Sections

Overview

Background

In 1952, Schwartz coined the term atrophica idiopathica mucosa oris to describe an oral fibrosing disease he discovered in 5 Indian women from Kenya.^[1]Joshi subsequently coined the termed oral submucous fibrosis (OSF) for the condition in 1953.^[2]

Oral submucous fibrosis is a chronic debilitating disease of the oral cavity characterized by inflammation and progressive fibrosis of the submucosal tissues (lamina propria and deeper connective tissues). Oral submucous fibrosis results in marked rigidity and an eventual inability to open the mouth.^{[3, 4]}The buccal mucosa is the most commonly involved site, but any part of the oral cavity can be involved, even the pharynx.^[5]

The condition is well recognized for its malignant potential and is particularly associated with areca nut chewing, the main component of betel quid.^[6]Betel quid chewing is a habit practiced predominately in Southeast Asia and India that dates back for thousands of years. It is similar to tobacco chewing in westernized societies. The mixture of this quid, or chew, is a combination of the areca nut (fruit of the Areca catechu palm tree, erroneously termed betel nut) and betel leaf (from the Piper betel, a pepper shrub), tobacco, slaked lime (calcium hydroxide), and catechu (extract of the Acacia catechu tree).^[3]Lime acts to keep the active ingredient in its freebase or alkaline form, enabling it to enter the bloodstream via sublingual absorption. Arecoline, an alkaloid found in the areca nut, promotes salivation, stains saliva red, and is a stimulant.

The ingredients and nomenclature of betel quid vary by region as detailed below^{[7, 8]}:

Pan: This is freshly prepared betel quid (with or without tobacco).
Gutka (gutkha, guttkha, or guthka): This is a manufactured version of betel quid with tobacco sold as a single-use sachet. It is primarily used on the Indian subcontinent (ie, India, Pakistan, Bangladesh). Betel quid without tobacco is mostly used in Southeast Asian countries (ie, Taiwan, Myanmar, Thailand, China, Papua New Guinea, Guam).
Pan masala: This is a commercially manufactured powdered version of betel quid without tobacco used in the Indian subcontinent.
Pan Parag: It is a brand name of pan masala and gutka used in India.
Mawa (kharra): This is a crude combination of areca, tobacco, and lime.
Mainpuri tobacco: Popular in parts of northern India, Mainpuri tobacco is a mixture of areca nut, tobacco, lime, and various condiments. Depending on local preferences, sweeteners or spices (ie, cardamom, saffron, clove, anise seed, turmeric, mustard) are also added as flavorings.

In most patients with oral submucous fibrosis, areca nut was chewed alone more frequently than it was chewed in combination with pan (ie, betel leaf plus lime plus betel catechu, with or without tobacco)^[4]or had a higher areca nut content.^[9]

Pathophysiology

The pathogenesis of the disease is not well established, but the cause of oral submucous fibrosis is believed to be multifactorial. A number of factors trigger the disease process by causing a juxtaepithelial inflammatory reaction in the oral mucosa. Factors include areca nut chewing, ingestion of chilies, genetic and immunologic processes, nutritional deficiencies, and other factors.

Areca nut (betel nut) chewing

The areca nut component of betel quid plays a major role in the pathogenesis of oral submucous fibrosis.^{[10, 11, 12, 13]}In a 2004 study, a clear dose-dependent relationship was observed for both frequency and duration of chewing areca nut (without tobacco) in the development of oral submucous fibrosis.^[14]Smoking and alcohol consumption alone, habits common to areca nut chewers, have been found to have no effect in the development of oral submucous fibrosis,^[15]but their addition to areca nut chewing can be a risk for oral submucous fibrosis.^[15]Commercially freeze-dried products such as pan masala, guthka, and mawa have higher concentrations of areca nut per chew and appear to cause oral submucous fibrosis more rapidly than self-prepared conventional betel quid, which contains smaller amounts of areca nut.^[9]

Arecoline, an active alkaloid found in betel nuts, stimulates fibroblasts to increase production of collagen by 150%.^[16]In one study, arecoline was found to elevate the mRNA and protein expression of cystatin C, a nonglycosylated basic protein consistently up-regulated in a variety of fibrotic diseases, in a dose-dependent manner in persons with oral submucous fibrosis.^[17]

In 3 separate but similar studies, keratinocyte growth factor-1, insulinlike growth factor-1, and interleukin 6 expression, which have all been implicated in tissue fibrogenesis, were also significantly up-regulated in persons with oral submucous fibrosis due to areca quid chewing, and arecoline may be responsible for their enhanced expression.^{[18, 19, 20]}Further studies have shown that arecoline is an inhibitor of metalloproteinases (particularly metalloproteinase-2) and a stimulator of tissue inhibitor of metalloproteinases, thus decreasing the overall breakdown of tissue collagen.^[21]

Insertion/deletion 5A polymorphism in the promoter region of the matrix metalloproteinase-3 gene, which results in alteration of transcriptional activities, has also been found in persons with oral submucous fibrosis but not in those with oral squamous cell carcinoma.^[22]Conversely, insertion/deletion 2G polymorphism in the promoter of the matrix metalloproteinase-1 gene has been implicated in oral squamous cell carcinoma but not oral submucous fibrosis.^[23]

Flavanoid, catechin, and tannin in betel nuts cause collagen fibers to cross-link, making them less susceptible to collagenase degradation.^[24]This results in increased fibrosis by causing both increased collagen production and decreased collagen breakdown.^[4]Oral submucous fibrosis remains active even after cessation of the chewing habit, suggesting that components of the areca nut initiate oral submucous fibrosis and then affect gene expression in the fibroblasts, which then produce greater amounts of normal collagen.^[25]Chewing areca quid may also activate NF-kappaB expression, thereby stimulating collagen fibroblasts and leading to further fibrosis in persons with oral submucous fibrosis.^[26]

Areca nuts have also been shown to have a high copper content, and chewing areca nuts for 5-30 minutes significantly increases soluble copper levels in oral fluids. This increased level of soluble copper supports the hypothesis that copper acts as an initiating factor in persons with oral submucous fibrosis by stimulating fibrogenesis through up-regulation of copper-dependent lysyl oxidase activity.^{[27, 28]}Further, a significant gradual increase in serum copper levels from precancer to cancer patients has been documented,^[29]which may have a role in oral fibrosis to cancer pathogenesis.

Ingestion of chilies

The role of chili ingestion in the pathogenesis of oral submucous fibrosis is controversial. The incidence of oral submucous fibrosis is lower in Mexico and South America than in India, despite the higher dietary intake of chilies.^[30]A hypersensitivity reaction to chilies is believed to contribute to oral submucous fibrosis.^[4]One study demonstrated that the capsaicin in chilies stimulates widespread palatal fibrosis in rats,^[31]while another study failed to duplicate these results.^[32]

Genetic and immunologic processes

A genetic component is assumed to be involved in oral submucous fibrosis because of the existence of reported cases in people without a history of betel nut chewing^{[10, 33]}or chili ingestion.^[33]Patients with oral submucous fibrosis have been found to have an increased frequency of HLA-A10, HLA-B7, and HLA-DR3.^[4]

An immunologic process is believed to play a role in the pathogenesis of oral submucous fibrosis.^{[34, 35]}The increase in CD4 and cells with HLA-DR in oral submucous fibrosis tissues suggests that most lymphocytes are activated and that the number of Langerhans cells is increased. The presence of these immunocompetent cells and the high ratio of CD4 to CD8 in oral submucous fibrosis tissues suggest an ongoing cellular immune response that results in an imbalance of immunoregulation and an alteration in local tissue architecture.^[36]These reactions may be the result either of direct stimulation from exogenous antigens, such as areca alkaloids, or of changes in tissue antigenicity that lead to an autoimmune response.^[36]

Further, the major histocompatibility complex class I chain–related gene A (MICA) is expressed by keratinocytes and other epithelial cells and interacts with gamma/delta T cells localized in the submucosa. MICA has a triplet repeat (GCT) polymorphism in the transmembrane domain, resulting in 5 distinct allelic patterns. In particular, the phenotype frequency of allele A6 of MICA in subjects with oral submucous fibrosis is significantly higher and suggests a risk for oral submucous fibrosis.^[37]

Some authors have demonstrated increased levels of proinflammatory cytokines and reduced antifibrotic interferon gamma (IFN-gamma) in patients with oral submucous fibrosis, which may be central to the pathogenesis of oral submucous fibrosis.^[38]

Nutritional deficiencies

Iron deficiency anemia, vitamin B complex deficiency, and malnutrition are promoting factors that derange the repair of the inflamed oral mucosa, leading to defective healing and resultant scarring.^[4]The resulting atrophic oral mucosa is more susceptible to the effects of chilies and betel nuts.

Other significant factors

Some authors have found a high frequency of mutations in the APC gene and low expression of the wild-type TP53 tumor suppressor gene product in patients with oral submucous fibrosis, providing some explanation for the increased risk of oral squamous cell carcinoma development in patients with oral submucous fibrosis.^[10]Other studies have suggested that altered expression of retinoic acid receptor-beta may be related to the disease pathogenesis.^[39]

Etiology

The term oral submucosal fibrosis derives from oral (meaning mouth), submucosal (meaning below the mucosa of the mouth), and fibrosis (meaning hardening and scarring).^[4]Chewable agents, primarily betel nuts (Areca catechu), contain substances that irritate the oral mucosa, making it lose its elasticity. Nutritional deficiencies, ingestion of chilies, and immunologic processes may also have a role in the development of oral submucous fibrosis.^[3]See Pathophysiology.

Frequency

United States

Oral submucous fibrosis is rare in the United States and is found only in the immigrant members of the South Asian population who chew betel nuts.

International

Worldwide, estimates of oral submucous fibrosis indicate that 2.5 million people are affected, with most cases concentrated on the Indian subcontinent, especially southern India.^[3]The rate varies from 0.2-2.3% in males and 1.2-4.57% in females in Indian communities.^[4]Oral submucous fibrosis is widely prevalent in all age groups and across all socioeconomic strata in India. A sharp increase in the incidence of oral submucous fibrosis was noted after pan parag came onto the market, and the incidence continues to increase. Oral submucous fibrosis also occurs in other parts of Asia and the Pacific Islands.^[3]Migration of endemic betel quid chewers has also made oral submucous fibrosis a public health issue in many parts of the world, including the United Kingdom, South Africa, and many Southeast Asian countries.^[40]

Race

Oral submucous fibrosis occurs on the Indian subcontinent, in Indian immigrants to other countries, and among Asians and Pacific Islanders as a result of the traditional use of betel quid endemic to these areas.^[3]

Sex

The male-to-female ratio of oral submucous fibrosis varies by region, but females tend to predominate. In a study from Durban, South Africa, a distinct female predominance was demonstrated, with a male-to-female ratio of 1:13.^[41]This was later confirmed by others, with a male-to-female ratio of 1:7.^[42]In addition, a female predominance in areca nut chewing was also noted in this region. Studies in Pakistan reported a male-to-female ratio of 1:2.3.^[4]

Conversely, a case-control study of 185 subjects in Chennai, South India revealed a male-to-female ratio 9.9:1.^[15]In Patna, Bihar (also in India), the male-to-female ratio was 2.7:1.^[43]With the onset of new commercial betel quid preparations, trends in sex predominance and age of occurrence may shift.

Age

The age range of patients with oral submucous fibrosis is wide and regional; it is even prevalent among teenagers in India. In a study performed in Saipan, 8.8% of teenagers with a mean age of 16.3 years (± 1.5 y) were found to have oral submucous fibrosis.^[44]Generally, patient age ranges from 11-60 years^{[4, 43]}; most patients are aged 45-54 years and chew betel nuts 5 times per day.^[4]

Prognosis

Oral submucous fibrosis has a high rate of morbidity because is causes a progressive inability to open the mouth, resulting in difficulty eating and consequent nutritional deficiencies. Oral submucous fibrosis also has a significant mortality rate because of it can transform into oral cancer, particularly squamous cell carcinoma, at a rate of 7.6%.^[4]

No treatment is effective in patients with oral submucous fibrosis, and the condition is irreversible.^[45]Reports claim improvement of the condition if the habit is discontinued following diagnosis at an early stage.^[46]

Patients with oral submucous fibrosis have an increased risk of developing oral cancer. The malignant potential and the origin of cancer are attributed to the generalized epithelial atrophy associated with oral submucous fibrosis.^[45]Tobacco is the component of the quid believed to be most associated with cancer development. However, the carcinogenic property of the areca nut was discovered after noticing that cancer occurred in patients who chewed the nut without tobacco.^[25]In vitro, betel nut extracts increase the rate of cell division, reduce cell cycle time, induce DNA strand breaks, and induce unscheduled DNA synthesis.^[47]Whether the use of tobacco in addition to areca nuts is responsible for the increased risk of oral cancer is controversial because evidence is conflicting.^{[48, 49]}

Patient Education

Instruct patients regarding the importance of discontinuing the habit of chewing betel quid.

Inform patients that eliminating tobacco from the quid product may reduce the risk of oral cancer.

Instruct patients to avoid spicy foodstuffs.

Instruct patients to eat a complete and healthy diet to avoid malnutrition.

Instruct patients regarding maintaining proper oral hygiene and scheduling regular oral examinations.

Intervention studies and public health campaigns against oral habits linked to oral submucous fibrosis may be the best way of controlling the disease at the community level. Educate the community regarding the local adverse effects of chewable agents, which although not inhaled, are still not harmless.

For patient education resources, visit the Cancer Center. In addition, see the patient education article Cancer of the Mouth and Throat.

Clinical Presentation

Schwartz J. Atrophia Idiopathica Mucosae Oris. London: Demonstrated at the 11th Int Dent Congress; 1952.
Joshi SG. Fibrosis of the palate and pillars. Indian J Otolaryngol. 1953. 4:1:
Cox SC, Walker DM. Oral submucous fibrosis. A review. Aust Dent J. 1996 Oct. 41(5):294-9. [QxMD MEDLINE Link].
Aziz SR. Oral submucous fibrosis: an unusual disease. J N J Dent Assoc. 1997 Spring. 68(2):17-9. [QxMD MEDLINE Link].
Paissat DK. Oral submucous fibrosis. Int J Oral Surg. 1981 Oct. 10(5):307-12. [QxMD MEDLINE Link].
Chattopadhyay A, Ray JG. Molecular Pathology of Malignant Transformation of Oral Submucous Fibrosis. J Environ Pathol Toxicol Oncol. 2016. 35 (3):193-205. [QxMD MEDLINE Link].
Centers for Disease Control and Prevention. Fact Sheet. Betel Quid with Tobacco (Gutka). Centers for Disease Control and Prevention. Available at http://www.cdc.gov/tobacco/data_statistics/fact_sheets/smokeless/betel_quid.htm. Accessed: February 2007.
Gupta PC. UICC Tobacco Control Fact Sheet No. 17: Areca Nut. International Union Against Cancer. Available at http://www.globalink.org/tobacco/fact_sheets/17fact.htm. Accessed: February 1996.
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link]. [Full Text].
Pant I, Rao SG, Kondaiah P. Role of areca nut induced JNK/ATF2/Jun axis in the activation of TGF-β pathway in precancerous Oral Submucous Fibrosis. Sci Rep. 2016 Oct 6. 6:34314. [QxMD MEDLINE Link].
Hernandez BY, Zhu X, Goodman MT, Gatewood R, Mendiola P, Quinata K, et al. Betel nut chewing, oral premalignant lesions, and the oral microbiome. PLoS One. 2017. 12 (2):e0172196. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
Hamner JE 3rd, Looney PD, Chused TM. Submucous fibrosis. Oral Surg Oral Med Oral Pathol. 1974 Mar. 37(3):412-21. [QxMD MEDLINE Link].
Seedat HA, van Wyk CW. Submucous fibrosis in non-betel nut chewing subjects. J Biol Buccale. 1988 Mar. 16(1):3-6. [QxMD MEDLINE Link].
Canniff JP, Harvey W, Harris M. Oral submucous fibrosis: its pathogenesis and management. Br Dent J. 1986 Jun 21. 160(12):429-34. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link]. [Full Text].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
Seedat HA, van Wyk CW. Betel-nut chewing and submucous fibrosis in Durban. S Afr Med J. 1988 Dec 3. 74(11):568-71. [QxMD MEDLINE Link].
VanWyk CW. Oral submucous fibrosis. The South African experience. Indian J Dent Res. 1997 Apr-Jun. 8(2):39-45. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
Anil S, Beena VT. Oral submucous fibrosis in a 12-year-old girl: case report. Pediatr Dent. 1993 Mar-Apr. 15(2):120-2. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
Pindborg JJ. Oral submucous fibrosis: a review. Ann Acad Med Singapore. 1989 Sep. 18(5):603-7. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
Eipe N. The chewing of betel quid and oral submucous fibrosis and anesthesia. Anesth Analg. 2005 Apr. 100(4):1210-3. [QxMD MEDLINE Link].
Ahmed A, Amjad M. Localized morphoea associated with oral submucous fibrosis. J Coll Physicians Surg Pak. 2006 Feb. 16(2):141-2. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
Agarwal RK, Hebbale M, Mhapuskar A, Tepan M. Correlation of ultrasonographic measurements, histopathological grading, and clinical staging in oral submucous fibrosis. Indian J Dent Res. 2017 Sep-Oct. 28 (5):476-481. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link]. [Full Text].
Pindborg JJ. Oral precancer. Barnes L, ed. Surgical Pathology of the Head and Neck. New York, NY: Marcel Dekker; 1995. 279-331.
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
Kakar PK, Puri RK, Venkatachalam VP. Oral submucous fibrosis--treatment with hyalase. J Laryngol Otol. 1985 Jan. 99(1):57-9. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
Liu J, Chen F, Wei Z, Qiu M, Li Z, Dan H, et al. Evaluating the efficacy of pentoxifylline in the treatment of oral submucous fibrosis: A meta-analysis. Oral Dis. 2017 Jul 24. [QxMD MEDLINE Link].
Hosein M. Oral cancer in Pakistan. The problem and can we reduce it?. Oral Oncology. Kluwer Academic: 1994.
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link]. [Full Text].
Kale S, Srivastava N, Bagga V, Shetty A. Effectiveness of Long Term Supervised and Assisted Physiotherapy in Postsurgery Oral Submucous Fibrosis Patients. Case Rep Dent. 2016. 2016:6081905. [QxMD MEDLINE Link].
Borle RM, Borle SR. Management of oral submucous fibrosis: a conservative approach. J Oral Maxillofac Surg. 1991 Aug. 49(8):788-91. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
Shah PH, Venkatesh R, More CB, Vassandacoumara V. Comparison of Therapeutic Efficacy of Placental Extract with Dexamethasone and Hyaluronic Acid with Dexamethasone for Oral Submucous Fibrosis - A Retrospective Analysis. J Clin Diagn Res. 2016 Oct. 10 (10):ZC63-ZC66. [QxMD MEDLINE Link].

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Author

Nektarios I Lountzis, MD Dermatologist/Dermatopathologist, Dermatology Partners

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

Disclosure: Nothing to disclose.

Coauthor(s)

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.

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.

Specialty Editor Board

David F Butler, MD Former 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: Alpha Omega Alpha, American Academy of Dermatology, Association of Military Dermatologists, Phi Beta Kappa, Texas Dermatological Society

Disclosure: Nothing to disclose.

Drore Eisen, MD, DDS Consulting Staff, Dermatology of Southwest Ohio

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: Received income in an amount equal to or greater than $250 from: Elsevier; WebMD<br/>Served as a speaker for various universities, dermatology societies, and dermatology departments.

Oral Submucous Fibrosis