What every physician needs to know:
Biliary tree cancers include tumors of the intrahepatic, extrahepatic and hilar biliary ducts (Klatskin tumors), and tumors of the gallbladder. Ampullary carcinomas are variably included in this group as well. Chronic inflammation of the gallbadder or bile ducts, whatever the cause, increases the risk for malignancy.
Clinical presentation is usually either biliary obstruction or anorexia and weight loss, which are associated with advanced disease. These tumors typically behave aggressively and present at an advanced stage. The only cure is complete surgical resection. In the advanced setting, chemotherapy has been shown to improve survival and quality of life.
Are you sure your patient has biliary tree cancer? What should you expect to find?
The presenting symptoms of biliary tree cancer depend upon the location of the tumor along the biliary tree. Biliary obstruction is the most common cause of symptoms and is associated with pruritis (66%), abdominal pain (30-50%), light colored stools, and dark urine.
The abdominal pain is generally described as dull and located in the right upper quadrant. Rarely, a patient may present with ascending cholangitis, typified by fever, right upper quadrant pain, jaundice and sometimes confusion. Fatigue and weight loss (30-50%) usually signal advanced stage disease. Mental status changes (encephalopathy) are also a sign of biliary obstruction and/or advanced disease.
Jaundice is the most common physical sign (90%) along with palpable hepatomegaly (25-40%) and a right upper quadrant mass on exam (10%). See Figure 1.
Beware of other conditions that can mimic biliary tree cancer:
Biliary tree cancers can be confused with several benign and malignant diseases.
Symptoms from gallbladder cancer (GBC) are frequently mistaken for much more common benign processes, such as cholelithiasis or cholecystitis.
Similarly, for cholangiocarcinoma, benign causes of biliary stricture should be considered as up to 33% of patients with symptoms suggesting biliary tree cancer are eventually diagnosed with a benign disease. Common benign causes of biliary obstruction are primary sclerolosing cholangitis, choledocholithiasis, post-operative complications, and pancreatitis.
Confidently distinguishing primary sclerosing cholangitis from cholangiocarcinoma may be particularly challenging since the chronic inflammation of primary sclerosing cholangitis (PSC) can appear radiologically and even pathologically similarly to malignancy.
Pancreatic cancers can present in the same fashion as biliary tree cancers. Intrahepatic biliary tree carcinoma can be mistaken for hepatocellular carcinoma, which has a very different management.
Additionally, other cancers can metastasize to the biliary region and can cause symptoms of biliary compression. The immunohistochemistry profile of biliary tree cancers is similar to other tumors derived from the embryologic foregut.
Typically biliary cancers are positive for CK7 and negative for TTF-1, CDX2 and CK 20, although this can be variable. Clinical correlation is essential to distinguish these tumors from breast, upper gastrointestinal tract, pancreas or even lung cancers.
Which individuals are most at risk for developing biliary tree cancer:
Anyone with an underlying condition that causes localized prolonged biliary inflammation is at increased risk for biliary tree cancer.
In the recent decades, extrahepatic cholangiocarcinoma has been decreasing while intrahepatic cholangiocarcinoma rates have been increasing in the U.S., Europe, Asia and Austrialia. The reasons for this trend are not completely clear. Cholangiocarcinoma is slightly more common among men and the risk increases progressively with age.
PSC is a significant risk factor for cholangiocarcinoma evidenced by the fact that 30% of all cholangiocarcinomas are diagnosed among patients with PSC. Liver fluke infestation, caused by Opisthorchis viverrini or Clonorchis sinensis, represents an infectious exposure risk factor for cholangiocarcinoma. Congenital biliary tree abnormalities, such as a choledochal cyst or pancreaticobiliary maljunction anomalies, are known risk factors for cholangiocarcinoma. And it has been suggested that hepatitis B and C, and HIV, confer a 6 times greater risk of intrahepatic cholangiocarcinoma.
Gallbladder cancer rates are increasing worldwide, likely reflecting the increasing rates of obesity. Chronic gallbladder inflammation is a risk factor whether it be caused by gallstones or infections. In the developing world, infections with Salmonella typhi and possibly Helicobacter place patients at an increased risk of gallbladder cancer. Patients with symptomatic gallstones are 34 times more likely to have gallbladder cancer than the average person.
Because of the relationship between chronic gallbladder disease and gallbladder cancer, there are varying rates epidemiologically. Gallbladder cancer becomes more common as people age and unlike cholangiocarcinoma, women are affected roughly 5 times more often than men.
South America and particularly Chile have comparatively high rates of gallbladder cancer. Moreover, in contrast to the general American population, gallbladder cancer is the most common GI malignancy among Mexican Americans and Southwestern Native Americans.
What laboratory and imaging studies should you order to characterize this patient's tumor (ie, stage, grade, CT/MRI vs PET/CT, cellular and molecular markers, immunophenotyping, etc.) How should you interpret the results and use them to establish prognosis and plan initial therapy?
Routine labs with liver function tests may reveal biliary obstruction. Tumor markers, specifically CA-19-9, CEA, and pyruvate kinase isoenzyme type M2 (M2-PK), may provide some information in the diagnosis of biliary tree cancer but are not specific for it, especially in the setting of cholangitis or cholestasis.
Ideally, these levels are drawn after biliary obstruction is relieved. They are best used in combination with imaging and biopsy results and may be helpful in monitoring a patient’s response to therapy. CA-19-9 is reported to be elevated in 85% of biliary tree cancers while CEA is elevated in about 30%.
While the screening accuracy of these assays vary widely in the literature, one series among patients with PSC demonstrated a serum CEA level greater than 5.2 ng/mL to have a sensitivity of 68% and specificity of 82%. In another series, also among PSC patients, CA-19-9 values above 63.2 U/mL provided 90% sensitivity, 98% specificity, and a positive predictive value of 42%.
Given the markedly elevated risk for cholangiocarcinoma among patients with PSC, many experts recommend surveillance with interval radiologic assessments such as magnetic resonance imaging (MRI), magnetic resonance cholangiopancreatography (MRCP), or ultrasound.
The staging of biliary tree cancers is primarily intended to define resectability in this highly vascular anatomic region. Imaging is the cornerstone of staging of biliary tree cancers. Frequently, abdominal ultrasound (US) is obtained initially. However, US is limited in detecting small tumors, defining potential resectability, and is operator dependant.
Contrast enhanced triple phase helical computed tomography (CT) is widely available and is useful in defining benign from malignant bile duct lesions. CT is only about 60% accurate in predicting a patient’s possibility of resection and it is not reliable to differentiate benign from malignant gallbladder pathology, see Figure 2.
The role of positon emission tomography (PET) is still undefined for biliary tree cancers. PET, in combination with CT has been reported in some series to better identify occult metastases. However, there have been other conflicting results which find that the additive benefit of PET is minimal, especially in the role of staging regional lymph nodes. Sensitivities and specificities for the use of PET scans vary widely, and false positive rates are notably concerning in the setting of biliary obstruction or PSC.
Magnetic resonance cholangiopancreatography (MRCP) is emerging as an important tool because it is non-invasive, does not require contrast and can reconstruct a three dimensional image of both the biliary tree and the surrounding vascular structures. Unfortunately, it too, can understage the extent of disease in up to 20% of cases. Moreover, in contrast to endoscopic approaches, procedures such as biopsy, stone extraction, or stent placement cannot be performed via MRCP.
Invasive imaging modalities include endoscopic retrograde cholangiopancreatography (ERCP), percutaneous transhepatic cholangiogram (PTC) and endoscopic ultrasound (EUS.) When an invasive procedure is required for biopsy or intervention upon the cholangiocarcinoma, an ERCP is typically performed for distal lesions while a PTC may be required for lesions inaccessible endoscopically. This decision is complex, taking into account the expertise of the proceduralist as well as the anatomic limitations from the disease.
It is advisable to perform ERCP upon patients with known PSC, if at all possible, because biliary stricturing makes it technically difficult to perform PTC. Biliary cytology (30% sensitivity), brushings (35-69% sensitive) and biopsy from suspected lesions (45-88% sensitivity) should be obtained.
Because of the low rates of detection, a negative study should not preclude a malignant diagnosis, and biopsy should be re-attempted either via repeat endoscopic guidance, percutaneous biopsy or in rare cases laparoscopically.
EUS is helpful to visualize possible lymph node involvement, vascular involvement of the tumor and it is possible to obtain both biopsies of the primary lesions and of the questionable lymph nodes. The biopsy data is very sensitive. EUS is sensitive (92%) and specific (88%) in diagnosing GBC and is emerging as a useful tool in this rare cancer. Since EUS requires specialized training and is not yet universally available, its appropriate role is still being determined.
TNM staging for biliary tree cancers are below. The staging varies mostly according to the anatomic location and invasion of the primary tumor.
See Table I TNM staging for intrahepatic bile duct cancer, Table II TNM staging for distal bile duct cancer, Table III TNM staging for gallbladder cancer.
What therapies should you initiate immediately ie, emergently?
Biliary obstruction with the risk of ascending cholangitis can be the initial presentation of biliary tree cancer. This can be a life-threatening situation. Abdominal imaging, usually an ultrasound or a CT is obtained and antibiotics that target gastrointestinal flora are indicated. An emergent gastroenterology consultation is also necessary to plan for likely ERCP to obtain a biopsy and possibly to mechanically stent the biliary duct.
What should the initial definitive therapy for the cancer be?
Complete surgical resection is the only cure for biliary tree cancers.
Surgery – cholangiocarcinoma
Surgical resectability of cholangiocarcinomas has been variably defined. In general, resectability requires no distant metastases, no retropancreatic or celiac node involvement, no involvement of the portal vein or the main hepatic artery and no extrahepatic invasion by the tumor.
Surgical resection is more difficult when tumors are closer to the liver and often, vascular involvement cannot be determined with imaging alone. Therefore, resectability is often ultimately decided at the time of exploratory surgery. Laparascopy may detect an additional one-third of patients who have an advanced malignancy.
For cholangiocarcinomas, selection of the best surgical procedure to obtain negative margins varies according to the location of the tumor along the biliary tract. For most distal cholangiocarcinomas, those nearer the duodenum, a pancreaticoduodenectomy i.e. Whipple procedure is required.
For hilar or more proximal cholangiocarcinomas, those near the liver, bile duct resection, hepatic resection and occasionally a hepatic lobectomy may be required to achieve a complete resection. Pre-operative portal vein embolization in order to induce hypertrophy of the portion of the liver that will remain after resection can be considered in selected patients as a method to permit larger liver resections.
Surgery – gallbladder cancer
Patients with gallbladder cancer are deemed unresectable if they have distant, liver or peritoneal metastases, if the great vessels are encased, or if the hepatoduodenal ligament is involved. Direct tumor invasion of an adjacent organ, such as liver or colon is not a contraindication to surgery.
During the last decade, improved survival rates among gallbladder cancer patients who have undergone resection has been observed presumably because of more aggressive surgical management, with a review estimating 5 year survival rates after resection, ranging from 42-81%.
Most gallbladder cancer is discovered during surgery or realized after cholecystectomy on pathologic review. If a cancer is suspected before surgery, an open surgical approach is recommended to permit a thorough assessment of surrounding structures and lymph nodes. There have also been reports of seeding of the laparoscopic port sites, again encouraging an open surgical approach with suspected malignancies.
Surgical options for gallbladder cancer include simple cholecystectomy, radical cholecystectomy and also possibly liver resection. Radical cholecystectomy entails removing the gallbladder, removing 2cm of the gallbladder bed, regional lymph node dissection and removal of the bile duct if the cystic duct margin is positive.
Adjuvant chemotherapy alone has no definitive role for biliary tree cancers. Retrospective trials using the combination of gemcitabine, mitomycin and 5-fluorouracil suggested improved survival for gallbladder cancer patients who had undergone non-curative surgery.
Other prospective trials have not demonstrated an improvement in recurrence free or overall survival. However, because these tumors are known to be responsive to chemotherapy in the metastatic setting, adjuvant chemotherapy is an active area of investigation, and clinical trial participation is encouraged.
Chemoradiation may have a role in the adjuvant setting for biliary tree cancers. Some experts recommend considering it among patients with positive surgical margins or with involved lymph nodes.
Adjuvant chemoradiotherapy regimen options include infusional 5-fluorouracil at 200-300 mg/m2;/day, Gemcitabine (1,000 mg/m2 weekly, or capecitabine 825-1500 mg/m2;/day as radiosensitizers. In this setting, a common radiation dose is 45 Gy administered over several weeks.
Some small retrospective studies suggest that neoadjuvant chemoradiation for biliary tree cancers may increase resectability rates and likewise overall survival; however this has not yet been confirmed prospectively.
Localized therapies can be considered for patients with locally advanced tumors for palliative purposes, although there are no randomized trials that prove benefit. The exact method used depends mostly upon the expertise of the local interventional radiologist. Radiofrequency ablation (RFA), transarterial bland chemoembolization (TACE) and radioablation using Y-90 are options.
Chemotherapy for advanced biliary tree cancer
Chemotherapy is active in advanced biliary tree cancers. When compared with best supportive care, 5-FU-based therapy improved median survival from 2.5 months to 6 months and there was an improvement in quality of life scores with chemotherapy as well.
Additional agents and combination chemotherapy have been explored for biliary cancers. A retrospective analysis showed that the highest historical response rates were achieved with either 5FU or gemcitabine, in combination with a platinum-based chemotherapy agent.
Prospectively, the ABC-02 trial randomized patients with advanced biliary tree cancers to either gemcitabine (1000 mg/m2; on days 1,8,15 every 28 days) or gemcitabine (1000 mg/m2😉 in combination with low-dose cisplatin (25 mg/m2😉 on days 1 and 8 given every 21 days for 8 cycles.
The combination arm demonstrated a significant improvement in survival without additional grade 3 or 4 toxicity compared to gemcitabine alone. Based on this, gemcitabine plus cisplatin is considered the front-line standard for advanced disease. Patients are typically treated until progression. Upon progression, or as a front-line alternative, there are many other active regimens:
mFOLFOX6: Oxaliplatin 85 mg/m2;, Leucovorin 400 mg/m2;, 5FU 400 mg/m2; bolus, and 5FU 2400 mg/m2; continuous infusion for 46 hours, every 14 days.
GEMOX: Gemcitabine 1000 mg/m2; on day 1 and oxaliplatin 100 mg/m2; on day 2 every 14 days.
Gem/Cape: Gemcitabine 1000 mg/m2; days 1, 8/capecitabine 650 mg/m2; BID for 14 days every 21 days.
Cape/Ox: Capcitabine 1000 mg/m2; BID for 14 days and oxalaplatin 130 mg/m2; on day 1.
Irinotecan as a single agent, can be given in a variety of ways, most often 350 mg/m2; every 21 days.
Single agent gemcitabine, 5FU, or capecitabine are also reasonable options for patients with marginal performance status.
What other therapies are helpful for reducing complications?
Patients who have biliary obstruction related to compression from the biliary tree cancer benefit from drainage by endoscopic or percutaneous stent placement. Stent placement is necessary to prevent ascending cholangitis and is effective for symptom palliation.
If possible, endoscopic stent placement is typically attempted first (>70% success) as this is preferable for patients in its avoidance of external drainage. If the biliary system cannot successfully be decompressed, percutaneous drainage is performed.
For patients whose candidacy for curative surgery has been ruled out with certainty and whose life expectancy is <6 months, permanent metal stents are often recommended, because they are less likely to occlude. For patients whose resectability is still being determined, plastic stents have traditionally been advised since they are easily removed. However, more frequently, metal stents are placed for patients who may become resectable with chemotherapy, and a successful oncologic resection can still be performed.
What should you tell the patient and the family about prognosis?
Historically, following resection of cholangiocarcinomas, 5-year survival rates range from 23-50% for distal tumors and 15-40% for hilar or proximal biliary tumors. Patients who achieved negative surgical margins (R0) fare better. Survival is adversely affected by multiple primary tumors (staged as a T2b) and by vascular invasion; even so, there are still some patients (10-20%) surviving more than 5 years from resection.
For gallbladder cancer, patients with T1 disease (invading only through the lamina propria) have nearly 100% survival at 5 years, while patients with T2 and greater tumors who underwent surgical resection have a much lower chance of survival at 5 years. Lymph node positivity is the most important adverse prognostic factor with 5-year survival rates of 10% or less.
Following complete surgical resection, cholangiocarcinomas typically recur locally (59%), while gallbladder cancers are more likely to metastasize distally (85%).
For patients with advanced biliary tree cancers, the median survival with best supportive care (BSC) alone is 2-3 months. With chemotherapy, this is improved by about a year.
What if scenarios.
Gallbladder cancer frequently presents peri-operatively for what was originally thought to be a benign biliary process. Attention to the post-operative pathologic review is very important. If the initial surgical specimen is staged as a Tis or T1a with negative margins, then the already performed cholecystectomy is adequate. But for any tumor with more advanced staging or with positive margins, the patient needs further evaluation by an experienced hepatobiliary surgeon in consideration of other treatment options.
If a gallbladder cancer is realized after a routine cholecystectomy is completed, further management depends upon pathologic staging. For either a Tis or T1a tumor, defined as invading only through the lamina propria which are less than 10% of tumors, the patient needs only a simple cholecystectomy.
For T1b lesions, those that are muscle invasive, a radical cholecystectomy is advised based upon retrospective data that shows 5 year survivals of 40% with simple cholecystectomy versus 90% with radical cholecystectomy for T1b disease. Locally advanced T3 tumors usually directly invade other organs and a radical cholecystectomy is advised.
T4 tumors invade 2 adjacent structures or involve the nearby central vasculature and are not usually resectable. Support for aggressive surgical management of locally advanced gallbladder cancer is increasing and surgical opinion as to the best management of T3 and T4 lesions vary.
Liver transplantation for cholangiocarcinoma has not been established as a standard therapy. Early experiences led to 5-year survivals of 10-30%, making this a poor utilization of transplantation.
Conversely, some more recent protocols, which have strictly selected early stage unresectable cholangiocarcinoma, have demonstrated cure rates around 80%. Research protocols of liver transplantation for cholangiocarcinoma are ongoing in certain centers and may have a role in highly selected patients.
Follow-up surveillance and therapy/management of recurrences.
Aggressive surveillance has not been validated prospectively and depending upon the patients specific presentation, different follow-up strategies may be necessary. For patients who have undergone curative surgery, consider imaging with CT scan every 6 months for 2 years.
As intrahepatic cholangiocarcinoma often recurs locally, the value of re-resection has been explored. Obviously, these are highly selected cases, but there are reports of long-term survival following re-resection
Biliary tree cancers are pathologically greater than 90% adenocarcinomas with the remainder being mostly squamous cell carcinomas. Biliary epithelium likely incurs several genetic mutations that cause it to evolve pathologically into a malignancy over many years.
The rates of epidermal growth factor receptor (EGFR) expression among biliary tract cancers varies with estimates ranging from 15-60% but in vitro studies have shown that EGFR inhibitors slow the growth of cholangiocarcinomas. Preliminary clinical data also suggest activity of EGFR inhibitors in the setting of advanced biliary tract cancer.
Human epidermal growth factor receptor 2 (HER-2) overexpression in biliary tree cancers has been reported with a wide range of rates from 0-33%. There is hope that trastuzumab could offer benefit for patients who have HER2+ tumors but prospective trials have not confirmed this. Unfortunately, lapatinib as a single agent did not have significant activity in a phase II trial.
Cyclooxygenase-2 (COX-2) upregulation by HER2 is also postulated as an important target in biliary tract cancers.
The MAP kinase pathway, most commonly through KRAS mutations, also appears to become hyperactivated in biliary cancers. Inhibition of MEK has demonstrated preliminary clinical activity in phase II trials, specifically with trametinib and selumitinib.
What other clinical manifestations may help me to diagnose biliary tree cancer?
Porcelain gallbladder is an uncommon finding caused by calcification of the gallbladder wall and can be visualized on abdominal plain films or CT imaging. Patients with a porcelain gallbladder have an increased risk (11-33%) of gallbladder cancer and should be treated surgically.
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- What every physician needs to know:
- Are you sure your patient has biliary tree cancer? What should you expect to find?
- Beware of other conditions that can mimic biliary tree cancer:
- Which individuals are most at risk for developing biliary tree cancer:
- What laboratory and imaging studies should you order to characterize this patient's tumor (ie, stage, grade, CT/MRI vs PET/CT, cellular and molecular markers, immunophenotyping, etc.) How should you interpret the results and use them to establish prognosis and plan initial therapy?
- What therapies should you initiate immediately ie, emergently?
- What should the initial definitive therapy for the cancer be?
- What other therapies are helpful for reducing complications?
- What should you tell the patient and the family about prognosis?
- What if scenarios.
- Follow-up surveillance and therapy/management of recurrences.
- What other clinical manifestations may help me to diagnose biliary tree cancer?