouth or gums? Is there any pain, numbness or bleeding without a known cause? Is it difficult to chew or swallow? Do dentures fit poorly? Has there been a recent unintentional weight loss? Does the patient smoke or consume alcohol? How much and for how long? What is the patient’s typical nutritional intake? What is the degree of sun exposure?34

Minimal equipment is needed to conduct an oral examination: adequate light, a tongue depressor, two 2-inch-by-2-inch gauze pads and gloves. The patient should be seated and remove any dentures prior to the exam.34

The World Health Organization recommends that the assessment progress in a stepwise fashion from extraoral to intraoral, using both inspection and palpation.34 The most valuable skill is direct visualization because early lesions rarely have a palpable mass or depth.2,34 Palpation is useful, however, to determine asymmetry, textural changes (roughness or granulation), tenderness, edema and nodal characteristics, as well as the extent of induration and depth of a neoplasm.34 Nodes that are soft, tender and freely mobile indicate possible inflammation, whereas firm, hard, nontender and fixed nodes suggest possible tumor formation.34

Pay careful attention to suspicious lesions. If the lesion in question is a self-limited patch of leukoplakia, advise the patient to avoid all oral irritants for 2 weeks.34 If the condition persists past the 2-week follow-up period, refer the patient to an otolaryngologist. Immediate referral is necessary if the patient presents with widespread leukoplakia, lesions in areas difficult to visualize, large or ulcerated lesions, or any erythroplakia.40

Upon referral, the otolaryngologist will perform a biopsy and examination with hematoxylin and eosin staining of the lesion in question. These techniques are the only confirmatory tests in the diagnosis of oral mucosal SCCA.43,44

Differential Diagnoses
As mentioned previously, SCCA of the oral cavity may be difficult to diagnose because leukoplakic and erythroplakic lesions often mimic other, less threatening conditions. A lesion may be a benign or malignant tumor; the result of mechanical injury; a vascular, metabolic, hematologic or mucocutaneous disorder; a viral or inflammatory condition; or a benign oral condition that could potentially become malignant.45

Malignant tumors of the oral cavity are either basal cell (BCCA) or squamous cell carcinomas.45 Of the two, SCCA accounts for more than 90 percent of all oral cancers and causes 95 percent of tongue malignancies.29,44 These lesions, which tend to grow slowly, appear erythematous with ill-defined borders and bleed easily. On the other hand, BCCA appears primarily on the lips as a small scab that progresses to an ulcer with a pearly border. Generally, people exposed to excess ultraviolet light, especially those with fair skin, are the most vulnerable to BCCA.46

Mechanical injuries usually result from sharp objects, dentures or cheek biting and appear as lesions, abrasions or ulcerations that may become infected.2

A hemangioma, a vascular tumor that may present at birth and regress during puberty, looks like a small, erythematous, soft mass on the lip, tongue or gum, or appears as a purplish-red plaque on the buccal mucosa.46,47 Other benign tumors of the oral cavity include fibromas (painless, smooth, firm, circumscribed lesions in varying sizes that are sessile or pedunculated); neurofibromas (firm and pedunculated lesions usually on the tongue and palate); and lipomas (soft, symmetric and easily movable subcutaneous adipose tumors). 46-48

Metabolic disorders that cause oral mucosal changes result from various nutrient and vitamin deficiencies, such as:

* scurvy (vitamin C deficiency): gingivitis, bleeding gums and hemorrhages

* ariboflavinosis (riboflavin or B2 deficiency): atrophic glossitis, angular cheilitis and gingivostomatitis

* pellagra (niacin or B3 deficiency): red beefy tongue, patchy papillae loss and occasional ulcers

* iron deficiency: smooth red tongue with papillae loss and angular cheilosis

* amyloidosis: macroglossia with yellow nodules along the dorsal or lateral tongue and gingiva

* pernicious anemia (B12 deficiency): shiny, smooth, red tongue, loss of papillae, and increased susceptibility to oral ulcers

* menopause: diffuse gingivostomatitis and erythema, with occasional fissuring of the mucobuccal fold 25,49,50

Assessment of the oral cavity in someone with a hematologic disorder may reveal acute atrophic glossitis and angular cheilitis (Plummer-Vinson syndrome); mucosa easily traumatized with a red-purple tinge (polycythemia vera); or necrotic sloughing of the oral mucosa with underlying ulcerations in the absence of an inflammatory response (mucositis after chemotherapy).51,52

Mucocutaneous disorders also affect the oral cavity. Recurrent aphthous stomatitis (canker sore) is precipitated by high stress levels or viral infection, and is preceded by a prodrome of burning and pain. These lesions are well-circumscribed erythematous macular lesions on the tongue or buccal mucosa that progress to ulcers and spontaneously heal in 1-2 weeks. Erythema multiforme results in the formation of bullae surrounded by intraoral edema and inflammation that burst, forming ulcers. Pemphigus vulgaris arises on the buccal mucosa, palate and gingiva in the form of large, painful, persistent bright red erosions with gray-white remnants of ruptured bullae.34,42

Lesions caused by viral or inflammatory conditions might raise unnecessary cause for concern. Herpes simplex virus occurs at the mucocutaneous junction of the lips and face as clear vesicular lesions on an erythematous base. 34,42 Adenotonsillitis or pharyngitis presents with intense oropharyngeal erythema and purulent exudate of the tonsils with hypertrophic swelling.45 Lichen planus, a chronic inflammatory disease, causes small white papules surrounded by bright red mucosa to appear on the buccal mucosa, gingiva and tongue, often as a response to stress.53,54

Acanthosis nigricans is a benign oral condition associated with distant malignancy, which appears as wart-like eruptions on the tongue, buccal mucosa and lips.55

Treatment
Several treatment options are available and depend on the stage of the lesion at diagnosis. These modalities are best utilized in collaboration with a head and neck surgeon, oral surgeon or oncologist.

Premalignant lesions may be treated with retinoic acid or laser surgery to slow possible progression.56 Some early-stage lesions are successfully treated via excisional biopsy and surgery, while radiotherapy proves equally efficacious.8 Lower success rates result when advanced lesions are treated. They frequently require a combination of surgery, chemotherapy and radiation; follow-up reconstruction and rehabilitation is often necessary.2,3,57

Chemoprevention (interferon, retinoids) has become a major weapon in the oral cancer prevention arsenal.58

New developments on the horizon include immunotherapy (vaccines), gene therapy (TSGs, p53), new chemotherapeutic techniques (intrathecal, intralesional) and new radiotherapy approaches (bid versus qd irradiations).2

Prevention
The key to diminishing the impact of oral cancer is prevention. Prevention involves increasing awareness and stimulating questions through education, as well as utilizing methods to detect diseases at early, presymptomatic and treatable stages.

Patients young and old must be counseled at every healthcare encounter to avoid known carcinogens.2,3,6 Smoking cessation is associated with a 50 percent decreased risk of oral cancer within 3-5 years of quitting, and a return to normal risk levels in 10 years. Abstaining from, or moderation in, alcoholic beverage consumption will also result in a lower incidence. Increasing fruit, vegetable and fiber intake decreases risk by 30-50 percent. Wearing lip balms or lipsticks with SPF lowers lip cancer risk, as does wearing wide-brimmed hats and avoiding the outdoors during midday when UV rays are strongest. 2,3,6

Performing oral exams routinely, especially on high-risk patients, is a must. Prevention efforts also include educating patients about risk factors, signs and symptoms, as well as how to perform an oral self-exam (Table 3). Through education, patients gain knowledge and become empowered. Therefore, people with better knowledge of risk factors, signs and symptoms will more likely be screened.

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