Gastroenterology Grand Rounds October 31, 2013 Fellow: David Tang, M.D. Faculty: Clark Hair, M.D.

Case Presentation 30 year old Hispanic woman [2010] Diagnosed with Ulcerative Colitis Started on Mesalamine and Azathioprine Three flares since diagnosis each resolved after starting steroid taper

Case Presentation [8/26] Presented to Houston area hospital with RUQ abdominal pain x 4 days AST 144 ALT 266 Alk Phos 522 Total Bilirubin 4.1 Direct Bilirubin 3.6 Total Protein 7.2 Albumin 3.7

Case Presentation [8/26] RUQ Abdominal Ultrasound [8/29] MRCP Hydropic gallbladder with an associated stone at the gallbladder neck. No intrahepatic or extrahepatic biliary ductal dilation. [8/29] MRCP Subtle contour irregularity within the intrahepatic biliary system suggesting PSC 1.2 cm segment of proximal extrahepatic common bile duct is smoothly narrowed with possible adjacent are of soft tissue prominence

[8/30] ERCP 1. Beading appearance of the intra and extra hepatic bile ducts 2. 2cm distal CHD/proximal CBD stricture s/p biopsies and brushings 3. S/p 10F x 7cm biliary stent placement

[9/4] Colonoscopy Path: CHRONIC ACTIVE COLITIS WITH CRYPT ARCHITECTURAL DISARRAY AND CRYPT LOSS; No dysplasia, no granulomas

[9/23] EUS There was an ill-defined heterogeneous hypoechoic 23 x 18mm porta hepatis lesion around the proximal-mid bile duct

Courtesy of Dr. Zarrin-Khameh, Pathology FNA of the porta hepatis has large cells (red circle) with high nuclear to cytoplasmic ratio and prominent nucleoli. This is a Pap stain. Red cells are seen in the background. You can compare the size of these cells with a lymphocytes (red arrow) Courtesy of Dr. Zarrin-Khameh, Pathology

Courtesy of Dr. Zarrin-Khameh, Pathology This is the cell block (we spin down the material and make a cell block; which we treat like a small biopsy). This is H&E stain (hematoxilin and eosin). The tumor cells with high nuclear to cytoplasmic ratio and prominent nucleoli are seen. A tumor giant cell is note (green). A huge tumor cells with irregular nuclear borader and very large nucleoli is seen (blue) Courtesy of Dr. Zarrin-Khameh, Pathology

Pathological Diagnosis Cholangiocarcinoma

Clinical Questions What is the epidemiological relationship of Cholangiocarcinoma to PSC? Is concomitant IBD a risk for developing Cholangiocarcinoma? What are the other risk factors? What is the utility of CA 19-9 in the diagnosis of Cholangiocarcinoma? How should it be used in screening patients with PSC?

Prevalence of CCA in PSC Cohort Size Prevalence Median Follow Up Broome 305 8% 5.3 years Bergquist 604 13.3% 5.7 years Boberg 394 12.2% 4.7 years Burak 161 6.8% 11.5 years Tischendorf 273 14.3% 6.3 years Fevery 123 6.9% 9 years Charatcharoenwitthaya 230 10% 4.1 years Claessen 211 7.1%

Prevalence of IBD in PSC Size Population Concomitant IBD Concomitant UC Concomitant CD Berquist 604 Sweden 79% 69% 7% Boberg 394 Europe 82% 65% - Weisner 174 Minnesota 71% Takikawa 192 Japan 21% 19.8% 1% Kochlar 18 India 50%

Does concomitant IBD increase risk of CCA in PSC? Multicenter European retrospective cohort study with 394 PSC patients Median follow up 4.7 years 12.2% of patients developed Cholangiocarcinoma

Does concomitant IBD increase risk of CCA in PSC?

Predisposing factors for Cholangiocarcinoma in PSC Retrospective cohort study of 161 patients with PSC at Mayo Clinic Median follow up 11.5 years 6.8 % of patients developed Cholangiocarcinoma History of variceal bleeding, lack of symptoms at baseline, and proctocolectomy associated with increased risk of Cholangiocarcinoma Burak

Predisposing factors for Cholangiocarcinoma in PSC Multicenter case-control study of 26 cases of Cholangiocarcinoma in PSC matched with 87 patients with PSC alone Duration of IBD was not a significantly associated with Cholangiocarcinoma from 8 cases and 33 controls However, a smaller case control trial showed no difference for duration of IBD. Chalasani

Predisposing factors for Cholangiocarcinoma in PSC In the same study, Mayo risk score and CP class did not differ. Chalasani

Predisposing factors for Cholangiocarcinoma in PSC Chalasani

Utility of CA 19-9 in Diagnosis of Cholangiocarcinoma CA 19-9 cut off of > 100 U/mL was 75% sensitive and 80% specific for Cholangiocarcinoma AUC = 0.84 Chasani

Utility of CA 19-9 in Diagnosis of Cholangiocarcinoma Cross sectional study of 333 patients with PSC from 1984 to 1997 13% with Cholangiocarcinoma CA 19-9 cut off of > 180 U/mL was 75% sensitive and 97% specific for Cholangiocarcinoma AUC = 0.76 Siqueira

Utility of CA 19-9 in Diagnosis of Cholangiocarcinoma Retrospective cohort study of 208 patients at Mayo clinic who had PSC and serial CA 19-9 measurements Mean follow up 2.6 years CA 19-9 cut off of > 129 U/mL was 78.6% sensitive and 98% specific for Cholangiocarcinoma Only 2 out of 14 patients with Cholangiocarcinoma were resectable AUC = 0.95 Levy 14/208 6.7% with CCA

Utility of CA 19-9 in Diagnosis of Cholangiocarcinoma AUC 0.79 Cutoff 20 U/mL Sn 78 Sp 67 23/230 4.1 years Charat

Combination of cross sectional imaging and CA 19-9 for diagnosis of Cholangiocarcinoma

Combination of cross sectional imaging and CA 19-9 for diagnosis of Cholangiocarcinoma

Proposed algorithm for screening and diagnosis of Cholangiocarcinoma