Epidemiology, Demographics/Disparity

Stacey A. Fedewa

Amy Y. Chen

Cancer may involve many sites in the head and neck including the oral cavity, pharynx, larynx, salivary glands, thyroid, and sinonasal cavity. These cancers have a variety of biologic behaviors, and whereas some of these subsites share common risk factors, others do not. Smoking is a major risk factor for cancers of the oral cavity and larynx but is not considered a risk factor for cancer of the thyroid. Human papillomavirus (HPV) is a risk factor for squamous cell carcinoma of the oropharynx but not for other more common cancers of the head and neck such as larynx and thyroid. The risk factors for cancers of the head and neck vary by site (location); therefore, the incidence of cancers of the head and neck, as shown in Tables 4.1 and 4.2, varies markedly across sites, time, and gender. The risk factors, incidence, prognosis, and survival will be presented separately for each site. The discussion in this chapter is mostly confined to the United States. Information on global trends in cancer of the head and neck appears elsewhere in this book (see Chapter 25).

CANCER OF THE ORAL CAVITY AND PHARYNX

Approximately 29,620 men and 11,760 women in the United States are diagnosed each year with cancer of the oral cavity and pharynx.¹ Cancer of the oral cavity and pharynx (OCPC) includes several subsites: lip, tongue, salivary glands, floor of the mouth, gum and other mouth, nasopharynx, tonsil, oropharynx, hypopharynx and other oral cavity, and pharynx. Other oral cavity and pharynx cancers include Waldeyer ring, overlapping lesions of lip, oral cavity, and oropharynx as well as not otherwise specified (NOS) cancers. As shown in Figure 4.1, the most common type of OCPC is cancer of the tongue (28%), followed by tonsil (15%) and gum and other mouth (14%). Squamous cell carcinoma is the most common cancer (82%) of OCPCs. Other less common histopathologies include adenocarcinomas, mucoepidermoid carcinomas, as well as ductal and lobular cancers.²

Table 4.1 Male Age-Adjusted Incidence by Cancer Site, 1973-2009

	1973-1989	1990-1999	2000-2009	APC 2000-2009
Oral cavity and pharynx	20.19	17.55	15.80	-0.1
Lip	3.67	2.06	1.08	-6.7^a
Tongue	3.55	3.69	4.40	2.7^a
Salivary gland	1.40	1.56	1.64	0.7^a
Floor of the mouth	2.19	1.55	0.98	-3.9^a
Gum and other mouth	1.10	0.97	0.79	-2.0^a
Tonsil	1.83	2.00	2.59	4.0^a
Oropharynx	0.52	0.50	0.54	0.2
Nasopharynx	1.01	1.05	0.95	-0.2
Hypopharynx	2.11	1.78	1.20	-3.3^a
Other oral cavity and pharynx	0.64	0.62	0.31	—
Larynx	8.29	7.01	5.50	-2.3^a
Nasal cavity and paranasal sinuses	0.80	0.66	0.57	-1.3^a
Thyroid	2.88	3.47	5.45	5.8^a
^aIndicates significant change in p-value (α = 0.05). Annual percent change (APC). APCs could not be calculated for some sites due to sparse data.

Risk Factors

The International Agency for Research on Cancer (IARC) has classified smoking tobacco as a cause of cancer of the oral cavity.³ Studies have consistently shown an increased risk of cancer of the oral cavity and pharynx among smokers.⁴^,⁵^,⁶^,⁷^,⁸^,⁹ Case-control studies have reported up to 11 to 12 times risk of OCPC among current smokers compared to never smokers,⁴^,⁵ and the risk of OCPC increases with amount and duration of smoking.⁶^,⁷^,⁸^,⁹ In addition, the synergistic effect of alcohol on smoking has been established in several studies.⁶^,⁷^,¹⁰ For example, among never drinkers, the odds of oral cavity and pharyngeal cancer are 1.7 to 1.9 higher for cigarette smokers,
and for heavy drinkers, these odds are 9.60 to 11.37 higher.⁶ There is some heterogeneity in the effect of cigarette smoking by OCPC subsite as tobacco exposure is found to be more strongly associated with cancers of the soft palate than other sites.¹¹ Additionally, the use of black versus blond tobacco may have an even greater risk of oral cavity and pharyngeal cancer.¹² Among former smokers, the risk of cancer of the oral cavity is less than that of smokers, and one study reported that after 10 years of quitting, former smokers had the same risk of OCPC as never smokers.⁹^,¹³

Table 4.2 Female Age-Adjusted Incidence by Cancer Site, 1973-2009

	1973-1989	1990-1999	2000-2009	APC 2000-2009
Oral cavity and pharynx	7.49	6.92	6.32	-0.9^a
Lip	0.36	0.32	0.25	—
Tongue	1.57	1.57	1.71	0.4^a
Salivary gland	0.92	0.96	1.03	0.2
Floor of the mouth	0.83	0.60	0.40	—
Gum and other mouth	0.61	0.59	0.54	-1.2^a
Tonsil	0.74	0.61	0.56	-1.2^a
Oropharynx	0.18	0.15	0.15	—
Nasopharynx	0.39	0.41	0.38	—
Hypopharynx	0.52	0.42	0.28	—
Other oral cavity and pharynx	0.24	0.21	0.12	—
Larynx	1.45	1.49	1.12	-2.6^a
Nasal cavity and paranasal sinuses	0.39	0.35	0.31	—
Thyroid	6.71	8.95	15.84	6.8^a
^aIndicates significant change in p-value (α = 0.05). Annual percent change (APC). APCs could not be calculated for some sites due to sparse data.

Figure 4.1. Distribution of cancer of the oral cavity and pharynx by subsite in SEER 18 2000-2009. (Surveillance, Epidemiology, and End Results (SEER) Program. SEER*Stat Database: Incidence—SEER 9 Regs Research Data, Nov 2011 Sub (1973-2010) <Katrina/Rita Population Adjustment>— Linked To County Attributes—Total U.S., 1969-2010 Counties. National Cancer Institute, DCCPS, Surveillance Research Program, Surveillance Systems Branch, released April 2013, based on the November 2012 submission. http://www.seer.cancer.gov)

Several forms of smokeless tobacco are associated with cancer of the oral cavity and pharynx. Smokeless tobacco in the form of snuff, which is found most commonly in the United States, is independently associated with cancer of the oral cavity and pharynx in US studies.¹⁴ However, studies of smokeless tobacco in Sweden and Norway, where moist snuff or snus is more common, have not reported increased odds of oral or pharyngeal cancer.¹⁵^,¹⁶ Another form of chewing product called betel quid used in Asia that may or may not contain tobacco, is also associated with OCPC. IARC concluded that betel quid with tobacco causes cancer of the oral cavity and pharynx, whereas betel quid without tobacco causes cancer of the oral cavity only.¹⁷^,¹⁸

Not only does alcohol interact with tobacco to increase the risk of cancer of the oral cavity and pharynx, but also there is an independent contribution of alcohol on OCPC.¹⁶^,¹⁹^,²⁰ Among nonsmokers, the risk of cancer of the oral cavity and pharynx is elevated among alcohol drinkers compared to nondrinkers.²¹^,²² A dose-response relationship between alcohol consumption and cancer of the oral cavity and pharynx has also been observed as heavy drinkers have a particularly high risk of cancer of the oral cavity and pharynx.¹⁰^,¹⁶^,¹⁹^,²¹ A meta-analysis found a 4.6- and 6.6-fold increase in odds of cancers of the oral cavity and pharynx among heavy drinkers compared to never
drinkers, respectively.²³ Some studies have suggested variations in the effect of alcohol by subsite; however, the pattern is inconsistent across studies.¹⁰^,¹²^,²⁴

Although historically, cancers of the oral cavity and oropharynx have been attributed to tobacco and alcohol, in recent years, an increasing number of cases of squamous cell carcinoma, particularly those in the oropharynx, have been associated with HPV infection. Several case-control studies have demonstrated an association between HPV and the risk of squamous cell carcinoma of the head and neck, independent of tobacco and alcohol use.²⁵^,²⁶^,²⁷^,²⁸ A multicenter case-control study containing 1,670 cases and 1,732 controls from nine countries reported a positive association between HPV deoxyribonucleic acid (DNA) positivity in oral biopsies and oropharyngeal cancer (OR 4.9, 95% CI 2.6 to 9.1), after having been adjusted for demographic information as well as smoking and alcohol intake.²⁶ In the same study, the association was even stronger when the presence of high-risk HPV 16 was considered.²⁶ A subsequent case-control study in the United States also reported a strong association between cancer of the oropharynx and HPV oral infection (adjusted OR 14.6, 95% CI 6.3 to 36.6) as well as HPV 16 E6 and E7 positivity (OR 58.4, 95% CI 24.2 to 138.3).²⁷

HPV 16 accounts for the majority of HPV-related cancers, followed by HPV-18, and even more rare are HPVs 33, 6, and 11.²⁶^,²⁹^,³⁰ Case series report a wide range of HPV prevalence from 4% to 80% among oral cavity squamous cell carcinoma (OCSCC) and 14% to 57% among oropharyngeal squamous cell carcinoma (OPSCC), which is likely due to variations in populations, risk factors, and HPV detection methods.²⁹ A pooled analysis of over 2,500 OCSCC cases across several continents including Asia, Europe, Australia, North America, and South America reported a 23.5% (95% CI 21.9 to 25.1) prevalence, whereas the prevalence of HPV positive among 969 OPSCC cases in this pooled analysis was higher (35.6%, 95% CI 32.6 to 38.7).³⁰ Though the aforementioned pooled study reported an overall higher HPV positivity among North American cases of OPSCC (47%) and OSCC (16%) than the worldwide combined estimate, other multinational studies have shown no differences in HPV prevalence among OPSCC and OSCC across continents.²⁶

The potential synergistic effect of tobacco, alcohol, and HPV positivity is less well understood. Several investigators have studied this issue using a variety of methods including hospital- and population-based case-control studies with incidence of cancers of the head and neck, whereas some studies included only cancers of the oropharynx. A population-based study of oral cavity and oropharyngeal cancer reported a higher prevalence of smoking in HPV-seropositive cancers (31.3%) compared to HPV-seronegative cancers (20.1%).²⁷ The finding of additive interaction for tobacco and HPV exposure has been observed in other studies as well.²⁶ However, a hospital-based case-control study found a similar proportion of smokers in HPV-positive (63%) and HPV-negative (67%) cases.³¹ Similarly, other studies have found no interaction between HPV and smoking.²⁵^,³²

Some occupational studies have found increased odds of cancer of the oral cavity and pharynx among workers exposed to aromatic amines, polycyclic aromatic hydrocarbons, solvents, and nitrosamines³³^,³⁴; however, these associations are not consistent across studies and some studies were unable to control for tobacco use. Consumption of mate, a popular infused drink in parts of Latin America, may be related to increased cancer of the oral cavity though it is not known if the increased risk is due to its hot temperature, a potential carcinogenic effect of mate, or a combination of the two.³⁵^,³⁶ Fruits and vegetables are protective against OCPC; a pooled analysis indicated that high vegetable consumption was associated with a 50% reduction in OCPC.³⁷ In contrast, individuals with diets high in meat and dairy, controlling for alcohol and tobacco consumption, are at an increased risk of cancer of the oral cavity.³⁸ Other factors related to oral cavity cancer include a family history as cases with a first-degree relative with cancer of the oral cavity are at an increased risk for the disease after taking into account their consumption of alcohol and tobacco.³⁹ Inheritable disorders, including Fanconi anemia, are also linked to cancer of the oral cavity.⁴⁰ Additional genetic mutations that may be related to oral cavity mutation include germline mutations in p16.⁴¹

Descriptive Statistics

Incidence Patterns

Cancer of the oral cavity and pharynx is more common in males than females as shown in Tables 4.1 and 4.2.⁴² The higher incidence among males compared to females is likely due to higher smoking rates and alcohol consumption among males. Incidence increases with age; incidence rates among those <40 years of age are <7 per 100,000 and increase to 11.7 among those aged 45 to 49. Incidence rates continue to increase to 19.9 per 100,000 for ages 50 to 54 and double by the age of 70 to 74 where the incidence rate is 40.1 per 100,000.⁴² Globally, the age-standardized incidence rates for cancer of the oral cavity in developed and developing countries are estimated at 6.9 per 100,000 men and 4.6 per 100,000 men, respectively.⁴³ Cancer of the oral cavity and pharynx is nearly equivalent among women in developed (2.4 per 100,000 women) and developing (2.6 per 100,000 women) countries.⁴³ Among men in the United States, Whites have the highest age-adjusted incidence of cancer of the oral cavity and pharynx (16.7 cases per 100,000 men) followed by Blacks (14.9 per 100,000 men), Asian/Pacific Islanders (11 per 100,000 men), American Indian/Alaska Natives (11.1 cases per 100,000 men), and Hispanic men (9.3 per 100,000) (Fig. 4.2).² For females, the incidence of OCPC is also highest among whites; however, the differences by race are less marked than patterns observed for males (Fig. 4.3).² The overall higher incidence of cancer of the oral cavity and pharynx among whites compared to blacks reflects higher smoking rates among whites compared to blacks.⁴⁴ Furthermore, the prevalence of adult blacks who report any alcohol consumption and heavy alcohol consumption is less than that of whites.⁴⁵ Incidence patterns by race vary by subsite where the incidence of cancer of the palate, tonsil, and pharynx was higher among blacks than whites for males and females. Cancer of the lip is more common in whites than blacks; this difference may in part be due to higher susceptibility to solar keratosis among whites.⁴⁶

Most recent studies of trends in cancer of the oral cavity and pharynx have been examined in the context of HPV-associated and non-HPV-associated cancers. HPV-associated cancers include lingual tonsil, palatine tonsil, and Waldeyer ring, whereas non-HPV-associated cancers include tongue, gum, floor of the mouth, and palate.⁴⁷ HPV-related squamous cell carcinoma (SCC) of the oral cavity and oropharynx have been increasing, whereas non-HPV-associated SCC of the oral cavity and oropharynx have been

decreasing as depicted in Figure 4.4.⁴⁷^,⁴⁸^,⁴⁹ Between 1988 and 2004, HPV-related OPSCC increased 225% whereas HPV-unrelated OPSCC declined 50% during the same time period.⁴⁹ Starting in 2004, the incidence of HPV-related OPSCC and OCSCC approached non-HPV-related OPSCC and OCSCC.⁴⁷ Declines in HPV-unrelated OPSCC are attributed to the reduced prevalence of cigarette smoking in the United States as well as decreases in per capita use of hard alcohol.⁴⁷ Smoking prevalence for adults in the United States has decreased from 42.4% in 1965 to 18.9% in 2011.⁴⁴ HPV-related OPSCC and OCSCC have increased across all age groups; however, there are particularly marked increases in more recent birth cohorts, suggesting differences in sexual practices over time. Though data on HPV prevalence in cancers of the oral cavity over time are limited, a study in Colorado reported that the prevalence of HPV in cancer of the oropharynx rose from 33% in the 1980s to 82% in the mid-2000s.⁵⁰

Figure 4.2. Age-adjusted incidence of cancer of the oral cavity and pharynx by race/ethnicity among males, SEER 18 2006-2010. (Surveillance, Epidemiology, and End Results (SEER) Program. SEER*Stat Database: Incidence—SEER 9 Regs Research Data, Nov 2011 Sub (1973-2010) <Katrina/Rita Population Adjustment>— Linked To County Attributes—Total U.S., 1969-2010 Counties. National Cancer Institute, DCCPS, Surveillance Research Program, Surveillance Systems Branch, released April 2013, based on the November 2012 submission. http://www.seer.cancer.gov)

Figure 4.3. Age-adjusted incidence of cancer of the oral cavity and pharynx by race/ethnicity among females, SEER 18 2006-2010. (Surveillance, Epidemiology, and End Results (SEER) Program. SEER*Stat Database: Incidence—SEER 9 Regs Research Data, Nov 2011 Sub (1973-2010) <Katrina/Rita Population Adjustment>—Linked To County Attributes—Total U.S., 1969-2010 Counties. National Cancer Institute, DCCPS, Surveillance Research Program, Surveillance Systems Branch, released April 2013, based on the November 2012 submission. http://www.seer.cancer.gov)

Figure 4.4. Incidence of HPV-related and HPVunrelated squamous cell carcinomas of the oral cavity, 1975-2004. (Chaturvedi AK, Engels EA, Anderson WF, et al. Incidence trends for human papillomavirus-related and -unrelated oral squamous cell carcinomas in the United States. J Clin Oncol. 2008;26:612-619.)

In general, HPV-related OPSCC and OCSCC incidence has increased among white men; however, the incidence among black males has declined.⁵¹ This opposing temporal trend for black and white males has led to dwindling overall differences in black-white incidence rates as shown in Figure 4.5 where incidence trends for squamous cell carcinoma of the oral cavity and pharynx (excluding lip, salivary glands, and nasopharynx) are displayed. For example, the incidence of HPV-related OSCC for black men was double that compared to white men between 1973 and 1991, and between 1992 and 2007, the increased incidence among black men was only 43% higher.⁵¹ A recent study also found that HPV-related OSCC incidence rates particularly increased for men residing in low socioeconomic neighborhoods.⁵² For women, HPV-related OPSCC and OCSCC have recently declined for both black and white women, though the incidence among black women remains 25% higher relative to white women. Asian/Pacific Islanders and Hispanics have significantly lower HPV-related OCSCC and OPSCC compared to whites for both males and females.⁵¹ These temporal differences in incidence by race may reflect differences in sexual practices by race/ethnicity.⁵¹

Figure 4.5. Age-adjusted HPVrelated and HPV-unrelated squamous cell carcinoma of the oral cavity by diagnosis year, race, and gender, 1977-2007. (Brown LM, Check DP, Devesa SS. Oropharyngeal cancer incidence trends: diminishing racial disparities. Cancer Causes Control. 2011;22:753-763.)

Prognosis

Approximately one-third of cases of cancer of the oral cavity and pharynx are diagnosed with localized disease, 47% are diagnosed with regional disease, 17% are diagnosed with distant-stage disease, and 6% are unstaged. The prognosis for cancer of the oral cavity and pharynx is not favorable; the overall survival rate for cancer of the oral cavity and pharynx is 62% and ranges from 36.3% among distant stage to 82.7% for localized stage. Stage-specific survival rates have improved throughout time; between 1977 and 1991, the 5-year relative survival rate among localized cancers was 61.4% and increased to 72.9% between 1992 and 2006. During the same time intervals, the gains observed for regional- and distantstage disease were even more noticeable as survival increased from 36.8% to 52.5% among regional disease and 15% to 27.6% for distant-stage disease.⁵¹ There has been some improvement in the 5-year survival of cancer of the oral cavity and pharynx across all race and gender categories since the mid-1970s as well (Fig. 4.6).² The 5-year relative survival rates among black males have increased the most with a 36% increase in survival from the mid-1970s to mid-2000s. During the same time period, white males experienced a 20% increase whereas white females and black females’ 5-year relative survival increased by 17% and 11%, respectively.

Despite gains in survival over time, there remains a considerable survival disparity by race. Recent 5-year relative survival rates are 63.6% for white males and 38.6% for black males, whereas the 5-year relative survival for white and black women is 64.6% and 53.0%, respectively. Some of these survival disparities are attributed to later stage at diagnosis.⁵³^,⁵⁴ Figure 4.7 demonstrates that blacks are disproportionately diagnosed at advanced stage, which may be attributed to delays in diagnosis and access to care. One study examining cancer of the oropharynx did not observe increased advancedstage disease among blacks when insurance was adjusted for, which supports the hypothesis that access to care is one component of advanced-stage disease among blacks.⁵⁵ However,

blacks have poorer survival even among those with localized cancer, indicating that other factors, including lower socioeconomic status (SES) and suboptimal treatment, also contribute to poorer survival among blacks than whites.⁵³ Black patients with cancer of the oral cavity and pharynx were less likely to receive cancer-directed surgery and more likely to receive radiation without chemotherapy.⁵⁶ Even after adjusting for treatment, insurance, and other sociodemographic factors, blacks had a 45% increased risk of all-cause death in a recent study of over 20,000 cases of cancer of the oropharynx.⁵⁷ Some of the increased hazard of death among blacks could be due to other competing causes of death as this study examined overall survival; however, after adjusting for comorbidity, blacks still had a higher hazard of death in this study.

Figure 4.6. A 5-year relative survival for cancers of the oral cavity and pharynx by race and gender, SEER 18 1975-2005. (Surveillance, Epidemiology, and End Results (SEER) Program. SEER*Stat Database: Incidence—SEER 9 Regs Research Data, Nov 2011 Sub (1973-2010) <Katrina/Rita Population Adjustment>—Linked To County Attributes—Total U.S., 1969-2010 Counties. National Cancer Institute, DCCPS, Surveillance Research Program, Surveillance Systems Branch, released April 2013, based on the November 2012 submission. http://www.seer.cancer.gov)

Figure 4.7. Stage distribution among cancers of the oral cavity and pharynx by race/ethnicity, SEER 18 2000-2010. (Surveillance, Epidemiology, and End Results (SEER) Program. SEER*Stat Database: Incidence—SEER 9 Regs Research Data, Nov 2011 Sub (1973-2010) <Katrina/Rita Population Adjustment>—Linked To County Attributes—Total U.S., 1969-2010 Counties. National Cancer Institute, DCCPS, Surveillance Research Program, Surveillance Systems Branch, released April 2013, based on the November 2012 submission. http://www.seer.cancer.gov)

Table 4.3 Five-Year Relative Survival for Pharynx Cancers of the Oral Cavity by Race/Ethnicity, Stage, and Gender, SEER 18 2003-2009

	Total	Males			Total	Females
	Total	Localized	Regional	Distant	Total	Localized	Regional	Distant
Non-Hispanic White	63.7%	81.5%	63.4%	37.9%	64.8%	83.4%	56.1%	35.6%
Hispanic	57.0%	81.9%	56.9%	34.0%	69.1%	90.0%	58.6%	44.5%
Black	38.7%	72.6%	38.0%	23.2%	51.3%	82.3%	40.5%	29.1%
Asian	64.8%	86.4%	62.8%	50.6%	71.5%	85.3%	70.4%	50.8%
Surveillance, Epidemiology, and End Results (SEER) Program. SEER*Stat Database: Incidence—SEER 9 Regs Research Data, Nov 2011 Sub (1973-2010) <Katrina/Rita Population Adjustment>—Linked To County Attributes—Total U.S., 1969-2010 Counties. National Cancer Institute, DCCPS, Surveillance Research Program, Surveillance Systems Branch, released April 2013, based on the November 2012 submission. http://www.seer.cancer.gov

Interestingly, the proportion of Asian Americans diagnosed at late stage (26%) is similar to that of Blacks (27%). Despite this similarity, the 5-year relative survival among Asian Americans is higher than that of any other race/ethnicity overall (Table 4.3). Among cases with distant stage, Asian Americans’ survival is considerably higher than that of other race/ethnicities where survival among Asian Americans is ˜50% compared to <40% among non-Hispanic Whites. Adjusting for stage in addition to other sociodemographic and clinical factors, the survival benefit among Asian Americans with cancer of the oropharynx, nasopharynx, and hypopharynx compared to Whites was not statistically significant.⁵⁸ However, similar factors including receipt of treatment, SES, and age were important predictors of survival among Asians, which is what is observed for other race/ethnicities.⁵⁸

Studies have shown that HPV-positive patients with squamous cell carcinomas of the head and neck have better survival than do patients who are HPV negative.⁵⁹ In addition, significant reductions (59% to 83%) in cause-specific hazards of death for HPV-positive head and neck squamous cell carcinoma (HNSCC) have been reported, after adjusting for important confounders including age, clinical characteristics, and tobacco and alcohol consumption.³¹^,⁶⁰ A meta-analysis reported a 15% reduction in overall hazard of death as well as marked disease-free survival among HPV-positive versus HPV-negative patients with cancer of the head and neck.⁵⁹ Although some of the aforementioned factors, including younger age at diagnosis, may explain some of the survival advantage among HPV-related OSCC tumors, it does not explain it entirely as several studies have adjusted for age and other prognostic factors. Improved survival among patients with squamous cell carcinoma of the oropharynx is likely multifactorial and is in part due to increased sensitivity of the cancers to radiation and response to chemoradiation.⁶¹

CANCER OF THE SALIVARY GLANDS

Cancer of the salivary glands is often included with cancers of the oral cavity and pharynx for etiologic and descriptive epidemiologic studies. Cancer of the salivary glands includes major salivary glands, including parotid, sublingual, and submandibular, as well as minor salivary glands found in the mucosa of the upper aerodigestive tract.

Cancer of the Major Salivary Glands

Cancer of the major salivary glands is uncommon, representing only 11% of the 41,380 cancers of the oral cavity and pharynx diagnosed each year; however, unlike other cancers of the oral cavity and pharynx that are almost all squamous cell cancer, the histology of cancer of the salivary glands is heterogeneous.⁶² The incidence of cancer of the major salivary glands varies by histologic type; the most common histologic type is mucoepidermoid carcinoma (2.85 per 100,000), followed by squamous cell carcinoma (1.83 per 100,000), acinic cell carcinoma (1.38 per 100,000), adenoid cystic carcinoma (1.30 per 100,000), and adenocarcinoma NOS (1.22 per 100,000).⁶² The remaining histologic types, which include salivary duct carcinoma, basal cell carcinoma, oncocytic carcinoma, clear cell adenocarcinoma NOS, cystadenocarcinoma, mucinous adenocarcinoma, polymorphous low-grade adenocarcinoma, sebaceous carcinoma, malignant mixed tumors, and other rare carcinomas, have incidence rates that are <1 per 100,000.⁶² The most common site of cancer of the major salivary glands is the parotid gland (80%) followed by the submandibular (15%) and sublingual glands (4%).

Though major salivary glands have been included in some case-control studies as part of investigations of etiologic factors related to cancer of the oral cavity and pharynx, few studies have examined the etiologic factors specific to major salivary glands. In a case-control study with 150 cases of cancer of the major salivary glands and 191 controls, current smoking was associated with salivary gland risk among males. However, this study did not observe an association between smoking among women.⁶³ Additionally, two other case-control studies did not observe an association between smoking for men or women.⁶⁴^,⁶⁵ The association between alcohol consumption and salivary gland cancer occurrence is also unclear as some
studies have reported a positive association among males,⁶³ whereas another reports a significant association for females only⁶⁴ and another study reported null findings for both males and females.⁶⁵ Studies have more consistently reported an association between radiation exposure and cancer of the major salivary glands.⁶³^,⁶⁴^,⁶⁶ Some studies have reported an association between occupational exposures and cancer of the major salivary glands,⁶³^,⁶⁶ whereas others have not.⁶⁵

The age-adjusted incidence rate of cancer of the major salivary glands is ˜1.62 per 100,000 among males and 1.01 per 100,000 among females as shown in Table 4.4.² The incidence of cancer of the major salivary glands varies by age, sex, and histology. Among mucoepidermoid salivary gland cancers as well as all WHO-classified cancers combined, women have a slightly higher incidence compared to men until the fifth decade of life, and after that, the incidence of cancer of the major salivary glands is higher among males.⁶² This age-gender interaction has not been explained though it is hypothesized that a hormonal component may be related to these findings.⁶² A study of reproductive and hormonal factors related to major salivary glands did find a positive association between early menarche and null parity and cancer of the salivary glands, which is congruent with the hypothesis that hormones may be involved with salivary gland tumorgenesis.⁶⁷ However, the incidence of squamous cell carcinoma and non-WHO-classified tumors for men is markedly higher than that for females across all ages, which may indicate more distinct risk factors by histologic type.⁶²

As shown in Table 4.4, the incidence of cancer of the major salivary glands among white males is slightly higher (1.69 per 100,000) compared to black (1.27 per 100,000) and men of other races (1.09 per 100,000). For females, there is little difference in age-adjusted incidence rates where the incidences for white, black, and other females are 1.01, 0.94, and 0.86 per 100,000, respectively. A study examining incidence patterns by histology and race noted significantly lower incidence rates among blacks compared to whites for squamous cell carcinoma, and acinic cell carcinoma, but not for other histologic types.⁶² The same study reported lower incidence rates of squamous cell, acinic cell, adenocarcinoma NOS, and non-WHO-classified tumors for Asian/Pacific Islanders compared to Whites.⁶²

Table 4.4 Age-Adjusted Incidence of Cancer of the Major Salivary Glands by Sex, Site and Race/Ethnicity, and Age per 100,000 Person-Years, SEER 18 1990-2009

	Males	Females
Primary site
Parotid gland	1.32	0.77
Submandibular gland	0.22	0.17
Sublingual gland	0.01	0.02
Overlapping lesion	<0.01	<0.01
Major salivary gland, NOS	0.06	0.05
Age
<50 y	0.39	0.45
50-69 y	2.97	1.89
≥70 y	8.61	3.58
Race
White	1.69	1.01
Black	1.27	0.94
Other	1.09	0.86
Surveillance, Epidemiology, and End Results (SEER) Program. SEER*Stat Database: Incidence—SEER 9 Regs Research Data, Nov 2011 Sub (1973-2010) <Katrina/Rita Population Adjustment>— Linked To County Attributes—Total U.S., 1969-2010 Counties. National Cancer Institute, DCCPS, Surveillance Research Program, Surveillance Systems Branch, released April 2013, based on the November 2012 submission. http://www.seer.cancer.gov