Cholangiocarcinoma (CCA)

The National Comprehensive Cancer Network (NCCN) represents an alliance of cancer centers that focus on research, education and patient care.1 The NCCN creates clinical practice guidelines that are an important source of information not only for patients but also for stakeholders that work in the health care system.1 The NCCN Guidelines for Hepatobiliary Cancers has been made available recently detailing recommendations concerning diagnosis, staging, treatment and management of the cancer of the bile ducts, extrahepatic and intrahepatic presentations.2

Intrahepatic and Extrahepatic Recommendations

In patients presenting an isolated intrahepatic mass with imaging characteristics that are consistent with malignancy (not related to hepatocellular carcinoma), NCCN recommends that diagnosis occur through2:

  •  a history and physical examination;
  •  a multiphasic abdominal/pelvic computed tomography (CT)/magnetic resonance imaging (MRI) with intravenous (IV) contrast;
  •  a chest CT that can be performed with or without contrast;
  •  the evaluation of the baselines for carcinoembryonic antigen (CEA) and CA 19-9 markers, even though these results should not be used for a diagnosis confirmation;
  • liver function tests (LFTs) and referral to a hepatologist;
  • esophagogastroduodenoscopy (EGD) and colonoscopy;
  • studies on viral hepatitis should be considered, as well as alpha fetoprotein (AFP) testing. A surgery consultation can be considered, as well as a biopsy.

NCCN recommends the following strategy for allowing to diagnose extrahepatic CCA in patients presenting with pain, jaundice, abnormal LFTs, and obstruction or an abnormality on imaging2:

  •  a history and physical examination;
  •  a multiphasic abdominal/pelvic CT/MRI with IV contrast that will allow observing potential vascular invasion;
  •  a chest CT with or without contrast;
  •  a cholangiography, preferably a magnetic resonance cholangiopancreatography (MRCP);
  •  the evaluation of the baselines for carcinoembryonic antigen (CEA) and CA 19-9 markers, even though these results should not be used for a diagnosis confirmation;
  • LFTs and IgG4 that allows to exclude a diagnosis of autoimmune cholangitis;
  • an endoscopic ultrasound (EUS) after surgical consultation may be considered.

Staging of Cholangiocarcinoma

CCA can be staged according to the American Joint Committee on Cancer (AJCC) TMN system,3 however, there is no definite staging system for the disease.4 In this system, cancer is staged depending on the extension of the primary tumor (T), regional lymph node infiltration (N) and on the existence of distant metastases (M).5 The AJCC is updated regularly and is in its 8th edition.3 Staging is performed for the different CCA subtypes, intrahepatic, perihilar and distal.3 While the TMN system is well correlated with prognosis, there are few limitations. These are associated with the reduced ability of the system in discriminating tumors from a multifocal disease from other invasive tumors, with the limited prognostic impact introduced by cut-off size of only 5 cm for solitary and confined tumors and with the fact that the classification system does not account with symptoms that are associated with cancer, such as abdominal pain, malaise, or a degree of liver function impairement.4

CCA Treatment Recommendations 

Cholangiocarcinoma (CCA) patients should be followed by a multidisciplinary team that includes specialists, such as medical oncologists, radiologists, surgeons and hepatologists.2

Curative treatment can only be achieved through surgery with free margins, however, only a reduced number of patients are candidates for this procedure as it is common to diagnose these biliary tract tumors in advance stages of the disease where metastasis already exist.2,6

When intrahepatic tumors are resectable, extensive hepatic resections should be considered as they allow achieving clearer margins. Optimal adjuvant therapy for these patients is not completely defined and recurrence is common.2 In extrahepatic presentations, major hepatectomy with caudate lobectomy is recommended for hilar tumors. Patients may be recommended to go through preoperative treatments, such as biliary drainage. Liver transplantation should be considered for selected patients that show no metastases and a reduced tumor size (less than 3 cm in radial diameter).2

Recommended treatment for intrahepatic unresectable tumors or for metastatic disease includes systemic therapy, enrollment in a clinical trial, chemoradiation with fluoropyrimidine and supportive care.2 Locoregional therapies such as radiofrequency ablation (RFA)when no extrahepatic disease is observed is recommended for treating these patients. Intra-arterial chemotherapy can be also recommended for patients within clinical trials or that present locally advanced disease.2 

In unresectable or metastatic disease in extrahepatic CCA, a biopsy is first recommended. Targeted treatment can be applied, microsatellite instability (MSI), and/or mismatch repair (MMR) testing, and additionally molecular testing which involves tumor mutational burden (TMB) testing are recommended for further guidance.2 Treatment options for these patients include systemic therapy, enrollment in clinical trials, radiation therapy and fluoropyrimidine chemoradiation. Biliary drainage should be considered using a surgical bypass, an endoscopic retrograde cholangiopancreatography (ERCP) or a Percutaneous transhepatic cholangiography (PTC) that typically includes biliary state placement.2


1. About NCCN. National Comprehensive Cancer Network. Accessed July 4, 2021

2. [Guideline] NCCN clinical practice guidelines in oncology. hepatobiliary cancers. National Comprehensive Cancer Network. Version 3.2021; – June 15, 2021; Accessed July 4, 2021 

3. Amin MB, Greene FL, Edge SB, Compton CC, Gershenwald JE, Brookland RK, et al. The Eighth edition AJCC cancer staging manual: continuing to build a bridge from a population-based to a more “personalized” approach to cancer staging. CA Cancer J Clin. 2017 Mar;67(2):93-99. doi:10.3322/caac.21388

4. Banales JM, Marin JJG, Lamarca A, Rodrigues PM, Khan SA, Roberts LR et al. Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nat Rev Gastroenterol Hepatol. 2020 Sep;17(9):557-588. doi:10.1038/s41575-020-0310-z

5. Forner A, Vidili G, Rengo M, Bujanda L, Ponz-Sarvisé M, Lamarca A. Clinical presentation, diagnosis and staging of cholangiocarcinoma. Liver Int. 2019 May;39 Suppl 1:98-107. doi:10.1111/liv.14086

6. Gómez-España MA, Montes AF, Garcia-Carbonero R, Mercadé TM, Maurel J, Martín AM, Pazo-Cid R et al. SEOM clinical guidelines for pancreatic and biliary tract cancer (2020). Clin Transl Oncol. 2021 May;23(5):988-1000. doi:10.1007/s12094-021-02573-1

Reviewed by Debjyoti Talukdar, MD, on 7/1/2021.