Cholangiocarcinoma; clinical features and diagnosis.

Clinical presentation

Cholangiocarcinomas usually become symptomatic when the tumor obstructs the biliary drainage system, causing painless jaundice.

Common symptoms include:

• pruritus (66 percent)

• abdominal pain (30 to 50 percent)

The pain is generally described as a constant dull ache in the right upper quadrant.

• weight loss (30 to 50 percent), and

In later stages of the disease, weight loss and inanition may appear.

• fever (up to 20 percent)

• fatigue

• anorexia and nausea

Rarely, the first manifestation of disease is pancreatitis, which is initiated by pancreatic duct obstruction by tumour emboli that have travelled down the bile duct.

• Cholangitis is an unusual presentation.

Patients with primary sclerosing cholangitis and cholangiocarcinoma tend to present with a declining performances status and increasing cholestasis.

Extrahepatic cholangiocarcinomas, whether in the lower duct or in the hilum, present with painless jaundice or jaundice with mild pain in more than 90% of cases.

Intrahepatic cholangiocarcinomas usually present consequent to detection of a mass or abdominal fullness by the patient or as upper abdominal discomfort or pain.

• Sometimes, the initial presentation is that of weight loss and inanition.

• Jaundice may occur as a result of compression of hilar structures by centrally placed tumours, secondary to tumour embolizing into major bile ducts or due to compromise of overall liver function in endstage disease.

• Occasionally, the tumour is detected by imaging done for investigation of an unrelated problem.

Sometimes, the first sign of disease is an abnormality in blood chemistry or an unexpected finding on imaging for another indication in an otherwise healthy individual.

• It is not uncommon for newly diagnosed patients to have recently had a cholecystectomy, presumably because it was believed that gallstones were the source of symptoms, or mild abnormalities in liver function tests.

A palpable gallbladder, caused by obstruction distal to the takeoff of the cystic duct (Courvoisier's sign), occurs rarely.

Diagnosis and surgical staging

Surgical staging questions for cholangiocarcinoma.

1. What is the macroscopic extent of the tumour along the bile ducts?
2. What is the relationship of the tumour to blood vessels?
3. What is the extent of hepatic atrophy?
4. What is the extent of local hepatic invasion by the tumour?
5. What is the extent of lymph node involvement?
6. Are there distant intrahepatic metastases?
7. Are there peritoneal metastases?
8. Are there extra-abdominal metastases?
   

Hilar cholangiocarcinoma

Surgical staging of a hilar cholangiocarcinoma is subservient to the goals of surgical resection.

• These are to remove all gross and microscopic tumour, while preserving adequate liver function.
  
• To achieve these goals, there must be no evidence of tumour spread outside the confines of the resection, such as lymph node metastases outside the resection zone, peritoneal metastases or extra-abdominal metastases.
  
• The upper extent of the tumour must be limited to the extent that a clear resection margin on the bile ducts can be obtained without the need to remove so much liver tissue that the risk of postoperative liver failure becomes prohibitive.
  
• This will be discussed further under surgical planning and preparation.
  
• If vascular invasion is present, it must be located on the side of a planned resection.
  
• Invasion of the main portal or proper hepatic arteries is a relative contraindication.
  
• If atrophy has affected one hemiliver, it must be on the side chosen for resection.
  
• If there is local invasion of the tumour into the liver, it must be limited to the extent that clear resection margins can be obtained during the planned resection.
  
• Tumour nodules within the liver distant from the hilum are considered to be a contraindication.
  
• These criteria are modified when the resection is part of an orthotopic liver transplant.

Serum and bile markers

The remarks in this section on serum and bile markers pertain to cholangiocarcinoma at all levels of the biliary tree.

• When the obstruction is complete, as it usually is at the time of presentation of hilar and lower duct tumours, the bilirubin rises over several weeks to a level of about 30 mg/dL.
  • The direct reacting fraction accounts for more than 50% of the total bilirubin.

• Marked elevation of serum alkaline phosphatase and γ- glutamyltransferase levels and mild elevation of transaminase levels are also usual.
  
• In intrahepatic cholangiocarcinoma, bile drainage from the unaffected side is usually unimpaired, and bilirubin levels are usually normal, but alkaline phosphatase levels are often elevated.

CA19-9 is the most commonly used tumour marker for diagnosis of cholangiocarcinoma.

• In a large study of 322 patients with biliary cancer, the sensitivity and specificity of CA19-9 were 78% and 83%, respectively, at the cutoff value of 37 U/mL in patients without cholangitis or cholestasis.
  
• In patients with cholangitis or cholestasis, the sensitivity and specificity of CA19-9 were 74% and 42%, respectively, whereas the specificity reached 87% at 300 U/mL.
  
• As many patients with cholangiocarcinoma have cholestasis or cholangitis, CA19-9 is most useful when the levels are quite elevated.
  

• In cholangitis, the level may be extremely high; therefore, it is advisable to obtain blood for measurement of CA19-9 in the jaundiced patient prior to instrumentation of the ducts.
  
• CA19-9 is not specific for cholangiocarcinoma and may be elevated in pancreatic cancer and in intestinal and gynaecological malignancies.
  
• In patients with PSC, the specificity of CA19-9 is low if the cutoff value of 37 U/mL is used. A cutoff value of 100 U/mL seems to provide the most satisfactory balance between sensitivity and specificity in PSC.

Serum carcinoembryonic antigen (CEA) levels may also be mildly elevated in cholangiocarcinoma and have been used by Ramage et al. to increase diagnostic accuracy for cholangiocarcinoma in PSC by combining CEA with CA19-9 levels to form an index, although others have found the index to be less useful. CA125 has a low sensitivity for detection of cholangiocarcinoma, but a high specificity as it is rarely elevated in inflammatory conditions.

CA19-9 and CEA in bile Attempts have been made to improve diagnostic sensitivity and specificity for the detection of cholangiocarcinoma by measurement of these markers in bile, but the results have been disappointing.

Endoscopic retrograde cholangiopancreatography (ERCP) and percutaneous transhepatic cholangioscopy (PTC)

ERCP and PTC are considered together as they both involve direct intubation of the bile ducts and the injection of contrast into potentially obstructed ducts.

• With both tests, ducts that have been injected with contrast must remain intubated because of the risk of infection.
  
• Often, ERCP is chosen as the first investigation when a patient presents with obstructive jaundice.
  
• In the case of hilar cholangiocarcinoma, the unfortunate result may be insertion of bilateral stents, including a stent into the hemiliver to be resected.
  • This is undesirable because the goal in the preoperative period is to encourage hypertrophy of the hemiliver to be retained and atrophy of the hemiliver to be resected.
    
  • Insertion of bilateral stents works against this purpose.
    
  • Also, if the malignant stricture is tight, ERCP may only show the lower limit of the stricture.
    
  • In the past, this problem has been approached by supplementing the ERCP findings with PTC, although PTC is uncommonly used for this particular purpose today.
    

Beginning the investigation of the jaundiced patient with axial imaging such as computerized tomography (CT) or magnetic resonance imaging (MRI) rather than ERCP has distinct advantages.

• If a hilar cholangiocarcinoma is present, it will be suspected by the presence of intrahepatic bile duct dilation in the absence of extrahepatic ductal dilation.
  
• Atrophy of a hemiliver or section may also be seen.
  
• Whether to use stents or not in hilar cholangiocarcinoma is debatable but, if a stent is inserted, only the side to be retained should be intubated.
  
• The side to be surgically removed should be intubated only if there is evidence of cholangitis on that side or if that side is inadvertently injected with contrast.
  
• Another disadvantage of early intubation of the biliary tree is that it interferes with staging by MRI.
  
• Even if the patient is not a surgical candidate, intubation of both sides of the liver by ERCP is disadvantageous because it commits the patient to bilateral rather than unilateral stenting.

One advantage of endoluminal techniques is that biopsies may be obtained by brushings, fine-needle aspiration or forceps biopsy.

• However, the individual sensitivity of these test is less than 50% and only 65% when combined.
  
• Attempts to improve the results of routine cytology include digital image analysis (DIA), which uses aneuploidy as a marker for malignancy, and fluorescence in situ hybridization (FISH).
  
• DIA was found to increase sensitivity from 18% to 40% but lower specificity from 98% to 77% in 100 patients.
  
• The FISH assay uses a mixture of fluorescently labelled probes to centromeres of chromosomes to identify cells with chromosomal abnormalities.
  
• In 100 patients, the sensitivity for the detection of malignancy in bile duct brushing specimens was 15% and 34% for routine cytology and FISH, respectively, and the specificity was 91% and 98%.
  

Percutaneous intubation of the bile ducts has been used to obtain biopsy material and to determine the upper extent of the lesion in the bile ducts.

Cholangioscopy may be useful in determining whether a focal biliary stricture is benign or malignant.

• Of particular interest is whether cholangioscopy might be able to determine reliably whether a focal stricture is benign and thus avoid unnecessary surgery or reduce the extent of surgical resection.
  
• However, as benign focal hilar strictures are uncommon and the case series are small, good data on this point are lacking.
  
• MRI and cholangioscopic findings were found to be highly correlated with respect to determining the upper extent of the lesion, a finding which indicates that cholangioscopy may no longer be required for this purpose.
  
• Cholangioscopy may be of most value when the upper limit of the lesion is indefinite on MRI and the tumour is mucin producing.
  
• In this case, percutaneous cholangiography is hampered by the thick mucin.
  
• With cholangioscopy, the mucin may be aspirated and the upper limit of the tumour defined.

Magnetic resonance imaging

MRI has been increasingly favoured for the diagnosis and staging of hilar tumours as this one study can provide a clinical diagnosis.

• In terms of bile duct involvement, MRI cholangiography has the same sensitivity (80%) and specificity (100%) as ERCP for the detection of malignancy.
  
• Furthermore, MRI is far superior to ERCP in detecting the upper extent of the lesion, for the reasons noted above.
• On MRI, an MF hilar lesion appears as a nodule 1–2 cm in diameter.
  • The tumour is usually hypointense on T1-weighted images but hyperintense on T2-weighted images.
    
• In the PI type, the tumour appears as a concentric, sometimes irregular, thickening with gradual or abrupt transition to normal duct.
  • The periductal tissue may appear to be invaded, and lymph node metastases are frequently seen.
    
• The IG type is seen as an intraductal enhancing mass confined to the lumen of the bile duct.
  • It may have a rounded or bullet shape or appear as a cast of the duct.
    
  • Usually, the bile duct wall can be visualized where it passes around the mass, i.e. as the tumour does not penetrate the duct, the outer bile duct margin is intact.
    
  • Portions of the tumour may break off and be seen in the lower ducts.
    
  • There may be multiple tumours along different segments of the bile ducts.
    
• In all three morphological types, obstruction of the bile duct is usually present so that the bile ducts peripheral to the tumour are dilated, although they usually display normal wall thickness.
  
• When atrophy has been induced in a hemiliver or hepatic section, the dilated bile ducts will make up much of the residual volume of the affected part, giving the appearance of ‘crowding’ of the ducts.
  
• Sometimes, MRI cholangiography may not give the fine detail required for surgical staging.
  • This is especially true when the tumour appears to encroach on sectional ducts on the side to be retained.
    
• Direct cholangiography by PTC remains superior to MRI when this level of detail is needed.
  
• MRI also accurately depicts the extent of liver invasion and secondary tumours in the liver.

Computerized tomography

• The typical PI cholangiocarcinoma is seen on the portal or delayed phases as an enhancing thickened bile duct and the MF type as a hypoattenuating mass.
  
• While usual spiral CT images have not been able to stage hilar cholangiocarcinomas with the detail provided by MRI, the newer multidetector row CT scanners provide high-quality images of the biliary tree and blood vessels after administration of intravenous contrast agents.
  
• These images provide the same information as MRI images.
  
• A disadvantage of the agents used in CT is that they are nephrotoxic, unlike MRI contrast agents, a feature that may be of importance, particularly in elderly patients.
  
• Thin section CT accurately predicted the upper extent of PG-type hilar tumours in 65% of cases in one study.
  

Ultrasonography

• Sonography may detect all three types of hilar cholangiocarcinoma and is generally more sensitive in the hilum than at lower levels of the biliary tree, where intestinal gas is more likely to interfere with visibility.
  
• It can often display the extent of the tumour in the biliary tree.
  
• Flow Doppler sonography is particularly useful for defining vascular invasion.
  
• The disadvantages of sonography is that it is more operator dependent than axial imaging techniques and its images are somewhat more difficult for the surgeon to use as a guide in the operating room.
  

Positron emission tomography (PET)
The role of 2-[18F]fluoro-2-deoxy-d-glucose (FDG)-PET in the diagnosis and staging of cholangiocarcinoma is incompletely investigated. At present, it is not a standard part of preoperative investigation.

Endoscopic ultrasound —

• For distal bile duct lesions, endoscopic ultrasound (EUS) can visualize the local extent of the primary tumor, and the status of regional lymph nodes.
  
• EUS-guided fine needle biopsy of tumors and enlarged nodes can also be performed. EUS with fine needle aspiration biopsy has a greater sensitivity for detecting malignancy in distal tumors than does ERCP with brushings.
  
• This technique also avoids contamination of the biliary tree, which can occur with ERCP.

Angiography

Angiography can accurately document vascular encasement or thrombosis of the portal vein and hepatic artery. However, with the advent of multiphasic CT and MRCP, it is rarely necessary before surgery.

Establishing a preoperative tissue diagnosis

The necessity of establishing a tissue diagnosis prior to surgery depends upon the clinical situation.

• It is not critical for planning surgery in patients with characteristic findings of malignant hilar biliary obstruction, and may not be necessary for planning palliative therapy, such as biliary drainage, in unresectable cases.

Tissue diagnosis is most important in the following circumstances :

• Strictures of clinically indeterminate origin (eg, in patients with a history of biliary tract surgery, bile duct stones, or PSC).

• A situation where the physician or patient would be reluctant to proceed with surgery without a tissue diagnosis, or if the patient's or family's acceptance and adjustment to the diagnosis would be facilitated by having a definitive diagnosis.

• Prior to chemotherapy or radiation therapy, particularly if the patient will be enrolling on a therapeutic clinical trial.

Staging laparoscopy

Despite the enhanced diagnostic capability of newer radiologic studies such as MRCP and dynamic CT, unless there is clear evidence of metastatic disease, true resectability can be determined only by operative evaluation.

• Laparoscopy can identify the majority of patients with unresectable hilar and distal cholangiocarcinoma, thereby reducing the number of unnecessary laparotomies.
  
• However, true resectability can often be determined only after a complete abdominal exploration.