Cholangiocarcinoma – current classification and challenges towards personalised medicine

Cholangicarcinoma (CCA) is a rare malignancy that arises in connection to the bile ducts and show various degrees of cholangiocyte differentiation. Cholangiocarcinomas are classified based on anatomical location (Figure 1) as intrahepatic (iCCA) and extrahepatic (eCCA). Extrahepatic CCA has then been further divided into perihilar (pCCA), also known as Klatskin tumours, and distal (dCCA).[1] In the current classification of CCA, iCCA arises in the liver parenchyma, pCCA arises between the second order bile ducts and the insertion of the cystic duct, and dCCA arises between the insertion of the cystic duct and to, but not including, the ampulla of Vater.[2,3] In the 7th edition of the American Joint Committee on Cancer staging manual published in 2010, a unique staging system was introduced for pCCA and dCCA. This represented an improvement from the 6th edition, in which eCCA was staged in the same way regardless of perihilar or distal location.[3] Cholangiocarcinomas are sometimes investigated together with gallbladder cancer, as well as ampullary carcinomas and the term biliary tract cancer is applied.

Figure 1. Current classification of cholangiocarcinoma: dCCA: distal cholangiocarcinoma; eCCA: extrahepatic cholangiocarcinoma; iCCA: intrahepatic cholangiocarcinoma; pCCA: perihilar cholangiocarcinoma.

In the International classification of disease of oncology (ICD-O), third edition CCA is topographically classified in the category C22 “liver and intrahepatic bile ducts” or the category C24 “other and unspecified parts of the biliary tract”.[4] Current epidemiological data can therefore only be used to evaluate iCCA and eCCA, and any unique epidemiological characteristics of pCCA and dCCA has not been recorded. The incidence of cholangiocarcinoma shows great variation between and within countries.[5] In western countries, the age specified incidence rates are between 0.5 and 1.5 per 100,000 persons/year.[6] Several authors have suggested that the misclassification of “Klatskin” tumours in the ICD-O second edition, as intrahepatic lesions, have influenced epidemiological trends.[7,8] However, other investigators have found this to have an overall marginal impact.[9]

Cholangiocarcinoma has a dismal prognosis with an overall 5-year survival of <5%.[6] The only treatment that offers a possibility of cure is surgical resection. However, this is currently only possible for about one-third of patients and the rate of recurrence after surgery is high.[10] The differences in diagnostic and surgical approaches have been the rationale underlying the current classification into iCCA, pCCA and dCCA, and a significant number of studies has looked into the surgical treatment and outcome in the different subcategories.[11] Furthermore, several authors have suggested that this subclassification is warranted not only due to differences in clinical management, but also due to differences in tumour biology.[12–14] Differences between intrahepatic and extrahepatic cholangiocarcinomas have been well documented from different fields, as presented below:

• Epidemiological research has shown different trends in incidence for iCCA and eCCA with the worldwide incidence of iCCA increasing substantially, and the incidence of eCCA remaining stable or even slightly decreasing.[5,15]

• Studies elucidating the cellular origin of CCA have shown the possibility of iCCA arising from transdifferentiated hepatocytes or hepatic progenitors, whilst eCCA are believed to arise from the biliary epithelium or peribiliary glands.[14,16] In one study, iCCA could be divided based on expression of mucins into a group being clinicopathological similar to pCCA, and another similar to hepatocyte progenitors, possibly reflecting either large bile ducts or primary liver cells as cellular origin.[17]

• In a meta-analysis of immunohistochemical markers, 18 of 57 markers were found to be significantly differentially expressed between iCCA and eCCA. These included potential pharmacological targets like EGFR, c-erbB-2, and VEGF-A. In addition, only 16 markers had a similar prevalence with narrow confidence intervals.[18]

• Genomic profiling has identified different somatic mutations in iCCA and eCCA, respectively.[19] In the currently largest genomic profiling of eCCA mutations in potential pharmacological targets, such as KRAS, ERBB2, PTEN and more, were identified. Notably, no mutations were found in IDH1/2 or FGFR2 gene fusions, which has been described as important potential targets in iCCA.[20,21]

A limited number of studies have investigated differences within the extrahepatic group and the conclusions that currently can be drawn are limited. One example is the differential expression of cell cycle related proteins between pCCA and dCCA, where some studies has shown that dCCA expressed a pattern more closely resembling pancreatic ductal adenocarcinoma (PDAC).[22,23]

Previous research in the field of cholangiocarcinoma, such as identifying genetic and epigenetic alterations, differentially expressed proteins and disease biomarkers in tissue or biofluids, has often grouped iCCA, pCCA and dCCA together. This sometimes also have included gallbladder or ampullary carcinomas, without taking into account the validity problem of the various causes, with various outcomes. The same goes for oncological treatment studies. One important first step towards a more personalised medicine strategy in the treatment of patients with cholangiocarcinoma is a proper characterisation of the unique subcategories of cholangiocarcinomas and the identification of unique biomarkers for diagnosis, prognosis and therapeutic outcome prediction. This development has been ongoing, primarily in iCCA, in which several studies have investigated the molecular pathogenesis and identified potential biomarkers, as well as goals for targeted therapy.[20] The number of studies characterising eCCA is significantly lower and there is a need of elucidating the molecular pathogenesis, as well as identifying unique biomarkers of pCCA and dCCA, respectively. This division will be necessary, not only because there are underlying differences in tumour biology, but also to deal with unique clinical problems in pCCA and dCCA. One of the most promising improvements is the possibility of treating pCCA with neoadjuvant therapy followed by liver transplantation. In a highly selected group of patients, this regime has shown a 5-year survival as high as 68%.[24,25] Finding biomarkers for response to neoadjuvant treatment, and the identification of prognostic biomarkers in this setting could further improve patient selection and survival. In dCCA, a differential diagnostic problem exists versus other periampullary tumours, such as PDAC and ampullary carcinoma. Several studies are investigating the place of neoadjuvant regimes for PDAC [26,27] and the need of separation between dCCA and PDAC preoperatively will be warranted for optimal management.

For the forthcoming research, in patients with assumed cholangiocarcinomas, in order to improve understanding of the different types of malignancies, and provide novel possibilities of personalised treatment options and improved outcome, we propose the following:

• First, studies investigating molecular pathogenesis, biomarkers and treatment should define patient cohorts as iCCA, pCCA and dCCA, and analyse them as separate entities. If tumour groups are mixed, the validity problem this causes has to be considered. Secondly, further research efforts has to be put into characterising the molecular pathogenesis and identifying diagnostic, prognostic and predictive biomarkers for pCCA, and dCCA, as the current knowledge is poor. Finally, in upcoming versions, the ICD system should incorporate separate topographical classification codes for pCCA and dCCA.

Acknowledgements

We would like to express our gratitude to Martin Berntsson for assistance in creating the illustration of the different subcategories of cholangiocarcinoma.

Disclosure statement

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.