Gastroenterology Hepatology

Cholangiocarcinoma

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How can I be sure that the patient has cholangiocarcinoma?

The symptoms seen in a patient with cholangiocarcinoma can be variable. Initially, patients are typically asymptomatic. Since these tumors usually become symptomatic only when they begin to obstruct the bile ducts, symptoms are more likely to accompany advanced disease. Constitutional symptoms such as anorexia, fatigue, and malaise are often the initial symptoms. In addition, pruritus can be seen in up to 60% of patients, and weight loss in 30% to 50%.

Less common, patients may experience abdominal pain (20-50%), and this pain is described as a dull pain located in the right upper quadrant (RUQ). Fever can be seen in up to 20% of cases, but cholangitis is not common in the absence of endoscopic manipulation. Other symptoms include nausea, vomiting, and diarrhea. In more advanced disease, once the bilirubin is significantly elevated and the patient is jaundiced, the patient may also report clay-colored stools and dark urine.

The initial symptoms and timing of presentation will depend to some degree on the location of the tumor. Since a more proximal cholangiocarcinoma obstructs the drainage of a smaller portion of the liver, the symptoms may be less marked and present later. This is particularly true if the lesion is more peripheral. Therefore, an intrahepatic cholangiocarcinoma located in a more peripheral duct is less likely to cause significant symptoms, whereas an extrahepatic cholangiocarcinoma (which is responsible for draining the entire liver parenchyma) is more likely to present with symptoms and jaundice.

Similarly, the signs of cholangiocarcinoma are usually minimal and not seen until the tumor grows and starts to block the bile duct. On physical exam, jaundice is the most common finding and is seen in up to 90% of cases. Other signs include hepatomegaly (25-40%), RUQ mass (10%), and, rarely, a Courvoisier's sign (distended, palpable gallbladder in a jaundiced patient) can be seen. Of note, the patient's jaundice is usually a painless jaundice or, less frequently, is accompanied by a dull RUQ pain. This differs from the sharper pain that accompanies jaundice caused by stone disease.

A tabular or chart listing of features and signs and symptoms

While there are no pathognomonic or characteristic features suggestive of cholangiocarcinoma, signs and symptoms that can be seen are listed below. It should also be emphasized that the most common initial presentation is an asymptomatic patient with no associated sign and symptom.

Symptoms: more common

– Weight loss

– Anorexia

– Fatigue

– Pruritus

Symptoms: less common

– Dull RUQ pain

– Nausea

– Vomiting

– Diarrhea

– Fever

Signs: more common

– Jaundice

– Dark urine

– Clay-colored stools

Sign: less Common

– Courvoisier's sign

Differential diagnoses

Pancreatic cancer. Can often be differentiated using imaging with pancreatic protocol demonstrating a mass.

Pancreatitis. Usually accompanied by significant pain and pancreatic abnormalities on cross-sectional imaging, and significant elevations in amylase and lipase in acute pancreatitis. In chronic pancreatitis, amylase and lipase may not be significantly elevated, computed tomography (CT) scan should demonstrate findings consistent with chronic pancreatitis, such as calcifications.

Choledocholithiasis. Magnetic resonance cholangiopancreatography (MRCP), endoscopic ultrasound (EUS), or endoscopic retrograde cholangiopancreatography (ERCP) should be able to detect common bile duct (CBD) stones. Can be missed on CT scan or abdominal ultrasonography.

Hepatitis. Usually a more significant increase in transaminases. Usually, no stricture or mass is noted on imaging.

Autoimmune pancreatitis or overlap syndrome. A stricture or even mass-like appearance can be noted on imaging. Often accompanied by an elevation in serum IGG4.

Sclerosing cholangitis. May be associated with ulcerative colitis. Primary sclerosing cholangitis (PSC) and cholangiocarcinoma can overlap, so a high index of suspicion must be maintained (see above).

Flu-like illness. Often the other associated symptoms. Imaging should not demonstrate any pancreatobiliary abnormalities.

How can I confirm the diagnosis?

Due to the often vague nature of the patient's symptoms and their late presentation, a high index of suspicion must be maintained in order to make a timely diagnosis. Initial tests include blood work for liver function tests.

Liver function tests

Depending on the level of the tumor (and therefore the level of the biliary obstruction), serum levels of bilirubin, alkaline phosphatase, and gamma-glutamyltransferase (GGT) will be elevated, whereas the aminotransferase levels will be minimally affected. Another less commonly used laboratory test, 5' nucleotidase, may also be elevated. The more peripheral an intrahepatic tumor is, the more likely is there an isolated elevation of the alkaline phosphatase and GGT independent of the bilirubin. Tumor markers should not be ordered in the initial panel of blood work because these lack both sensitivity and specificity.

After obtaining blood work, radiographic studies are essential in the evaluation for possible masses or strictures and to rule out other disease processes, such as stone disease that could be causing the patient's symptoms or blood work abnormalities. Which test to proceed with is often center-dependent, based on local expertise and experience.

Abdominal ultrasound

Abdominal ultrasound is often the first radiographic test ordered because it is inexpensive and noninvasive. Ultrasound can be useful to confirm biliary ductal dilation. It can localize the site of biliary obstruction by determining the level of transition from normal-caliber bile duct to dilated ducts. In addition, it can be used to exclude entities related to cholelithiasis, such as cholecystitis. An obstructing lesion is suggested by ductal dilation in the absence of stone disease.

Computed tomography

Computed tomography (CT) scan has proven to be an invaluable tool in the evaluation of a possible cholangiocarcinoma due to its widespread availability and ability to evaluate the bile ducts, liver parenchyma, and vasculature and lymph nodes. Contrast-enhanced triple-phase helical or dynamic CT increases the yield of this study.

CT is useful for detecting the level of biliary obstruction and for evaluating the liver parenchyma for intrahepatic masses/ tumors, the presence of liver atrophy, vascular invasion, and lymph node metastases. In addition, in the jaundiced patient, a pancreatic protocol can also be incorporated if clinically indicated to rule out a pancreatic process, such as cancer.

A major limitation associated with CT scan includes intravenous contrast administration, which can be a relative or absolute contraindication in patients with renal impairment. CT scan performed without IV contrast is not considered to be adequate.

Magnetic resonance imaging

While magnetic resonance imaging (MRI) with MRCP is not as readily available as CT scan, it is emerging as an excellent tool to evaluate patients with jaundice of unclear etiology and to evaluate patients with suspected cholangiocarcinoma prior to surgery. Similar to CT scan, MRI can provide imaging of the liver parenchyma and detect intrahepatic or pancreatic lesions. In addition, it can create a three-dimensional image of the biliary tree and vascular structures.

Several advantages of MRI include its ability to visualize and map the bile ducts noninvasively and without radiation exposure. It can sometimes locate a small mass or stricture even in the absence of significant bile duct dilation. A limitation of MRI, however, is that patients must be able to tolerate the test and stay still to help obtain adequate images. This is particularly difficult for patients who are claustrophobic, elderly, or ill and have difficulty lying flat. Open MRI's at this time, are not typically adequate in obtaining the images needed.

One also must not forget the potential concerns of using gadolinium in patients with renal impairment. Although MRCP can be performed without IV contrast, the MRI portion of the examination is not adequate without IV contrast.

CT scan versus MRI

Whether to proceed with CT scan or MRI is somewhat patient- and center-dependent. While there is insufficient data to compare the two modalities adequately, the authors believe that a good quality MRI with MRCP along with the appropriate liver protocol is superior to CT scan. In centers where MRI expertise is high, MRI with MRCP is generally a better test because it provides a more detailed roadmap over CT scan in the preoperative evaluation of cholangiocarcinoma.

On the other hand, for patients who are not surgical candidates or who cannot lie still for prolonged periods of time, or who are in centers where MRI expertise is not optimal, CT scan is an excellent imaging modality and usually can provide the information desired. Another option involving patients who cannot tolerate lying still for prolonged periods is for them to undergo CT scan first and then, if more detailed imaging is needed of the bile ducts, MRCP alone, without the remainder of the MRI exam, can be performed in 10 to 15 minutes. This is sometimes useful in patients with hilar lesions, details regarding degree of ductal involvement of which are needed.

Pathology

For patients who are clearly operative candidates and in whom a clear mass is seen, a preoperative tissue diagnosis is not always required. Indeed, biopsies are not 100% sensitive and can be associated with risks. For instance, ERCP carries a risk of pancreatitis and, to a lesser degree, bleeding. Percutaneous biopsy carries a higher risk of bleeding and a potential concern for seeding of tumor. In addition, both procedures can contaminate the biliary tree and put the patient at risk for preoperative cholangitis.

On the other hand, if preoperative drainage of the bile ducts is needed, then taking biopsies during the procedure adds minimal risk. The last point that must be made is that not every radiographically detected mass represents a biliary malignancy. Occasionally, autoimmune conditions, lymphomas, and metastatic malignancies can present with jaundice and mass-like appearances on imaging.

In the absence of a clear mass, however, even in the setting of a known stricture, biopsy is often desired over proceeding directly to surgery since up to one-third of bile duct stricture has been found to be associated with benign processes, such as PSC, autoimmune overlap syndromes, choledocholithiasis, or pancreatitis. In addition, the pancreatobiliary system can be a site for metastatic disease.

ERCP is the most common method used for tissue acquisition in the setting of bile duct strictures. The most commonly employed methods used during ERCP to obtain a cancer diagnosis are cytology on bile aspirate and brushings of strictures. Unfortunately, the diagnostic yield of these modalities is disappointing.

Bile aspirate will result in a positive cytology in about 30% of cholangiocarcinoma cases. The diagnostic yield from brushings varies and is reported to be between 35% and 69%. It has been shown that the yield will be in the higher part of this range if the epithelial layer of the stricture is disrupted. This has been accomplished in various ways, including dilating the stricture, taking biopsies of the stricture, and using a basket or other instruments to disturb the epithelial lining.

The addition of biopsies of the stricture either using biopsy forceps under fluoroscopic guidance or under direct visualization during choledochoscopy results in a yield of 43% to 88%. On an investigational level, two advanced cytologic techniques for detecting aneuploidy are FISH and DIA analysis of specimens.

FISH stands for "fluorescence in situ hybridization" and is a test performed on cytologic specimens that uses labeled DNA probes to detect abnormal loss or gain of chromosomes or chromosomal loci.

DIA stands for "digital imaging analysis" and quantifies the amount of cellular DNA by measuring the intensity of nuclei stained with Feulgen dye (a cytochemical stain that stoichiometrically binds to nuclear DNA).

The role of both FISH and DIA techniques in the diagnosis of cholangiocarcinoma is still under evaluation, but in limited studies, both DIA and FISH show promise in increasing the sensitivity of cytology in the detection of cholangiocarcinoma.

Other less commonly available tools that are in the armamentarium of endoscopists during ERCP include choledochoscopy, intraductal ultrasound (IDUS), and confocal microscopy. Choledochoscopy can be helpful not only in directing biopsies but also in providing direct visualization of the bile duct, and in detecting subtle changes in the lining of the wall of the bile duct, as well as nodules or masses.

It has been suggested that IDUS may help improve the accuracy of local tumor staging (by evaluating right hepatic artery, portal vein, and hepatoduodenal ligament) and more accurately determine the longitudinal tumor extent. In addition, various IDUS criteria have been proposed to help distinguish between malignant- and benign-appearing strictures in the bile ducts. Confocal imaging of the bile ducts at this point is still investigational and not widely available but holds promise as a helpful tool in differentiating malignant and benign strictures.

Other options for tissue acquisition include both CT-guided percutaneous biopsy and surgical biopsy. Unfortunately these biopsies are often difficult to perform and provide lower yield due to the small size of lesions. Another concern involving CT-guided biopsy is the potential for tumor seeding. Lastly, biopsies also can be obtained in the operating room during either laparoscopy or open surgical exploration.

Less commonly needed tests

Other less commonly used imaging modalities include position emission tomography (PET) scan, EUS, angiography, and staging laparoscopy.

Pet scans. These scans are sometimes able to detect cholangiocarcinomas because of the high glucose uptake of the bile duct epithelium. PET scans can potentially detect nodular cholangiocarcinomas that are approximately 1 cm in size or larger. A PET scan is not as successful, however, in the detection of infiltrating tumors as it is in the detection of mass-like tumors. In addition, metastases can sometimes be detected once they reach approximately 7 to 10 mm or more in diameter. Due to common false positive findings, and unacceptably low sensitivity and specificity rate, the role for routine PET scans in the diagnosis and evaluation of cholangiocarcinoma has not been established.

EUS. This can be used to evaluate distal bile duct lesions, particularly in the setting where biliary decompression (and therefore ERCP) is not required. In addition to visualizing the extent of the tumor, regional lymph nodes can be seen and sampled if needed. In addition, EUS can be used to sample liver lesions.

The role for EUS in the evaluation of proximal bile duct lesions is more challenging and less clear. In addition, EUS with side-viewing endoscopy is often utilized to visualize the ampulla in a patient with a dilated bile duct because the ampulla is known to be a radiologic "blind spot" and not well evaluated by cross-sectional imaging.

The disadvantage of EUS is that it is a procedure that requires sedation, but complications related to EUS itself are only minimally increased in comparison to standard endoscopy alone. EUS, however, can be particularly beneficial in patients with renal impairment who are not able to receive IV contrast during their cross-sectional imaging.

Angiography. Although angiography can be helpful in evaluating vascular involvement of the portal vein and hepatic artery, it has largely been replaced by CT scan and MRI.

ERCP. This is not routinely used as a diagnostic study in the preoperative evaluation of a patient with cholangiocarcinoma. When MRCP is available, it has largely replaced diagnostic ERCP. As a result, ERCP is now reserved for those cases that require tissue diagnosis during biliary decompression. (Refer to Pathology section for more information on ERCP.)

What tests should be used to confirm the initial tests?

After blood work, transabdominal ultrasound, CT scan, and/or MRI is performed routinely, depending on local expertise and clinical suspicion.

– If cholecystitis is suspected or if the goal is to evaluate for bile duct dilation, abdominal ultrasound is a good initial test.

– If there is a suspicion for choledocholithiasis, MRI with MRCP should be the next study.

– CT scan and MRI are comparable in evaluating most patients with suspected cholangiocarcinoma, although MRCP may provide additional information on the extent of a tumor, particularly in the evaluation of a Klatskin tumor.

What are useful tests if the diagnosis is still in doubt?

When the diagnosis remains in doubt, surgical exploration sometimes is needed to confirm the suspected diagnosis and evaluate for resectability.

Unfortunately, serum tumor markers are not commonly used because they lack both sensitivity and specificity. The two most commonly used tumor markers are CEA and CA 19-9. In addition, it is important to keep in mind that in patients with cholestasis or cholangitis, the CA 19-9 often will be elevated even in the setting of benign disease. For this reason, if the CA 19-9 is checked in the setting of cholestasis or cholangitis, it should be rechecked after biliary decompression and/ or recovery from cholangitis is achieved.

CA 19-9 has also been studied as an adjunct test to determine which patients with PSC and dominant strictures are at greater risk of harboring a malignancy. A cutoff value of 200 U/mL has been suggested in this clinical setting. Both markers, CEA and CA 19-9, can be elevated in many benign diseases as well. (See below.)

This algorithm is dependent on local expertise:

First: Blood work/liver function tests (LFTS).

Second:

– If any abnormalities in LFTs and/or suspicion remains for cholangiocarcinoma or another biliary process → perform transabdominal ultrasound to evaluate for bile duct dilation and level of obstruction and to rule out cholecystitis and choledocholithiasis.

Third:

– If suspicion is high for a distal bile duct lesion → proceed with dynamic CT scan with liver and pancreatic protocols or MRI with MRCP.

– If suspicion is high for proximal bile duct lesion or choledocholithiasis → perform MRI with MRCP with liver protocol. If MRI is not available → then proceed with dynamic CT scan with liver protocol.

– If suspicion is high for choledocholithiasis and MRI is not available → perform EUS +/- ERCP.

Fourth:

– If mass and stricture are seen, suspicion is high for cholangiocarcinoma, and the patient is a surgical candidate → proceed directly to surgery.

– If unclear on diagnosis or candidacy for surgery →consider biopsy via ERCP, EUS, or percutaneous route.

Although tumor markers are often followed in patients with PSC and dominant strictures, their routine use is not incorporated in the algorithm.

A listing of laboratory tests, radiographic studies, and endoscopic evaluations

Laboratory tests

LFTs. Aminotransferases, direct and indirect bilirubin, alkaline phosphatase.

With proximal or peripheral lesions, there may be an isolated elevation in alkaline phosphatase. In more distal lesions, an increase in bilirubin would be expected, as well. Aminotransferases should not be significantly elevated. In addition, amylase and lipase should not be significantly elevated.

Tumor markers (CEA and CA 19-9). These are not routinely checked because they lack sensitivity and specificity.

Radiographic studies

Transabdominal ultrasound. Ultrasound is useful for evaluation of cholelithiasis and bile duct dilation. Ultrasonography carries a 94% sensitivity for localizing the site/level of obstruction. A major limitation of ultrasonography concerns the evaluation of the common bile duct. Therefore, if choledocholithiasis is suspected, an MRCP is more useful. In addition, ultrasound cannot provide a detailed view of the bile ducts or liver parenchyma. Both CT scan and MRI are more useful in the evaluation of the liver parenchyma (particularly if a liver protocol is utilized). If a more detailed evaluation of the bile ducts is warranted, then MRCP is the procedure of choice and can sometimes locate a small mass or stricture even in the absence of significant bile duct dilation.

CT scan. This is a very useful tool, with widespread availability and ability to evaluate the bile ducts, liver parenchyma, and vasculature and lymph nodes.

MRI with MRCP. Similar to CT scan, MRI can provide imaging of the liver parenchyma and detect intrahepatic or pancreatic lesions, and vasculature and lymph nodes. In addition, it can create a three-dimensional image of the biliary tree and vascular structures. If available, MRI with MRCP may provide a more detailed map, particularly in patients with hilar lesions.

Less commonly used tests

PET scan. The PET scan lacks sensitivity and specificity, and is not routinely used. In the appropriate clinical setting, it can be helpful in detecting occult metastases

Angiography. This has largely been replaced by CT and MRI.

Endoscopic evaluations

ERCP. This is used if tissue diagnosis or biliary drainage is needed. Bile duct stricture can be visualized on fluoroscopy and, pending local expertise, direct visualization using choledochoscopy. A stricture can then be sampled and a stent can be placed.

EUS. This can be helpful in evaluating distal bile duct lesions and sampling lymph nodes, if needed. Examination of proximal lesions is more challenging, and therefore utility is less clear.

What other diseases, conditions, or complications should I look for in patients with cholangiocarcinoma?

Major risk factors for patients with cholangiocarcinoma

Although a specific risk factor for cholangiocarcinoma cannot always be identified, it does seem that chronic infection or inflammation of the biliary tree plays a significant role. This is similar to GI cancers in other parts of the body. In the United States and Europe, the main risk factors for the development of cholangiocarcinoma are PSC and choledochal cysts. In areas of Asia, however, infectious etiologies seem to play a bigger role.

PSC. An inflammatory disorder of the bile ducts that can lead to fibrosis and stricturing of the bile ducts. Almost one-third of cholangiocarcinomas are diagnosed in patients with PSC. Patients with PSC have a lifetime risk of 10% to 15% of developing cholangiocarcinoma. In addition, cholangiocarcinoma tends to develop at a significantly younger age in patients with PSC, ages 30 to 50 years.

Choledochal cysts. Congenital cystic dilations of the bile ducts. Patients who have these cysts have up to a 28% chance of developing cancer.

Cholelithiasis and hepatolithiasis. Although there appears to be an association between cholelithiasis and cholangiocarcinoma, it is not as strong as the association between cholelithiasis and gallbladder cancer. There is a clearer association, however, between cholangiocarcinoma and hepatolithiasis. While intrahepatic stone disease – independent of extrahepatic stone disease – is rare in the West, it is endemic in parts of Southeast Asia, hence the name Oriental cholangiohepatitis.

For instance, in Taiwan, 50% to 70% of patients undergoing resection for cholangiocarcinoma are found to have concomitant hepatolithiasis. While the etiology of these stones is not known, chronic inflammation from bacterial or parasitic infections have been implicated as have factors associated with diet and perhaps congenital ductal abnormalities. These stones are usually brown-pigment stones composed of calcium bilirubinate as opposed to the cholesterol stones seen more frequently in the West.

Parasitic infections. More commonly seen in Asia and, in particular, Thailand. Infection with liver flukes (Clonorchis and Opisthorchis) is associated with cholangiocarcinoma in the intrahepatic ducts. Humans become infected by consuming undercooked fish, from which adult worms inhabit and lay eggs in the human bile ducts. This in turn results in a chronic inflammatory state in the bile ducts.

Genetic disorders (such as Lynch Syndrome and biliary papillomatosis). Associated with an increased risk of cholangiocarcinoma. Lynch syndrome, also known as HNPCC (hereditary nonpolyposis colon cancer syndrome) is an autosomal dominant condition that has been associated with an increased risk of hepatobiliary cancers.

Other cancers associated with Lynch syndrome include cancers of the colon, endometrium, ovary, stomach, small intestine, urinary tract, brain, and skin. The increased risk of cancers in these patients is due to inherited mutations that impair DNA mismatch repair. Biliary papillomatosis is a rare, inherited disorder characterized by multiple adenomatous polyps in the bile ducts. Patients with this disorder commonly experience repeated episodes of abdominal pain, jaundice, and cholangitis.

Chronic liver disease. Associated with the development of intrahepatic cholangiocarcinoma. Both Hepatitis B and Hepatitis C viral infection have been associated with an increased risk of cholangiocarcinoma. In addition, chronic nonviral liver disease and liver cirrhosis, regardless of etiology, have also both been found to be risk factors for intrahepatic cholangiocarcinoma.

Toxic exposures. Determined to be a risk factor for cholangiocarcinoma. Exposure to the radiologic contrast agent, Thorotrast, was found to cause cholangiocarcinoma 30 to 35 years after exposure. There also seems to be an increased risk with exposure to rubber, wood finishing, and other chemical agents. The association between tobacco exposure and alcohol intake is less clear and the data are conflicting.

Commonly encountered complications

The complications of cholangiocarcinoma that are commonly encountered are usually related to either obstruction of the bile ducts or, less commonly, to involvement of the local vasculature. When the bile ducts become obstructed by a tumor, the liver parenchyma that depends on that bile duct for drainage will atrophy. If the cholangiocarcinoma (and therefore the level of the bile duct obstruction) is located more proximally and in the periphery, usually the affected segment of the liver will atrophy and another segment will hypertrophy. If, however, the lesion is located more distally, such as is seen in a distal cholangiocarcinoma or even in a hilar lesion, then a significant portion of liver parenchyma will not be able to drain and, in turn, this could lead to liver failure. Drainage of at least 25% to 30% of the liver is necessary to avoid liver failure.

Cholangiocarcinomas can also cause complications when they involve the local vasculature by either direct encasement or thrombosis of the hepatic arteries or portal vein.

Complications associated with cholangiocarcinoma

Biliary obstruction: High

Liver failure: Low, unless a distal biliary obstruction is left untreated

Portal vein involvement: Low; more likely with advanced disease

Hepatic artery involvement: Low; more likely with advanced disease

What is the right therapy for the patient with cholangiocarcinoma?

What treatment options are effective?

In general, cholangiocarcinoma has a very poor prognosis, with average 5-year survival rates of 5% to 10%. Surgical resection provides the only possibility for cure. The following general criteria are used to determine resectability:

-- Absence of retropancreatic and paraceliac nodal metastases

-- Absence of liver metastases

-- Absence of invasion of the portal vein or main hepatic artery (It should be noted that some centers perform en bloc resection with vascular reconstruction)

-- Absence of extrahepatic adjacent organ invasion

-- Absence of disseminated disease

In addition, the following conditions generally preclude resection:

-- For perihilar tumors: bilateral hepatic duct involvement up to the secondary radicles

-- Encasement or occlusion of the main portal vein proximal to its bifurcation

-- Atrophy of one liver lobe with encasement of the contralateral portal vein branch

-- Atrophy of one liver lobe with contralateral secondary biliary radicle involvement

-- Involvement of bilateral hepatic arteries

Even in patients who undergo a potentially curative resection, the literature suggests that tumor-free margins are obtained only in 50% of patients with distal cholangiocarcinomas and in 20% to 40% of patients with proximal tumors. Several advances have been made in surgical procedures that have resulted in higher success rates and significant decreases in morbidity and mortality within the last decade. Resectability rates have increased due in part to more aggressive operative strategies that have broadened the criteria for resectability.

Preoperative portal venous embolization is a widely accepted therapy to increase remnant hepatic volume. This is especially important when the future liver volume will be less than 20% of the total liver volume or in patients with less than 40% of the total liver volume, with a comprised liver parenchyma.

With regard to orthotropic liver transplantation, recent data have shown good survival rates and lower recurrence rates when transplantation is reserved for highly selected patients. In addition, while neoadjuvant and adjuvant therapy have not always been incorporated in the treatment of these patients, several retrospective studies have demonstrated that tumor recurrence was significantly lower in patients who received such therapy. At this point, further studies are required to determine whether such therapy provides benefit.

Unfortunately, the majority of patients present with unresectable disease and these patients have been shown to have dismal prognoses. There are few proven palliative treatment options. Decompression of the bile ducts has been shown to decrease morbidity and prolong survival in these patients.

Photodynamic therapy (PDT) is the first and only palliative treatment that has proven efficacy and safety to date. In a recent pilot study, however, radiofrequency ablation applied within the bile ducts during ERCP has shown early efficacy to improve patency and safety. Long-term follow up and randomized studies are still needed. The use of other treatment options such as chemotherapy and radiotherapy are still controversial and randomized studies are needed.

Options; lifestyle; medical, endoscopic, surgical; and other estimates of efficacy

Surgical

– Surgical resection with or without neoadjuvant or adjuvant therapy

– Surgical resection with preoperative portal venous embolization

– Liver transplantation

Endoscopic

– Stenting to provide biliary drainage

– Photodynamic therapy

– Radiofrequency ablation

Interventional radiology

– Percutaneous biliary drainage

Medical

– Chemotherapy

– Radiotherapy

Note: Surgical options are the most effective and the only chance for cure.

Neoadjuvant and adjuvant therapy with surgery may decrease tumor recurrence, but this has not been proven.

Preoperative portal vein embolization may increase chances of a negative margin and thus tumor recurrence in select cases.

What is the most effective initial therapy?

Initial therapy

The most effective initial therapy is surgical resection. Since surgery provides the only chance for cure, if a patient is diagnosed with resectable disease, a surgical resection should be offered. Preoperative portal venous embolization of the lobe involved with tumor is a widely accepted therapy to increase remnant hepatic volume. Orthotropic liver transplantation has shown good survival rates and lower recurrence rates when it is reserved for highly selected patients.

A complete caudate lobectomy and resection of the inferior part of Couinaud’s segment coupled with right or left hemihepatectomy has become the standard surgical procedure for hilar cholangiocarcinoma, and a Whipple operation is the first choice for distal bile duct cancer. Limited resection for middle bile duct cancer is indicated only for highly selected cases.

The authors reviewed several studies and the corresponding analyses on surgical resection for hilar bile duct cancer in these studies (Table I). A total of 2283 patients received surgery for mostly curative purposes, and 68% (mean range, 14-90%) of the patients achieved R0 resection. An overall 5-year survival rate in the range of 20% to 42% (mean 32%) has been reported. For patients whose resection was considered successful (R0), the 5-year survival rate was 32% (mean range, 22-62%). Operative mortality in the range of 0% to 15% (mean 5%) was reported.

Table I.

Review of the literature on hepatectomy for hilar bile duct cancer.

Unfortunately, several reports have demonstrated that recurrence rates after resection have been as high as 50% to 75%. Various factors have been found to effect the recurrence rate and prognosis after curative-intent surgery for cholangiocarcinoma. The most frequently reported factors that affect recurrence-free survival include resection margin status, histologic grade, pathology, extent of bile duct resection, perineural invasion, and nodal stage.

One method that has been thought to increase the chances of resectability and cure is to increase the remnant liver functional volume by performing portal vein embolization. By embolizing the portal vein, hypertrophy in a healthy liver occurs and therefore increases liver volume. Studies have reported that the volume of the future liver remnant increased significantly (up to 27.2% after embolization). Currently, it is believed that the patients who will benefit most from portal vein embolization are those with an anticipated future liver remnant volume that would be less than 20% of the total liver volume, or patients with compromised liver function when the anticipated future liver remnant volume is less than 40% of the total liver volume.

In attempts to address local relapse, adjuvant radiotherapy has been suggested as a reasonable therapeutic option after curative resection. Whether to provide neoadjuvant or adjuvant therapy to increase survival rates has been evaluated. Recently, some retrospective studies have demonstrated the benefits of adjuvant therapy. To date, there is no consensus of adjuvant or neoadjuvant therapy, and further studies are needed.

Postoperative therapy

The National Comprehensive Cancer Network (NCCN) updated guidelines for postoperative therapy in patients with cholangiocarcinoma suggest the following:

Extrahepatic cholangiocarcinoma

-- For patients with resected, margin-negative extrahepatic cholangiocarcinoma with negative regional nodes, observation, or fluoropyrimidine-based chemoradiotherapy are acceptable options.

-- For patients with positive regional lymph nodes, carcinoma in situ at the margins, or positive margins with invasive disease, fluoropyrimidine-based chemoradiotherapy should be considered.

Intrahepatic cholangiocarcinoma

-- For no residual local disease, no adjuvant therapy recommendations are made.

-- For patients with positive margins, options include re-resection, ablation, or fluoropyrimidine- or gemcitabine-based chemotherapy.

The European Society of Medical Oncology (ESMO) guidelines suggest the following:

– Supportive care or palliative chemotherapy and/or radiotherapy after a noncurative resection and consideration of postoperative chemoradiotherapy as an option after complete surgical resection in patients with either intrahepatic or extrahepatic cholangiocarcinoma.

Other therapeutic options

Another area of debate has been whether preoperative biliary drainage has proved to be beneficial in decreasing perioperative morbidity and mortality. Currently, preoperative drainage is believed to decrease perioperative morbidity and mortality in the presence of cholangitis, severe malnutrition, and coagulation abnormalities. Some centers advocate performing preoperative drainage when the bilirubin reaches the 10 to 15 range. Percutaneous drainage should be avoided after a recent study has demonstrated the possibility of tumor seeding. Therefore, every effort should be made to offer aggressive endoscopic biliary drainage.

There still is debate regarding bilateral versus unilateral biliary decompression. Current experts recommend "road mapping" with cross-sectional imaging, followed up by selective drainage of dilated segments.

Orthotopic liver transplantation (OLT) has been shown to be another surgical option and potentially offers the advantage of resection of all structures that may be involved by tumor, including portal vein, bilateral hepatic ducts, and atrophic liver lobes. Early experience with OLT for hilar cholangiocarcinoma was disappointing, with early recurrence rates of more than 50% and a 5-year survival rate of 10% to 20%.

Recently, however, several criteria for selection of patients suitable for liver transplantation have been suggested. In 2005, the Mayo Clinic group reported their 14-year experience of treating a highly selected group of patients with cholangiocarcinoma with a strict regimen of preoperative staging and neoadjuvant chemoradiation followed by OLT. In 38 patients who underwent this protocol, an 82% 5-year survival rate was reported (compared with 21% 5-year survival after resection, which included patients with nodal disease [P = 0.022]).

The inclusion criteria of the Mayo protocol include the following:

1. Locally advanced unresectable disease with positive intraluminal brush cytology, positive intraluminal biopsy, or CA 19-9, in the setting of a radiographic malignant stricture,

2. Primary sclerosing cholangitis with resectable disease,

3. Absence of medical contraindications for OLT.

The exclusion criteria include the following:

1. Extrahepatic disease including regional lymph node involvement,

2. Uncontrolled infection,

3. Prior attempt at resection,

4. Prior treatment with radiation or chemotherapy,

5. Previous malignancy within 5 years.

In conclusion, indication for OLT for the treatment of cholangiocarcinoma is reserved for highly selected patients in specialized centers.

Listing of usual initial therapeutic options, including guidelines for use, along with expected results of therapy.

Surgical resection. Should be offered systematically if a patient is a candidate for a curative resection.

Liver transplantation. Can be offered in lymph node negative disease confined to the bile duct or with patients with cirrhosis precluding partial hepatectomy.

A listing of a subset of second-line therapies, including guidelines for choosing and using these salvage therapies

Palliative management

The first goal in the palliative management of patients with nonresectable cholangiocarcinoma is to treat the biliary obstruction. This helps to preserve liver function and to reduce morbidity and mortality. Relieving biliary obstruction also helps alleviate symptoms, such as intractable pruritus. In addition, after successful biliary decompression, patients often report decreased malaise and increased appetite.

Maintaining hepatic function is also vital prior to beginning nonoperative therapies, such as chemotherapy or radiotherapy. Biliary drainage can be accomplished via surgical approaches, such as bypass surgery (hepaticojejunostomy), endoscopic stenting via ERCP, or stenting of the bile ducts via interventional radiologic/percutaneous approaches.

Success rates of endoscopic or percutaneous biliary decompression have been reported to be between 69% and 97%. When possible, ERCP is performed due to its relatively low complication rates and ability to provide internal biliary drainage. Percutaneous approaches often result in external drainage either temporarily or permanently, which can lead to significant patient dissatisfaction.

Operative approaches are associated with a significantly higher morbidity and mortality, with mortality rates between 7% and 24%. In addition, prolonged recovery from surgery can impact quality of life and delay chemotherapy.

In addition to providing biliary drainage, several modalities have been studies to increase stent patency and decrease tumor growth. One such modality is PDT, which is a local ablative therapy that is applied in the bile ducts. This involves the injection of intravenous porphyrin, a photosensitizer, followed by laser irradiation of a distinct wavelength in the tumor bed using cholangioscopy. PDT with biliary stenting has proven to be superior to biliary stenting alone in survival prolongation of patients with unresectable cholangiocarcinoma. (See Table II, which compares PDT vs. stent alone.) And it also has been proven that PDT can decrease cholestasis and improve quality of life. In a recent study about PDT using single operator cholangioscopy (SOC), median survival was not improved compared with a PDT-only group (168 vs. 200 days, respectively, p = 0.45) but a statistically significant decrease in fluoroscopy time (1 1.1 vs. 21.1 minutes, p<0.0001) was noted

Table II.

Comparative studies: PDT vs. stenting alone.

A significant disadvantage, however, of PDT is that the patient is considered photosensitive and must avoid sunlight. Another modality that does not involve photosensitivity is radiofrequency ablation. Very recently, Steel et al. performed a pilot study of endobiliary RFA to 22 patients with unresectable malignant bile duct obstruction. Of 21 patients receiving successful RFA, 16 patients showed patent stent at 90 days, and median stent patency day was 114 days (range 0-495). There were asymptomatic pancreatitis (n = 1), cholecystitis requiring percutaneous gallbladder drainage (n = 2), and rigor (n = 1) after procedure, but no procedure-related mortality. This report demonstrates 30-day safety and early efficacy data and shows that application of heat energy within a malignant bile duct can be safely performed. To prove efficacy of endobiliary RFA, further randomized studies with prolonged follow up are warranted.

Finally, palliative radiotherapy and chemotherapy have also been evaluated for patients with unresectable nonmetastatic tumors. Unfortunately, a recent study evaluating palliative radiotherapy did not demonstrate survival benefit. However, concurrent chemoradiotherapy with helical tomotherapy intensity-modulated radiotherapy and chemotherapy (capecitabine), in combination with PDT has been reported to be well tolerated in patients with hilar cholangiocarcinoma. Chemotherapy has limited effect on the course of this disease in the palliative setting. (See Table III.)

Table III.

Summary of previous Phase II chemotherapy studies in advanced cholangiocarcinoma.

So far, there is clearly no standard regimen identified that prolongs survival. Recently, gemcitabine has been suggested as an alternative for patients with unresectable CCA, but a survival benefit remains to be proven in a randomized controlled trial. Additional data are awaited for other targeted therapies, including anti-VEGF/R and multiple RTK inhibitors, such as sunitinib, lapatinib, sorafenib.

Listing of these, including any guidelines for monitoring side effects.

Watch for complications post procedure.

ERCP. Watch for pancreatitis or infectious complications with incomplete drainage. (The latter can be avoided using cross-sectional imaging as a guide prior to ERCP and avoiding injection of bile ducts that will not be targeted for drainage.) Bleeding post-sphincterotomy is a less common complication.

Percutaneous drainage. Watch for bleeding (immediate and delayed). Watch for infectious complications.

– Monitor for stent occlusion to avoid cholangitis.

– Monitor LFTs and CBC. Isolated elevation in alkaline phosphatase can be an early sign of stent occlusion.

PDT. Patients are photosensitive and need to be counseled on avoidance of sun exposure and the need to use sunblock, protective clothing, and sunglasses.

There seems to be an increased risk of cholangitis by induction of necrosis. Aggressive decompression is always advocated.

How should I monitor the patient with cholangiocarcinoma?

How should I monitor complications of cholangiocarcinoma?

– Monitor for stent occlusion to avoid cholangitis.

– Monitor LFTs and CBC. Isolated elevation in alkaline phosphatase can be an early sign of stent occlusion.

– Plastic stents need to be changed approximately every 3 months. Permanent metal stents may need manipulation, based on symptoms and liver tests.

– In patients who are considered resected and cured, repeat cross-sectional imaging should be performed in any patients with recurrent biliary symptoms.

Measures of disease progression

There is no current recommendation for monitoring of disease progression, which is typically based on the clinical presentation and the availability of cross-sectional imaging: CT scan versus MRI-MRCP.

What's the evidence?

Signs and symptoms of cholangiocarcinoma

Nakeeb, A, Pitt, HA, Sohn, TA. "Cholangiocarcinoma: a spectrum of intrahepatic, perihilar, and distal tumors". Ann Surg. vol. 224. 1996. pp. 463.

Diagnosis of cholangiocarcinoma

Siqueira, E, Schoen, RE, Silverman, W. "Detecting cholangiocarcinoma in patients with primary sclerosing cholangitis". Gastrointest Endosc. vol. 56. 2002. pp. 40.

(On PSC and cholangiocarcinoma.)

Manfredi, R, Barbaro, B, Masselli, G. "Magnetic resonance imaging of cholangiocarcinoma". Semin Liver Dis. vol. 24. 2004. pp. 155.

Baron, TH, Harewood, GC, Rumalla, A. " A prospective comparison of digital image analysis and routine cytology for the identification of malignancy in biliary tract strictures". Clin Gastroenterol Hepatol. vol. 2. 2004. pp. 214-19.

(On DIA.)

Kipp, BR, Stadheim, LM, Halling, SA. " A comparison of routine cytology and fluorescence in in situ hybridization for the detection of malignant bile duct strictures". Am J Gastroenterol. vol. 99. 2004. pp. 1675-81.

(On FISH.)

Anderson, CD, Rice, MH, Pinson, CW. "Fluorodeoxyglucose PET imaging in the evaluation of gallbladder carcinoma and cholangiocarcinoma". J Gastrointest Surg. vol. 8. 2004. pp. 90.

Treatment of cholangiocarcinoma

Hemming, AW, Reed, AI, Fujita, S. "Surgical management of hilar cholangiocarcinoma". Ann Surg. vol. 241. 2005. pp. 693-9.

Dinant, S, Gerhards, MF, Rauws, EA. "Improved outcome of resection of hilar cholangiocarcinoma (Klatskin tumor)". Ann Surg Oncol. vol. 13. 2006. pp. 872-80.

Baton, O, Azoulay, D, Adam, DV. "Major hepatectomy for hilar cholangiocarcinoma type 3 and 4: prognostic factors and long-term outcomes". J Am Coll Surg. vol. 204. 2007. pp. 250-60.

Tsao, JI, Nimura, Y, Kamiya, J. "Management of hilar cholangiocarcinoma: comparison of an American and a Japanese experience". Ann Surg. vol. 232. 2000. pp. 166.

Rea, DJ, Heimbach, JK, Rosen, CB. "Liver transplantation with neoadjuvant chemoradiation is more effective than resection for hilar cholangiocarcinoma". Ann Surg. vol. 242. 2005. pp. 451.

Sewnath, ME, Karsten, TM, Prins, MH. "A meta-analysis on the efficacy of preoperative biliary drainage for tumors causing obstructive jaundice". Ann Surg. vol. 236. 2002. pp. 17-27.

Kahaleh, M, Mishra, R, Shami, V. "Unresectable cholangiocarcinoma: comparison of survival in biliary stenting alone versus stenting with photodynamic therapy". Clin Gastro Hep. vol. 6. 2008. pp. 290-7.

Ortner. "Successful photodynamic therapy for nonresectable cholangiocarcinoma: a randomized prospective study". Gastroenterology. vol. 125. 2003. pp. 1355-63.

Wiedmann, M, Berr, F, Schiefke, I. "Photodynamic therapy in patients with non-resectable hilar cholangiocarcinoma: 5-year follow-up of a prospective phase II study". Gastrointest Endosc. vol. 60. 2004. pp. 68-75.

Bonet Beltrán, M, Abdelkarim, S, Allal, Ignasi, Gich. "Is adjuvant radiotherapy needed after curative resection of extrahepatic biliary tract cancers? A systematic review with a meta-analysis of observational studies". Cancer Treat Rev. vol. 38. 2012. pp. 111-19.

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