1. Primary carcinoma of the liver

2. Introduction/epidemiology Primary carcinoma of the liver (Hepatocellular carcinoma) is one of the common cancers in China with high mortality It may either originate from hepatocytes or bile duct epithelium There is a geographic distribution with high incidence in Asia, South part of African, whilst low incidence in North American, North European It also varies even in one country

4. Sex distribution Male predominance is more obvious in populations at high risk (ratio 3.7:1) than in those whose risk is low or intermediate (2.4:1) However, in patients in developed countries who have hepatocellular carcinoma but not cirrhosis, the sex distribution is approximately equal

5. Age distribution Middle aged man in predominance It rises progressively with age, although it tends to level off in the oldest age group In some sub-Saharan countries, there is a definite shift toward younger age It is rare in children

6. Etiology & Pathogenesis Hepatocarcinogenesis is a complex incremental process that evolved over many years Four major (and several minor) causal associations of the tumor have been identified The etiologic agents differs in different parts of the world, and this may explain the diverse biologic characteristics of hepatocellular carcinoma in different world

7. Risk factors Major Chronic HBV infection Chronic HCV infection Repeated exposure to aflatoxin β 1 Cirrhosis

8. Risk factors Minor Oral contraceptive steroids cigarette smoking Hereditary hemochromatosis Wilson disease α 1 –antitrypsin deficiency Type 1 hereditary tyrosinemia Glycogen stroge disease (types 1 and 2) Hypercitrullinemia Ataxia telangiectasia Membranous obstruction of the inferior vena cava

9. Hepatitis B virus Chronic infection with HBV may cause as much as 80% of human hepatocellular carcinoma It is closest in ethnic Chinese and black Africans As many as 80% of whom are still infected when they develop hepatocellular carcinoma Early infection carries a greater risk than does infection in adulthood

10. Hepatitis B Virus HBV DNA is integrated into cellular DNA in about 95% of patients with HBV-related tumors The site of integration is random Integration perturbing the function of cellular oncogenes or tumor suppressor genes, which may contribute to hepatocellular carcinogenesis

11. Hepatitis C Virus HCV is carcinogenic in human In Japan, Italy, Spain, chronic HCV infection is the major risk factor for hepatocellular carcinoma A far smaller percentage of ethnic Chinese and black African have HCV-induced tumors HCV does not integrate into host DNA, its mechanism differs from that of HBV

12. Cirrhosis HCC frequently coexists with cirrhosis In ethnic Chinese and black Africans, it is usually of the macronodular variety and is the result of chronic HBV infection In other populations, it is commonly of the mixed micro- macronodular or micronodular variety and is usually caused by chronic HCV infection, alcohol abuse, or both Male sex, age, duration of cirrhosis are the main risk factors for HCC

13. Aflatoxin β 1 It is a major risk factor for HCC in certain geographic regions Epidemiologic studies have shown a positive correlation betweeen exposure to aflatoxin β 1 and the incidence of HCC

14. Minor risk factors As many as 45% of persons who suffer from hereditary hemochromatosis develop hepatocellular carcinoma This complication was thought to occur only in the presence of cirrhosis Patients with Wilson disease occasionally develop HCC, although only in the presence of cirrhosis Other inherited metabolic disturbances that predispose to HCC may also cause cirrhosis( α 1 –antitrypsin deficiency Type 1 hereditary tyrosinemia)

15. Minor Risk Factors In patients with the use of contraceptive steroids, the risk is related directly to the duration of use Controversy exists over whether cigarette smoking

16. Pathology Gross appearance Microscopic appearance Well-Differentiated appearance Moderate-Differentiated appearance Undifferentiated appearance Fibrolamellar hepatocellular carcinoma

17. Gross appearance Hepatocellular carcinoma may take three forms Nodular <5cm, usually coexists with cirrhosis If <3cm (either single or two) Massive > or =5cm, most common form most prone to rupture Diffuse It is rare, may be difficult to distinguish from regenerating nodules of cirrhosis

18. Small HCC <3cm It is based on the histologic finding and biological characteristic Well differentiated, low grade malignancy Usually encapsulated cancer embolism rate is low with relative good liver function

19. Microscopic appearance Fibrolamellar hepatocellular carcinoma Typically occurs in young patients Equal sex distribution Does not secrete alpha-fetoprotein It is not caused by HBV or HCV infection Almost always arises in a noncirrhotic liver It is more often amenable to resection and has a good prognosis

20. Metastasis of HCC Intrahepatic metastasis Extrahepetic metastasis Five most common sites of HCC metastasis are: regional lymph nodes lung adrenal glands bone peritoneal surface

21. Clinical manifestation Symptoms Prevalence(%) Abdominal pain 59-95 Weight loss 34-71 Weakness 22-53 Abdominal swelling 28-43 Nonspecific 25-28 Gastrointestinal symptoms

22. Clinical manifestation Physical signs Prevalence(%) Hepatomegaly 54-98 Hepatic bruit 6-25 Ascites 35-61 Splenomegaly 27-42 Jaundice 4-35 Wasting 25-41 Fever 11-54

23. Paraneoplastic syndromes associated with hepatocellular carcinoma Hypoglycemia Polycythemia (erythrocytosis) Hypercalcemia Sexual changes: isosexual precocity gynecomastia feminization Systemic arterial hypertension Watery diarrhea syndrome Porphyria Carcinoid syndrome Osteoporosis Hypertrophic osteoarthropathy Thyrotoxicosis Thrombophlebitis migrans Polymyositis Neuropathy

24. Clinical stages Stage I (subclinical stage) The outcome of screening to high risk population, hepatitis history more than 5 years or HbsAg positive No specific symptoms Elevated AFP Single or multiple nodules, <=5cm size No vascular invasion

25. Clinical stages Stage IIa Present some symptoms or signs of HCC Abnormal laboratory findings Single or double nodules >5~10cm No portal vein cancerous embolism No lymph nodes enlargement No distant metastasis

26. Clinical stages Stage IIb Single or double nodules >=10cm or triple <=10cm in one hepatic lobule Single or double nodules 5~10 cm in two hepatic lobule Portal vein cancerous embolism

27. Clinical stages Stage III More advanced than stage IIb Or with vascular invasion/intrahepatic or peritoneal lymph nodes enlargement or distant metastasis

28. Complications Hepatic encephalopsy end stage deadly complication, 1/3 death cause Gastrointestinal bleeding esophageal varices, erosive GI mucosa Rupture of hepatic cancer mass accounts for 9~14% Secondary infection

29. Laboratory tests and others Tumor markers of HCC Radiologic investigations Needle biopsy

30. Tumor markers Alpha-Fetoprotein γ –Glutamyl Transferase α –L-Fucosidase Des- γ -Carboxy Prothrombin

31. Alpha-Fetoprotein Alpha-Fetoprotein is an α 1-globulin normally present in high concentration in fetal serum but in only minute amounts thereafter (<20 μ g/L) Reappearance of high serum levels of alpha-fetoprotein in serum (>500 μ g/L) is a strong pointer to the diagnosis of HCC Below this level may be found in patients with variety of acute and chronic benign hepatic disease or GI tumor with lever metastasis In patients with pregnancy, neonatal, testis tumor or ovarian tumor, the serum alpha-fetoprotein may also elevated

32. Fucosylated Alpha-Fetoprotein Reactivity of alpha-fetoprotein with Lens culinaris agglutinin A in the differentiation between HCC and benign hepatic parenchymal disease Reactivity with concanavalin A in distinguishing HCC from other tumor capable of producing this protein To measure fucosylated alpha-fetoprotein is rather complex

33. γ –Glutamyl Transferase Normal serum contains as many as 10 isoenzymes of γ –Glutamyl Transferase As many as three tumor-associated isoenzymes may be present in serum from patients with HCC I’ 60% I’’ 27% II’ 30%

34. Des- γ -Carboxy Prothrombin It is raised in the majority of patients with HCC ≥ 250 μ g /L is considered positive In populations where incidence of this tumor is low, the abnormal prothrombin may prove to be a better marker than alpha-fetoprotein

35. α –L-Fucosidase It was first reported to have a sensitivity of 75% and specificity 90% in HCC In a subsequent study, it failed to distinguish between cirrhosis and HCC In black Africans, this marker is less sensitive,less specific and has lower predictive value than alpha-fetoprotein

36. Tumor markers Sensitivity(%) Specificity (%) Advantages Disadvantages Alpha-fetoprotein 80~90(high) 90 Relatively quick Relative 50~70(low) easy to measure expansive DES- γ –carboxy 58-91 84 Easy and quick Far more prothrombin to measure expansive α –L-fucosidase 75 70-90 Easy and quick to measure, relative inexpansive Isoenzymes of γ- 60 96 Relatively easy and Expansive Glutamyl transferase quick to measure

37. Hepatic imaging Ultrasonography Computed Tomography Magnetic Resonance Imaging Hepatic Arteriography Position emission computed tomography

38. Ultrasonography Detects tumor which size >2cm Shows the size, sharp, site and its relationship with vessel Identifies the hepatic vein, portal vein cancerous embolism Doppler sonography are useful

39. CT It usually shows the tumor size greater than 2 cm It may detect small HCC by using contrast materials It is the best method for detecting small and micro HCC

40. MRI Useful for detecting both primary and tumor spread Useful in distinguishing between small HCC and small hemangiomas uncovered during surveillance

41. Hepatic arteriography It is the best modality for detecting the tumor site It may show tumor with 0.5~1.0cm tumor

42. CT Hepatic arteriography

43. Diagnosis AFP >400 μ g/L, exclude chronic active liver disease, pregnancy, congenital tumors or metastatic liver tumor, signs suggesting the hepatic tumor AFP <400 μ g/L, two of the radiologic investigations indicating the liver tumor or two tumor markers are positive Manifestations of HCC with confirmed extrahepatic sighs

44. Differential Diagnosis Hepatic cirrhosis/hepatitis Secondary liver cancer Benign hepatic tumors Liver abscess

45. Treatment Surgical resection Alcohol injection Liver transplantation Embolization and chemoembolization Chemotherapy

46. Surgical resection Offers the best chance of cure of HCC For this treatment to be contemplated The tumor must be confined to one hepatic lobe Ideally, the nontumorous liver tissue should not be cirrhotic The recurrence rate after resection is high

47. Alcohol injection It is also called percutaneous ethanol injection (PEI) Small tumor not suitable for resection Either because they are multiple or because theirposition in the liver or because of severe hepatic dysfunction It carries the risk of disseminating the tumor

48. Liver transplatation It has been performed in patients whose tumors was not amenable to resection, but not spread beyond the liver The early results were characterized by an unacceptable high recurrence rate (around 70%), and this was accompanied by a surprisingly short survival after the recurrence

49. Embolization/Chemoembolization In selected patients, bland embolization or embolization with simultaneous administration of lipiodol and anticancer drugs has been used to reduce the viable tumor mass before surgery It has not yet been clearly established that the advantage gained is offset by the disadvantage Patients receiving transarterial chemoembolization may survival longer than untreated patients

50. Chemotherapy A large number of anticancer agents can be employed The predictable response rate has always been less than 20% Current trials are investigating the use of agents that reverse multidrug resistance

51. Prognosis In general, the prognosis is poor