|Year : 2020 | Volume
| Issue : 4 | Page : 399-404
Malignant transformation rate of oral leukoplakia: A meta analysis
P Ramaswamy, Ch Sai Kiran, B Mrudula Raju, Munipati Swathi Kiranmai
Department of Oral Medicine and Radiology, St. Joseph Dental College, Duggirala, Eluru, Andhra Pradesh, India
|Date of Submission||16-Apr-2020|
|Date of Decision||18-Oct-2020|
|Date of Acceptance||29-Oct-2020|
|Date of Web Publication||28-Dec-2020|
Dr. Munipati Swathi Kiranmai
Department of Oral Medicine and Radiology, St. Joseph Dental College, Duggirala, Eluru, Andhra Pradesh
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Oral squamous cell carcinoma is the most common form of head and neck cancer which is sometimes preceded by potentially malignant disorders such as leukoplakia. Oral leukoplakia is a potentially malignant lesion that has been considered to confer increased risk for the development of oral cancer. Tobacco smoking and alcohol intake have been attributed as major risk factors. Many articles were published connecting the malignant transformation rate to lifestyle modifications. As contemporary sources of information regarding malignant transformation rate of oral leukoplakia are lacking, there is a need to have a comprehensive evaluation of leukoplakia and its malignant transformation potential. Aim: This study aims to provide a systematic review of research on the current malignant transformation rate of oral leukoplakia. Objective: To find association between malignant transformation rate and other parameters in oral leukoplakia. Results: The malignant transformation rate of oral leukoplakia was observed to be 5.7% from the year 1963 and has increased by two-fold from year 1996 to 10.9%. Malignant transformation rate of verrucous leukoplakia was 28.2%. Dysplastic malignant transformation rate of leukoplakia was 53.7% [95% Confidential interval: 32.9%, 74.5%] overall malignant transformation rate of oral leukoplakia was 10.9%. Conclusion: The two-fold increase in the malignant transformation rate since 1990s should be considered as an alarming issue, and necessary steps have to be taken in this regard.
Keywords: Follow up, Leukoplakia, malignant transformation, oral leukoplakia, oral malignancy, pre cancer, premalignant lesions
|How to cite this article:|
Ramaswamy P, Kiran CS, Raju B M, Kiranmai MS. Malignant transformation rate of oral leukoplakia: A meta analysis. J Indian Acad Oral Med Radiol 2020;32:399-404
|How to cite this URL:|
Ramaswamy P, Kiran CS, Raju B M, Kiranmai MS. Malignant transformation rate of oral leukoplakia: A meta analysis. J Indian Acad Oral Med Radiol [serial online] 2020 [cited 2021 Jan 22];32:399-404. Available from: https://www.jiaomr.in/text.asp?2020/32/4/399/305275
| Introduction|| |
Oral leukoplakia is a common potentially malignant disorder that can be seen in oral cavity, with a global prevalence rate of 2.60%. The term leukoplakia is commonly used to describe a white patch on the mucosa that could not be scrapped off and could not be classified as any other known lesion. Oral leukoplakia is known as a precancerous change of oral carcinoma developed in later stages, in oral mucosa. Oral cancer is the 6th most common malignancy in men and 12th most common malignancy in women. Every year, nearly 46000 deaths are reported in men with oral cancer. This high incidence of deaths can be attributed to life threatening habits like smoking, tobacco chewing, and alcohol consumption, which were observed to be relatively higher in males when compared to females.
The etiology of potentially malignant lesions like leukoplakia and erythroplakia, and their association with smoking and alcohol consumption is poorly understood. All leukoplakia lesions do not necessarily transform into malignancy. The malignant transformation rate of leukoplakia changes from region to region in oral cavity. It also depends on the type of leukoplakia, duration of habit, age, gender and genetics of the patient. Warnakulasuriya in his study advocated that the most challenging situation faced by oral physicians is to estimate the risk status or the potentially malignant status of oral leukoplakia.
The histopathological aspects of oral leukoplakia may vary from atrophic epithelium to severe hyperplasia with or without hyperkeratosis and dysplasia. The presence of moderate to severe dysplasia in these histopathological sections suggests greater risk for malignant transformation. Currently epithelial dysplasia is a well-known predictive indicator for malignant transformation. Advancement in molecular genetics has provided greater advantage in assessing the malignant potential of these lesions. Mutation in p53 genes, loss of heterozygosity and chromosomal polysomy are major indicators of malignant transformation. Multiple immuno histo-chemistry markers (tumor markers) have been developed to assess the malignant status of leukoplakia.
Numerous studies with follow ups on malignant transformation potential of leukoplakia were widely published in literature. But a contemporary source of information regarding the complete review on leukoplakia's malignant transformation rate (MTR) is lacking. Hence, there is a need to have a comprehensive evaluation of Leukoplakia and its malignant transformation potential using or adding the present-day data. In this regard a systematic review with meta-analysis was conducted by collecting the contemporary data on malignant transformation potential of leukoplakia. The study was conducted with the following objectives:
- Calculating the present malignant transformation rate of Oral Leukoplakia
- Evaluating the effect of lifestyle habits like smoking, alcohol consumption, and tobacco chewing on MTR
- Effect of site of involvement on MTR
- To calculate the Dysplastic transformation rate in Oral Leukoplakia.
| Materials and Method|| |
Following protocol was followed for materials and methods. Pub med/Medline search was conducted from 1960 to 2018, using different combinations of the following keywords: MeSH terms like leukoplakia; Oral leukoplakia; malignant transformation; premalignant lesions; oral malignancy, pre cancer and follow up.
Eligible articles were evaluated using titles and abstracts, and only those articles which are in the scope of the study, were included. Later, a manual search was also carried out using the citations of the included articles. The articles which are published only in English language were included.
Literature search of only observational and case control studies were included. Journal articles with systematic reviews were given more weightage. Letter to editors, abstracts, case reports, experimental/laboratory studies, clinical trials, and interventional studies were excluded. After selecting articles an in-depth evaluation of these articles was carried out to remove duplicates and studies with incomplete data.
Data selection criterion was according to the guidelines given by Preferred Reporting Items for Systematic review and Meta-analysis (PRISMA) [Picture 1].
The PROSPERO registration number was CEC/9/2017-18.
Collected data were analyzed by two reviewers. Statistical analysis was done using REVMAN 5.
| Results|| |
The article search was completed with a successful procurement of 1236 articles. After removing duplicates, which were included unintentionally due to use of many keywords and due to combination of Medline and manual search, a total of 1008 articles were retrieved. After analyzing the titles and abstracts of these articles only 171 articles were observed to be within the scope of our study. After going through 171 articles, only 65 articles were found to be eligible for the study. The full texts of these 65 articles were studied and 17 articles were excluded due to the following reasons:
- 6 articles were excluded due to lack of follow ups in the study
- 4 articles were excluded due to lack of histopathological confirmation
- 3 articles were excluded as they were considered as mere case reports than case series.
- 4 articles were excluded as they lack complete data regarding the study.
Finally, 48 articles were included in the studies which were subjected to meta-analysis. Of these 23 articles were included in the qualitative analysis of the study.
The follow up data were collected from 26 articles and tabulated in [Table 1]. The earliest study recorded was in 1967 by Einhorn et al. The recent study recorded was in 2018 by Jasbir et al., where the study has a follow up of 7.6 years. The largest study recorded till now was by Silverman sol in 1976 from India, where the study was conducted on 4762 leukoplakia lesions which were observed for a period of 2 years. The Mean malignant transformation rate (MMTR) was calculated based on the follow-up periods using ANOVA. Significant differences in MMTR were observed based on follow-up (p-value: 0.04).When the collected data were graphically analyzed with mean malignant transformation rate on Y-axis and duration of follow-up on X-axis, more interesting features were observed [Graph 1]. The Mean Malignant transformation rate (MMTR) of leukoplakia was found to be only 4.3% in first 5 years of follow-up. But there was a significant increase in the MMTR to 28.1% between 5 and 10 years of follow-up (p value: 0.04, ANOVA). After 10 years the MMTR was stabilized at 26.2%.
Twenty-one studies have given detailed information on the type of leukoplakia, included in their study. Out of them 10 studies included verrucous leukoplakia. Hence, we have segregated these articles into 2 groups: The Verrucous leukoplakia group and Non-verrucous leukoplakia group. The MMTR was observed to be significantly higher in verrucous leukoplakia group when compared to other forms of leukoplakia (Non verrucous leukoplakia group). A 2.5-fold increase in the MMTR in verrucous leukoplakia group (40%) when compared to non-verrucous variants of Leukoplakia (15%), [Graph 2]. But no statistical significant difference was observed between the groups.
The role of dysplasia in malignant transformation rate of leukoplakia was evaluated from 9 articles successfully. We found an overall effect size of 53.7% [95% CI: 32.9%, 74.5%] with heterogeneity of 98.32% [Graph 3].
Data on predominant site for malignant transformation were collected from 18 articles [Picture 2]. Highest number of cases with malignant transformation was observed on Tongue (33.33%) followed by Gingiva (27.78%) and buccal mucosa (11.11%).
Meta-analysis of proportions in the studies containing Verrucous leukoplakia revealed an effect size (overall Malignant transformation rate (MTR) of 28.2% [95% CI: 19.8%, 36.6%] [Graph 4]. But the overall heterogeneity of the studies was calculated to be 97.6% which is considered as high [Graph 4].
The overall effect size on malignant transformation rate (MTR) of leukoplakia was observed to be 10.9% with an overall heterogeneity of 96.97% [Graph 4]. Cumulative meta-analysis is considered as a reliable statistical method in analyzing the temporal trends of the outcome of the study. Hence, we have applied cumulative analysis to evaluate any change in the trend of MTR. Interestingly we found that the malignant transformation rate of oral leukoplakia has increased drastically from 20th century. The malignant transformation rate was observed to be only 5.76% till 1996, but later there was a huge shift in MTR which was calculated to be 10.9% in 2018. This 2-fold increase or 100% increase in the MTR can be attributed to many reasons like lifestyle changes, food habits, female smoking, stress, increased working hours, and genetic mutations.
| Discussion|| |
Meta-analysis is a statistical procedure designed to accumulate results of all independent studies and to draw a refined and reliable conclusion from them. They are a bit different from conventional studies. It is a study on various studies related to a specific topic. Meta-analysis is a better way of analyzing large data for a reflective conclusion.
The principle risk factors for oral leukoplakia are smoking, alcohol consumption and tobacco chewing. C-H Lee et al. in his study observed that addition of tobacco to one's habit can drastically increase risk of oral cancer. Liu et al. in his study on 218 Chinese patients advocated that high risk dysplasia in leukoplakia, can increase malignant transformation rate by four fold when compared to its counterpart. Similar results were obtained in our meta-analysis. We found studies which advocated that leukoplakia with dysplasia have 54% more chances to turning into malignancy.
The mortality rate for oral cancer has been increasing radically. MN Shiu et al. has advocated an increased malignant transformation rate from 3.6 per 1000 in 1971 to 6.4 per 1000 in 1994, in Taiwan population. He advocated that the incidence of malignant transformation from leukoplakia increases with time. Similar results were observed in present Meta –analysis. We found a huge impact of duration of leukoplakia on malignant transformation rate. The Mean malignant transformation rate increased by 7-fold from 5th year of leukoplakia when compared to first 5 years.
The overall malignant transformation rate was observed to be 10.9% in patients with leukoplakia. Bzark et al. has observed the least malignant transformation rate of 1.9% in leukoplakia. Zakrzewska et al. has observed the maximum malignant transformation rate (100%) in his study in London. The result in our analysis was in par with many studies.,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,
Cumulative analysis is a part of meta analysis where the studies are summarized from the earliest to the latest and the impact of each study on the analysis is assessed at every step of its addition. In simple words, when a new study is added, cumulative analysis will identify whether the new study has produced any profound impact on the over-all result of the analysis or not. Cumulative meta-analysis has given a broader and elegant view of malignant transformation rate in leukoplakia. In our analysis we have observed interesting phenomena in the trend of malignant transformation rate of Oral Leukoplakia. Till 1996, the malignant transformation rate was observed to be 5.7%, but after 1996 till 2018 the rate has increased by two-fold and has reached to 10.9%. This can be attributed to lifestyle changes, food habits, female smoking, and increased stress in working environment, prolonged working hours, and genetic mutations.
Recent malignant transformation rate of oral leukoplakia according to Gandara-vila et al., 2018 is 8.2% and Andrea Rubert et al., 2020 is 8.3%.,
Limitation of the study: Large scale studies with long term follow up are lacking and are needed for better prognosis of the lesion averting Oral squamous cell carcinoma.
| Conclusion|| |
Better prognosis comes for a virtuous and opportune diagnosis. The 2-fold increase in the malignant transformation rate since 1990s should be considered as an alarming issue, and necessary steps have to be taken in this regard. In-depth screening tests have to be advocated to evaluate the dysplastic nature of the lesion and to analyses its malignant potential as early as possible. Large scale community based oral health programs have to be conducted in order to educate people on the harmful effects of leukoplakia on oral cancer.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
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;40:677-3.
Roed-Petersen B, Renstrup G, Pindborg JJ. Candida in oral leukoplakias: A histologic and exfoliative cytologic study. Scand J Dent Res 1970;78:323-8.
Shiu MN, Chen TH, Chang SH, Hahn LJ. Risk factors for leukoplakia and malignant transformation to oral carcinoma: A leukoplakia cohort in Taiwan. Br J Cancer 2000;82:1871-4.
Lee C-H, Ko Y-C, Huang H-L, Chao Y-Y, Tsai C-C, Shieh T-Y, et al
. The precancer risk of betel quid chewing, tobacco use and alcohol consumption in oral leukoplakia and oral submucous fibrosis in southern Taiwan. Br J Cancer 2003;88:366-2.
Cooke B. Leucoplakia buccalis: An enigma. Proc R Soc Med 1975;68:337-1.
Einhorn J, Wersäll J. Incidence of oral carcinoma in patients with leukoplakia of the oral mucosa. Cancer 1967;20:2189-3.
Moher D, Liberati A, Tetzlaff J, Altman DG, Group TP. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Med 2009;6:e1000097.
Upadhyaya JD, Fitzpatrick SG, Islam MN, Bhattacharyya I, Cohen DM. A retrospective 20-year analysis of proliferative verrucous leukoplakia and its progression to malignancy and association with high-risk human papillomavirus. Head Neck Pathol 2018;12:500-10.
Silverman S, Bhargava K, Mani NJ, Smith LW, Malaowalla AM. Malignant transformation and natural history of oral leukoplakia in 57,518 industrial workers of Gujarat, India. Cancer 1976;38:1790-5.
Liu W, Wang Y-F, Zhou H-W, Shi P, Zhou Z-T, Tang G-Y, et al
. Malignant transformation of oral leukoplakia: A retrospective cohort study of 218 Chinese patients. BMC Cancer 2010;10:685.
Brzak BL, Mravak-Stipetic M, Canjuga I, Balicevic M, Sikora M, Filipovic Zore I, et al.
The Frequency and Malignant Transformation Rate of Oral Lichen Planus and Leukoplakia-A Retrospective Study. Coll Antropol 2012;36:773-7.
Liu W, Shi L-J, Wu L, Feng J-Q, Yang X, Li J, et al.
Oral Cancer Development in Patients with Leukoplakia-Clinicopathological Factors Affecting Outcome. PLoS One 2012;7:e34773.
Sugar L, Banoczy J. Follow-up studies in oral leukoplakia. Bull World Health Organ 1969;41:289-3.
Kramer IRH, Lucas RB, El-Labban N, Lister L. A Computer-aided Study on the Tissue Changes in Oral Keratoses and Lichen Planus and an Analysis of Case Groupings by Subjective and Objective Criteria. Br J Cancer 1970;24:407-6.
Pindborg JJ, Mehta FS, Gupta PC, Daftary DK, Smith CJ. Reverse smoking in Andhra Pradesh, India: A study of palatal lesions among 10,169 villagers. Br J Cancer 1971;25:10-20.
Gangadharan P, Paymaster JC. Leukoplakia--an epidemiologic study of 1504 cases observed at the Tata Memorial Hospital, Bombay, India. Br J Cancer 1971;25:657-8.
Banoczy J. Follow-up studies in oral leukoplakia. J Maxillofac Surg 1977;5:69-5.
Kramer IR, El-Labban N, Lee KW. The clinical features and risk of malignant transformation in sublingual keratosis. Br Dent J 1978;4:171-0.
Pogrel MA. Sublingual keratosis and malignant transformation. J Oral Pathol Med 1979;8:176-8.
Gupta PC. A study of dose-response relationship between tobacco habits and oral leukoplakia. Br J Cancer 1984;50:527-1.
Roch-Berry CSB. Malignant changes in glossal leukoplakia. Clin Radiol 1981;32:693-4.
Warnakulasuriya KA, Ekanayake AN, Sivayoham S, Stjernswärd J, Pindborg JJ, Sobin LH, et al.
Utilization of primary health care workers for early detection of oral cancer and precancer cases in Sri Lanka. Bull World Health Organ 1984;62:243-50.
Silverman S, Gorsky M, Lozada F. Oral leukoplakia and malignant transformation. A follow-up study of 257 patients. Cancer 1984;53:563-8.
Lind PO. Malignant transformation in oral leukoplakia. Scand J Dent Res 1987;95:449-5.
Hogewind WFC, van der Kwast WAM, van der Waal I. Oral leukoplakia, with emphasis on malignant transformation. J Cranio-Maxillofacial Surg 1989;17:128-3.
Zakrzewska JM, Lopes V, Speight P, Hopper C. Proliferative verrucous leukoplakia: A report of ten cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1996;82:396-1.
Barfi Qasrdashti A, Habashi MS, Arasteh P, Torabi Ardakani M, Abdoli Z, Eghbali SS. Malignant Transformation in Leukoplakia and Its Associated Factors in Southern Iran: A Hospital Based Experience. Iran J Public Health 2017;46:1110-7.
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;34:270-5.
Schepman K, der Meij E, Smeele L, der Waal I. Concomitant leukoplakia in patients with oral squamous cell carcinoma. Oral Dis 1999;5:206-9.
Saito T, Sugiura C, Hirai A, Notani K, Totsuka Y, Shindoh M, et al
. High malignant transformation rate of widespread multiple oral leukoplakias. Oral Dis 1999;5:15-9.
Purohit JP, Sharma VK, Singh PN. Leukoplakia: A correlative study of clinical picture and cytohistopathology. Indian J Otolaryngol Head Neck Surg 1999;52:33-6.
Hamidi S, Salo T, Kainulainen T, Epstein J, Lerner K, Larjava H. Expression of alpha (v) beta6 integrin in oral leukoplakia. Br J Cancer 2000;82:1433-40.
Napier SS, Cowan CG, Gregg TA, Stevenson M, Lamey PJ, Toner PG. Potentially malignant oral lesions in Northern Ireland: Size (extent) matters. Oral Dis 2003;9:129-7.
Femiano F, Scully C. DNA cytometry of oral leukoplakia and oral lichen planus. Med Oral Patol Oral Cir Bucal 2006;11:E22.
Holmstrup P, Vedtofte P, Reibel J, Stoltze K. Long-term treatment outcome of oral premalignant lesions. Oral Oncol 2006;42:461-4.
Ishida K, Ito S, Wada N, Deguchi H, Hata T, Hosoda M, et al
. Nuclear localization of beta-catenin involved in precancerous change in oral leukoplakia. Mol Cancer 2007;6:62.
Hsue S-S, Wang W-C, Chen C-H, Lin C-C, Chen Y-K, Lin L-M, et al
. 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;36:25-9.
Bagan J V, Jimenez Y, Murillo J, Poveda R, Diaz JM, Gavalda C, et al
. Epstein-Barr virus in oral proliferative verrucous leukoplakia and squamous cell carcinoma: A preliminary study. Med Oral Patol Oral Cir Bucal 2008;1:E110-3.
Michailidou E, Markopoulos A, Antoniades D. Mast cells and angiogenesis in oral malignant and premalignant lesions. Open Dent J 2008;2:126-2.
Hosni ES, Gonçalves Salum F, Cherubini K, Soares Yurgel L, Antonia M, Figueiredo Z, et al
. Oral Erythroplakia and Speckled Leukoplakia: Retrospective analysis of 13 cases. Braz J Otorhinolaryngol 2009;75:295-9.
Arduino PG, Surace A, Carbone M, Elia A, Massolini G, Gandolfo S, et al
. Outcome of oral dysplasia: A retrospective hospital-based study of 207 patients with a long follow-up. J Oral Pathol Med 2009;38:540-4.
Poveda-Roda R, Bagan J, Jimenez-Soriano Y, Diaz-Fernandez J, Gavalda-Esteve C. Retinoids and proliferative verrucous leukoplakia (PVL). A preliminary study. Med Oral Patol Oral Cir Bucal 2010;15:e3-9.
Harish Hande A, Chaudhary MS. Cytomorphometric analysis of buccal mucosa of tobacco chewers. Rom J Morphol Embryol 2010;51:527-2.
Ho MW, Risk JM, Woolgar JA, Field EA, Field JK, Steele JC, et al
. The clinical determinants of malignant transformation in oral epithelial dysplasia. Oral Oncol 2012;48:969-6.
Silverman S, Gorsky M. Proliferative verrucous leukoplakia: A follow-up study of 54 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997;84:154-7.
Monteiro L, Barbieri C, Warnakulasuriya S, Martins M, Salazar F, Pacheco J-J, et al
. Type of surgical treatment and recurrence of oral leukoplakia: A retrospective clinical study. Med Oral Patol Oral Cir Bucal 2017;22:520-6.
Pindborg JJ, Jolst O, Renstrup G, Roed-Petersen B. Studies in oral leukoplakia: A preliminary report on the period prevalence of malignant transformation in leukoplakia based on a follow-up study of 248 patients. J Am Dent Assoc 1968;76:767-1.
Rubert A, Bagan L, Bagan JV. Oral leukoplakia clinical -histopathological study in 412 patients. J Clinc Exp Dent 2020;12:540-6.
Woo S-B. Oral epithelial dysplasia and premalignancy. Head Neck Pathol 2019;13:423-39.
Warnakulasuriya S, Ariyawardana A. Malignant transformation of oral leukoplakia: A systematic review of observational studies. J Oral Pathol Med 2016;45:155-66.