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, 145 (6), 1215-29

Pathogenesis, Diagnosis, and Management of Cholangiocarcinoma


Pathogenesis, Diagnosis, and Management of Cholangiocarcinoma

Sumera Rizvi et al. Gastroenterology.


Cholangiocarcinomas (CCAs) are hepatobiliary cancers with features of cholangiocyte differentiation; they can be classified anatomically as intrahepatic CCA (iCCA), perihilar CCA (pCCA), or distal CCA. These subtypes differ not only in their anatomic location, but in epidemiology, origin, etiology, pathogenesis, and treatment. The incidence and mortality of iCCA has been increasing over the past 3 decades, and only a low percentage of patients survive until 5 years after diagnosis. Geographic variations in the incidence of CCA are related to variations in risk factors. Changes in oncogene and inflammatory signaling pathways, as well as genetic and epigenetic alterations and chromosome aberrations, have been shown to contribute to the development of CCA. Furthermore, CCAs are surrounded by a dense stroma that contains many cancer-associated fibroblasts, which promotes their progression. We have gained a better understanding of the imaging characteristics of iCCAs and have developed advanced cytologic techniques to detect pCCAs. Patients with iCCAs usually are treated surgically, whereas liver transplantation after neoadjuvant chemoradiation is an option for a subset of patients with pCCAs. We review recent developments in our understanding of the epidemiology and pathogenesis of CCA, along with advances in classification, diagnosis, and treatment.

Keywords: CA19-9; CAF; CCA; CT; CXCR4; Cancer-Associated Fibroblasts; Distal Cholangiocarcinoma; ECM; EGFP; EGFR; EMT; ERBB2; ERC; ERK; FGFR; FISH; HBV; HCC; HCV; HGF; IDH; IL 6; Intrahepatic Cholangiocarcinoma; KRAS; Kirsten rat sarcoma viral oncogene homolog; MAPK; MCL1; MET; MMP; MRI; Molecular Pathogenesis; OR; PDGF; PI; PI3K; PSC; STAT; TP53; cancer-associated fibroblast; carbohydrate antigen 19-9; chemokine (C-X-C motif) receptor 4; cholangiocarcinoma; computed tomography; dCCA; distal cholangiocarcinoma; endoscopic retrograde cholangiography; enhanced green fluorescent protein; epidermal growth factor–receptor; epithelial–mesenchymal transition; extracellular matrix; extracellular signal regulated kinase; fibroblast growth factor receptor; fluorescence in situ hybridization; hepatitis B virus; hepatitis C virus; hepatocellular carcinoma; hepatocyte growth factor; iCCA; interleukin 6; intrahepatic cholangiocarcinoma; isocitrate dehydrogenase; magnetic resonance imaging; matrix metalloproteinase; met proto-oncogene; miR; microRNA; mitogen-activated protein kinase; myeloid cell leukemia sequence 1; odds ratio; pCCA; perihilar cholangiocarcinoma; phosphatidyl inositol; phosphatidylinositol-4,5-bisphosphate 3-kinase; platelet-derived growth factor; primary sclerosing cholangitis; signal transducer and activator of transcription; tumor protein 53; v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2; α-SMA; α-smooth muscle actin.


Figure 1
Figure 1. Anatomic localization of CCA and cells of origin in CCA
(A)Anatomic localization of CCA. CCA is divided into 3 subtypes, based on anatomic location. Modified with permission from Razumilava et al. (B) Cells of origin in CCA. CCA, cholangiocarcinoma; dCCA, distal cholangiocarcinoma, iCCA, intrahepatic cholangiocarcinoma, pCCA, perihilar cholangiocarcinoma.
Figure 2
Figure 2. IDH mutations
(A) Function of wild-type and mutant IDH. Wild-type enzymes catalyze a reaction that converts isocitrate to α-ketoglutarate and reduction of NADP to NADPH. The mutant enzymes acquire a neomorphic activity that converts the normal metabolite α-KG to 2-HG and consumption rather than production of NADPH. 2-HG leads to inhibition of certain dioxygenases, which has been postulated to result in cancer promoting events. (B) Potential of personalized medicine for CCA, using mIDH inhibitors, as an example. α-KG, α-ketoglutarate; 2-HG, 2-hydroxyglutarate; IDH, isocitrate dehydrogenase; mIDH, mutant isocitrate dehydrogenase; NADPH, nicotinamide adenine dinucleotide phosphate.
Figure 3
Figure 3. Microenvironment of cholangiocarcinoma
(A) Components of the tumor microenvironment in CCA. (B) Micrograph of a stromal CCA. (C) Factors secreted by cancer-associated fibroblasts. CCA, cholangiocarcinoma; CTGF, connective tissue growth factor; ECM, extracellular matrix; HGF, hepatocyte growth factor; MMP, matrix metalloproteinase; PDGF-β, platelet-derived growth factor beta; SDF-1, stromal cell-derived factor 1; TGF-β, transforming growth factor beta.
Figure 4
Figure 4. Diagnostic modalities used for cholangiocarcinoma
(A) MRI image of a pCCA mass (outlined in circle). (B) CT image of a pCCA mass with right portal vein encasement (indicated by black arrow). (C) MRCP image of common hepatic duct involvement by tumor (indicated by white arrow). (D) ERC image depicting excluded segmental ducts (white arrows) in a patient with a hilar biliary stricture extending into the right main hepatic duct. CT, computed tomography; ERC, endoscopic retrograde cholangiography; MRCP, magnetic resonance cholangiopancreatography; MRI, magnetic resonance imaging; pCCA, perihilar cholangiocarcinoma.
Figure 5
Figure 5
Time to diagnosis of cholangiocarcinoma based on FISH analysis and CA 19-9 levels. CA 19-9, carbohydrate antigen 19-9; FISH, fluorescence in situ hybridization. Reused with permission from Wiley InterScience and Barr et al.

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