Decision-Making Analysis for Surveillance Population at Risk: PSC Surveillance Strategy: Available Accessible Acceptable Early Detection: Treatment Improved Outcomes: Survival Cost Effectiveness

PSC: Important CCA Risk Factor 26% 37% 37% Proportion of all CCAs (%) 1 10 Time since PSC Diagnosis (years) Leading source of mortality (1/3rd all deaths) 10-15% lifetime risk Annual incidence ~1-2% ↑ CCA: late onset PSC, longer IBD duration. ↓ CCA: small duct & pediatric patients (very rare) Weismuller TJ,. Gastroenterology 2017 Gulamhusein AF. Am J Gastroenterol 2016 Boonstra K, et al. Hepatology 2013 Eaton JE, J Gastroenterol Hepatol 2017

MRI/MRCP Imaging Modality of Choice for pCCA Sensitivity Specificity Ultrasound 57% - CT scan 75% 79% PET Scan* 55% 33% MRI/MRCP 88% 85% Mass lesion with delayed venous enhancement nearly 100% specific for CCA Alkhawaldeh Clin Nucl Med 2011 Schramm, Eaton Hepatology 2017

CP1081584-2

Diagnosis

ROC for CA 19-9 in Identifying Cholangiocarcinoma in PSC 41 128 100 180 Chalasani et al: Hepatology 31:7-11, 2000 Sensitivity 200 CA 19-9>100 Sensitivity 75% Specificity 80% 1-specificity CP925977-1

Causes of Elevated CA 19-9 in PSC Patients without Cholangiocarcinoma Normalization after endoscopic treatment n=7 Extrahepatic malignancy n=1 Persistent Cholestasis n=5 Recurrent bacterial cholangitis n=6 Sinakos et al. Clinical Gastroenterology and Hepatology 2011

Routine Cytology Normal Atypical Suspicious Positive

Limitations of Conventional Cytology Difficult to access and obtain specimens Cancers are highly desmoplastic Specimens are frequently paucicellular Diagnostic criteria are subjective Sensitivity for malignancy 10-40% Specificity ~100% - Still a Gold Standard

FISH chrom 3= red, chrom 7= green, chrom 17= aqua, locus 9p21= gold Normal Polysomy >5 cells 2 signals per color ≥ 2 signals in ≥ colors

Conventional Cytology and FISH Polysomy: PSC-Associated Strictures Sensitivity Specificity 100 100 % 47 18

Unresectable, perihilar Criteria for LTx Unresectable, perihilar Mass, radial diameter <3 cm, no cut off for longitudinal diameter If PSC, any ductal tumor <3 cm CP1041236-3

Treatment Protocol External beam radiation therapy Brachytherapy Capecitabine Hand Assisted Laparoscopy Liver transplantation

Recurrence-Free Survival: PSC vs. non-PSC 82% (76-88) 72% (63-81) 62% (48-76) Recurrence-free survival (%) 70% (58-82) 51% (37-65) 51% (37-65) Primary sclerosing cholangitis (PSC) P=0.06 No PSC Years No. at risk 143 109 94 69 52 34 21 14 11 7 6 5 4 Cumulative 0 20 24 29 33 33 35 35 36 36 36 37 37 no. events PSC No PSC No. at risk 71 52 35 26 17 15 11 8 7 5 4 4 3 Cumulative 10 10 19 25 26 27 27 27 27 27 27 27 27 no. events Murad et al: Gastroenterology, 2012 ©2012 MFMER | 3205680-20

Suspicious Cytology, FISH (-) Indeterminate Stricture on MRI/MRCP ERCP with Biopsy + Cytology + FISH Cytology/Biopsy (+) Cytology/Biopsy (-) FISH (polysomy) Suspicious Cytology, FISH (-) Cytology/Biopsy, FISH All (-) CCA CA19-9 ≥ 129 U/mL CA19-9 <129 U/mL MRI/MRCP Surveillance How do we synthesize that information and apply it to our clinical practice. This illustrates a guidance algorithm Repeat ERCP Probable CCA Cytology (+) Cytology (-) FISH (polysomy) Cytology (-) FISH (-) Probable CCA MRI/MRCP surveillance

CCA Surveillance in PSC