Control of Oral Cancer for Oral Health Promotion Shieh Tien-Yu Dean of College of Dental Medicine Kaohsiung Medical University
1. Of the 267,000 new oral cancer cases around the year of 2000 worldwide, 48%（128,000）occured in South and South-East Asia Cancer of the oral cavity (ICD-9:140-145) in (a) men and (b) women (Fig.1)
2. A number of 123,000 cases of oro-and hypopharyngeal cancer estimated to occur globally annually, South and South-East Asia will account for 51% (63,000) Oropharyngeal and hypopharyngeal cancers (ICD-9:146, 148-149) in (a) men and (b) women (Fig.2)
3. Global Incidence and mortality of Oral Cancer（Fig.3） 5 10 15 20 (Male population) Taiwan Melanesia France Hungary Western Europe India South Central Asia Australia /New Zealand South Europe Eastern European South American Caribbean Polynesia Northern American Northern Europe Africa Incidence Mortality Source：Dr. Chiang Wei-Fan Chi Mei Medical Center
4. The percentage of oral cancer among all type of cancers diagnosed in hospitals or groups of hospitals in Asia was much higher than western countries（3-5%）. Investigators have obtained histories of chewing betel quid from series of patients with oral cancer whose chewing habits are extremely large. Chewing habit and percentage of oral cancer among all cancers (Tab.1)
5. Several authors also commented that oral cancer generally develops at the place where the quid is kept. Global estimates report up to 600 million chewers （Gupts & Warnakulasuriya, 2002） （Fig.4）
6. Prevalence of betel quid chewing among Taiwanese adults from 1996 to 2002 was estimated around 10.9 to 9.1; the prevalence of female was much lower than that of male（Tab.2）
7. The effects of alcohal drinking（A）, betel quid chewing（B）and cigarette smoking（c）on the incidence of oral cancer or sites of occurrence and mean age at diagnosis were different. Betel quid chewing was considered to be the most important risk factor for oral cancer. By stratified analysis incorporating the three factors simultaneously, relative risks were estimated at 122.8, for A+B+C factor, 89.1 for B+C, 54.0 for A+B and 28.2 for B only, as compared with participants abstaining from all three habits. （Tab.3） CI. confidnce interval; A, Alcohal drinking; B, Betel quid chewing; C, Cigarette smoking
8. Our other study realized that sites of occurrence, habits and mean age at diagnosis of oral cancer were quite different according to the oral habits（Tab.4） (Tab.4)
9. Relative risk of death among oral squamous cell carcinoma patients according to oral habits (Tab.5)
10. Tab.6 shows that although oropharyngeal cancer in Taiwan increased every year but from age-special, period-special and cohort-special incidence can realize that merely oral caner was augmented while pharyngeal cancer was declined .
40 Male incidence Male mortality Female incidence 30 Female mortality Rate 20 10 0 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 Year 11. Age-adjusted incidence and mortality of oral cancer in Taiwan for the past 10 years （Fig.5） (/105) Source: Bureau of Health Promotion Taiwan
12. Male incidence and mortality of the leading five cancers in Taiwan （Tab.7） Tab.7 Male Incidence and Mortality of the leading Five cancers in Taiwan (unit: per 105 men) Source: Bureau of Health Promotion Taiwan
13. The changing pattern of main cancer-site adjusted mortality rate in male Taiwanese（2006 vs 1996）(Fig. 6). The oral cancer is the fastest growing cancer in male Taiwaneses Source: Bureau of Health Promotion Taiwan
14. Age-specific incidence rate of oral cancer of males in Taiwan（Fig.7） Source：Bureau of Health Promotion Taiwan
15. Age-specific mortality rate of oral cancer of males in Taiwan（Fig.8） Source：Bureau of Health Promotion Taiwan
16. Betel quid chewing not only causes oral cancer but also induces precancerous lesions including leukoplakia, oral submucous fibrosis(OSF) and verrucous hyperplasia（VH）. Dose- response effects of areca/betel quid chewing on OSF and leukoplakia （Community base）（Tab.8） Yang, Lee, Tung, Shieh (J Oral Pathol Med 2001:30:213-9)
17. Epidemiological studies Chewing areca for an average 24.4 years（Fig.9） (with an average of 17.3±18.5 portions a day) Oral precancerous lesion prevalence OSF :17.6% leukoplakia :24.4% Yang, Lee, Tung, Shieh et al., J Oral Pathol Med 2001; 30: 213-9
18. After 3 years follow-up we found that the malignant transformation rate （100 person-year）for dysplasia, VH, leukoplakia and OSF are 7.98, 5.91, 3.37, and 2.85 respectively（Tab.9） Source：KMUH data
19. In our study, the malignant transformation for old age（＞45 years）, dysplasia, VH, and tongue lesions were more severe than that under 45 years, OSF and buccal lesions（Tab.10） Source：KMUH data
21. In 1999 the Betel Quid Association estimated consumption of betel quid of around 80 million grains daily（$2.7 million/day）
22. Medical expenditure for oral cancer in 2003 was high and attained an amount of $90,000,000(12.3%) （Tab.11） Source： http://www.doh.gov.tw/statistic/medical annual report/92.htm
23. Stage at diagnosis （Tab.12） Source: Taiwan Cancer Data Bank,2004
24. Health Risk Awareness（Tab.13） In 2005 national health survey on health risk awareness on “betel quid itself is carcinogenic ”, only 47% interviewed persons answered “agree” Source: National Health Survay, 2005
25. Strategies for prevention and control of oral cancer in Taiwan（Tab.14） 1). Objectives Our objectives are increasing “awareness” to 60%; increasing percentage of screened chewers to 45%; decreasing prevalence of adult chewers to 14% in 2112.
2). Proceedings 1997-2001 • Scheme of betel quid problem management • Improve awareness and reshape social norm（continuing） • Create supportive environment （continuing） 2002-2004 • Community oral cancer screening program • Provide screening services on a much larger scale（continuing） 2005-2009 • National cancer prevention and control initiatives • Help chewers to quit • --Oral cancer prevention and control • Regulations and legislation
3) Source：S-L Koong Chief, and C-Y Wu, Division of Cancer Control and Prevention Bureau of Health Promotion. Department of Health, Taiwan
26. Oral cancer screening, 2000~2005（Tab.15） Source： S-L Koong, Chief of Division of Cancer control and Prevention, Bureau of Health Promotion Department of Health, Taiwan
Establish a self-rating screening test for betel quid abusers or addicts In order to divide betel quid chewers into abusers, addicts or non-abusers three groups to develop different abstinence strategies. We have already established a self-report screening test for areca quid abusers（SSTAA）. An areca quid chewer’s answers with a score of 4 or more in these 11 qestions would be considered a betel quid abuser. （Tab.16） Public Health（2002）116, 195-200.
27. Strategies to help chewers quit 1) In conjunct with Association of Oral and Maxillofacial Surgery in Taiwan, a guide book on how to diagnose oral precancerous and oral cancer and what should be assessed for further evaluation will be published. 2) According to the guide book, the Taiwan Dentist Association should provide adequate training to dentists, family physicians and public health nurses for oral cancer screening. 3) Establish a national oral cancer surveillance system. 4) Establish an oral health self-examining activity (include oral cancer examination) such as a new ’333’ activity: the first ‘3’－oral health self examining ’3’ minutes after teeth brushing in every morning. the second ‘3’－everyday practice ’3’ minutes of oral health exercise including gnashing teeth, tongue movement, gum massage the third ’3’－every ’3’ months visiting dental clinic for oral examination 5) Taxation The Bureau of Health Promotion of the Department of Health would consider planning the possible procedures to levy tax from betel-quid chewers. With taxation, the chewers might think to quit the chewing habit. Consequently, chewers’ extra medical expenditure can be avoided.
Research Scheme Center of Excellence for Environmental Medicine ENT for pharynx and larynx Patients from KMUH,OS Gastroenterology for Endoscope Questionnaire Blood Tissue epidemiology Paraffin block Serum (Protein) DNA / RNA Buffy coat (DNA) ＋ Molecular Epidemiology Stain Lip N2 / -80℃ Already：ACE、TNF-α、MMP-2、VEGF、P53、COX-2、TIMP Further：KLK、SCCA、BIRC5、HOX1、BUB1、CDHP、EPR1、KB20、 MOP9、CLIF…
Global Center of Excellence for Oral Health Research and Development • Gene bank :patient sample size • Oral cancer tissue Oral precancer tissue • Oral cancer blood Oral precancer blood • Normal blood DNA methylation tissue Real time PCR RNA PROTEIN IHC DNA SNP blood ELISA PROTEIN activity
Current and previous studies for genetic susceptibility to oral squamous cell squamous carcinoma • Detoxification: microsomal epoxide hydrolase and MnSOD • DNA repair: OGG1, MUTYH, and MTH1 • Immune surveillance and apoptosis: Fas and FasL • Cell cycle: cyclin D1 and p53 • Inflammation: COX-2 • Cytokines and its signal transduction factor: TGFB1, IL-8, IL-10 and NFKB1 • Angiogenesis: VEGF • Receptor and signal tranduction: Her-2/neu and PPARMatrix degradation: MMP-9 and MMP-2
Mechanism of OSF（Fig.10） Oral submucosal Fibroblasts Abnormal accumulation of collagen (1) Lysyl oxidase activity ↑ collagens ↑ (I, III, V) (2) Collagenase activity ↓ (3) TIMP-1 ↑ Betel quid chewing (4)(5) Phagocytosis activity ↓ (individual or same person) Influences cytokines production (1) R-H Ma, C-C Tsai, T-Y Shieh: Increased lysyl oxidase activity in fibroblasts cultrues from oral submucous fibrosis associated with betel nut chewing in Taiwan J Oral Pathol Med 24: 407-412, 1995. (2) I-Y Huang, T-Y Shieh: Collagen content and types in oral submucous fibrosis. Kaohsiung J Med Sci 5: 162-171, 1989. (3) D-H Shieh, L-C Chiang, T-Y Shieh: Augmented mRNA expression of tissue inhibitor of metalloproteinase-1(TIMP-1) in buccal mucosal fibroblasts by arecoline and safrole as a possible pathogenesis for oral submucous fibrosis. Oral Oncology 39:728-735, 2003. (4) D-H Shieh, L-C Chiang, C-H Lee, Y-H Yang, T-Y Shieh: Effects of arecoline, safrole, and nicotine on collagen phagocytosis by human buccal mucosal fibroblasts as a possible mechanism for oral submucous fibrosis in Taiwan. J Oral Pathol Med 33;581-7,2004. (5) C-C Tsai, R-H Ma, T-Y Shieh: Deficiency in collagen and fibronectin phagocytosis by human buccal mucosa fibroblasts in vitro as a possible mechanism for oral submucous fibrosis. J Oral Pathol Med 28: 59-63, 1999.
Response of immune system（Fig.11） Oral submucosal Fibroblasts (6) (7) IL-1β: SCC > VH > normal > OSF (8) TGF-β: OSF > normal Abnormal immune response (9) TNF-α:SCC>normal>SCC+betel IFN-γ:normal > normal+betel IL-2, TGF-β, IFN-γ:OSF < normal & SCC Betel quid chewing (10) mRNA→ TNF-α, TGF-β: SCC > normal IFN-γ: SCC < normal (11) sTNF-RI & sTNF-RII: SCC > normal (TNF-α/ sTNF-RII)*100 ratio: SCC < normal Influences cytokines production (12) Longitudinal study: TNF-α/sTNF-RII: recurred SCC > non-recurred SCC (pre-OP) sTNF-RII/sTNF-RI: recurred SCC > non-recurred SCC (post-OP 6 months) (6) C-C Tsai, C-C Chen, C-C Lin, C-H Chen, T-S Lin, T-Y Shieh. Kaohsiung J. Med. sci. 15(9): 513-9, 1999 (7) T-S Lin, T-Y Shieh. Chin J Oral Maxillofac Surg. 6:34-42, 1995. (8) C-H Huang, T-Y Shieh. J Academy Formosan Stomatology 15: 227-239,1999. (9) H-J Hsu, K-L Chang, Y-H Yang, T-Y Shieh. Kaohsiung J Med Sci 17：175-182,2001. (10) M-C Chang, T-Y Shieh. Thesis of Master of Dental Science, KMU 2000. (11) T-R Su, K-L Chang, C-H Lee, C-H Chen, Y-H Yang, T-Y Shieh. Oral Oncology 40;804-810,2004. (12) C-Y Huang, T-Y Shieh. Thesis of Master of Dental Science, KMU 2006.
In betel quid chewers: 1.The frequency of homozygote for ACE D variant is significantly higher in the case subjects than that of the controls (OR=6.06, P<0.0108). 2.The odds ratio of ACE DD genotype for the risk of oral cancer was 4.29(p=0.0006)
total Margin/Normal Cancer/Normal Cancer/Margin up 2806 4224 1931 down 2365 3218 1663 Database Source • Cooperated with Nihon University School of Dentistry at Matsudo. • Three patients’ tissue ( OSCC tissue/margin/normal) • Affymetrix GeneChip, HG-U133A
Ingenuity Pathway Analysis (IPA) • IPA is software that helps researchers model, analyze, and understand the complex biological and chemical systems at the core of life science research. Search and Explore Biological and Chemical Knowledge. IPA's Search & Explore capabilities offer researchers access to the most current Findings available on genes, drugs, chemicals, protein families, normal cellular and disease processes, and signaling and metabolic pathways.
fold name Margin/ normal Cancer/ normal Cancer/ margin Gene bank KLK6 7.247 17.54 2.576 NM_002774 KLK7 KLK10 6.808 25.71 3.547 AK026045 Up-regulation genes---Kallikrein (KLK)