Cystic lesions of the pancreas

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1 & 2007 USCAP, Inc All rights reserved /07 $ Cystic lesions of the pancreas N Volkan Adsay Department of Pathology, Harper Hospital and Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA Although cystic tumors of the pancreas are relatively rare, they constitute an increasingly important category. Advances in imaging and interventional techniques and the sharp drop in the mortality rate of pancreatic surgery have rendered pancreatic biopsies and resections commonplace specimens. Consequently, in the past two decades, the nature of many cystic tumors in this organ has been better characterized. The names of some existing entities were revised; for example, what was known as papillary-cystic tumor is now regarded as solidpseudopapillary tumor. New entities, in particular, intraductal papillary mucinous neoplasm and its variants, such as oncocytic and intestinal subtypes were recognized. The importance of clinical and pathologic correlation in the evaluation of these lesions was appreciated, in particular, with regards to the multifocality of these lesions, their association with invasive carcinomas, and thus their preinvasive nature. Consensus criteria for the distinction of these from the ordinary precursors of adenocarcinoma, the pancreatic intraepithelial neoplasia, were established. The definition of mucinous cystic neoplasms was refined; ovarian-like stroma has now become almost a requirement for the diagnosis of mucinous cystic neoplasia, and defined as such, the propensity of these tumors to occur in perimenopausal women became even more striking. The validity and clinical value of classifying the pancreatic cysts of mucinous type as adenoma, borderline, CIS and invasive have been established. Related to this, the importance of thorough sampling in accurate classification of these mucinous lesions was recognized. Greater accessibility of the pancreas afforded by improved invasive as well as noninvasive modalities has also increased the detection of otherwise clinically silent cystic tumors, which has led to the recognition of more innocuous entities such as acinar cell cystadenoma and squamoid cyst of pancreatic ducts. As the significance of the cystic lesions emerged, cystic forms of otherwise typically solid tumors were also better characterized. Thus, significant developments have taken place in the classification and our understanding of pancreatic cystic tumors in the past few years, and experience with these lesions is likely to grow exponentially in the coming years.. doi: /modpathol Keywords: pancreas; cyst; intraductal; mucin; papillary; carcinoma Dorland s Medical Illustrated dictionary defines a cyst as any closed cavity or sac, normal or abnormal, lined by epithelium, and especially one that contains a liquid or semisolid material. 1 In the pancreas, however, this term has been applied to a variety of lesions, ranging from radiologically low-attenuated tumors, to any process that forms a cavity, and in some cases, whether it has an epithelial lining or not. Therefore, the term cyst has become associated with some pancreatic lesions that do not fulfill the dictionary definition of the term. Overall, cystic tumors of the pancreas are significantly less common than solid ones. It is estimated that less than 1% of pancreatic tumors Correspondence: Associate Professor Dr, MD, Department of Pathology, Harper Hospital and Wayne State University, 3990 John R Street, Detroit, MI 48201, USA. adsayv@med.wayne.edu Received 1 August 2006; revised and accepted 2 August 2006 seen in oncology clinics are cystic; however, in resection specimens cystic ones are becoming increasingly more common, reportedly up to 15% of the cases in some institutions. There are important reasons for this increase in frequency, particularly among resection specimens: (1) recent developments in imaging techniques have led to increased detection of clinically silent tumors, (2) most cystic lesions are noninfiltrative, and are thus resectable, (3) most cystic tumors are biologically curable, (4) advances in surgical and perioperative care have decreased the mortality rate of pancreatectomy procedures from 20 to 30% in 1980s to below 5% in very high-volume institutions, and therefore, most cystic tumors undergo resection, such that there is a remarkable increase in the exposure of surgical pathologists to these lesions. This contrasts with invasive ductal (pancreatobiliary-type) adenocarcinoma in this organ, which is the most common tumor type (485% of all cases), is

2 S72 Table 1 Estimated relative frequency of the cystic lesions in the pancreas I. No lining Pseudocyst : pancreatitisassociated II. True lining III. Degenerative/necrotic change in a neoplasm a Numbers reflect approximate percentages. mostly unresectable (80%), and associated with a dismal prognosis (5-year survival o5%). The relative frequencies of cystic lesions in the pancreas vary substantially from institution to institution, from primary vs tertiary care centers, and presumably even from region to region. 2,3 The lesions below are discussed in an order that reflects both the frequency and clinical significance of different cystic lesions in this author s experience based upon a large surgical and autopsy database from an institution that serves both as a primary and tertiary care center, as well as the author s consultation material and the published data in the literature. Estimated relative frequency of cystic lesions accordingly is shown in Table 1. There is no formal classification of cystic neoplasms of the pancreas. For the purpose of this text, they will be categorized based on the presence and type of cyst lining at the microscopic level (Table 2). Pseudocysts (no lining) Conventional Pseudocysts Cystic lesions of the pancreas Most cavity-forming lesions of the peripancreatic region are pseudocysts. 4 6 The entity referred to as pseudocyst is a non-neoplastic complication of pancreatitis caused by alcoholic, biliary, or traumatic acute pancreatitis. 7,8 It develops when a focus of peripancreatic fat necrosis is resorbed, producing a debris-filled space rich in pancreatic exocrine enzymes. Pseudocysts may measure up to several centimeters. The pathologic findings may vary depending on the stage of the process. The cyst contents, originally necrotic fat, transform into a mixture of necrotic cells, enzymes, scavenger cells, hematoidin pigment, cholesterol clefts, and sometimes neutrophils. There is no epithelial lining. The adjacent stroma may be hypercellular (Figure 1). The tissue that surrounds the necrotic material first produces granulation tissue, and eventually becomes a fibrotic pseudocapsule. Depending on the 30 a Mucinous Intraductal papillary 20 mucinous neopl. Mucinous cystic neopl. 10 Serous 20 Others (squamous, acinar, o5 endothelialy) Solid-pseudopapillary neoplasm Cystic ductal adenocarcinoma Others (endocrine, mets., etc) o5 o5 o5 Table 2 Types of cystic lesions in the pancreas based on their lining Pseudocysts (no lining) Conventional pseudocysts Paraduodenal wall cyst (cystic dystrophy) Infection-related pseudocysts Cysts with mucinous epithelium Intraductal papillary mucinous neoplasms and intraductal oncocytic papillary neoplasms Mucinous cystic neoplasms Mucinous non-neoplastic cysts, mucoceles and retention cysts Serous (clear-cell) cystic tumors Serous cystadenoma VHL-associated pancreatic cysts Serous cystadenocarcinomas Squamous-lined cysts Lymphoepithelial cysts Epidermoid cysts within intrapancreatic accessory spleen Dermoid cysts Squamoid cyst of pancreatic ducts Cysts lined by acinar cells Acinar cell cystadenocarcinomas Acinar cell cystadenomas (cystic acinar transformation) Endothelial-lined cysts Lymphangiomas Degenerative or necrotic changes in solid tumors Solid-pseudopapillary tumor Cystic change in ordinary ductal adenocarcinoma Cystic pancreatic endocrine neoplasia (islet cell tumors) Cystic change in other invasive carcinomas Cystic mesenchymal neoplasms Other rare cystic lesions Cystic hamartomas Enterogenous (congenital; duplication) cysts and duodenal diverticula Endometriotic cyst Secondary tumors Congenital or developmental cysts Others Unclassified cysts severity and duration of the pancreatitis, the pseudocyst may resolve spontaneously, or may achieve a size that is no longer self-resorbable, and require surgical intervention. Pseudocysts do not present a risk of malignant degeneration, and the treatment of pseudocysts differs dramatically from that of cystic neoplasms of the pancreas. Fortunately, the clinical diagnosis of a pseudocyst is usually straightforward; however, neoplasms may mimic a pseudocyst and conversely. There are case reports of virtually every pancreatic neoplasm presenting like a pseudocyst Solidpseudopapillary neoplasms often undergo massive cystic degeneration, and mucinous cystic neoplasms. 15 have a tendency to become infected and exhibit suppurative contents. The ovarian stroma characteristic of the latter may be confused microscopically with the granulation tissue of pseudo-

3 Cystic lesions of the pancreas S73 Figure 1 Pseudocyst. Pseudocyst is defined by the lack of an epithelial lining. The constituents of the wall vary depending on the stage of the lesion; in the earlier phase, necrotic debris and precipitated acinar secretions are present in the lumen, and granulation tissue on the wall. Later on, fibrosis becomes more prominent. In this example, histiocytes are prominent adjacent to the lumen of the cyst, and there is a cellular stroma around it. This can mimick ovarian-type stroma of mucinous cystic neoplasms. cysts and vice versa. Proper sampling is essential for the correct diagnosis in such cases. It should also be kept in mind that ductal adenocarcinoma, although rarely, may undergo central necrosis and clinically mimic pseudocysts. 2,16 19 Paraduodenal wall cyst (cystic dystrophy) This is one of the complications of a subset of chronic pancreatitis that we refer to as paraduodenal pancreatitis. 20 These cysts appear to occur as a consequence of chronic fibrosing inflammation in the periampullary region in which one or more of the accessory ducts form a cyst on the duodenal wall, and mimic duodenal duplication. 5,21,22 This usually occurs in the background of microcystic trabeculation of the duodenal wall by myo-adenomatosis type changes that form a pseudotumor which may also involve the adjacent pancreas in the groove area (the so-called groove pancreatitis 23 ). The cyst wall may be partly lined by ductal epithelium and partly by inflammation as well as granulation tissue. 24 In our experience, 21,22 this process is often located in the second portion of the duodenum, (Figure 2) centered around the accessory ampulla, and may be associated with the scarring of common bile duct, mimicking pancreas cancer. We believe paraduodenal wall cysts are closely related to the socalled cystic dystrophy. 25 In our experience, they occur predominantly in males, at age years, often with a history of alcohol abuse, and in the context of severe abdominal symptoms. 20 Some were interpreted to be associated with pancreatic heterotopia in the duodenal wall. 26 Figure 2 Paraduodenal wall cyst. In some patients with pancreatitis, in particular of the paraduodenal type (also called cystic dystrophy of duodenal wall), one or more of the cysts may become fairly large, and located on the duodenal wall, mimicking duodenal duplication. These may be partly lined by ductal epithelium, but are mostly lined by granulation tissue. Infection-related pseudocysts Other rare inflammatory cysts that can occur in the pancreas include parasitic cysts such as echinococcal cyst and necrotic tuberculous infections. 30,31 Cysts with mucinous epithelium Intraductal Papillary Mucinous Neoplasms Intraductal papillary mucinous neoplasms (IPMNs) are characterized by cystic dilatation of pancreatic ducts in which an intraductal proliferation of neoplastic mucin-producing cells is usually arranged in papillary patterns 14,32 51 (Figure 3). The papillae may range from microscopic to large nodular masses. Mucin production by the neoplastic cells is usually associated with intraluminal mucin secretion which leads to cystic dilatation of the ducts, and at times, to mucin extrusion from the ampulla of Vater, a finding that is virtually diagnostic of an IPMN. Depending upon the location of the primary process and subsequent mechanical changes in the ducts, IPMNs may present as a spectrum of multilocular cystic masses, villous/papillary nodules or with mucin extrusion from the ampulla. This spectrum is reflected in the variety of designations that had been given to these neoplasms including mucinous duct ectasia 52 (ductectatic mucinous cystadenoma), 53 mucin-producing tumor, 54,55 and villous adenoma 56 or papillary carcinoma. 57,58 The term coined by Günter Klöppel, IPMN, is now widely accepted as the designation of these neoplasms. 44,50,59 IPMNs are estimated to account for B5% of pancreatic neoplasms, however, they are being reported in increasing numbers and may be more common than previously recognized. 35,39

4 S74 Cystic lesions of the pancreas Figure 3 IPMNs. In this example, the main duct is markedly dilated, and there is a polypoid nodule filling the lumen of the proximal segment of the duct (arrows). Clinically, patients with an IPMN usually present in the 7 8th decade of life with nonspecific abdominal symptoms, although in some, a history of pancreatitis is noted. Approximately, 30% of the patients have tumors in other organs, some synchronous and others metachronous. 34,60,61 Endoscopic findings, particularly mucin extrusion from the ampulla of Vater, and radiologic findings, especially ectasia of the pancreatic ducts, are virtually diagnostic for these neoplasms. IPMN occurs predominantly in the head of the pancreas. Macroscopic examination of IPMNs is imperative for documenting involvement of the pancreatic ductal system and the distribution of the disease within the ductal system, especially since there are no basal or myoepithelial cells in pancreatic ducts to distinguish native ducts. In some cases, the IPMN primarily involves the main pancreatic duct, (Figure 3) and in others the branch ducts; the latter is predominant particularly in those that arise in the uncinate process. The latter have been referred to as branch-duct -type IPMNs. 49,62 65 Some authors believe this variant is a biologically distinct entity, and therefore every attempt should be made during macroscopic examination to determine the distribution of the lesion. 47,49,60,62,64 67 IPMNs may be localized, multicentric or, rarely, the entire ductal system may be involved. Careful examination and sampling of the specimen for an invasive carcinoma component is of vital importance. Microscopically, the cystically dilated ducts of IPMNs contain mucin-producing cells with various degrees of atypia (Figure 4). Papillae with three distinct morphologic patterns may be seen 34,68 73 (1) intestinal, which is morphologically similar to that of colonic villous adenomas of the colon (Figure 5) and (2) pancreatobiliary, in which the papillae are more complex and are lined by cuboidal cells with prominent nucleoli. (3) gastric, rarely some papillas have gastric foveolar appearance (Figure 6). As this phenotype is also common in the nonpapillary areas of these tumors, it is also referred to as null type. The first group does in fact show molecular characteristics of intestinal differentiation as evidenced by MUC2 and CDX2 expression, which are regarded as having key roles in intestinal programming, in addition to their tumor-suppressor properties. 73 Invasive carcinomas associated with this group is typically of colloid type, (Figure 7) and conversely, colloid carcinoma is also often associated with intestinal type papillae. 73 Papillae with the pancreatobiliary pattern, on the other hand, typically do not express CDX2 and MUC2, but may instead express MUC1, a marker of aggressive phenotype in the pancreas. 73 Although IPMNs and mucinous cystic neoplasms have some features that overlap, the two can be distinguished by clinical, gross, and microscopic findings 74 (see Table 3). Mucinous cystic neoplasms occur predominantly in perimenopausal female subjects and in the tail of the pancreas. IPMNs are seen predominantly in the head of the pancreas and in elderly males. 33,75,76 Whereas IPMNs involve the pancreatic ducts, mucinous cystic neoplasms typically do not communicate with the ductal system. Mucinous cystic neoplasms often have thick cyst walls. The presence of ovarian stroma is diagnostic for mucinous cystic neoplasms and has almost become a requirement for the diagnosis of this tumor type. 74 The differential diagnosis of IPMNs should also include ampullary adenomas that may extend intraluminally into the pancreatic ducts. IPMNs also need to be distinguished both conceptually and practically from the smaller (microscopic) lesions of the pancreatic ducts known as pancreatic intraepithelial neoplasia (PanIN), 77 and from non-neoplastic localized duct-ectasia (Kimura lesions 78 and retention cysts). The separation of IPMNs and PanIN is based primarily on size. 79 IPMNs are larger (41 cm) and usually form a macroscopic and/or radiologic detectable mass. 79,80 This is analogous to the dichotomy 80 in other organs, for example, flat-type urothelial CIS vs papillary urothelial neoplasms, and mammary intraductal proliferations vs intracystic papillary carcinoma of the breast, which incidentally, is also seen in elder patients. 81,82 As advocated by the World Health Organization classification, 83,84 noninvasive IPMNs are graded as adenoma, borderline-tumor and in situ carcinoma. 35,36 Invasive adenocarcinoma, which is seen in B30% of cases is usually either of the colloid 85 or tubular (ordinary ductal) types. 33,34 The former has been found to have indolent behavior, analogous to the colloid carcinomas of the breast, regardless of whether it is associated with IPMN or not. 85 Overall 5-year survival for patients with an IPMN is 470% ,42 44,86,87 This is not surprising, considering that most IPMNs are noninvasive. Interestingly, some patients with surgically resected noninvasive IPMNs later develop recurrence and

5 Cystic lesions of the pancreas S75 Figure 4 IPMNs, adenoma (left), borderline (middle) and carcinoma in situ (right). The papilla on the left shows virtually no atypia and exhibits a gastric foveolar appearance. The one in the middle is reminiscent of villous adenoma, and exhibits low-grade dysplastic changes that fall into the borderline category. The papilla on the right shows marked cytologic disorganization and atypia (ie CIS). Figure 5 IPMN. Many examples exhibit a pattern virtually indistinguishable from colonic villous adenomas. some even develop metastases. These cases most likely represent multifocal disease, a finding uncommon with mucinous cystic neoplasms. 88 Multi- Figure 6 IPMN in smaller ducts. These tumors can involve any component of the ductal system. The larger cyst in this example is in fact a markedly dilated branch duct. Smaller units are often involved (lower left) with what is presumed to be pagetoid spread of the lesion. In some cases, it can be difficult, if not impossible, to distinguish these from incidental/independent PanINs. This example also illustrates the gastric foveolar-type of papillae.

6 S76 Cystic lesions of the pancreas focality of disease and haphazard distribution of carcinoma, which can be grossly invisible, necessitates the careful evaluation of these neoplasms, with complete removal and thorough pathologic examination. 34,38 That invasive carcinoma may develop both adjacent to and away from the IPMN, 89 as well as its potential for multifocal disease, have rendered the management of these tumors rather problematic. A multidisciplinary approach by experts familiar with this tumor type may be crucial. It seems that IPMNs that are of the branch-duct type (as determined by their location and radiologic findings), and those that are simple (small, predominantly cystic, and without complex nodularities) usually prove to be adenomas and are highly amenable to conservative approach. 74 On the other hand, main-duct type IPMNs, and those that are large, complex and nodular often prove to be carcinomas, and require more aggressive therapy. Some authors advocate even total pancreatectomy for some cases. 38 Another problematic area in the management of IPMNs is the status of surgical resection margins. 38 In general, it is felt that the presence of carcinoma at the surgical margins bears too high a risk for the patient, and further therapy is probably warranted for these patients, if clinically feasible. On the other hand, the presence of adenomatous epithelium at the pancreatic parenchymal margin is probably negligible 49,62 65 (based on what we extrapolate from the branch-duct literature); however, the relative risk of later developing an invasive carcinoma in these patients is also rather difficult to determine. IPMNs appear to be genetically much more stable than conventional infiltrating ductal adenocarcinomas, and lack (or exhibit at much lower levels) the molecular/genetic alterations of the latter. Mutations in the KRAS, p16 and TP53 genes are significantly less common in IPMNs, and SMADH4/DPC4 loss is not usually detected. 44,90 93 Also, as noted earlier, IPMNs frequently express MUC2 and CDX2, 73 which have tumor-suppressor activity and encode for intestinal type mucin-related glycoproteins. The molecular alteration characteristic of Peutz-Jeghers syndrome is detectable in one-third of IPMNs. 94 There are also differences in the molecular phenotype of IPMNs vs PanINs. PanINs lack MUC2 expression, and high-grade PanINs may show MUC1 expression and SMADH4/DPC4 loss. Whether some of these molecular alterations may have utility in prognostication and stratification of patients into different treatment categories is too soon to tell. Some studies have found MUC1 expression, 70,80,95 p53 overexpression 96 and telomerase activity 97 to be associated with a more aggressive clinical course. These and other potential markers ought to be studied further. Figure 7 Colloid carcinoma. Invasive colloid carcinomas are often associated with IPMNs. These are indistinguishable from colloid carcinomas of the breast, and have been found to have an indolent prognosis. Intraductal Oncocytic Papillary Neoplasms Intraductal oncocytic papillary neoplasm (IOPN) 98 is regarded a special subtype of IPMN, 74 although recent molecular findings suggest that it may be different from IPMNs. 93 Grossly, these neoplasms exhibit cystic dilatation of the pancreatic ducts, many of which contain large, tan and friable nodular proliferations. The neoplasms are relatively large (mean size: 5.2 cm) at the time of diagnosis. The papillae of IOPNs exhibit a pancreaticobiliary (PB) pattern 99 (also called compact cell type), which is characterized by exuberant, arborizing papillae lined by 1 5 cell layers of cuboidal cells (Figure 8). Table 3 The differential diagnosis of mucinous cystic neoplasms and intraductal papillary mucinous neoplasms Features Mucinous cystic neoplasms Intraductal papillary mucinous neoplasms Age Gender Females (495%) MalesBFemales Specific endoscopic finding None Mucin extrusion from ampulla Specific radiologic finding Multilocular thick-walled cyst ( CYST IN CYST ) Cystically dilated ducts ( CYST BY CYST ) Location Tail (490%) Head (480%) Gross ductal communication No Yes Specific histologic findings Ovarian Stroma (almost a requirement) Cystically dilated native ducts with villous nodules

7 The nuclei in IOPNs contain single, prominent, and eccentric nucleoli (Figure 9). One distinctive feature that appears to be relatively specific for these neoplasms is the presence of intraepithelial lumina which are round, punched-out spaces within the epithelium that often give the proliferation a cribriform architecture, similar to that seen in oncocytic schneiderian papillomas of the sinonasal tract. These intraepithelial lumina often contain mucin. The cells of IOPNs are oncocytic, due to an abundance of mitochondria and the paucity of other Cystic lesions of the pancreas organelles, which is reflected histologically as abundant, granular, acidophilic cytoplasm. In most cases, the degree of cytoarchitectural atypia, the exuberance of the papillae, and the presence of mitoses qualify for the diagnosis of at least carcinoma in situ. In other organs, oncocytic change (which is probably a degenerative phenomenon secondary to oxidative stress on the cells) is associated with a different biologic behavior than the nononcocytic counterparts of these neoplasms. Whether this applies also to the pancreas remains to be seen. Preliminary molecular analyses have shown that IOPNs may differ from the conventional IPMNs, by the lack of KRAS gene mutations and alternate MUC phenotypes. Furthermore, IOPNs have a much higher incidence of HepPar-1 expression, and MUC6 is more diffuse and strong than any other types or components of IPMNs. 100,101 The data on the clinical course of IOPNs is limited, 98, however, it seems to be similar to that of IPMNs, but may be even more indolent. S77 Figure 8 IOPN. This cystically dilated duct is filled with complex (arborizing) papillae characteristic of this tumor type. Often, the papillary cores show edematous changes. Figure 9 IOPN. Even more so than the complexity of the papillae, these tumors are characterized by oncocytic cells (with abundant acidophilic cytoplasm, round nuclei with fine chromatin, single prominent and eccentric nucleoli, and distinctive intraepithelial lumina formation. Mucinous Cystic Neoplasms Mucinous cystic neoplasms are presumably de novo cystic tumors (unlike IPMNs which give rise to cystic dilatation of native ducts), and they are characterized by an ovarian type of stroma. Mucinous cystic neoplasms have distinctive clinicopathologic characteristics: they are seen almost exclusively in perimenopausal female patients (mean age ¼ 48 years, M/F ¼ o1/20; only rare male patients with ovarian-stroma are on record) and the neoplasm is most often located in the tail of the pancreas. 76, Macroscopically, these neoplasms are composed of large multilocular cysts ranging in size from one to several centimeters. The cysts have thick fibrotic walls (Figure 10). Unless there is fistula formation, the cysts do not visibly communicate with the pancreatic ductal system (although recent reports from Japan indicate that there is often subtle communication at the microscopic level evidenced by the passage of dye injected into the ducts into the cysts). The wall of the cysts may have velvety papillations, appear trabeculated, and thickened. The cyst contents are often mucoid, but hemorrhage and a more watery consistency may also be noted. Solid areas within the neoplasm should be sampled extensively for microscopic examination, as they may harbor an invasive component. Morphologically, mucinous cystic neoplasms of the pancreas are similar to mucinous cystic neoplasms that occur in the retroperitoneum, ovary, and liver. This resemblance includes the presence of a distinctive stroma (referred to as ovarian-like) around the cysts (Figure 11). This stroma is a very common and an entity-defining feature of these neoplasms, to an extent that it has almost become a requirement for the diagnosis. 74 There are two

8 S78 Cystic lesions of the pancreas Figure 10 Mucinous cystic neoplasm. A thick-walled multilocular cystic tumor is a characteristic finding of mucinous cystic neoplasms. Figure 11 Mucinous cystic neoplasm (with ovarian-type stroma). The distinctive hypercellular stroma, which shows all the morphologic and immunophenotypic characteristics of ovarian stroma, has become nearly a requirement for the diagnosis of this tumor type. The epithelium in mucinous cystic neoplasia may show various degrees of atypia, ranging from adenoma (lower left) to frank carcinoma in situ (upper). hypotheses on the origin of a neoplasm in the pancreas with ovarian-type stroma. The first hypothesis is that these neoplasms arise from rests of embryologic ovarian tissue deposited in the pancreas. This hypothesis is supported by the close proximity of the left ovarian primordium to the tail of the pancreatic anlage in fetal life. The second hypothesis proposed to account for these neoplasms is that the stroma represents a recapitulation of periductal fetal mesenchyme, the primitive mesenchyme seen around the pancreatic and hepatic ducts in the developing fetus. 111 Regardless of its origin, it is clear that this stroma is hormone sensitive; it is often admixed with luteal-type cells and it regularly expresses progesterone receptors. Moreover, some mucinous cystic neoplasms are reported to be associated with ovarian thecomas, 112 further suggesting a hormone influence in the pathogenesis of these neoplasms. The cysts in mucinous cystic neoplasms are lined by tall, columnar, mucin-producing epithelium, which may exhibit gastric foveolar-type intracellular mucin or goblet cells. Scattered neuroendocrine cells are present in the majority of cases and they can be demonstrated by immunohistochemical labeling for neuroendocrine markers such as chromogranin and synaptophysin. The epithelium in the predominantly cystic and adenoma components of MCNs are virtually indistinguishable from those of IPMNs, or for that matter, also from those of PanINs. The papillary components, however, show some differences. MCNpapillae do not typically have the full-blown villous adenoma-like appearance and diffuse MUC2/CDX2 expression characteristic of the intestinal (darkcell, columnar-cell) subset of IPMNs. 113 Instead, they often show MUC1 expression similar to the pancreatobiliary subtype of IPMNs. Some mucinous cystic neoplasms have purulent contents and these may be misdiagnosed as pseudocysts both intraoperatively as well as histopathologically especially if the epithelium is denuded, and the remaining ovarian stroma resembles the granulation tissue of pseudocysts. Inflammation may also impart a more complex architecture to an otherwise simple mucinous cystic neoplasm and raise the suspicion of malignancy. 114 Mucinous cystic neoplasms can show a wide range of cytologic and architectural atypia: Some are histologically bland, with uniform, basally oriented nuclei, and minimal architectural atypia, while others exhibit prominent papillary proliferations that form intraluminal polypoid masses with cribriform architecture and substantial cytologic atypia (Figure 11). The epithelial atypia may be patchy, and there is often an abrupt transition between histologically bland epithelium and epithelium with severe atypia. Numerous sections may be required to properly evaluate these neoplasms. This may explain why the studies from the Armed Forces Institute of Pathology (AFIP), 106,110 a referral center where the diagnosis is generally based on a few selected slides submitted for consultation, have failed to demonstrate that dysplasia and even the presence of an invasive cancer are prognostically relevant. For that reason, the authors from the AFIP regard all MCNs, regardless of their grade, as lowgrade malignant neoplasms, that is, cystadenocarcinoma. 106,110 However, more recently, a number of studies from other authors who performed more complete examination and extensive sampling of the neoplasms concluded that grade does accurately predict the outcome. 76,108,109,115 It is also our experience that patients with completely resected mucinous cystic neoplasms without atypia (mucinous cystadenomas) are almost always cured. These tend to be small as well (o3 cm). Mucinous cystic

9 neoplasms with moderate atypia are classified as mucinous cystic neoplasms with moderate dysplasia, while those with significant architectural and cytologic atypia are classified as mucinous cystic neoplasm with carcinoma in situ 83,116 (Figure 11). Patients with these latter two grades of noninvasive mucinous cystic neoplasms are also often cured if their tumors are resected completely. If an invasive carcinoma is present, the neoplasm should be classified as a mucinous cystadenocarcinoma. 83,116 In fact, we prefer to report these as invasive carcinoma of type, cm, arising in association with mucinous cystic neoplasms ( cm), just as we do for IPMNs or in situ neoplasia of other organs such as the breast. The invasive carcinomas that arise in association with mucinous cystic neoplasms are usually tubular/ductal type. Interestingly, these have been found to pursue a more indolent course than ordinary infiltrating ductal adenocarcinoma. 110 It is difficult to determine whether this implies that the invasive carcinomas arising from MCNs are biologically different (although they may look morphologically identical to ductal adenocarcinoma) or whether MCN allows for earlier diagnosis of invasive carcinoma. The same concept also holds true for IPMNs (as previously discussed). In addition to its association with invasive tubular adenocarcinomas, some MCNs may be associated with undifferentiated carcinoma with osteoclast-like giant cells, 117,118 or high-grade sarcoma. 119 Pure colloid carcinoma, which is the predominant type of invasive carcinoma in IPMNs, is exceedingly uncommon in MCNs, 113 once the latter is defined by the presence of ovarian-stroma. Intraductal Tubular Adenocarcinomas This is an emerging entity that has yet to be fully characterized. 120 These are mostly solid tumors, but fall into the differential diagnosis of cystic neoplasia because of their intraductal growth. Some examples do show cystic changes in the ducts (cavity without intraluminal nodules). These tumors are characterized by intraductal neoplasia that have prominent tubular growth, morphologically resembling acinar tumors, but also showing ductal features. Mucin formation is minimal. Many examples have densely packed tubular units tightly packed with only minimal intervening stroma, but in some, there is significant desmoplastic-type stroma. In a subset of these cases, squamoid zones and comedo-like necrosis are seen in the ducts. Mucinous Non-Neoplastic Cysts, Mucoceles, and Retention Cysts In general, the vast majority of mucinous cysts (cysts lined by mucinous epithelium) in the pancreas are considered neoplastic. However, it is Cystic lesions of the pancreas known that obstruction and fibrosis may lead to cystic dilatation of the upstream ducts 5,121 (ie a retention cyst, or if mucus filled, a mucocele). 122,123 Epithelial-lined examples of paraduodenal wall cysts can be regarded as part of the same phenomenon. Mucinous non-neoplastic cyst is also possibly a related concept. 124,125 There is no precise definition for these lesions or specific criteria to distinguish them from IPMNs, mucinous cystic neoplasms, or for those that are small, from PanIN. Our approach to these lesions is to accept them as non-neoplastic only if they are simple (unilocular), lined by either low-cuboidal, or attenuated cells. In these cases, finding an obstruction of the pancreatic duct helps establish the diagnosis. However, we classify those lesions lined by tall-columnar-mucinous cells, forming papillae or that are more complex (multilocular) as neoplastic (PanIN if they are smaller than 1 cm and IPMN if they are 41 cm). Admittedly, these criteria are rather arbitrary and may not be widely agreed upon. Serous (clear-cell) cystic tumors In the pancreas, the term serous is defined somewhat differently than it is in some other sites, in particular, the female reproductive tract. In the pancreas, it describes a distinctive cell type with clear cytoplasm, and immunophenotypic characteristics suggestive of centroacinar/intercalated-duct differentiation. Serous Cystadenoma Serous cystadenoma is a benign neoplasm composed of uniform cuboidal glycogen-rich epithelial cells that form small cysts containing serous fluid. Serous cystadenomas are the prototypical and almost sole example of microcystic pancreatic neoplasms. In fact, the gross appearance of most serous cystadenomas numerous, tightly packed small cysts and a stellate scar, creating a sponge-like appearance is diagnostic of the entity (Figure 12). Serous cystadenomas usually present as relatively large masses measuring up to 25 cm, mostly in the body or tail of the pancreas, and are seen predominantly in female patients (F:M ¼ 3:1). The mean age of the patients is 61 years Microscopically, these neoplasms have distinctive morphologic features. The cells lining the small cysts have clear cytoplasm, well-defined cytoplasmic borders, and small, round uniform nuclei with dense, homogeneous chromatin (Figure 13). These cytologic features are also characteristic and very helpful in needle biopsies. A rare macrocystic variant of the serous cystadenoma has been reported (discussed below) as has a solid variant. 136 Serous cystadenomas are presumed to arise from (or recapitulate) the centroacinar cell-intercalated duct system, 137 and accordingly express MUC6. S79

10 Cystic lesions of the pancreas S80 composed of fewer but larger loculi ,137,151 The epithelial lining of these cysts may become denuded, and it may be difficult to distinguish oligocystic serous cystadenomas from mucinous neoplasms or pseudocysts. 152 unless the lesion is extensively sampled and examined carefully to identify the characteristic glycogen-rich clear cells. VHL-Associated Pancreatic Cysts The cysts seen in the pancreas of the patients with von Hippel-Lindau disease are virtually indistinguishable from those of serous cystadenomas, but instead are distributed more irregularly (hamartomatously), rather than forming a distinct lesion. VHL gene alterations are present in these lesions. Figure 12 Serous cystadenoma. Serous cystadenomas are typically composed of innumerable small cysts, most of which are in the range of millimeters, hence the synonym microcystic adenoma. This sponge-like appearance of serous adenomas is so characteristic that these tumors can virtually be diagnosed by their gross appearance alone. Figure 13 Serous cystadenoma. The cytologic features of serous adenomas are also as characteristic and specific as their gross appearance. The cells have glycogen-rich clear cytoplasm, distinct cytoplasmic borders, and round, uniform nuclei with dense homogenous chromatin. They are negative for mucin stains, and the glycogen can be highlighted by the PAS stain. They do not harbor the molecular genetic alterations that are characteristic of mucinous-type ductal neoplasia of the pancreas, such as mutations in the k-ras, SMADH4/DPC4, TP53, and p16 genes. 138,139 Instead, von Hippel-Lindau gene alterations, detected in 40% of the cases 137,140 have been implicated in the pathogenesis of serous cystadenomas. Glut-1, a molecule involved in glycogen metabolism, is also expressed consistently in serous tumors. 141 Of interest, serous cystadenomas are often reported to coexist or collide with other pancreatic neoplasms and with congenital pathologic conditions. 149,150 Oligocystic (macrocystic) variant of serous cystadenoma Although the vast majority of serous cystadenomas exhibit a microcystic growth pattern, rare examples are oligocystic (megacystic, macrocystic), that is, Serous Cystadenocarcinomas Most serous cystic neoplasms of the pancreas are benign serous cystadenomas. A handful of malignant serous cystic neoplasms, serous cystadenocarcinomas, have been reported. 129, Most of these were microscopically identical to serous cystadenomas, and no morphologic findings, other than behavior, have been found to distinguish these malignant variants from their benign counterparts. In fact, in some, the diagnosis of malignancy was established only after metastases to the liver were detected. The possibility of these liver lesions representing a metachronous neoplasm rather than a metastasis is difficult to exclude and renders serous cystadenocarcinoma a dubious entity. On the other hand, in two other reported cases, an otherwise classical serous cystadenoma showed focal malignant appearing morphologic features; 155,159 however, in these cases, the clinical and biologic significance of these morphologic changes could not be determined due to the lack of follow-up information. For practical purposes, although the vast majority of serous cystic neoplasms are benign, there are very rare examples of metastasis developing from these neoplasms. 129,154 We have seen examples of metastatic ovarian clear-cell adenocarcinoma and clearcell renal cell carcinoma that were mistaken for serous cystadenocarcinomas. Squamous-lined cysts Lymphoepithelial Cysts Lymphoepithelial cysts (LECs) are benign cystic lesions seen predominantly in males, in the fifth to sixth decade of life. 162 They may be unilocular or multilocular. The cyst contents may vary from serous to cheesy/casseous-appearing (Figure 14) depending on the degree of keratin formation. The cyst wall and trabeculae are usually thin. Microscopically, the cysts are lined by well-differentiated stratified squamous epithelium, which may or may

11 Cystic lesions of the pancreas S81 Figure 14 LEC. Some cases have abundant keratinization that leads to granular debris in the lumen, as seen in this example, creating a picture reminiscent of sebaceous cyst, although some have serosangineous contents. not have prominent keratinization. In some areas, the lining may appear more transitional, and in others, flat, cuboidal, and focally denuded. Cases with denuded epithelium may cause diagnostic problems. Sebaceous elements and mucinous cells are uncommon. The squamous epithelium is surrounded by a band of dense lymphoid tissue composed of mature T-lymphocytes with intervening germinal centers formed by B cells, which may be abundant in some cases. In many cases, the lymphoid tissue is immediately adjacent to the epithelium, while in others, there is a band of fibrous tissue separating them. In some examples, the lymphoid tissue has a thin capsule and a subcapsular sinus, suggesting that the process may have arisen in a peripancreatic lymph node. Solid lymphoepithelial islands (microscopic clusters of epithelial cells admixed with lymphocytes, akin to the so-called epimyoepithelial islands in the salivary gland LECs) may also be present. Some of these epithelial nests form microcysts. It is uncommon for LECs to become infected or acutely inflamed; however, the adjacent pancreas may contain granulomas, collections of foamy histiocytes and fat necrosis, thereby mimicking acute pancreatitis. LECs of the pancreas do not appear to be associated with any autoimmune conditions, human immunodeficiency virus infection, lymphoma, or carcinoma, all of which have been documented to occur in their salivary gland counterparts. Epidermoid Cysts within Intrapancreatic Accessory Spleen These are rare. They occur almost exclusively in the tail of the pancreas where accessory spleens are not too uncommon. They are seen in younger patients (2nd 3rd decades). The cysts are lined by Figure 15 Squamoid cyst of pancreatic ducts. These usually have a thin wall lined by transitional/squamous cells without keratinization or granular layer (see inset). The cysts are more commonly unilocular and typically contain concentric enzymatic concretions as seen in this example, which indicates their communication with the acinar system. attenuated squamous cells, usually nonstratified, surrounded by normal-appearing splenic tissue. Dermoid Cysts Dermoid cysts are also exceedingly rare tumors in the pancreas region. 163 They are reported in younger patients (2nd 3rd decades) and are morphologically similar to the teratomas seen in other sites, although some examples are composed predominantly of epidermal elements, such that they are difficult to distinguish from LECs. The presence of sebaceous glands or hair follicules is more typical for dermoid cysts. Squamoid Cyst of Pancreatic Ducts This is a recently recognized type of cystic lesion in the pancreas, 166 in which cystically dilated ducts are lined by a squamous/transitional epithelium (Figure 15) without keratinization. The larger and clinically manifested examples reported were unilocular. The cells in the basal/parabasal region express p63 (transitional/squamous cell marker, not detected in any normal pancreas or nonsquamous neoplasia). The superficial cells are positive for MUC1 and MUC6 (markers present in intercalated duct cells), and negative for GLUT-1 (consistent marker of serous adenomas, another tumor of presumed centroacinar cell origin). These cystic lesions are believed to be the larger versions of a relatively common incidental change in the acinar lobules. These microscopic lesions have abortive septae, irregular contours, are found lying within compact

12 S82 Cystic lesions of the pancreas acinar tissue, and appear to be transforming from intercalated ducts, often showing adjacent tightly packed clusters of ducts with similar morphology. The cysts typically contain distinctive acidophilic acinar secretions that form concretions (Figure 15), more evident in medium-sized examples, confirming their communication with the acinar system, and suggesting a localized obstruction in their pathogenesis. cysts contained enzymatic concretions (Figure 16) admixed with crystalline material, presumably composed of enzymatic secretions. Acinar cell cystadenocarcinomas are often large. Their biology seems not to be significantly different from their solid counterparts, with liver metastases developing early in the course of the disease, although some with intraductal growth had protracted clinical courses. 176 Cysts lined by acinar cells Acinar Cell Cystadenocarcinomas A cystic form of acinar cell carcinoma is well documented but is extremely uncommon; only a handful of cases have been documented in the literature It should be kept in mind, however, that the term cystic acinar cell carcinoma had also been erroneously applied during the 1980s to the neoplasm currently known as solid-pseudopapillary neoplasm, at which time solid-pseudopapillary tumors (SPTs) were mistaken to be of acinar origin. True acinar cell cystadenocarcinomas ,174 are composed of neoplastic cells that form acini with prominent lumen formation (Figure 16) (in contrast to ordinary acinar cell carcinomas which have a more solid growth pattern 175 ). Some show significant cystic dilatation that may measure up to several centimeters. In fact, some ACCs show prominent intraductal growth and/or papillary/ papillocystic patterns that fall into the differential diagnosis of intraductal neoplasia. 176 The cysts in these neoplasia are true cysts with an epithelial lining composed of cells with acinar differentiation rather than a degenerative phenomenon. The cells often contain abundant apical, acidophilic (zymogenic) granules, and immunolabeling will reveal the expression of pancreatic exocrine enzymes. In the examples we have seen, the Acinar Cell Cystadenomas Until recently, the conventional thought was that all acinar neoplasms in the pancreas are malignant, albeit solid or cystic. In 2000, however, an entity referred to as acinar cell cystadenoma (also called cystic acinar transformation) was described. 5,177 This phenomenon is uncommon, often incidental, but may on occasion produce a clinically detectable cystic mass (measuring up to several centimeters), in which the cysts are lined by cytologically bland acinar cells Immunohistochemical labeling for markers of acinar differentiation (trypsin and others) are positive. Interestingly, they are also cytokeratin 7 positive while normal acinar cells are negative for this marker. Acinar cell cystadenoma is seen in young adults and children, and the consensus is that it is a benign process. Endothelial-lined cysts Lymphangiomas Lymphangiomas may also present as pancreatic and peripancreatic cystic masses, 181,182 and may closely mimic LECs (especially those with denuded epithelium) because they also contain prominent lymphoid tissue. Lymphangiomas are lined by endothelial cells as demonstrated by immunohistochemical labeling for endothelial markers (CD31, CD34 or D2 40) and lack staining for epithelial markers (cytokeratins). Lymphangiomas may become very large, measuring up to 25 cm. 183 They are benign. Figure 16 Acinar cell cystadenocarcinoma. The cysts contain precipitated secretory material composed of pale acidophilic mucoproteinaceous substance with concentric laminations, which is characteristic of enzymatic secretions of acinar cells. Degenerative or necrotic changes in solid tumors Degenerative necrotic changes with cavity formation have been described virtually in all otherwise typically solid pancreatic tumors. 184 Altogether, this group constitutes an estimated 10% of the pancreatic cysts (Table 1). It is important to recognize this group, because unlike the tumors in the other categories discussed, these are often either lowgrade malignancies as in the case of SPT, or even true carcinomas as in the case of cystic change in ductal adenocarcinoma.

13 Solid-Pseudopapillary Tumor (SPT) Cystic lesions of the pancreas SPT is the most recent name advocated by the WHO 83,84 for a distinctive tumor type in the pancreas that often presents as a cystic mass, and for this reason was previously (and is sometimes still) referred to as solid and cystic, 185,186 solid and papillary 187 cystic and papillary and papillarycystic. 188,189 The plethora of names used previously for SPT reflects the enigmatic nature of this neoplasm. It is now known that the cavities that form in SPTs are not true cysts (there is no epithelial lining) but rather represent a necrotic/ degenerative process 59,190 (Figure 17). The cystic areas often contain blood, necrotic debris, and clusters of foamy macrophages. In the cavity wall, characteristic morphologic features of these neoplasms include pseudopapillary architecture (that creates an ependymoma-like appearance), hyaline globules, clusters of uniform cells mimicking neuroendocrine neoplasia (but lacking neuroendocrine chromatin), and grooved nuclei (Figure 18). SPT remains somewhat of an enigma although its clinical and pathologic features are well characterized and the tumors show remarkable fidelity from one case to another. However, it is one of very few neoplasms in which the direction of differentiation of the neoplastic cells has yet to be established. SPT is practically unique to the pancreas, with no close kindred in any other organ. Meanwhile, it does not show clear-cut pathogenetic relationship to any of the cells normally found in the pancreas; there is no evidence for ductal, acinar, or frank endocrine differentiation. 59,190 Even the epithelial differentiation of this tumor type is incomplete and dubious. Immunohistochemically, the neoplastic cells express nonspecific markers such as vimentin, CD56, alpha-1-antitrypsin and neuron-specific ( non-specific ) enolase; meanwhile, epithelial markers (keratins) can be focal or weak. Synaptophysin and NSE are commonly positive in SPTs; however, chromogranin, the most specific endocrine marker, is typically negative. SPTs reported to be diffusely/ strongly chromogranin-positive in the literature most likely represent pancreatic endocrine neoplasms with cystic degeneration. Similarly, the reports on high-grade pancreatic tumors that expressed CD99 (Ewing s marker) and t(11:22) translocation, in our opinion, may represent primitive neuroectodermal tumor of this organ. 191 Recently, CD10 expression and APC/b-catenin pathway and cyclin-d1 alterations were found to be almost uniformly present (490%) in SPTs. This interesting finding is very helpful diagnostically, and may prove to be important in unraveling the pathogenesis of this peculiar tumor. Recently, c-kit (CD117) expression was detected in a substantial portion of SPTs. 192 Another puzzling aspect of SPTs is that they almost exclusively occur in young female subjects 186,190 (mean age, 25 years, M/Fo1/20). Moreover, the neoplastic cells consistently express progesterone receptors 10 and also the beta form of estrogen receptors, 193 suggesting a role for hormones in the evolution of these neoplasms. Yet another peculiar aspect of the SPT is its clinical behavior. 190 More than 80% of SPTs are cured by surgical resection. Metastases (either to liver or peritoneum, but only seldom to lymph nodes) may be seen in a small percentage of patients, but even some patients with metastases are cured. Seldom has any death been attributed to solidpseudopapillary neoplasm. There do not appear to be any reliable histopathologic criteria to distinguish SPTs that can metastasize from those that do not. 194 Perineural invasion and infiltration to the S83 Figure 17 SPT. Typical macroscopic appearance of this tumor type with solid areas showing hemorrhagic material, patchy fleshy areas, and a cystic component. The tumor appears deceptively well-demarcated, but often proves to have streaks of neoplastic cells projecting beyond the gross boundaries of the lesion. Figure 18 SPT. These lesions often present clinically like a pseudocyst, and the reasons for this may also be reflected at the microscopic level as seen in this example. The cyst wall is inflamed and congested, and there are fibrinous changes on the external surfaces (lower left). The cyst contents are granular and hemorrhagic. There is only a thin rim of neoplastic tissue clinging to the cyst wall (box and inset).

14 Cystic lesions of the pancreas S84 adjacent pancreas are common findings even in nonmetastastasizing examples. Recently, cases with anaplastic transformation and aggressive clinical course were reported. 195 Cystic Change in Ordinary Ductal Adenocarcinoma Rarely, conventional infiltrating ductal adenocarcinoma of the pancreas may undergo cystic change. 2,16 19 In our experience, this occurs in less than 1% of the cases. 16 In some pancreatic cancers, a large, radiologically detectable cyst may form because of central necrosis. In these cases, what appears radiologically to be a cyst (a macrocyst), however, often proves microscopically to be solid, nonviable tissue surrounded by a cuff of viable carcinoma. Such cases can be misdiagnosed preoperatively as pseudocysts. 18 In other cases, infiltrating ductal adenocarcinoma can obstruct the pancreatic duct and lead to cystic dilatation of the upstream duct. The dilated upstream duct can show reactive epithelial changes, which may be indistinguishable from IPMNs or mucinous cystic neoplasms. There is also a large-duct (microcystic) variant of ductal adenocarcinoma 196 in which the infiltrating tubular units are larger than those of ordinary ductal adenocarcinoma. This variant mimics IPMNs or mucinous cystic neoplasms at the microscopic level, but not at the clinical or macroscopic levels, 197 because the dilatation in the infiltrating tubules is of a minimal degree, and creates a microcystic pattern at most. Cystic Pancreatic Endocrine Neoplasia (Islet Cell Tumors) Cystic pancreatic endocrine neoplasms are rare. 184, They constitute 5 10 % of pancreatic endocrine neoplasms. 184,209 In contrast to the cystic change in other solid tumors (especially those in ductal adenocarcinomas), the cyst formation in pancreatic endocrine neoplasms does not appear to be due to necrosis. Rather, the cysts are lined by a ragged cuff of well-preserved neoplastic endocrine cells, (Figure 19) and filled with a clear serosanguineous fluid instead of necrotic debris. The cyst formation is usually unilocular and at the center of the tumor. In some cases, however, the process is more microcystic with multiple small cysts. 210 Some cystic pancreatic endocrine neoplasms achieve significant sizes, up to 25 cm. 211 Cystic pancreatic endocrine neoplasms are predominantly clinically nonfunctioning. The pathologic diagnosis of these cystic pancreatic endocrine neoplasms is relatively simple if attention is paid to the cytologic features of the lesion. Microscopic examination of the solid areas of the tumors reveal characteristic cytomorphologic features of a well-differentiated pancreatic endocrine neoplasm, including round, monotonous cells with a moderate amount of cytoplasm and Figure 19 Pancreatic endocrine neoplasm. Approximately 5% of pancreatic endocrine neoplasms (islet cell tumor) present as a cyst containing degenerative serosangineous fluid which is reflected as granular material on the left in this picture. The cuff of tumor shows the characteristic trabecular pattern and monotonous cells of endocrine neoplasia. distinctive nuclear chromatin pattern. Often the neoplastic cells have a trabecular pattern of growth (Figure 19). Cystic Change in other Invasive Carcinomas Other invasive malignant neoplasms of the pancreas such as undifferentiated carcinoma with osteoclastlike giant cells 12 or squamous cell carcinomas. 212 have also been occasionally reported to present as cystic masses. Cystic Mesenchymal Neoplasms Some mesenchymal neoplams that occur in the pancreatic region may present as cystic lesions. Schwannomas in the pancreas especially tend to be cystic We have seen an example in which the spindle cells surrounding the cysts mimicked the ovarian-like stroma of the mucinous cystic neoplasms. Some sarcomas, 216 especially GISTs, may also be cystic. Other nonepithelial tumors of this region such as paragangliomas have also been reported to present as a cyst. 2,217 Other rare cystic lesions Cystic Hamartomas Most cases reported in the literature as hamartomas appear to be examples of chronic pancreatitis in which pancreatic elements are haphazardly distributed (in a hamartomatous fashion). Recently, true hamartomas of this organ have been characterized, and some are cystic. 218,219 These solid and cystic

15 hamartomas form a sharply delimited lesion similar to the multicystic hamartomas of children, and is composed of haphazardly distributed cystic ductal elements lined by cuboidal to flattened epithelium, surrounded by well-differentiated acini embedded in fibro-inflammatory stroma. Scattered ill-formed clusters of endocrine cells composed predominantly of PP-cells type and unaccompanied by any insulin positive cells are also present and support the hamartomatous nature of the process. Enterogenous (Congenital; Duplication) Cysts and Duodenal Diverticula Congenital cysts of foregut derivation may also occur in the pancreas although very rarely. Essentially, these are regarded as gastrointestinal (enteric) duplications, 223 and some appear to be true diverticula. 224 They may have respiratory (bronchogenic) or simple ciliated epithelium We have also seen two examples with ciliated epithelium. One of these contained inner and outer muscular coats typical of intestinal wall, and had an associated high-grade papillary adenocarcinoma with pancreatobiliary-type features. Although the carcinoma in this case appeared to be confined to the cyst wall, the patient developed widespread metastases. Endometriotic Cyst Endometriotic cysts, 228 some with massive hemorrhage 229 may be seen in the pancreas. Secondary Tumors Rarely, metastatic neoplasms (or neoplasms that secondarily involve the pancreas) can exhibit cystic change. 217,230 We have seen examples of metastatic ovarian and renal cell carcinoma in the pancreas that presented as cystic masses. Cystic lesions of the common bile duct (eg, choledochal cyst) and duodenum may also mimic pancreatic cysts. 14,224,231 Congenital or Developmental Cysts Cystic lesions of the pancreas A variety of congenital or developmental disorders may be associated with cyst formation in the pancreas, in addition to vhl-associated cystic changes discussed previously in the serous lesions section. Some of the others are the following: Polycystic kidney disease and medullary cystic kidney: Patients with polycystic kidney disease, both adult and infantile types, may have cystic lesions in the pancreas. 232 Rarely, patients with medullary cystic kidneys may also have pancreatic cysts. 233 Cystic fibrosis: In patients with cystic fibrosis, the genetic defect in the cystic fibrosis transmembrane conductance regulator protein increases the viscosity of pancreatic secretions, which in turn leads to the cystic dilatation of the pancreatic ducts 121,234 by causing intraluminal impaction, in addition to lobular atrophy and parenchymal fibrosis. This dilatation in the ducts, however, is generally not clinically detectable. Other congenital syndromes: Cystic transformation of the pancreas has been described in a variety of congenital syndromes 235 including Ivemark, trisomy 13 or 15, Meckel-Gruber, Elejalde, glutaric aciduria, chondrodyplasia, short rib polydactyly (Jeune s and Saldino-Noonan), 236 a newly described syndrome (Balci 237 ) and others with no specific name. 238 A patient with choledochal cyst was also reported to have multiple pancreatic cysts. 239 Familial fibrocystic pancreatic atrophy: This is an interesting phenomenon described in a pancreas cancer family from Seattle, Washington, USA, and is characterized by a lobulocentric pancreatic atrophy associated with fibrocystic (microcystic) changes and endocrine cell proliferation. 240 These do not appear to form clinically detectable cysts. In the background of this peculiar fibrocystic process, PanINs and a variety of invasive neoplasia including anaplastic carcinoma as well as small cell carcinoma have developed in some members of this family. Other pancreas cancer families may also show similar cystic changes. 241 Cysts associated with congenital infections: Cytomegalovirus infection has also been implicated in cyst formation in the pancreas of newborns. Unclassified Cysts Some cysts cannot be classified into one of the welldocumented entities. An example is the case reported by HD Friedman as nonmucinous, glycogen-poor cystadenocarcinoma of the pancreas. 242 We have also seen cases that do not fit pathologically into any of the well-described categories. If such a case is encountered, an attempt ought to be made to determine the potential biologic nature of the lesion based on the degree of cellularity, atypia, and architectural complexity of the process. Needless to say that, such cases ought to be examined completely, and the possibility of an invasive neoplasm effectively ruled out. Conclusions Cystic neoplasms of the pancreas are relatively rare but constitute an increasingly important category with a challenging differential diagnosis. In contrast with solid tumors of this organ, most of which are ductal adenocarcinomas with dismal outcomes, the vast majority of cystic neoplasia is either benign tumors or low-grade malignancies with indolent behavior. Serous and squamous cystic lesions of the pancreas are typically benign. Cysts with mucinous lining, however, carry the risk of S85

16 S86 malignant transformation. Many are associated with invasive carcinoma, and therefore their thorough sampling and careful examination are of utmost importance. Macroscopic examination plays a crucial role in the diagnosis of cystic neoplasia, especially those of the mucinous type. First of all, it is important to document the lesion is cystic or has a cystic component, which may not be as appreciable on the slides. Identifying and documenting the suspect foci (granular, irregular areas within or on the cyst wall) are essential to rule out papillary nodules or carcinomas. Also, subclassification of IPMNs into branch or main duct types relies heavily on macroscopic examination and guided sampling. Along the same lines, the lack of gross ductal communication, an important criterion for the diagnosis of MCNs, is also established by the macroscopic findings. The importance of careful examination and thorough sampling in the evaluation of pancreatic cysts cannot be overemphasized. 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J Gastrointest Surg 2002;6: Ligneau B, Lombard-Bohas C, Partensky C, et al. Cystic endocrine tumors of the pancreas: clinical, radiologic, and histopathologic features in 13 cases. Am J Surg Pathol 2001;25: Kotoulas C, Panayiotides J, Antiochos C, et al. Huge non-functioning pancreatic cystic neuroendocrine tumour: a case report. Eur J Surg Oncol 1998;24: Colarian J, Fowler D, Schor J, et al. Squamous cell carcinoma of the pancreas with cystic degeneration. South Med J 2000;93: Tan G, Vitellas K, Morrison C, et al. Cystic schwannoma of the pancreas. Ann Diagn Pathol 2003;7: Lee JS, Kim HS, Jung JJ, et al. Ancient schwannoma of the pancreas mimicking a cystic tumor. Virchows Arch 2001;439: Hsiao WC, Lin PW, Chang KC. Benign retroperitoneal schwannoma mimicking a pancreatic cystic tumor: case report and literature review. Hepatogastroenterology 1998;45: Liu DM, Jeffrey Jr RB, Mindelzun RE. Malignant fibrous histiocytoma presenting as cystic pancreatic mass. Abdom Imag 1999;24: Adsay NV, Andea A, Basturk O, et al. Secondary tumors of the pancreas: an analysis of a surgical and autopsy database and review of the literature. Virchows Arch 2004;444: Pauser U, da Silva MT, Placke J, et al. Cellular hamartoma resembling gastrointestinal stromal tumor: a solid tumor of the pancreas expressing c-kit (CD117). Modern Pathol 2005;18: Pauser U, Kosmahl M, Kruslin B, et al. Pancreatic solid and cystic hamartoma in adults: characterization of a new tumorous lesion. Am J Surg Pathol 2005;29: Andronikou S, Sinclair-Smith C, Millar AJ. An enteric duplication cyst of the pancreas causing abdominal pain and pancreatitis in a child. Pediatr Surg Int 2002;18: Dipaola G, Camoglio FS, Chironi C, et al. Congenital true pancreatic cyst in pediatric age: case report. Pediatr Med Chir 2002;24: Caillot JL, Rongieras F, Voiglio E, et al. A new case of congenital cyst of the pancreas. Hepatogastroenterology 2000;47: Keller MS, Weber TR, Sotelo-Avila C, et al. Duodenal duplication cysts: a rare cause of acute pancreatitis in children. Surgery 2001;130: Macari M, Lazarus D, Israel G, et al. Duodenal diverticula mimicking cystic neoplasms of the pancreas: CT and MR imaging findings in seven patients. AJR Am J Roentgenol 2003;180: Andersson R, Lindell G, Cwikiel W, et al. Retroperitoneal bronchogenic cyst as a differential diagnosis of pancreatic mucinous cystic tumor. Dig Surg 2003;20: Majeski J, Harmon J. Benign enterogenous cyst of the pancreas. South Med J 2000;93: Munshi IA, Parra-Davila E, Casillas VJ, et al. Ciliated foregut cyst of the pancreas. HPB Surg 1998;11: Lee DS, Baek JT, Ahn BM, et al. A case of pancreatic endometrial cyst. Korean J Intern Med 2002;17: Sumiyoshi Y, Yamashita Y, Maekawa T, et al. A case of hemorrhagic cyst of the pancreas resembling the cystic endometriosis. Int Surg 2000;85: Ramirez Plaza CP, Suarez Munoz MA, Santoyo Santoyo J, et al. Pancreatic cystic metastasis from pulmonary carcinoma. Report of a case. Ann Ital Chir 2001;72: Vogel JD, Yeo CJ. Choledochal cyst or pancreatic (retention) cyst: a case report. J Gastrointest Surg 2003;7: Silverman JF, Prichard J, Regueiro MD. Fine needle aspiration cytology of a pancreatic cyst in a patient with autosomal dominant polycystic kidney disease. A case report. Acta Cytol 2001;45: Valentini AL, Brizi MG, Mutignani M, et al. Adult medullary cystic disease of the kidney and pancreatic cystic disease: a new association. Scand J Urol Nephrol 1999;33: Monti L, Salerno T, Lucidi V, et al. Pancreatic cystosis in cystic fibrosis: case report. Abdom Imag 2001;26:

23 235 Boulanger SC, Borowitz DS, Fisher JF, et al. Congenital pancreatic cysts in children. J Pediatr Surg 2003;38: Balci S, Altinok G, Teksen F, et al. A 34-week-old male fetus with short rib polydactyly syndrome (SRPS) type I (Saldino-Noonan) with pancreatic cysts. Turk J Pediatr 2003;45: Balci S, Bostanoglu S, Altinok G, et al. New syndrome? Three sibs diagnosed prenatally with situs inversus totalis, renal and pancreatic dysplasia, and cysts. Am J Med Genet 2000;90: Drut R, Drut M. Pancreatic cystic dysplasia (dysgenesis) presenting as a surgical pathology specimen in a patient with multiple malformations and familial ear pits. Int J Surg Pathol 2002;10: Cystic lesions of the pancreas 239 Xie XY, Strauch E, Sun CC. Choledochal cysts and multilocular cysts of the pancreas. Hum Pathol 2003;34: Meckler KA, Brentnall TA, Haggitt RC, et al. Familial fibrocystic pancreatic atrophy with endocrine cell hyperplasia and pancreatic carcinoma. Am J Surg Pathol 2001;25: Brune KA, Abe T, Canto MI, et al. 5.Multifocal neoplastic precursor lesions associated with lobular atrophy of the pancreas in patients having a strong family history of pancreatic Cancer. Modern Pathol 2005;19:269A. 242 Friedman HD. Nonmucinous, glycogen-poor cystadenocarcinoma of the pancreas. Arch Pathol Lab Med 1990;114: S93

24 Pancreatic Cysts Pathologic Classification, Differential Diagnosis, and Clinical Implications Olca Basturk, MD; Ipek Coban, MD; N. Volkan Adsay, MD Context. Cystic lesions of the pancreas are being recognized with increasing frequency and have become a more common finding in clinical practice because of the widespread use of advanced imaging modalities and the sharp drop in the mortality rate of pancreatic surgery. Consequently, in the past 2 decades, the nature of many cystic tumors in this organ has been better characterized, and significant developments have taken place in the classification and in our understanding of pancreatic cystic lesions. Objective. To provide an overview of the current concepts in classification, differential diagnosis, and clinical/biologic behavior of pancreatic cystic tumors. Data Sources. The authors personal experience, based on institutional and consultation materials, combined with an analysis of the literature. Conclusions. In contrast to solid tumors, most of which are invasive ductal adenocarcinomas with dismal prognosis, cystic lesions of the pancreas are often either benign or low-grade indolent neoplasia. However, those that are mucinous, namely, intraductal papillary mucinous neoplasms and mucinous cystic neoplasms, constitute an important category because they have well-established malignant potential, representing an adenoma-carcinoma sequence. Those that are nonmucinous such as serous tumors, congenital cysts, lymphoepithelial cysts, and squamoid cyst of pancreatic ducts have no malignant potential. Only rare nonmucinous cystic tumors that occur as a result of degenerative/necrotic changes in otherwise solid neoplasia, such as cystic ductal adenocarcinomas, cystic pancreatic endocrine neoplasia, and solid-pseudopapillary neoplasm, are also malignant and have variable degrees of aggressiveness. (Arch Pathol Lab Med. 2009;133: ) Until the end of the 1970s, the spectrum of cystic lesions of the pancreas was relatively narrow and consisted mainly of mucinous and serous neoplasms. 1 3 From the 1980s onward, the development and widespread use of new imaging techniques led to an increase in the number of resected cystic lesions. 4 This, in turn, advanced our knowledge of these tumors. New entities were described, and the pathogenesis, morphology, and biology of the entities already known were studied in more detail. 5 This article reviews the currently available information on the clinicopathologic features, differential diagnosis, and biologic behavior of the pancreatic cystic lesions. The lesions discussed below follow an order that, in the authors experience, reflects their frequency, presumed cell of origin, and clinical significance, as well as the published data in the literature. 5,6 Estimated relative frequency of cystic lesions is shown in Table 1. INJURY-RELATED AND INFLAMMATION-RELATED CYSTS Pseudocyst Pseudocysts are the most common type of cystic lesions of the pancreas, 7 although they rarely come to the atten- Accepted for publication November 4, From the Department of Pathology, New York University, New York, New York (Dr Basturk); and the Department of Pathology, Emory University, Atlanta, Georgia (Drs Coban and Adsay). The authors have no relevant financial interest in the products or companies described in this article. Reprints: N. Volkan Adsay, MD, Department of Pathology, Emory University Hospital, 1364 Clifton Rd NE, Atlanta, GA ( volkan.adsay@emory.edu). tion of surgical pathologists because, often, they are managed medically or by surgical drainage without resection. They develop as a complication of alcoholic, biliary, or traumatic acute pancreatitis, 8,9 predominantly in adult men. Those resulting from biliary disease or trauma occur in younger patients and have an equal predilection for both sexes. 7 The lesions develop when a focus of peripancreatic fat necrosis is resorbed, thereby producing a debris-filled space surrounded by granulation tissue that is ultimately enclosed within a fibrous capsule. Some pseudocysts arise from the release of pancreatic enzymes into an anatomic sac. There is no epithelial lining (Figure 1). The adjacent stroma may be hypercellular and may mimic ovarian-type stroma, characteristic of mucinous cystic neoplasm (MCN). Depending on the severity and duration of the pancreatitis, the pseudocyst may resolve spontaneously, or it may achieve a size that is no longer self-resorbable and will require surgical intervention. The clinical diagnosis of a pseudocyst is usually straightforward; however, on occasion, the differential diagnosis includes neoplastic cysts and vice versa. There are case reports in which virtually every pancreatic neoplasm presents as a pseudocyst For example, solid-pseudopapillary neoplasms often undergo massive cystic degeneration, and mucinous cystic neoplasms 16 have a tendency to become infected and contain suppurative contents. Moreover, although rare, ductal adenocarcinomas may undergo central necrosis and clinically mimic pseudocysts. 5,17,18 Proper sampling is crucial for correct diagnosis in such cases. Any epithelial element within the cyst wall suggests an alternative diagnosis to pseudocyst. Cyst fluid analysis for amylase and carcinoembryonic antigen (CEA) Arch Pathol Lab Med Vol 133, March 2009 Pancreatic Cysts Basturk et al 423

25 Types of Cystic Lesions in the Pancreas Injury-related and inflammation-related cysts (30%) Pseudocyst Paraduodenal wall cyst Infection-related cysts Neoplastic cysts (60%) Ductal lineage Mucinous type (30%) Intraductal papillary mucinous neoplasm Mucinous cystic neoplasm Intraductal oncocytic papillary neoplasm Retention cyst, mucocele, and mucinous nonneoplastic cyst Cystic change in ordinary ductal adenocarcinoma and other invasive carcinomas Serous (clear-cell) type (20%) Serous cystadenoma Oligocystic (macrocystic) variant of serous cystadenoma von Hippel-Lindau syndrome associated pancreatic cysts Serous cystadenocarcinoma Not otherwise specified Intraductal tubular carcinoma Endocrine lineage ( 5%) Cystic pancreatic endocrine neoplasm Acinar lineage ( 1%) Acinar cell cystadenoma (cystic acinar transformation) Acinar cell cystadenocarcinoma Cystic/Intraductal acinar cell carcinoma Endothelial lineage ( 1%) Lymphangioma Mesenchymal lineage ( 1%) Undetermined lineage (5%) Solid-pseudopapillary neoplasm Other Mature cystic teratoma Congenital cysts ( 1%) Duplication (enterogenous) cysts Duodenal diverticula Others Miscellaneous cysts ( 5%) Lymphoepithelial cyst Squamoid cyst of pancreatic ducts Epidermoid cysts within intrapancreatic accessory spleen Cystic hamartoma Endometriotic cysts Secondary tumors are also helpful in distinguishing pseudocysts from neoplastic cysts that are mucinous. 19 While amylase concentrations are consistently elevated in pseudocysts, typically many thousands of units per liter, elevated cyst fluid CEA levels higher than 200 ng/ml suggest a mucinous epithelium-lined cyst. Paraduodenal Wall Cyst A distinct form of chronic pancreatitis occurring predominantly in the periampullary region, and often associated with cysts on the duodenal wall/adjacent pancreas, has been reported under various names, including cystic dystrophy of heterotopic pancreas, pancreatic hamartoma of duodenum, paraduodenal wall cyst, myoadenomatosis, and groove pancreatitis. 7,20,21 In our experience, most pa- Figure 1. Pseudocyst. Depending on the stage of pseudocyst formation, the wall of a pseudocyst consists of inflammation and granulation tissue or variably organized fibroinflammatory tissue. By definition, there is no epithelial lining; instead, the cyst wall merges with the cyst contents composed of fibrin, necrotic fat cells, debris, hematoidin pigment, and aggregates of histiocytes (hematoxylin-eosin, original magnification 4). Figure 2. Intraductal papillary mucinous neoplasm. Dilatation of the ducts leads to a multilocular cyst formation, with many cysts filled with tan, friable papillary nodules. Figure 3. Intraductal papillary mucinous neoplasm. The main duct is filled with tall papillary fronds lined by mucin-producing cells (hematoxylin-eosin, original magnification 4). 424 Arch Pathol Lab Med Vol 133, March 2009 Pancreatic Cysts Basturk et al

26 tients are men aged 40 to 50 years, and history of alcohol abuse and cigarette smoking is characteristic Macroscopically, there is mucosal thickening, marked duodenal wall scarring, trabeculation of duodenal musculature, and macrocystic and microcystic changes in the duodenal wall. Presumably because they arise from the heterotopic ducts on the duodenal wall or accessory ampulla, the cysts may sometimes be partially lined by ductal epithelium and partially by granulation tissue, unlike conventional pseudocysts which have no association with the ducts. The walls of the cysts are composed of markedly inflamed fibrous tissue, with evidence of foreign-body type giant cell reaction, in which mucoprotein material is engulfed, and of myofibroblastic proliferation. Luminal and mural calcifications are common. Infection-Related Cysts Rarely, hydatid cysts, necrotic tuberculosis infections, 28,29 and other entities can occur in the pancreas and mimic primary cystic neoplasms. NEOPLASTIC CYSTS Ductal Lineage, Mucinous Type Intraductal Papillary Mucinous Neoplasm. Intraductal papillary mucinous neoplasms (IPMNs) were thought to be very rare; however, in recent years, better recognition of this neoplasm has led to an increase in its recognized incidence Among pancreatic resection specimens, the incidence of IPMN is approximately 5%; among cystic lesions, it is about 20%. Pathologically, IPMNs are characterized by intraductal proliferation of neoplastic mucinous cells, which usually form papillae and lead to cystic dilation of the pancreatic ducts and formation of clinically and macroscopically detectable masses 30,31,33 47 (Figures 2 and 3). Clinically, IPMNs occur slightly more frequently in men than in women. The mean age at diagnosis is 68 years, with a range of 25 to 94 years. Patients usually present with nonspecific abdominal symptoms, although in some, a history of pancreatitis is noted. Approximately 30% of patients have tumors in other organs (particularly the colorectum and stomach), some synchronous and others metachronous. 35,48,49 Intraductal papillary mucinous neoplasms have also been reported in patients with the Peutz- Jeghers syndrome 50 and with familial adenomatous polyposis. 51 Mucin extrusion from the ampulla of Vater during endoscopy is virtually diagnostic for these neoplasms. Radiologically, a markedly distended main pancreatic duct, or numerous cysts representing dilated branch ducts, can be seen. Today, the more common presentation is as an incidental small cyst in the pancreas on a computed tomography scan obtained for other reasons. Seventy percent of IPMNs occur in the head of the pancreas. The lesions may be localized, multicentric or, rarely, the entire ductal system may be involved. By definition, they are larger than 1 cm. Macroscopic examination of IPMNs is imperative for documenting involvement of the pancreatic ductal system and the distribution of the disease within the ductal system. In some cases, the IPMN primarily involves the main pancreatic duct (main duct type), and in others, it is mostly confined to the branch ducts (branch duct type); the latter is predominant particularly in IPMNs that arise in younger patients and is more likely to involve the uncinate process. 44,52,53 Some authors believe the branch duct type is a biologically distinct entity, and therefore every attempt should be made during macroscopic examination to determine the distribution of the lesion, as discussed below 42,44,48,53 55 The adjacent pancreatic parenchyma is usually firm and pale white because of scarring and atrophies from chronic obstruction in main duct type IPMNs, whereas it is generally normal in branch duct type IPMNs. Associated solid or gelatinous nodules may correspond to an invasive component. Microscopically, papillae with 3 distinct morphologic patterns can be seen. 35,56 61 (1) In most branch duct type IPMNs, the papillae are lined by tall columnar cells with basally oriented nuclei and abundant pale supranuclear mucin, creating a pattern reminiscent of gastric foveolar epithelium or low-grade pancreatic intraepithelial neoplasia (PanIN) 1A. These IPMNs are classified as gastric-foveolar (Figure 4, A). Because this phenotype is also common in the nonpapillary areas of main duct type IPMNs, it is also referred to as null type. The pattern does appear to be full recapitulation of gastric mucosa, with small glandular elements at the base that express MUC6 mucin and more papillary areas expressing MUC5AC. Scattered goblet cells, however, are quite common and can be highlighted by immunolabel for MUC2. (2) Most main duct type IPMNs show papillae that are lined by columnar cells with cigar-shaped nuclei and variable amounts of apical mucin, closely resembling colonic villous adenomas and are classified as villous-intestinal 61 (Figure 4, B). They do, in fact, show molecular characteristics of intestinal differentiation, as evidenced by CDX2 and MUC2 expression, which have tumor suppressor activity. 61 The papillae are also positive for MUC5AC. When these IPMNs are associated with an invasive cancer, it is typically of colloid type, 61 and colloid carcinomas also express CDX2 and MUC2, but not MUC1. 59 (3) In a small proportion of IPMNs, the papillae are more complex and are lined by cuboidal cells, often with round nuclei containing a single prominent eccentric nucleolus (Figure 4, C). These are referred to as pancreatobiliary. They typically do not express CDX2 and MUC2, but may instead express MUC1 (a marker of aggressive phenotype in the pancreas) and MUC5AC. 61 Invasive carcinoma associated with this group is usually of tubular type, with all the morphologic features of ordinary ductal adenocarcinoma. The invasive component also expresses MUC1, but not MUC2. 59 Both villous-intestinal and pancreatobiliary types of IPMN may transition to areas with gastric-foveolar morphology; however, it is uncommon to find both intestinaland pancreatobiliary-type papillae within the same IPMN. Noninvasive IPMNs have a spectrum of cytoarchitectural atypia (Figure 5). Those that have a single layer of neoplastic cells with well-oriented, small, and uniform nuclei without mitoses or necrosis are classified as either an adenoma 62 or, more recently, as an IPMN with low-grade dysplasia. 32 When there is nuclear stratification, slight loss of polarity, nuclear enlargement, and some nuclear pleomorphism, the lesions are classified as borderline tumor (IPMN with moderate dysplasia). Carcinoma in situ (IPMN with high-grade dysplasia) exhibits architectural atypia with cribriforming, significant loss of polarity, and severe nuclear pleomorphism. Mitoses are often present. 30,36,63,64 Until recently, approximately 30% of IPMNs resected have had an associated invasive carcinoma, either of the colloid 65 or ordinary ductal type 34,35 ; however, this number Arch Pathol Lab Med Vol 133, March 2009 Pancreatic Cysts Basturk et al 425

27 Figure 4. The category of intraductal papillary mucinous neoplasms encompasses 3 morphologically distinct types of papillae. A, Gastric-foveolar or null type. Tall columnar cells with basally located nuclei and abundant apical mucin resemble gastric-mucosa or pancreatic intraepithelial neoplasia 1 lesions. B, Villous-intestinal type. Similar to colonic villous adenomas, with tall, fingerlike projections lined by pseudostratified, basophilic columnar cells with cigar-shaped nuclei. A variable amount of mucin is present in the cytoplasm. C, Pancreatobiliary type. More complex branching papillae lined by relatively cuboidal cells, some with prominent nucleoli (hematoxylin-eosin, original magnifications 40). seems to be highly population-dependent and appears to be decreasing because of increased diagnosis of smaller lesions. Invasion may develop both adjacent to and away from the IPMN 66 and can be invisible at gross examination. It seems that main duct type IPMNs, and those that are large, complex, and nodular, often prove to be carcinomas and require more aggressive therapy. Given the high prevalence of cancer and the data from the literature, it is unlikely that any combination of clinical and radiologic parameters will accurately discriminate between malignant and nonmalignant main duct type IPMNs. 52,67,68 Management of IPMNs is rather problematic and, therefore, some authors even advocate total pancreatectomy for such cases. 69 On the other hand, branch duct type IPMNs, and those that are small and without complex nodularities, usually prove to be IPMNs with low-grade dysplasia. 67 Less than 15% of these clinically innocuous-appearing branch duct IPMNs prove to have carcinoma in longterm follow-up. 67 Accordingly, current consensus protocol 67 advocates a watchful wait approach if a branch duct IPMN is (1) less than 3 cm, (2) does not have any complexities or mural nodules, (3) shows no changes during follow-up, and (4) is asymptomatic. 52,55,67,68 However, this approach is applicable only if the patient can be kept under close supervision, as outlined in the consensus protocol. Another problematic area in the management of IPMNs is the status of surgical resection margins. 69 Our current approach is mostly extrapolated from anecdotal observations and from our current view of the biology of these tumors. If there is no or only minimal atypia (IPMN with low-grade dysplasia) at the margin, we do not recommend additional surgery, provided that clinically, there is no other lesion in the remaining pancreas. At the other end of the spectrum, when there is carcinoma in situ or invasive carcinoma at the margin, additional surgery is warranted, if clinically feasible. Florid papillary nodules at a margin also require careful evaluation and possibly additional surgery, because their presence suggests the likelihood that more tumor is present in the remaining pancreas. The scenario that is probably most problematic is the presence of denuded epithelium and inflammation on a frozen-section specimen. In our opinion, this is worrisome and we and others (G. Zamboni, MD, oral communication, May 2008) advocate extra margin evaluation for such cases. Overall 5-year survival for patients with IPMN is higher than 70%. 32 Recent studies have shown that the prognosis for patients with resected and carefully examined lowgrade dysplasia and borderline tumors is excellent, but patients with carcinoma in situ may experience recurrences and metastases. The aggressive behavior of cases with carcinoma in situ is attributed to missed foci of invasive cancer that are either unresected because of unrecognized multifocality or undiagnosed during pathologic examination. In some series, patients with invasive carcinoma, 426 Arch Pathol Lab Med Vol 133, March 2009 Pancreatic Cysts Basturk et al

28 Figure 5. Intraductal papillary mucinous neoplasms with high-grade dysplasia (carcinoma in situ) exhibit significant architectural and nuclear atypia, including loss of polarity and marked pleomorphism (hematoxylin-eosin, original magnification 20). which may follow an aggressive clinical course, had a 5- year survival rate as low as 36% 42,54,69,70 Intraductal papillary mucinous neoplasms have several overlapping features with mucinous cystic neoplasia, as discussed below. These neoplasms also need to be distinguished from PanIN. 71 The separation of IPMNs from PanIN is based primarily on size: IPMNs are usually larger ( 1 cm) and form a macroscopically and/or radiologically detectable mass. 72,73 In other words, they represent a mass-forming type of dysplastic process, whereas PanINs are detected microscopically/incidentally. Mucinous Cystic Neoplasm. Mucinous cystic neoplasms are presumably de novo cystic tumors and have distinctive clinicopathologic characteristics. They are seen almost exclusively in perimenopausal female patients (mean age, 48 years; male to female ratio 1:20) and most arise in the body or tail of the pancreas. 2,74 78 Macroscopically, MCNs are composed of thick-walled multilocular cysts that can become very large (up to 35 cm). The lesions often have a thick pseudocapsule, and the outer surface is usually smooth and well demarcated (Figure 6). Focal calcifications are sometimes present at the periphery of the neoplasms. Unless there is fistula formation, the cysts do not visibly communicate with the pancreatic ductal system. The individual locules, seen grossly, are typically between 1 and 3 cm and have thick walls. Especially in larger samples, the wall of the cysts may have velvety papillations and even solid mural nodules that correspond to papillary elements. The cyst contents are often mucoid, but watery fluid, hemorrhagic fluid, or even necrotic debris may also be noted. Microscopically, the cysts are lined by tall, columnar, mucin-producing epithelium (Figure 7) that resembles endocervical epithelium. Scattered goblet-type cells may be seen. Immunohistochemically, the epithelial component of MCNs stains for cytokeratin (CK) 7, CK8, CK18, CK19, CEA, and MUC5AC. Only gobletlike cells express MUC2. Scattered neuroendocrine cells are present and can be demonstrated by immunohistochemical labeling for neuroendocrine markers, such as chromogranin and synaptophysin. On the cyst wall and septae, a distinctive ovarian-type stroma composed of densely packed spindle cells with sparse cytoplasm and uniform, elongated nuclei is seen (Figure 7). This stroma is an entity-defining feature of MCNs, and its presence has become a quasi-requirement for the diagnosis. 67 It regularly expresses progesterone receptors, and to a lesser degree, estrogen receptors. Moreover, some MCNs are reported to be associated with ovarian thecomas, 79 further suggesting a hormone influence in the pathogenesis of these neoplasms. Cells of the stromal component also stain for -inhibin and calretinin. 80 Just as with IPMNs, MCNs also exhibit characteristics of an adenoma-carcinoma sequence. Those without atypia are classified as MCNs with low-grade dysplasia 32 or mucinous cystadenomas. 62 In such cases, the cysts are lined by flat, mucin-producing, cuboidal to columnar epithelium with basally oriented uniform nuclei (Figure 7). These are typically devoid of papillae and no mitoses are seen. Those MCNs with mild to moderate architectural and cytologic atypia are classified as MCNs with moderate dysplasia or borderline tumor. The epithelium may be several cells thick and often forms papillae. The columnar nature of the cells is maintained, with no significant pleomorphism or nuclear irregularities. The nuclei vary slightly in size and shape; nucleoli may be present. Occasional mitoses may be seen. Those MCNs that exhibit prominent papillary proliferations that form intraluminal polypoid masses with cribriform architecture and severe cytologic atypia are classified as MCNs with high-grade dysplasia 63,81 or carcinoma in situ 63,81 (Figure 8). Significantly increased mitoses are characteristic. Not surprisingly, the incidence of carcinoma in situ increases with the size and complexity of the lesion. It should be remembered, however, that foci of carcinoma in situ can be very patchy or focal, not visible grossly, often with an abrupt transition between histologically bland epithelium and epithelium with severe atypia. The neoplasm is classified based on the highest, rather than the average, degree of atypia. 75,76,78,82 Less than one-fifth of all MCNs are associated with invasive carcinoma. 82,83 The invasive component can be very focal, and numerous sections may be required to properly evaluate these neoplasms. Grossly papillary or nodular areas should be sampled first, as these areas are most likely to harbor a carcinoma component. If an invasive carcinoma is not identified in this initial sampling, then the entire neoplasm should be submitted for histologic examination. The invasive carcinomas that arise in association with MCNs are usually of tubular/ductal type. Additionally, some MCNs may be associated with undifferentiated carcinoma with osteoclast-like giant cells, 84,85 adenosquamous carcinoma, 86 choriocarcinoma, or even high-grade sarcoma. 87 Pure mucinous (colloid) carcinoma is exceedingly uncommon with MCNs. 88 If an invasive carcinoma is present, 63,81 it is preferable to report these entities as invasive carcinoma of type, cm, arising in association with MCNs ( cm). Recent studies indicate that grade does accurately pre- Arch Pathol Lab Med Vol 133, March 2009 Pancreatic Cysts Basturk et al 427

29 Figure 6. Mucinous cystic neoplasm typically forms a thick-walled cyst in the tail of pancreas. Figure 7. Mucinous cystic neoplasm with low-grade dysplasia (mucinous cystadenoma). The cells have tall mucin-laden cytoplasm with basally located bland-appearing nuclei. Note the underlying ovarian-like cellular stroma (hematoxylin-eosin, original magnification 10). Figure 8. Mucinous cystic neoplasm with high-grade dysplasia (carcinoma in situ) exhibits prominent papillary proliferations that form intraluminal polypoid masses with cribriform architecture and loss of nuclear polarity. The nuclei show significant pleomorphism, prominent nucleoli and increased mitoses (hematoxylin-eosin, original magnification 20). Figure 9. Intraductal oncocytic papillary neoplasms are characterized by complex branching papillae, oncocytic cells and intraepithelial lumina that often contain mucin (hematoxylin-eosin, original magnifications 4 and 40 [inset]). Figure 10. Large-duct variant of ductal adenocarcinoma is composed of irregularly distributed invasive glandular elements that are larger than those of ordinary ductal adenocarcinoma. Some may show abortive papilla formation (hematoxylin-eosin, original magnification 2). Figure 11. Serous cystadenoma is characterized by a well-demarcated tumor composed of innumerable small cysts creating a spongelike or honeycomb appearance. A stellate scar is commonly present. 428 Arch Pathol Lab Med Vol 133, March 2009 Pancreatic Cysts Basturk et al

30 dict outcome, 75,76,78,82 but this statement holds true only for cases that can be graded properly. Patients with completely resected MCNs, in whom the presence of even a minute in situ or invasive carcinoma has been effectively excluded by through examination and extensive sampling, are almost always cured. However, those with invasive carcinoma often have a relatively aggressive clinical course with recurrences and metastasis. Some tumors may have more indolent behavior, presumably because of the small size (early stage) of the invasive carcinoma, which is brought to clinical attention with a large MCN. In fact, in their analysis of 56 MCNs, Zamboni et al 78 have reported that the extent of invasion is the most significant prognostic factor. Patients with in situ carcinoma may, on occasion, also experience recurrences and metastases, presumably due to undocumented foci of invasive carcinoma. Although MCNs and IPMNs have some features that overlap, the two can be distinguished by clinical, gross, and microscopic findings. 67 While IPMNs are seen predominantly in the head of the pancreas and in older men (60 70 years), 34,78,89 most MCNs occur in the tail of the pancreas in patients who are perimenopausal women. Intraductal papillary mucinous neoplasms involve the pancreatic ducts, whereas MCNs typically do not communicate with the ductal system. Most importantly, the presence of ovarian stroma is diagnostic for MCNs and has become a requirement for the diagnosis of this tumor type. 67 The only instance in which the requirement for the presence of an ovarian stroma may perhaps be waived is when a tumor, with all the clinicopathologic characteristics of a classical MCN, occurs in an older woman. Typically, however, even in these cases, the tumor would give the impression that an atrophied and hyalinized ovarian-like stroma forms a band around the cyst. Intraductal Oncocytic Papillary Neoplasm. Intraductal oncocytic papillary neoplasm (IOPN) 90 is regarded as a special subtype of IPMN, 74 although recent molecular findings suggest that it may be different from IPMN. The IOPNs typically lack the KRAS2 mutations, which are seen in 70% of IPMNs. 91,92 Regardless, many of the attributes discussed above for IPMNs also apply to IOPNs. The features that characterize and delineate IOPNs from other IPMNs are the following. The unilocular or multilocular lesions exhibit cystic dilatation of the pancreatic ducts, many of which contain large, tan, and friable nodular proliferations. Microscopically, they are characterized by very tall and complex arborizing papillae 93 (Figure 9). One distinctive feature that appears to be relatively specific for these neoplasms is the presence of intraepithelial lumina, which are round, punched-out spaces within the epithelium that often give the proliferation a cribriform architecture (Figure 9). These intraepithelial lumina often contain mucin. The cells of IOPNs are oncocytic, because of an abundance of mitochondria, and the nuclei contain single, prominent, and eccentric nucleoli (Figure 9). Scattered goblet cells may be identified. In contrast to other IPMN types, labeling of IOPNs for MUC6 is usually positive, 94 whereas MUC5AC and MUC2 are largely restricted to goblet cells, or are present only focally. Most IOPNs qualify for classification as carcinomas in situ based on the exuberance of papillary elements, the large nuclei, prominent nucleoli, and mitotic activity; however, the relationship between this cytoarchitectural complexity and the potential for malignancy has yet to be fully documented. In our experience, despite their highly proliferative nature and large size (with a mean of 6 cm), invasive carcinomas arising from IOPNs are typically uncommon, and such cases may have a long protracted clinical course. In other organs, such as the kidney, oncocytic change is associated with a biologic behavior different from that of nononcocytic neoplasms. Whether this observation applies also to the pancreas remains to be seen. Retention Cyst, Mucocele, and Mucinous Nonneoplastic Cyst. In general, most cysts lined by mucinous epithelium in the pancreas are considered neoplastic. This has become especially true since the inclusion of the entity formerly called mucinous metaplasia or mucinous hypertrophy into the PanIN category as PanIN-1A. 72 However, obstruction and fibrosis may lead to cystic dilatation of the upstream ducts 7 (ie, a retention cyst, or if mucus filled, a mucocele). 95,96 Most patients with this type of cyst are asymptomatic adults and the cysts are detected incidentally. The lesions are usually single and unilocular with a smooth and glistening lining. Microscopically, they have a simple epithelial lining. Most authors restrict the term retention cyst to unilocular cysts lined by cuboidal cells lacking significant apical mucin, 7 but controversy exists when these cysts exhibit columnar mucinous lining. Some authors classify such cases as mucinous nonneoplastic cysts, 97,98 whereas others prefer to include them in the category of IPMNs with low-grade dysplasia. In other words, there are no specific criteria that distinguish these innocuous mucin-lined cysts from IPMNs, or for small cysts, from PanINs, except the presence of papillae, which allows an unequivocal diagnosis of branch duct IPMN. The authors current approach is to classify a grossly detectable cystic lesion, larger than 1 cm and lined by mucinous epithelium, as an IPMN; however, it is quite possible that this approach will change as more facts about these lesions are elucidated. Since retention cysts may result from ductal obstruction, it is important to ensure that they are not caused by a tumor, such as a small invasive carcinoma located proximal to the cyst. Cystic Change in Ordinary Ductal Adenocarcinoma and Other Invasive Carcinomas. Rarely, conventional infiltrating ductal adenocarcinomas of the pancreas may undergo cystic change. 5,17,18 In our experience, this occurs in less than 1% of cases. 17 In some pancreatic cancers, a large, radiologically detectable cyst may form because of central necrosis. Such cases can be misdiagnosed preoperatively as pseudocysts. 99 In other cases, infiltrating ductal adenocarcinomas can obstruct the pancreatic duct and lead to cystic dilatation of the upstream duct. A large duct (microcystic) variant of ductal adenocarcinoma also exists, with infiltrating tubular units that are larger than those of ordinary ductal adenocarcinomas (Figure 10). This variant mimics noninvasive pancreatic tumors characterized by cystic and papillary patterns such as MCNs or IPMNs. It may be distinguished from the latter group of neoplasms by the smaller size of its cysts, irregularity of the duct contours, clustering of the ducts, presence of intraluminal neutrophils and granular debris, degree of cytologic pleomorphism, and myxoid quality of the stroma. Clinically it behaves like ordinary grade 1 ductal adenocarcinoma. Other invasive malignant neoplasms of the pancreas, such as undifferentiated carcinoma with osteoclast-like giant cells 13 or squamous cell carcinomas, 103 occasionally present as cystic masses. Arch Pathol Lab Med Vol 133, March 2009 Pancreatic Cysts Basturk et al 429

31 Figure 12. Serous cystadenoma. Numerous, tightly packed small cysts lined by low cuboidal tumor cells with clear cytoplasm, and small, round uniform nuclei that have dense, uniform chromatin (hematoxylin-eosin, original magnification 20). Figure 13. Oligocystic variant of serous cystadenoma showing a large unilocular cavity. Figure 14. Intraductal tubular carcinoma with nodular and smooth-contoured growth resembling intraductal papillary mucinous neoplasm. Inset shows tightly packed small tubular glands lined by cuboidal cells with round to oval atypical nuclei (hematoxylin-eosin, original magnifications 2 and 40 [inset]). 430 Arch Pathol Lab Med Vol 133, March 2009 Pancreatic Cysts Basturk et al

32 Ductal Lineage, Serous (Clear Cell) Type Serous Cystadenoma. Serous cystadenoma (SCA) is a benign neoplasm composed of uniform glycogen-rich epithelial cells that form innumerable small cysts containing serous fluid. 1,104 The mean age of affected patients is 61 years. Up to one-third of the patients with SCA are asymptomatic and the neoplasms are discovered incidentally. Almost two-thirds of SCAs occur in the body-tail region of the pancreas and are seen predominantly in female patients (female to male ratio, 3:1). The lesions usually present as relatively large masses measuring up to 25 cm. Macroscopic appearance is very distinctive and readily diagnostic for this tumor type. Their cut surface shows numerous, tightly packed, small, thin-walled cysts (spongelike or honeycomb appearance) arranged around a central stellate scar, which may contain calcifications (Figure 11). The cysts usually do not communicate with the pancreatic duct system. Microscopically, the single layer of cuboidal or flattened cells lining the small cysts have well-defined cytoplasmic borders, pale to clear cytoplasm, and small, round uniform nuclei with dense, homogeneous chromatin and inconspicuous nucleoli (Figure 12). The nuclear contours are very smooth. Atypia and mitosis are absent. The tumor cells are intimately admixed with prominent capillary network akin to other clear-cell tumors also associated with von Hippel-Lindau (VHL) syndrome (renal cell carcinoma, capillary hemangioblastoma, etc). 105 The central stellate scar and the stroma separating the cysts are composed of acellular collagenous connective tissue. Special stains highlight the abundant intraepithelial glycogen with absence of mucin. Serous cystadenomas are presumed to arise from the centroacinar cell/intercalated duct system 106 and express cytokeratins (AE1/AE3, CAM 5.2, CK7, CK8, CK18, CK19), -inhibin, and MUC6. Characteristically, there is no immunoreactivity to CEA. 107 They do not harbor the molecular genetic alterations that are characteristic of mucinous-type ductal neoplasia of the pancreas. 108,109 Instead, VHL gene alterations (loss of heterozygosity at chromosome 3p25 and a VHL-gene germline mutation) are detected in 40% of cases. 106,110 GLUT-1, a molecule involved in glycogen metabolism, is also expressed consistently. 111 Currently, with the advances in radiologic methods, it is more feasible to recognize SCAs preoperatively, and deciding which patients are candidates for surgery becomes an issue. Some authors recommend nonoperative tumor management with clinical follow-up for patients with asymptomatic and small ( 4 cm) tumors and reserve the option of resection for symptomatic patients, larger tumors ( 4 cm), or for tumors that show rapid growth rate (doubling time of a few months) in clinical follow-up. 112 Oligocystic (Macrocystic) Variant of Serous Cystadenoma. A rare oligocystic (macrocystic) variant of SCA is composed of fewer but larger loculi and lacks the central stellate scar (Figure 13). 106,113 This variant occurs predominantly in the head of the pancreas, where it may obstruct the common bile duct and cause jaundice. 114 It shows no evidence of sex predilection. The epithelial lining of these cysts may become denuded, and it may be difficult to distinguish oligocystic SCAs from mucinous neoplasms or pseudocysts unless the lesion is extensively sampled. VHL-Associated Pancreatic Cysts. Pancreatic involvement is seen in 50% to 80% of patients with VHL syndrome. The pancreatic cysts are virtually indistinguishable from those of SCAs when taken out of context, but they affect the pancreas diffusely or in a patchy fashion rather than forming a distinct, well-demarcated tumor. Gene alterations associated with VHL are present in these lesions. Serous Cystadenocarcinoma. Although extremely rare, serous cystic neoplasms of the pancreas that involve lymph nodes and the liver have been reported 104, and form the basis for their designation as serous cystadenocarcinomas. Most are microscopically identical to SCAs, and no morphologic findings, other than tumorigenic behavior, distinguish these malignant variants from their benign counterparts. Ductal Lineage, Not Otherwise Specified Intraductal Tubular Carcinoma. Intraductal tubular carcinoma is a distinct clinicopathologic entity that has yet to be fully characterized By its intraductal nature, it resembles IPMNs and may occasionally have a similar cystic component. Microscopically, the lesions are composed of intraductal nodules of tightly packed, small tubular glands and solid areas lined by predominantly cuboidal cells with modest amounts of cytoplasm, which do not contain any apparent mucin. The nuclei are round to oval and atypical. Mitotic figures are readily identifiable (Figure 14). Necrosis has been reported in some cases, focally showing comedo pattern. 125 Immunohistochemically, all the tumors are positive for CK7 and CK19, most express MUC1 and MUC6, and all are negative for CK20, CDX2, MUC2 and MUC5AC. Approximately one-third of intraductal tubular carcinomas have an associated, typically grossly invisible, invasive adenocarcinoma. 125 Therefore, careful sampling and evaluation is warranted. Limited data indicate that if there is no associated invasive carcinoma despite the histologic indicators of a high-grade malignancy, overall outcome is relatively favorable. Endocrine Lineage Cystic Pancreatic Endocrine Neoplasm. A mild cystic change is not uncommon in pancreatic endocrine neoplasms, particularly in the larger tumors, but marked cystic alteration is rarely seen Although 25% of patients with these neoplasms have hereditary multiple endocrine neoplasia syndrome, most tumors are clinically nonfunctioning. They exhibit either a unilocular cyst (Figure 15) or a multilocular microcystic pattern. The cysts are lined Figure 15. Pancreatic endocrine neoplasm with extensive cystic and hemorrhagic degeneration. Figure 16. Cystic and intraductal acinar cell carcinoma forms papillary nodules that are punctuated by glandular and microcystic areas. The cysts vary in size and configuration, and some contain intraluminal pale, acidophilic, amorphous material that is characteristic of enzymatic acinar products (hematoxylin-eosin, original magnification 10). Figure 17. Solid-pseudopapillary neoplasm characterized by marked hemorrhage and cystic degeneration. Arch Pathol Lab Med Vol 133, March 2009 Pancreatic Cysts Basturk et al 431

33 by a ragged cuff of well-preserved neoplastic endocrine cells and filled with a clear serosanguineous fluid instead of necrotic debris. The solid areas of the tumors reveal characteristic cytomorphologic features of a well-differentiated pancreatic endocrine neoplasm, including round, monotonous cells with a moderate amount of cytoplasm and distinctive nuclear chromatin pattern. Although the tumors are large, malignant behavior is not as high as expected, which raises the question of whether the cystic component leads to an overestimation of size without contributing to the effective tumor volume. Acinar Lineage Acinar Cell Cystadenoma (Cystic Acinar Transformation). This uncommon phenomenon is seen in adults with a mean age of 47 years, and the consensus is that it is a benign process. 7,140,141 The lesion is usually discovered incidentally but may produce a clinically detectable unilocular or multilocular cystic mass ranging from 1.5 to 10 cm in greatest diameter. Multicentricity is common, and some lesions diffusely involve the pancreas. Microscopically, the cysts are lined by 1 to several layers of cytologically bland acinar cells with round, basally oriented nuclei and granular, eosinophilic apical cytoplasm. The cytoplasmic zymogen granules are positive for periodic acid Schiff and resistant to diastase digestion. Immunohistochemical labeling for markers of acinar differentiation (trypsin, chymotrypsin, and lipase) is also positive. Interestingly, the tumor cells express CK7, while normal acinar cells are negative for this marker. Acinar Cell Cystadenocarcinoma. The cystic form of acinar cell carcinoma (ACC) is well documented but is extremely uncommon; only a handful of cases have been documented in the literature The lesions are large (mean size, 24 cm), circumscribed, and diffusely cystic, with individual locules ranging from a few millimeters to several centimeters. Microscopically, the cysts are lined by single or several layers of neoplastic acinar cells, sometimes forming minute lumina within the epithelial lining. There is nuclear atypia with prominent single nucleoli. Solid nests of neoplastic cells, areas of necrosis, and easily identifiable mitotic figures support a malignant diagnosis. Special stains and immunohistochemical markers can be used to document the presence of acinar differentiation. Cystic/Intraductal Acinar Cell Carcinoma. Acinar cell carcinomas are typically solid tumors; however, some ACCs show prominent intraductal growth and/or papillocystic patterns, which brings in the differential diagnosis of intraductal neoplasia 147 (Figure 16), and may also have a cystic component. The correlation of macroscopic and microscopic findings, histochemical and immunohistochemical features can be helpful for distinguishing these tumors from intraductal neoplasms, especially IPMNs. Endothelial Lineage Lymphangioma. Lymphangiomas may also present as pancreatic and peripancreatic cystic masses that may measure as much as 25 cm. 6 Histologically, the lesions are lined by endothelial cells, as demonstrated by immunohistochemical labeling for endothelial markers (CD31, CD34, or D2-40). Labeling for epithelial markers (cytokeratins) is consistently negative. The stroma may contain smooth muscle cells, aggregates of mature lymphocytes, and foamy histiocytes. Mesenchymal Lineage Schwannomas in the pancreas and retroperitoneum tend to be cystic and are termed multicystic schwannomas They can be mistaken for MCN with denuded epithelium. Some sarcomas, 151 especially gastrointestinal stromal tumors, and other nonepithelial tumors of this region, such as paragangliomas, also present as a cyst. 5,152 Undetermined Lineage Solid-Pseudopapillary Neoplasm. Solid-pseudopapillary neoplasm (SPN) is a distinctive tumor type in the pancreas that often presents as a cystic mass, and for this reason was previously referred to as solid and cystic, 153,154 solid and papillary, 155 cystic and papillary, and papillary cystic. 156,157 It is now known that the cavities of SPNs are not true cysts, but rather represent a necrotic/degenerative process. 47,158 Most SPNs occur in women in their twenties or thirties 158 (mean age, 28 years; male to female ratio, 1:20). The lesions are relatively evenly distributed throughout the gland and are often large (with a mean diameter of 9 to 10 cm). 4 Some appear grossly encapsulated. The cut surface typically shows variable appearance depending on the degree of hemorrhage and necrosis. Some have a bloody appearance with only scattered, beige-tan solid tumor foci (Figure 17); others may be solid, fleshy tumors throughout. Small streaks extending to the adjacent pancreas are common. Often, the cellular areas show a delicate microvasculature that forms pseudorosettes, creating an ependymoma-like appearance (Figure 18), or they may be accompanied by hyalinized or myxoid stroma. This distinctive pattern is created by the differential dyscohesion of cells away form the vasculature, apparently related to the recently documented alterations in cell adhesion molecules such as E-cadherin and -catenin Clusters of uniform tumor cells usually have eosinophilic cytoplasm. Cytoplasmic vacuoles and foamy macrophages are also common. Some cells may contain periodic acid-schiff positive and diastase-resistant intracytoplasmic eosinophilic hyaline globules. The nuclei are round to oval and uniform (Figure 18) and have finely stippled chromatin and frequent longitudinal grooves. The overall appearance of SPNs closely resembles that of pancreatic endocrine neoplasia, but unlike endocrine tumors, the nests in SPNs tend to be less distinct. There are irregular clusters of cells, nuclei are more ovoid, and the chromatin pattern is more fine and diffuse rather than having a salt-and-pepper appearance. Solid-pseudopapillary neoplasm is one of very few neoplasms for which the direction of differentiation of the neoplastic cells has yet to be established. No evidence exists for ductal, acinar, or frank endocrine differentiation. 47,158 Immunohistochemically, the neoplastic cells diffusely and strongly express vimentin, 1 -antitrypsin, CD56, and neuron-specific enolase; meanwhile, expression of epithelial markers (AE1/AE3, CAM 5.2) can be focal or weak. Cells are commonly positive for synaptophysin and neuron-specific enolase; however, staining for chromogranin, the most specific endocrine marker, is typically negative or only very focal. Recently, CD10 expression 162 was found to be almost uniformly present, and c-kit (CD117) 163 and FLI expressions were detected in many SPNs. Moreover, the neoplastic cells consistently express progesterone receptors and also the beta form of estrogen 432 Arch Pathol Lab Med Vol 133, March 2009 Pancreatic Cysts Basturk et al

34 Figure 18. Solid-pseudopapillary neoplasm. Prominent pseudopapillary growth pattern is present (hematoxylin-eosin, original magnification 10). Figure 19. Nuclear and cytoplasmic -catenin staining in solid-pseudopapillary neoplasm (original magnification 40). receptors, 165 suggesting a role for hormones in the evolution of these neoplasms. The only known, generally consistent genetic aberration is a mutation in exon 3 of the -catenin gene, which results in nuclear -catenin staining 166,167 (Figure 19). The expression of CD56, progesterone receptor, and FLI-1, all located on chromosome 11q, points to the fact that chromosome 11q may be involved in a translocation or harbor a mutation that results in the expression of some or all of these proteins in SPNs. 164,168 Yet another peculiar aspect of SPNs is their clinical behavior. 158 More than 80% of SPNs are cured by surgical resection. Ten percent to 15% of affected patients may have metastases to the liver or peritoneum, rarely to the lymph nodes, but even patients with metastases are often cured by surgical resection. There do not appear to be any reliable histopathologic criteria to distinguish SPNs that can metastasize from those that do not. 169 Necrosis, mitotic activity, perineurial invasion, and invasion to adjacent pancreas have all failed to prove any correlation with metastatic behavior. However, recently, 2 cases of anaplastic transformation with aggressive clinical course were reported. 170 Other Mature Cystic Teratoma. Mature cystic teratomas are exceedingly rare neoplasms in the pancreas and, as in other sites, are recognized by the presence of mature tissue elements from three germlines. 171 Those reported in the pancreas are predominantly monodermal teratomas with only ectodermal derivatives and are referred to as dermoid cysts. 172 They are usually seen in younger patients (in their second or third decade of life) and are difficult to distinguish from lymphoepithelial cysts. The presence of sebaceous glands or hair follicles is more typical for dermoid cysts. Thorough macroscopic and microscopic examinations are warranted for areas of solid, fleshy, or necrotic tissue to assess the presence of a carcinoma arising within the teratoma. CONGENITAL CYSTS Duplication (Enterogenous) Cysts Very rarely, congenital cysts of foregut derivation may also occur adjacent to the pancreas They may cause pancreatitis and often present in childhood. Most are found in the head of the pancreas and some communicate with the pancreatic ducts. They are lined by a variety of epithelia including squamous, gastric, small intestinal, respiratory (bronchogenic), or simple ciliated epithelium The wall of the cyst contains bundles of smooth muscles. We have also seen 2 examples with ciliated epithelium and one of these had an associated high-grade papillary adenocarcinoma with pancreatobiliary-type features. Duodenal Diverticula Duodenal diverticula are outpouchings of the duodenum, and the lumen of the cyst (as well as mucosa) is contiguous with the duodenal lumen. These rare lesions may coexist with other anatomic abnormalities such as choledochocele, annular pancreas, or polysplenia syndrome. 181 Most are found at or near the ampulla of Vater and extend distally into the lumen of the duodenum. The common bile duct and pancreatic duct usually empty into the diverticulum, and then a second orifice in the diverticulum allows drainage of the duct contents into the intestine. 182 Patients may have complications such as intermittent duodenal obstruction, bleeding, abdominal pain, or occasionally pancreatitis. 182 In fact, some complications may result from a paraduodenal wall cyst associated with paraduodenal pancreatitis, as discussed above. Duodenal diverticula should be distinguished from foregut cysts, which do not communicate with the duodenal lumen. Others Patients with polycystic kidney disease, 183 both adult and infantile types, and with medullary cystic kidneys 184 may have cystic lesions in the pancreas. Cystic fibrosis may lead to the cystic dilatation of the pancreatic ducts, generally not clinically detectable, by causing intraluminal impaction. 185,186 Cystic transformation of the pancreas has also been described in a variety of congenital syndromes 187 including Ivemark syndrome, trisomy 13 or 15, Meckel-Gruber syndrome, Elejalde syndrome, glutaric aciduria, chondrodysplasia, short-rib polydactyly syndrome (Jeune syndrome Arch Pathol Lab Med Vol 133, March 2009 Pancreatic Cysts Basturk et al 433

35 and Saldino-Noonan type), 188 and others with no specific name. 189 Familial fibrocystic pancreatic atrophy is an interesting phenomenon described in a family with pancreatic cancer from Seattle, Washington, and is characterized by a lobulocentric pancreatic atrophy associated with fibrocystic (microcystic) changes and endocrine cell proliferation. 190 Other families with pancreatic cancer may also show similar cystic changes. 191 MISCELLANEOUS CYSTS Lymphoepithelial Cyst Lymphoepithelial cysts are multilocular (60%) or unilocular (40%) cystic lesions mostly seen in older adults (mean age, 56 years) with a male predominance (male to female ratio, 4:1). 172,192 They can be seen in any component of the pancreas and often project into the peripancreatic tissues. The cyst content may vary from serous to cheesy/ caseous appearing. If the cyst content is removed, the lining of the cysts is observed to be smooth or finely granular. The cyst wall and trabeculae are usually 1 to 3 mm thick. Microscopically, the cysts are lined by well-differentiated stratified squamous epithelium (Figure 20), usually with keratinization. In some areas, the lining may appear more transitional, and in others, appear flat, cuboidal, and focally denuded. Rarely, there are scattered sebaceous and mucinous gobletlike cells (Figure 20). A recent report indicates that goblet cells may be more common than previously appreciated. 193 Extensive sebaceous or mucinous elements are more suggestive of a teratoma. The squamous epithelium is surrounded by a band of dense lymphoid tissue (Figure 20) composed of mature T lymphocytes. Reactive germinal center formation is common. In some examples, the lymphoid tissue has a thin capsule and a subcapsular sinus, suggesting that the process may have arisen in a peripancreatic lymph node. Epithelioid granulomas, collections of foamy histiocytes, cholesterol clefts, and fat necrosis may be present. The adjacent pancreas is usually unremarkable. Lymphoepithelial cysts of the pancreas do not appear to be associated with conditions related to lymphoepithelial cysts of the parotid gland or head and neck region, such as autoimmune disorders, human immunodeficiency virus infection, lymphoma, or carcinoma, and their origin is uncertain. Squamoid Cyst of Pancreatic Ducts Squamoid cysts of pancreatic ducts are relatively small, unilocular cysts with a median size of 1.5 cm; however, some are large, may have high CEA levels, and thus undergo resection with the clinical impression of being an IPMN. The lesions have variable lining ranging from attenuated, flat, nonstratified squamous to transitional to mucosal-type stratified squamous epithelium without cornified layer or parakeratosis. They typically contain distinctive muco-proteinaceous acidophilic acinar secretions that form concretions, thus confirming communication with the acinar system. The wall of the cyst is composed of a thin band of fibrous tissue devoid of any lymphoid tissue. Neither acute nor chronic inflammation is a feature of this lesion. 194 Clinical, macroscopic, and microscopic findings indicate that squamoid cysts of pancreatic ducts represent cystic dilatation of the native ducts rather than a de novo cyst formation. The immunophenotype confirms Figure 20. Lymphoepithelial cyst. The cyst is lined by squamous-type epithelium with scattered goblet cells surrounded by a distinct band of lymphoid tissue (hematoxylin-eosin, original magnification 20). Figure 21. Epidermoid cyst within intrapancreatic accessory spleen. The cyst has a thin squamous epithelial lining surrounded by splenic red and white pulps (hematoxylin-eosin, original magnification 4). the squamous/transitional nature of the epithelial lining (p63 nuclear expression, which is not otherwise detected in other components of the pancreas), 195 and also suggests a relationship to the centroacinar/intercalated duct system (MUC1 and MUC6 expression). Epidermoid Cysts Within Intrapancreatic Accessory Spleen These cysts are extremely rare. All the reported cases have occurred in the tail of the pancreas, 172, where accessory spleens are not too uncommon. They are seen in adults (mean age, 37 years), and occur equally in men and women. The lesions can be unilocular or multilocular 434 Arch Pathol Lab Med Vol 133, March 2009 Pancreatic Cysts Basturk et al