HEPATOCELLULAR CARCINOMA

[HCC]

Dr. D.K.SharmaM.S., MCh. (GI Surgery)

Prof. & Head, Deptt. Of Surgery

RNT Medical College, Udaipur, Raj.

EPIDEMIOLOGY

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

Tumor incidence varies significantly, depending on geographicallocation.

Epidemiology

Epidemiology

5th most common malignancy worldwide

3rd most common cause of cancer related death 5 yr survival < 10%

Most common primary liver malignancy

Reversal in cirrhosis Metastases >> Primary Primary > Metastases

80%-90% of HCC cases occur in cirrhotic livers

Epidemiology

Male-to-female ratio

5:1 in Asia

2:1 in the United States

Overall- 4:1

Increases with age. 53 years in Asia

67 years in the United States.

HCC incidence has tripled over last three decades

• Rising incidence of cirrhosis

• HCV (main reason)

• HBV

• Other (?NAFLD/insulin resistance)

• Improved survival of patients with cirrhosis

ETIOLOGY

• Hepatitis B• increased risk 100 -200 fold• 90% of HCC are positive for

HBs Ag• Hepatitis C• Cirrhosis- Any Cause

• 70% of HCC arise on top ofcirrhosis

• HBV, HCV, Alcoholic, NAFLD,PBC

• Toxins -Alcohol -Tobacco -Aflatoxins

• States of insulin resistance• Overweight in males• Diabetes mellitus

• Inherited metabolic diseases• Hemochromatosis• Alpha-1 antitrypsin deficiency• Glycogen storage disease• Porphyria cutanea tarda• Tyrosinemia• Autoimmune hepatitis

• Other Risk Factors• Hepatic Adenomas• Alcohol : Bad with concurrent

virus• Aflatoxin- 3x

Etiology

PATHOGENESIS

Malignant TransformationMultistep

Potential Targets

Oxidative stress and

inflammation

Viral oncogenes Carcinogens

Growth factors Telomere

shortening

Cancer stem

cells

Loss of cell cycle

checkpoints

Antiapoptosis Angiogenesis

Normal liver

Liver cirrhosis

Hepatitis C

Hepatitis B

Ethanol

NASH

Epigenetic alterations

Genetic alterations

HCC[2]

Dysplastic nodules[1]

1. Tornillo L, et al. Lab Invest. 2002;82:547-553. 2. Verslype C, et al. AASLD 2007. Abstract 24.

Fibrolamellar HepatocellularCarcinoma

- Distinctive clinical and pathologic subtype of hepatocellular carcinoma (HCC)

-Young adults (20-40 y/o) withoutunderlying parenchymal liver disease

- AFP usually not elevated

- Non-encapsulated but well circumscribed and contains fibrous lamellae

- Arterial Enhancement

- Central Scar- 40% (Hypo, Delayed enhancement

- Slowly growing tumor

- Better Prognosis

Signs & symptoms

Nonspecific symptoms

Abdominal pain

Fever, chills

Anorexia, Weight loss

jaundice

Physical findings

Abdominal mass in one third

Splenomegaly

Ascites

Abdominal tenderness

SCREENING / SURVEILLANCE FOR HEPATOCELLULAR CARCINOMA

SOC

AASLD Practice Guidelines

AASLD recommends surveillance using AFP + US every 6-12 months for at-risk patient groups:

Hepatitis B carriers

Asian males >40 years

Asian females >50 years

All cirrhotic hepatitis B carriers

Family history of HCC

Africans >20 years

Non-cirrhotic hepatitis B carriers with high HBV DNA levels or more severe current/past levels of inflammatory activity

Cirrhosis due to hepatitis C, alcohol, or other causes

HCV: No screening before cirrhosis; and should screen once cirrhosis develops, but no specific methods.

Rationale for 6-month screening/surveillance interval Doubling time: median = 6 mo (range, 1-19 mo)

Growth from 1 to 3 cm: 4 mo for most aggressive, 18 mo for moderately aggressive, 5 yr for indolent HCC

Median detectable subclinical period for HCC = 3.2 yr

(a) which patients are at high risk for the development of HCC &

should be offered surveillance

DIAGNOSIS OF HCC

Diagnosis

(b) What investigations are required to make a definitediagnosis

I. AFP produced by 70% of HCC

a) > 400ng/ml

b) AFP over time

II. Imaging

a) Focal liver lesion cirrhotic patient highly likely to be HCC

b) Spiral CT of the liver

c) MRI with contrast enhancement

III. Biopsy is rarely required for diagnosis

a) Seeding in 1–3%.

b) Biopsy of potentially operable lesions should be avoided wherepossible

STAGING

Staging Systems for HCC

•Okuda Staging System• Cancer of the Liver Italian Program (CLIP)• American Joint Commission on Cancer (AJCC)/Union

Internacional Contra la Cancrum (UICC) Tumor Node Metastasis (TNM)

• Japanese Staging System and Japan Integrated Staging score (JIS)

• Chinese University Prognostic Index (CUPI)• Barcelona Clinic Liver Cancer (BCLC)•Group d’Etude de Traitement du Carcinoma Hepatocellulaire

(GRETCH)

Staging Systems for Hepatocellular Carcinoma

MANAGEMENT

Management

Liver transplantation

Resection

Tumor ablation Radiofrequency thermal ablation

Cryotherapy

Alcohol injection

Chemoembolization

Targeted molecular therapy

Chemotherapy Regional/systemic

Potentially curative

SURGICAL TREATMENT

Surgery

Only proven potentially curative therapy

Hepatic resection or liver transplantation

Resection: HCC and a non-cirrhotic liver (including fibrolamellar variant)

Highly selected patients with cirrhosis Well preserved hepatic function (Child-Pugh A) who are unsuitable for liver transplantation Carries a high risk of postoperative decompensation. Recurrence rates of 50–60% after 5 years after resection are usual (intrahepatic)

Patients with single small HCC (≤5 cm) or up to three lesions ≤3 cm

Involvement of large vessels (portal vein, Inferior vena cava) doesn’t automatically mitigateagainst a resection; especially in fibrolamellar histology

No RCTs comparing the outcome of resection and transplantation for HCC.

Perioperative mortality in experienced centres remains between 6% and 20% depending on the extent of the resection and the severity of preoperative liver impairment.

The majority of early mortality is due to liver failure.

Liver Transplantation

The only treatment with a major chance of cure for HCC

Should be considered in any patient with cirrhosis

Patients with replicating HBV/ HCV- Worse outlook Recurrence previously not considered candidates for transplantation.

Effective antiviral therapy is now available and patients with small HCC, should be assessed for transplantation

Liver Transplant for HCC in cirrhosisMilan Criteria (Stage I+II)

+

Absence of Macroscopic Vascular Invasion

Absence of Extrahepatic Spread

Single, not > 5cm Up to 3, none > 3cm

Mazzaferro V, et al. N Engl J Med. 1996;334:693-699.

NON-SURGICAL TREATMENT

Should only be used where surgical therapy is not possible.

1. Percutaneous ethanol injection (PEI)2. Radiofrequency ablation (RFA)3. Cryotherapy4. Chemoembolization5. Selective Internal Radiation Therapy [SIRT]6. Systemic chemotherapy7. Hormonal therapy8. Interferon-alfa9. Retinoids and adaptive immunotherapy (adjuvant)10.Targeted Therapy11.Other Agents

Selection of agents for targeted therapy

Name Target

Gefitinib

Erlotinib

Lapatanib

Cetuximab

Bevacizumab

Sorafenib (Nexavar)

Sunitinib

Vatalanib

Cediranib

Rapamycin

Everolimus

Bortezomib (Velcade)

EGFR

EGFR

EGFR

EGFR

VEGF

Raf1, B-Raf, VEGFR , PDGFR

PDGFR, VEGFR, c-KIT, FLT-3

VEGFR, PDGFR, c-KIT

VEGFR

mTOR (mammalian target of rapamycin)

mTOR

Proteasome

Treatment (non-Surgical)

Summary

Hepatocellular Carcinoma HCC is one the most rapidly increasing cancers Risk driven by cirrhosis

Viral load in HBV Prevention is possible by vaccine Treatment of underlying disease decreases risk Treatment is mainly palliative The 5-year survival is 8-12% Less than 20% are candidates for surgery/transplant at

diagnosis HCC is curable in some patients Screening to detect early HCC is the main priority of

primary care physicians Referral to a tertiary center indicated Team approach is current standard to manage HCC