Clinical
p r a c t i c EContact Author
Oral Submucous Fibrosis, a Clinically Benign but Potentially Malignant Disease:
Report of 3 Cases and Review of the Literature
Ajit Auluck, MDS; Miriam P. Rosin, PhD; Lewei Zhang, BDS, PhD, FRCD(C);
Sumanth KN, MDS
ABSTRACT
Oral submucous fibrosis (OSF) is a premalignant condition mainly associated with the practice of chewing betel quid containing areca nut, a habit common among South Asian people. It is characterized by inflammation, increased deposition of submucosal collagen and formation of fibrotic bands in the oral and paraoral tissues, which increasingly limit mouth opening. Recently, OSF has been reported among South Asian immigrants in Canada, the United Kingdom and Germany. Dentists in western countries should enhance their knowledge of this disease as it seems to be increasing with population migration.
In this paper, we review the literature on OSF and present 3 cases representing different stages of the disease to help dentists make an early diagnosis and reduce the morbidity and mortality associated with this condition.
For citation purposes, the electronic version is the definitive version of this article: www.cda-adc.ca/jcda/vol-74/issue-8/735.html
Dr. Auluck Email: drajitauluck@
gmail.com
O
ral submucous fibrosis (OSF) is a disease mainly associated with the chewing of areca nut, an ingredient of betel quid, and is prevalent in South Asian populations. It causes significant morbidity (in terms of loss of mouth function as tissues become rigid and mouth opening becomes difficult) and mor- tality (when transformation into squamous cell carcinoma occurs). The introduction of chewing tobacco containing areca nut into the market has been associated with a sharp increase in the frequency of OSF.1 According to Statistics Canada,2 in 2006 about 1.26 mil- lion people in Canada identified themselves as South Asians. With an increase in immigra- tion from South Asia, there will likely be an increase in the frequency of OSF in westerncountries (Table 1) including Canada.3–15 In this article, we review the literature on OSF and present 3 cases to increase awareness of this condition among Canadian dentists.
Literature Review Etiology
The strongest risk factor for OSF is the chewing of betel quid containing areca nut.
The amount of areca nut in betel quid and the frequency and duration of chewing betel quid are clearly related to the development of OSF.16 The direct contact of the quid mixture with oral tissues results in their continuous irritation by various components, including biologically active alkaloids (arecoline,
arecaidine, arecolidine, guvacoline, guvacine, flavonoids (tannins and catechins) and copper.
Other factors, such as genetic and immunologic pre- disposition, probably also play a role as OSF has been reported in families (both children and adults) whose members are not in the habit of chewing betel quid or areca nut.17
Pathogenesis
The pathogenesis of OSF is not well established, al- though a number of possible mechanisms have been suggested (Fig. 1). Pathogenesis is believed to involve juxta-epithelial inflammatory reaction and fibrosis in the oral mucosa, probably due to increased cross-linking of collagen through up-regulation of lysyl oxidase activity.18
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 degradation.19,20 Thus, OSF is now considered a collagen metabolic disorder.16
Clinical Features
The period between initiation of the chewing habit and the development of clinical symptoms of OSF varies tremendously, ranging from a few months to several dec- ades depending on the type of areca nut consumed, dur- ation and practice of the habit, individual susceptibility and other factors. 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. Patients complain that these vesicles form after they eat spicy food, suggesting the pos- sibility of an allergic reaction to capsaicin. These features can be observed at all stages of OSF.
In the more advanced stage of the disease, the essen- tial feature is a fibrous band restricting mouth opening and causing difficulty in mastication, speech, swallowing and maintaining oral hygiene. Development of fibrous bands in the lip makes the lip thick, rubbery and dif- ficult 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 ex- tensively 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 swallowing because of esophageal fibrosis.
Pathology
The initial pathology of OSF is characterized by juxta-epithelial inflammation including edema, large fibroblasts and an inflammatory infiltrate, consisting pri- marily of neutrophils and eosinophils.21 Later, collagen bundles with early hyalinization are seen and the acute inflammatory infiltrate contains more chronic cell types, such as lymphocytes and plasma cells, occasionally re- sembling lichenoid mucositis.
In more advanced stages, OSF is characterized by formation of thick bands of collagen and hyalinization extending into the submucosal tissues and decreased vascularity. The epithelium lining frequently becomes thin and loses melanin or becomes hyperkeratotic.
Occasionally dysplastic changes occur in the epithelium.
Inflammation and fibrosis of minor salivary glands can also be seen. Muscle degeneration will occur in advanced stages of OSF.
Treatment
No known treatment for OSF is effective, although some conservative and surgical interventions may result Table 1 Summary of oral submucous fibrosis cases reported
in western countries Country
Ethnic origin of patient
Number of cases reported
Canada3 India 2
Canada4 India 1
Canada5 India 3
United Kingdom6 Bangladesh 1
United Kingdom7 Bangladesh 1
United Kingdom8 India (2)
Pakistan (1) 3
France9 India 1
Germany10 India 1
Russia11 Greece 1
Melbourne, Australia12 India 1
South Africa13 India 14
Durban, South Africa14 Not mentioned 6
Not available15 Saudi Arabia 1
in improvement.7,22 Currently, intralesional steroids are the main treatment modality. These are injected into the fibrotic bands weekly for 6–8 weeks with regular monitoring of mouth opening. Patients are advised to do mouth-opening exercises, for example, by placing ice cream sticks in their mouth and gradually increasing the number. Hyaluronidase,23 which facilitates the break- down of connective tissue, can be combined with the steroids for injection.
The list of other treatment modalities (Table 2)23–31 is extensive and includes use of micronutrients and min- erals, carbon dioxide laser, pentoxifylline, lycopene, im- munized milk, interferon gamma, turmeric, hyalase, chymotrypsin and collagenase. As fibrosis cannot be re- versed, when mouth opening is severely limited surgical
interventions, such as myotomy, coronoidectomy32 and excision of fibrotic bands, are required.
Reconstruction using such tech- niques as buccal pad flap, super- ficial temporal flap and forearm flap, can also be performed.22,33,34 Alternative procedures, such as insertion of an oral stent, physio- therapy, local heat therapy, mouth exercises using acrylic carrots and ice cream sticks, have been tried with variable rates of success.
In most cases, depending on the stage of disease and extent of oral involvement, therapy con- sisting of a combination of the above-mentioned drugs and sur- gery might be useful.
Outcome
Outcomes of OSF are charac- terized by 2 features: the per- sistence of the disease and its potential to become malignant.
OSF does not regress spon- taneously or on cessation of areca nut chewing. Once the disease is present, it either persists or be- comes more severe with involve- ment of additional areas of the oral mucosa.35
OSF is strongly associated with a risk of oral cancer, although the biology underlying this associa- tion is still unresolved.36 OSF may cause atrophy in the epithelium, increasing carcinogen penetration.
Studies suggest that dysplasia is seen in about 25% of biopsied OSF cases and the rate of transformation to malignancy varies from 3% to 19%.37
Case Reports Case 1
A 23-year-old man presented with a complaint of a burning sensation in the buccal mucosa while chewing spicy food, but no other systemic or dermatologic problem. The patient reported a habit of chewing dried areca nut powder 3–4 times a day for the past 2–3 years.
He occasionally mixed calcium oxide with the areca nut powder and drank alcohol (approximately 750 mL of local undistilled alcohol) on weekends for the previous 5 years. His mouth opening was normal. Intraoral exam- ination revealed that his entire oral mucosa was pale,
Habit of chewing betel quid containing areca nut (impact related to duration and frequency)
Chronic irritation eliciting chronic inflammatory response
Activation of T cells and macrophages at the site
Increase in cytokines (IL-6, IF-alpha) Increase in growth factor (TGF-beta)
Activation of procollagen genes
Increase in collagen (soluble form)
Increase in collagen (insoluble form)
Increased activity of copper- stimulated lysyl oxidase and action of flavonoids such as catechin and tannins in areca nut
Activation of TIMP and PAI genes
Inhibition of activated collagenase and conversion of procollagenase
to collagenase
Decrease in collagen degradation
Increase in insoluble form of collagen
Oral submucous fibrosis
Note: IF-alpha = interferon alpha, IL-6 = interleukin-6, PAI = plasminogen activator inhibitor, TGF-beta = transforming growth factor beta, TIMP = tissue inhibitor of matrix metalloproteinase.
Figure 1: Etiopathogenesis of oral submucous fibrosis.
especially the buccal mucosa, which showed areas of ero- sion (Fig. 2), and the hard palate, which was completely blanched. His tongue, uvula and soft palate were normal.
No fibrotic bands were palpable in the oral cavity.
A biopsy of the buccal mucosa showed nonspecific ulcer and mucositis consisting of prominent fibro- blasts, increased vascularity, edema and an inflamma- tory infiltrate that included numerous neutrophils and eosinophils. Although histologic evidence alone was not specific, it was highly consistent with OSF when consid- ered in combination with the patient’s chewing habit and clinical presentation. A diagnosis of early OSF was made.
This patient was advised to stop chewing areca nut and return for follow-up in 1 month. He did not return until 8 months later, when he had developed difficulty in mouth opening. He had not stopped chewing areca nut although he reported a reduction in frequency of use.
Case 2
A 43-year-old woman presented with a complaint of progressive difficulty in opening her mouth over the past 2 years. She had a longstanding habit of chewing fresh areca nut (4–5 pouches a day for 20–25 years).
Examination revealed that her lips were thin and her mouth opening was limited to about 26 mm (average normal opening is 40 mm). There was erosion at the cor- ners of her mouth (Fig. 3). The entire oral mucosa was pale, with focal blanched areas (Fig. 4). The tongue was devoid of papillae and extensive fibrosis had occurred on its ventral surface and the floor of the mouth (Figs. 3 and 5). The patient could not stick out her tongue or touch the hard palate with the tip of her tongue.
Thick fibrotic bands were palpable bilaterally on the buccal mucosa. Intraoral examination was problematic as it was difficult to retract the patient’s fibrotic cheeks.
During examination the mirror often stuck to the oral mucosa, suggesting dry mouth. When the patient was asked to blow out air with closed lips, the usual puffed- cheek appearance was not seen, suggesting loss of cheek elasticity. General examination was normal.
A diagnosis of OSF at a moderately advanced stage was made based on the characteristic oral features: gener- alized blanching of mucosa, extensive fibrosis and limited mouth opening.
Case 3
A 60-year-old man, with diagnosed OSF of 10 years duration, reported to our clinic for evaluation of a swell- ing in his cheek and on the floor of the mouth apparent for the past 6 months. The patient had begun treatment with intralesional steroids 10 years earlier on diagnosis of OSF. However, after a few visits, he ceased treatment and continued to chew areca nut over subsequent years.
His mouth opening was restricted to about 16 mm.
His oral cavity was fully blanched and the buccal mucosa completely fibrotic. The uvula was fibrotic and deformed (Fig. 6). The tongue was completely devoid of papillae. A diagnosis of OSF at an advanced stage was made based on the habit and the classical clinical presentation.
In addition to the above changes, 2 masses were noted.
One mass (about 3 × 2 cm) with an irregular margin was located on the right buccal mucosa extending from the corner of his mouth to the molar area. It was firm on palpation and fixed to the underlying tissues. The mucosa surrounding the mass was indurated. The other mass, about 1 cm in diameter, was on the floor of the mouth, in the lingual sulcus of the right mandibular premolar region. Its surface had numerous small finger-like projec- tions (Fig. 7). On palpation, the swelling was firm and fixed to the underlying structures; however, a panoramic radiograph revealed no bony involvement. Biopsies of both masses revealed squamous cell carcinoma.
Table 2 Treatment modalities for oral submucous fibrosis
Treatment Treatment details
Micronutrients
and minerals24 Vitamin A, B complex, C, D and E, iron, copper, calcium, zinc, magnesium, selenium and others
Milk from
immunized cows25 45 g milk powder twice a day for 3 months
Lycopene26 8 mg twice a day for 2 months Pentoxyfilline27 400 mg 3 times a day for
7 months
Interferon gamma28 Intralesional injection of interferon gamma (0.01–
10.0 U/mL) 3 times a day for 6 months
Steroids29 Submucosal injections twice a week in multiple sites for 3 months
Steroids29 Topical for 3 months Hyalase +
dexamethasone23 — Placental extracts23 —
Turmeric30 Alcoholic extracts of turmeric (3 g), turmeric oil (600 mg), turmeric oleoresin (600 mg) daily for 3 months
Chymotripsin, hyaluronidase and dexamethasone31
Chymotripsin (5000 IU), hyaluronidase (1500 IU) and dexamethasone (4 mg), twice weekly submucosal injections for 10 weeks
Discussion
The 3 cases reported here represent different stages of OSF. In the first case, the disease was at a very early stage and the patient showed the classical clinical presentation of burning sensation, ulceration, localized areas of pale and blanching mucosa and a habit of chewing areca nut.
This case illustrates the importance of clinical informa- tion, as a diagnosis of early-stage OSF cannot be based on histology alone but rather on a combination of histology, chewing habit and clinical information. It is critical to provide the pathologist with clinical information. In the second case, the disease was at a more advanced stage, and the patient showed diffuse blanching and fibrosis of the oral mucosa. In the third case, an advanced stage of OSF, the patient had diffuse oral fibrosis and severely limited ability to open his mouth. In addition, 2 late-stage squamous cell carcinomas were found, a disease associ- ated with a poor survival rate in the late stages.
The rate of development of OSF varied among the 3 patients. The first patient developed early OSF after only 2–3 years of chewing areca nut, whereas the second developed the disease only after more than 20 years of using areca nut. The first patient went on to experience difficulty in mouth opening in a short time (8 months) despite a reduction in areca nut use.
The cases illustrate the relentless progression of OSF and its significant morbidity and mortality; they also em- phasize the importance of close follow-up of such cases.
Because of the significant cancer risk among these pa- tients, periodic biopsies of suspicious regions of the oral mucosa are essential for early detection and management of high-risk oral premalignant lesions and prevention of cancer. Dentists can play an important role in both the education of patients about the perils of chewing betel quid and in the early diagnosis of high-risk premalignant lesions and cancer. a
Figure 2: Case 1. Intraoral photo- graph of the buccal mucosa showing blanched oral mucosa with erosions in the initial stages of oral submucous fibrosis.
Figure 3: Case 2. Extraoral photograph showing reduced mouth opening with atro- phied lips and erosions at the corners of the mouth.
Figure 4: Case 2. Intraoral photograph showing blanched fibrosed oral mucosa and restricted mouth opening.
Figure 5: Case 2. Intraoral photo- graph showing extensive blanching and fibrosis of the ventral surface of the tongue.
Figure 6: Case 3. Intraoral photograph showing fibrosed and deformed uvula and a small ulcer in the palate.
Figure 7: Case 3. Intraoral photograph showing 2 proliferative growths in the buccal mucosa and sulcus (because of restricted mouth opening, it was impossible to obtain a high-quality image).
THE AUTHORS
Dr. Auluck is a PhD student in the British Columbia Oral Cancer Prevention Program, oral medicine and pathology, fac- ulty of dentistry, University of British Columbia, Vancouver, British Columbia.
Dr. Rosin is a professor and director, Cancer Control Research, British Columbia Cancer Agency, Vancouver, British Columbia.
Dr. Zhang is professor and chair of oral medicine and path- ology, faculty of dentistry, University of British Columbia, Vancouver, British Columbia.
Dr. KN is an associate professor of oral medicine and radi- ology, Manipal College of Dental Sciences, Mangalore, India.
Correspondence to: Dr. Ajit Auluck, British Columbia Oral Cancer Prevention Program and Faculty of Dentistry, University of British Columbia, Room No. 2-119, 675 West 10th Avenue, Vancouver BC V5Z 1L3.
The authors have no declared financial interests.
This article has been peer reviewed.
References
1. Nair U, Bartsch H, Nair J. Alert for an epidemic of oral cancer due to use of the betel quid substitutes gutkha and pan masala: a review of agents and causative mechanisms. Mutagenesis 2004; 19(4):251–62.
2. Statistics Canada. 2006 census: Ethnic origin, visible minorities, place of work and mode of transportation. The Daily 2008; April 2. Available: www.
statcan.ca/Daily/English/080402/d080402a.htm (accessed 2008 July 20).
3. Morawetz G, Katsikeris N, Weinberg S, Listrom R. Oral submucous fi- brosis. Int J Oral Maxillofac Surg 1987; 16(5):609–14.
4. Hayes PA. Oral submucous fibrosis in a 4-year-old girl. Oral Surg Oral Med Oral Pathol 1985; 59(5):475–8.
5. Hardie J. Oral submucous fibrosis. A review with case reports. J Can Dent Assoc 1987; 53(5):389–93.
6. Shah B, Lewis MA, Bedi R. Oral submucous fibrosis in a 11-year- old Bangladeshi girl living in the United Kingdom. Br Dent J 2001;
191(3):130–2.
7. Yusuf H, Yong SL. Oral submucous fibrosis in a 12-year-old Bangladeshi boy: a case report and review of literature. Int J Paediatr Dent 2002;
12(4):271–6.
8. McGurk M, Craig GT. Oral submucous fibrosis: two cases of malignant transformation in Asian immigrants to the United Kingdom. Br J Oral Maxillofac Surg 1984; 22(1):56–64.
9. Vilmer C, Civatte J. [Oral submucous fibrosis. Review of the literature apropos of a case]. Ann Dermatol Venereol 1986; 113(2):107–12. French.
10. Reichart PA, Philipsen HP. [Oral submucous fibrosis in a 31-year-old Indian women: first case report from Germany]. Mund Kiefer Gesichtschir 2006; 10(3):192–6. German.
11. Laskaris G, Bovopoulou O, Nicolis G. Oral submucous fibrosis in a Greek female. Br J Oral Surg 1981; 19(3):197–201.
12. Oliver AJ, Radden BG. Oral submucous fibrosis. Case report and review of the literature. Aust Dent J 1992; 37(1):31–4.
13. Seedat HA, van Wyk CW. Submucous fibrosis (SF) in ex-betel nut chewers: a report of 14 cases. J Oral Pathol 1988; 17(5):226–9.
14. Seedat HA, van Wyk CW. Submucous fibrosis in non-betel nut chewing subjects. J Biol Buccale 1988; 16(1):3–6.
15. Mani NJ, Kim HW, Sastry KA. Oral submucous fibrosis in a Saudi female.
Ann Dent 1985; 44(2):12–3.
16. Rajalalitha P, Vali S. Molecular pathogenesis of oral submucous fibrosis
— a collagen metabolic disorder. J Oral Pathol Med 2005; 34(6):321–8.
17. Rajendran R, Vidyarani. Familial occurrence of oral submucous fibrosis:
report of eight families from northern Kerala, south India. Indian J Dent Res 2004; 15(4):139–44.
18. Trivedy CR, Warnakulasuriya KA, Peters TJ, Senkus R, Hazarey VK, Johnson NW. Raised tissue copper levels in oral submucous fibrosis. J Oral Pathol Med 2000; 29(6):241–8.
19. Shieh TY, Yang JF. Collagenase activity in oral submucous fibrosis. Proc Natl Sci Counc Repub China B 1992; 16(2):106–10.
20. Yang SF, Hsieh YS, Tsai CH, Chen YJ, Chang YC. Increased plasminogen activator inhibitor-1/tissue type plasminogen activator ratio in oral submu- cous fibrosis. Oral Dis 2007; 13(2):234–8.
21. Chiang CP, Hsieh RP, Chen TH, Chang YF, Liu BY, Wang JT, and others.
High incidence of autoantibodies in Taiwanese patients with oral submucous fibrosis. J Oral Pathol Med 2002; 31(7):402–9.
22. Lai DR, Chen HR, Lin LM, Huang YL, Tsai CC. Clinical evaluation of dif- ferent treatment methods for oral submucous fibrosis. A 10-year experience with 150 cases. J Oral Pathol Med 1995; 24(9):402–6.
23. Kakar PK, Puri RK, Venkatachalam VP. Oral submucous fibrosis — treat- ment with hyalase. J Laryngol Otol 1985; 99(1):57–9.
24. Maher R, Aga P, Johnson NW, Sankaranarayanan R, Warnakulasuriya S.
Evaluation of multiple micronutrient supplementation in the management of oral submucous fibrosis in Karachi, Pakistan. Nutr Cancer 1997; 27(1):41–7.
25. Tai YS, Liu BY, Wang JT, Sun A, Kwan HW, Chiang CP. Oral administration of milk from cows immunized with human intestinal bacteria leads to signifi- cant improvements of symptoms and signs in patients with oral submucous fibrosis. J Oral Pathol Med 2001; 30(10):618–25.
26. Kumar A, Bagewadi A, Keluskar V, Singh M. Efficacy of lycopene in the management of oral submucous fibrosis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007; 103(2):207–13. Epub 2006 Oct 24.
27. Rajendran R, Rani V, Shaikh S. Pentoxifylline therapy: a new adjunct in the treatment of oral submucous fibrosis. Indian J Dent Res 2006; 17(4):190–8.
28. Haque MF, Meghji S, Nazir R, Harris M. Interferon gamma (IFN-gamma) may reverse oral submucous fibrosis. J Oral Pathol Med 2001; 30(1):12–21.
29. Borle RM, Borle SR. Management of oral submucous fibrosis: a conserva- tive approach. J Oral Maxillofac Surg 1991; 49(8):788–91.
30. Hastak K, Lubri N, Jakhi SD, More C, John A, Ghaisas SD, and other. Effect of turmeric oil and turmeric oleoresin on cytogenetic damage in patients suf- fering from oral submucous fibrosis. Cancer Lett 1997; 116(2):265–9.
31. Gupta D, Sharma SC. Oral submucous fibrosis — a new treatment regimen. J Oral Maxillofac Surg 1988; 46(10):830–3.
32. Chang YM, Tsai CY, Kildal M, Wei FC. Importance of coronoidotomy and masticatory muscle myotomy in surgical release of trismus caused by submu- cous fibrosis. Plast Reconstr Surg 2004; 113(7):1949–54.
33. Mokal NJ, Raje RS, Ranade SV, Prasad JS, Thatte RL. Release of oral submucous fibrosis and reconstruction using superficial temporal fascia flap and split skin graft — a new technique. Br J Plast Surg 2005; 58(8):1055–60.
Epub 2005 Aug 1.
34. Lee JT, Cheng LF, Chen PR, Wang CH, Hsu H, Chien SH, and other.
Bipaddled radial forearm flap for the reconstruction of bilateral buccal de- fects in oral submucous fibrosis. Int J Oral Maxillofac Surg 2007; 36(7):615–
9. Epub 2007 May 11.
35. Hammer JE, Mehta FS, editors. Tobacco related oral mucosal lesions and conditions in India. Mumbai: Basic Dental Research Unit, Tata Institute of Fundamental Research; 1993. p. 67.
36. Mithani SK, Mydlarz WK, Grumbine FL, Smith IM, Califano JA. Molecular genetics of premalignant oral lesions. Oral Dis 2007; 13(2):126–33.
37. 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.
