原發性肝癌,韓國宏 第四軍醫大學第一附屬醫院內科教研室,Long-Term Relative Survival Rates for Patients (Diagnosed, SEER Program, All Races, Men and Women),一、組織學分型 肝細胞癌（HCC） 85-90% Hepatocellular carcinoma 膽管細胞癌（CCC） 5% Cholangiocellular carcinoma 混合細胞癌（HCC+CCC） 5%,二、流行病學,肝細胞癌發生于世界范圍，尤其是我國等亞洲和非洲國家 全球第六位的癌癥和第三位最常見引起死亡的癌癥全球每年60萬人新診斷，中國占50% 全球每年60萬人，中國每年30萬人（50%）死于肝癌,Worldwide Incidence of Hepatocellular Carcinoma,High ( 30:100,000),Low or data unavailable ( 3:100,000),Intermediate (3-30:100,000),Worldwide Incidence of Hepatocellular Carcinoma,HCC Epidemiology,El-Serag HB, Gastroenterology 2004,肝癌的全球發病情況,Parkin DM, et al. CA Cancer J Clin 2005;55:74108,* 包括HCC及膽管細胞癌（5cm，最常見,2、結節型：5cm,3、彌漫型： 較少見,4、小癌型： 單結節3cm， 兩癌結節之和10 cm,塊狀型5 cm,結節型,Multiple smallfoci of HCC,HCV Cirrhosis and HCC,正常肝臟,病毒性肝炎,肝硬化,原發性肝癌,肝癌發生“三部曲”,: high-grade dysplastic nodule,: well-differentiated,: moderately differentiated HCC,De novo hepatocarcinogenesis,?,?,Evolution of Hepatocellular Carcinoma,五、轉移（1）1、肝內轉移侵犯門靜脈 癌栓 肝內多發病灶門脈主干癌栓 門脈高壓,五、轉移（2）,2、肝外轉移血行轉移：最早，肺（1/2）、腦、腎上腺淋巴轉移：肝門、腹主動脈旁、腹膜后種植轉移：腹膜、橫膈 （肝癌破裂）,肝癌肺轉移,局部：肝區疼痛肝腫大血管雜音,全身： 黃疸發熱肝硬化征象轉移灶癥狀,六、臨床表現 （1）,Clinical Features at Presentation,SymptomsPercent of PatientsNone23%Abdominal Pain32%Ascites 8%Jaundice 8%Anorexia/weight loss10%Malaise 6%Bleeding 4%Encephalopathy 2%,Gastroenterology 2002,HCC Diagnosis,六、臨床表現（2）,肝性腦病靜脈曲張上消化道出血肝癌破裂出血繼發感染,并發癥,Diagnosis of Hepatocellular Carcinoma,七、診斷 早發現、早診斷、早治療,1、AFP HCC特異性最強，早期診斷指標 HCC普查、診斷、療效判定和預測復發 HCC的陽性率70-90% 假陽性：肝炎、肝硬化、生殖胚胎瘤及肝轉移瘤,2、影像學診斷,(1) 超聲 肝癌影像診斷中的首選方法,(2) CT,Plain CT Dynamic CT Delayed CT,(3) MRI,(4) DSA,Dual Blood Supply of Liver,The vascular supply of HCC arises from the hepatic artery through neovascularization. Imaging of the liver has to be performed in a triple phase manner to account for the early arterial phase followed by the portal venous phase and the delayed phases,Yu JS, et al, Am J Roentgenol 1999,HCC Diagnosis,Arterial phase,Venous phase,Arterial phase,Washout in HCC,Washout in HCC,HCC Diagnosis,Venous phase,Arterial phase,Washout in HCC,Washout in HCC,HCC Diagnosis,Non-contrast,: high-grade dysplastic nodule,: well-differentiated,: moderately differentiated HCC,De novo hepatocarcinogenesis,?,?,小肝癌的早期診斷- CTAP 和 CTHA,Portal,supply,Arterial,supply,LRN,LDN, HDN,wd-HCC,Classicl HCC,Portal supply,Hepatic arterial supply,Abnormal arterial supply,Stepwise Hepatocarcinogenesis and Changes of Intranodular Blood Supply,LDN: low-grade dysplastic nodule, HDN: high-grade dysplastic nodule,S.M. vein,Celiac a.,Intestine,CT during Arterial Portography (CTAP),Contrast injection,into sup. mesenteric a.,S.M. vein,Sup. mesenteric a.,Celiac a.,Intestine,CT during Hepatic Arteriography (CTHA),Contrast injection,into hepatc a.,A combined DSA and helical CT system,(CT/ANGIO system, Toshiba,Japan),CT/ANGIO System,Moderately differentiated HCC (classical HCC),CTHA,CTAP,CTAP CTHA,肝細胞癌診斷標準 (BCLC、AASLD),病理診斷： 細胞學或組織學診斷流程1、小于1cm: 隨診 每3-4月 超聲2、1-2cm: 兩種特征性影像學表現 或 活檢 3、大于2cm者： 肝硬化背景 + 一種特征性影像學表現 肝硬化背景 + AFP(200) + 一種影像學診斷影像學：增強CT、MRI、超聲造影 特征性表現： 動脈期造影劑的攝取伴靜脈期的快速清除,Guidelines for Diagnosis of HCC,Typical features of HCC = vascular nodule on arterial phase with washout in delayed phases,Ultrasound findings,Bruix J, et al, Hepatology 2005,HCC Diagnosis,Screening / Surveillance for Hepatocellular Carcinoma,Recommendations Screening,Surveillance should be performed using US (level II)AFP should not be used for screening (level II)Screening should be done / 6 months (level II)Higher risk does not imply shorter interval (level III),八、鑒別診斷,肝海綿狀血管瘤肝膿腫脂肪肝肝硬化轉移性肝癌鄰近肝區的肝外腫瘤,轉移性肝癌,九、肝癌治療現狀,外科切除： 30%（腫瘤大小、部位、多中心、肝功） 肝移植: Milan criteria (單結節5 cm 或 兩到三個3 cm) 介入治療：肝動脈化療栓塞 (TACE) 不能手術切除或術后復發肝癌的首選療法 消融治療：Imaging-guided delivery of energy for ablation 經皮肝穿無水酒精注射治療 經皮肝穿射頻治療 經皮肝穿微波治療 經皮肝穿（或手術）冷凍治療,BCLC 分期系統，2010,Semin Liver Dis 1999;19:329338 to 2010;30:61-74,多個腫瘤,門脈轉移,N1,M1,Tumor Stage (number & size, MVI, EHS) Liver functionHealth status, PST/ECOG,單發結節,2cm,3 個結節, 3cm,Efficacy of treatment,Child Pugh A-B,Child Pugh A,Child Pugh C,隨機對照試驗（50%） 中位生存時間11-20月,對癥(20%) 生存期3月,BCLC 分期系統及治療策略,TACE,多個腫瘤,門脈轉移,N1,M1,新藥治療,索拉非尼,Radiofrequency Ablation for Hepatocellular Carcinoma,Probe insertion,Deployment of tines and treatmentof tumor and surrounding region,HCC Treatment,大血管旁的HCC,Embolic Materials(Lipiodol+doxorubicin+contrast),Lipiodol (iodized poppy seed oil),Gelatin sponge particles,EMULSIONS,EMULSIONS,Water (Drug) in Oil (Lip) Oil (Lip) in Water (Drug),-in blood- -in blood-,D,LIP,D,LIP,Portal vein,Hepatic vein and liver Segments in Angio,Subsegmental Transarterial Chemoembolization of HCC,Subsegmental Transarterial Chemoembolization of HCC,Dynamic CT,Lipiodol CT,Celiac a.,Catheter in A8,Subsegmental TACE for small HCC in S8,原發性肝癌治療難點,大多合并嚴重肝硬化易發生肝內播散和遠處轉移手術切除率低(20%)術后復發率高,Molecular Events in the Multi-Step Development of Hepatocellular Carcinoma,Normal liver,HBVHCValcohol,Chronichepatitiscirrhosis,p53 mutationreduced p21WAF1/CIP1expression,Rbdysfunction,EarlyHCC,Advanced/Metastatic HCC,E cadherininactivation,p16INK4inactivation,Aberrant DNAmethylation,Dysplasia,p53 mutation,Dietary aflatoxin,Molecular Events in the Multi-Step Development of Hepatocellular Carcinoma,Hui and Makuuchi, Scand J Gastroenterol 1999,HCC Pathogenesis,Llovet et al. NEJM 2008;