Pathogenesis, Diagnosis, and Management of Cholangiocarcinoma

doi:10.1053/j.gastro.2013.10.013

Gastroenterology

Volume 145, Issue 6, December 2013, Pages 1215-1229

https://doi.org/10.1053/j.gastro.2013.10.013 Get rights and content

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.

Section snippets

Epidemiology

Cholangiocarcinoma accounts for 3% of all gastrointestinal tumors. Over the past 3 decades, the overall incidence of CCA appears to have increased.⁶ The percentage of patients who survive 5 years after diagnosis has not increased during this time period, remaining at 10%.7, 8

In the United States, 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). African

Risk Factors

There are several established risk factors for CCA, and most cases are sporadic.6, 8, 17 Geographic variations in incidence rates of CCA are related in part to variations in risk factors. For example, in Southeast Asia, which has one of the highest incidence rates of CCA, infection with the hepatobiliary flukes Opisthorchis viverrini and Clonorchis sinensis has been associated with the development of CCA. Both parasites cause chronic inflammation and are considered carcinogens.8, 18

Cells of Origin

iCCA is a histologically diverse hepatobiliary malignancy considered to develop from biliary epithelial cells or hepatic progenitor cells (Figure 1B). A recently proposed classification of iCCAs subdivided these tumors into the conventional, bile ductular, or intraductal neoplasm type, or rare variants (combined hepatocellular CCA, undifferentiated type, squamous/adenosquamous type). The conventional type includes small-duct or peripheral type and large-duct or perihilar type.³⁰ Neural cell

Inflammation

CCAs frequently arises under conditions of inflammation, which is believed to contribute to pathogenesis. A variety of cytokines, growth factors, tyrosine kinases, and bile acids can contribute to alterations in proliferation, apoptosis, senescence, and cell-cycle regulation required for cholangiocarcinogenesis.⁵ Inflammatory cytokines activate inducible nitric oxide synthase, leading to excess nitric oxide with resultant single-stranded, double-stranded, and oxidative DNA lesions, as well as

Genetics

A few studies have assessed the roles of genetic factors, such as chromosome aberrations or genetic and epigenetic alterations in tumor suppressor genes and oncogenes, in the pathogenesis of human CCA. However, these studies have produced no definitive results because they analyzed a limited number of genes in combined CCA specimens, without separate analyses of different subtypes.⁶¹ A comparative genomics hybridization analysis of 32 CCA samples from patients (7 iCCA, 13 pCCA, and 12 dCCA)

Developmental Pathways

The Notch signaling pathway regulates embryonic development and proliferation of the biliary tree.⁸⁵ Not surprisingly, therefore, Notch dysregulation also has been implicated in cholangiocarcinogenesis. Two recent studies in mice have shown that Notch activation is required for conversion of normal adult hepatocytes to biliary cells that are precursors of iCCA.35, 36 Overexpression of intracellular domain of the Notch 1 receptor in liver cells of mice resulted in formation of iCCAs.⁸⁶ In this

Tumor Microenvironment

Carcinogenesis in CCA includes alterations in the stroma, recruitment of fibroblasts, remodeling of the extracellular matrix (ECM), changing patterns of immune cell migration, and promotion of angiogenesis (Figure 3A).⁹¹ iCCAs and pCCAs are characterized by a dense and reactive desmoplastic stroma (Figure 3B) that contains many α-smooth muscle actin (α-SMA)–positive myofibroblasts, also known as cancer-associated fibroblasts (CAFs). The tumor stroma surrounds the malignant ducts and glands and

Animal Models

Animal models are essential for the development of new therapeutic strategies and diagnostic tools.¹¹¹ Animal models of CCA (Table 1) include mice with xenograft tumors,43, 112, 113, 114, 115, 116, 117, 118, 119 mice with genetic changes that lead to CCA formation,86, 120, 121, 122, 123, 124 rats with orthotopic tumors,125, 126 and animals that develop CCAs after exposure to carcinogens.55, 127, 128, 129 Although these models offer an opportunity to bridge the chasm between in vitro findings

Diagnosis and Management

It can be a challenge to diagnose CCA because of its paucicellular nature, anatomic location, and silent clinical character. Diagnosis requires a high index of suspicion and a multidisciplinary approach that involves clinical, laboratory, endoscopic, and radiographic analyses.

Future Directions

Treatment options for CCA are limited and overall survival rates are low. Earlier detection of CCA increases the chance of having curative treatment options. However, despite recent advances in diagnosis, such as improved imaging and cytology techniques, including FISH, further work is necessary to overcome the challenge of diagnosing 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

Acknowledgments

The authors would like to thank Dr Thomas Smyrk for kindly providing the stromal cholangiocarcinoma photomicrograph and Ms Courtney Hoover for outstanding secretarial support.

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Characterization of indeterminate biliary strictures (IDBS) still represents a major challenge. Digital single-operator cholangioscopy (DSOC) could potentially overcome limits of conventional biopsy and brush sampling. The aim of this study was to compare diagnostic accuracy of visual evaluation and DSOC-guided biopsies to conventional trans-papillary sampling techniques and to evaluate the inter-observer agreement (IOA) on visual diagnosis.
All consecutive patients undergoing DSOC-guided biopsy after conventional sampling techniques for IDBS during a six—year period were retrospectively evaluated. Final diagnosis was based on histological evaluation of the surgical specimen if available or a clinical follow-up of at least 6 months. For IOA, 20-second DSOC clips were retrospectively reviewed by 6 experts and 6 trainees and classified according to the Monaco Classification.
Thirty-five patients underwent DSOC for IDBS in the study period; 14 patients (F = 9) with a median age of 64 years (range 53–76) met the study aim. After DSOC, strictures location was changed in three patients (additional yield of 21.4 %). Intraductal DSOC-guided biopsy were technically successful in all cases, with an adequacy of 92.8 %. No adverse events were recorded. Final diagnosis was benign disease in five cases and cholangiocarcinoma in the others. For IOA, 29 videos were evaluated with almost perfect agreement for final diagnosis (kappa 0.871; agreement 93.1, p <0.001), although overall accuracy of DSOC visual finding was 73.6 % and 64.4 % for experts and trainees, respectively.
DSOC could improve diagnostic accuracy for IDBS, since it showed high sensitivity for visual finding and high specificity for DSOC guided-biopsy. Visual diagnosis seems reliable for diagnosis using the Monaco Classification.
Liver transplantation as an alternative for the treatment of perihilar cholangiocarcinoma: A critical review
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Perihilar cholangiocarcinoma (phCCC) is a dismal malignancy. There is no consensus regarding the best treatment for patients with unresectable phCCC. The present review aimed to gather the current pieces of evidence for liver transplantation and liver resection as a treatment for phCCC and to build better guidance for clinical practice.
The search was conducted in PubMed, Embase, Cochrane, and LILACS. The related references were searched manually. Inclusion criteria were: reports in English or Portuguese literature that a) patients with confirmed diagnosis of phCCC; b) patients treated with a curative intent; c) patients with the outcomes of liver resection and liver transplantation. Case reports, reviews, letters, editorials, conference abstracts and papers with full-text unavailability were excluded from the analysis.
Most of the current literature is based on observational retrospective studies with low grades of evidence. Liver resection has better long-term outcomes than systemic chemotherapy or palliation therapy and liver transplantation is a good alternative for selected patients with unresectable phCCC. All candidates for resection or transplantation should be medically fit and free of intrahepatic or extrahepatic diseases. As a general rule, patients presenting with a tumor having a longitudinal size > 3 cm or extending below the cystic duct, lymph node disease, confirmed extrahepatic dissemination; intraoperatively diagnosed metastatic disease; a history of other malignancies within the last five years, and did not complete chemoradiation regimen and were medically unfit should not be considered for transplantation. Some of these criteria should be individually assessed. Liver transplantation or resection should only be considered in highly experienced hepatobiliary centers, and any decision-making must be based on a multidisciplinary evaluation.
phCCC is a complex condition with high morbidity. Surgical therapies, including hepatectomy and liver transplantation, are the best option for better long-term disease-free survival.
Liver transplantation as an alternative for the treatment of intrahepatic cholangiocarcinoma: Past, present, and future directions
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Intrahepatic cholangiocarcinoma (iCCA) is a rare biliary tract cancer with high mortality rate. Complete resection of the iCCA lesion is the first choice of treatment, with good prognosis after margin-negative resection. Unfortunately, only 12%-40% of patients are eligible for resection at presentation due to cirrhosis, portal hypertension, or large tumor size. Liver transplantation (LT) offers margin-negative iCCA extirpation for patients with unresectable tumors. Initially, iCCA was a contraindication for LT until size-based selection criteria were introduced to identify patients with satisfied post-LT outcomes. Recent studies have shown that tumor biology-based selection can yield high post-LT survival in patients with locally advanced iCCA. Another selection criterion is the tumor response to neoadjuvant therapy. Patients with response to neoadjuvant therapy have better outcomes after LT compared with those without tumor response to neoadjuvant therapy. Another index that helps predict the treatment outcome is the biomarker. Improved survival outcomes have also opened the door for living donor LT for iCCA. Patients undergoing LT for iCCA now have statistically similar survival rates as patients undergoing resection. The combination of surgery and locoregional and systemic therapies improves the prognosis of iCCA patients.
Non-coding RNA and Drug resistance in cholangiocarcinoma
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Cholangiocarcinoma is a highly aggressive cancer with a dismal prognosis and limited resectability. Chemotherapy has demonstrated tremendous benefits for patients with advanced and inoperable cancer, but drug resistance poses a significant obstacle. Despite recent progress in cancer therapy, the mechanisms driving drug resistance are multifaceted and not completely comprehended. Non-coding RNA refers to RNA molecules that are endogenous and do not code for proteins. Particularly microRNAs, long non-coding RNAs, circular RNAs, are widely acknowledged to be involved in cancer initiation, proliferation, and metastasis. Recently, evidences suggests that abnormal expression of non-coding RNAs contributes to resistance to different type of cancer therapies in cholangiocarcinoma. This occurs via the rewiring of signaling pathways including the reduction of anticancer drugs, apoptosis, interaction between cholangiocarcinoma and tumor-infiltrating immune cells, and cancer stemness. Thus, our review aims to demonstrate the potential of targeting non-coding RNA to override drug resistance and summarize the molecular mechanisms of how non-coding RNA contributes to drug resistance in cholangiocarcinoma.
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Targeting PKM2 improves the gemcitabine sensitivity of intrahepatic cholangiocarcinoma cells via inhibiting β-catenin signaling pathway
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Gemcitabine is considered the standard first-line chemotherapeutic agent for patients with intrahepatic cholangiocarcinoma (ICC). However, its therapeutic efficacy is hampered by the development of chemoresistance. Pyruvate kinase M2 (PKM2), a crucial mediator of the final step in glycolysis, has been implicated in the origination and advancement of diverse malignancies. Its expression is increased in many tumor types and this may correlate with increased drug sensitivity. However, the specific effect of PKM2 on the gemcitabine sensitivity in ICC remains to be elucidated. In this research, we aimed to elucidate the role and functional significance of PKM2 in ICC, as well as the heightened susceptibility of ICC cells to gemcitabine by targeting PKM2 and the underlying molecular mechanisms. Immunohistochemical and immunofluorescence analyses revealed elevated expression of PKM2 in both tumor cells and macrophages in human ICC tissues. Reducing PKM2 levels significantly restrained the proliferation of tumor cells, impeded cell cycle advance, induced programmed cell death, and suppressed metastasis. In addition, knockdown or pharmacological inhibition of PKM2 could enhance the response of ICC cells to gemcitabine in vitro. Interestingly, conditioned medium co-culture system suggested that conditioned medium from M2 macrophages increased gemcitabine sensitivity of ICC cells. However, silencing PKM2 or pharmacological inhibition of PKM2 in M2 macrophages did not ameliorate the gemcitabine resistance mediated by M2 macrophages derived conditioned medium. Mechanistically, downregulation of PKM2 repressed the expression of β-catenin and its downstream transcriptional targets, thereby hindering the propagation of β-catenin signaling cascade. Finally, the results of the subcutaneous xenograft experiment in nude mice provided compelling evidence of a synergistic interaction between PKM2-IN-1 and gemcitabine in vivo. In summary, we reported that PKM2 may function as an advantageous target for increasing the sensitivity of ICC to gemcitabine treatment. Targeting PKM2 improves the gemcitabine sensitivity of ICC cells via inhibiting β-catenin signaling pathway.

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: Conflicts of interest The authors disclose no conflicts.

: Funding This work was supported by National Institutes of Health grants DK59427 (G.J.G.) and T32 DK007198 (S.R.), and the Mayo Foundation.

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Reviews and PerspectivesReviews in Basic and Clinical Gastroenterology and HepatologyPathogenesis, Diagnosis, and Management of Cholangiocarcinoma

Section snippets

Epidemiology

Risk Factors

Cells of Origin

Inflammation

Genetics

Developmental Pathways

Tumor Microenvironment

Animal Models

Diagnosis and Management

Future Directions

Acknowledgments

Gastroenterology

J Hepatol

HPB (Oxford)

Hepatology

J Hepatol

Clin Gastroenterol Hepatol

J Am Coll Surg

J Hepatol

Gastroenterology

Clin Gastroenterol Hepatol

Cancer Lett

Gastroenterology

Gastroenterology

J Hepatol

Gastroenterology

Gastroenterology

J Hepatol

Gastroenterology

HPB (Oxford)

Cancer Genet Cytogenet

Cancer Genet Cytogenet

J Hepatol

Hum Pathol

Biomed Pharmacother

Gastroenterology

Gastroenterology

Hum Pathol

Cancer Cell

J Hepatol

Dig Liver Dis

Gastroenterology

Cancer Cell

Hepatology

Cancer Cell

Am J Pathol

Impact of classification of hilar cholangiocarcinomas (Klatskin tumors) on the incidence of intra- and extrahepatic cholangiocarcinoma in the United States

J Natl Cancer Inst

Clinical diagnosis and staging of cholangiocarcinoma

Nat Rev Gastroenterol Hepatol

New staging system and a registry for perihilar cholangiocarcinoma

Hepatology

Cholangiocarcinoma: thirty-one-year experience with 564 patients at a single institution

Ann Surg

Guidelines for the diagnosis and treatment of cholangiocarcinoma: an update

Gut

Risk factors for cholangiocarcinoma

Hepatology

The epidemiology of cholangiocarcinoma

Semin Liver Dis

Cholangiocarcinoma: lessons from Thailand

Curr Opin Gastroenterol

A comparison of trends in the incidence of hepatocellular carcinoma and intrahepatic cholangiocarcinoma in the United States

Cancer Epidemiol Biomarkers Prev

Worldwide trends in mortality from biliary tract malignancies

BMC Cancer

Descriptive epidemiology of cholangiocarcinoma and clonorchiasis in Korea

J Korean Med Sci

Relation of hepatolithiasis to helminthic infestation

J Gastroenterol Hepatol

Management of congenital bile duct cysts

Dig Surg

Increased risk of death in thorotrast-exposed patients during the late follow-up period

Jpn J Cancer Res

Reviews and Perspectives
Reviews in Basic and Clinical Gastroenterology and Hepatology
Pathogenesis, Diagnosis, and Management of Cholangiocarcinoma