Malignant Transformation of Oral Submucous Fibrosis: Risk Factors and Biomarkers – A Comprehensive Review
DOI:
https://doi.org/10.48165/ajm.2026.9.01.27Keywords:
Oral submucous fibrosis, Malignant transformation, Oral squamous cell carcinoma, Areca nut, BiomarkersAbstract
Oral submucous fibrosis (OSMF) is a chronic, progressive, potentially malignant disorder predominantly associated with areca nut consumption. It is characterized by fibrosis of the oral mucosa, leading to restricted mouth opening and increased risk of malignant transformation into oral squamous cell carcinoma (OSCC). The rate of malignant transformation varies widely, emphasizing the need for early identification of high-risk individuals. This review aims to summarize the key risk factors and emerging biomarkers associated with malignant transformation in OSMF. Major risk factors include prolonged areca nut use, tobacco consumption, genetic susceptibility, nutritional deficiencies, and chronic inflammation. Recent advances have highlighted the role of molecular biomarkers such as p53, Ki-67, cyclin D1, and various salivary and serum markers in predicting malignant potential. Understanding these factors is crucial for early diagnosis, risk stratification, and timely intervention. The integration of clinical assessment with molecular diagnostics may improve patient outcomes and reduce the burden of oral cancer.References
Shih, Y. H., Wang, T. H., Shieh, T. M., & Tseng, Y. H. (2019). Oral submucous fibrosis: A review on etiopathogenesis, diagnosis, and therapy. International Journal of Molecular Sciences, 20(12), 2940. https://doi.org/10.3390/ijms20122940
Xu, H., Lyu, F. Y., Song, J. Y., Xu, Y. M., Jiang, E. H., Shang, Z. J., Chen, L. L., & Xu, Z. (2021). Research achievements of oral submucous fibrosis: Progress and prospect. BioMed Research International, 2021, Article 6631856. https://doi.org/10.1155/2021/6631856
Rao, N. R., Villa, A., More, C. B., Jayasinghe, R. D., Kerr, A. R., & Johnson, N. W. (2020). Oral submucous fibrosis: A contemporary narrative review with a proposed inter-professional approach for early diagnosis and clinical management. Journal of Otolaryngology - Head & Neck Surgery, 49(1), 3. https://doi.org/10.1186/s40463-019-0398-5
Arakeri, G., & Brennan, P. A. (2013). Oral submucous fibrosis: An overview of the aetiology, pathogenesis, classification, and principles of management. British Journal of Oral and Maxillofacial Surgery, 51(7), 587–593. https://doi.org/10.1016/j.bjoms.2012.08.014
Hazare, V. K., Goel, R. R., & Gupta, P. C. (1998). Oral submucous fibrosis, areca nut and pan masala use: A case-control study. National Medical Journal of India, 11(6), 299–300.
Lin, F., Xiao, T., Wang, B., Wang, L., Liu, G., Wang, R., Xie, C., & Tang, Z. (2024). Mechanisms and markers of malignant transformation of oral submucous fibrosis. Heliyon, 10(1), e23314. https://doi.org/10.1016/j.heliyon.2023.e23314
Warnakulasuriya, S., et al. (2021). Oral potentially malignant disorders: A consensus report from an international seminar on nomenclature and classification. Oral Diseases, 27(8), 1862–1880. https://doi.org/10.1111/odi.13704
Warnakulasuriya, S., et al. (2022). Areca nut and oral cancer: Evidence from studies conducted in humans. Journal of Dental Research, 101(10), 1139–1146. https://doi.org/10.1177/00220345221091568
Kujan, O., Mello, F. W., & Warnakulasuriya, S. (2021). Malignant transformation of oral submucous fibrosis: A systematic review and meta-analysis. Oral Diseases, 27(8), 1936–1946. https://doi.org/10.1111/odi.13727
You, J. R., Chen, Y. T., Hsieh, C. Y., Chen, S. Y., Lin, T. Y., Shih, J. S., Chen, G. T., Feng, S. W., Peng, T. Y., & Lee, I. T. (2023). Exploring possible diagnostic precancerous biomarkers for oral submucous fibrosis: A narrative review. Cancers, 15(19), 4812. https://doi.org/10.3390/cancers15194812
Zhou, S., Zhu, Y., Mashrah, M., Zhang, X., He, Z., Yao, Z., Zhang, C., Guo, F., Hu, Y., & Zhang, C. (2017). Expression pattern of DKK3 in the malignant progression of oral submucous fibrosis. Oncology Reports, 37(2), 979–985. https://doi.org/10.3892/or.2016.5317
Surboyo, M. D. C., Merdietio Boedi, R., Mahdani, F. Y., Ayuningtyas, N. F., Shalgm, B., Paramananda, D. B., & Indriyani, I. (2024). Alteration of salivary biomarkers in oral submucous fibrosis: A three-level meta-analysis study. Clinical Biochemistry, 130, 110790. https://doi.org/10.1016/j.clinbiochem.2024.110790
Naik, V., Kumar, M., Solomon, M. C., Chandrashekhar, C., & Guddattu, V. (2025). Clinical and histological indicators for malignant transformation of oral submucous fibrosis. BMC Oral Health, 25(1), 1053. https://doi.org/10.1186/s12903-025-04606-1
Hazarey, V. K., Erlewad, D. M., Mundhe, K. A., & Ughade, S. N. (2007). Oral submucous fibrosis: Study of 1000 cases from central India. Journal of Oral Pathology & Medicine, 36(1), 12–17. https://doi.org/10.1111/j.1600-0714.2006.00462.x
Jian, X. C., Peng, J. Y., Tang, Z. G., Shen, Q., & Su, T. (2000). Three cases of oral cancer associated with oral submucous fibrosis. Journal of Clinical Stomatology, 18, 130–131.
Bohra, A., Maheswari, T. N. U., & Harsh, A. (2025). Artificial intelligence innovations in understanding oral submucous fibrosis: A systematic review. Asian Pacific Journal of Cancer Prevention, 26(11), 3925–3930.
Dinesh, Y., Ramalingam, K., Ramani, P., & Mohan Deepak, R. (2023). Machine learning in the detection of oral lesions with clinical intraoral images. Cureus, 15(8), e44018. https://doi.org/10.7759/cureus.44018
Chaudhary, N., Rai, A., Rao, A. M., Faizan, M. I., Augustine, J., Chaurasia, A., et al. (2024). High-resolution AI image dataset for diagnosing oral submucous fibrosis and squamous cell carcinoma. Scientific Data, 11(1), 1050. https://doi.org/10.1038/s41597-024-03659-4
