Oral cavity and lip cancer in the world: An epidemiological review

Use your smartphone to scan this QR code and download this article ABSTRACT Background: One of themost common cancers is squamous cell carcinoma of the head and neck which is a serious health challenge worldwide. Considering the importance of knowledge of incidence, death and risk factors in prevention programs, this study was conducted to investigate the incidence, mortality and risk factors for oral cavity and lip cancer in the world. Methods: A search was performed in Web of Science, PubMed and Scopus. The search keywords included: oral cavity or lip cancer, epidemiology, incidence, mortality, risk factors, and a combination of these terms. Studies that referred to epidemiological aspects of oral cavity and lip cancer epidemiology and risk factors were included in the review. Results: The five countries with the highest number of cancer of the oral cavity and lip included India, the United States, China, Pakistan and Bangladesh. The standard incidence of these cancers in the world was 4 per 100,000 people (in men versus women, 5.5 and 2.5 per hundred thousand, respectively). The five countries with the highest number of deaths from oral cavity cancer were India, China, Pakistan, Bangladesh and Russia. In 2012, the standardized death rate for this type of cancer was 1.9 per 100,000 people in the world (2.7 vs. 1.2 in every 100,000 of men vs. women, respectively). The most important risk factors for oral and lip cancer include tobacco smoke, alcohol drinking, viral infections, exposure to sunlight, and socioeconomic status. Conclusion: In order to reduce the burden of this cancer, there are the strategies for preventing risk factors such as tobacco and alcohol control, and vaccination against HPV infection to prevent oral cancers. Also, early detection by screening high-risk populations for oral cancer as well as risk reduction through training programs for physician and patients are effective.


INTRODUCTION
Squamous cell carcinoma of the head and neck belong to a non-homogeneous group of cancers that are located at various places in the body 1 and are one of the most common cancers in the world with more than 450,000 new cases and 350,000 deaths annually 2 . Squamous cell carcinoma consists of oral cavity, oropharynx, nasal cavity, para nasal sinus, nasopharynx, hypopharynx, larynx, tongue, tonsils, parotid glands, salivary glands 3 , and lip 4 . Each of the head and neck cancers is associated with various risk factors and prognosis 5 . The oral cavity is the most common cancer in the head and neck region 2 , with an annual incidence of 300,373 and a mortality rate of 145,353 5 . Cancer of the lip is a typical malignant tumor that consists of 25 -30 % of all cancers in the mouth 6 . Oral and lip cancer is a serious health challenge worldwide 4 . The incidence and mortality of this cancer is very different in various parts of the world and has a wide geographical variation. On the other hand, there is no comprehensive estimate of the inci-dence and mortality of this cancer. Considering the importance of being informed about the incidence, death and risk factors in prevention programs, this study aimed to determine the incidence, mortality and risk factors for oral cavity and lip cancer worldwide.

METHODS
A search was performed in Web of Science, PubMed and Scopus. The search keywords included: oral cavity or lip cancer, epidemiology, incidence, mortality, risk factors, and a combination of these terms. Studies that referred to epidemiological aspects of oral cavity and lip cancer epidemiology and risk factors were included in the review.

Incidence and mortality
Regarding the incidence and mortality rate of oral cavity cancer in the world, in 2012, there were a total of 300,373 cases of this cancer worldwide, of which 1989,755 were males and 101,398 were females 4  In 2012, the standardized death rate for this cancer in the world was 1.9 per 100,000 people (2.7 in men and 1.2 in women for every 100,000) 4 . In 2012, cancer of the oral cavity and lip was the 12 th most common cancer in Asia and was the 8 th highest among cancers in men. Lip and oral cavity malignancy is the 2 nd most common cancer among men in South Asia.
In fact, in 2012, Sri Lanka had the highest ASR of South Asia; this cancer was the most common among men in this country 8 . In Australia, lip and oral cavity ranked as the 9 th most common cancer among men with a standardized incidence age of 8.8%, while in New Zealand, it ranked as the 14 th most common cancer among men with an ASR of 5.5 per 100,000. Papua New Guinea and Solomon Islands reported a high incidence rate of oral cancer due to tobacco and paan, while Vanuatu Island showed lower incidence 8,9 .

RISK FACTORS FOR ORAL CAVITY CANCER Tobacco
Excessive use of tobacco (both smoked and chewable) is a potential risk factor for oral cavity cancer 10 .
The onset of consumption, duration and frequency of chewing of bidis or smoked cigarettes on a daily basis are strongly linked to oral cancer 11 .

Smoked tobacco
Smoked tobacco is a risk factor for the upper respiratory tract 12 , and there is a positive relationship between the risk of using tobacco smoke and oral cavity cancer 13,14 . This relationship has been confirmed in several studies [15][16][17] . The risk for oral cavity cancer in people who use tobacco is 1.4 -1.7 times higher than those who do not consume tobacco [15][16][17][18] . Several case-control studies have reported that the lower the age of tobacco consumption onset, the higher the risk for oral cavity cancer 19,20 . A study in India illustrated that the risk of oral cavity cancer in traditional tobacco (bidi, chutta and cheroot) users is twice as high as industrial tobacco users because traditional tobacco has a higher alkalinity and carcinogenicity 21 .

Smoke-free tobacco
Toxicants in smoke-free tobacco appear to increase the risk of oral cavity cancer 12 . The risk of oral cavity cancer depends on the length of time 22 , duration of use 12 , and onset in the early age 22 .

Exposure to tobacco smoke
Studies of the association between the effects of environmental exposure and tobacco smoke and the risk of oral cancer cavity are scarce 12 . In a study conducted on the relationship between tobacco smoke in the home or workplace with oral and pharyngeal cancers, it was found that the risk of oral cavity cancer was lower than that of pharyngeal cancer (not significant), and that the unauthorized use of tobacco for more than 15 years had no risk for oral cavity at home or in the workplace 23 .

Marijuana smoke
Marijuana increases the risk of oral and lip cancer 24 .
Marijuana is mostly smoked with carcinogenic smoke included aromatic multi-ring hydrocarbons, which can be higher than those in tobacco smoke 25 . Generally, marijuana consumers are tobacco or alcohol consumers 26 .

Alcohol consumption
The risk of oral cavity malignancy is increased by drinking alcohol; the higher the daily intake and duration of use, the higher the risk of oral cavity cancer 12 .
Alcohol consumption of more than 150 g per day extends the risk of oral cavity cancer 27

Paan (betel quid chewing)
Paan consumption also increases the risk of oral cavity cancer. Paan contains arecanut, betel leaves, slaked lime (which may include tobacco); other ingredients (such as spices, sweets and essence) may be added to the paan, according to taste 29 . The use of paan and gutkha is abundant in most countries and is difficult to control it despite that fact that excessive use of both causes cancer 30 . In Asia, taking paan with or without tobacco is a stronger risk factor than tobacco or alcohol 31,32 . In fact, the risk of oral cavity cancer in people who consume paan is about 1.5 -3 times greater than that of tobacco consumption and about 2-11 times greater than that of alcohol consumption [31][32][33] . Due to the lack of awareness and education, people who generally use paan and gutkha are not aware of their harmful effects. Generally, they believe that these products are used to clean the mouth (like mouthwash), help digestion, aid germ astringency, and boost or relieve the mood 34 .

Diet
It seems that inequality in the diet (or its misuse) is responsible for 11-15% of oral cavity and larynx cancers 12 . Low consumption of vegetables and fruits increases the risk of oral cavity malignancy 35,36 . As well, red meat consumption of greater than once a week elevates the risk of oral malignancy compared to white meats like chicken and fish 10 . Moreover, the use of hot drinks such as tea can increase the risk of oral cancer, which may be due to repeated heat damage due to mucosal contraction of the oral cavity 10,37 . Regarding the consumption of coffee, the results of the studies have been contradictory 12 .

Body Mass Index (BMI)
In some studies, weight gain has been reported as a protective factor, but weight loss has been reported as a potential risk factor for oral cavity cancer 38 .

Human papillomavirus and sexual behaviors
Viral papillomavirus infection is one of the most principal causes of squamous cell carcinoma of the head and neck 39,40 . The apparent increase in the incidence of oral HPV in the general population has been observed, which has led to an increase in concerns about human papillomavirus (HPV) infection and the risk of oral cavity cancer 41,42 . The number of sexual partners plays a main role in the transmission of the HPV virus, which can increase the risk of oral cancer 43 . About 25 % of cases of oral cavity cancer are related to HPV 44,45 . Given the recent global trend of oral HPV infections, the incidence of oral cancer is expected to increase in the coming decades 46 .

Family history of cancer
Family history of oral malignancy in different populations may depend on various environmental and genetic factors, including the prevalence of genetic dissimilarity in genes and exposure to diverse environmental factors 47 . This variation is more dependent on differences in exposure to tobacco and alcohol, which are very significant factors for oral cavity cancer 48 . Furthermore, genetic polymorphisms can expand the sensitivity of oral carcinoma through interactions with alcohol, tobacco and possibly diet components 47 . Besides, the use of these can be the reason for oral cavity carcinoma 49 . These finding indicate genetic instability is a risk factor for oral carcinoma 49 .

Oral and dental health
Oral health behaviors are a risk factor for oral cavity cancer 10 . Various factors have been used to assess oral and dental health; these include daily brushing, used materials, number of teeth lost, number of filled or damaged teeth, frequency of check-ups, gingival bleeding, and overall teeth status 12 . Missing more than five teeth is considered as an indicator of increased risk for oral malignancy 10 . Effective brushing eliminates dental plaques and subsequently improves oral and dental health; therefore, it reduces the risk of cancer of the head and neck region 50 . Dental plaque is a reservoir for the growth of pathogens and the production of nitrosamines that help to increase inflammation of the mouth 10 . Regular brushing can eliminate dental plaque, alcohol, nicotine, fungi, nitrosamines, and other toxic toxins, thereby delaying or preventing carcinogenesis 10 .

Use of mouthwash
The relationship between alcohol mouthwash and oral cancer growth over the past decade has been the topic of debate 12 . Some studies have confirmed a positive relationship between mouthwash and oral malignancy 12 . However, the concentration of alcohol in the mouthwash has not been sufficiently evaluated 12 .

Oral mucus diseases
Potentially malignant oral disorders such as leukoplakia, submucous erythroplasia T fibrosis, lichen planus, and chronic oral candidiasis may increase the risk of squamous cell carcinoma 51,52 . Some systemic diseases can have an effect on oral health, leading to malignancy or even cancer of the mouth 12 . Although most oral lesions are benign, many of them may appear with potential abnormalities in the mouth 46 .
One of the most common oral lesions is squamous cell papilloma -a malignant, neuromuscular lesion that is swollen and usually has a monopoly of small white or red designs on the surface 53 . Also, lesions of the oral cavity of leukoplakia are also white plaques that can be considered as potential lesions 46 .

Social inequality
According to the study, the risk of oral cavity cancer is higher in the lower classes 12 .

Occupational exposure
In many occupations and industries, the risk of this cancer has been observed. The relationship between exposure to perchlorethylene (organic solvents used in cleaning laundry) and oral cavity cancer has been demonstrated 12 . An increased risk of this cancer in India has been confirmed among male farmers and industrial laborers 12 . Also, in one study, an elevated risk of this cancer was observed among male workers who worked at a cane factory in Puerto Rico 12 .

Exposure to sunlight
Exposure to sunlight is a principal risk factor for lip cancer 54 ; it increases the incidence of illness in people who are working outdoors or live in the countryside 55 . In particular, UV -especially UVB (wavelengths of 320 -900 nm) -is considered as the most salient environmental factor. UVA (wavelength 320-400 nm) may also play a role in carcinogenesis 56 . Evidence related to the association between exposure to sunlight and lip cancer has been shown through examinations of changes in lip cancer that are associated with sun rays and ethnic characteristics 55 .

Tobacco smoke
Smoking is a principal risk factor for lip cancer, which can affect both lips equally 57 . Malignant lesions typically occur in a place where the cigar or pipe cigar is placed 58 . Traditional tobacco smoking, especially pipe smoking, is related with lip cancer. The nitrosamines found in tobacco are one of the main carcinogenic agents for cancer induction 56 .

Viral infection
Viruses are one of the most important features in the development of this cancer 57 . The relationship between this cancer and herpes labialis infection has been observed. Herpes simplex virus type 1 and also HPV (especially HPV-16) have the potential for carcinogenicity 56 . The most common pathogenesis of lip cancer is the recurrence of herpes virus 57 .

Race
People with bright eyes, hair and skin are at high risk of lip cancer 56,57 ; about half of cancers occur in the North European countries 59 . Lip cancer is negligible in people with darker skin and among blacks and Eastern folks 56,57 . This variation is due to the natural pigmentation of the natural melanin at the vermilion border, which is found in non-white races and creates a protection against sunlight 56 .

Familial and genetic factors
Genetic or familial factors are one of the factors which contribute to the development of lip cancer 57 . Different diseases are more common among relatives than ordinary people 59 and it has been proven that there is an inherited basis for lip cancer. Also, the exposure to common risk factors, such as environmental exposure, increases the risk of inheritance and family life 56 .

Immunosuppression and immunodeficiency
An increase in the prevalence of various malignancies has been reported in transplant recipients 56 . Kidney transplant patients in immuno-suppressive states have reported the most prevalence of obstructive and malignant lip lesions among renal transplant patients 57 ; indeed, the risk of lip cancer increases with long-term treatment of immunosuppression 56 .

Occupation
Exposure to sunlight, especially outdoor activity, is a risk factor for lip cancer 60 . Fishing, agriculture, forestry and agriculture, creosote exposure, and work in the greenhouse are linked to lip cancer 56,57 . The number of cases of lip cancer in men is greater than that of women, which may be related to occupation and behavioral differences between the sexes since a high percentage of men work outdoors 58 . Some researchers believe that using lipstick could act as a protective agent, contributing to the observed gender differences 61 .

Residential area
Lip cancer is more common in people living in rural areas than those living in urban areas, and the most likely cause is exposure to sunlight 62 .

Socioeconomic status
Low socioeconomic status is strongly related to the high risk of lip cancer. However, the correlation between socioeconomic status and other risk factors (such as high smoking, rural and occupational status) may increase the risk of lip cancer 56,57 .

AUTHOR'S CONTRIBUTIONS
All authors equally contributed to this article. All authors read and approved the final manuscript.

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