Advances in the endoscopic management of patients with pancreatic and biliary malignancies.

Abstract: Major advances in endoscopic techniques to diagnose and manage pancreatic biliary diseases have fundamentally changed the approach to these difficult clinical challenges. The diagnosis of benign and malignant pancreatic-biliary diseases is much more readily obtained through a combination of cross-sectional imaging and endoscopic procedures. Endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic ultrasound (EUS) are the most important endoscopic tools for imaging and accessing the pancreatic biliary system. The review summarizes the major imaging methods for providing a diagnosis of bile duct malignancy, including ERCP, transhepatic cholangiography (THC), and magnetic resonance cholangiopancreatography (MRCP). High quality image examples of cholangiocarcinoma are provided. EUS has provided a new imaging modality for the detection of pancreatic and biliary malignancy. EUS is particularly sensitive for the detection of early pancreatic malignancy. Furthermore, EUS excels at the guidance of fine needle aspiration of pancreatic lesions. Diagnostic tissue acquisition for cholangiocarcinoma remains an important challenge. The endoscopic therapy for pancreatic-biliary malignancy involves the use of stenting which relieves the biliary obstruction commonly seen in these patients.

Key Words: pancreatic cancer, cholangiocarcinoma, endoscopic retrograde cholangiopancreatography, endoscopic ultrasound, magnetic resonance cholangiopancreatography, transhepatic cholangiography

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Major advances in endoscopic techniques to diagnose and manage pancreatic biliary diseases have fundamentally changed the approach to these difficult clinical challenges. The diagnosis of benign and malignant pancreatic-biliary diseases is much more readily obtained through a combination of cross-sectional imaging and endoscopic procedures. ERCP (endoscopic retrograde cholangiopancreatography) and EUS (endoscopic ultrasound) are the most important endoscopic tools for imaging and accessing the pancreatic biliary system.

This review examines the major recent advances in the diagnosis of malignant diseases of the pancreatic-biliary system using ERCP and EUS.

Endoscopic Techniques

ERCP has traditionally been the dominant technique for diagnosis and treatment of both benign and malignant diseases. Over the past 10 years, the use of EUS for the diagnosis of pancreatic-biliary diseases has increased dramatically. ERCP excels in providing detailed imaging of the ductal systems of the pancreas and biliary system. With the ability to access the ductal systems, ERCP has also been an important tool in providing a tissue diagnosis of ductal malignancies through the use of brush cytology. Most importantly, ERCP provided therapeutics for stone disease and ductal stenosis.

EUS complements many of the features of ERCP by providing imaging of the pancreatic parenchyma, ductal malignancies, and adjacent lesions such as metastases to lymph nodes, liver, and peritoneum. A high frequency ultrasound transducer placed at the tip of the endoscope provides the imaging by EUS. Complementing EUS is the use of fine needle aspiration cytology for the diagnosis of malignancies and at times, benign lesions (Table 1 and 2).

Biliary Malignancy

Cholangiocarcinomas and ampullary carcinomas make up the vast majority of biliary malignancies. Cholangiocarcinomas arise from the biliary ductal epithelium, most commonly in the bifurcation of the intrahepatic bile ducts. (1) Patients generally present with vague abdominal pain, jaundice, and weight loss. A diagnosis is most often sought initially with the use of cross-sectional imaging, such as MRI and CT scanning. Since biliary malignancies often affect the bile ducts through obstruction, the most common finding is an obstructed, dilated bile duct. At times, it is difficult to detect the actual malignant mass with cross-sectional testing.

With a presentation consistent with biliary malignancy and a cross-sectional imaging result suggestive of obstruction, the patient is often referred to the gastroenterologist for additional testing with ERCP and EUS. ERCP is often performed when the patient has a high-grade obstruction, jaundice, and evidence of an extrahepatic biliary malignancy. (2) ERCP will provide a detailed cholangiogram and brush cytology of a focal stenosis. (3) Following the diagnostic maneuvers, ERCP may direct the placement of temporary plastic stents into patients considered for surgical resection and a metal stent in those patients who are not operative candidates. (4)

Classic Cholangiographic Findings

Solitary biliary strictures are the most common manifestation of cholangiocarcinoma. A contrast injection of the bile duct will determine many key features of the malignancy, including the location, length, number of ducts involved, and associated biliary diseases. Although the ERCP images themselves do not provide definitive evidence of malignancy, there are three classic cholangiographic findings that are highly diagnostic of malignant or benign diseases. The most common diagnostic finding of a malignant stricture is a long, irregular, asymmetric narrowing in the extrahepatic bile duct. (5) Secondly, the finding of a focal stricture in the bile duct, in close association with a stricture in the main pancreatic duct, is termed the 'double duct sign.' This finding is highly suggestive of a pancreatic malignancy involving the distal bile duct. Thirdly, the finding of multiple irregular, intrahepatic strictures is suggestive of a benign process; sclerosing cholangitis. (6)

Diagnostic Cholangiography

Cholangiography is the most important imaging tool in the diagnosis of a bile duct tumor. Cholangiography may be provided with either of three techniques, MRCP (magnetic resonance cholangiopancreatography), ERCP (endoscopic retrograde cholangiopancreatography), or THC (transhepatic cholangiography) (Fig. 1-3). MRCP is the least invasive of the three techniques and is the preferred imaging test for the initial evaluation of patients with complaints or findings suggestive of bile duct malignancy. (3) Although ERCP can provide detailed images of the biliary system, the quality of the cholangiograms is very similar to high-quality MRCP and THC. The use of THC, an interventional radiologic technique, is usually reserved for cases where ERCP and MRCP have failed.

When ERCP and MRCP scans are compared for accuracy of the diagnosis of cholangiocarcinoma, the imaging criteria for the diagnosis of malignancy are similar. Biliary malignancy is suggested when there are findings of irregular, asymmetric strictures. In contrast, smooth, symmetric strictures are often considered benign. Using these criteria, the diagnostic accuracy of both techniques is approximately 70 to 80%. (7,8) CT scanning provided slightly lower rates of diagnosis compared with MRCP and ERCP.

The advantage of MRCP for imaging of the biliary system is the noninvasive nature of the procedure and the ability to provide images of the entire biliary system despite a high degree of obstruction. (3) In contrast, ERCP is more invasive and may not be able to image bile ducts above a tight or inaccessible stricture. The chief advantage of ERCP in terms of diagnosis is the ability to provide tissue for a definitive diagnosis of malignancy. (9)

Ampullary malignancies are less common than bile duct tumors but represent an important opportunity for an early diagnosis and aggressive therapy for a biliary malignancy. (10) The common presentation for ampullary malignancy is chronic gastrointestinal bleeding and/or abnormal liver function tests. Patients with familial adenomatous polyposis (FAP) are at high risk of developing ampullary adenomas that progress to adenocarcinomas. Along with colonoscopy, these patients should undergo surveillance with upper GI endoscopy and examination of the ampulla. Lesions of the ampulla should be biopsied to determine the presence of adenomas or more advanced lesions. The traditional role of ERCP in patients with ampullary malignancy is to provide stenting in patients not suitable for surgical resection. Recently, ERCP techniques have been used to resect the ampulla for a tissue diagnosis of an ampullary lesion or treatment of a localized malignancy. Endoscopic ampullectomy and transduodenal ampullectomy have proven to be highly successful for benign lesions and superficial early malignancies. (11)

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Role of EUS in Biliary Malignancy

EUS is used to detect and stage biliary malignancies. Endoscopic ultrasound imaging of the biliary system is usually performed with an endosonoscope, but small probes can also be used during ERCP. (12) EUS is used to assist in differentiating between benign and malignant strictures or in the staging of cholangiocarcinoma. (13) Intraductal high frequency ultrasound suggests the presence of malignancy when a hypoechoic infiltration is seen invading through the biliary wall. The findings of a pancreatic mass, irregular bile duct wall, or a bile duct wall of more than 3 mm are suggestive of a malignancy causing biliary obstruction. (14) Most commonly, a tissue diagnosis of the bile duct lesion is used to provide a definitive diagnosis of malignancy.

Ampullary Malignancy

The diagnosis of ampullary malignancy is usually made during ERCP through the inspection of the ampulla. The presence of a mucosal mass arising from the ampullary mucosa in conjunction with biliary obstruction is nearly diagnostic of ampullary malignancy. However, an endoscopic biopsy will provide a tissue diagnosis in nearly 80% of tumors. (15) With the use of a sphincterotomy, more tissue can be obtained from the distal common bile duct. With small ampullary lesions, an ampullectomy is performed to diagnose and stage the malignancy. EUS is used primarily to diagnose and stage the malignancy. A focal hypoechoic mass is readily seen in the duodenal wall, representing the ampullary malignancy and its local infiltration of the duodenum.

Tissue Diagnosis

Tissue collection during ERCP or EUS is one of the most important issues in the management of patients with early pancreatic-biliary malignancy. (1) Unfortunately, ERCP-guided biopsies and brush cytology of biliary strictures can provide a definitive diagnosis of malignant disease in less than half of patients. (9) The yield of cytology is not improved with stricture dilation, but repeated brush cytology attempts of a bile duct stricture will increase the tissue yield. EUS-guided fine-needle aspiration supplements the use of ERCP and provides a cytologic diagnosis in 45% of patients. (16) Other centers report even higher rates of malignancy diagnosis when EUS-FNA is used. (17) Endoscopic directed biopsies of a bile duct mass with tissue forceps will provide higher rates of diagnostic tissue using histology compared with brush cytology. (18) Cytologists have reported that the use of two separate interpretations will increase the sensitivity of brush cytology of bile duct strictures. (19)

One of the major limitations of endoscopic-directed brushings of bile duct strictures is the poor quality of cytologic samples. The Mayo Clinic has examined the use of DNA histograms for detecting aneuploidy, but with disappointing results. (20) In a series of 100 patients (56 with malignancy and 44 with a benign stricture), the sensitivity of routine cytology was only 18%. When digital image analysis of the DNA histograms was employed there was an increase in the diagnostic sensitivity to 39%. Overall, the accuracy of digital image analysis was not thought to be significantly better than routine cytology.

Recently, linear EUS has been used to detect bile duct malignancy (Fig. 4). (21) Linear EUS coupled with FNA has been associated with a cytology yield of 86%, surpassing that of all other techniques. The vast majority of the malignancies in this study, however, arose from hepatocellular carcinomas. The procedure appears to be the ideal approach for patients with a focal hilar mass that cannot be readily diagnosed with ERCP (Fig. 5-9).

Endoscopic Treatment of Bile Duct Malignancy

The endoscopic approach to the treatment of cholangiocarcinoma and biliary obstruction has consisted of bile duct stenting. The use of ERCP to guide and place stents into the intra-and extrahepatic bile duct has provided a significant improvement in the long-term management of patients. However, the use of plastic stents is associated with recurrent stent occlusion or tumor extension, requiring stent replacement (22) A recent study has suggested that temporary stenting of the bile duct may result in colonization of the biliary system and increase the risk of operative mortality and morbidity. (23) Others have demonstrated that biliary stenting increases the risk of wound infections with-out increasing the risk of major complications. (4) Nevertheless, endoscopic stenting remains an important palliative procedure for patients with biliary malignancy.

The deployment of metal stents for advanced pancreatic-biliary malignancy has significantly reduced the need for re-stenting and proven to be cost-effective when compared with surgical biliary bypass. (24) Furthermore, the use of metal stenting has significantly reduced the frequency of cholangitis as a result of stent occlusion. Patients stented with a metal stent have fewer episodes of cholangitis and fewer days of hospitalization. The cost-effectiveness of metal stents has been clearly demonstrated. (25)

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Since metal stents are not removable and since they may interfere with surgical resection or bypass, it is critical to identify suitable candidates. Patients undergoing metal stent placement should have a definitive diagnosis of malignancy and the option for surgical resection or bypass should have been resolved before metal stent placement.

The use of radiotherapy in conjunction with endoscopic stenting has failed to reduce the need for restenting in patients with bile duct tumors. (26) Photodynamic therapy (PDT) is a new modality of therapy that has recently been applied to local control of bile duct malignancies using ERCP guidance. After the administration of IV Photofrin (porfimer sodium), the bile duct epithelium is exposed to a specific wavelength of light using a laser source. In the initial German report, the use of PDT in cholangiocarcinoma patients undergoing stent change resulted in prolongation of survival (median 493 d versus 98 d). It also improved biliary drainage and quality of life. In the initial American experience at Mayo Clinic, the median survival was 276 days, similar to the German experience. (27) Further technical improvements will be required to allow the use of PDT as a routine adjunctive treatment for biliary malignancy.

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Role of ERCP in the Diagnosis of Pancreatic Malignancy

ERCP has been the traditional endoscopic test for the diagnosis of pancreatic malignancy. Most often, ERCP is employed in patients who present with jaundice and suspected pancreatic malignancy. Although the primary role of ERCP in these patients is to provide biliary stenting, contrast injection into the bile duct will demonstrate a focal distal bile duct obstruction. The biliary obstruction is most often a result of compression of the bile duct by the pancreatic head malignancy. If retrograde injection of the pancreatic duct is also provided, a focal obstruction of the pancreatic duct will be demonstrated. The combination of a focal obstruction of the bile duct in close continuity with an obstructed pancreatic duct is nearly diagnostic of pancreatic head malignancy and is termed a 'double duct sign.' Pancreatic malignancies in the body and tail may also be diagnosed with the finding of a focal stricture in the main pancreatic duct. Although cytologic sampling is possible in the head of the pancreas, it is difficult to provide brush cytology specimens beyond the head of the pancreas.

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With the increasing accuracy of CT and MRI for the diagnosis of pancreatic malignancy, the need for diagnostic ERCP has decreased. EUS excels in the detection of pancreatic malignancy and has also decreased the need for diagnostic ERCP. Although EUS is very sensitive in the detection of pancreatic malignancy, the finding of a focal hypoechoic mass is not very specific. (28) This finding can be mimicked by focal chronic pancreatitis. However, with the use of EUS-directed FNA, the specificity of EUS has been dramatically increased.

EUS is also used to stage focal pancreatic malignancy by concentrating on tumor or T staging. Stages T1-2 pancreatic malignancies are intrapancreatic lesions without evidence of extrapancreatic extension. Stage T3 pancreatic cancer has focally involved local structures such as the duodenum and bile duct. T4 lesions have invaded the portal vein and its branches, making surgical resection difficult. Metastatic lesions in the liver, peritoneum, and lymph nodes can also be detected and aspirated for cytology. (29)

Lymph node (N) staging of pancreatic cancer is easily performed through imaging of abnormal lymph nodes, usually in the peripancreatic areas. Since the ultrasound appearance of lymph nodes is not specific for malignancy, fine needle aspiration is commonly performed. The specificity of cytology is very high when malignant cytologic material is found. The sensitivity is in the range of 60 to 70%. The finding of malignant lymph nodes remote from the site of malignancy may have a significant impact on the decision making for resection.

The staging of metastatic lesions (M) by EUS is commonly performed by examining the liver and the peritoneal space between the stomach and liver. Although EUS is highly sensitive for the presence of metastatic lesions within the left lobe of the liver, the right lobe of the liver is incompletely examined with EUS. Fine needle aspiration is commonly performed on lesions in the liver that are suspicious for metastasis. The sensitivity and specificity are very high, approaching more than 90%. There are few complications from fine needle aspiration of lymph nodes and liver lesions.

Cystic lesions of the pancreas are composed of a broad range of neoplastic cysts and inflammatory pseudocysts. (30) The neoplastic cysts span the spectrum of malignancy, from frankly malignant to premalignant lesions, and benign cystadenomas. With the widespread use of abdominal imaging, the lesions are increasingly identified in the early stages of asymptomatic patients.

There are three basic types of pancreatic cystic lesions, serous, mucinous, and inflammatory. (31) Serous cysts are considered to be benign lesions without malignant potential. In contrast, mucinous cystic neoplasms are considered to be premalignant or frankly malignant. Inflammatory cystic lesions are composed of peripancreatic fluid collections that occur during episodes of acute pancreatitis or chronically, in association with chronic pancreatitis.

Epidemiology

Serous cystadenomas have been estimated to account for about 25% of all cystic tumors of the pancreas, but the true incidence is difficult to determine. (32) Using surgical pathology studies, it has been estimated that serous cystadenomas account for about 1 to 2% of all exocrine pancreatic neoplasms.

Serous cystadenomas occur only in adults and are more commonly found in men. In reported cases, patients have ranged in age from 18 to 91 years, with a median age in the seventh decade. Traditionally, about 1/3 of serous cystade-nomas are discovered as incidental findings during abdominal imaging, surgery, or at autopsy.

Mucinous cystic neoplasms account for approximately 2 to 5% of all exocrine pancreatic neoplasms and are more common than serous cystadenomas. (33) Women are affected far more commonly than men (9:1 female:male ratio), with a mean age at diagnosis in the fifth decade.

Intraductal papillary mucinous neoplasms (IPMNs) are closely associated with mucinous cystic neoplasms (MCNs). Their true incidence is uncertain, but estimates range from 1 to 8% of all pancreatic neoplasms. IPMNs affect men and women equally or men predominantly, depending on the reported series, and they tend to occur in an older age group than MCNs.

Pathology

Serous Cystadenomas

These solitary microcystic lesions are usually round and arise from the pancreatic parenchyma without involvement of the ductal system. Microcystic serous cystadenomas are the most common. They are composed of innumerable small cysts with a honeycomb-like appearance on cross-section. (32) Microcystic serous cystadenomas may achieve a large diameter over the long term and the large lesions often have a fibrotic or calcified central scar. The cyst fluid from serous cystadenomas is thin, clear, and contains no mucin.

Mucinous Cystic Neoplasms

Grossly, mucinous cystic neoplasms are characteristically macrocystic with discrete individual cavities that vary in diameter. (34) In the absence of an associated mass, malignant transformation may be suspected with focal thickening, irregularity, or ulceration of the cyst lining. MCNs are lined by mucin-producing cells with mucin vacuoles. The World Health Organization classification classifies MCNs into three types, based on the degree of epithelial dysplasia: benign, borderline, and malignant. (35) The entire tumor is classified according to the most advanced degree of dysplasia/carcinoma present.

Mucinous cystic neoplasms of the pancreas often contain a highly cellular (so-called 'ovarian') stroma. It occurs almost exclusively in female patients, although rare cases of MCNs with ovarian stroma in male patients have been encountered. Many authorities have restricted the very definition of MCNs to include only those cystic mucinous neoplasms that contain ovarian stroma.

IPMNs originate in the distal main pancreatic duct in 80% of cases. (36) As a result, they tend to cause duct obstructive complications such as acute pancreatitis, chronic pancreatitis, or jaundice. The presence of a papillary neoplasm causes dilation of the ducts as a result of tumor growth. The degree of dysplasia exhibited by the epithelium may range from mild to moderate to severe (carcinoma in situ), and the entire tumor is classified according to the greatest degree of dysplasia present.

Clinical Presentation

Most patients with a pancreatic cystic lesion have no signs or symptoms related to the pancreatic lesion. Often the lesion is found with CT or US imaging performed for the evaluation of another condition such as another malignancy or liver lesion. (37) When symptoms are present, the most common presentation is recurrent abdominal pain, nausea, and vomiting as a result of mild pancreatitis. These symptoms often reflect the presence of a lesion causing ductal obstruction or a connection with the main ductal system. Chronic abdominal pain is a rare presentation of a benign cystic lesion and suggests a malignancy or a pseudocyst. Patients with a cystic neoplasm will present with symptoms and signs similar to pancreatic cancer, ie, pain, weight loss, and jaundice.

Diagnostic Methods

CT is an excellent test for cystic lesions of the pancreas because of its widespread use and ability to detect cysts. (38) MR imaging is used increasingly because of the lack of radiation exposure and the ability to image the pancreatic duct with MRCP (MR cholangiopancreatography). Transabdominal ultrasonography may aid in differentiating between solid and cystic lesions, but complete evaluation of the pancreas is often difficult due to overlying bowel gas.

Although seen in less than 20% of lesions, demonstration of a central scar by CT or MR is a highly diagnostic feature of a serous cystadenoma. (39) Mucinous cystic neoplasms, in contrast, are commonly diagnosed with CT based on the unilocular or macrocystic characteristics. Although not frequently seen, the finding of peripheral calcification by CT is specific for a mucinous cystic neoplasm. Intraductal papillary mucinous neoplasms (IPMN) may involve the main pancreatic duct exclusively, a side-branch or both. MRCP can demonstrate the diagnostic findings of pancreatic duct dilation, mural nodules, and ductal connection. (40)

Despite these imaging features, the ability to accurately diagnose a specific cystic lesion and to determine whether malignancy is present by CT and MR remains uncertain. The diagnosis of a pancreatic pseudocyst is more dependent upon the clinical history and the associated findings of chronic pancreatitis. Pancreatic pseudocysts appear as unilocular fluid-filled cavities associated with parenchymal changes such as calcifications and atrophy. A pseudocyst complicated by infection or bleeding may have high-density lesions seen within the fluid.

Recently, endoscopy and endoscopic ultrasound (EUS) have been used to diagnose cystic lesions of the pancreas and guide fine needle aspiration (FNA). (41) Using the high resolution imaging of endoscopic ultrasound, the morphologic features of various cystadenomas have recently been defined. However, the detailed imaging features of cystic neoplasms by EUS do not appear to be sufficiently accurate to differentiate between benign and malignant cystadenomas unless there is evidence of a solid mass or invasive tumor. Fine needle aspiration under EUS guidance can be performed on small lesions within the pancreas.

Cyst fluid, aspirated using EUS guidance, can be analyzed through the use of cytology and a variety of tumor markers. (42) However, the low cellular content of cyst fluid has hampered the use of the cytologic analysis of cyst fluid. Small, cuboidal cells in cytologic specimens are diagnostic of serous cystadenomas. In contrast, mucinous cystic neoplasms may have epithelial cells with evidence of mucin secretion or atypica. Only inflammatory cells should be present in the fluid aspirated from pseudocysts.

A variety of cyst fluid tumor markers have been studied to help differentiate between the major types of cystic neoplasms. Several studies suggest that carcinoembryonic antigen (CEA) or CA 72-4 are useful for identifying mucinous lesions. (43) These carbohydrate antigens are secreted by the epithelium lining mucinous lesions and are present in high concentrations. Cyst fluid concentrations of CEA and CA 72-4 are very low in serous cystadenomas. Unfortunately, there is considerable overlap in cyst fluid concentration of CEA in benign and malignant mucinous cystic lesions and pseudocysts. (44)

Intraductal papillary mucinous neoplasms can be imaged with endoscopic retrograde cholangiopancreatography (ERCP) or EUS. The endoscopic appearance of mucin extrusion from a widely patent ampulla is diagnostic of an intraductal papillary mucinous neoplasm. Contrast retrograde pancreatography will demonstrate the characteristic findings of mucinous filling defects within the duct, diffuse ductal dilation, and cystic dilation of side branches. (45) EUS may assist in the detection of malignancy arising from intraductal papillary mucinous neoplasms by demonstrating wall invasion and guiding fine needle aspiration. (46)

In summary, the endoscopic procedures, ERCP and EUS, have had a major impact on the management of patients with pancreatic malignancy. Early diagnosis may improve the patient management and length of survival from these aggressive malignancies.

References

1. Olnes MJ, Erlich R. A review and update on cholangiocarcinoma. Oncology 2004;66:167-179.

2. Kumar R, Sharma BC, Singh J, et al. Endoscopic biliary drainage for severe acute cholangitis in biliary obstruction as a result of malignant and benign diseases. J Gastroenterol Hepatol 2004;19:994-997.

3. Di Cesare E, Puglielli E, Michelini O, et al. Malignant obstructive jaundice: comparison of MRCP and ERCP in the evaluation of distal lesions. Radiol Med (Torino) 2003;105:445-453.

4. Pisters PW, Hudec WA, Hess KR, et al. Effect of preoperative biliary decompression on pancreaticoduodenectomy-associated morbidity in 300 consecutive patients. Ann Surg 2001;234:47-55.

5. Catalano MF, Linder JD, George S, et al. Treatment of symptomatic distal common bile duct stenosis secondary to chronic pancreatitis: comparison of single vs. multiple simultaneous stents. Gastrointest Endosc 2004;60:945-952.

6. Bjornsson E, Lindqvist-Ottosson J, Asztely M, et al. Dominant strictures in patients with primary sclerosing cholangitis. Am J Gastroenterol 2004;99:502-508.

7. Park MS, Kim TK, Kim KW, et al. Differentiation of extrahepatic bile duct cholangiocarcinoma from benign stricture: findings at MRCP versus ERCP. Radiology 2004;233:234-240.

8. Rosch T, Meining A, Fruhmorgen S, et al. A prospective comparison of the diagnostic accuracy of ERCP, MRCP, CT, and EUS in biliary strictures. Gastrointest Endosc 2002;55:870-876.

9. de Bellis M, Fogel EL, Sherman S, et al. Influence of stricture dilation and repeat brushing on the cancer detection rate of brush cytology in the evaluation of malignant biliary obstruction. Gastrointest Endosc 2003;58:176-182.

10. Yoon YS, Kim SW, Park SJ, et al. Clinicopathologic analysis of early ampullary cancers with a focus on the feasibility of ampullectomy. Ann Surg 2005;242:92-100.

11. Dixon E, Vollmer CM Jr, Sahajpal A, et al. Transduodenal resection of peri-ampullary lesions. World J Surg 2005;29:649-652.

12. Chak A, Catanzaro A. Innovative methods of biliary tract diagnosis: intraductal ultrasound and tissue acquisition. Gastrointest Endosc Clin N Am 2003;13:609-622.

13. Brugge WR. Endoscopic techniques to diagnose and manage biliary tumors. J Clin Oncol 2005;23:4561-4565.

14. Biankin AV, Kench JG, Biankin SA, et al. Pancreatic intraepithelial neoplasia in association with intraductal papillary mucinous neoplasms of the pancreas: implications for disease progression and recurrence. Am J Surg Pathol 2004;28:1184-1192.

15. Cheng CL, Sherman S, Fogel EL, et al. Endoscopic snare papillectomy for tumors of the duodenal papillae. Gastrointest Endosc 2004;60:757-764.

16. Byrne MF, Gerke H, Mitchell RM, et al. Yield of endoscopic ultrasound-guided fine-needle aspiration of bile duct lesions. Endoscopy 2004;36:715-719.

17. Eloubeidi MA, Chen VK, Jhala NC, et al. Endoscopic ultrasound-guided fine needle aspiration biopsy of suspected cholangiocarcinoma. Clin Gastroenterol Hepatol 2004;2:209-213.

18. Domagk D, Poremba C, Dietl KH, et al. Endoscopic transpapillary biopsies and intraductal ultrasonography in the diagnostics of bile duct strictures: a prospective study. Gut 2002;51:240-244.

19. Wight CO, Zaitoun AM, Boulton-Jones JR, et al. Improving diagnostic yield of biliary brushings cytology for pancreatic cancer and cholangiocarcinoma. Cytopathology 2004;15:87-92.

20. Baron TH, Harewood GC, Rumalla A, et al. A prospective comparison of digital image analysis and routine cytology for the identification of malignancy in biliary tract strictures. Clin Gastroenterol Hepatol 2004;2:214-219.

21. Fritscher-Ravens A, Broering DC, Knoefel WT, et al. EUS-guided fine-needle aspiration of suspected hilar cholangiocarcinoma in potentially operable patients with negative brush cytology. Am J Gastroenterol 2004;99:45-51.

22. Rumalla A, Baron TH. Evaluation and endoscopic palliation of cholangiocarcinoma: management of cholangiocarcinoma. Dig Dis 1999;17:194-200.

23. Jagannath P, Dhir V, Shrikhande S, et al. Effect of preoperative biliary stenting on immediate outcome after pancreaticoduodenectomy. Br J Surg 2005;92:356-361.

24. Martin RC II, Vitale GC, Reed DN, et al. Cost comparison of endoscopic stenting vs surgical treatment for unresectable cholangiocarcinoma. Surg Endosc 2002;16:667-678.

25. Wasan SM, Ross WA, Staerkel GA, et al. Use of expandable metallic biliary stents in resectable pancreatic cancer. Am J Gastroenterol 2005;100:2056-2061.

26. Bowling TE, Galbraith SM, Hatfield AR, et al. A retrospective comparison of endoscopic stenting alone with stenting and radiotherapy in non-resectable cholangiocarcinoma. Gut 1996;39:852-855.

27. Harewood GC, Baron TH, Rumalla A, et al. Pilot study to assess patient outcomes following endoscopic application of photodynamic therapy for advanced cholangiocarcinoma. J Gastroenterol Hepatol 2005;20:415-420.

28. Volmar KE, Vollmer RT, Jowell PS, et al. Pancreatic FNA in 1000 cases: a comparison of imaging modalities. Gastrointest Endosc 2005;61:854-861.

29. Prasad P, Schmulewitz N, Patel A, et al. Detection of occult liver metastases during EUS for staging of malignancies. Gastrointest Endosc 2004;59:49-53.

30. Brugge WR, Lauwers GY, Sahani D, et al. Cystic neoplasms of the pancreas. N Engl J Med 2004;351:1218-1226.

31. Balcom JH IV, Rattner DW, Warshaw AL, et al. Ten-year experience with 733 pancreatic resections: changing indications, older patients, and decreasing length of hospitalization. Arch Surg 2001;136:391-398.

32. Compton CC. Serous cystic tumors of the pancreas. Semin Diagn Pathol 2000;17:43-55.

33. Madura JA, Wiebke EA, Howard TJ, et al. Mucin-hypersecreting intraductal neoplasms of the pancreas: a precursor to cystic pancreatic malignancies. Surgery 1997;122:786-792; discussion 792-793.

34. Buetow PC, Rao P, Thompson LD. From the archives of the AFIP: mucinous cystic neoplasms of the pancreas: radiologic-pathologic correlation. Radiographics 1998;18:433-449.

35. Fukushima N, Mukai K, Kanai Y, et al. Intraductal papillary tumors and mucinous cystic tumors of the pancreas: clinicopathologic study of 38 cases. Hum Pathol 1997;28:1010-1017.

36. Hruban RH, Takaori K, Klimstra DS, et al. An illustrated consensus on the classification of pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasms. Am J Surg Pathol 2004;28:977-987.

37. Fernandez-del Castillo C, Targarona J, Thayer SP, et al. Incidental pancreatic cysts: clinicopathologic characteristics and comparison with symptomatic patients. Arch Surg 2003;138:427-423; discussion 433-434.

38. Curry CA, Eng J, Horton KM, et al. CT of primary cystic pancreatic neoplasms: can CT be used for patient triage and treatment? AJR Am J Roentgenol 2000;175:99-103.

39. Khurana B, Mortele KJ, Glickman J, et al. Macrocystic serous adenoma of the pancreas: radiologic-pathologic correlation. AJR Am J Roentgenol 2003;181:119-123.

40. Johnson CD, Stephens DH, Charboneau JW, et al. Cystic pancreatic tumors: CT and sonographic assessment. AJR Am J Roentgenol 1988;151:1133-1138.

41. Brugge WR. Evaluation of pancreatic cystic lesions with EUS. Gastrointest Endosc 2004;59:698-707.

42. Centeno BA, Warshaw AL, Mayo-Smith W, et al. Cytologic diagnosis of pancreatic cystic lesions: a prospective study of 28 percutaneous aspirates. Acta Cytol 1997;41:972-980.

43. van der Waaij LA, van Dullemen HM, Porte RJ. Cyst fluid analysis in the differential diagnosis of pancreatic cystic lesions: a pooled analysis. Gastrointest Endosc 2005;62:383-389.

44. Brugge WR, Lewandrowski K, Lee-Lewandrowski E, et al. Diagnosis of pancreatic cystic neoplasms: a report of the cooperative pancreatic cyst study. Gastroenterology 2004;126:1330-1336.

45. Albert J, Schilling D, Breer H, et al. Mucinous cystadenomas and intraductal papillary mucinous tumors of the pancreas in magnetic resonance cholangiopancreatography. Endoscopy 2000;32:472-476.

46. Bounds BC. Diagnosis and fine needle aspiration of intraductal papillary mucinous tumor by endoscopic ultrasound. Gastrointest Endosc Clin N Am 2002;12:735-745.

When you forgive, you in no way change the past--but you sure do change
the future.
--Bernard Meltzer

William R. Brugge, MD

From Massachusetts General Hospital, Boston, MA.

Reprint requests to William R. Brugge, MD, GI Unit, Blake 452c, Massachusetts General Hospital, Boston, MA 02114. Email: [e-mail]

Accepted March 30, 2006.

RELATED ARTICLE: Key Points

* Cholangiography can be provided by transhepatic, endoscopic, or radiologic (MRI) approaches.

* A focal, irregular, extrahepatic bile duct stricture is the hallmark for the imaging diagnosis of cholangiocarcinoma.

* Brush cytology of the bile duct is an insensitive test for the diagnosis of cholangiocarcinoma.

* Endoscopic ultrasound provides a new imaging modality for the detection and biopsy of pancreatic and bile duct masses.

* Endoscopic stenting is the method of choice for providing palliation from malignant biliary obstruction.

Table 1. Endoscopic and radiologic tests for imaging of the biliary
system

Procedure for imaging
of the biliary tree    Method of testing          Invasiveness

ERCP                   Endoscopic injection of    Moderate
                         contrast
MRCP                   Magnetic resonance         Noninvasive
                         imaging of the bile
                         duct
Transhepatic           Fluoroscopically guided    Moderate
  cholangiography        placement of a catheter
                         through the liver
Endoscopic ultrasound  Endoscopic placement       Moderate
Biliary T tube         Surgically placed          High

Procedure for imaging
of the biliary tree    Advantages                Disadvantages

ERCP                   Stones easily removed;    Requires endoscopic
                         stents in extrahepatic    access to the
                         ducts easily removed      duodenum
MRCP                   Visualization of the      Only diagnostic;
                         entire biliary            difficult to
                         tree and pancreatic       differentiate between
                         duct                      benign and malignant
                                                   strictures
Transhepatic           Provides imaging and      Stone removal is not
  cholangiography        drainage of               possible; internal
                         intrahepatic ducts        stenting is difficult
Endoscopic ultrasound  Staging of bile duct      May not be able to
                         malignancy                differentiate between
                                                   benign and malignant
                                                   lesions
Biliary T tube         Long term drainage of     Tissue sampling is
                         biliary tree              difficult

ERCP, endoscopic retrograde cholangiopancreatography; MRCP, magnetic
resonance cholangiopancreatography.

Table 2. Clinical features of pancreatic cystic neoplasms

Tumor              Sex     Age          Appearance

Mucinous           Female  Middle aged  Unilocular
  cystadenoma
Mucinous cystic    Female  Middle aged  Associated mass
  neoplasm
Intraductal        Mixed   Elderly      Unilocular, septated,
  papillary                               associated dilated ducts
  mucinous tumor
Serous             Female  Middle aged  Microcystic
  cystadenoma
Cystic endocrine   Mixed   Middle aged  Associated mass
  tumor
Solid cystic       Female  Young        Mixed solid and cystic
  pseudopapillary
  tumor

                                             Risk
Tumor              Histology                 of malignancy

Mucinous           Mucinous                  Moderate
  cystadenoma
Mucinous cystic    Malignant mucinous        High
  neoplasm
Intraductal        Papillary mucinous        Moderate
  papillary
  mucinous tumor
Serous             Serous (PAS positive for  Low
  cystadenoma        glycogen)
Cystic endocrine   Endocrine                 Low
  tumor
Solid cystic       Endocrine-like            Low
  pseudopapillary
  tumor