Cholangiocarcinoma

Cholangiocarcinoma – 8 Interesting Facts

Cholangiocarcinoma is a relatively rare and highly proliferative malignant tumor originating from the bile duct epithelium; it usually occurs in the sixth or seventh decade of life ¹
Patients are asymptomatic in early stages of disease; they may present with jaundice, abdominal pain and mass, ascites, and hepatomegaly in the later stages
Diagnosis is based on symptoms and signs suggestive of hepatic mass or biliary obstruction, abnormal liver function test results and imaging findings, and histopathologic analysis ²
Method of tissue sampling for histology is based on results of initial imaging and may include direct biopsy of tumor, cytologic brushing, or sampling of regional lymph nodes ²³
Endoscopic retrograde cholangiopancreatography is the procedure of choice for direct biopsy or cytologic brushing
First line curative option for the minority of patients with limited disease is complete resection with adjuvant systemic therapy
Most cases are nonresectable, and prognosis is poor
Complications may result from disease progression or treatment and can include liver failure, severe infections (eg, cholangitis), distant metastasis, bleeding, and bowel perforation

Pitfalls

Intrahepatic cholangiocarcinoma is often asymptomatic and extremely difficult to diagnose early; it may present with painless jaundice or with abdominal pain developing with disease progression and obstruction of bile ducts

Introduction

Cholangiocarcinoma is a relatively rare and highly proliferative malignant tumor originating from the bile duct epithelium; it usually occurs in the sixth or seventh decade of life ¹
Second most common liver malignancy after hepatocellular carcinoma ⁴
Incidence rates in the United States are 1.6 per 100,000 population ⁵
Incidence rates in Southeast Asia are as high as 85 per 100,000 population (northern Thailand) ⁵

Classification

Classification is based on anatomic location on the biliary tree ⁶
Anatomic classification guides clinical evaluation and contributes to determination of appropriate treatment and of prognosis ²⁶
- Intrahepatic: located proximal to second-degree bile ducts ⁷⁸
  - Macroscopic subtypes include: ⁹
    - Mass forming (nodular)
    - Periductal infiltrating (infiltrating along the bile duct)
    - Mass forming and periductal infiltrating (infiltrating along the bile duct with concurrent invasion into adjacent liver parenchyma, causing a mass)
    - Intraductal growing (now reclassified as intraductal papillary neoplasm)
  - Histologic subtypes based on duct type involved ⁹
    - Large duct type; occurs in chronic cholangitis caused by primary sclerosing cholangitis, hepatolithiasis, and liver fluke infection
    - Small duct type: often associated with nonbiliary chronic liver diseases (eg, viral hepatitis), and long-term outcomes are better because they are often amenable to targeted therapy
- Perihilar: located between second-degree bile ducts and insertion of cystic duct into common bile duct ¹⁰
  - Subtypes include intraductal and exophytic ²
    - Intraductal papillary lesions carry a favorable prognosis
    - Exophytic tumor is likely to metastasize and carries a poor prognosis
  - Bismuth-Corlette staging classification ¹¹
    - Provides an anatomic description of tumor location and tumor extension along biliary tree
    - Does not describe the radial extension of tumor
    - Provides a practical way to describe the lesion and the anticipated extent of liver resection required for complete excision
- Distal: located between origin of cystic duct and ampulla of Vater ²
  - Subtypes include nodular, sclerosing, and papillary ¹²
    - Papillary tumors have a more favorable prognosis
    - Nodular and sclerosing tumors carry a poor prognosis
- Mixed hepatocellular-cholangiocellular
  - Recently classified as a distinct type ¹³
  - Associated with worse prognosis than hepatocellular carcinoma
TNM classification according to American Joint Committee on Cancer (2018) allows disease staging to further direct treatment and provide crucial prognostic information ¹⁴¹⁵
- Intrahepatic tumor (includes intrahepatic and hepatocellular-cholangiocellular subtypes) ¹⁵
  - Tumor status
    - TX: primary tumor cannot be assessed
    - T0: no evidence of primary tumor
    - Tis: carcinoma in situ (intraductal tumor)
    - T1: solitary tumor without vascular invasion
      - T1a: solitary tumor of 5 cm or less without vascular invasion
      - T1b: solitary tumor greater than 5 cm without vascular invasion
    - T2: solitary tumor with vascular invasion or multiple tumors; none larger than 5 cm
    - T3: multiple tumors larger than 5 cm or tumor involving a major branch of the portal or hepatic veins
    - T4: tumor or tumors with direct invasion of adjacent organs other than the gallbladder or with perforation of visceral peritoneum
  - Lymph node status
    - NX: regional lymph nodes cannot be assessed
    - N0: no regional lymph node metastasis
    - N1: regional lymph node metastasis
  - Metastasis
    - MX: distant metastasis cannot be assessed
    - M0: no distant metastasis
    - M1: distant metastasis
  - Prognostic stage grouping ¹⁶
    - Stage 0: Tis, N0, M0
    - Stage IA: T1a, N0, M0
    - Stage 1B: T1b, N0, M0
    - Stage II: T2, N0, M0
    - Stage IIIA: T3, N0, M0
    - Stage IIIB: T4, N0, M0
    - Stage IIIB: any T, N1, M0
    - Stage IV: any T, any N, M1
- Extrahepatic tumor (includes perihilar and distal subtypes) ¹⁴
  - Tumor status
    - TX: primary tumor cannot be assessed
    - Tis: carcinoma in situ or high-grade dysplasia
    - T1: tumor invades bile duct wall with a depth less than 5 mm
    - T2: tumor invades bile duct wall with a depth of 5 to 12 mm
    - T3: tumor invades bile duct wall with a depth more than 12 mm
    - T4: tumor invades the celiac axis, superior mesenteric artery, and/or common hepatic artery
  - Lymph node status
    - NX: regional lymph nodes cannot be assessed
    - N0: no regional lymph node metastasis
    - N1: metastasis in 1 to 3 regional lymph nodes
    - N2: metastasis in 4 or more regional lymph nodes
  - Metastasis
    - M0: no distant metastasis
    - M1: distant metastasis
  - Prognostic stage grouping ¹⁶
    - Stage 0: Tis, N0, M0
    - Stage I: T1, N0, M0
    - Stage IIA: T1, N1, M0
    - Stage IIIA: T1, N2, M0
    - Stage IIA: T2, N0, M0
    - Stage IIB: T2, N1, M0
    - Stage IIIA: T2, N2, M0
    - Stage IIB: T3, N0, M0
    - Stage IIB: T3, N1, M0
    - Stage IIIA: T3, N2, M0
    - Stage IIIB: T4, N0, M0
    - Stage IIIB: T4, N1, M0
    - Stage IIIB: T4, N2, M0
    - Stage IV: any T, any N, M1 (distal extrahepatic bile duct cancer)
    - Stage IVA: any T, N2, M0 (perihilar bile duct cancer)
    - Stage IVB: any T, any N, M1 (perihilar bile duct cancer)

Diagnosis

Clinical Presentation

History

Asymptomatic in early stages of disease, especially for patients with intrahepatic disease
Patients with intrahepatic cholangiocarcinoma may present with only malaise, weight loss, and abdominal pain
Patients with perihilar or distal disease may present with symptoms of biliary obstruction, including painless jaundice, pale stools, dark urine, and pruritus
Other symptoms may include the following: ¹⁷
- Fatigue
- Anorexia
- Nausea and vomiting (with severe obstruction)

Physical examination

Scleral icterus or frank jaundice
Abdomen ¹⁷
- Tender palpable mass in right upper quadrant
- Hepatomegaly
- Ascites

Causes and Risk Factors

Causes

Cause is unknown

Risk factors and/or associations

Age

Age of onset is usually in the sixth or seventh decade of life, but the disease can occur earlier ¹

Sex

Incidence worldwide is higher in males than in females; however, the difference in rates between males and females has narrowed in recent years ¹⁸

Genetics

Several acquired genetic variants are present in a subset of patients ²¹⁹
- Sequence variants can be associated with increased risk of developing cholangiocarcinoma and with poorer prognosis

Ethnicity/race

Increased incidence in populations with Asian ethnicity and in those with Hispanic ethnicity ²⁰
In the United States, mortality rates from intrahepatic cholangiocarcinoma are highest in American Indian, Alaskan native, and Asian American populations ²⁰
Highest incidence rates worldwide are in Southeast Asia and China ²¹

Other risk factors/associations

Established risk factors account for less than 30% of all cases ²²
- Parasitic (liver fluke) infections, including Opisthorchis viverrini and Opisthorchis sinensis (also called Clonorchis sinensis)
  - Chronic infection with liver flukes is the main cause of cholangiocarcinoma in northeast Thailand and surrounding areas (which have highest cholangiocarcinoma rates globally) ¹⁰
- Primary sclerosing cholangitis
  - Results in chronic inflammation and segmental stenosis of bile ducts and in biliary cirrhosis
  - Main risk factor in the Western world but accounts for no more than 10% of all cases ¹⁰ ²³
- Choledochal cysts
  - Congenital condition characterized by cystic dilation of bile ducts that results in reflux of pancreatic enzymes and cholestasis
  - Incidence is higher in Asian populations
- Hepatolithiasis
  - Calculi form in bile ducts, resulting in cholestasis, inflammation, and infection
  - Prevalence is higher in East Asian populations
- Exposure to Thorotrast (radiographic contrast agent) ²⁴
  - Thorotrast was used until the 1950s
  - 16- to 45-year latency between exposure and malignancy
- Cirrhosis
- Hepatitis B
- Hepatitis C
- Less-established risk factors include the following:
  - Obesity
  - Diabetes
  - Inflammatory bowel disease
  - Smoking
  - Alcohol consumption
  - Choledocholithiasis and cholangitis
  - Lynch syndrome (hereditary nonpolyposis colorectal cancer) ²⁵
  - Biliary papillomatosis ²⁵

Diagnostic Procedures

Classification of cholangiocarcinoma.From Rizvi SH et al: Tumors of the bile ducts, gallbladder, and ampulla. In: Feldman M et al, eds: Sleisenger and Fordtran’s Gastrointestinal and Liver Disease. 11th ed. Elsevier; 2021:1096-112.e5, Figure 69.1.

Primary diagnostic tools

Suspect diagnosis on basis of symptoms and signs suggestive of hepatic mass or biliary obstruction, abnormal liver function test results, and imaging findings ²⁶
- Intrahepatic cholangiocarcinoma is often asymptomatic and detected on imaging
Confirm diagnosis with tumor biopsy, cytologic brushings, or fine-needle lymph node biopsy; may not be required before resection if malignancy is highly likely ² ¹⁷ ²⁷
Subsequent investigations to determine nature of mass, presence and degree of obstruction, and extent of disease, and to guide treatment, vary by whether malignancy is intrahepatic or extrahepatic; they may include: ²⁷
- Laboratory
  - Viral hepatitis serology
  - Diagnostic tumor biomarker testing (eg, carcinoembryonic antigen, carbohydrate antigen 19-9, alpha fetoprotein)
  - Comprehensive molecular profiling is recommended for patients with unresectable or metastatic tumors who are candidates for systemic therapy (specifically microsatellite instability, mismatch repair testing, tumor mutation burden testing, and NTRK gene fusion testing) ¹⁶ ²⁷
  - Serum IgG4 level
- Imaging ²
  - CT or MRI of abdomen and pelvis
  - Chest CT
  - Endoscopic ultrasonogram
  - Magnetic resonance cholangiopancreatography (preferred)
  - Endoscopic retrograde cholangiopancreatography
  - Percutaneous transhepatic cholangiogram
- Other investigations that may be considered include:
  - Upper gastrointestinal endoscopy and colonoscopy
  - Staging laparoscopy

- Staging laparoscopy

Laboratory

Liver function tests ¹⁷
- Markers for biliary obstruction include levels of the following:
  - Bilirubin
  - Alkaline phosphatase
  - 5′-nucleotidase
  - γ-glutamyltransferase
- All of these test results may be within reference range in early stages of disease
- Elevations in liver function test results will be determined by degree and duration of bile duct obstruction
- Isolated elevation of alkaline phosphatase level, γ-glutamyltransferase level, or both is found in biliary disease
- Markers for hepatic dysfunction (AST and ALT) initially may be within reference range but will become elevated in the setting of chronic biliary obstruction; these markers also initially may be elevated in the setting of preexisting liver disease (eg, hepatitis or cirrhosis)
Diagnostic tumor biomarker tests
- There is no single effective biomarker test for diagnosis ² ¹⁷ ²⁸
- Do not use carbohydrate antigen 19-9 or carcinoembryonic antigen alone to diagnose ²⁷
- Blood, urine, and tissue may be tested for presence of tumor markers ¹⁷²⁸
  - Carbohydrate antigen 19-9 ²¹⁷
    - Most useful as prognostic indicator when obtained preoperatively; consider baseline measurement after biliary decompression in patients with extrahepatic cholangiocarcinoma ²⁷
    - In unexplained biliary disease, carbohydrate antigen 19-9 levels of 100 units/mL or higher are considered suggestive of cholangiocarcinoma in the absence of an inflammatory process ¹⁷
    - Concentrations higher than 1000 units/mL are consistent with advanced disease, often involving the peritoneum
    - May be elevated in other malignancies and infections ²⁸
      - Intrahepatic cholangiocarcinoma
        
        Sensitivity of only 62%
        
        Specificity of only 63%
    - May be elevated in primary sclerosing or bacterial cholangitis ²⁹
      - Cholangiocarcinoma with primary sclerosing cholangitis
        
        Sensitivity from 50% to 100%
        
        Specificity from 50% to 98%
  - Carcinoembryonic antigen ²¹⁷
    - Has been used to detect cholangiocarcinoma, but elevated levels have significant overlap with other benign diseases and low sensitivity for early-stage disease
    - Cholangiocarcinoma
      - Sensitivity from 33% to 84% ³⁰ ³¹
      - Specificity from 33% to 100%
Tissue biopsy or cytologic brushing obtained during endoscopic retrograde cholangiopancreatography or transhepatic cholangiogram
- Cytology includes conventional analysis and, if available, fluorescence in situ hybridization ³²
Fine-needle aspiration
- Fine-needle aspiration of lymph node tissue is a valuable aid in confirmation of metastatic perihilar cholangiocarcinoma diagnosis ³
- Do not use during endoscopic ultrasonography to evaluate perihilar cholangiocarcinoma, because there is a high risk of needle tract seeding of tumor ³³ ³⁴

Imaging

MRI or magnetic resonance cholangiopancreatography
- Intrahepatic tumors
  - Gadolinium-enhanced MRI with magnetic resonance cholangiopancreatography is considered the optimal imaging modality ⁸
  - MRI and CT scans are equally valuable for distinguishing between cholangiocarcinoma and hepatocellular carcinoma in tumors larger than 2 cm ²⁸
- Perihilar and distal tumors
  - MRI is the preferred first line imaging method to evaluate the primary tumor
  - MRI can detect bile duct dilation and any perihilar mass
  - Magnetic resonance cholangiopancreatography delineates the extent of the bile duct lesion more effectively than CT scan
CT scan
- Intrahepatic tumors
  - CT has been validated for diagnosis of intrahepatic tumors ³⁵
  - CT will frequently show characteristic arterial enhancement (known as rim enhancement) of tumor margins ²
  - MRI and CT scans are equally valuable for distinguishing between cholangiocarcinoma and hepatocellular carcinoma for tumors larger than 2 cm ²⁸
- Perihilar and distal tumors
  - CT is primarily used to determine portal vein and arterial involvement during preoperative planning, but it has a low sensitivity for detecting lymph node metastasis (54%) ⁸ ²⁸
  - CT is often used with MRI for staging and preoperative planning
Endoscopic ultrasonography
- May be helpful when bile duct is dilated but no mass seen on CT or MRI; can be used to obtain tissue for histological diagnosis and provide access to relieve biliary obstruction ²⁷
  - May perform in conjunction with endoscopic retrograde cholangiopancreatography ¹⁰
  - Patients should first have triple-phase CT scan of the abdomen/pelvis and chest along with dynamic MRI and magnetic resonance cholangiopancreatography if proximal biliary obstruction is suspected ¹⁰

Procedures

Contrast material is injected through a fiberoptic endoscope to visualize biliary tree ²⁸
Tissue samples are obtained via brushing, bile samples, and core needle biopsies (preferred ²⁷) ²⁸
May also include placement of obstruction-relieving stent
Assess morphology of bile ducts in suspected cholangiocarcinoma ¹⁷
Distinguish benign from malignant strictures in biliary tract ¹⁷
Has additional palliative therapeutic role: biliary stent insertion for therapeutic decompression of obstruction ³⁶
History of the following may increase risk of procedure-related pancreatitis: ³⁷
- Previous occurrence of such (ie, endoscopic retrograde cholangiopancreatography–related pancreatitis)
- Recurrent pancreatitis
- Abdominal surgery and other surgeries
Contraindicated in patients at high risk of infection, such as cholangitis or sepsis ¹⁷ ³⁷
Bowel perforation
Bleeding
Perforation of bile duct
Air embolism
Hepatic hematoma
Cholangitis
Imaging finds areas of obstruction in bile ducts
Molecular analysis of fine-needle aspirate biopsies may find tumor cells ³⁶
Advanced cytology techniques may detect aneuploidy or aneusomy ³⁶
Invasive procedure in which an ultrasonography-guided thin needle is inserted into bile ducts for injection of contrast agent for imaging ³⁸
Tissue samples obtained via brushing, bile samples, and core needle biopsies (preferred) ³⁸
To visualize bile ducts in place when endoscopic retrograde cholangiopancreatography is not feasible owing to contraindication or patient refusal ³⁸
To assess morphology of bile ducts ¹⁷
To sample tissue for histologic and cytologic confirmation of malignancy ¹⁷
Hemorrhagic diathesis
Abdominal ascites
Bowel or bile duct perforation
Intra-abdominal bleeding or hepatic hematoma
Inadequate sampling
Imaging finds areas of obstruction in bile ducts
Histologic analysis of fine-needle aspirate biopsies may find tumor cells, and advanced cytology techniques may detect aneuploidy or aneusomy from brush samples ³⁶

Differential Diagnosis

Most common

Hepatocellular carcinoma
- Malignancy derived from hepatocytes
- Major risk factors include chronic hepatitis B and C and cirrhosis
- Most common in East Asia and sub-Saharan Africa
- Initially may be asymptomatic or may present with abdominal pain, most often in the setting of cirrhosis
- Clinical appearance is similar to intrahepatic mass-forming and mixed hepatocellular-cholangiocellular types
- Can be distinguished via immunohistochemistry or CT imaging
Benign strictures
- Occur most commonly as a result of trauma or inflammation
- Most traumatic benign strictures are result of previous surgery
- Most inflammatory benign strictures are the result of previous pancreatitis or cholangitis, primary sclerosing cholangitis, or inflammatory pseudotumors
- May be confused with intrahepatic periductal lesions
- No associated lymph node enlargement compared with cholangiocarcinoma
- Have symmetrical narrowing and short segments as compared with cholangiocarcinoma; visible with MRI
Hepatolithiasis
- Stone formation associated with bacterial infection, bile stasis, and hypersecretion of mucus in biliary tree
- Occurs most commonly in middle-aged and older adults in East Asian countries
- Patients may have a history of recurring fever, abdominal pain, and cholangitis
- May be confused with intrahepatic intraductal lesions
- Stones show no contrast enhancement on MRI

Treatment

Goals

Completely resect tumor while maintaining continuity of bilioenteric system
Provide palliative care for patients with nonresectable cholangiocarcinoma to alleviate pain and associated physiologic and psychological stress

Disposition

Admission criteria

Send patient to emergency department or admit to hospital if complications of tumor or treatment exist, including the following:
- Cholangitis
- Sepsis
- Biliary obstruction
- Bile leakage into abdomen

Recommendations for specialist referral

Refer patients with suspected cholangiocarcinoma to the following specialists:
- Hepatologist for biliary tract, liver, and pancreatic procedures
- Oncologist for management of radiation and chemotherapy
- Gastroenterologist for extrahepatic types

Treatment Options

General overview ²⁷

Approach to treatment is based on tumor type and extent of disease
Intrahepatic and mixed hepatocellular-cholangiocellular types
- Complete surgical excision of tumor is the treatment of choice for patients with resectable tumors. Patients with intrahepatic or lymph node metastases or vascular invasion should not undergo resection
  - May be accomplished by means of wedge or segmental resection or may require major hepatic resection; also perform regional lymphadenectomy of porta hepatis ²⁷
  - After R0 resection, preferred options are systemic therapy or participation in a clinical trial; observation is also an option ²⁷
  - For patients with positive microscopic margins or regional lymph nodes, systemic therapy or participation in a clinical trial is preferred; other options include fluoropyrimidine-based chemoradiation or fluoropyrimidine- or gemcitabine-based chemotherapy followed by chemoradiation or vice versa ³⁹ ⁴⁰
  - Capecitabine is the preferred agent for systemic therapy; Us and European guidelines recommend 6-month course ⁹ ¹⁰ ²⁷ ⁴¹
- Options specific for intrahepatic unresectable or metastatic disease include:
  - Locoregional therapies (eg, external beam radiation therapy, arterially directed therapies such as transarterial chemoembolization ⁴² and transarterial radioembolization, radiofrequency ablation)
- Chemotherapy or combined chemotherapy plus radiation therapy may be effective in downstaging locally advanced tumors, allowing for resection in patients with initially unresectable disease ⁹ ⁴³ ⁴⁴ ⁴⁵
- Liver transplant is not recommended owing to high recurrence rates; however, liver transplant for early-stage intrahepatic cholangiocarcinoma (3 cm or less) arising in the setting of cirrhosis is being investigated and may be considered under study protocols ⁹
Extrahepatic cholangiocarcinoma
- Consider biliary drainage for patients with jaundice before initiating definite treatment
- Determine whether patient is candidate for resection of tumor or liver transplant
- Complete surgical excision of tumor is the treatment of choice for patients with resectable tumors; typically requires pancreaticoduodenectomy (Whipple procedure) for distal tumors and major hepatic resection for hilar tumors
  - Neoadjuvant chemotherapy before surgery is not routinely recommended ¹⁰
  - After R0 resection, preferred options are systemic therapy or participation in a clinical trial; others include observation or fluoropyrimidine-based chemoradiation ²⁷
  - After resection, patients with positive microscopic margins or regional lymph nodes should preferably undergo systemic therapy or participate in a clinical trial; other options include fluoropyrimidine-based chemoradiation, or fluoropyrimidine- or gemcitabine-based chemotherapy followed by chemoradiation or vice versa ²⁷
    - Adjuvant radiation therapy in combination with chemotherapy improved overall survival in patients with resected extrahepatic cholangiocarcinoma ⁴⁶
- Referral to transplant center if patient is a candidate (those with unresectable perihilar or hilar tumors 3 cm or less in diameter, no extrahepatic or intrahepatic metastases, and no nodal disease, and patients with primary sclerosing cholangitis); neoadjuvant therapy is given ²⁷⁴⁷⁴⁸
  - Long-term survival benefit reported in carefully selected patients undergoing neoadjuvant chemoradiation followed by transplant ⁴⁹
Treatment options available for both intrahepatic and extrahepatic unresectable or metastatic disease ²⁷
- Systemic therapy
  - First line therapy regimen for advanced disease consists of cisplatin and gemcitabine with either durvalumab or pembrolizumab ⁹ ¹⁰ ²⁷ ⁵⁰
  - Patients with advanced cholangiocarcinomas (both intrahepatic and extrahepatic) who harbor certain molecular alterations may be candidates for targeted treatments
    - FGFR2 gene fusion or rearrangement: pemigatinib, futibatinib
    - IDH1 variants: ivosidenib ⁵¹
    - BRAF V600E variants: dabrafenib and trametinib
    - Deficient mismatch repair/microsatellite instability–high: pembrolizumab, dostarlimab-gxly
    - RET gene fusions: pralsetinib, selpercatinib
    - NTRK gene fusions: entrectinib, larotrectinib
    - HER-2 (ERBB2) variants: trastuzumab and pertuzumab
    - TMB-H (tumor mutation burden–high): nivolumab + ipilimumab, pembrolizumab
- Enrollment in a clinical trial
- Best supportive care
- Radiation therapy with or without concurrent fluoropyrimidine-based chemotherapy

Outcomes

Only 20% of patients have resectable disease at diagnosis ⁵²
Intrahepatic and mixed hepatocellular-cholangiocellular types
- 5-year overall survival rate after complete surgical excision is 15% to 40% ⁵³
- Overall survival for transarterial chemoembolization is 12 to 15 months ⁵⁴
- Overall survival for chemotherapy is 11.7 months ⁵⁵
- Overall survival for transarterial chemoembolization and transarterial radioembolization is up to 22 months ⁵⁶
Perihilar type
- 5-year survival rate after surgery is 20% to 30% ⁵⁷
- 5-year recurrence-free survival rate after liver transplant is 68%, and 5-year recurrence rate is 12% ⁴⁷ ⁴⁸
- Life expectancy with biliary drainage is up to 19 months ⁵⁸
Distal type
- 5-year survival rate is only 27% after surgical excision with negative surgical margins ³

Drug therapy

Drug Therapy: Cholangiocarcinoma.

Medication	Common regimens	Life-threatening or dose-limiting adverse reactions	Notable or nonemergent adverse reactions	Special considerations
Alkylating agent: platinum
Cisplatin	• Durvalumab + gemcitabine + cisplatin • Pembrolizumab + gemcitabine + cisplatin	• Anaphylaxis • Bone marrow suppression • Nausea and/or vomiting • Nephrotoxicity • Ocular toxicity • Peripheral neuropathy	• Injection site reaction • Ototoxicity • Secondary malignancy	• Avoid coadministering nephrotoxic or ototoxic agents • Ensure adequate hydration • Effective contraception required during and after therapy for 14 months for females of reproductive potential and for 11 months for males with female partners of reproductive potential

Oxaliplatin	• Oxaliplatin + leucovorin + fluorouracil	• Anaphylaxis • Bleeding • Bone marrow suppression • Gastrointestinal toxicity • Peripheral sensory neuropathy • PRES • Pulmonary fibrosis • QT prolongation and ventricular arrhythmias • Rhabdomyolysis	• Fatigue • Increased hepatic enzymes	• Effective contraception required during and after therapy for 9 months for females of reproductive potential and for 6 months for males with female partners of reproductive potential
Antimetabolite: nucleoside metabolic inhibitor
Capecitabine	• Capecitabine monotherapy	• Bone marrow suppression • Cardiotoxicity • Dehydration • Dermatologic toxicity • Diarrhea • Hyperbilirubinemia • Nephrotoxicity • Palmar-plantar erythrodysesthesia (hand-foot syndrome)	• Abdominal pain • Fatigue • Nausea and/or vomiting	• Increased risk of serious or fatal adverse reactions in patients with low or absent dihydropyrimidine dehydrogenase activity • Effective contraception required during and after therapy for 6 months for females of reproductive potential and for 3 months for males with female partners of reproductive potential
Fluorouracil	• Fluorouracil monotherapy • Oxaliplatin + leucovorin + fluorouracil	• Bone marrow suppression • Cardiotoxicity • Diarrhea • Hyperammonemic encephalopathy • Mucositis • Neurotoxicity • Palmar-plantar erythrodysesthesia (hand-foot syndrome)		• Closely monitor PT and INR during concomitant warfarin use due to risk for excessive prolongation of PT or INR and bleeding • Increased risk of serious or fatal adverse reactions in patients with low or absent dihydropyrimidine dehydrogenase activity • Effective contraception required during and after therapy for up to 3 months for females of reproductive potential and for 3 months for males with female partners of reproductive potential
Gemcitabine	• Durvalumab + gemcitabine + cisplatin • Pembrolizumab + gemcitabine + cisplatin	• Bone marrow suppression • Capillary leak syndrome • Hemolytic uremic syndrome • Hepatotoxicity • PRES • Pulmonary toxicity • Radiation sensitization/recall	• Edema • Fever • Hematuria • Increased hepatic enzymes • Nausea and/or vomiting • Proteinuria • Rash	• Effective contraception required during and after therapy for 6 months for females of reproductive potential and for 3 months for males with female partners of reproductive potential
CTLA-4–blocking antibody
Ipilimumab	• Nivolumab + ipilimumab	• Adrenal insufficiency • Colitis • Diabetic ketoacidosis • Exfoliative dermatitis • Hepatitis • Hyperthyroidism • Hypophysitis • Hypothyroidism • Infusion-related reactions • Myocarditis • Nephritis • Neurotoxicity • Ocular toxicity • Pneumonitis • Thyroiditis	• Anorexia • Diarrhea • Fatigue • Fever • Headache • Insomnia • Nausea and/or vomiting • Pruritus • Rash • Weight loss	• Effective contraception required during and after therapy for 3 months for females of reproductive potential
HER2/neu receptor antagonist
Pertuzumab	• Pertuzumab + trastuzumab	• Anaphylaxis • Cardiomyopathy • Infusion-related reactions	• Alopecia • Constipation • Diarrhea • Fatigue • Nausea and/or vomiting • Neutropenia	• Effective contraception required during and after combined therapy with trastuzumab for 7 months for females of reproductive potential
Trastuzumab	• Pertuzumab + trastuzumab	• Cardiomyopathy • Infusion-related reactions • Neutropenia • Pulmonary toxicity	• Anemia • Chills • Cough • Diarrhea • Dysgeusia • Fatigue • Fever • Headache • Infection • Insomnia • Mucosal inflammation • Nasopharyngitis • Nausea • Rash • Stomatitis • Thrombocytopenia • Weight loss	• Effective contraception required during and after therapy for 7 months for females of reproductive potential
IDH1 inhibitor
Ivosidenib	• Ivosidenib monotherapy	• Differentiation syndrome • Guillain-Barre syndrome • Leukocytosis • QT prolongation	• Abdominal pain • Anorexia • Arthralgia • Ascites • Bone marrow suppression • Diarrhea • Electrolyte loss • Fatigue • Hyperbilirubinemia • Hyperglycemia • Hyperuricemia • Hypoalbuminemia • Increased hepatic enzymes • Mucositis • Myalgia • Nausea and/or vomiting • Pruritus	• Drug interactions: may need to avoid or adjust dosage of certain drugs
Kinase inhibitor
Dabrafenib	• Dabrafenib + trametinib	• Bleeding • Cardiomyopathy • Dermatologic toxicity • Fever • New primary malignant neoplasm • Uveitis	• Alopecia • Arthralgia • Headache • Hyperglycemia • Papilloma	• Potential risk of hemolytic anemia in patients with G6PD deficiency • Effective nonhormonal contraception required during and after therapy for 2 weeks for females of reproductive potential and males with female partners of reproductive potential
Entrectinib	• Entrectinib monotherapy	• Bone marrow suppression • Heart failure • Hepatotoxicity • Hyperuricemia • Neurotoxicity • QT prolongation • Skeletal fractures • Vision disorders	• Arthralgia • Cognitive impairment • Constipation • Cough • Diarrhea • Dizziness • Dysesthesia • Dysgeusia • Dyspnea • Edema • Fatigue • Fever • Myalgia • Nausea and/or vomiting • Weight gain	• Drug interactions: may need to avoid or adjust dosage of certain drugs • Effective contraception required during and after therapy for at least 5 weeks for females of reproductive potential and for 3 months for males with female partners of reproductive potential
Futibatinib	• Futibatinib monotherapy	• Hyperphosphatemia • RPED • Soft tissue mineralization	• Abdominal pain • Alopecia • Anorexia • Arthralgia • Bone marrow suppression • Constipation • Diarrhea • Dry eye, mouth, or skin • Dysgeusia • Electrolyte abnormalities • Fatigue • Hyperbilirubinemia • Hyperglycemia • Hypoalbuminemia • Hypoglycemia • Increased hepatic enzymes • Increased PT or INR • Increased serum creatinine • Myalgia • Nail toxicity • Nausea and/or vomiting • Palmar-plantar erythrodysesthesia (hand-foot syndrome) • Prolonged aPTT • Stomatitis • Urinary tract infection	• Effective contraception required during and after therapy for at least 1 week for females of reproductive potential and males with female partners of reproductive potential
Larotrectinib	• Larotrectinib monotherapy	• Hepatotoxicity • Neurotoxicity • Skeletal fractures	• Abdominal pain • Anemia • Constipation • Cough • Diarrhea • Dizziness • Fatigue • Fever • Hypoalbuminemia • Hypocalcemia • Leukopenia • Lymphopenia • Musculoskeletal pain • Nausea and/or vomiting • Neutropenia	• Drug interactions: may need to avoid or adjust dosage of certain drugs • Effective contraception required during and after therapy for at least 1 week for females of reproductive potential and males with female partners of reproductive potential
Pemigatinib	• Pemigatanib monotherapy	• Hyperphosphatemia • RPED • Soft tissue mineralization	• Abdominal pain • Alopecia • Anemia • Anorexia • Arthralgia • Back pain • Constipation • Diarrhea • Dizziness • Dry eye, mouth, or skin • Dysgeusia • Dyspepsia • Epistaxis • Extremity pain • Fatigue • Hypophosphatemia • Nail toxicity • Nausea and/or vomiting • Peripheral edema • Rash • Stomatitis • Vision blurred	• Drug interactions: may need to avoid or adjust dosage of certain drugs • Effective contraception required during and after therapy for at least 1 week for females of reproductive potential and males with female partners of reproductive potential
Pralsetinib	• Pralsetinib monotherapy	• Bleeding • Hepatotoxicity • Hypertension • Impaired wound healing • Interstitial lung disease or pneumonitis • Tumor lysis syndrome	• Bone marrow suppression • Constipation • Cough • Diarrhea • Edema • Electrolyte abnormalities • Fatigue • Fever • Hyperbilirubinemia • Myalgia	• Drug interactions: may need to avoid or adjust dosage of certain drugs • Withhold therapy for at least 5 days before elective surgery and for at least 2 weeks after major surgery and until adequate wound healing • Effective nonhormonal contraception required during and after therapy for 2 weeks for females of reproductive potential and for 1 week for males with female partners of reproductive potential
Selpercatinib	• Selpercatinib monotherapy	• Bleeding • Hepatotoxicity • Hypersensitivity reactions • Hypertension • Hypothyroidism • Impaired wound healing • Interstitial lung disease/pneumonitis • QT prolongation • Tumor lysis syndrome	• Abdominal pain • Constipation • Diarrhea • Dry mouth • Edema • Fatigue • Headache • Hypertension • Hypocalcemia • Hyponatremia • Increased hepatic enzymes • Lymphopenia • Nausea • Rash	• Drug interactions: may need to avoid or adjust dosage of certain drugs • Withhold therapy for at least 1 week before elective surgery and at least 2 weeks after major surgery and until adequate wound healing • Effective contraception required during and after therapy for 1 week for females of reproductive potential and males with female partners of reproductive potential
Trametinib	• Dabrafenib + trametinib	• Bleeding • Cardiomyopathy • Colitis and gastrointestinal perforation • Dermatologic toxicity • Fever • Interstitial lung disease/pneumonitis • New primary malignancy • RPED • RVO • Venous thromboembolism	• Diarrhea • Hyperglycemia • Lymphedema	• Effective contraception required during and after therapy for 4 months for females of reproductive potential and males with female partners of reproductive potential
PD-L1 blocking antibody
Durvalumab	• Durvalumab + gemcitabine + cisplatin	• Adrenal insufficiency • Colitis • Diabetic ketoacidosis • Exfoliative dermatitis • Hepatitis • Hyperthyroidism • Hypophysitis • Hypothyroidism • Infusion-related reactions • Intestinal perforation • Myocarditis • Nephritis • Neurotoxicity • Pancreatitis • Pneumonitis • Thyroiditis	• Cough • Dyspnea • Fatigue • Rash • Upper respiratory tract infection	• Effective contraception required during and after therapy for at least 3 months for females of reproductive potential
PD-1 blocking antibody
Dostarlimab	• Dostarlimab monotherapy	• Adrenal insufficiency • Colitis • Diabetic ketoacidosis • Exfoliative dermatitis • Hepatitis • Hyperthyroidism • Hypophysitis • Hypothyroidism • Infusion-related reactions • Myocarditis • Nephritis • Neurotoxicity • Pneumonitis • Thyroiditis	• Anemia • Asthenia • Diarrhea • Fatigue • Hypoalbuminemia • Hyponatremia • Lymphopenia • Nausea	• Effective contraception required during and after therapy for 4 months for females of reproductive potential
Nivolumab	• Nivolumab monotherapy • Nivolumab + ipilimumab	• Adrenal insufficiency • Colitis • Diabetic ketoacidosis • Exfoliative dermatitis • Hepatitis • Hyperthyroidism • Hypophysitis • Hypothyroidism • Infusion-related reactions • Myocarditis • Nephritis • Neurotoxicity • Pneumonitis • Thyroiditis	• Abdominal pain • Anorexia • Arthralgia • Asthenia • Back pain • Constipation • Cough • Diarrhea • Dyspnea • Fatigue • Fever • Headache • Myalgia • Nausea and/or vomiting • Pruritus • Rash • Upper respiratory tract infection • Urinary tract infection	• Effective contraception required during and after therapy for 5 months for females of reproductive potential
Pembrolizumab	• Pembrolizumab monotherapy	• Adrenal insufficiency • Anaphylaxis • Colitis • Diabetic ketoacidosis • Exfoliative dermatitis • Hepatitis • Hyperthyroidism • Hypophysitis • Hypothyroidism • Infusion-related reactions • Myocarditis • Nephritis • Neurotoxicity • Pneumonitis • Thyroiditis	• Abdominal pain • Anorexia • Constipation • Cough • Diarrhea • Dyspnea • Fatigue • Fever • Myalgia • Nausea • Pain • Pruritus • Rash	• Effective contraception required during and after therapy for 4 months for females of reproductive potential

Caption: aPTT, activated partial thromboplastin; CTLA-4, cytotoxic T-lymphocyte antigen 4; IDH1, isocitrate dehydrogenase-1; INR, international normalized ratio; G6PD, glucose-6-phosphate dehydrogenase; PD-L1, programmed death-ligand 1; PRES, posterior reversible encephalopathy syndrome; PT, prothrombin time; RPED, retinal pigment epithelial detachment; RVO, retinal vein occlusion.

Citation: Data from Cisplatin. Package insert. Accord Healthcare, Inc.; February 2020. Oxaliplatin. Package insert. Sandoz Inc.; July 2023. Xeloda (capecitabine). Package insert. Genentech, Inc; December 2022. Fluorouracil injection. Package insert. Accord Healthcare, Inc; February 2017. Gemcitabine. Package insert. Armas Pharmaceuticals, Inc; August 2019. Yervoy (ipilimumab). Package insert. Bristol-Myers Squibb Company; February 2023. Perjeta (pertuzumab). Package insert. Genentech USA, Inc: January 2020. Herceptin (trastuzumab). Package insert. Genentech USA, Inc.; February 2021. Tibsovo (ivosidenib). Package insert. Servier Pharmaceuticals LLC; October 2023. Tafinlar (dabrafenib). Package insert. Novartis Pharmaceuticals Corporation; February 2024. Rozlytrek (entrectinib). Package insert. Genentech USA, Inc.; October 2023. Lytgobi (futibatinib). Package insert. Taiho Oncology, Inc.; September 2022. Vitrakvi (larotrectinib). Package insert. Bayer HealthCare Pharmaceuticals Inc.; November 2023. Pemazyre (pemigatinib). Package insert. Incyte Corporation: February 2021. Gavreto (pralsetinib). Package insert. Genentech USA, Inc.; August 2023. Retevmo (selpercatinib). Package insert. Eli Lilly and Company; September 2022. Mekinist (trametinib). Package insert. Novartis Pharmaceuticals Corporation; February 2024. Imfinzi (durvalumab). Package insert. AstraZeneca Pharmaceuticals LP; June 2023. Jemperli (dostarlimab). Package insert. GlaxoSmithKline LLC; March 2024. Opdivo (nivolumab). Package insert. Bristol-Myers Squibb Company; March 2024. Keytruda (pembrolizumab). Package insert. Merck Sharp and Dohme Corp, January 2024.

Nondrug and supportive care

External beam radiation therapy

Used as adjuvant or neoadjuvant therapy, with or without chemotherapy, in resectable cases ¹⁰
- Routinely consider adjuvant radiotherapy after resection of distal cholangiocarcinoma irrespective of margins and nodal status ⁵⁹
May be used as primary therapy for nonresectable cases and as palliative treatment of intrahepatic cholangiocarcinoma ¹⁰ ⁶⁰ ⁶¹

Hospice care and support groups are recommended with significant disease progression at stages III and IV

Procedures

Surgery

General explanation

Removal of bile duct tumors
- Resection of intrahepatic cholangiocarcinoma is best performed at high-volume hepatobiliary centers; refer patients to these centers when resection is being considered ⁵³
- Intrahepatic type
  - Partial hepatectomy ²
    - In most cases, this is a palliative procedure
    - 5-year survival and overall survival rates after surgical resection of intrahepatic cholangiocarcinoma range from 15% to 40% ⁵³
- Perihilar type ⁶²
  - Partial hepatectomy, with removal of bile duct, gallbladder, and nearby lymph nodes
  - 5-year survival rate for perihilar cholangiocarcinoma after surgery is 20% to 30% ⁵⁷
- Distal type
  - Removal of bile duct, nearby lymph nodes, part of pancreas, and part of small intestine. Surgical treatment of distal cholangiocarcinoma usually is a Whipple procedure ⁶²
  - 5-year survival rate after surgical resection with negative margins is 27% ³
Mechanical and operational techniques for palliative care include the following:
- Biliary bypass to allow bile drainage to the small bowel ⁶²
- Placement of metal or plastic expandable stent into bile duct to maintain duct patency ⁶²

Indication

Surgery is performed to completely resect bile duct tumor (only curative option), or to perform hepatectomy for liver transplant
May be used for palliative care when cure is not possible
- Partial hepatectomy
- Insertion of biliary stents
- Biliary bypass

Contraindications

Portal hypertension ⁶²
Cirrhosis ⁶²
Do not consider curative surgery if the patient has the following:
- Main portal vein encasement ⁶²
- Atrophy of 1 lobe with either involvement of secondary biliary radicles or encasement of contralateral portal vein branch ⁶²
- Involvement of both sides of secondary biliary radicles ⁶²
- N2 lymph node metastasis ⁶²
- Peritoneal or distant metastasis

Complications

Infection
Bowel perforation
Bleeding
Hepatic failure

Orthotopic liver transplant

General explanation

Liver is surgically removed and transplanted with a donor liver ⁶³
- Associated with the best outcomes in perihilar cholangiocarcinoma; however, few patients meet criteria for this option ⁴⁸
- 5-year recurrence-free survival rate after liver transplant with neoadjuvant chemoradiation therapy is 68% ⁴⁷
- 5-year recurrence rate after liver transplant with neoadjuvant chemoradiation therapy is 12% ⁴⁸
Currently used in pilot clinical trials of nonresectable cases as therapeutic option ⁶³

Indication

Unresectable perihilar cholangiocarcinoma up to 3 cm in radial diameter without intrahepatic or extrahepatic metastasis ⁴⁸

Contraindications

Prior treatment with chemotherapy or radiation ²⁸
Prior hepatic or biliary resection ²⁸
Prior endoscopic ultrasonography-guided fine-needle aspiration ²⁸
Intrahepatic cholangiocarcinoma or metastasis ²⁸
Uncontrolled infection ²⁸
Gallbladder involvement ⁶³
Tumor larger than 3 cm ⁶³
Cancer history in past 5 years ²⁸

Complications

Bowel perforation
Hepatic failure
Infection
Bleeding
Graft rejection

Comorbidities

Cirrhosis and other liver disease may exacerbate clinical impact of biliary obstruction³²
Poor baseline performance status resulting from commonly encountered chronic diseases such as diabetes, ischemic heart disease, heart failure, and others may preclude surgical intervention or palliative chemotherapy

Monitoring

Monitor for the following, depending on clinical stage, performance status, and treatment modalities chosen:
- Direct adverse effects of surgery, chemotherapy, or radiation
- Patency of biliary drainage
- Effective palliative care, particularly pain control and other symptom relief (eg, pruritus, ascites)
After resection, obtain imaging every 3 to 6 months for 2 years, then every 6 to 12 months for up to 5 years ²⁷

Complications

Complications include liver failure, severe infection (including cholangitis), regional disease progression and distant metastasis
- Liver failure will occur in patients with unrelieved bile duct obstruction
- Cholangitis is more likely to occur in patients treated with obstruction-relieving stent

Prognosis

Overall prognosis is very poor
Intrahepatic and mixed hepatocellular-cholangiocellular type, with treatment
- 5-year overall survival rate after complete surgical excision is 15% to 40% ⁵³
- Overall survival for transarterial chemoembolization has been reported as 12 to 15 months ⁵⁴
- Overall survival for chemotherapy has been reported as 11.7 months ⁵⁵
- Overall survival for transarterial chemoembolization and transarterial radioembolization has been reported as up to 22 months ⁵⁶
Perihilar type, with treatment
- 5-year survival rate after surgery is 20% to 30% ⁵⁷
- 5-year recurrence-free survival rate after liver transplant is 68%, and 5-year recurrence rate is 12% ⁴⁷
- Life expectancy with biliary drainage has been reported as up to 19 months ⁵⁸
Distal type, with treatment
- 5-year survival rate is only 27% after surgical excision with negative surgical margins ³
Most important factor in prognosis is tumor resectability ⁴
Most tumors explored are not resectable ⁶²
Patients who have primary sclerosing cholangitis and cholangiocarcinoma have the lowest 5-year survival rate at 10% ⁶⁴

Screening

At-risk populations

Patients with primary sclerosing cholangitis
- Up to 50% of cholangiocarcinomas are diagnosed within 1 year of primary sclerosing cholangitis diagnosis ⁶⁵
- Overall incidence of cholangiocarcinoma in patients with primary sclerosing cholangitis is about 7% ⁵
Other patients at risk include those with cirrhosis, gallbladder polyps, and chronic liver fluke infection

Screening tests

Patients with primary sclerosing cholangitis
- Annual surveillance for cholangiocarcinomas improves survival of patients with primary sclerosing cholangitis ⁹
- Suggested method is imaging of the biliary tract (MRI with or without magnetic resonance cholangiopancreatography) in combination with carbohydrate antigen 19-9 measurement every 12 months ⁹
In patients with cirrhosis, ultrasonography and serum alpha fetoprotein every 6 months ⁹
In patients with gallbladder polyps, ultrasonography every 6 months ⁹
In patients infected with liver flukes, ultrasonography every 6 months ⁹

Prevention

Reduction in rates of liver fluke infection, hepatitis B and C, HIV, and other preventable risk factors (smoking cessation and decreased alcohol consumption) could theoretically reduce the incidence of cholangiocarcinoma, but there are no studies of the effectiveness of such prevention or recommendations for prevention

References

1.Tyson GL et al: Risk factors for cholangiocarcinoma. Hepatology. 54(1):173-84, 2011

Cholangiocarcinoma – 8 Interesting Facts

Pitfalls

Introduction

Classification

Diagnosis

Clinical Presentation

History

Physical examination

Causes and Risk Factors

Causes

Risk factors and/or associations

Age

Sex

Genetics

Ethnicity/race

Other risk factors/associations

Diagnostic Procedures

Primary diagnostic tools

Laboratory

Imaging

Procedures

Differential Diagnosis

Most common

Treatment

Goals

Disposition

Admission criteria

Recommendations for specialist referral

Treatment Options

Nondrug and supportive care

Procedures

Surgery

Orthotopic liver transplant

Comorbidities

Monitoring

Complications

Prognosis

Screening

At-risk populations

Screening tests

Prevention

References

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