Management

Hepatocellular
Carcinoma

Tugas program pendidikan dokter spesialis II

Ilmu bedah Digestif
Univ. hasanudin RS. Wahidin Sudirohusodo
Makasar
 Pendahuluan
Karsinoma hepatoseluler (HCC) adalah
neoplasia yang sering terjadi dan angka
kematian yang tinggi.
Peningkatan manajemen secara signifikan
selama beberapa tahun terakhir
BCLC (Barcelona Clinic Liver Cancer) sistem,
untuk prediksi, prognosis dan pendekatan
pengobatan yang lebih baik
Terapi kuratif (reseksi, transplantasi, ablasi)
dapat meningkatkan kelangsungan hidup
pada pasien yang didiagnosis HCC stadium
 Definisi

Karsinoma Hati Primer (Primary

Hepatocellular Carcinoma) adalah
tumor primer hati yang biasanya
berkembang pada penyakit hati
kronis terutama pada hepatitis viral
 Insidensi

Liver cancer penyebab kematian

karena kanker urutan ke-4 di dunia
dan urutan ke-3 pada pria.
Insidensi berbeda secara geografis.
Indonesia termasuk negara dengan
insidensi intermediate untuk
Hepatitis B
 Age-specific incidence of hepatocellular
carcinoma
 Faktor Resiko

Viral hepatitis B dan C.

Toksin: aflatoksin dan toksin yang
terkandung pada air minum.
Hepatitis kronis dan sirosis hati
 Screening & Surveillance
HCC has poor prognosis if diagnosed at advanced
stage (5 yr survival rate 0 10%) compared if is
treated in the early stages (5 yr survival rate up to
70%) need to screening & surveillance for high
risk population
Strategy of surveillance aimed to detecting early
disease
Surveillance for HCC in high risk population is
recommended cirrhotic patients with HBV and
HCV
Screening & Surveillance
Surveillance for HCC should be performed
by Ultrasonography (US) and -fetoprotein
(AFP) every 6 months
AFP alone not recommended for diagnosis of HCC
Small HCC ( 3 cm) do not secrete AFP to achieve
a diagnostic level
AFP elevated in patients with both HCC and
chronic liver disease
US is a screening test and not a diagnostic test for
confirmation
 Surveillance
Recommendation
 Surveillance
The incidence and mortality of hepatocellular
carcinoma (HCC) is high
The main risk of HCC in Asia is chronic
infection of HBV
The best strategy is prevent infection of HBV
through universal vaccination and Public
health-education to educate about viral
transmission protection
Other strategy are :
Prevent and detect alcohol dependence syndrome, and
toreduce contamination of food by aflatoxin
Therapy which have beneficial to reduce disease
progression in HBV & HCV patients
Screening & surveillance in high risk population
 Main risk factors for HCC

EASLEORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma

European Association for the Study of the Liver*, European Organisation for Research and Treatment of Cancer
(European Journal of Cancer(2012)48, 599641)
 Hepatitis B: the primary cause
of HCC in AsiaPacific

Chronic HBV infection associated with 100 fold increase risk of HCC compared to
non infected
HBV associated cirrhosis, increased risk 1000 fold
 Frequency of Complications in
Patients with Compensated Liver
Cirrhosis
Development of Liver
Cirrhosis
ETIOLOGI
anatomi
 Hepatitis B dan HCC
Taiwan: HBsAg (+) resiko utk menjadi HCC
223 x dibanding HBsAg (-).
Resiko utk populasi Asia > nonAsia.
HBeAg (+) menambah resiko utk HCC (RR
60,2 dgn 95% CI 35.5-102.1), dibandingkan
hanya HBsAg (+) saja (RR 9.6 dgn 95% CI
6.0-15.2).
Koinfeksi dgn HCV meningkatkan resiko
HCC
 Aflatoksin

Suatu mycotoxin yang sering

mengkontaminasi jagung, kedelai
dan kacang tanah. Asupan aflatoxin
yang tinggi dari makanan
berhubungan dengan timbulnya
HCC. Tempe?
Aflatoksin mutasi pada codon 249
tumor supressor gen p53.
Potensiasi karsinogenik dgn infeksi
HBV
Patogenesis
 Histopathological
progression and molecular
features of HCC
 Patogenesis

Hepatocarcinogenesis bisa memakan

waktu 30 tahun setelah infeksi HBV /
HCV.
Sitokin dari selsel inflamasi, proses
regenerasi sel dan transaktivasi virus
hepatitis peningkatan ekspresi
Transforming Growth Factor (TGF)
dan Insulin Growth Factor-2 (IGF-2)
melalui mekanisme epigenetik
meningkatkan proliferasi hepatocyte.
 Gejala Klinis
Gejala = gejala sirosis hati.
Curigai pada yang semula sirosis hati
kompensata asites, hepatik
ensefalopati, jaundice, perdarahan varises.
Massa tumor icterus, nyeri.
Tumor ruptur perdarahan
intraperitoneal: distensi dan nyeri
abdomen, pucat.
Gejala metastase: paru; dyspnoe, tulang ;
nyeri tulang.
Paraneoplastic syndrome.
 Clinical Presentation
Aged > 40 years and men more likely
Symptoms (only present in advanced disease)
:
Pain in the right upper quadrant of the abdomen
Weight loss
Symptom of cirrhosis and / or liver failure
Liver mass in examination
Metastases causes sign and symptom
extrahepatic :
Bone pain
Diarrhea
Dyspnoe
Cutaneous sign
 Diagnosis
Des-gamma-carboxy prothrombin (prothrombin
USG produced by vitamin K absence or antagonism II
[PIVKA II])
CTscan
MRI
AFP Biopsi perkutan hanya dilakukan bila diagnosanya
tidak jelas

Kalau lesinya hypervascular, dengan peningkatan intensitas sinyal T2

pada MRI, adanya invasi vena, or is disertai dengan peningkatan AFP

Diagnosa HCC
 Diagnostic algorithm for the diagnosis
of liver malignancy depending on tumor
size
 Diagnosis of HCC
Medical history & Physical Examination
Laboratory tests (with visible mass on US in screening
test)
AFP Cutoff value is different among literature (range 200
500ng/mL)
- APASL recommendation is 200 ng/mL
AFP-L3 or DCP may also be used
Imaging studies
CT
MRI
Biopsy
Only performed if diagnosis is in doubt due to potential
complications
 Diagnosis HCC

Guidelines of the APASL and the

AASLD on the definition of imaging
features of classical HCC.
The presence of arterial
hypervascularity and washout on
portal vein or delay phase
HCC receives predominant vascular
supply via the hepatic artery
 Diagnosis HCC

Diagnosis Liver Nodule

Clinical Features , Age , Gender
Morphology and enhancement
characteristic : mosaic patern
,nodule in nodule appearance,
central scar, ring, pseudocapsule
Background liver : cirhosis Patient
History
 Imaging Studies
US is generally used in screening, guiding percutaneous
biopsies and interventional therapy
Dynamic CT / MRI useful for diagnosis assessment,
characterization and staging of tumor
HCC tumors grow, they need supply from hepatic artery,
whereas normal liver have supply from hepatic portal
venous
typical pattern with arterial enhancement and portal
venous washout on dynamic CT / MRI
Imaging useful for assess the extent of disease within liver
(invasion of vascular structure) or distant metastases
 Multiphasic contrast
protocol

1. Hepatic arterial phase : 25 s

Early arterial : 5-10 s
Late arterial : 15-25 s
2. Portal venous phase : 60 s
3. Interstitial phase (hepatic venous
phase ): 90 s
4. Delayed phase
Early delayed : 3-5 minutes
Late delayed : 10-15 minutes
 Biopsy
Beneficial to confirm the HCC
diagnosis, especially in lesion < 2 cm
Unfortunately Biopsy carries :
Risk of bleeding (particularly in patients
with advanced cirrhosis)
Slight risk of tumor seeding along the
needle track ( 1%)
 Diferential Diagnosis

Shouldbe remember that

hypervascularity on arterial
phase and washout in portal
vein phase not only found on
HCC
Hepatic adenoma
Focal Nodular Hypertrophy
Hypervascular metastasis
 STAGING OF HCC
There are many staging systems for HCC none
are universally accepted
In Europe & USA
Tumour Node Metastasis (TNM)
Model for End Stage Liver Disease (MELD)
Cancer of the Liver Italian Program (CLIP)
Barcelona Cancer of the Liver Clinic (BCLC)
In Japan Okuda System Staging
Status Child-Pugh one of the best predictor
of outcome of HCC
 Primary tumor (T)
TNM staging
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
T1 Solitary tumor without vascular invasion
T2 Solitary tumor with vascular invasion, or multiple tumors none more than 5 cm
T3 Multiple tumors more than 5 cm or tumor involving a major branch of the portal or hepatic
vein(s)
T4 Tumors with invasion of adjacent organs other than the gallbladder or with perforation of the
visceral peritoneum
Regional lymph nodes (N)
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Regional lymph node metastasis N1 Regional lymph node metastasis
Distant metastasis (M)
MX Distant metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis
Fibrosis score (F)*
F0 Fibrosis score 0-4 (none to moderate fibrosis)
F1 Fibrosis score 5-6 (severe fibrosis or cirrhosis)
Stage grouping
Stage I T1 N0 M0
Stage II T2 N0 M0
Stage IIIA T3 N0 M0
Stage IIIB T4 N0 M0
Stage IIIC Any T N1 M0
Stage IV Any T Any N M1
Staging in HCC
BCLC Staging
 Penatalaksanaan
Median survival 6-20 bulan.
Reseksi bedah, namun mayoritas tak bisa
dilakukan.
Pilihan terapi:
Liver transplantation
Radiofrequency ablation (RFA)
Percutaneous ethanol or acetic acid ablation
Transarterial chemoembolization (TACE)
Cryoablation
Radiation therapy
Systemic chemotherapy
 Guide Treatment

Penyebaran tumor atau staging

Keterlibatan pembuluh darah
hepar
Ada tidaknya kapsul tumor
Ada tidaknya penyebaran diluar
hepar
Vaskularisasi pembuluh darah
tumor
 KRETERIA TUMOR
UNRESECTABLE
Adanya kelainan extrahepatik
Adanya disfungsi hepar
Extensi tumor yang luas dimana hanya
sedikit hepar yang disisakan setelah
reseksi
Terbukti adanya metastasis/ekstensi
extrahepatik
Tumor melibatkan vena hepatik vena
porta
Ahmad, Syed A. Hepatobiliary Cancers. 2010
`
 Partial hepatectomy

Berpotensi kuratif.
Reseksi ideal: solitary HCC tanpa
bukti radiologis adanya invasi
vaskularisasi liver, tidak ada
hipertensi dan dengan cadangan
fungsi hati yang baik.
Long-term relapse-free survival
40%, dan five-year survival 90%.
Resected specimen of cirrhotic liver

Copyright Science Press Internet Services

 LIVER
TRANSPLANTATION

Milan Criteria :
Single HCC 5 cm or
Up to three nodules 3 cm
No extra hepatic spread

( 5 years survival : 70%

dengan rekuren 5 15% )
 Radio Frequency
Ablation
RFA = aplikasi lokal energi
thermal dari gelombang
radiofrequency melalui elektroda
peningkatan suhu lokal lesi >
60C nekrosis.
Sebaiknya dengan single tumor
diameter <4 cm dan dengan
Child-Pugh A atau B
 Trans Arterial Chemo
Embolization (TACE)
Mayoritas suplai pembuluh darah HCC
berasal dari arteri hepatika.
Penyuntikan ke arteri hepatika suatu
bahan kemoterapi dengan atau tanpa
lipiodol atau bahan procoagulant.
Lipiodol suatu zat kontras yang
meningkatkan retensi obat
kemoterapi intratumoral.
Kontraindikasi: trombosis vena porta,
ensefalopati, obstruksi saluran
empedu.
 TACE

Infusion chemotherapeutic agents

with or without iodized oil followed
by embolization with particle
Introduced in 1977 by Yamada
in unresectable HCC
gelatine
sponge
mitomycin or doxorubicin
 ADVANTAGES TACE

High local concentration of

the cytotoxin agents
lower systemic toxicity
Cut off tumor blood supply
Induce tumor necrosis
 INDICATION TACE

Unresectable HCC
Adequate liver function (childs class
A,B)
Without macrovascular invasion
Without extrahepatic spread
 CONTRAINDICATION
TACE
Absolut:
1. Tumour resectability
2. Extensive intractable infective
3. Extensive liver disease
 CONTRAINDICATION TACE

Relative:
1. Inadequat liver function
2. Total bill > 4mg/dl
3. Portal vein trombosis
4. Uncorrectable coagulopathy
5. Poor general healthy
6. Significant A-V shunt through the
tumour
7. Encephalopathy
 Radioterapi
HCC merupakan tumor yang
radiosensitive, yang hanya sanggup
menerima rata-rata 20 Gy,
stereotactic body radiation therapy
(terarah) atau selective internal RT
dengan iodine-131 [131I]- labeled
lipiodol atau yttrium-90 [90Y]-tagged
glass Microspheres)
 Kemoterapi

HCC dianggap suatu tumor yang

relatif chemorefrakter. Karena
tingginya ekspresi drug resistance
gene seperti p-glycoprotein,
glutathione-S-transferase, heat shock
proteins dan mutasi p53.
 DRUGS

Cysplatin
Doxorubicin
Mytomycin
5-FU
 Targeted Therapy

Sorafenib = multitargeted tyrosine

kinase inhibitor.
SHARP trial sorafenib monotherapy
sebagai standar monoterapi untuk
advanced HCC.
 Summary
First line diagnostic tools for HCC are
Dynamic CT or MRI when screening test
results is abnormal
To get a better of prognosis & outcome of
treatment, recommended to include; tumor
stage, liver function (Child Pugh), patients
physical status, effects of treatment in the
staging HCC
Provide a multidisciplinary and individualized
approach for each patient
TERIMA
KASIH