eMedicine Specialties > Oncology > Carcinomas of the Gastrointestinal Tract

Cholangiocarcinoma: Differential Diagnoses & Workup

Author: Peter E Darwin, MD, Associate Professor, Director of GI Endoscopy, Department of Medicine, Division of Gastroenterology, University of Maryland School of Medicine
Coauthor(s): Andrew Scott Kennedy, MD, Co-Medical Director, Wake Radiology Oncology; Jennifer Lynn Bonheur, MD, Attending Physician, Division of Gastroenterology, Lenox Hill Hospital
Contributor Information and Disclosures

Updated: Jan 8, 2009

Differential Diagnoses

Other Problems to Be Considered

Cholangiohepatitis

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.
  • 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), in which clinical features and imaging findings overlap.
  • 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.⁹
  • In PSC, an index of markers, carcinoembryonic antigen (CEA) and CA 19-9, has an accuracy of 86% using the following formula: CA 19-9 + (CEA × 40).
  • Cholangiocarcinoma does not produce alpha-fetoprotein.

Imaging Studies

• A number of potential imaging modalities are available (see Image 2). In general, ultrasonography or computed tomography (CT) is performed initially, followed by a type of cholangiography.
• 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
  • Preliminary evaluation with positron emission tomography (PET) has shown promise in diagnosing underlying PSC.¹⁰ 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.¹¹
  • Endoscopic ultrasonography (EUS) enables both bile duct visualization and nodal evaluation. This technique also has the capability to aspirate for cytologic studies. EUS-guided fine-needle aspiration results may be positive when other diagnostic tests are inconclusive.¹²
  • Intraductal EUS allows direct ultrasonographic evaluation of the lesion.
• Cholangiography includes MR cholangiography (as noted above), endoscopic retrograde cholangiopancreatography (ERCP), and percutaneous transhepatic cholangiography (PTC).

Other Tests

• Angiography: Evaluation of vascular involvement is important if considering surgical treatment. 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.

Procedures

• 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.
• 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 EUS fine-needle aspiration.

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. It tends 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.

Staging

The American Joint Committee on Cancer guidelines in the AJCC Cancer Staging Manual, Fifth Edition, following the tumor, node, and metastasis (TNM) classification system, with depth of tumor penetration and regional spread defined pathologically, should be followed.

• T - Primary tumor
  • TX - Primary tumor cannot be assessed
  • T0 - No evidence of primary tumor
  • TIS - Carcinoma in situ
  • T1a - Tumor invades mucosa
  • T1b - Tumor invades muscularis
  • T2 - Tumor invades perimuscular connective tissue
  • T3 - Tumor invades liver, gallbladder, duodenum, stomach, pancreas, or colon
• N - Regional lymph nodes
  • NX - Regional lymph nodes cannot be assessed
  • N0 - No metastases in regional lymph nodes
  • N1 - Metastases in cystic duct or pericholedochal or hilar lymph nodes of hepatoduodenal ligament
  • N2 - Metastases in peripancreatic (head only), periduodenal, posterior pancreatoduodenal, periportal, celiac, or superior mesenteric regional lymph nodes
• M - Metastasis
  • MX - Presence of metastases cannot be assessed
  • M0 - No distant metastases
  • M1 - Distant metastases (includes lymph node metastases beyond N2)
• TNM groupings by stage
  • Stage 0 - TIS N0 M0
  • Stage I - T1 N0 M0
  • Stage II - T2 N0 M0
  • Stage III - T1-2 N1-2 M0
  • Stage IVa - T3 N0-2 M0
  • Stage IVb - T1-3 N0-2 M1

• Search for CME/CE on This Topic »

• Cholangiocarcinoma (Radiology)
• Gallbladder Cancer (Oncology)
• Bile Duct Tumors (General Surgery)
• Inflammatory Bowel Disease (Gastroenterology)

• High-Dose Ursodeoxycholic Acid May Worsen Outcome of Cholangitis

• Endothelin inhibits cholangiocarcinoma growth by a decrease in the vascular endothelial growth factor expression
• Endoscopic Tissue Diagnosis of Cholangiocarcinoma
• Digestive Cancer in the Elderly