Pancreatic cysts: pathologic classification, differential diagnosis, and clinical implications.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
Pseudocysts are the most common type of cystic lesions of the pancreas, (7) although they rarely come to the atten 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 debrisfilled 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. (10-15) 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) 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 epitheliumlined 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 patients are men aged 40 to 50 years, and history of alcohol abuse and cigarette smoking is characteristic. (21-23) 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.
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Rarely, hydatid cysts, (24-27) necrotic tuberculosis infections, (28,29) and other entities can occur in the pancreas and mimic primary cystic neoplasms.
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. (30-32) 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 PeutzJeghers 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-intestinal61 (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 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.
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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 low-grade 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, which may follow an aggressive clinical course, had a 5-year survival rate as low as 36% (42,54,69,70)
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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 ovariantype 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 [alpha]-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 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 al78 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.
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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 (100-102) 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.
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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), [alpha]-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 germlinemutation) 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 (104,115-122) 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. (123-125) 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.
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. (126-139) 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 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 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. (142-146) 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.
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.
Schwannomas in the pancreas and retroperitoneum tend to be cystic and are termed multicystic schwannomas. (148-150) 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)
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 [beta]-catenin. (159-161) 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, [[alpha].sub.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-1 (164) expressions were detected in many SPNs. Moreover, the neoplastic cells consistently express progesterone receptors and also the beta form of estrogen receptors, (165) suggesting a role for hormones in the evolution of these neoplasms.
[FIGURE 18 OMITTED]
[FIGURE 19 OMITTED]
The only known, generally consistent genetic aberration is a mutation in exon 3 of the [beta]-catenin gene, which results in nuclear [beta]-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)
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.
Duplication (Enterogenous) Cysts
Very rarely, congenital cysts of foregut derivation may also occur adjacent to the pancreas. (173-177) 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. (178-180) 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 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.
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 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)
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 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).
[FIGURE 20 OMITTED]
[FIGURE 21 OMITTED]
Epidermoid Cysts Within Intrapancreatic Accessory Spleen
These cysts are extremely rare. All the reported cases have occurred in the tail of the pancreas, (172,196-198) 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 and are lined by attenuated keratinizing squamous cells, surrounded by unremarkable splenic tissue (Figure 21).
The haphazard distribution of the abnormal pancreatic elements in chronic pancreatitis may be reminiscent of hamartoma. Therefore, many of the cases reported in the literature as hamartomas of the pancreas appear to represent subsets of chronic pancreatitis; however, rare lesions exist that would qualify as true hamartomas in the pancreas, some of which are cystic. (199,200) These form a sharply delimited lesion and are 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 pancreatic-polypeptide-producing cells are also present.
Endometriotic cysts, (201,202) some associated with massive hemorrhage, (203) have been rarely reported in the pancreas. As in other locations, they occur in females of reproductive age and are lined by endometrial epithelium and are accompanied by endometrial stroma.
Rarely, metastatic neoplasms can exhibit cystic change. (152,204) We have seen examples of metastatic ovarian and renal cell carcinomas in the pancreas that presented as cystic masses.
In contrast to solid tumors of the pancreas, most of which are invasive ductal adenocarcinomas with dismal prognosis, most of the cystic neoplasia in this organ are either benign tumors or low-grade malignancies with relatively indolent behavior. However, their differential diagnosis can be quite challenging. It is important to recognize the mucinous lesions because they often exhibit an adenoma-carcinoma sequence. Therefore, careful macroscopic examination and thorough sampling of these lesions are mandated, not only to rule out carcinoma, but also for proper subclassification of these tumors. For example, gross examination and dissection play an important role in verifying the radiologic impression that a given IPMN falls into the branch or main duct type. Along the same lines, it is important to examine a cystic lesion thoroughly before it can be diagnosed as a "pseudocyst" because SPNs and even ordinary ductal adenocarcinomas or endocrine neoplasia may present as a pseudocyst.
Accepted for publication November 4, 2008.
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Olca Basturk, MD; Ipek Coban, MD; N. Volkan Adsay, MD
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 30322 (e-mail: email@example.com).
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