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 - Aflatoxins

Autoimmune hepatitis
 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) AFP produced by 70% of HCC

> 400ng/ml
AFP over time

2) 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

diagnosis
seeding

in 13%.
Biopsy of potentially operable lesions
should be avoided where possible
Diagnosis
Cirrhosis +
Mass > 2 cm

Raised Normal
AFP AFP

Confirmrd CT, MRI

diagnosis
Diagnosis
Cirrhosis + Mass < 2 cm

Raised Normal AFP

AFP

CT, MRI

Assess for
surgery
lesion by exam

Confirmed FNAB or biopsy

diagnosis
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 non-
cirrhotic 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 EGFR
Erlotinib EGFR
Lapatanib EGFR
Cetuximab EGFR
Bevacizumab VEGF
Sorafenib (Nexavar) Raf1, B-Raf, VEGFR , PDGFR
Sunitinib PDGFR, VEGFR, c-KIT, FLT-3
Vatalanib VEGFR, PDGFR, c-KIT
Cediranib VEGFR
Rapamycin mTOR (mammalian target of rapamycin)
Everolimus mTOR
Bortezomib (Velcade) 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 Terminal
Single < 2 cmSingle or 3 nodules Multinodular, PST 0 Portal invasion, stage
3 cm, PST 0 N1, M1, PST 1-
2
Single 3 nodules 3 cm

Portal pressure/bilirubin Portal invasion,

Increased Associated N1, M1
diseases

Normal No Yes No Yes

Resection Liver transplant PEI/RF TACE Sorafenib

Curative treatments Symptomatic

(unless LT)
Llovet JM, et al. J Natl Cancer Inst.
2008;100:698-711.