Definisi

Epidemiologi
Klasifikasi
Etiologi & Faktor Risiko
Manifestasi Klinis
Diagnosis
Sistem staging
Terapi

An estimated 22,620 people diagnosed in the United

States in 2009; more common in other parts of the
world
Sixth most frequent cause of cancer-related death
among men and the ninth most common among
women
A disease in which normal liver cells grow
uncontrollably and form a tumor or tentacle-like
growth
Primary liver cancer is cancer that begins in the liver
Three types of primary liver cancer: hepatocellular
carcinoma (HCC), cholangiocarcinoma (bile duct
cancer), and angiosarcoma
HCC accounts for 90% of primary liver cancer cases

6th most common cancer world wide

(626,000 or 5.7% of new cancer cases)

Third most common cause of cancer

mortality
Deaths = 598,000

Survival rates 3% - 5% for the US and

developing countries
Fastest growing cause of cancer-related
death in men in the US
19,160 cases and 16,780 deaths

Parkin, D.M., et al., Global cancer statistics, 2002. CA Cancer J Clin, 2005. 55(2): p. 74-108.

#6

Estimated Numbers
of New Cancer
Cases and Deaths in
2002
6% 5 yr survival rate
#7

Parkin, D. M. et al. CA Cancer J Clin 2005;55:74-108.

Age-standardized Incidence Rates for Liver

Cancer

Parkin, D. M. et al. CA Cancer J Clin 2005;55:74-108.

In the US HCC rates are

Asian>African Americans>Whites
Male>Female (2-4 fold)
Men are more likely to be infected with HBV

and HCV, consume EtOH, smoke, have

increased iron stores

Peak age >65 in the US

Incidence and death rates are
increasing in the US

El-Serag, H.B. and A.C. Mason, Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med, 1999. 340(10): p. 745-50.

JINAK

GANAS
Tumor Epitelial

Adenoma hepatoselular
Adenoma bilier intrahepatik
Sistadenoma bilier intrahepatik
Papilomatosis bilier

Karsinoma hepatoselular
Karsinoma fibrolamelar
Hepatoblastoma
Kolangiokarsinoma
Sistadenokarsinoma

Tumor Mesenkimal
Hemangioma
Fibroma
Leiomioma
Lipoma
Angiomiolipoma
Limfangioma
Mesotelioma

Angiosarkoma
Fibrosarkoma
Leiomiosarkoma
Liposarkoma
Rabdomiosarkoma
Limfoma hepatik primer
Hemangioendoteliomaepitelioid

Virus hepatitis B
Virus hepatitis C
Faktor-faktor risiko:
Sirosis hati, pada 60-80% SH makronodular dan 3-10% SH
mikronodular
Aflatoksin
Obesitas
Diabetes melitus hiperinsulinemia dan peningkatan insulinlike growth factors.
Alkohol
Penyakit hati autoimun
Penyakit hati metabolik (hemokromatosis, defisiensi alfa-1antitripsin, penyakit Wilson)
Kontrasepsi oral
Senyawa kimia (vinyl chloride, thorotrast, nitrosamin,
insektisida organoklorin, asam tanik)
Tembakau (masih kontroversi)

HBV
5-15 fold increased risk
70-90% of cases occur in setting
of cirrhosis
Treatment does NOT decrease risk
Risk highest in carriers and lower
in immune
HCV
1-3% of cirrhotic patients develop
HCC
Treatment seems to decrease risk
Co-infection
Aflatoxins (Aspergillus fumigatus)
4 fold increased risk HCC
Alcohol
>50-70g/day
No link to direct carcinogenic
effect
Synergistic with HCV and HBV
Nonalcoholic Steatohepatitis?

El-Serag, H.B. and K.L. Rudolph, Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology, 2007. 132(7): p. 2557-76.
Brunetto M.R., O.F., Koehler M., et al., Effect of interferon-alpha on progression of cirrhosis to hepatocellular carcinoma: a retrospective cohort study.
International Interferon-alpha Hepatocellular Carcinoma Study Group. Lancet, 1998. 351(9115): p. 1535-9.

Obesity
Diabetes Mellitus
Hemochromatosis
Alpha-1 antitrypsin deficiency
Autoimmune hepatitis
Porphyrias
15-50% of HCC in the US have no
established risk factors

Gejala yang paling sering dikeluhkan:

Nyeri atau perasaan tak nyaman di kuadran kananatas abdomen, malaise, penurunan berat badan
dan ikterus.
Keluhan gastrointestinal lain adalah anoreksia,
kembung, konstipasi atau diare.
Sesak nafas sebagai akibat besarnya tumor yang
menekan diafragma atau karena metastasis di paru.

Tanda-tanda klinis: Hepatomegali dengan atau

tanpa bruit hepatik, splenomegali, asites, ikterus,
demam dan atrofi otot.

Perdarahan varises esofagus, peritonitis bakterialis

spontan.
Tanda-tanda sindroma neuropsikiatrik/mental
confusion akibat kerusakan hebat sel-sel hati
(ensefalopati hepaticum)

Alfa-fetoprotein: Protein serum normal yang

disintesis oleh sel hati fetal, sel yolk-sac dan
sedikit sekali oleh saluran gastrointestinal fetal.
Nilai diagnostik atau sugestif untuk HCC bila
kadar AFP > 400 ng/mL.
DCP (des-gamma carboxy prothrombin) atau
PIVKA-2, pada HCC kadarnya akan meningkat.
AFP-L3 (suatu subfraksi AFP), memiliki angka
sensitifitas dan spesifisitas paling baik untuk
HCC.

Ultrasonografi, memiliki sensitivitas 70-80%.

Pada HCC yang kecil tampak gambaran
mosaik, formasi septum, bagian perifer
sonolusen (berhalo), bayangan lateral
yang dibentuk oleh pseudokapsul fibrotik,
serta penyangatan eko posterior.
USG color Doppler sangat berguna untuk
membedakan HCC dari tumor hepatik lain.
CT-scan, MRI serta angiografi kadangkadang diperlukan.
Laparoskopik biopsi Histopathology

Hepatocellular carcinoma with cholangiolar features, m

Numerous staging systems exist and NO

CONSCENSUS
E.g. TNM, Okuda, CLIP, and BCLC

Incorporate 4 determinants of survival

Severity of underlying liver disease

Size of tumor
Extension of the tumor into adjacent structures
Presence of metastases

Primary staging should be clinical staging,

and the CLIP is preferred
Secondary staging with the AJCC - TNM
staging system for patients undergoing
surgery
Staging work up includes Bone Scan and CT
chest

Child Pugh Stage

Score

Tumor Morphology

AFP

Score

Average survival

31 Mon.

Uninodular , <50%

27 Mon.

Multinodular, <50%

13 Mon.

Massive, >50%

8 Mon.

<400

> 4

2 Mon.

>400

Portal Vein Thrombosis No

yes

1
Bilirubin
Albumin
INR
Ascites
Encephalop
athy

<2
>3.5

2-3
3.5-2.8

>3
<2.8

<1.7
Absen
t
Absen
t

1.7-2.3
MildModerate
Mild (I-II)

>2.3
Severe /
Refractory
Severe (III-IV)

A=5-6 (2 yr survival 85%)

B=7-9 (2 yr survival 57%)
C=10-15 (2 yr survival 35%)
Online Calculator: http://homepage.mac.com/sholland/contrivances/childpugh.html
Child CG, Turcotte JG. Surgery and portal hypertension. In: The liver and portal hypertension. Edited by CG Child. Philadelphia: Saunders 1964:50-64.
Pugh RNH, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the esophagus in bleeding oesophageal varices. Br J Surg 1973;60:64852

Berdasarkan Barcelona EASL Conference

Kriteria sito-histologis
Kriteria non-invasif (khusus untuk pasien sirosis hati):
Kriteria radiologis: koinsidensi 2 cara imaging (USG/CT
scan/MRI/angiografi)
- lesi fokal > 2 cm dengan hipervaskularisasi arterial
Kriteria kombinasi : satu cara imaging dengan kadar
AFP serum:
- lesi fokal > 2 cm dengan hipervaskularisasi arterial
- kadar AFP serum 400 ng/mL

Dipakai sistem TNM (Tumor-Node-Metastases)

yang dikelompokkan oleh American Joint
Committee on Cancer (AJCC) sebagai berikut:
Primary tumor (T)
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: Tumor(s) with direct 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
Note: The regional lymph nodes are the hilar (i.e.,
those in the hepatoduodenal ligament, hepatic,
and periportal nodes). Regional lymph nodes also
include those along the inferior vena cava,
hepatic artery, and portal vein.

Distant metastasis (M)

MX: Distant metastasis cannot be assessed
M0: No distant metastasis
M1: Distant metastasis
[Note: Metastases occur most frequently in bones
and lungs. Tumors may extend through the
capsule to adjacent organs (adrenal glands,
diaphragm, and colon) or may rupture, causing
acute hemorrhage and peritoneal
carcinomatosis.]

Stage I

T1

N0

M0

Stage II

T2

N0

M0

N0

M0

N0
N1

M0
M0

Stage
T3
IIIA
IIIB T4
IIIC Any T
T definitions

55% 5 yr
survival
37% 5 yr
survival
16% 5 yr
survival

Stage
T1 solitary
nodule
IV Any
T without
Any Nvascular
M1 invasion
T2 solitary tumor with vascular invasion or multiple

nodules all <5cm

T3 multinodular >5cm, or tumor with major vasculature
invasion
T4 Tumor with invasion of adjacent organs
AJCC Cancer Staging Manual, Sixth Edition (2002) published by Springer-Verlag New York, Inc

Criteria
Tumor size

Positive
>50%

Negative
<50%

Ascites

Clinically
detectable
<3

Abscent

Albumin
Bilirubin

Stage I

>3

No positive

>3
<3

8.3 mos
survival
Stage II
1-2 positive
2 mos survival
Stage III
3-4 positive
0.7 mos
survival
Adapted from Okuda, K, Ohtuiki, T, Obata, H,
et al, Cancer 1985; 56:918

Localized resectable: cancer is in one place in

the liver, can be removed through surgery and
the other part of the liver is healthy
Localized unresectable: cancer is found in one
part of the liver, but it cannot be removed by
surgery
Advanced: cancer has spread throughout the
liver and/or to other parts of the body, such as
the lungs and bones
Recurrent: cancer has come back after
treatment. It may recur in the liver or another
part of the body

More than one treatment may be used

Surgery, including liver transplantation
Radiation therapy
Chemotherapy: systemic and regional
Targeted therapy
Ablative therapies, including
percutaneous ethanol injection and
radiofrequency ablation
Arterial chemoembolization
Clinical trials

Large tumor size, vascular invasion, poor

functional status, and nodal metastases
DNA microarrays
Signatures can predict OS, recurrence and

change with advanced HCC

Since 2000 over 30 articles have been published

Thorgeirsson. J Hepatology. 2006. 4

Lee Hepatology. 2004. 40(3):667

Primary prevention
Taiwan: HBV immunization of newborns

introduced in 1984 resulting in decrease in

incidence of HCC
0.7 to 0.36 per 100,000 children

Infant vaccination estimated to prevent 84%

of HBV related deaths

94% of deaths occur from cirrhosis and HCC

Chang, M.H., et al., Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children.
Taiwan Childhood Hepatoma Study Group. N Engl J Med, 1997. 336(26): p. 1855-9.

Liver transplantation / Resection (<5% of

cases)
5 yr survival 41-93%

Radiofrequency ablation (RFA) (20-30% of

cases)
5 yr survival 33-40%
Solitary tumors, max 3-5cm

Percutaneous ethanol or acetic acid ablation

5 yr survival 29-71%
Solitary tumors, max 3-5cm

Transarterial chemoembolization
(TACE)
2 yr survival 24-63%
No vascular invasion, preserved liver

function, no extrahepatic spread

Radiation therapy
Systemic chemotherapy
>100 trials over the last 30 years

Transarterial chemoembolization
(TACE)
2 yr survival 24-63%
No vascular invasion, preserved liver

function, no extrahepatic spread

Radiation therapy
Systemic chemotherapy
>100 trials over the last 30 years

Llovt et al. Lancet 362(9399), 6 December 2003, Pages 1907-1917

Reseksi hepatik: untuk pasien dalam kelompok nonsirosis (klasifikasi Child Pugh A) dan fungsi hati normal.
Reseksi juga pada kelompok HCC lokalisata (kelainan
pada satu lobus hati/(Selected T1 and T2; N0; M0) ),
bagian hati yang direseksi termasuk bagian normal hati
1cm.
Transplantasi hati: untuk pasien HCC dan sirosis hati.
Pada pasien HCC lokalisata yang parah/advance
(Selected T1, T2, T3, and T4; N0; M0), bila tidak
dilakukan reseksi Ablasi tumor perkutan: Injeksi etanol
perkutan; Radiofrequency ablation; Polyprenoic acid.
Terapi paliatif: Transarterial embolization/chemo
embolization khususnya pada HCC difus dua lobus atau
belum ada metastase ekstrahepatik. Bila ada metastase
ekstrahepatik, angka mortalitasnya tinggi. (Any T, N1 or
M1)

HCC has been considered to be a

relatively chemotherapy refractory
tumor
Survival is often determined by degree
of hepatic dysfunction
Systemic chemotherapy not well
tolerated by patients with significant
underlying hepatic dysfunction

Systemic chemotherapy is injected into a vein and travels

through the bloodstream to the whole body

Regional chemotherapy uses a small pump surgically

placed in the body to deliver anticancer drugs directly to
the blood vessels that feed the tumor

Hepatic arterial infusion is chemotherapy injected into a

catheter in the major artery supplying blood to the liver

Chemoembolization is similar to hepatic arterial infusion

except the flow of blood through the artery is blocked for
a short time, so the anticancer drug stays in the tumor
longer; the blocking of the blood supply to the tumor also
kills the cancer cells

Targets faulty genes or proteins that

contribute to cancer growth and development

Sorafenib (Nexavar), an anti-angiogenic and

anti-proliferative drug (starves the tumor by
disrupting its blood supply), may be used to
treat tumors that cannot be removed with
surgery

Approved in 2007 for treating patients with

advanced HCC