Epidemiology and risk factors for head and neck cancer

INTRODUCTION — Head and neck cancer is common in several regions of the world. The primary risk factors associated with head and neck cancer include tobacco use, alcohol consumption, human papillomavirus (HPV) infection (for oropharyngeal cancer), and Epstein-Barr virus (EBV) infection (for nasopharyngeal cancer). The chronic exposure of the upper aerodigestive tract to these carcinogenic factors can result in dysplastic or premalignant lesions in the oropharyngeal mucosa and ultimately result in head and neck cancer. The relative prevalence of these risk factors contributes to the variations in the observed distribution of head and neck cancer in different areas of the world.

The epidemiology of head and neck cancer and the risk factors for and pathogenesis of these tumors will be reviewed here. Issues related to pathology, diagnosis, staging, and therapy are considered separately. (Refer to appropriate topic reviews.)

EPIDEMIOLOGY — Worldwide, head and neck cancer accounts for approximately 900,000 cases and over 400,000 deaths annually [1]. In the United States, head and neck cancer accounts for approximately 67,000 cases annually and 15,400 deaths [2]. In Europe, there were approximately 250,000 cases (an estimated 4 percent of the cancer incidence) and 63,500 deaths in 2012 [3].

Males are affected significantly more than females, with a ratio ranging from 2:1 to 4:1. The incidence rate in males exceeds 20 per 100,000 in regions of France, Hong Kong, the Indian subcontinent, Central and Eastern Europe, Spain, Italy, and Brazil, and among African Americans in the United States. Mouth and tongue cancers are more common in the Indian subcontinent, nasopharyngeal cancer is more common in Hong Kong, and pharyngeal and/or laryngeal cancers are more common in other populations; these factors contribute disproportionately to the overall cancer burden in these Asian countries [4,5].

The incidence of laryngeal cancer, but not oral cavity and pharyngeal cancer, is approximately 50 percent higher in African American men [6]. The mortality associated with both laryngeal and oropharyngeal cancer is significantly higher in African American men, which may reflect the lower prevalence of human papillomavirus (HPV) positivity [7].

RISK FACTORS — The risk factors most frequently associated with head and neck cancer include smoking, alcohol consumption, human papillomavirus (HPV) infection (especially for oropharyngeal cancers), and Epstein-Barr virus (EBV) infection (especially for nasopharyngeal cancers in Asia) [8].

Tobacco products — Smoking tobacco products (cigarettes, cigars, pipes) is an important risk factor for the development of head and neck cancer [9].

In heavy cigarette smokers, there is a 5- to 25-fold increased risk of cancer compared with nonsmokers [9-11]. There appears to be a dose-response relationship, as illustrated by the following observations:

●A case-control study compared 605 patients with head and neck cancer with 756 controls [12]. The relative risk (RR) in current tobacco users was 6.5. The RR increased with the duration of smoking and gradually declined after smoking cessation, with no excess risk at 20 years.

●In another case-control study, patients who smoked more than one pack of cigarettes per day had a 13-fold increase in risk of head and neck cancer [13]. The age of starting smoking (below 18 years of age) and duration of smoking (over 35 years) were high-risk factors. Cessation of smoking was associated with a significant decrease in RR.

Other tobacco exposures are also associated with an increased risk of head and neck cancer. Both cigar and pipe smoking are associated with an increased incidence of head and neck cancer, and this increase in risk is present even in those who have never smoked cigarettes [9]. Smokeless tobacco (both chewing tobacco and snuff) is associated with an increased risk of cancer of the oral cavity and pharynx [14].

Secondhand smoke exposure may be a contributing factor. One report evaluated 59 patients with head and neck cancer who did not use tobacco and, with rare exceptions, did not abuse alcohol [15]. These patients had a significantly higher risk of exposure to environmental tobacco smoke in both the workplace and home than a control population without cancer. This relationship primarily occurred in women and those with tongue cancer.

In never smokers, the use of smokeless tobacco products appears to be associated with an increased risk of head and neck cancer, particularly for malignancies arising in the oral cavity [14]. In never smokers using snuff, the risk of head and neck cancer was significantly increased compared with never users of snuff (odds ratio [OR] 1.71, 95% CI 1.08-2.7, and OR for oral cavity cancers 3.01, 95% CI 1.63-5.55). The association with chewing tobacco was weaker and was statistically significant only for cancers of the oral cavity (OR 1.81, 95% CI 1.04-3.17).

Evidence regarding the association of marijuana use and the development of head and neck cancer is somewhat conflicting [16-19]. Reporting and selection bias as well as confounding by alcohol and tobacco use limit the ability of observational studies to exclude or confirm this relationship.

Alcohol — Alcohol consumption independently increases the risk of cancer in the upper aerodigestive tract, although it is often difficult to separate the effects of smoking and alcohol [10,20-22]. The RR of developing head and neck cancer due to alcohol appears to be dose dependent [12,21,22]. As an example, one study reported a five- to sixfold increased risk for head and neck cancer with alcohol intake greater than 50 g/day versus less than 10 g/day (one drink contains approximately 12 g of alcohol) [22]. Alcohol intake and tobacco smoking appear to have an interactive and multiplicative effect on the risk of developing head and neck cancer [10-13,21,23].

There may be an interaction of genetic susceptibility and alcohol intake on the risk of developing head and neck cancer with genetic polymorphisms of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) [24].

Opium — The use of opium has been associated with an increased risk of laryngeal cancer [25-27]. Opium is an illicit substance derived from the poppy plant, specifically from the juice of the unripe seedpod, and contains multiple alkaloids. Per the International Agency for Research on Cancer, opium is considered to be carcinogenic to humans when smoked or ingested in various forms (eg, raw, dross, or sap opium) [28]. As an example, in the Galeston Cohort Study (GCS) of 50,045 patients in Iran, opium use was associated with an increased, dose-dependent risk of developing laryngeal cancer [25]. Of note, these data do not include other opiates such as heroin, morphine, codeine, or fentanyl.

Viral infection — Multiple types of viral infections have been associated with an increased risk of head and neck cancer, including particularly EBV, HPV, hepatitis C virus (HCV), and human immunodeficiency virus (HIV).

Epstein-Barr virus — Nasopharyngeal carcinoma is a relatively rare malignancy in most populations but is one of the most common cancers in southern China. A large body of evidence supports the role of EBV as the primary etiologic agent in the pathogenesis of nasopharyngeal carcinoma. (See "Epidemiology, etiology, and diagnosis of nasopharyngeal carcinoma", section on 'Epstein-Barr virus' and "Epidemiology, etiology, and diagnosis of nasopharyngeal carcinoma".)

While several investigators report finding EBV in oral squamous cell carcinomas (SCC) [29,30], others refute such a relationship [31,32]. (See "Clinical manifestations and treatment of Epstein-Barr virus infection", section on 'Malignancies and HIV infection'.)

Human papillomavirus — Epidemiologic and molecular evidence has established a causal role for HPV, primarily type 16, in patients with head and neck cancer, particularly that arising in the base of the tongue and the tonsils. HPV associated oropharyngeal cancers are typically seen in younger men who are nonusers of tobacco and alcohol. HPV associated head and neck cancer is discussed separately. (See "Epidemiology, staging, and clinical presentation of human papillomavirus associated head and neck cancer".)

Herpes simplex virus — Herpes simplex virus (HSV) is less strongly correlated with the development of oral carcinomas than EBV or HPV. Serologic studies have shown that patients with head and neck cancer have higher levels of the immunoglobulin M (IgM) antibody to HSV type 1 than control subjects [33,34]. HSV can transform cells in vitro into a malignant phenotype. This may be due to an HSV-encoded peptide that increases the mutagenicity of infected cells. In one series of 31 young adults with head and neck cancer, antipeptide antibody levels were significantly higher in the patients than in the control subjects [35].

Hepatitis C virus — Chronic infection with HCV is strongly associated with the development of hepatocellular carcinoma and has also been associated with other malignancies, including lymphoproliferative disorders.

A cohort study that included 409 patients with head and neck cancer and 694 controls with lung, esophageal, or urinary bladder cancer analyzed the incidence of HCV positivity and HCV infection, defined by the presence of HCV ribonucleic acid (RNA) in serum [36]. HCV antibodies were present in a significantly higher proportion of patients with both oropharyngeal and nonoropharyngeal cancers compared with the control group (14.0 and 20.0 versus 6.5 percent), as was HCV RNA (10.7 and 15.5 versus 3.4 percent). This effect persisted when adjusting for potential confounding variables. An exploratory subgroup analysis found this effect was limited to HPV positive oropharyngeal cancers, oral cavity cancer, and larynx cancer, but not HPV negative oropharyngeal cancer, nasopharyngeal cancer, or hypopharyngeal cancer.

Immunodeficiency — Immunodeficiency due to infection with HIV or solid organ transplantation has been associated with an increased risk of cancer in the head and neck region.

●Patients infected with HIV have an increased incidence of a variety of non-acquired immunodeficiency syndrome (AIDS)-defining malignancies. There is an approximately two- to threefold increase in the incidence of SCC of the head and neck in patients infected with HIV; other histologic types of cancer may also be increased. (See "HIV infection and malignancy: Management considerations", section on 'Head and neck cancer'.)

●Patients who have undergone a solid organ transplantation have an increased risk of cancer, including that arising in the head and neck region. As an example, in a series of 2817 organ recipients, 175 patients developed 391 head and neck malignancies [37]. However, the great majority of these were cutaneous malignancies, with 51 percent being SCC and 42 percent being basal cell carcinomas. An additional 2 percent were papillary thyroid cancer, 1 percent SCC of the tongue, and 3 percent of miscellaneous mucosal sites, including the larynx, oral cavity, nasal cavity, oropharynx, nasopharynx, and salivary duct. (See "Malignancy after solid organ transplantation" and "Prevention and management of skin cancer in solid organ transplant recipients".)

●Patients who have received bone marrow transplant and without classic risk factors are at increased risk for head and neck cancer, especially oral cavity site [38,39].

Betel nut chewing — Betel nut chewing, which is widespread in certain regions of Asia, is an independent risk factor for the development of squamous cell head and neck cancer [40]. The effects appear to be synergistic with tobacco and alcohol. Betel nut chewing is also implicated in the development of hepatocellular and esophageal cancer. (See "Epidemiology and risk factors for hepatocellular carcinoma" and "Epidemiology and pathobiology of esophageal cancer".)

Occupational exposure — Multiple other occupational or environmental toxins have been studied for a potential relationship with head and neck cancer. These include the dry cleaning agent perchloroethylene [41], asbestos, pesticides, man-made mineral vitreous fibers (MMMF), polycyclic aromatic hydrocarbons [42,43], textile workers, wood workers [44], manufacturers of mustard gas, plastic and rubber products, naphthalene refiners, ethanol, sulfuric acid mist, leather and paint workers, automobile mechanics, construction workers (cement) [45], farmers, and metal workers [46]. Formaldehyde was classified as a carcinogen in 2004 because of its association with nasopharyngeal cancer and possibly cancers of the nasal cavity and paranasal sinuses [47-49]. SCCs of the oropharynx, nasopharynx, larynx, and thyroid have also been associated with exposure to Agent Orange [50].

Radiation — Prior irradiation for either malignant or benign disease has been linked to thyroid cancer, salivary gland tumors, SCCs, and sarcomas [51-56]. Although this relationship appears to be real, there is a long latency period [52,53], and the overall risk is low [53]. (See "Salivary gland tumors: Epidemiology, diagnosis, evaluation, and staging".)

Diet — Some dietary factors may have a role in protecting individuals from head and neck cancer, while others may increase susceptibility for specific diseases. Several studies have shown a protective effect associated with increased consumption of fruits and vegetables [57,58]. In contrast, case-control studies suggest that the risk of nasopharyngeal carcinoma is increased in frequent consumers of preserved meats that contain high levels of added nitrites [59].

Genetic factors — Multiple genetic factors and pathways may contribute to an increase in the risk of head and neck cancer, and these factors may interact with other known risk factors [60-63]. Examples of these factors include metabolic polymorphisms that influence exposure to the carcinogens in tobacco smoke, DNA repair gene polymorphisms, and variations in other pathways contributing to carcinogenesis.

Patients with Fanconi anemia are at high risk for developing a malignancy, including SCC of the head and neck, myelodysplastic syndrome, and acute myelocytic leukemia [39,64-66]. Head and neck cancers in these patients tend to arise at an earlier age and in the absence of other risk factors (tobacco, alcohol). The management of patients with head and neck cancer arising with Fanconi anemia is complicated by the significant increase in susceptibility to complications of radiation therapy [66].

Mouthwash — Mouthwashes have been postulated to be associated with head and neck cancer because of the carcinogenicity of alcohol, a major component of most such products. In a study from the International Head and Neck Cancer Epidemiology Consortium, there was no increase for all head and neck cancers in ever users (OR 1.01), but there was a significant increase for oral cavity and oropharyngeal cancers (OR 1.11 and 1.28, respectively), and there was a significant increase in the overall incidence for those using mouthwash more than 35 years (OR 1.15) and for those using it more than once a day (OR 1.31) [67]. Similarly, another meta-analysis showed increased risk of head and neck cancers in patients using alcohol-based mouthwash in association with other carcinogenic risk factors [68].

Other risk factors — Other factors also may contribute to the development of head and neck cancer in selected patients. These include poor oral hygiene and periodontal disease, which has been linked with carcinoma of the oral cavity [69]. On the other hand, dental prostheses or poorly fitting dentures do not appear to be independent risk factors for the development of oral carcinoma [70-73].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Head and neck cancer".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Throat cancer (The Basics)")

SUMMARY

●General principles – The head and neck region is a frequent site for the development of primary cancers, accounting for approximately 550,000 new cases annually around the world. Substantial geographic variations are heavily influenced by key risk factors. (See 'Epidemiology' above.)

●Tobacco products – There is a 5- to 25-fold increased risk of head and neck cancer in heavy cigarette smokers compared with nonsmokers, and there is a significant increase in risk associated with pipe and cigar smoking as well. Smokeless tobacco products increase the risk of oral cavity cancer in those who do not smoke tobacco. (see 'Tobacco products' above)

●Alcohol consumption – Alcohol consumption significantly increases the risk of cancer in the upper aerodigestive tract, although it is often difficult to separate the effects of smoking and alcohol in epidemiologic studies. (See 'Alcohol' above.)

●Epstein Barr virus – Epstein Barr virus (EBV) is the primary etiologic agent in the pathogenesis of nasopharyngeal carcinoma. Although nasopharyngeal carcinoma is a relatively rare malignancy in most populations, it is one of the most common cancers in southern China. (See "Epidemiology, etiology, and diagnosis of nasopharyngeal carcinoma", section on 'Etiology and risk factors' and "Epidemiology, etiology, and diagnosis of nasopharyngeal carcinoma", section on 'Epstein-Barr virus'.)

●Human papillomavirus – Human papillomavirus (HPV) is implicated as a primary cause of oropharyngeal cancer in the United States and Europe. Head and neck cancers due to HPV have important clinical and prognostic differences compared with those typically associated with tobacco and alcohol use. (See "Epidemiology, staging, and clinical presentation of human papillomavirus associated head and neck cancer".)