皮膚癌和唇癌的主要類別包括黑色素細胞癌和非黑色素細胞皮膚癌。非黑色素細胞皮膚癌則包括鱗狀細胞癌，基底細胞癌，以及皮脂腺和汗腺的惡性腫瘤。皮膚癌是台灣前十種最常見的癌症類型之一。基底細胞癌和鱗狀細胞癌是最常見的兩種，是手術後可去除的，但是會導致外觀變形且花費昂貴。 黑色素細胞癌，第三常見，是更危險，且導致最多的死亡。
這三種類型癌症最主要的共同風險因子是長期或過量暴露於紫外線光。鱗狀細胞癌和基底細胞癌的最常見風險因素：長期紫外線光照射，電離輻射暴露，免疫抑制狀態（器官移植患者）。暴露於環境致癌物質也是重要危險因素。
越來越多的證據表明某些類型的癌症在某些內科疾病患者中更為常見。例如糖尿病，慢性阻塞性肺疾病，慢性腎臟疾病和全身炎性自身免疫性風濕病。糖尿病人容易產生包括肝臟，膽道，胰腺，胃，結腸直腸，腎，膀胱，乳腺和子宮內膜的癌症，但相反地前列腺癌的風險降低。而在台灣，關於糖尿病和皮膚癌的關聯，以及唇癌的臨床病理特徵和其風險因子的研究還是很少。
本研究目的在調查台灣糖尿病患者發生皮膚癌的風險因子，以及一醫院唇癌患者臨床病理特徵和其風險因子。
第一項研究採用國家健康保險縱向研究數據庫進行回溯性世代研究，研究台灣糖尿病患者皮膚癌的風險。通過泊松(Poisson)回歸分析和Cox回歸分析，來比較在新診斷糖尿病和非糖尿病人二群組之間的整體皮膚癌的風險，包括非黑色素細胞皮膚癌（NMSC）和黑色素細胞癌的風險。新診斷的糖尿病人與非糖尿病人二群組以1比1配對，配對項目包括年齡，性別，指標日期和共病（冠狀動脈疾病，高脂血症，高血壓，慢性腎臟疾病，慢性阻塞性肺病，和肥胖）。把糖尿病和非糖尿病人二群組相比較，對於年齡≥60歲的糖尿病患者而言，整體皮膚癌和非黑色素細胞皮膚癌總發病率明顯較高[總體皮膚癌：糖尿病 /非糖尿病人群組（n= 99/76，發生率比（IRR）= 1.44，P = 0.02; 非黑色素細胞皮膚癌：糖尿病/非糖尿病人群組：n = 94/66，IRR = 1.57，P = 0.005]。通過Cox回歸分析，調整性別，共病和所有具免疫抑制狀態的疾病，總體皮膚癌或非黑色素細胞皮膚癌發生風險顯著升高，（總體皮膚癌：風險比（AHR）= 1.46，P = 0.01; 非黑色素細胞皮膚癌： AHR = 1.6，P =0.003）。皮膚癌的其他重要風險因素之一是老年男性 （總體皮膚癌：AHR = 1.68，P = 0.001; 非黑色素細胞皮膚癌：AHR = 1.59，P = 0.004; 黑色素細胞癌：AHR = 3.25，P = 0.04），慢性阻塞性肺疾病對於非黑色素細胞皮膚癌（AHR = 1.44，P = 0.04），冠狀動脈疾病對於黑色素細胞癌（AHR = 4.22，P = 0.01）。發生黑色素細胞癌的風險在糖尿病群組中低於非糖尿病人群組，但無顯著意義（AHR = 0.56，P =0 .28; 總體糖尿病 /非糖尿病人群組：n = 5/10）。結論是老年糖尿病群組患者的總體皮膚癌和非黑色素細胞皮膚癌的發生率和風險明顯高於老年非糖尿病人。糖尿病群組老年患者的其他重要風險因素為男性之於非黑色素細胞皮膚癌和黑色素細胞癌，慢性阻塞性肺疾病之於非黑色素細胞皮膚癌，冠狀動脈疾病之於黑色素細胞癌。
第二項研究是通過高雄榮民總醫院病理報告系統檢索找出從1995到2013年所有唇癌的病例，方法是回溯摘錄其醫院病歷，包括所有病理確診的唇鱗狀細胞癌（LSCC，n = 112）和唇基底細胞癌（LBCC，n = 21）患者的門診住院記錄。記錄其臨床病理特徵，高風險生活方式因素（慢性暴露於陽光，檳榔，酒精和煙草），以及預後因素。通過卡方檢驗和邏輯斯回歸分析來比較唇鱗狀細胞癌和唇基底細胞癌，上下唇部位，第二原發性腫瘤有無狀態之間，的臨床病理特徵差異。通過Cox回歸分析唇鱗狀細胞癌的預後因素。結果如下：與唇基底細胞癌患者相比，唇鱗狀細胞癌患者中以男性佔多數（P <0.001），發病年齡較小（P <0.001），下唇部位（P < 0.001）和有高風險生活方式因素的患者佔的比例較高。患有第二原發性腫瘤的患者與癌症發生在下唇有高度相關聯（調整的優勢比adjusted odds ratio= 2.91，P = 0.03）。患有下唇癌的患者具有更多種的高風險生活方式因素，並有線性增加的趨勢 (P = 0.004）。唇鱗狀細胞癌患者其疾病特異性生存分析之較差的預後因子是癌疾病晚期III / IV期（粗風險比（CHR）= 11.16，P <0.001），腫瘤尺寸> 4cm（CHR = 8.19，P = 0.006），有淋巴結轉移(CHR = 11.48，P < 0.001）和復發（CHR = 3.96，P = 0.01）;而無病生存期分析的較差預後因子是為病理中度至惡分化的唇鱗狀細胞癌（CHR = 4.97，P = 0.002）和經常飲酒（CHR = 3.13，P = 0.04）。結論為唇鱗狀細胞癌和下唇癌與高風險生活方式的因素高度相關。

The major categories of skin and lip cancer include melanoma and non-melanoma skin cancers (NMSC). NMSC include squamous cell carcinoma, basal cell carcinoma, and malignant neoplasm of sebaceous glands and sweat glands. Skin cancer was among the top 10 most common types of cancers in Taiwan. The two most common types, basal cell carcinoma and squamous cell carcinomas, are highly curable, but can be disfiguring and costly. Melanoma, the third most common, is more dangerous and causes the most deaths.
The majority of these three types of skin and lip cancer are caused by exposure to ultraviolet light. The most common etiologies for squamous cell carcinoma and basal cell carcinoma: ultraviolet light exposure, ionizing radiation exposure, and immunosuppression (patients with organ transplant). Exposure to environmental carcinogens is the other important risk factor.
Increasing evidence suggests that certain types of cancers are more common in people with certain systemic medical disease, such as diabetes mellitus (DM), chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), and inflammatory systemic autoimmune rheumatic diseases (ISARDs). The people with diabetes mellitus (DM) have increased risk of cancer of the liver, biliary tract, pancreas, stomach, colorectum, kidney, urinary bladder, breast, and endometrium, but conversely a decreased risk of prostate cancer.
The aims of the studies were to investigate the risk of skin cancer in patients with diabetes mellitus, and the clinicopathological features and risk factors of patients with lip cancer in Taiwan.
The first study is a retrospective cohort study that investigated the risk of skin cancer in patients with DM in Taiwan by using Taiwan Longitudinal National Health Insurance Research Database. The risk of developing overall skin cancer, including non-melanoma skin cancer (NMSC) and melanoma, between the DM and non-DM cohorts was compared by Poisson regression analysis and Cox regression analysis. The DM cohort with newly-diagnosed DM (n=41,898) and a non-DM cohort were one-to-one matched by age, sex, index date, and co-morbidities (coronary artery disease, hyperlipidemia, hypertension, chronic kidney disease, chronic obstructive pulmonary disease, and obesity). Compared with non-DM cohort statistically, for the people with DM aged ≥ 60 years, the incidence rates of overall skin cancer and NMSC were significantly higher [overall: DM/non-DM: number (n) = 99/76, incidence rate ratio (IRR) = 1.44, P = 0.02; NMSC: DM/non-DM: n = 94/66 , IRR=1.57, P = 0.005]. By Cox regression analysis, the risk of developing overall skin cancer or NMSC were significantly higher after adjusting for gender, co-morbidities and overall diseases with immunosuppression status (overall: adjusted hazard ratio (AHR) =1.46, P = 0.01; NMSC: AHR = 1.6, P =0.003). Other significant risk factors were older males for skin cancer (overall: AHR=1.68, P = 0.001; NMSC: AHR=1.59, P = 0.004; melanoma: AHR=3.25, P = 0.04), chronic obstructive pulmonary disease for NMSC (AHR=1.44, P = 0.04) and coronary artery disease for melanoma (AHR= 4.22, P = 0.01). The risk of developing melanoma was lower in the DM cohort than in the non-DM cohort but without significance (AHR= 0.56, P = 0.28; DM/non-DM: n = 5/10). Conclusions were that the incidence rate and risk of developing overall skin cancer, including NMSC, was significantly higher in older adults with DM. Other significant risk factors for older adults with DM were males for NMSC and melanoma, chronic obstructive pulmonary disease for NMSC, and coronary artery disease for melanoma.
The second study is a retrospective hospital-based study that investigated the clinicopatholoical characteristics, high-risk lifestyle factors (HRLF: chronic exposure to sun, betel quid, alcohol, and tobacco), and prognostic factors of lip cancer by retrieving the lip cancer from pathological report system in Kaohsiung Veterans General Hospital during 1995-2013. The hospital records of patients with pathologically confirmed lip squamous cell carcinoma (LSCC, n=112) and lip basal cell carcinoma (LBCC, n=21) were reviewed. Differences of clinicopathological characteristics between LSCC and LBCC, upper and lower lip, and status of second primary tumors were compared by Chi-square test and logistic regression. The prognostic factors for LSCC were analyzed by Cox regression. Compared to LBCC patients, LSCC patients were men-predominant (P < 0.001), had younger ages at onset (P < 0.001), and higher rates of lower lips involvement (P < 0.001) and HRLFs. Patients with second primary tumors were highly associated with lower lip cancer involvement (adjusted odds ratio=2.91, P = 0.03). Patients with lower lip cancer had more HRLFs with an increasing linear trend (P = 0.004). The poorer prognostic factors of LSCC for disease-specific survival were advanced stage III/IV [crude hazard ratio (CHR) = 11.16, P < 0.001), tumor dimension >4cm (CHR = 8.19, P = 0.006), lymph node involvement (CHR = 11.48, P < 0.001), and recurrence (CHR = 3.96, P = 0.01); whereas for disease-free survival were moderately to poorly-differentiated LSCC (CHR = 4.97, P = 0.002) and alcohol consumption (CHR = 3.13, P = 0.04). Conclusions were that LSCC and lower lip cancer were highly associated with HRLFs.

Table of Contents page
國立中山大學研究生學位論文審定書................................................................. i
誌謝........................................................................................................................ ii
中文摘要................................................................................................................ iii
Abstract................................................................................................................. vi
Abbreviation......................................................................................................... x
1. Introduction: the risk factors of skin and lip cancer................................. 1
1.1. Types of skin and lip cancer............................................................... 1
1.2. The risk factors of skin cancer........................................................... 2
1.3. The risk factors of lip cancer............................................................. 5
1.4. High-risk lifestyles factors and cancer.............................................. 7
1.5. Inflammation and cancer................................................................... 8
1.6. Systemic medical diseases and cancer............................................... 10
1.7. DM and cancer. ................................................................................... 10
2.
The first study: Risk of Skin Cancer in Patients with Diabetes Mellitus: A Nationwide Retrospective Cohort Study in Taiwan........................................14
2.1. Backgrounds, specific objectives, and theoretical basis................... 15
2.2. Methods................................................................................................ 16
2.2.1. Data sources: National Health Insurance Research Da-tabase (NHIRD)....................................... 16
2.2.2. Design, inclusion criteria, exclusion criteria, covariates and definition. ...........................................17
2.2.3. Statistical methods, statistical analysis, and software….. 20
2.3. Results..................................................................................................... 21
2.4. Discussion............................................................................................... 25
2.5. Tables...................................................................................................... 30
Table 2.5.1. ICD-9-CM codes used for diseases diagnosis and ATC codes for immunosuppressant in this study................30
Table 2.5.2. Demographic characteristics, comorbidities, and skin cancer of the DM and Non-DM Cohorts.....31
Table 2.5.3. The incidence rate ratios of skin cancer in the DM and Non-DM cohorts by age and gender subgroups............. 32
Table 2.5.4. The crude and adjusted hazard ratios for skin cancer in the DM and Non-DM cohorts by age subgroup and adjustment for gender and comorbidities....................... 33
2.6. Figures.................................................................................................. 34

Figure 2.6.1.
Flowchart of study design and patient selection of the study cohorts.......................................................34
Figure 2.6.2. Kaplan-Meier survival curves of overall skin cancer after index date of DM...................................35
Figure 2.6.2A. Comparison of cumulative incidence of overall skin cancer in all patients with and without DM......35
Figure2.6.2B. In subgroup of age <60 years, comparison of cu-mulative incidence of overall skin cancer in patients with and without DM................................... 36
Figure 2.6.2C. In subgroup of age ≥60 years, comparison of cu-mulative incidence of overall skin cancer in patients with and without DM...................................37
Figure 2.6.3. Kaplan-Meier survival curve of nonmelanoma skin cancer after index date of DM..........................38
Figure 2.6.3A.
Comparison of cumulative incidence of melanoma in all patients with and without DM.........................38
Figure 2.6.3B.
In subgroup of age <60 years, comparison of cu-mulative incidence of nonmelanoma skin cancer in patients with and without DM............................... 39
Figure 2.6.3C. In subgroup of age ≥60 years, comparison of cu-mulative incidence of nonmelanoma skin cancer in patients with and without DM............................... 40
Figure 2.6.4. Kaplan-Meier survival curve of melanoma after in-dex date of DM..................................................41
Figure 2.6.4A. Comparison of cumulative incidence of melanoma in all patients with and without DM...................41
Figure 2.6.4B. In subgroup of age <60 years, comparison of cu-mulative incidence of melanoma in patients with and without DM. ...................................................... 42
Figure 2.6.4C. In subgroup of age ≥60 years, comparison of cu-mulative incidence of melanoma in patients with and without DM. ...................................................... 43
Appendix: NHIRD, data protection, regulation, registration files and subsets. 44
3.
The second study: Clinicopathological study of lip cancer: a retrospective hospital-based study in Taiwan. .................49
3.1. Backgrounds, specific objectives, and theoretical basis. .................. 50
3.2. Methods.................................................................................................. 51
3.2.1. Data sources.......................................................................... 51
3.2.2. Design, inclusion and exclusion criteria, and definition. 51
3.2.3. Statistical methods, statistical analysis, and software….. 54
3.3. Results................................................................................................... 54
3.4. Discussion.............................................................................................. 60
3.5. Tables….................................................................................................. 62
Table 3.5.1. AJCC stages at the first diagnosis, status of local re-currence, regional recurrence and distant metastasis of patients with LSCC and LBCC..................................65
Table 3.5.2. The demographic data, high-risk lifestyles, and clinicopathologic characteristics of LSCC and LBCC..66
Table 3.5.3. The demographic characteristics, subsites, and high-risk lifestyles factors of second primary tumor.....67
Table 3.5.4. The comparison of the demographic characteristics and high-risk lifestyle factors of upper and lower lip cancer 68
Table 3.5.5. The disease-specific survival and disease-free survival of lip squamous cell carcinoma on demographic data, high-risk lifestyles, and clinicopathological factors by Cox regression analysis...............................................69
4. Conclusions, strength and limitations.......................................................... 70
4.1. Conclusions for the study of DM and skin cancer............................. 70
4.2. Strength and limitation for the study of DM and skin cancer.......... 70
4.3. Conclusion of the study for lip cancer............................................... 71
4.4. Strength and limitation for the study of lip cancer.......................... 72
5. References...................................................................................................... 73

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