Cholangio

Carcinoma
4 JUNE 2023
DEFINISI
Cholangiocarcinoma (CCA) : keganasan yang heterogen yang muncul di
saluran bilier.
CCA dibagi menjadi tiga subtipe berdasar lokasi anatomi asal :
intrahepatik (iCCA), perihilar(pCCA) dan distal (dCCA) CCA

iCCA : keganasan hati primer kedua yang paling umum setelah karsinoma
hepatoseluler (HCC). Sekitar 15% dari semua tumor hati primer dan 3%
dari kanker gastrointestinal

NAture RevIewS | GASTROENTEROLOgy & HEPATOLOgy volume 17 | September 2020 |

557
 . On the basis of the anatomical site of origin, cholangiocarcinoma (CCA) is classified into intrahepatic CCA (iCCA), perihilar CCA (pCCA)
and distal CCA (dCCA). iCCA is defined as a malignancy located in the periphery of the second-order bile ducts, pCCA arises in the right and/or
left hepatic duct and/or at their junction, and dCCA involves the common bile duct (that is, the choledochus). Grossly, CCA can show three main
patterns of growth: mass-forming, periductal-infiltrating, and intraductal-growing. Mass-forming CCA is a mass lesion in the hepatic
parenchyma. Periductal-infiltrating iCCA grows inside the duct wall and spreads longitudinally along the wall. Intraductal-growing CCA is a
polypoid or papillary tumour growing towards the duct lumen
Up-to-Date Pathologic Classification and Molecular Characteristics of Intrahepatic Cholangiocarcinoma. Front. Med. 9:857140
 EPIDEMIOLOGI
Kejadian bervariasi dari 85 per 100.000 di timur laut Thailand (tertinggi di dunia)
sampai 0,4 per 100.000 di Kanada.
Variasi prevalensi  perbedaan faktor risiko lokal dan predisposisi genetik
Kematian CCA : Laki-laki > Wanita ; Negara di Asia > Negara barat.

NAture RevIewS | GASTROENTEROLOgy & HEPATOLOgy volume 17 | September 2020 |

 Risk Factors for Cholangiocarcinoma in Thailand: A
Systematic Review and Meta-Analysis
Conclusion: There are unique risk factors of cholangiocarcinoma in Thailand, including age,
Opisthorchis viverrini infection, eating raw cyprinoid fish, family history of cancer, liquor
consumption, and taking praziquantel

Asian Pac J Cancer Prev. 2018 Mar 27;19(3):605-614

NAture RevIewS | GASTROENTEROLOgy & HEPATOLOgy volume 17 | September 2020 |
FAKTOR RISIKO
Risk factor Study type OR or RR from selected studies
OR 26.71 for iCCA
Choledochal cyst Meta-analysis
OR 34.94 for eCCA
OR 10.08 for iCCA
Choledocholithiasis Meta-analysis
OR 18.58 for eCCA
OR 3.38 for iCCA
Cholelithiasis Meta-analysis
OR 5.92 for eCCA
OR 1.75 for iCCA
Cholecystolithiasis Meta-analysis
OR 2.94 for eCCA
OR 38 for iCCA
Caroli disease Population-based study
OR 97 for eCCA
OR 22 for iCCA
Primary sclerosing cholangitis Population-based study
OR 41 for eCCA
OR 15.32 for iCCA
Cirrhosis Meta-analysis
OR 3.82 for eCCA
OR 4.57 for iCCA
Chronic hepatitis B Meta-analysis
OR 2.11 for eCCA
NAture RevIewS | GASTROENTEROLOgy & HEPATOLOgy volume 17 | September 2020 |
Caroli’s Disease: Current Knowledge of Its Biliary Pathogenesis Obtained from an Orthologous Rat Model
FAKTOR RISIKO
Risk factor Study type OR or RR from selected studies
OR 4.28 for iCCA
Chronic hepatitis C Meta-analysis
OR 1.98 for eCCA
Haemochromatosis Population-based study OR 2.1 for iCCA
OR 2.68 for iCCA
Inflammatory bowel disease Meta-analysis
OR 2.37 for eCCA
OR 2.7 for iCCA
Chronic pancreatitis Population-based study
OR 6.6 for eCCA
Liver fluke (Opisthorchis
viverrini, Clonorchis sinensis)
Meta-analysis OR 5 iCCA > eCCA

Type 2 diabetes mellitus Meta-analysis OR 5 iCCA > eCCA

OR 2.2 for iCCA
Nonalcoholic fatty liver disease Meta-analysis
OR 1.5 for eCCA
OR 1.14 for iCCA
Obesity Meta-analysis
OR 1.2 for eCCA

NAture RevIewS | GASTROENTEROLOgy & HEPATOLOgy volume 17 | September 2020 |

FAKTOR RISIKO
Risk factor Study type OR or RR from selected studies
OR 1.10 for iCCA
Hypertension Meta-analysis
OR 1.21 for eCCA
OR 3.15 for iCCA
Alcohol consumption Meta-analysis
OR 1.75 for eCCA
OR 1.25 for iCCA
Cigarette smoking Meta-analysis
OR 1.69 for eCCA
Environmental toxins

Thorotrast (banned 1969) Retrospective study RR >300

1,2-Dichloropropane Retrospective study RR 15

OR 4.8 for iCCA
Asbestos Case–control study
OR 2.1 for eCCA
OR 1.1–1.7 for iCCA
Asbestos Case–control study
No association with eCCA

NAture RevIewS | GASTROENTEROLOgy & HEPATOLOgy volume 17 | September 2020 |

Lesi Pre Maligna CHOLANGIO
CARCINOMA

• CCA dapat didahului oleh lesi pra-invasif.

Biliary Intraepithelial Neoplasia (BIN)  invisible gross
Intraductal Papillary Neoplasm of the Bile Duct (IPNB)  grossly seen

Up-to-Date Pathologic Classification and Molecular Characteristics of Intrahepatic Cholangiocarcinoma. Front. Med. 9:857140
 (A) Low-grade BilIN composed of columnar cells with intact
nuclear polarity and minimal atypia. (B) High-grade BilIN
showing stratification of cells with marked nuclear atypia and
loss of polarity

Up-to-Date Pathologic Classification and Molecular Characteristics of Intrahepatic Cholangiocarcinoma. Front. Med. 9:857140
 PATOLOGI CHOLANGIO
CARCINOMA

Intraductal Papillary Neoplasm

of the Bile Duct

Intraductal Papillary Neoplasm of Bile Duct: Updated Clinicopathological

Characteristics and Molecular and Genetic Alterations. J. Clin. Med. 2020, 9, 3991
 (C) Low-grade IPNB showing a papillary growth of columnar
biliary type epithelial cells with mild pleomorphism and
preserved nuclear polarity. (D) High-grade IPNB showing
irregular papillary projections, composed of highly pleomorphic
and stratified cells with increased nuclear-cytoplasmic ratio.

Up-to-Date Pathologic Classification and Molecular Characteristics of Intrahepatic Cholangiocarcinoma. Front. Med. 9:857140
PATOLOGI CHOLANGIO
CARCINOMA

• Secara histologis, mayoritas pCCA dan dCCA adalah adenokarsinoma

penghasil musin. Sedangkan iCCA memiliki beberapa varian histologis.

• Secara gross : iCCA menunjukkan tiga pola pertumbuhan :

massforming, periductal-infiltrating, and intraductal growing.
pCCA dan dCCA : nodul tumor sclerosis atau tumor intraductal

Up-to-Date Pathologic Classification and Molecular Characteristics of Intrahepatic Cholangiocarcinoma. Front. Med. 9:857140
 Mass-forming CCA is a mass lesion in the hepatic parenchyma. Periductal-infiltrating iCCA
grows inside the duct wall and spreads longitudinally along the wall. Intraductal-growing CCA is
a polypoid or papillary tumour growing towards the duct lumen

Up-to-Date Pathologic Classification and Molecular Characteristics of Intrahepatic Cholangiocarcinoma. Front. Med. 9:857140
PATOLOGI CHOLANGIO
CARCINOMA
iCCA secara histologi dapat dibedakan berdasar ukuran ductus bilier yang terafek :
PATOLOGI CHOLANGIO
CARCINOMA

Mass-forming CCA is a mass lesion in the hepatic parenchyma. Periductal-infiltrating iCCA grows
inside the duct wall and spreads longitudinally along the wall. Intraductal-growing CCA is a polypoid
or papillary tumour growing towards the duct lumen
PATOLOGI CHOLANGIO
CARCINOMA

pCCA dan dCCA : nodul tumor sclerosis atau tumor intraductal

Surgical Case Reports volume 3, Article number: 110 (2017) Scientific Reports volume 8, Article number: 10826 (2018) 

 GEJALA KLINIS CHOLANGIO
CARCINOMA
Awal penyakit : asymptomatic
Stadium lanjut : painless Jaundice terutama pada pCCA – dCCA. Sedangkan iCCA
lebih lambat jaundice, itchy (gatal yang tidak membaik dengan antihistamin)
Klinis Abdomen : Tidak teraba massa, kecuali pada dCCA teraba gall bladder (hydrop)
Seringkali datang dengan cholangitis (demam, jaundice, nyeri perut, lekositosis)

Biliary cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
DIAGNOSIS CHOLANGIO
CARCINOMA
• Diagnosis pasti : Histopatology (Sulit terutama pada pCCA, dCCA). Tidak perlu pada
pasien yang direncanakan operasi.
• Histopatologi : ERCP Cholangioscopy biopsy (Spy glass), ERCP brush citology
(sensitifitas 50%). EUS FNAB, FNAB percutan
• Pencitraan : MRI dan MRCP contrast. CT Scan Abdomen contrast – evaluasi vascular
• Tumor marker : Carbohydrate antigen (CA) 19-9 . CA19-9 meningkat pada 85%
pasien CholangioCa. Sensitivitas 40-70%, spesifisitas 50-80%

International Journal of Gastrointestinal Intervention 8(4):155-159

Anticancer Research March 2011, 31 (3) 1011-1017
 Diagnosis Banding Cholangio Carcinoma
• Lesi jinak : IgG4 cholangiopathy

• iCCA harus dibedakan dari HCC dan tumor metastasis adenocarcinoma (kolon,
paru, pancreas) dengan bantuan Imunohistokimia (IHK)

• iCCA mix HCC

Biliary cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Annals of Oncology 27 (Supplement 5): v28–v37, 2016
Staging
• Staging CCA adalah berdasar system TNM. Pada
TNM edisi 7 : iCCA sudah dipisah dari HCC. Dan
iCCA, pCCA, dCCA juga sudah dipisah
• pCCA lebih jauh diklasifikasikan menggunakan
Bismuth–Corlette classification

Annals of Oncology 27 (Supplement 5): v28–v37, 2016

Staging
 TATALAKSANA CHOLANGIO
CARCINOMA
• Pembedahan : satu-satunya pengobatan kuratif untuk CCA (< 1/3 dapat direseksi
saat diagnosis. Peritoneal & metast jauh (10-20 % saat diagnosis) -- kontraindikasi reseksi
• Systemic kemoterapi ( gemcitabine, oxaloplatin)
• Radioterapi, radioembolisasi, targeted terapy (?)
• Radio Frequensi Ablation (RFA)

Annals of Oncology 27 (Supplement 5): v28–v37, 2016

Diagnostics 2020, 10 :390
Annals of Oncology 27 (Supplement 5): v28–v37, 2016
 Prognosis
• 5 years survival rate : setelah reseksi iCCA, dCCA, pCCA = 22–44%, 27–37%,
11–41% masing-masing.
• Survival rate ditentukan : status R0 atau R1, invasi vascular, metastasis kelenjar
getah bening.
Kesimpulan
1. CCA adalah tumor yang heterogen.
2. iCCA, pCCA dan dCCA memiliki karakter histologi, gross, factor risiko,
mutase genetic, diagnosis, staging, tatalaksana dan prognosis yang berbeda
3. Ketiganya sulit diagnosis, sulit diterapi dan prognosis buruk
4. In the future : survailence pada kelompok risiko tinggi dan metode diagnosis
serta terapi yang lebih baik sangat dibutuhkan
TERIMA
KASIH
4 MARET 2023