The definition of oral leukoplakia has not much changed during the past five decades and is still a definition by exclusion of ‘known’ lesions. Therefore, a diagnosis of leukoplakia is not always a straightforward one for the clinicians and, to some extent, also for the pathologists. The traditional clinical classification in homogeneous and nonhomogeneous leukoplakia may just be simplified into leukoplakia (thin and thick/verrucous) and erythroleukoplakia. In spite of numerous reported predictive molecular and genetic parameters of malignant transformation, the presence and grade of epithelial dysplasia as assessed by histopathological examination is still the most important one. Of the various treatment modalities, surgery and CO2 laser evaporation are still the most common ones. Treatment may delay or prevent recurrence, but does not seem to prevent malignant transformation or the occurrence of cancer development elsewhere in the mouth or the head and neck region or beyond. There is a strong need for randomized prospective studies and uniform reporting of treatment results..

1. van der Waal I. Historical perspective and nomenclature of potentially malignant or potentially premalignant oral epithelial lesions with emphasis on leukoplakia-some suggestions for modifications. Oral Surg Oral Med Oral Pathol Oral Radiol. 2018; 125(6):577-81.

2. Tovaru S, Costache M, Perlea P, Caramida M, Totan C, Warnakulasuriya S, Parlatescu I. Oral leukoplakia: A clinicopathological study and malignant transformation. Oral Dis. 2023; 29(4):1454-63.

3. Mignogna MD, Fortuna G, Leuci S, Adamo D, Siano M, Makary C, Cafiero C. Frictional keratoses on the facial attached gingiva are rare clinical findings and do not belong to the category of leukoplakia. J Oral Maxillofac Surg. 2011; 69(5):1367-74.

4. Almazyad A, Li CC, Woo SB. Benign alveolar ridge keratosis: Clinical and histopathologic analysis of 167 cases. Head Neck Pathol. 2020; 14(4):915-22.

5. Jurczyszyn K, Gedrange T, Kozakiewicz M. Theoretical background to automated diagnosing of oral leukoplakia: A preliminary report. J Healthc Eng. 2020; 2020:8831161.

6. Issa N, Leonas J, Jham BC, Mitchell JC, CuevasNunez MC. Early detection of oral potentially malignant disorders using machine learning: A retrospective pilot study. Gen Dent. 2022; 70(6):60-4.

7. Hansen LS, Olson JA, Silverman S Jr. Proliferative verrucous leukoplakia. A long-term study of thirty patients. Oral Surg Oral Med Oral Pathol. 1985; 60(3):285-98.

8. Upadhyaya JD, Fitzpatrick SG, Cohen DM, Bilodeau EA, Bhattacharyya I, Lewis JS Jr, Lai J, Wright JM, Bishop JA, Leon ME, Islam MN, Seethala R, Padilla RJ, Carlos R, Müller S, Thompson LDR. Inter-observer variability in the diagnosis of proliferative verrucous leukoplakia: Clinical implications for oral and maxillofacial surgeon understanding: A collaborative pilot study. Head Neck Pathol. 2020; 14(1):156-65.

9. Gon zález-Moles M Á, R a mos- Ga rcía P, Warnakulasuriya S. A scoping review on gaps in the diagnostic criteria for proliferative verrucous leukoplakia: A conceptual proposal and diagnostic evidence-based criteria. Cancers (Basel). 2021; 13(15):3669.

10. van der Waal I. The term ‘Proliferative verrucous leukoplakia’ should be abandoned and this is why. Oral Oncol. 2021; 123:105621.

11. Macey R, Walsh T, Brocklehurst P, Kerr AR, Liu JL, Lingen MW, Ogden GR, Warnakulasuriya S, Scully C. Diagnostic tests for oral cancer and potentially malignant disorders in patients presenting with clinically evident lesions. Cochrane Database Syst Rev. 2015; 2015(5):CD010276.

12. Mahmoud SAM, Latif MKA, Dahmoush HM, Hussein EA. Diagnostic accuracy of colposcopic examination in patients with oral dysplastic lesions. Oral Surg Oral Med Oral Pathol Oral Radiol. 2020; 130(6):692-9.

13. Bishop KW, Maitland KC, Rajadhyaksha M, Liu JTC. In vivo microscopy as an adjunctive tool to guide detection, diagnosis, and treatment. J Biomed Opt. 2022; 27(4):040601.

14. Holmstrup P, Vedtofte P, Reibel J, Stoltze K. Oral premalignant lesions: Is a biopsy reliable? J Oral Pathol Med. 2007; 36(5):262-6.

15. Villa A, Hanna GJ, Kacew A, Frustino J, Hammerman PS, Woo SB. Oral keratosis of unknown significance shares genomic overlap with oral dysplasia. Oral Dis. 2019; 25(7):1707-14.

16. Bunn B, Hunter K, Khurram SA, van Heerden WF. Adenoid dysplasia of the oral mucosa. Oral Surg Oral Med Oral Pathol Oral Radiol. 2014; 118(5):586-92.

17. Ramdoss R, Yuwanati M, Viola E A, Ramani P, Murugan MS. Can koilocytes without dysplasia in OPMDs be an early indicator and prognostic factor for oral squamous cell carcinoma? Oral Oncol. 2022; 124:105672.

18. Farah CS, Fox S, Shearston K, Newman L, Babic S, Vacher M. Lichenoid dysplasia is not a distinct pathological entity. Oral Oncol. 2021; 119:105362.

19. Reibel J, Gale N, Hille J, Hunt JL, Lingen M, Muller S, et al. Oral potentially malignant disorders and oral epithelial dysplasia. In: el-Naggar AK, Chan JKC, Grandis JR, Takata T, Slootweg PJ, editors. WHO classification of tumours of the head and neck. 4th ed. Lyon: IARC Press; 2017.

20. Gupta S, Jawanda MK, Madhushankari GS. Current challenges and the diagnostic pitfalls in the grading of epithelial dysplasia in oral potentially malignant disorders: A review. J Oral Biol Craniofac Res. 2020; 10(4):788-99.

21. Sathasivam HP, Sloan P, Thomson PJ, Robinson M. The clinical utility of contemporary oral epithelial dysplasia grading systems. J Oral Pathol Med. 2022; 51(2):180-7.

22. Senarath NH, Jayasooriya PR, Siriwardena BM, Kumarage HN, Wadusinghearachchi S, Liyanage P, Wijetunge S, Waduge R, Ratnayake P, Tilakaratne WM. Inter-examiner variability in grading of oral epithelial dysplasia may cause suboptimal management of oral potentially malignant disorders. J Dent Indones. 2019; 26(1):32-6.

23. Mahmood H, Shaban M, Indave BI, Santos-Silva AR, Rajpoot N, Khurram SA. Use of artificial intelligence in diagnosis of head and neck precancerous and cancerous lesions: A systematic review. Oral Oncol. 2020; 110:104885.

24. Nikitakis NG, Pentenero M, Georgaki M, Poh CF, Peterson DE, Edwards P, Lingen M, Sauk JJ. Molecular markers associated with development and progression of potentially premalignant oral epithelial lesions: Current knowledge and future implications. Oral Surg Oral Med Oral Pathol Oral Radiol. 2018; 125(6):650-69.

25. Celentano A, Glurich I, Borgnakke WS, Farah CS. World workshop on oral medicine VII: Prognostic biomarkers in oral leukoplakia and proliferative verrucous leukoplakia-A systematic review of retrospective studies. Oral Dis. 2021; 27(4):848-80.

26. Monteiro L, Mello FW, Warnakulasuriya S. Tissue biomarkers for predicting the risk of oral cancer in patients diagnosed with oral leukoplakia: A systematic review. Oral Dis. 2021; 27(8):1977-92.

27. Cousins M, Carney K. Can tissue biomarkers be used to determine the prognosis of oral leukoplakia lesions with regards to malignant transformation? Evid Based Dent. 2022; 23(1):18-9.

28. Jing F, Zhang J, Cai X, Zhou X, Bai J, Zhang H, Li T. Screening for biomarkers for progression from oral leukoplakia to oral squamous cell carcinoma and evaluation of diagnostic efficacy by multiple machine learning algorithms. Cancers (Basel). 2022; 14(23):5808.

29. Wils LJ, Poell JB, Brink A, Evren I, Brouns ER, de Visscher JGAM, Bloemena E, Brakenhoff RH. Elucidating the genetic landscape of oral leukoplakia to predict malignant transformation. Clin Cancer Res. 2023; 29(3):602-13.

30. Kierce J, Shi Y, Klieb H, Blanas N, Xu W, Magalhaes M. Identification of specific clinical risk factors associated with the malignant transformation of oral epithelial dysplasia. Head Neck. 2021; 43(11):3552-61.

31. Holmstrup P, Vedtofte P, Reibel J, Stoltze K. Long-term treatment outcome of oral premalignant lesions. Oral Oncol. 2006; 42(5):461-74.

32. Lorenzo-Pouso AI, Pérez-Jardón A, Caponio VCA, Spirito F, Chamorro-Petronacci CM, Álvarez-Calderón-Iglesias Ó, Gándara-Vila P, Lo Muzio L, Pérez-Sayáns M. Oral chronic hyperplastic candidiasis and its potential risk of malignant transformation: A systematic review and prevalence meta-analysis. J Fungi (Basel). 2022; 8(10):1093.

33. Weerasekera MM, Wijesinghe GK, Sampath A, Dilhari A, Madhumal T, Dilrukshi R, Willaddara R, Karunathilaka S, Gunasekara C, Fernando N, Samaranayake L. The genotypes and virulence attributes of C. albicans isolates from oral leukoplakia. Med Oral Patol Oral Cir Bucal. 2021; 26(6):e786-94.

34. Anderson A, Ishak N. Marked variation in malignant transformation rates of oral leukoplakia. Evid Based Dent. 2015; 16(4):102-3.

35. Zhang X, Gleber-Netto FO, Wang S, MartinsChaves RR, Gomez RS, Vigneswaran N, Sarkar A, William WN Jr, Papadimitrakopoulou V, Williams M, Bell D, Palsgrove D, Bishop J, Heymach JV, Gillenwater AM, Myers JN, Ferrarotto R, Lippman SM, Pickering CR, Xiao G. Deep learningbased pathology image analysis predicts cancer progression risk in patients with oral leukoplakia. Cancer Med. 2023; 12(6):7508-18.

36. Roosaar A, Yin L, Johansson AL, SandborghEnglund G, Nyrén O, Axéll T. A long-term followup study on the natural course of oral leukoplakia in a Swedish population-based sample. J Oral Pathol Med. 2007; 36(2):78-82.

37. Gupta SR, Xess I, Singh G, Sharma A, Gupta N, Mani K, Sharma S. Therapeutic implications of candida phenotypes, virulence factors and antifungal sensitivity in Oral leukoplakia. J Oral Biol Craniofac Res. 2021; 11(2):354-60.

38. Li Y, Wang B, Zheng S, He Y. Photodynamic therapy in the treatment of oral leukoplakia: A systematic review. Photodiagnosis Photodyn Ther. 2019; 25:17-22.

39. Karagozoglu KH, Buter J, Leemans CR, Rietveld DH, van den Vijfeijken S, van der Waal I. Subset of patients with verrucous carcinoma of the oral cavity who benefit from treatment with methotrexate. Br J Oral Maxillofac Surg. 2012; 50(6):513-8.

40. Lodi G, Franchini R, Warnakulasuriya S, Varoni EM, Sardella A, Kerr AR, Carrassi A, MacDonald LC, Worthington HV. Interventions for treating oral leukoplakia to prevent oral cancer. Cochrane Database Syst Rev. 2016; 7(7):CD001829.

41. Vilar-Villanueva M, Somoza-Martín JM, BlancoCarrión A, García-García A, García-Carnicero T, Marichalar-Mendía X, Gallas-Torreira M, Gándara-Vila P. Importance of the vaporization margin during CO2 laser treatment of oral leukoplakia: A survival study. Oral Dis. 2022; 2022:14345.

42. Bagan J, Martorell M, Cebrián JL, Rubert A, Bagán L, Mezquida C, Hervás D. Effect of clinical and histologic features on time to malignancy in 224 cases of oral leukoplakia treated by surgery. Clin Oral Investig. 2022; 26(8):5181-8.

43. de Pauli Paglioni M, Migliorati CA, Schausltz Pereira Faustino I, Linhares Almeida Mariz BA, Oliveira Corrêa Roza AL, Agustin Vargas P, Franco Paes Leme A, Bianca Brandão T, Prado Ribeiro AC, Ajudarte Lopes M, Santos-Silva AR. Laser excision of oral leukoplakia: Does it affect recurrence and malignant transformation? A systematic review and meta-analysis. Oral Oncol. 2020; 109:104850.

44. Einhorn J, Wersall J. Incidence of oral carcinoma in patients with leukoplakia of the oral mucosa. Cancer. 1967; 20(12):2189-93.

45. Vladimirov BS, Schiodt M. The effect of quitting smoking on the risk of unfavorable events after surgical treatment of oral potentially malignant lesions. Int J Oral Maxillofac Surg. 2009; 38(11):1188-93.

46. Holmstrup P, Dabelsteen E. Oral leukoplakia-to treat or not to treat. Oral Dis. 2016; 22(6):494-7.

47. Brouns ER, Baart JA, Bloemena E, Karagozoglu H, van der Waal I. The relevance of uniform reporting in oral leukoplakia: definition, certainty factor and staging based on experience with 275 patients. Med Oral Patol Oral Cir Bucal. 2013; 18(1):e19-26.

48. van der Waal I, Axéll T. Oral leukoplakia: A proposal for uniform reporting. Oral Oncol. 2002; 38(6):521-6.

49. Saldivia-Siracusa C, González-Arriagada WA. Difficulties in the prognostic study of oral leukoplakia: Standardisation proposal of followup parameters. Front Oral Health. 2021; 2:614045.

50. Tang JA, Amadio G, Ridge JA. Clinical and histologic features associated with malignant transformation of oral cavity dysplasia managed at a single North American institution. JAMA Otolaryngol Head Neck Surg. 2022; 148(1):28-34