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Basic Information ⬇

Author: Fred F. Ferri, MD

Definition

Cholangiocarcinoma is a cancer that originates from the epithelial lining of bile ducts. Most commonly an adenocarcinoma, this tumor is classified based on its location within the biliary tree as intrahepatic, perihilar, or extrahepatic.

Synonym

  • Bile duct carcinoma
ICD-10CM CODES
C22.1Intrahepatic bile duct carcinoma
C24.0Malignant neoplasm of extrahepatic bile duct
Epidemiology & Demographics
Incidence:

  • •The incidence rate of cholangiocarcinoma varies by region. A low rate of 1 to 2 per 100,000 occurs in the U.S., while incidence peaks at 80 per 100,000 in Thailand.
  • •It is the second most common primary hepatic malignancy after hepatocellular carcinoma, making up 15% of all primary liver tumors and 3% of all GI cancers.
  • •Incidence rate of intrahepatic cholangiocarcinoma appears to be increasing.
  • •Higher incidence in Hispanic and Asian populations, also associated with a worse 5-yr survival.
Predominant Sex & Age:

  • •Slightly more common in men
  • •Most often diagnosed between 50 and 70 yr of age
  • •Patients with primary sclerosing cholangitis (PSC) can present as early as 30 yr old
Risk Factors (Box E1):

  • •PSC causes inflammation of the bile ducts leading to fibrosis and stricturing of the biliary tree. PSC is the most common risk factor for development of cholangiocarcinoma, with a lifetime risk of up to 15%.
  • •Other risk factors include infection with hepatitis B and C, liver cirrhosis, chronic hepatolithiasis, choledochal cysts, and parasitic infections of the liver.

PSC, Primary sclerosing cholangitis.

BOX E1 Risk Factors for Cholangiocarcinoma

Definite

  • Caroli disease
  • Choledochal cyst
  • Hepatolithiasis
  • Opisthorchis viverrini infection
  • PSC
  • Thorotrast
Probable

  • Biliary-enteric drainage procedures
  • Cirrhosis
  • Clonorchis sinensis infection
  • Heavy alcohol consumption
  • Hepatitis C
  • Toxins (dioxins, polyvinyl chloride)

From Feldman M et al: Sleisenger and Fordtran’s gastrointestinal and liver disease, ed 11, Philadelphia, 2021, Elsevier.

Physical Findings & Clinical Presentation

  • •With early-stage cholangiocarcinoma, the patient may be completely asymptomatic, and diagnosis is made incidentally on imaging or during the workup for elevation of liver enzymes.
  • •Later-stage cholangiocarcinoma may present as biliary obstruction.
  • •The clinical presentation is also dependent on the location of the tumor. Cholangiocarcinoma involving the intrahepatic ducts tends to cause nonspecific symptoms of dull, aching right upper quadrant pain and weight loss. A tumor of the extrahepatic ducts most often causes symptoms of biliary obstruction including jaundice, pale stools, and dark urine.
  • •Findings on physical examination may include jaundice, pain on palpation of the right upper quadrant, hepatomegaly, and fever.

Diagnosis ⬆ ⬇

Differential Diagnosis

The differential diagnosis includes other conditions that may cause right upper quadrant pain, fever, and symptoms of biliary obstruction or those that present with a mass on imaging.

  • •Primary sclerosing cholangitis
  • •Choledocholithiasis
  • •Acute cholangitis
  • •Liver metastases
  • •Pancreatic head cancer
Workup

Fig. E1 describes an algorithm for the diagnosis of intrahepatic cholangiocarcinoma. The approach to the diagnosis of perihilar cholangiocarcinoma is summarized in Fig. E2. The Bismuth-Corlette classification of cholangiocarcinoma based on location is illustrated in Fig. E3. Staging systems for cholangiocarcinoma are described in Tables E1 to E3.

TABLE E1 TNM and American Joint Committee on Cancer (AJCC)/International Union Against Cancer (UICC) Staging Systems for Intrahepatic Cholangiocarcinoma

TNM StageCriteria
TxPrimary tumor cannot be assessed
T0No evidence of primary tumor
TisCarcinoma in situ (intraductal tumor)
T1aSolitary tumor ≤5 cm without vascular invasion
T1bSolitary tumor >5 cm without vascular invasion
T2Solitary tumor with vascular invasion OR multiple tumors, with or without vascular invasion
T3Tumor perforating the visceral peritoneum
T4Tumor involving the local extrahepatic structures by direct invasion
NxRegional lymph nodes cannot be assessed
N0No regional lymph node metastases
N1Regional lymph node metastases present
M0No distant metastases
M1Distant metastases
AJCC/UICC StageTumorNodeMetastasis
0TisN0M0
IAT1aN0M0
IBT1bN0M0
IIT2N0M0
IIIAT3N0M0
IIIBT4N0M0
Any TN1M0
IVAny TAny NM1

TNM, Tumor, node, metastasis.

From Feldman M et al: Sleisenger and Fordtran’s gastrointestinal and liver disease, ed 11, Philadelphia, 2021, Elsevier.

TABLE E2 MSKCC Staging System for Perihilar Cholangiocarcinoma

StageCriteria
T1Tumor involving biliary confluence ± unilateral extension to secondary radicles
T2
  • Tumor involving biliary confluence ± unilateral extension to secondary radicles
  • AND ipsilateral portal vein involvement ± ipsilateral hepatic lobe atrophy
T3
  • Tumor involving biliary confluence + bilateral extension to secondary radicles
  • OR unilateral extension to secondary radicles + contralateral portal vein involvement
  • OR main or bilateral portal vein involvement

MSKCC, Memorial Sloan Kettering Cancer Center.

From Feldman M et al: Sleisenger and Fordtran’s gastrointestinal and liver disease, ed 11, Philadelphia, 2021, Elsevier.

TABLE E3 Mayo Clinic Staging System for Perihilar Cholangiocarcinoma

StageCriteria
I
  • Unicentric mass ≤3 cm
  • ECOG performance status 0
  • Serum CA 19-9 level (U/ml) <1000
  • No vascular encasement
  • No metastasis
II
  • Unicentric mass ≤3 cm
  • ECOG performance status 1-2
  • Serum CA 19-9 level (U/ml) <1000
  • Vascular encasement present
  • No metastasis
III
  • Unicentric mass >3 cm or multicentric
  • ECOG performance status 0-2
  • Serum CA 19-9 level (U/ml) ≥1000
  • Lymph node metastasis present
IV
  • ECOG performance status 3-4
  • Peritoneal (or other organ) metastasis present

ECOG, Eastern Cooperative Oncology Group.

From Feldman M et al: Sleisenger and Fordtran’s gastrointestinal and liver disease, ed 11, Philadelphia, 2021, Elsevier.

Figure E1 Algorithm for the diagnosis of intrahepatic cholangiocarcinoma.

!!flowchart!!

In cases of an intrahepatic mass lesion and in the absence of known extrahepatic primary malignancy, dynamic imaging with either computed tomography (CT) or magnetic resonance image (MRI) of the liver should be performed. Contrast enhancement throughout the arterial phase with "washout" in the portal venous phase indicates a hepatocellular carcinoma. Contrast enhancement throughout the arterial and portal venous phases should raise the suspicion of an intrahepatic cholangiocarcinoma; in such cases, the resectability of the tumor should be determined. If the lesion is deemed resectable, the patient should be referred for surgical resection without biopsy. If an intrahepatic cholangiocarcinoma is deemed unresectable, a biopsy should be performed to confirm the diagnosis and guide appropriate treatment.

(From Feldman M et al: Sleisenger and Fordtran’s gastrointestinal and liver disease, ed 11, Philadelphia, 2021, Elsevier.)

Figure E2 Algorithm for the diagnosis of perihilar cholangiocarcinoma.

!!flowchart!!

In cases of clinically suspected perihilar cholangiocarcinoma, a serum CA 19-9 level, ERCP, and conventional as well as molecular cytologic analysis of endoscopically obtained biliary brushings of malignant-appearing areas should be performed. If the results of these tests are normal or negative, close follow-up of the patient is recommended. Management of cholangiocarcinoma should be prompted by identification of a dominant stricture, a serum CA 19-9 level above 129 U/ml, or a biopsy or cytology result that is positive for carcinoma or polysomy. In indeterminate cases, gadolinium-enhanced MRI of the liver is recommended. If a mass lesion or vascular encasement is identified, management of cholangiocarcinoma should be initiated. If the MRI study is negative but clinical concern about cholangiocarcinoma persists, PET can be performed. If "hot spots" are identified on PET (positive result), treatment for cholangiocarcinoma should be initiated. If the result of the PET scan is negative, close follow-up of the patient is recommended. If MRI is negative and cholangiocarcinoma is considered unlikely, the patient can be followed expectantly. DIA, Digital image analysis; ERCP, endoscopic retrograde cholangiopancreatography; FISH, fluorescence in situ hybridization; MRI, magnetic resonance imaging; neg., negative; PET, positron emission tomography; pos., positive.

(From Feldman M et al: Sleisenger and Fordtran’s gastrointestinal and liver disease, ed 11, Philadelphia, 2021, Elsevier.)

Figure E3 Classification of cholangiocarcinoma.

A, Anatomic classification of intrahepatic, perihilar, and extrahepatic cholangiocarcinoma. B, Bismuth-Corlette classification of hilar cholangiocarcinoma as types I to IV. Tumor is depicted in yellow and normal bile ducts in green.

(From Feldman M et al: Sleisenger and Fordtran’s gastrointestinal and liver disease, ed 11, Philadelphia, 2021, Elsevier.)

Laboratory Tests

  • •Liver enzymes
  • •International normalization ratio
  • •Bilirubin

Blood work may reveal an "obstructive pattern" with predominant elevation of alkaline phosphatase and bilirubin.

  • •Tumor markers:
    1. 1.CEA
    2. 2.CA19-9

It is important to note that these tumor markers may be elevated even in the setting of benign inflammation of the biliary tree, for example, during an episode of acute cholangitis. These markers are neither sensitive nor specific for cholangiocarcinoma, but if they are elevated at the time of diagnosis, they may be helpful in tracking response to therapy or in monitoring for disease recurrence.

Imaging Studies

Abdominal ultrasound:

  • •Initial test of choice in patients presenting with nonspecific symptoms of obstruction or elevated liver enzymes

Computed tomography scan/MRI, magnetic resonance cholangiography (MRCP) (Fig. E4):

  • •Improved visualization of the biliary tree to allow for identification of the tumor, level of obstruction, and extent of disease

Figure E4 Computed Tomography (CT) Scan (A), Magnetic Resonance Cholangiogram (B), and Image from Biliary Drainage (C) in a Patient with Hilar Cholangiocarcinoma

(A) The CT Scan Shows the Tumor (Arrows) at the Level Where the Right and Left Bile Ducts (Star and Cross, Respectively, in B) Would Be Expected to Join. (B) Magnetic Resonance Cholangiography Confirms This. (C) At the Time of Biliary Drainage, Contrast Opacifies Only the Right-Sided Bile Ducts. The Tumor is Obstructing the Duct to the Level of the Common Bile Duct at the Insertion of the Cystic Duct.

(From Niederhuber JE et al: Abeloff’s clinical oncology, ed 6, Philadelphia, 2020, Elsevier.)

Endoscopic retrograde cholangiopancreatography (ERCP) (Fig. E5):

  • •Can be used to obtain brushings or biopsies of the biliary tree, but diagnostic yield is poor (35% to 86%), and there is a risk of cholangitis in patients with significant obstruction of bile drainage

Figure E5 Imaging of extrahepatic cholangiocarcinoma.

A, Film from endoscopic retrograde cholangiography in a patient with perihilar cholangiocarcinoma demonstrating dominant strictures of the biliary tract consistent with Bismuth-Corlette type IV. B, Gadolinium-enhanced magnetic resonance image with ferumoxide in the same patient. The arrow points to the biliary tumor seen on a T2-weighted image. C, Positron emission tomography/computed tomography scan of the same patient. The biliary tumor is seen as an enhancing region (arrow).

(From Feldman M et al: Sleisenger and Fordtran’s gastrointestinal and liver disease, ed 11, Philadelphia, 2021, Elsevier.)

Endoscopic ultrasound (EUS):

  • •Allows local ultrasound visualization of tumor extent and regional lymphadenopathy, as well as diagnostic fine-needle aspiration of distal biliary duct tumors and involved lymph nodes

Treatment ⬆ ⬇

Acute General Rx

  • •The only curative treatment option for cholangiocarcinoma is surgical extirpation. Eligibility for surgical resection with curative intent is based both on the location of the tumor and the stage of disease. Box E2 summarizes criteria for unresectability of perihilar cholangiocarcinoma.
  • •Surgical approaches include partial liver resection, pancreaticoduodenectomy, pancreaticojejunostomy, or even liver transplantation in carefully selected patients.
  • •Adjuvant chemotherapy, first line with gemcitabine and cisplatin, has been shown to reduce mortality in patients with both positive margins postresection and/or involved lymph nodes.
  • •Alterations in fibroblast growth factor receptor (FGFR2) have emerged as promising drug targets for intrahepatic cholangiocarcinoma, a rare cancer with a poor prognosis. Futibatinib, a next-generation, covalently binding FGFR 1-4 inhibitor, has been shown to have both antitumor activity in patients with FGFR-altered tumors and strong preclinical activity against acquired resistance mutations associated with ATP-competitive FGFR inhibitors.1
  • •The use of adjuvant radiation remains an area of controversy, but there is evidence of improved survival in inoperable patients with localized disease.
  • •In the setting of biliary obstruction, stenting via ERCP or percutaneous drain insertion should be performed to facilitate bile flow and avoid stasis.

BOX E2 Criteria for Unresectability of Perihilar Cholangiocarcinoma

  • Atrophy of one liver lobe with encasement of the contralateral portal vein branch
  • Atrophy of one liver lobe with contralateral secondary biliary radical involvement
  • Bilateral portal vein branch encasement
  • Bilateral hepatic artery encasement
  • Distant lymph node metastases
  • Hilar cholangiocarcinoma, Bismuth-Corlette type IV
  • Intrahepatic or distant metastases
  • Primary sclerosing cholangitis
  • Significant comorbid conditions

From Feldman M et al: Sleisenger and Fordtran’s gastrointestinal and liver disease, ed 11, Philadelphia, 2021, Elsevier.

Disposition

  • •Surveillance imaging for recurrence is recommended every 6 mo for a total of 2 yr.
  • •Recurrence can occur locally or as metastatic disease, most commonly to liver, lung, or peritoneum.
  • •5-yr survival rates vary between 15% and 60% based on the stage of disease. Unfortunately, even those patients with node-negative disease who undergo resection with curative intent have a high rate of disease recurrence.
Referral

Referral should be made to a hepatobiliary surgeon for consideration of surgical resection and to a medical oncologist for possible adjuvant chemotherapy.

Related Content

Reference(s) ⬆

  1. Goyal L : Futibatinib for FGFR2-rearranged intrahepatic cholangiocarcinomaN Engl J Med. 388(3):228-239, 2023.