肝炎相關膽管癌的臨床病理和分子分析

The Clinicopathologic and Molecular Analysis of Hepatitis-associated Cholangiocarcinoma

余燦華(Tsan-Hua Yu)

指導教授 ： 鄭永銘

國立臺灣大學/醫學院/病理學研究所/博士(2011年)

https://doi.org/10.6342/NTU.2011.01485

摘要

簡介：膽管癌是致命性癌症的一種，主要是因膽道上皮細胞癌化所造成。在全球胃腸道癌症病例中，膽管癌病例約佔了3%，若以肝臟惡性腫瘤而言，則估計有15%之多，排位僅次於肝細胞癌。膽管癌可大略的分成肝內膽管癌和肝外膽管癌兩類。在許多國家有很多關於引致肝內膽管癌的危險因子已經成功被證實並且在不同的結果間有其變異性。造成這些變異的情形，有可能是因為國家或區域間的地理、種族、飲食、年齡、環境、癌登系統和疾病分類不同所導致。已有許多流行病學上和分子表現的證據顯示肝寄生蟲、肝內結石、硬化性膽管炎、影像顯影劑Thorotrast的暴露等等是肝內膽管癌的危險因子。而病毒性肝炎與肝內膽管癌之關連性角色最近也被提出，但是直到現在為止，病毒性肝炎導致的肝內膽管癌在組織形態學上和基因性的特徵，仍然不清楚。我們在這研究分析了病毒性肝炎與肝內膽管癌臨床病理和分子表現的關聯。材料與方法：在2000至2010年期間，計有170位在國立台灣大學附設醫院追蹤治療和接受詳細病理評估的肝內膽管癌患者為本研究的研究對象。收集研究對象的臨床病理學資料和組織切片之組織形態學、分子表現、基因突變檢測資料，以進行分析。結果：在170位肝內膽管癌研究對象中，有69位（41%）是B 型和/或C型肝炎陽性患者。肝內膽管癌伴有病毒性肝炎患者較常發生在男性（68% vs. 42%, P=0.002）。而平均年齡則為肝內膽管癌伴有病毒性肝炎（57.88 ± 12.73 years）較無病毒性肝炎（62.14 ± 11.62 years）患者年輕約4歲（P=0.04）。至於血清AFP濃度在肝內膽管癌伴有病毒性肝炎患者有較多提高的情形，但血清CA19-9（OR=0.89, P=0.770）和CEA濃度（OR=1.13, P=0.750）並没有提高的情形。形態學上，肝內膽管癌伴有病毒性肝炎患者是較偏向mass-forming類型（R=3.52, P=0.027）和小膽管分化亞型（OR=2.71, P=0.008）。肝內膽管癌之N-cadherin表現是和感染病毒性肝炎高度相關（OR=5.06, P=0.0002）並且是唯一的獨立相關因子（Adjusted Odds Ratio=6.322, P=0.001）。使用N-cadherin 做為免疫化學染色標記，成功地識別出一群肝內膽管癌次分類。N-cadherin表現的肝內膽管癌患者之B型肝炎感染盛行率是75%，N-cadherin無表現的患者之B型肝炎感染盛行率是則僅有37%，N-cadherin表現是強烈和B型肝炎感染相關（P=0.0003）。表現N-cadherin的肝內膽管癌患者較為年輕，而且血清的AFP濃度較為提高（P=0.013），但是CA19-9（P=0.128）和CEA（P=0.155）之血清濃度則没有差別。另外，肝內膽管癌患者肝內結石病史則和N-cadherin表現負相關（P=0.003）。而N-cadherin表現的肝內膽管癌患者，形態上大部分是Mass-forming型（P=0.00002），呈小膽管分化組織形態（P=0.000003），Muc-2（P=0.000001）和CEA（P=0.0000005）不表現，同時K-RAS 也較没有發生突變（P=0.042）。結論：具膽管分化型和N-cadherin表現特徵的肝內膽管癌患者強烈和病毒性肝炎相關。

關鍵字

肝內膽管癌 ； 病毒性肝炎 ； 臨床病理特徵 ； 組織形態 ； 分子表現

並列摘要

INTRODUCTION: Cholangiocarcinoma is a lethal malignant tumor that arises from transformation of epithelial cells lining the bile ducts. Cholangiocarcinoma accounts for 3% of all gastrointestinal cancers and 15% of liver cancer worldwide and is the second most primary liver tumor following hepatocellular carcinoma. Cholangiocarcinoma is classified as intrahepatic and extrahepatic cholangiocarcinoma according to the location. Several risk factors of cholangiocarcinoma have successfully identified and the results are quite different in different countries. The phenomenon might be due to a variety of factors including geography, race, diet, environmental exposure, registration system, and different classification of disease among countries or areas. The most well known risk factors are liver fluke infestation, hepatolithiasis, sclerosing cholangitis, and Thorotrast exposure. The role of viral hepatitis in intrahepatic cholangiocarcinoma is recently emerging but until now the histomorphological and genetic features of viral hepatitis-associated intrahepatic cholangiocarcinoma is still unknown. In the study, we have analyzed the associated of viral hepatitis with clinicopathologic, histomorphological and molecular features of intrahepatic cholangiocarcinoma. MATERIALS AND METHODS: From 2000 to 2010, 170 intrahepatic cholangiocarcinoma patients who received detailed pathological assessment and regular follow-up at the National Taiwan University Hospital were selected and formed the basis of this study. Clinicopathological features, histomorphology, molecular expression, and gene mutation from these tumors were collected and analyzed. RESULTS: Of 170 patients, 69 (41%) were positive for hepatitis B and/or C virus. Viral hepatitis-associated intrahepatic cholangiocarcinoma patients were more frequent in male (68% vs. 42%, P=0.002). The mean age of patients with viral hepatitis (57.88 ± 12.73 years) was approximately 4 years less than that of those without (62.14 ± 11.62 years). More intrahepatic cholangiocarcinoma patients with viral hepatitis had elevated serum AFP levels (OR=3.52, P=0.025), but the serum levels of CA19-9 (OR=0.89, P=0.770) and CEA (OR=1.13, P=0.750) were not different. Morphologically, viral hepatitis-associated intrahepatic cholangiocarcinoma was more likely to be of the mass-forming rather than the intraductal/periductal type (OR=3.52, P=0.027). Cholangiolar subtype was strongly associated viral hepatitis compared to the bile duct subtype of intrahepatic cholangiocarcinoma (OR=2.71, P=0.008). N-cadherin expression was highly correlated with viral hepatitis infection (OR=5.06, P=0.0002) and is the only independent factor associated with viral hepatitis (Adjusted Odds Ratio=6.322, P=0.001). Using N-cadherin as an immunohistochemical marker, we have successfully identified a subgroup of intrahepatic cholangiocarcinoma strongly associated with viral hepatitis. The prevalence of viral hepatitis in patients with N-cadherin positive was 75% and N-cadherin-negative patients was only 37%. Furthermore, patients with N-cadherin-positive intrahepatic cholangiocarcinoma were younger with elevated serum AFP levels (P=0.013), but the serum levels of CA19-9 (P=0.128) and CEA (P=0.155) were not statistically different. N-cadherin expression was significantly negative associated with intrahepatic lithiasis (P=0.003). Grossly, all these tumors were mass-forming type (P=0.00002). N-cadherin expression is associated with cholangiolar differentiation (P=0.000003), lack of CEA (P=0.0000005) and Muc-2 expression (P=0.000001), and K-RAS mutations were less frequent (P=0.042). CONCLUSION: A subgroup of intrahepatic cholangiocarcinoma characterized by cholangiolar differentiation and N-cadherin expression is strongly associated with viral hepatitis.

並列關鍵字

intrahepatic cholangiocarcinoma ； viral hepatitis ； clinicopathological features ； histomorphology ； molecular expression

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