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J Orofac Sci, 3(2)2011

Journal of

Case Report

Oral submucous fibrosis turning into malignancy-A case report and review of literature
Shamimul Hasana*, Osama Sherwania, Sameer Ahmeda, Mohd Abbas Khana

Dept. of Oral Medicine & Radiology, Z. A Dental College & Hospitals, A.M.U ; Aligarh- 202002, U.P.

Article History : Received : 16 July, 2011 Received in revised form : 4 Aug, 2011 Accepted : 10 Oct, 2011 Key Words : Oral submucous fibrosis, Areca nut habit Malignant potential

Oral submucous fibrosis is a disease of individuals of Indian-south east asian subcontinent, related to the use of areca nuts, also found in Pan masala and guthka. It is possible that it is due to the copper content which increases collagen cross-linking. pale, blanched mucosa and palpable fibrotic bands may progress to severely restricted oral opening. It can also affect the soft palate and tongue and produces epithelial atrophy. Oral submucous fibrosis is a premalignant condition; carcinoma develops possibly in upto 8% cases. Diagnosis is based on history of betel chewing; typical clinical features; biopsy and haematology. Often anaemia is present. Treatment includes discontinuation of habits, oral physiotherapy, nutritional supplements, intralesional steroids and placental extracts and surgical interventions. This paper deals with a case of malignancy developing from oral submucous fibrosis in a 47 year old patient.

* Corresponding author :
Dr. Shamimul Hasan M.D.S C/o Mr. Mohd Javed Khan, C-4, Duplex Quarters (New) Sir Syed Nagar, Aligarh 202002, U.P. e-mail :

2011 SIDS. All Rights Reserved

INTR ODUCTION INTRODUCTION Sushruta - a renowned Indian physician, in his book " mouth and throat diseases" mentioned about a condition "Vidari", the features of which simulate oral submucous fibrosis1. Oral submucous fibrosis is a chronic and potentially malignant condition of the oral cavity, characterized by a juxta-epithelial inflammatory reaction followed by a fibroblastic changes in the lamina propria and associated epithelial atrophy. The disease affects most parts of the oral cavity as well as the upper third of the esophagus2. In 1952, Schwartz described a fibrosing condition and coined the term Atropica Idiopathica Tropica Mucosae Oris3. Although the terms Idiopathic scleroderma of the mouth4 and juxta-epithelial fibrosis5

have also been used, the term Oral submucous fibrosis6 is the most widely accepted. Oral Submucous fibrosis is an oral condition described by Joshi in 19537, and causes changes similar to those of systemic sclerosis but limited to oral tissues. Various etiological factors have been proposed for OSMF. Several predisposing factors or causative agents include chilli consumption, nutritional deficiency, areca nut chewing, genetic susceptibility, autoimmunity and saliva8,9. It has been reported mainly from india, but has also been reported in Srilanka, Malaysia, Nepal, South Vietnam, and Thailand10. Majority of OSMF patients belong to 20-40 year old age group with a male predominance, usually presenting with intolerance

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to hot and spicy food and progressive inability to open the mouth leading to difficulty in mastication and speech. Most OSMF cases occur in lower socio-economic groups11. Histopathologic features are less vascularised collagenous submucosa with a range of atrophy in the neighbouring striated muscle fibres, mild to moderate chronic inflammation, and epithelial changes consisting of atrophy and a variable degree of dysplasia12. Various treatment modalities include corticosteroids, antioxidants, physiotherapy and nutritional support13,14. The possible precancerous nature of submucous fibrosis was first mentioned by Pay Master in 1956, who described the development of slow-growing squamous cell carcinoma in one third of cases with submucous fibrosis15. CASE REPOR T REPORT A 47 year old male patient reported to Oral Medicine and Radiology department, Z.A Dental college and Hospitals, AMU, Aligarh with a complaint of progressive difficulty in mouth opening and burning sensations in the mouth over the past 3 years. The patient also complaint of a growth in the oral cavity since past 6 months. The patient had a long standing habit of betel nut chewing (6-7 packets for more than 30 years). Patient's medical and dental history was non significant. Patient's general examination was non-contibutory except that the right submandibular lymph node was palpable, tender, hard in consistency and not movable. The mouth opening was restricted (around 25mm) (Fig.1). Intraoral examination revealed pale, blanched buccal mucosa with palpable fibrotic bands running vertically and extending to the retromolar region. (Fig.2). The tongue was devoid of papillae along with restricted protrusive tongue movements. The uvula was deformed and shrunken. The patient was not able to blow out air with closed lips and the usual puffed-cheek appearance was not seen, suggesting loss of cheek elasticity. In addition, a single localized ulcero-proliferative growth about 4cm x 3cm was present in the right side involving the buccal mucosa, alveolus, gingiva from 16 to 18 region and on the palate and maxillary tuberosity area (Fig.3).The surface of the growth was rough, ulcerated mildly tender and was covered by a white necrotic slough. Areas of bleeding from the surface of the growth was seen. Mucosa surrounding the growth was errythmatous in nature The margin and edges were everted. The base was indurated The teeth associated with the growth 17 was mobile.

Correlating the history of chronic betel nut chewing and clinical observation of limitation of mouth opening, along with pale, blanched buccal mucosa with palpable fibrotic bands, a provisional diagnosis of oral submucous fibrosis was made. An ulcerated , rapidly enlarging growth, with everted margins and indurated base was seen in the right side of buccal mucosa,. The rapidity of growth and the indurated nature along with palpable, fixed right submandibular lymph node, suggests that it was a carcinoma. Investigations : Radiographs were taken to depict bony involvement. OPG, PA view mandible, and Para nasal sinus (PNS) view showed no abnormality in the bone. ( Fig. 4,5 & 6). MRI : Heterogeneous T2 hyper intense mass in the right cheek infiltrating into the buccal space and retromolar trigone was seen. A soft tissue lesion with fluid restriction was noticed in the axial DWI (Diffussion Weightage Image), features suggestive of a malignancy (Fig 7). After the informed consent from the patient, an incisional biopsy was taken and histopathology revealed buccal mucosa with irregular focal areas of acanthosis, severe dysplasia and focal cell carcinoma in situ and small foci of early submucosal micro invasion. Rest of submucosa shows dense chronic inflammation suggestive of carcinoma(Fig.8&9). Clinical diagnosis : Correlating the history, clinical findings, radiographic features and histopathology a final clinical diagnosis of "oral submucous fibrosis progressing into malignancy was made ". The patient was referred to dept of oral and maxillofacial surgery ZA Dental college and hospitals, AMU, ALIGARH for surgical excision of the growth. DISCUSSION OSMF, a potentially premalignant condition of the oral cavity and oropharynx has been a subject of extensive research since the last 50 years. Earlier literature emphasises on the studies done by Joshi, Sirsat and Khanolkar, ABN Rao and other workers, related to etiology, clinical features, histopathological features and malignant potential of the disease16. Oral Submucous fibrosis is a "insidious chronic disease affecting any part of the oral cavity and sometimes the pharynx, occasionally preceded

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by vesicle formation, always associated with juxtraepithelial inflammatory reaction followed by a fibroelastic change of lamina propria with epithelial atrophy leading to stiffness of the oral mucosa, trismus and inability to eat"13. Prevalence rate is 0.2 to 0.5% with higher percentage reported from the southern states in India17. Unlike other precancerous lesions, OSMF is insidious in origin and does not regress, either spontaneously or with cessation of habits18. The condition may remain either stationary or become severe, leaving an individual handicapped both physically and psychologically19. Etiology : Pillai et al 20 establishaed that OSMF has an unknown, but multifactorial etiology. A variety of factors trigger the disease process. Factors include areca nut chewing, genetic basis, nutritional deficiencies, auto immunity, and saliva. eca nut che 1. Ar Areca chewing wing : The introduction of chewing tobacco containing areca nut into the market has been associated with a sharp increase in the frequency of OSMF21. The amount of areca nut in betel quid and the frequency and duration of chewing betel quid are clearly related to the development of OSMF22. The direct contact of the quid mixture with oral tissues results in their continous irritation by various components, including biologically active alkaloids (arecoline, arecaidine, arecolidine, guavacoline, guavacine) and copper. 2. Nutritional deficiencies : OSMF was proposed by Ramanathan as an Asian version of Sideropenic dysphagia wherin the chronic iron deficiency leads to mucosal susceptibility to irritants such as chilli and areca nut11. The role of deficiency of vitamins and iron has been implicated in the etiology of OSMF. A significant alteration in serum copper and Zinc ratio is reported with a decrease in Zinc content23. Iron is essential for overall integrity and health of epithelia of the digestive tract and its importance may lie in its contribution to normal enzymes11. The normal maturation of epithelium is dependent upon an iron containing enzyme, cytochrome oxidase. Moreover , one of the most common signs seen in OSMF is pallor or blanching of oral mucosa which can occur in a variety of other conditions, most commonly being anemia1 .

3. A uto immunity : The similarities of this condition Auto with other collagen disorders like scleroderma which is presumed to have an auto immune pathogenesis has evoked a possibility of auto immune basis for the disease16. Sirsat and Khanolkar observed refractive eosinophilic material and marked increase in PAS positive material with metachromasia in ground substance of OSMF. Thus, OSMF was considered to be a localized collagen disease16. Pathak observed Hyperglobulinemia in immunological studies of OSMF, thus favouring OSMF as an auto immune disorder16. An increase in DR-3 antigen, alteration in serum immunoglobulin and presence of auto antibodies in OSMF were reported by Cannif et al. The betel nut alkaloids may act as haptens which may produce antibodies to parietal cells12. 4. Genetic basis : OSMF cases were observed in the absence of any chewing habits in families (children and adults) which provoked researchers to probe the possibility of genetic susceptibility24. HLA tissue typing showed signifcant difference in frequencies of HLA-10, DR-3, and DR-7 in OSMF patients than the controls12. 5. Salivary constituents : OSMF was considered as a local coagulopathy , produced by thrombin like fibrin producing factor in saliva. Fibrin producing factor, acting locally produced fibrin glue phenomenon in the submucous zone of oral cavity and acting systematically, produced cryofibrinogen, which gets attached to submucous zone through the action of fibronectin25. 6. Allergy to capsaicin : Patients complain that the vesicles form after they eat spicy food, suggesting the possibility of an allergic reaction to capsaicin. Pathogenesis : The pathogenesis of OSMF is not well established, although a number of possible mechanisms have been suggested. Pathogenesis is believed to involve juxtaepithelial inflammatory reaction and fibrosis in the oral mucosa, probably due to increased cross-linking of collagen through up-regulation of lysyl oxidase activity26. Fibrosis, or the build up of collagen, results from the effects of areca nut, which increases collagen production (e.g., stimulated by arecoline, an alkaloid) and decreases collagen degradation27,28. Thus, OSMF is now considered a collagen metabolic disorder16. Clinical F eatur es: The disorder primarily affects the Featur eatures: males. Male- female ratio was found to be 2.3: 129. Buccal

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mucosa is the most common site of involvement16, followed by soft palate, uvula, lips, tongue and floor of the mouth29 .OSMF is a chronic disorder characterized by fibrosis of the lining mucosa of the upper digestive tract involving the oral cavity, oro- and hypo pharynx and the upper third of the oesophagus. The fibrosis involves the lamina propria and the sub mucosa and may often extend into the underlying musculature resulting in the deposition of dense fibrous bands, which give rise to the limited mouth opening which is a hallmark of this disorder. The symptoms and signs of OSF are due to inflammation and, primarily, fibrosis. The most common initial symptoms and signs are a burning sensation, dry mouth, blanching oral mucosa and ulceration. The burning sensation usually occurs while chewing spicy food. Blanching of the oral mucosa is caused by impairment of local vascularity because of increasing fibrosis and results in a marble-like appearance. Blanching may be localized, diffuse or reticular. In some cases, blanching may be associated with small vesicles that rupture to form erosions. These features can be observed at all stages of OSMF. In the more advanced stage of the disease, the essential feature is a fibrous band restricting mouth opening and causing difficulty in mastication, speech, swallowing and maintaining oral hygiene. The severity of disease and and the degree of mouth opening were co-related by Jain P and Suman V et al as30: Normal mouth opening- 40-60 mm Grade - I- 40-42mm Grade-II- 31-39mm Grade-III- 21-30mm Grade- IV- 10mm- 20mm However, Rajendran et al found no such co-relation, as the extent of mouth opening was also dependent on various other factors such as the site of involvement, extent of fibrosis, involvement of underlying musculature, and duration of the disease 31 . Development of fibrous bands in the lip makes the lip thick, rubbery and difficult to retract or evert; a band around the lips gives the mouth opening an elliptical shape. Fibrosis makes cheeks thick and rigid. When a patient blows a whistle or tries to inflate a balloon, the usual puffed-out appearance of the cheeks is missing. In the tongue, depapillation of mucosa around the tip and

lateral margins may occur with blanching or fibrosis of the ventral mucosa. Fibrosis of the tongue and the floor of the mouth interfere with tongue movement. Hard palate involvement includes extensively blanched mucosa. Fibrosis may extend posteriorly to involve the soft palate and uvula. The latter may appear shrunken and, in extreme cases, budlike. Gingival involvement is relatively uncommon and is characterized by fibrosis, blanching and loss of normal stippling. In rare cases of extensive involvement, there may be loss of hearing due to blockage of eustachian tubes and difficulty in swallowing because of esophageal fibrosis. Histopathology32 : Very early stage (Grade I) O A finely fibrillar collagen, dispersed with marked edema. O The fibroblastic response is strong. O The blood vessels are sometimes normal, but more often they are dilated and congested. O Inflammatory cells, mainly polymorphonuclear leukocytes with an occasional eosinophil. Early stage (Grade II) O The juxta-epithelial area shows early hyalinization. O Plump young fibroblasts are present in moderate numbers. O The blood vessels are dilated and congested. O The inflammatory cells are mostly mononuclear lymphocytes, eosinophils and an occasional plasma cell. Moderately advanced stage (Grade III) O The collagen is moderately hyalinized. O The fibroblastic response is less marked, the cells present being mostly adult fibrocytes. O Blood vessels are normal or constricted. O The inflammatory exudates consist of lymphocytes and plasma cells, although an occasional eosinophil is seen. Advanced stage (Grade IV ) O The collagen is completely hyalinized. O The hyalinized areas are devoid of fibroblasts. O Blood vessels are completely obliterated or narrowed. O The inflammatory cells are Lymphocytes and plasma cells. Grading and treatment modalities33 : Grade I : Only blanching of oral mucosa without symptoms

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Grade II : Burning sensations ; Dryness of mouth ; vesicles / ulcers in the mouth without tongue involvement Grade III : In addition to grade II restriction of mouth III: opening Grade IV : In addition to grade III palpable bands all over the mouth without tongue involvement Grade V : Grade IV and tongue involvement GradeVI : Oral submucous fibrosis along with histologicaly proven oral cancer. The various treatment modalities used in OSMF can be divided into different groups : GR OUP I : GROUP

Dexamethasone 1.5 ml with 0.5 ml of lignocaine HCL intra lesionally biweekly for 5 weeks. Placental extracts (PLACENTRIX) -2 ml intra lesionally once a week for 4 weeks ; along with injection ranidone ( Iodine & vit B complex ) I.M HYALURONIDASE causes collagen destruction as collagen of OSMF patients ( as compared to controls) is attacked rapidly by Hyaluronidase. Also it breaks down Hyaluronic acid and causes lowered viscosity of intercellular cementing substance34.

Removal of etiological factors : Discontinuation of habits ( paan, beetel nut, tobacco chewing and intake of spicy food ) Nutritional Therapy : Multivitamin therapy and Iron therapy to boost up the nutritional status of the patients. Topical Therapy : For patient's in grade I & II and to prevent relapse after other treatment modalities. Triamcinolone acetate 0.1 % with neomycin - to be applied to the oral mucosa three times daily and the patients were advised to let the saliva drool for 15 minutes. This one month course was repeated after two months. Pappain and urea mixture : to be applied intra orally 2-3 times daily for 15 days and to be repeated after one month

STER OIDS : Functions as immune suppressive STEROIDS agents by opposing the action of the soluble factors released by the sensitized lymphocytes following activation by non specific antigens. Also suppresses the inflammatory reaction. Thus fibrosis is prevented by a decrease in fibroblastic proliferation and deposition of collagen. Placentrix : Acts by biogenic stimulation. Ranidone , an iodine and vit B complex preparation stimulates the metabolic processes in the body. Vit B complex potentiates the action of Iodine and makes it non toxic. Micro wave Diathermy using " microtone 200 " unit producing microwaves of 2450 MC / S : for patients in grade IV & V One sitting of 20 min a day for 15 days to give an energy of 20 watts Microwave Diathermy causes physio fibrolysis of bands. Surgical treatment for patients with grade IV & V or with isolated bands in retromolar region and in patients in grade VI Forceful mouth opening : Patients with severe trismus and having unerupted / partially erupted 3rd molars had their mouth forcefully opened, and the patients were asked to apply Kamillosan ointment to reduce scar formation and promote healing. Topical steroids are used to prevent relapse. Rotated tongue flap or skin grafting- for patients with Isolated bands in retromolar region and trismus .



Papain mixtur e : The mode of action of papain mixture mixture is by biogenic stimulation and the proteolytic action. UREA : is a keratolytic agent, induces surface lysis of keratin layer of oral mucosa and early absorption at the lesional site , breaking the fibro peptide linkages of the fibrous layer, leading to slight laxity of the oral mucous membrane stiffness33. GR OUP III : GROUP


Injectable therapy : For patients in grade III, IV, V Injectable Hyaluronidase 1500 I.U, 0.5 ml injected intra lesionally twice a week for 10 weeks.

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OSMF AND CANCER : OSMF is considered as a premalignant condition. A malignant transformation rate of 7.6% over a period of 10 years was described in an Indian cohort and the relative risk for malignant transformation may be as high as 397.3.35 Thomas et al from South India suggested tobacco chewing was the most important risk factor for multiple oral premalignant lesions and may be a major etiological factor for cancers on the oral epithelium in the Indian population36. Reactive oxygen species produced during the auto oxidation of areca nut poly phenols in the saliva of commercial areca nut chewers are crucial in the initiation and promotion of oral cancer37. Nitrosation of areca nut alkaloids also produces areca nut specific nitrosamines that have been demonstrated to be mutagenic, genotoxic and are capable of inducing tumours in experimental animals. Oral cancer can develop in

individuals who use areca nut but donot use tobacco in any form38. Epithelial atrophy and lack of proper maturation of epithelium are the two important histological changes observed in the oral mucosa of patients with iron deficiency anaemia39. Further Fe deficiency results in improper vascular channel formation and concomitant decreased vascularity, thus making easy percolation of esters of arecoline. These esters stimulate fibrogenesis and the resultant fibrous tissue deposition could manifest as fibrotic bands. Cytochrome oxidase, an Fe containing enzyme is responsible for the normal maturation of epithelium. In Fe deficiency anaemia, low levels of this enzyme are seen, thus epithelial atrophy and lack of maturation occurs. It is well documented that Post cricoids carcinoma, esophageal carcinoma and oral carcinomas show an increased inherent association with Fe deficiency anaemias. Malignant transformation in OSMF could be explained in a similar manner.










Fig.1: Reveals restricted mouth opening of 26 mm. Fig.2 : Pale blanched buccal mucosa with palpable fibrotic bands, showing loss of cheek elasticity. Fig.3 : An ulcero-proliferative growth involving right maxillary tuberosity ,gingiva and palate with everted margins and indurated base. Fig.4, 5& 6 : Radiographs (OPG, PA SKULL & PNS View) do not reveal any bony involvement. Fig.7: Diffussion Weightage Image MRI: shows soft tissue lesion with fluid restriction, appearing white in colour, suggestive of a malignant lesion. Fig 8&9: Histopathology revealing buccal mucosa with irregular focal areas of acanthosis, severe dysplasia and focal cell carcinoma in situ and small foci of early submucosal micro invasion. Rest of submucosa shows dense chronic inflammation suggestive of carcinoma.

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