|Ahead of print publication
Clinicopathological characteristics of oral squamous cell carcinoma arising from oral submucous fibrosis: A systematic review
Bose Divya1, V Vasanthi1, Ramya Ramadoss2, A Ramesh Kumar1, Krishnan Rajkumar1
1 Department of Oral Pathology and Microbiology, SRM Dental College, Chennai, Tamil Nadu, India
2 Department of Oral Pathology and Microbiology, Saveetha Dental College, Chennai, Tamil Nadu, India
|Date of Submission||26-Aug-2021|
|Date of Acceptance||29-Oct-2021|
|Date of Web Publication||03-May-2022|
Department of Oral Pathology and Microbiology, SRM Dental College, Bharathi Salai, Ramapuram, Chennai - 600 089, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Introduction: Oral submucous fibrosis (OSMF) is considered to be a potentially malignant oral disorder with high risk of malignant transformation. Oral squamous cell carcinoma (OSCC) arising from OSMF has peculiar clinical and histopathological features.
Aim: To assess the clinicopathological features of OSCC arising in the background of OSMF in an attempt to identify the patients with OSMF who are at increased risk of developing OSCC.
Methodology: A systematic review was performed based on PRISMA guidelines to include articles published until May 2021 in English, relating the clinicohistopathological characteristics of OSCC arising from OSMF (OSMF-OSCC) or OSMF associated with OSCC (OSCC-OSMF). All the eligible articles were analyzed and relevant data were extracted.
Results: Seventeen articles were included for systematic review after following strict inclusion and exclusion criteria. The malignant transformation rate of OSMF-OSCC ranged from 1.9 to 9.13 and the prevalence of OSCC-OSMF ranged from 2.8 to 66. The mean age of the patients ranged from 36.6 years to 47.2 years and buccal mucosa was the common site to be affected. Majority of the OSCC-OSMF was well-to-moderately differentiated and majority of them did not metastasize to the lymph nodes.
Conclusion: OSCC associated with OSMF presents at a younger age with early tumor stage, better differentiation, and better prognosis when compared to OSCC not associated with OSMF. However, more multicentric prospective studies with large sample size are required to determine the true biologic behavior of OSCC arising in the background of OSMF to establish less aggressive treatment strategies considering them as a separate entity.
Keywords: Malignant transformation, oral squamous cell carcinoma, oral submucous fibrosis
|How to cite this URL:|
Divya B, Vasanthi V, Ramadoss R, Kumar A R, Rajkumar K. Clinicopathological characteristics of oral squamous cell carcinoma arising from oral submucous fibrosis: A systematic review. J Can Res Ther [Epub ahead of print] [cited 2022 Nov 29]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=344712
| > Introduction|| |
It has been estimated that about 354,864 new cases of lip and oral cancer and 51,005 deaths from lip and oral cancer have occurred worldwide in 2018. The death rate associated with oral cancer is still high owing to a delay in the diagnosis. Tobacco, alcohol, and areca nut are some of the well-established common etiologic factors of oral cancer. A proportion of the oral cancers are often preceded by oral potentially malignant disorders like oral submucous fibrosis (OSMF), and it is vital to prevent their malignant transformation. OSMF is a chronic, debilitating, premalignant condition of the oral cavity occurring predominantly in South East Asians and Indians. It is considered to have the highest risk for transformation to oral squamous cell carcinoma (OSCC) than any other potentially malignant disorders reported rate. In 1956, Paymaster described the development of OSCC in one-third of the patients with localized submucous fibrosis. Areca nut, being a group I human carcinogen, is the prime etiologic factor associated with OSMF.
OSCC arising from OSMF has been considered as clinicopathologically distinct disease due to the difference in the mechanism of carcinogenesis induced by areca nut. OSCC is often preceded by OSMF or coexists with OSMF. Pindborg et al. considered OSMF as premalignant condition based on the observation of higher occurrence of OSMF in OSCC patients as well as higher incidence of OSCC in OSMF patients. In their study, oral cancer coexisting with OSMF was observed in 10% of the cases and malignant transformation in 4.5% of the cases. It has been suggested that coexistence must be considered as malignant transformation due to the chronic nature of OSMF which would have preceded oral cancer. Accordingly, existing literature consist of studies observing the OSMF patients for the incidence of OSCC (OSMF-OSCC) and studies investigating the patients with coexisting OSCC and OSMF (OSCC-OSMF). The present systematic review was aimed to critically analyze the studies that document the clinicopathological features of OSCC related to OSMF including OSMF-OSCC as well as OSCC-OSMF.
This systematic review was performed based on PRISMA guidelines. The literature search was done in PubMed database to include articles published until May 2021 in English, using the key words like “OSMF to OSCC,” “OSCC AND OSMF,” “malignant transformation of OSMF,” and “OSCC arising in OSMF.” Studies assessing the clinical and/or histopathological characteristics of OSCC arising from OSMF (OSMF-OSCC) or OSMF associated with OSCC (OSCC- OSMF) were included in the study. Articles without full text, published in languages other than English, and articles published before May 2001 were not included in the study. Case–control studies, case series, case reports, review articles, hypothesis, and letter to editor were excluded. All the eligible studies were reviewed, and relevant data like author name, year and type of study, sample size, prevalence of coexisting OSCC and OSMF, malignant transformation rate of OSMF, patient demographics, histopathology of OSCC, and nodal metastasis of OSCC were extracted.
| > Results|| |
Seventeen articles were included for systematic review after following strict inclusion and exclusion criteria [Figure 1]. Out of 17 articles, 8 articles were related to OSMF-OSCC from which the malignant transformation rate was assessed and 9 articles were linked to OSCC-OSMF from which the prevalence of coexisting OSCC and OSMF was evaluated in percentage. From the remaining 2 articles, both malignant transformation rate and prevalence of OSCC-OSMF were derived. The malignant transformation rate of OSMF-OSCC ranged from 1.9 to 9.13 [Table 1], and the prevalence of OSCC-OSMF ranged from 2.8 to 66 [Table 2]. All the articles except for the one by Hazarey et al. investigated the OSCC patients for the coexistence of OSMF.
|Table 1: Studies related to oral squamous cell carcinoma arising from oral submucous fibrosis|
Click here to view
|Table 2: Studies related to oral submucous fibrosis coexisting with oral squamous cell carcinoma|
Click here to view
Demographics: Only 7 articles described the patient demographics like age and gender [Table 3]. The mean age of the patients ranged from 36.6 years to 64.6 years. Five studies revealed higher incidence in males and the remaining 2 showed female preponderance.
|Table 3: Demographics of patients with oral squamous cell carcinoma arising from oral submucous fibrosis|
Click here to view
Site of OSCC: Only 3 articles depicted the site of cancer development and buccal mucosa was the most common site followed by tongue. The mean duration of malignant transformation ranged from 30 to 52.3 months [Table 4].
Tumor differentiation and lymph node metastasis [Table 5]: Majority of the OSCC-OSMF was well-to-moderately differentiated and majority of them did not metastasize to the lymph nodes. [Figure 2] shows the peculiar features associated with OSCC arising in the background of OSMF when compared to the OSCC not related to OSMF.
|Table 5: Tumor size, nodal metastasis and tumor differentiation of oral squamous cell carcinoma arising from oral submucous fibrosis|
Click here to view
|Figure 2: Features peculiar to oral squamous cell carcinoma arising in the background of oral submucous fibrosis|
Click here to view
| > Discussion|| |
Patients with OSMF are at 19.1 times greater risk of developing oral cancer than patients without OSMF. The pathogenesis of OSCC arising in the background of OSMF involves a complex process encompassing different pathways, mainly related to the gene alterations caused by the active metabolite of areca nut and arecoline. Reactive oxygen species generated during auto-oxidation of areca nut polyphenols, along with constant exposure to methylating agents and reactive metabolic intermediates of areca nut and betel quid, can result in DNA damage, which in turn contributes to malignant transformation. Areca nut-specific nitrosamines like N-nitrosoguvacoline, N-nitrosoguvacine, 3-propionaldehyde, and 3-propionitrile also play a role in tumor initiation and progression. The current evidence suggests that carcinoma arising from OSMF is a distinct disease; however, the clinical course of progression is not clearly discussed. Hence, there is a need to investigate the various aspects of this entity. The literature search revealed the paucity of prospective studies analyzing the development of OSCC in patients previously diagnosed with OSMF. Most of the studies have reported the concomitant presence of OSMF and OSCC at the time of diagnosis since long-term follow-up is a difficult task, especially in countries like India where the patient compliance is poor and record maintenance is inadequate. Hence, both types of studies have been considered separately in this systematic review.
The variation observed in the malignant transformation rate could be due to the difference in the sample size, sample population, and duration of follow-up period. The study by Hazarey et al. was the only study that analyzed OSMF patients for the concurrent presence of OSCC accounting for the lowest prevalence of OSCC-OSMF (2.8%). The highest prevalence of OSCC-OSMF (66%) was noted in a comparative study by Singh et al. in 2017. However, their sample size was very less.
Most of the studies revealed that OSCC that developed from OSMF presented at a young age. Patients with OSMF tend to present at an earlier stage because of the associated symptoms. However, the study done by Murti et al. in 1985 showed that the mean age of OSMF patients at the time of OSCC development was higher than that for OSCC patients without OSMF. Studies have shown that the frequencies and duration of tobacco chewing and smoking habits were increased in patients with OSCC-OSMF, implying that young patients are exposed early to tobacco products for a longer duration and frequency enhancing the vulnerability of early development of OSMF and its subsequent transformation to OSCC.,,
In majority of the studies, OSCC-OSMF was found to be more common in males which could be attributed to the higher habit association among males. However, one study from Pakistan and one study from India showed a remarkable increase in malignant transformation among females. The reasons that have been postulated for the female predilection are:
- Childhood stunting due to nutritional deprivation in females resulting in reduced immunity and resistance to cellular injury
- Peer pressure and depression, as a result of which they habitually use tobacco to relieve stress
- Poverty, illiteracy, and multiple pregnancies in women which aggravate stress
- Lack of awareness or access.
The risk of malignant transformation was found to be increased when OSMF coexists with oral leukoplakia or lichen planus., Lian et al. observed a 5-year OSCC rate [ >15%] in patients with coexisting OSMF and oral leukoplakia when compared to OSMF or leukoplakia alone [5%], suggesting a synergistic effect between OSMF and oral leukoplakia on the progression of OSCC. Yang et al. pointed out that patients with OSMF and leukoplakia had less mean duration of transformation (2.2 years) when compared to the patients with OSMF alone (2.7 years).
Buccal mucosa followed by tongue was the common site of presentation. The reason is that the buccal mucosa is constantly subjected to trauma and chronic inflammation exposing the deeper parts of the tissue to carcinogens. Loss of papilla in the tongue, which is commonly observed in OSMF, results in loss protective barrier predisposing the site to cancer development. It was also observed by Chaturvedi et al. in 2017 that infiltrative and ulceroinfiltrative morphology of tumor was less prevalent in patients with OSCC-OSMF. The tumor thickness of (1 cm) was also found to be lesser than those without OSMF (1.3 cm).
Histologically, OSMF with dysplasia had a greater and rapid malignant transformation when compared to OSMF alone. With regard to tumor differentiation, studies indicate that OSMF-OSCC is better differentiated when compared to OSCC not arising from OSMF. This could be accounted by the rapid epithelial turn over evidenced in OSMF and genetic memory retained in the transformed epithelial cells for faster differentiation and maturation. The presence of fibrotic bands in OSMF could be the cause for less prevalent infiltrative growth and less tumor thickness observed in OSCC-OSMF patients.
It can be postulated that patients with OSMF present with early T stage because of the early symptoms associated with OSMF. However, in a case series by Rangaswamy et al., greater proportion of patients with OSCC-OSMF had T4 lesions. The authors hypothesize that the restricted mouth opening associated with OSMF could have resulted in failure to observe the malignant changes. The lower incidence of nodal metastasis in OSCC-OSMF was attributed to the blockade of lymphatics as a result of preceding sub mucosal fibrosis of the connective tissue. The beneficial effect on the survival outcome could be due to several factors such as less tumor thickness, less tumor size, lesser nodal metastasis, extracapsular spread, and well-differentiated tumor.
This literature review clearly points out that OSCC associated with OSMF is a distinctive disease both clinicopathologically and prognostically. Age of the patient, duration and frequency of tobacco chewing, coexistence of other potentially malignant disorders like leukoplakia or lichen planus, and histopathologically evident dysplasia are the potential risk factors for malignant transformation of OSMF. The OSCC arising in the background of OSMF follows a different molecular mechanism of carcinogenesis related to the use of areca nut resulting in smaller, thinner tumors of better grade presenting at an early T stage with lesser chance of metastasis to the nodes and with better prognosis.
| > Conclusion|| |
In the literature, much has been stated regarding the prognostic factors for OSCC, whereas prognostic indicators for OSCC related to OSMF are yet to be explored. Future multicentric prospective studies with large sample size assessing all the essential clinical, histopathological, and prognostic parameters are required to determine the true biologic behavior of OSCC arising in the background of OSMF, so that less aggressive treatment strategies can be implemented to reduce the associated morbidity, considering them as a separate entity.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394-424.
Das M, Manjunath C, Srivastava A, Malavika J, Ameena MV. Epidemiology of oral submucous fibrosis: A review. Int J Oral Health Med Res 2017;3:126-9.
Paymaster JC. Cancer of the buccal mucosa; a clinical study of 650 cases in Indian patients. Cancer 1956;9:431-5.
Pindborg JJ, Murti PR, Bhonsle RB, Gupta PC, Daftary DK, Mehta FS. Oral submucous fibrosis as a precancerous condition. Scand J Dent Res 1984;92:224-9.
Gupta PC, Mehta FS, Daftary DK, Pindborg JJ, Bhonsle RB, Jalnawalla PN, et al.
Incidence rates of oral cancer and natural history of oral precancerous lesions in a 10-year follow-up study of Indian villagers. Community Dent Oral Epidemiol 1980;8:283-333.
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;13:340-1.
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;36:25-9.
Lian IeB, Tseng YT, Su CC, Tsai KY. Progression of precancerous lesions to oral cancer: Results based on the Taiwan National Health Insurance Database. Oral Oncol 2013;49:427-30.
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.
Chourasia NR, Borle RM, Vastani A. Concomitant association of oral submucous fibrosis and oral squamous cell carcinoma and incidence of malignant transformation of oral submucous fibrosis in a population of central India: A retrospective study. J Maxillofac Oral Surg 2015;14:902-6.
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;46:1040-5.
Pindborg JJ, Poulsen HE, Zachariah J. Oral epithelial changes in thirty Indians with oral cancer and submucous fibrosis. Cancer 1967;20:1141-6.
Pindborg JJ, Mehta FS, Gupta PC, Daftary DK. Prevalence of oral submucous fibrosis among 50,915 Indian villagers. Br J Cancer 1968;22:646-54.
Hazarey VK, Erlewad DM, Mundhe KA, Ughade SN. Oral submucous fibrosis: Study of 1000 cases from central India. J Oral Pathol Med 2007;36:12-7.
Fatima N, Mohiuddin S, Hosein S, Mervyn M. Socio-economic implications of a younger aged female predilection in malignant transformation of oral sub mucous fibrosis. J Ayub Med Coll Abbottabad 2019;31:16-20.
Chaturvedi P, Vaishampayan SS, Nair S, Nair D, Agarwal JP, Kane SV, et al.
Oral squamous cell carcinoma arising in background of oral submucous fibrosis: A clinicopathologically distinct disease. Head Neck 2013;35:1404-9.
Mohiuddin S, Fatima N, Hosein S, Fatima N. High risk of malignant transformation of oral submucous fibrosis in Pakistani females: A potential national disaster. J Pak Med Assoc 2016;66:1362-6.
Chaturvedi P, Malik A, Nair D, Nair S, Mishra A, Garg A, et al.
Oral squamous cell carcinoma associated with oral submucous fibrosis have better oncologic outcome than those without. Oral Surg Oral Med Oral Pathol Oral Radiol 2017;124:225-30.
Gadbail AR, Chaudhary M, Gawande M, Hande A, Sarode S, Tekade SA, et al.
Oral squamous cell carcinoma in the background of oral submucous fibrosis is a distinct clinicopathological entity with better prognosis. J Oral Pathol Med 2017;46:448-53.
Singh G, Rana AS, Kumar A, Prajapati A, Kumar S, Singh P. Nodal involvement in Oral Squamous Cell Carcinoma (SCC) patients with and without Oral Sub Mucous Fibrosis (OSMF): A comparative study. J Oral Biol Craniofac Res 2017;7:171-7.
Merchant A, Husain SS, Hosain M, Fikree FF, Pitiphat W, Siddiqui AR, et al.
Paan without tobacco: An independent risk factor for oral cancer. Int J Cancer 2000;86:128-31.
Arakeri G, Patil SG, Aljabab AS, Lin KC, Merkx MA, Gao S, et al.
Oral submucous fibrosis: An update on pathophysiology of malignant transformation. J Oral Pathol Med 2017;46:413-7.
Acharya S, Rahman S, Hallikeri K. A retrospective study of clinicopathological features of oral squamous cell carcinoma with and without oral submucous fibrosis. J Oral Maxillofac Pathol 2019;23:162.
] [Full text]
Zhou S, Guo F, Li L, Zhou Y, Lei Y, Hu Y, et al.
Multiple logistic regression analysis of risk factors for carcinogenesis of oral submucous fibrosis in mainland China. Int J Oral Maxillofac Surg 2008;37:1094-8.
Rangaswamy S, Chikkalingaiah RG, Sanjeevarayappa PN, Govindraju P. Carcinoma arising in the background of oral submucous fibrosis. Ann Maxillofac Surg 2019;9:247.
] [Full text]
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]