HEPATOCELLULAR

CARCINOMA
Dr. Isbandiyah, SpPD

Epidemiology
Hepatocellular carcinoma is the 5th most common
malignancy worldwide & the 3rd cause of cancer related
death with male-to-female ratio
5:1 in Asia
2:1 in the United States

Tumor incidence varies significantly, depending on

geographical location.
HCC

with age.
53 years in Asia
67 years in the United States.

Etiology
Hepatitis B
-increase risk 100 -200 fold
- 90% of HCC are positive for (HBs Ag)

Hepatitis C
Cirrhosis
- 70% of HCC arise on top of cirrhosis

Toxins

-Alcohol

-Tobacco

Autoimmune hepatitis

- Aflatoxins

Incidence according to
etiology

Abbreviations: WD, Wilsons disease; PBC, primary biliary cirrhosis, HH, hereditary
hemochromatosis; HBV, hepatitis B virus infection; HCV, hepatitis C virus infection.

Malignant Transformation
Multistep
HCC[2]
Epigenetic
alterations
Genetic
Dysplastic nodules[1]
alterations
Liver cirrhosis
Hepatitis C
Hepatitis B
Ethanol
NASH
Normal liver

Phatology
Microscopically, there are four cytological
types:
fibrolamellar,
pseudoglandular (adenoid),
pleomorphic (giant cell) and
clear cell.

Signs & symptoms

Nonspecific symptoms

abdominal pain
Fever, chills
anorexia, weight loss
jaundice

Physical findings

abdominal mass in one third

splenomegaly
ascites
abdominal tenderness

Guidlines
(a) which patients are at high risk for
the development of HCC and should
be offered surveillance
(b) what investigations are required to
make a definite
diagnosis
(c) which treatment modality is most
appropriate in a given clinical context.

Guidlines
(a) which patients are at high risk for the development of HCC &
should be offered surveillance

M &F with established cirrhosis due to HBV and/ or HCV,

particularly those with ongoing viral replication

- M &F with established cirrhosis due to genetic haemochromatosis

- M with alcohol related cirrhosis who are abstinent from alcohol or
likely to comply with treatment
- M with primary biliary cirrhosis
Abdominal USG and AFP/ 6 months

Diagnosis
(b) what investigations are required to make a
definite diagnosis
1)

2)

AFP produced by 70% of HCC

> 400ng/ml
AFP over time

Imaging
- focal lesion in the liver of a patient with cirrhosis is highly likely
to
be HCC
- Spiral CT of the liver
- MRI with contrast enhancement

Diagnosis

3)

Biopsy is rarely required for

seeding
diagnosis
in 13%.
Biopsy of potentially operable lesions
should be avoided where possible

Diagnosis
Cirrhosis +
Mass > 2 cm

Raised
AFP

Normal
AFP

Confirmrd
diagnosis

CT, MRI

Diagnosis
Cirrhosis + Mass < 2 cm

Normal AFP

Raised
AFP

CT, MRI
Assess for
surgery

lesion by exam

Confirmed
diagnosis

FNAB or biopsy

AJCC/UICC Classification
System

Chronic liver disease is classified into

Child-Pugh class A to C, employing
the added score from above.

Treatment (Surgery)

The only proven potentially curative therapy for HCC

Hepatic resection or liver transplantation

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

lesions 3 cm

Involvement of large vessels (portal vein, Inferior vena

cava) doesnt automatically mitigate against a resection;
especially in fibrolamellar histology

No randomised controlled trials comparing the outcome of

surgical resection and liver transplantation for HCC.

Treatment (Surgery)

Hepatic resection should be considered in HCC and a noncirrhotic liver (including fibrolamellar variant)

Resection can be carried out in highly selected patients with

cirrhosis and well preserved hepatic function (Child-Pugh A)
who are unsuitable for liver transplantation.

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.

Treatment (Surgery)

Recurrence rates of 5060% after 5 years after resection are

usual (intrahepatic)

Liver transplantation should be considered in any patient

with cirrhosis

Patients with replicating HBV/ HCV had a worse outlook due

to recurrence and were previously not considered
candidates for transplantation.

Effective antiviral therapy is now available and patients with

small HCC, should be assessed for transplantation

Treatment (non-Surgical)
should only be used where surgical
therapy is not possible.
1) Percutaneous ethanol injection (PEI)

has been shown to produce necrosis of small HCC.

It is best suited to peripheral lesions, less than 3 cm
in diameter

2) Radiofrequency ablation (RFA)

High frequency ultrasound to generate heat

good alternative ablative therapy
No survival advantage
Useful for tumor control in patients awaiting liver
transplant

Treatment (non-Surgical)
3) Cryotherapy

intraoperatively to ablate small solitary tumors

outside a planned resection in patients with bilobar
disease

4) Chemoembolisation

Concurrent administration of hepatic arterial

chemotherapy (doxirubicin) with embolization of
hepatic artery

Produce tumour necrosis in 50% of patients

Effective therapy for pain or bleeding from HCC

Affect survival in highly selected patients with good

liver reserve

Treatment (non-Surgical)
5) Systemic chemotherapy
very limited role in the treatment of HCC with poor
esponse rate
Best single agent is doxorubicin (RR: 10- 20%)
Combination chemotherapy didnt
response
but
survival
should only be offered in the context of clinical
trials

6) Hormonal therapy
- Nolvadex, stilbestrol and flutamide

7) Interferon-alfa
8) retinoids and adaptive immunotherapy (adjuvant)

Targeted therapy for HCC

Selection of agents for targeted

therapy in HCC
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

Investigational combination
therapies in HCC
Combinations under investigations

Bevacizumzb + erlotinib
Sorafenib +erlotinib

Combination therapy will likely be

used to treat HCC in the future

HCC (Whats ahead?)

Combinations therapy
Bevacizumzb or Sorafenib + Erlotinib
Sorafenib + mTOR inhibitor

Early sequential therapies

Staging Strategy and Treatment for

Patients With HCC
HCC
PST 0, Child-Pugh A

PST 0-2, Child-Pugh A-B

PST > 2, Child-Pugh C

Very early stage Early stage Intermediate stage Advanced stage

Single < 2 cmSingle or 3 nodules Multinodular, PST 0 Portal invasion,
3 cm, PST 0
N1, M1, PST 12
Single

3 nodules 3 cm

Portal pressure/bilirubin
Increased
Normal
Resection

Terminal
stage

Portal invasion,
N1, M1

Associated
diseases

No
Liver transplant

Yes
PEI/RF

Curative treatments

Llovet JM, et al. J Natl Cancer Inst.

2008;100:698-711.

No
TACE

Yes

Sorafenib
Symptomatic
(unless LT)