Head and Neck Cancer

Oral Cavity

The margins of the oral cavity extend superiorly from the skin-vermillion border of the upper lip to the junction of the soft and hard palates, inferiorly from the skin-vermillion border of the lower lip to the circumvallate papillae, and laterally to the anterior tonsillar pillars. The structures of the oral cavity include the mucosal lip, buccal mucosa, upper and lower alveolar ridges, retromolar trigone, floor of the mouth, hard palate, and oral or mobile tongue.

Nasopharynx

The margins of the nasopharynx start anteriorly at the posterior choana and extend along the superior, posterior, and lateral walls to a theoretical plane between the free edge of the soft palate and the posterior pharyngeal wall. The structures of the nasopharynx include the fossae of Rosenmüller, the superior surface of the soft palate, and the mucosal linings of the eustachian tube and choanal orifices.

Oropharynx

The margins of the oropharynx extend from the plane of the superior surface of the soft palate to the superior surface of the vallecula, or hyoid bone. The structures of the oropharynx include the base of the tongue (the lingular tonsil), the palatine tonsils, the glossotonsillar sulcus, the inferior surface of the soft palate and uvula, the anterior and posterior tonsillar pillars, and the continuity of the lateral and posterior pharyngeal walls. Oropharyngeal squamous cell carcinoma largely arises from the rich lymphoreticular tissue of the lingular and palatine tonsils.

Hypopharynx

The margins of the hypopharynx extend from the plane of the superior border of the vallecula to the plane of the lower border of the cricoid cartilage. The structures of the hypopharynx include the pyriform sinuses, the lateral and posterior hypopharyngeal walls, and the postcricoid region.

Larynx

The margins of the larynx include anteriorly the anterior surface of the epiglottis, the thyroid cartilage, and the anterior arch of the cricoid cartilage; posterolaterally the aryepiglottic folds and arytenoids; superolaterally the tip and lateral borders of the epiglottis; and inferiorly the plane of the inferior border of the cricoid cartilage. The structures of the larynx include the epiglottis and false cords (supraglottic larynx), the true vocal cords (glottis), and the subglottis.

Salivary Glands

The salivary glands of the head and neck comprise the major salivary glands, which include the parotid, submandibular, and sublingual glands, as well as the minor salivary glands, which are scattered throughout the lining of paranasal sinuses, oral cavity, pharynx, and larynx. Approximately 6 to 8% of head and neck cancers arise from the salivary glands. Although the unified biologic function of salivary glands is the production and secretion of saliva, salivary gland tumors are histologically, genetically, and prognostically diverse. The three most common histologies are mucoepidermoid carcinoma, adenoid cystic carcinoma, and salivary duct carcinoma, which presents de novo or arises from a preexisting pleomorphic adenoma.

Viruses

Environmental Carcinogens

The risk of environmental head and neck squamous cell carcinoma increases with age, with diagnosis at a median age of 66 years. Environmental risk factors can be proximal, when modifiable individual behavior causes direct carcinogen exposure from tobacco, alcohol, or the areca nut ( Chapter 165 ). Depending upon the world region, approximately half of attributable risk for head and neck cancer is explained by such proximal environmental risk factors. Distal environmental risk factors also pose a substantial burden in developing countries when unavoidable exposures to secondhand smoke, industrial pollution, pestilence, or war are especially associated with low socioeconomic status. Incidence patterns for head and neck cancer caused by environmental carcinogenesis vary in relationship to exposure patterns. In the populations of the United States, Hong Kong, and the Republic of Korea, for example, the incidence of environmental head and neck squamous cell carcinoma is declining in parallel to decreased overall use of tobacco, whereas the incidence is rising in Taiwan, England, and Peru.

Occupational exposures associated with head and neck cancer include the group 1 human carcinogen solvents, polycyclic aromatic hydrocarbons, and heavy metals. For head and neck cancer, the strongest data point to formaldehyde for nasopharynx cancer, polycyclic aromatic hydrocarbons for larynx cancer, chlorinated solvents for all head and neck squamous cell carcinoma anatomic sites, and wood dust for sinonasal cancer.

Leukoplakia

The minority of oral squamous cell cancers are preceded by precancerous lesions, termed oral potentially malignant disorders . Acquired potentially malignant disorders, including leukoplakia (mucosal white patches or plaques that cannot be rubbed off) and erythroplakia (a fiery red patch that cannot be characterized clinically or pathologically as any other diagnosis; Chapter 393 ), are associated with the consumption of tobacco and alcohol. The presence of loss of heterozygosity within an oral potentially malignant lesion is associated with higher risk of progression to oral cancer within the lesion itself or at another site within the carcinogen-exposed epithelium and is useful for risk stratification.

Sex and Genetic Risk Factors

Males demonstrate a significantly higher risk than females for head and neck squamous cell carcinoma, whether caused by environmental carcinogens or oncogenic viruses. The male:female ratio for HPV-unrelated head and neck squamous cell carcinoma parallels the sex-specific prevalence of tobacco, alcohol, or areca nut use in any geographic area. For instance, the age-adjusted incidence rate of oral cavity cancer among men ranges from 1 to 16 per 100,000 population as compared with 0 to 10 per 100,000 among women. Despite a similar prevalence of anogenital HPV infection between adult males and females, males have significantly higher rates of oral HPV infection. In a population-based, cross-sectional study in the United States, 1.6% of men versus 0.3% of women harbored oral HPV 16. The disparity in HPV oral infection is reflected in the incidence rate of HPV-associated oropharyngeal squamous cell carcinoma, in which the male:female ratio ranges from 2.7 to 5.7. Plausible biologic explanations for this disparity are two-fold: oral HPV infections are cleared more slowly by males, and the linear dose-response relationship between lifetime number of sexual partners and the prevalence of oral HPV infection exists uniquely among males, thereby suggesting that males less frequently develop protective anti-HPV antibodies when exposed to anogenital HPV than do females.

Genetically inherited disorders associated with oral leukoplakia and high risk of progression to head and neck squamous cell carcinoma include the rare bone marrow failure syndromes dyskeratosis congenita, which is caused by aberrant telomere biology, and Fanconi anemia, which is caused by inherited mutations in DNA repair genes ( Chapter 151 ).

Dietary Factors

A reduced risk for head and neck squamous cell carcinoma has been associated with diets rich in fruits and vegetables, in particular the Brassica genus of cruciferous vegetables. Crucifers are rich in isothiocyanates, which are phytochemicals that potently induce cytoprotective enzymes that could mitigate the impact of environmental carcinogens including benzene, polycyclic aromatic hydrocarbons, and mutagenic aldehydes found in tobacco smoke and air pollution. People with incident environmental head and neck squamous cell carcinoma have lower serum levels of several micronutrients, including vitamin A and beta carotene, which may be surrogates for lower intake of fruits and vegetables.

Ionizing Radiation

Ionizing radiation was first recognized as a risk factor for both benign and malignant salivary gland tumors among long-term survivors of the Hiroshima and Nagasaki, Japan, atomic bombs. Increased odds of salivary gland tumors are also observed in people treated with therapeutic radiation during childhood, with evidence of a dose-response relationship. Unlike head and neck squamous cell carcinoma, salivary gland tumors are not associated with tobacco exposure, with the single exception of the benign Warthin tumor.

Environmental Carcinogenesis

The transformation of oral epithelial cells by environmental carcinogens is based on the principle of multistep carcinogenesis, in which the accumulation of structural and functional DNA damage drives stepwise clonal evolution. Loss of heterozygosity, also known as allelic imbalance, has been quantified across the histopathologic spectrum of hyperplasia, dysplasia, and carcinoma in situ to model malignant transformation. In essence, environmentally induced head and neck squamous cell carcinoma is characterized by loss of function of tumor suppressor genes and genes that influence NOTCH signaling. A central, early molecular event is loss of heterozygosity at 9p21, which is the locus of the CDKN2A gene. CDKN2A encodes p16, which is a tumor suppressor that regulates cell cycle traversal from the G1 to S-phase. Mutation of TP53 is a later molecular event. Mutations of CDKN2A and TP53 are the most common genetic alterations in HPV-negative head and neck squamous cell carcinoma and are observed in 57% and 84% of cases, respectively. Moreover, expression of p16 is lost due to epigenetic silencing in an additional 30% of tumors, thereby leading to the histopathologic classification of HPV-negative head and neck squamous cell carcinoma as “p16-negative.” PIK3CA , which encodes the alpha subunit of phosphoinositide-3-kinase (PI3K), is the most commonly mutated oncogene in HPV-negative head and neck squamous cell carcinoma. Nongenomic activation of the oncogenes epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX2) is induced by tobacco smoke and also increases during oral epithelial transformation. Aberrant activation of PI3K, EGFR, and COX2 contributes to uncontrolled cellular proliferation while subverting an appropriate apoptotic response to DNA damage.