head and neck cancer, epidemiology, etiology, staging


Anatomically and histologically, the head and neck region is one of the most diverse and complex parts of the human body. This diversity gives rise to a myriad of neoplastic processes with diverse behaviors and outcomes. The combination of anatomic and functional intricacies combined with the neoplastic spectrum necessitates a basic understanding of cancer biology, in addition to a working knowledge of all therapeutic options for delivering optimal care to patients with head and neck neoplasms. Moreover, the head and neck surgeon must appreciate and optimize the anatomic (esthetic) and physiologic (functional) impact of treatment. The vast majority of head and neck neoplasms arise from the mucosa of the upper aerodigestive tract, including the oral cavity, pharynx, larynx, nasal cavity, and sinuses, but neoplasms also can originate from the salivary glands, thyroid and parathyroid glands, soft tissue, bone, and skin. The most common malignant neoplasms of the head and neck are squamous cell carcinoma and papillary thyroid carcinoma. Salivary gland cancers and sarcomas of the soft tissue and bone are relatively infrequent.

Surgery has been the mainstay of therapy for tumors in the head and neck for more than a century. With the introduction of ionizing radiation in the latter half of the 20th century, radiotherapy became an important modality used either independently or in combination with chemotherapy as primary treatment or as an adjuvant to surgery. Although initially chemotherapy was used primarily as palliative treatment, it is now used as a component of curative treatment approaches when combined with radiation, producing significant improvements in outcomes in patients with squamous cell carcinomas of the head and neck at certain sites. Similarly, biological or targeted agents also are evolving to become part of standard therapy. Immunotherapy also has a role in the treatment of head and neck cancers and is expected to play an increasing role in the future. Accordingly, understanding and implementing multidisciplinary management strategies are cornerstones for achieving optimal therapeutic outcomes.


Most cancers result from a complex interplay between host and environmental factors. Environmental carcinogenic signals that promote the development of most human cancers remain ill-defined. In contrast, correlative studies have shown that alcohol and tobacco exposure are key causative factors for carcinomas of the mucosa of the upper aerodigestive tract. Head and neck cancers are typically tobacco-related cancers, with initial risk for the development of cancer and subsequent risk for additional primary cancers directly attributable to the duration and intensity of tobacco use. Similarly, the chronic consumption of alcohol is estimated to increase the risk for upper aerodigestive tract cancers by two-fold to three-fold in a dose-dependent manner. Moreover, persons who both smoke and consume alcohol regularly have a multiplicative increase in risk that is up to 10 to 20 times higher than that of nonsmokers/nondrinkers, as reflected by a geometric rise in the incidence with increasing use of tobacco and increasing consumption of alcohol ( Fig. 1.1 ). It is now well established that human papilloma virus (HPV) is associated with the development of oropharyngeal carcinomas. Genetic predisposition to the development of head and neck cancers in patients with Fanconi anemia is thought to be related to HPV infection. Similarly, immune-compromised patients with human immunodeficiency virus infection and patients undergoing chronic immunosuppressive treatment after organ transplantation have an increased risk for the development of head and neck cancers. Several other factors also are known to play a role in the pathogenesis of tumors in the head and neck region. For example, exposure to ionizing radiation increases the risk for the development of primary malignant tumors of the thyroid gland and salivary glands as well as for cancers of the skin, soft tissues, and bone. Similarly, Epstein-Barr virus infection is thought to promote the development of nasopharyngeal cancer.

Figure 1.1

Risk of development of squamous cell carcinoma of the head and neck with alcohol and tobacco consumption.

Global Epidemiology

Head and neck cancers form the sixth most common cancer type and cause for cancer-related deaths worldwide. Significant geographic variation exists in the incidence of squamous cell carcinomas of the head and neck. The highest incidence of carcinomas of the oral cavity and hypopharynx are reported in Southeast Asia, and particularly in India, where chewing tobacco with betel quid (“paan”) is a common practice. High rates of oral cancer are also reported in Brazil. The global incidence of squamous carcinomas of the oral cavity is shown in Figs. 1.2 and 1.3 . Lip cancer had the highest incidence in Australia and central and eastern Europe, and rising incidence of oropharyngeal cancers in North America and Europe, especially in Hungary, Slovakia, Germany, and France, is associated with alcohol use, tobacco smoking, and HPV infection. Nasopharyngeal cancers are most commonly reported from Northern Africa and Eastern and Southeast Asia, suggestive of genetic susceptibility combined with Epstein-Barr virus (EBV) infection. On the other hand, significantly higher rates of laryngeal and hypopharyngeal carcinomas are reported in Italy, France, and Spain as a consequence of higher rates of alcohol consumption and smoking. In the past two decades a rising incidence of head and neck cancer has been reported in Eastern European countries, particularly in Hungary; the exact reasons for this phenomenon remain unclear. The global incidence of lip, oral cavity, and pharyngeal cancers of approximately 530,000 corresponds to 3.8% of all cancers. However, it is predicted to rise by 62% to 856,000 cases by 2035.

Figure 1.2

Age Standardized Incidence Rates (per 100,000) of Lip, Oral Cavity, and Pharyngeal Cancers by Subsite in 2012 Among Men. International Classification of Diseases 10 th Revision codes are indicated for each subsite.

(With permission from Shield KD, Ferlay J, Jemal A et al. The global incidence of lip, oral cavity, and pharyngeal cancers by subsite in 2012. CA Cancer J Clin 2017;67(1):51–64.)

Figure 1.3

Age Standardized Incidence Rates (per 100,000) of Lip, Oral Cavity, and Pharyngeal Cancers by Subsite in 2012 Among Women. International Classification of Diseases 10 th Revision codes are indicated for each subsite.

(With permission from Shield KD, Ferlay J, Jemal A et al. The global incidence of lip, oral cavity, and pharyngeal cancers by subsite in 2012. CA Cancer J Clin 2017;67(1):51–64.)

An increased incidence of differentiated carcinoma of the thyroid gland in children has been reported in Belarus and the Ukraine following the Chernobyl accident in 1986. Although initially the adult population in these areas did not show an increase in thyroid cancer, the adult population exposed to the Chernobyl accident is now manifesting an increase in thyroid cancer. It is anticipated that a similar rise in thyroid cancers may occur following the Fukushima nuclear accident in Japan. In addition, during the course of the past two decades, a rising incidence of differentiated carcinoma of the thyroid gland has been reported worldwide, likely due to the early increased diagnosis of clinically occult tumors resulting from increasing awareness and frequent utilization of routine sonography of the neck and other imaging studies.

Head and Neck Squamous Cell Cancer Biology: Overview

Despite its anatomic and histologic diversity, head and neck squamous cell carcinoma (HNSCC), like all human cancers, is a genetic malady in which genetic aberrations accumulate in cells consequent to an imbalance between mutagenic signals and inherent protective mechanisms. In some cases, the development of head and neck cancer may be subject to inherited predispositions, with the strongest association observed for patients with Fanconi anemia, a disease that results from mutations in a group of genes that mediate DNA damage repair. In some patients, head and neck cancers of mucosal origin are associated with exposure to mutagens, chief among which is tobacco. Tobacco use is a strong risk factor for the development of head and neck squamous cell cancer, with alcohol use representing a comparatively smaller level of risk, but the two agents appear to work synergistically and are likely responsible for up to 75% of cases. In parts of Asia, betel quid chewing also plays a significant role in the development of squamous cancer.

More recently, in the United States and developed world, oncogenic strains of the HPV (mainly HPV-16) have been linked with the development of squamous cell cancer arising in the oropharynx; specifically, the lymphoid-rich regions of the tonsil and base of tongue. Most HPV-positive cancers occur in nonsmokers and nondrinkers and are instead associated with sexual behavior as a means of transmitting the virus. In the developed world, the incidence of HPV-associated head and neck cancer is rising, while the incidence of tobacco-associated HPV-negative cancer is declining. HPV-associated cancers differ significantly from HPV-negative cancers in their genetic complexity and content, natural history, response to treatment, and outcomes. Due to these substantial differences, HPV-positive and HPV-negative cancers are best thought of as biologically distinct entities. The differences in the behavior of these two entities has led to the development of a different and separate staging system for HPV-positive oropharynx cancers.

Finally, many patients have no history of either an inherited cancer syndrome or exposure to tobacco or alcohol. The exact cause for the development of head and neck cancer in these patients remains to be defined. Although genetic aberrations appear to develop randomly, those directly contributing to carcinogenesis are selected for in a darwinian manner through the process of clonal selection. As such, cancers are a model for cellular evolution in that they constantly adapt to environmental stimuli through alterations in their genetic complement. As genetic events accumulate, these malignancies progress through several stages, ultimately resulting in invasive cancer. Head and neck cancers, especially head and neck squamous cell carcinomas and thyroid carcinomas, represent a prototypic model for cancer progression ( Fig. 1.4 ). Moreover, with diffuse exposure to tobacco carcinogens, it is not uncommon to see multiple lesions at varying stages of progression within the upper aerodigestive tract, representing a process of field cancerization. Preclinical changes in the cellular structure of the exposed mucosa occur several years before the manifestation of clinical features suspicious for carcinoma, making field cancerization much more common than is appreciated clinically.

Figure 1.4

Progression model for squamous cell carcinoma of the head and neck showing increasing genomic instability from histologically normal mucosa to invasive carcinoma.

Given that the behavior of a cancer is directly attributable to its genetic content, the study of cancer genetics offers an opportunity to predict cancer behavior and direct targeted therapy. The study of cancer genetics has been bolstered in recent years by the completion of, first, the Human Genome Project and, subsequently, the large-scale tumor-sequencing studies of the Cancer Genome Atlas project. Despite these advances, the direct application of genetic information to head and neck cancer prognostication and treatment remains limited. Buoyed by successes such as anti–epidermal growth factor receptor targeting and, more recently, immunotherapy in head and neck squamous cell carcinomas and the promise of more significant contributions, the field of head and neck cancer genetics continues to advance and likely will influence cancer treatment in the years to come.

Genetic Predisposition to Head and Neck Squamous Cell Cancer

Only a small fraction of cases are familial in nature. The clearest link is observed in patients with Fanconi anemia, an autosomal recessive genomic-instability syndrome associated with bone marrow failure, leukemia, congenital defects, and sensitivity to cross-linking chemotherapy agents. The risk of developing head and neck cancer is elevated several hundred-fold, and most patients develop a solid tumor by age 45 years. Treatment of these patients is clinically challenging, because these patients have significant hypersensitivity to chemotherapy and radiation therapy.

It is not clear whether there is any clear genetic predisposition for head and neck cancer, apart from syndromic families. While initial studies seemed to show a genetic predisposition was common in first-degree relatives, more recent analyses now demonstrate that the association is mild. It is quite possible that inherited differences in relevant cellular pathways such as DNA repair, carcinogen metabolism, and cell cycle control may modulate the risk of cell sensitivity to carcinogen exposure.

Molecular Subtypes of Head and Neck Squamous Cell Cancer

The first analyses performing a broad molecular characterization of head and neck cancer utilized high throughput gene expression arrays. These first identified four distinct subgroups of HNSCC, which have been termed basal, atypical, mesenchymal, and classical. The “atypical” tumors are mostly HPV-associated, but the other subtypes do not have any clear association with patient factors such as age or smoking history. Of interest, however, is that these subtypes resemble similar subtypes in lung cancer, suggesting that there may be shared biology that is relevant for future research into factors that are prognostic or predict response to certain treatments.

Genetic Alterations in Head and Neck Squamous Cell Cancer

More recently, several large-scale projects have performed DNA sequencing of the exomes (the parts of the genome that are transcribed into RNA), in order to identify genes that are mutated in HNSCC. These studies have included large studies drawing tumors from multiple international centers, carried out by the Cancer Genome Atlas and the International Cancer Genome Consortium. Overall, HNSCC has the ninth highest mutational load of the 30 tumor types studied, with an average of 5 (range of 1–100) mutations per megabase. HPV-positive tumors tend to have lower mutation rates, and smoking-related tumors tend to have higher mutation rates.

HPV-negative tumors are predominantly characterized by multiple mutations in tumor suppressor genes (genes that normally function to protect cells from developing cancer), rather than oncogenes (genes that have the potential to cause cancer if altered). It has long been recognized that the most commonly altered gene in HNSCC is TP53, the gene that encodes the p53 protein, a protein that normally triggers cell cycle arrest in response to DNA damage or oncogenic stress. Mutations in TP53 can be observed early in the formation of HNSCC, for example in premalignant lesions, or in histologically normal-appearing mucosa on the margin of a tumor resection. TP53 mutations are present in 70% to 80% of HNSCC and are associated with poorer prognosis. Other commonly altered tumor suppressor genes in HNSCC include the cell cycle gene CDKN2A and genes involved in the differentiation and development of squamous cells, such as NOTCH1, TP63, and FAT1. The chief oncogenes that are altered in HNSCC include EGFR, which encodes the epidermal growth factor, driving downstream signaling that promotes cellular growth, invasion, and metastasis and is the target of EGFR -inhibiting therapeutic drugs such as cetuximab. Unlike in lung cancer, EGFR is rarely mutated in HNSCC but is often amplified, leading to overexpression. PIK3CA, a kinase gene that is the second-most commonly mutated gene in human cancer, is also mutated in up to 30% of HNSCC and plays an important role in promoting cellular growth and metabolism.

Biology of Human Papilloma Virus–Associated Head and Neck Cancers

HPV-positive HNSCCs have a completely distinct molecular profile from HPV-negative HNSCC. The HPV family of genes include both low-risk and high-risk strains, based on the ability of a strain to lead to malignant progression of an infected cell. HPV has long been known to induce malignancies such as cervical, anal, and vulvar cancers. Definitive evidence linking HPV as a causative agent in oropharyngeal cancer only began to emerge in the early 2000s. It is now clear that HPV-related oropharyngeal cancers are a distinct entity that have a better prognosis than traditional smoking- and alcohol-related HNSCC. In the United States and the developed world, where smoking rates have declined, HPV is now the cause of up to 80% of oropharyngeal cancers. HPV16 is the main subtype associated with HNSCC.

HPV chiefly causes HNSCC through its two viral oncogenes, E6 and E7, that inactivate tumor suppressor genes in the host cell. E6 inactivates p53 (described previously), and E7 inactivates Rb (the retinoblastoma tumor suppressor gene). As a result of these driving events, HNSCCs caused by HPV tend to require far fewer other mutations to develop into cancer.

Precision Medicine and Immunotherapy

The only molecularly targeted therapy currently used in HNSCC targets EGFR. Cetuximab, one of these drugs, is approved by the Food and Drug Administration (FDA) in the United States and has a 10% to 15% response rate as a single agent in advanced HNSCC. There is significant interest in exploring other targeted therapies, but our molecular understanding of HNSCC reveals that these approaches are most likely to be effective when matched to cancers with a corresponding alteration.

In recent years, a “precision” or “personalized” molecular oncology approach to advanced cancer has begun to be practiced in several large cancer centers. The premise of such an approach is that clinicians could use molecular or genetic approaches to comprehensively profile a patient’s tumor and identify targets of vulnerabilities that could be matched with a specific therapy. These approaches are currently the subject of intense investigation to determine whether in-depth molecular profiling of advanced cancer can lead to successful matching of tumors to new therapies and improved patient outcomes.

The most recent FDA-approved drugs for HNSCC are immunotherapies, specifically drugs that target checkpoints on T cells. In HNSCC, these drugs target the PD-1 (programmed cell death-1) protein, which is a receptor expressed on T cells that suppresses T cell activity. PD-1 binds to PD-L1, a protein that can be expressed (and upregulated) by cancer cells as a means of allowing tumors to evade the immune system. By inhibiting PD-1, these drugs are able to release the brakes on the immune system and unleash adaptive immunity targeting cancer cells. Current research seeks to improve the response rates of these immune checkpoint therapies against HNSCC and understand why some tumors respond and some are resistant to these treatments.


A detailed history and physical examination form the basis for initial diagnosis. In addition to tumor parameters, a complete history should include evaluation of factors that may influence the management of the primary neoplasm, including a detailed family history, lifestyle habits (including smoking and alcohol consumption), sexual behavior, and occupational exposures. The patient’s comorbid conditions, such as nutritional status, chronic obstructive pulmonary disease, liver functions, and general medical condition, should be assessed carefully.

Clinical examination should be performed with the patient sitting upright. A headlight and simple instruments such as a tongue depressor should be used to facilitate examination of the oral cavity, along with a flexible fiberoptic laryngoscope to allow adequate assessment of the nasal cavity, nasopharynx, oropharynx, hypopharynx, and larynx. The examination begins with evaluation of the skin of the scalp, face, and neck, followed by palpation of the neck for masses, especially in the cervical nodal basins, and palpation of the thyroid and parotid glands. Evaluation of the external auditory canals and eardrum and anterior rhinoscopy also should be routine. Assessment of cranial nerve functions is integral and should be performed systematically. Examination of the oral cavity and oropharynx should include not only visual inspection but also palpation of the mucosa and underlying soft tissues of the tongue, floor of mouth, buccal mucosa, palate, tonsil, and base of the tongue. Flexible fiberoptic endoscopic examination should include visualization of the nasal cavity, nasopharynx, oropharynx, hypopharynx, and larynx, not only to look for mucosal and submucosal lesions but also to assess the soft palate and vocal cord function.

If a primary tumor is identified, its site of origin, visual characteristics, palpatory findings, and physical signs of local extension and invasion of adjacent structures should be meticulously assessed and documented to allow for staging and treatment planning. Adequate palpation, preferably bimanual palpation of the lesion when feasible, is necessary to assess the depth of invasion (DOI), since that is required to assign appropriate T staging of oral cancer. All malignant tumors of the head and neck region must be staged according to the staging system developed by the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (UICC), published in the eighth edition of the AJCC Cancer Staging Manual.

Staging of Head and Neck Cancer

Cancers of the head and neck are staged according to their site of origin. Seven major sites are described in the AJCC/UICC (International Union Against Cancer) staging system. The seven major sites are (1) oral cavity; (2) pharynx; (3) larynx; (4) nasal cavity and paranasal sinuses; (5) thyroid gland; (6) salivary glands; and (7) skin cancers, including melanoma. The most recent revisions in the staging criteria for common tumors and the regional lymph nodes were published in the eighth edition of the AJCC staging manual and are shown in Tables 1.1 to 1.9 . Because of a different biological behavior, p16+ (HPV-positive) oropharyngeal carcinomas have a separate nodal staging system (see Chapter 11 ).

Table 1.1

Staging for Carcinoma of the Lip and Oral Cavity

(Used with the permission of the American Joint Committee on Cancer [AJCC], Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, 8th ed. Springer Science and Business Media LLC, 2016, .)

Definitions of AJCC TNM
Definition of Primary Tumor
TX Primary tumor cannot be assessed
Tis Carcinoma in situ
T1 Tumor ≤2 cm, ≤5 mm depth of invasion (DOI)
DOI is depth of invasion and not tumor thickness
T2 Tumor ≤2 cm, DOI >5 mm and ≤10 mm
or tumor >2 cm but ≤4 cm, and ≤10 mm DOI
T3 Tumor >4 cm
or any tumor >10 mm DOI
T4 Moderately advanced or very advanced local disease
T4a Moderately advanced local disease
Tumor invades adjacent structures only (e.g., through cortical bone of the mandible or maxilla, or involves the maxillary sinus or skin of the face)
Note: Superficial erosion of bone/tooth socket (alone) by a gingival primary is not sufficient to classify a tumor as T4
T4b Very advanced local disease
Tumor invades masticator space, pterygoid plates, or skull base and/or encases the internal carotid artery

Table 1.2

Staging for Carcinoma of the Major Salivary Glands

(Used with the permission of the American Joint Committee on Cancer [AJCC], Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, 8th ed. Springer Science and Business Media LLC, 2016, .)

Definitions of AJCC TNM
Definition of Primary Tumor (T)
T0 Primary tumor cannot be assessed
Tis No evidence of primary tumor
T1 Carcinoma in situ
T2 Tumor 2 cm or smaller in greatest dimension without extraparenchymal extension *
T3 Tumor larger than 4 cm and/or tumor having extraparenchymal extension
T4 Moderately advanced or very advanced disease
T4a Moderately advanced disease
Tumor invades skin, mandible, ear canal, and/or facial nerve
T4b Very advanced disease
Tumor invades skull base and/or pterygoid plates and/or encases carotid artery

* Extraparenchymal extension is clinical or macroscopic evidence of invasion of soft tissues. Microscopic evidence alone does not constitute extraparenchymal extension for classification purposes.

Table 1.3

Staging for Carcinoma of the Larynx

(Used with the permission of the American Joint Committee on Cancer [AJCC], Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, 8th ed. Springer Science and Business Media LLC, 2016, .)

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Sep 29, 2019 | Posted by in HEAD AND NECK SURGERY | Comments Off on Introduction
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