 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.

 Inthe 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 Karsinoma hepatoselular
Adenoma bilier intrahepatik Karsinoma fibrolamelar
Sistadenoma bilier intrahepatik Hepatoblastoma
Papilomatosis bilier Kolangiokarsinoma
Sistadenokarsinoma
Tumor Mesenkimal
Hemangioma Angiosarkoma
Fibroma Fibrosarkoma
Leiomioma Leiomiosarkoma
Lipoma Liposarkoma
Angiomiolipoma Rabdomiosarkoma
Limfangioma Limfoma hepatik primer
Mesotelioma Hemangioendotelioma-
epitelioid
 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 insulin-
like growth factors.
Alkohol
Penyakit hati autoimun
Penyakit hati metabolik (hemokromatosis, defisiensi alfa-1-
antitripsin, 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 kanan-atas
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 (ber’halo’), 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 kadang-kadang
diperlukan.
 Laparoskopik biopsi  Histopathology
“Hepatocellular carcinoma with cholangiolar features, moderately differentiated”
 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
A 0
B 1
C 2 Score Average survival
Tumor Morphology 0 31 Mon.
Uninodular , <50% 0 1 27 Mon.
Multinodular, <50% 1 2 13 Mon.
Massive, >50% 2 3 8 Mon.
AFP <400 0 > 4 2 Mon.
>400 1
Portal Vein Thrombosis No 0
yes 1
 1 2 3
Bilirubin <2 2-3 >3
Albumin >3.5 3.5-2.8 <2.8
INR <1.7 1.7-2.3 >2.3
Ascites Absent Mild-Moderate Severe / Refractory
Encephalopathy Absent Mild (I-II) 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;60:648-52
 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 55% 5 yr survival
Stage II T2 N0 M0 37% 5 yr survival
Stage IIIA T3 N0 M0 16% 5 yr survival
IIIB T4 N0 M0
IIIC Any T N1 M0
Stage IV Any T Any N M1

 T definitions
• T1 – solitary nodule without vascular 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 Positive Negative
Tumor size >50% <50%
Ascites Clinically detectable Abscent
Albumin <3 >3
Bilirubin >3 <3

Stage I No positive 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 non-
sirosis (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
 Targetsfaulty 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

 Approvedin 2007 for treating patients with

advanced HCC