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 Table of Contents  
CASE REPORT
Year : 2021  |  Volume : 12  |  Issue : 2  |  Page : 108-111

Oral submucous fibrosis: A case report and contemporary review of pathogenesis


1 PG Student, Department of Oral Pathology and Microbiology, SRM Dental College, SRMIST, Chennai, India
2 CRRI, Department of Oral Pathology and Microbiology, SRM Dental College, SRMIST, Chennai, India
3 Senior Lecturer, Department of Oral Pathology and Microbiology, SRM Dental College, SRMIST, Chennai, India

Date of Submission28-Feb-2021
Date of Decision09-Apr-2021
Date of Acceptance17-Apr-2021
Date of Web Publication30-Jun-2021

Correspondence Address:
Dr. V Vasanthi
Department of Oral Pathology and Microbiology, SRMIST, SRM Dental College, Ramapuram, Chennai - 600 089, Tamil Nadu
India
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DOI: 10.4103/srmjrds.srmjrds_18_21

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  Abstract 


Oral submucous fibrosis (OSF) is an oral potentially malignant disorder characterized by fibroelastic changes in the juxta-epithelial layer leading to trismus. Areca nut and its metabolites contribute to the etiopathogenesis. We report a case of a 53-year-old male patient with burning sensation and reduced mouth opening. Clinical findings and histopathologic findings were consistent with the diagnosis of OSF – intermediate stage. The patient was conservatively managed with lycopene 4 mg twice daily for 3 months and also advised oral physiotherapy. The patient was educated on the effects of areca nut and chances of malignant transformation.

Keywords: Malignant transformation, oral submucous fibrosis, pathogenesis


How to cite this article:
Vinitha K B, Alexander D, Shobika V M, Parveen H W, Raju S, Vasanthi V. Oral submucous fibrosis: A case report and contemporary review of pathogenesis. SRM J Res Dent Sci 2021;12:108-11

How to cite this URL:
Vinitha K B, Alexander D, Shobika V M, Parveen H W, Raju S, Vasanthi V. Oral submucous fibrosis: A case report and contemporary review of pathogenesis. SRM J Res Dent Sci [serial online] 2021 [cited 2021 Jul 31];12:108-11. Available from: https://www.srmjrds.in/text.asp?2021/12/2/108/319873




  Introduction Top


Oral submucous fibrosis (OSF) is a chronic, insidious, potentially malignant disorder affecting the oral mucosa, pharynx, upper third of esophagus, and characterized histopathologically by fibrosis. Although multifactorial etiology was proposed earlier, recent studies have confirmed the role of areca nut in causing the disease. Arecoline, arecaidine, guvacoline, and guvacine are the areca alkaloids. Among them, arecoline, the principal causative agent, is responsible for fibroblast proliferation. Genetic predisposition is also thought to play a role as only 1.2% of areca nut chewers develop the disease. OSF is predominant in South and Southeast Asia. The upsurge in these countries may be attributed to the availability of commercial preparations of areca nut.[1] We present a case report of a 53-year-old male patient with a chief complaint of burning sensation. The patient presented with clinical symptoms of OSF, which gradually subsided with proper counselling, oral physiotherapy, conservative management, and follow-up.


  Case Report Top


A 53-year-old male patient reported to the department with the complaint of burning sensation in the mouth for the past 2 months. The patient gave a history of chewing 5 packets of mawa, 9–10 times per day for the past 8 years. The patient developed burning sensation only to spicy food initially, but eventually to even nonspicy food. On clinical examination, right and left buccal mucosa were pale and blanched. Vertical fibrous bands were palpable from the corner of the mouth to pterygomandibular raphe on both right and left buccal mucosa [Figure 1] and [Figure 2]. Mouth opening was reduced as the distance between interincisal edges was 30 mm [Figure 3]. The patient had reduced protrusion of the tongue and was unable to blow his cheek. The uvula was normal. Considering the history and clinical findings, provisional diagnosis of OSF was given. Incisional biopsy was done under local anesthesia to look for malignant changes. Hematologic investigations were within normal limits.
Figure 1: Blanched right buccal mucosa

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Figure 2: Blanched left buccal mucosa

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Figure 3: Reduced mouth opening

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Microscopic findings revealed parakeratinized stratified squamous epithelium devoid of rete ridges and underlying connective tissue with juxta-epithelial hyalinization. Thickened collagen bundles with few fibroblast, chronic inflammatory infiltrate, compressed blood vessels, and muscle bundles were evident in the connective tissue [Figure 4]. Clinical findings and histopathologic findings were consistent with the diagnosis of OSF – intermediate stage. The patient was counseled and emphasized to quit the habit immediately. The patient was conservatively managed with lycopene 4 mg twice daily for 3 months. The patient was also advised oral physiotherapy such as ballooning exercises. On regular follow-up at intervals of 1 month for a period of 6 months, burning sensation reduced and mouth opening also improved. The patient was educated on the effects of areca nut and chances of malignant transformation.
Figure 4: Photomicrograph

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  Discussion Top


In 1952, Schwartz described OSF in five Indian females living in Kenya and coined the term “atrophica idiopathica mucosae oris.” Pindborg and Sirsat in 1966 described OSF as “chronic insidious disease affecting any part of the oral cavity and sometimes the pharynx”.[2] OSF is a potentially malignant disorder with 7%–13% malignant transformation rate. Characteristic male preponderance is reported in literature with strong association with chewing of smokeless tobacco. The present case report also describes OSF in male patient with a habit of chewing mawa for 8 years. The frequency and duration of chewing also contributes to the stage of the fibrosis. Arecoline in areca nut is the main causative agent.[3] Altered collagen metabolism contributes to the pathogenesis of OSF. Areca nut chewing causes mechanical and chemical trauma to the oral mucosa, leading to chronic inflammation. Inflammatory mediators such as interleukin-6, tumor necrosis factor, and transforming growth factor-β (TGF-β) are secreted by keratinocytes in response to the activation of macrophages and T cells from chronic inflammation.[1],[3],[4],[5] TGF-β is the main trigger for the altered collagen metabolism via the TGF-β signaling pathway. Collagen production and degradation pathway are modulated by TGF-β. Increased production of collagen is through the activation of procollagen genes, increase in levels of procollagen proteinase, and upregulation of lysyl oxidase (LOX) activity. Decrease in the degradation of collagen is from the activation of tissue inhibitors of matrix metalloproteinases (TIMPs) and plasminogen activator inhibitor gene. Extracellular matrix deposition is due to increased secretion of TIMP-1 and downregulation of matrix metalloproteinase-1. Apart from arecoline, polyphenols also contribute to collagen fiber cross-linking, making them less susceptible to degradation resulting in increased fibrosis. Buccal absorption of copper from areca nut also contributes to fibrosis. LOX, copper-dependent enzyme, also promotes collagen cross-linking and deposition of extracellular matrix.[1],[4],[5],[6],[7]

Pattern of extracellular matrix remodeling is almost similar to normal granulation tissue formation, but in increased amounts. Deposition of Type I and Type III collagen in early stages of OSF is identical to normal mucosa. Trismus may be attributed to the replacement of collagen Type III by Type I in advanced stages of OSF. As the disease progresses, tenascin, fibronectin, perlecan, and elastin are also replaced by type I collagen. Genetic predisposition to increased risk of OSF is reported to be associated with COL1A1, COL1A2 genotypes.[8],[9]

The extracts from areca nut induce cell injury and cell cycle arrest at G1/S phase. Reactive oxygen species produced from cell injury activates the Mitogen-activated protein kinase (MAPK) and Nuclear factor-κB (NF-κB)pathways, thus promoting epithelial–mesenchymal transition (EMT). Oral keratinocyte and fibroblast interaction is very important in the pathogenesis of OSF. Arecoline interacts with oral keratinocytes and induces the differentiation of fibroblasts to myofibroblasts.[1]

OSF is an epithelium-driven connective tissue disease as the pathology is in the connective tissue which is densely fibrosed. Arecoline is reported to induce cytotoxicity and cell cycle arrest. The hallmark of OSF is atrophy of the epithelium, reduced vascularity, and suppressed endothelial cell proliferation from prolonged exposure to arecoline. To sustain the effects of hypoxia and reduced vascularity from fibrosis, the mucosa responds with increase in vasculature and angiogenesis. Atrophy of the epithelium from loss of vascularity and hypoxia results in overexpression of hypoxia-inducible factor (Hif-1α, Hif-2α), thus promoting carcinogenesis. Arecoline also upregulates cyclooxygenase-2 and αvβ6 integrin expression in oral keratinocytes and promotes malignant transformation. Connective tissue growth factor is also overexpressed in OSF, which promotes the fibrotic activity. The expression of tumor suppressor gene, PTEN, is reported to be decreased in OSF undergoing malignant transformation. Senescence in fibroblasts is induced by the areca alkaloids, which promotes secretion of TGF-β. Senescence-associated secretory phenotype is reported to induce EMT and promote carcinogenesis in OSF.[1],[3],[4],[5],[7],[10],[11],[12],[13]

Pathogenesis of OSF is quite extensive and many theories have been proposed to explain the malignant transformation of OSF. The biomarkers might play an important role in early diagnosis and management of OSF.


  Conclusion Top


Proper awareness and preventive measures toward areca nut usage is the need of the hour for this underrecognized entity. Despite the available literature on pathogenesis and malignant transformation of OSF, there exist lacunae in the management of the potentially malignant disorder. Future research in targeting the molecular pathways would provide therapeutic benefits in preventing malignant transformation.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Tilakaratne WM, Ekanayaka RP, Warnakulasuriya S. Oral submucous fibrosis: A historical perspective and a review on etiology and pathogenesis. Oral Surg Oral Med Oral Pathol Oral Radiol 2016;122:178-91.  Back to cited text no. 1
    
2.
Pindborg JJ, Sirsat SM. Oral submucous fibrosis. Oral Surg Oral Med Oral Pathol 1966;22:764-79.  Back to cited text no. 2
    
3.
Ekanayaka RP, Tilakaratne WM. Oral submucous fibrosis: Review on mechanisms of malignant transformation. Oral Surg Oral Med Oral Pathol Oral Radiol 2016;122:192-9.  Back to cited text no. 3
    
4.
Yoithapprabhunath TR, Maheswaran T, Dineshshankar J, Anusushanth A, Sindhuja P, Sitra G. Pathogenesis and therapeutic intervention of oral submucous fibrosis. J Pharm Bioallied Sci 2013;5:S85-8.  Back to cited text no. 4
    
5.
Shih YH, Wang TH, Shieh TM, Tseng YH. Oral submucous fibrosis: A review on etiopathogenesis, diagnosis, and therapy. Int J Mol Sci 2019;20:2940.  Back to cited text no. 5
    
6.
Rajalalitha P, Vali S. Molecular pathogenesis of oral submucous fibrosis–A collagen metabolic disorder. J Oral Pathol Med 2005;34:321-8.  Back to cited text no. 6
    
7.
Sudharshan R, Annigeri RG, Vijayabala GS. Pathogenesis of oral submucous fibrosis: The past and current concepts. Int J Oral Maxillofac Pathol 2012;3:27-36.  Back to cited text no. 7
    
8.
Tilakaratne WM, Klinikowski MF, Saku T, Peters TJ, Warnakulasuriya S. Oral submucous fibrosis: Review on aetiology and pathogenesis. Oral Oncol 2006;42:561-8.  Back to cited text no. 8
    
9.
Cheng RH, Wang YP, Chang JY, Pan YH, Chang MC, Jeng JH. Genetic susceptibility and protein expression of extracellular matrix turnover-related genes in oral submucous fibrosis. Int J Mol Sci 2020;21:8104-22.  Back to cited text no. 9
    
10.
Ekanayaka RP, Tilakaratne WM. Oral submucous fibrosis: Review on mechanisms of pathogenesis and malignant transformation. J Carcinog Mutagen 2013;S5:002.  Back to cited text no. 10
    
11.
Angadi PV, Krishnapillai R. Evaluation of PTEN immunoexpression in oral submucous fibrosis: Role in pathogenesis and malignant transformation. Head Neck Pathol 2012;6:314-21.  Back to cited text no. 11
    
12.
Joseph I, Elizabeth J, Rao UK, Ranganathan K. Study of hypoxiainducible factor2α expression in the malignant transformation of oral submucous fibrosis. J Oral Maxillofac Pathol 2020;24:33-9.  Back to cited text no. 12
  [Full text]  
13.
Phulari RG, Dave EJ. A systematic review on the mechanisms of malignant transformation of oral submucous fibrosis. Eur J Cancer Prev 2020;29:470-3.  Back to cited text no. 13
    


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  [Figure 1], [Figure 2], [Figure 3], [Figure 4]



 

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