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Malignant Biliary Obstruction: Distal
Malignant strictures of the pancreaticobiliary tree are often difficult to diagnose and treat. Therefore the majority present in more advanced stages of disease, contributing to poor prognosis and outcome. Jaundice is the most common presenting sign and symptom of malignant biliary obstruction. Different etiologies cause distal malignant biliary obstruction and include pancreatic cancer, carcinoma of the ampulla of Vater, distal cholangiocarcinoma (CCA), and metastatic disease that involves the head of the pancreas or the common bile duct (CBD) ( Table 39.1 ). Obstructive jaundice often presents in the context of advanced disease and negatively affects the patient's quality of life. This chapter reviews the role of endoscopic retrograde cholangiopancreatography (ERCP) in the management of malignant distal biliary obstruction. Management of biliary obstruction in the setting of proximal biliary obstruction is discussed in Chapter 40 .
TABLE 39.1
Causes of Malignant Biliary Obstruction
| Primary Cancer | Metastatic Cancer |
|---|---|
| Pancreatic cancer | Gastric cancer |
| Carcinoma of ampulla of Vater | Colon cancer |
| Cholangiocarcinoma | Breast cancer |
| Gallbladder carcinoma | Lung cancer |
| Renal cell carcinoma | |
| Melanoma | |
| Hepatocellular cancer | |
| Malignant lymphadenopathy |
Epidemiology
The most common cause of malignant distal biliary obstruction is pancreatic cancer. During 2014 there were more than 40,000 deaths from pancreatic cancer, which ranks as the fourth most common cause of overall cancer mortality. The number of pancreatic cancer–related deaths is expected to increase in the United States, and pancreatic cancer may soon become the second leading cause of cancer-related deaths. Worldwide, pancreatic cancer is a leading cause of cancer mortality, with more than 330,000 new cases and similar number of deaths annually. In 2017 it is estimated that the overall pancreatic cancer mortality will level off in US and European men but will increase in Japan. Unfortunately, in women, pancreatic cancer–related mortality will continue to rise in most countries except the United States. Based on evidence that the occurrence of pancreatic cancer varies greatly across different global areas, lifestyle and environmental factors have been implicated in its pathogenesis. Various risk factors have been found to play a pathogenic role. Advanced age is the most significant risk factor for pancreatic cancer. The median age at diagnosis of pancreatic cancer in the United States is 72 years. About 5% to 10% of patients develop pancreatic cancer before the age of 50 years, but this group is more likely to include those with predisposing genetic disorders or those who have previously undergone cancer treatments, such as radiation. Cigarette smoking has been strongly associated with pancreatic cancer, and the risk increases 70% to 100% compared with nonsmokers. Daily alcohol consumption (≥3 drinks or equal to 30 to 40 g of alcohol per day) is associated with a 22% increase in the risk of pancreatic cancer incidence. Underlying chronic pancreatitis also increases the risk for developing pancreatic cancer. Other implicated risk factors for pancreatic cancer include vitamin D and ultraviolet B (UVB) radiation, occupational exposure, and obesity. A family history of pancreatic cancer is associated with a twofold increase in pancreatic cancer risk. Genetic factors that increase the risk of pancreatic cancer include familial atypical multiple mole melanoma (FAMMM) syndrome, hereditary pancreatitis, Peutz-Jeghers syndrome, familial pancreatic cancer, cystic fibrosis, familial adenomatous polyposis, and hereditary nonpolyposis colorectal cancer (HNPCC) syndrome.
Malignant distal biliary obstruction can also be caused by CCA. CCA can originate either within the liver or in the extrahepatic bile ducts. Worldwide, CCA is the second most common primary hepatic malignancy after hepatocellular carcinoma. Recent epidemiologic studies show that the incidence and mortality rates of intrahepatic CCA are increasing, whereas those of extrahepatic CCA are falling globally. The peak age for CCA is the seventh decade of life and the overall incidence is higher in men. The majority of cases are sporadic, and specific risk factors are identified only in a minority of patients. Various factors causing ongoing chronic inflammation of the biliary system are often implicated. These risk factors include advanced age; male gender; and underlying conditions such as primary sclerosing cholangitis (PSC), fibropolycystic liver disease, Caroli's disease, choledochal cysts (see Chapter 35 ), HNPCC, and bile duct adenomas. PSC (see Chapter 48 ) in particular is associated with earlier onset of CCA. CCA has been associated with diabetes, obesity, viral hepatitis (hepatitis C and possibly hepatitis B); lifestyle factors such as smoking and alcohol use; and exposure to toxins such as asbestos, dioxins, nitrosamines, and thorotrast. In Asia, especially Thailand and China, infestation with liver flukes Clonorchis sinensis and Opisthorchis viverrini is strongly associated with CCA.
Adenocarcinoma of the gallbladder is another cause of distal biliary obstruction. In the United States, gallbladder cancer is the fifth most common gastrointestinal cancer and the most common cancer involving the biliary tract. Over 5000 new cases are diagnosed each year in the United States. Among Southwestern Native Americans and Mexican Americans, gallbladder cancer is the most common gastrointestinal malignancy. Cholelithiasis is a well-described and strong risk factor for gallbladder cancer. Most of the patients diagnosed with gallbladder cancer will be diagnosed incidentally during investigation for cholelithiasis. Other risk factors for gallbladder malignancy include advanced age, female gender, and specific geographic areas. In South American countries such as Chile, Ecuador, and Bolivia and in Asian countries such as India, Pakistan, Japan, and Korea, the incidence of gallbladder cancer is higher. Underlying gallbladder conditions such as porcelain gallbladder, gallbladder polyps, congenital biliary cysts, and abnormal pancreaticobiliary duct junction are associated with higher risk of cancer of the gallbladder. Smoking and obesity have also been implicated, although the evidence linking them to gallbladder cancer is weak. Risk factors for pancreaticobiliary malignancies are summarized in Table 39.2 .
TABLE 39.2
Risk Factors for Pancreaticobiliary Cancers
| Pancreatic Cancer | Cholangiocarcinoma | Gallbladder Cancer |
|---|---|---|
|
|
|
FAMMM, Familial atypical multiple mole melanoma; HIV, human immunodeficiency virus.
Natural History
Malignant distal biliary obstruction may occur as a consequence of extrinsic bile duct compression or may involve the duct intrinsically either through a primary process or from metastasis directly to the bile duct. The most frequent cause of malignant biliary obstruction is adenocarcinoma of the pancreas located at the head or uncinate process, which accounts for more than 90% of cases. Other cancers include gallbladder cancer, cancer of the ampulla of Vater, CCA, metastatic cancers, and malignant lymphadenopathy. In most cases, advanced disease is detected at the time of detected biliary obstruction.
The role of the endoscopist in the management of these conditions extends to providing both diagnostic and therapeutic/palliative solutions depending on the type and stage of cancer. Endoscopic diagnostic procedures include endoscopic ultrasonography (EUS) with fine-needle aspiration (FNA) and fine-needle core biopsy (FNB) and ERCP with brush cytology. Alternatively, therapeutic endoscopic procedures such as ERCP with biliary stenting, placement of duodenal/pyloric stenting, EUS-guided fiducial placement to facilitate radiotherapy, and EUS-guided celiac plexus neurolysis for pain control can become part of overall management. Despite current advances in the diagnostic and therapeutic aspects of pancreaticobiliary cancers, the majority of patients have unresectable disease at presentation, with a median survival of 4 months without treatment.
Clinical Features and Initial Evaluation
The most common clinical presentations of pancreatic and biliary malignancies include painless jaundice, weight loss, and anorexia. Biliary obstruction leads to scleral icterus, clay-colored stools, dark urine, pruritus, nausea, and emesis. Advanced forms of pancreatic cancer can present with epigastric pain radiating to the back, suggesting pancreatic duct obstruction and infiltration of retroperitoneal structures, palpable gallbladder, dyspepsia, early satiety because of gastric outlet obstruction, new-onset glucose intolerance or diabetes mellitus, and acute pancreatitis. CCA presents with abdominal pain mostly in the right upper quadrant, jaundice, pruritus, and weight loss.
Risk factors for pancreaticobiliary malignancies should be evaluated during history taking. For pancreatic cancer, these include a history of tobacco smoking and smokeless tobacco usage, family history of pancreatic cancer, and personal history of diabetes, pancreatitis, and obesity.
For CCA, a history of previously known conditions should be obtained. Relevant conditions include inflammatory bowel disease; PSC; cholelithiasis; choledochal cysts; Caroli's disease; HNPCC; human immunodeficiency virus (HIV); hepatitis C and hepatitis B exposure; diabetes; and exposure to toxins such as asbestos, dioxins, nitrosamines, and thorotrast. A complete physical examination should include identification of icterus and palpation to identify organomegaly, including liver, gallbladder, and lymph nodes. Migratory thrombophlebitis can be recognized via positive Trousseau sign or swollen visible blood vessels that resolve and then appear at another area of the body. The various symptoms and physical examination findings of pancreaticobiliary malignancies are summarized in Table 39.3 .
TABLE 39.3
Common Symptoms Associated With Pancreaticobiliary Malignancies
| Symptoms | Signs |
|---|---|
|
|
Laboratory tests should include total bilirubin, fractionated bilirubin, alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and tumor markers such as cancer antigen (CA) 19-9 and carcinoembryonic antigen (CEA). Further testing with imaging studies such as transabdominal ultrasonography (TUS), pancreas protocol computed tomography (CT), or magnetic resonance cholangiopancreatography (MRCP) should be based on the initial suspicion of pancreaticobiliary malignancy from the history, physical examination, and initial laboratory test results.
Differential Diagnosis of Distal Biliary Malignancies and Imaging Techniques
Ampullary Carcinoma
Ampullary carcinoma often presents with obstructive jaundice and is suspected if imaging studies detect dilation of the pancreaticobiliary ducts. TUS should be the first imaging test, based on its ability to detect intrahepatic and extrahepatic bile duct dilatation and to confirm the presence of gallstones. However, TUS has poor sensitivity for detection of ampullary carcinoma because of the small size of the tumor and overlying bowel gas that limits views of retroperitoneal structures. CT scan provides more accuracy than ultrasonography in this regard. Water may be used as oral contrast to distend the duodenal wall. Even though CT is more sensitive than TUS, a substantial number of ampullary lesions can be missed, especially small lesions. Skordilis et al. reported CT scan to have an overall accuracy of 20% in detecting ampullary carcinoma. MRCP is also a noninvasive technique and superior to CT in detecting biliary obstruction. Ampullary carcinomas appear as filling defects protruding into the duodenal lumen, with characteristic delayed enhancement and hyperintensity on diffusion-weighted imaging. Domagk et al. reported 76% overall accuracy of MRCP in detecting ampullary carcinoma. However, MRCP cannot differentiate between tumors and other benign causes of ampullary obstruction such as stones and benign strictures.
ERCP can be both diagnostic, by detecting an ampullary mass and providing tissue samples ( Fig. 39.1 ), and therapeutic, for relieving obstructive jaundice. Overall diagnostic accuracy of ERCP for detecting ampullary carcinoma is up to 88%, with tissue acquisition performed at least 48 hours after sphincterotomy, which includes multiple biopsies and the use of polymerase chain reaction or immunohistochemical staining to detect p53 or K-ras gene mutations.
EUS and ERCP are comparable in terms of detecting ampullary cancers. EUS is the most accurate imaging modality to provide local tumor staging for ampullary neoplasms. The choice of surgery performed as local resection versus pancreaticoduodenectomy is determined by the staging information obtained from the previously mentioned techniques (see Chapter 38 ).
Pancreatic Cancer
The pancreatic malignancies that cause distal biliary obstruction involve the head or uncinate process of the pancreas, although large lesions involving other areas of the pancreas can also obstruct the biliary system. Metastasis to the porta hepatis can cause more proximal obstruction. The workup for suspected pancreatic cancer often begins with one or more of the following, depending on clinical and institutional protocols: TUS, CT scan, magnetic resonance imaging (MRI), EUS, and ERCP. These options enable cancer diagnosis and staging, determine tumor resectability, and provide a histopathologic diagnosis. TUS with and without contrast has a diagnostic accuracy of about 82% to 86% for diagnosing pancreatic head malignancies. The diagnostic accuracy of TUS is lower for pancreatic head cancers less than 3 cm in diameter.
CT scan improves tumor detection and provides information about local staging and invasion of vascular structures. Dynamic contrast-enhanced multidetector CT scan has significantly improved pancreatic cancer imaging, with an ability to provide enhanced three-dimensional reconstructions of pancreatic tumors and their vascular involvement ( Fig. 39.2 ). The sensitivity of multidetector CT ranges from 89% to 97%, and this is currently the preferred modality for preoperative staging and assessment of resectability of patients with pancreatic malignancy.
MRI with either gadolinium-enhanced or mangafodipir-enhanced sequences is as sensitive as CT in detecting pancreatic cancers. MRI for the pancreas includes conventional MRI, MRCP, and magnetic resonance angiography. In a recent study Fusari et al. compared the diagnostic accuracy of multidetector CT scan and MRI and reported comparable diagnostic accuracies for tumor identification and resectability between the two techniques. Rao et al. showed comparable results of CT and MRI for characterization of small pancreatic tumors ≤2 cm. A recent study of multidetector (64-detector row) CT scan compared with gadobenate dimeglumine–enhanced 3.0-T MRI imaging (compared with previously used 1.5-T MRI imaging) also showed similar sensitivities and specificities for the two techniques in detecting pancreatic cancer. Although in routine practice it is common to use both CT and MRI in the evaluation of patients with known or suspected pancreatic cancer, MRI is especially useful in cases where iodinated contrast material cannot be administered because of contrast allergy or renal insufficiency.
EUS allows the ability to place a high-frequency transducer in close proximity to the tumor and provides high-resolution images and enhanced detection of pancreatic cancer. Dewitt et al. published a systematic review comparing the diagnostic sensitivity of CT scan and EUS in the detection of pancreatic cancer; this publication included 11 studies and 678 patients and concluded that EUS had higher sensitivity than CT scan in detecting pancreatic tumors. Another study that evaluated the accuracy of EUS, dynamic CT, and MRI in detecting pancreatic tumors <3 cm in diameter found sensitivities of 93%, 53%, and 67%, for EUS, CT, and MRI, respectively. However, multidetector CT scanning was developed and introduced to clinical use after most of the previously mentioned studies were published.
Recently, multiple studies comparing different modalities for the staging of pancreatic cancer based on the tumor, node, metastasis (TNM) staging proposed by the American Joint Committee on Cancer (AJCC) were published. Dewitt et al. and Soriano et al. found that EUS was superior to multidetector CT in terms of T-staging, with an overall lower rate of overstaging compared with CT and MRI.
Comparing the accuracy of EUS and CT scan for N-staging, different reports have not conclusively established the superiority of one technology over the other.
For M-staging, the advantage of multidetector CT scan over EUS rests with the fact that, in addition to local spread, CT scan also provides information about distant metastasis. Therefore CT scan currently is more commonly used for the initial staging of pancreatic cancer. EUS becomes a valuable staging tool in situations where CT scan provides equivocal results about surrounding lymph nodes or when small solid tumors less than 3 cm are detected on CT scan.
With improvements in cross-sectional imaging and EUS in the last decade, the role of ERCP in the diagnosis and staging of pancreatic cancer has greatly diminished. Nevertheless, certain signs, such as combined dilation of the CBD and the main pancreatic duct (double-duct sign) and abrupt cutoff of the pancreatic duct or a single long stricture (>1 cm) of the pancreatic duct observed during ERCP, should alert the clinician to the possibility of pancreatic cancer.
If the initial imaging studies are suggestive of pancreatic malignancy and the patient is an appropriate operative candidate, it is rational to refer the patient for surgical resection with the hope of curative intent. Currently, select medical centers in the United States use multidisciplinary clinics (MDCs) for their pancreatic cancer care. The MDC model enables convenience and improves communication by having patients assessed during their initial visit by each main member of the care team, including surgical oncology, medical oncology, gastroenterology, radiation therapy, and genetics.
Because of late presentation of this disease, only a small proportion of patients are considered to be surgical candidates (15% to 20%). More frequently, cytologic diagnosis of pancreatic cancer is obtained by performing FNA/FNB (ultrasonography-guided, CT-guided, or EUS-guided) and brush cytology (obtained during ERCP). A recent meta-analysis published by Chen et al. of EUS-guided FNA in the diagnosis of pancreatic cancer showed a sensitivity of about 92% and a specificity of about 96%. A second meta-analysis including 41 papers was published by Puli et al. and found that EUS-guided FNA has a sensitivity of 89% and a specificity of 96%. The accuracy (calculating true-positive cases plus true-negative cases) was found to be lower in the setting of chronic pancreatitis. Therefore a negative EUS-FNA result does not exclude the presence of cancer. A recent randomized trial published by Horwhat et al. comparing EUS-guided FNA with other modalities for tissue acquisition, such as CT-guided FNA, found no significant differences in the sensitivities of the two techniques. However, EUS is the test of choice when tumor size is <3 cm ( Fig. 39.3 ).
The adverse events of EUS-FNA include bleeding, pancreatitis, perforation, and tumor seeding. In a prospective study from high-volume centers, 355 patients with solid pancreatic tumors underwent EUS-FNA with an overall adverse event rate of 2.54% (3 cases of pancreatitis), with 1.9% of patients requiring hospitalization. The same group found that even when performed by less experienced operators, the adverse event rate with EUS-FNA was reported to be as low as 1.1%. There have been three reports of tumor seeding into the gastrointestinal wall as a result of EUS-FNA. There have also been reports of development of peritoneal carcinomatosis. However, compared with TUS-guided or CT scan–guided percutaneous biopsy, the risk of peritoneal tumor seeding can occur and is greater than that seen with EUS-FNA (16.3% vs 2.2%).
Ikezawa et al. found that peritoneal carcinomatosis ultimately developed during the course of disease in patients who had undergone EUS-guided FNA for pancreatic cancer in 17.9% compared with 14.9% when ERCP with brush cytology was performed, suggesting that EUS-FNA is not a risk factor for peritoneal seeding.
In the process of improving diagnostic yield and tissue acquisition, newer biopsy needles have been developed. Mizrahi et al. showed that the use of a forked-tip FNB needle had a higher diagnostic yield for pancreatic cancer compared with FNA.
In addition to obtaining tissue by EUS-guided FNA/FNB, cytology specimens can be taken at the time of biliary decompression during ERCP. Brush cytology has a sensitivity that ranges from 30% to 60%. Increasing the number of samples by obtaining multiple brush cytology samples before and after stricture dilation and sending the entire brush for analysis can increase diagnostic yield. Brush cytology has a high positive predictive value but poor negative predictive value. Ramchandani et al. showed that, when brush cytology was nondiagnostic, cholangioscopy-guided biliary duct biopsies were accurate in up to 82%.
Cholangiocarcinoma
Intrahepatic CCA may present as one or more mass lesions on imaging studies. Hilar and distal CCA are suspected in patients presenting with biliary obstruction, right-upper-quadrant abdominal pain, and cholangitis. Noninvasive biliary imaging with MRCP is the radiologic modality of choice to determine the extent of the disease. In addition, obtaining MRCP before ERCP may offer additional information to serve as a road map to direct placement of biliary stents (see Chapter 40 ). ERCP with brush cytology and/or cholangioscopy with bile duct biopsies may be required. Newer cytologic techniques, such as digital image analysis (DIA) and fluorescence in situ hybridization (FISH), have been incorporated into the cytologic evaluation of bile duct brushings to enhance the sensitivity of cytology ( Fig. 39.4 ; see also Chapter 41 ). Both techniques identify aneuploidy, which is a hallmark of chromosomal instability and cancer. Malhi and Gores found that the combination of DIA and FISH offers the highest sensitivity for the diagnosis of malignant biliary strictures in patients both with and without PSC. EUS might be valuable in determining the extent of disease and when sampling regional lymph nodes for staging is needed. Choice of surgical resectability and type of surgery can be aided by the Bismuth-Corlette classification of hilar CCA ( Fig. 39.5 ). Although surgical resection is the mainstay of curative treatment for CCA in the absence of PSC, surgery is not recommended in patients with PSC because of multifocality of the disease. There is a poor impact on overall disease mortality after surgery. In patients with PSC with early CCA, liver transplantation has been considered as a curative option. Surgical resection for distal CCA requires pancreaticoduodenectomy, as for pancreatic cancer. Factors that may influence surgical decision include poor performance status, presence of cirrhosis, and other comorbidities. Five-year survival in patients with distal bile cancers is 37%.
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