R.Sotoudehmanesh, MD Professor of Gastroenterology Digestive Disease Research Institute Tehran University of Medical Sciences Pancreatobiliary

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1 R.Sotoudehmanesh, MD Professor of Gastroenterology Digestive Disease Research Institute Tehran University of Medical Sciences Pancreatobiliary /Advanced Endoscopy group

2 Most common biliary malignancy and the second most common hepatic malignancy after HCC. Poor prognosis; median survival of 24 months. Surgery, for early stage disease.

3 3% of all gastrointestinal tumors. Over the past 3 decades, the overall incidence of CCA appears to have increased. Survival 5 years after diagnosis remaining at 10%.

4 Hispanics and Asians have the highest incidence of CCA (2.8 per 100,000 and 3.3 per 100,000, respectively), whereas African Americans have the lowest incidence of CCA (2.1 per 100,000). With the exception of patients with PSC, a diagnosis of CCA is uncommon before age 40 years. Globally, hepatobiliary malignancies account for 13% of cancer-related deaths; 10% 20% attributable to CCA. The mean age at diagnosis of CCA is 50 years.

5 The global incidence varies; 113 per 100,000 in Thailand to 0.1 per 100,000 in Australia. Differences ;genetic and other risk factors. The age-adjusted mortality rate for icca is increasing, whereas the mortality rate from pcca and dcca could be decreasing.

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7 Conversion from normal to malignant bile epithelium ;similar to the sequence of events that underlies colorectal carcinogenesis. Mutations in p53 and loss of SMAD4. Molecular defects involving both oncogenes (K-ras, c- erbb-2, BRAF, the epidermal growth factor receptor (EGFR) PIK3CA, beta-catenin (CTNNB1)) and tumor suppressor genes (eg, p53, SMAD4, CDKN2A) have been described in specimens of invasive biliary tract tumors.

8 One-third of tumors over-express p53 while abnormal expression of K-ras is found in 45 to 54 % of intrahepatic cholangiocarcinomas, and 10 to 15 % of extrahepatic cholangiocarcinomas. These genetic alterations seem to be associated with a more aggressive tumor phenotype. At least some data suggest that p16ink4a promoter point mutations contribute to initiation and progression of cholangiocarcinoma in the setting of PSC. Loss of heterozygosity (LOH) of chromosomes 4q and 6q, and/or inactivation of tumor suppressor genes on chromosome 1p. Molecular abnormalities may also permit an escape from immune surveillance in vivo.

9 Geographic variations; Southeast Asia, which has one of the highest incidence rates of CCA, infection with the hepatobiliary flukes Opisthorchis viverrini and Clonorchis sinensis. (Both parasites cause chronic inflammation and are considered carcinogens). Hepatolithiasis is another risk factor for CCA (mainly icca) in Asian countries.(chronic biliary inflammation secondary to calculi).

10 Choledochal cysts ;10-30% (Age;32y) Types; I &IV Thorotrast In the West, PSC is the most common predisposing condition for CCA (annual risk of development of CCA is 0.5% 1.5%, with a lifetime prevalence of 5% 10%).

11 HBV or HCV hepatitis and cirrhosis have been proposed as potential etiologies of icca. A recent meta-analysis of 11 studies ;cirrhosis, HBV, and HCV were major risk factors for icca, with odds ratios (ORs) of 22.92, 5.1, and 4.8, respectively. Other risk factors; IBD independent of PSC, alcohol, smoking, fatty liver disease, diabetes, cholelithiasis, an choledocholithiasis.

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13 Inflammation: >DNA damage >blocking the apoptosis >cell proliferation >cell transformation Cholestasis ;activating growth factors > cell proliferation.

14 isocitrate dehydrogenase

15 icca is divided into mass-forming, periductal infiltrating, and intraductal growth types. The clinical manifestations :nonspecific ;abdominal pain, cachexia, malaise, fatigue, and night sweats. Frequently: intrahepatic mass lesion; imaging modalities including CT and MRI aid in the diagnosis (Size,Sattelites).

16 The use of contrast enhancement improves the sensitivity of MRI for detection of icca because these tumors typically have progressive uptake of contrast during the venous phase (HCC has contrast uptake during arterial phase). CT may be better for assessment of vascular encasement, identification of extrahepatic metastasis, and determination of resectability.

17 Serum levels of CA19-9 ; only 62% sensitivity and 63% specificity. Benign diseases causing elevated CA19-9; bacterial cholangitis or choledocholithiasis. Nonetheless, very high levels of CA19-9 (1000 U/mL) have been associated with metastatic icca, ; disease staging rather than diagnosis.

18 Mixed tumors ;HCC and Icca: IHC;cytokeratins 7 and 19 ;mixed hepatocellular CCA. A definitive diagnosis of icca ;liver biopsy. According to the WHO classification criteria, iccas can be adenocarcinomas or mucinous carcinomas.

19 Resectable icca should be resected! After surgical resection, the median time of disease-free survival is 26 months; reported rates of recurrence are 60% 65%. Approximately 60% of patients survive for 5 years after resection.

20 Recurrence and reduced survival : vascular invasion, lymph node metastasis, multiple tumors, and cirrhosis. Nuclear expression of S100A4, a member of the S100 family of calcium-binding proteins, in neoplastic ducts was associated with metastasis and reduced time of survival after surgical resection in a subset of patients with CCA.

21 Liver Transplantation (L.Tx) ;highly controversial; High recurrence rate and low survival. Patients with very small iccas (<2 cm) in the context of cirrhosis, however, do as well as patients undergoing liver transplantation for HCC. Locoregional therapy, including TAC and RFA, has garnered interest as a therapeutic option for patients with unresectable icca. The standard practice of care for advanced-stage icca is systemic chemotherapy with gemcitabine and cisplatin.

22 pccas can have exophytic or intraductal macroscopic growth patterns. The exophytic or mass-forming type can be of the nodular subtype or the periductal subtype (the most common subtype). Clinical; nonspecific symptoms including abdominal discomfort, cachexia, weight loss, and malaise.

23 Typically obstructive jaundice. Less commonly cholangitis. Hypertrophy of the unaffected liver lobe and atrophy of the affected lobe, presents as palpable prominence Laboratory ;cholestasis CA19-9 ; less specific in pcca than icca.

24 ERC ; assess / sample the biliary tree ;brush cytology, biopsy, as well as dilatation and stenting. Imagings; MRI,CT, MRCP, ERCP and EUS MRI + MRCP ;preferred; resectability and extention: accuracy of up to 95%. EUS aids in evaluation for the presence of regional LAPs and omental metastasis via FNA. FNA should not be performed on the primary tumor because it can disseminate the tumor.

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27 Notoriously difficult to diagnose cytologically Sensitivity ranged from 35-70% Specificity typically exceeded 90%

28 Fluorescence in situ hybridization (FISH) analysis increases the sensitivity of cytology in diagnosing pcca. FISH >>polysomy or amplification of : tetrasomy and trisomy. Polysomy + a dominant stricture : pcca, especially if the polysomy can be confirmed over time. Trisomy 7 often is observed with inflammation of the biliary tree. Detection of polysomy by FISH ;prediction the development of malignancies in patients with PSC with no mass and equivocal cytology. In a recent study, patients with PSC who had polysomy and CA19-9 > 129 U/mL all went on to develop cancer, mainly within 2 years.

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32 Small caliber intraductal ultrasould miniprobes Better image resolution than standard EUS Evaluate the proximal biliary system and surrounding periductal tissue Distinguish benign from malignant strictures

33 Cholangiocarcnoma Bismuth Classification Type I Type IIIa Type II Type IIIb Type IV

34 Assessment of tumor resectability by CT or MRI may be affected by the presence of biliary stents (Evidence level 2+). In Bismuth Corlette type 2, better biliary drainage might be achieved with fewer infective complications by the percutaneous as compared with the endoscopic route (Evidence level 1 ). Based on MRI or CT, with the aim of draining >50% of the liver volume. Bile duct(s) unintentionally opacifie upstream from an MHS should be drained during the same procedure.(evidence level 2 ). If a decision for palliative treatment is taken, insertion of SEMSs is recommended in patients with life expectancy >3 months or with biliary infection (Recommendation grade B).

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38 Curative options ; surgical resection and neoadjuvant chemoradiation followed by LTx. Contraindications to resection ; contralateral or bilateral vascular encasement and pcca extension bilaterally to the level of the secondary biliary branches. In the case of limited volume; preoperative relief of biliary obstruction and portal vein embolization of the affected lobe : compensatory hyperplasia of the contralateral unaffected liver lobe. Rates of 5-year survival after surgical resection with negative margins range from 11% to 41%.

39 65% of patients who were treated with neoadjuvant therapy followed by liver transplantation at 12 largevolume transplant centers survived for 5 years. Rigorous selection is imperative for successful outcomes. Because of the presence of parenchymal liver disease, patients with PSC typically require L.Tx rather than surgical resection. Systemic chemotherapy with gemcitabine and cisplatin for others.

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42 dcca arises from the point of insertion of the cystic duct to the ampulla of Vater. Clinic; painless cholestatic jaundice, and laboratory analysis is consistent with biliary obstruction. Imaging; EUS and ERC

43 Diagnosis ; dominant stricture and positive cytology and/or detection of polysomy by FISH. Surgical treatment ;Whipple procedure. Only 27% of patients survive for 5 years after surgical resection that attains negative margins. The role of neoadjuvant chemoradiation is limited. Not surgical resection; chemotherapy may be considered.

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45 Treatment options for CCA ; limited with low survival rates. Earlier detection of CCA increases the chance of having curative treatment options. Further work for the diagnose CCA at an earlier stage. CCA often still is diagnosed based on clinical criteria, such as a malignant-appearing bile duct stricture, increased serum levels of CA19-9, appearance of a mass during MRI, normal IgG4 level, and so forth.

46 Inflammatory and oncogenic signaling pathways also are involved in CCA, and are potential therapeutic targets. Further studies are necessary to elucidate the role of genetic aberrations, particularly in regions encoding key components of signaling pathways.

47 Potential therapeutic targets could include the MET tyrosine receptor kinase, FGFR2, the PI3K Akt mtor pathway, and IDH mutations. Molecular profiling of tumors, to identify their specific mutations; targeted therapies in personalized treatments. Although cancer cells contain many genetic and functional aberrations, the tumor stroma appears to be more uniform and has strong potential as a target for new combination therapies.

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