Malignant tumors are popularly referred to as ‘cancer’. However, the term ‘tumor’ is scientifically more appropriate. Tumor is defined as an autonomous new growth of tissue or an abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of normal tissue and persists in the same excessive manner even after the cessation of stimuli which evoked the change.
Hippocrates described various types of cancers. He referred to benign tumors as oncos (swelling in Greek) and malignant tumors as carcinos (crab or crayfish in Greek). He compared malignant tumors to a crab since the sectional morphology of the tumor along with its vascular supply mimicked the body of a crab with its claws and feet outstretched.
Aulus Cornelius Celsus, a Roman encyclopedist, translated carcinos into the Latin cancer, which also means crab. Galen, the Roman physician used oncos to describe all tumors, which laid the foundation for the use of the present day term ‘oncology’.
Oral malignancies may arise from the epithelium, muscle mass, odontogenic structures, specialized structures like the tongue and the eye, from the salivary glands both major and minor and also from the bone. However, it is virtually impossible to describe all the forms of cancer in this chapter.
As oral carcinoma is one of the most prevalent cancers and is one of the 10 major causes of death, this chapter will attempt to highlight the etiology, clinical features, diagnosis, investigations and the treatment options.
According to the World Health Report (2004), cancer accounted for 7.1 million deaths in 2003 and it is estimated that the overall number of new cases will rise by 50% in the next 20 years. Oropharyngeal cancer is more common in developing countries than developed countries. The prevalence of oral cancer is particularly high among men, the eighth most common cancer worldwide. Incidence rates for oral cancer vary in men from 1 to 10 cases per 100,000 population in many countries. In South-Central Asia, cancer of the oral cavity ranks among the three most common types of cancer. In India, the age standardized incidence rate of oral cancer is 12.6 per 100,000 population. More than 90% of all oropharyngeal cancers occur in patients over the age of 45. As with other head and neck tumors, male predominance is common, with a male to female ratio of 4:1, because of the greater use of tobacco by men.
It has been estimated that 43% of cancer deaths worldwide are due to tobacco, unhealthy diet, physical inactivity and infections. Tobacco use and excessive alcohol consumption have been estimated to account for about 90% of cancers in the oral cavity; the oral cancer risk increases when tobacco is used in combination with alcohol or areca nut.
About 96% of all oral cancers are carcinomas and the remaining 4% are sarcomas. Majority of oral carcinomas are squamous cell carcinomas. It is estimated that 9 out of every 10 oral malignancies is squamous cell carcinoma. It is a disease of increasing age with 95% of the patients older than 40 years of age.
In India, it is estimated that there are 2–2.5 million cancer patients at any given point of time with about 0.7 million new cases diagnosed every year and nearly half of them die every year. Two-thirds of the new cancers is diagnosed at a very advanced and incurable stage. More than 60% of these affected patients are in the age group of 35 and 65 years. Fifty percent of all male and 25% in female are tobacco related cancers.
The exact etiology for oral cancer is still questionable. However, it is well known that a plethora of factors predispose an individual to developing oral cancers. Historically, the widely known six “S” has been mentioned in literature, namely, smoking, spirit, sharp teeth, sunlight, syphilis, spicy food and sepsis. However, over a period of time many predisposing factors have been proposed and suggested such as genetic susceptibility, environmental factors, systemic health of an individual and abusive habits such as the consumption of tobacco and alcohol.
Family history of oral cancer is considered a risk factor. Head and neck cancer patients show an increased susceptibility to chromosome damage by mutagens. Some studies suggest that lip cancers have shown some amount of genetic predisposition. Mork et al (1999) reported a significantly increased odds ratio for developing head and neck squamous cell carcinoma in female patients, aged less than 45 years, who had first-degree relatives with cancer. It is suggested that familial oral cancer may be attributed to both shared environmental factors within families and a common oral cancer susceptibility gene with low penetrance.
It has been noticed that immunosuppressed individuals tend to show an increased incidence of oral malignancies. It is also a well-known fact that the host response diminishes with advancing age. HIV-positive immunocompromised individuals, may usually exhibit Kaposi’s sarcoma and non-Hodgkin’s lymphomas.
There is enough evidence in literature to show that skin and lip cancers are more frequently seen in individuals whose occupation necessitates long working hours in the sun such as fishermen and farmers.
It has been reported that fair skinned individuals, people residing in high latitudes with clear atmosphere (UV light can penetrate easily) such as Finland and Sweden, residents closer to the equator (long periods of sunshine) such as Greece are more susceptible to develop lip cancers. The wavelengths of the light thought to be responsible for the actinic damage are in the range of 2,900–3,200 A. Sunscreen lotions are effective in protecting the lip from the damaging effects of UV light. Melanin pigment acts as a protective agent against actinic radiation.
Air pollution arising from industrial wastes and automobile exhausts are particularly harmful. Other sources include gases emitted from burning firewood/coal for domestic purposes. Sulfur dioxide, carbon monoxide, nitrogen gases have been implicated in causing pharyngeal, laryngeal and lower respiratory tract cancers.
All the forms of tobacco (smoke and the smokeless/ chewable/inhaled) such as cigarettes, pipes, cigars, beedis, paan and snuff have been implicated in the development of oral cancers. It is believed that tobacco use is responsible for 90% of the oral cancers in males.
It is estimated that 80–85% of tobacco is consumed for smoking either as beedis or cigarettes (Figure 1). Almost 13% chew tobacco in the form of paan (Figure 2, betel leaf, areca nut, tobacco, slaked lime and flavoring agents) or gutkha. Almost 15% are addicted to both habit of chewing and smoking. Only about 1–3% use tobacco in the form of snuff.
Figure 1 A typical road-side shop selling various tobacco products ranging from cigarettes, beedis, paan to gutkha. Ironically displaying the fact that tobacco causes cancer. Courtesy: Department of Oral Medicine and Radiology, Manipal College of Dental Sciences, Mangalore
People in the Indian subcontinent exhibit various forms of tobacco chewing habits such as khaini, mishri, zarda, gutkha (Figure 3), mawa and nass. Paan is chewed (betel quid) and the quid is usually placed in the buccal vestibule.
Tobacco is also used in the form of a powder for inhalation (Figure 4, snuff). Tobacco (Figure 5) contains nicotine (nitrosamine), nitrosodiethanolamine, nitrosoproline, polonium and polycyclic aromatic hydrocarbon (tars). Areca nut (Figure 6 contains cholinergic muscarinic alkaloids such as arecholine and guavacoline) chewing is also widely practiced in India.
Figure 4 Snuff used for inhalation. One of the risk factors for causing nasopharyngeal and maxillary sinus cancers. Courtesy: Department of Oral Medicine and Radiology, Manipal College of Dental Sciences, Mangalore
In India, beedi (Figure 7), cigarette and chutta smoking is commonly seen. However, other popular forms of smoking include use of pipe, cigar and hookah. It is believed that cigar and pipe smoking is more hazardous than cigarette smoking. Palatal cancers are more common in individuals who place the lit end of the beedis and cigarettes inside the mouth (reverse smoking). It has been proposed that smoking causes pooling of carcinogens in saliva thereby increasing the incidence of cancers of the floor of the mouth, ventral and lateral surface of tongue.
Figure 7 Beedis made of tobacco wrapped in a tendu (Diospyros melanoxylon) leaf, and secured with thread at one end. The tobacco content in beedis is approximately 10–20%. Courtesy: Department of Oral Medicine and Radiology, Manipal College of Dental Sciences, Mangalore
It is estimated that in the combustion mainstream of one cigarette (Figure 8), there are approximately 500 mg (92%) of gaseous content (mainly oxygen, nitrogen and carbon dioxide and to a little extent carbon monoxide) and 8% of particulate matter. Aromatic hydrocarbons in the form of ‘tars’ may constitute less than 1 g to 35 mg. Nicotine content varies from 1 to 3 mg. Other constituents of tobacco smoke include carbon monoxide, hydrogen cyanide and thiocyanate. Benzopyrene is considered the most potent carcinogen. It preferentially binds to nucleoproteins. The enzyme aryl hydrocarbon hydroxylase that is principally produced in human leukocytes, is said to increase the carcinogenic potential of benzopyrene.
The carcinogenic properties of marijuana smoke are similar to those of tobacco. Marijuana may interact with mutagen sensitivity and other risk factors to increase the risk of head and neck cancer. Marijuana smoke has a four times higher tar burden and 50% higher concentrations of benzpyrene and aromatic hydrocarbons than are present in tobacco smoke.
Alcohol consumption is the most important risk factor for development of oral cancer in non-smokers. It is also considered as the second independent major risk factor for the development of oral cancer. It is estimated that an average consumption of over 30 ml of alcohol per day increases the risk of oral cancer linearly with the quantity of alcohol consumed. Though any form of alcohol when consumed in large quantities is dangerous, it is believed that dark colored drinks are more hazardous (as they may contain higher beverage congeners such as nitrosamines, hydrocarbons and other impurities which are known carcinogens). Carcinogens present in the tar are insoluble in saliva but are highly soluble in alcohol and easily absorbed in the oropharynx.
Ethyl alcohol increases the permeability of oral mucosa. It also dehydrates the mucosa. It has a solvent action on the keratinocyte membrane thereby allowing the passage of carcinogens into proliferating cells where they may exert a mutagenic action.
Alcohol, owing to its high calorific value, suppresses appetite in heavy drinkers. This predisposes to nutritional deficiency which in turn is a risk factor for cancers. Compared to non-users, alcohol users are 3.6 times more likely to have oropharyngeal cancer, 5.8 times for tobacco users, and 19 times for users of both alcohol and tobacco.
Autoimmune polyendocrinopathy candidiasis-ectodermal dystrophy an autosomal recessive disease associated with a limited T lymphocyte defect, presumably supports the growth of Candida albicans and predisposes to chronic mucositis and oral cancer.
In diabetic patients, alterations occur in the oxidative equilibrium of free radicals. Elevated blood glucose levels can lead to excessive formation of free radicals. Moreover, due to protein breakdown, the activity of anti-oxidant cavengers and enzymes is reduced. Both the increase in free radicals and oxidative stress promote carcinogenesis.
It has been suggested that poor diabetic control is associated with an increased cancer risk due to enhanced oxidative damage to DNA. Production of reactive oxygen species and lipid peroxidation are increased in diabetic patients, especially in those with poor diabetic control and hypertriglyceridemia. Increased oxidative damage can be due to superoxide radical generation by monocytes through nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Superoxide can undergo either enzymatic or non-enzymatic dismutation to generate hydrogen peroxide. In the presence of transition metals, such as Fe++ and Cu++, both these substances contribute to the generation of highly reactive hydroxyl radicals causing damage to cells. Hence, patients with poorly controlled diabetes are at great risk of developing oral cancer.
In the older literature, syphilis was considered an important predisposing factor for oral leukoplakia and oral cancer. It was suggested that syphilitic infection caused endarteritis and subsequently atrophy of the overlying epithelium. This made the tongue more vulnerable to the etiological factors. In modern times, tertiary syphilis is rarely encountered in clinical practice due to effective treatment.
Trieger et al (1958) reported a study that suggests an increased prevalence of syphilis (approximately up to 60%) in patient groups with squamous cell carcinoma of the tongue. It was seen that this association was stronger in males than females.
Michalek et al (1994) reported a study of 16,420 people with syphilis resident in the United States that showed a significantly raised frequency of cancer of the tongue (and Kaposi’s sarcoma) in males. Dickenson et al (1995) screened 63 patients of United Kingdom suffering from squamous cell carcinoma of the tongue. Five of these patients had serological evidence of past syphilis when detected by both specific and non-specific tests.
Exposure to large amounts of ionizing radiation such as in a nuclear mishap is a known risk for causing cancers. Radiation exposure, known to cause DNA damage, may be a potential source of field cancerization of the upper aerodigestive tract.
Hashibe et al (2005) evaluated the possible risk of developing second primary cancers following radiotherapy for head and neck cancers in 30,221 oral squamous cell carcinoma patients. Patients treated with radiation only or radiation with surgery had elevated risks of developing a second primary tumor, whereas patients treated with surgery only did not appear to be at increased risk. They also suggested that the expected latent period between radiation exposure and tumor occurrence, radiation became a risk factor after 10 years of follow-up for solid cancers of the oral cavity, pharynx, esophagus, and lung, and after 1–5 years of follow-up for second primary leukemia.
The role of viruses remains unclear. Varying viral genomes have been frequently found within cancer cells. Viruses have been known to modify the DNA and the chromosomal structures and induce proliferative changes in the cells they infect.
Evidence of a viral carcinogenesis is perhaps strongest for infection with human papilloma viruses (HPV). D’souza et al (2007) in a multicenter case-control study reported that infection with HPV-16 increased the risk of cancer of the oral cavity and particularly oropharynx.
The role of infection with Epstein–Barr virus (EBV) and herpes simplex viruses (HSV) remains uncertain. The role of HSV, HSV-1 and HSV-2, as co-factors in association with tobacco, alcohol, or HPV-16 infection has also been proposed in causing oral cancers.
Human immunodeficiency virus (HIV), due its effect on immunosurveillance, acts as a cofactor along with other viruses such as EBV and cytomegalovirus in predisposing the affected individual to oral cancer.
Various studies have shown that a diet with low vitamin A, vitamin C, vitamin E, iron, selenium, folate and other trace element content is associated with an increased risk of oral, laryngeal, lung, gastric, ovarian, breast and cervical cancers. Certain dietary deficiencies may cause epithelial atrophy which renders the epithelium vulnerable to the action of carcinogens. The relationship between sideropenic dysphagia and oral cancer is well recognized (sideropenic dysphagia may be associated with epithelial atrophy in the upper alimentary tract).
Garewal (1994) summarized the findings of 54 studies that evaluated fruit and vegetable intake in the development of cancers in the upper aerodigestive tract; he found that 52 of the studies demonstrated a protective effect of the antioxidant content of fruits and vegetables.
It has been shown that patients who ingest high levels of vitamin C and fiber have half the risk of developing oral cancer as those with minimal level of consumption. Block (1991) and Mirvish (1986) showed that a low intake of vitamin C is associated with an increased risk of cancers of the stomach, esophagus, oral cavity, larynx, and cervix.
Though the exact etiological role of poor oral hygiene, faulty restorations, ill-fitting dentures, sharp teeth in causing oral cancers is not substantiated, these may be the possible contributing factors. It is believed that chronic trauma along with other carcinogens may aid in the malignant transformation of epithelial cells.
Shah (2003) suggests that the microorganisms from dental plaque, by way of chemical carcinogenesis, may produce nitrosating enzymes which are toxic. It is also believed that individuals who do not maintain good oral hygiene (inadequate brushing) may fail to dilute the carcinogens present in the oral cavity, especially derived from various tobacco-related habits.
Though no one truly understands how these conditions either in their individual standing or in conjunction with other entities leads to cancer, the greater understanding of the importance of genetics and the role of pro-oncogenes and tumor suppressor genes has given us a more detailed insight into the evolution of a cancerous growth. Cellular and molecular basis of malignancy though needs more detailed discussion it could be best summarized under the following sections.
Generation time is the time required for a quiescent cell to enter the cell cycle and give rise to two daughter cells. Malignant cells usually have a shorter generation time than non-malignant cells and a smaller percentage of cells in G0 (resting phase), so a larger proliferation fraction exists. Initial exponential tumor growth is followed by a plateau phase when cell death equals the rate of formation of daughter cells. Compared to large tumors, small tumors have a greater percentage of actively dividing cells and thus show greater rates of proliferation.
As a tumor grows, nutrients are provided by direct diffusion from the circulation. Local growth is facilitated by enzymes (e.g. collagenases) and cytokines that alter or destroy adjacent tissues. As the ratio of surface area to volume becomes smaller with increased tumor growth, tumor angiogenesis factors are produced, forming the independent vascular supply required for further tumor growth. Almost from inception, a tumor may shed cells into the circulation. From animal models, it is estimated that a 1-cm tumor sheds more than 1 million cells/24 h into the venous circulation. Although most circulating tumor cells die as a result of intravascular trauma, a tiny number (much less than 1 in 1 million) adhere to the vascular endothelium and penetrate into surrounding tissues, generating independent tumors (metastases) at distant sites. Metastatic tumors grow in much the same manner as primary tumors and may subsequently give rise to other metastases. Experiments suggest that metastasis is not a random event and that the primary tumor may regulate the growth of metastatic tumors, for example, removal of the primary tumor sometimes results in rapid growth of the metastases.
Genetic mutations are largely responsible for the generation of malignant cells. These mutations alter the quantity or function of protein products that regulate cell growth and division and DNA repair. Two major categories of mutated genes are oncogenes and tumor suppressor genes.
Oncogenes are abnormal forms of normal genes (protooncogenes) that regulate cell growth. Mutation of these genes may result in direct and continuous stimulation of the molecular biologic pathways (e.g. intracellular signal transduction pathways, transcription factors, secreted growth factors) that control cellular growth and division.
There are more than 100 known oncogenes that may contribute to human neoplastic transformation, for example, the ras gene encodes the Ras protein, which regulates cell division. Mutations may result in the inappropriate activation of the Ras protein, leading to uncontrolled cell growth and division. In fact, the Ras protein is abnormal in about 25% of human cancers. Other oncogenes have been implicated in specific cancers. These include various protein kinases (bladder cancer, breast cancer), bcr-abl (chronic myelocytic leukemia, B-cell acute lymphocytic leukemia), C-myc (small cell lung cancer), N-myc (small cell lung cancer, neuroblastoma), and C-erb B-2 (breast cancer).
Specific oncogenes may have important implications for diagnosis, therapy, and prognosis (see individual discussions under the specific cancer type). Oncogenes typically result from acquired somatic cell mutations secondary to point mutations (e.g. from chemical carcinogens), gene amplification (e.g. an increase in the number of copies of a normal gene), or from insertion of viral genetic elements into host DNA. Occasionally, mutation of germ cell lines results in vertical transmission and a higher incidence of cancer development in an offspring.
Tumor suppressor genes are inherent genes that play a role in cell division and DNA repair and are critical for detecting inappropriate growth signals in cells. If these genes, as a result of inherited or acquired mutations, become unable to function, genetic mutations in other genes can proceed unchecked, leading to neoplastic transformation.
As with most genes, two alleles are present that encode for each tumor suppressor gene. A defective copy of one gene may be inherited, leaving a person with only one functional allele for the individual tumor suppressor gene. If an acquired mutation occurs in the other allele, the normal protective mechanisms of the tumor suppressor gene are lost, and dysfunction of other protein products or DNA damage may escape unregulated, leading to cancer.
Another mechanism that results in defective function and transcription of tumor suppressor genes is aberrant methylation of the promoter region of these genes, which inhibits gene transcription. Greater degrees of aberrant methylation and greater numbers of affected genes cause tumors to be more malignant and are associated with shortened survival in lung, bladder, and prostate cancers. In vitro alteration of the aberrant methylation has caused reversion to a non-malignant, non-proliferative phenotype, suggesting a potential therapeutic target.
Another important regulatory protein, p53, prevents replication of damaged DNA in normal cells and promotes cell death (apoptosis) in cells with abnormal DNA. Inactive or altered p53 allows cells with abnormal DNA to survive and divide. Mutations are passed to daughter cells, conferring a high probability of neoplastic transformation. The p53 gene is defective in many human cancers.
Gross chromosomal abnormalities can occur through deletion, translocation, or duplication. If these alterations activate or inactivate genes that result in a proliferative advantage over normal cells, then a tumor may develop. Chromosomal abnormalities occur in certain human cancers. In some congenital diseases (Bloom syndrome, Fanconi syndrome, Down’s syndrome), chromosomes break easily, putting children at high risk of developing acute leukemia and other cancers.
Most cancers are likely to involve several of the mechanisms described above that lead to neoplastic conversion. As with oncogenes, mutation of tumor suppressor genes in germ cell lines may result in vertical transmission and a higher incidence of cancer in an offspring. Telomeres are nucleoprotein complexes that cap the ends of chromosomes and maintain their integrity. Telomere shortening (with aging) results in replicative senescence, increased genetic instability, and potential tumor formation. Telomerase is an enzyme that carries out telomere synthesis and maintenance, thus telomerase may potentially allow for cellular immortality. Telomerase activity may promote tumors through multiple, complex mechanisms, especially by subverting the normal DNA synthetic checkpoints.
The hardest part of treating cancer is diagnosing it early, but it is also the most easiest part of treating cancer because if discovered early, the lesions are amenable to simple excision and patients have a good chance of a 5-year disease-free survival rate. It makes it easier to remember if the clinical signs are discussed based on the regional anatomy.
The clinical presentation varies in most cases and there are no two cases that are similar in presentation and treatment. However, there could be a few similarities that are peculiar to the geographic area that could be grouped together and explained as an entity, for example, carcinoma of the buccal mucosa and the gingivobuccal sulcus that are peculiar to the Indian subcontinent and have been nicknamed as ‘Indian Cancers’. Cancers of the floor of the mouth are more common in the western countries because of their habits. The following section is just a brief explanation of the various clinical signs and symptoms based on their area of presentation.
The lesions develop most frequently along or inferior to a line opposite the plane of occlusion. It usually occurs at the regions of the third molar area (Figure 9) as there is a habit of keeping the quid (tobacco) in that area for a long period of time. The tumor may appear as small nodules and enlarges to from a wart-like growth which ultimately ulcerates or may even begin as an ulceration that does not heal. The lesion is often not painful and is noticed by the patient only when there is a secondary infection of the ulcer. There is induration and infiltration into the deeper tissues. Extension into the muscle of mastication, buccinators, alveolar mucosa and ultimately into the bone may occur and if left unchecked which may cause perforation of the overlying skin (Figure 10). The induration of the skin is a bad clinical sign and necessitates wider excision along with the overlying skin.
Some cases appear to be growing outward from the surface rather than invading the tissues is called exophytic or verrucous growth. The most common site of metastasis is the submandibular lymph nodes as they are the primary echelon nodes for these regions.