Potentially malignant disorders

25

Potentially malignant disorders

Key Points Potentially malignant (sometimes termed premalignant) clinically obvious disorders include actinic cheilitis, erythroplakia (erythroplasia – red patch), leukoplakia (white patch), submucous fibrosis and lichenoid lesions (Ch. 29) ■ Risk factors for erythoplakia and leukoplakia may include tobacco use, alcohol use, betel nut chewing and sunlight exposure ■ Diagnosis and prognosis are aided by biopsy ■ Factors predictive of future malignant transformation may include dysplasia, history of cancer in the upper aerodigestive tract, and changes in expression of P53 tumour suppressor protein, DNA and chromosomes 3p or 9p ■ Treatment involves removing risk factors, and excision of dysplastic lesions ■

INTRODUCTION Most mouth cancers are oral squamous cell carcinomas (OSCC) and appear to arise in apparently normal mucosa, in apparently otherwise healthy people but some are preceded by clinically obvious potentially malignant (sometimes termed premalignant) disorders (PMD) and OSCC is also increased in patients who: have had previous oral malignancy ■ have had previous malignancy in the upper aerodigestive tract (nose, pharynx, trachea, lungs, oesophagus) ■ are immune incompetent. ■

PMD include (Table 25.1) mainly: Actinic cheilitis (solar elastosis) (Ch. 26). Erythroplakia (erythroplasia – red patch; Fig. 25.1) (Ch. 27): defined by the World Health Organization (WHO) as ‘any lesion of the oral mucosa that presents as bright red velvety plaques which cannot be characterized clinically or pathologically as any other recognizable condition’. This is rare but has a very high malignant potential and many cases are already a carcinoma on microscopic examination. ■ Leukoplakia (white patch; Figs  25.2–25.6) (Ch. 28): defined by the WHO as ‘clinical white patches that cannot be wiped off the mucosa and cannot be classified clinically or microscopically as another specific disease entity (such as lichen planus)’. Leukoplakia is, thus, a clinical diagno174 sis only and can only be made by exclusion. A workshop ■ ■

c­ oordinated by the WHO Collaborating Centre for Oral Cancer and Precancer agreed that the term leukoplakia should be used to recognize ‘white plaques of questionable risk having excluded (other) known diseases or disorders that carry no increased risk for cancer’. ■ Lichen planus/lichenoid lesions (Ch. 29): in many ­geographic areas these are the most common PMDs. ■ Submucous fibrosis (Ch. 30). ■ Palatal lesions in reverse smokers. Apart from the conditions noted above, rare conditions that predispose to OSCC include: ■ ■ ■

discoid lupus erythematosus (Ch. 57) dyskeratosis congenita (Ch. 57) epidermolysis bullosa (Ch. 57) Fanconi anaemia (Ch. 56) Paterson–Kelly syndrome (sideropenic Plummer–Vinson syndrome) (Ch. 56) ■ Xeroderma pigmentosum (Ch. 57). ■ ■

dysphagia;

There are also occasional associations of OSCC with: diabetes, and the metabolic syndrome scleroderma.

■ ■

Erythroplakia has a very high malignant potential. Leukoplakia can have a malignant potential – particularly high in the ­following types (Table 25.2): speckled leukoplakia (red and erythroleukoplakia) ■ nodular or verrucous leukoplakia. ■

white

patch

–

AETIOLOGY AND PATHOGENESIS Although genetics clearly predispose to PMD in some cases (such as in dyskeratosis congenita, Fanconi ­anaemia and ­xeroderma pigmentosum), lifestyle habits are often ­implicated, and most of these have psychotropic actions and are habit-forming or addictive. Those habits that are known to predispose to potential malignancy include: ■ ■ ■ ■

tobacco use (Fig. 25.6) alcohol use betel nut chewing and possibly other chewing habits. sunlight exposure.

Marijuana use, and oro-genital or oro-anal sex (via human papillomavirus (HPV) transmission) may also be implicated as discussed below and in Ch. 31.

POTENTIALLY MALIGNANT DISORDERS

Table 25.1

25

Potentially malignant oral disorders

Disorder

Aetiological factors

Features

Actinic cheilitis (solar elastosis)

Sunlight

White plaque/erosions

Erythroplasia

Tobacco/alcohol/betel

Flat red plaque

Leukoplakia

Homogeneous

Tobacco/alcohol/betel, human papilloma virus

White plaque

Leukoplakia

Speckled (erythroleukoplakia)

Tobacco/alcohol/betel, human papilloma virus Tobacco/alcohol/betel, human papilloma virus Tobacco/alcohol Tobacco/alcohol Candida albicans Syphilis

Speckled plaque

Lichen planus

Idiopathic

White plaque/erosions

Submucous fibrosis

Areca nut/betel

Immobile mucosa, white plaque

Palatal lesions in reverse smokers

Tobacco

White or speckled plaque

Immunocompromised patients

Papilloma viruses Candidosis

White or speckled plaques

Discoid lupus erythematosus

Idiopathic

White plaque/erosions

Dyskeratosis congenita

Genetic

White plaques

Epidermolysis bullosa

Genetic

Scarring

Fanconi anaemia

Genetic

White plaques Periodontal disease

Paterson–Kelly syndrome (sideropenic dysphagia; Plummer–Vinson syndrome)

Iron deficiency

Postcricoid web

Xeroderma pigmentosum

Genetic

White plaque/erosions

Nodular/verrucous Proliferative verrucous leukoplakia Sublingual leukoplakia Candidal leukoplakia Syphilitic leukoplakia

Nodular white plaque White or speckled nodular plaque White plaque White or speckled plaque White plaque

RISK FACTORS: TOBACCO Many studies have shown an association between tobacco use and oral PMD and OSCC. The relative risk of having an oral dysplastic lesion for smokers compared with non-smokers was estimated at 7.0. Oral leukoplakia can be related to tobacco use. Tobacco users are also predisposed to a number of other cancers and potentially malignant conditions (oesophageal, breast, stomach, colorectal, bladder, lung and hepatocellular cancer), and other systemic and oral health issues. Tobacco contains at least 50 compounds including polycyclic aromatic hydrocarbons such as benzpyrene, nitrosamines, aldehydes and aromatic amines. The precise role of tobacco however, is surprisingly difficult to define, not least because many heavy smokers also drink alcohol – which is carcinogenic. However, studies of those who are teetotal and abstain from such habits (e.g. Mormons, Seventh Day Adventists) have shown a very low incidence of OSCC. Different tobacco habits have varied effects: ■

Fig. 25.1 Erythroplakia: usually a potentially malignant disorder, or carcinoma

Cigarette smokers appear about five times more likely to develop OSCC than do non-smokers and, in contrast, those who abstain have had a lower incidence. In one recent study, the odds ratio for consumption of > 20 cigarettes/day 175

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Fig. 25.2 lesion

CANCER AND POTENTIALLY MALIGNANT DISORDERS

Speckled leukoplakia: often a potentially malignant Fig. 25.4 Dysplasia: moderate

Fig. 25.3 No dysplasia detectable from this biopsy and thus the lesion is presumed benign

■

■

■

■

176

was double that of smokers consuming < 20 cigarettes/ day. Compared to non-smokers, the risk of OSCC to low/medium cigarette smokers was 8.5 and for high tar cigarette smokers was significantly greater at 16.4 in one European study. Black tobacco seems more carcinogenic than blonde. Bidi smoking (reverse smoking) is strongly associated with leukoplakia and oral cancer. Palatal or other oral carcinoma can result. Bidi (unfiltered cigarettes containing a small amount of flaked tobacco), widely prevalent in south Asia (mainly India, Taiwan and the Philippines) and in South America, are smoked with the lit end within the mouth. Cigar smoking may predispose to OSCC, and some studies have shown an association with floor of mouth leukoplakia in women smokers. Pipe smoking is most often associated with nicotinic stomatitis, a non-premalignant condition, but there is evidence from some countries that pipe smoking may be associated with a predisposition to OSCC. Smokeless tobacco (ST), for example, snuff-dipping (placing snuff in the buccal sulcus) in women in southeastern USA, has been shown to predispose to gingival and alveolar carcinoma close to the area snuff is placed.

Fig. 25.5 Dysplasia: severe, and suggestive of a potentially malignant disorder

Fig. 25.6 Leukoplakia in a person who for most of his adult life drank a bottle of vodka and smoked 20 cigarettes daily; he also incidentally developed myeloma

POTENTIALLY MALIGNANT DISORDERS

Table 25.2

25

Malignant potential in the most important oral potentially malignant disorders Malignant potential

Main entities

High (> 60%)

Medium (< 30%)

Low (< 10%)

Erythroplakia

Leukoplakia (non-homogeneous) Candidal leukoplakia

Leukoplakia (homogeneous) Lichen planus/lichenoid lesions

Actinic cheilitis Submucous fibrosis

Discoid lupus erythematosus

Uncommon entities Rare entities

Dyskeratosis congenita*

Fanconi anaemia*

*Malignant potential unclear but involves OSCC (mainly tongue) and other neoplasms, especially acute myeloid leukaemia.

■

ST predisposes to OSCC and the products include paan, chaalia, gutka and naswar, and are used in all sections of South Asian society. In India, different forms of chewing tobacco are used such as betel (Table  25.3), khaini, pattiwala tobacco, maiwpuri tobacco, zarda, kiwam and gadakhu. Tobacco-chewing, along with a variety of ingredients in a ‘betel quid’ (betel vine leaf, betel (areca) nut, catechu, and slaked lime, often together with tobacco) appears to predispose to OSCC, particularly when started early in life and used frequently and for prolonged periods (see below). It is common in peoples from parts of Asia. Many migrants to the West and other countries also continue to use ST products even several decades after migration. Asian ethnic migrants to the UK have a significantly higher incidence of oral cancer compared with the native UK

Table 25.3

populations presumably related to ST use. Bangladeshis in particular are likely to retain the habit of betel use. The combined effect of alcohol and tobacco is far greater than the sum of the two effects and is multiplicative.

RISK FACTORS: ALCOHOL Increased consumption of any alcohol-containing beverages is associated with a risk of PMD and OSCC. The risk is greatest among the heaviest drinkers of alcohol (ethanol). The type of alcoholic beverage also appears to influence the risk – spirits confer higher risks than wine or beer. Ecological studies suggest that the impact of alcohol on oral cancer deaths has increased in recent years. Alcoholic beverages may contain carcinogens or procarcinogens, including ethanol; this is

Main forms of smokeless tobacco use

Name

Constituents

Used mainly in populations from

Betel (paan)

3 basic types: Areca nut no tobacco e.g. sweet pan (Gutkha; or Gutaka) Tobacco no areca nut Areca nut plus tobacco products

South Asia, Papua New Guinea

Chewing tobacco

Tobacco

Western Europe, North America

Gudakhu

Tobacco, molasses, other ingredients

Southeast Asia

Khaini

Tobacco powdered mixed with slake lime paste, sometimes used with areca nut; placed inside the mouth

Southeast Asia

Kiwam

Tobacco leaf, boiled in rose water and spices added

Southeast Asia

Maiwpuri

Tobacco, slaked lime, areca nut and spices

Southeast Asia

Mishri

Tobacco dark roasted powdered, used as tooth cleaning agents

Southeast Asia

Nass

Tobacco, cotton ash or sesame oil, lime and gum

Iran, Central Asia, Afghanistan and Pakistan

Naswar

Tobacco powdered, slaked lime and indigo

Afghanistan, Pakistan

Pattiwala

Tobacco leaf, with or without lime

South Asia

Shammah

Tobacco leaf powdered, ash, lime

Saudi Arabia

Toombak

Tobacco and sodium bicarbonate

Sudan

Zarda

Tobacco leaf boiled with spices and lime

India and Middle East

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metabolized by alcohol dehydrogenase (ADH) and to some extent by cytochrome p450 (CYP) to acetaldehyde, which may be carcinogenic. Acetaldehyde is degraded by aldehyde dehydrogenses (ALDH) to acetic acid. Genetic variations in the activities of ADH and ALDH (and other enzymes) may influence the outcome of exposure to alcohol, and thus its carcinogenicity in any individual. Many alcoholic drinks also contain congeners and some local brews may contain carcinogens such as nitrosamines or urethane contaminants. For example, in parts of France, such as Brittany, there is a close relationship between consumption of Calvados, a pot-stilled spirit, and cancer of the mouth and oesophagus. Furthermore, alcohol users are also predisposed to a number of other cancers and potentially malignant conditions, and other systemic and oral health issues. The risk of OSCC decreases after stopping alcohol use but the effects appear to persist for several years. The carcinogenic potential of proprietary alcoholcontaining mouthwashes remains controversial.

Other conditions: ■ hypertension ■ metabolic syndrome ■ adverse birth outcomes ■ liver cirrhosis ■ chronic kidney disease ■ contact dermatitis ■ periodontitis. Other chewing habits, usually involving tobacco and stimulants, are used in different cultures (e.g. Qat (Khat), Shammah, Toombak).

■

RISK FACTORS: SUNLIGHT AND TANNING BEDS Actinic radiation may predispose to lip cancer. Facts that support such a relationship include: ■

■

RISK FACTORS: CHEWING HABITS Betel quid is widely used across the world, in south Asian communities particularly, though contents vary in different parts of the world and cultures. The betel quid contents are betel leaf, tobacco, areca nut, spices, and sometimes slaked lime. A large variety of additives may be incorporated. Betel (paan; the leaf, stem or inflorescence of Piper betel) leaves are from the betel vine, a relative of the pepper family. The leaf contains allylbenzene compounds such as chavibetol, chavicol, estragole, eugenol and methyl eugenol. Areca nut, sometimes referred to as betel nut (although it is from a different plant than the betel leaf) is the seed of Areca catechu – the areca palm. Betel quid can be made up at home or purchased as ready to chew. The betel quid is placed in the mouth, usually the cheek, and gently chewed and sucked sometimes for hours. Betel use not only causes discolouration of the oral mucosa and teeth, but can also predispose to PMD such as submucous fibrosis, erythroplakia and leukoplakia, and also to OSCC. CYP genes may play a role in betel-induced OSCC. Furthermore, betel users are also predisposed to a number of other cancers and potentially malignant conditions (oesophageal, pancreatic and hepatocellular cancer), and other systemic health issues, including; ■

Cancers: ■ oral ■ oesophageal ■ pancreatic ■ hepatocellular. Table 25.4

178

■

lip cancer involves the more exposed lower lip, rather than the upper lip there is a higher incidence of lip cancer in outdoor workers and rural populations than in office workers or urban populations fair-skinned people in sunny climates tend to develop lip cancer more than dark-skinned people (as well as skin cancer and melanoma).

Sunlight contains: ■ ■ ■

visible light infrared radiation ultraviolet (UV) radiation.

It is the ultraviolet (UV) radiation that can cause harmful effects to the skin and lip. There are three basic types of UV: ■ ■ ■

UVA (long-wave UV) UVB (sunburn UV) UVC (short-wave UV).

The effects of UV are shown in Table 25.4; UVB appears to be most carcinogenic. Tanning beds typically emit about 97% UVA and 3% UVB, and there is no available reliable evidence that these cause oral or lip cancer.

RISK FACTORS: OTHERS The carcinogenicity of other psychotropic products such as marijuana remains controversial. Immune defects may predispose to OSCC, especially lip cancer. This is increased in, for example, immunosuppressed renal transplant recipients – possibly due to human papillomavirus (HPV) infection and patients with chronic mucocutaneous candidosis.

Types of ultraviolet radiation

UV type

Filtered out in atmosphere by ozone layer

Effects on skin

Other features

UVA

No

Some tan and harmful long-term

Passes through glass: levels relatively constant through the day

UVB

Partially

Burns, tans, wrinkling, aging and cancer

Some does not pass through glass: highest intensity at noon

UVC

Yes

Burns and cancer

Major artificial sources are germicidal lamps

POTENTIALLY MALIGNANT DISORDERS HPV is increasingly linked to the rise in oropharyngeal cancer in young people.

■

■

Diet Charcoal-grilled red meat and fried foods have been implicated as risk factors. An increased consumption of fruits and vegetables is associated with lower risk of oral cancer.

NATURAL HISTORY AND MALIGNANT TRANSFORMATION The natural history of PMDs is not absolutely clear but cessation of smoking habits appears to result in some lesions regressing or resolving. The risk of malignant development does not seem to be predictable but is greatest in: ■ ■ ■ ■ ■

■ ■

older patients females never-users of tobacco non-homogenous PMD PMD on the lateral and ventral tongue, floor of mouth and retromolar/soft palate complex large lesions covering several intraoral subsites PMD of long duration.

Factors predictive of future malignant transformation may also include: ■ ■ ■ ■

■

epithelial dysplasia history of cancer in the upper aerodigestive tract expression of P53 tumour suppressor protein changes involving chromosomes 3p or 9p; these are termed ‘ loss of heterozygosity,’ or LOH chromosomal polysomy.

Epithelial dysplasia (from Greek dys = poor and plasia = a moulding) is a term describing the combination of disorderly maturation and disturbed cell proliferation (Box 25.1) seen in OSCC and some PMD. Although not all clinically PMD show dysplasia on biopsy examination (Fig. 25.3), most do show dysplasia, and this is one of the main histological features that appears to precede the onset of malignancy and it appears to be the most predictive marker for malignant potential in current use. Cellular atypia is the main feature of dysplasia. Dysplasia is in general, graded as: ■

Mild dysplasia: atypical and immature basal cells extend above the basal layers into the lower third of the epithelium. BOX 25.1 ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■

Features of epithelial dysplasia

Drop-shaped rete processes Basal cell hyperplasia Irregular epithelial stratification Nuclear hyperchromatism Increased nuclear-cytoplasmic ratio Increased normal and abnormal mitosis Enlarged nucleoli Individual cell keratinization Loss or reduction of cellular cohesion Cellular pleomorphism Loss of basal cell polarity

■

25

Moderate dysplasia: atypical and immature basal cells extend above the basal layers into the middle third of the epithelium. Severe dysplasia: atypical and immature basal cells extend throughout the epithelium. Carcinoma: atypical and immature basal cells extend throughout the epithelium together with invasion of the lamina propria.

Dysplasia thus varies in severity from mild to moderate dysplasia – where few of the features of dysplasia are present and the epithelium is reasonably well organized (Fig. 25.4), to the more severe grades where epithelial organization is disrupted and many cellular abnormalities present (Fig.  25.5), the epithelial basement membrane is not seen to be breached but there is a malignant potential. Dysplasia however, does not always indicate a malignant potential, since it can also be seen in regenerating tissue and some non-precancerous lesions such as some: ■ ■ ■ ■

ulcers viral infections candidal infections granular cell tumours.

Nevertheless, many now believe that seeing severe dysplasia is often tantamount to a diagnosis of early carcinoma – since the epithelial basement membrane may well be breached though not detected in the biopsy specimen.

DIAGNOSIS Most PMD mandate biopsy; the specimen should be taken from the most clinically suspicious area, such as redness, an area of surface thickening or a symptomatic area. To improve the sensitivity and specificity of identification of an area to biopsy, vital tissue staining may be used, with a dye, such as toluidine (tolonium) blue – an acidophilic metachromatic thiazine dye that selectively stains tissue acids, particularly DNA and RNA. Staining is based on the fact that dysplastic cells usually contain more nucleic acid than normal cells. Vital staining is not totally specific or sensitive, but can assist in deciding where to perform a biopsy. Nevertheless, despite the assistance of vital staining, a negative biopsy cannot reliably exclude the presence of carcinoma or dysplastic foci within a lesion. Biomarkers with potential predictive value and which may prove to be clinically relevant include DNA ploidy, computerized nuclear image analysis and microsatellite instability at chromosomes 3p and 9p.

TREATMENT (see also Chs 4 and 5) Management of patients with PMD is a controversial issue (Algorithm  25.1), discussed in more depth in relation to the specific entities. A specialist opinion is advised. Fully informed consent is crucial, all the uncertainties being discussed with the patient. Surgery may have a beneficial effect, but there is no evidence that this will reliably reduce the risk of later recurrence, nor malignant transformation of PMD, at the same or another site. Medical measures that lessen the size, extent or histopathological features of dysplasia within PMD are associated with a risk of adverse effects, particularly with systemic agents (which 179

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CANCER AND POTENTIALLY MALIGNANT DISORDERS

themselves may be contra-indicated in some individuals), and relapse or later malignant transformation can still occur.

There is neither evidence base nor absolute consensus as to the optimum review interval or protocol. Since there is no hard evidence as to the ideal frequency of follow-up, it has been suggested that patients with PMD be re-examined by a health professional: ■ ■

within 1 month at 3 months at 6 months

Clinical potentially malignant disorder

Eliminate tobacco, friction

Response

No cause

No response

Biopsy

Dysplasia

Moderate; remove

Algorithm 25.1

■

at 12 months annually thereafter.

Any changes in clinical features, especially the appearance of a lump or ulcer, merit a specialist opinion and usually a biopsy.

FOLLOW-UP OF PATIENTS

■

■

No dysplasia

Mild Severe; remove

Management of PMD

Other diagnosis

PREVENTION AND DETECTION OF POTENTIALLY MALIGNANT DISORDERS AND CANCER Unfortunately, many of the population – especially those at highest risk, such as older men who smoke and drink – rarely seek regular dental care or examination. In a recent study, risk factors in patients with tongue OSCC were being: age > 80, widowed, social marginalized, a current smoker, or a smoker-heavy drinker. Risk factors in people with floor of mouth cancer were being: age > 70, and socially marginalized. Having a regular dentist was protective. Patients thus often present late to physicians and with advanced cancers, and furthermore, physicians and surgeons have often received little or no training in the examination of the mouth. It should be noted also that clinically differentiating PMD and OSCC from lesions that are benign can be difficult even for highly trained professionals, because these lesions do not always display well-defined clinical features. Not uncommonly, PMD and OSCC are asymptomatic, appear innocuous and can be overlooked. Clinicians should be aware that single ulcers, lumps, red patches or white patches, particularly if any of these are persisting for > 3 weeks, may also be manifestations of frank malignancy: biopsy is invariably indicated. Even common, benign-looking oral lesions attributed to friction or trauma require evaluation when they persist. Despite this fewer than 27% of leukoplakias, a common PMD, are ever subjected to biopsy. As a result, many are left to progress to more advanced stages or cancer. Late cancer diagnosis results in treatment that is usually more mutilating, with higher morbidity and costs, and a worse prognosis.

USEFUL WEBSITES Medscape, Premalignant Conditions of the Oral Cavity: http://emedicine.medscape.com/ article/1491418-overview

FURTHER READING

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Alexander, R.E., Wright, J.M., Thiebaud, S., 2001. Evaluating, documenting and following up oral pathological conditions. A suggested protocol. J. Am. Dent. Assoc. 132, 329–335. Chen, P.H., Lee, K.W., Chen, C.H., et al., 2011. CYP26B1 is a novel candidate gene for betel quid-related oral squamous cell carcinoma. Oral. Oncol. 47 (7), 594–600.

Gallagher, R.P., Lee, T.K., 2006. Adverse effects of ultraviolet radiation: a brief review. Prog. Biophys. Mol. Biol. 92 (1), 119–131. Gandolfo, S., Pentenero, M., Broccoletti, R., et al., 2006. Toluidine blue uptake in potentially malignant oral lesions in vivo: clinical and histological assessment. Oral. Oncol. 42, 89–95.

Groome, P.A., Rohland, S.L., Hall, S.F., et al., 2011. A population-based study of factors associated with early versus late stage oral cavity cancer diagnoses. Oral. Oncol. 47 (7), 642–647. Hashibe, M., Jacob, B.J., Thomas, G., et al., 2003. Socioeconomic status, lifestyle factors and oral premalignant lesions. Oral. Oncol. 39 (7), 664–671.

POTENTIALLY MALIGNANT DISORDERS Holmstrup, P., Vedtofte, P., Reibel, J., Stoltze, K., 2006. Long-term treatment outcome of oral premalignant lesions. Oral. Oncol. 42 (5), 461–474. Holmstrup, P., Vedtofte, P., Reibel, J., Stoltze, K., 2007. Oral premalignant lesions: is a biopsy reliable? J. Oral. Pathol. Med. 36 (5), 262–266. Hsue, S.S., Wang, W.C., Chen, C.H., et al., 2007. Malignant transformation in 1458 patients with potentially malignant oral mucosal disorders: A follow-up study based in a Taiwanese hospital. J. Oral. Pathol. Med. 36, 25–29. Jaber, M.A., Porter, S.R., Speight, P., et al., 2003. Oral epithelial dysplasia: clinical characteristics of western European residents. Oral. Oncol. 39, 589–596. Kim, J., Shin, D.M., El-Naggar, A., et al., 2001. Chromosome polysomy and histological

characteristics in oral premalignant lesions. Cancer Epidem. 10, 319–325. Lippman, S.M., Hong, W.K., 2001. Molecular markers of the risk of oral cancer. N. Engl. J. Med. 344, 1323–1326. Lodi, G., Porter, S., 2008. Management of potentially malignant disorders: evidence and critique. J. Oral. Pathol. Med. 37 (2), 63–69. Napier, S.S., Speight, P.M., 2008. Natural history of potentially malignant oral lesions and conditions: an overview of the literature. J. Oral. Pathol. Med. 37 (1), 1–10. Pentenero, M., Carrozzo, M., Pagano, M., et al., 2003. Oral mucosal dysplastic lesions and early squamous cell carcinomas: underdiagnosis from incisional biopsy. Oral. Dis. 9, 68–72.

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Scully, C., Sudbo, J., Speight, P.M., 2003. Progress in determining the malignant potential of oral lesions. J. Oral. Pathol. Med. 32 (5), 251–256. Thomas, G., Hashibe, M., Jacob, B.J., et al., 2003. Risk factors for multiple oral premalignant lesions. Int. J. Cancer 107 (2), 285–291. Warnakulasuriya, S., Kovacevic, T., Madden, P., et al., 2011. Factors predicting malignant transformation in oral potentially malignant disorders among patients accrued over a 10-year period in South East England. J. Oral. Pathol. Med. 40, 665–732. Yen, A.M., Chen, S.L., Chiu, S.Y., Chen, H.H., 2011. Association between metabolic syndrome and oral pre-malignancy: A community- and populationbased study (KCIS No. 28). Oral. Oncol. 47 (7), 625–630.

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