Cholangiocarcinoma Workup

Updated: Aug 30, 2018
  • Author: Peter E Darwin, MD; Chief Editor: N Joseph Espat, MD, MS, FACS  more...
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Workup

Laboratory Studies

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 hepatic function (ie, albumin, prothrombin time [PT]) are normal in early disease.

With prolonged obstruction, the prothrombin time (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. [15]

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.  [18]

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. [19]

Cholangiocarcinoma does not produce alpha-fetoprotein.

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Imaging Studies

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).

Tight stricture of a common hepatic duct in a pati Tight stricture of a common hepatic duct in a patient presenting with jaundice. Cytologic studies confirmed cholangiocarcinoma.

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.

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.

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.

New techniques

In preliminary evaluations, positron emission tomography (PET) has shown promise in diagnosing underlying PSC. [20] Small lesions (ie, < 1 cm) have been demonstrated. PET is accurate for detecting nodular carcinomas, but the sensitivity diminishes for infiltrating lesions. PET should be interpreted with caution in patients with PSC and stents in place. PET/CT has been shown to be valuable in detecting unsuspected distant metastases. [21]

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

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Procedures

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.

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Histologic Findings

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.

 

 

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Staging

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. [23]  See Biliary Tract Cancer Staging.

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

T - Primary tumor

TX

Primary tumor cannot be assessed

T0

No evidence of primary tumor

Tis

Carcinoma in situ (intraductal tumor)

T1

Solitary tumor without vascular invasion, ≤5 cm or > 5 cm

 

T1a

Solitary tumor ≤5 cm without vascular invasion

 

T1b

Solitary tumor > 5 cm without vascular invasion

T2

Solitary tumor with intrahepatic vascular invasion, or multiple tumors with or without vascular invasion

T3

Tumor perforating the visceral peritoneum

T4

Tumor involving local extrahepatic structures by direct invasion

N – Regional lymph nodes

NX

Regional lymph nodes cannot be assessed

N0

No regional lymph node metastasis

N1

Regional lymph node metastasis present

M – Distant metastasis

M0

No distant metastasis

M1

Distant metastasis present

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

T - Primary tumor

TX

Primary tumor cannot be assessed

T0

No evidence of primary tumor

Tis

Carcinoma in situ – high-grade dysplasia

T1

Tumor confined to the bile duct, with extension up to the muscle layer or fibrous tissue

T2

Tumor invades beyond the wall of the bile duct to surrounding adipose tissue, or tumor invades adjacent hepatic parenchyma

 

T2a

Tumor invades beyond the wall of the bile duct to surrounding adipose tissue

 

T2b

Tumor invades adjacent hepatic parenchyma

T3

Tumor invades unilateral branches of the portal vein or hepatic artery

T4

Tumor invades main portal vein or its branches bilaterally, or the common hepatic artery; or unilateral second-order biliary radicals bilaterally with contralateral portal vein or hepatic artery involvement

N – Regional lymph nodes

NX

Regional lymph nodes cannot be assessed

N0

No regional lymph node metastasis

N1

One to three positive lymph nodes typically involving the hilar, cystic duct, common bile duct, hepatic artery, posterior pancreatoduodenal, and portal vein lymph nodes

N2

Four or more positive lymph nodes from the sites described for N1

M – Distant metastasis

M0

No distant metastasis

M1

Distant metastasis 

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

T - Primary tumor

TX

Primary tumor cannot be assessed

T0

No evidence of primary tumor

Tis

Carcinoma in situ – high-grade dysplasia

T1

Tumor invades the bile duct wall with a depth less than 5 m

T2

Tumor invades the bile duct wall with a depth of 5–12 m

T3

Tumor invades the bile duct wall with a depth greater than 12 mm

T4

Tumor involves the celiac axis, superior mesenteric artery, and/or common hepatic artery

N – Regional lymph nodes

NX

Regional lymph nodes cannot be assessed

N0

No regional lymph node metastasis

N1

Metastasis in 1-3 regional lymph nodes

N2

Metastasis in ≥4 regional lymph nodes

M – Distant metastasis

M0

No distant metastasis

M1

Distant metastasis

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Angiography

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.

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