1
Epidemiology and Etiology
BRUCE J. DAVIDSON, MD, FACS
INCIDENCE
Current Incidence Data
The global incidence of cancers of the oral cavity,
pharynx and larynx is about 500,000 cases per year
with mortality of 270,000 cases per year.1 Excluding
skin cancers, this represents about 6 percent of the
incidence and 5 percent of the mortality of all can-
cers.1 About three-fourths of these are cancers of the
oral cavity and pharynx and the remainder are laryn-
geal cancers. Figure 1–1 describes the incidence of
oral and pharyngeal cancers by world region. As
demonstrated here, the areas of the world with the
greatest incidence are Melanesia (Papua, New
Guinea and adjacent islands), Western Europe and
South Central Asia (India and the Central Asian
republics of the former Soviet Union).1
Figure 1–2 details the oral and pharyngeal cancer
mortality rates for selected countries. In 2001, oral,
pharyngeal and laryngeal cancers are expected to
occur in approximately 40,100 individuals in the
United States and result in death in 11,860.2 In
United States males, oral and pharyngeal cancer
comprise the seventh most common cancer and lar-
ynx cancer ranks fifteenth.2 In females, the incidence
of oral and pharyngeal cancers ranks fourteenth and
laryngeal cancer and anal cancer (2,000 each) share
the twenty-seventh and twenty-eighth positions.2
Trends Over Time
United States
Head and neck cancer incidence in the United States
has shown declines in the past 2 decades after pre-
vious increases. From 1940 to 1985, there was an
increase in laryngeal cancer incidence in men and
women reflecting the increase in cigarette use in this
century.3 Oral and pharyngeal cancer incidence was
stable in men and increased in women over this time
period.3 Between 1973 and 1997, a decrease in oral
and pharyngeal cancer and in laryngeal cancer
appeared.4 This decrease was primarily determined
by large rate decreases in men. During this same
period, females showed an increase in laryngeal can-
cer rates and no change in oral cancer.4 Most
recently, 1990s United States cancer registry data
shows a significant drop in the incidence rates of
oral cavity and pharyngeal cancers for both sexes.5
A steady drop in oral and pharyngeal cancer mortal-
ity has also been noted.6 Mortality trends differ by
race, which will be explored later in this chapter.
Europe
While United States’ rates (incidence and mortality)
for oral and pharyngeal cancer have recently been
falling, European mortality rates for these cancers
among males rose between 1983 and 1993.7 Laryn-
geal cancer mortality increased in Eastern Europe.7
Studies from individual European countries tend to
reflect a rising mortality from oral,8,9 pharyngeal,9,10
and laryngeal9,10 cancers from the early 1950s
through about 1980. One exception to this is a Swiss
study showing a decrease in laryngeal cancer mor-
tality in males, but an increase in females.11 More
recent studies, spanning the mid 1970s into the
1990s, show decreases in oral cancer mortality in
France12 and laryngeal cancer mortality in France,12
Italy,13 Switzerland,11 and Sweden.14 These reduc-
tions may be secondary to decreased cigarette con-
1
2 CANCER OF THE HEAD AND NECK

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

sumption or a change to less carcinogenic tobacco Variations in alcohol use may also explain some
products (eg, filtered cigarettes or less carcinogenic cancer incidence changes over time. A Scottish study
blond tobacco products). showed an increased incidence of oropharyngeal and

Figure 1–2. World map with death rates for oral and pharyngeal cancer in males indicated for selected
countries. Units are age-adjusted death rates per 100,000 population. Countries shown are: Canada (4.0),
United States (3.4), Chile (2.2), Norway (2.8), United Kingdom (3.0), France (12.0), Spain (7.0), Hungary
(18.5), Russian Federation (9.2), Israel (1.5), China (2.6), Japan (2.5), and Australia (4.4). Source docu-
ment does not include data from several high-incidence areas such as Melanesia, India and Brazil. (Data
from: Landis SH, Murray T, Bolden S, Wingo PA. Cancer statistics, 1998. CA Cancer J Clin 1998;48:6–29.)

hypopharyngeal cancers with stable incidence of
nasopharyngeal cancer between 1960 and 1989.15 As a
possible predictor of future trends, young adult males
(ages 20 to 44) have shown an increase in oral and pha-
ryngeal cancer mortality between the 1950s and the
late 1980s in a Swiss study16 as well as in studies across
Europe.17 Increased incidence and mortality rates from
hypopharyngeal cancers in individuals under 60 years
of age have also been shown since 1960 in an Austrian
study.18 These data are thought to be a reflection of
increased alcohol consumption over time.15
Former Soviet Union
A long-term study of cancer mortality in the former
Soviet Union showed an increase in oral, pharyngeal
and laryngeal cancer mortalities between 1965 and
1990.19 Estonia (former Eastern European Soviet
Union member) showed increased mortality rates for
cancers of the oral cavity, pharynx and larynx in men
and oral cavity and pharynx in women, between 1965
and 1989.20 Trends in the former Soviet Union and in
Eastern Europe appear to reflect continued high rates
of tobacco consumption. Figure 1–3 shows oral and
pharyngeal mortality rates for several countries in
Western Europe, Eastern Europe and the former
Figure 1–3. Death rates for oral and pharyngeal cancer in males indicated for Europe and
Russia. Units are age-adjusted death rates per 100,000 population. (Data from: Landis SH,
Murray T, Bolden S, Wingo PA. Cancer statistics, 1998. CA Cancer J Clin 1998;48:6–29.)
Epidemiology and Etiology 3
Soviet Union. From the figure, wide variations in
mortality are indicated.
Asia
Japanese males showed an increase in oral and pha-
ryngeal cancers mortality between 1950 and 1994,
although no change was seen in females. Analysis
specified by tumor site showed a decrease in oral
tongue and tongue-base cancer mortality, with
increases in mortality from other oral and oropha-
ryngeal sites. It was suggested that these changes
were reflective of increased tobacco consumption
for pharyngeal cancers, increased alcohol consump-
tion for oral cancers and were unrelated to tobacco
or alcohol for tongue cancers.21
The incidence of head and neck cancer in India is
variable, with some areas showing rates of cancer
among the highest in the world and other areas with
rates comparable to the United States. Oral and pha-
ryngeal cancers are highest in the area of Ahmedabad
in West India. Between the 1960s and 1980s, a drop in
head and neck cancer incidence was seen across India.
This decrease has been attributed to decreased con-
sumption of oral tobacco and an increase in cigarette
and bidi (tobacco rolled in a tendu leaf) smoking.22
4 CANCER OF THE HEAD AND NECK

EPIDEMIOLOGY (all 10–15/100,000).4 The rates for females were

Geographic Variation
Incidence and Tumor Site Differences
As indicated in Figure 1–1, the incidence of head
and neck cancer varies throughout the world. For
instance, mouth cancers are 45 times more common
in certain areas of France than in The Gambia.4 The
Basque region of Spain has an incidence of laryn-
geal carcinoma (20/100,000) that is about 200 times
greater than the incidence of laryngeal cancer in
Qidong, China (0.1/100,000).4
Mortality also differs throughout the world. Mor-
tality differences are influenced by incidence of dis-
ease as well as survival rates after diagnosis. The 5-
year survival rate for cancers of the oral cavity and
pharynx is 46 percent worldwide, but differs
between developed (59%) and developing (39%)
countries. The larynx cancer 5-year survival rate is
46 percent with similar differences between devel-
oped (51%) and developing (41%) countries.1
Table 1–1 lists the countries with the highest
rates of oral and pharyngeal cancer mortality over
two periods in the past 20 years. Unfortunately, the
source documents fail to report mortality data on
several high-incidence areas such as India, Melane-
sia and Brazil. In the mid 1980s, the highest rates of
oral and pharyngeal cancer mortality for males were
seen in Hong Kong, France, Singapore and Hungary
highest in Singapore, Hong Kong, and Kuwait
(2–5/100,000).4 In the more recent period, four of
the five countries with the highest mortality in males
are in Eastern Europe.117 Hungary has shown a rise
in mortality rates from 12.5 to 18.5 in less than a
decade. In females, two of the top five are in Eastern
Europe and the other three are in the Central Asian
republics of the former Soviet Union.117 The com-
parison between 1986 to 1988 and 1992 to 1995
shows the effect of geopolitical changes on cancer
statistics with several newly independent countries
reporting high mortality rates from these cancers.
Race
Significant racial differences are seen in cancer
demographics in the United States. According to
SEER statistics from 1973 to 1997, the incidence of
oral and pharyngeal cancer was shown to be higher
in blacks than in whites from 1975 onward. Simi-
larly, the incidence of laryngeal cancer has been
higher in blacks since 1973.118 While oral/
pharyngeal cancer is the sixth most common cancer
in the United States, this represents the fourth most
common cancer in blacks.119 An exploration of this
observation has found that most of the increased inci-
dence in blacks can be attributed to higher tobacco
and alcohol consumption among this group. Control-
ling for these exposures results in almost equivalent
risk of oral and pharyngeal cancers by race.120

Table 1–1. COUNTRIES WITH THE HIGHEST MORTALITY RATES FOR ORAL AND PHARYNGEAL CANCER
(AGE-ADJUSTED DEATH RATES / 100,000)

1986–1988 1992–1995

Male Female Male Female

Country Rate Country Rate Country Rate Country Rate

Hong Kong 14.8 Singapore 4.8 Hungary 18.5 Hungary 2.4

France 14.3 Hong Kong 4.8 France 12 Kazakhstan 1.9
Singapore 12.8 Kuwait 2.4 Croatia 11.7 Turkmenistan 1.7
Hungary 12.5 Cuba 1.8 Slovenia 11.2 Albania 1.6
Puerto Rico 9 Malta 1.7 Romania 11.1 Uzbekistan 1.5
Czechoslovakia 8.2 Panama 1.7 Ukraine 9.6 Denmark 1.4
Luxembourg 7.6 Hungary 1.6 Russian Federation 9.2 France 1.3
Uruguay 6.9 Australia 1.4 Estonia 9 Australia 1.3
Soviet Union 6.6 Denmark 1.4 Belarus 8.8 United States 1.2
Switzerland 6.5 Venezuela 1.4 Lithuania 8.3 Canada 1.2

Adapted from Ries LAG. Rates. In: Harras A, editor. Cancer: Rates and risks. Washington, DC, National Institutes of Health; 1996. p.9–55. and from Li FP,
Correa P, Fraumeni JF. Testing for germ line p53 mutations in cancer families. Cancer Epidemiol Biomarkers Prev 1991;1:91–4.

Trends in oral and pharyngeal cancer and laryn-
geal cancer incidence are favorable when evaluated
by race. For oral and pharyngeal cancers, the trend
in cancer incidence is downward since about 1984 in
whites and since 1980 in blacks. For laryngeal can-
cer the negative trend began in 1988 in whites and
1990 in blacks.118
Mortality rates are also significantly higher for
blacks than for whites for both oral/pharyngeal and
laryngeal cancers. For both types of cancer, between
1973 and 1997, mortality was higher in blacks every
year, and from 1993 to 1997, mortality rates in
blacks were approximately double that seen in
whites. Oral and pharyngeal cancer mortality has
been trending downward since 1973 for whites, but
for blacks, mortality rates rose from 1973 to 1980
and since then have been falling. For laryngeal can-
cer, mortality has also fallen since 1973 in whites,
but rose in blacks from 1973 to 1992. Mortality rates
in blacks have more recently been trending down-
ward (trend not statistically significant).118
The differences in oral and pharyngeal cancer
mortality between African Americans and Cau-
casians have been attributed in part to differences in
survival rates. Five-year survival rates for these can-
cers from 1989 to 1996 were 56 percent for Cau-
casians and 35 percent for African Americans.118
Data shows that African Americans are more likely
to be diagnosed at a higher tumor stage, but that
even after adjustment for stage, the mortality is
greater in African Americans (see Figure 1–8).2
Access to health care may play a role as 21 percent
of African American adults lack a health care plan
while only 13 percent of Caucasians are without
coverage.119 Racial differences in prevention appear
to exist, in that a higher proportion of African
Americans over Caucasians continue to smoke—34
percent versus 28 percent respectively.119
Gender
Gender differences in head and neck cancer incidence
and mortality appear to reflect differences in risk fac-
tor exposure. The rise in tobacco consumption by
women since the 1950s has resulted in an increased
proportion of female cancer incidence and mortality
for these cancers. A study from Houston compared the
Epidemiology and Etiology 5
male-to-female ratio of laryngeal cancer over two peri-
ods in the past four decades. The proportion of male-
to-female cases dropped from 5.6:1 to 4.5:1 between
the periods 1959 to 1973 and 1974 to 1988.121 Other
studies have reflected similar trends.122,123 Significant
differences in the site of laryngeal cancer development
has been suggested, with a ratio of glottic to supra-
glottic sites of 22.1:1 in men and 0.6:1 in women.124
Among nonsmokers who develop oral and pha-
ryngeal cancer, a higher proportion of women than
men is seen in patients over the age of 50.29 Analyz-
ing oral cancers by site relative to gender reveals that
the ratio of males to females is highest for floor-of-
mouth cancers (ratio=3.4:1), and lowest for gingival
cancers (ratio=0.5:1).125
SEER data suggests a downward trend for oral and
pharyngeal cancer incidence for both males and
females since the early 1980s. Mortality has also been
declining for both males and females since 1979. For
laryngeal cancer, incidence has declined since the
mid to late 1980s for both males and females. Mor-
tality has been falling since 1973 for males, but rose
until 1992 in females. Recently a downward trend in
laryngeal cancer mortality rate (not statistically sig-
nificant) has been seen in females.118
ETIOLOGY
It has been estimated that in the United States, well
over three-fourths of all head and neck cancers can
be attributed to tobacco and alcohol use.23 This sec-
tion will explore these risk factors for head and neck
squamous cell carcinoma and will describe other fac-
tors that may play a role in the etiology of these can-
cers. As with most cancers, age itself may be a risk
factor for the development of head and neck cancer.
In nonsmokers and nondrinkers, the average age of
onset of laryngeal cancer is about 10 years later than
in patients with a history of tobacco or alcohol use.24
Tobacco
Cigarettes
Cigarette smoking is the single most important risk
factor in head and neck cancer. For oral cancers in
men, 90 percent of cancer risk can be attributed to
6 CANCER OF THE HEAD AND NECK
tobacco. The attributable risk of tobacco for oral can-
cer development is lower in females at 59 percent.4
The smoking attributable risk for laryngeal cancer in
males and females is more similar at 79 and 87 per-
cent respectively.4 The relative risk of laryngeal can-
cer between smokers and nonsmokers is 15.5 in men
and 12.4 in women.14 In support of the association
between tobacco and head and neck cancer is infor-
mation associating cigarette consumption with oral
dysplasia (Odds Ratio [OR] = 4.1), a premalignant
oral lesion.25
Discontinuation of smoking reduces the risk of
head and neck premalignant and malignant lesions.
Smoking cessation results in a decreased risk of
oral dysplasia that reaches that of “never-smokers”
after 15 years.25 The risk of oral cancer has been
suggested to be reduced by 30 percent for those
who have discontinued tobacco for 1 to 9 years and
by 50 percent for those who have abstained for over
9 years.26 No excess risk of oral and pharyngeal
cancer has been shown among individuals who
have abstained for over 10 years.23,27 These results
emphasize the importance of smoking cessation
efforts.
Tobacco contains over thirty known carcinogens.
The majority of these are polycyclic aromatic hydro-
carbons and nitrosamines.28 Increasing tar consump-
tion has been associated with oral and pharyngeal
cancer in a dose-dependent manner. Interestingly,
when this is evaluated by gender, the risks of cancer
associated with tar exposure increase more sharply
for women than men.29 Specific tobacco use habits
appear to alter the risk of head and neck cancer.
Exclusive use of filtered cigarettes is protective when
compared to unfiltered cigarette use.27,30 Inhalation
increases the risk of cancer of the endolarynx,
although it does not alter the risk of hypopharyngeal
or epilaryngeal (suprahyoid epiglottis and aryepiglot-
tic folds) cancer.31
Cigars, Pipe Smoking
An increased risk of incidence for cancers of the
oral cavity, pharynx and larynx has been shown for
pipe and cigar smokers.28 Risk of cancer from pipe
smoking tends to be higher for oral cavity sites than
pharyngeal or laryngeal sites.32 Mashberg found
that cigar or pipe smoking without a history of cig-
arette smoking was associated with a relative risk of
oral and pharyngeal cancer of 3.3. When mixed
exposures (ie, pipe and cigarette or cigar and ciga-
rette) were analyzed, the relative risk of oral and
pharyngeal cancer was 2.6 for cigar smokers and
3.2 for pipe smokers.27
Smokeless Tobacco
Smokeless tobacco use has gained popularity in the
United States over the past 25 years. The habit was
traditionally practiced by women in the rural south
as an alternative to cigarette smoking. In this popu-
lation, a four- to six-fold increase in risk of oral can-
cer has been shown.23,33 Cancers are typically well-
differentiated and occur on the alveolar ridge or
buccal mucosa.34 Snuff-related oral cancer appears
to require prolonged exposure. Patients developing
oral cancers who have a history of snuff use without
other risk factors typically are in their 60s and have
been using oral tobacco for 40 years.34
Recent attempts to define the risk of oral can-
cer related to this increasingly popular practice has
been difficult. The state with the highest per capita
consumption of smokeless tobacco, West Virginia,
has not shown an increased incidence of or mor-
tality from oral or pharyngeal cancer when com-
pared with national averages.35 These results are
possibly reflective of the low prevalence of alcohol
abuse in West Virginia. In addition, a Swedish
case-control study showed no increased risk for
oral cancer in current or former snuff users.36
These results may be a reflection of the prolonged
exposure to oral tobacco required for the develop-
ment of oral cancer.
Types of Tobacco
Two major types of tobacco exist. Black or dark (air-
cured) tobacco is used in the manufacture of cigars,
pipe-blends and certain cigarettes. Blond (flue-
cured) tobacco is used more commonly for ciga-
rettes. A major difference in these two tobacco types
is that the alkalinity of black tobacco causes it to be
irritating to the respiratory mucosa. Deep inhalation
is less well-tolerated than with blond tobacco prod-

ucts. For this reason, it is theorized that black
tobacco products might exert a greater effect on the
upper aerodigestive mucosa while blond products
have a greater effect on the lower respiratory
mucosa. This is supported by data showing a greater
risk of larynx cancer than lung cancer in persons
using black tobacco products.32
Experimental studies have shown the extract of
black tobacco cigarettes to be more carcinogenic
than blond tobacco cigarettes.37 As a reflection of
this, epidemiologic studies have shown that the
type of tobacco consumed is associated with the
risk of aerodigestive tract cancer. Dark (air-cured)
tobacco use was associated with a 59-fold
increased risk of laryngeal cancer while blond
(flue-cured) tobacco was associated with a 25-fold
risk.38 After control for socioeconomic factors,
alcohol consumption, length of smoking exposure,
and filter use, the user of black tobacco cigarettes
has a threefold relative risk of oral cavity and pha-
ryngeal cancer when compared with the user of
blond tobacco cigarettes.39
When studies compare the use of blond tobacco
only, with black tobacco only, with mixed expo-
sures, a dose-response effect is demonstrated. A
multi-institutional case-control study from Europe
showed such an effect with an increased relative
risk of cancer of the endolarynx, epilarynx and
hypopharynx associated with increasing use of
black tobacco relative to blond tobacco.31 Analo-
gous data from Thailand has shown that certain
Thai tobacco preparations, specifically the more
alkaline and less easily inhaled varieties, are associ-
ated with an increased risk of laryngeal cancer over
other Thai preparations.40
The difference in popularity of black and blond
tobacco cigarettes is likely to influence the geo-
graphic variations in laryngeal cancer incidence and
subsite distribution throughout the world (Figure
1–4, A and B). Countries with the highest death rates
from laryngeal cancer are France, Uruguay, Spain
and Italy. Each of these countries, along with Cuba,
Argentina, Brazil, Columbia and Greece has a rela-
tively high prevalence of black tobacco cigarette
consumption. Several of these countries also show a
greater prevalence of supraglottic cancers than glot-
tic cancers.38 This is in contrast to the United States
Epidemiology and Etiology 7
where blond tobacco cigarettes are typical and
laryngeal glottic cancer is more common.
Alcohol
Head and neck squamous cell carcinoma is a disease
occurring most often in individuals with heavy
tobacco and alcohol use. Tobacco has gained the
majority of attention in terms of public health edu-
cation and many lay persons are unaware of the
association of alcohol with upper aerodigestive
squamous cell carcinoma. The cancer risk associated
with alcohol consumption varies among upper
aerodigestive tract sites.
The association between alcohol and head and
neck cancer is stronger for pharyngeal cancer than
for other head and neck sites. A dose-response effect
has been shown between alcohol and pharyngeal
cancer in a German study. After adjustment for
tobacco consumption, the relative risk of pharyngeal
cancer is seen to rise progressively from 1.0 for
those consuming < 25 g/day (> 2 drinks) to 125 for
those consuming > 100 g/day (> 7 drinks).41 High
alcohol consumption (> 100 g/day) represents less
of a risk for oral cancers (RR=11)42 and laryngeal
cancers (RR=15) (unpublished data described in41).
Figure 1–5 describes the difference in relative risk of
cancer for several head and neck sites when com-
pared to various levels of alcohol consumption.43
These data support a strong association between
alcohol use and pharyngeal cancer.
This variation in the risk of alcohol on the devel-
opment of head and neck cancer has also been
shown to differ for subsites of the larynx. Patients
with glottic cancer are more likely than those with
supraglottic cancer to be nondrinkers.43 When com-
parison is made between drinkers and nondrinkers,
the nondrinkers more often develop glottic cancer
than supraglottic cancer. By comparison, the distri-
bution is about equal for drinkers. Similarly, the
association between alcohol and cancer varies
between oral cavity sites, with a higher risk of buc-
cal cancer than floor-of-mouth cancer in the non-
drinkers and a higher risk of lateral tongue cancer
than other tongue cancers in the nondrinkers. In
drinkers, lateral tongue cancer is less common than
other tongue cancers (includes base of tongue), and
8 CANCER OF THE HEAD AND NECK
floor-of-mouth cancer is twice as common as buc-
cal mucosa cancer.43
Multiplicative Effect of Alcohol and Tobacco
The synergistic effects of tobacco and alcohol have
been shown in head and neck cancer in multiple stud-
ies.38,44–46 Figure 1–6 shows data from a multicenter
case-control study for oral and pharyngeal cancers in
the United States. The combined use of tobacco and
alcohol increases the risk of laryngeal cancer by about
50 percent over the estimated risk if these factors are
B
Figure 1–4. A, Worldwide incidence of supraglottic cancer. B, Worldwide incidence
of glottic cancer.
considered using an additive risk model.47 Other stud-
ies have also supported a synergistic effect of tobacco
and alcohol on head and neck cancer risk.38,44
Types of Alcohol and Risk
There are significant differences of content between
various alcoholic beverages. Beer contains the car-
cinogen nitrosodimethylamine, while distilled wines
have a high content of tannin, another carcinogen.
When comparing various hard liquors, dark liquors
(eg, whiskey, dark rum, cognac) contain greater
 Epidemiology and Etiology 9

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

amounts of organic compounds than light liquors
(eg, vodka, gin, light rum). These include higher
alcohols, esters and acetaldehyde.48 The risk of
laryngeal and hypopharyngeal cancers is increased
with dark liquor intake when compared with light
liquor intake. The risk is greater for hypopharyngeal
cancer than for laryngeal cancers.48
The relationship between type of liquor consumed
and cancer risk has not been consistent. Mashberg
reported on a series of oral cavity cancers and found

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

that after controlling for total alcohol consumption,
beer and wine intake were more strongly associated
with oral cancer risk than was whiskey consump-
tion.49 On the other hand, Blot showed increased risk
of oral and pharyngeal cancer for beer and whiskey
intake, but no excess risk for wine consumption.23
The type of alcohol consumed may influence the
site of aerodigestive cancer development. A study
from the Institut Curie in France attempted to evaluate
these differences, but was limited by the fact that > 90
percent of patients were wine drinkers, and the major-
ity drank other liquors as well.43 However, tongue can-
cer was associated with wine drinking while supra-
glottic cancer was associated with aniseed liquor
consumption.
The synergistic effect of tobacco and alcohol
consumption has been shown to vary with the type
of tobacco used as well as the type of alcohol. Upon
comparing the level of consumption of blond and
black tobacco as well as the level of wine intake ver-
sus spirits, heavy use of black tobacco and heavy
wine consumption showed the greatest synergistic
effect. Blond tobacco and spirit consumption
showed a lesser, but still considerable synergistic
effect (Figure 1–7).50
Alcohol and Carcinogenesis
The mechanisms by which alcohol use contributes to
the risk of head and neck cancer is not clearly
defined, while systemic and local effects have been
proposed. While alcohol itself is not a known car-
cinogen, it may act as a solvent, allowing increased
cellular permeability of other carcinogens through
mucosa of the upper aerodigestive tract. As noted
above, the non-alcohol constituents of various alco-
holic beverages may have carcinogenic activities.48
As summarized in Maier,41 chronic alcohol use
may upregulate enzymes of the cytochrome P-450
system. This enzyme system can contribute to acti-
vation of procarcinogens to carcinogens. This up-
regulation may be critical to activation of many car-
cinogens, as the vast majority of environmental
carcinogens exist in their procarcinogenic form.
Alcohol has also been shown to decrease the activ-
ity of DNA-repair enzymes, and increased chromo-
somal damage has been documented in chronic alco-
hol users. Other possible effects of alcohol include
impaired immunity resulting from a reduction in T
cell number, decreased mitogenic activity and/or
reduced macrophage activity.

Figure 1–7. Graph demonstrating the odds ratio for exposure to alcohol and tobacco exposure
in pharyngeal and laryngeal cancer patients. Odds ratio highest with heavy wine and black
tobacco consumption. (Data from: Sancho-Garnier H, Theobald S. Black (air-cured) tobacco and
blond (flue-cured) tobacco and cancer risk II: Pharynx and larynx cancer. Eur J Cancer 1993;
29A:273–6.).

The greater significance of the solvent activity of
alcohol, as opposed to its systemic effect, is supported
by data comparing dark and light liquor intake and the
risk of hypopharyngeal cancer. Only dark liquor con-
sumption was related to the risk of hypopharyngeal
cancer. After controlling for total alcohol use and
tobacco use, heavy dark liquor consumption was
associated with an increased risk of cancer while no
such risk was seen with light liquor intake.48 These
data argue against a systemic effect of alcohol on
hypopharyngeal cancer risk and instead argue for the
solvent effect of alcohol along with the carcinogenic-
ity of the nonalcoholic components of dark liquors.
Injury to mucosa of the upper aerodigestive tract
may relate to a toxic metabolite of alcohol,
acetaldehyde. The enzyme aldehyde dehydroge-
nase-2 (ALDH-2) is a strong determinant of blood
acetaldehyde concentration following alcohol
ingestion. A small group of Japanese patients was
studied, and those with an inactive ALDH-2 pheno-
type more often had multiple primary esophageal
cancers (77%) versus those with an active ALDH-2
phenotype (31%).51
Other Carcinogens
Betel Quid
In India and parts of Asia, oral tobacco is commonly
consumed in a preparation known as “pan,” which
combines tobacco with betel leaf, slaked lime and
areca nut. These betel quid are associated with the
risk of oral cancer. Oral cancer risk increases in a
dose-dependent manner when classified by years of
betel quid use and by numbers of betel quid per
day.52 Like the relationship between tobacco and
alcohol exposure, the use of betel quid has been
shown to act synergistically with tobacco and alco-
hol to promote oral cancer.53
Maté
Maté is a hot drink made from the herb Ilex
paraguariensis and is commonly consumed in South
America. It has been associated with an increased
risk of cancer of the esophagus and larynx. It has
been estimated that up to 20 percent of head and neck
Epidemiology and Etiology 11
squamous cell carcinoma in southern South America
may be linked to maté ingestion.54 The odds ratio for
maté ingestion has been reported as 3.0 for glottic
cancer and 3.3 for cancer of the supraglottis.38 Oth-
ers have demonstrated a significant association with
oral cancers.54 Maté consumption is more strongly
associated with the risk of laryngeal cancer in
patients with a history of heavy tobacco or alcohol
use. Maté itself has not been shown to be carcino-
genic but, similar to alcohol, may act as a solvent for
other carcinogens or as a promoter.38
Dental Considerations
Hygiene
Poor oral hygiene is associated with oral cancer, but
no causal relationship has been established. A case-
control study of patients with upper aerodigestive
tract squamous cell carcinoma matched 100 patients
with 214 age- and sex-matched controls and found
significantly worse oral hygiene and dental status in
the tumor patients. Chronic inflammation of the gin-
giva was more often seen in the cancer patients.55
Similarly, oral cancers have been significantly asso-
ciated with a history of chronic oral infections
(OR = 3.8).56
Other studies have also supported the relationship
between poor oral hygiene and increased risk of oral
cancer.57 Less-than-daily brushing has been associ-
ated with an approximate twofold increased risk of
tongue and other oral cancers in a Brazilian popula-
tion,58 but no association was seen in a United States
study.59 The absence of multiple teeth may represent
a surrogate marker of dental hygiene and has been
associated with oral cancer in multiple studies.60,61
However, a history of multiple broken teeth has not
been associated with oral cancer risk.59,62
The frequent use of mouthwash has been dis-
couraged due to the fact that several preparations
contain ethanol. The association between mouth-
wash use and risk of oral or pharyngeal cancer has
been the subject of previous studies with mixed
results.59,63,64 When controlled for total tobacco and
alcohol intake, users of alcohol-containing mouth-
washes appear to be at increased risk.64 Women,
especially those who are not tobacco users, appear to
12 CANCER OF THE HEAD AND NECK
be most consistently associated with this risk fac-
tor.65 However, it is possible that the cancer risk of
mouthwash use may be confounded by other unmea-
sured factors. In one study of oral cancer in women,
the reasons for mouthwash use were explored. While
mouthwash use per se was not associated with a risk
of cancer in this particular study, the use to “disguise
the smell of tobacco” or “disguise the smell of alco-
hol” was seen more commonly in cancer cases.60
Dentures
A large Brazilian case-control study has demon-
strated an association between oral sores from loose-
fitting dentures and risk of oral cancer. 58 Painful or
ill-fitting dentures have also been associated with
oral or oropharyngeal cancer in a study from Wis-
consin.59 However, in these and other studies, long-
term use of dentures has not been shown to increase
the risk of oral cancers.62,66,67 These results and those
relating hygiene to oral cancer may describe the role
of chronic inflammation as a risk for oral cancer.
Occupational Exposure
Occupational risks for head and neck squamous cell
cancer development have been suggested in epi-
demiologic data. Wood dust exposure is associated
with the risk of oral cancer68 as well as pharyngeal
and laryngeal cancer.69 Other occupations associated
with increased risk of head and neck squamous cell
carcinoma include machinists70–72 and automobile
mechanics.70 Occupations which involve exposure
to organic chemicals, coal products, cement, and
paint, laquer or varnish are also associated with
increased risk of head and neck cancer.69 A risk of
cancer of the upper aerodigestive tract has also been
shown in cases of long-term exposure to high con-
centrations of sulfuric or hydrochloric acid as found
in battery plant workers.73 While it has been sug-
gested that an increased risk of oral and pharyngeal
cancer is seen in bartenders,27 no excess risk has
been found when analysis includes adjustment for
alcohol and tobacco consumption.74
Premalignant laryngeal lesions have also been
associated with occupational exposures, with a rela-
tive risk of 10 for laryngeal dysplasia for blue-collar
compared with white-collar workers even after con-
trolling for tobacco use.75 Laryngeal cancers have
been associated with nickel and mustard gas expo-
sure.4 An association between asbestos exposure and
laryngeal cancer has been suggested, but contradic-
tory results have been reported.4,71,76,77
Social and Economic Factors
Associations between oral, pharyngeal and laryngeal
cancers and marital status (cancer patients more
often unmarried or divorced) and educational status
(cancer patient less often with college education)
have been described.78 However, a study in the
United States failed to show any relationship
between oropharyngeal cancer and education or
occupational status. This United States study did
show an inverse relationship between the percentage
of potential working life spent in employment and
the risk of cancer.79 While this study attempted to
adjust for tobacco and alcohol consumption, alcohol
consumption may confound the employment mea-
sure used. Regularity and consistency of employment
may be reduced by excessive alcohol use which, in
turn, contributes to cancer risk.
Infections
Human Papillomavirus
Evidence of human papillomavirus (HPV) genetic
material has been identified in a proportion of head
and neck squamous cell cancers.80 Verrucous carcino-
mas have the squamous histology with the strongest
association with HPV, as HPV genomic material is
found in 30 to 100 percent of these tumors.80 For squa-
mous cell cancers in general, the proportion of cancers
with evidence of HPV genomic material appears to
vary, depending upon the upper aerodigestive tract site
analyzed. As reviewed and compiled by Steinberg,80
the tumor site most often revealing HPV infection is
tonsil (74%), with lesser evidence of HPV in larynx
(30%), tongue (22%), nasopharynx (21%) and floor-
of-mouth (5%) carcinomas. The role of HPV in these
cancers is confounded by the fact that HPV genomic
material may also be found in normal head and neck
mucosa in up to 64 percent of samples.80,81
Cofactors for HPV induction of oral cancers have
been investigated in a handful of studies. Tobacco
 Epidemiology and Etiology 13

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

and alcohol habits have not been associated with the
likelihood of detecting HPV in tumor tissue.82 How-
ever, use of betel quid has been associated with HPV
detection in 9 of 11 (82%) cases of tongue cancer.83
Human Immunodeficiency Virus
Human immunodeficiency virus (HIV) has shown
an emerging association with head and neck squa-
mous cell carcinoma. In a recent study from New
York, HIV infection was present in almost 5 percent
of patients with head and neck cancer.84 Patients
with HIV were younger than non-HIV patients and
HIV infection was present in over 20 percent of
head and neck cancer patients who were under 45
year of age. The site of tumor presentation did not
vary with respect to HIV status, but tumors were
larger and more advanced in the HIV group. As in
most cases of head and neck squamous cell carci-
noma, a history of tobacco and alcohol use is preva-
lent in the HIV population.85
Herpes Simplex Virus
Herpes simplex virus (HSV) has been associated
with cancer of the oral cavity. In a study utilizing
patient questionnaires for data collection, a history
of proven HSV-1 infections was associated with oral
cancer (OR=1.9). A stronger association was seen
with a history of a suspected HSV-1 infection
(OR=3.3).56 While this study raises concerns about
reporting bias, support for this association is pro-
vided by a finding of HSV type 1 protein in 42 per-
cent of patients with oral cancer and no positive
results in control patients.86
Epstein-Barr Virus
Epstein-Barr virus (EBV) has been associated with
nasopharyngeal carcinoma. The association appears
strongest with World Health Organization (WHO)
types II and III while a minority of WHO type I car-
cinomas have revealed EBV.87 Type I tumors make up
one-third of cancers in non-endemic populations.
The presence of EBV DNA in upper aerodigestive
mucosa samples seems to vary geographically. An 81
percent prevalence has been found in Greenland
Eskimos, a population with a high incidence of
undifferentiated nasopharyngeal cancer. Among the
Danish population, the prevalence is only 35 per-
cent.88 Despite the fact that over 90 percent of the
world’s population shows serologic evidence of prior
EBV infection, evidence of persistent EBV DNA
was seen in less than 1 percent of normal upper
aerodigestive mucosa samples in a large North
American series.89 These results suggest that an EBV
14 CANCER OF THE HEAD AND NECK
chronic carrier state exists in endemic populations.
However, the detection of EBV in nasopharyngeal
samples is not a specific enough assessment to
require nasopharyngeal cancer screening.88
Inflammatory
Gastroesophageal Reflux Disease
Chronic irritation from gastric reflux into the phar-
ynx and larynx has been suggested to be a risk fac-
tor for cancers of these sites.90,91 The presence of
reflux has been documented by 24-hour pH probe
study in 36 to 54 percent of patients with laryngeal
and pharyngeal carcinomas.92,93 While this preva-
lence is significant, it is not dissimilar to the preva-
lence in patients undergoing pH probe study for
nonmalignant conditions.93 While causation has
been difficult to establish, previous case series have
described the development of laryngeal and pharyn-
geal cancers in nonsmoking and nondrinking
patients with documented reflux.90,91
Nutritional Considerations
Diet and Cancer Risk
Several studies have repeatedly associated high fruit
and vegetable intake with a decreased risk of head and
neck squamous cell carcinoma.38,94–98 The association
between fruit and vegetable consumption and a
reduced cancer risk may reflect increased intake of
such micronutrients as vitamins C and E and beta
carotene. In a nested case-control study correlating
serum micronutrient levels to later risk of developing
upper aerodigestive tract carcinoma (up to 20 years
after serum collection), an association between low
alpha and beta carotene levels and subsequent devel-
opment of cancer was shown.99 When other elemental
dietary components are compared to head and neck
and esophageal cancer risk, an association with pro-
tein intake and an inverse association with vitamin C
and flavonoid intake is shown.100 Other studies have
shown that increased iron and zinc intake are associ-
ated with a reduced risk of laryngeal or esophageal
cancers.101 Significant reduction in risk of oral, pha-
ryngeal and esophageal cancers has been associated
with high intake of tomatoes, an important source of
vitamin C in some parts of the world.102,103
Other studies have suggested an increased risk of
head and neck squamous cell cancer with red meat
intake.94,104 Salted meat intake has been associated
with oropharyngeal cancer risk,105 and processed
meat consumption associated with oral and oropha-
ryngeal cancer.94 On the other hand, a multi-institu-
tional European study showed an inverse association
between preserved meat intake and risk of laryngeal
and hypopharyngeal cancers.96
Heavy tobacco use appears to double the risk
associated with low fruit consumption.38 On the
other hand, a high intake of vegetables and fish has
been shown to modify the risk of aerodigestive tract
cancer in smokers.106 It has been estimated that
among smokers/drinkers, the low intake of fruits and
vegetables may contribute to between 25 and 50 per-
cent of laryngeal cancers.107
GENETIC AND IMMUNOLOGIC
PREDISPOSITION
The strong influence of tobacco and alcohol on the
development of cancers of the upper aerodigestive
tract obscure underlying genetic predispositions that
may exist. However, a subset of patients may have
factors that increase their cancer susceptibility. The
Li-Fraumeni syndrome, inherited as an autosomal
dominant trait, involves mutation of one allele of the
p53 tumor suppressor gene. This has been associated
with head and neck cancer in some patients with min-
imal tobacco exposure, and may indicate increased
susceptibility to environmental carcinogens in these
patients.108 Fanconi’s anemia, Bloom syndrome and
ataxia-telangiectasia are autosomal recessive disor-
ders that are associated with increased chromosomal
fragility and cancer susceptibility. Patients with head
and neck squamous cell carcinoma have been
reported to be diagnosed with each syndrome.109–111
Patients previously treated with bone marrow and
organ transplantation appear to have an increased
risk of skin and oral cavity squamous cell carcinoma.
The risk of oral cancer is well under 5 percent in
long-term bone marrow transplant recipients.112 The
risk may be associated with chronic graft versus host
disease and long-term use of immunosuppressive
medications.112 Viral etiologies have been suggested,
but a clear cause has not yet been demonstrated.113

Field Cancerization
While the etiologic factors described above may
allow one to make an estimation of head and neck
cancer risk, one of the strongest predictors of cancer
risk is a history of previous head and neck cancer.
Patients with head and neck squamous cell carcino-
mas have long been shown to have an increased risk
of multiple aerodigestive tract tumors. When fol-
lowed over time, patients previously treated for these
cancers have a risk of developing second cancers of
the head and neck, esophagus, and lung that approx-
imates 4 percent per year.114 The risk does not
appear to taper off with long-term follow-up.114
The risk of second cancers appears to relate to
tobacco and alcohol exposure.115 Long-term expo-
sure to these carcinogens appears to place large
areas of aerodigestive tract mucosa at increased risk
for carcinogenesis. This condemned mucosa may be
grossly and histologically normal, yet may harbor
detectable abnormalities in tumor suppressor genes
such as p53.116
CONCLUSION
The epidemiology of head and neck squamous cell
carcinoma has changed considerably in this century.
Risk factors appear to explain most of the geo-
graphic, racial and gender variations seen as well as
incidence changes over time. Accurately measuring
these risk exposures is complex. This chapter has
described variations in risk related to tobacco types
and delivery methods and has also detailed informa-
tion regarding the risk of alcohol consumption. In
addition to these exposures, other risk factors for
head and neck cancer are described that may act in
concert with tobacco and alcohol exposure to con-
tribute to the epidemiology of this disease. While it
is encouraging that the rate of head and neck cancer
development in the United States has been decreas-
ing, areas of the world with high rates of head and
neck cancer remain and therefore merit further
attention in cancer prevention and treatment.
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