Oral submucous fibrosis: an update

Figures & data

Table 1 Histopathological classifications of oral submucous fibrosis

Very early (stage I)	Early (stage II)	Moderately advanced (stage III)	Advanced (stage IV)
A finely fibrillar collagen, dispersed with marked edema	The juxta-epithelial area shows early hyalinization	The collagen is moderately hyalinized	The collagen is completely hyalinized
The fibroblastic response is strong	Plump young fibroblasts are present in moderate numbers	The fibroblastic response is less marked, the cells present being mostly adult fibrocytes	The hyalinized areas are devoid of fibroblasts
The blood vessels are sometimes normal, but more often they are dilated and congested	The blood vessels are dilated and congested	Blood vessels are normal or constricted	Blood vessels are completely obliterated or narrowed
Inflammatory cells, mainly polymorphonuclear leukocytes with an occasional eosinophil, are present	Inflammatory cells are mostly mononuclear lymphocytes, eosinophils, and an occasional plasma cell	Inflammatory exudates consist of lymphocytes and plasma cells, although an occasional eosinophil is seen	Inflammatory cells are lymphocytes and plasma cells

Figure 1 Handmade and commercial forms of betel.

Notes: (A) Typical ingredients of hand-made betel quid: green piper betel leaves (left), areca nut (lower right), slaked lime (upper left), and a mixture of spices (upper right). (B) Some commercial brands ready to use.

Figure 2 Dental staining and irregular cobble-stone pattern of oral mucosa.

Figure 3 Blanching of buccal mucosa in oral submucous fibrosis.

Figure 4 Redness and irregular cobble-stone appearance in oral submucous fibrosis.

Note: In such cases a biopsy is recommended to exclude initial oral squamous cell carcinoma.

Figure 5 Blanching present on soft palate of patient with oral submucous fibrosis.

Figure 6 Decreased mouth opening in patient with advanced-stage oral submucous fibrosis.

Figure 7 Advanced-stage oral submucous fibrosis.

Notes: (A) Severe decreased mouth opening and blanching seen on buccal mucosa. (B) Leukoplakia of the tongue; a biopsy is indispensable to exclude cancer of the tongue.

Figure 8 Oral squamous cell carcinoma in a patient with oral submucous fibrosis.

Table 2 Factors associated with malignant transformation of oral submucous fibrosis

Molecules	Description	Findings	References
0(6)-methylguanine-DNA	Methyltransferase DNA repair enzyme	Low levels associated with advanced oral SCC and lymph node involvement	^Citation65
Mutations of p53	Tumor suppressor gene	Degree of p53 staining increased with morphologic transformation of epithelial cells, associated with progression of oral SCC	^Citation66^–^Citation72
p16INK4alpha/p19ARF mutations	p16 regulated G1 proliferation	p53 independent pathway of tumorigenesis	^Citation68
MDM2-P2 promoter	Transcriptional target of p53	Elevated levels of MDM2 protein in dysplastic lesions and oral SCCs	^Citation72
C-jun	Protooncogene	Chronic stimulation by areca nut and arecoline leading to oral SSC	^Citation73
mtDNA mutations	Mitochondrial DNA	Contributor to the early phase of oral carcinogenesis	^Citation74
HSP70	Heat shock protein	Significant correlation of HSP70 expression with consumption of betel and tobacco; in patients with premalignant lesions median transition time (premalignancy to malignancy) was significantly shorter in HSP70 overexpressing cases; oral cancer patients with elevated levels of HSP70 showed decreased median disease-free survival time	^Citation75
HSP27	Heat shock protein	Increased in betel nut-induced oral SCC due to direct action of arecoline	^Citation76

Abbreviation: SCC, squamous cell carcinoma.

Figure 9 Histopathological picture showing initial stage of oral submucous fibrosis.

Note: Hematoxylin and eosin staining, ×10.

Figure 10 Histopathological picture showing advanced stage of oral submucous fibrosis.

Notes: (A) Hematoxylin and eosin staining, ×100. (B) Closer view (hematoxylin and eosin staining, ×400).

Table 3 Treatment of oral submucous fibrosis (controlled trials)

Treatment(s)	Outcome	References
Cessation of betel quid chewing	Common sense	No studies at all
Oxitard twice daily orally	Better than aloe vera gel three times/day	^Citation98
Aloe vera gel topical	Better than hyaluronidase + dexamethasone submucous injection	^Citation101
Triamcinolone acetonide + salvianolic acid B submucous injections	Better than triamcinolone or salvianolic acid alone	^Citation102
Isoxuprine10 mg four times/day + physiotherapy	Better than physiotherapy alone	^Citation103
Pentoxifylline 400 mg/day	Better than placebo	^Citation93
Hydrocortisone acetate/hyaluronidase versus triamcinolone acetonide/hyaluronidase	Equal efficacy	^Citation104
Physiotherapy five times/week	Better than no treatment or local injections with hyaluronidase and steroids	^Citation105
Lycopene 16 mg/day	Better than placebo	^Citation106
Immunized milk + physiotherapy	Better than physiotherapy alone	^Citation107

Table 4 Potential compounds for pharmacological treatment of oral submucous fibrosis

Compound(s)	Effect(s)	Remarks
Vitamins	Oxygen radical scavengers	In conjunction with other treatments
Flavons	Oxygen radical scavengers	In conjunction with other treatments
Pentoxifyllin, isoxuprine	Anti-inflammatory, improves microcirculation	In conjunction with other treatments
Corticosteroids	Anti-inflammatory	In early stages
TNF-α inhibitors, HMG-CoA inhibitors, ACE inhibitors, angiotensin receptor blockers	Antifibrotic	Not yet proven in OSF
N-acetyl cysteine	Anti-inflammatory, anti-oxidant	Not yet proven in OSF
Protein kinase inhibitors	Antifibrotic	Not yet proven in OSF
Immunized milk	Anti-inflammatory	Uncontrolled trials
Lactoferrin	Anti-inflammatory	Not yet proven in OSF

Abbreviations: ACE, angiotensin-converting enzyme; HMG-CoA, 3-hydroxy-3-methylglutaryl-coenzyme A; OSF, oral submucous fibrosis; TNF, tumor necrosis factor.

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