Internal medicine 2: Hepatic carcinoma review

Hepatic carcinoma 1. Hepatocellular carcinoma (definition) Malignant neoplasms of the liver that arise from hepatocyte(HCC) or bile duct epithelium 2. Two origin of hepatocellular carcinoma • originate in the liver--from hepatocyte, bile duct epithelium, or mesenchymal tissue • originate out of the liver-- metastasis to the liver from primary lesions in remote or adjacent organs.

3. Age, gender • Age: 40-50 years • Gender: Male: female (3-4 : 1) 4. Etiology  Viral hepatitis • HBV • HCV  Cirrhosis  Environmental or chemical toxins • Alflatoxin B1  Inheritance background • Inherited hemochromatosis • Deficiency of α-anti-trypsin • Inherited tyrosenemia 5. HCV infection—the major risk factor for hepatocellular carcinoma  A 30-50 nm RNA virus  HCV infection—the major risk factor for hepatocellular carcinoma  HCV-direct and indirect carcinogen  Inducing chronic hepatitis, cirrhosis  Not integrate into host DNA 6. Classification of hepatocellular carcinoma (according to size, characteristic)

Massive HCC  Most common HCC in China  A large circumscribed mass(≥5cm) with small satellite nodules  Most common in the noncirrhotic livers in younger patients  easily to rupture (Mass≥10cm) Nodular HCC:  Accounts for about 75% of HCC in the west countries Usually coexists with cirrhosis  Consist of numerous round or irregular nodules of various sizes scattered throughout the liver Minute HCC:  diameter of single nodule(or fused nodule) ＜3cm Small presymptomatic HCC  Diameter ≤3cm  Well differentiated form  Complete envelope

 Large amounts of lymphocytes infiltration around the tumor  Progress slowly  Low rates of embolism of portal vein or other blood vessels Diffuse type:  rare type of HCC  The liver is infiltrated by indistinct minute tumor nodules  difficult to distinguish from regenerative nodules of cirrhosis 7. Metastasis (Intrahepatic, Extrahepatic) Hematogenous metastasis: Intrahepatic hematogenous metastasis is earliest and most common (Violation of the portal vein (Violation of the hepatic vein

tumor embolus

portal hypertension, ascites)

general circulation

extrahepatic metastasis, Pulmonary is most common)

Lymphatic metastasis: cholangiocarcinoma is most common Implantation metastasis Direct diffusion: rarely 8. Histology (4 types) • HCC: originate from hepatocytes（ 90％） • Cholangiocarcinoma: originate from small intrahepatic bile ducts(called peripheral cholangiocarcinoma),large

intrahepatic bile ducts (hilar cholangiocarcinoma) （ 10％） • Mixed type: rare • Special types: clear-cell carcinoma fibrolamellar hepatocellular carcinoma 9. Symptoms (Digestive tract abnormalities, Systemic findings of tumor, Paraneoplastic syndromes, Manifestation due to metastasis)

Digestive tract abnormalities:  poor appetite, early satiety, abdominal distension, nausea, vomiting, diarrhea  As a result of tumor compression, ascites, hepatic failure, and generalized swelling of the abdomen Systemic findings of tumor:  Progressive weakness, weight loss, malnutrition, fever, cachexia Paraneoplastic syndromes:  Result from biological active substance that synthetic and secreted by tumor  Earlier than the local effects of the tumor  Indication of tumor presence  Some have therapeutic implications 10. Definition of paraneoplastic syndromes

• • • •

Result from biological active substance that synthetic and secreted by tumor Earlier than the local effects of the tumor Indication of tumor presence Some have therapeutic implications

11. Signs (Enlargement of liver, Splenomegaly, Ascites, Jaundice)

Splenomegaly: due to passive congestion Ascites:  as the result of portal hypertension, vascular invasion, involvement of peritoneum by primary tumor or metastasis

 Yellow or blood-stained in color  Tumor cell may be found in the ascites Jaundice  An infrequent initial complaint  When present, it may be obstructive  As a result of bile duct metastasis or tumor compression Others:  arterial bruit(rough, systolic in timing, not affected by changing the position of the patient)  Friction rub(characteristic of hepatic metastasis or abscess)

12. Clinical stage

Clinical stage I subclinical stage

II a

II b III

Characteristics Asymptomatic ↑ serum fetoprotein Nodular lesion ≤ 5cm No thrombosis No lymphatic or remote metastasis Symptomatic Obvious sign 5-10 cm nodular lesion in 1 lobe or ≤ 5cm nodular lesion in 2 lobes No portal embolism No lymphatic or remote metastasis 1 or 2 tumors ≥ 10cm or 3 nodular lesions ≤ 10 cm involved 1 lobe, or 5-10 cm tumors involved 2 lobes Thrombosis of portal vein present or not Thrombosis of portal vein or lymphatic or remote metastasis present

13. Complications

• Hepatic encephalopathy • Gastrointestinal bleeding: as a result of hepatic failure, erosion of mucous, or coagulation disorder • Tumor rupture: spontaneous or traumatic rupture with the result of hemoperitoneum or blood-stained ascites • Secondary infection: pneumonia, infection of fungi, virus 14. Alpha-fetoprotein (important), Isoenzymes of γ-glutamyl tranferase, Des-γ-carboxy prothrombin, Alpha-L-fucosidase (significance)

Alpha-fetoprotein • high concentration in fetal serum/minute amounts after birth • Elevated serum α-fetoprotein(＞500μg/L) is a strong pointer to the diagnosis of HCC; • Sensitivity:70%~90%,Specificity:90% • Low concentration( ＜ 500μg/L ) may be found in patients with a variety of acute or chronic active hepatitis/pregnancy/tumor from embryonal cell/metastasis) • False positive results may also be obtained with tumors of the ovary or testis • The serum value elevated higher in the younger patient • No obvious correlation between the serum level of α-fetoprotein and the tumor size, clinical stage, or prognosis

isoenzymes of γ-glutamyl tranferase • Primary or metastatic tumor of the liver: Sensitivity:90%, Specificity:97.1% • AFP negative HCC: Sensitivity72.7%, • Small asymptomatic HCC: Sensitivity78.6% • Valuable in early diagnosis of HCC Des-γ-carboxy prothrombin • Prothrombin produced by Vit K absence • A better marker of HCC in the low incidence districts • Both sensitivity and specificity are lower than α-fetoprotein • Detected by ELISA: positive ≥250μg/L Alpha-L-fucosidase • HCC: Sensitivity: 75%, Specificity:95% • AFP negative HCC: Sensitivity76% • AFP negative small HCC: Sensitivity70% Other laboratory examination: • ALT, AST, bilirubin, total protein, albumin • Blood cell counting, etc.

15. Imaging examination (tumor size)

• • • • • • •

Ultrasonic examination:≥2cm Computerized tomography: ≥2cm Enhanced contrast CT: ≥1cm Magnetic resonance image(MRI) Hepatic arteriography Laparoscopy Biopsy: CT guided needle aspiration or biopsy

16. Three diagnosis criteria of HCC (AFP is very important)

Criteria 1 • AFP≥400μg/L 4 weeks, excluded false positive • Firm or stony hard enlarged liver • Imagine result Criteria 2 • AFP≤400μg/L 8 weeks, excluded false positive • Two kinds of imaging result • Or two specific tumor marker positive Criteria 3 • Obvious clinical manifestations of HCC • Documented extrahepatic metastasis • Metastatic hepatic tumors excluded

17. Differential diagnosis

• Cirrhosis and hepatitis: serum level of ALT and AFP(≥500μg/L) • Metastatic hepatic tumors • Benign tumor or disease of liver: hepatic cyst, hepatic adenoma, cavernous hemangioma,focal nodular hyperplasia • Hepatic abscess

18. Treatment

Operation  Indication: tumor localized in one lobe, no hepatic failure, especially small presymptomatic HCC  Overall 5-year survival rates are up to 56% for patients with localized resectable HCC;  Recurrence rate after resection is high.

Alcohol injection  Indication: small tumor(≤3cm) not suitable for resection multiple lesions with two lobes involved HCC accompanied by severe cirrhosis  Contraindication: coagulation disorder  Carry the risk of disseminating the tumor by facilitating the passage of malignant cells into blood stream .

Embolization or chemoembolization  Bland embolization or embolization with simultaneous administration of Lipiodol and anticancer drugs(5FU,mitomycin, CDDP density-dependent phosphoprotein, etc) before resction  Patients receiving transarterial chemoembolization(TACE) may survive longer than untreated patients.

Chemotherapy: no documented effect Radiotherapy: especially brachyradiotherapy : is effective for some patients Biological agents: TNF-α, IL-2, IFN-α, IFN- γ, LAK (lymphokine-activated killer cells),etc.

Liver transplantation:  Indication: tumor was not suitable to resection but had not spread beyond the liver  With encouraging results because advancement of anti-immune drugs and operation technique.