D. ALVARO, Univ. Sapienza, Rome, Italy.

MONOTEMATICA AISF, The future of Liver Diseases,

Milano 13-15 Ottobre 2016

Colangiocarcinoma “on the rise” !

Domenico ALVARO, MD.SAPIENZA, ROMA

Il sottoscritto dichiara di non aver avuto/di aver avuto negli ultimi

12 mesi conflitto d’interesse in relazione a questa presentazione

e

che la presentazione non contiene/contiene discussione

di farmaci in studio o ad uso off-label

Distal (dCCA)

2-5%

INTRAHEPATIC

(iCCA)

10-20%

CHOLANGIOCARCINOMA (CCA): a more recent classification

based on anatomic location (EASL, ILCA guidelines 2013/2014, ENS-CCA))

Perihilar

(pCCA)

70-85%

Klatskin t.

second-order bile ducts

This classification overcomes the difficulties in classifying pCCA

as intra- or extra-hepatic

but ..

In ICD-O3, CCA is topographically classified as

C22 ‘‘liver and intrahepatic bile ducts’’ or

C24 ‘‘other and unspecified parts of the biliary tract’’.

Current epidemiological data evaluate only iCCA and eCCA !

Therefore, CCA classification in iCCA,

pCCA, dCCA is clinically useful

but ..

clashes with current epidemiologic

studies…… including risk factors!

2014

CCA: Worldwide incidence (cases/100,000), Banales JM…Alvaro D. Nature Rev. 2016.

Temporal trends in IH- and EH-CCA

incidence/mortality in 1980-2009.

In different countries, 1980-2009 yrs

incidence/mortality…

↑ for IH-CCA

=↓ for EH-CCA

Real or false increasing

incidence of IH-CCA ?

Bias ???

The reported increasing incidence of IH-CCA is biased

by:

- misclassification of perihilar-CCA as IH-CCA ?

- improved diagnostic tools ?

- less diagnosis of carcinoma of unknown primary site

(CUP).

Real or false increasing

incidence of IH-CCA ?

Bias ???

CHOLANGIOCARCINOMA: epidemiology !

Biases and criticisms !

USA SEER-9 registries, Welzel TM et al. (J Natl Cancer Inst 2006)

ICD-02: overreporting of IH-CCA by 13%

underreporting of EH-CCA by 15 %

IH-CCA

EH-CCA

Morphology

Morphology+

topography

Italian Cancer registries

(Capocaccia P. et al. DLD 2010)

IH-CCA = 20-30 %

EH-CCA = 40-50 %

NOS = 20-40%

13 SEER registries

(9,840 CC cases, 1992–2007)

90 % Klatskin ..as ICC 1992–2000

45% “ 2001–2007

TASSI DI INCIDENZA STANDARDIZZATI PER IH-CCA

ED EH-CCA NELLE POPOLAZIONI OSSERVATE DA

9 REGISTRI (PERIODO 1988-2002) E DA 13 REGISTRI

(PERIODO 1997-2005) ITALIANI. (Alvaro D. et al. DLD 2009)

0,0

2,0

4,0

6,0

8,0

10,0

12,0

14,0

16,0

18,0

20,0

1988 1990 1992 1994 1996 1998 2000 2002 2004

anno di diagnosi

tass

o s

tan

dar

diz

zato

x m

ilio

ne

Extra-Epatico9 registri 13 registri

Intra-Epatico

+ 3%/anno

+ 6%/anno + 4%/anno

Cancer Deaths in USA in 2030 Liver and intrahepatic bile ducts

2014

The reported increasing incidence of IH-CCA is biased

by:

- misclassification of perihilar-CCA as IH-CCA ?

- improved diagnostic tools ?

- less diagnosis of carcinoma of unknown primary site

(CUP).

Real or false increasing

incidence of IH-CCA ?

Bias ???

The proportion of patients with different disease stages

shown in successive 5-year cohorts(Shaib Y. J. Hepatology 2004).

The reported increasing incidence of IH-CCA is biased

by:

- missclassification of perihilar-CCA as IH-CCA ?

- improved diagnostic tools ?

- less diagnosis of carcinoma of unknown primary site

(CUP).

Real or false increasing

incidence of IH-CCA ?

Bias ???

American Hepato-Pancreato-Biliary Association

92-gene biomarker panel (RT-PCR–based protocol) and

computational approach ….

American Hepato-Pancreato-Biliary Association2015

ICCs N. 83

HCC N. 42

Non hepatic origin N. 332

(perihilar-CCA, pancreas, stomach, esophagus, colon, breast, ovary,

endometrium, kidney, and urinary bladder)

Albumin RNA ISH positive in 82 (99 %) ICCs and in

42 (100 %) HCC

Perihilar and distal-CCA = 100% negative

22 % of previously diagnosed CUP

tested positive for albumin-RNA !

IH-CCA 22% of CUP !!!!!!!

The reported increasing incidence of IH-CCA is biased

by:

- misclassification of perihilar-CCA as IH-CCA ?

- improved diagnostic tools ?

- less diagnosis of carcinoma of unknown primary site

(CUP).

Real or false increasing

incidence of IH-CCA ?

Bias ???

Real increasing

incidence of IH-CCA !

Why ??

PSC

O.Viverrini

C. Sinensis

Choledochal

cysts , Caroli’s

Thorotrast

pCCA

22.92A meta-analysis of risk factors for

intrahepatic cholangiocarcinoma.

Palmer WC, Patel T. J. Hepatology 2012

AISF commissione colangiocarcinoma, DLD 2009.

IH-CCA EH-CCAn= 116 n= 102

Cirrhosis 16 (13.8%) 5 (4.3%)

Cirrhosis viral 12 (10.3%) 3 (2.9%)

HCV-Ab+ 18 (15.5%) 8 (7.8%)

HBsAg+ 17 (14.6%) 10 (9.8%)

2016

Experimental Diabetes

Human Diabetes2016

Metabolic Syndrome and Gastrointestinal Cancer Risk !

Working Hypothesis

Activation of stem/progenitor cells in PBGs, pancreatic duct

glands and colon crypts, and differentiation toward insulin-

producing cells, could represent the biologic basis for GI cancer

risk ?

CCA risk factors

iCCA pCCA

n= 116 n= 102

Positive hepatitis

virus markers 35 (30.2%) 19 (18.6%) p= 0.048

No putative risk factorin 60% CCA !

CCA: probable risk factors

Biliary-enteric

drainage

Toxins: dioxins,

asbestos

Choledocolithiasis

Cholangitis

Liver

Cirrhosis Cholelithiasis/cholecystectomy

Diabetes, Alcohol

Obesity, tobacco

IBD

Hepatic

Schistosmiasis

EH-CCA

IH-CCA

Chronic inflammation and CCA

Chronic

Inflammation

(flukes,PSC..)

Apoptosis

Proliferation

iNOS

NO

Nitrosylation DNA basis

and DNA repair proteins, caspase 9

Mutagenesis

IL6

TNF

COX-2

PgE2

Prof. E. Gaudio

Acknowledgments

Prof L. Reid at UNC

Dr V. CardinaleThanks for the attention

Dr G. Carpino

Prof. P. Berloco Prof. M. Nuti/Dr. Napolitano

Prof. A.F. Attili/Prof. A. DeSantis