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.1,2,3,4 CCCs are encountered in 3 geographic regions: intrahepatic, extrahepatic (ie, perihilar), and distal extrahepatic. Perihilar tumors are the most common CCCs, and intrahepatic tumors are the least common. Perihilar tumors, also called Klatskin tumors (after Klatskin's description of them in 19655 ), occur at the bifurcation of right and left hepatic ducts.6 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.
Bismuth classification for perihilar cholangiocar...
Bismuth classification for perihilar cholangiocarcinoma. Shaded areas represent tumor location.
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Bismuth classification for perihilar cholangiocar...
Bismuth classification for perihilar cholangiocarcinoma. Shaded areas represent tumor location.
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. Intrahepatic cholangiocarcinoma may be associated with chronic ulcerative colitis and chronic cholecystitis.
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
United States
Each year, approximately 2500 cases of CCC 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.
International
Incidence in most Western countries ranges from 2 to 6 cases per 100,000 people per year. The highest annual 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. The overall survival is approximately 6 months.
Race
Native Americans have the highest annual incidence in North America, at 6.5 cases per 100,000 people. This rate is about 6 times higher than that in non – Native American populations. The high prevalence of cholangiocarcinoma in people of Asian descent is attributable to endemic chronic parasitic infestation.
Sex
The male-to-female ratio for cholangiocarcinoma is 1:2.5 in patients in their 60s and 70s and 1:15 in patients younger than 40 years. According to the American Cancer Society, the number of new cases of liver and intrahepatic bile duct cancer in 2007 is estimated to be 13,650 for men and 5,510 for women, with estimated mortality of 11,280 and 5,500, respectively. The estimated number of new cases of gallbladder and other biliary cancers (extrahepatic cholangiocarcinoma) are 4,380 for men and 4,870 for women, with estimated mortality rates of 1,260 and 1,990, respectively.7
Age
Highest prevalence rate occurs in males and females in their 60s and 70s.
Clinical
History
Symptoms of cholangiocarcinoma 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 tend 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. 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 cholangiocarcinoma 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 cholangiocarcinoma. Chronic viral hepatitis and cirrhosis also do not appear to be risk factors.
* Infections
o In Southeast Asia, chronic infections with liver flukes, Clonorchis sinensis, and Opisthorchis viverrini have been causally related to cholangiocarcinoma.
o Other parasites, such as Ascaris lumbricoides, have been implicated in the pathogenesis of cholangiocarcinoma.
o Observations have raised the possibility that bacterial infections with Helicobacter species may play an etiologic role in biliary cancer.8
* Inflammatory bowel disease
o A strong relationship exists between cholangiocarcinoma and primary sclerosing cholangitis. Cholangiocarcinoma generally develops in patients with long-standing ulcerative colitis and primary sclerosing cholangitis.9
o The lifetime risk of developing this cancer in the setting of primary sclerosing cholangitis is 10-20%. At increased risk are patients with ulcerative colitis without symptomatic primary sclerosing cholangitis and a small subset of patients with Crohn disease.
* Chemical exposures
o Certain chemical exposures have been implicated in the development of bile duct cancers, primarily in workers in the aircraft, rubber, and wood-finishing industries.
o Cholangiocarcinoma 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 cholangiocarcinoma.
* Other conditions rarely associated with cholangiocarcinoma include bile duct adenomas, biliary papillomatosis, and alpha 1 -antitrypsin deficiency.Differential Diagnoses
Bile Duct Strictures
Cholecystitis
Bile Duct Tumors
Choledochal Cysts
Biliary Disease
Choledocholithiasis
Biliary Obstruction
Cholelithiasis
Cholangitis
Other Problems to Be Considered
Cholangiohepatitis
Workup
Laboratory Studies
* Routine lab studies
o 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.
o 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.
o 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
o 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.
o 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
o 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).
o Cholangiocarcinoma does not produce alpha-fetoprotein.
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 a type of cholangiography.
*
Tight stricture of a common hepatic duct in a pat...
Tight stricture of a common hepatic duct in a patient presenting with jaundice. Cytologic studies confirmed cholangiocarcinoma.
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Tight stricture of a common hepatic duct in a pat...
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.
o Small lesions and distal cholangiocarcinomas are difficult to visualize.
o Patients with underlying primary sclerosing cholangitis (PSC) may have limited ductal dilatation secondary to ductal fibrosis.
o Doppler ultrasound may show vascular encasement or thrombosis.
* CT resembles ultrasound in that it may demonstrate ductal dilatation and large mass lesions.
o CT also has the capability to evaluate for pathologic intra-abdominal lymphadenopathy.
o 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.
o MR cholangiography enables imaging of bile ducts and, in combination with MR angiography, permits staging (excluding vascular involvement). Hepatic involvement can also be detected.
o This technique likely will replace angiography for vascular evaluation.
* New techniques
o 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
o 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
o 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.
o Brush cytology, biopsy, needle aspiration, and shave biopsies via ERCP can provide material for histologic studies.
o 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
o TX - Primary tumor cannot be assessed
o T0 - No evidence of primary tumor
o TIS - Carcinoma in situ
o T1a - Tumor invades mucosa
o T1b - Tumor invades muscularis
o T2 - Tumor invades perimuscular connective tissue
o T3 - Tumor invades liver, gallbladder, duodenum, stomach, pancreas, or colon
* N - Regional lymph nodes
o NX - Regional lymph nodes cannot be assessed
o N0 - No metastases in regional lymph nodes
o N1 - Metastases in cystic duct or pericholedochal or hilar lymph nodes of hepatoduodenal ligament
o N2 - Metastases in peripancreatic (head only), periduodenal, posterior pancreatoduodenal, periportal, celiac, or superior mesenteric regional lymph nodes
* M - Metastasis
o MX - Presence of metastases cannot be assessed
o M0 - No distant metastases
o M1 - Distant metastases (includes lymph node metastases beyond N2)
* TNM groupings by stage
o Stage 0 - TIS N0 M0
o Stage I - T1 N0 M0
o Stage II - T2 N0 M0
o Stage III - T1-2 N1-2 M0
o Stage IVa - T3 N0-2 M0
o Stage IVb - T1-3 N0-2 M1Treatment
Medical Care
* Stenting may relieve pruritus and improve quality of life.
o 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.
o Plastic stents usually occlude in 3 months and require replacement.
o 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.13,14
* 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.13,14
* PDT is effective in restoring biliary drainage and improving quality of life in patients with nonresectable disseminated cholangiocarcinomas. Survival times may be longer than those reported previously. A prospective, multicenter study showed a significant survival benefit in the PDT treatment group.13 An additional multicenter study is being planned.
* In addition, other endoscopic forms of palliation, such as brachytherapy, have been used.15
* 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.16,17
* 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]). See the image below for treatment planning technique.
*
Three-dimensional treatment planning uses CT scan...
Three-dimensional treatment planning uses CT scan slices to reconstruct the patient as a volume. Shown here is the display for planning external-beam radiotherapy to the cholangiocarcinoma (green structure). A biliary catheter (red tube) runs through the tumor volume and was used to deliver brachytherapy, which was given in addition to external-beam radiotherapy. Such technology has assisted greatly in the delivery of high doses to the tumor, while sparing vital normal structures, such as the kidney and spinal cord.
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Three-dimensional treatment planning uses CT scan...
Three-dimensional treatment planning uses CT scan slices to reconstruct the patient as a volume. Shown here is the display for planning external-beam radiotherapy to the cholangiocarcinoma (green structure). A biliary catheter (red tube) runs through the tumor volume and was used to deliver brachytherapy, which was given in addition to external-beam radiotherapy. Such technology has assisted greatly in the delivery of high doses to the tumor, while sparing vital normal structures, such as the kidney and spinal cord.
* 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, which has a partial response rate of about 12%. Gemcitabine has a similar response rate. Although fluoropyrimidines and doxorubicin have been reported to have response rates as high as 30-40%, partial responses lasting from weeks to months have been observed in only 10-35% of trials.16,17 Marimastat in early trials has been reported to be associated with a higher rate of response, but the number of patients treated with this agent is small. Overall, the duration of any response seen has been no better than 3-6 months, and median survival has been 11 months or less.
* For palliative treatment, celiac-plexus block via regional injection of alcohol or other sclerosing agent can relieve pain in the mid back that is 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 tumors6 require liver resection, which may not be an option for older patients with comorbid conditions. In one report, 15% of patients with proximal lesions were candidates for complete resections, with higher rates in patients with mid-ductal tumors (33%) or distal tumors (56%). The survival rate for patients with proximal tumors can be 40% if negative margins are obtained. The National Comprehensive Cancer Network suggests reresection, ablation, or chemotherapy for intrahepatic cholangiocarcinomas that are resected with microscopic margins or residual local disease.18 Those with no residual local disease after resection can be followed with imaging periodically.
* 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. One study has demonstrated a 5-year survival rate greater than 80% in select patients.19
* 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, the regional node failure rate is approximately 50%, and the distal metastases rate is 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 the 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 cholangiocarcinomas since the early 1980s.Follow-up
Further Outpatient Care
* Most patients with cholangiocarcinoma 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 cholangiocarcinoma and subsequent obstruction of the duct.
* Between 10 and 20% of patients with cholangiocarcinoma develop cirrhosis. This may be secondary biliary cirrhosis resulting from neoplastic obstruction of the bile ducts or related to underlying fibrosis from primary sclerosing cholangitis.
* 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 photodynamic therapy.
* The poorest prognosis is for the patient with unresectable disease, with or without overt metastatic disease, who can tolerate only palliative stent placement.
Miscellaneous
Medicolegal 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.
