Abstract
The presence of epithelial dysplasia (ED) in oral leukoplakia is the single most important predictor of malignant transformation (MT). The majority of leukoplakias, however, do not show evidence of ED and yet MT of these lesions is well-recognized. These lesions have been referred to as “hyperkeratosis/hyperplasia, no dysplasia,” “keratosis of unknown significance” and “hyperkeratosis, not reactive (HkNR).” This study evaluates the MT rate of such leukoplakias. A literature review was performed to identify cohort studies on leukoplakias where (1) there was a recorded histopathologic diagnosis, (2) cases of “hyperkeratosis/hyperplasia, no dysplasia” comprised part of the cohort, and (3) follow-up information was available. There were 9,358 leukoplakias, of which 28.5% exhibited ED while 37.7% consisted of HkNR. Follow-up ranged from 15 to 73 months. The incidence of MT in leukoplakia exhibiting HkNR was 4.9%, compared to 15.3% for ED. Among oral squamous cell carcinomas (SCC) with previously biopsied, site-specific precursor lesions, 55.7% arose from ED/carcinoma in situ and 28.0% arose from HkNR. Leukoplakia exhibiting HkNR has a substantial MT rate, similar to that of mild ED, and must be recognized and managed appropriately to reduce oral SCC incidence.
Similar content being viewed by others
Data Availability
Not applicable.
Code Availability
Not applicable.
References
Villa A, Woo SB. Leukoplakia-a diagnostic and management algorithm. J Oral Maxillofac Surg. 2017;75(4):723–34.
Woo SB, Lin D. Morsicatio mucosae oris–a chronic oral frictional keratosis, not a leukoplakia. J Oral Maxillofac Surg. 2009;67(1):140–6.
Muller S. Oral lichenoid lesions: distinguishing the benign from the deadly. Mod Pathol. 2017;30(s1):S54–67.
Almazyad A, Li CI, Woo SB. Benign Alveolar Ridge keratosis: clinical and histopathologic analysis of 167 cases. Head and neck pathology. 2020;14:915.
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;101(4):472–80.
Woo SB, Grammer RL, Lerman MA. Keratosis of unknown significance and leukoplakia: a preliminary study. Oral Surg Oral Med Oral Pathol Oral Radiol. 2014;118(6):713–24.
Warnakulasuriya S, Ariyawardana A. Malignant transformation of oral leukoplakia: a systematic review of observational studies. J Oral Pathol Med. 2016;45(3):155–66.
Graveland AP, Bremmer JF, de Maaker M, Brink A, Cobussen P, Zwart M, et al. Molecular screening of oral precancer. Oral Oncol. 2013;49(12):1129–35.
Brouns E, Baart J, Karagozoglu K, Aartman I, Bloemena E, van der Waal I. Malignant transformation of oral leukoplakia in a well-defined cohort of 144 patients. Oral Dis. 2014;20(3):e19-24.
El-Naggar AKCJ, Grandis JR, Takata T, Slootweg PJ, editors. WHO classification of head and neck tumors. Lyon: IARC Press; 2017.
Dost F, Le Cao KA, Ford PJ, Farah CS. A retrospective analysis of clinical features of oral malignant and potentially malignant disorders with and without oral epithelial dysplasia. Oral Surg Oral Med Oral Pathol Oral Radiol. 2013;116(6):725–33.
Schepman KP, van der Meij EH, Smeele LE, van der 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;34(4):270–5.
Warnakulasuriya S, Kovacevic T, Madden P, Coupland VH, Sperandio M, Odell E, et al. 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. 2011;40(9):677–83.
Thompson LDR, Fitzpatrick SG, Muller 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;15:572.
van der Waal I. Potentially malignant disorders of the oral and oropharyngeal mucosa; terminology, classification and present concepts of management. Oral Oncol. 2009;45(4–5):317–23.
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.
Rosin MP, Cheng X, Poh C, Lam WL, Huang Y, Lovas J, et al. Use of allelic loss to predict malignant risk for low-grade oral epithelial dysplasia. Clin Cancer Res. 2000;6(2):357–62.
Holmstrup P, Vedtofte P, Reibel J, Stoltze K. Long-term treatment outcome of oral premalignant lesions. Oral Oncol. 2006;42(5):461–74.
Hsue SS, Wang WC, Chen CH, Lin CC, Chen YK, Lin LM. Malignant transformation in 1458 patients with potentially malignant oral mucosal disorders: a follow-up study based in a Taiwanese hospital. J Oral Pathol Med. 2007;36(1):25–9.
Ho PS, Chen PL, Warnakulasuriya S, Shieh TY, Chen YK, Huang IY. Malignant transformation of oral potentially malignant disorders in males: a retrospective cohort study. BMC Cancer. 2009;9:260.
Wang YY, Tail YH, Wang WC, Chen CY, Kao YH, Chen YK, et al. Malignant transformation in 5071 southern Taiwanese patients with potentially malignant oral mucosal disorders. BMC Oral Health. 2014;14:99.
Kuribayashi Y, Tsushima F, Morita KI, Matsumoto K, Sakurai J, Uesugi A, et al. Long-term outcome of non-surgical treatment in patients with oral leukoplakia. Oral Oncol. 2015;51(11):1020–5.
Mogedas-Vegara A, Hueto-Madrid JA, Chimenos-Kustner E, Bescos-Atin C. The treatment of oral leukoplakia with the CO2 laser: a retrospective study of 65 patients. J Cranio-Maxillo-Facial Surg. 2015;43(5):677–81.
Lima JS, Correa L, Klingbeil MF, de Sousa SC. c-Jun, pc-Jun, and p27 are differently expressed in oral leukoplakias in smokers and never-smokers. Oral Surg Oral Med Oral Pathol Oral Radiol. 2016;121(1):73–80.
Gandara-Vila P, Perez-Sayans M, Suarez-Penaranda JM, Gallas-Torreira M, Somoza-Martin J, Reboiras-Lopez MD, et al. Survival study of leukoplakia malignant transformation in a region of northern Spain. Medicina oral, patologia oral y cirugia bucal. 2018;23(4):e413–20.
Wang T, Wang L, Yang H, Lu H, Zhang J, Li N, et al. Development and validation of nomogram for prediction of malignant transformation in oral leukoplakia: a large-scale cohort study. J Oral Pathol Med. 2019;48(6):491–8.
Wu W, Wang Z, Zhou Z. Risk factors associated with malignant transformation in patients with oral leukoplakia in a Chinese population: a retrospective study. J Oral Maxillofac Surg. 2019;77(12):2483–93.
Sakata J, Yoshida R, Matsuoka Y, Kawahara K, Arita H, Nakashima H, et al. FOXP3 lymphocyte status may predict the risk of malignant transformation in oral leukoplakia. J Oral Max Surg Med. 2020;32(1):33–9.
Jayasooriya PR, Dayaratne K, Dissanayake UB, Warnakulasuriya S. Malignant transformation of oral leukoplakia: a follow-up study. Clin Oral Investig. 2020;24(12):4563–9.
Li J, Liu Y, Zhang H, Hua H. Association between hyperglycemia and the malignant transformation of oral leukoplakia in China. Oral Dis. 2020;26:1402.
Goodson ML, Sloan P, Robinson CM, Cocks K, Thomson PJ. Oral precursor lesions and malignant transformation: who, where, what, and when? Br J Oral Maxillofac Surg. 2015;53(9):831–5.
Chaturvedi AK, Udaltsova N, Engels EA, Katzel JA, Yanik EL, Katki HA, et al. Oral leukoplakia and risk of progression to oral cancer: A population-based cohort study. J Natl Cancer Inst. 2019;112:1047.
Barnes EL. Diseases of the larynx, hypopharynx and esophagus. In: Surgical Pathology of the Head and Neck. Marcel Dekker: New York, pp 127–237. 2001.
Wenig BM. Squamous cell carcinoma of the upper aerodigestive tract: dysplasia and select variants. Mod Pathol. 2017;30(s1):S112–8.
Sperandio M, Brown AL, Lock C, Morgan PR, Coupland VH, Madden PB, et al. Predictive value of dysplasia grading and DNA ploidy in malignant transformation of oral potentially malignant disorders. Cancer Prev Res. 2013;6(8):822–31.
Isenberg JS, Crozier DL, Dailey SH. Institutional and comprehensive review of laryngeal leukoplakia. Ann Otol Rhinol Laryngol. 2008;117(1):74–9.
Warnakulasuriya S, Reibel J, Bouquot J, Dabelsteen E. Oral epithelial dysplasia classification systems: predictive value, utility, weaknesses and scope for improvement. J Oral Pathol Med. 2008;37(3):127–33.
Mehanna HM, Rattay T, Smith J, McConkey CC. Treatment and follow-up of oral dysplasia—a systematic review and meta-analysis. Head Neck. 2009;31(12):1600–9.
Dost F, Le Cao K, Ford PJ, Ades C, Farah CS. Malignant transformation of oral epithelial dysplasia: a real-world evaluation of histopathologic grading. Oral Surg Oral Med Oral Pathol Oral Radiol. 2014;117(3):343–52.
Li CC, Almazrooa S, Carvo I, Salcines A, Woo SB. Architectural alterations in oral epithelial dysplasia are similar in unifocal and proliferative leukoplakia. Head Neck Pathol. 2020;15:443.
Woo SB. Oral epithelial dysplasia and premalignancy. Head Neck Pathol. 2019;13(3):423–39.
Wils LJ, Poell JB, Evren I, Koopman MS, Brouns E, de Visscher J, et al. Incorporation of differentiated dysplasia improves prediction of oral leukoplakia at increased risk of malignant progression. Mod Pathol. 2020;33(6):1033–40.
Yang B, Hart WR. Vulvar intraepithelial neoplasia of the simplex (differentiated) type: a clinicopathologic study including analysis of HPV and p53 expression. Am J Surg Pathol. 2000;24(3):429–41.
Hoang LN, Park KJ, Soslow RA, Murali R. Squamous precursor lesions of the vulva: current classification and diagnostic challenges. Pathology. 2016;48(4):291–302.
Cowan CG, Gregg TA, Napier SS, McKenna SM, Kee F. Potentially malignant oral lesions in Northern Ireland: a 20-year population-based perspective of malignant transformation. Oral Dis. 2001;7(1):18–24.
Vogelstein B, Kinzler KW. The path to cancer—three strikes and you’re out. N Engl J Med. 2015;373(20):1895–8.
Arnaoutakis D, Bishop J, Westra W, Califano JA. Recurrence patterns and management of oral cavity premalignant lesions. Oral Oncol. 2013;49(8):814–7.
Aguirre-Urizar JM, Lafuente-Ibanez de Mendoza I, Warnakulasuriya S. Malignant transformation of oral leukoplakia: systematic review and meta-analysis of the last 5 years. Oral Dis. 2021. https://doi.org/10.1111/odi.13810.
Funding
None.
Author information
Authors and Affiliations
Contributions
Both authors contributed equally do conceptual study design, article review and inclusion, and manuscript preparation.
Corresponding author
Ethics declarations
Conflict of interest
None.
Consent to Participate
Not applicable.
Consent for Publication
Both authors consent to publication of the manuscript.
Ethical Approval
Not applicable.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Stojanov, I.J., Woo, SB. Malignant Transformation Rate of Non-reactive Oral Hyperkeratoses Suggests an Early Dysplastic Phenotype. Head and Neck Pathol 16, 366–374 (2022). https://doi.org/10.1007/s12105-021-01363-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12105-021-01363-z