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研究生:陳世昌
研究生(外文):Shih-Chang
論文名稱:纖粘連蛋白於原發性肝癌中的表現與轉移相關性之研究
論文名稱(外文):Fibronectin Expression Pattern In Primary Hepatocellular Carcinoma as a Predictive Factor for Metastasis
指導教授:李 輝 博士王約翰 博士
指導教授(外文):Huei Lee, Ph.DJohn Wang, Ph.D
學位類別:碩士
校院名稱:中山醫學大學
系所名稱:醫學分子毒理學研究所
學門:醫藥衛生學門
學類:其他醫藥衛生學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:中文
論文頁數:93
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壹、中文摘要

肝癌(Hepatocellular Carcinoma, HCC),世界五大癌症之ㄧ,在台灣,位居男性癌症死亡首位。由於肝癌高度轉移及復發特性,導致肝癌在治療成效及預後無法得到滿意的結果,肝癌轉移機制非常複雜,到目前為止仍有許多機制有待釐清。回顧文獻指出,細胞初癌化轉為癌細胞其組織存在不同病理型態與變化。然而,免疫組織化學染色中發現,不同時期肝癌組織存在不同型態纖粘連蛋白表現與分布。瞭解原發性肝癌中腫瘤細胞纖粘連蛋白表達型態,或許能提供肝癌轉移與復發的評估指標?本研究採用回溯性方式追蹤五年原發性肝癌病患,探討纖粘連蛋白於肝癌中的表現與轉移及復發相關性。針對肝癌纖粘連蛋白的表達型態,提供臨床評估肝癌轉移的一項新指標。
針對中台灣地區(台中榮民總醫院)2002年至2006年罹患肝癌組織切片隨機取樣進行分析,個案總數為106位病人,區分如下:再復發者51位,轉移現象者30位,合併復發及轉移者21位,沒有復發及轉移者46位; 結果以敏感度與特異度分析,纖粘連蛋白在正常肝細胞和腫瘤肝細胞染色,以實證醫學分析評估,發現竇狀隙所得數值最差,而最好為細胞核,其次為細胞膜與細胞質,所以,以整體指標看來,細胞核染色是具有最佳判斷力與敏感度。以敏感度與特異度來看轉移與纖粘連蛋白染色,細胞膜所得數值最差,而最好為竇狀隙,其次為細胞核與細胞質,所以,整體指標看來,以竇狀隙與細胞質染色在轉移方面具有較好判斷力與敏感度在腫瘤復發方面,以敏感度與特異度而言,最好為細胞核竇狀隙,其次為細胞膜,最差為細胞質。纖粘連蛋白竇狀隙染色比例與腫瘤復發與轉移有顯著關係存在,其中以竇狀隙染色比例1+比例最高。不同組織型態肝癌細胞和復發有顯著的關係,其中以trabecular比例最高,而不同組織型態肝癌細胞和轉移也有相關,其中pseudoglandular比例最高。而數據顯示感染B型肝炎或C型肝炎與腫瘤復發和轉移並無明顯的關聯性存在。藉此長時間的追蹤研究發現對於早期(early stage)肝癌病人其纖粘連蛋白的表現型態或許可以提供臨床上另一個新的指標,讓罹患肝癌的病人可藉由此方法提早用標的藥物以減少病症轉移,更可提高存活率。


貳、英文摘要
Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world and is the first leading cause of cancer-related death in Taiwan. Since HCC is a highly metastatic and recurrent malignant neoplasm, the treatment and prediction of prognosis of HCC are unsatisfactory. So far, the mechanisms of metastasis remained unclear due to its complicated process. Reviewing the literature, tumorgenesis of HCC and the related immunohistochemical studies of fibronectin (FN) had been discussed. However, the small case number using previous reports and the clinical significance of FN staining patterns were still uncertain. We designed this study to compare the expression of FN staining in different patterns of HCC with long-term clinical follow-up. The retrospective study was employed to examine FN immunostaining in tumors from 106 HCC for five year follow-up. The worst indicator is sinusoidal staining and the best one is nuclear staining, followed by the cell membrane and cytoplasm. To evaluate the sensitivity and specificity in fibronectin staining and tumor metastasis, the worst indicator is cell membrane, and the best indicator is sinusoidal staining, followed by the nucleus and cytoplasm. In tumor recurrence, the best indicator is nuclear staining and sinusoidal staining, followed by the cell membrane. The worst one is cytoplasmic staining. The proportion of tumor cells showing sinusoid fibronectin staining has a significant relationship of tumor recurrence and metastasis. The tumor cells which sinusoidal staining proportion is 1+, having the highest probability of tumor recurrence and metastasis. Different morphologic patterns of tumor cells had a significant relationship between tumor recurrences and metastasis. In recurrence, the highest one is trabecular pattern. In consider of tumor metastasis and tumor morphology, the highest proportion is pseudoglandular pattern. The data show that no matter type B or C hepatitis and tumor recurrence and metastasis, and there is no clear correlation. You should give a conclusion for your study!


目錄
壹、中文摘要 1
貳、英文摘要 3
參、文獻綜論 5
一、肝癌之流行病學 5
二、肝癌的相關危險因子 6
2.1病毒感染與肝癌之關係 7
2.2食物感染與肝癌之關係 13
2.3酒精與肝癌之關係 15
三、肝癌細胞之分期 16
3.1 Okuda分類系統 16
3.2 TMN分類系統 16
3.3 FRENCH分類系統 17
3.4 CLIP分類系統 17
3.5 BCLC分類系統 17
3.6 CUPI分類系統 17
四、肝癌的分型與分類 18
4.1原發性肝癌巨觀分型 18

4.2原發性肝癌組織學分類 19
4.3原發性肝癌的轉移 19
五、纖粘連蛋白(fibronectin;FN)的生物學作用 20
5.1纖粘連蛋白的構造與功能 21
5.2纖粘連蛋白與癌症轉移之相關性 23
5.3纖粘連蛋白和肝癌的關聯性 24
六、基質金屬蛋白酶的種類與構造 25
6.1基質金屬蛋白酶與腫瘤的作用 28
6.2基質金屬蛋白酶於轉移過程中所扮演的角色 29
6.3基質金屬蛋白酶和纖粘連蛋白之關係 29
肆、研究動機 30
伍、材料與方法 31
一、材料與試劑 31
二、檢體收集 33
三、實驗方法 34
3.1實驗流程 34
3.2 H&E染色法及病理判讀 35
3.3免疫組織化學染色及判讀 35
3.4統計分析 37

陸、結果 39
一、纖粘連蛋白在正常肝細胞和腫瘤肝細胞染色 39
二、纖粘連蛋白在腫瘤細胞中染色形態與轉移及復發關係 41
三、纖粘連蛋白竇狀隙染色的比例與腫瘤轉移與及復發 44
四、不同組織型態的肝癌細胞和轉移與復發關係 45
五、病毒型肝炎和腫瘤轉移與復發 46
柒、討論 47
一、纖粘連蛋白在正常肝細胞和腫瘤肝細胞染色之探討 47
二、纖粘連蛋白在腫瘤細胞中染色形態與轉移及復發之探討 48
三、纖粘連蛋白竇狀隙染色的比例與腫瘤轉移之探討 49
四、不同組織型態的肝癌細胞和轉移與預後之探討 50
五、病毒型肝炎和腫瘤轉移與復發之探討 51
捌、結論 52
玖、參考文獻 53
拾、表與圖 61
拾壹、附錄 82


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