Cholangiocarcinoma

Cholangiocarcinomas arise from the intrahepatic or extrahepatic biliary epithelium. More than 90% are adenocarcinomas, and the remainder are squamous cell tumors. The etiology of most bile duct cancers remains undetermined. Long-standing inflammation, as with primary sclerosing cholangitis (PSC) or chronic parasitic infection, has been suggested to play a role by inducing hyperplasia, cellular proliferation, and, ultimately, malignant transformation. Intrahepatic cholangiocarcinoma may be associated with chronic ulcerative colitis and chronic cholecystitis.

Cholangiocarcinomas tend to grow slowly and to infiltrate the walls of the ducts, dissecting along tissue planes. Local extension occurs into the liver, porta hepatis, and regional lymph nodes of the celiac and pancreaticoduodenal chains. Life-threatening infection (cholangitis) may occur that requires immediate antibiotic intervention and aggressive biliary drainage.

Frequency

United States

Each year, approximately 2500 cases of cholangiocarcinoma occur, compared with 5000 cases of gallbladder cancer and 15,000 cases of hepatocellular cancer. The average incidence is one case per 100,000 population per year.

A study by Singal et al found that the frequency of intrahepatic cholangiocarcinoma has increased over time and is most commonly noted in women older than 60 years.[9]

International

Worldwide, cholangiocarcinoma is the second most common primary hepatic malignancy, after hepatocellular carcinoma, comprising about 15% of all primary liver tumors. The incidence and mortality rates of cholangiocarcinoma have increased steadily over the past decades. Currently, cholangiocarcinoma has an incidence rate of 0.3-6/100,000 inhabitants per year, with a mortality rate of 1-6/100,000 inhabitants per year. Incidence rates are particularly elevated in certain regions, such as South Korea, China, and Thailand.[10] The highest annual incidences are in Japan, at 5.5 cases per 100,000 people, and in Israel, at 7.3 cases per 100,000 people.

Occupational cholangiocarcinoma has been documented in workers at printing companies in Japan who had been exposed to high concentrations of chemical compounds, including 1,2-dichloropropane (1,2-DCP) and/or dichloromethane.[11] Heavy infestation by the liver flukes Clonorchis sinensis (endemic predominantly in Asian countries, including Korea, China, Taiwan, Vietnam, and far eastern Russia) and Opisthorchis viverrini (the Southeast Asian liver fluke) has been linked to the development of cholangiocarcinoma.[12]

Mortality/Morbidity

Despite aggressive anticancer therapy and interventional supportive care (ie, wall stents or percutaneous biliary drainage), the median survival rate is low, since most patients (90%) are not eligible for curative resection. The overall survival is approximately 6 months.

Race-, sex-, and age-related demographics

Native Americans have the highest annual incidence in North America, at 6.5 cases per 100,000 people. This rate is about 6 times higher than that in non–Native American populations. The high prevalence of cholangiocarcinoma in people of Asian descent is attributable to endemic chronic parasitic infestation.

In both males and females, cholangiocarcinoma is most common in persons in their 60s and 70s. The male-to-female ratio for cholangiocarcinoma is 1:2.5 in patients in their 60s and 70s and 1:15 in patients younger than 40 years. According to the American Cancer Society, the number of new cases of liver and intrahepatic bile duct cancer in 2022 is estimated to be 28,600 for men and 12,660 for women, with deaths estimated at 20,420 and 10,100, respectively. The estimated number of new cases of gallbladder and other biliary cancers (extrahepatic cholangiocarcinoma) are 5710 for men and 6420 for women, with estimated deaths of 1830 and 2570, respectively.[13]  

Signs and symptoms of cholangiocarcinoma include the following:

• Jaundice
• Clay-colored stools
• Bilirubinuria (dark urine)
• Pruritus
• Weight loss
• Abdominal pain

Jaundice is the most common manifestation of bile duct cancer and, in general, is best detected in direct sunlight. The obstruction and subsequent cholestasis tend to occur early if the tumor is located in the common bile duct or common hepatic duct. Jaundice often occurs later in perihilar or intrahepatic tumors and is often a marker of advanced disease. The excess of conjugated bilirubin is associated with bilirubinuria and acholic stools.

Pruritus usually is preceded by jaundice, but itching may be the initial symptom of cholangiocarcinoma. Pruritus may be related to circulating bile acids.

Weight loss is a variable finding. It may be present in one third of patients at the time of diagnosis.

Abdominal pain is relatively common in advanced disease. It often is described as a dull ache in the right upper quadrant.

If the cholangiocarcinoma is located distal to the cystic duct takeoff, the patient may have a palpable gallbladder, which is commonly known as Courvoisier sign.

An abdominal mass or palpable lymphadenopathy is uncommon, but hepatomegaly may be noted in as many as 25% of patients.

The etiology of most bile duct cancers remains undetermined. Autoimmune conditions, especially primary sclerosing cholangitis, appear to increase the risk for cholangiocarcinoma.[14] Currently, gallstones are not believed to increase the risk. Chronic viral hepatitis and cirrhosis also do not appear to be risk factors. 

Infections

In Southeast Asia, chronic infections with liver flukes (Clonorchis sinensis and Opisthorchis viverrini) have been causally related to cholangiocarcinoma.

Other parasites, such as Ascaris lumbricoides, have been implicated in the pathogenesis of cholangiocarcinoma.

Observations have raised the possibility that bacterial infections with Helicobacter species may play an etiologic role in biliary cancer.[15]

Inflammatory bowel disease

A strong relationship exists between cholangiocarcinoma and primary sclerosing cholangitis. Cholangiocarcinoma generally develops in patients with long-standing ulcerative colitis and primary sclerosing cholangitis.[16] The lifetime risk of developing this cancer in the setting of primary sclerosing cholangitis is 10-20%. At increased risk are patients with ulcerative colitis without symptomatic primary sclerosing cholangitis and a small subset of patients with Crohn disease.

Chemical exposures

Certain chemical exposures have been implicated in the development of bile duct cancers, primarily in workers in the aircraft, rubber, and wood-finishing industries.

Cholangiocarcinoma has developed decades after administration of the radiologic contrast medium thorium dioxide (ie, Thorotrast). This product, which results in lifelong alpha particle irradiation by thorium decay products, was in use from the 1930s until the 1950s.[17]

Miscellaneous conditions

Congenital diseases of the biliary tree, including choledochal cysts and Caroli disease, have been associated with cholangiocarcinoma.

Other conditions rarely associated with cholangiocarcinoma include bile duct adenomas, biliary papillomatosis, and alpha1-antitrypsin deficiency. Obesity may also be a risk factor.[18]

Routine lab studies

Extrahepatic cholestasis is reflected in elevated conjugated (ie, direct) bilirubin levels. Alkaline phosphatase levels usually rise in conjunction with bilirubin levels. Because alkaline phosphatase is of biliary origin, gamma-glutamyltransferase (GGT) also will be elevated.

Levels of aminotransferases (ie, aspartate aminotransferase [AST], alanine aminotransferase [ALT]) may be normal or minimally elevated. Biochemical tests of liver function (ie, albumin, prothrombin time [PT]) are normal in early disease.

With prolonged obstruction, the PT can become elevated because of vitamin K malabsorption. Hypercalcemia may occur occasionally in the absence of osteolytic metastasis.

Tumor markers

A variety of markers have been tested in bile and serum, with limited success. This becomes a significant issue in primary sclerosing cholangitis (PSC), whose clinical features and imaging findings overlap with those of cholangiocarcinoma.

The tumor marker carbohydrate antigen 19-9 (CA 19-9) can be evaluated in pancreatic and bile duct malignancies, as well as in benign cholestasis. A serum CA 19-9 level greater than 100 U/mL (normal < 40 U/mL) has 75% sensitivity and 80% specificity in identifying patients with PSC who have cholangiocarcinoma.[16]

In PSC, an index of carcinoembryonic antigen (CEA) and CA 19-9, has an accuracy of 86% using the following formula: CA 19-9 + (CEA × 40). In a study of patients with PSC, values were over 400 U in 10 of the 15 cases of cholangiocarcinoma but in none of 22 comparable cases with no tumor. [19]

Bergquist et al reported that in patients with intrahepatic cholangiocarcinoma, an elevated CA 19-9 level is an independent risk factor for mortality. In their study of 2816 patients, those with elevated CA19-9 had more nodal metastases and decreased stage-specific survival. Patients with CA19-9 elevation were less likely to undergo resection, and those who underwent resection had decreased long-term survival. CA19-9 elevation independently predicted increased mortality with an impact similar to that of node positivity, positive-margin resection, and non-receipt of chemotherapy.[20]

Li et al reported that in patients with perihilar cholangiocarcinoma, the preoperative bilirubin level may effectively reflect the severity of disease and provide prognostic information. In patients with a low bilirubin (≤12 mg/dL), 1-, 3-, and 5-year overall survival rates after resection were 75.9%, 36.5%, 21.7%; in those with bilirubin > 12 mg/dL, corresponding overall survival rates were 53.6%, 13.9%, and 0%. In addition, rates of early tumor recurrence were significantly higher in patients with high preoperative bilirubin levels than in those with lower levels.[21]

Cholangiocarcinoma does not produce alpha-fetoprotein.

A number of potential imaging modalities are available, as depicted in the image below. In general, ultrasonography or computed tomography (CT) is performed initially, followed by some form of cholangiography. Techniques used for cholangiography include magnetic resonance cholangiography, endoscopic retrograde cholangiopancreatography (ERCP), and percutaneous transhepatic cholangiography (PTC).

Ultrasound may demonstrate biliary duct dilatation and larger hilar lesions. Small lesions and distal cholangiocarcinomas are difficult to visualize. Patients with underlying primary sclerosing cholangitis (PSC) may have limited ductal dilatation secondary to ductal fibrosis. Doppler ultrasound may show vascular encasement or thrombosis.

Endoscopic ultrasonography (EUS) enables both bile duct visualization and nodal evaluation. This technique also permits aspiration for cytologic studies.[22] EUS-guided fine-needle aspiration results may be positive when other diagnostic tests are inconclusive (see Workup/Procedures.[23] Intraductal EUS allows direct ultrasonographic evaluation of the lesion.

CT resembles ultrasound in that it may demonstrate ductal dilatation and large mass lesions. CT also has the capability to evaluate for pathologic intra-abdominal lymphadenopathy. Helical CT scans are accurate in diagnosing the level of biliary obstruction. Three-dimensional and multiphase CT images may improve CT yield.[24]

Magnetic resonance imaging (MRI) demonstrates hepatic parenchyma. MR cholangiography enables imaging of bile ducts and, in combination with MR angiography, permits staging (excluding vascular involvement). Hepatic involvement can also be detected. This technique likely will replace angiography for vascular evaluation.

Positron emission tomography

Although early reports suggested that positron emission tomography (PET) scanning may be useful for surveillance or investigation of suspected cholangiocarcinoma in patients with PSC, subsequent research demonstrated disappointing detection rates, especially in cases of extrahepatic disease with infiltrating rather than mass-forming disease. Therefore, PET is not routinely recommended for surveillance or diagnosis of cholangiocarcinoma in these patients.[25]  However, PET/CT has been shown to be valuable in detecting unsuspected distant metastases in patients with cholangiocarcinoma.[26]

Endoscopic retrograde cholangiopancreatography (ERCP) demonstrates the site of obstruction by direct retrograde dye injection and excludes ampullary pathology by endoscopic evaluation. Brush cytology, biopsy, needle aspiration, and shave biopsies via ERCP can provide material for histologic studies. Palliative stenting to relieve biliary obstruction can be performed at the time of evaluation.

Percutaneous transhepatic cholangiography (PTC) may allow access to proximal lesions with obstruction of both right and left hepatic ducts. Material for cytologic studies may be obtained and drainage performed. Other methods to obtain tissue include CT- or ultrasound-guided needle aspiration, if a mass lesion is present, and endoscopic ultrasonography–guided fine-needle aspiration. However, while ultrasonography with fine-needle aspiration has a greater sensitivity for detecting malignancy than ERCP with brush cytology, it has the potential for tumor seeding, so transenteric tissue sampling should be avoided in patients who are surgical candidates.[22]

Classic cholangiocarcinomas are well- to moderately-differentiated adenocarcinomas that exhibit glandular or acinar structures; intracytoplasmic mucin is almost always observed. Characteristically, cells are cuboidal or low columnar and resemble biliary epithelium. In more poorly differentiated tumors, solid cords of cells without lumina may be present. Mitotic figures are rare. A dense fibrous stroma is characteristic and may dominate the histologic architecture.

These tumors tend to invade lymphatics, blood vessels, perineural and periductal spaces, and portal tracts. Spread along the lumen of large bile ducts can be seen, especially with hilar tumors.

Tumor cells provoke variable desmoplastic reactions. Cytologic studies on material obtained by any method often yield nondiagnostic results secondary to desmoplastic reaction. For this reason, sensitivity and positive predictive value of brush cytologic studies are rather poor for dominant strictures in primary sclerosing cholangitis.

 

 

The American Joint Committee on Cancer guidelines in the AJCC Cancer Staging Manual, Eighth Edition, following the tumor, node, and metastasis (TNM) classification system, with depth of tumor penetration and regional spread defined pathologically, should be followed. Different staging definitions and prognostic groups apply for intrahepatic, perihilar, and distal bile duct tumors.[27]  See Biliary Tract Cancer Staging.

Table 1. TNM staging for intrahepatic bile duct tumors (Open Table in a new window)

Table  2. TNM staging for perihilar bile duct tumors. (Open Table in a new window)

Table 3.  TNM staging for distal bile duct tumors. (Open Table in a new window)

Evaluation of vascular involvement is important if surgical treatment is being considered. Arteriography demonstrating extensive encasement of the hepatic arteries or portal vein precludes curative resection. Combining the findings on cholangiography with those on arteriography has been found to have a greater accuracy in predicting unresectability. However, an occasional patient has compression of vascular structures rather than true malignant invasion.

Complete surgical resection is the only therapy to afford a chance of cure for cholangiocarcinoma. Unfortunately, many patients present with unresectable disease. Additional treatment measures in cholangiocarcinoma may include the following[8] :

• Stenting
• Photodynamic therapy (PDT)
• Radiation therapy
• Pharmacotherapy

For palliative treatment, celiac-plexus block via regional injection of alcohol or other sclerosing agent can relieve pain in the mid back from retroperitoneal tumor growth. In addition, other endoscopic forms of palliation, such as brachytherapy and radiofrequency ablation, have been used.[28, 29, 30]

Stents can be placed via endoscopic retrograde cholangiopancreatography (ERCP) or percutaneous transhepatic cholangiography (PTC) to relieve biliary obstruction. Stenting may relieve pruritus and improve quality of life.

Stents usually are used if the tumor is unresectable or if the patient is not a surgical candidate. Debate exists about whether preoperative stenting is warranted, but most surgeons believe that preoperative biliary decompression does not alter the outcome of surgery.

Either plastic or metal stents may be used. Plastic stents usually occlude in 3 months and require replacement. Metal stents are more expensive but expand to a larger diameter and tend to stay patent longer. Adequate biliary drainage can be achieved in a high percentage of cases. A study by Kida et al found that covered biliary self-expandable metal stents could be safely removed when they become occluded and that patency rates were similar for reintervention and initial stent placement.[31]

Photodynamic therapy (PDT) is an experimental local cancer therapy already in use for other gastrointestinal malignancies.[32, 33]  PDT is a two-step process: the first step is intravenous (IV) administration of a photosensitizer; the second step is activation by light illumination at an appropriate wavelength.[32, 33]

PDT is effective in restoring biliary drainage and improving quality of life in patients with nonresectable disseminated cholangiocarcinomas. Survival times may be longer than those reported previously. A prospective, multicenter study showed a significant survival benefit in the PDT treatment group.[32]  An additional multicenter study is being planned.

Adjuvant and preoperative radiation therapy has been used to reduce tumors in an effort to make them resectable. This therapy has been performed with and without concurrent chemotherapy as a radiation sensitizer.

Adjuvant radiotherapy has been to improve local control, with variable effect on overall survival after complete resection. Several series have shown an increase in median survival duration with postoperative radiation, from 8 months with surgery alone to more than 19 months.

Special radiation techniques have been used, such as intraluminal brachytherapy and external-beam therapy during surgery (ie, intraoperative radiotherapy [IORT]). See the image below for treatment planning technique.

In patients with medially inoperable or unresectable tumors, primary radiotherapy, with or without chemotherapy, has provided a survival advantage and significant palliation over stent placement or bypass surgery alone. A study of 66 patients with unresectable intrahepatic cholangiocarcinoma treated with hypofractionated radiation therapy reported 2-year outcomes of 84% local control and 58% overall survival.[34]

In a study of 1636 patients with unresectable localized intrahepatic cholangiocarcinoma, the addition of radiation to chemotherapy was associated with an improvement in overall survival. Two-year overall survival was 20% for the chemotherapy-alone cohort versus 26% for the chemoradiation therapy group.[35]

Radioembolization with yttrium-90 has been shown to be safe and effective in patients with unresectable/recurrent intrahepatic cholangiocarcinoma. Mosconi et al reported significantly longer survival in patients who received radioembolization as initial therapy, compared with patients in whom radioembolization was preceded by other treatments, including surgery (52 vs 16 months, P=0.009).[36]

Chemotherapy

Most often, chemotherapy is given in low doses to act as a radiation sensitizer during a 4- to 5-week course of external-beam radiotherapy. Primary chemotherapy has been evaluated as well, including gemcitabine and cisplatin as first-line chemotherapy in inoperable biliary tract carcinoma.[37, 38]  However, chemotherapy agents used without radiotherapy or surgery do not appear to provide any local control or meaningful survival benefit.

The most used agent has been 5-fluorouracil, which has a partial response rate of about 12%. Gemcitabine has a similar response rate. Although fluoropyrimidines and doxorubicin have been reported to have response rates as high as 30-40%, partial responses lasting from weeks to months have been observed in only 10-35% of trials.[37, 38]

A systematic review and meta-analysis found a significant improvement in overall survival with any adjuvant chemotherapy after cholangiocarcinoma surgery compared with surgery only (hazard ratio [HR] 0.74; 95% CI, 0.67 to 0.83; P <  0.001). The benefit of adjuvant therapy extended to patients with margin-positive surgery and node-positive disease.[39]

For patients with intrahepatic cholangiocarcinomas who have no residual local disease after resection, the National Comprehensive Cancer Network (NCCN) suggests observation or adjuvant gemcitabine-based chemotherapy. For lesions that are resected with microscopic margins or positive regional nodes, options include systemic therapy, fluoropyrimidine-based chemoradiation, fluoropyrimidine-based or gemcitabine-based chemotherapy followed by fluoropyrimidine-based chemoradiation, and fluoropyrimidine-based chemoradiation followed by fluoropyrimidine-based or gemcitabine-based chemotherapy.[40]

No data support a specific surveillance schedule. However, the NCCN suggests considering multiphasic abdominal/pelvic computed tomography (CT)/magnetic resonance imaging (MRI) with contrast and chest CT with contrast every 3–6 mo for 2 y, then every 6–12 months for up to 5 years, or as clinically indicated.[40]

For intrahepatic cholangiocarcinoma with residual local disease after resection, NCCN suggestions include systemic therapy, external beam radiation therapy (EBRT) with concurrent fluoropyrimidine, or best supportive care. The choice of care may be guided by the extent and/or location of disease and institutional capabilities.[40]

For unresectable extrahepatic cholangiocarcinoma, NCCN options include biliary drainage if indicated, biopsy for molecular testing of the tumor, or referral for transplantation. Subsequent primary treatment may consist of systemic therapy (with gemcitabine plus cisplatin being the preferred regimen), EBRT with concurrent fluoropyrimidine, palliative EBRT, or best supportive care. For metastatic extrahepatic cholangiocarcinoma, biliary drainage if indicated or biopsy for molecular testing of the tumor may be followed by systemic therapy or best supportive care.[40]

Targeted Therapy

Targeted agents are becoming available as second-line therapy for cholangiocarcinoma with specific driver mutations. These include fibroblast growth factor receptor 2 (FGFR2)–selective tyrosine kinase inhibitors for advanced cholangiocarcinoma harboring an FGFR2 gene fusion or rearrangement, and an isocitrate dehydrogenase 1 (IDH1) inhibitor for IDH1-mutated cholangiocarcinoma. 

Futibatinib 

The US Food and Drug Administration (FDA) approved futibatinib (Lytgobi) in October 2022 for treatment of adults with previously treated, unresectable, locally advanced or metastatic intrahepatic cholangiocarcinoma harboring FGFR2 gene fusions or other rearrangements. Approval was based on results of FOENIX-CCA2, a global phase 2 open-label trial in which 103 patients received futibatinib 20 mg/day PO until disease progression or unacceptable toxicity. The objective response rate was 41.7% and the median duration of response was 9.5 months, with 74% of responses lasting at least 6 months.[41]   

Pemigatinib

In 2020, the FDA approved pemigatinib (Pemazyre) for previously treated, unresectable, locally advanced or metastatic cholangiocarcinoma with an FGFR2 fusion or other rearrangement as detected by an FDA-approved test. Pemigatinib is a small molecule kinase inhibitor that targets FGFR1, 2, and 3 by inhibiting FGFR1-3 phosphorylation and signaling. FGFR inhibition disrupts tumor cell proliferation, survival, migration, and angiogenesis. 

Approval was supported by the FIGHT-202 study, which included 107 patients with FGFR2 fusions or rearrangements, 20 with other alterations in FGF/FGFR, 18 with no alterations, and 1 with an undetermined alteration. Thirty-eight (35.5%) of the 107 patients with FGFR2 fusions or rearrangements achieved an objective response (3 complete responses; 35 partial responses) to pemigatinib treatment.[42]

Infigratinib

Infigratinib is indicated for adults with previously treated, unresectable, locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement. It is an orally bioavailable inhibitor of FGFR types 1, 2, and 3 phosphorylation and signaling, and thereby decreases cell viability in cancer cell lines with activating FGFR amplifications and fusions.

Accelerated approval was granted by the FDA in May 2021 based on results from a single-arm, phase 2 trial. Among 108 patients, 83 (77%) had FGFR2 fusions. The overall response rate (ORR) was 23.1% including 1 complete response complete response and 24 partial responses. Median duration of response (DOR) was 5 months (range 0.9–19.1 months). Among responders, 8 (32%) patients had a DOR of 6 months or greater. Median progression-free survival was 7.3 months. Subgroup analysis included an ORR of 34% (17/50) in the second-line setting and 13.8% (8/58) in the third-/later-line setting (3-8 prior treatments).[43]

Ivosidenib

In August 2021 the FDA approved ivosidenib (Tibsovo) for treatment of adults with previously treated locally advanced or metastatic IDH1-mutated cholangiocarcinoma. Ivosidenib was previously approved for use in IDH1-mutated acute myeloid leukemia. Approval of ivosidenib for cholangiocarcinoma was based on findings from the randomized phase III ClarIDHy trial in which 70.5% of patients in the placebo group crossed over to ivosidenib at the time of progression as permitted by the study protocol.

The primary efficacy endpoint was progression-free survival (PFS); the trial demonstrated a statistically significant improvement in PFS for patients randomized to ivosidenib (HR, 0.37; P < .0001).

[44]

Complete surgical resection is the only therapy to afford a chance of cure. Unfortunately, only 10% of patients present with early-stage disease and are candidates for curative resection. Intrahepatic and Klatskin tumors[7] require liver resection, which may not be an option for older patients with comorbid conditions. In one report, 15% of patients with proximal lesions were candidates for complete resections, with higher rates in patients with mid-ductal tumors (33%) or distal tumors (56%). The survival rate for patients with proximal tumors can be 40% if negative margins are obtained.

Orthotopic liver transplantation is considered for some patients with proximal tumors who are not candidates for resection because of the extent of tumor spread in the liver. The largest series reports a 53% 5-year survival rate and a 38% complete pathologic response rate with preoperative radiation therapy and chemotherapy. Liver transplantation may have a survival benefit over palliative treatments, especially for patients with tumors in the initial stages. One study has demonstrated a 5-year survival rate greater than 80% in select patients.[45]

Distal tumors are resected via Whipple procedure; periampullary region tumors have a uniformly better prognosis, with a long-term survival rate of 30-40%.

Patterns of treatment failure after curative surgery show disappointingly high rates of tumor bed and regional nodal recurrence. This finding may be due in part to the narrow pathologic margins; however, the regional node failure rate is approximately 50%, and the distal metastases rate is 30-40%. Failure rates correlate with TNM stage. Adjuvant transcatheter arterial chemoembolization for intrahepatic cholangiocarcinoma has been used post attempted curative surgery, with better survival in patients with early recurrence.[46]

Palliative procedures are required if internal stenting cannot be accomplished and/or external stenting is not desirable or cannot be obtained. Surgical bypass, particularly for tumors in the common bile duct, should be performed in such cases.

Gastroenterologists, interventional radiologists, and transplant/biliary surgeons play a key role in diagnosis and management. Radiation oncology and medical oncology specialists are part of the multidisciplinary team taking part in the treatment of both patients with curatively resected tumors and those with unresectable tumors. Radiation oncologists have taken a more significant role in therapy for cholangiocarcinomas since the early 1980s.

Guidelines Contributor:  Elwyn C Cabebe, MD Physician Partner, Valley Medical Oncology Consultants; Medical Director of Oncology, Clinical Liason Physician, Cancer Care Committee, Good Samaritan Hospital

Diagnosis

The National Comprehensive Cancer Network (NCCN) recommends the following intrahepatic cholangiocarcinoma workup in patients with an isolated intrahepatic mass that has imaging characteristics consistent with malignancy but not consistent with hepatocellular carcinoma[40] :

• History and physical examination
• Multiphasic abdominal/pelvic computed tomography (CT)/magnetic resonance imaging (MRI) with intravenous contrast
• Chest CT with or without contrast
• Consider baseline carcinoembryonic antigen (CEA) and CA 19-9 testing
• Liver function tests (LFTs)
• Surgical consultation
• Esophagogastroduodenoscopy (EGD) and colonoscopy (to assess for T3 disease and rule out endobiliary metastasis from colorectal cancer mimicking intrahepatic cholangiocarcinoma ^[47] )
• Consider viral hepatitis serologies
• Consider biopsy
• Consider alpha fetoprotein (AFP) testing

For the workup of extrahepatic cholangiocarcinoma, in patients who present with pain, jaundice, abnormal LFTs, and obstruction or abnormality on imaging, the NCCN recommends the following workup[40] :

• History and physical examination
• Multiphasic abdominal/pelvic CT/MRI (to assess for vascular invasion) with IV contrast
• Chest CT with or without contrast
• Cholangiography
•  Consider baseline CEA and CA 19-9
• LFTs
• Consider endoscopic ultrasound (EUS) after surgical consultation
• Consider serum IgG4 to rule out autoimmune cholangitis

Guidelines from the American Society for Gastrointestinal Endoscopy (ASGE) recommend magnetic resonance cholangiography (MRCP) to assess for resectability if a CT scan suggests cholangiocarcinoma. ERCP is recommended to obtain tissue or facilitate further evaluation of indeterminate strictures.[48]

Staging

Cholangiocarcinoma cancer staging follows the tumor-node-metastasis (TNM) classification of the American Joint Cancer Committee/Union for International Cancer Control/ (AJCC/UICC) and is staged separately for intrahepatic, perihilar, and distal bile duct tumors.[27]

TNM groupings by stage are as follows for each group:[27]

Table. 1 (Open Table in a new window)

Table. 2 (Open Table in a new window)

Table. 3 (Open Table in a new window)

Treatment

The NCCN and ESMO guidelines concur that the only potentially curative treatment for cholangiocarcinoma is complete surgical resection with negative margins. However, few patients are diagnosed with early-stage resectable tumors.[40, 49]

With cholangiocarcinomas that are resected with negative margins and negative regional nodes, the NCCN recommends observation or systemic therapy (with gemcitabine as the preferred agent) for both intrahepatic and extrahepatic cholangiocarcinomas; for extrahepatic cholangiocarcinomas, fluoropyrimidine chemoradiation is also an option. 

For intrahepatic and extrahepatic cholangiocarcinomas resected with microscopic margins or positive regional nodes, options include the following:

• Systemic therapy
• Fluoropyrimidine-based chemoradiation
• Fluoropyrimidine- or gemcitabine-based chemotherapy followed by fluoropyrimidine-based chemoradiation
• Fluoropyrimidine-based chemoradiation followed by fluoropyrimidine- or gemcitabine-based chemotherapy

For intrahepatic or extrahepatic resections with residual local disease, or unresectable disease, NCCN suggestions include systemic therapy, external beam radiation therapy (EBRT) with concurrent fluoropyrimidine, or best supportive care. The choice of care may be guided by the extent and/or location of disease and institutional capabilities.[40]  

For metastatic disease, options for intrahepatic cholangiocarcinomas include systemic therapy, consideration of locoregional therapy (eg, EBRT, arterially directed therapies), or best supportive care. For extrahepatic cholangiocarcinomas, options are systemic therapy or best supportive care.[40]

Few patients are diagnosed with early-stage resectable tumors. Guidelines for unresectable or metastatic disease include various chemotherapy regimens. Targeted agents are available as second-line therapy for cholangiocarcinoma with specific driver mutations, including fibroblast growth factor receptor 2 (FGFR2)–selective tyrosine kinase inhibitors for advanced cholangiocarcinoma harboring an FGFR2 gene fusion or rearrangement, and an isocitrate dehydrogenase 1 (IDH1) inhibitor for IDH1-mutated cholangiocarcinoma.

Class Summary

Inhibition of FGFR disrupts tumor cell proliferation, survival, migration, and angiogenesis.

Pemigatinib (Pemazyre)

Pemigatinib is a small molecule kinase inhibitor that targets FGFR1, 2, and 3 by inhibiting FGFR1-3 phosphorylation and signaling. Indicated for previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement as detected by an FDA-approved test.

Infigratinib (Truseltiq)

Infigratinib is indicated for adults with previously treated, unresectable, locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement. 

Futibatinib (Lytgobi)

Indicated for previously treated, unresectable, locally advanced or metastatic intrahepatic cholangiocarcinoma in adults harboring fibroblast growth factor receptor 2 (FGFR2) gene fusions or other rearrangements.

Class Summary

Inhibitors of isocitrate dehydrogenase type 1 (IDH1) specifically inhibit a mutated form of IDH1 in the cytoplasm, which inhibits the formation of the oncometabolite, 2-hydroxyglutarate (2HG). This may lead to both an induction of cellular differentiation and an inhibition of cellular proliferation in IDH1-expressing tumor cells. IDH1, an enzyme in the citric acid cycle, is mutated in a variety of cancers; it initiates and drives cancer growth by both blocking cell differentiation and catalyzing the formation of 2HG. 

Ivosidenib (Tibsovo)

Indicated for locally advanced or metastatic cholangiocarcinoma in previously treated adults with IDH1 mutation.

Most patients with cholangiocarcinoma require follow-up care for acute and late adverse effects of therapy. Aggressive follow-up care also is necessary to treat symptoms from tumor recurrence and persistence. Patients with the best prognosis may be seen every 2-3 months with periodic laboratory and imaging studies (eg, CT scan).

Patients treated palliatively should enter hospice programs rapidly, as median survival duration is only 2-8 months.

Complications include the following:

• Infection of the biliary tree (ie, cholangitis) may result from cholangiocarcinoma and subsequent obstruction of the duct.

• Cirrhosis develops in 10-20% of patients with cholangiocarcinoma. This may be secondary biliary cirrhosis resulting from neoplastic obstruction of the bile ducts or related to underlying fibrosis from primary sclerosing cholangitis.

• Other complications are usually the result of diagnostic and therapeutic procedures.

Patients with perihilar tumors that are completely resected may achieve long-term survival. Prognosis is poorest for patients with intrahepatic tumors.

Patients with distal extrahepatic tumors may have the best hope for survival if tumors are excised completely; tumors at this site are the most likely to be resectable. These patients may experience a 5-year survival rate as high as 40%. The median survival duration in patients who undergo resection and postoperative chemoradiation may be as high as 17-27.5 months. A study by Polistina et al found that chemoradiation given by stereotactic body radiotherapy plus gemcitabine offers high local control rates and is a promising treatment.[50]

An intermediate prognosis (ie, median survival duration of 7-17 mo) is achieved for patients who are unable to undergo resection but can tolerate adjuvant chemoradiation or possibly photodynamic therapy.

The poorest prognosis is for the patient with unresectable disease, with or without overt metastatic disease, who can tolerate only palliative stent placement.

In a study of surgically resected hilar cholangiocarcinoma specimens, the presence of necrosis was associated with a worse prognosis. Necrosis was evident in 19 of 47 tumor samples. Compared with patients whose tumors showed no necrosis, those whose tumors showed necrosis had significantly lower 5-year recurrence-free survival (37.9% vs. 25.7%) and 5-year overall survival (42.6% vs.12.4%).[51]

A study by Ghafoori et al found that patients with locally advanced extrahepatic cholangiocarcinoma have poor survival with rare long-term survival. Most patients treated with external beam radiation therapy (EBRT) had local control at the time of death, which suggests that symptoms related to the local tumor effect may be controlled using radiation therapy. The authors concluded that novel approaches are indicated in the therapy for this condition.[52]

A study of prognostic scores in 219 patients with unresectable perihilar cholangiocarcinoma concluded that the modified Glasgow Prognostic Score (mGPS)[53] and the neutrophil-to-lymphocyte ratio (NLR)[54] each have prognostic value, but the platelet-to-lymphocyte ratio and Prognostic Nutritional Index do not. In addition, the combination of mGPS and NLR stratified survival well: mean survival time was 12.8 months in patients with an mGPS of 0 and an NLR of 1 or 2, but was only 3.0 months in patients with an mGPS of 1 or 2 and an NLR of 2.[55]