MALIGNANT TRANSFORMATION OF ORAL SUBMUCOUS FIBROSIS - A SYSTEMATIC REVIEW OF OBSERVATIONAL STUDIES

Shilpa Syam^1*, T.N Uma Maheswari²

ABSTRACT

Oral submucous fibrosis (OSMF) is a potentially premalignant oral lesion. The disorder is insidious and chronic in nature. It has the potential to transform into oral squamous cell carcinoma (OSCC), the rate at which it may happen is described by the term Malignant Transformation rate (MTR). Different studies in various populations have reported varying rates of malignant transformation for OSMF. This study aims to establish the malignant transformation rate of OSMF and to record associated risk factors. The search was performed using MeSH terms and keywords in electronic databases PubMed, Cochrane, Science Direct, and Google Scholar. Out of 190 articles obtained from the initial keyword search, 7 articles were chosen after applying the inclusion and exclusion criteria. The overall malignant transformation rate of OSMF was found to vary from 3.72 – 38.15 % across the 7 studies reviewed in this study with betel quid chewing being the associated risk factor favoring the transformation to oral cancer. The results revealed a higher malignant transformation rate compared to the frequently quoted values. Hence, clinicians need to manage such lesions with utmost care and must subject them to biopsy fo ruling out dysplasia/malignancy. The number of follow-up studies assessing the malignant transformation of OSMF, especially in the Indian population was scarce in the literature highlighting the need for more research in this area.

Keywords: Oral potentially malignant disorder, Oral submucous fibrosis, Malignant transformation rate, Follow-up, Risk factors

Introduction

Oral Submucous Fibrosis (OSMF) is a chronic, progressive, precancerous condition affecting the oral mucosa and pharynx and was first described in the year 1952 [1]. The main etiological agent causing OSMF has been established as arecoline in areca nut [2]. The characteristic clinical features of the disease include pallor of the mucosa, burning sensation, leathering mucosa, and progressive fibrosis resulting in limited mouth opening causing difficulty in speech and swallowing [3]. Areca nut chewing is now the fourth most common addiction habit globally [4]. It is used in various combinations along with betel quid, tobacco, and slaked lime. There are many regional variations within India as well as between different countries [5].

Malignant transformation rates (MTR) of OSMF have been assessed by many researchers in various studies and different populations. One study reported an MTR of 7.6% after a long 17-year follow-up whereas another study from India reported a 2.6% transformation rate [5]. The highest value reported in the Indian population was that of 7.6% by IARC [6]. Assessing the risk status of potentially malignant disorders like OSMF is crucial for a clinician for timely diagnosis and intervention thereby helping provide a better quality of life for these patients. Hence, we aimed to conduct a systematic review to assess the MTR of OSMF and to record the associated risk factors.

Materials and Methods

Ethical clearance was obtained from the scientific review board, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences, Chennai. Studies published from the year 2014 to 2019 were searched for in electronic databases of PubMed, Cochrane, Science Direct, and Google Scholar. All observational follow-up studies on OSMF patients recording MTR, follow-up studies on OPMD that include OSMF and its MTR, and studies on MTR of OSMF / OPMD on any population were included for review. Interventional studies on OSMF/OPMD studies not following the observational study design, follow-up studies on OSMF without assessing MTR, and studies on OPMDs other than OSMF were excluded.

Results and Discussion

The included studies were studied for the overall MTR and annual malignant transformation rate (ATR) values (Table 1). Out of a total of 5043 lesions/ cases of OSMF followed up in all the seven included studies 706 lesions/ cases transformed into malignancy. Malignant transformation in terms of type, frequency, and duration of habits (Table 2) was recorded. Quality assessment of the included studies was done using the BSA Medical Sociology Group tool for cross-sectional studies.

Table 1. Characteristics of included studies – Malignant transformation rate

P- Prospective study, R- Retrospective study, H- Hospital-based, C- Cohort

Table 2. MTR and Risk habits

This review attempted to establish the MTR of OSMF from observational studies in the literature. An earlier hospital-based study done in the Taiwanese population estimated the MTR to be 7-13 % which is frequently cited [7]. But we found a wider range of MTR of OSMF patients, 3.72- 38.15% across the 7 studies done in varied populations. Wang et al. [8], reported the lowest overall MTR (3.72%), followed by Jayasinghe et al. [9], (5.90%), Chuang et al. [10] (7.69%), Yang et al. [11] (9.13%), Nayak et al. [12] (10.34%) and Chien – Yang Yeh et al. [13] (11.0%). The highest as well as a significantly differing MTR of 38.15 % was reported by Mohiuddin et al. [14]. It was a multicenter study conducted at public and private tertiary hospitals and clinics in Pakistan that enrolled 765 cases of OSMF, more than one-third of which transformed into OSCC (472 cases) during a mean follow-up period of 8 years. For the rest of the studies, the follow-up period ranged from 3.6 years to 10 years. The annual transformation rate (ATR) is a valuable guide to the oral medicine specialist since it takes into account the individual time for transformation into cancer [15]. In our review, a single study done by Chuang et el., reported the ATR value as 8.6 per 1000 while the remaining studies assessed only the overall transformation rate [10].

The association of OSMF with betel quid and areca nut chewing, and the increasing incidence of oral cancer in this group has been reported for long [16-18]. The combined use of betel quid and tobacco has been reported to have carcinogenic potential in a dose-dependent way [19]. Jayasinghe et al. grouped the patients mainly into two based on chewing habits areca nut chewers and betel quid chewers [9]. Betel quid chewers were further grouped based on additional habits of smoking, alcohol, or both. The highest MTR was seen to be associated with the group with betel quid chewing habit alone whereas none of those in the areca nut chewing group underwent a malignant transformation. Mohiuddin et al. have considered chewing habits classifying risk habits into areca nut, betel quid with tobacco, betel quid without tobacco, naswar, and no habits group and have excluded cigarette smoking and alcohol [14]. They reported the MTR to be highest in the betel quid with the tobacco group followed by areca nut chewers. An ideal grouping of risk habits is seen in the study by Chuang et al. who grouped the patients based on single habits as well as various combinations of multiple habits which will aid in assessing the habit combination most susceptible to malignant transformation. Unfortunately, the study has not recorded the MTR for the multiple habit groups [10]. The frequency and duration of the risk habits are consequential in the transformation of an OSMF case into OSCC. But only one of the included studies has recorded these aspects of the risk habits to assess their role in MTR. Jayasinghe et. al. grouped the betel quid chewers based on the number of quids per day and habit duration ranging between 0 and 25 years or more. Their observations suggested no significant differences in MTR with frequency [9].

Conclusion

The overall MTR of OSMF varies from 3.72 – 38.15 % across the 7 studies reviewed in this study. Betel quid chewing was found to be a habit with higher chances of malignant transformation.

Acknowledgments: None

Conflict of interest: None

Financial support: None

Ethics statement: None

1.        Passi D, Bhanot P, Kacker D, Chahal D, Atri M, Panwar Y. Oral submucous fibrosis: Newer proposed classification with critical updates in pathogenesis and management strategies. Natl J Maxillofac Surg. 2017;8(2):89-94.

2.        Rao NR, Villa A, More CB, Jayasinghe RD, Kerr AR, Johnson NW. Oral submucous fibrosis: a contemporary narrative review with a proposed inter-professional approach for an early diagnosis and clinical management. J Otolaryngol Head Neck Surg. 2020;49(1):3.

3.        Shih YH, Wang TH, Shieh TM, Tseng YH. Oral Submucous Fibrosis: A Review on Etiopathogenesis, Diagnosis, and Therapy. Int J Mol Sci. 2019;20(12):2940.

4.        Tungare S, Myers AL. Retail availability and characteristics of addictive areca nut products in a US Metropolis. J Psychoactive Drugs. 2021;53(3):256-71.

5.        Murti PR, Bhonsle RB, Pindborg JJ, Daftary DK, Gupta PC, Mehta FS. Malignant transformation rate in oral submucous fibrosis over a 17‐year period. Community Dent Oral Epidemiol. 1985;13(6):340-1.

6.        World Health Organization, IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, International Agency for Research on Cancer. Betel-quid and areca-nut chewing and some areca-nut-derived nitrosamines. IARC; 2004.

7.        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.

8.        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(1):1-9.

9.        Jayasinghe R, Manoja K, Gunasinghe M, Gurusinghe S, Sitheeque M, Hettiarachchi R, et al. An analysis of rate and factors affecting malignant transformation of oral submucous fibrosis in patients attending the Oral Medicine Clinic, Dental Hospital Peradeniya, Sri Lanka-A retrospective study. Sri Lanka J Med. 2015;24(2):3-10.

10.     Chuang SL, Wang CP, Chen MK, Su WW, Su CW, Chen SL, et al. Malignant transformation to oral cancer by subtype of oral potentially malignant disorder: A prospective cohort study of Taiwanese nationwide oral cancer screening program. Oral Oncol. 2018;87:58-63.

11.     Yang PY, Chen YT, Wang YH, Su NY, Yu HC, Chang YC. Malignant transformation of oral submucous fibrosis in Taiwan: a nationwide population‐based retrospective cohort study. J Oral Pathol Med. 2017;46(10):1040-5.

12.     Nayak S, Goel MM, Makker A, Bhatia V, Chandra S, Kumar S, et al. Fibroblast growth factor (FGF-2) and its receptors FGFR-2 and FGFR-3 may be putative biomarkers of malignant transformation of potentially malignant oral lesions into oral squamous cell carcinoma. PLoS One. 2015;10(10):e0138801.

13.     Yeh CY, Lin CL, Chang MC, Chen HM, Kok SH, Chang SH, et al. Differences in oral habit and lymphocyte subpopulation affect malignant transformation of patients with oral precancer. J Formos Med Assoc. 2016;115(4):263-8.

14.     Mohiuddin S, Fatima N, Hosein S, Hosein M. High risk of malignant transformation of oral submucous fibrosis in Pakistani females: A potential national disaster. J Pak Med Assoc. 2016;66(11):1362-6.

15.     Evren I, Brouns ER, Wils LJ, Poell JB, Peeters CFW, Brakenhoff RH, et al. Annual malignant transformation rate of oral leukoplakia remains consistent: A long-term follow-up study. Oral Oncol. 2020;110:105014.

16.     Elmahi OM, Aldai SM, Alhassan GS, Adam GB, Eltayeb LB, Waggiallah HA. Alterations Caused by Hormonal Contraceptives on Cytomorphometric of Buccal Mucosa Detected by Computer-Assisted Method. Int J Pharm Phytopharmacol Res. 2020;10(5):129-35.

17.     Pham DT, Ninh NT, Hoang TN, Pham CT, Nguyen LH, Tran TQ, et al. The Effectiveness of Oral Nutritional Supplements Improves the Micronutrient Deficiency of Vietnamese Children with Stunting. Arch Pharm Pract. 2020;11(1):7-13

18.     Harouak H, Ibijbijen J, Nassiri L. Comparison between Medicinal Plants Used Against Oral Diseases and Pharmaceutical Dental Products In Morocco. Ann Dent Spec. 2019;7(2):1-4.

19.     World Health Org., Betel-Quid and Areca-Nut, 100-E-10 IARC Monograph. 2018. Available from: https://monographs.iarc.fr/ENG/https://monographs.iarc.who.int/wp-content/uploads/2018/06/mono100E-10.pdf