Colangiocarcinoma

Types of Cholangiocarcinoma

Peripheral

• 20-30% • Intrahepatic mass • Cirrhosis uncommon

Perihilar

• 40-60% • Biliary confluence • Most common

Distal

• 20-30% • 10-15% of peripancreatic tumors

Epidemiology of Cholangiocarcinoma

Epidemiology of ICC

• Second most frequent primary liver tumor

• Increasing incidence and mortality worldwide

Changes in age standardized mortality rate

Khan SA, et al. Lancet 2005;366>1313

Etiology Cholangiocarcinoma

• Primary sclerosing cholangitis • Mainly associated with pCC.

• Hepatobiliary flukes (40% ICC) • Clonorchis sinensis and Opistorchis viverrini (OR up to 27)

• Biliary tract cysts • Choledochal cystic disease types I and IV (OR: 10 to 37)

• Hepatholithiasis • OR: 6 to 50

• Hepatotoxins • Nitrosamines

Etiology of ICC

81,8

8

3,6

2,6

1,6

1

10

100

Biliary Dis Cirrhosis DM HCV Smoking

Re

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ve R

isk

Chaiiteerakij D et al. Hepatology 2013; 57:648

• Cirrhosis • Of any nature.

• Chronic viral hepatitis • HBV and HCV.

• Obesity

• Diabetes • Conflicting results.

• Alcohol

• Smoking

Genetic variation and risk of cancer

A

Single nucleotide polymorphism (SNP)

G

* *

Normal Individuals Cancer Patients

RISK FACTORS

GENETIC DIFFERENCES

Etiology of ICC

• Several genetic polymorphisms have been identified

Bridgewater J, et al. J Hepatol 2014;60:1268

DNA preservation Toxin clearance Inflammation

Gene regulation Cyclin

CDK

p53 cell proliferation

Oncogenes y Cáncer

PI3K

AKT

RAS

RAF

MEK

GSK3b

APC

G Protein

Adenylate cyclase

JAK

mTOR MEKK MAPK MKK

b-Catenin PKA

STAT

myc ERK JNK

fos jun b-Catenin

CREB

STAT

RTK RTK

Survival Factors (e.g. IGF1)

Chemokines, Hormones (e.g. Interleukins, serotonin)

Growth Factors (e.g. TGF, EGF, HGF)

WNT

Cytokines (e.g. IFN)

Mecanismos de activación de oncogenes

Normal gene

Normal protein

Mecanismos de activación de oncogenes

gene mutation

gene deletion

novel regulatory sequences

hyperactive growth-stimulating protein in normal amount

gene amplification

normal growth-stimulating protein in excess

chromosome rearrangements

fusion transcripts

normal growth-stimulating protein in excess

hyperactive growth-stimulating protein in normal amount or excess

Cambios en la metilación y cáncer

Pathogenesis of ICC

Sia D, et al. Oncogene 2013;32:4861

Molecular Classification of ICC

Sia D, et al. Gastroenterology 2013; 144:829

Clinical Presentation of ICC

• Patients with early stage are usually asymptomatic.

• At more advanced stages, they may have non-specific symptoms

• weight loss, malaise, abdominal discomfort, night sweats, fever, or a palpable mass.

• Jaundice due to biliary tract obstruction is infrequent.

• CCA should be considered in patients with underlying disease (hepatolithiasis or PSC) with worsening performance status or unexplained loss of weight.

• Changes in liver function tests are non-specific, mainly with increased APh and GGT

Imaging of ICC Computed Tomography

arterial portal venous

Imaging of ICC Magnetic Resonance

arterial portal venous

T1 T2

Imaging of ICC

arterial portal venous

Imaging of ICC

arterial portal venous

T1 T2 DWI

Imaging of ICC

25 patients with ICC on cirrosis. Median diameter 25 mm.

Rimola J, et al. Hepatology 2009;50:791

Tumor Markers

• CA 19-9 has significant overlap with benign diseases.

• Sensitivity is 62%

• Specificity is 63%

• CA 19-9 has some prognostic power:

• Preoperative values > 100 U/ml are associated with worse RFS.

• Bile duct obstruction may affect CA 19-9 levels (it should be reassessed after biliary intervention or drainage).

Pathological Diagnosis

• Typically an adenocarcinoma with tubular and/or papillary structures and a variable fibrous stroma.

• Similar to metastatic adenocarcinoma especially those of foregut origin (lung, pancreas, esophagus, and stomach).

• The expression of CK7 and CK20 may be helpful to establish a biliary origin.

• Differentiation from mixed HCC tumors may require evaluation of specific markers of hepatocellular or progenitor cell features

• Hep-Par-1, GPC3, HSP70, GS, EpCAM, and CK19.

• Pathological diagnosis is • required for definitive diagnosis, particularly those with cirrhosis and small

hepatic mass lesions.

• recommended for all patients who will be undergoing systemic chemotherapy or radiation therapy, or enrolling in a therapeutic clinical trial.

Colangiocarcinoma Intrahepático

Estadio I Estadio II Estadio III Estadio IV

Tumor único Multiple Invasión vascular (IV)

Perforación peritoneo visceral, Invasión hepática local

Invasión periductal, N1M1

Colangiocarcinoma Intrahepático

Estadio I Estadio II Estadio III Estadio IV

Tumor único Multiple Invasión vascular (IV)

Perforación peritoneo visceral, Invasión hepática local

Invasión periductal, N1M1

Resecable (30-40 %) No resecable (60-70 %)

Enfermedad sólo intrahepática

Enfermedad extrahepática

Resección curativa

Resección no curativa

Terapia Locorregional

Terapia Sistémica

Observación Ensayos Clínicos

Supervivencia a 5 años R0: 40 % Supervivencia a 5 años N1 e IV: 20 %

RF/TACE: mediana supervivencia 15 meses Quimioterapia: mediana supervivencia 12 meses

Bridgewater J, et al. J Hepatol 2014;60:1268

Liver Transplantation

• ICC has been considered a contraindication to LT based on very poor outcomes in historical series

• However, “very early” tumors may have much better outcomes

• A retrospective cohort multicenter study in 16

Spanish transplant centers.

• 29 patients found to have an iCCA on

pathology examination AND cirrhosis of

etiologies other than PSC.

• Indication for LT: HCC, or liver dysfunction with

pre-transplant identification of a liver nodule;

incidental tumors also included.

Sapisochin G, et al. Am J Transplant 2014; 14: 660

Liver Resection

Spolverato G, et al. JAMA Surg. 2015;150:538

• The main determinants of resectability are • extrahepatic disease

• tumor number and location

• involvement of portal vein and bile ducts

• Resectability rates are 20-40%

• Portal vein embolization may allow surgical rescue.

• Prolonged survival is infrequent, even in good surgical candidates.

535 resected patients (1990-2013)

Liver Resection

Spolverato G, et al. JAMA Surg. 2015;150:538

• Multicenter, international, retrospective study

• 584 patients who underwent resection of ICC (1990-2013)

Transarterial Therapies

TACE for ICC

TACE for ICC

Variable Burger Herber Schiffman Park

No. of patients 17 15 24 72

Drugs CDDP- DOX-MMC MMC DEBIRI CDDP

ECOG > 0 53% 26% 35%

Multifocal 29% 53% 87% 57%

• Chemo 35% 26% 80% 0

• Resection 6% 29% 0

Tumor Response 47%* 6% 25% 23%

Median survival from RE 23 21.1 17.5 12.2 * EASL criteria

Radioembolization for ICC

Before Y90 MAA-PET/CT

Y90-PET/CT 3-months post-Y90

Radioembolization for ICC

Variable Ibrahim Saxena Hoffman Rafi Mouli

No. of patients 24 25 33 19 46

ECOG > 0 58% 40% 49% 95% 48%

Multifocal 54% 70% 68% 35%

Burden < 25% 83% 40% 75% 78%

• Chemo 29% 72% 79% 100% 35%

• Resection 40% 36% 11%

Tumor Response 27% 24% 36% 11% 25%

Survival since RE 14.9 9.3 22 11.5

Systemic Chemotherapy

Valle J, et al. N Engl J Med 2010;362:1273.

Systemic Chemotherapy

• Cisplatin (25 mg/m2) + Gemcitabine (1000 mg/m2) days 1 and 8 every 3 weeks is currently the standard of practice

• There is currently no targeted therapy which is applicable in CAA.

• There is no evidence which supports a second line chemotherapy

Valle J, et al. N Engl J Med 2010;362:1273.

Okusaka T, et al. Br J Cancer 2010;103:469. Eckel and Schmid. Br J Cancer 2007;96:896.

Schweitzer and Vogel. Best Practice & Research Clinical Gastroenterology 2015, 29:345.

Targeted Agents Under Investigation