3 Premalignant Oral Lesions
Oral premalignant lesions/oral premalignant disease/oral premalignant conditions are referred as “oral potentially malignant disorders” since they are defined as “a morphologically altered tissue in which cancer is more likely to occur than its normal counterpart” by the World Health Organization (WHO). The histological indicator of increased risk of oral cancer progression is the oral epithelial dysplasia, which is explained as “the histopathologic changes seen in a chronic, progressive, and premalignant disorder of the oral mucosa which may present itself clinically as leukoplakia, erythroplakia, or leukoerythroplakia, or may also be seen in verrucous or papillary leukoplakias, in the margins of a chronic mucosal ulcer, or in the adjacent mucosa of invasive squamous cell carcinoma.” In addition to leukoplakia and erythroplakia, oral lichen planus and submucous fibrosis which is mostly observed in certain geographical areas have been included in the clinical definition of oral potentially malignant epithelial lesions (OPMEL). In this chapter, the epidemiology, incidence, major causes comprising tobacco, alcohol, age and gender, molecular alterations/chromosome instability/genetics, human papillomavirus (HPV), inflammation, infections of oral microbiota, socioeconomic status, immunosuppression, and the clinical characteristics of OPMEL are presented. The most common adjunct methods and devices utilized for assistance to the clinical practitioner for detection and evaluation of OPMEL are also discussed.
WHO has advocated the term “oral potentially malignant disorders” (OPMD) for “a morphologically altered tissue in which cancer is more likely to occur than its normal counterpart” rather than “premalignant lesions,” “premalignant disease,” or “premalignant conditions,” since only some of those lesions may transform into oral malignancies. 1 Oral epithelial neoplasia is initiated with a focal clonal overgrowth of altered cells near the oral basement membrane, which expands both upward and laterally, and replaces the healthy oral mucosal epithelium. 2 , 3 This pathobiology of a neoplastic process begins with normal tissue progressing through various stages of alteration and finally leading to invasive carcinoma. 4 , 5 Thus, it is considered that carcinogenesis most often occurs as a multistep process through the continuum from normal mucosa to oral carcinoma. 5 , 6 Continuous exposure to potentially carcinogenic factors eventually leads to cellular alterations in a localized area or within the region exposed to the potential carcinogen, 5 , 7 – 9 leading to risk of oral premalignant lesions/conditions/OPMD. 4 , 8 – 11 This regional exposure hypothesis has been referred as “the field cancerization” first described in 1851 after increased risk of oral cancer in the oral mucosa of pipe smokers had been established. 12 It has been supported by the lateral expansion of oral malignant areas rather than infiltration in depth, 7 observation of multiple second primary tumors with higher prevalence than primary oral cancers, 5 , 8 and the development of synchronous distant tumors within the upper aerodigestive tract. 2 , 7 , 8 , 13 A definition for field cancerization is “the presence of one or more areas of oral mucosa consisting of epithelial cells with genetic alterations with a monoclonal origin, without invasive growth and metastatic behavior.” 4 High incidence of local recurrences and second primary tumors are considered to be the result of a process where a single cell is transformed to produce a premalignant field by clonal expansion. 2 In this field of various subclones, two separate tumors with the same clonal origin may develop, and may be erroneously referred to as local recurrences. 2 Also, histological evaluation of the margins may appear cancer free, but tumor-associated genetic alterations may be retained within the adjacent tissue to the operation area, leading to more than 25% of head and neck cancers following surgical removal of the cancer lesions. 4
Oral epithelial dysplasia is considered a histological indicator of premalignancy that carries an increased risk of oral cancer development. 14 – 16 It is defined as “the histopathologic changes seen in a chronic, progressive, and premalignant disorder of the oral mucosa which may present itself clinically as leukoplakia, erythroplakia, or leukoerythroplakia, or may also be seen in verrucous or papillary leukoplakias, in the margins of a chronic mucosal ulcer, or in the adjacent mucosa of invasive squamous cell carcinoma.” 14
Generally, a premalignant lesion may contain cytological features similar to that of oral malignant ones, 10 may be present prior to the diagnosis of malignant changes at the same location, 17 – 19 and may be observed within the whole epithelial layers. 10 Hyperplastic basal cells, enlarged and hyperchromatic nuclei, and drop-shaped rete ridges have been considered the elementary criteria for diagnosis of an epithelial dysplasia. 14 The structural and cellular alterations that are considered the indicators of dysplasia have been reported elsewhere in detail. 12 , 16 , 20 , 21
The grading of oral epithelial dysplasia has been controversial in the literature, with the most commonly used histological grading system for oral epithelial dysplasia including four steps with increasing severity of histological transformation: 10 , 12 , 14 , 20 (1) mild epithelial dysplasia, with minimal dysplastic alterations showing immature basal cell proliferation confined to the lower third of the epithelium; (2) moderate epithelial dysplasia, demonstrating dysplastic changes extending into the middle one-third of the epithelium; (3) severe epithelial dysplasia, with abnormal proliferation of dysplastic cells from the basal layer to the upper third of the epithelium; and (4) carcinoma in situ, with dysplastic cells with enlarged, hyperchromatic nuclei and various typical and atypical mitotic activities through the entire thickness of the epithelium but without evidence of connective tissue invasion.
Hyperplasia was included in the most initial stage of dysplasia in some reports, 20 but was later excluded since it was not an indicator of malignant risk. 15 , 22 Also, carcinoma in situ has not been included in dysplasia staging and was not considered as dysplasia, but an actual preinvasive malignancy due to the presence of undifferentiated, primitive cells from the basal to the top layer of the epithelium 12 , 15 because connective invasion cannot be ruled out.
The subjectivity of grading of dysplasia, low agreement among and between observers because of the subjective nature of the assessment, lack of established objective criteria, the inability to define the exact criteria to predict the malignant risk on histologic grounds, and arbitrary classification of dysplasia have been reported. 12 , 15 , 21 , 23 – 25 To overcome the shortcomings of conventional grading system advocated by the WHO, a binary system that combines the mild and moderate dysplasia as low risk and severe dysplasia and carcinoma in situ as high-risk lesions has been proposed. 10 , 15 , 21 , 24 Similarly, the Ljubljana grading system, which has focused on the clinical decision points to classify the oral hyperplastic lesions as simple and abnormal hyperplasia (no need for close follow-up), atypical hyperplasia (needs close follow-up), and carcinoma in situ (requires treatment), has been presented. 22 , 26
Even though the presence of dysplasia has been associated with a risk of progression to cancer, 12 , 14 , 24 , 27 other reports describe an independent nature of oral oncogenesis from the degree of dysplasia. 13 , 15 Continuing research suggests that in future, various markers of the genetic and molecular changes of the cells involved in malignant transformation should be included in any lesion classification for accurate evaluation. 15 , 26
Considering that oral cancer represents the end stage of a continuum of oral epithelial alterations and provided that oral premalignant lesions may precede oral cancer, 3 , 17 – 19 the etiological factors for development of oral premalignant lesions are thought to be those recorded for oral cancer. 16 Thus, the well-known effects of tobacco and alcohol have been considered the major causes of oral premalignant lesions. 28 – 34 However, it should be noted that both internal and external factors including betel quid use, aging, gender, UV radiation, infections (candida and the human papilloma virus), 31 , 32 , 35 decreased immune response, 36 – 38 genetic susceptibility, 3 and chronic oral trauma 39 , 40 may play a role in oral carcinogenesis.
3.2.1 Incidence, Causes, Clinical Characteristics
Tobacco has been accepted as a primary etiologic factor in oral cavity and oropharyngeal cancers. 30 Heavy use of smokeless tobacco in the form of nass, naswar, khaini, pan masala, gutkha, and betel quid (a combination of betel leaf, slaked lime, areca nut, and catechu) or smoking in the form of cigarette, bidi, chutta, reverse type of smoking, and hookah have been associated with higher risk of upper respiratory tract carcinogenesis. 3 , 33 Even though the exact interactive mechanism is not clearly defined, the carcinogenic action of tobacco and alcohol is synergistic 30 and the risk of developing oral cancer is 38 times higher among heavy drinkers and smokers when compared to nonusers. 32 A dose-response relationship for smoking frequency, duration, and cumulative consumption has been documented. 29 Estimated risk of 1.4-fold for oral cavity cancers for “ever users” versus “never smokers” among “never drinkers” of alcohol has been reported, supporting a causal relationship. 29
Tobacco chewing has been considered a risk factor for oral premalignant lesions probably being a potential cause of field cancerization of oral mucosa. 28 , 41 The odds ratio for ever tobacco chewers was 37.8 when adjusted for other confounding etiological factors, 28 with a linear dose-response association between oral cancer and chewing tobacco in terms of age at initiation, duration, and frequency of chewing per day. 41 Tobacco chewing has also been associated with the risk of multiple OPMD and alcohol was linked with the risk of multiple oral premalignant lesions. 28
Electronic cigarettes (EC) present aerosol toxicants and carcinogens, which are present in cigarette smoke, such as carcinogenic tobacco-specific nitrosamines, aldehydes, volatile organic compounds, phenolic compounds, polycyclic aromatic hydrocarbons, tobacco alkaloids, heavy metals, flavors, nicotine, 42 and radionuclides. 43 The levels of potentially toxic compounds in their aerosol have been controversial: some suggest that EC aerosols expose users to carcinogenic substances that induce deoxyribonucleic acid (DNA) damage and reactive oxygen species, decrease the cellular total antioxidant capacity, and increase cancer risk, 42 , 44 whereas others provide comparable results with EC to tobacco. 43 , 45 , 46
Although making a distinct assessment of the etiological impact of individual alcoholic beverages on oral cavity cancer development has been difficult because of combined consumption of alcohol and tobacco, 29 an increased risk for oral cancer with alcoholic beverage consumption increased the odds ratios from 3.0 to 14.8 with heavy consumption even after controlling for smoking. 47 , 48 All studies from the United States, Europe, and Asia have shown that alcohol abuse was significantly associated with oropharyngeal cancer. 47 The adjusted relative risks were between 6.2 and 9.22 for more than four drinks a day and 3.9 for consumption of four to seven times per week. When only oral cancer is taken into account, a positive and dose-related association with alcoholic beverage consumption has been reported in various regions of the world. 47 , 49 The ethanol content of the alcoholic beverages has been attributed as the cause of carcinogenic effect, mostly because of its activity as a solvent for other carcinogens and the potential to damage DNA. 29
Age and Gender
Oral squamous cell carcinoma (OSCC) is mostly observed in older patients, 39 , 50 – 54 and especially noticed in males. 50 , 52 However, more recent studies are identifying OSCC at earlier ages and without known risk factors. Others stated either equal incidence of OSCC in females and males 55 or higher incidence of OSCC in female patients, 54 especially in those younger than 40 years. 56
Generally, oral cancer risk increases with age, 32 with the highest incidence (26.8%) observed between 55 and 64 years in the United States from 2003 to 2007, 53 which has been attributed to immunosenescence-related changes in cellular and serological immune responses affecting the process of generating specific responses, 57 and cumulative risk factor exposure. More recently, possibly due to the changes in etiological factors, the number of patients younger than 40 years and in their 40s and 50s has been increasing, 32 , 58 with a prevalence of 11.3% of oral cancer among patients younger than 45 years. 59
Similar to OSCC, oral dysplasia is observed more commonly in patients between the age of 50 and 69 years, with a mean age of 59.3 years. 14 Mild, moderate dysplasia and carcinoma in situ were identified at 57 to 58 years of age, whereas severe dysplasia and verrucous hyperplasia with dysplasia were observed in older patients, around 65 years of age. 14
Molecular Alterations/Chromosome Instability/Genetics
Oral cancer development is initiated with autonomous proliferation of cells harboring DNA damage, which are not controlled by cell-growth regulation mechanisms. 3 Clinically healthy-appearing oral mucosa may contain insidious early dysplastic changes with chromosomal aberrations that precede the malignant transformation. 10 , 60 – 62 Risk of the genomic alterations has been associated with increased probability of oral cancer development, 3 , 24 , 63 and a genetic progression model involving microsatellite markers at 10 commonly altered chromosomal loci has been proposed for oral premalignant lesions. 60
Loss of heterozygosity (LOH), microsatellite instability (MSI), and loss of regions at chromosome arms 1p, 2q, 3q, 5q21-22, 8p21-23, 9p21-22, 11q13, 11q23, 13q, 14q, 17p, 18q, and 22q have been observed in oral cancer tissues. 3 , 31 , 63 , 64 The lack of protective effects of tumor suppressor genes p16 (9p21), APC (5q21-22), and p53 (17p13) due to mutations has also been related to oral cancerogenesis. 3 , 63 Invasive tumors presented chromosomal changes mostly within arms 5p, 9q, 11q, and 19p, suggesting that the genetic mutation may be different during the initial phases and invasion. 63 As the severity of histopathologic findings increases, the allelic loss also increases showing that oral carcinogenesis is a dynamic process 8 in which a single mutated cell could progress to cancer, whereas other daughter cells could wait to develop cumulative molecular changes to become malignant. 60
Additionally, second primary tumors in oral cancer patients have been considered to originate from one clonal population, sharing a common genotype. 2 , 4 Histologically normal mucosa of tumor adjacent areas of the patients with multiple oral mucosal primary tumors may indeed contain TP53 mutated cells, which may be present within more than 200-cell diameter area. 4
Oral mucosa may be a site of HPV infections and recurring HPV-associated lesions, and a prevalence of HPV (from 0.6-81%) has been reported. 65 HPV transmission to the oral cavity may be associated with sexual contacts, perinatal transmission of the neonate during birth, 65 , 67 and autoinfection via anogenital HPV infection. 68
In recent decades, infection by high-risk genotypes of HPV has been presented as a risk factor for oral cancer, 66 , 69 – 72 although more specifically for the malignant lesions in the oropharynx, including the base of the tongue, soft palate, tonsils, and pharyngeal wall. 65 , 68 , 73 , 74 The prevalence of HPV infection in oropharyngeal squamous cell carcinoma (OPSCC) has been reported to be up to 90%, 69 , 72 – 74 and associated with increasing prevalence of HPV-associated head and neck squamous cell carcinoma (HNSCC) in the United States, Western Europe, Canada, and Australia. 68 , 71 , 74 Patients with HPV-related OSCC are generally younger, more commonly male, have a higher socioeconomic status, 67 , 68 , 71 , 72 a higher lifetime number of sex partners, 66 , 72 and mostly present as smaller lesions, 66 , 67 at a higher stage and with large metastatic lymph nodes. 65 – 67
The type and oncogenic phenotype of HPV are determined by differences in the DNA base sequences of E6 and E7, and high- and low-risk HPV subtypes have been defined. The most common high-risk subtypes include HPV-16 and HPV-18, 66 , 72 , 74 , 75 whereas low-risk subtypes include HPV-6 and HPV-11. 65 , 76 HPV-positive tumors are associated with a better prognosis compared to HPV-negative SCC. 65 – 67 , 73 , 74 , 77
The role of HPV in oral cancer has been investigated using polymerase chain reaction that showed the presence of HPV DNA in 0 to 80% of OSCC cases; 65 , 71 mostly, HPV-16 or HPV-18 were observed among 16 to 73% of the patients. 75 , 78 , 79 HPV-16 and HPV-18 were three times more common in oral dysplastic lesions and invasive cancers than benign mucosal lesions. In a study of oral dysplasia, HPV-16 and HPV-18 rates were not associated with the severity of oral dysplastic lesions. 75 Other studies suggest variable presence of high-risk HPV subtypes associated with the severity of dysplasia, with the highest proportion in severe dysplasia or greatest risk for malignancy reported. 78 , 80 – 82
Malignant transformation of oral mucosal cells is associated with high-risk HPV subtypes, including HPV-16 and HPV-18. 67 HPV-6, HPV-16, and HPV-18 were noted in oral leukoplakia (OL), whereas HPV-6, HPV-11, and HPV-18 were reported in oral erythroplakia (OE) lesions. 67 HPV-16 and HPV-18 were also observed in 9.2% of oral lichen planus (OLP) lesions, suggesting a possible impact of HPV upon the transformation of OLP to OSCC. 81 HPV-18 was the most frequently detected genotype among OLP and OL patients, followed by HPV-16, HPV-33, HPV-31, and HPV-6. 83
In addition to molecular epithelial change, the effect of chronic inflammation in tumor initiation, promotion, and progression by altering the local environment has been reported. 35 , 84 – 86 It is suggested that an environment that incubates the components of a persistent reactive response such as the chronic inflammatory cells, cytokines, growth factors, and DNA-damaging elements in the tissues surrounding the foci with malignant challenges may contribute to the development of neoplasia via stimulation of cell division stimulated by a continuous repair process despite antitumor responses of the host. 11 , 84 , 86 – 89 In addition to chronic inflammatory conditions of the epithelium, further accumulation of acquired immune response to cancerous development may also intervene with the whole process. 86 , 87 The malignant transformation of OPMD has been attributed to a cascade of molecular stimuli originating with chronic inflammatory infiltrate. 89 , 90 Expression of hypoxia-related proteins, 6 regulatory T cells, and tumor-associated macrophages, and expression of anti-inflammatory cytokines, proinflammatory cytokines, and inflammatory-induced endogenous oncogenic alterations containing micro-RNAs (miRNAs) or transcriptional changes may play a role in progression of oral premalignant lesions to OSCC. 89 – 91
In the literature, poor oral hygiene, 31 , 35 , 40 , 49 periodontal disease, 35 , 49 , 92 significant tooth loss (over 6-20 teeth), 40 , 48 , 49 , 92 – 94 five or more defective teeth, 40 trauma associated with improper complete dentures, 40 and infrequent dental controls 94 have been noted as risk factors for oral cancer after adjusting for tobacco and alcohol consumption, whereas regular dental checkups and tooth brushing were associated with decreased risk. 40 , 92 – 95 The risk is higher for alcohol consumers, and may be due to oral microflora and mucosal cell conversion of ethanol within saliva to carcinogenic acetaldehyde. 35 , 92 , 94
Individuals from low socioeconomic populations have been reported to be at increased risk of oral cancer because of less awareness about preventable risk factors of oral cancer like tobacco and alcohol use, 59 , 97 , 98 poor nutrition, 39 , 97 , 99 and less access to health care. 48 Both the incidence and survival rates of cancer have been associated with socioeconomic factors. 30 , 48 People with low income had a higher prevalence of tobacco and alcohol use and poorer diet lacking fruits and vegetables. 39 , 97 However, even in nonsmoking alcohol-consuming groups and in both high- and low-income countries, the odds of developing oral cancer was high when associated with low income, low occupational social class, and low education level. 39 , 48 , 49 , 97
The world-standardized incidence rate for oral cancer among males is higher in more developed countries, whereas the mortality rates is almost the same. 48 On the other hand, for females, both the world-standardized incidence rate and the mortality rate for oral cavity cancer are higher in less developed countries, 48 possibly due to delayed diagnosis and limited health care access for treatment in those areas, 48 , 97 in addition to prevalence and duration of exposure to known risk factors for cancer.
Long-term immunodeficiency observed in patients with solid organ or hematologic cell transplants or chronic autoimmune diseases has been attributed as a contributing factor in carcinogenesis due to the lack of protective activity against oncoviruses including Epstein-Barr virus (EBV), human herpes virus 8 (HHV-8), and HPV, compromised immune surveillance of malignant cells, and pro-oncogenic properties of some immunosuppressive agents. 37 Because of the decrease in T and natural killer (NK) cells, which are vital for cellular immunity and management of cancerogenesis, malignant transformations may be increased in patients receiving immunosuppressive therapy. 36 – 38
3.3 Clinical Presentation
OPMD and OSCC patients may infrequently complain of bleeding of the mouth and throat, unilateral pain/numbness/discomfort, ear pain, trismus, limited movement of involved tissue, teeth mobility, neck mass, sore throat, difficulty in speaking, chewing, and swallowing, weight loss, and malodor. 51 , 100 – 103 These symptoms are associated with advanced stage of cancer and are related to the location of the lesion. 103 However, as OPMD and initial OSCC lesions are commonly asymptomatic or minimally symptomatic until the advanced stages of the disease, which then leads to diagnosis, 51 , 102 – 104 the presence of symptoms that are not indicative of malignancy might mislead clinicians. 18 , 105 Increased 106 or similar levels of physical pain between patients with oral premalignant conditions and OSCC 107 have also been reported. The significant challenge is detection and differentiation of OPMD and OSCC from variations of normal mucosa and from more common benign/inflammatory mucosal lesions. 18 , 102
The list of oral premalignant lesions varies in the literature. The broadest list includes proliferative verrucous leukoplakia, 12 , 19 erythroplakia, 12 , 19 , 25 reverse smokers palate, 12 oral submucous fibrosis (OSMF), 12 , 19 speckled/granular/nonhomogeneous leukoplakia, 12 , 25 tobacco pouch keratosis, 19 leukoplakia tobacco keratosis/nicotine stomatitis, 12 , 19 and OLP. 12 , 19
Clinically, these lesions induce oral mucosal changes in surface texture, color, and size; cause loss of surface integrity and contour deviations; and may also influence the mobility of intraoral or extraoral structures. 31 , 108 Even though over 30% of patients with OSCC and OPSCC receive oral cancer screening within 3 years before a diagnosis of OSCC, 109 the unpredictable nature of potential progression of OPMD can lead to occurrence of malignant lesions at any time.
Mixed color of OPMD has been reported as a potential indicator of increased risk of malignant nature. 103 , 110 – 112 Similarly, irregular/mixed texture of the lesion is also an indicator of malignant nature and smooth texture was a sign of benign nature. 111 , 113
Chronic oral mucosal ulcers with nonelevated borders have been suggested as a clinical feature of oral malignancy. 50 , 111 – 115 The confined nature of the lesion, which was depicted with defined and regular margins, was suggestive of benign lesions, while irregular and undetectable margins were reported as indicators of malignant potential. 111 , 113
3.3.1 Oral Leukoplakia
OL is the most common form of OPMD, 19 , 32 , 116 which is observed clinically in up to 4.9% of the world population. 11 , 19 , 24 , 32 , 117 , 118 It is defined by the WHO as “a white patch or plaque that cannot be characterized clinically or histologically as any other disease” 118 or “white plaques of questionable risk having excluded (other) known diseases or disorders that carry no increased risk for cancer.” 24 , 119 , 120 Smoking, alcohol, HPV infection, candidiasis, and reduced concentrations of serum vitamin A and C, beta-carotene, and folic acid 24 , 117 , 118 are etiological factors of OL.
A provisional diagnosis is made when a lesion at clinical examination cannot be clearly diagnosed as any other disease of the oral mucosa with a white appearance; a definitive diagnosis of OL is made as a result of the identification and elimination of suspected etiological factors and, in the case of persistent lesions following a period of 2 to 4 weeks, histopathological examination. 116 , 117
Clinically, OL is broadly classified into homogeneous and nonhomogeneous subtypes. 24 , 117 , 119 , 120 Homogeneous plaques are predominantly white, of uniform flat, thin appearance with shallow cracks of surface keratin, and have a smooth, wrinkled, or corrugated surface with a consistent texture throughout 24 , 119 (▶ Fig. 3.1). This clinical pattern shows a low risk of malignant transformation (5%). 118 , 119 , 121 Nonhomogeneous variants include mixed, white and red, but retaining predominantly white character (speckled), small polypoid outgrowths, rounded red or white excrescences (nodular), and wrinkled or corrugated surface appearance (verrucous). 24 , 116 , 119 Malignant transformation is reported as 25% of nonhomogenous OLs, revealing a higher risk than homogenous lesions. 118 Proliferative verrucous OL is an independent entity from the set of leukoplakias, more often observed in elderly women, usually in the gingival region that may affect large areas of mucosa, as whitish verrucous lesions, or in a less keratinized polypoid form with well-defined borders. 118 These lesions are characterized by a multifocal presentation, resistance to treatment, 24 and high rate of malignant transformation of up to 80%. 24 , 118
The majority of OL represent benign conditions, and should be differentiated from candidiasis, lupus erythematosus, lichen planus, traumatic/irritative lesions, chemical burns, syphilis, papilloma, hereditary white lesions, and geographic tongue, 13 because long-standing OL lesions may be potential precursors of oral cancer. 11 , 117 , 120 The reported malignant transformation rate ranges from 0.13 to 36.4%, depending upon the study design, 11 , 24 , 110 , 118 , 120 , 122 , 123 within a period of 1 to 30 years. 12 , 123 Histological analysis of the lesions is the current standard to examine their biological potential. 24 , 116 , 117
Having nonhomogenous nature, 24 , 117 , 120 , 124 being larger than 200 mm, 117 , 120 , 124 location on the tongue or floor of the mouth, 117 , 125 female gender, 117 , 125 age older than 60 years, 24 presence of dysplasia, 117 previous history of SCC, 118 regular consumption of alcohol or cigarettes, 118 and occurrence in nonsmokers 117 , 125 are correlated with higher risk of transformation. Nonhomogeneous OL on tongue/floor of the mouth had a 43.10-fold higher risk compared to homogeneous lesions located on the other sites, 125 but histological analysis of the lesions is mandatory to discover their biological potential. 24 , 117 , 124