Cholangiocarcinoma

Synonyms and related keywords: cholangiocarcinoma, CCC, biliary duct system, perihilar tumors, Klatskin tumors, adenocarcinoma, primary sclerosing cholangitis, PSC


INTRODUCTION

Background: Cholangiocarcinomas (CCCs) are malignancies of the biliary duct system that may originate in the liver and extrahepatic bile ducts, which terminate at the ampulla of Vater. CCCs are encountered in 3 geographic regions: intrahepatic, extrahepatic (ie, perihilar), and distal extrahepatic. Perihilar tumors are the most common, and intrahepatic tumors are the least common. Perihilar tumors, also called Klatskin tumors (after Klatskin's description of them in 1965), occur at the bifurcation of right and left hepatic ducts. Distal extrahepatic tumors are located from the upper border of the pancreas to the ampulla. More than 95% of these tumors are ductal adenocarcinomas; many patients present with unresectable or metastatic disease.

Pathophysiology: Cholangiocarcinoma is a tumor that arises 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.

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:

• In the US: Each year, approximately 2500 cases occur, compared to 5000 cases of gallbladder cancer and 15,000 cases of hepatocellular cancer. Average incidence is 1 case per 100,000 persons per year.

• Internationally: Incidence in most Western countries ranges from 2-6 cases per 100,000 people per year. The highest incidences are in Japan at 5.5 cases per 100,000 people and in Israel at 7.3 cases per 100,000 people.

Mortality/Morbidity: Despite aggressive anticancer therapy and interventional supportive care (ie, wall stents or percutaneous biliary drainage), median survival rate is low since most patients (90%) are not eligible for curative resection.

Race: Native Americans have the highest occurrence rate in North America at 6.5 cases per 100,000 people. The high prevalence of cholangiocarcinoma among people of Asian decent is attributable to endemic chronic parasitic infestation.

Sex: The male-to-female ratio is 1.5:1.

Age: Highest prevalence rate occurs in patients aged approximately 60 years.

CLINICAL

History: Symptoms may include jaundice, clay-colored stools, bilirubinuria (dark urine), pruritus, weight loss, and 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 tends 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 (CCC). Pruritus may be related to circulating bile acids.

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

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

Physical:

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

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

Causes: The etiology of most bile duct cancers remains undetermined. Currently, gallstones are not believed to increase the risk of CCC. 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 CCC.

• Other parasites, including Ascaris lumbricoides, have been implicated in the pathogenesis.

• Inflammatory bowel disease

• A strong relationship exists between CCC and PSC. CCC generally develops in patients with long-standing ulcerative colitis and PSC.

• The lifetime risk of developing this cancer in the setting of PSC is 10-20%. At increased risk are patients with ulcerative colitis without symptomatic PSC 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 among workers in the aircraft, rubber, and wood finishing industries.

• CCC occasionally has developed years after administration of the radiopaque medium thorium dioxide (ie, thorotrast).

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

• Other conditions rarely associated with CCC include bile duct adenomas, biliary papillomatosis, and alpha1-antitrypsin deficiency.

DIFFERENTIALS

Bile Duct Strictures
Bile Duct Tumors
Biliary Disease
Biliary Obstruction
Cholangitis
Cholecystitis
Choledochal Cysts
Choledocholithiasis
Cholelithiasis

Other Problems to be Considered:

Cholangiohepatitis

WORKUP

Lab Studies:

• Routine labs

• Extrahepatic cholestasis is reflected in elevated conjugated (ie, direct) bilirubin. Alkaline phosphatase usually rises in conjunction with bilirubin. As 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, PT can become elevated from 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 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 benign cholestasis. A serum CA 19-9 level greater than 100 U/mL (normal less than 40 U/mL) has 75% sensitivity and 80% specificity in identifying patients with PSC who have CCC.

• An index of markers, carcinoembryonic antigen (CEA) and CA19-9, using the formula (CA19-9 + [CEA x 40]) in PSC, has an accuracy of 86% in diagnosis.

• Cholangiocarcinoma (CCC) does not produce alpha-fetoprotein (AFP).

Imaging Studies:

• A number of potential imaging modalities are available. In general, ultrasound or computed tomography (CT) scan is performed initially, followed by a type of cholangiography.

• Ultrasound may demonstrate biliary ductal dilatation and larger hilar lesions.

• Small lesions and distal CCCs are difficult to visualize.

• Patients with underlying PSC may have limited ductal dilatation secondary to ductal fibrosis.

• Doppler ultrasound may show vascular encasement or thrombosis.

• CT scan resembles ultrasound in that it may demonstrate ductal dilatation and large mass lesions.

• CT scan also has the capability to evaluate for pathologic intraabdominal lymphadenopathy.

• Helical CT scans are accurate in diagnosing the level of biliary obstruction. 3D and multiphase CT images may improve CT yield.

• MRI demonstrates hepatic parenchyma.

• MR cholangiography enables imaging bile ducts and, in combination with MR angiography, permits staging (excluding vascular involvement).

• 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. Small lesions (ie, less than 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 metastasis (Petrowsky, 2006)

• 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.

• 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 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 lumens 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 for dominant strictures in PSC are rather poor.

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

TREATMENT

Medical Care:

• Stenting may relieve pruritus and improve quality of life.

• Palliative plastic or metal stents can be placed by ERCP or PTC to relieve biliary obstruction. They 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.
• 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.

• Photodynamic therapy (PDT) is a new experimental local cancer therapy already in use for other GI malignancies.
  • PDT is a 2-step process: the first step is intravenous (IV) administration of a photosensitizer; the second step is activation by light illumination at an appropriate wavelength.
  • PDT is effective in restoring biliary drainage and improving quality of life in patients with nonresectable disseminated cholangiocarcinomas (CCCs). Survival times may be longer than those reported previously. A recent prospective, multicenter study showed a significant survival benefit in the PDT treatment group (Ortner, 2003). An additional multicenter study is being planned.
  • In addition, other endoscopic forms of palliation, such as brachytherapy, have been used (Simmons, 2006).

• 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.
• 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.
• The value of adjuvant radiotherapy has been to improve local control, with variable effect on overall survival rate 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]).
  

• Primary radiotherapy without surgery, with or without chemotherapy, has provided a survival advantage and significant palliation over stent placement or bypass surgery alone in patients with medially inoperable or unresectable tumors.
• Chemotherapy agents used without radiotherapy or surgery do not appear to provide any local control or meaningful survival benefit.
• The most used agent is 5-fluorouracil, but many agents have been tested in phase I/II trials. Partial responses, lasting from weeks to months, have been observed in 10-35% of trials (Thongprasert, 2005).
• For palliative treatment, celiac-plexus block via regional injection of alcohol or other sclerosing agent can relieve pain in the mid back associated with retroperitoneal tumor growth.

Surgical Care: 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 considered for curative resection. Intrahepatic and Klatskin tumors require liver resection, which may not be an option for older patients with comorbid conditions. In a recent series report, 15% of patients with proximal lesions were candidates for complete resections, with higher rates in patients with mid ductal (33%) or distal tumors (56%). 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. A more recent study has demonstrated a 5-year survival rate greater than 80% in select patients.

• 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, regional node failure rate is approximately 50% and distal metastases rate 30-40%. Failures are correlated with TNM stage.

• 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 common bile duct, should be performed.

Consultations: 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 CCC since the early 1980s.

FOLLOW-UP

Further Outpatient Care:

• Most patients with cholangiocarcinoma (CCC) 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 may enter hospice programs rapidly, as median survival duration is only 2-8 months.

Complications:

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

• Ten to 20% of patients with CCC develop cirrhosis. This may be secondary biliary cirrhosis resulting from neoplastic obstruction of the bile ducts or related to underlying fibrosis from PSC.

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

Prognosis:

• 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.

• 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 PDT.

• The poorest prognosis is for the patient with unresectable disease, with or without overt metastatic disease, who can tolerate only palliative stent placement. These patients survive for only a few weeks.

MISCELLANEOUS

Medical/Legal Pitfalls:

• The diagnosis of cholangiocarcinoma should be considered in patients with obstructive jaundice.

• Absence of biliary ductal dilatation may be misleading in patients with long-standing sclerosing cholangitis. Fibrotic ducts may not dilate readily. In addition, the fibrotic nature of the stenosis may yield false-negative brush cytology results.