|Year : 2016 | Volume
| Issue : 2 | Page : 51-62
An overview of oral carcinogenesis
Shanmugam Manoharan1, Sekar Karthikeyan2, Musthafa Mohamed Essa3, Asokan Manimaran2, Renganathan Selvasundram2
1 Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Chidambaram, Tamil Nadu, India
2 Department of Biochemistry and Biotechnology, Annamalai University, Chidambaram, Tamil Nadu, India
3 Department of Food Science and Nutrition, Sultan Qaboos University, Muscat, Sultanate of Oman
|Date of Web Publication||11-Apr-2016|
Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalai Nagar, Chidambaram - 608 002, Tamil Nadu
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Cancer, a life-threatening global burden, is characterized by clonality, autonomy, anaplasia, invasion, and metastasis. Each and every year, the incidence of cancer is increasing worldwide. Most of the cancers arise due to changes in the lifestyle, including tobacco, smoking, and alcohol abuse. Although 100 different types of cancers were reported so far worldwide, oral cancer, skin cancer, mammary cancer, lung cancer, and cervical cancer are the most predominant cancers. Cancer of the oral cavity remains life-threatening disease for more than 50% of the newly diagnosed patients. Lack of awareness, delay in diagnosis, and patient's delay are attributed to the high incidence of oral cancer, despite easy physical examination of the oral cavity. Moreover, the survival outcome of oral cancer patients was not drastically improved despite recent advancement in the treatment of oral cancers. The present review presents the epidemiology and etiology of oral cancer in detail. Furthermore, the biochemical and molecular changes occurring in oral carcinogenesis are also explored. The chemopreventive agents that are evaluated against experimental carcinogenesis are also briefly summarized.
Keywords: Alcohol, chemoprevention, oral cancer, tobacco
|How to cite this article:|
Manoharan S, Karthikeyan S, Essa MM, Manimaran A, Selvasundram R. An overview of oral carcinogenesis. Int J Nutr Pharmacol Neurol Dis 2016;6:51-62
|How to cite this URL:|
Manoharan S, Karthikeyan S, Essa MM, Manimaran A, Selvasundram R. An overview of oral carcinogenesis. Int J Nutr Pharmacol Neurol Dis [serial online] 2016 [cited 2020 Jan 19];6:51-62. Available from: http://www.ijnpnd.com/text.asp?2016/6/2/51/179964
| Introduction|| |
Cancer, a life-threatening global burden, is characterized by clonality, autonomy, anaplasia, invasion, and metastasis. It comprises a large group of diseases and affects all age groups. Although 100 different types of cancers were reported so far worldwide, oral cancer, skin cancer, mammary cancer, lung cancer, and cervical cancer are the most predominant cancers. The symptoms of cancer depend on its location, size, invasion, and metastasis. Early detection and diagnosis could definitely improve the survival rate as well as the life quality of the patients. Cancer patients, depending on the nature and location of tumors, are subjected to surgery, chemotherapy, radiotherapy, gene therapy, or immunotherapy. ,
Each and every year, the incidence of cancer is increasing worldwide. Most of the cancers arise due to changes in the lifestyle, including tobacco, smoking, and alcohol abuse.  Bacteria, viruses, and other environmental factors are also responsible for rapid increase in the incidence of cancers.  Cancer, a burgeoning threat to the world health, has profound economic and social consequence for people worldwide. According to Ferlay et al. 14.1 million new cancer cases were diagnosed in the year 2012 worldwide.  They also reported that 8.2 million deaths occurred due to cancer in 2012. Epidemiological studies from the USA reported that around 1,658,370 newly diagnosed cancer cases and 589,430 deaths due to these cancers are projected to occur by the year 2015.  In UK, cancer affects around 530 males and 510 females per 100,000 cases every year.  Cancer registry reports from Russia reported that approximately 2.1% of the total country populations are affected by cancer every year.  In Russia, malignant cancers accounts for 15% of all deaths.  Around 2.8 million newly diagnosed cancer cases and 1.96 million cancer-related deaths are reported from China every year. 
In India, cancer is responsible for increased morbidity and mortality and each year around 1 million new cancer cases are diagnosed and around 600,000-700,000 Indians died due to cancer by the year 2012.  Epidemiological studies highlighted that overall cancer incidence in India was lower as compared to developed countries.  At the same time, these studies focused that the relative rates of cancer mortality were higher in India.  The Indian council of medical research recently pointed out that 2.5 million Indians live with a clinical history of cancer. In India, 92.4/100,000 men and 97.4/100,000 women are affected by cancer each year. 
| Oral Cancer|| |
Oral cancer, the cancer of the oral cavity, arises due to the accumulation of multiple genetic alterations in the squamous cells of the oral cavity. Squamous cell carcinoma is the predominant form of oral cancer and accounts for 90% of all oral cancers.  Cancer of the oral cavity remains a life-threatening disease for more than 50% of the newly diagnosed patients. Despite readily available diagnostic tools, lack of awareness, and delayed prognosis have heightened the incidence of oral cancer.  Most of the oral cancer patients' survival outcome depend on the location and stages of the tumors.  It is predicted that the 5 years survival outcome is still at 50% for oral cancer patients, and the survival years have decreased for tongue cancer patients.  Moreover, the survival outcome of oral cancer patients was not drastically improved despite recent advancement in the treatment of oral cancers. Thus, the only key criteria, which could reduce the morbidity and mortality of oral cancer is the early diagnosis.
| Epidemiology Of Oral Cancer|| |
Epidemiological studies from various countries pointed out that around 300,000 people are newly diagnosed with oral cancer every year worldwide and of these two-thirds are from developing countries.  Global variance in the annual incidence rate of oral cancer is due to variation in the consumption or exposure to the risk factors such as tobacco and alcohol.  Cancer of the oral cavity is the sixth most common cancer in the USA, where the annual incidence rate is 10/100,000.  Furthermore, around 8000 deaths due to oral cancer are reported from the USA each year. Around 35,000 Americans are newly diagnosed with oral cancer every year.  The annual incidence rate for oral cancer for men and women together is 10.5/100,000 in the USA. Oral cancer together with pharyngeal cancer attained 7 th position in the incidence in the European Union, where 70,000 new cases are reported each year.  It has been estimated that 1.17% Europeans have lifetime risk for oral cancer development.  Higher oral cancer incidences are reported from France, Hungary, Slovakia, Slovenia, Brazil, and Uruguay every year.  South and Southeast Asia have been pointed out as high incidence regions for oral cancer. India, Bangladesh, Sri Lanka, and Pakistan are regarded as high-risk countries, where oral carcinoma constitutes around 40-50% of all malignancies.  Oral cancer incidence is found to be higher in some of the regions of Hong Kong, Brazil, and Europe.  In Brazil, the annual incidence of oral cancer has been estimated to be 13 cases/100,000.  Taiwan reports that the annual incidence of oral cancer is increasing rapidly and this form of cancer is responsible for the major cause of death in males, ranging in ages between 25 and 44.  In the UK and Canada, oral cancer affects approximately 4000 individuals each year.  In African countries, the incidence of oral cancer is very low and, therefore, it is not a serious problem. However, a study from Sudan reported men are affected by oral cancer more than women.  The incidence and mortality rate of oral cancer was found to be 3.5/100,000 and 1.5/100,000, respectively in China.  The World Health Organization highlighted India as a global epicenter of oral cancer and pointed out oral cancer as a major health challenge and burden in this country.  Furthermore, oral carcinoma accounts for 40% of all cancer-related deaths in India.  In India, every year around 70,000 new cases emerge, and around 48,000 deaths due to oral carcinoma are reported.  In India, the annual incidence is estimated to be 19/100,000, according to databases. 
| Age And Sex Distribution|| |
The persons aged between 40 and 70 years are mainly affected by oral cancer. It has been pointed out that oral cancer patients are mostly at sixties of life at the time of diagnosis.  Male preponderance than female has been reported for oral cancer incidence worldwide.  This might be due to the habits such as tobacco and alcohol use, which are more prevalent in males. Oral cancer affects more men than women in USA.  However, in developing countries such as India, the male-female ratio is closer to 1:1.  The male-female ratio for oral cancer in Japan is estimated to be 3:2. 
| Site Distribution|| |
While tongue cancer is the most predominant cancer among USA and European populations, buccal cancer is found to be more common in Asian countries including India.  Lip, floor of mouth, palate, and gingivae are other less common intraoral sites of the cancer of the oral cavity.
| Risk Factors Of Oral Cancer|| |
The substance or agents that enhance the chances of getting a particular disease are represented as risk factors. Long-term abuse of tobacco and alcohol are identified as the major risk factors in the oral cancer pathogenesis [Figure 1]. Tobacco and betel quid chewing, tobacco, bidi and cigarette smoking and alcohol consumption are important risk factors of oral cancer in India.  Other contributing factors including viral pathogens, increased exposure to sun, nutritional deficiency stemming from low socioeconomic status are recognized as additional risk factors of oral cancer. 
Tobacco, in the form of smoking and chewing, is widely prevalent irrespective of age groups and genders worldwide. Teenagers and youngsters adopt these detrimental habits either from their parents or from the society (friends and relatives etc.).  Despite mounting evidences highlighted the serious health problems associated with tobacco smoking, chewing, and alcohol abuse, these risk factors are still responsible for 30-40% of all cancer-related deaths.  Tobacco contains life-threatening chemicals such as benzo(a)pyrene and nitrosamines. These chemicals cause extensive damage to DNA, contributing to malignant transformation.  A firm association was established between tobacco use and the duration of habits as well as the frequency of tobacco smoking or chewing. 
Worldwide, one billion men and 250 million women are identified as daily smokers.  Cigarette and bidi smokers are 3-4 times more at of developing oral cavity cancers.  Passive smokers are also at increased risk if they were exposed for 10-15 years.  The frequency and the duration of the bidi smoking has been correlated well with the incidence of oral cancer.  Bidi smokers have 3-fold risk to develop oral cancer as compared to cigarette smokers.  The higher amount of nicotine and tar released during bidi smoking is responsible for oral carcinogenesis.  Worldwide meta-analysis data warned that the current smokers have the relative risk rate of 3.43 to get oral carcinoma.  Pipe smoking mainly causes lip cancer and the malignant transformation occurs in the lip area that touches the pipe stem.  Around 100 million Indians are habituated to bidi smoking. The habits of bidi and cigar smoking are more common in rural regions of India. 
Smokeless tobacco refers to the habits of tobacco use other than smoking. Smokeless tobacco includes tobacco chewing, betel quid chewing, and snuffs. Smokeless tobacco has around 25 powerful carcinogens, which can cause extensive damage to DNA. Some of the potent carcinogens in smokeless tobacco include tobacco-specific nitrosamines, formaldehyde, and benzo(a)pyrene.  It has been reported that smokeless tobacco consumption is highly prevalent in Indian populations as compared to tobacco smoking and alcohol consumption.  Long-term smokeless tobacco usage increased the oral cancer risk and is mainly attributed to the presence of tobacco-specific nitrosamines. 
Betel quid chewing
In many parts of the world, especially South Asia and South East Asia, the habits of betel quid (made up of areca nut and lime wrapped in a betel leaf) chewing is commonly prevalent and is accepted as a social custom.  It has been reported that those who are habituated to betel quid chewing for 20 years and chewing 10 times daily have an increased risk to get oral cancer.  Betel quid chewing enhances the risk of oral cancer development to a several fold. Betel quid mediates carcinogenic process through carcinogenic nitrosamines and by generating excess reactive oxygen species (ROS) in the oral cavity.  Excessive ROS generation is due to auto-oxidation of polyphenols present in the areca nut. Areca nut chewing is also recognized as an important risk factor of oral cancer.  It has been pointed out that keeping the betel quid for a longer time in the mouth enhance the risk to a greater extent. 
World health organization reported that around 2 billion people are habituated to alcohol consumption worldwide. Approximately, 80 million people worldwide are affected by alcohol-induced disorders.  Alcohol drinkers have a 3-fold increased risk for oral cancer than nondrinkers.  It has been documented that heavy alcohol drinking accounts for 7-19% of all oral cancers.  Acetaldehyde, the carcinogenic metabolite of alcohol, is responsible for oral carcinogenesis.  A case study highlighted that 70% of oral cancer patients are heavy consumers of alcohol.  Alcohol in combination with tobacco profoundly enhances the risk of oral cancer development.  Habituation or addiction to tobacco and alcohol use is on the rise in younger generations.  A 35-40-fold increase in risk was reported in subjects who are habituated to both alcohol consumption and tobacco use.  In India, tobacco and alcohol use together, are recognized as the primary behavioral risk factors in more than 75% of oral cancer.  An Indian study reported that the synergetic risk of tobacco and alcohol to induce oral cancer was 24-fold. 
Diet and nutrition
Poor nutrition, lack of exercise, and obesity accounts for 30-40% of all cancers. A diet deficient in antioxidants, vitamins, minerals, and trace elements predisposes toward oral cancer development.  People who do not consume enough vegetables and fruits are at increased risk of oral cancer development.  High consumption of red meat and low intake of leafy vegetables enhance the risk of developing oral cancer.  Fish and milk consumption reduced the risk of oral cancer. 
Human papillomaviruses (HPV), especially the subtypes HPV 16 and HPV 18, and herpes simplex viruses are significantly associated with the development of oral cancer.  The biopsy from 25% of the oral cancer patients revealed the presence of HPV. 
Other risk factors of oral cancer
A significant positive association has been reported between periodontal disease and oral cancer risk.  Dry snuff use has been associated with an increased risk than moist snuff.  Individuals who work outdoors are constantly exposed to ultraviolet (UV) rays from sunlight. Lip cancer is the predominant form of cancer in these outdoor workers.  Some of the unproven or controversial risk factors of oral cancer include mouthwash use and irritation from poorly fitting dentures.  Immunocompromised individuals were found to be more susceptible to oral cancer.  Reports pointed out that patients' first-degree relatives are more susceptible to develop oral cancer.  Individuals with a defect in enzymes involved in the xenobiotic metabolizing pathway could be at enhanced risk to develop oral carcinoma. 
| Precancerous Lesions|| |
The sequential histological alterations occurring in oral malignant transformation involves alterations from normal to hyperkeratosis, hyperplasia, and dysplasia and then to carcinoma in situ and invasive malignant cancer. 
Oral malignant cancer proceeds in a step-wise manner and usually emerges as precancerous lesions such as leukoplakia, erythroplakia, and oral submucous fibrosis.  The term oral leukoplakia represents a white patch in the mouth which cannot be eliminated by scraping and can either transform into invasive carcinoma or regress spontaneously.  It has been pointed out that the rate of leukoplakia transformation into malignant cancer varies between 17% and 24% in the United States.  However, lower rates of malignant transformation have been reported in developing countries.  Around 10% of leukoplakia turn into malignant cancer, according to Jayanthi et al.  It has been reported that 53% of patients with Candida positive leukoplakia developed oral carcinoma. 
This precancerous condition is diagnosed with fiery red patch on the mucosa. The red patch cannot be characterized clinically as any other definable diseases and more likely to turn into dysplasia or malignancy than leukoplakia. Bleeding occur if erythroplakia is scraped. 
Oral submucous fibrosis
Long-term betel quid chewing leads to a precancerous condition in the oral mucosa known as oral submucous fibrosis. This condition is more prevalent in India and South East Asia.  Oral submucous fibrosis, if untreated, definitely turn into malignant cancer. Oral submucous fibrosis is characterized by inflammation and fibrosis of the submucosa tissues with difficulty while opening mouth. 
| Signs And Symptoms Of Oral Cancer|| |
Although early precancerous and cancerous lesions are symptomless or unable to elicit symptoms, cancer patients with advanced tumor stage may suffer from significant pain, difficulty swallowing, chewing, and eating. An unheal sore in the mouth is the most common symptom of oral cancer. Red or white lesions in the mouth, voice hoarseness, and bad breath are other signs and symptoms of oral cancer. 
| Diagnosis|| |
Tumor tissues of various cancers have different blend of genetic and epigenetic alterations. The diagnostic modalities to confirm the presence of malignant tumors in the oral cavity include cytology and brush biopsy (oralCDx Brush Test), fine-needle aspiration, toludine blue staining, visualization based adjunctive techniques (optical coherence tomography, and autofluorescence technique), and imaging studies (computed tomography, magnetic resonance imaging and position emission tomography).  Self-examination by the individuals could help to detect oral cancer at an early stage. Routine screening exams on the oral cavity could help detect the abnormal lesions early.  Delay in the diagnosis often results either from the unsuspecting patient's neglect to have a check-up, or the clinician's late recommendation to further evaluate the suspected tissue.  The clinician should thoroughly check any abnormal findings, not only in the internal site but also in the extraoral head and neck tissues. The diagnostic delay could lead to poor life quality as well as low survival outcome.  Histopathological examinations in the suspected biopsy by the pathologist serve as the best diagnostic criteria to diagnose oral precancerous and cancerous lesions.  Recent advancement in molecular biology techniques could help detect the precancerous and cancerous lesions at an early stage. 
| Tumor Staging|| |
Tumor-lymph node-metastasis (TNM) staging is commonly employed to assess the tumor stage of the patients suffering from oral cancer. TNM assess the tumor stage based on the size of the tumor (T), lymph node involvement (N), and metastasis (M). The staging of TNM is given in [Figure 2].
|Figure 2: Clinical staging of oral cancer, treatment modalities, and prognosis by clinical stage|
Click here to view
| Biochemical And Molecular Changes In Oral Cancer|| |
Malignant tumors progress, invade and spread to other parts of the body through dysregulation in novel biochemical and molecular events such as apoptosis, cell proliferation, inflammation, and angiogenesis. Dysregulation in these mechanistic pathways could help the transformed cells to grow and progress further. Inactivation of tumor suppressor genes or amplification of oncogenes is documented as hallmark of several carcinogenesis. Overproductions of ROS accompanied by insufficient antioxidant potential and defect in Phase I and II detoxification mechanism could also contribute to neoplastic transformation. The molecular changes that are reported in oral carcinogenesis is given in [Table 1].
| Prevention|| |
Oral cancer development can be prevented by avoiding the use of tobacco, alcohol, and betel nuts. Quitting the habits of tobacco, bidi and cigarette smoking, and alcohol consumption could reduce the development of oral malignancy.  The risk of developing oral carcinoma can also be prevented by limiting the exposure to UV light and eating lots of fruits and leafy vegetables. 
| Treatment|| |
The anatomical constraint of the head and neck make the treatment of oral cancer difficult. The current treatment employed for oral cancer patients include surgery, radiation therapy, and chemotherapy. The treatment is recommended in combination or alone based on the severity of the tumor (tumor stage) and health status and life style of the patients.  The treatment plan is discussed and developed by multidisciplinary team, which include surgeons, oncologist, radiologist, dentists, and rehabilitation specialists.  Moreover, the concurrence from patient's family should also be obtained before beginning the treatment. The patients have to face a lot of problems such as changes in appearance and organ dysfunctions, even after a successful treatment.
| 7,12-Dimethylbenz(A)Anthracene Induced Oral Carcinogenesis|| |
The polycyclic aromatic hydrocarbon, 7,12-dimethylbenz(a)anthracene (DMBA), is commonly utilized as a carcinogen to induce tumors in the buccal pouches of golden Syrian hamsters. Buccal pouches, a pocket like anatomy, exposed to repeated topical application of DMBA resulted in well-developed oral squamous cell carcinoma. DMBA can cause neoplasm by inducing severe inflammation and dysplasia in the buccal pouches in addition to causing extensive oxidative damage to DNA.  Accumulated evidences pointed out that DMBA mediated oral carcinogenesis resembles human oral cancer in several aspects including at histological, morphological, biochemical, and molecular aspects.  DMBA induced hamster buccal pouch carcinogenesis is therefore preferred to study the tumor preventive potential of natural products and their bioactive constituents.
| Chemoprevention|| |
The strategy, which uses the natural products, phytoconstituents or synthetic entities to suppress, inhibit, reverse or regress the neoplastic transformation, is known as chemoprevention. Chemopreventive agents exert their anticarcinogenic potential through their diverse pharmacological efficacy, including anti-inflammatory, antioxidant, apoptotic, and anti-angiogenic properties.  Biomarkers, biochemical, or molecular markers, plays a vital role in determining the health status of the patients. The level or the status of a particular cancer biomarker could help assess the cancer stage as well as to plan the treatment strategy.  Biomarker status could also reflect the safety and efficacy of the chemopreventive agents.  Easy anatomical access of the oral cavity could help to assess and follow the chemopreventive potential of the test compound in various stages of tumorigenesis.  The chemopreventive agents evaluated against oral carcinogenesis is given in [Table 2].
|Table 2: Chemopreventive agents tested against experimental oral carcinogenesis |
Click here to view
| Conclusion|| |
Oral carcinoma, the cancer of the oral cavity, has multifactorial etiology and arises mainly due to tobacco and alcohol addiction, which cause divergent biochemical and molecular abnormalities in the oral cavity. Since it is a well-known fact that the risk factors of oral cancer are modifiable, the government should take intensive effort to create awareness on oral cancer among the society to control the incidence of oral cancer. Thus, this form of cancer not only imposes a significant health burden, but also affects the overall life quality of the oral cancer patients.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2]