HEPATOCELLULAR CARCINOMA

Dairion Gatot, Soegiarto Gani, Savita Handayani

Division of Medical Oncology and Hematology Department of Internal Medicine Medan-Kepala Batas 2010

Definition
Primary Hepatocellular Carcinoma is primary liver tumor usually developed in chronic liver disease especially viral hepatitis

Incidence
Liver cancer the fourth cause of death due to cancer worldwide and the third in men. Incidence differs geographically. Indonesia : one of the countries in which the incidence of Hepatitis B is intermediate.

Risk Factors
Viral hepatitis B and C. Toxin: aflatoxin and toxin found in drinking water. Chronic hepatitis and liver cirrhosis due to any cause. Iron overload in hereditary hemochromatosis.

Hepatitis B dan HCC

Taiwan: HBsAg (+) HCC risk 223 x compared with HBsAg (-). Canada & Austria: Risk for Asian population > non Asia. HBeAg (+) increase HCC risk (RR 60,2 dgn 95% CI 35.5-102.1), compared with only HBsAg (+) (RR 9.6 with 95% CI 6.0-15.2). HBV DNA load goes in line with HCC risk. HCV co-infection increases HCC risk.

Hepatitis C and HCC

Carcinogenesis mechanism of HCV has not been clear yet, its suspected that HCV rapid cell turnover and chronic inflammatory state. USA: one third of HCC cases have a correlation with HCV. HCC almost always occurs in liver cirrhosis or chronic HCV with high grade liver fibrosis, meanwhile HCC in chronic Hepatitis B can manifests in all condition.

Aflatoxin
A mycotoxin that commonly contaminates corns, soya beans,and peanuts. High aflatoxin diet is associated with HCC development. Tempe (fermented soybeans)? Aflatoxin mutation in codon 249 tumor supressor gene p53. Carcinogenic potentiation with HBV infection.

Contaminated drinking water

China: drinking water from ponds contaminated by blue-green algal toxin Microcystin.

Pathogenesis
Hepatocarcinogenesis can take a period of 30 years after HBV / HCV infection. Cytokines from inflammatory cells, cell regeneration process and viral transactivation increase of Transforming Growth Factor (TGF) expression and Insulin Growth Factor-2 (IGF-2) through epigenetic mechanism increase the hepatocyte proliferation.

Pathogenesis
Methylation disorders (hypo- or hypermethylation also occurs in CpG

Clinical Symptoms
Symptoms =liver cirrhosis symptoms. Make a suspicion in patients with the initial diagnosis compensated liver cirrhosis ascites, hepatic encephalopathy, jaundice, variceal bleeding. Tumor mass icterus, pain. Tumor rupture intraperitoneal bleeding: distension and abdominal pain, anemia. Metastatic symptoms: lungsdyspnoe, bones bone pain. Paraneoplastic syndrome.

Paraneoplastic syndrome in HCC

Hipoglicaemia: due to high grade metabolism IGF-2 increase. Erythrocytosis: 23% HCCEPO Hypercalcemia: metastatic bones or PTHrp secretion. Diarrhea: due to vasoactive intestinal polypeptide secretion, gastrin, and peptide with prostaglandin-like immunoreactivity

Diagnosis
USG CTscan MRI AFP
Des-gamma-carboxy prothrombin (prothrombin produced by vitamin K absence or antagonism II [PIVKA II])

Percutaneous biopsy is only performed if the diagnosis is unclear

If the lession is hypervascular, with increase of T2 signal intensity in MRI, vein invasion, or accompanied with AFP increase.

HCC diagnosis

TNM staging
Primary tumor (T) TX Primary tumor cannot be assessed T0 No evidence of primary tumor T1 Solitary tumor without vascular invasion T2 Solitary tumor with vascular invasion, or multiple tumors none more than 5 cm T3 Multiple tumors more than 5 cm or tumor involving a major branch of the portal or hepatic vein(s) T4 Tumors with direct invasion of adjacent organs other than the gallbladder or with perforation of the visceral peritoneum Regional lymph nodes (N) NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Regional lymph node metastasis Distant metastasis (M) MX Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis Fibrosis score (F)* F0 Fibrosis score 0-4 (none to moderate fibrosis) F1 Fibrosis score 5-6 (severe fibrosis or cirrhosis) Stage grouping Stage I T1 N0 M0 Stage II T2 N0 M0 Stage IIIA T3 N0 M0 Stage IIIB T4 N0 M0 Stage IIIC Any T N1 M0 Stage IV Any T Any N M1

Management
Median survival 6-20 months. Surgery resection, but majority can not be performed Treatment of choice:
Liver transplantation Radiofrequency ablation (RFA) Percutaneous ethanol or acetic acid ablation Transarterial chemoembolization (TACE) Cryoablation Radiation therapy Systemic chemotherapy

Partial hepatectomy
Potentially curative. Ideal resection: solitary HCC without radiological proof showing invasion of liver vascularisation, no hypertension with good liver function reserve. Long-term relapse-free survival 40%, and five-year survival 90%.

Radio Frequency Ablation

RFA = localized thermal energy application from radiopfrequency wave throuigh electrodes increase of local lession temperature > 60C necrosis. It had better performed in single tumor < 4 cm in diameter and with Child-Pugh A or B.

Trans Arterial Chemo Embolization (TACE)

Majority of HCC supply vessels are originated from hepatic vein. Insertion with syringe to hepatic vein : a chemotherapeutic agent with or lipiodol procoagulant agent. Lipiodol is a contrast agent that increase intratumoral chemotherapy retention. Contraindication :portal vein thrombosis,encephalopathy, biliary duct obstruction.

Radiotheraphy
HCC is a radiosensitive tumor but liver is a very radiosensitive organ, that can only receive approximately 20 Gy stereotactic body radiation therapy (targeted) or selective internal RT with iodine-131 [131I]- labeled lipiodol or yttrium-90 [90Y]-tagged glass microspheres)

Chemotherapy
HCC is regarded as a relatively chemo refractory. Because of the high expression of drug resistance gene such as p-glycoprotein, glutathione-S-transferase, heat shock proteins and p53 mutation.

Targeted Therapy
Sorafenib = multitargeted tyrosine kinase inhibitor. SHARP trial sorafenib monotherapy as standard monotherapy for advanced HCC.