The term cholangiocarcinoma (CCA) comprises a heterogeneous group of tumors that affect the bile duct. It originates from the epithelial cells of the bile duct, both intrahepatic and extrahepatic, with the exception of the gallbladder and Vater's ampulla.

The intrahepatic variant is the second primary liver tumor, after hepatocellular carcinoma (HCC), thus constituting 5-10% of all primitive liver neoplasms, compared to 90% for HCC. It is infrequent before 50 years of age (<10% of cases) and its peak incidence is between 60 and 70 years of age, with a male-female ratio of 2:3.

The CCA are classified according to their anatomical position in:

  • Intrahepatic cholangiocarcinoma (i-CCA, representing less than 10% of all CCAs),
  • Peri-hilar cholangiocarcinoma (p-CCA or Klatskin tumor, 50% of CCAs),
  • Distal cholangiocarcinoma (d-CCA, 40% of CCAs).

Each one presents particular characteristics that imply a different treatment and a specific management.

Risk factors

Known predisposing factors are:

  • Cystic formations of the bile duct, choledochal cyst
  • Caroli's disease, characterized by congenital and irregular dilatations of the bile duct
  • Hepatolithiasis
  • Parasitic infections: more frequent in eastern countries, through the consumption of raw or undercooked fish
  • Cirrhosis of the liver: a condition characterized by nodular degeneration and regeneration of the liver, due to alcohol abuse or hepatitis B (HBV) or C (HCV) virus infection, or by some rare hereditary disease of metabolism, such as hemochromatosis, tyrosinemia, alpha-1-antitrypsin deficiency, hypercitrullinemia, glycogenosis, or Wilson's disease. Viruses predispose mainly to the intrahepatic form of CCA (i-CCA).
  • Exposure to physical and chemical agents such as radium, asbestos, thorotrast, nitrosamines and diosmin.
  • Diabetes, obesity, alcohol and smoke can increase the risk of CCA, but available studies have so far been inconclusive.
  • Primitive sclerosing cholangitis (a disease in which the intrahepatic and extrahepatic bile ducts narrow, impeding bile drainage, often associated with ulcerative colitis and Crohn's disease), is the most studied risk factor.


It is still underdiagnosed, mainly due to the few initial symptoms, making the diagnostic approach difficult. Approximately one third of patients do not have relevant symptoms until they present a mass of between 5-7 centimeters. When they do occur, the most frequent is jaundice, a sign of involvement of the extrahepatic bile duct (p-CCA and d-CCA), while it is less frequent in patients with i-CCA. Other forms of common clinical presentation in case of biliary obstruction are: slightly colored stools, dark urine, pruritus; furthermore, the clinical signs are enlargement of the liver, also in the form of a mass in the upper right abdominal region, sometimes associated with pain, weight loss and fever, night sweats, weakness.


The diagnosis of CCA is often incidental. Ultrasound is the starting image. A pre-operative tomography is crucial to evaluate the anatomy, the secondary evaluation, carry out a volumetry and planning the surgical approach, so it must always be carried out. MRI (magnetic resonance imaging), especially associated with cholangiopancreatography, can assess the intrahepatic biliary anatomy and localize the affected ducts with greater precision. PET-CT is most useful for identifying the most voluminous CCA-i, and can identify occult metastases on CT and MRI in 20-30% of patients. In case of doubt, brushing can also be performed during ERCP (endoscopic cholangiopancreatography).

Sometimes, the radiological image alone is not enough to reach an accurate diagnosis and it is necessary to obtain confirmation by biopsy (which, however, is not usually indicated when surgery has already been decided). However, a negative biopsy is not necessarily definitive, as sampling errors are always possible.

Among the laboratory tests, the dosage of bilirubin, alkaline phosphatase, glutamyltransferase, as well as the CEA tumor markers and especially CA 19-9, whose values also seem important to rule out residual disease after surgery, to document an initial recurrence of the disease or to assess the effects of medical therapies, especially chemotherapy. When ALP, prealbumin, CA 19–9, and CEA are elevated, they are independent prognostic factors associated with a poorer prognosis. The measurement of the markers cannot be used as the only test to identify a neoplastic pathology and is used only as an accessory investigation.


The surgical option is, in fact, the only potentially curative treatment for CCA. Multiple tumors have a very high recurrence rate, >90%, and usually preclude curative surgery.

  • For i-CCA, resection of the liver associated with removal of the hepatoduodenal ligament lymph nodes represents the standard intervention.
  • For p-CCA without infiltration of the liver parenchyma, resection of the simple bile duct with removal of the regional lymph nodes and possibly one lobe (the caudate) of the liver is indicated; if there is hepatic infiltration, on the other hand, an extended resection of the right or left half of the liver is necessary.
  • For d-CCA, similar to tumors of the head of the pancreas, the surgery of choice is duodenocephalopancreatectomy; when the tumor is not resectable, palliative interventions are indicated.

Liver transplantation continues to be a controversial practice due to the high recurrence rate and low chances of survival; It has been performed only in a few centers in the world, and only for i-CCA cases.

When the tumor is disseminated or is not radically surgically resectable or when there are metastases in other organs, palliative surgery is performed, sometimes under emergency conditions, whose purpose is to alleviate the symptoms produced by the tumor mass. These procedures usually consist of biliodigestive bypasses and endoscopic or percutaneous stent placement.

If it is intended to continue with chemotherapy, a biopsy of the lesion is required, in order to obtain information on the characteristics of the tumor and thus initiate a more specific treatment. There are no validated guidelines or definitive recommendations on which therapy is better than the others. Chemotherapy may be neoadjuvant (this is, given before surgery), adjuvant (if given after surgery), or palliative (when it replaces surgery, in patients not amenable to radical surgical treatment) intent. Recent studies suggest a possible benefit from the use of biologic drugs. Other targeted therapies, which can replace or complement surgery, are transarterial chemoembolization (TACE) and selective yttrium-90 radiotherapy (SIRT) and hepatic intra-arterial infusion (HAI).

The role of radiotherapy (which uses radiation from X-rays or other radiant sources to destroy tumor cells) is not yet well established, since there are still no large studies capable of defining whether it can be considered a standard treatment . Some evidence seems to demonstrate its usefulness in the case of inoperable and symptomatic neoplasms (external radiotherapy + brachytherapy), without however contributing to prolonging patient survival.


In cholangiocarcinoma, the prognosis depends on:

  • state of the resection margins (greater when negative)
  • lymph node involvement
  • histological variant (better for papillary variant)
  • degree of differentiation (better for the more differentiated, worse for the poorly differentiated)
  • presence of metastases
  • presence of vascular invasion

Some studies have reported that the 5-year survival rate is better in patients with i-CCA (63%) than in those with p-CCA (30%) or d-CCA (27%). The main cause of death after resection is disease recurrence, which occurs in more than 50% of patients and is intrahepatic in 61% of cases. i-CCA presents high rates of post-resection disease recurrence (46-68%), even after a curative intervention, and occurs mostly within the first postoperative year.