Christopher M. Harris1 and Allen O. Mitchell2
1Department of Oral and Maxillofacial Surgery, Naval Medical Center Portsmouth, Portsmouth, Virginia, USA
2Otolaryngology—Head and Neck Surgery, Naval Medical Center Portsmouth, Portsmouth, Virginia, USA
Malignant tumors of the maxillofacial structures include oral and oropharyngeal cancers, salivary gland malignancies, skin cancers, and various types of non-oral epithelial malignancies (i.e., sarcomas, melanomas, and metastatic disease). Squamous cell carcinoma (SCCA) constitutes approximately 90% of all malignancies found in the oral cavity and oropharynx. This chapter will focus on the basic epidemiology, etiology, diagnosis, and staging of oral cancer lesions.
Oral-cavity SCCA, when compared to all sites, is relatively uncommon in North America. However, worldwide oral and oropharyngeal carcinomas together represent the sixth most common cancer in the world. Approximately 40,000 new cases will be diagnosed this year, representing 3–4% of all new cancer cases in the United States. Compared to major cancer types, the incidence of oral cancer in all races is higher than leukemia and pancreatic cancer in the United States. The incidence is higher in other parts of the world, especially in South Central–East Asia, where 8–10% of new cancers are oral SCCA. The majority of patients, including all racial groups, presenting with new disease are males. The incidence rate is higher in African American males especially. The overall male incidence rate is approximately 2.5 times that of females of any racial group. However, overall there has been a decreasing incidence over the last 30 years. Historically, the higher male incidence rates have been associated with higher tobacco and alcohol use in comparison to women. Newer data demonstrate high adolescent tobacco usage among females. This changing trend, along with other risk factors such as human papilloma virus (HPV) exposure, may alter the male-versus-female incidence rates in the future.
Mortality rates in oral SCCA have recently fallen slightly compared to historical data. The factors for this decrease are thought to be better diagnostic modalities, and surgical and adjunctive therapies. However, a likely factor for such a small decrease in mortality over the past three decades is the continued presentation of the majority of patients with late-stage (e.g., stage III or IV) disease and continued use of tobacco products with and without heavy alcohol consumption. Logically, improved early disease diagnosis by better screening and minimization of highly modifiable risk factors (i.e., smoking and alcohol abuse) would likely make significant steps in decreasing incidence and mortality.
The etiology of oral and oropharyngeal cancers can primarily be attributed to tobacco and alcohol abuse. The overwhelming number of new cases can be linked to these two risk factors. Cigarette smoking has been associated with up to 90% of all oral cancers. The oral cancer risk in smokers is 2–12 times the risk in nonsmokers. Concurrent heavy alcohol use appears to synergistically increase the risk of cancer development in smokers by up to 30 times that of the nonsmoking population. Factors, such as HPV and other genetic issues, do play a role as well.
Cigarette smoking is the single most important etiologic factor associated with oral cancer. Cigarettes have over 50 known carcinogens in them. The most commonly found are nitrosamines and polycyclic aromatic hydrocarbons. The carcinogenic effects of alcohol have not been completely identified. However, alcohol’s role as a solvent that may increase the cellular permeability of carcinogens is thought to be a major factor. Inhibition of genetic repair mechanisms and the role of alcohol in disrupting the immune response may be other ways it increases cancer risks.
Multiple genetic changes are required to alter normal mucosal epithelial cell lines to malignant cell lines. The primary mechanisms include the inactivation of tumor suppressor genes and activation of proto-oncogenes. The majority of genetic changes leading to malignancy are believed to occur early in mutagenesis and have a cumulative effect as the cell line progresses.
Viral-mediated changes have also been demonstrated in head and neck cancers as well, particularly those of the oropharynx. The viruses commonly associated with oral and oropharyngeal cancers are HPVs, in particular HPV 16. With HPV infection, the E6 and E7 viral oncoproteins result in the inactivation of tumor suppressor genes p53 and Rb. This can eventually lead to cellular immortalization, with continued accumulation of mutations that ultimately lead to carcinoma.
Early sexual contact and frequent sexual and orogenital sexual contacts have also been associated with HPV-related oral and oropharyngeal cancers, especially in younger populations who are nonsmokers. HPV-positive tumors tend to have earlier lymph node metastasis, yet also hold a better prognosis than HPV-negative tumors. HPV status is commonly reported with pathology specimens in most centers, but it plays no role currently in the staging of tumors.
These genetic changes do not directly correlate with clinical findings. The point of cellular transformation at which benignity becomes malignancy has yet to be elucidated and is typically thought to occur in a stepwise transition. The genetically altered cell lines cannot repair genetic damage and continue to accumulate genetic abnormalities with time. Eventually, the cell line transforms into a malignant phenotype, produces angiogenic factors to gain blood supply, evades immune surveillance, and extends beyond the basement membrane to become a clinical carcinoma.
Clinically, however, it is impossible to visually identify histological malignancy or this transformation period. For example, a leukoplakic lesion that may not make the clinician overly suspicious may in fact be a frank malignancy. A highly suspicious erythroleukoplakic lesion may only show dysplasia histologically. Several genetic changes could also likely be identified in histologically normal or dysplastic tissue that may not be present in a malignant lesion. The role of genetic alterations in the transformation of benign to malignant cell lines is an area of intense research and will hopefully yield better molecular- and genetic-level testing in the future, eventually giving surgeons better diagnostic and treatment modalities.
A premalignant lesion is a morphologically altered tissue with a higher likelihood of developing into a frank malignancy than normal tissue. Clinically, premalignant lesions are described as leukoplakia, erythroplakia, or erythroluekoplakia. Histologically, these premalignant lesions are described as dysplasia or carcinoma in situ.
Leukoplakia is defined as a white patch or plaque that cannot be removed by scraping or rubbing and cannot be characterized as another disease entity. Erythroplakia is a red plaque or patch that cannot be removed by scraping or rubbing and cannot be characterized as another disease entity. Leukoplakic lesions may be unifocal or multifocal, and they can occur anywhere in the oral cavity. Lesions located on the tongue (except the dorsal surface) and the floor of mouth are more worrisome, as more than 20% of tongue and lip lesions, and more than 40% of floor-of-mouth lesions, exhibit premalignant histologic features. Malignant transformation of leukoplakic lesions is poorly understood. Rates from less than 1% upward to 17.5% have been reported. Erythroplakic lesions and erythroleukoplakic lesions are more serious lesions. The large majority of these lesions harbor some degree of histologic premalignancy or malignancy. Malignant transformation rates are thought to approach more than 20%.
There is no molecular marker, despite advances in research that can identify those lesions that will progress to malignancy. There is also no evidence that removal prevents the progression toward malignancy. Thus, there is debate about the management of leukoplakic premaligant lesions, with some practitioners advocating removal of the lesions, while some recommend close observations and biopsies as needed for clinical changes. Erythroleukoplakic lesions should be completely excised and sent for histopathologic evaluation.
The American Joint Committee on Cancer subdivides the oral cavity into distinct anatomical sites. These seven sites are an attempt to define the biological behavior and treatment modalities of the lesions within them. These sites are the mucosal lip, alveolar ridge (gingiva), buccal mucosa, floor of mouth, tongue (oral), retromolar region, and maxilla (hard palate).
Mucosal lip cancers are most commonly seen on the lower lip in elderly white male patients with a history of chronic sun exposure. This is one of the oral cancers whose primary etiology is not considered to be associated strongly with tobacco use. From 2% to 42% of oral cavity cancers have been reported on the mucosal lip. Lymphatic drainage is typically level I and level II nodes, perhaps bilaterally if the primary lesion is on or approaches the midline.
Alveolar ridge cancers, including gingival tumors, can be seen in the maxilla but predominantly involve the mandibular alveolar mucosa and gingiva. They range from 25% to 28% of all oral cancers, and approximately one-third involve the underlying bone. Typical nodal involvement occurs in level I and level II and occurs in approximately 25% of cases. These diagnoses of the lesions are frequently delayed due to misdiagnosis as periodontal lesions or traumatic and inflammatory gingival lesions.
Buccal mucosa cancers represent 2–10% of all oral cavity cancers. Lymphatic involvement is typically noted in level I and level II regions. Involvement of regional lymphatics occurs in up to 30% of presenting cases. There is some evidence arguing to electively treat the neck in many buccal mucosa lesions due to the high incidence of neck metastasis with even smaller lesions.
The floor of mouth is a common location for oral cancer. Approximately 25% of oral cancers are found in this area. Nearly one-half of all patients presenting with floor-of-mouth lesions will have regional metastasis. Tumor depth in this region is critical when evaluating the primary lesion/>