Cystic lesions of the pancreas are composed of a broad

2C: Pancreaticobiliary Problems cystic lesions in the pancreas William R. Brugge, MD, FACG Cystic lesions of the pancreas are composed of a broad range of neoplastic cysts and inflammatory pseudocysts. The neoplastic cysts span the spectrum of malignancy, from benign cystadenomas to premalignant and frankly malignant lesions. With the widespread use of abdominal imaging, the lesions are increasingly identified in early stages of asymptomatic patients. There are three basic types of pancreatic cystic lesions: serous, mucinous, and inflammatory 1,2 (Table 74.1). Serous cysts are considered benign lesions without malignant potential, while mucinous cystic lesions are considered premalignant or malignant. Inflammatory cystic lesions result from peri-pancreatic fluid collections that occur during episodes of acute pancreatitis or in association with chronic pancreatitis. Epidemiology Prevalence The prevalence of pancreatic cysts has been examined with autopsy and imaging studies. The reported prevalence of pancreatic cystic lesions ranges from 0.21% on ultrasound imaging 3 to 24.3% in an autopsy study. 4 Screening magnetic resonance imaging (MRI) studies in 1,444 patients in a general hospital population in the U.S. have demonstrated a prevalence rate of 19.6%. 5 This study included patients with known pancreatitis, jaundice, and biliary obstruction. A more recent study utilizing multi-detector computed tomography (CT) reported a prevalence of 2.6% in a series of 2,832 consecutive patient examinations and found that age and Asian race strongly correlated with the presence of a cyst. 6 Patients with a history of pancreatic lesion or predisposing factors for pancreatic disease were excluded from the study. Although the true prevalence of cystic lesions in the general population is unknown, it is clear that more frequent imaging and improved imaging modalities have resulted in a higher rate of detecting incidental cysts of the pancreas. Clinical Epidemiology Surgical pathology studies estimate that serous cystadenomas (SCAs) account for approximately 1 2% of all exocrine pancreatic neoplasms. 7 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 Reprinted with permission. Turner BG, Brugge WR. Cysts and Pseudocysts of the Pancreas. In: Hawkey C, Richter JE, Bosch J, Garcia-Tsao G, Chan F, Eds. Textbook of Clinical Gastroenterology and Hepatology. Wiley-Blackwell, Oxford, UK. In press 2011. a median age in the seventh decade of life. Mucinous cystic neoplasms (MCNs) account for approximately 2 5% of all exocrine pancreatic tumors and are more common than serous cystadenomas. 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 MCNs. Their true incidence is uncertain, but estimates range from 1% to 8% of all pancreatic tumors. 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. Finally, pancreatic pseudocysts have an incidence of 1.6 4.5% or 0.5-1 per 100,000 adults per year 8,9 and can complicate the clinical course in up to 30% to 40 % of patients with chronic pancreatitis. 10 Causes, Risk Factors, Disease Associations There are few known causes or risk factors for cystic neoplasms of the pancreas. Von Hippel-Lindau (VHL) disease is the best described genetic, inherited disorder associated with cystic lesions. 11 A French group prospectively evaluated 158 patients with VHL. Pancreatic involvement was observed in 122 patients (77.2%) and included true cysts (91.1%), serous cystadenomas (12.3%), neuroendocrine tumors (12.3%), or combined lesions (11.5%). Pancreatic pseudocysts are peripancreatic fluid collections that arise in association with inflammatory conditions of the pancreas in patients with pancreatitis and disruption of the pancreatic duct due to surgery or trauma. Pathogenesis (see Table 2) Completion of the global pancreatic cancer genome project permitted better understanding of genetic alterations leading to the development of pancreatic ductal carcinoma. 12 The pathogenesis of cystic neoplasms of the pancreas is also becoming better understood. Serous cystadenomas are strongly associated with mutations of the VHL gene, located on chromosome 3p25. 13 The VHL gene is likely to play a sentinel role in the pathogenesis of sporadic serous cystadenomas. In one study, 70% of the sporadic SCAs studied demonstrated loss of heterozygosity (LOH) at 3p25 with a VHL gene mutation in the remaining allele. 14 The mutations in the VHL gene probably affect most commonly the centro-acinar cell and result in hamartomatous proliferation of these small cuboidal cells. MCNs and IPMNs are thought to have a different pathogenesis compared to SCAs. MCNs frequently contain mutations of 240 2C: Pancreaticobiliary Problems

Table 1: Types of Cystic Lesions Serous (benign without malignant potential) Mucinous (pre-malignant or malignant) Inflammatory (fluid collections, pseudocysts) Figure 1: Serous cystadenoma. Gross pathology of a serous cystadenoma. Table 2: Pathogenesis of Cystic Lesions Type of Cystic Lesion Genetic Alterations Serous Mutations of VHL gene (3p25) Mucinous Cystic Mutations of K-ras, p53 Neoplasms IPMN Mutations of PIK3CA, Expression of CDX2, MUC1, MUC2 Inflammatory None the K-ras oncogene and p53 tumor suppressor gene, and the frequency of this mutation increases with increasing degrees of dysplasia in the tumor. The frequency of K-ras mutation in MCNs is linearly related to the grades of atypia. 15 However, the degree of atypia in IPMNs does not seem to correlate with the presence of K-ras mutations. LOH of the p16 gene was observed with increasing degrees of histological atypia in IPMNs, whereas LOH of the p53 gene was seen only in invasive carcinomas. Other genetic alterations including an inactivating mutation in p16/cdkn2a and the strong expression of MUC1 and MUC2 have been found in IPMNs. More specifically, mutations in PIK3CA and the strong expression of CDX2 are associated with specific intestinal-type IPMNs. 16 Finally, it is worth noting that DPC4 (deleted in pancreatic cancer) is expressed in all IPMNs, but appears inactivated in about half of pancreatic tumors. Pseudocysts have no epithelium lining the focal fluid collections and the fluid originates from the leakage of fluid and debris from an inflammatory or traumatic process in the adjacent pancreas. Two basic mechanisms describe pancreatic pseudocyst formation. 17 In the ductal-leakage mechanism, localized necrosis of a pancreatic duct may allow the leakage of fluid out of the pancreas and into spaces formed by organs adjacent to the pancreas. Over time, the fluid collection becomes better organized and walled-off by a thick, fibrotic wall. Communication between the ductal system and the pseudocyst cavity will often persist, resulting in a chronic pancreatic pseudocyst. A minority of pseudocysts have no association with the pancreatic ductal system. Presumably, the origin of the fluid is not leakage, but liquefactive necrosis of pancreatic tissue in severe acute pancreatitis. This type of focal fluid collection often resolves spontaneously. Pathology Serous Cystadenomas (Figure 1) Serous tumors have three variants based on gross morphology: microcystic, macrocystic, and solid. Microcystic SCAs are the most common and are composed of innumerable small cysts with a honeycomb-like appearance on cross-section. Microcystic SCAs may achieve a large diameter over the long term and the large lesions often have a fibrotic or calcified central scar. Macrocystic SCAs are composed of far fewer cysts and the presence of discrete, large cystic cavities mimics the appearance of mucinous lesions. The cyst fluid from SCAs is thin, clear, and contains no mucin. The epithelial cells of all types of serous cystadenomas are similar in appearance with a cuboidal shape, glycogen-rich, clear cytoplasm, and small, regular centrally located nuclei. 18 The appearance of the surrounding stroma is variable and ranges from highly vascular to fibrotic. Mucinous Cystic Neoplasms (Figure 2) Grossly, MCNs are characteristically macrocystic with discrete individual cavities that vary in diameter. 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 divides MCNs into three types, based on the degree of epithelial dysplasia: benign, borderline, and malignant. The entire tumor is classified according to the most advanced degree of dysplasia/carcinoma present. MCNs 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 2C: Pancreaticobiliary Problems 241

Figure 2: Mucinous cystic lesion. Gross pathology of a mucinous cystic lesion. definition of MCNs to include only those cystic mucinous tumors that contain ovarian stroma. IPMNs originate in the distal main pancreatic duct in 80% of cases. The presence of a papillary tumor causes dilatation of the ducts as a result of tumor growth. The degree of ductal ectasia varies with the degree of mucin production, but duct dilatation evident on imaging studies or gross pathologic examination is a sine qua non of the diagnosis. Mucin production may be so exuberant that extrusion from papilla of Vater is seen. 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. Pancreatic Pseudocysts Pathologic examination of pancreatic pseudocysts can reveal a fluid collection of necrotic fat, as well as a mixture of necrotic cells with surrounding granulation tissue. Persistence of the inflammatory collection results in the formation of a fibrotic pseudocapsule around the fluid. In a recent study of 42 patients with pseudocysts, 75% of cysts had histocytes, neutrophils, or both. In addition, 31% contained yellow, pigmented material and 24% showed fat necrosis. 19 Clinical Presentation Most patients with a pancreatic cystic lesion have no signs or symptoms related to the pancreatic lesion. Often the lesion is incidentally found with computed tomography (CT) or ultrasound (US) imaging performed for a variety of indications. Symptomatic patients commonly present with recurrent abdominal pain, nausea, and vomiting as a result of mild pancreatitis. These symptoms often reflect the presence of a lesion connected to the main ductal system or duct obstruction. Chronic abdominal pain is a rare presentation of a benign cystic lesion and suggests a malignancy or a pseudocyst. Patients with a cystic malignancy will present with symptoms and signs similar to pancreatic cancer, i.e., pain, weight loss, and jaundice. Pseudocysts may arise after an episode of acute pancreatitis or insidiously in the setting of chronic pancreatitis and are associated with chronic abdominal pain. Large pseudocysts can compress the stomach, duodenum, or bile duct, causing early satiety, vomiting, or jaundice. Differential Diagnosis The finding of a cystic lesion of the pancreas by imaging exams presents the clinician with a wide range of possible diagnoses. The most important differentiation is between a cystic neoplasm and a pseudocyst. Although pancreatic pseudocysts usually arise in association with pancreatitis, the acute episode of pancreatitis may not have been clinically apparent or the patient may have mild chronic pancreatitis. Evidence of inflammatory changes or calcifications in the pancreas suggests an associated cystic lesion is a pseudocyst. However, in the acute setting of mild pancreatitis it may be difficult to differentiate between a cystic neoplasm that has caused pancreatitis and a pseudocyst that has formed as a result of pancreatitis. If a pancreatic pseudocyst can be excluded on the basis of a clinical history or imaging findings, attention should be focused on the differential between the types of cystic neoplasms. The principal differentiation is between mucinous and serous lesions because the fundamental difference in management is based on the neoplastic potential of mucinous lesions. Serous lesions may not require resection unless the patient suffers complications, while mucinous cystic lesions are often resected because of the propensity towards growth and malignant degeneration. Diagnostic Methods CT is an excellent test for cystic lesions of the pancreas because of its widespread use and ability to detect cysts 20 (Figure 3). MR imaging is used increasingly because of the lack of radiation exposure and the ability to image the pancreatic duct with MR cholangiopancreatography (MRCP). Transabdominal ultrasonography is limited as a diagnostic tool due to poor visualization of the pancreas as a result of intervening bowel gas. Although seen in less than 20% of lesions, demonstration of a central scar by CT or MRI is a highly diagnostic feature of a serous cystadenoma. The honeycombed or microcystic appearance of the lesion is commonly used to provide a diagnosis. However, macrocystic serous cystadenomas are difficult to diagnose with cross-sectional imaging because of the morphologic similarities with mucinous lesions. MCNs, 242 2C: Pancreaticobiliary Problems

Figure 3: Pseudocyst. Abdominal CT scan of a simple, thin-walled pseudocyst indicated by white arrows. Table 3: Diagnosis of Cystic Lesions Fluid CEA Cytology Serous Thin Low Cuboidal cells, glycogen-rich Mucinous Viscous High Mucinous cells Pseudocyst Thin Low Macrophages, other inflammatory cells in contrast, are commonly diagnosed with CT based on their unilocular or macrocystic characteristics (Figure 4). Though infrequent, the finding of peripheral calcification by CT is specific for a MCN. IPMNs 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. Despite these imaging features, the ability to diagnose a specific cystic lesion accurately and to determine whether malignancy is present using CT and MRI remains a challenge. 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 fluidfilled 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. IPMNs can be imaged with endoscopic retrograde cholangiopancreatography (ERCP) or endoscopic ultrasound (EUS). The endoscopic appearance of mucin extrusion from a widely patent ampulla is diagnostic of an IPMN. Contrast retrograde pancreatography will demonstrate the characteristic findings of mucinous filling defects within the duct, diffuse ductal dilation, and cystic dilation of side branches. EUS has been increasingly used to diagnose cystic lesions of the pancreas and guide fine needle aspiration (FNA). Despite the high-resolution imaging of EUS, the detailed imaging features of cystic neoplasms by EUS are not always sufficient to accurately differentiate between benign and malignant cystadenomas; however, the presence of an intramural nodule, mass lesion, or invasive tumor accurately predict malignancy (Figure 5). Cyst material, aspirated using EUS guidance, can be analyzed through the use of cytology and a variety of tumor markers. Small, cuboidal cells in cytologic specimens are diagnostic of serous cystadenomas (Table 3). In contrast, mucinous cystadenoma may have epithelial cells with evidence of mucin secretion or atypia. Only inflammatory cells should be present in the fluid aspirated from pseudocysts. However, the low cellular content of cyst fluid has resulted in poor sensitivity in cytologic distinction between mucinous and non-mucinous lesions. 21 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) and CA 72-4 concentrations are high in mucinous lesions and quite low in serous cystadenomas. 21,22 Unfortunately, there is considerable overlap in cyst fluid CEA concentration in benign and malignant mucinous cystic lesions and pseudocysts. A recent study offers hope that cyst fluid DNA analysis can accurately diagnose malignancy in the cases of negative cytology and help to identify mucinous lesions. 23 The use of cyst fluid kras to identify mucinous lesions is highly specific (greater than 95%) and moderately sensitive (45%). Cyst fluid amylase levels are used to differentiate between cystadenomas and pseudocysts. Treatment and Prevention Cystic Neoplasms Surgical resection is the treatment of choice for premalignant cystic neoplasms. The decision to resect a lesion, however, is based on the presence or absence of symptoms, the risk of malignancy, and the surgical risk of the patient. High-risk patients with low-grade cystic neoplasms may be monitored with periodic CT/MRI scanning or EUS-FNA. In 2006, the Sendai Consensus Guidelines for the management of IPMNs and MCNs of the pancreas was established. MCNs are typically located in the tail of the pancreas and a distal pancreatectomy is sufficient for these premalignant lesions. Unless invasive carcinoma is suspected or discovered at surgery, the spleen can often be preserved. SCAs are resected by removing the involved portion of the pancreas: head (Whipple), body (middle pancreatectomy), or tail (tail resection). Since IPMNs invade the pancreas along ductal 2C: Pancreaticobiliary Problems 243

Figure 3: Pseudocyst. Abdominal CT scan of a simple, thin-walled pseudocyst indicated by white arrows. Figure 5: Mucinous lesion. Endoscopic ultrasound of a malignant mucinous lesion with a mass filling the cystic space. The white arrow indicates the outer wall of the cyst. structures, frozen section histology is used during surgery to ensure negative margins. High-risk IPMNs involving the entire pancreas require total pancreatectomy. These surgical approaches often require that the patients be managed in centers with considerable experience in cystic tumors of the pancreas. Pancreatic Pseudocysts Pseudocysts less than 4 cm in diameter often resolve spontaneously and are rarely associated with clinical symptoms. Only 40% of pseudocysts less than 6 cm in diameter will require drainage due to complications or persistence. Small pseudocysts located in the tail of the pancreas and arising from acute biliary pancreatitis have a very high rate of spontaneous drainage. Prior to drainage, it is critical to confirm the diagnosis of a pseudocyst using fluid analysis and cytology. Mistakenly diagnosed pseudocysts that are drained with percutaneous drainage often do not resolve and may harbor occult malignancy. Drainage of Pseudocysts Pancreatic pseudocysts may be drained using a variety of approaches. External drainage using CT/US guidance is the most common approach and involves the percutaneous placement of a small drainage catheter. 25 Fluid is drained into an external collection system carried by the patient. The short-term success rate for this relatively simple technique is very high, more than 90%. Patients with communicating pseudocysts, however, should not have percutaneous drainage because of the high risk of prolonged drainage and fistula formation. Surgical drainage of pseudocysts is performed by providing a large anastomosis between the pseudocyst wall and the stomach or small bowel. The anastomosis should be located in the most dependent portion of the cystic cavity in order to maximize drainage. Surgical drainage is probably the best approach when the pseudocyst is complicated by areas of necrosis, infection, or involves adjacent organs such as the spleen. However, maturation of a pseudocyst wall over 4 6 weeks will allow the formation of a thick wall that will provide a more secure anastomosis. Cyst-gastrostomy is the easiest approach and requires less operating time than cystjejunostomy. However, the risk of bleeding is greater with cyst-gastrostomy. Studies report overall success rates for surgical drainage of 90% with major complication rates of 9% and recurrence rates of 3%. Endoscopic drainage of pseudocysts is an alternative to surgical or radiologic drainage. 26 This type of drainage is used most commonly for uncomplicated, unilocular pseudocysts. Pseudocyst drainage is accomplished with either a transpapillary approach with ERCP or direct endoscopic stent placement across the stomach or duodenal wall. (Video 74.1) 27 A transpapillary approach with drainage is used when the pseudocyst communicates with the main pancreatic duct, usually in the head of the pancreas. A transgastric or duodenal approach is used when the pseudocyst is directly adjacent to the gastroduodenal wall. EUS is often used to determine the size, location, and thickness of the pseudocyst wall and may reduce the rate of complications. 28 A wall thickness of more than 1 cm or the presence of large intervening vessels or varices as made evident by the EUS exam precludes endoscopic drainage. In the absence of a visible bulge in the stomach or duodenal wall, EUS localization of the pseudocyst is required prior to the placement of a transmural catheter or stent. One-step EUS-directed drainage can be performed with the use of pseudocyst drainage catheters that can be used in 244 2C: Pancreaticobiliary Problems

Table 4: Drainage Procedures for Pseudocyst Type Procedure Surgical Cyst-gastrostomy Radiologic Percutaneous cyst drainage Endoscopic Transgastric cyst-gastrostomy stenting with and without EUS guidance therapeutic echoendoscopes. Overall, the complication rate of elective endoscopic drainage is about 13% with success rates up to 90% and recurrence rates of 10 20%. A recent study of laparoscopic, endoscopic, and open pancreatic cystgastrostomy for pancreatic pseudocyst demonstrated no significant difference in the overall success rates between the three groups. 29 Complications and Their Management Complications of cystic neoplasms are rare and consist of malignant invasion of local structures, such as the bile duct. Endoscopic stenting is the treatment of choice unless the lesion is surgically resectable. Bleeding and infection are the most common complications of pancreatic pseudocysts. Arterial pseudoaneurysms are the most common cause of intracystic and intraductal bleeding and should be managed with angiography. The treatment of choice for infected pseudocysts is external drainage. Prognosis With and Without Treatment The prognosis for resected cystic tumors of the pancreas is excellent. 30 There have been only rare reports of tumor recurrence in cases where the lesion was completely resected and there was no evidence of malignant tissue in the resected specimen. Even for IPMNs containing carcinoma (which comprises almost 60% of resected tumors) the 5-year survival is over 50%. 31 The worst prognosis is for advanced, transmural adenocarcinomas arising from mucinous lesions; the 5-year survival is only 30% for resected lesions. Current Controversies With the widespread use of CT/MRI and EUS-FNA, cystic lesions continue to be identified at an early stage. Without a firm understanding of the natural history of mucinous cystadenomas, it is difficult to know when and if surgical resection should be performed. Non-invasive therapies such as chemical ablation of pancreatic cysts would offer alternatives to surgical therapy. Groups have used ethanol injection, in the Ethanol Pancreatic Injection of Cysts (EPIC) trial, 32 as well as combination ethanol/paclitaxel injection. 33 The EUS 2008 Working Group has offered comments on the current state of these promising therapies. 34 Sources of Information for Patients and Doctors www.pancreasfoundation.org REFERENCES 1. Brugge WR, Lauwers GY, Sahani D, et al. Cystic neoplasms of the pancreas. N Engl J Med 2004;351:1218-26. 2. Hamilton SR, Aaltonen, LA. Pathology and Genetics. Tumors of the Digestive System. World Health Organization Classification of Tumours. Volume 2. 3rd ed. Lyon: IARC Press, 2000. 3. Ikeda M, Sato T, Morozumi A, et al. Morphologic changes in the pancreas detected by screening ultrasonography in a mass survey, with special reference to main duct dilatation, cyst formation, and calcification. Pancreas 1994;9:508-12. 4. Kimura W, Nagai H, Kuroda A, et al. Analysis of small cystic lesions of the pancreas. Int J Pancreatol 1995;18:197-206. 5. Zhang XM, Mitchell DG, Dohke M, et al. Pancreatic cysts: Depiction on single-shot fast spin-echo MR images. Radiology 2002;223:547-53. 6. Laffan TA, Horton KM, Klein AP, et al. Prevalence of unsuspected pancreatic cysts on MDCT. AJR Am J Roentgenol 2008;191:802-7. 7. Compton CC. Serous cystic tumors of the pancreas. Semin Diagn Pathol 2000;17:43-55. 8. Sandy JT, Taylor RH, Christensen RM, et al. Pancreatic pseudocyst. Changing concepts in management. Am J Surg 1981;141:574-6. 9. Wade JW. Twenty-five year experience with pancreatic pseudocysts. Are we making progress? Am J Surg 1985;149:705-8. 10. Boerma D, Obertop H, Gouma DJ. 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Clonality and K-ras mutation analyses of epithelia in intraductal papillary mucinous tumor and mucinous cystic tumor of the pancreas. Virchows Arch 2002;441:437-43. 16. Hruban RH, Adsay NV. Molecular classification of neoplasms of the pancreas. Hum Pathol 2009;40:612-23. 17. Byrne MF, Mitchell RM, Baillie J. Pancreatic pseudocysts. Curr Treat Options Gastroenterol 2002;5:331-338. 18. Pyke CM, van Heerden JA, Colby TV, et al. The spectrum of serous cystadenoma of the pancreas. Clinical, pathologic, and surgical aspects. Ann Surg 1992;215:132-9. 19. Gonzalez Obeso E, Murphy E, Brugge W, et al. Pseudocyst of the pancreas: The role of cytology and special stains for mucin. Cancer Cytopathol 2009;117:101-7. 20. 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. 2C: Pancreaticobiliary Problems 245

21. Brugge WR, Lewandrowski K, Lee-Lewandrowski E, et al. Diagnosis of pancreatic cystic neoplasms: A report of the cooperative pancreatic cyst study. Gastroenterology 2004;126:1330-6. 22. Frossard JL, Amouyal P, Amouyal G, et al. Performance of endosonography-guided fine needle aspiration and biopsy in the diagnosis of pancreatic cystic lesions. Am J Gastroenterol 2003;98:1516-24. 23. Khalid A, Zahid M, Finkelstein SD, et al. Pancreatic cyst fluid DNA analysis in evaluating pancreatic cysts: A report of the PANDA study. Gastrointest Endosc 2009;69:1095-102. 24. Tanaka M, Chari S, Adsay V, et al. International consensus guidelines for management of intraductal papillary mucinous neoplasms and mucinous cystic neoplasms of the pancreas. Pancreatology 2006;6:17-32. 25. Andersson R, Cwikiel W. Percutaneous cystogastrostomy in patients with pancreatic pseudocysts. Eur J Surg 2002;168:345-8. 26. De Palma GD, Galloro G, Puzziello A, et al. Endoscopic drainage of pancreatic pseudocysts: A long-term follow-up study of 49 patients. Hepatogastroenterology 2002;49:1113-5. 27. Varadarajulu S. EUS followed by endoscopic pancreatic pseudocyst drainage or all-in-one procedure: A review of basic techniques (with video). Gastrointest Endosc 2009;69:S176-81. 28. Sanchez Cortes E, Maalak A, Le Moine O, et al. Endoscopic cystenterostomy of nonbulging pancreatic fluid collections. Gastrointest Endosc 2002;56:380-6. 29. Melman L, Azar R, Beddow K, et al. Primary and overall success rates for clinical outcomes after laparoscopic, endoscopic, and open pancreatic cystgastrostomy for pancreatic pseudocysts. Surg Endosc 2009;23:267-71. 30. Harper AE, Eckhauser FE, Mulholland MW. Resectional therapy for cystic neoplasms of the pancreas. Am Surg 2002;68:353-7; discussion 357-8. 31. Kanazumi N, Nakao A, Kaneko T, et al. Surgical treatment of intraductal papillary-mucinous tumors of the pancreas. Hepatogastroenterology 2001;48:967-71. 32. Dewitt J, McGreevy K, Schmidt CM. Ethanol Pancreatic Injection of Cysts (EPIC): Preliminary results of a prospective multicenter, randomized, double blinded study. Gastrointest Endosc 2007;65:AB106. 33. Oh HC, Seo DW, Lee TY, et al. New treatment for cystic tumors of the pancreas: EUS-guided ethanol lavage with paclitaxel injection. Gastrointest Endosc 2008;67:636-42. 34. Ho KY, Brugge WR. EUS 2008 Working Group document: Evaluation of EUS-guided pancreatic-cyst ablation. Gastrointest Endosc 2009;69:S22-7. 246 2C: Pancreaticobiliary Problems