口腔黏膜下纖維化症，是眾所週知的口腔癌前病變，本研究的目的在於探討台灣地區口腔黏膜下纖維化症惡性轉化成口腔癌的情形。本篇文章透過全民健康保險研究資料庫，選取出被診斷為口腔黏膜下纖維化症的實驗組別，剩下不曾被診斷出纖維化的群體，再根據年紀、性別及指標日期配對出對照組別，比較兩個組別之間的差異性。同時將口腔白斑列入分析，評估是否造成口腔黏膜下纖維化症惡性轉化協同效果。結果顯示，在778個纖維化症患者中有71人 ( 9.13% ) 觀察到惡性轉化成口腔癌。經過校正後，發現纖維化症的組別中，惡性轉化的風險比率為對照組別的29.26倍 ( 95%信賴區間為20.55-41.67 )。而同時罹患口腔白斑與口腔黏膜下纖維化症的患者，有更高的惡性轉化風險( 52.46倍 ; 95%信賴區間為 34.88-78.91 )。存活分析 ( The Kaplan-Meier plot ) 的結果顯示出，在觀察的期間，兩個組別之間有顯著性差異 ( log-rank test, p<0.001 )。平均發生惡性轉化的時間如下：非纖維化症組別為5.1年、纖維化症組別為2.7年、同時罹患口腔白斑與纖維化症組別為2.2年。綜合以上結果我們發現，台灣地區的口腔黏膜下纖維化症患者比起非纖維化症患者來說，有較高的風險發生惡性轉化成口腔癌。同時口腔白斑可能會提高黏膜下纖維化症患者發生惡性轉化的風險。

Background : Oral submucous fiﾞbrosis ( OSF ) is one of the well-recognized oral potentially malignant disorders. In this study, we investigated the malignant transformation of OSF in a Taiwanese population. Methods : A retrospective cohort study was analyzed from Taiwan’s National Health Insurance Research Database.
A comparison cohort was randomly frequency matched with the OSF cohort according to age, sex, and index year. Oral leukoplakia ( OL ) was further stratifiﾞed to evaluate for the possible synergistic effects of OSF-associated malignant transformation. Results : In this cohort, 71 ( 9.13% ) of 778 cases of OSF were observed to transform into oral cancer. The malignant transformation rate was
29.26-fold in the OSF cohort than in the comparison cohort after adjustment ( 95% confiﾞdence intervals 20.55-41.67 ). To further stratify with OL, OSF with OL( 52.46%; 95% confiﾞdence intervals 34.88-78.91 ) had higher risk of malignant transformation rate than OSF alone ( 29.84%; 95% confiﾞdence intervals 20.99-42.42 ). The Kaplan-Meier plot revealed the rate free of malignant transformation was signifiﾞcant over the 13-year follow-up period ( log-rank test, P<.001 ). The mean duration of malignant transformation was 5.1, 2.7, and 2.2 years for non-OSF, OSF alone, and OSF with OL, respectively. Conclusion : Oral submucous fiﾞbrosis patients exhibited a signifiﾞcantly higher risk of malignant transformation
than those without OSF. OL could enhance malignant transformation in patients with OSF.

中⽂文摘要...........................................................................................1
英⽂文摘要...........................................................................................2
第一章緒論...........................................................................................3
第一節口腔黏膜下纖維化症的介紹.......................................................4
1.1 ⼝腔黏膜下纖維化症的流⾏行病學.................................................4
1.2 檳榔的⾷食⽤用習慣及流⾏行病學.................................................6
1.3 口腔黏膜下纖維化症的組織學特徵.................................................7
1.4 檳榔的成份.....................................................................................9
1.5 口腔黏膜下纖維化症的治療⽅方法...............................................13
1.6 口腔黏膜下纖維化症的基因多形性...............................................14
第二節口腔黏膜下纖維化症的惡性傾向..............................................15
2.1 口腔潛在惡性疾病........................................................................15
2.2 口腔黏膜下纖維化症惡性轉化的機制............................................17
第三節其他⼝口腔潛在惡性疾病.........................................................25
3.1 口腔白斑......................................................................................25
3.2 口腔扁平苔蘚...............................................................................28
第四節口腔癌.....................................................................................32
第五節台灣全民健康保險研究資料庫..................................................35
5.1 醫療保險系統介紹........................................................................35
5.2 全民健康保險研究資料庫.............................................................38
第六節研究動機.................................................................................41
第⼆章實驗設計及⽅方法...................................................................42
第⼀節資料來源.................................................................................42
第⼆節研究對象.................................................................................43
第三節觀察終點..................................................................................45
第四節統計方法及資料分析................................................................46
第三章結果.........................................................................................47
第四章討論.........................................................................................50
第五章結論.........................................................................................56
第六章圖表說明..................................................................................58
第七章參考文獻.......................................,,,........................................69
第八章附錄.........................................................................................77

Angadi PV, Rao S. Management of oral submucous fiﾞbrosis: an overview. Oral
Maxillofac Surg 2010;14:133-142.
Arakeri G, Brennan PA. Oral submucous fiﾞbrosis: an overview of the aetiology,
pathogenesis, classifiﾞcation, and principles of management. British Journal of Oral
and Maxillofacial Surgery 2013;51(7):587-593.
Byakodi R, Shipurkar A, et al.. Prevalence of oral soft tissue lesions in Sangli, India. J
Community Health 2011;36:756-759.
Charlson ME, Pompei P,et al.. A new method of classifying prognostic comorbidity
in longitudinal studies: development and validation. J Chronic Dis 1987;40:373-383.
Chang YC, Hu CC, et al.. Synergistic effects of nicotine on arecoline‐induced
cytotoxicity in human buccal mucosal fiﾞbroblasts. Journal of oral pathology &
medicine 2001;30(8):458-464.
Choudhury Y, Sharan RN. Altered BRCA1 and BRCA2 responses and mutation of
BRCA1 gene in mice exposed chronically and transgenerationally to aqueous extract
of betel nut (AEBN). Environ Toxicol Pharmacol 2011;31:57-69.
Ekanayaka RP, Tilakaratne WM. Oral submucous fiﾞbrosis: review on mechanisms
of malignant transformation. Oral surgery, oral medicine, oral pathology and oral
radiology 2016;122(2):192-199.
Gupta PC, Warnakulasuriya S. Global epidemiology of areca nut usage. Addict Biol 2002;7:77-83.

Haque MF, Meghji S, et al.. Oral submucous fibrosis patients have altered levels of cytokine production. Journal of oral pathology & medicine 2000;29(3):123-128.

Hazarey VK, Erlewad DM, et al.. Oral sub mucous fibrosis: a study of 1000 cases from central India. J Oral Pathol Med 2007;36:12-17.

Hsue SS, Wang WC, et al.. Malignant transformation in 1458 patients with potentially malignant oral mucosal disorders: a follow-up study based in a Taiwanese hospital. J Oral Pathol Med 2007;36:25-29.

Huang S, Ling T, et al.. Experimental study on aqueous areca nut extracts inducing oral submucous fibrosis in rats. II. Effect of mast cells on collagen metabolism. Hua Xi Kou Qiang Yi Xue Za Zhi 1997;15:94-96.

Ji WT, Yang SR, et al.. Arecoline downregulates level of p21 and p27 through the reactive oxygen species/mTOR complex 1 pathway and may contribute to oral squamous cell carcinoma. Cancer Sci 2012;103:1221-1229.

Khanna JN, Andrade NN. Oral submucous fibrosis: a new concept insurgical management. Report of 100 cases. Int J Oral Maxillofac Surg 1995;24:433-439.

Khanna S, Udas AC, et al.. Trace elements (copper, zinc, selenium and molybdenum) as markers in oral sub mucous fibrosis and oral squamous cell carcinoma. Journal of Trace Elements in Medicine and Biology 2013;27(4)307-311.
Ko YC, Chiang TA, et al.. Prevalence of betel quid chewing habit in Taiwan and related sociodemographic factors. J Oral Pathol Med 1992;21:261-264.

Lee PH, Chang MC, et al.. Prolonged exposure to arecoline arrested human KB epithelial cell growth: regulatory mechanisms of cell cycle and apoptosis. Toxicology 2006;220:81-89.

Li S, Lee YC, et al.. Oral lesions, chronic diseases and the risk of head and neck cancer. Oral Oncol 2015;51:1082-1087.

Lian IB, Tseng YT, et al.. Progression of precancerous lesions to oral cancer: results based on the Taiwan National Health Insurance Database. Oral Oncol 2013;49:427-430.

Mehanna HM, Rattay T, et al.. Treatment and follow-up of oral dysplasia – a systematic review and meta-analysis. Head Neck 2009;31:1600-1609.

Mignogna MD, Lo Muzio L, et al.. Clinical guidelines in early detection of oral squamous cell carcinoma arising in oral lichen planus: a 5-year experience. Oral Oncol 2001;37:262-267.

Moutasim KA, Jenei V et al.. Betel‐derived alkaloid up‐regulates keratinocyte alphavbeta6 integrin expression and promotes oral submucous fibrosis. The Journal of pathology 2011;223(3):366-377.
Murti P, Bhonsle R, et al.. Malignant transformation rate in oral submucous fibrosis over a 17-year period. Community Dent Oral Epidemiol 1985;13:340-341.

National Health Insurance Administration, Ministry of Health and Welfare, Taiwan, R.O.C. National health insurance annual report 2014-2015.

National health insurance research database. Data subsets. https://nhird.nhri.org.tw/en/Data_Subsets.html. Accessed June 9, 2016.

Paymaster JC, Cancer of the buccal mucosa. A clinical study of 650 cases in Indian patients. Cancer 1956;9:431-435.

Pindborg JJ, Chawla TN, et al.. Clinical aspects of oral submucous fibrosis. Acta Odontol Scand 1964;22:679–691.

Pindborg JJ, Murti PR, et al.. Oral submucous fibrosis as a precancerous condition. Scand J Dent Res 1984;92:224-229.

Pitiyage GN, Slijepcevic P, et al.. Senescent mesenchymal cells accumulate in human fibrosis by a telomere‐independent mechanism and ameliorate fibrosis through matrix metalloproteinases. The Journal of pathology 2011;223(5):604-617.

Pujari R, Vidya N. Mast cell density in oral submucous fibrosis: a possible role in pathogenesis. Int J Health Sci (Qassim) 2013;7:23-29.

Ranganathan K, Devi MU, et al.. Oral submucous fibrosis: a case‐control study in Chennai, South India. Journal of oral pathology & medicine 2004;33(5):274-277.
Ray JG, Ranganathan K, et al.. Malignant transformation of oral submucous fibrosis: overview of histopathological aspects. Oral surgery, oral medicine, oral pathology and oral radiology. 2016;122(2):200-209.

Reichart PA, Nguyen XH. Betel quid chewing, oral cancer and other oral mucosal diseases in Vietnam: a review. J Oral Pathol Med 2008;37:511-514.

Reid TR. The Healing of America: A Global Quest for Better, Cheaper, and Fairer Health Care, New York. The Penguin Press 2009, 277p.

Sabarinath B, Sriram G, et al.. Immunohistochemical evaluation of mast cells and vascular endothelial proliferation in oral submucous fibrosis. Indian J Dent Res 2011;22:116-121.

Shieh TM, Tu HF, et al.. Association between lysyl oxidase polymorphisms and oral submucous fibrosis in older male areca chewers. Journal of oral pathology & medicine 2009;38(1):109-113.

Shirasuna K. Oral lichen planus: Malignant potential and diagnosis. Oral science international 2014;11(1):1-7.

Sirsat SM, Pindborg JJ. Subepithelial changes in oral submucous fibrosis. APMIS, 1967;70(2):161-173.

Stich HF, Rosin MP, et al.. Oral lesions, genotoxicity and nitosamines in betel quid chewers with no obvious increase in oral cancer risk. Cancer Lett 1986;31:15-25.
Su CC, Yang HF, et al.. Distinctive features of oral cancer in Changhua country: high incidence, buccal mucosa preponderance, and a close relation to betel quid chewing habit. J Formos Med Assoc 2007;106:225-233.

Sumeth Perera MW, Gunasinghe D, et al.. Development of an in vivo mouse model to study oral submucous fibrosis. J Oral Pathol Med 2007;36:273-280.

Tang JG, Jian XF, et al.. Epidemiological survey of oral submucous fibrosis in Xiangtan city, Hunan province, China. Community Dent Oral Epidemiol 1997;25:177–180.

Teh MT, Tilakaratne WM, et al.. Fingerprinting genomic instability in oral submucous fibrosis. J Oral Pathol Med 2008;37:430-436.

Thangjam GS, Agarwal P, et al.. Transglutaminase-2 regulation by arecoline in gingival fibroblasts. Journal of dental research 2009;88(2):170-175.

Tilakaratne WM, Klinikowski MF,et al.. Oral submucous fibrosis: review on aetiology and pathogenesis. Oral Oncol 2006;42:561-568.

Tilakaratne WM, Ekanayaka RP, et al.. Oral submucous fibrosis: a historical perspective and a review on etiology and pathogenesis. Oral surgery, oral medicine, oral pathology and oral radiology 2016;122(2):178-191.

Tilakaratne WM, Iqbal Z, et al.. Upregulation of HIF-1calpha in malignant transformation of oral submucous fibrosis. J Oral Pathol Med 2008;37:372-377.
Tsai CC, Ma RH, et al.. Deficiency in collagen and fibronectin phagocytosis by human buccal mucosa fibroblasts in vitro as a possible mechanism for oral submucous fibrosis. Journal of oral pathology & medicine 1999;28(2):59-63.

Van der Meij EH, Mast H wt al.. The possible premalignant character of oral lichen planus and oral lichenoid lesions: a prospective five-year follow-up study of 192 patients. Oral Oncology 200743(8):742-748.

Van der Waal I. Potentially malignant disorders of the oral and oropharyngeal mucosa; terminology, classification and present concepts of management. Oral Oncol 2009;45:317-323.


Wang YY, Tail YH, et al.. Malignant transformation in 5071 southern Taiwanese patients with potentially malignant oral mucosal disorders. BMC Oral Health 2014;14:99.

Warnakulasuriya KA, Trivedy C, et al.. Aetiology oforal submucous fibrosis. Oral Dis 1997;3:286-287.

Warnakulasuriya S, Ariyawardana A. Malignant transformation of oral leukoplakia: a systematic review of observational studies. Journal of Oral Pathology & Medicine 2015.

Yang YH, Lee HY, et al.. Epidemiological survey of oral submucous fibrosis and leukoplakia in aborigines of Taiwan. J Oral Pathol Med 2001;30:213-219.
Yang SF, Wang YH, et al.. Changes in prevalence status of pre-cancerous oral submucous fibrosis from 1996-2013 in Taiwan: a nationwide population-based retrospective study. J Formos Med Assoc. https://doi.org/10.1016/j.jfma.2017.01.012.

Ye X, Zhang J, et al.. HBO: a possible supplementary therapy for oral potentially malignant disorders. Med Hypotheses 2014;83:131-136.

Yen AM, Chen SL, et al.. Association between metabolic syndrome and oral pre-malignancy: a community and population-based study (KCIS No. 28). Oral Oncol 2011;47:625-630.