HEPATOCELLULAR

CARCINOMA

Presented by

Suman Raj Baral

Introduction The most common primary tumor of the liverSixth most common malignancy in the world

• Incidence – 10-20/100,000 in South East Asia – 1-3/100,000 in North America– 28/100000 in Singapore

(d/t increase incidence of HCV related cirrhosis apart from HBV)

• Two to eight times more common in males than in females in low and high incidence areas

• Higher incidence in males

• Related to higher rates of associated risk factors such as HBV infection, cirrhosis, smoking, alcohol abuse, and higher hepatic DNA synthesis in cirrhosis

Pathogenesis • The precise mechanisms of carcinogenesis

– unknown• Repeated circle of cell death & regeneration

mutation of hepatocytes• Preneoplastic changes – hepatocytes

dysplasia can be seen.

• Associations between hepatic viral infections, environmental exposures, alcohol use, smoking, genetic metabolic diseases, cirrhosis, OCPs, and the development of HCC recognized.

• 75% to 80% of HCC related to HBV (50%-55%) or HCV (25%-30%) infection.

• The development of HCC is a complex and multistep process that involves any number of these risk factors.

• Studies estimate relative risks of 5 to 100 for the development of HCC in HBV-infected individuals compared with noninfected individuals

• geographic areas high in HBV infection have high rates of HCC; HBV infection precedes the development of HCC; the sequence of HBV infection to cirrhosis to HCC is well documented; and the HBV genome is found in the HCC genome.

• Next proposed is the HCV infection.

It appears to be one of chronic infection with a benign early course but with ultimate development of cirrhosis and HCC.

• Proposed mechanism is related to cirrhosis and chronic hepatic inflammation, which is present in 60% to 90% of patients with HBV infection and HCC.

• Cirrhosis, however, is not a prerequisite for the

development of HBV-related HCC.

• Note that the risk for HCC is not simply related to HBV exposure but requires chronic infection.

Noted…!!!!

• HBV and HCV infection are both independent risk factors for the development of HCC

However, Act synergistically when an individual is

infected with both viruses.

• Chronic alcohol abuse has been associated with an increased risk for HCC, and there may be a synergistic effect with HBV and HCV infection.

• Cigarette smoking linked to the development of HCC, but the evidence is not consistent

• Aflatoxin, produced by Aspergillus species, is a powerful hepatotoxin that acts as a carcinogen and increases the risk for HCC.

Others• Nitrites, hydrocarbons, solvents, pesticides,

and vinyl chloride.

• Inherited metabolic liver diseases, such as hereditary hemochromatosis, a1-antitrypsin deficiency, and Wilson's disease

• Hormones ???? ( OCP/Anabolic Steroids)

P53, PIKCA, B-Catenin

Pathology• Three distinct patterns grosslyHanging type: easily resectable with vascular

stalkPushing type : characterized by growth that

displaces vascular structures rather than invading them, usually resectable

Infiltrative type : Invade vascular structures and difficult to resect

• Right upper quadrant abdominal pain and weight loss and have a palpable mass.

• Nonspecific symptoms of advanced malignancy such as anorexia, nausea, lethargy, and weight loss are common

• HCC can present as a rupture with the sudden onset of abdominal pain followed by hypovolemic shock secondary to intraperitoneal bleeding.

Clinical Features

• Rare presentations include hepatic vein occlusion (Budd-Chiari syndrome), obstructive jaundice, hemobilia, or fever of unknown origin.

• As a paraneoplastic syndrome, most commonly hypercalcemia, hypoglycemia, and erythrocytosis ( <1 %)

Laboratory• Laboratory studies should include a

Complete blood count, electrolytes, liver function tests, coagulation studies ( INR, PTT), and alpha-fetoprotein determination.

Determining disease severity• Anemia: Low hemoglobin may be related to bleeding

from varices or other sources.• Thrombocytopenia: A platelet count below 100,000/mL

is highly suggestive of significant portal hypertension/splenomegaly.

• Hyponatremia is commonly found in patients with cirrhosis and ascites and may be a marker of advanced liver disease.

• Increased serum creatinine level may reflect intrinsic renal disease or hepatorenal syndrome.

• Prolonged PT/INR reflects significant impairment of hepatic function that may preclude resection.

• Elevated liver enzymes (AST/ALT) reflect active hepatitis due to viral infection, current alcohol use, or other causes.

• Increased Bilirubin level usually indicates advanced liver disease.

• Hypoglycemia may represent end-stage liver disease (no glycogen stores).

Determining Etiology• HBsAg/anti-HBc, anti-HCV - Viral hepatitis

(current/past)• Increased iron saturation (>50%) - Underlying

hemochromatosis• Low alpha-1-antitrypsin levels - Alpha-1-

antitrypsine deficiency

• Increased alpha fetoprotein - Levels greater than 400 ng/mL considered diagnostic with appropriate imaging studies

• Hypercalcemia - Ectopic parathyroid hormone production possible in 5-10% of patients with hepatocellular carcinoma

• Thrombocytosis (normal/rapid increase in platelet count in patients with a history of thrombocytopenia)

Diagnosis Ultrasound Abdomen

CECT SCAN ABDOMEN

Magnetic Resonance Imaging

Alpha- FetoproteinA hypervascular mass consistent with HCC combined with an AFP higher than 400ng/mL is diagnostic

Particularly useful in monitoring treated patients for recurrence after normalization of levels

STAGING

Staging - AJCC

OKUDA STAGING

It adds up a single point for •presence of tumor involving more than 50% of the liver, •presence of ascites, •albumin less than 3 g/dL, and•bilirubin more than 3 mg/dL Reliably distinguishes patients with a prohibitively poor prognosis from those with potential for long-term survival

Stage 1 0Stage 2 1 or 2

Stage 3 3 or 4

CLINICAL PARAMETERS CUTOFF VALUES POINTSChild-Pugh stage A 0  B 1  C 2Tumor morphology Uninodular, <50%

extension0

  Multinodular, <50% extension

1

  Massive or extension >50%

2

AFP (ng/dL) <400 0  >400 1Portal vein thrombosis

No 0

  Yes 1

   The Cancer of the Liver Italian Group Score (CLIP)

Score ranges from 0 to 6; scores of 4 to 6 are generally considered advanced disease, whereas scores of 0 to 3 have the potential for long-term survival

Treatment Of HCCSurgicalResectionOrthotopic liver transplantationAblativeEtOH injectionAcetic acid injectionThermal ablation (cryotherapy, radiofrequency ablation, microwave)TransarterialEmbolizationChemoembolizationRadiotherapyCombination Transarterial and AblativeExternal-beam Radiation TherapySystemicChemotherapyHormonalImmunotherapy

Surgical Modality ( Resection VS Transplantation)• Depends upon Child Pugh score (A)• Only 10% to 20% of patients are considered to

have resectable disease• The overall postresection survival rates for HCC

are 58% to 100% at 1 year, 28% to 88% at 3 years, 11% to 75% at 5 years, and 19% to 26% at 10 years.

• commonly cited negative prognostic factors are tumor size, cirrhosis, infiltrative growth pattern, vascular invasion, intrahepatic metastases, multifocal tumors, lymph node metastases, margin less than 1 cm, and lack of a capsule.

• Ideal treatment is LIVER TRANSPLANTATION

• Patients with advanced cirrhosis (Child's B and C) and early-stage HCC are considered for transplantation.

University of California, Sanfrancisco

Others Modalities- Ethanol• a useful technique for ablating small tumors.

• Tumor killed by a combination of cellular dehydration, coagulative necrosis, and vascular thrombosis.

• Most tumors less than 2 cm in size can be ablated with a single application of PEI, but larger tumors may require multiple injections.

Radiofrequency Ablation

Temperature of 60 C created Can ablate tumors of about 7 cm

Cryotherapy

Freezing and thawing of the tumor

TACE

Percutaneous transarterial embolization can induce ischemic necrosis in HCC, resulting in response rates as high as 50%

Treatment is generally limited to patients with preserved liver function and asymptomatic multinodular tumors without vascular invasion

New approach : Therasphere /Radioembolisation

• TheraSphere, delivers low-dose brachytherapy to the tumor.

• Uses 20-40 micrometer glass beads that are loaded with radioactive yttrium and delivered angiographically in the tumor.

• The radiotherapy is then delivered over 10-12 days with a total dose of about 150 Gray. 

Systemic Chemotherapy• Systemic chemotherapy with a variety of

agents has been ineffective for the treatment of HCC and has a minimal role in the treatment of HCC. Response rates are generally less than 20% and of short duration.

• doxorubicin-based regimens appear to have the greatest efficacy with response rates of 20-30% and a minimal impact on survival. 

• Immunotherapy and hormonal therapy results not promising. (tamoxifen, antiandrogens (eg, cyproterone, ketoconazole), interferon, interleukin 2 (IL-2), and octreotide.)

SORAFENIB• Sorafenib is a small molecular inhibitor of several tyrosine

protein kinases (VEGFR and PDGFR) (tyrosine kinase inhibitor or TKI) and Raf kinases (more avidly C-Raf than B-Raf).

• Sorafenib also inhibits some intracellular serine/threonine kinases (e.g. C-Raf, wild-type B-Raf  and mutant B-Raf).

• Improvement in median survival and time of progression.• However, various studies under trial

Follow UP• Follow-ups should be scheduled

– Once monthly up to 6 months, – then once every 3 months up to 1 year, – than twice a year up to 2 years and – once a year every year thereafter

The follow-up is aimed- at drug dosage adjustment, - early diagnosis of eventual immunosupression-

related infection,- early detection of rejection or transplant

dysfunction, and - later also at detection of immunosupression-related

neoplasia

THANK

YOU