Colangiocarcinoma on the rise!
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1 Colangiocarcinoma on the rise! D. ALVARO, Univ. Sapienza, Rome, Italy. MONOTEMATICA AISF, The future of Liver Diseases, Milano Ottobre 2016
2 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
3 CHOLANGIOCARCINOMA (CCA): a more recent classification based on anatomic location (EASL, ILCA guidelines 2013/2014, ENS-CCA)) This classification overcomes the difficulties in classifying pcca INTRAHEPATIC Therefore, as intra- or CCA extra-hepatic classification in icca, (icca) pcca, dcca is clinically useful but % In ICD-O3, second-order CCA is bile topographically ducts classified as but.. Klatskin t. C22 liver and intrahepatic bile ducts or clashes C24 with other current and epidemiologic unspecified parts of the biliary tract. studies including risk factors! Current epidemiological data evaluate only icca and ecca! Distal (dcca) 2-5% Perihilar (pcca) 70-85%
4 CCA: Worldwide incidence (cases/100,000), Banales JM Alvaro D. Nature Rev
5 Temporal trends in IH- and EH-CCA incidence/mortality in In different countries, yrs incidence/mortality Real or false increasing incidence of IH-CCA? for IH-CCA Bias??? = for EH-CCA
6 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).
7 CHOLANGIOCARCINOMA: epidemiology! Biases and criticisms! Morphology Morphology+ topography Italian Cancer registries IH-CCA (Capocaccia P. et al. DLD 2010) IH-CCA = % EH-CCA = % NOS = 20-40% USA SEER-9 registries, Welzel TM et al. (J Natl Cancer Inst 2006) EH-CCA ICD-02: overreporting of IH-CCA by 13% underreporting of EH-CCA by 15 %
8 90 % Klatskin..as ICC % SEER registries (9,840 CC cases, )
9
10 tasso standardizzato x milione TASSI DI INCIDENZA STANDARDIZZATI PER IH-CCA ED EH-CCA NELLE POPOLAZIONI OSSERVATE DA 9 REGISTRI (PERIODO ) E DA 13 REGISTRI (PERIODO ) ITALIANI. (Alvaro D. et al. DLD 2009) 20,0 18,0 9 registri 13 registri Extra-Epatico 16,0 14,0 12,0 + 3%/anno 10,0 8,0 Intra-Epatico 6,0 4,0 2,0 0,0 + 6%/anno + 4%/anno anno di diagnosi
11 Cancer Deaths in USA in 2030 Liver and intrahepatic bile ducts
12 2014
13 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).
14 The proportion of patients with different disease stages shown in successive 5-year cohorts(shaib Y. J. Hepatology 2004).
15 Real or false increasing incidence of IH-CCA? Bias??? 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).
16
17 American Hepato-Pancreato-Biliary Association
18 92-gene biomarker panel (RT-PCR based protocol) and computational approach.
19 ICCs N HCC N. 42 Non hepatic origin N. 332 American Hepato-Pancreato-Biliary Association (perihilar-cca, pancreas, stomach, esophagus, colon, breast, ovary, endometrium, 22 % of kidney, previously and urinary diagnosed bladder) CUP tested positive for albumin-rna! Albumin RNA ISH positive in 82 (99 %) ICCs and in IH-CCA 22% of CUP 42!!!!!!! (100 %) HCC Perihilar and distal-cca = 100% negative
20 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).
21 Real increasing incidence of IH-CCA! Why??
22 A meta-analysis of risk factors for intrahepatic cholangiocarcinoma. Palmer WC, Patel T. J. Hepatology AISF commissione colangiocarcinoma, DLD O.Viverrini pcca IH-CCA EH-CCA C. Sinensis n= 116 n= 102 Cirrhosis 16 (13.8%) 5 (4.3%) PSC Cirrhosis viral 12 (10.3%) 3 (2.9%) Choledochal cysts, Caroli s HCV-Ab+ 18 (15.5%) 8 (7.8%) Thorotrast HBsAg+ 17 (14.6%) 10 (9.8%)
23 Human Diabetes Experimental Diabetes Metabolic Syndrome and Gastrointestinal Cancer Risk! Working Hypothesis Activation of stem/progenitor cells in PBGs, pancreatic duct glands and colon crypts, and differentiation toward insulinproducing cells, could represent the biologic basis for GI cancer risk?
24 CCA risk factors icca pcca n= 116 n= 102 Positive hepatitis virus markers 35 (30.2%) 19 (18.6%) p= No putative risk factor in 60% CCA!
25 CCA: probable risk factors Hepatic Schistosmiasis Liver Cirrhosis IBD Cholelithiasis/cholecystectomy EH-CCA Biliary-enteric drainage Toxins: dioxins, asbestos Choledocolithiasis Cholangitis IH-CCA Diabetes, Alcohol Obesity, tobacco
26
27
28 Chronic inflammation and CCA Chronic Inflammation (flukes,psc..) IL6 TNF inos NO COX-2 PgE2 Apoptosis Proliferation Nitrosylation DNA basis and DNA repair proteins, caspase 9 Mutagenesis
29
30
31 Acknowledgments Prof. P. Berloco Prof. M. Nuti/Dr. Napolitano Prof. A.F. Attili/Prof. A. DeSantis Prof. E. Gaudio Thanks for the attention Dr G. Carpino Prof L. Reid at UNC Dr V. Cardinale
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