Epidemiology and Etiology

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BRUCE J. DAVIDSON, MD, FACS

INCIDENCE

Current Incidence Data

The global incidence of cancers of the oral cavity, pharynx and larynx is about 500,000 cases per year with mortality of 270,000 cases per year.1 Excluding skin cancers, this represents about 6 percent of the incidence and 5 percent of the mortality of all cancers.1 About three-fourths of these are cancers of the oral cavity and pharynx and the remainder are laryn-geal cancers. Figure 1-1 describes the incidence of oral and pharyngeal cancers by world region. As demonstrated here, the areas of the world with the greatest incidence are Melanesia (Papua, New Guinea and adjacent islands), Western Europe and South Central Asia (India and the Central Asian republics of the former Soviet Union).1

Figure 1-2 details the oral and pharyngeal cancer mortality rates for selected countries. In 2001, oral, pharyngeal and laryngeal cancers are expected to occur in approximately 40,100 individuals in the United States and result in death in 11,860.2 In United States males, oral and pharyngeal cancer comprise the seventh most common cancer and larynx cancer ranks fifteenth.2 In females, the incidence of oral and pharyngeal cancers ranks fourteenth and laryngeal cancer and anal cancer (2,000 each) share the twenty-seventh and twenty-eighth positions.2

Trends Over Time

United States

Head and neck cancer incidence in the United States has shown declines in the past 2 decades after pre vious increases. From 1940 to 1985, there was an increase in laryngeal cancer incidence in men and women reflecting the increase in cigarette use in this century.3 Oral and pharyngeal cancer incidence was stable in men and increased in women over this time period.3 Between 1973 and 1997, a decrease in oral and pharyngeal cancer and in laryngeal cancer appeared.4 This decrease was primarily determined by large rate decreases in men. During this same period, females showed an increase in laryngeal cancer rates and no change in oral cancer.4 Most recently, 1990s United States cancer registry data shows a significant drop in the incidence rates of oral cavity and pharyngeal cancers for both sexes.5 A steady drop in oral and pharyngeal cancer mortality has also been noted.6 Mortality trends differ by race, which will be explored later in this chapter.

Europe

While United States' rates (incidence and mortality) for oral and pharyngeal cancer have recently been falling, European mortality rates for these cancers among males rose between 1983 and 1993.7 Laryngeal cancer mortality increased in Eastern Europe.7 Studies from individual European countries tend to reflect a rising mortality from oral,8,9 pharyngeal,9,10

and laryngeal910 cancers from the early 1950s through about 1980. One exception to this is a Swiss study showing a decrease in laryngeal cancer mortality in males, but an increase in females.11 More recent studies, spanning the mid 1970s into the 1990s, show decreases in oral cancer mortality in France12 and laryngeal cancer mortality in France,12 Italy,13 Switzerland,11 and Sweden.14 These reductions may be secondary to decreased cigarette con

Aniline Based Sensing
Figure 1-1. Incidence (cases/100,000) of cancer of the lip, oral cavity and pharynx in males by geographic area. (Data from: Parkin DM, Pisani P, Ferlay J. Global cancer statistics. CA Cancer J Clin 1999;49:33-64.)

sumption or a change to less carcinogenic tobacco products (eg, filtered cigarettes or less carcinogenic blond tobacco products).

Variations in alcohol use may also explain some cancer incidence changes over time. A Scottish study showed an increased incidence of oropharyngeal and

Red Tide Human Poisoning

Figure 1-2. World map with death rates for oral and pharyngeal cancer in males indicated for selected countries. Units are age-adjusted death rates per 100,000 population. Countries shown are: Canada (4.0), United States (3.4), Chile (2.2), Norway (2.8), United Kingdom (3.0), France (12.0), Spain (7.0), Hungary (18.5), Russian Federation (9.2), Israel (1.5), China (2.6), Japan (2.5), and Australia (4.4). Source document does not include data from several high-incidence areas such as Melanesia, India and Brazil. (Data from: Landis SH, Murray T, Bolden S, Wingo PA. Cancer statistics, 1998. CA Cancer J Clin 1998;48:6-29.)

Figure 1-2. World map with death rates for oral and pharyngeal cancer in males indicated for selected countries. Units are age-adjusted death rates per 100,000 population. Countries shown are: Canada (4.0), United States (3.4), Chile (2.2), Norway (2.8), United Kingdom (3.0), France (12.0), Spain (7.0), Hungary (18.5), Russian Federation (9.2), Israel (1.5), China (2.6), Japan (2.5), and Australia (4.4). Source document does not include data from several high-incidence areas such as Melanesia, India and Brazil. (Data from: Landis SH, Murray T, Bolden S, Wingo PA. Cancer statistics, 1998. CA Cancer J Clin 1998;48:6-29.)

hypopharyngeal cancers with stable incidence of nasopharyngeal cancer between 1960 and 1989.15 As a possible predictor of future trends, young adult males (ages 20 to 44) have shown an increase in oral and pha-ryngeal cancer mortality between the 1950s and the late 1980s in a Swiss study16 as well as in studies across Europe.17 Increased incidence and mortality rates from hypopharyngeal cancers in individuals under 60 years of age have also been shown since 1960 in an Austrian study.18 These data are thought to be a reflection of increased alcohol consumption over time.15

Former Soviet Union

A long-term study of cancer mortality in the former Soviet Union showed an increase in oral, pharyngeal and laryngeal cancer mortalities between 1965 and 1990.19 Estonia (former Eastern European Soviet Union member) showed increased mortality rates for cancers of the oral cavity, pharynx and larynx in men and oral cavity and pharynx in women, between 1965 and 1989.20 Trends in the former Soviet Union and in Eastern Europe appear to reflect continued high rates of tobacco consumption. Figure 1-3 shows oral and pharyngeal mortality rates for several countries in Western Europe, Eastern Europe and the former

Soviet Union. From the figure, wide variations in mortality are indicated.

Asia

Japanese males showed an increase in oral and pharyngeal cancers mortality between 1950 and 1994, although no change was seen in females. Analysis specified by tumor site showed a decrease in oral tongue and tongue-base cancer mortality, with increases in mortality from other oral and oropha-ryngeal sites. It was suggested that these changes were reflective of increased tobacco consumption for pharyngeal cancers, increased alcohol consumption for oral cancers and were unrelated to tobacco or alcohol for tongue cancers.21

The incidence of head and neck cancer in India is variable, with some areas showing rates of cancer among the highest in the world and other areas with rates comparable to the United States. Oral and pharyngeal cancers are highest in the area of Ahmedabad in West India. Between the 1960s and 1980s, a drop in head and neck cancer incidence was seen across India. This decrease has been attributed to decreased consumption of oral tobacco and an increase in cigarette and bidi (tobacco rolled in a tendu leaf) smoking.22

Epidem Head And Neck Cancer Spain
Figure 1-3. Death rates for oral and pharyngeal cancer in males indicated for Europe and Russia. Units are age-adjusted death rates per 100,000 population. (Data from: Landis SH, Murray T, Bolden S, Wingo PA. Cancer statistics, 1998. CA Cancer J Clin 1998;48:6-29.)

EPIDEMIOLOGY Geographic Variation

Incidence and Tumor Site Differences

As indicated in Figure 1-1, the incidence of head and neck cancer varies throughout the world. For instance, mouth cancers are 45 times more common in certain areas of France than in The Gambia.4 The Basque region of Spain has an incidence of laryn-geal carcinoma (20/100,000) that is about 200 times greater than the incidence of laryngeal cancer in Qidong, China (0.1/100,000).4

Mortality also differs throughout the world. Mortality differences are influenced by incidence of disease as well as survival rates after diagnosis. The 5-year survival rate for cancers of the oral cavity and pharynx is 46 percent worldwide, but differs between developed (59%) and developing (39%) countries. The larynx cancer 5-year survival rate is 46 percent with similar differences between developed (51%) and developing (41%) countries.1

Table 1 -1 lists the countries with the highest rates of oral and pharyngeal cancer mortality over two periods in the past 20 years. Unfortunately, the source documents fail to report mortality data on several high-incidence areas such as India, Melanesia and Brazil. In the mid 1980s, the highest rates of oral and pharyngeal cancer mortality for males were seen in Hong Kong, France, Singapore and Hungary

(all 10-15/100,000).4 The rates for females were highest in Singapore, Hong Kong, and Kuwait (2-5/100,000).4 In the more recent period, four of the five countries with the highest mortality in males are in Eastern Europe.117 Hungary has shown a rise in mortality rates from 12.5 to 18.5 in less than a decade. In females, two of the top five are in Eastern Europe and the other three are in the Central Asian republics of the former Soviet Union.117 The comparison between 1986 to 1988 and 1992 to 1995 shows the effect of geopolitical changes on cancer statistics with several newly independent countries reporting high mortality rates from these cancers.

Race

Significant racial differences are seen in cancer demographics in the United States. According to SEER statistics from 1973 to 1997, the incidence of oral and pharyngeal cancer was shown to be higher in blacks than in whites from 1975 onward. Similarly, the incidence of laryngeal cancer has been higher in blacks since 1973.118 While oral/ pharyngeal cancer is the sixth most common cancer in the United States, this represents the fourth most common cancer in blacks.119 An exploration of this observation has found that most of the increased incidence in blacks can be attributed to higher tobacco and alcohol consumption among this group. Controlling for these exposures results in almost equivalent risk of oral and pharyngeal cancers by race.120

Table 1-1. COUNTRIES WITH THE HIGHEST MORTALITY RATES FOR ORAL AND PHARYNGEAL CANCER

(AGE-ADJUSTED DEATH RATES / 100,000)

1986-1988 1992-1995

Male Female Male Female

Country Rate Country Rate Country Rate Country Rate

Hong Kong 14.8 Singapore 4.8 Hungary 18.5 Hungary 2.4

France 14.3 Hong Kong 4.8 France 12 Kazakhstan 1.9

Singapore 12.8 Kuwait 2.4 Croatia 11.7 Turkmenistan 1.7

Hungary 12.5 Cuba 1.8 Slovenia 11.2 Albania 1.6

Puerto Rico 9 Malta 1.7 Romania 11.1 Uzbekistan 1.5

Czechoslovakia 8.2 Panama 1.7 Ukraine 9.6 Denmark 1.4

Luxembourg 7.6 Hungary 1.6 Russian Federation 9.2 France 1.3

Uruguay 6.9 Australia 1.4 Estonia 9 Australia 1.3

Soviet Union 6.6 Denmark 1.4 Belarus 8.8 United States 1.2

Switzerland 6.5 Venezuela 1.4 Lithuania 8.3 Canada 1.2

Adapted from Ries LAG. Rates. In: Harras A, editor. Cancer: Rates and risks. Washington, DC, National Institutes of Health; 1996. p.9-55. and from Li FP, Correa P, Fraumeni JF. Testing for germ line p53 mutations in cancer families. Cancer Epidemiol Biomarkers Prev 1991;1:91-4.

Trends in oral and pharyngeal cancer and laryn-geal cancer incidence are favorable when evaluated by race. For oral and pharyngeal cancers, the trend in cancer incidence is downward since about 1984 in whites and since 1980 in blacks. For laryngeal cancer the negative trend began in 1988 in whites and 1990 in blacks.118

Mortality rates are also significantly higher for blacks than for whites for both oral/pharyngeal and laryngeal cancers. For both types of cancer, between 1973 and 1997, mortality was higher in blacks every year, and from 1993 to 1997, mortality rates in blacks were approximately double that seen in whites. Oral and pharyngeal cancer mortality has been trending downward since 1973 for whites, but for blacks, mortality rates rose from 1973 to 1980 and since then have been falling. For laryngeal cancer, mortality has also fallen since 1973 in whites, but rose in blacks from 1973 to 1992. Mortality rates in blacks have more recently been trending downward (trend not statistically significant).118

The differences in oral and pharyngeal cancer mortality between African Americans and Caucasians have been attributed in part to differences in survival rates. Five-year survival rates for these cancers from 1989 to 1996 were 56 percent for Caucasians and 35 percent for African Americans.118 Data shows that African Americans are more likely to be diagnosed at a higher tumor stage, but that even after adjustment for stage, the mortality is greater in African Americans (see Figure 1-8).2 Access to health care may play a role as 21 percent of African American adults lack a health care plan while only 13 percent of Caucasians are without coverage.119 Racial differences in prevention appear to exist, in that a higher proportion of African Americans over Caucasians continue to smoke—34 percent versus 28 percent respectively.119

Gender

Gender differences in head and neck cancer incidence and mortality appear to reflect differences in risk factor exposure. The rise in tobacco consumption by women since the 1950s has resulted in an increased proportion of female cancer incidence and mortality for these cancers. A study from Houston compared the male-to-female ratio of laryngeal cancer over two periods in the past four decades. The proportion of male-to-female cases dropped from 5.6:1 to 4.5:1 between the periods 1959 to 1973 and 1974 to 1988.121 Other studies have reflected similar trends.122123 Significant differences in the site of laryngeal cancer development has been suggested, with a ratio of glottic to supra-glottic sites of 22.1:1 in men and 0.6:1 in women.124

Among nonsmokers who develop oral and pha-ryngeal cancer, a higher proportion of women than men is seen in patients over the age of 50.29 Analyzing oral cancers by site relative to gender reveals that the ratio of males to females is highest for floor-of-mouth cancers (ratio=3.4:1), and lowest for gingival cancers (ratio=0.5:1).125

SEER data suggests a downward trend for oral and pharyngeal cancer incidence for both males and females since the early 1980s. Mortality has also been declining for both males and females since 1979. For laryngeal cancer, incidence has declined since the mid to late 1980s for both males and females. Mortality has been falling since 1973 for males, but rose until 1992 in females. Recently a downward trend in laryngeal cancer mortality rate (not statistically significant) has been seen in females.118

ETIOLOGY

It has been estimated that in the United States, well over three-fourths of all head and neck cancers can be attributed to tobacco and alcohol use.23 This section will explore these risk factors for head and neck squamous cell carcinoma and will describe other factors that may play a role in the etiology of these cancers. As with most cancers, age itself may be a risk factor for the development of head and neck cancer. In nonsmokers and nondrinkers, the average age of onset of laryngeal cancer is about 10 years later than in patients with a history of tobacco or alcohol use.24

Tobacco

Cigarettes

Cigarette smoking is the single most important risk factor in head and neck cancer. For oral cancers in men, 90 percent of cancer risk can be attributed to tobacco. The attributable risk of tobacco for oral cancer development is lower in females at 59 percent.4 The smoking attributable risk for laryngeal cancer in males and females is more similar at 79 and 87 percent respectively.4 The relative risk of laryngeal cancer between smokers and nonsmokers is 15.5 in men and 12.4 in women.14 In support of the association between tobacco and head and neck cancer is information associating cigarette consumption with oral dysplasia (Odds Ratio [OR] = 4.1), a premalignant oral lesion.25

Discontinuation of smoking reduces the risk of head and neck premalignant and malignant lesions. Smoking cessation results in a decreased risk of oral dysplasia that reaches that of "never-smokers" after 15 years.25 The risk of oral cancer has been suggested to be reduced by 30 percent for those who have discontinued tobacco for 1 to 9 years and by 50 percent for those who have abstained for over 9 years.26 No excess risk of oral and pharyngeal cancer has been shown among individuals who have abstained for over 10 years.23,27 These results emphasize the importance of smoking cessation efforts.

Tobacco contains over thirty known carcinogens. The majority of these are polycyclic aromatic hydrocarbons and nitrosamines.28 Increasing tar consumption has been associated with oral and pharyngeal cancer in a dose-dependent manner. Interestingly, when this is evaluated by gender, the risks of cancer associated with tar exposure increase more sharply for women than men.29 Specific tobacco use habits appear to alter the risk of head and neck cancer. Exclusive use of filtered cigarettes is protective when compared to unfiltered cigarette use.27,30 Inhalation increases the risk of cancer of the endolarynx, although it does not alter the risk of hypopharyngeal or epilaryngeal (suprahyoid epiglottis and aryepiglot-tic folds) cancer.31

Cigars, Pipe Smoking

An increased risk of incidence for cancers of the oral cavity, pharynx and larynx has been shown for pipe and cigar smokers.28 Risk of cancer from pipe smoking tends to be higher for oral cavity sites than pharyngeal or laryngeal sites.32 Mashberg found that cigar or pipe smoking without a history of cigarette smoking was associated with a relative risk of oral and pharyngeal cancer of 3.3. When mixed exposures (ie, pipe and cigarette or cigar and cigarette) were analyzed, the relative risk of oral and pharyngeal cancer was 2.6 for cigar smokers and 3.2 for pipe smokers.27

Smokeless Tobacco

Smokeless tobacco use has gained popularity in the United States over the past 25 years. The habit was traditionally practiced by women in the rural south as an alternative to cigarette smoking. In this population, a four- to six-fold increase in risk of oral cancer has been shown.23,33 Cancers are typically well-differentiated and occur on the alveolar ridge or buccal mucosa.34 Snuff-related oral cancer appears to require prolonged exposure. Patients developing oral cancers who have a history of snuff use without other risk factors typically are in their 60s and have been using oral tobacco for 40 years.34

Recent attempts to define the risk of oral cancer related to this increasingly popular practice has been difficult. The state with the highest per capita consumption of smokeless tobacco, West Virginia, has not shown an increased incidence of or mortality from oral or pharyngeal cancer when compared with national averages.35 These results are possibly reflective of the low prevalence of alcohol abuse in West Virginia. In addition, a Swedish case-control study showed no increased risk for oral cancer in current or former snuff users.36 These results may be a reflection of the prolonged exposure to oral tobacco required for the development of oral cancer.

Types of Tobacco

Two major types of tobacco exist. Black or dark (air-cured) tobacco is used in the manufacture of cigars, pipe-blends and certain cigarettes. Blond (flue-cured) tobacco is used more commonly for cigarettes. A major difference in these two tobacco types is that the alkalinity of black tobacco causes it to be irritating to the respiratory mucosa. Deep inhalation is less well-tolerated than with blond tobacco prod ucts. For this reason, it is theorized that black tobacco products might exert a greater effect on the upper aerodigestive mucosa while blond products have a greater effect on the lower respiratory mucosa. This is supported by data showing a greater risk of larynx cancer than lung cancer in persons using black tobacco products.32

Experimental studies have shown the extract of black tobacco cigarettes to be more carcinogenic than blond tobacco cigarettes.37 As a reflection of this, epidemiologic studies have shown that the type of tobacco consumed is associated with the risk of aerodigestive tract cancer. Dark (air-cured) tobacco use was associated with a 59-fold increased risk of laryngeal cancer while blond (flue-cured) tobacco was associated with a 25-fold risk.38 After control for socioeconomic factors, alcohol consumption, length of smoking exposure, and filter use, the user of black tobacco cigarettes has a threefold relative risk of oral cavity and pha-ryngeal cancer when compared with the user of blond tobacco cigarettes.39

When studies compare the use of blond tobacco only, with black tobacco only, with mixed exposures, a dose-response effect is demonstrated. A multi-institutional case-control study from Europe showed such an effect with an increased relative risk of cancer of the endolarynx, epilarynx and hypopharynx associated with increasing use of black tobacco relative to blond tobacco.31 Analogous data from Thailand has shown that certain Thai tobacco preparations, specifically the more alkaline and less easily inhaled varieties, are associated with an increased risk of laryngeal cancer over other Thai preparations.40

The difference in popularity of black and blond tobacco cigarettes is likely to influence the geographic variations in laryngeal cancer incidence and subsite distribution throughout the world (Figure 1-4, A and B). Countries with the highest death rates from laryngeal cancer are France, Uruguay, Spain and Italy. Each of these countries, along with Cuba, Argentina, Brazil, Columbia and Greece has a relatively high prevalence of black tobacco cigarette consumption. Several of these countries also show a greater prevalence of supraglottic cancers than glottic cancers.38 This is in contrast to the United States where blond tobacco cigarettes are typical and laryngeal glottic cancer is more common.

Alcohol

Head and neck squamous cell carcinoma is a disease occurring most often in individuals with heavy tobacco and alcohol use. Tobacco has gained the majority of attention in terms of public health education and many lay persons are unaware of the association of alcohol with upper aerodigestive squamous cell carcinoma. The cancer risk associated with alcohol consumption varies among upper aerodigestive tract sites.

The association between alcohol and head and neck cancer is stronger for pharyngeal cancer than for other head and neck sites. A dose-response effect has been shown between alcohol and pharyngeal cancer in a German study. After adjustment for tobacco consumption, the relative risk of pharyngeal cancer is seen to rise progressively from 1.0 for those consuming < 25 g/day (> 2 drinks) to 125 for those consuming >100 g/day (> 7 drinks).41 High alcohol consumption (> 100 g/day) represents less of a risk for oral cancers (RR=11)42 and laryngeal cancers (RR=15) (unpublished data described in41). Figure 1 -5 describes the difference in relative risk of cancer for several head and neck sites when compared to various levels of alcohol consumption.43 These data support a strong association between alcohol use and pharyngeal cancer.

This variation in the risk of alcohol on the development of head and neck cancer has also been shown to differ for subsites of the larynx. Patients with glottic cancer are more likely than those with supraglottic cancer to be nondrinkers.43 When comparison is made between drinkers and nondrinkers, the nondrinkers more often develop glottic cancer than supraglottic cancer. By comparison, the distribution is about equal for drinkers. Similarly, the association between alcohol and cancer varies between oral cavity sites, with a higher risk of buccal cancer than floor-of-mouth cancer in the non-drinkers and a higher risk of lateral tongue cancer than other tongue cancers in the nondrinkers. In drinkers, lateral tongue cancer is less common than other tongue cancers (includes base of tongue), and floor-of-mouth cancer is twice as common as buccal mucosa cancer.43

Multiplicative Effect of Alcohol and Tobacco

The synergistic effects of tobacco and alcohol have been shown in head and neck cancer in multiple studies.38,44-46 Figure 1-6 shows data from a multicenter case-control study for oral and pharyngeal cancers in the United States. The combined use of tobacco and alcohol increases the risk of laryngeal cancer by about 50 percent over the estimated risk if these factors are considered using an additive risk model.47 Other studies have also supported a synergistic effect of tobacco and alcohol on head and neck cancer risk.38,44

Types of Alcohol and Risk

There are significant differences of content between various alcoholic beverages. Beer contains the carcinogen nitrosodimethylamine, while distilled wines have a high content of tannin, another carcinogen. When comparing various hard liquors, dark liquors (eg, whiskey, dark rum, cognac) contain greater

Thailand

m

Per 100,000

Philippines

China

Japan

India

■■L

Costa Rica

Ireland

m

Germany

M

Brazil

\ iP

England

1

Mew Zealand

j

1

Is net

Australia

Spain

France

U.S. White

U.S. Black

Hungary

Italy

A

I

1.5

2 2.6 3 3.9

Figure 1-4. A, Worldwide incidence of supraglottic cancer. B, Worldwide incidence of glottic cancer.

i 80

2 ftO

I 40

0-39g 40-99g 100-159g >159g Alcohol Consumption Per Day

Figure 1-5. Relative risk of cancer for various head and neck sites relative to history of daily alcohol consumption adjusted for tobacco use. (Data from: Brugere J, Guenel P, Leclerc A, Rodriguez J. Differential effects of tobacco and alcohol in cancer of the larynx, pharynx and mouth. Cancer 1986;57:391-5.)

■ Hypopharynx -Epilarynx

Oropharynx - Mouth Supraglottis

■ Glottis amounts of organic compounds than light liquors (eg, vodka, gin, light rum). These include higher alcohols, esters and acetaldehyde.48 The risk of laryngeal and hypopharyngeal cancers is increased with dark liquor intake when compared with light liquor intake. The risk is greater for hypopharyngeal cancer than for laryngeal cancers.48

The relationship between type of liquor consumed and cancer risk has not been consistent. Mashberg reported on a series of oral cavity cancers and found

Oral Cancer Risk Smoking And Alcohol

Figure 1-6. Relative risk of oral and pharyngeal cancer relative to tobacco and alcohol intake. The synergistic effect of tobacco and alcohol exposure is shown. One pack-year is equivalent to smoking 20 cigarettes perday per one year. (Data from: Blot WJ, McLaughlin JK, Winn DM, et al. Smoking and drinking in relation to oral and pharyngeal cancer. Cancer Res 1988;48:3282-7.).

Figure 1-6. Relative risk of oral and pharyngeal cancer relative to tobacco and alcohol intake. The synergistic effect of tobacco and alcohol exposure is shown. One pack-year is equivalent to smoking 20 cigarettes perday per one year. (Data from: Blot WJ, McLaughlin JK, Winn DM, et al. Smoking and drinking in relation to oral and pharyngeal cancer. Cancer Res 1988;48:3282-7.).

that after controlling for total alcohol consumption, beer and wine intake were more strongly associated with oral cancer risk than was whiskey consumption.49 On the other hand, Blot showed increased risk of oral and pharyngeal cancer for beer and whiskey intake, but no excess risk for wine consumption.23

The type of alcohol consumed may influence the site of aerodigestive cancer development. A study from the Institut Curie in France attempted to evaluate these differences, but was limited by the fact that > 90 percent of patients were wine drinkers, and the majority drank other liquors as well.43 However, tongue cancer was associated with wine drinking while supra-glottic cancer was associated with aniseed liquor consumption.

The synergistic effect of tobacco and alcohol consumption has been shown to vary with the type of tobacco used as well as the type of alcohol. Upon comparing the level of consumption of blond and black tobacco as well as the level of wine intake versus spirits, heavy use of black tobacco and heavy wine consumption showed the greatest synergistic effect. Blond tobacco and spirit consumption showed a lesser, but still considerable synergistic effect (Figure 1-7).50

Alcohol and Carcinogenesis

The mechanisms by which alcohol use contributes to the risk of head and neck cancer is not clearly defined, while systemic and local effects have been proposed. While alcohol itself is not a known carcinogen, it may act as a solvent, allowing increased cellular permeability of other carcinogens through mucosa of the upper aerodigestive tract. As noted above, the non-alcohol constituents of various alcoholic beverages may have carcinogenic activities.48

As summarized in Maier,41 chronic alcohol use may upregulate enzymes of the cytochrome P-450 system. This enzyme system can contribute to activation of procarcinogens to carcinogens. This up-regulation may be critical to activation of many carcinogens, as the vast majority of environmental carcinogens exist in their procarcinogenic form. Alcohol has also been shown to decrease the activity of DNA-repair enzymes, and increased chromosomal damage has been documented in chronic alcohol users. Other possible effects of alcohol include impaired immunity resulting from a reduction in T cell number, decreased mitogenic activity and/or reduced macrophage activity.

Tobacco Type (Cigarettes/day)

11-50 51-150 >150 Spirits (cc/day)

Figure 1-7. Graph demonstrating the odds ratio for exposure to alcohol and tobacco exposure in pharyngeal and laryngeal cancer patients. Odds ratio highest with heavy wine and black tobacco consumption. (Data from: Sancho-Garnier H, Theobald S. Black (air-cured) tobacco and blond (flue-cured) tobacco and cancer risk II: Pharynx and larynx cancer. Eur J Cancer 1993; 29A:273-6.).

11-50 51-150 >150 Spirits (cc/day)

Tobacco Type (Cigarettes/day)

Figure 1-7. Graph demonstrating the odds ratio for exposure to alcohol and tobacco exposure in pharyngeal and laryngeal cancer patients. Odds ratio highest with heavy wine and black tobacco consumption. (Data from: Sancho-Garnier H, Theobald S. Black (air-cured) tobacco and blond (flue-cured) tobacco and cancer risk II: Pharynx and larynx cancer. Eur J Cancer 1993; 29A:273-6.).

The greater significance of the solvent activity of alcohol, as opposed to its systemic effect, is supported by data comparing dark and light liquor intake and the risk of hypopharyngeal cancer. Only dark liquor consumption was related to the risk of hypopharyngeal cancer. After controlling for total alcohol use and tobacco use, heavy dark liquor consumption was associated with an increased risk of cancer while no such risk was seen with light liquor intake.48 These data argue against a systemic effect of alcohol on hypopharyngeal cancer risk and instead argue for the solvent effect of alcohol along with the carcinogenic-ity of the nonalcoholic components of dark liquors.

Injury to mucosa of the upper aerodigestive tract may relate to a toxic metabolite of alcohol, acetaldehyde. The enzyme aldehyde dehydroge-nase-2 (ALDH-2) is a strong determinant of blood acetaldehyde concentration following alcohol ingestion. A small group of Japanese patients was studied, and those with an inactive ALDH-2 pheno-type more often had multiple primary esophageal cancers (77%) versus those with an active ALDH-2 phenotype (31%).51

Other Carcinogens Betel Quid

In India and parts of Asia, oral tobacco is commonly consumed in a preparation known as "pan," which combines tobacco with betel leaf, slaked lime and areca nut. These betel quid are associated with the risk of oral cancer. Oral cancer risk increases in a dose-dependent manner when classified by years of betel quid use and by numbers of betel quid per day.52 Like the relationship between tobacco and alcohol exposure, the use of betel quid has been shown to act synergistically with tobacco and alcohol to promote oral cancer.53

Maté is a hot drink made from the herb Ilex paraguariensis and is commonly consumed in South America. It has been associated with an increased risk of cancer of the esophagus and larynx. It has been estimated that up to 20 percent of head and neck squamous cell carcinoma in southern South America may be linked to maté ingestion.54 The odds ratio for maté ingestion has been reported as 3.0 for glottic cancer and 3.3 for cancer of the supraglottis.38 Others have demonstrated a significant association with oral cancers.54 Maté consumption is more strongly associated with the risk of laryngeal cancer in patients with a history of heavy tobacco or alcohol use. Maté itself has not been shown to be carcinogenic but, similar to alcohol, may act as a solvent for other carcinogens or as a promoter.38

Dental Considerations

Hygiene

Poor oral hygiene is associated with oral cancer, but no causal relationship has been established. A case-control study of patients with upper aerodigestive tract squamous cell carcinoma matched 100 patients with 214 age- and sex-matched controls and found significantly worse oral hygiene and dental status in the tumor patients. Chronic inflammation of the gingiva was more often seen in the cancer patients.55 Similarly, oral cancers have been significantly associated with a history of chronic oral infections (OR = 3.8).56

Other studies have also supported the relationship between poor oral hygiene and increased risk of oral cancer.57 Less-than-daily brushing has been associated with an approximate twofold increased risk of tongue and other oral cancers in a Brazilian population,58 but no association was seen in a United States study.59 The absence of multiple teeth may represent a surrogate marker of dental hygiene and has been associated with oral cancer in multiple studies.60,61 However, a history of multiple broken teeth has not been associated with oral cancer risk.59,62

The frequent use of mouthwash has been discouraged due to the fact that several preparations contain ethanol. The association between mouth-wash use and risk of oral or pharyngeal cancer has been the subject of previous studies with mixed results.59,63,64 When controlled for total tobacco and alcohol intake, users of alcohol-containing mouth-washes appear to be at increased risk.64 Women, especially those who are not tobacco users, appear to be most consistently associated with this risk factor.65 However, it is possible that the cancer risk of mouthwash use may be confounded by other unmeasured factors. In one study of oral cancer in women, the reasons for mouthwash use were explored. While mouthwash use per se was not associated with a risk of cancer in this particular study, the use to "disguise the smell of tobacco" or "disguise the smell of alcohol" was seen more commonly in cancer cases.60

Dentures

A large Brazilian case-control study has demonstrated an association between oral sores from loose-fitting dentures and risk of oral cancer.58 Painful or ill-fitting dentures have also been associated with oral or oropharyngeal cancer in a study from Wisconsin.59 However, in these and other studies, long-term use of dentures has not been shown to increase the risk of oral cancers.62,66,67 These results and those relating hygiene to oral cancer may describe the role of chronic inflammation as a risk for oral cancer.

Occupational Exposure

Occupational risks for head and neck squamous cell cancer development have been suggested in epidemiologic data. Wood dust exposure is associated with the risk of oral cancer68 as well as pharyngeal and laryngeal cancer.69 Other occupations associated with increased risk of head and neck squamous cell carcinoma include machinists70-72 and automobile mechanics.70 Occupations which involve exposure to organic chemicals, coal products, cement, and paint, laquer or varnish are also associated with increased risk of head and neck cancer.69 A risk of cancer of the upper aerodigestive tract has also been shown in cases of long-term exposure to high concentrations of sulfuric or hydrochloric acid as found in battery plant workers.73 While it has been suggested that an increased risk of oral and pharyngeal cancer is seen in bartenders,27 no excess risk has been found when analysis includes adjustment for alcohol and tobacco consumption.74

Premalignant laryngeal lesions have also been associated with occupational exposures, with a relative risk of 10 for laryngeal dysplasia for blue-collar compared with white-collar workers even after con trolling for tobacco use.75 Laryngeal cancers have been associated with nickel and mustard gas expo-sure.4 An association between asbestos exposure and laryngeal cancer has been suggested, but contradictory results have been reported.4,71,76,77

Social and Economic Factors

Associations between oral, pharyngeal and laryngeal cancers and marital status (cancer patients more often unmarried or divorced) and educational status (cancer patient less often with college education) have been described.78 However, a study in the United States failed to show any relationship between oropharyngeal cancer and education or occupational status. This United States study did show an inverse relationship between the percentage of potential working life spent in employment and the risk of cancer.79 While this study attempted to adjust for tobacco and alcohol consumption, alcohol consumption may confound the employment measure used. Regularity and consistency of employment may be reduced by excessive alcohol use which, in turn, contributes to cancer risk.

Infections

Human Papillomavirus

Evidence of human papillomavirus (HPV) genetic material has been identified in a proportion of head and neck squamous cell cancers.80 Verrucous carcinomas have the squamous histology with the strongest association with HPV, as HPV genomic material is found in 30 to 100 percent of these tumors.80 For squamous cell cancers in general, the proportion of cancers with evidence of HPV genomic material appears to vary, depending upon the upper aerodigestive tract site analyzed. As reviewed and compiled by Steinberg,80 the tumor site most often revealing HPV infection is tonsil (74%), with lesser evidence of HPV in larynx (30%), tongue (22%), nasopharynx (21%) and floor-of-mouth (5%) carcinomas. The role of HPV in these cancers is confounded by the fact that HPV genomic material may also be found in normal head and neck mucosa in up to 64 percent of samples.80,81

Cofactors for HPV induction of oral cancers have been investigated in a handful of studies. Tobacco

Sj 1

White

African-American

Stage

9 Local • Regional O Distant

Figure 1-8. Incidence and survival of oral and pharyngeal cancer for Caucasian and African American males, 1986 to 1993. Circle position indicates percent 5-year survival for each stage. Circle size indicates stage distribution for each race. Numbers correspond to circle size and indicate percent of tumors presenting at each stage. Figure indicates a higher stage at diagnosis for African Americans and poorer survival at each stage. (Data from: Landis SH, Murray T, Bolden S, Wingo PA. Cancer statistics, 1998. CA Cancer J Clin 1998;48:6-29.)

and alcohol habits have not been associated with the likelihood of detecting HPV in tumor tissue.82 However, use of betel quid has been associated with HPV detection in 9 of 11 (82%) cases of tongue cancer.83

Human Immunodeficiency Virus

Human immunodeficiency virus (HIV) has shown an emerging association with head and neck squa-mous cell carcinoma. In a recent study from New York, HIV infection was present in almost 5 percent of patients with head and neck cancer.84 Patients with HIV were younger than non-HIV patients and HIV infection was present in over 20 percent of head and neck cancer patients who were under 45 year of age. The site of tumor presentation did not vary with respect to HIV status, but tumors were larger and more advanced in the HIV group. As in most cases of head and neck squamous cell carcinoma, a history of tobacco and alcohol use is prevalent in the HIV population.85

Herpes Simplex Virus

Herpes simplex virus (HSV) has been associated with cancer of the oral cavity. In a study utilizing patient questionnaires for data collection, a history of proven HSV-1 infections was associated with oral cancer (OR=1.9). A stronger association was seen with a history of a suspected HSV-1 infection (OR=3.3).56 While this study raises concerns about reporting bias, support for this association is provided by a finding of HSV type 1 protein in 42 percent of patients with oral cancer and no positive results in control patients.86

Epstein-Barr Virus

Epstein-Barr virus (EBV) has been associated with nasopharyngeal carcinoma. The association appears strongest with World Health Organization (WHO) types II and III while a minority of WHO type I carcinomas have revealed EBV87 Type I tumors make up one-third of cancers in non-endemic populations. The presence of EBV DNA in upper aerodigestive mucosa samples seems to vary geographically. An 81 percent prevalence has been found in Greenland Eskimos, a population with a high incidence of undifferentiated nasopharyngeal cancer. Among the Danish population, the prevalence is only 35 per-cent.88 Despite the fact that over 90 percent of the world's population shows serologic evidence of prior EBV infection, evidence of persistent EBV DNA was seen in less than 1 percent of normal upper aerodigestive mucosa samples in a large North American series.89 These results suggest that an EBV

chronic carrier state exists in endemic populations. However, the detection of EBV in nasopharyngeal samples is not a specific enough assessment to require nasopharyngeal cancer screening.88

Inflammatory

Gastroesophageal Reflux Disease

Chronic irritation from gastric reflux into the pharynx and larynx has been suggested to be a risk factor for cancers of these sites.90,91 The presence of reflux has been documented by 24-hour pH probe study in 36 to 54 percent of patients with laryngeal and pharyngeal carcinomas.92,93 While this prevalence is significant, it is not dissimilar to the prevalence in patients undergoing pH probe study for nonmalignant conditions.93 While causation has been difficult to establish, previous case series have described the development of laryngeal and pharyngeal cancers in nonsmoking and nondrinking patients with documented reflux.90,91

Nutritional Considerations

Diet and Cancer Risk

Several studies have repeatedly associated high fruit and vegetable intake with a decreased risk of head and neck squamous cell carcinoma.38,94-98 The association between fruit and vegetable consumption and a reduced cancer risk may reflect increased intake of such micronutrients as vitamins C and E and beta carotene. In a nested case-control study correlating serum micronutrient levels to later risk of developing upper aerodigestive tract carcinoma (up to 20 years after serum collection), an association between low alpha and beta carotene levels and subsequent development of cancer was shown.99 When other elemental dietary components are compared to head and neck and esophageal cancer risk, an association with protein intake and an inverse association with vitamin C and flavonoid intake is shown.100 Other studies have shown that increased iron and zinc intake are associated with a reduced risk of laryngeal or esophageal cancers.101 Significant reduction in risk of oral, pha-ryngeal and esophageal cancers has been associated with high intake of tomatoes, an important source of vitamin C in some parts of the world.102,103

Other studies have suggested an increased risk of head and neck squamous cell cancer with red meat intake.94,104 Salted meat intake has been associated with oropharyngeal cancer risk,105 and processed meat consumption associated with oral and oropha-ryngeal cancer.94 On the other hand, a multi-institutional European study showed an inverse association between preserved meat intake and risk of laryngeal and hypopharyngeal cancers.96

Heavy tobacco use appears to double the risk associated with low fruit consumption.38 On the other hand, a high intake of vegetables and fish has been shown to modify the risk of aerodigestive tract cancer in smokers.106 It has been estimated that among smokers/drinkers, the low intake of fruits and vegetables may contribute to between 25 and 50 percent of laryngeal cancers.107

GENETIC AND IMMUNOLOGIC PREDISPOSITION

The strong influence of tobacco and alcohol on the development of cancers of the upper aerodigestive tract obscure underlying genetic predispositions that may exist. However, a subset of patients may have factors that increase their cancer susceptibility. The Li-Fraumeni syndrome, inherited as an autosomal dominant trait, involves mutation of one allele of the p53 tumor suppressor gene. This has been associated with head and neck cancer in some patients with minimal tobacco exposure, and may indicate increased susceptibility to environmental carcinogens in these patients.108 Fanconi's anemia, Bloom syndrome and ataxia-telangiectasia are autosomal recessive disorders that are associated with increased chromosomal fragility and cancer susceptibility. Patients with head and neck squamous cell carcinoma have been reported to be diagnosed with each syndrome.109-111

Patients previously treated with bone marrow and organ transplantation appear to have an increased risk of skin and oral cavity squamous cell carcinoma. The risk of oral cancer is well under 5 percent in long-term bone marrow transplant recipients.112 The risk may be associated with chronic graft versus host disease and long-term use of immunosuppressive medications.112 Viral etiologies have been suggested, but a clear cause has not yet been demonstrated.113

Field Cancerization

While the etiologic factors described above may allow one to make an estimation of head and neck cancer risk, one of the strongest predictors of cancer risk is a history of previous head and neck cancer. Patients with head and neck squamous cell carcinomas have long been shown to have an increased risk of multiple aerodigestive tract tumors. When followed over time, patients previously treated for these cancers have a risk of developing second cancers of the head and neck, esophagus, and lung that approximates 4 percent per year.114 The risk does not appear to taper off with long-term follow-up.114

The risk of second cancers appears to relate to tobacco and alcohol exposure.115 Long-term exposure to these carcinogens appears to place large areas of aerodigestive tract mucosa at increased risk for carcinogenesis. This condemned mucosa may be grossly and histologically normal, yet may harbor detectable abnormalities in tumor suppressor genes such as p53.116

CONCLUSION

The epidemiology of head and neck squamous cell carcinoma has changed considerably in this century. Risk factors appear to explain most of the geographic, racial and gender variations seen as well as incidence changes over time. Accurately measuring these risk exposures is complex. This chapter has described variations in risk related to tobacco types and delivery methods and has also detailed information regarding the risk of alcohol consumption. In addition to these exposures, other risk factors for head and neck cancer are described that may act in concert with tobacco and alcohol exposure to contribute to the epidemiology of this disease. While it is encouraging that the rate of head and neck cancer development in the United States has been decreasing, areas of the world with high rates of head and neck cancer remain and therefore merit further attention in cancer prevention and treatment.

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