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Cancer Epidemiology and Prevention$

David Schottenfeld and Joseph F. Fraumeni

Print publication date: 2006

Print ISBN-13: 9780195149616

Published to Oxford Scholarship Online: September 2009

DOI: 10.1093/acprof:oso/9780195149616.001.0001

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Cancers of the Oral Cavity and Pharynx

Cancers of the Oral Cavity and Pharynx

(p.674) 35 Cancers of the Oral Cavity and Pharynx
Cancer Epidemiology and Prevention




Oxford University Press

Abstract and Keywords

This chapter reviews the epidemiology of cancers of the oral cavity, pharynx, lip, and salivary glands. In the United States (1996–2000), invasive cancers of the OCP/lip/salivary gland account for 2.7% of cancers among men and 1.5% of cancers among women. It is estimated that 27,700 cases will be diagnosed with these malignancies in the United States in 2003 and about 7,200 will die from these cancers. The lifetime risk of being diagnosed with OCP/lip/salivary gland cancers for a US male is 1.4% and 0.7% for a US female.

Keywords:   oral cavity, pharynx, lip cancer, salivary gland, cancer risk, cancer epidemiology, cancer prevention

This chapter reviews the epidemiology of cancers of the oral cavity, pharynx, lip, and salivary glands. The oral cavity and pharyngeal (hereafter referred to as OCP) cancers are composed of the following tumor sites/codes (International Classification of Diseases for Oncology, 3rd ed; Fritz et al., 2000): oral cancers [base of tongue (C01), other and unspecified parts of the tongue (C02), gum (C03), floor of mouth (C04), palate (C05), other and unspecified part of mouth (C06)], and pharyngeal cancers [tonsil (C09), oropharynx (C10), pyriform sinus (C12), hypopharynx (C13), and other and ill-defined sites in lip, oral cavity, and pharynx (C14)]. The OCP cancer sites are discussed together because they share risk factors. Cancers of the lip (ICD-O C00) and major salivary glands [parotid gland (C07), other and unspecified major salivary glands (C08)] are considered separately at the end of the chapter, given their different epidemiologic characteristics. Cancers of the nasopharynx (ICD-O code C11) are discussed elsewhere (see Chapter 31).

In the United States (1996–2000), invasive cancers of the OCP/lip/salivary gland account for 2.7% of cancers among men and 1.5% of cancers among women (Ries, 2003). It is estimated that 27,700 cases will be diagnosed with these malignancies in the United States in 2003 (18,200 men and 9500 women), and about 7200 will die from these cancers (Ries, 2003). The lifetime risk of being diagnosed with OCP/lip/salivary gland cancers for a US male is 1.4% and 0.7% for a US female (Ries, 2003). Worldwide, cancers of the OCP, lip, and salivary gland were responsible for an estimated 390,000 new cases and 207,000 deaths in 2000 (Parkin et al., 2001). The etiology of these cancers is reasonably well understood, with lifestyle factors, particularly tobacco and excessive alcohol exposures, accounting for the vast majority. Thus, efforts to reduce the burden of these cancers should emphasize primary prevention as discussed below.



Anatomic Distribution

The distribution of OCP cancers by anatomical site can vary by geographic region. In the United States (1996–2000), age-adjusted incidence rates for all races combined were highest for cancers of the tongue (Table 35–1).


Most OCP cancers are squamous cell carcinomas arising from the surface mucosa. Less frequently, other carcinomas, including those of the minor salivary glands, as well as sarcomas and a variety of rare and metastatic cancers may develop in the OCP. Based upon 1992–1999 data from 11 US SEER registries, squamous cell carcinoma accounted for approximately 90% of all invasive OCP cancers while an additional 5% of registered malignancies were classified as either adenocarcinoma or mucoepidermoid carcinoma (SEER, 2002). In the United States (1996–2000), 96% of malignant OCP cancers are histologically confirmed (SEER, 2003c).

Premalignant Lesions

Oral cavity and pharyngeal cancers are often preceded clinically by precursor lesions and conditions, the most established of which include oral leukoplakia, erythroplakia, and oral submucous fibrosis (OSF). Oral leukoplakia is a clinical term for “a predominantly white lesion of the oral mucosa that cannot be categorized as any other definable lesion” (Pindborg et al., 1997). Analogously, the term oral erythroplakia is used to designate similarly defined red lesions of the oral mucosa (Axell et al., 1996; Pindborg et al., 1997). Although not a lesion per se, OSF presents with “epithelial atrophy and fibrosis of the subepithelial connective tissue, resulting in stiffness of the oral mucosa” (Pindborg et al., 1997). Upon microscopic examination, pre-malignant lesions and conditions can exhibit oral epithelial dysplasia (OED), a histopathologic designation characterized by “cellular atypia and loss of normal maturation and stratification short of carcinoma in situ” (Pindborg et al., 1997).

Oral leukoplakia has a higher transformation rate to cancer than normal oral mucosa and is therefore considered precancerous. On the other hand, many leukoplakias, particularly those with a clinically homogeneous appearance, are benign hyperkeratotic lesions with a low malignant potential (Waldron and Shafer, 1975; Gupta et al., 1989). The probability of malignant transformation is much higher in those leukoplakic lesions characterized clinically with a red, speckled, verrucous, or nodular component and in those with a histopathologic diagnosis of epithelial dysplasia (Silverman et al., 1984; Gupta et al., 1989; Schepman et al., 1998; Cowan et al., 2001). In one US study, the malignant transformation rate after a mean follow-up of 7.2 years was 6.5% for homogeneous leukoplakia, 23.4% for leukoplakias with a red component, and 36.4% for leukoplakia with microscopically diagnosed dysplasia (Silverman et al., 1984); other studies, however, have reported lower rates. There is also evidence that the risk of malignant transformation among leukoplakia cases may be higher among non-smokers than among smokers (Einhorn and Wersall, 1967; Silverman et al., 1984; Schepman et al., 1998) and among betel quid chewers relative to nonusers (Shiu et al., 2000).

Erythroplakia is far more likely than most oral leukoplakias to contain epithelial dysplasia, putting these lesions at greater risk of impending malignancy; they are also more likely to contain carcinoma in situ, or invasive carcinoma (Shafer and Waldron, 1975; Mashberg, 1978). Estimates of the malignant transformation rate for OSF are limited; however, one Indian study reported a rate of 7.6% over a median observation period of 10 years (Murti et al., 1985). While the histopathologic examination of biopsied precancerous lesions and conditions remains the gold standard for assessing malignant risk, the use of various biomarkers, including loss of heterozygosity at specific microsatellite loci, and loss of pRb and accumulation of p53, has shown promise in predicting subsequent malignant transformation (Mao et al., 1996; Rosin et al., 2000; Soni et al., 2005).

Molecular Genetic Characteristics of Tumor

Carcinogenesis of the oral cavity and pharynx is a consequence of multiple molecular events. Both genes and the environment (chronic exposure to tobacco, alcohol, and possibly certain viruses such as HPV16) are responsible for producing and promoting these molecular alterations. This multitude of molecular events affects numerous chromosomes and genes, and it is believed that it is the accumulation of multiple genetic changes that pushes cells towards malignancy (see “Pathogenesis” below). Alterations in genes involved in cell signaling, cell cycles, tumor suppression, and angiogenesis are all found in OCP cancers. Cytogenetic and molecular studies have demonstrated that somatic mutations that activate oncogenes (e.g., Ras, Myc, ErbB2, (p.675)

Table 35–1. Distribution of Oral and Pharyngeal Cancer Incidence (Age-Adjusted to 2000 US Standard Population) by Anatomical Site, Race, Hispanic Origin, and Sex, 1996–2000

Incidence Rate per 100,000 Person-Years




M: F Ratio

Total oral and pharynx, lip, and salivary gland*





Total oral + pharynx*





Anatomic subsite*






Floor of mouth





Gum/other mouth




















Other oral cavity/pharynx
















American Indian/Alaskan Native



Asian or Pacific Islander





Hispanic Origin























American Indian/Alaskan Native

Asian or Pacific Islander

Hispanic Origin











Salivary gland
















American Indian/Alaskan Native

Asian or Pacific Islander





Hispanic Origin











Source:*Surveillance, Epidemiology, and End Results (SEER) Program ( SEER* Stat Database: Incidence—SEER 12 Regs, Nov 2002 (1973–2000), National Cancer Institute, DCCPS, Surveillance Research Program, Cancer Statistics Branch, released April 2003 (SEER, 2003c). Surveillance, Epidemiology, and End Results (SEER) Program ( SEER* Stat Database: Incidence—SEER 11 Regs, Nov 2002 Sub for Hispanics (1992–2000), National Cancer Institute, DCCPS, Surveillance Research Program, Cancer Statistics Branch, released April 2003 (SEER, 2003d). Surveillance Research Program, National Cancer Institute SEER* Stat software ( version 5.0.20. (Surveillance Research Program).

() Less than 25 cases.

EGFR, bcl2, int-2, hst-1, ems-1, cyclinD1) as well as point mutations, deletions, or hypermethylation that lead to tumor suppressor gene inactivation (e.g., p16, TP53, PTEN, Rb) are involved in and contribute to the development of these cancers (Tassi and Wellstein, 2003).

Demographic Patterns

Incidence and Mortality in the United States

The incidence rate (1996–2000) for OCP cancers is 7.9 in 100,000 persons per year in the United States, with higher incidence rates in men (11.6/100,000) than women (4.7/100,000)(SEER, 2003c). Corresponding mortality rates in the United States (SEER 2003a) are 2.5 in 100,000 for men and women combined, and 3.5 in 100,000 for men and 1.4 in 100,000 for women. OCP cancer mortality shows marked geographic variation in the United States, with high rates noted for white males and females along the eastern seaboard. Among black males and females, rates are high in the mid-Atlantic and Florida, with high rates also noted in parts of the Northeast for black males (Devesa et al., 1999).

United States Time Trends

In the United States, age-adjusted (US 2000 population) incidence rates for OCP cancers are available for 9 SEER sites over the years 1973–2000 (SEER, 2003b). During that period, the most notable trend was for black males, for whom annual rates increased from around 16 in 100,000 in the early 1970s to over 25 in 100,000 during much of the 1980s before declining to less than 20 in 100,000 by the year 2000 (Fig. 35–1). Through the 1970s and into the 1980s, rates also increased for black females and less notably for whites before showing signs of decline during much of the 1990s.

There are also differences in trends for different histologic types and by race and sex for specific anatomic sites. Between the 1975–1982 time period and the 1992–1998 time period, squamous cell carcinomas declined in both race and sex groups, whereas adenocarcinoma rates increased, a pattern also observed for esophageal cancer (Devesa et al., 1998). Among black and white males and females, declines were evident for lip cancer (except white females), gum, floor of mouth, other mouth, pyriform sinus, hypopharynx (except black males), and other and non-specified OCP cancer (except black females). Salivary gland cancer decreased by 10% among black men, but increased by 14% among white men, 5.9% among white females, and 39.7% among black females. Another cancer site that has been increasing over time is the tongue, which increased by 10.7% among white males and 5.2% among white females, but declined among black males (-5.5%) and females (-14.7%). Palate cancer increased among white males (8.0%), did not change among black males, and decreased among females by 15.2% among whites and 4.8% among blacks (Canto and Devesa, 2002).


Overall 5-year relative survival (Table 35–2) for OCP cancers is 57.2% (55.7% in men and 60.4% in women; Ries et al., 2003). Survival varies by site, with lip cancers having the highest survival rates (94.4%), and hypopharynx (30.9%) and oropharynx cancers (37.3%) having the lowest rates. Survival is also heavily dependent on stage at time of diagnosis, with 5-year overall survival of 82.1% for localized disease, 47.9% for regional disease, and 26.1% for distant disease. OCP cancers are most commonly diagnosed as regional disease (48%), with localized disease the next most common (34%). Survival is much poorer for blacks than whites at every stage at diagnosis.

Age, Sex, Race, and Ethnicity

As with most epithelial cancers, incidence rates for OCP cancer typically increase with age. Oral cancer is rare in children and young adults. By 35–39 years of age rates are 3.1 in 100,000 per year, increasing up to 41.1 by ages 65–69 up to 46.4 for 80–84 year olds, and declining to 41.3 in the oldest age group, 85 and older. Rates plotted on age, however, differ for black and white males and females (Fig. 35–2). As shown in Table 35–1, rates for total OCP cancer in males exceed those for females by 2.5-fold, with lip and tonsillar cancers having the highest sex ratios (4.8 and 4.2, respectively).

Overall OCP rates are highest among black men (18.2/100,000), followed by white men (11.5/100,000) (Table 35–1). Among men rates for American Indian/Alaskan natives (6.7/100,000) and Asian or Pacific Islanders (7.1/100,000) are less than half that for black males. Among females, rates for whites and blacks are similar, 4.8 in 100,000 and 5.1 in 100,000 respectively, and are considerably higher than for Asian and Pacific Islanders, 3.1 in 100,000. Among Hispanics, rates for males are 7.3 in 100,000 and for females 2.8 in 100,000; corresponding rates for non-Hispanics are 12.1 in 100,000 and 4.9 in 100,000.

Socioeconomic Status

Associations between low socioeconomic status, education and income, and OCP cancer have been observed in many studies in the United States (Williams and Horm, 1977; Greenberg et al., 1991; Kabat et al., 1994; Hayes et al., 1999) and other countries (Franco et al., (p.676)

                      Cancers of the Oral Cavity and Pharynx

Figure 35–1. Oral and pharyngeal cancer age-adjusted (2000 USA) incidence rates by race and sex, nine SEER Sites, all ages, 1973–2000 (excluding lip, major salivary glands, and nasopharynx).

1989; Franceschi et al., 1990; Dikshit and Kanhere, 2000). Low versus high educational attainment, social class, and income are associated with increased smoking and alcohol use (Shohaimi et al., 2003). However, the effect of low income and education appears to be independent of these risk behaviors in some (Zheng et al., 1990b; Dikshit and Kanhere, 2000), but not all (Greenberg et al., 1991) of the studies that have controlled for risk behaviors.

Table 35–2. Five-Year Relative Survival Rates (%) for US Men and Women with Oral and Pharyngeal Cancers by Anatomical Site, Race and Sex, and Stage at Diagnosis, 1992–1999




Anatomic subsite





Floor of mouth




Gum/other mouth
















Other oral cavity/pharynx








Salivary gland




Total all sites above










Total all sites above





By stage





















Stage distribution





















Stage distribution at diagnosis (%) is also shown.

Source: Ries et al., 2003.

                      Cancers of the Oral Cavity and Pharynx

Figure 35–2. Age-specific incidence rates for cancer of the oral cavity and pharynx by race and sex, 1990–2000, nine SEER Registries (excludes cancers of the lip, major salivary glands, and nasopharynx).

(Source: SEER Program, November, 2002, released April, 2003.)

(p.677) Low occupational status has also been linked to OCP cancer risk (Elwood et al., 1984). One US population-based case-control study compared the percent of potential working life spent in employment by male cases with OCP cancer with controls. A low percentage of years worked, possibly an indicator of discontinuity of work history and social and economic instability, was linked to risk of these cancers among men (Greenberg et al., 1991), controlling for tobacco, alcohol, and other risk factors.

Deprivation is also associated with oral cancer risk. In the Northeast of England, oral cancer incidence and mortality from the mid-1970s to the early 1990s were both positively correlated with geographic area indicators of deprivation (O’Hanlon et al., 1997). Dietary or immunologic factors could potentially explain some of these findings.

International Incidence Rates and Trends, By Sex

Oral cavity and pharyngeal cancer incidence varies by geographic area, and rates in a given region are almost always higher among males than females (Fig. 35–3). Based upon data reported in Cancer Incidence in Five Continents, Volume VIII for the period approximating 1993–1997, age-adjusted (world) annual incidence rates for males were highest in Somme and Bas-Rhin, France where rates exceeded 40 in 100,000 (Parkin et al., 2002). For females, the highest incidence rates were reported for South Karachi, Pakistan and Bangalore, India, with rates in excess of 10 in 100,000 per year. US rates are intermediate in comparison to other countries. The incidence of oral cavity (tongue and other mouth) cancer exceeds that of pharyngeal cancer in most geographic areas (Fig. 35–3); however, in some regions the reverse can occur, particularly among males. For example, in some areas of France (Manche, Bas-Rhin, Doubs) and Switzerland (Valais), pharyngeal cancer accounted for over 60% of the OCP cancer incidence among males.

Trends in OCP cancer incidence also vary by geographic area and gender (Figs. 35–4 and 35–5). Based upon those regions of the world included in Cancer Incidence in Five Continents, volumes III through VIII and approximating the period 1968–1972 to 1993–1997 (Waterhouse et al., 1976; Waterhouse et al., 1982; Muir et al., 1987; Parkin et al., 1992; Parkin et al., 1997; Parkin et al., 2002), age-adjusted (world) rates for males registered a net decline of over 30% in Puerto Rico, Mumbai (Bombay), India, and Cali, Columbia as well as among populations living in Israel (non-Jews, Jews born in Israel) and Singapore (Indians, Malays) (Fig. 35–4). Over the same time period, age-adjusted rates increased over 100% in portions of Germany (Saarland), Poland (Warsaw city, Cracow), Spain (Zaragoza), and Japan (Miyagi, Osaka) as well as in Denmark. For females (Fig. 35–5), age-adjusted incidence rates fell over 30% in Puerto Rico, among Singaporean Indians and among Jews born in Israel, but at least doubled in areas of Germany (Saarland), and Switzerland (Geneva) as well as in Denmark and Alberta, Canada.

During the last quarter of the 20th century, reports from the United States, Europe, and India identified increasing incidence and mortality trends among young adults (primarily males) for tongue

                      Cancers of the Oral Cavity and Pharynx

Figure 35–3. Age-adjusted (world) incidence rates for cancer of the oral cavity and pharynx (excluding the lip, major salivary glands, and nasopharynx), selected geographic regions, circa 1993–1997, all ages.

                      Cancers of the Oral Cavity and Pharynx

Figure 35–4. Age-adjusted (world) incidence rates for cancers of the oral cavity and pharynx, circa 1968–1972 to 1993–1997, selected geographic regions, males, all ages (excludes cancers of the lip, major salivary glands, nasopharynx, and pharynx, NOS).

(Depue, 1986; Davis and Severson, 1987; Swango, 1996), mouth (Gupta, 1999), and OCP cancer (Franceschi et al., 1994; Devesa et al., 1995; Levi et al., 1995). In the United States (9 SEER sites), for example, incidence rates for cancer of the tongue among persons aged 0–39 years increased with an estimated annual percentage change of 6.7% from 1973 until 1985 before plateauing for the remainder of the century while rates for persons aged 40+ increased only modestly (Schantz and Yu, 2002; SEER, 2003c). The explanation for the reported increase in rates among young persons remains unclear.

In regions of Europe (Denmark, Slovakia, Scotland, England/Wales) and the United States (Connecticut) as well as in New Zealand, trends in age-standardized incidence rates reported for various time periods during the second half of the 20th century were, in many instances, birth-cohort based, particularly among males. Rates began to increase for cohorts born in the early decades of the century, and continued to rise for subsequent cohorts in a number of geographic regions (Moller, 1989; Macfarlane et al., 1992; Plesko et al., 1994; Cox et al., 1995; Hindle et al., 1996; Morse et al., 1999; Robinson and Macfarlane, 2003). In Slovakia, rising incidence rates during 1968–1989 were in keeping with increases in the per capita consumption of both tobacco and alcohol (Plesko et al., 1994) while in Denmark, Scotland, England, and Wales, trends in incidence were more consistent with changes in the consumption of alcohol than with that of tobacco (Moller, 1989; Macfarlane et al., 1992; Hindle et al., 2000). In Taiwan, increasing rates of OCP cancer observed during the 1980s and 1990s have been attributed to a rise in the consumption of alcohol and use of betel quid (Ho et al., 2002).


Migrants tend to retain the risks of oral cancer from their country of origin. Migrants to Australia from the British Isles, Southern Europe, and Eastern Europe all had lower death rates for OCP cancer initially and after 30 years compared with Australian natives (McCredie et al., 1994; Warnakulasuriya, 2002). In the Thames region in Southern England, oral cancer incidence was strongly correlated with the percentage of the population in the local area who were Asian (Warnakulasuriya et al., 1999). Also, migrants from the Indian subcontinent to England and Wales have higher death rates from OCP cancer than natives (Swerdlow et al., 1995). These relationships presumably are due to the immigrants retaining their tobacco behaviors in their new home country (Khan et al., 2000).

Demographic Patterns: Oral Premalignant Lesions

The prevalence of oral premalignant lesions and conditions varies by geographic region, population exposure patterns, and the case definition employed. The reported prevalence of oral leukoplakia in adult populations is generally within the range of less than 1%–5%, although substantially higher estimates have been reported for

                      Cancers of the Oral Cavity and Pharynx

Figure 35–5. Age-adjusted (world) incidence rates for cancers of the oral cavity and pharynx, circa 1968–1972 to 1993–1997, selected geographic regions, females, all ages (excludes cancers of the lip, major salivary glands, nasopharynx, and pharynx, NOS).

(p.679) populations engaging in high-risk behaviors (Sciubba, 1995; Banoczy et al., 2001; Yang et al., 2001). There are few reports of erythroplakia prevalence, but available estimates are near or below 0.1% (Lay et al., 1982; Zain et al., 1997). OSF is observed primarily in areas of the Indian subcontinent, Southeast Asia, Taiwan, and Melanesia as well as in their migrant populations (Gupta and Warnakulasuriya, 2002). The prevalence of OSF generally ranges from less than 1%–3% (Trivedy et al., 2002), but can exceed 10% in some sub-populations (Gupta et al., 1998b; Yang et al., 2001).

Environmental Factors


Both tobacco use and alcohol consumption are well-established, important risk factors for OCP cancer, regardless of the type of tobacco product or alcoholic beverage. Tobacco can be used in smoked or unsmoked forms and formulated using a wide range of tobaccos, with varied processing procedures, inclusion of other ingredients, usage patterns, and vehicles for delivery, such as cigarette, bidi, pipe, and cigar.

Cigarette Smoking.

Human evidence supporting a causal role for smoking in the etiology of OCP cancer comes from numerous case-control and cohort studies. In large cohort studies, smokers had 1.5–4.9-fold greater mortality rates of OCP cancer than nonsmokers (National Cancer Institute, 1997). Based on data from case-control studies in which cigarette smoking was the smoking product used by nearly all of the study participants, relative risks for current smokers range from 3–12 controlling statistically for alcohol use and other potential confounding factors (Blot et al., 1988; Franceschi et al., 1990; Zheng et al., 1990b; Mashberg et al., 1993; Kabat et al., 1994; Lewin et al., 1998; Schlecht et al., 1999). Corresponding ranges for former smokers are 1.1–4.5 (Blot et al., 1988; Franceschi et al., 1990; Zheng et al., 1990b; Mashberg et al., 1993; Kabat et al., 1994; Lewin et al., 1998; Bosetti et al., 2000). Among non-users of alcohol, the group in which confounding by alcohol can be most easily ruled out, risks range from twofold to fivefold (Zheng et al., 1990b; Castellsague and Munoz, 1999; Hayes et al., 1999).

Strong positive dose-response relationships between amounts used per day are nearly always evident (Blot et al., 1988; Franceschi et al., 1990; Mashberg et al., 1993; National Cancer Institute, 1997; De Stefani et al., 1998; Hayes et al., 1999). Heavy smoking was associated with excess risks of at least threefold for smokers of more than 25 cigarettes per day (Franceschi et al., 1990; De Stefani et al., 1998) or 40 per day (Blot et al., 1988; Mashberg et al., 1993; National Cancer Institute, 1997; Hayes et al., 1999) except for lower risks in a large study in China (Zheng et al., 1990b), and in many a greater than fivefold increased risk with heavy smoking was observed. In many studies, modest elevated risks are evident for smokers of less than one pack per day with most of the excess risk generally among those smoking 10–19 cigarettes per day (Franceschi et al., 1990; Zheng et al., 1990b; Mashberg et al., 1993), but only in females in one large US study (Blot et al., 1988). In addition to being influenced by numbers of cigarettes smoked, risks also increase with years of use (Zheng et al., 1990b; Mashberg et al., 1993; De Stefani et al., 1998) and overall cumulative amounts used (usually measured by pack years) (Zheng et al., 1990b; Marshall et al., 1992; Mashberg et al., 1993; De Stefani et al., 1998; Lewin et al., 1998) in a wide range of cultures. Persons who inhale the smoke are at greater risk than those who do not (Lewin et al., 1998).

In some (Mashberg et al., 1993; De Stefani et al., 1998; Lissowska et al., 2003), but not all studies (Blot et al., 1988; Franco et al., 1989; Kabat et al., 1994; Hayes et al., 1999), persons smoking filter cigarettes experience higher risks of OCP cancer compared to those smoking non-filtered cigarettes. Hand-rolled cigarettes are more strongly associated with risk than commercially made cigarettes (De Stefani et al., 1998). OCP cancer risks for use of black tobacco (a high tar content noncommercial cigarette rolled in cornhusk leaves) were similar to those for commercial cigarettes in a study in Brazil (Schlecht et al., 1999), but were higher in comparison with blond tobacco cigarettes in Uruguay (De Stefani et al., 1998) and in Italy (Merletti et al., 1989).

Cigarette smoking cessation leads to lower risks of OCP cancer after a period of years (Lissowska et al., 2003). In one study risks reached the level of never smokers within 10 years of cessation (Blot et al., 1988). In other studies in the United States and Sweden, risk levels reached that of nonsmokers only after about 20 years (Lewin et al., 1998; Hayes et al., 1999). In another study, risks did not reach those of nonsmokers even 20 or more years after quitting smoking commercial cigarettes (Schlecht et al., 1999).

The decline with years of cessation also varies by the type of tobacco smoked and possibly the anatomic subsite involved. A Brazilian study found that odds ratios for OCP cancer among former smokers of commercial cigarettes were close to one but still slightly elevated even after 20 or more years of not smoking black tobacco (Schlecht et al., 1999). In another Brazilian study, tongue cancer rates were higher after 10 years of smoking cessation than for other mouth sites (Franco et al., 1989).

Bidi Smoking.

Bidi smoking is widespread in many parts of South Asia, particularly India (Gupta, 1996). Bidis are similar to cigarettes except that the tobacco is rolled in paper or leaves, usually by hand, and then smoked. Oral cancer risks are higher in bidi smokers than in nonsmokers even when other smoking behaviors, smokeless tobacco, and/or alcohol are taken into account (Sankaranarayanan et al., 1989; Sankaranarayanan et al., 1990; Rao and Desai, 1998; Dikshit and Kanhere, 2000; Balaram et al., 2002).

Cigars and Pipes.

Declines in the prevalence of cigar smoking in the United States occurred until 1993, but increased 50% in the subsequent 4 years (Gerlach et al., 1998). Based on a cohort of more than 500,000 persons observed for 12 years, current cigar smoking increased mortality from OCP cancers by fourfold. Mortality rates for former smokers were 2.5 and were higher for persons who smoked three or more cigars per day, inhaled, or smoked cigars for 25 years or more (Shapiro et al., 2000). In case-control studies, risks ranged from 3–9 and also were dependent on dose measured by frequency, duration, or cumulative dose (Boffetta et al., 1999; Schlecht et al., 1999; Garrote et al., 2001). The prevalence of pipe smoking has also been declining in the United States, to only a few percent by the early 1990s (Nelson et al., 1996). Controlling for other confounders such as cigarettes and alcohol consumption, pipe smoking increases risks for OCP cancer (Zheng et al., 1990b; Boffetta et al., 1999; Schlecht et al., 1999).

Environmental Tobacco Smoke.

In a New York case-control study of OCP cancers, environmental tobacco smoke was linked to an odds ratio of 2.8, after controlling for multiple risk factors including alcohol, cigarette smoking, and marijuana use (Zhang et al., 2000). Risks were evident even among nonsmokers and were greater among the more heavily exposed groups. There was greater than multiplicative interaction between environmental tobacco smoke exposure and mutagen sensitivity.

Smoking and Anatomic Subsites.

Some intra-oral sites appear to be more susceptible to the effects of cigarette smoking. The most conspicuous example is for reverse smoking, in which the lit end of the cigarette is placed in the mouth. This behavior is associated with high risks of hard palate cancer (Reddy et al., 1975).

Greater effects of smoking on pharynx compared with oral cavity cancer risk have been noted by some investigators (De Stefani et al., 1998; Lewin et al., 1998; Franceschi et al., 1999b), but not consistently in all studies (Hayes et al., 1999; Schlecht et al., 1999). Investigators in Milan observed that odds ratios for oral cavity sites were about two times higher than for pharyngeal sites at every joint smoking and drinking consumption level (Franceschi et al., 1999b).

In larger case-control studies, where there are more cases in each anatomic subsite, the floor of the mouth was the intra-oral site with the highest cigarette smoking risks in both men and women (Macfarlane et al., 1995), but the soft palate sites were at highest risk in another (p.680) (Boffetta et al., 1992). Differences among studies in grouping anatomic subsites make risk comparisons difficult. Pipe and cigar smoking risks are higher for floor of mouth/buccal mucosa (Blot et al., 1988) and soft palate sites (Boffetta et al., 1992) compared with other subsites.

Smokeless Tobacco—Western Countries.

In many cultures, use of smokeless tobacco products, in which the tobacco product is not smoked during use, is common and also is associated with an increased risk of OCP cancer. These products come in many forms (National Cancer Institute, 2002); this is the source for the descriptions of the products described in the “Smokeless Tobacco” sections. The United States and Sweden are countries where smokeless tobacco use is common. In the United States, moist snuff and chewing tobacco are most common, whereas moist snuff accounts for almost all of the smokeless tobacco used in Sweden. In South Asia, many forms are used and are combined with other ingredients.

United States and Swedish snuffs, which are placed and retained between the cheeks or lips and the gums, are made from air- or fire-cured tobacco that is cut into a powder or small strips. Chewing tobacco consists of tobacco leaves and sweeteners. A recent systematic review noted the difficulties in evaluating the literature on smokeless tobacco and OCP cancer including small sample sizes of smokeless tobacco users and lack of control for confounding by smoking. Nevertheless, there are studies that restricted the analysis to only nonsmokers; significantly elevated odds ratios were observed in two studies in the United States (Winn et al., 1981; Blot et al., 1988) and in one (Lewin et al., 1998) of two in Sweden (Lewin et al., 1998; Schildt et al., 1998). N-nitrosamines are present in smokeless tobacco; other carcinogens in these products include polonium (Hoffmann et al., 1986). The amounts of nitrosamines vary considerably, but tend to be lower in Swedish snuff than US-manufactured snuff and can be affected by factors such as storage (Djordjevic et al., 1993).

Smokeless Tobacco and Related Products—Asian, African, Pacific Island Countries.

Areca nuts, the fruit of the Areca catechu palm, are chewed alone or in combination with other ingredients, including the Piper betle leaf, tobacco, slaked lime, and various spices, by an estimated 600 million persons (about 10%–20% of the world population), particularly cultures in Asia and the South Pacific (Gupta and Warnakulasuriya, 2002). Common terms for these combinations of ingredients are betel quid or pan. Tobacco is commonly added in some cultures, but not in others (Gupta and Warnakulasuriya, 2002).

The use of areca nut and areca nut-based preparations has been linked to an increased risk of both oral leukoplakia and OSF. In one Taiwanese study, nonsmokers who chewed areca nut quid without tobacco had a 10-fold increase in the risk of oral leukoplakia and a 39-fold increase in the risk of OSF (Lee et al., 2003). Other studies have reported odds ratios of 100 or more for the frequent use of areca nuts or areca nut-containing products in relation to OSF (Maher et al., 1994; Hazare et al., 1998; Shah and Sharma, 1998).

A large case-control study conducted in India observed elevated oral cancer odds ratios of 6 for men and 42 for women for use of tobacco-containing betel quid, adjusting for smoking (Balaram et al., 2002). Increasing risks with increasing amount and duration of tobacco-containing pan have been observed, with dose being defined according to frequency and/or duration (Sankaranarayanan et al., 1989; Sankaranarayanan et al., 1990; Rao et al., 1994; Wasnik et al., 1998; Balaram et al., 2002). The buccal mucosa is the cancer site most strongly associated with the practice (Rao et al., 1994; Merchant et al., 2000). A greater than additive interaction among smoking, drinking, and betel on the risk of oral cancer has been observed (Ko et al., 1995).

Both pan with and without tobacco are classified as human carcinogens by the International Agency for Research on Cancer (IARC) (IARC Working Group on the Evaluation of the Carcinogenic Risk of Chemicals to Humans et al., 1985; IARC Working Group on the Evaluation of the Carcinogenic Risk of Chemicals to Humans, 2004). Areca nuts contain 3-(methylnitrosamino)proprionaldehyde, classified by the IARC as having limited evidence of carcinogenicity in humans, and 3-(methylnitrosamino)proprionitrile, which is possibly carcinogenic (IARC Working Group on the Evaluation of the Carcinogenic Risk of Chemicals to Humans, 2004).

Other Asian tobacco practices in which the product is kept in the mouth and not smoked linked to increased oral cancer risks include khaini, used in India and consisting of tobacco, slaked lime paste, and sometimes areca nut (Ghosh et al., 1996) and tobacco used as a dentifrice (Wasnik et al., 1998).

As in US and Swedish smokeless tobaccos, nitrosamines are also in many smokeless tobaccos used in other cultures. The Sudanese product, called toombak, consists of sodium bicarbonate added to tobacco that has been fermented for several weeks, and has extremely high nitrosamine levels (Idris et al., 1998). A case-control study found excess risks reaching four- to seven-fold among users (Idris et al., 1995). Nass and naswar, made from tobacco, slaked lime, ash, and coloring and flavoring agents, are used in Central Asia, Pakistan, and India. Case-control studies have linked use of these high nitrosaminecontaining mixtures (Zaridze et al., 1991) with premalignant oral lesions in Uzbekistan (Zaridze et al., 1985). In one study, naswar was associated with a 10-fold increased risk of oral cancer controlling for smoking and alcohol (Merchant et al., 2000).

Marijuana Smoking.

In one case-control study, marijuana smoking was associated with nearly a threefold increased risk of head and neck cancer. Risks increased with frequency and years of use. Some carcinogens found in tobacco smoke are present in marijuana and may occur in greater amounts in marijuana, and also there may be mutagens derived from the marijuana that are not present in tobacco smoke. In this study there were greater than additive interactions between mutagen sensitivity and marijuana use, tobacco smoking and marijuana use, and possibly marijuana and alcohol drinking (Zhang et al., 1999).

Tobacco and Oral Premalignant Lesions.

Most studies investigating tobacco as a risk factor for oral premalignancy have focused on oral leukoplakia. Both smoking and smokeless forms of tobacco have been linked to an elevated risk of leukoplakia, and smoking tobacco has been associated with an increased risk of epithelial dysplasia (Mehta et al., 1981; Baric et al., 1982; Grady et al., 1990; Evstifeeva and Zaridze, 1992; Morse et al., 1996; Hashibe et al., 2000b; Shiu et al., 2000). The reported risks are generally highest in current users and tend to increase with frequency of use (Gupta, 1984b; Evstifeeva and Zaridze, 1992; Morse et al., 1996; Hashibe et al., 2000b). For example, in a recent Indian study, odds ratios for oral leukoplakia in relation to current and past smoking were 3.4 and 1.7, respectively, while the corresponding odds ratios for tobacco used primarily as an ingredient in betel quid or pan were 9.4 and 3.9 (Hashibe et al., 2000b). In the United States where smokeless tobacco is generally used without other major ingredients, one study of professional baseball players found that the prevalence of oral leukoplakia was 15- and 87-fold greater among users of either chewing tobacco or snuff, respectively, relative to nonusers (Grady et al., 1990). Tobacco cessation is associated with a reduction in the risk of both oral leukoplakia and OED (Gupta et al., 1995; Morse et al., 1996), and leukoplakic lesions often show partial or complete remission when tobacco use is discontinued (Roed-Petersen, 1982; Martin et al., 1999).

The body of evidence relating tobacco use to erythroplakia and OSF is limited. Smoking tobacco has not been consistently linked to either erythroplakia or OSF (Shah and Sharma, 1998; Hashibe et al., 2000a; Hashibe et al., 2002; Lee et al., 2003); however, studies conducted in Kerala, India have revealed strong associations between these premalignancies and the use of chewing tobacco, which is most often consumed as part of an areca nut-containing quid (Hashibe et al., 2000a; Hashibe et al., 2002).


Epidemiologic evidence demonstrates that alcohol is an independent risk factor for OCP cancers. Overall risks associated with alcohol consumption vary among populations. In a large US study, drinking 15–29 drinks per week was associated with increased risks of OCP cancer of (p.681) threefold for men and twofold for women, controlling for smoking (Blot et al., 1988), whereas in an Italian study persons drinking more than 60 drinks per week had lower smoking-adjusted risks of about 3.5 (Franceschi et al., 1990). Based on a meta-analysis (Bagnardi et al., 2001), smoking-adjusted alcohol-related relative risks were 1.8 for drinking the equivalent of 2 drinks per day, 2.9 for 4, and 6.0 for 8. No excess risk was observed for drinking between 1 and 4 drinks per week in a large US study (Blot et al., 1988) and 1–7 drinks per week in a study in Puerto Rico (Hayes et al., 1999). Alcohol risks are evident among nonsmokers (Blot et al., 1988; Franco et al., 1989; Hayes et al., 1999), providing evidence of alcohol as a cancer-initiating agent.

Risks increase with increasing frequency of consumption and cumulative lifetime consumption (Blot et al., 1988; Franco et al., 1989; Franceschi et al., 1990; Zheng et al., 1990b; Mashberg et al., 1993; Lewin et al., 1998; Hayes et al., 1999; Bagnardi et al., 2001). Duration of use of alcohol in years is not strongly associated with OCP cancer risk (Blot et al., 1988; Merletti et al., 1989; Franceschi et al., 2000).

Cessation of alcohol drinking appears to be associated with a decreasing risk. In one study, reductions in risks were observed only after 10 years of nondrinking (Franceschi et al., 2000). Risks were similar to that of never drinkers only after 20 or more years of cessation among men in Puerto Rico (Hayes et al., 1999).

The alcohol type that predominates in a given culture tends to be the one that is associated with the highest risks at equivalent levels of consumption; for example, hard liquor and beer in the United States (Blot et al., 1988; Merletti et al., 1989; Lewin et al., 1998) and wine in Italy (Franceschi et al., 1990). This may be due to greater overall alcohol consumption in users of the most common type of alcohol. In a large US study, darker alcoholic beverages were associated with a two-times higher risk than lighter-colored ones for each anatomic subsite (Day et al., 1994a). Regionally popular alcoholic beverages linked to an increased oral cancer risk include among others cachaça, a distilled sugar-cane product (Franco et al., 1989) consumed in Brazil, and sake in Japan (Takezaki et al., 1996).

Ways of consuming alcoholic beverages that would tend to increase the contact of ethyl alcohol with the oral mucosa may also play an important role in modifying alcohol-related risks. A case-control study in Puerto Rico (Huang et al., 2003) showed that risks were greater for beverages consumed in a more concentrated form. Drinking alcohol outside of meals is associated with a higher and similar risk of oral and of pharyngeal cancer, respectively, than alcohol taken with meals at each level of alcohol drinking (Dal Maso et al., 2002). The anatomic sites that are at highest risk of cancer from drinking alcoholic beverages have varied from study to study (Blot et al., 1988; Boffetta et al., 1992; Franceschi et al., 1999b; Hayes et al., 1999).

Most studies that have examined interactions of alcohol and tobacco on risk find that those with the heaviest alcohol and tobacco behaviors have relative risks that are greater than additive and exceed 30-fold in many studies (Franco et al., 1989; Zheng et al., 1990b; Mashberg et al., 1993; Franceschi et al., 1999b; Hayes et al., 1999; Lissowska et al., 2003). In addition, synergism between smoking and drinking was observed for the oral cavity as well as the pharynx (Blot et al., 1988; Franceschi et al., 1999b).

Nonsmokers and Nondrinkers.

Data are limited on characteristics of OCP cancers occurring in nonsmokers who also do not drink alcohol. These patients are more likely to be female (consistent with tobacco and alcohol drinking rates among women vs. men) (Blot et al., 1988; Boffetta et al., 1992; Hayes et al., 1999), are less likely to have a family history of OCP, larynx, and esophageal cancer combined (Brown et al., 2001), and have a similar median number of genetic aberrations as tobacco and alcohol users (Singh et al., 2002).

Mechanisms of Alcohol Carcinogenesis.

Proposed mechanisms of alcohol carcinogenesis with some experimental laboratory support involve alcohol as an initiator of carcinogenesis through the action of specific carcinogens contained in particular alcoholic beverages or via metabolism of ethyl alcohol to carcinogenic acetaldehyde in oral tissues. Alcohol may also act as a promoter of carcinogenicity through enhancement of the permeability of the oral mucosa to carcinogens such as those from cigarette smoke, mucosal atrophy, potentiation of genotoxicity from tobacco, and inhibition of DNA repair (Wight and Ogden, 1998). While some carcinogens are present in some alcoholic beverages (Wight and Ogden, 1998), the consistency of findings of higher risks of OCP cancer with greater frequency of use of different alcoholic beverages used in different cultures throughout the world, even among nonsmokers, suggests that metabolism of ethyl alcohol is the most important contributor to alcoholic beverage-related carcinogenesis. Additionally, if alcohol is also a promoter, this might explain the synergism between alcohol and tobacco use in greatly increasing risks of OCP cancer in users of both products.

Alcohol and Oral Premalignant Lesions.

The role of alcohol consumption as an independent risk factor for oral leukoplakia has not been clearly established, with some investigations reporting generally weak to moderate associations and others finding no relationship (Gupta, 1984a; Macigo et al., 1995; Hashibe et al., 2000b; Evstifeeva and Zaridze, 1992; Lee et al., 2003). Associations between alcohol consumption and OSF are also equivocal (Hashibe et al., 2002; Lee et al., 2003). There is evidence implicating alcohol as a risk factor for both oral erythroplakia (Hashibe et al., 2000a) and epithelial dysplasia (Morse et al., 1996), but the number of studies is limited. Use of alcohol-containing mouthwashes has not been associated with an increased risk of OED (Morse et al., 1997).


Foods/Food Groups.

The literature on food, nutrients, and risk of OCP cancers was comprehensively reviewed by the World Cancer Research Fund in 1997 (World Cancer Research Fund/American Institute for Cancer Research, 1997). As for foods, 13 of 15 case-control studies of fruit and/or vegetable intake and OCP cancer risk reported a significant protective association for at least one vegetable and/or fruit category. One cohort study from Japan similarly found an inverse association between risk of OCP cancer and consumption of green and yellow vegetables (Hirayama, 1985). Five of seven studies that examined vegetables as a category reported inverse associations while eight of ten studies reported likewise for fruit.

Several studies on diet and risk of OCP cancer have been published subsequent to this review. In agreement with prior studies, the most consistent finding to emerge is an inverse association with fruit and/or vegetable intake (Levi et al., 1998; De Stefani et al., 1999; Franceschi et al., 1999a; Negri et al., 2000; Takezaki et al., 2000; Garrote et al., 2001; Petridou et al., 2002; Uzcudun et al., 2002; Weinstein et al., 2002; Lissowska et al., 2003; Sanchez et al., 2003). The Joint WHO/UN Food and Agriculture Organization Expert Committee recently concluded that an inverse association between fruit and vegetable intake and oral cavity cancers is “probable,” the highest level of evidence given for any dietary association with any tumor site (Joint WHO/FAO Expert Consultation, 2003). Statistically significant odds ratios for total vegetable intake and OCP risk range from 0.14–0.6; corresponding odds ratios for total fruit intake range from 0.2–0.6 (Chainani-Wu, 2002). Statistically significant dose-response relationships are noted in approximately half of these studies (Chainani-Wu, 2002).

Several studies also report a positive association between meat intake and risk of OCP cancers (Levi et al., 1998; De Stefani et al., 1999; Franceschi et al., 1999a; Garrote et al., 2001; Petridou et al., 2002; Uzcudun et al., 2002). Case-control studies of diet and cancer risk are susceptible to many biases including recall bias, so supporting data from cohort studies are helpful to the interpretation of associations. One recent cohort study of diet and risk of upper aerogastric tract cancers (oral, pharyngeal, laryngeal, esophageal) in Norwegian men reported that high consumption of oranges was associated with a significant risk reduction while frequent consumption of beef and bacon was associated with increased cancer risk (Kjaerheim et al., 1998). Another cohort study of US women reported that consumption of the highest versus lowest tertile of yellow/orange vegetables was (p.682) associated with a 31% reduction in the risk of OCP cancer (Kasum et al., 2002).

Dietary patterns are known to track with smoking behaviors (Dallongeville et al., 1998) so the interpretation of dietary associations with cancers that are strongly linked to tobacco is complex. Smokers consume fewer fruits and vegetables on average compared with nonsmokers, and there is the possibility that associations observed may at least in part reflect residual confounding by smoking. However, inverse associations with fruit and vegetable intake are noted throughout the globe and with use of different types of tobacco products and with control for tobacco use statistically or among non-tobacco users. For example, a case-control study of precancerous lesions from Kerala, India found that among women (none of whom smoked), an inverse association with beta-carotene (found in fruits and vegetables) was noted (55% reduction in risk per 1000mg consumed) (Gupta et al., 1999). Also, results from both animal studies and intervention trials of micronutrients support the concept that diet relates to risk of OCP cancers as discussed in greater detail below.


Fruits and vegetables are the primary food sources for certain micronutrients such as carotenoids and vitamin C. Given the consistent inverse association noted for fruits and vegetables and risk of OCP cancers, it should not be surprising that these same nutrients are frequently inversely associated with risk. The World Cancer Research Fund review (World Cancer Research Fund/American Institute for Cancer Research, 1997) noted that five of five case-control studies that examined an association between vitamin C intake and risk of OCP cancer reported statistically significant inverse associations, a finding supported by more recent studies as well (Negri et al., 2000). Similarly, dietary intake of carotene/carotenoids has been inversely associated with risk in numerous studies (Franco et al., 1989; Gridley et al., 1990; Negri et al., 1993; Zheng et al., 1993a; Negri et al., 2000). Pre-diagnostic bloods from patients who subsequently developed OCP cancer had lower serum concentrations of all individual carotenoids (Zheng et al., 1993b). Because fruits and vegetables are the primary contributors to carotenoid and vitamin C levels, observational studies are inadequate to determine whether these nutrients per se are involved in the etiology of OCP cancers. Human intervention trials (see “Preventive Measures,” below) and animal studies of these nutrients, however, are informative. The animal model most closely related to human oral carcinomas is the hamster buccal pouch model. Numerous studies have evaluated the ability of micronutrients to regress or inhibit tumors in this model. Beta-carotene has been widely studied; evidence that beta-carotene as a single nutrient can inhibit tumor formation in this animal model has been deemed “convincing” by the International Agency for Research on Cancer (International Agency for Research on Cancer, 1998).

Diet and Oral Premalignant Lesions.

Relatively few observational epidemiologic studies have investigated the relationship between oral precancer and diet. Most consistently, these investigations have identified an apparent, although not always statistically significant, inverse association with the consumption of at least some fruits and/or vegetables and risk of oral premaligancy (Gupta et al., 1998a; Gupta et al., 1999; Hashibe et al., 2000a; Morse et al., 2000).

Human Papillomaviruses

A possible viral etiology for OCP cancers was suggested following the recognition that viral DNA (herpes simplex virus and/or human papillomavirus) was present in some OCP tumor tissues (Loning et al., 1985; Cox et al., 1993). Subsequent studies have particularly focused on HPV, with numerous studies showing that HPV DNA is present in OCP cancers, although with widely discordant prevalence rates (Shah, 1998), likely due to various assay methodologies and geographic differences in infection rates. HPV DNA has also been detected in normal buccal mucosa (Scully, 2002); however, case-control studies suggest that HPV DNA is more commonly detected in case as compared to control tissues. In a US study, infection with HPV 16 was associated with a 6.2-fold increased risk of oral cancer (Maden et al., 1992). In a large US case-control study (284 cases, 477 controls), the proportion of sera positive for HPV type 16 capsid antibody was 35% in controls, 51.4% overall in cases, and 75.7% in the 37 case subjects whose tumors were found to contain HPV16 DNA (Schwartz et al., 1998). The odds ratio for oral cancer was 6.8 for those who were HPV 16-positive in both sera and tissue as compared to controls with HPV negative sera. The largest study to date was a multi-country study that enrolled 1670 case patients and 1732 controls (Herrero et al., 2003). HPV DNA was found in biopsy specimens (case only analysis) from 3.9% of oral cavity cancers and 18.3% of oropharyngeal tumors. Having antibodies against HPV 16 E6 or E7 (case-control analysis) was associated with 2.9- and 9.2-fold increased risks of oral and oropharyngeal cancers, respectively.

The presence of viral DNA in tumors does not necessarily imply a causal role, because the cancer may have activated the virus, but prospective data also support an association. Using a nested case-control design, serum samples from 292 OCP cancer cases and 1568 matched controls were evaluated for antibodies against HPV 16, HPV18, HPV33, and HPV73 (Mork et al., 2001). Subjects who were seropositive for HPV 16 had a 2.2-fold increased risk of subsequent OCP cancer with an average of 9.4 years of follow-up. No risk was observed for other HPV types. Paraffin-embedded tissues from cases were also evaluated; 50% of oropharyngeal tumors (9/18) contained HPV 16 DNA, as did 14% of tongue tumors (4/29).

Other evidence supporting the temporal relationship between HPV infection and subsequent malignancy comes from analyses of tumor registry data. In a US study using SEER data, standardized incidence rates of buccal cavity cancers were elevated for both white (standardized incidence ratio 2.0) and black (standardized incidence ratio 3.5) women with prior cervical malignancies (Spitz et al., 1992). In another analysis of SEER data, patients with HPV-associated anogenital cancers had a 4.3-fold increased risk of tonsillar squamous cell carcinoma (Frisch and Biggar, 1999). An excess of tonsillar cancer among husbands of women with HPV-associated neoplastic lesions of the cervix was also noted in a Swedish study (Hemminki et al., 2000).

HPV, especially16, may be an etiologic factor for a subset of OCP cancers characterized by a better prognosis (Gillison and Shah, 2001). In one study, HPV was detected in 62 (25%) of 253 cases (Gillison et al., 2000). High-risk HPV16 was detected in 90% of the HPVpositive tumors. OCP patients with HPV-positive tumors had a significant 59% reduction in the risk of cancer death as compared to those with HPV-negative tumors. In another study, patients with HPV 16 DNA in their tumors had significantly reduced all-cause mortality (HR = 0.34) and disease-specific mortality (HR = 0.17) (Schwartz et al., 2001b). Future HPV vaccine trials in patients with HPV16-positive oropharyngeal cancers (Erdmann, 2003) may help to further clarify this association.

Mouthwash Use

Interest in a possible link between mouthwash use and oral cancer arose when Weaver et al. reported that 10 of 11 oral cancer cases who were both nondrinkers and nonsmokers had a history of frequent daily mouthwash use for over 20 years, with the majority of cases having used undiluted mouthwash high in alcohol content (25%) (Weaver et al., 1979). Since that report, a number of case-control studies have evaluated the association between mouthwash use and risk (Blot et al., 1983; Wynder et al., 1983; Kabat et al., 1989; Winn et al., 1991; Talamini et al., 2000; Garrote et al., 2001; Winn et al., 2001). Although some investigations have reported findings suggestive of an association in one or another subgroup or when evaluating one or another frequency- or duration-response trend, there has been an overall lack of consistency in findings across studies, and to date, a relationship between oral cancer and mouthwash use remains equivocal.

Oral Hygiene, Missing Teeth, and Other Dental Factors

A growing number of case-control studies from disparate geographic regions have evaluated various measures of oral hygiene and dentition as potential risk factors for oral cancer while controlling for known confounders, including tobacco and alcohol. Studies often report a weak-to-moderate positive association between oral cancer and infrequent (p.683) toothbrushing; however, odds ratios do not always achieve statistical significance (Franco et al., 1989; Kabat et al., 1989; Zheng et al., 1990a; Velly et al., 1998; Talamini et al., 2000; Garrote et al., 2001). Similarly, a number of investigations have identified a positive association between oral cancer and having more, relative to fewer, missing teeth (Zheng et al., 1990a; Marshall et al., 1992; Bundgaard et al., 1995; Garrote et al., 2001; Balaram et al., 2002). There is, however, little evidence that wearing dentures per se increases risk (Franco et al., 1989; Kabat et al., 1989; Zheng et al., 1990a; Winn et al., 1991; Velly et al., 1998; Talamini et al., 2000; Garrote et al., 2001; Balaram et al., 2002). Other potential oral cancer risk factors such as broken or jagged teeth (Franco et al., 1989; Zheng et al., 1990a; Marshall et al., 1992; Velly et al., 1998) and a history of dental X-rays (Zheng et al., 1990a; Winn et al., 1991; Marshall et al., 1992) have received relatively little attention; findings to date suggest little, if any, excess risk.

It is possible that the bacteria associated with poor oral hygiene and dentition may increase the amounts of acetaldehyde produced from ingested alcohol (Homann et al., 1997; Tillonen et al., 1999; Muto et al., 2000), thus providing an explanation for the relationship between poor oral hygiene and dentition and oral cancer.


Several studies have specifically examined the role of occupation in the etiology of OCP cancers, and working in certain occupational groups has been associated with increased risks of OCP cancers. Occupational groups where excess risk has been noted include butchers (Boffetta et al., 2000), male carpet installers (Huebner et al., 1992), machinists (Merletti et al., 1991; Huebner et al., 1992), male leather-workers (Decoufle, 1979), textile workers (Whitaker et al., 1979), women in the electronics industry (Winn et al., 1982), sugarcane farmers (Coble et al., 2003), and a variety of other occupations wherein blue collar workers are exposed to dusts, inhaled organic agents, or inhaled inorganic agents (Maier et al., 1990). There is little consistency to these findings, and interpretation is further complicated in that smoking, drinking, and socioeconomic status can vary across occupational groupings, making it difficult to isolate specific occupational effects. A large study linked data from the Finnish Cancer Registry to occupational codes from the population census, and concluded that the role of direct occupational factors in the etiology of any oral/pharyngeal sites seems to be minimal (Pukkala et al., 1994). In OCP cancer cases with pronounced tobacco and alcohol consumption, it thus seems that occupation plays a minor role; however, a role in less heavily exposed cases cannot be ruled out.

Host Factors

Diseases Predisposing to Risk

A number of medical conditions in addition to oral premalignant lesions have been associated in cohort studies with an increased risk of OCP cancer. Among them are alcohol-related conditions including alcoholism (Boffetta et al., 2001b) and cirrhosis of the liver (Keller, 1983). Two other conditions are Fanconi anemia (Kutler et al., 2003; Rosenberg et al., 2003), an inherited condition possibly involving DNA repair deficits (Tischkowitz and Hodgson, 2003), and psoriasis, possibly due to confounding by tobacco and alcohol or cell cycle and cell proliferation problems that might be associated with both psoriasis and cancer development (Boffetta et al., 2001a).

Familial Aggregation

There is a modest to moderate degree of aggregation of OCP cancer in families. Patients with OCP cancer are 2–3 times more likely than other persons to have first-degree family members with OCP cancers (Goldgar et al., 1994; Goldstein et al., 1994; Brown et al., 2001), with upper aerodigestive tract cancers (includes OCP plus larynx and/or esophagus) (Jovanovic et al., 1992; Jovanovic et al., 1993a; Jovanovic et al., 1993b; Li and Hemminki, 2003; Goldstein et al., 1994; Jovanovic et al., 1994a; Jovanovic et al., 1994b; Copper et al., 1995; Foulkes et al., 1995; Foulkes et al., 1996; Mork et al., 1999), and with tobacco- and alcohol-related cancers more generally (Li and Hemminki, 2003). The risks of OCP cancer associated with having a relative with upper aerodigestive tract cancers may be higher for younger than older cases (Brown et al., 2001) and higher for cases who have multiple primary OCP cancers (Mork et al., 1999).

These patterns may be due to the increased prevalence of smoking and heavy alcohol drinking in the relatives of smokers and alcohol drinkers. However, these findings for first-degree relatives also may be due to shared inherited genotypes such as those involved in the metabolism of tobacco carcinogens and alcohol, DNA repair, or predisposition to tobacco and alcohol behaviors and addictions (Cheng et al., 2000b; Swan et al., 1997) and alcoholism (Cheng et al., 2000a). By measuring DNA repair assessed by a mutagen sensitivity assay, odds ratios of three for having one or seven for having multiple family members with cancer were observed in one study (Bondy et al., 1993) and a linear relationship of risk with number of relatives affected with cancer in another (Bondy et al., 1993; Yu et al., 1999). In the latter study, an additive interaction between having a family history of cancer and mutagen sensitivity was observed (Yu et al., 1999).

Very limited data are available on risk behaviors for relatives of the probands in many of these studies of familial aggregation, making it difficult to distinguish between environmental and genetic influences. In one study in which the tobacco and alcohol behaviors of index cases with OCP cancers, their spouses, and the first-degree relatives were assessed, a fourfold risk of the relatives developing OCP cancers was observed after controlling statistically for these risk behaviors (Foulkes et al., 1996). This suggests an inherited component above the effect of tobacco and alcohol behaviors. In addition, segregation analysis findings in one study rejected the model of a purely environmental cause for oral cancer, a Mendelian model had a better fit (De Andrade et al., 1998), and risks for OCP cancers among heterozygotes for a susceptibility gene were restricted to those who smoked and drank alcohol. Tobacco and alcohol use as well as infrequent consumption of fruits and vegetables interact in a multiplicative fashion with family history of upper aerodigestive tract cancers, which also suggests both environmental and hereditary influences on risk (Foulkes, 1995; De Andrade et al., 1998).

Multiple Primaries and Cancers Associated with Oral and Pharyngeal Cancers

Patients with OCP cancer are sometimes diagnosed with several primary cancers in the oral cavity and pharynx at the same time; for example, 7% in one study (Barbone et al., 1996). Second primary cancers subsequent to the first are also relatively common among persons with OCP cancer. Based on follow-up of patients diagnosed with cancer between 1935 and 1982, patients with OCP cancer experienced the highest risk of subsequent new primaries compared with patients with any other form of cancer. After a diagnosis of cancer of the tongue, other mouth, and pharynx, risks ranged from 9–25-fold for the development of new primaries in the tongue and other mouth, 12–16-fold in the esophagus, 3–8-fold in the larynx, and threefold in the lung (Curtis et al., 1985).

Patients with cancers of the esophagus, larynx, lung, and cervix— cancer sites associated with cigarette smoking—also were at greater risk of cancer of the tongue, other oral cavity sites, and pharynx than expected. Digestive tract cancers, especially liver/biliary tract cancer, are also somewhat higher among patients with tongue and other mouth cancer (Curtis et al., 1985). Alcohol drinking is a known risk factor for liver cancer (IARC Working Group on the Evaluation of the Carcinogenic Risk of Chemicals to Humans et al., 1988). Persons with squamous cell carcinomas of the skin may also have an elevated risk of several OCP cancer sites.

In examining the determinants of second primary aerodigestive tract cancers, several studies have observed an association between smoking prior to initial OCP cancer diagnosis and risk of second primary OCP cancers (Barbone et al., 1996; Cianfriglia et al., 1999). In one study, quitting smoking at or after diagnosis did not confer protection, but quitting before initial diagnosis did (Day et al., 1994b). Risk of second cancers was 40%–60% lower among those in the highest versus lowest quartile of prediagnostic intake of total vegetables and most vegetable subgroups in one study (Day et al., 1994c) (p.684) and 60% lower among those in the highest beta-carotene tertile in another (Barbone et al., 1996).

Genetic Susceptibility

Genes that may influence the occurrence of OCP cancer include those that affect metabolism of carcinogens and nutrients, DNA repair, and cell cycle control. Many of the studies are of patients with “head and neck” cancer, a grouping that includes patients with laryngeal and occasionally esophageal in addition to OCP cancer. It was possible in some studies of metabolic genes to distinguish OCP cancer findings from esophageal and laryngeal findings, and these are the studies cited in the discussion of metabolic genes. Nearly all of the studies of DNA repair and cell cycle control genes present findings only for patients with head and neck cancer—oral, pharyngeal, and laryngeal cancer combined. All studies have a case-control design with hospital-based or population-based study participants. Studies described below include those with at least 150 study participants. Nearly all of the studies included fewer than 300 cases.

Glutathione S-transferases (GST).

This family of genes includes GSTM1 and GSTT. Among other functions, this class of genes facilitates detoxification of carcinogens such as benzo(a)pyrene, a carcinogen found in tobacco smoke. Deletions in these genes lead to reduced enzyme activity (Geisler and Olshan, 2001).

GSTM1 deletion genotypes are common in a wide range of populations (Geisler and Olshan, 2001). A review article reported on 11 studies worldwide that examined GSTM1 and risk of OCP cancers (Geisler and Olshan, 2001). Based on this review and subsequent studies in Asian populations, five of eight studies of Asian populations showed higher risks of OCP cancers associated with having GSTM1 deletion genotypes (Nomura et al., 2000; Sreelekha et al., 2001; Geisler and Olshan, 2001; Buch et al., 2002), while none of four studies of Europeans and one of two US studies observed similar associations (Geisler and Olshan, 2001). A dose-response relationship was observed of increasing risk of oral cancer associated with the deletion genotype with increasing lifetime dose of cigarette smoking in one study (Sato et al., 2000) and chewing Indian tobacco in another (Buch et al., 2002).

In studies of the GSTT gene, risks in three (Geisler and Olshan, 2001; Sreelekha et al., 2001) of four (Geisler and Olshan, 2001; Sreelekha et al., 2001; Buch et al., 2002) studies of Asians were elevated for the GSTT deletion genotype, and the odds ratios for the four European studies ranged from 1–2 (Geisler and Olshan, 2001).

Cytochrome P450 Pathways (CYP).

CYP1A1 influences activation of polycyclic aromatic hydrocarbons as well as aromatic amines, which are carcinogens present in tobacco smoke and other substances. The m2 vs. wildtype or m1 genotype has been associated with an increased risk of OCP cancers with odds ratios between 1.5 and 5.7 (Katoh et al., 1999; Morita et al., 1999; Bartsch et al., 2000; Sato et al., 2000; Sreelekha et al., 2001), while m1 findings were inconsistent (Matthias et al., 1998; Tanimoto et al., 1999).

CYP2E1 findings have been inconsistent (Katoh et al., 1999; Bartsch et al., 2000) in terms of whether the c1 or c2 genotypes confer risk and associations were observed only in subpopulations that differed across studies, for example, among non-users of betel quid (Hung et al., 1997), those with a lower number of cigarette packyears (Liu et al., 2001), or heavy drinkers (Bouchardy et al., 2000). Limited and conflicting data are available on CYP2D6 (Bartsch et al., 2000).

N-Acetyltransferases (NAT).

NAT1 and NAT2 are involved in the detoxification of aromatic amines via acetylation. Aromatic amines are present in tobacco smoke and some occupational settings (Lazarus and Park, 2000). Case-control studies have found no association of NAT2 and oral (Katoh et al., 1998; Chen et al., 2001), pharyngeal (Morita et al., 1999), or oral, pharynx, and larynx cancer risk combined (Olshan et al., 2000), although increased oral cancer risk associated with having the rapid/intermediate genotypes and increasing numbers of alcoholic drinks consumed per week was found in one study (Chen et al., 2001).

Microsomal Epoxide Hydrolase (mEH).

The microsomal epoxide hydrolase (mEH) gene is involved in metabolism of carcinogens such as benzo(a)pyrene, and a variant has been linked to oral cancer in one study (Jourenkova-Mironova et al., 2000).

Alcohol Dehydrogenase (ADH2, ADH3).

The alcohol dehydrogenase 3 gene (ADH3) is involved in the metabolism of alcohol to acetaldehyde, and the alcohol dehydrogenase 2 gene (ADH2) metabolizes acetaldehyde to acetic acid (Olshan et al., 2001). Acetaldehyde, the intermediate compound, is carcinogenic in animals (IARC, 1999). It also has been suggested that the ADH3 2–2 genotype may reduce the conversion of retinol to retinoic acid (Schwartz et al., 2001a).

In US and European studies, the evidence for a role of ADH3 in OCP cancers is contradictory, with studies showing that having fast-metabolizing alleles places persons at greater risk (Harty et al., 1997; Bouchardy et al., 1998), lesser risk (Zavras et al., 2002), and neither greater nor lesser risk of OCP cancer (Bouchardy et al., 2000; Schwartz et al., 2001a; Sturgis et al., 2001). Effect modification by alcohol consumption has been noted in a few studies, for example higher risks in alcohol drinkers homozygous for the fast-metabolizing genotype (Harty et al., 1997). In a Japanese population, a mutant gene that inactivates ADH2 is common; the ADH2 inactive genotype was associated with a threefold increased risk of oral cancer (Nomura et al., 2000).

DNA Repair.

Case-control studies have compared head and neck cancer cases with controls with respect to indicators of DNA damage and repair and genes involved in these processes (Berwick and Vineis, 2000a; Goode et al., 2002). Bleomycin-induced sensitivity in lymphocytes, also known as mutagen sensitivity, is one measure of DNA damage to cells and thus an indicator of failure of DNA repair mechanisms. In studies that have controlled for tobacco, or tobacco and alcohol (Cloos et al., 1996a; Cloos et al., 1996b; Spitz et al., 1989; Spitz et al., 1993), mutagen sensitivity was associated with risks in the range of 4–10 (Berwick and Vineis, 2000b). Benzo(a)pyrene diol epoxide (BPDE) sensitivity, another indicator of DNA damage and repair, also has been linked to risk of oral premalignant lesions (Wu et al., 2002) and head and neck cancers (Cheng et al., 1998; Wang et al., 1998; Wu et al., 1998; Berwick and Vineis, 2000a; Li et al., 2001).

In one study patients with multiple primary head and neck cancers had greater mutagen sensitivity compared with head and neck cancer patients with only one tumor (Schantz and Ostroff, 1997). Evidence for a multiplicative interaction between mutagen sensitivity and tobacco use has been described (Spitz et al., 1993). Another study reported odd ratios of 6 for bleomycin sensitivity, 14 for BPDE sensitivity, and 36 for both sensitivities (Wu et al., 1998).

DNA repair genes investigated are those involving base excision repair, nucleotide excision repair, and mismatch repair (Cheng et al., 2002; Goode et al., 2002). The base excision repair gene hOGG1 is involved in the excision repair of 8-hydroxy-2′-deoxyguanine from oxidatively damaged DNA (Goode et al., 2002). In one study, cases with oral cavity, tonsil, and oropharyngeal cancer were more likely to have the low activity genotype compared with community-based controls. Another gene in this family is XRCC1, which facilitates endonuclease activity and the creation of a scaffold for reconstruction of the damaged site (Goode et al., 2002). Positive (Hsieh et al., 2003; Sturgis et al., 1999) as well as negative (Olshan et al., 2002) associations with the XRCC1 variants have been observed.

Variants in the nucleotide repair genes XPC (Shen et al., 2001), which is involved in recognizing DNA damage, and XPD, which is involved in unwinding of DNA after damaged DNA is recognized, were not associated with head and neck cancer risk (Sturgis et al., 2000; Sturgis et al., 2002). However, expression of a number of nucleotide excision repair genes including these two was reduced in a study of head and neck cancer cases relative to controls (Cheng et al., 2002).

A study that controlled for smoking and alcohol (Wei et al., 1998) found that oral cancer cases were more likely to have low expression (p.685) of hMLH1, which is involved in mismatch repair, compared with controls, but there was no difference for hMLH2, a related gene.

Interactions have been noted. For example, no association between the hOGG1 326cys/326cys vs. 326ser hetero- or homozygote genotypes and OCP cancer risk was observed among nonsmokers or non-alcohol drinkers. However, these genotypes were associated with significantly increased risk among smokers and among drinkers (Elahi et al., 2002).

Cell Cycle Control.

No association with risk of head and neck cancer was observed for two p 16 tumor suppressor haplotypes (Zheng et al., 2001b). However, CPG island hypermethylation within the gene promoter region of the p16 and other genes resulting in transcriptional inactivation was common in head and neck cancer cases compared with controls (Rosas et al., 2001). Associations were observed in a study of checkpoint kinase 2 (Zheng et al., 2001a), another tumor suppressor gene, and cyclin D1 (Zheng et al., 2001b), which controls how cells with damage pass through a checkpoint in the cell cycle.


Clinical Applications of Molecular Markers for Oral and Pharyngeal Cancers

Molecular analyses of OCP cancers are not currently incorporated into routine clinical practice. However, research studies indicate that molecular analysis of OCP cancer tumor specimens and oral epithelial cells, saliva, and blood has considerable potential clinical utility; for example, in early detection of malignancies, differentiation of OCP recurrences from second primary tumors, prognostic evaluation, and treatment planning for invasive malignancies and premalignancies (Hu et al., 2002).

Progression Model

Evidence suggests that a series of losses of genetic material at specific chromosomal sites leads to the development of the progressive histologic changes that culminate in invasive OCP cancers (Sidransky, 2002). This model has been developed by comparing the frequency of each type of loss in normal tissue and lesions from patients with upper aerodigestive tract lesions of varying degrees of severity. Califano and colleagues suggested that chromosomal loss at 9p is associated with the development of benign squamous hyperplasia and some other precursor lesions, 3p and 17p with dysplasia, 11q, 13q, 14q with carcinoma in situ, and 6p, 8p and 8q, and 4q with invasive cancer (Califano et al., 1996). Mitochondrial C-tract alterations also increased with histological severity of lesions (Ha et al., 2002). These chromosomal losses correspond to aberrations in specific genes. For example, the earliest and most common aberration may be inactivation of the tumor suppressor gene p16 on 9p21 (Reed et al., 1996). The 8p21–22 losses may be associated with the gene for a tumor necrosis-related apoptosis-inducing ligand receptor, DR4 (Fisher et al., 2001). These aberrations can result from several different processes including hypermethylation of the promoting regions of tumor suppressor genes, deletions, and point mutations (Reed et al., 1996; Rosas et al., 2001).

Field Cancerization

Second or multiple primary cancers occur relatively frequently in patients with OCP cancers. This may be the result of either of two processes, the development of independent, transformed cells or the spread of cells derived from a single transformed cell to other areas of the mucosa. Based on molecular analysis of tumor tissue from multiple sites within the same individuals, it appears that both phenomenona occur (Bedi et al., 1996; Califano et al., 1999; Partridge et al., 2001).

Preventive Measures

Primary Prevention

Most OCP cancers develop in persons with chronic exposures to tobacco, alone or in concert with exposure to alcohol, so most of these cancers should be preventable. Avoidance of tobacco initiation, along with promotion of tobacco cessation, is likely to have the greatest impact in preventing these cancers. Evidence suggests that even relatively brief periods of tobacco cessation (e.g., 6–10 years) may significantly lower risk, although in some studies the full benefit was only realized after more prolonged cessation. Current declines in rates of OCP cancers in white men in the United States are consistent with the decline in smoking prevalence noted in this group.

While tobacco prevention/control should be the cornerstone of prevention efforts for these cancers, reducing excessive exposures to alcohol is also an important aspect of primary prevention. Research studies do not indicate that low levels of alcohol consumption increase risk of OCP cancers, but heavier drinking clearly does and should be avoided. As is the case with tobacco, cessation of alcohol lowers risk (Franceschi et al., 2000) but estimates of the number of years required vary.

Studies suggest that dietary practices also contribute to the etiology of OCP cancers. Campaigns to increase fruit and vegetable consumption, such as the US Five-A-Day For Better Health Program (Stables et al., 2002), may also contribute to reducing the incidence of these cancers. While the evidence for an association between dietary practices and risk is not considered definitive, this dietary pattern is prudent and likely to reduce the risk of a variety of cancers and other chronic diseases. Specific nutrients also are of interest for prevention; selected nutrient supplements have been evaluated in randomized clinical trials for efficacy as summarized below.

Chemoprevention: Oral Premalignant Lesions

As discussed previously, oral precancerous lesions are indicators of field cancerization and some proportion may progress into malignancies. Chemoprevention of these lesions has direct clinical relevance and can be used to screen agents that may have efficacy in the prevention of OCP cancers. As reviewed elsewhere (Mayne et al., 2003), at least 13 randomized chemoprevention trials in oral leukoplakia have been conducted using the following agents: retinoids, vitamin A, beta-carotene, the algae Spirulina fusiformis, tea, and bleomycin. Other agents (e.g, vitamin E, selenium, protease inhibitors (Bowman Birk Inhibitor Concentrate)) have been evaluated in non-randomized trials. Retinoids and beta-carotene have established efficacy in the regression of oral precancerous lesions (Mayne et al., 2003). The most widely studied retinoid (13-cis-retinoic acid) and carotenoid (beta-carotene), however, have been shown to interact with tobacco smoke to increase the risk of lung cancer (recurrences for 13-cis-retinoic acid (Lippman et al., 2001) and primary lung cancers for beta-carotene (AlphaTocopherol Beta-Carotene Cancer Prevention Study Group, 1994; Omenn et al., 1996)). Given this, long-term preventive therapy of these agents for oral precancerous lesions, at least in smokers, is unlikely. Some suggestions of efficacy have also been obtained in randomized trials of Spirulina fusiformis (a nutrient-rich algae (Mathew et al., 1995)), green tea (Li et al., 1999), and bleomycin (Epstein et al., 1994), but none is considered to have established chemopreventive efficacy in oral premalignant lesions.

Secondary Prevention

Many patients diagnosed with OCP cancers will survive their primary cancer, particularly those with early-stage cancers (Table 35–2). These patients, however, are at substantial risk of failure due to local recurrences and second primary cancers; recent data indicate that 5% of Stage I/II patients will develop second primary tumors yearly (Khuri et al., 2001). These second cancers are a consequence of field cancerization, and are the leading cause of death in patients diagnosed with early-stage OCP cancers (Lippman and Hong, 1989). Retinoids, vitamin A, and beta-carotene have all been evaluated for secondary prevention in this setting. The first trial tested high-dose 13-cisretinoic acid vs. placebo in 103 OCP cancer patients (Hong et al., 1990). The rate of second primary tumors was significantly lower in the retinoid arm than in the placebo group, developing in two (4%) of the 13 cRA-treated patients compared with 12 (24%) of the placebo-treated patients (P = .005). Side effects, however, were substantial. A multicenter US trial of a lower dose of 13-cis-retinoic acid (Khuri et al., 2003) saw no overall benefit, although there was a suggestion that local recurrences were reduced while patients were receiving drugs.

(p.686) Another randomized trial evaluated the synthetic retinoid etretinate in 316 patients following definitive therapy of OCP squamous cell carcinoma (Bolla et al., 1994). In this French trial, the rate of second primary tumor development in the two arms was not significantly different. The Euroscan trial evaluated 2 years of retinyl palmitate and N-acetylcysteine (factorial design) in preventing second primary tumors in 2592 patients with prior cancers of the oral cavity, larynx, and lung (van Zandwijk et al., 2000). Retinyl palmitate, N-acetylcysteine, or both produced no improvement in event-free survival, survival, or incidence of second primary tumors. Another trial evaluated beta-carotene vs. placebo in 264 patients with prior oral/pharyngeal/laryngeal cancers (Mayne et al., 2001). Patients randomized to supplemental beta-carotene had a nonsignificant reduction in second OCP/larynx cancer (RR 0.69) and a nonsignificant increase in lung cancer (RR 1.44). The results of these trials thus indicate that agents with efficacy in oral premalignancy (e.g., 13-cis-retinoic acid, beta-carotene) appear to have some efficacy in the prevention of invasive disease, but emphasize the need to identify agents with minimal toxicity and without adverse effects on other sites (e.g., lung).

Fruit/vegetable intervention trials have been considered as another approach for secondary prevention of OCP/larynx cancers. Completed trials to date show that this patient population can successfully increase fruit/vegetable intake (Le Marchand et al., 1994), although data are not available to evaluate the efficacy of such a change with respect to cancer incidence.

Screening/Early Detection

Screening for OCP cancer in asymptomatic persons generally involves inspection and palpation of the oral cavity. However, the sensitivity and specificity of screening for oral cancer in the United States has not been characterized, and controlled trials of screening also have not been done. Despite this, the American Cancer Society recommends that primary care doctors examine the mouth and throat as part of a routine cancer-related checkup. The US Preventive Services Task Force concluded that there is “insufficient evidence to recommend for or against routine screening of asymptomatic persons for oral cancer by primary care clinicians. All patients should be counseled to discontinue use of all forms of tobacco, and limit consumption of alcohol. Clinicians should remain alert to signs and symptoms of oral cancer and premalignancy in persons who use tobacco or regularly use alcohol” (US Preventive Services Task Force, 1996).


The ICD-O-3 topography code for the lip, C00, includes malignant neoplasms arising on the vermilion border, commissure, and labial mucosa, but excludes cancers originating on the skin of the lip (Fritz et al., 2000). The lower lip is most frequently affected, and the majority of lip cancers are squamous cell carcinomas. During the period 1992–1999 and based upon data from 11 SEER sites in the United States, 79% of all reported invasive lip cancers arose on the vermilion border, 80% were located exclusively on the lower lip, and 95% were squamous cell carcinomas (SEER, 2002). In the United States during 1996–2000, the age-adjusted incidence rate was 1 in 100,000 per year (Table 35–1) (Ries et al., 2003).

Five-year relative survival for cancer of the lip is high and the mortality rate low (Table 35–2). Based upon SEER data from nine areas of the United States for the period 1992–1999, the 5-year relative survival for lip cancer was 95% for males and 90% for females. During 1996–2000, the age-adjusted (2000 US) mortality rate for cancer of the lip in the United States was less than 0.1 in 100,000 (0.05/100,000 for males and 0.01/100,000 for females) (Ries et al., 2003; SEER, 2003a).

There is geographic variation in lip cancer incidence, with rates generally higher among men than women and in light-skinned populations relative to those of color (Fig. 35–6) (Dardanoni et al., 1984; Pogoda and Preston-Martin, 1996). For the period approximating 1993–1997 and for most regions of the world, the annual age-adjusted (world) incidence of lip cancer was generally less than 4 in 100,000 for males and below 1 in 100,000 for females (Parkin et al., 2002). During the same time period, however, annual age-adjusted rates (world) approached or exceeded 10 in 100,000 for males living in regions of Canada (Newfoundland), Australia (Queensland, Tasmania), and Spain (Cuenca, Granada, Albacete) (Parkin et al., 2002). For females, the highest age-adjusted rates (2 to 3/100,000) were reported in Canada (Yukon), Australia (Tasmania, Queensland, South, Western), and Thailand (Khon Kaen) (Parkin et al., 2002).

Over recent decades, the incidence of lip cancer has declined in many geographic regions of the world, particularly among males. For example, based upon SEER data for nine geographic regions in the United States, age-adjusted incidences rates declined over 70% for males and 40% for females during the period 1973–2000 (SEER, 2003b).

Lip cancer is associated with low socioeconomic status (Dardanoni et al., 1984; Pukkala et al., 1994), rural residence (Lindqvist and Teppo, 1978; Doll, 1991; Schouten et al., 1996), and outdoor occupation, particularly fishing and farming (Keller, 1970; Spitzer et al., 1975; Khuder, 1999; Hakansson et al., 2001). Evidence also suggests that both solar radiation and tobacco are important risk factors for lip cancer.

Solar radiation has long been considered a probable risk factor for lip cancer (Ahlbom, 1937; Ebenius, 1943). The fact that both outdoor occupation and rural residence are associated with an increased risk of lip cancer is consistent with a solar component although it does not preclude the possibility that other outdoor elements or associated factors are involved. The observation that lip cancer most often occurs on the lower lip has led some to suggest that the disparity in anatomical risk is a consequence of the differential exposure of the lower lip to direct sunlight (Ju, 1973). The finding that lip cancer is more frequent in light-skinned individuals and populations has led to the proposition that higher levels of melanin within the lip protect against the effects of solar radiation (Ebenius, 1943; Bernier and Clark, 1951), and that the use of lipstick by women may partially explain the generally lower incidence in women (Pogoda and Preston-Martin, 1996).

Studies regarding the geographic distribution of lip cancer have not all been consistent with a primary etiologic role for ultraviolet (UV) light (Keller, 1970; Szpak et al., 1977; Lindqvist and Teppo, 1978; de Visscher et al., 1998); however, a case-control study of lip cancer in Los Angeles females found that lip cancer risk tended to increase with both average annual residential UV flux and average hours of outdoor activities (Pogoda and Preston-Martin, 1996). Studies have also identified strong associations between lip cancer and a previous history of skin cancer (Keller, 1970; Pogoda and Preston-Martin, 1996; Wass-berg et al., 1999), although the decline in lip cancer incidence stands in contrast to increasing incidence rates for cutaneous malignant melanoma (SEER, 2003b).

Another link in the relationship between sunlight exposure and lip cancer risk is chronic actinic cheilitis, a precancerous condition of the lip that presents as a hyperkeratosis interspersed with areas of erythema on the vermilion border. Actinic cheilitis is generally attributed to solar damage and may harbor epithelial dysplasia, carcinoma in situ, or squamous cell carcinoma (Nicolau and Balus, 1964; Kaugars et al., 1999). As with lip cancer, actinic cheilitis predominates on the lower lip and is seen most often in males, light-skinned persons, and outdoor workers.

Evidence for a relationship between smoking tobacco and lip cancer risk is based largely upon findings from case-control studies. Most investigations conducted in the early through mid 20th century implicated primarily pipe smoking (Broders, 1920; Ahlbom, 1937; Ebenius, 1943; Levin et al., 1950; Spitzer et al., 1975). However, pipe smoking has declined dramatically in the United States (Nelson et al., 1996; Psoter and Morse, 2001), and studies during the latter decades of the 20th century identified cigarette smoking and/or smoking in general as risk factors (Keller, 1970; Wigle et al., 1980; Pogoda and Preston-Martin, 1996). Further evidence of a link between smoking and lip cancer is provided by the observation that lip cancer cases are at an elevated risk of second primary cancers known to be associated with smoking (lung, larynx) and vice versa (Curtis et al., 1985; Winn and Blot, 1985; Soderholm et al., 1994).


                      Cancers of the Oral Cavity and Pharynx

Figure 35–6. Age-adjusted (world) incidence rates for cancer of the lip, selected geographic regions, circa 1993–1997, all ages.

There is little consistent evidence that alcohol consumption (Wynder et al., 1957; Keller, 1970; Spitzer et al., 1975; Pogoda and Preston-Martin, 1996), syphilis (Wynder et al., 1957; Keller, 1970), or herpetic lesions (Spitzer et al., 1975; Lindqvist, 1979; Dardanoni et al., 1984; Pogoda and Preston-Martin, 1996) are important etiologic factors for lip cancer.


Salivary gland cancer (SGC) can arise in either the major or minor salivary glands. Current topography codes (ICD-O-3, ICD-10) for malignant neoplasms of the major salivary glands (C07-08) include the parotid, submandibular, and sublingual glands as well as their associated ducts, while cancers of the minor salivary glands are classified separately according to their anatomical site. Based largely upon these coding practices, population-based reports on the incidence of salivary gland cancer are generally restricted to malignant neoplasms of the major salivary glands of which the parotid is the most frequently affected. In one report providing population-based incidence data for both major and minor SGCs, the major glands accounted for 77% of all reported incident cases in Sweden during 1960–1989 while the minor glands accounted for the remaining 23% (Ostman et al., 1997).

The histopathologic classification of SGCs is complex and has undergone change over time. In the United States (11 SEER areas) during the period 1992–1999, the majority of SGCs were classified histopathologically as either adenocarcinomas (26%) or mucoepidermoid carcinomas (25%) followed by squamous cell (18%) and acinar cell (12%) carcinomas (SEER, 2002).

Salivary gland cancers are rare, with reported annual incidence rates of 1.2 in 100,000 in the United States (12 SEER sites, 1996–2000; Table 35–1) (SEER, 2003c) and rates generally well below 2 in 100,000 in most geographic regions during the period 1993–1997 (Fig. 35–7). While there is geographic variation in incidence rates, and while rates are most often higher in males, the absolute differences are generally small. Reported incidence rates are highest among persons living in the Canadian Northwest Territories and among Circumpolar Inuits for whom rates approach or exceed 4 in 100,000 for both males and females (Lanier and Alberts, 1996; Parkin et al., 2002).

During the period approximating 1968–1972 to 1993–1997 and among those regions included in Cancer Incidence in Five Continents, volumes III through VIII (Waterhouse et al., 1976; Waterhouse et al., 1982; Muir et al., 1987; Parkin et al., 1992; Parkin et al., 1997; Parkin et al., 2002), age-adjusted incidence rates for SGCs in males showed a net decline of at least 50% in regions of Germany (Saarland) and the United Kingdom (West Midlands, Oxford), but increased over 50% in Mumbai (India), Zaragoza (Spain), Puerto Rico, and among Singaporean Chinese. Among females during the same period, incidence rates declined 50% or more in areas of Canada (Manitoba, Quebec, Saskatchewan), Germany (Saarland), and the United Kingdom (West Midlands, Oxford, South and Western Region), but rose by 50% or more in Mumbai (India), Miyagi (Japan), and Utah (US). Some portion of the net change in reported rates, however, may reflect modifications in ICD coding practices or the histopathologic classification of these tumors over time. In the United States (9 SEER registries) (p.688)

                      Cancers of the Oral Cavity and Pharynx

Figure 35–7. Age-adjusted (world) incidence rates for cancer of the major salivary glands, selected geographic regions, circa 1993–1997, all ages.

during the years 1973 through 2000, SGC incidence rates rose with an average percentage change of 0.9% for males and 0.2% for females (SEER, 2003b).

In the United States, 5-year relative survival for SGC is moderately high and mortality relatively low. During 1992–1999 (9 SEER areas), the 5-year relative survival for SGC was 70% for males and 80% for females (Table 35–2) while mortality (1996–2000) was 0.4 and 0.2 in 100,000 for males and females, respectively (Ries et al., 2003; SEER, 2003a). Between 1969 and 2000, age-adjusted mortality rates for SGC in the United States declined with a statistically significant annual percent change of -1.3% for males and -1.8% for females (SEER, 2003a).

Radiation is an established risk factor for SGCs, with elevated risks and dose-response relationships observed among atomic bomb survivors (Land et al., 1996; Saku et al., 1997) and persons exposed to prior therapeutic head or neck irradiation (Spitz et al., 1984; Preston-Martin et al., 1988; Preston-Martin, 1989; Spitz et al., 1990; Horn-Ross et al., 1997a; Modan et al., 1998; Rubino et al., 2003). SGC risk has also been associated with diagnostic radiation directed to the head or neck, most notably among persons exposed to frequent full-mouth dental X-rays, and particularly for those exposed prior to the 1960s when substantially higher doses were used (Preston-Martin et al., 1988; Preston-Martin and White, 1990; Zheng et al., 1996; Horn-Ross et al., 1997a).

In one study, ultraviolet light treatments to the head and neck, used primarily to treat acne, were linked to an elevated risk of SGC, most notably among whites and particularly for exposures prior to 1955 (Horn-Ross et al., 1997a). SGC risk has also been linked to a previous history of UV-related, nonmelanoma skin cancer (Spitz et al., 1984; Teppo et al., 1985; Frisch and Melbye, 1995; Wassberg et al., 1999; Milan et al., 2000). However, studies have not consistently observed a clear relationship between average UVB intensity by geographic region and age-adjusted SGC incidence among whites living in the United States (Spitz et al., 1988; Sun et al., 1999), and mortality rates in the United States show little north-south gradient (Devesa et al., 1999).

There is evidence to link some occupational groups to increased risks of SGC. Elevated risks have been identified among women working in beauty shops (Swanson and Burns, 1997), male woodworkers employed in automobile plants (Swanson and Belle, 1982), rubber industry workers (Horn-Ross et al., 1997a; Mancuso and Brennan, 1970), persons occupationally exposed to nickel compounds or alloys (Horn-Ross et al., 1997a), radioactive materials (Horn-Ross et al., 1997a), or silica dust (Zheng et al., 1996), as well as among employees of an Australian underground colliery (Corbett and O’Neill, 1988) and residents of asbestos-mining counties in Quebec (Graham et al., 1977).

While alcohol and tobacco use are clearly related to OCP cancer, their relationship with SGC is equivocal. Most case-control investigations have reported little or no consistent evidence in support of a tobacco-SGC association (Keller, 1969; Spitz et al., 1984; Preston-Martin et al., 1988; Spitz et al., 1990; Zheng et al., 1996; Swanson and Burns, 1997; Muscat and Wynder, 1998); however, cigarette smoking was a strong risk factor in a case-control study conducted in Puerto Rico (Hayes et al., 1999), and current smoking was associated with a twofold increase in SGC, and a nearly sevenfold increase in adenocarcinoma risk among men, but not women, in a study carried out in northern California (Horn-Ross et al., 1997a). Also consistent with a tobacco-SGC relationship are reports that find an excess risk of lung cancer among previous cases of SGC and vice versa (Boice and Fraumeni, 1985; Winn and Blot, 1985; Sun et al., 1999). With regard to alcohol consumption, one case-control study found that drinking doubled SGC risk among women, but not men (Spitz et al., 1990), while another investigation reported an OR of 2.5 for heavy drinking and an associated dose-response trend for SGC among men, but not women (Horn-Ross et al., 1997a). Other studies, however, provide little additional support for a link between alcohol consumption and SGC (Keller, 1969; Spitz et al., 1984; Zheng et al., 1996; Muscat and Wynder, 1998; Hayes et al., 1999).

Diet has received little attention in relation to SGC risk; however, in a Chinese study, the consumption of dark yellow vegetables and liver was inversely related to risk (Zheng et al., 1996), while a US study found protective effects associated with a high, relative to low, intake of fiber from bean sources and total vitamin C, but an increased risk with high cholesterol consumption (Horn-Ross et al., 1997b).

In general, viruses have also received relatively little consideration in relation to SGC risk although a number of case reports and series suggest a strong link between Epstein-Barr virus (EBV) and lymphoepithelial carcinomas of the salivary glands, cancers observed primarily in Eskimos and the southern Chinese (Hamilton-Dutoit et al., 1991; Lanier et al., 1991; Chan et al., 1994; Sheen et al., 1997). The possible etiologic role of HPV for SGC has been discounted by the observation that HPV-related cancers (anal, cervical) do not occur in excess after SGC (Sun et al., 1999).

A possible hormonal link to SGC was supported by early reports of an excess risk of secondary breast cancer after SGC and vice versa (Berg et al., 1968; Prior and Waterhouse, 1977); however, most subsequent studies involving larger cohorts revealed little, if any, increased breast cancer risk (Schou et al., 1985; Winn and Blot, 1985; Sun et al., 1999). Although parity was not associated with SGC in one US-based case-control study (Spitz et al., 1984), age at menarche, number of births, age at first full-term delivery, and length of oral contraceptive use were all inversely related to SGC risk in another (Horn-Ross et al., 1999).

Other potential risk factors for SGC have been identified; however, the epidemiological evidence is often limited to one investigation; these factors include the use of hair dye (women only) (Spitz et al., 1990), mouthwash use (Spitz et al., 1990), kerosene used as a cooking fuel in Shanghai (Zheng et al., 1996), and familial clustering of SGC in Greenland (Merrick et al., 1986). There is little evidence of an association between SGC and the use of chewing tobacco or snuff (Preston-Martin et al., 1988; Spitz et al., 1990), cellular telephones (Johansen et al., 2001; Auvinen et al., 2002), or diagnostic X-rays to the chest or limbs (Preston-Martin et al., 1988; Zheng et al., 1996).

One study suggests that the pattern of allelic losses from chromosomes in SGC differs from that described for the progression model (p.689) in OCP cancers and that allelic loss patterns for salivary gland subtypes—pleomorphic adenomas, adenoid cystic carcinomas, and mucoepidermoid cancers—may differ from each other (Johns et al., 1996).


Effective prevention and control of OCP cancers in the future will require research strategies and public health resources to overcome the following key challenges:

  1. 1. Increasing rates of smoking in many countries and within segments of the US population require continued attention. Smokeless tobacco use is especially common in Asia (Gupta, 1996; Gupta and Warnakulasuriya, 2002). Also, new tobacco products are being developed (Slade et al., 2002), with unknown long-term effects on the risk of OCP cancers.

  2. 2. Despite major improvements in the past decade in identifying smoking and alcohol prevention and cessation interventions that are evidence-based, overall quit rates are still relatively low, and for persons with heavy tobacco and alcohol behaviors, cessation rates are even lower (US DHHS, 2003).

  3. 3. Serious disparities among race and ethnic groups in risk persist and require concerted attention.

  4. 4. Effective and non-toxic chemopreventive agents for oral precancerous lesions or for secondary prevention of OCP cancers have yet to be identified and verified.

  5. 5. Future molecular epidemiologic studies aimed at clarifying the role of genetic susceptibility must recognize and address key limitations in the current literature, including: assessment of the effect of genetic polymorphisms on risk may be affected by population stratification; lack of matching on alcohol and tobacco; small sample sizes; failure to consider HPV status; risk variation within subsites of the OCP; and effect of polymorphisms on survival (Olshan et al., 2000).

Future progress in these five areas is critical to reduce the morbidity and mortality associated with these cancers.


Bibliography references:

Ahlbom HE. 1937. Pradisponierende faktoren fur plattenepithelkarzinom in mund, hals und speiserohre. Eine statistische untersuchung am material des radiumhemmets, Stockholm. Acta Radiol (Stockholm) 18:163–185.

Alpha-Tocopherol Beta-Carotene Cancer Prevention Study Group. 1994. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group [comment]. N Engl J Med 330(15):1029–1035.

Auvinen A, Hietanen M, Luukkonen R, Koskela RS. 2002. Brain tumors and salivary gland cancers among cellular telephone users. Epidemiol 13(3):356–359.

Axell T, Pindborg JJ, Smith CJ, van der Waal I. 1996. Oral white lesions with special reference to precancerous and tobacco-related lesions: Conclusions of an international symposium held in Uppsala, Sweden, May 18–21, 1994. International Collaborative Group on Oral White Lesions. J Oral Pathol Med 25(2):49–54.

Bagnardi V, Blangiardo M, La Vecchia C, Corrao G. 2001. A meta-analysis of alcohol drinking and cancer risk. Br J Cancer 85(11):1700–1705.

Balaram P, Sridhar H, Rajkumar T, et al. 2002. Oral cancer in southern India: The influence of smoking, drinking, paan-chewing and oral hygiene. Int J Cancer 98(3):440–445.

Banoczy J, Gintner Z, Dombi C. 2001. Tobacco use and oral leukoplakia. J Dent Educ 65(4):322–327.

Barbone F, Franceschi S, Talamini R, et al. 1996. A follow-up study of determinants of second tumor and metastasis among subjects with cancer of the oral cavity, pharynx, and larynx. J Clin Epidemiol 49(3):367–372.

Baric JM, Alman JE, Feldman RS, Chauncey HH. 1982. Influence of cigarette, pipe, and cigar smoking, removable partial dentures, and age on oral leukoplakia. Oral Surg Oral Med Oral Pathol 54(4):424–429.

Bartsch H, Nair U, Risch A, Rojas M, Wikman H, Alexandrov K. 2000. Genetic polymorphism of CYP genes, alone or in combination, as a risk modifier of tobacco-related cancers. Cancer Epidemiol Biomarkers Prev 9(1):3–28.

Bedi GC, Westra WH, Gabrielson E, Koch W, Sidransky D. 1996. Multiple head and neck tumors: Evidence for a common clonal origin. Cancer Res 56(11):2484–2487.

Berg JW, Hutter RV, Foote FW, Jr. 1968. The unique association between salivary gland cancer and breast cancer. J Am Med Assoc 204(9):771–774.

Bernier JL, Clark ML. 1951. Squamous cell carcinoma of the lip: A statistical and morphologic analysis of 835 cases. Milit Surg 109:379–397.

Berwick M, Vineis P. 2000a. Markers of DNA repair and susceptibility to cancer in humans: An epidemiologic review. J Natl Cancer Inst 92(11):874–897.

Berwick M, Vineis P. 2000b. RESPONSE re: markers of DNA repair and susceptibility to cancer in humans: An epidemiologic review. J Natl Cancer Inst 92(18):1537.

Blot WJ, Winn DM, Fraumeni JF, Jr. 1983. Oral cancer and mouthwash. J Natl Cancer Inst 70(2):251–253.

Blot WJ, McLaughlin JK, Winn DM, et al. 1988. Smoking and drinking in relation to oral and pharyngeal cancer. Cancer Res 48(11):3282–3287.

Boffetta P, Mashberg A, Winkelmann R, Garfinkel L. 1992. Carcinogenic effect of tobacco smoking and alcohol drinking on anatomic sites of the oral cavity and oropharynx. Int J Cancer 52(4):530–533.

Boffetta P, Pershagen G, Jockel K-H, et al. 1999. Cigar and pipe smoking and lung cancer risk: A multicenter study from Europe. JNCI Cancer Spectrum 91(8):697–701.

Boffetta P, Gridley G, Gustavsson P, et al. 2000. Employment as butcher and cancer risk in a record-linkage study from Sweden. Cancer Causes Control 11(7):627–633.

Boffetta P, Gridley G, Lindelof B. 2001a. Cancer risk in a population-based cohort of patients hospitalized for psoriasis in Sweden. J Invest Derm 117(6):1531–1537.

Boffetta P, Ye W, Adami HO, Mucci LA, Nyren O. 2001b. Risk of cancers of the lung, head and neck in patients hospitalized for alcoholism in Sweden. Br J Cancer 85(5):678–682.

Boice JD, Jr., Fraumeni JF, Jr. 1985. Second cancer following cancer of the respiratory system in Connecticut, 1935–1982. Natl Cancer Inst Monogr 68:83–98.

Bolla M, Lefur R, Ton Van J, et al. 1994. Prevention of second primary tumours with etretinate in squamous cell carcinoma of the oral cavity and oropharynx. Results of a multicentric double-blind randomised study [comment]. Eur J Cancer 30A(6):767–772.

Bondy ML, Spitz MR, Halabi S, et al. 1993. Association between family history of cancer and mutagen sensitivity in upper aerodigestive tract cancer patients. Cancer Epidemiol Biomarkers Prev 2(2):103–106.

Bosetti C, Negri E, Franceschi S, et al. 2000. Risk factors for oral and pharyngeal cancer in women: A study from Italy and Switzerland. Br J Cancer 82(1):204–207.

Bouchardy C, Coutelle C, Ward PJ, Dayer P, Benhamou S. 1998. Re: Alcohol dehydrogenase 3 genotype and risk of oral cavity and pharyngeal cancers. J Natl Cancer Inst 90(12):937–939.

Bouchardy C, Hirvonen A, Coutelle C, Ward PJ, Dayer P, Benhamou S. 2000. Role of alcohol dehydrogenase 3 and cytochrome P-4502E1 genotypes in susceptibility to cancers of the upper aerodigestive tract. Int J Cancer 87(5):734–740.

Broders AC. 1920. Squamous-cell epithelioma of the lip: A study of five hundred and thirty-seven cases. J Am Med Assoc 74(10):656–664.

Brown LM, Gridley G, Diehl SR, et al. 2001. Family cancer history and susceptibility to oral carcinoma in Puerto Rico. Cancer 92(8):2102–2108.

Buch SC, Notani PN, Bhisey RA. 2002. Polymorphism at GSTM1, GSTM3 and GSTT1 gene loci and susceptibility to oral cancer in an Indian population. Carcinogenesis 23(5):803–807.

Bundgaard T, Wildt J, Frydenberg M, Elbrond O, Nielsen JE. 1995. Case-control study of squamous cell cancer of the oral cavity in Denmark. Cancer Causes Control 6(1):57–67.

Califano J, van der Riet P, Westra W, et al. 1996. Genetic progression model for head and neck cancer: Implications for field cancerization. Cancer Res 56(11):2488–2492.

Califano J, Leong PL, Koch WM, Eisenberger CF, Sidransky D, Westra WH. 1999. Second esophageal tumors in patients with head and neck squamous cell carcinoma: An assessment of clonal relationships. Clin Cancer Res 5(7):1862–1867.

Canto MT, Devesa SS. 2002. Oral cavity and pharynx cancer incidence rates in the United States, 1975–1998. Oral Oncol 38(6):610–617.

Castellsague X, Munoz N. 1999. Re: Cancer of the oral cavity and pharynx in nonsmokers who drink alcohol and in nondrinkers who smoke tobacco. J Natl Cancer Inst 91(15):1336–1338.

Chainani-Wu. 2002. Diet and oral, pharyngeal, and esophageal cancer. Nutr Cancer 44(2):104–126.

(p.690) Chan JK, Yip TT, Tsang WY, Poon YF, Wong CS, Ma VW. 1994. Specific association of Epstein-Barr virus with lymphoepithelial carcinoma among tumors and tumorlike lesions of the salivary gland. Arch Pathol Lab Med 118(10):994–997.

Chen C, Ricks S, Doody DR, Fitzgibbons ED, Porter PL, Schwartz SM. 2001. N-Acetyltransferase 2 polymorphisms, cigarette smoking and alcohol consumption, and oral squamous cell cancer risk. Carcinogenesis 22(12):1993–1999.

Cheng L, Eicher SA, Guo Z, Hong WK, Spitz MR, Wei Q. 1998. Reduced DNA repair capacity in head and neck cancer patients. Cancer Epidemiol Biomarkers Prev 7(6):465–468.

Cheng L, Sturgis EM, Eicher SA, Spitz MR, Wei Q. 2002. Expression of nucleotide excision repair genes and the risk for squamous cell carcinoma of the head and neck. Cancer 94(2):393–397.

Cheng LS, Carmelli D, Swan GE, Pfefferbaum A. 2000a. Segregation analysis of drinking problem in elderly men and their first-degree relatives from the Western Collaborative Group Study. Ann Epidemiol 10(5):309–315.

Cheng LS, Swan GE, Carmelli D. 2000b. A genetic analysis of smoking behavior in family members of older adult males. Addiction 95(3):427–435.

Cianfriglia F, Di Gregorio DA, Manieri A. 1999. Multiple primary tumours in patients with oral squamous cell carcinoma. Oral Oncol 35(2):157–163.

Cloos J, Reid CB, Snow GB, Braakhuis BJ. 1996a. Mutagen sensitivity: Enhanced risk assessment of squamous cell carcinoma. Eur J Cancer B Oral Oncol 32B(6):367–372.

Cloos J, Spitz MR, Schantz SP, et al. 1996b. Genetic susceptibility to head and neck squamous cell carcinoma. J Natl Cancer Inst 88(8):530–535.

Coble JB, Brown LM, Hayes RB, et al. 2003. Sugarcane farming, occupational solvent exposures, and the risk of oral cancer in Puerto Rico. J Occup Environ Med 45(8):869–874.

Copper MP, Jovanovic A, Nauta JJ, et al. 1995. Role of genetic factors in the etiology of squamous cell carcinoma of the head and neck. Arch Otolaryngol Head Neck Surg 121(2):157–160.

Corbett S, O’Neill BJ. 1988. A cluster of cases of lymphoma in an underground colliery. Med J Aust 149(4):178–179, 181–182, 184–185.

Cowan CG, Gregg TA, Napier SS, McKenna SM, Kee F. 2001. Potentially malignant oral lesions in northern Ireland: A 20-year population-based perspective of malignant transformation. Oral Dis 7(1):18–24.

Cox B, Taylor K, Treasure E. 1995. Trends in oral cancer by subsite in New Zealand. Eur J Cancer B Oral Oncol 31B(2):113–117.

Cox M, Maitland N, Scully C. 1993. Human herpes simplex-1 and papillomavirus type 16 homologous DNA sequences in normal, potentially malignant and malignant oral mucosa. Eur J Cancer B Oral Oncol 29B(3):215–219.

Curtis RE, Boice JD, Jr., Kleinerman RA, Flannery JT, Fraumeni JF, Jr. 1985. Summary: Multiple primary cancers in Connecticut, 1935–82. Natl Cancer Inst Monogr 68:219–242.

Dal Maso L, La Vecchia C, Polesel J, et al. 2002. Alcohol drinking outside meals and cancers of the upper aero-digestive tract. Int J Cancer 10(24):435–437.

Dallongeville J, Marecaux N, Fruchart JC, Amouyel P. 1998. Cigarette smoking is associated with unhealthy patterns of nutrient intake: A meta-analysis. J Nutr 128(9):1450–1457.

Dardanoni L, Gafa L, Paterno R, Pavone G. 1984. A case-control study on lip cancer risk factors in Ragusa (Sicily). Int J Cancer 34(3):335–337.

Davis S, Severson RK. 1987. Increasing incidence of cancer of the tongue in the United States among young adults. Lancet 2(8564):910–911.

Day GL, Blot WJ, McLaughlin JK, Fraumeni JF. 1994a. Carcinogenic risk of dark vs light liquor. Int J Cancer 59(3):319–321.

Day GL, Blot WJ, Shore RE, et al. 1994b. Second cancers following oral and pharyngeal cancers: Role of tobacco and alcohol. J Natl Cancer Inst 86(2):131–137.

Day GL, Shore RE, Blot WJ, et al. 1994c. Dietary factors and second primary cancers: A follow-up of oral and pharyngeal cancer patients. Nutr Cancer 21(3):223–232.

De Andrade M, Amos CI, Foulkes WD 1998. Segregation analysis of squamous cell carcinoma of the head and neck: Evidence for a major gene determining risk. Ann Hum Genet 62(6):505–510.

De Stefani E, Boffetta P, Oreggia F, Mendilaharsu M, Deneo-Pellegrini H. 1998. Smoking patterns and cancer of the oral cavity and pharynx: A case-control study in Uruguay. Oral Oncol 34(5):340–346.

De Stefani E, Deneo-Pellegrini H, Mendilaharsu M, Ronco A. 1999. Diet and risk of cancer of the upper aerodigestive tract—I. Foods. Oral Oncol 35(1):17–21.

de Visscher JG, Schaapveld M, Otter R, Visser O, van der Waal I. 1998. Epidemiology of cancer of the lip in The Netherlands. Oral Oncol 34(5):421–426.

Decoufle P. 1979. Cancer risks associated with employment in the leather and leather products industry. Arch Env Health 34(1):33–37.

Depue RH. 1986. Rising mortality from cancer of the tongue in young white males. N Engl J Med 315(10):647.

Devesa SS, Blot WJ, Stone BJ, Miller BA, Tarone RE, Fraumeni JF, Jr. 1995. Recent cancer trends in the United States. J Natl Cancer Inst 87(3):175–182.

Devesa SS, Blot WJ, Fraumeni JF, Jr. 1998. Changing patterns in the incidence of esophageal and gastric carcinoma in the United States. Cancer 83(10):2049–2053.

Devesa SS, Grauman DG, Blot WJ, Pennello G, Hoover RN, Fraumeni JF, Jr. 1999. Atlas of cancer mortality in the United States, 1950–94. Washington DC: US Government Printing Office.

Dikshit RP, Kanhere S. 2000. Tobacco habits and risk of lung, oropharyngeal and oral cavity cancer: A population-based case-control study in Bhopal, India. Int J Epidemiol 29(4):609–614.

Djordjevic MV, Brunnemann KD, Hoffmann D. 1993. The need for regulation of carcinogenic N-nitrosamines in oral snuff. Food Chem Toxicol 31(7):497–501.

Doll R. 1991. Urban and rural factors in the aetiology of cancer. Int J Cancer 47(6):803–810.

Ebenius B. 1943. Cancer of the lip: A clinical study of 778 cases with particular regard to predisposing factors and radium therapy. Acta Radiol (Stockholm) 48:1–232.

Einhorn J, Wersall J. 1967. Incidence of oral carcinoma in patients with leukoplakia of the oral mucosa. Cancer 20(12):2189–2193.

Elahi A, Zheng Z, Park J, Eyring K, McCaffrey T, Lazarus P. 2002. The human OGG1 DNA repair enzyme and its association with orolaryngeal cancer risk. Carcinogenesis 23(7):1229–1234.

Elwood JM, Pearson JC, Skippen DH, Jackson SM. 1984. Alcohol, smoking, social and occupational factors in the aetiology of cancer of the oral cavity, pharynx and larynx. Int J Cancer 34(5):603–612.

Epstein JB, Wong FL, Millner A, Le ND. 1994. Topical bleomycin treatment of oral leukoplakia: A randomized double-blind clinical trial. Head Neck 16(6):539–44.

Erdmann J. 2003. Recent studies attempt to clarify relationship between oral cancer and human papillomavirus. J Natl Cancer Inst 95(9):638–639.

Evstifeeva TV, Zaridze DG. 1992. Nass use, cigarette smoking, alcohol consumption and risk of oral and oesophageal precancer. Eur J Cancer B Oral Oncol 28B(1):29–35.

Fisher MJ, Virmani AK, Wu L, et al. 2001. Nucleotide substitution in the ectodomain of trail receptor DR4 is associated with lung cancer and head and neck cancer. Clin Cancer Res 7(6):1688–1697.

Foulkes WD, Brunet JS, Kowalski LP, Narod SA, Franco EL. 1995. Family history of cancer is a risk factor for squamous cell carcinoma of the head and neck in Brazil: A case-control study. Int J Cancer 63(6):769–773.

Foulkes WD, Brunet JS, Sieh W, Black MJ, Shenouda G, Narod SA. 1996. Familial risks of squamous cell carcinoma of the head and neck: Retrospective case-control study. Br Med J 313(7059):716–721.

Franceschi S, Talamini R, Barra S, et al. 1990. Smoking and drinking in relation to cancers of the oral cavity, pharynx, larynx, and esophagus in northern Italy. Cancer Res 50(20):6502–6507.

Franceschi S, Levi F, Lucchini F, Negri E, Boyle P, La Vecchia C. 1994. Trends in cancer mortality in young adults in Europe, 1955–1989. Eur J Cancer 30A(14):2096–2118.

Franceschi S, Levi F, Conti E, et al. 1999a. Energy intake and dietary pattern in cancer of the oral cavity and pharynx. Cancer Causes Control 10(5):439–444.

Franceschi S, Levi F, La Vecchia C, et al. 1999b. Comparison of the effect of smoking and alcohol drinking between oral and pharyngeal cancer. Int J Cancer 83(1):1–4.

Franceschi S, Levi F, Dal Maso L, et al. 2000. Cessation of alcohol drinking and risk of cancer of the oral cavity and pharynx. Int J Cancer 85(6):787–790.

Franco EL, Kowalski LP, Oliveira BV, et al. 1989. Risk factors for oral cancer in Brazil: A case-control study. Int J Cancer 43(6):992–1000.

Frisch M, Melbye M. 1995. New primary cancers after squamous cell skin cancer. Am J Epidemiol 141(10):916–922.

Frisch M, Biggar RJ. 1999. Aetiological parallel between tonsillar and anogenital squamous-cell carcinomas. Lancet 354(9188):1442–1443.

Fritz A, Percy C, Jack A, Shanmugaratnam K, Sobin L, Parkin DM, Whelan S. 2000. International Classification of Diseases for Oncology. Geneva: World Health Organization.

Garrote LF, Herrero R, Reyes RM, et al. 2001. Risk factors for cancer of the oral cavity and oro-pharynx in Cuba. Br J Cancer 85(1):46–54.

Geisler SA, Olshan AF. 2001. GSTM1, GSTT1, and the risk of squamous cell carcinoma of the head and neck: A mini-HuGE review. Am J Epidemiol 154(2):95–105.

(p.691) Gerlach KK, Cumings KM, Hyland A, Gilpin EA, Johnson MD, Pierce JP. 1998. Trends in cigar consumption and smoking prevalence. In: National Cancer Institute. Cigars: Health Effects and Trends. Smoking Tob Control Monog 9. Bethesda, MD: National Cancer Institute. NIH Publ. No. 98-4302.

Ghosh S, Shukla HS, Mohapatra SC, Shukla PK. 1996. Keeping chewing tobacco in the cheek pouch overnight (night quid) increases risk of cheek carcinoma. Eur J Surg Oncol 22(4):359–360.

Gillison ML, Koch WM, Capone RB, et al. 2000. Evidence for a causal association between human papillomavirus and a subset of head and neck cancers [comment]. J Natl Cancer Inst 92(9):709–720.

Gillison ML, Shah KV. 2001. Human papillomavirus-associated head and neck squamous cell carcinoma: Mounting evidence for an etiologic role for human papillomavirus in a subset of head and neck cancers. Curr Opin Oncol 13(3):183–188.

Goldgar DE, Easton DF, Cannon-Albright LA, Skolnick MH. 1994. Systematic population-based assessment of cancer risk in first-degree relatives of cancer probands. J Natl Cancer Inst 86(21):1600–1608.

Goldstein AM, Blot WJ, Greenberg RS, et al. 1994. Familial risk in oral and pharyngeal cancer. Eur J Cancer B Oral Oncol 30B(5):319–322.

Goode EL, Ulrich CM, Potter JD. 2002. Polymorphisms in DNA repair genes and associations with cancer risk. Cancer Epidemiol Biomarkers Prev 11(12):1513–1530.

Grady D, Greene J, Daniels TE, et al. 1990. Oral mucosal lesions found in smokeless tobacco users. J Am Dent Assoc 121(1):117–123.

Graham S, Blanchet M, Rohrer T. 1977. Cancer in asbestos-mining and other areas of Quebec. J Natl Cancer Inst 59(4):1139–1145.

Greenberg RS, Haber MJ, Clark WS, et al. 1991. The relation of socioeconomic status to oral and pharyngeal cancer. Epidemiol 2(3):194–200.

Gridley G, McLaughlin JK, Block G, et al. 1990. Diet and oral and pharyngeal cancer among blacks. Nutr Cancer 14(3–4):219–225.

Gupta PC. 1984a. Epidemiologic study of the association between alcohol habits and oral leukoplakia. Commun Dent Oral Epidemiol 12(1):47–50.

Gupta PC. 1984b. A study of dose-response relationship between tobacco habits and oral leukoplakia. Br J Cancer 50(4):527–531.

Gupta PC, Bhonsle RB, Murti PR, Daftary DK, Mehta FS, Pindborg JJ. 1989. An epidemiologic assessment of cancer risk in oral precancerous lesions in India with special reference to nodular leukoplakia. Cancer 63(11):2247–2252.

Gupta PC, Murti PR, Bhonsle RB, Mehta FS, Pindborg JJ. 1995. Effect of cessation of tobacco use on the incidence of oral mucosal lesions in a 10-yr follow-up study of 12,212 users. Oral Dis 1(1):54–58.

Gupta PC. 1996. Survey of sociodemographic characteristics of tobacco use among 99,598 individuals in Bombay, India using handheld computers. Tob Control 5:114–120.

Gupta PC, Hebert JR, Bhonsle RB, Sinor PN, Mehta H, Mehta FS. 1998a. Dietary factors in oral leukoplakia and submucous fibrosis in a population-based case control study in Gujarat, India. Oral Dis 4(3):200–206.

Gupta PC, Sinor PN, Bhonsle RB, Pawar VS, Mehta HC. 1998b. Oral submucous fibrosis in India: A new epidemic? Natl Med J India 11(3):113–116.

Gupta PC. 1999. Mouth cancer in India: A new epidemic? J Indian Med Assoc 97(9):370–373.

Gupta PC, Hebert JR, Bhonsle RB, Murti PR, Mehta H, Mehta FS. 1999. Influence of dietary factors on oral precancerous lesions in a population-based case-control study in Kerala, India. Cancer 85(9):1885–1893.

Gupta PC, Warnakulasuriya S. 2002. Global epidemiology of areca nut usage. Addict Biol 7(1):77–83.

Ha PK, Tong BC, Westra WH, et al. 2002. Mitochondrial C-tract alteration in premalignant lesions of the head and neck: a marker for progression and clonal proliferation. Clin Cancer Res 8(7):2260–2265.

Hakansson N, Floderus B, Gustavsson P, Feychting M, Hallin N. 2001. Occupational sunlight exposure and cancer incidence among Swedish construction workers. Epidemiol 12(5):552–557.

Hamilton-Dutoit SJ, Therkildsen MH, Neilsen NH, Jensen H, Hansen JP, Pallesen G. 1991. Undifferentiated carcinoma of the salivary gland in Greenlandic Eskimos: Demonstration of Epstein-Barr virus DNA by in situ nucleic acid hybridization. Hum Pathol 22(8):811–815.

Harty LC, Caporaso NE, Hayes RB, et al. 1997. Alcohol dehydrogenase 3 genotype and risk of oral cavity and pharyngeal cancers [see comments]. J Natl Cancer Inst 89(22):1698–1705.

Hashibe M, Mathew B, Kuruvilla B, et al. 2000a. Chewing tobacco, alcohol, and the risk of erythroplakia. Cancer Epidemiol Biomarkers Prev 9(7):639–645.

Hashibe M, Sankaranarayanan R, Thomas G, et al. 2000b. Alcohol drinking, body mass index and the risk of oral leukoplakia in an Indian population. Int J Cancer 88(1):129–134.

Hashibe M, Sankaranarayanan R, Thomas G, et al. 2002. Body mass index, tobacco chewing, alcohol drinking and the risk of oral submucous fibrosis in Kerala, India. Cancer Causes Control 13(1):55–64.

Hayes RB, Bravo-Otero E, Kleinman DV, et al. 1999. Tobacco and alcohol use and oral cancer in Puerto Rico. Cancer Causes Control 10(1):27–33.

Hazare VK, Goel RR, Gupta PC. 1998. Oral submucous fibrosis, areca nut and pan masala use: A case-control study. Natl Med J India 11(6):299.

Hemminki K, Dong C, Frisch M. 2000. Tonsillar and other upper aerodigestive tract cancers among cervical cancer patients and their husbands. Eur J Cancer Prev 9(6):433–437.

Herrero R, Castellsague X, Pawlita M, et al. 2003. Human papillomavirus and oral cancer: the International Agency for Reseach on Cancer Multicenter Study. J Natl Cancer Inst 95(23):1772–1783.

Hindle I, Downer MC, Speight PM. 1996. The epidemiology of oral cancer. Br J Oral Maxillofac Surg 34(5):471–476.

Hindle I, Downer MC, Moles DR, Speight PM. 2000. Is alcohol responsible for more intra-oral cancer? Oral Oncol 36(4):328–333.

Hirayama T. 1985. A large scale cohort study on cancer risks by diet—with special reference to the risk reducing effects of green-yellow vegetable consumption. Princess Takamatsu Symposia 16:41–53.

Ho PS, Ko YC, Yang YH, Shieh TY, Tsai CC. 2002. The incidence of oropharyngeal cancer in Taiwan: An endemic betel quid chewing area. J Oral Pathol Med 31(4):213–219.

Hoffmann D, Harley NH, Fisenne I, Adams JD, Brunnemann KD. 1986. Carcinogenic agents in snuff. J Natl Cancer Inst 76(3):435–437.

Homann N, Jousimies-Somer H, Jokelainen K, Heine R, Salaspuro M. 1997. High acetaldehyde levels in saliva after ethanol consumption: Methodological aspects and pathogenetic implications. Carcinogenesis 18(9):1739–1743.

Hong WK, Lippman SM, Itri LM, et al. 1990. Prevention of second primary tumors with isotretinoin in squamous-cell carcinoma of the head and neck [comment]. N Engl J Med 323(12):795–801.

Horn-Ross PL, Ljung BM, Morrow M. 1997a. Environmental factors and the risk of salivary gland cancer. Epidemiol 8(4):414–419.

Horn-Ross PL, Morrow M, Ljung BM. 1997b. Diet and the risk of salivary gland cancer. Am J Epidemiol 146(2):171–176.

Horn-Ross PL, Morrow M, Ljung BM. 1999. Menstrual and reproductive factors for salivary gland cancer risk in women. Epidemiol 10(5):528–530.

Hsieh LL, Chien HT, Chen IH, et al. 2003. The XRCC1 399Gln polymorphism and the frequency of p53 mutations in Taiwanese oral squamous cell carcinomas. Cancer Epidemiol Biomarkers Prev 12(5):439–443.

Hu YC, Sidransky D, Ahrendt SA. 2002. Molecular detection approaches for smoking associated tumors. Oncogene 21(48):7289–7297.

Huang WY, Winn DM, Brown LM, et al. 2003. Alcohol concentration and risk of oral cancer in Puerto Rico. Am J Epidemiol 157(10):881–887.

Huebner WW, Schoenberg JB, Kelsey JL, et al. 1992. Oral and pharyngeal cancer and occupation: A case-control study. Epidemiol 3(4):300–309.

Hung HC, Chuang J, Chien YC, et al. 1997. Genetic polymorphisms of CYP2E1, GSTM1, and GSTT1; environmental factors and risk of oral cancer. Cancer Epidemiol Biomarkers Prev 6(11):901–905.

IARC Working Group on the Evaluation of the Carcinogenic Risk of Chemicals to Humans, International Agency for Research on Cancer, World Health Organization. 1999. Volume 71. Re-Evaluation of Some Organic Chemicals, Hydrazine and Hydrogen Peroxide. Lyon, France: International Agency for Research on Cancer.

IARC Working Group on the Evaluation of the Carcinogenic Risk of Chemicals to Humans, International Agency for Research on Cancer, World Health Organization. 1985. Volume 37. Tobacco habits other than smoking, betel-quid and areca-nut chewing, and some related nitrosamines. Lyon, France: International Agency for Research on Cancer.

IARC Working Group on the Evaluation of the Carcinogenic Risk of Chemicals to Humans, International Agency for Research on Cancer, World Health Organization. 1988. Volume 44. Alcohol drinking. Lyon, France: International Agency for Research on Cancer.

IARC Working Group on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. 2004. Volume 85. Betel-quid and areca-nut chewing and some areca-nut related nitrosamines. Lyon, France: International Agency for Research on Cancer.

Idris AM, Ahmed HM, Malik MO. 1995. Toombak dipping and cancer of the oral cavity in the Sudan: A case-control study. Int J Cancer 63(4):477–480.

Idris AM, Ibrahim SO, Vasstrand EN, et al. 1998. The Swedish snus and the Sudanese toombak: Are they different? Oral Oncol 34(6):558–566.

International Agency for Research on Cancer. 1998. IARC Handbooks of Cancer Prevention, Volume 2, Carotenoids. Lyon, France: International Agency for Research on Cancer.

(p.692) Johansen C, Boice J, Jr., McLaughlin J, Olsen J. 2001. Cellular telephones and cancer—a nationwide cohort study in Denmark. J Natl Cancer Inst 93(3):203–207.

Johns MM, 3rd, Westra WH, Califano JA, Eisele D, Koch WM, Sidransky D. 1996. Allelotype of salivary gland tumors. Cancer Res 56(5):1151–1154.

Joint WHO/FAO Expert Consultation. 2003. Diet, Nutrition and the Prevention of Chronic Diseases. WHO Technical Report Series 916. Geneva: World Health Organization.

Jourenkova-Mironova N, Mitrunen K, Bouchardy C, Dayer P, Benhamou S, Hirvonen A. 2000. High-activity microsomal epoxide hydrolase genotypes and the risk of oral, pharynx, and larynx cancers. Cancer Res 60(3):534–536.

Jovanovic A, Kostense PJ, Schulten EA, Snow GB, van der Waal I. 1992. Delay in diagnosis of oral squamous cell carcinoma; a report from The Netherlands. Eur J Cancer B Oral Oncol 28B(1):37–38.

Jovanovic A, Schulten EA, Kostense PJ, Snow GB, van der Waal I. 1993a. Tobacco and alcohol related to the anatomical site of oral squamous cell carcinoma. J Oral Pathol Med 22(10):459–462.

Jovanovic A, Schulten EA, Kostense PJ, Snow GB, van der Waal I. 1993b. Squamous cell carcinoma of the lip and oral cavity in The Netherlands; an epidemiological study of 740 patients. J Craniomaxillofac Surg 21(4):149–152.

Jovanovic A, van der Tol IG, Kostense PJ, et al. 1994a. Second respiratory and upper digestive tract cancer following oral squamous cell carcinoma. Eur J Cancer B Oral Oncol 30B(4):225–229.

Jovanovic A, van der Tol IG, Schulten EA, et al. 1994b. Risk of multiple primary tumors following oral squamous-cell carcinoma. Int J Cancer 56(3):320–323.

Ju DM. 1973. On the etiology of cancer of the lower lip. Plast Reconstr Surg 52(2):151–154.

Kabat GC, Hebert JR, Wynder EL. 1989. Risk factors for oral cancer in women. Cancer Res 49(10):2803–2806.

Kabat GC, Chang CJ, Wynder EL. 1994. The role of tobacco, alcohol use, and body mass index in oral and pharyngeal cancer. Int J Epidemiol 23(6):1137–1144.

Kasum CM, Jacobs DR, Jr., Nicodemus K, Folsom AR. 2002. Dietary risk factors for upper aerodigestive tract cancers. Int J Cancer 99(2):267–272.

Katoh T, Kaneko S, Boissy R, Watson M, Ikemura K, Bell DA. 1998. A pilot study testing the association between N-acetyltransferases 1 and 2 and risk of oral squamous cell carcinoma in Japanese people. Carcinogenesis 19(10):1803–1807.

Katoh T, Kaneko S, Kohshi K, et al. 1999. Genetic polymorphisms of tobacco-and alcohol-related metabolizing enzymes and oral cavity cancer. Int J Cancer 83(5):606–609.

Kaugars GE, Pillion T, Svirsky JA, Page DG, Burns JC, Abbey LM. 1999. Actinic cheilitis: A review of 152 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 88(2):181–186.

Keller AZ. 1969. Residence, age, race and related factors in the survival and associations with salivary tumors. Am J Epidemiol 90(4):269–277.

Keller AZ. 1970. Cellular types, survival, race, nativity, occupations, habits and associated diseases in the pathogenesis of lip cancers. Am J Epidemiol 91(5):486–499.

Keller AZ. 1983. Selected factors in the risks of upper alimentary cancers. Prev Med 12(4):541–553.

Khan FA, Robinson PG, Warnakulasuriya KA, Newton JT, Gelbier S, Gibbons DE. 2000. Predictors of tobacco and alcohol consumption and their relevance to oral cancer control amongst people from minority ethnic communities in the South Thames health region, England. J Oral Pathol Med 29(5):214–219.

Khuder SA. 1999. Etiologic clues to lip cancer from epidemiologic studies on farmers. Scand J Work Environ Health 25(2):125–130.

Khuri FR, Kim ES, Lee JJ, et al. 2001. The impact of smoking status, disease stage, and index tumor site on second primary tumor incidence and tumor recurrence in the head and neck retinoid chemoprevention trial. Cancer Epidemiol Biomarkers Prev 10(8):823–829.

Khuri FR, Lee JJ, Lippman SM, et al. 2003. Isotretinoin effects on head and neck cancer recurrence and second primary tumors. Proc Am Soc Clin Oncol 22(90), abstr 359.

Kjaerheim K, Gaard M, Andersen A. 1998. The role of alcohol, tobacco, and dietary factors in upper aerogastric tract cancers: A prospective study of 10,900 Norwegian men. Cancer Causes Control 9(1):99–108.

Ko YC, Huang YL, Lee CH, Chen MJ, Lin LM, Tsai CC. 1995. Betel quid chewing, cigarette-smoking and alcohol-consumption related to oral-cancer in Taiwan. J Oral Path Med 24(10):450–453.

Kutler DI, Singh B, Satagopan J, et al. 2003. A 20-year perspective on the International Fanconi Anemia Registry (IFAR). Blood 101(4):1249–1256.

Land CE, Saku T, Hayashi Y, et al. 1996. Incidence of salivary gland tumors among atomic bomb survivors, 1950–1987. Evaluation of radiation-related risk. Radiat Res 146(1):28–36.

Lanier AP, Clift SR, Bornkamm G, Henle W, Goepfert H, Raab-Traub N. 1991. Epstein-Barr virus and malignant lymphoepithelial lesions of the salivary gland. Arctic Med Res 50(2):55–61.

Lanier AP, Alberts SR. 1996. Cancers of the buccal cavity and pharynx in Circumpolar Inuit. Acta Oncol 35(5):545–552.

Lay KM, Sein K, Myint A, Ko SK, Pindborg JJ. 1982. Epidemiologic study of 6000 villagers of oral precancerous lesions in Bilugyun: preliminary report. Commun Dent Oral Epidemiol 10(3):152–155.

Lazarus P, Park JY. 2000. Metabolizing enzyme genotype and risk for upper aerodigestive tract cancer. Oral Oncol 36(5):421–431.

Le Marchand L, Hankin JH, Carter FS, et al. 1994. A pilot study on the use of plasma carotenoids and ascorbic acid as markers of compliance to a high fruit and vegetable dietary intervention. Cancer Epidemiol Biomarkers Prev 3(3):245–251.

Lee CH, Ko YC, Huang HL, et al. 2003. The precancer risk of betel quid chewing, tobacco use and alcohol consumption in oral leukoplakia and oral submucous fibrosis in southern Taiwan. Br J Cancer 88(3):366–372.

Levi F, La Vecchia C, Randimbison L, Te VC. 1995. Cancer incidence and mortality in young adults in Vaud, Switzerland, 1974–1992. Int J Cancer 61(5):606–610.

Levi F, Pasche C, La Vecchia C, Lucchini F, Franceschi S, Monnier P. 1998. Food groups and risk of oral and pharyngeal cancer. Int J Cancer 77(5):705–709.

Levin ML, Goldstein H, Gerhardt PR. 1950. Cancer and tobacco smoking. J Am Med Assoc 143(4):336–338.

Lewin F, Norell SE, Johansson H, et al. 1998. Smoking tobacco, oral snuff, and alcohol in the etiology of squamous cell carcinoma of the head and neck: A population-based case-referent study in Sweden. Cancer 82(7):1367–1375.

Li D, Firozi PF, Chang P, et al. 2001. In vitro BPDE-induced DNA adducts in peripheral lymphocytes as a risk factor for squamous cell carcinoma of the head and neck. Int J Cancer 93(3):436–440.

Li N, Sun Z, Han C, Chen J. 1999. The chemopreventive effects of tea on human oral precancerous mucosa lesions. Proc Soc Exp Biol Med 220(4):218–224.

Li X, Hemminki K. 2003. Familial upper aerodigestive tract cancers: Incidence trends, familial clustering and subsequent cancers. Oral Oncol 39(3):232–239.

Lindqvist C, Teppo L. 1978. Epidemiological evaluation of sunlight as a risk factor of lip cancer. Cancer 37(6):983–989.

Lindqvist C. 1979. Risk factors in lip cancer: a questionnaire survey. Am J Epidemiol 109(5):521–530.

Lippman SM, Hong WK. 1989. Second malignant tumors in head and neck squamous cell carcinoma: The overshadowing threat for patients with early-stage disease. Int J Radiation Oncol Biol Physics 17(3):691–694.

Lippman SM, Lee JJ, Karp DD, et al. 2001. Randomized phase III intergroup trial of isotretinoin to prevent second primary tumors in stage I non-smallcell lung cancer. J Natl Cancer Inst 93(8):605–618.

Lissowska J, Pilarska A, Pilarski P, et al. 2003. Smoking, alcohol, diet, dentition and sexual practices in the epidemiology of oral cancer in Poland. Eur J Cancer Prev 12(1):25–33.

Liu S, Park JY, Schantz SP, Stern JC, Lazarus P. 2001. Elucidation of CYP2E1 5′ regulatory RsaI/Pstl allelic variants and their role in risk for oral cancer. Oral Oncol 37(5):437–445.

Loning T, Ikenberg H, Becker J, Gissmann L, Hoepfer I, zur Hausen H. 1985. Analysis of oral papillomas, leukoplakias, and invasive carcinomas for human papillomavirus type related DNA. J Invest Derm 84(5):417–420.

Macfarlane GJ, Boyle P, Scully C. 1992. Oral cancer in Scotland: Changing incidence and mortality. Br Med J 305(6862):1121–1123.

Macfarlane GJ, Zheng T, Marshall JR, et al. 1995. Alcohol, tobacco, diet and the risk of oral-cancer—a pooled analysis of 3 case-control studies. Oral Oncol Eur J Cancer B 31B(3):181–187.

Macigo FG, Mwaniki DL, Guthua SW. 1995. The association between oral leukoplakia and use of tobacco, alcohol and khat based on relative risks assessment in Kenya. Eur J Oral Sci 103(5):268–273.

Maden C, Beckmann AM, Thomas DB, et al. 1992. Human papillomaviruses, herpes simplex viruses, and the risk of oral cancer in men. Am J Epidemiol 135(10):1093–1102.

Maher R, Lee AJ, Warnakulasuriya KA, Lewis JA, Johnson NW. 1994. Role of areca nut in the causation of oral submucous fibrosis: A case-control study in Pakistan. J Oral Pathol Med 23(2):65–69.

Maier H, de Vries N, Weidauer H. 1990. [Occupation and cancer of the oral cavity, pharynx and larynx]. [German]. HNO 38(8):271–278.

(p.693) Mancuso TF, Brennan MJ. 1970. Epidemiological considerations of cancer of the gallbladder, bile ducts and salivary glands in the rubber industry. J Occup Med 12(9):333–341.

Mao L, Lee JS, Fan YH, et al. 1996. Frequent microsatellite alterations at chromosomes 9p21 and 3p14 in oral premalignant lesions and their value in cancer risk assessment. Nat Med 2(6):682–685.

Marshall JR, Graham S, Haughey BP, et al. 1992. Smoking, alcohol, dentition and diet in the epidemiology of oral cancer. Eur J Cancer B Oral Oncol 28B(1):9–15.

Martin GC, Brown JP, Eifler CW, Houston GD. 1999. Oral leukoplakia status six weeks after cessation of smokeless tobacco use. J Am Dent Assoc 130(7):945–954.

Mashberg A. 1978. Erythroplasia: the earliest sign of asymptomatic oral cancer. J Am Dent Assoc 96(4):615–620.

Mashberg A, Boffetta P, Winkelman R, Garfinkel L. 1993. Tobacco smoking, alcohol drinking, and cancer of the oral cavity and oropharynx among U.S. veterans. Cancer 72(4):1369–1375.

Mathew B, Sankaranarayanan R, Nair PP, et al. 1995. Evaluation of chemoprevention of oral cancer with Spirulina fusiformis. Nutr Cancer 24(2):197–202.

Matthias C, Bockmuhl U, Jahnke V, et al. 1998. Polymorphism in cytochrome P450 CYP2D6, CYP1A1, CYP2E1 and glutathione S-transferase, GSTM1, GSTM3, GSTT1 and susceptibility to tobacco-related cancers: Studies in upper aerodigestive tract cancers. Pharmacogenetics 8(2):91–100.

Mayne ST, Cartmel B, Baum M, et al. 2001. Randomized trial of supplemental beta-carotene to prevent second head and neck cancer. Cancer Res 61(4):1457–1463.

Mayne ST, Cartmel B, Morse DE. 2003. Chemoprevention of oral premalignant lesions. In: Head and Neck Cancer: Emerging Perspectives. JF Ensley, JS Gutkind, JR Jacobs and SM Lippman editors. New York: Academic Press, pp. 261–269.

McCredie M, Coates M, Grulich A. 1994. Cancer incidence in migrants to New South Wales (Australia) from the Middle East, 1972–91. Cancer Causes Control 5(5):414–421.

Mehta FS, Gupta PC, Pindborg JJ. 1981. Chewing and smoking habits in relation to precancer and oral cancer. J Cancer Res Clin Oncol 99(1–2):35–39.

Merchant A, Husain SS, Hosain M, et al. 2000. Paan without tobacco: An independent risk factor for oral cancer. Int J Cancer 86(1):128–131.

Merletti F, Boffetta P, Ciccone G, Mashberg A, Terracini B. 1989. Role of tobacco and alcoholic beverages in the etiology of cancer of the oral cavity/oropharynx in Torino, Italy. Cancer Res 49(17):4919–4924.

Merletti F, Boffetta P, Ferro G, Pisani P, Terracini B. 1991. Occupation and cancer of the oral cavity or oropharynx in Turin, Italy. Scand J Work Environ Health 17(4):248–254.

Merrick Y, Albeck H, Nielsen NH, Hansen HS. 1986. Familial clustering of salivary gland carcinoma in Greenland. Cancer 57(10):2097–2102.

Milan T, Pukkala E, Verkasalo PK, et al. 2000. Subsequent primary cancers after basal-cell carcinoma: A nationwide study in Finland from 1953 to 1995. Int J Cancer 87(2):283–288.

Modan B, Chetrit A, Alfandary E, et al. 1998. Increased risk of salivary gland tumors after low-dose irradiation. Laryngoscope 108(7):1095–1097.

Moller H. 1989. Changing incidence of cancer of the tongue, oral cavity, and pharynx in Denmark. J Oral Pathol Med 18(4):224–229.

Morita S, Yano M, Tsujinaka T, et al. 1999. Genetic polymorphisms of drug-metabolizing enzymes and susceptibility to head-and-neck squamous-cell carcinoma. Int J Cancer 80(5):685–688.

Mork J, Moller B, Glattre E. 1999. Familial risk in head and neck squamous cell carcinoma diagnosed before the age of 45: A population-based study. Oral Oncol 35(4):360–367.

Mork J, Lie AK, Glattre E, et al. 2001. Human papillomavirus infection as a risk factor for squamous-cell carcinoma of the head and neck [comment]. N Engl J Med 344(15):1125–1131.

Morse DE, Katz RV, Pendrys DG, et al. 1996. Smoking and drinking in relation to oral epithelial dysplasia. Cancer Epidemiol Biomarkers Prev 5(10):769–777.

Morse DE, Katz RV, Pendrys DG, et al. 1997. Mouthwash use and dentures in relation to oral epithelial dysplasia. Oral Oncol 33(5):338–343.

Morse DE, Pendrys DG, Neely AL, Psoter WJ. 1999. Trends in the incidence of lip, oral, and pharyngeal cancer: Connecticut, 1935–94. Oral Oncol 35(1):1–8.

Morse DE, Pendrys DG, Katz RV, et al. 2000. Food group intake and the risk of oral epithelial dysplasia in a United States population. Cancer Causes Control 11(8):713–720.

Muir C, Waterhouse J, Mack T, Powell J, Whelan S, editors. 1987. Cancer Incidence in Five Continents, Volume V. Lyon, France: International Agency for Research on Cancer. IARC Scientific Publications No. 88.

Murti PR, Bhonsle RB, Pindborg JJ, Daftary DK, Gupta PC, Mehta FS. 1985. Malignant transformation rate in oral submucous fibrosis over a 17-year period. Commun Dent Oral Epidemiol 13(6):340–341.

Muscat JE, Wynder EL. 1998. A case/control study of risk factors for major salivary gland cancer. Otolaryngol Head Neck Surg 118(2):195–198.

Muto M, Hitomi Y, Ohtsu A, et al. 2000. Acetaldehyde production by nonpathogenic Neisseria in human oral microflora: implications for carcinogenesis in upper aerodigestive tract. Int J Cancer 88(3):342–350.

National Cancer Institute. 1997. Changes in cigarette-related disease risks and their implication for prevention and control. Smoking Tob Control Monog 8. Bethesda, MD: National Cancer Insitute. (NIH Publ. No. 97–4213).

National Cancer Institute 2002. Smokeless Tobacco Fact Sheets ( 10–23–02.pdf) accessed December 2003.

Negri E, La Vecchia C, Franceschi S, Tavani A. 1993. Attributable risk for oral cancer in northern Italy. Cancer Epidemiol Biomarkers Prev 2(3):189–193.

Negri E, Franceschi S, Bosetti C, et al. 2000. Selected micronutrients and oral and pharyngeal cancer. Int J Cancer 86(1):122–127.

Nelson DE, Davis RM, Chrismon JH, Giovino GA. 1996. Pipe smoking in the United States, 1965–1991: Prevalence and attributable mortality. Prev Med 25(2):91–99.

Nicolau SG, Balus L. 1964. Chronic actinic cheilitis and cancer of the lower lip. Br J Dermatol 76:278–289.

Nomura T, Noma H, Shibahara T, Yokoyama A, Muramatusu T, Ohmori T. 2000. Aldehyde dehydrogenase 2 and glutathione S-transferase M 1 polymorphisms in relation to the risk for oral cancer in Japanese drinkers. Oral Oncol 36(1):42–46.

O’Hanlon S, Forster DP, Lowry RJ. 1997. Oral cancer in the North-East of England: Incidence, mortality trends and the link with material deprivation. Commun Dent Oral Epidemiol 25(5):371–376.

Olshan AF, Weissler MC, Watson MA, Bell DA. 2000. GSTM1, GSTT1, GSTP1, CYP1A1, and NAT1 polymorphisms, tobacco use, and the risk of head and neck cancer. Cancer Epidemiol Biomarkers Prev 9(2):185–191.

Olshan AF, Weissler MC, Watson MA, Bell DA. 2001. Risk of head and neck cancer and the alcohol dehydrogenase 3 genotype. Carcinogenesis 22(1):57–61.

Olshan AF, Watson MA, Weissler MC, Bell DA. 2002. XRCC1 polymorphisms and head and neck cancer. Cancer Lett 178(2):181–186.

Omenn GS, Goodman GE, Thornquist MD, et al. 1996. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med 334(18):1150–1155.

Ostman J, Anneroth G, Gustafsson H, Tavelin B. 1997. Malignant salivary gland tumours in Sweden 1960–1989—an epidemiological study. Oral Oncol 33(3):169–176.

Parkin DM, Muir CS, Whelan SL, Gao Y-T, Ferlay J, Powell J, eds. 1992. Cancer Incidence in Five Continents, Volume VI. Lyon, France: International Agency for Research on Cancer. IARC Scientific Publications No. 120.

Parkin DM, Whelan SL, Ferlay J, Raymond L, Young J, eds. 1997. Cancer Incidence in Five Continents, Volume VII. Lyon, France: International Agency for Research on Cancer. IARC Scientific Publications No. 143.

Parkin DM, Bray FI, Devesa SS. 2001. Cancer burden in the year 2000. The global picture. Eur J Cancer 37 Suppl 8:S4–66.

Parkin DM, Whelan SL, Ferlay J, Teppo L, Thomas D, eds. 2002. Cancer Incidence in Five Continents, Volume VIII. Lyon, France: International Agency for Research on Cancer. IARC Scientific Publications No. 155.

Partridge M, Pateromichelakis S, Phillips E, Emilion G, Langdon J. 2001. Profiling clonality and progression in multiple premalignant and malignant oral lesions identifies a subgroup of cases with a distinct presentation of squamous cell carcinoma. Clin Cancer Res 7(7):1860–1866.

Petridou E, Zavras AI, Lefatzis D, et al. 2002. The role of diet and specific micronutrients in the etiology of oral carcinoma. Cancer 94(11):2981–2988.

Pindborg JJ, Reichart PA, Smith CJ, van der Waal I, in collaboration with Sobin LH, eds. 1997. Histological Typing of Cancer and Precancer of the Oral Mucosa. New York: Springer.

Plesko I, Macfarlane GJ, Evstifeeva TV, Obsitnikova A, Kramarova E. 1994. Oral and pharyngeal cancer incidence in Slovakia 1968–1989. Int J Cancer 56(4):481–486.

Pogoda JM, Preston-Martin S. 1996. Solar radiation, lip protection, and lip cancer risk in Los Angeles County women (California, United States). Cancer Causes Control 7(4):458–463.

Preston-Martin S, Thomas DC, White SC, Cohen D. 1988. Prior exposure to medical and dental x-rays related to tumors of the parotid gland. J Natl Cancer Inst 80(12):943–949.

(p.694) Preston-Martin S. 1989. Prior x-ray therapy for acne related to tumors of the parotid gland. Arch Dermatol 125(7):921–924.

Preston-Martin S, White SC. 1990. Brain and salivary gland tumors related to prior dental radiography: Implications for current practice. J Am Dent Assoc 120(2):151–158.

Prior P, Waterhouse JA. 1977. Second primary cancers in patients with tumours of the salivary glands. Br J Cancer 36(3):362–368.

Psoter WJ, Morse DE. 2001. Annual per capita apparent consumption of tobacco products in the United States: 1900–1990. Prev Med 32(1):1–9.

Pukkala E, Soderholm AL, Lindqvist C. 1994. Cancers of the lip and oropharynx in different social and occupational groups in Finland. Eur J Cancer B Oral Oncol 30B(3):209–215.

Rao DN, Ganesh B, Rao RS, Desai PB. 1994. Risk assessment of tobacco, alcohol and diet in oral cancer–a case-control study. Int J Cancer 58(4):469–473.

Rao DN, Desai PB. 1998. Risk assessment of tobacco, alcohol and diet in cancers of base tongue and oral tongue—a case control study. Indian J Cancer 35(2):65–72.

Reddy CR, Kameswari VR, Chandramouli KB, Prahlad D, Ramulu C. 1975. Evaluation of oral, pharyngeal, laryngeal and esophageal cancer risk in reverse smokers of chuttas. Int Surg 60(5):266–269.

Reed AL, Califano J, Cairns P, et al. 1996. High frequency of p16 (CDKN2/MTS-1/INK4A) inactivation in head and neck squamous cell carcinoma. Cancer Res 56(16):3630–3633.

Ries LAG, Eisner MP, Kosary CL, et al. 2003. SEER Cancer Statistics Review, 1975–2000: National Cancer Institute. Bethesda, MD.

Robinson KL, Macfarlane GJ. 2003. Oropharyngeal cancer incidence and mortality in Scotland: are rates still increasing? Oral Oncol 39(1):31–36.

Roed-Petersen B. 1982. Effect on oral leukoplakia of reducing or ceasing tobacco smoking. Acta Derm Venereol 62(2):164–167.

Rosas SL, Koch W, da Costa Carvalho MG, et al. 2001. Promoter hypermethylation patterns of p16, O6-methylguanine-DNA-methyltransferase, and death-associated protein kinase in tumors and saliva of head and neck cancer patients. Cancer Res 61(3):939–942.

Rosenberg PS, Greene MH, Alter BP. 2003. Cancer incidence in persons with Fanconi anemia. Blood 101(3):822–826.

Rosin MP, Cheng X, Poh C, et al. 2000. Use of allelic loss to predict malignant risk for low-grade oral epithelial dysplasia. Clin Cancer Res 6(2):357–362.

Rubino C, De Vathaire F, Dottorini ME, et al. 2003. Second primary malignancies in thyroid cancer patients. Br J Cancer 89(9):1638–1644.

Saku T, Hayashi Y, Takahara O, et al. 1997. Salivary gland tumors among atomic bomb survivors, 1950–1987. Cancer 79(8):1465–1475.

Sanchez MJ, Martinez C, Nieto A, et al. 2003. Oral and oropharyngeal cancer in Spain: Influence of dietary patterns. Eur J Cancer Prev 12(1):49–56.

Sankaranarayanan R, Duffy SW, Padmakumary G, Day NE, Padmanabhan TK. 1989. Tobacco chewing, alcohol and nasal snuff in cancer of the gingiva in Kerala, India. Br J Cancer 60(4):638–643.

Sankaranarayanan R, Duffy SW, Padmakumary G, Day NE, Krishan Nair M. 1990. Risk factors for cancer of the buccal and labial mucosa in Kerala, southern India. J Epidemiol Commun Health 44(4):286–292.

Sato M, Sato T, Izumo T, Amagasa T. 2000. Genetically high susceptibility to oral squamous cell carcinoma in terms of combined genotyping of CYP1A1 and GSTM1 genes. Oral Oncol 36(3):267–271.

Schantz SP, Ostroff JS. 1997. Novel approaches to the prevention of head and neck cancer. Proc Soc Exp Biol Med 216(2):275–282.

Schantz SP, Yu GP. 2002. Head and neck cancer incidence trends in young Americans, 1973–1997, with a special analysis for tongue cancer. Arch Otolaryngol Head Neck Surg 128(3):268–274.

Schepman KP, van der Meij EH, Smeele LE, van der Waal I. 1998. Malignant transformation of oral leukoplakia: A follow-up study of a hospital-based population of 166 patients with oral leukoplakia from The Netherlands. Oral Oncol 34(4):270–275.

Schildt EB, Eriksson M, Hardell L, Magnuson A. 1998. Oral snuff, smoking habits and alcohol consumption in relation to oral cancer in a Swedish case-control study. Int J Cancer 77(3):341–346.

Schlecht NF, Franco EL, Pintos J, Kowalski LP. 1999. Effect of smoking cessation and tobacco type on the risk of cancers of the upper aero-digestive tract in Brazil. Epidemiol 10(4):412–418.

Schou G, Storm HH, Jensen OM. 1985. Second cancer following cancers of the buccal cavity and pharynx in Denmark, 1943–80. Natl Cancer Inst Monogr 68:253–276.

Schouten LJ, Meijer H, Huveneers JA, Kiemeney LA. 1996. Urban-rural differences in cancer incidence in The Netherlands 1989–1991. Int J Epidemiol 25(4):729–736.

Schwartz SM, Daling JR, Doody DR, et al. 1998. Oral cancer risk in relation to sexual history and evidence of human papillomavirus infection. J Natl Cancer Inst 90(21):1626–1636.

Schwartz SM, Doody DR, Fitzgibbons ED, Ricks S, Porter PL, Chen C. 2001a. Oral squamous cell cancer risk in relation to alcohol consumption and alcohol dehydrogenase-3 genotypes. Cancer Epidemiol Biomarkers Prev 10(11):1137–1144.

Schwartz SR, Yueh B, McDougall JK, Daling JR, Schwartz SM. 2001b. Human papillomavirus infection and survival in oral squamous cell cancer: A population-based study. Otolaryngol Head Neck Surg 125(1):1–9.

Sciubba JJ. 1995. Oral leukoplakia. Crit Rev Oral Biol Med 6(2):147–160.

Scully C. 2002. Oral squamous cell carcinoma; from an hypothesis about a virus, to concern about possible sexual transmission. Oral Oncol 38(3):227–234.

SEER. 2002. Program Public-use Data (1973–1999): National Cancer Institute, DCCPS, Surveillance Research Program, Cancer Statistics Branch.

SEER. 2003a. ( SEER*Stat Database: Mortality—All COD, Public-Use With State, Total U.S. for Expanded Races/Hispanics (1990–2000): National Cancer Institute, DCCPS, Surveillance Research Program, Cancer Statistics Branch, released April 2003. Underlying mortality data provided by NCHS (

SEER. 2003b. ( SEER*Stat Database: Incidence—SEER 9 Regs Public-Use, Nov 2002 Submission (1973–2000), released April 2003: National Cancer Institute, DCCPS Surveillance Program, Cancer Statistics Branch.

SEER. 2003c. ( SEER*Stat Database: Incidence—SEER 12 Regs Public-Use, Nov 2002 Submission (1973–2000), released April 2003: National Cancer Institute, DCCPS Surveillance Program, Cancer Statistics Branch.

SEER. 2003d. ( SEER*Stat Database: Incidence—SEER 11 Regs Public-Use, Nov 2002 Submission for Hispanics (1992–2000), released April 2003: National Cancer Institute, DCCPS Surveillance Program, Cancer Statistics Branch.

Shafer WG, Waldron CA. 1975. Erythroplakia of the oral cavity. Cancer 36(3):1021–1028.

Shah KV. 1998. Do human papillomavirus infections cause oral cancer? J Natl Cancer Inst 90(21):1585–1586.

Shah N, Sharma PP. 1998. Role of chewing and smoking habits in the etiology of oral submucous fibrosis (OSF): A case-control study. J Oral Pathol Med 27(10):475–479.

Shapiro JA, Jacobs EJ, Thun MJ. 2000. Cigar smoking in men and risk of death from tobacco-related cancers. J Natl Cancer Inst 92(4):333–337.

Sheen TS, Tsai CC, Ko JY, Chang YL, Hsu MM. 1997. Undifferentiated carcinoma of the major salivary glands. Cancer 80(3):357–363.

Shen H, Sturgis EM, Khan SG, et al. 2001. An intronic poly (AT) polymorphism of the DNA repair gene XPC and risk of squamous cell carcinoma of the head and neck: a case-control study. Cancer Res 61(8):3321–3325.

Shiu MN, Chen TH, Chang SH, Hahn LJ. 2000. Risk factors for leukoplakia and malignant transformation to oral carcinoma: a leukoplakia cohort in Taiwan. Br J Cancer 82(11):1871–1874.

Shohaimi S, Luben R, Wareham N, et al. 2003. Residential area deprivation predicts smoking habit independently of individual educational level and occupational social class. A cross sectional study in the Norfolk cohort of the European Investigation into Cancer (EPIC-Norfolk). J Epidemiol Commun Health 57(4):270–276.

Sidransky D. 2002. Emerging molecular markers of cancer. Nat Rev Cancer 2(3):210–219.

Silverman S, Jr., Gorsky M, Lozada F. 1984. Oral leukoplakia and malignant transformation. A follow-up study of 257 patients. Cancer 53(3):563–568.

Singh B, Wreesmann VB, Pfister D, et al. 2002. Chromosomal aberrations in patients with head and neck squamous cell carcinoma do not vary based on severity of tobacco/alcohol exposure. BMC Genet 3(1):22.

Slade J, Connolly GN, Lymperis D. 2002. Eclipse: Does it live up to its health claims? Tob Control 11(Suppl 2):ii64–70.

Soderholm AL, Pukkala E, Lindqvist C, Teppo L. 1994. Risk of new primary cancer in patients with oropharyngeal cancer. Br J Cancer 69(4):784–787.

Soni S, Kaur J, Kumar A, Chakravarti N, Mathur M, Bahadur S, Shukla NK, Deo SV, Ralhan R. 2005. Alterations of rb pathway components are frequent events in patients with oral epithelial dysplasia and predict clinical outcome in patients with squamous cell carcinoma. Oncol 68(4–6):314–325.

Spitz MR, Tilley BC, Batsakis JG, Gibeau JM, Newell GR. 1984. Risk factors for major salivary gland carcinoma. A case-comparison study. Cancer 54(9):1854–1859.

(p.695) Spitz MR, Sider JG, Newell GR, Batsakis JG. 1988. Incidence of salivary gland cancer in the United States relative to ultraviolet radiation exposure. Head Neck Surg 10(5):305–308.

Spitz MR, Fueger JJ, Beddingfield NA, et al. 1989. Chromosome sensitivity to bleomycin-induced mutagenesis, an independent risk factor for upper aerodigestive tract cancers. Cancer Res 49(16):4626–4628.

Spitz MR, Fueger JJ, Goepfert H, Newell GR. 1990. Salivary gland cancer. A case-control investigation of risk factors. Arch Otolaryngol Head Neck Surg 116(10):1163–1166.

Spitz MR, Sider JG, Schantz SP, Newell GR. 1992. Association between malignancies of the upper aerodigestive tract and uterine cervix. Head Neck 14(5):347–351.

Spitz MR, Fueger JJ, Halabi S, Schantz SP, Sample D, Hsu TC. 1993. Mutagen sensitivity in upper aerodigestive tract cancer: A case-control analysis. Cancer Epidemiol Biomarkers Prev 2(4):329–33.

Spitzer WO, Hill GB, Chambers LW, Helliwell BE, Murphy HB. 1975. The occupation of fishing as a risk factor in cancer of the lip. N Engl J Med 293(9):419–424.

Sreelekha TT, Ramadas K, Pandey M, Thomas G, Nalinakumari KR, Pillai MR. 2001. Genetic polymorphism of CYP1A1, GSTM1 and GSTT1 genes in Indian oral cancer. Oral Oncol 37(7):593–598.

Stables GJ, Subar AF, Patterson BH, et al. 2002. Changes in vegetable and fruit consumption and awareness among US adults: Results of the 1991 and 1997 5 A Day for Better Health Program surveys. J Am Dietetic Assoc 102(6):809–817.

Sturgis EM, Castillo EJ, Li L, et al. 1999. Polymorphisms of DNA repair gene XRCC1 in squamous cell carcinoma of the head and neck. Carcinogenesis 20(11):2125–2129.

Sturgis EM, Zheng R, Li L, et al. 2000. XPD/ERCC2 polymorphisms and risk of head and neck cancer: a case-control analysis. Carcinogenesis 21(12):2219–2223.

Sturgis EM, Dahlstrom KR, Guan Y, et al. 2001. Alcohol dehydrogenase 3 genotype is not associated with risk of squamous cell carcinoma of the oral cavity and pharynx. Cancer Epidemiol Biomarkers Prev 10(3):273–275.

Sturgis EM, Castillo EJ, Li L, et al. 2002. XPD/ERCC2 EXON 8 Polymorphisms: Rarity and lack of significance in risk of squamous cell carcinoma of the head and neck. Oral Oncol 38(5):475–477.

Sun EC, Curtis R, Melbye M, Goedert JJ. 1999. Salivary gland cancer in the United States. Cancer Epidemiol Biomarkers Prev 8(12):1095–1100.

Swan GE, Carmelli D, Cardon LR. 1997. Heavy consumption of cigarettes, alcohol and coffee in male twins. J Stud Alcohol 58(2):182–190.

Swango PA. 1996. Cancers of the oral cavity and pharynx in the United States: An epidemiologic overview. J Public Health Dent 56(6):309–318.

Swanson GM, Belle SH. 1982. Cancer morbidity among woodworkers in the U.S. automotive industry. J Occup Med 24(4):315–319.

Swanson GM, Burns PB. 1997. Cancers of the salivary gland: workplace risks among women and men. Ann Epidemiol 7(6):369–374.

Swerdlow AJ, Marmot MG, Grulich AE, Head J. 1995. Cancer mortality in Indian and British ethnic immigrants from the Indian subcontinent to England and Wales. Br J Cancer 72(5):1312–1319.

Szpak CA, Stone MJ, Frenkel EP. 1977. Some observations concerning the demographic and geographic incidence of carcinoma of the lip and buccal cavity. Cancer 40(1):343–348.

Takezaki T, Hirose K, Inoue M, et al. 1996. Tobacco, alcohol and dietary factors associated with the risk of oral cancer among Japanese. Japanese J Cancer Res 87(6):555–562.

Takezaki T, Shinoda M, Hatooka S, et al. 2000. Subsite-specific risk factors for hypopharyngeal and esophageal cancer (Japan). Cancer Causes Control 11(7):597–608.

Talamini R, Vaccarella S, Barbone F, et al. 2000. Oral hygiene, dentition, sexual habits and risk of oral cancer. Br J Cancer 83(9):1238–1242.

Tanimoto K, Hayashi S, Yoshiga K, Ichikawa T. 1999. Polymorphisms of the CYP1A1 and GSTM1 gene involved in oral squamous cell carcinoma in association with a cigarette dose. Oral Oncol 35(2):191–196.

Tassi E, Wellstein A. 2003. Angiogenesis, basic mechanisms, and role in head and neck squamous cell carcinoma. In: Head and Neck Cancer: Emerging Perspectives. JF Ensley, JS Gutkind, JR Jacobs, SM Lippman eds. New York: Academic Press, pp. 81–100.

Teppo L, Pukkala E, Saxen E. 1985. Multiple cancer—an epidemiologic exercise in Finland. J Natl Cancer Inst 75(2):207–217.

Tillonen J, Homann N, Rautio M, Jousimies-Somer H, Salaspuro M. 1999. Role of yeasts in the salivary acetaldehyde production from ethanol among risk groups for ethanol-associated oral cavity cancer. Alcohol Clin Exp Res 23(8):1409–1415.

Tischkowitz MD, Hodgson SV. 2003. Fanconi anaemia. J Med Genet 40(1):1–10.

Trivedy CR, Craig G, Warnakulasuriya S. 2002. The oral health consequences of chewing areca nut. Addict Biol 7(1):115–125.

U.S. DHHS. 2003. Those who continue to smoke. Is achieving abstinence harder and do we need to change our interventions? Smoking and Tobacco Control Monograph 15. Bethesda, MD: Public Health Service, National Institutes of Health, National Cancer Institute.

U.S. Preventive Services Task Force. 1996. Screening for Oral Cancer. In: Guide to Clinical Preventive Services, 2nd ed: National Library of Medicine.

Uzcudun AE, Retolaza IR, Fernandez PB, et al. 2002. Nutrition and pharyngeal cancer: Results from a case-control study in Spain. Head Neck 24(9):830–840.

van Zandwijk N, Dalesio O, Pastorino U, de Vries N, van Tinteren H. 2000. EUROSCAN, a randomized trial of vitamin A and N-acetylcysteine in patients with head and neck cancer or lung cancer. For the European Organization for Research and Treatment of Cancer Head and Neck and Lung Cancer Cooperative Groups. J Natl Cancer Inst 92(12):977–986.

Velly AM, Franco EL, Schlecht N, et al. 1998. Relationship between dental factors and risk of upper aerodigestive tract cancer. Oral Oncol 34(4):284–291.

Waldron CA, Shafer WG. 1975. Leukoplakia revisited. A clinicopathologic study 3256 oral leukoplakias. Cancer 36(4):1386–1392.

Wang LE, Sturgis EM, Eicher SA, Spitz MR, Hong WK, Wei Q. 1998. Mutagen sensitivity to benzo(a)pyrene diol epoxide and the risk of squamous cell carcinoma of the head and neck. Clin Cancer Res 4(7):1773–1778.

Warnakulasuriya KA, Johnson NW, Linklater KM, Bell J. 1999. Cancer of mouth, pharynx and nasopharynx in Asian and Chinese immigrants resident in Thames regions. Oral Oncol 35(5):471–475.

Warnakulasuriya S. 2002. Areca nut use following migration and its consequences. Addict Biol 7(1):127–132.

Wasnik KS, Ughade SN, Zodpey SP, Ingole DL. 1998. Tobacco consumption practices and risk of oro-pharyngeal cancer: A case-control study in Central India. Southeast Asian J Trop Med Public Health 29(4):827–834.

Wassberg C, Thorn M, Yuen J, Ringborg U, Hakulinen T. 1999. Second primary cancers in patients with squamous cell carcinoma of the skin: A population-based study in Sweden. Int J Cancer 80(4):511–515.

Waterhouse J, Muir C, Correa P, Powell J, eds. 1976. Cancer Incidence in Five Continents, Volume III. Lyon: IARC Scientific Publications No. 15.

Waterhouse J, Muir C, Shanmugaratnam K, Powell J, eds. 1982. Cancer Incidence in Five Continents, Volume IV. Lyon, France: International Agency for Research on Cancer. IARC Scientific Publications No. 42.

Weaver A, Fleming SM, Smith DB. 1979. Mouthwash and oral cancer: Carcinogen or coincidence? J Oral Surg 37(4):250–253.

Wei Q, Eicher SA, Guan Y, et al. 1998. Reduced expression of hMLH1 and hGTBP/hMSH6: A risk factor for head and neck cancer. Cancer Epidemiol Biomarkers Prev 7(4):309–314.

Weinstein SJ, Gridley G, Harty LC, et al. 2002. Folate intake, serum homocysteine and methylenetetrahydrofolate reductase (MTHFR) C677T genotype are not associated with oral cancer risk in Puerto Rico. J Nutr 132(4):762–767.

Whitaker CJ, Moss E, Lee WR, Cunliffe S. 1979. Oral and pharyngeal cancer in the North-west and West Yorkshire regions of England, and occupation. Br J Industrial Med 36(4):292–298.

Wight AJ, Ogden GR. 1998. Possible mechanisms by which alcohol may influence the development of oral cancer—a review. Oral Oncol 34(6):441–447.

Wigle DT, Mao Y, Grace M. 1980. Relative importance of smoking as a risk factor for selected cancers. Can J Public Health 71(4):269–275.

Williams RR, Horm JW. 1977. Association of cancer sites with tobacco and alcohol consumption and socioeconomic status of patients: Interview study from the Third National Cancer Survey. 58(3):525–547.

Winn DM, Blot WJ, Shy CM, Pickle LW, Toledo A, Fraumeni JF, Jr. 1981. Snuff dipping and oral cancer among women in the southern United States. N Engl J Med 304(13):745–749.

Winn DM, Blot WJ, Shy CM, Fraumeni JF, Jr. 1982. Occupation and oralcancer among women in the South. Am J Industrial Med 3(2):161–167.

Winn DM, Blot WJ. 1985. Second cancer following cancers of the buccal cavity and pharynx in Connecticut, 1935–1982. Natl Cancer Inst Monogr 68:25–48.

Winn DM, Blot WJ, McLaughlin JK, et al. 1991. Mouthwash use and oral conditions in the risk of oral and pharyngeal cancer. Cancer Res 51(11):3044–3047.

Winn DM, Diehl SR, Brown LM, et al. 2001. Mouthwash in the etiology of oral cancer in Puerto Rico. Cancer Causes Control 12(5):419–429.

World Cancer Research Fund/American Institute for Cancer Research. 1997. Food, Nutrition and the Prevention of Cancer: A Global Perspective. Washington, D.C.: American Institute for Cancer Research.

Wu X, Gu J, Hong WK, et al. 1998. Benzo[a]pyrene diol epoxide and bleomycin sensitivity and susceptibility to cancer of upper aerodigestive tract. J Natl Cancer Inst 90(18):1393–1399.

(p.696) Wu X, Lippman SM, Lee JJ, et al. 2002. Chromosome instability in lymphocytes: A potential indicator of predisposition to oral premalignant lesions. Cancer Res 62(10):2813–2818.

Wynder EL, Bross IJ, Feldman RM. 1957. A study of the etiological factors in cancer of the mouth. Cancer 10(6):1300–1323.

Wynder EL, Kabat G, Rosenberg S, Levenstein M. 1983. Oral cancer and mouthwash use. J Natl Cancer Inst 70(2):255–260.

Yang YH, Lee HY, Tung S, Shieh TY. 2001. Epidemiological survey of oral submucous fibrosis and leukoplakia in aborigines of Taiwan. J Oral Pathol Med 30(4):213–219.

Yu GP, Zhang ZF, Hsu TC, Spitz MR, Schantz SP. 1999. Family history of cancer, mutagen sensitivity, and increased risk of head and neck cancer. Cancer Lett 146(1):93–101.

Zain RB, Ikeda N, Razak IA, et al. 1997. A national epidemiological survey of oral mucosal lesions in Malaysia. Commun Dent Oral Epidemiol 25(5):377–383.

Zaridze DG, Blettner M, Trapeznikov NN, et al. 1985. Survey of a population with a high incidence of oral and oesophageal cancer. Int J Cancer 36(2):153–158.

Zaridze DG, Safaev RD, Belitsky GA, Brunnemann KD, Hoffmann D. 1991. Carcinogenic substances in Soviet tobacco products. IARC Sci Publ 105:485–488.

Zavras AI, Wu T, Laskaris G, et al. 2002. Interaction between a single nucleotide polymorphism in the alcohol dehydrogenase 3 gene, alcohol consumption and oral cancer risk. Int J Cancer 97(4):526–530.

Zhang Z-F, Morgenstern H, Spitz MR, et al. 1999. Marijuana use and increased risk of squamous cell carcinoma of the head and neck. Cancer Epidemiol Biomarkers Prev 8(12):1071–1078.

Zhang Z-F, Morgenstern H, Spitz MR, et al. 2000. Environmental tobacco smoking, mutagen sensitivity, and head and neck squamous cell carcinoma. Cancer Epidemiol Biomarkers Prev 9(10):1043–1049.

Zheng T, Boyle P, Willett WC, et al. 1993a. A case-control study of oral cancer in Beijing, People’s Republic of China. Associations with nutrient intakes, foods and food groups. Eur J Cancer B Oral Oncol 29B(1):45–55.

Zheng TZ, Boyle P, Hu HF, et al. 1990a. Dentition, oral hygiene, and risk of oral cancer: A case-control study in Beijing, People’s Republic of China. Cancer Causes Control 1(3):235–241.

Zheng TZ, Boyle P, Hu HF, et al. 1990b. Tobacco smoking, alcohol consumption, and risk of oral cancer: A case-control study in Beijing, People’s Republic of China. Cancer Causes Control 1(2):173–179.

Zheng W, Blot WJ, Diamond EL, et al. 1993b. Serum micronutrients and the subsequent risk of oral and pharyngeal cancer. Cancer Res 53(4):795–798.

Zheng W, Shu XO, Ji BT, Gao YT. 1996. Diet and other risk factors for cancer of the salivary glands: A population-based case-control study. Int J Cancer 67(2):194–198.

Zheng Y, Li L, Shen H, Sturgis EM, et al. 2001a. Polymorphic hCHK2/hCds1 codon 84 allele and risk of squamous cell carcinoma of the head and neck—a case-control analysis. Carcinogenesis 22(12):2005–2008.

Zheng Y, Shen H, Sturgis EM, et al. 2001b. Cyclin D1 polymorphism and risk for squamous cell carcinoma of the head and neck: A case-control study. Carcinogenesis 22(8):1195–1199.