
==== Front
Braz Oral Res
Braz Oral Res
bor
Brazilian Oral Research
1806-8324
1807-3107
Sociedade Brasileira de Pesquisa Odontológica - SBPqO

39109766
03101
10.1590/1807-3107bor-2024.vol38.0069
Original Research/Stomatology
Oral leukoplakia and erythroplakia in young patients: a southern Brazilian multicenter study
https://orcid.org/0000-0001-6445-0658
SOARES Alini Cardoso (a)
https://orcid.org/0000-0003-2214-5246
GOMES Ana Paula Neutzling (a)
https://orcid.org/0000-0003-0188-7435
CALDERIPE Camila Barcellos (b)
https://orcid.org/0000-0001-7842-619X
SALUM Fernanda Gonçalves (c)
https://orcid.org/0000-0003-0913-477X
CHERUBINI Karen (c)
https://orcid.org/0000-0001-8662-5965
MARTINS Manoela Domingues (d)
https://orcid.org/0000-0002-0993-936X
SCHUCH Lauren Frenzel (b)
https://orcid.org/0000-0002-9411-3713
KIRSCHNICK Laura Borges (b)
https://orcid.org/0000-0003-2258-8071
ABREU Lucas Guimarães (e)
https://orcid.org/0000-0003-2040-6617
SANTOS-SILVA Alan Roger (b)
https://orcid.org/0000-0001-6560-9536
VASCONCELOS Ana Carolina Uchoa (a)
(a) Universidade Federal de Pelotas – UFPel, Dental School, Diagnostic Center for Oral Diseases, Pelotas, RS, Brazil.
(b) Universidade Estadual de Campinas – Unicamp, Piracicaba Dental School, Department of Oral Diagnosis, Piracicaba, SP, Brazil.
(c) Pontifícia Universidade Católica do Rio Grande do Sul – PUCRS, Division of Oral Medicine, Porto Alegre, RS, Brazil.
(d) Universidade Federal do Rio Grande do Sul – UFRGS, School of Dentistry, Department of Oral Pathology, Porto Alegre, RS, Brazil.
(e) Universidade Federal de Minas Gerais – UFMG, School of Dentistry, Department of Child and Adolescent Oral Health, Belo Horizonte, MG, Brazil.
Corresponding Author: Ana Carolina Uchoa Vasconcelos E-mail: carolinauv@gmail.com
Declaration of Interests: The authors certify that they have no commercial or associative interest that represents a conflict of interest in connection with the manuscript.

05 8 2024
2024
38 e06919 10 2023
6 3 2024
15 4 2024
https://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract

The objective of the present study was to investigate the frequency of oral leukoplakia and oral erythroplakia among young patients from three Brazilian reference centers in Oral and Maxillofacial Pathology. A retrospective study was carried out from 2011 to 2021 on 861 patients diagnosed with oral leukoplakia and oral erythroplakia. Demographic and clinicopathological data were evaluated. Fisher’s exact test was used to evaluate the association among sex, age, anatomical location, and histopathological diagnosis. A total of 83 (9.64%) cases involved young patients (aged <40 years). Among these, biopsy records were included in 31 (37.34%) cases, all of which received a clinical diagnosis of oral leukoplakia. Seventeen (54.84%) patients were female, mostly in their fourth decade of life (n = 22/70.97%), and their mean age at diagnosis was 32.61(± 5.21) years. Among informed cases, seven (22.58%) patients were smokers. The lateral border of the tongue (n = 9/29.03%) was the most affected site. In 13 (41.94%) cases, oral leukoplakias showed a homogeneous appearance. The mean size of the lesions was 1.47 cm (0.2–3.0 cm) and the mean time of disease progression was 64.37 (± 65.90) months. The histopathological analysis showed that 11 cases (35.48%) exhibited some degree of epithelial dysplasia. Acanthosis and/or hyperkeratosis were observed in 20 cases (64.52%). No significant associations were observed between sex and anatomical location, age and anatomical location, nor between sex and histological diagnosis (p > 0.05). Oral leukoplakia and oral erythroplakia are uncommon diseases in young patients. In this population, oral leukoplakia shows a slight predilection for women aged between 30 and 39 years.

Leukoplakia
CNPq001
==== Body
pmcIntroduction

Oral potentially malignant disorders (OPMDs) are clinical conditions involving the risk of cancer development, observed both in a clinically defined precursor lesion and in clinically normal mucosa. 1 The WHO Collaborating Centre for Oral Cancer classified 11 oral disorders as OPMDs, including oral leukoplakia (OL) and oral erythroplakia (OE), 1 and OL was the most frequent finding in clinical practice. 1 The worldwide prevalence of OL ranges between 2.60% and 4.11%, and males after the fourth decade of life are the most affected individuals. 2

Clinically, the disease is classified according to appearance as homogeneous or non-homogeneous (speckled/erythroleukoplakia, nodular or verrucous). 1 OE is less frequent than OL and exhibits a higher risk for malignant transformation. 3-5 It is estimated that the prevalence of OE varies between 0.02% and 0.83%, and the condition is predominantly observed in male adults between the sixth and seventh decades of life. 4 The rate of overall malignant transformation is 9.8% in OL and varies from 14% to 50% in OE. 4,6

Most oral squamous cell carcinomas (OSCCs) are diagnosed between the fifth and sixth decades of life. 4 However, epidemiological studies have demonstrated an increased incidence of OSCCs among young patients, eventually accompanied by an increased incidence of OPMDs and/or an increased risk of malignant transformation in this population. 7 To date, limited information about OL and OE in young patients has been published in the literature. 8-12 Considering the importance of these diseases for public health, the objective of the present study was to evaluate the frequency and demographic and clinicopathological characteristics of OL and OE in young patients based on a retrospective analysis of cases diagnosed and treated at three Brazilian reference centers in Oral and Maxillofacial Pathology.

Methods

Study design, setting, and ethical issues

Records of patients with a clinical diagnosis of OL and OE were retrieved in a retrospective study of data obtained from 2011 to 2021. Data were obtained from a consortium of three services of Oral and Maxillofacial Pathology located in the southern Brazilian region: Federal University of Pelotas (UFPel), Federal University of Rio Grande do Sul (UFRGS), and Pontifical Catholic University of Rio Grande do Sul (PUCRS). The study was approved by an institutional Research Ethics Committee (process no. 62023922.0.1001.5317) and followed the Declaration of Helsinki guidelines.

Sampling

The study followed the STROBE guidelines. 13 The clinical diagnosis of OL and OE was established according to Warnakulasuriya et al. 1 Patients aged less than 40 years with a clinical diagnosis of OL or OE and with histological evaluation related to the clinical diagnosis were selected. OL and OE are clinical diseases that can receive a histological diagnosis of acanthosis, hyperkeratosis, and oral epithelial dysplasia. Patients with lesions located on the lips were excluded due to the distinct etiopathogenesis. Cases with histological features of OSCC were not included in the sample. Finally, records of patients lacking information about the histopathological diagnosis were also excluded.

Data collection

When available, the following data were collected: patient’s age (in years), sex (male or female), habits (smoking and/or alcohol drinking), anatomical location (base of the tongue, dorsal tongue, lateral border of the tongue, floor of the mouth, buccal mucosa, gingiva, hard palate, soft palate, lip commissure, or multiple sites, the latter when in more than one location), appearance (homogeneous or non-homogeneous, for OL), size (in cm), time of disease progression (in months), and histopathological diagnosis (acanthosis and/or hyperkeratosis, oral epithelial dysplasia, carcinoma in situ).

Regarding habits, patients who had smoked more than 100 cigarettes in their lifetime and who had smoked at least once in the last 30 days were considered smokers. 14 Regarding alcohol consumption, patients who drank about five or more alcoholic beverages (approximately 60 grams of ethanol) at least once a month were considered alcoholics. 15

Oral epithelial dysplasia grading remains a controversial issue, as the assessment and classification of dysplasia can be highly subjective. The WHO classification of oral epithelial dysplasia considers 16 architectural features and 11 cytological features. The diagnostic categories were separated into three levels of dysplasia (mild, moderate, and severe) and the classification was carried out according to the number of affected thirds. 16 According to the latest WHO classification, mild dysplasia can be defined by cytological atypia limited to the basal third, moderate dysplasia by atypia at the middle third, and severe dysplasia by atypia at the upper third. 16 Cases that were originally diagnosed as carcinoma in situ were reclassified as severe dysplasia. 16 The cases were diagnosed by an oral and maxillofacial pathologist at their respective services.

Statistical analysis

The statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS) for Windows, version 25.0 (ISPSS Inc., Chicago, USA). Descriptive statistics were carried out to characterize the cases regarding the following information: patient’s sex, age and habits, anatomical location of the lesion, appearance, and histopathological diagnosis. Fisher’s exact test was used to evaluate the association among sex, age, anatomical location, and histopathological diagnosis.

Results

Of the 861 patients diagnosed (clinical diagnosis) with OL or OE during the study period, 83 (9.64%) were 40 years old or younger. The remaining patients (n = 778/90.36%) were aged over 40 years. Among these 83 cases, 31 (37.34%) received histopathological diagnosis compatible with OL (clinical diagnosis) (Figure 1). No cases of OE (clinical diagnosis) were found in the 40-year-old or younger patients. The remaining patients (n = 52/62.66%) were excluded after the application of clinical and histopathological criteria. Seventeen (54.84%) patients were female and 14 (45.16%) were male (female-to-male ratio 1.2:1). Individuals in the fourth decade of life were the most affected (n = 22/70.97%). The mean age at clinical diagnosis was 32.61(± 5.21) years (range: 18 to 39 years). Data on habits were available in 12 cases, among which seven (22.58%) were smokers, three (9.67%) were nonsmokers or alcoholics, one (3.23%) was an alcoholic, and one (3.23%) was a smoker and an alcoholic. Regarding anatomical location, nine (29.03%) cases were on the lateral border of the tongue, eight (25.80%) in the buccal mucosa, and eight (25.80%) at multiple sites. Regarding clinical appearance, 13 (41.94%) cases were homogeneous and eight (25.80%) were non-homogeneous. The mean size of the lesions was 1.47 cm (range 0.2–3.0 cm). Information about time of disease progression was available in eight (25.81%) cases, with a mean time of 64.37 (± 65.9) months. The histopathological diagnosis included acanthosis and/or hyperkeratosis (n = 20/64.84%), mild dysplasia (n = 8/25.80%), moderate dysplasia (n=2/6.45%), or severe dysplasia (n = 1/3.23%) (Figure 2). The demographic and clinical data of the sample are displayed in Table 1. No statistical associations were observed between sex and anatomical location (p-value = 0.399), age and anatomical location (p-value = 0.112), or sex and histological diagnosis (p-value = 0.296). Data are displayed in Tables 2 and 3.

Figure 1 Flow diagram of the selection process.

Figure 2 Oral leukoplakia. A, Non-flat, white plaque exhibiting sharp and well-defined borders in a 34-year-old man. B, Epithelium with a brightly eosinophilic keratin surface showing architectural and cytological changes of dysplasia (hematoxylin & eosin [H&E], 200×). C, Severe dysplasia showing loss of basal cell polarization, budding rete ridges, increased hyperchromasia (*), and mitotic figures (arrows) confined to the basal and parabasal layers (H&E, 400×).

Table 1 Demographic and clinical characteristics of the sample.

Variable	n (%)	
Sex (n = 31)	
Female	17 (54.84)	
Male	14 (45.16)	
Female-to-male ratio	1.8–2.2	
Age (n = 31)	 	
Mean	32.61 ± 5.21	
Range	18–39	
Decades of life (n = 31)	
10–19	1 (3.23)	
20–29	8 (25.80)	
30–39	22 (70.97)	
Habits (n = 31)	
Alcohol	1 (3.23)	
Tobacco	7 (22.58)	
Alcohol and tobacco	1 (3.23)	
No alcohol and tobacco	3 (9.67)	
Not informed	19 (61.29)	
Anatomical location (n = 31)	
Dorsal tongue	1 (3.23)	
Lateral tongue	9 (29.03)	
Buccal mucosa	8 (25.80)	
Gingiva	3 (9.68)	
Soft palate	1 (3.23)	
Lip commissure	1 (3.23)	
Multiple sites	8 (25.80)	
Appearance (n = 31)	
Homogeneous	13 (41.94)	
Non-homogeneous	8 (25.80)	
Not informed	10 (32.26)	
Size (n = 23)	
Mean	1.47 (± 0.99)	
Range	0,2-3,0	
Time of disease progression (n = 8)	
Mean	64.37 (± 65.90)	
Range	1–180	
Histopathological diagnosis (n = 31)	
Acanthosis and/or hyperkeratosis	20 (64.52)	
Mild dysplasia	8 (25.80)	
Moderate dysplasia	2 (6.45)	
Severe dysplasia	1 (3.23)	

Table 2 Relation between age, sex, and anatomical location.

Age	10–19	20–29	30–39	Total	
Anatomical location	♂	♀	♂	♀	♂	♀	♂ + ♀	
Dorsal tongue	1	0	0	0	0	0	1	
Lateral tongue	0	0	0	4	2	3	9	
Buccal mucosa	0	0	1	0	3	4	8	
Gingiva	0	0	0	1	1	1	3	
Soft palate	0	0	0	1	0	0	1	
Lip commissure	0	0	0	0	1	0	1	
Multiple	0	0	1	0	4	3	8	
Total	1	0	2	6	11	11	31	
p-value (sex and anatomical location) = 0.399 – Fisher’s exact test/ p-value (age and anatomical location) = 0.112 – Fisher’s exact test.

Table 3 Relation between sex, location, and oral histological diagnosis.

Oral histological diagnosis	Acanthosis and/or hyperkeratosis	Mild dysplasia	Moderate dysplasia	Severe dysplasia	Total	
Location	♂	♀	♂	♀	♂	♀	♂	♀	♂ + ♀	
Dorsal tongue	0	0	1	0	0	0	0	0	1	
Lateral tongue	1	5	0	1	0	0	1	0	8	
Buccal mucosa	2	4	2	1	0	0	0	0	9	
Gingiva	1	1	0	1	0	0	0	0	3	
Soft palate	0	1	0	0	0	0	0	0	1	
Lip commissure	0	0	1	0	0	0	0	0	1	
Multiple	3	2	1	0	1	1	0	0	8	
Total	7	13	5	3	1	1	1	0	31	
p-value (sex and location) = 0.399/ p-value (sex and histological diagnosis) = 0.296.

Discussion

The epidemiology and clinical profile of OL and OE have not been well documented in young patients. In the present study, 3.60% (31 cases) of 861 clinical diagnoses of OL involved young patients. As observed in our research, Azevedo et al. 17 reported no OE cases in patients aged less than 40 years in a sample of 953 OPMDs, suggesting that cancerization is time-dependent. In a recent systematic review of the clinical and demographic characteristics of 1,246 individuals with OL, Roza et al. 7 observed that young patients comprised 9.23% of the sample (n = 115). In a Brazilian epidemiological survey of 107 OLs, a total of 30 (28.04%) cases involved patients aged 25 to 45 years. 18 In a South African cross-sectional study of 95 patients with a clinical diagnosis of OL, Chandran et al. 8 reported that 21 (22.11%) of them were individuals aged 20 to 39 years. In a Chinese study on the malignant transformation of oral epithelial dysplasia, only six (16.22%) out of 37 cases of OL were patients aged less than 40 years. 10 The literature emphasizes that OL is the most common OPMD, a distribution probably related to local cultural habits and different socioeconomic status among populations. 19 Also, studies reporting opposite results were mainly based on different sample sizes. 20,21 Finally, some researchers have shown that, in developed countries, OL tends to be diagnosed after the age of 40 years due to the use of samples recruited from hospitals rather than from the community. 20,21

In our study, there was a slight predilection for female patients (n=17/54.84%), whereas Roza et al. 7 observed a predominance of males (87.8%) among young patients with OL. According to Mello et al., 3 most OPMDs occur in men, and the difference in distribution between sexes can be explained by cultural habits, especially tobacco use. Interestingly, the literature emphasizes that females, despite being less affected, exhibit a higher risk of malignant transformation of OLs, with an overall rate of 13.1%. 5,19 However, it is unclear why women are more predisposed to malignant transformation compared to men. Some studies have already indicated that non-smoking women have an additional risk of malignant transformation, which can be explained by global genomic arrays that may illustrate a differential gene expression. 5,22 These young women with OL will possibly be the group with a growing number of oral cancer, as discussed by Toner and O’Regan, 23 i.e., non-smoking young females aged <40 years. This profile of cancer patients seems to be increasing, and clinical and biological understanding remains minimal. 24 Conversely, a recent large multicenter study that assessed the frequency of OSCC in young patients showed that 5.8% (n = 626) of the patients were 40 years old or younger. 25 Among them, 268 (42.8%) were women. These contrasting data suggest a need for future studies to explore the possible genetic role of sex in young patients with OL and OSCC.

The anatomical site, clinical appearance, and size of OLs are classical features that may influence the risk of malignant transformation of OPMDs. 5,26 A recently published systematic review demonstrated that the rate of malignant transformation is approximately 6.9% among young patients. 7 Lee et al. 9 showed that the relative risk for malignancy in leukoplakias on the tongue/floor of mouth was 28.13 times higher compared to malignancy on the buccal mucosa. The literature emphasizes that the ventral and lateral borders of the tongue and the floor of the mouth comprise the areas of overexposure to carcinogens as a result of the accumulation of saliva in alcohol and tobacco users. 5 Interestingly, eight cases in our sample had multiple locations. We carefully investigated whether proliferative verrucous leukoplakia (PVL) might be present in these patients. The leadership of the American Academy of Oral and Maxillofacial Pathology (AAOMP) and the North American Society of Head and Neck Pathologists (NASHNP) has recently approved a consensus guideline on PVL that was presented by a team of experts. The guideline stated that, “it is imperative to consider both the clinical presentation and history in concert with the histopathology of representative specimens in order to establish a PVL diagnosis”. 27 Due to the cross-sectional design of the study, sufficient information on the OLs was lacking, with consequent difficulty in identifying these multiple-site cases as PVL. Finally, it is important to consider that, as pointed out by Müller, 28 some white lesions, such as frictional keratosis, are still misdiagnosed as OL.

In the present study, no statistical correlation was observed between anatomical site and the presence of oral dysplasia. Oral epithelial dysplasia is the most significant feature associated with the risk of malignant transformation to oral cancer. 29 In their study, Roza et al. 7 noted that most cases did not have any degree of oral epithelial dysplasia (n = 73/64.6%), similar to what was observed in our sample (n = 20/64.52%). 7 Chandran et al. 8 also reported the absence of epithelial dysplasia in 11 (52.38%) out of 21 young patients with OL. The results of different investigations concerning the relationship between epithelial dysplasias need to be interpreted with caution because the exercise of grading epithelial dysplasia is highly subjective, with low interpersonal reproducibility. Considering the slow process of oral carcinogenesis, it is important to emphasize the need for a periodic clinical evaluation of any OPMDs, considering their risk of malignant transformation.

It is a consensus in the literature that non-homogeneous OLs exhibit a higher risk of malignant transformation than homogeneous OLs. 1,3-20 In their systematic review of 24 retrospective surveys, Warnakulasuriya and Ariyawardana 19 detected a malignant transformation rate of 3% and 14.5% for homogeneous and non-homogeneous OL, respectively. Curiously, among our cases, no oral epithelial dysplasia was observed in five out of eight non-homogeneous OLs. OL lesions exceeding 200 mm2 are at increased risk for malignant transformation 19 and most studies agree that malignant transformation of OPMDs is higher within the first 5 years after diagnosis. 5 In the present study, three of the four cases that exceeded 200 mm2 received the histopathological diagnosis of acanthosis and/or hyperkeratosis. Unfortunately, no research evaluated size, time of disease progression or follow-up in young OL patients.

Tobacco use and alcohol consumption are well-established etiological factors for the development of OPMDs, and the literature states that the risk of progression of OSCC is directly related to these habits. 5 Farquhar et al. 30 analyzed the risk and survival factors of oral tongue carcinoma among young patients and reported that, out of a total of 117 patients aged up to 45 years, 59 (50%) were female and less likely to use tobacco (n=59/51%) and alcohol (n = 102/90%). 30 Some authors have demonstrated increased genomic instability in young patients, suggesting the presence of genetic differences between young and older individuals affected by OSCC. 31 Moreover, unidentified etiological agents or even unknown risk factors for oral carcinogenesis should be considered in young people. Unfortunately, just a few studies specified information about tobacco and alcohol consumption, and the absence of standardization regarding the concepts of these habits did not allow for a more accurate interpretation.

The results of this research have limitations that should be addressed. First, the limited number of cases may not accurately represent the true frequency of OL in the Brazilian population. Second, some information was missing or lost over time due to the retrospective study design. The absence of electronic records in current Brazilian services and the lack of protocols used to describe patient details hinder data collection and subsequent evaluation. Clinical centers must find ways to implement standardized instruments in order to provide better data collection. Third, it was difficult to find works in the literature that classify OPMDs by age group, not allowing for data extraction. Finally, no studies evaluating the genetic profile of young patients with OPMDs were found in the English, Spanish, or Portuguese literature. Therefore, we emphasize the importance of well-designed prospective clinical studies for a better understanding of OL in young patients. In addition, journals should encourage the use of protocol guides (for example, STROBE in observational studies) in order to standardize the description of the clinical and demographic data of the patients.

Conclusion

In summary, this multicenter study shows that OL and OE are uncommon lesions in young patients. In this population, OL shows a slight predilection for women aged 30 to 39 years. Considering the potential risk of malignant transformation of OPMDs, general dentists should be aware of all patients with suspicious oral lesions, regardless of their age.

Acknowledgments

Manoela D. Martins, Lucas G. Abreu and Alan R. Santos-Silva are research fellows funded by the Brazilian National Council for Scientific and Technological Development (CNPq). The authors thank the Coordination for the Improvement of Higher Education Personnel (Capes, Finance Code 001), Brazil. Alini C. Soares, Camila B. Calderipe, and Laura B. Kirschnick are the recipients of fellowships.
==== Refs
References

1 Warnakulasuriya S Kujan O Aguirre-Urizar JM Bagan JV González-Moles MÁ Kerr AR et al Oral potentially malignant disorders: A consensus report from an international seminar on nomenclature and classification, convened by the WHO Collaborating Centre for Oral Cancer Oral Dis 2021 11 27 8 1862 1880 10.1111/odi.13704 33128420
2 Warnakulasuriya S Clinical features and presentation of oral potentially malignant disorders Oral Surg Oral Med Oral Pathol Oral Radiol 2018 06 125 6 582 590 10.1016/j.oooo.2018.03.011 29673799
3 Mello FW Miguel AF Dutra KL Porporatti AL Warnakulasuriya S Guerra EN et al Prevalence of oral potentially malignant disorders: a systematic review and meta-analysis J Oral Pathol Med 2018 08 47 7 633 640 10.1111/jop.12726 29738071
4 Reichart PA Philipsen HP Oral erythroplakia: a review Oral Oncol 2005 07 41 6 551 561 10.1016/j.oraloncology.2004.12.003 15975518
5 Speight PM Khurram SA Kujan O Oral potentially malignant disorders: risk of progression to malignancy Oral Surg Oral Med Oral Pathol Oral Radiol 2018 06 125 6 612 627 10.1016/j.oooo.2017.12.011 29396319
6 Aguirre-Urizar JM Lafuente-Ibáñez de Mendoza I Warnakulasuriya S Malignant transformation of oral leukoplakia: systematic review and meta-analysis of the last 5 years Oral Dis 2021 11 27 8 1881 1895 10.1111/odi.13810 33606345
7 Roza AL Kowalski LP William WN Jr Castro G Jr Chaves AL Araújo AL et al Oral leukoplakia and erythroplakia in young patients: a systematic review Oral Surg Oral Med Oral Pathol Oral Radiol 2021 01 131 1 73 84 10.1016/j.oooo.2020.09.002 33187936
8 Chandran R Meer S Feller L Oral leukoplakia in a South African sample: a clinicopathological study Oral Dis 2013 09 19 6 592 597 10.1111/odi.12040 23210506
9 Lee JJ Hung HC Cheng SJ Chen YJ Chiang CP Liu BY et al Carcinoma and dysplasia in oral leukoplakias in Taiwan: prevalence and risk factors Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2006 04 101 4 472 480 10.1016/j.tripleo.2005.07.024 16545712
10 Liu W Bao ZX Shi LJ Tang GY Zhou ZT Malignant transformation of oral epithelial dysplasia: clinicopathological risk factors and outcome analysis in a retrospective cohort of 138 cases Histopathology 2011 10 59 4 733 740 10.1111/j.1365-2559.2011.03938.x 21916948
11 Delavarian Z Mohtasham N Mosannen-Mozafari P Pakfetrat A Shakeri MT Ghafoorian-Maddah R Evaluation of the diagnostic value of a Modified Liquid-Based Cytology using OralCDx Brush in early detection of oral potentially malignant lesions and oral cancer Med Oral Patol Oral Cir Bucal 2010 09 15 5 e671 e676 10.4317/medoral.15.e671 20383114
12 Jahanbani J Prevalence of oral leukoplakia and lichen planus in 1167 Iranian textile workers Oral Dis 2003 11 9 6 302 304 10.1034/j.1601-0825.2003.00967.x 14629331
13 Elm E Altman DG Egger M Pocock SJ Gøtzsche PC Vandenbroucke JP The strengthening the reporting of observational studies in epidemiology (STROBE) Statement: guidelines for reporting observational studies Int J Surg 2014 12 12 12 1495 1499 10.1016/j.ijsu.2014.07.013 25046131
14 Callaghan L Yong HH Borland R Cummings KM Hitchman SC Fong GT What kind of smoking identity following quitting would elevate smokers relapse risk? Addict Behav 2021 01 112 106654 10.1016/j.addbeh.2020.106654
15 World Health Organization Global status report on alcohol and health 2018 Geneve World Health Organization 2019
16 Muller S Tilakaratne WM Update from the 5th Edition of the World Health Organization Classification of Head and Neck Tumours: Tumours of the oral cavity and mobile tongue Head Neck Pathol 2022 16 54 62 10.1007/s12105-021-01402-9 35312982
17 Azevedo AB Santos TC Lopes MA Pires FR Oral leukoplakia, leukoerythroplakia, erythroplakia and actinic cheilitis: analysis of 953 patients focusing on oral epithelial dysplasia J Oral Pathol Med 2021 09 50 8 829 840 10.1111/jop.13183 33817883
18 Dogenski LC Ribeiro SF Gambin DJ Maso PC Linden MS Trentin MS et al Oral leukoplakia-epidemiological survey and histochemical analysis of 107 cases in Brazil Clin Oral Investig 2021 04 25 4 1859 1867 10.1007/s00784-020-03488-x
19 Warnakulasuriya S Ariyawardana A Malignant transformation of oral leukoplakia: a systematic review of observational studies J Oral Pathol Med 2016 03 45 3 155 166 10.1111/jop.12339 26189354
20 Villa A Woo SB Leukoplakia: a diagnostic and management algorithm J Oral Maxillofac Surg 2017 04 75 4 723 734 10.1016/j.joms.2016.10.012 27865803
21 Napier SS Speight PM Natural history of potentially malignant oral lesions and conditions: an overview of the literature J Oral Pathol Med 2008 01 37 1 1 10 10.1111/j.1600-0714.2007.00579.x 18154571
22 Schepman KP Meij EH Smeele LE Waal I Malignant transformation of oral leukoplakia: a follow-up study of a hospital-based population of 166 patients with oral leukoplakia from The Netherlands Oral Oncol 1998 07 34 4 270 275 https://doi.org/10.1016/S1368-8375 (98)80007-9 9813722
23 Toner M O'Regan EM Head and neck squamous cell carcinoma in the young: a spectrum or a distinct group? Part 1 Head Neck Pathol 2009 09 3 3 246 248 10.1007/s12105-009-0135-0 20596979
24 Santos-Silva AR Andrade MAC Jorge J Almeida OP Vargas PA Lopes MA Tongue squamous cell carcinoma in young nonsmoking and nondrinking patients: 3 clinical cases of orthodontic interest Am J Orthod Dentofacial Orthop 2014 145 1 103 107 10.1016/j.ajodo.2012.09.026 24373660
25 Ferreira E CostaR Leão ML Sant?Ana MS Mesquita RA Gomez RS Santos-Silva AR et al Oral squamous cell carcinoma frequency in young patients from referral centers around the world Head Neck Pathol 2022 09 16 3 755 762 10.1007/s12105-022-01441-w 35316511
26 Jayasooriya PR Dayaratne K Dissanayake UB Warnakulasuriya S Malignant transformation of oral leukoplakia: a follow-up study Clin Oral Investig 2020 12 24 12 4563 4569 10.1007/s00784-020-03322-4
27 Thompson LD Fitzpatrick SG Müller S Eisenberg E Upadhyaya JD Lingen MW et al proliferative verrucous leukoplakia: an expert consensus guideline for standardized assessment and reporting Head Neck Pathol 2021 06 15 2 572 587 10.1007/s12105-020-01262-9 33415517
28 Müller S Frictional keratosis, contact keratosis and smokeless tobacco keratosis: features of reactive white lesions of the oral mucosa Head Neck Pathol 2019 03 13 1 16 24 10.1007/s12105-018-0986-3 30671762
29 Odell E Kujan O Warnakulasuriya S Sloan P Oral epithelial dysplasia: Recognition, grading and clinical significance Oral Dis 2021 11 27 8 1947 1976 10.1111/odi.13993 34418233
30 Farquhar DR Tanner AM Masood MM Patel SR Hackman TG Olshan AF et al Oral tongue carcinoma among young patients: an analysis of risk factors and survival Oral Oncol 2018 09 84 7 11 10.1016/j.oraloncology.2018.06.014 30115478
31 Santos-Silva AR Ribeiro AC Soubhia AM Miyahara GI Carlos R Speight PM et al High incidences of DNA ploidy abnormalities in tongue squamous cell carcinoma of young patients: an international collaborative study Histopathology 2011 Jun 58 7 1127 1135 10.1111/j.1365-2559.2011.03863.x 21707713
