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Oral Submucous Fibrosis Workup

  • Author: Nektarios I Lountzis, MD; Chief Editor: William D James, MD  more...
Updated: Aug 11, 2014

Laboratory Studies

See the list below:

  • No specific laboratory tests are available for oral submucous fibrosis, and abnormalities may be related to secondary nutritional deficiencies. Some oral submucous fibrosis studies have reported the following laboratory findings:
    • Decreased hemoglobin levels
    • Decreased iron levels
    • Decreased protein levels
    • Increased erythrocyte sedimentation rate
    • Decreased vitamin B complex levels

Other Tests

See the list below:

  • Cytologic smears may be performed.
  • A neural network–based oral precancer stage detection method has been proposed. [37] This new technique uses wavelet coefficients from transmission electron micrography images of subepithelial fibrillar collagen in healthy oral submucosa and in oral submucous fibrosis tissues. These wavelet coefficients are used to choose the feature vector, which, in turn, can be used to train an artificial neural network. This trained network is able to classify normal and oral precancer stages (less advanced and advanced) after obtaining the image as an input. This technology is not readily available but could theoretically be used as an adjunct to hematoxylin and eosin histologic evaluations.


See the list below:

  • Currently, oral biopsy for hematoxylin and eosin provides the most definitive diagnosis and is crucial because of the association of oral submucous fibrosis with oral cancer. [4]
  • Some authorities have reported benefit with immunohistochemical techniques such as Masson trichrome staining when pathology involved muscle. [44] Alteration of cytokeratin expression, as is seen in leukoplakia and oral cancer, has also been noted in oral submucous fibrosis. Increased intensity of staining for pancytokeratin and high molecular weight cytokeratin, aberrant expression of cytokeratin 8, and decreased expression of cytokeratins 5 and 14 suggest their potential as surrogate markers for malignant transformation. [45]

Histologic Findings

Histologic findings vary according to the stage of the disease.

Very early stage

Fine fibrillar collagen, marked edema, large fibroblasts, dilated and congested blood vessels, and inflammatory infiltrates (primarily polymorphonuclear leukocytes and eosinophils) are found.

Early stage

Early hyalinization is characterized by thickened collagen bundles, moderate numbers of fibroblasts, and inflammatory cells (primarily lymphocytes, eosinophils, and plasma cells).[46]

Moderately advanced and advanced stages

Dense bundles and sheets of collagen, thick bands of subepithelial hyalinization extending into the submucosal tissues (replacing fat or fibrovascular tissue), decreased vascularity, no edema, and inflammatory cells (lymphocytes and plasma cells) are found.[46]

Oral submucous fibrosis is generally characterized by diffuse hyalinization of the subepithelial stroma with pigment incontinence from the overlying epithelial melanin.[47] Other histologic findings include an atrophic epithelium and intercellular edema, with or without hyperkeratosis, parakeratosis, or orthokeratosis; epithelial dysplasia (25% of patients who underwent biopsy); squamous cell carcinoma histologically identical to typical squamous cell carcinomas; chronic inflammation and fibrosis in the minor salivary glands in the area of quid placement; and atrophy of the underlying muscle.[31]

Ultrastructural changes in oral submucous fibrosis include an increase in collagen type I; however, fibrils retain the normal structure.[48]



In addition to the above clinical staging, in 1995 Khanna and Andrade[43] developed a group classification system for the surgical management of trismus.

  • Group I: This is the earliest stage and is not associated with mouth opening limitations. It refers to patients with an interincisal distance of greater than 35 mm.
  • Group II: This refers to patients with an interincisal distance of 26-35 mm.
  • Group III: These are moderately advanced cases. This stage refers to patients with an interincisal distance of 15-26 mm. Fibrotic bands are visible at the soft palate, and pterygomandibular raphe and anterior pillars of fauces are present.
  • Group IVA: Trismus is severe, with an interincisal distance of less than 15 mm and extensive fibrosis of all the oral mucosa.
  • Group IVB: Disease is most advanced, with premalignant and malignant changes throughout the mucosa.
Contributor Information and Disclosures

Nektarios I Lountzis, MD Consulting Staff, Advanced Dermatology Associates, Ltd, Lehigh Valley Health Network

Nektarios I Lountzis, MD is a member of the following medical societies: American Academy of Dermatology, American Society of Dermatopathology, American Contact Dermatitis Society, International Society of Dermatopathology

Disclosure: Nothing to disclose.


Nada Macaron, MD Consultant Pathologist, Institute of Pathology and Laboratory Medicine, Sheikh Khalifa Medical city, UAE

Nada Macaron, MD is a member of the following medical societies: College of American Pathologists, United States and Canadian Academy of Pathology

Disclosure: Nothing to disclose.

Amy Howard, MD Fellow, Department of Dermatopathology, Emory University

Disclosure: Nothing to disclose.

Tammie Ferringer, MD Dermatopathology Section Head, Dermatopathology Fellowship Director, Departments of Dermatology and Pathology, Geisinger Medical Center

Tammie Ferringer, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Society of Dermatopathology, International Society of Dermatopathology

Disclosure: Nothing to disclose.

Specialty Editor Board

David F Butler, MD Section Chief of Dermatology, Central Texas Veterans Healthcare System; Professor of Dermatology, Texas A&M University College of Medicine; Founding Chair, Department of Dermatology, Scott and White Clinic

David F Butler, MD is a member of the following medical societies: American Medical Association, Alpha Omega Alpha, Association of Military Dermatologists, American Academy of Dermatology, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Phi Beta Kappa

Disclosure: Nothing to disclose.

Drore Eisen, MD, DDS Consulting Staff, Department of Dermatology, Dermatology Research Associates of Cincinnati

Drore Eisen, MD, DDS is a member of the following medical societies: American Academy of Dermatology, American Academy of Oral Medicine, American Dental Association

Disclosure: Nothing to disclose.

Chief Editor

William D James, MD Paul R Gross Professor of Dermatology, Vice-Chairman, Residency Program Director, Department of Dermatology, University of Pennsylvania School of Medicine

William D James, MD is a member of the following medical societies: American Academy of Dermatology, Society for Investigative Dermatology

Disclosure: Nothing to disclose.

  1. Schwartz J. Atrophia Idiopathica Mucosae Oris. London: Demonstrated at the 11th Int Dent Congress; 1952.

  2. Joshi SG. Fibrosis of the palate and pillars. Indian J Otolaryngol. 1953. 4:1:

  3. Cox SC, Walker DM. Oral submucous fibrosis. A review. Aust Dent J. 1996 Oct. 41(5):294-9. [Medline].

  4. Aziz SR. Oral submucous fibrosis: an unusual disease. J N J Dent Assoc. 1997 Spring. 68(2):17-9. [Medline].

  5. Paissat DK. Oral submucous fibrosis. Int J Oral Surg. 1981 Oct. 10(5):307-12. [Medline].

  6. Centers for Disease Control and Prevention. Fact Sheet. Betel Quid with Tobacco (Gutka). Centers for Disease Control and Prevention. Available at Accessed: February 2007.

  7. Gupta PC. UICC Tobacco Control Fact Sheet No. 17: Areca Nut. International Union Against Cancer. Available at Accessed: February 1996.

  8. Tilakaratne WM, Klinikowski MF, Saku T, Peters TJ, Warnakulasuriya S. Oral submucous fibrosis: review on aetiology and pathogenesis. Oral Oncol. 2006 Jul. 42(6):561-8. [Medline].

  9. Liao PH, Lee TL, Yang LC, Yang SH, Chen SL, Chou MY. Adenomatous polyposis coli gene mutation and decreased wild-type p53 protein expression in oral submucous fibrosis: a preliminary investigation. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2001 Aug. 92(2):202-7. [Medline].

  10. Chang MC, Chen YJ, Chang HH, Chan CP, Yeh CY, Wang YL, et al. Areca Nut Components Affect COX-2, Cyclin B1/cdc25C and Keratin Expression, PGE2 Production in Keratinocyte Is Related to Reactive Oxygen Species, CYP1A1, Src, EGFR and Ras Signaling. PLoS One. 2014. 9(7):e101959. [Medline]. [Full Text].

  11. Jacob BJ, Straif K, Thomas G, et al. Betel quid without tobacco as a risk factor for oral precancers. Oral Oncol. 2004 Aug. 40(7):697-704. [Medline].

  12. Ranganathan K, Devi MU, Joshua E, Kirankumar K, Saraswathi TR. Oral submucous fibrosis: a case-control study in Chennai, South India. J Oral Pathol Med. 2004 May. 33(5):274-7. [Medline].

  13. Canniff JP, Harvey W. The aetiology of oral submucous fibrosis: the stimulation of collagen synthesis by extracts of areca nut. Int J Oral Surg. 1981. 10:163-7. [Medline].

  14. Chung-Hung T, Shun-Fa Y, Yu-Chao C. The upregulation of cystatin C in oral submucous fibrosis. Oral Oncol. 2007 Aug. 43(7):680-5. [Medline].

  15. Tsai CH, Yang SF, Chen YJ, Chou MY, Chang YC. Raised keratinocyte growth factor-1 expression in oral submucous fibrosis in vivo and upregulated by arecoline in human buccal mucosal fibroblasts in vitro. J Oral Pathol Med. 2005 Feb. 34(2):100-5. [Medline].

  16. Tsai CH, Yang SF, Chen YJ, Chu SC, Hsieh YS, Chang YC. Regulation of interleukin-6 expression by arecoline in human buccal mucosal fibroblasts is related to intracellular glutathione levels. Oral Dis. 2004 Nov. 10(6):360-4. [Medline].

  17. Tsai CH, Yang SF, Chen YJ, Chou MY, Chang YC. The upregulation of insulin-like growth factor-1 in oral submucous fibrosis. Oral Oncol. 2005 Oct. 41(9):940-6. [Medline].

  18. Chang YC, Yang SF, Tai KW, Chou MY, Hsieh YS. Increased tissue inhibitor of metalloproteinase-1 expression and inhibition of gelatinase A activity in buccal mucosal fibroblasts by arecoline as possible mechanisms for oral submucous fibrosis. Oral Oncol. 2002 Feb. 38(2):195-200. [Medline].

  19. Tu HF, Liu CJ, Chang CS, et al. The functional (-1171 5A-->6A) polymorphisms of matrix metalloproteinase 3 gene as a risk factor for oral submucous fibrosis among male areca users. J Oral Pathol Med. 2006 Feb. 35(2):99-103. [Medline].

  20. Lin SC, Chung MY, Huang JW, Shieh TM, Liu CJ, Chang KW. Correlation between functional genotypes in the matrix metalloproteinases-1 promoter and risk of oral squamous cell carcinomas. J Oral Pathol Med. 2004 Jul. 33(6):323-6. [Medline].

  21. Harvey W, Scutt A, Meghji S, Canniff JP. Stimulation of human buccal mucosa fibroblasts in vitro by betel-nut alkaloids. Arch Oral Biol. 1986. 31(1):45-9. [Medline].

  22. van Wyk CW, Stander I, Padayachee A, Grobler-Rabie AF. The areca nut chewing habit and oral squamous cell carcinoma in South African Indians. A retrospective study. S Afr Med J. 1993 Jun. 83(6):425-9. [Medline].

  23. Ni WF, Tsai CH, Yang SF, Chang YC. Elevated expression of NF-kappaB in oral submucous fibrosis--evidence for NF-kappaB induction by safrole in human buccal mucosal fibroblasts. Oral Oncol. 2007 Jul. 43(6):557-62. [Medline].

  24. 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 Jul. 29(6):241-8. [Medline].

  25. Mohammed F, Manohar V, Jose M, Fairozekhan Thapasum A, Mohamed S, Halima Shamaz B, et al. Estimation of copper in saliva and areca nut products and its correlation with histological grades of oral submucous fibrosis. J Oral Pathol Med. 2014 Jul 22. [Medline].

  26. Khanna SS, Karjodkar FR. Circulating immune complexes and trace elements (Copper, Iron and Selenium) as markers in oral precancer and cancer : a randomised, controlled clinical trial. Head Face Med. 2006 Oct 16. 2:33. [Medline].

  27. Pillai R, Balaram P, Reddiar KS. Pathogenesis of oral submucous fibrosis. Relationship to risk factors associated with oral cancer. Cancer. 1992 Apr 15. 69(8):2011-20. [Medline].

  28. Sirsat SM, Khanolkar VR. Submucous fibrosis of the palate in diet-preconditioned Wistar rats. Induction by local painting of capsaicin--an optical and electron microscopic study. Arch Pathol. 1960 Aug. 70:171-9. [Medline].

  29. Hamner JE 3rd, Looney PD, Chused TM. Submucous fibrosis. Oral Surg Oral Med Oral Pathol. 1974 Mar. 37(3):412-21. [Medline].

  30. Seedat HA, van Wyk CW. Submucous fibrosis in non-betel nut chewing subjects. J Biol Buccale. 1988 Mar. 16(1):3-6. [Medline].

  31. Canniff JP, Harvey W, Harris M. Oral submucous fibrosis: its pathogenesis and management. Br Dent J. 1986 Jun 21. 160(12):429-34. [Medline].

  32. Rajendran R, Deepthi K, Nooh N, Anil S. a4ß1 integrin-dependent cell sorting dictates T-cell recruitment in oral submucous fibrosis. J Oral Maxillofac Pathol. 2011 Sep. 15(3):272-7. [Medline]. [Full Text].

  33. Haque MF, Harris M, Meghji S, Speight PM. An immunohistochemical study of oral submucous fibrosis. J Oral Pathol Med. 1997 Feb. 26(2):75-82. [Medline].

  34. Liu CJ, Lee YJ, Chang KW, Shih YN, Liu HF, Dang CW. Polymorphism of the MICA gene and risk for oral submucous fibrosis. J Oral Pathol Med. 2004 Jan. 33(1):1-6. [Medline].

  35. Haque MF, Meghji S, Khitab U, Harris M. Oral submucous fibrosis patients have altered levels of cytokine production. J Oral Pathol Med. 2000 Mar. 29(3):123-8. [Medline].

  36. Kaur J, Chakravarti N, Mathur M, Srivastava A, Ralhan R. Alterations in expression of retinoid receptor beta and p53 in oral submucous fibrosis. Oral Dis. 2004 Jul. 10(4):201-6. [Medline].

  37. Paul RR, Mukherjee A, Dutta PK, et al. A novel wavelet neural network based pathological stage detection technique for an oral precancerous condition. J Clin Pathol. 2005 Sep. 58(9):932-8. [Medline].

  38. Seedat HA, van Wyk CW. Betel-nut chewing and submucous fibrosis in Durban. S Afr Med J. 1988 Dec 3. 74(11):568-71. [Medline].

  39. VanWyk CW. Oral submucous fibrosis. The South African experience. Indian J Dent Res. 1997 Apr-Jun. 8(2):39-45. [Medline].

  40. Ahmad MS, Ali SA, Ali AS, Chaubey KK. Epidemiological and etiological study of oral submucous fibrosis among gutkha chewers of Patna, Bihar, India. J Indian Soc Pedod Prev Dent. 2006 Jun. 24(2):84-9. [Medline].

  41. Oakley E, Demaine L, Warnakulasuriya S. Areca (betel) nut chewing habit among high-school children in the Commonwealth of the Northern Mariana Islands (Micronesia). Bull World Health Organ. 2005 Sep. 83(9):656-60. [Medline].

  42. Pindborg JJ. Oral submucous fibrosis: a review. Ann Acad Med Singapore. 1989 Sep. 18(5):603-7. [Medline].

  43. Ahmed A, Amjad M. Localized morphoea associated with oral submucous fibrosis. J Coll Physicians Surg Pak. 2006 Feb. 16(2):141-2. [Medline].

  44. Rooban T, Saraswathi TR, Al Zainab FH, Devi U, Eligabeth J, Ranganathan K. A light microscopic study of fibrosis involving muscle in oral submucous fibrosis. Indian J Dent Res. 2005 Oct-Dec. 16(4):131-4. [Medline].

  45. Ranganathan K, Kavitha R, Sawant SS, Vaidya MM. Cytokeratin expression in oral submucous fibrosis--an immunohistochemical study. J Oral Pathol Med. 2006 Jan. 35(1):25-32. [Medline].

  46. Kadani M, B N V S S, B M, K M P, Hugar D, Allad U, et al. Evaluation of plasma fibrinogen degradation products and total serum protein concentration in oral submucous fibrosis. J Clin Diagn Res. 2014 May. 8(5):ZC54-7. [Medline]. [Full Text].

  47. Pindborg JJ. Oral precancer. Barnes L, ed. Surgical Pathology of the Head and Neck. New York, NY: Marcel Dekker; 1995. 279-331.

  48. van Wyk CW, Seedat HA, Phillips VM. Collagen in submucous fibrosis: an electron-microscopic study. J Oral Pathol Med. 1990 Apr. 19(4):182-7. [Medline].

  49. Sur TK, Biswas TK, Ali L, Mukherjee B. Anti-inflammatory and anti-platelet aggregation activity of human placental extract. Acta Pharmacol Sin. 2003 Feb. 24(2):187-92. [Medline].

  50. Anil S, Beena VT. Oral submucous fibrosis in a 12-year-old girl: case report. Pediatr Dent. 1993 Mar-Apr. 15(2):120-2. [Medline].

  51. Kakar PK, Puri RK, Venkatachalam VP. Oral submucous fibrosis--treatment with hyalase. J Laryngol Otol. 1985 Jan. 99(1):57-9. [Medline].

  52. Haque MF, Meghji S, Nazir R, Harris M. Interferon gamma (IFN-gamma) may reverse oral submucous fibrosis. J Oral Pathol Med. 2001 Jan. 30(1):12-21. [Medline].

  53. 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 Feb. 103(2):207-13. [Medline].

  54. Rajendran R, Rani V, Shaikh S. Pentoxifylline therapy: a new adjunct in the treatment of oral submucous fibrosis. Indian J Dent Res. 2006 Oct-Dec. 17(4):190-8. [Medline].

  55. Hosein M. Oral cancer in Pakistan. The problem and can we reduce it?. Oral Oncology. Kluwer Academic: 1994.

  56. Nayak DR, Mahesh SG, Aggarwal D, Pavithran P, Pujary K, Pillai S. Role of KTP-532 laser in management of oral submucous fibrosis. J Laryngol Otol. 2008 Oct 10. 1-4. [Medline].

  57. Chaudhry Z, Gupta SR, Oberoi SS. The Efficacy of ErCr:YSGG Laser Fibrotomy in Management of Moderate Oral Submucous Fibrosis: A Preliminary Study. J Maxillofac Oral Surg. 2014 Sep. 13(3):286-94. [Medline]. [Full Text].

  58. Chole RH, Gondivkar SM, Gadbail AR, Balsaraf S, Chaudhary S, Dhore SV, et al. Review of drug treatment of oral submucous fibrosis. Oral Oncol. 2011 Dec 27. [Medline].

  59. Borle RM, Borle SR. Management of oral submucous fibrosis: a conservative approach. J Oral Maxillofac Surg. 1991 Aug. 49(8):788-91. [Medline].

  60. Gupta SC, Khanna S, Singh M, Singh PA. Histological changes to palatal and paratubal muscles in oral submucous fibrosis. J Laryngol Otol. 2000 Dec. 114(12):947-50. [Medline].

  61. Eipe N. The chewing of betel quid and oral submucous fibrosis and anesthesia. Anesth Analg. 2005 Apr. 100(4):1210-3. [Medline].

  62. 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 Dec. 13(6):340-1. [Medline].

  63. Jeng JH, Kuo ML, Hahn LJ, Kuo MY. Genotoxic and non-genotoxic effects of betel quid ingredients on oral mucosal fibroblasts in vitro. J Dent Res. 1994 May. 73(5):1043-9. [Medline].

  64. Maher R, Lee AJ, Warnakulasuriya KA, Lewis JA, Johnson NW. Role of areca nut in the causation of oral submucous fibrosis: a case-control study in Pakistan. J Oral Pathol Med. 1994 Feb. 23(2):65-9. [Medline].

  65. Mehrotra D, Agarwal GG, Kumar S, Shukla A, Asthana A. Development and Validation of a Questionnaire to Evaluate Association of Tobacco Abuse With Oral Submucous Fibrosis. Asia Pac J Public Health. 2011 Dec 22. [Medline].

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