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.
