Cystic, mucin-producing neoplasms of the pancreas: the distinguishing features of mucinous cystic neoplasms and intraductal papillary mucinous neoplasms

Seminars in Diagnostic Pathology (2005) 22, 318-329

Cystic, mucin-producing neoplasms of the pancreas: the distinguishing features of mucinous cystic neoplasms and intraductal papillary mucinous neoplasms David S. Klimstra, MD From the Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York. KEYWORDS Pancreas; Intraductal; Mucinous; Cyst; Papillary

Perhaps due to the increasing use of sensitive cross-sectional imaging of the abdomen, cystic lesions of the pancreas are being increasingly recognized. In many such cases, biopsy or resection reveals a multilocular cyst lined by columnar mucinous epithelium. Over the past two to three decades, there have been many advances in our understanding of the clinical, pathological, and molecular features of cystic mucin-producing pancreatic neoplasms, most of which are now broadly classified as either mucinous cystic neoplasms (MCNs) or intraductal papillary mucinous neoplasms (IPMNs). Although both share certain histological features and both are regarded to represent preinvasive neoplasms with the potential to progress to invasive carcinoma, there are many significant differences in their pathology and clinical management. The purpose of this review is to highlight the clinical and pathological characteristics of MCNs and IPMNs, with an emphasis of the features that distinguish them and allow proper pathological subclassification. © 2005 Elsevier Inc. All rights reserved.

General features of mucinous cystic neoplasms Clinical features Mucinous cystic neoplasms were first distinguished from serous cystic neoplasms in 19781; previously both categories had been lumped together as “cystadenomas” of the pancreas. Once the distinguishing histological features were defined, a distinctive clinical picture emerged. Almost all mucinous cystic neoplasms arise in females.2-7 Some reports have included a number of male patients,8 but once intraductal papillary mucinous neoplasms (IPMNs) were better defined and separated from MCNs, the proportion of Address reprint requests and correspondence: David S. Klimstra, MD, Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021. E-mail address: [email protected].

0740-2570/$ -see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1053/j.semdp.2006.04.005

male patients fell to less than 5%, and one series of 130 patients contained only females.6 Also characteristic is the age at presentation. MCNs have been reported between the ages of 14 and 95 years, but most occur in the fifth decade.2-7 Finally, the location in the pancreas is relatively constant: most MCNs involve the tail or body of the gland, and less than 10% of well-characterized MCNs arise within the head. The presenting symptoms depend on the size of the neoplasm. Since MCNs predominantly involve the distal pancreas, biliary obstruction is uncommon, as is exocrine insufficiency due to chronic obstructive pancreatitis.2-7 Large MCNs may compress adjacent structures, causing nausea and vomiting or abdominal pain. Some MCNs are discovered incidentally by abdominal imaging studies. Cross-sectional imaging and ultrasound reveal large (mean, 7-10 cm), well-delineated cysts, sometimes with calcification of the periphery.9-11 The cystic locules are large, placing MCN in the macrocystic category, in contrast to the

Klimstra

Cystic, Mucin-Producing Neoplasms of the Pancreas

Figure 1 Gross appearance of mucinous cystic neoplasm. The cyst is well circumscribed and surrounded by a fibrous pseudocapsule. Large cystic locules contain thick, mucinous fluid.

classic microcystic pattern of most serous cystadenomas. By endoscopic retrograde cholangiopancreatography (ERCP) or magnetic resonance cholangiopancreatography (MRCP), there is no communication between the cystic neoplasm and the major pancreatic ducts, which can be displaced around the mass.

Pathological findings The gross findings recapitulate the radiographic images. MCNs are well circumscribed multilocular cysts surrounded by a thick fibrous pseudocapsule (Figure 1). The cyst contents are moderately viscous, colorless, and mucoid in most cases. Depending on the degree of epithelial proliferation, the septa may have a smooth, glistening lining or there may be soft tan nodules of exophytic tumor projecting into the cystic locules. Solid areas between the cystic spaces are worrisome for invasive carcinoma. If a probe is inserted into the pancreatic duct, there should be no communication with the cyst except in rare cases with fistula formation. The pancreas proximal to the MCN is usually grossly normal. Microscopically, MCNs are composed of variably sized cystic locules, each predominantly lined by tall columnar mucinous cells (Figure 2). Some MCNs have regions with cuboidal epithelium that does not contain obvious mucin, but essentially all cases show mucinous epithelium somewhere, and the intracellular mucin can be demonstrated with histochemical stains. Goblet cells can be found as well. There are varying degrees of cytologic and architectural atypia in MCNs, and even within the individual neoplasm there may be regions with minimal atypia adjacent to regions with high grade dysplasia or frankly invasive carcinoma (Figure 3A). Cells with uniform basally oriented nuclei form a flat epithelial lining in the least atypical areas. Elsewhere, the cells can lose polarity, the nuclei can become pseudostratified and more atypical, mitoses can be found, and the epithelium can become more complex, with papilla formation, micropapillae, and cribriforming (Figure 3B).

319 These highly dysplastic cells have less intracellular mucin. A histological hallmark of MCNs is the presence of densely cellular subepithelial stroma lining the septa of the cysts.7,12-14 This “ovarian-like” stroma, now regarded as essential to the diagnosis of MCN, is composed of fascicles of spindle cells with serpiginous nuclei and scant cytoplasm (Figure 3). Clusters of epithelioid cells with eosinophilic cytoplasm, round nuclei, and prominent nucleoli are found within the stroma and resemble luteinized stromal cells of the ovary (Figure 4). MCNs are often surrounded by a densely fibrotic pseudocapsule that sharply separates the epithelial and stromal elements from the nonneoplastic pancreatic parenchyma. In some cases, however, there is extension of the cellular stroma of the MCN into the adjacent parenchyma, with growth of these spindle cells around ducts and collections of acini. Some MCNs have degenerative changes, including hemorrhage, inflammation, and denudation of the epithelium, that can simulate the appearance of a pseudocyst, both grossly and microscopically.15 The finding of the characteristic cellular stroma in denuded areas can be helpful in excluding a pseudocyst. In addition, most patients with pseudocysts have a clinical history of pancreatitis, and the surrounding pancreas is markedly abnormal on radiographic and gross examination. Invasive carcinomas are found in 35% of MCNs,4,12,16 usually those with high grade dysplasia in the cyst lining epithelium (Figure 5). The extent of the invasive carcinoma varies from microscopic foci limited to the septa of the cysts to large gross tumors that extend outside of the pancreas into adjacent structures.7 Usually the invasive carcinomas are histologically similar to conventional tubular type ductal adenocarcinomas, but most of the histological types of carcinoma that can arise in the pancreas have been reported in association with MCNs, including colloid (mucinous) carcinoma, adenosquamous carcinoma, anaplastic carcinoma, and undifferentiated carcinoma with osteoclast-like giant cells.2,4,5,17-20 Rarely a spindle cell malignancy can be found. Although initially interpreted to represent sarcomatous transformation of the

Figure 2 Low power appearance of mucinous cystic neoplasm. There are variably sized cystic spaces lined by a predominantly flat mucinous epithelium. The periphery is well demarcated.

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Figure 3 High power appearance of mucinous cystic neoplasm. The epithelium ranges from low grade and moderate dysplasia (A) to areas with marked cytoarchitectural atypia that constitute high grade dysplasia (B). The subepithelial stroma is hypercellular (“ovarianlike”).

ovarian-like stroma,21 due to their molecular genetic characteristics, these spindle cell neoplasms are now believed to be sarcomatoid carcinomas that have lost evidence of epithelial differentiation.22 It is important when evaluating an invasive carcinoma with gross cystic change to confirm the presence of a preexisting benign MCN (including its ovarian-like stromal component) before accepting the neoplasm as an invasive mucinous cystadenocarcinoma, since cystic changes can occur in conventional ductal adenocarcinomas via a variety of mechanisms.23

Classification and grading The most recent (2000) WHO histological classification24 separates MCNs into different categories depending on the most advanced epithelial dysplasia identified (Table 1). When there is minimal cytoarchitectural atypia, the term

Figure 4 Clusters of epithelioid cells in the stroma of an MCN resemble the luteinized stroma of the ovary.

“mucinous cystadenoma” can be used. Moderate cytoarchitectural atypia is found in “mucinous cystic neoplasm, borderline,” and severe atypia is found in “mucinous cystadenocarcinomas.” When invasive carcinoma is also present, the neoplasm is termed “invasive mucinous cystadenocarcinoma.” The authors of the Fourth Series AFIP Fascicle on the pancreas recommend modifying this terminology,4 instead designating all cases as mucinous cystic neoplasm with the extent of dysplasia to be graded (see Table 1). In this schema, invasive components are diagnosed separately (“mucinous cystic neoplasm with invasive carcinoma”) and are subtyped, graded, and staged like other ductal-type infiltrating adenocarcinomas.

Prognosis In their 1978 seminal paper on MCNs,1 Compagno and Oertel referred to mucinous cystadenocarcinoma and muci-

Figure 5 MCN.

Invasive carcinoma arising within the septa of an

Klimstra Table 1

Cystic, Mucin-Producing Neoplasms of the Pancreas

321

Classification of mucinous cystic neoplasms

WHO classification (2000)

4th Series Fascicle classification

Mucinous cystadenoma Mucinous cystic neoplasm, borderline Mucinous cystadenocarcinoma, non-invasive Invasive mucinous cystadenocarcinoma

Mucinous Mucinous Mucinous Mucinous

nous cystadenoma as having “overt and latent malignancy,” in reference to the finding that two of their cases that lacked invasive carcinoma and one that even lacked epithelial atypia recurred and killed the patients. These observations fostered the idea that all mucinous cystic neoplasms have a risk of malignant behavior, even if no carcinoma is identified. In retrospect it appears that these and other reported fatal MCNs6 that appeared to lack invasive carcinoma were either incompletely resected or inadequately sampled for histology, making it likely that foci of invasive carcinoma were missed. More recent studies have demonstrated that when completely resected and thoroughly sampled (see Cytology, Frozen Sections, and Histological Sampling, below), MCNs lacking invasive carcinoma do not recur.7,8 In fact, Zamboni and coworkers7 divided MCNs with invasive carcinoma into those with the invasive elements limited to the septa of the cysts, those with invasion into the tumor wall (ie, the pseudocapsule), and those with peritumoral (ie, extracapsular) invasion, and only those with invasion into or through the tumor pseudocapsule recurred. These findings emphasize that all MCNs lacking invasive carcinoma are biologically benign and that it is very important to quantify the amount and depth of invasion of any invasive carcinoma. Once extrapancreatic invasive carcinoma is present, the prognosis rapidly approaches that of conventional infiltrating ductal adenocarcinoma, but overall only approximately 10% of patients with MCNs will die of their disease.2-7 There are inadequate data to identify other significant prognostic factors, including the subtypes of invasive carcinoma.

General features of intraductal papillary mucinous neoplasms Clinical features Since the first description of an intraductal papillary mucinous neoplasm by Ohhashi in 1982,25 the category of IPMN has evolved to encompass a variety of other reported entities, including a number of recently described related intraductal neoplasms that have widely varying histological patterns.26-29 The characteristic endoscopic and gross findings of ductal dilation and mucin hypersecretion led to various clinical terms for IPMNs, such as “mucinous duct ectasia” and “mucin producing tumor” among many oth-

cystic cystic cystic cystic

neoplasm neoplasm neoplasm neoplasm

with with with with

low grade dysplasia moderate dysplasia high grade dysplasia invasive carcinoma (specify type, grade, stage)

ers,30,31 but histological comparison of these neoplasms revealed significant overlap, and the unifying term IPMN is now used to refer to the family of predominantly intraductal neoplasms characterized by frequent (but not universal) papilla formation, a mucinous epithelial lining, and varying degrees of cytoarchitectural atypia.17,31-37 Similar to infiltrating ductal adenocarcinomas, IPMNs arise in older patients (mean age, 63 years; range, 25-94 years).17,31-37 Men slightly outnumber women, with a ratio of 3:2. IPMNs may arise anywhere in the pancreas, but they most commonly involve the head of the gland (70%). About 20% occur in the tail and 10% diffusely involve the gland.17,31-37 Based on whether IPMNs involve the major ducts or the secondary ducts, they are divided into main duct type and branch duct type,38-40 and there are also combined patterns. Patients present with abdominal pain, anorexia, weight loss, and pancreatitis, presumably due to ductal obstruction by the tumor, and many patients have symptoms for years before the diagnosis is established.4,5,17 Jaundice is uncommon. Increasingly, asymptomatic patients are found to have ductal dilation or cysts in the pancreas by cross-sectional imaging. The endoscopic findings in patients with main duct IPMNs are characteristic. The ampulla of Vater is dilated, and mucin can be seen streaming into the duodenum.41 By ERCP or MRCP, the pancreatic ducts are dilated and tortuous, with filling defects that correspond to either papillary masses of tumor or adherent, thick mucus.42,43 In the case of branch duct IPMNs, with cystic ducts can be shown to communicate with the major ducts by ERCP. By crosssectional imaging, branch duct IPMNs are prone to appear as separate cysts, and communication with the major ducts can be difficult to demonstrate, raising a radiographic differential diagnosis that includes many other cystic lesions.

Pathological findings The gross appearance depends on the type of IPMN (main duct versus branch duct), its extent, and the amount of mucin hypersecretion. Some IPMNs have diffuse dilation of the main pancreatic duct, with thick mucin adherent to the duct wall and soft, exophytic nodules of papillary tumor projecting into the lumen (Figure 6A). Others have simple dilation of the ducts with an apparently smooth lining. Branch duct IPMNs can appear as separated thin-walled cysts (Figure 6B), and their communication with the uninvolved ducts can be hard to find.38,40 The surrounding pancreatic tissue is often densely fibrotic. Gritty, firm areas

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Figure 6 Gross appearance of intraductal papillary mucinous neoplasms. The main duct type (A) has dilation of the major pancreatic ducts, which are filled with soft papillary fronds. In the branch duct type (B), the main duct is minimally dilated but secondary ducts appear cystic.

or collections of extraductal mucin are grossly worrisome for invasive carcinoma. Microscopically, the intraductal proliferation varies from a simple, flat mucinous epithelium lining dilated ducts to exuberant, complex papilla formation, and the full range can be encountered in a single IPMN.4,17,31-37 In most cases, well-formed papillae are at least focally present (Figure 7). The papillae may have a single layer of epithelium or they may be quite complex, with multiple layers of cells, secondary micropapilla formation, or cribriforming. The degree of cytological atypia also varies. The least dysplastic regions have columnar mucinous cells with basally located, uniform nuclei. Greater degrees of dysplasia are characterized by loss of cellular polarity and greater nuclear atypia, with mitotic activity. IPMNs have been subclassified based on the morphology of the papillae (Figure 8).17,32,33,44 Those predominantly lined by tall columnar cells with abundant apical mucin, resembling gastric foveolar cells, represent the gastric type of IPMN (Figure 8A). Intestinal type IPMNs have long, parallel villiform papillae with less apical mucin

Figure 7 Low power appearance of intraductal papillary mucinous neoplasm. Exuberant papillae fill the dilated ducts.

and pseudostratification of elongate nuclei; goblet cells may also be found (Figure 8B). Pancreatobiliary type IPMNs have markedly complex papillae lined by cuboidal cells containing round nuclei, resembling the papillary neoplasms more common in the bile ducts (Figure 8C). Gastric type papillae can be found in IPMNs that elsewhere harbor either intestinal or pancreatobiliary type papillae. Invasive carcinoma is found in roughly 35% of IPMNs,17,31-37,45 more commonly associated with the main duct and combined types and usually occurring in the presence of high grade dysplasia in the intraductal component.38-40 About half of the invasive carcinomas are composed of tubular glands associated with a desmoplastic stromal response (Figure 9A), resembling conventional ductal adenocarcinoma.32,33 The remainder are colloid carcinomas composed of large pools of extracellular mucin that contain relatively scant floating neoplastic epithelium arranged in strips, clusters, or individual signet ring cells (Figure 9B).46,47 Colloid carcinomas usually arise in association with intestinal type IPMNs.48 They must be distinguished from the acellular pools of mucin that may be found in the stroma due to ductal rupture and spillage. Two other pancreatic intraductal neoplasms have been described that also likely represent variants of IPMNs. Intraductal oncocytic papillary neoplasms (IOPNs)26,49 are formed of complex branching papillae, architecturally similar to those of the pancreatobiliary type IPMNs, lined by cells with abundant granular eosinophilic cytoplasm (Figure 10). The nuclei are large and round and contain single prominent nucleoli. The epithelium commonly forms cribriform structures, with intraepithelial lumina, and intracellular lumina are also found. Fusion of the papillae may result in a solid architecture resembling an invasive neoplasm and obscuring the intraductal nature of the tumor. Invasive carcinomas may occur IOPNs, including both colloid and oncocytic types.26 Intraductal

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Figure 8 Papilla type in intraductal papillary mucinous neoplasms. Gastric type papillae have a single layer of columnar cells with basally oriented nuclei and abundant apical mucinous cystoplasm (A). Intestinal type papillae have pseudostratified, elongate nuclei and resemble villous adenomas of the bowel (B). Pancreatobiliary type papillae have a complex lining epithelium with pseudopapillae formed by cells with more rounded nuclei (C).

tubular neoplasm27-29,50 may be even more difficult to recognize as intraductal, as the ducts are often completely filled with back-to-back tubules, with obliteration of the lumen and complete replacement of the native ductal epithelium. The tubular glands have minimal mucinous cytoplasm or no apparent intracellular mucin at all. Nuclear

atypia is moderate to marked, and necrosis may occur in the center of the intraductal tumor masses. Because the profiles of the original ducts are often obliterated, it may be difficult to determine the extent of any invasive carcinoma, although in some cases obvious infiltrating adenocarcinoma extends away from the periphery of the involved ducts.

Figure 9 Invasive carcinoma arising in IPMNs. Some cases resemble conventional tubular type ductal adenocarcinomas (A), whereas other are colloid carcinomas (B).

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Seminars in Diagnostic Pathology, Vol 22, No 4 also have high grade dysplasia (intraductal tubular carcinoma).28,29

Prognosis Compared with conventional ductal adenocarcinomas, IPMNs have an excellent prognosis.17,31-37,45 Most completely resected cases lacking an invasive component do not recur or metastasize,34,39,51 and the rare metastases reported in such cases can be explained by either inadequate sampling for histology or the presence of an invasive component elsewhere in the pancreas, not included in the resection.32 Intraductal recurrences have been described34,52 and seem to be independent of the status of the pancreatic margin, raising the possibility of multicentricity.33 Certainly the presence of invasive carcinoma adversely affects the prognosis, and the tubular type carcinomas appear to be nearly as aggressive as conventional ductal adenocarcinomas not associated with IPMNs.32,53-55 In contrast, colloid carcinomas have a relatively favorable prognosis, with a 55% survival at 5 years,33,46 even among patients with large tumors and lymph node metastases.

Figure 10 Intraductal oncocytic papillary neoplasm, with markedly complex papillae lined by cells with abundant oncocytic cytoplasm, intracellular lumina, and prominent nucleoli.

Classification and grading The classification of IPMNs parallels that for MCNs (Table 2). According to the WHO,35 IPMNs with no significant atypia are termed “intraductal papillary mucinous adenomas,” those with moderate atypia are “intraductal papillary mucinous neoplasms, borderline,” and those with severe cytoarchitectural atypia are “intraductal papillary mucinous carcinomas.” When invasive carcinoma is present, it is recommended to drop the “intraductal” modifier (“papillary mucinous carcinoma”). In the 4th series AFIP Fascicle,4 it is proposed to designate all IPMNs as “intraductal papillary mucinous neoplasms” with the degree of dysplasia to be graded as low grade, moderate, and high grade. In this system, foci of invasive carcinoma are diagnosed separately, classified, graded, and staged. Interestingly, the various papilla types are usually associated with different grades of dysplasia.17,44 Gastric type papillae usually have low grade dysplasia, intestinal type can have either moderate or high grade dysplasia, and pancreatobiliary type almost always have high grade dysplasia. IOPNs also usually have high grade dysplasia.26 When intraductal tubular neoplasms have low grade dysplasia they resemble pyloric gland adenomas of the gallbladder and are reported as intraductal tubular adenoma, pyloric gland type.27 Most reported intraductal tubular neoplasms

Table 2

Differential diagnosis Based on the preceding discussion, it is clear that the distinction of MCNs from IPMNs can be challenging. Both neoplasms are cystic and are composed of mucinous epithelium that can have a range of cytoarchitectural atypia. Both are considered precursors to infiltrating carcinoma. Features useful in their distinction are summarized in Table 3 and more fully explored below.

Clinical presentation Often the clinical and radiographic findings are sufficient to strongly suggest the correct diagnosis. The strong female predilection and younger age of occurrence of MCNs makes it highly unlikely that a cystic neoplasm in an elderly male will be an MCN. Likewise, a cystic neoplasm in the head of the pancreas is unlikely to be an MCN. Radiographically, MCNs are more sharply circumscribed than IPMNs. MCNs are solitary multilocular cysts, whereas IPMNs often appear as mul-

Classification of intraductal papillary mucinous neoplasms

WHO classification (2000)

4th Series Fascicle classification

Intraductal papillary mucinous adenoma Intraductal papillary mucinous neoplasm, borderline Intraductal papillary mucinous carcinoma, non-invasive Papillary mucinous carcinoma

Intraductal papillary mucinous Intraductal papillary mucinous Intraductal papillary mucinous Intraductal papillary mucinous (specify type, grade, stage)

neoplasm neoplasm neoplasm neoplasm

with with with with

low grade dysplasia moderate dysplasia high grade dysplasia invasive carcinoma

Klimstra Table 3

Cystic, Mucin-Producing Neoplasms of the Pancreas

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Differential diagnosis of MCN and IPMN

Age Gender Location Radiographic appearance Connection to ducts Cyst contents Mucin streaming from ampulla Villiform papillae Periductal glands Stroma Intestinal differentiation Invasive carcinoma

Mucinous cystic neoplasm

Intraductal papillary mucinous neoplasm

40–50 years Female⬎⬎⬎Male Body/Tail Dilated ducts, multiple separate cysts Usually not Mucoid No No Not present Ovarian-like No May occur

60–70 years Male⬎Female Head⬎Body/Tail Well demarcated multilocular cyst Always Mucoid Sometimes Sometimes Present Collagenized Sometimes May occur

tiple separate cysts on cross-sectional imaging, with each cystic locule representing a dilated, tortuous pancreatic duct.

Gross pathological features Grossly, MCNs are surrounded by a thick, fibrotic pseudocapsule and do not communicate with the pancreatic ducts, which generally are not dilated. Main duct IPMNs are characterized by significant ductal dilation, even in areas away from the predominant region of involvement, and the cystic spaces communicate with the remainder of the ductal system. Branch duct IPMNs, on the other hand, may not show obvious continuity with the ductal system, and the major ducts may not be dilated. Careful gross dissection is required to identify a point of communication, and in some cases it may be impossible to prove that the cystic spaces are dilated ducts grossly.

Microscopic pathological features Many of the histological features of the lining epithelium are similar between MCNs and IPMNs, but there are some important differences. Ducts involved by IPMNs often retain the periductal glands normally found in the walls of the larger pancreatic ducts; these ductules may be involved by the neoplastic epithelium. The pancreatic parenchyma between the involved ducts of an IPMN is often fibrotic and atrophic, but residual acinar elements separating the mucinous locules are another clue that they represent dilated ducts. Both MCNs and IPMNs often have epithelium resembling gastric foveolar cells, and both can have a range of cytological atypia. However, only IPMNs of intestinal type have well-formed villous papillae resembling a villous adenoma of the large bowel. Areas with high grade dysplasia may lose their characteristic intestinal morphology, and IPMNs with pancreatobiliary type papillae may be hard to distinguish from MCNs with high grade dysplasia. Some of the variants of IPMNs have very distinctive patterns of epithelium that are not reported in MCNs, such as intraduc-

tal oncocytic papillary neoplasms or intraductal tubular neoplasms. But the single most helpful microscopic feature to distinguish MCNs and IPMNs is the cellular, ovarian-like stroma that is virtually pathognomonic of MCNs. Although the density of the stroma is not always uniform throughout the neoplasm, examination of multiple sections is usually more than sufficient to identify it. Once invasive carcinoma is present, it is essential to identify the preinvasive cystic components to properly classify the neoplasm, since the histological types of invasive carcinoma that may arise in MCNs and IPMNs are numerous and are not entirely specific.

Immunohistochemical features By immunohistochemistry, both MCNs and IPMNs express keratins including cytokeratins 7, 8, 18, and 19. Glycoproteins such as carcinoembryonic antigen, DUPAN-2, and CA19-9 are also expressed, and none of these markers are useful in the distinction of these neoplasms.2 In fact, the immunoprofile of MCNs overlaps extensively with that of both gastric and pancreatobiliary type IPMNs. However, intestinal type IPMNs have some distinctive staining patterns. Expression of markers of intestinal differentiation is found, including CK20, MUC2, and CDX2.48,56,57 These markers have only limited expression in MCNs and in IPMNs of gastric and pancreatobiliary types, where MUC2 and CDX2 label individual goblet cells.58 The expression of other MUC proteins has been studied in many pancreatic neoplasms with ductal differentiation.56,57,59 MUC5AC is expressed in the full range of IPMNs and in MCNs. MUC1 expression is found in IPMNs of pancreatobiliary type and is not usually detected in gastric type IPMNs or in MCNs, although expression in regions with high grade dysplasia may be found.48,56,57,60,61 Both IPMNs and MCNs may contain scattered endocrine cells within the epithelium that can be identified by staining for chromogranin or synaptophysin.62,63

326 The ovarian-like stromal cells of MCNs often express hormone receptors, progesterone receptors more commonly than estrogen receptors. Markers of steroid cells such as inhibin, calretinin, and Melan-A highlight the clusters of epithelioid, luteinic cells within the stroma.7,13,14 Other positive stromal markers include CD99, bcl2, actin, and desmin.12 Since IPMNs lack this stromal component, these markers (in particular the hormone receptors) can be useful in the differential diagnosis. Sometime the cellular stroma is attenuated in MCNs or there is inflammation and reactive myofibroblastic proliferation that obscures the stromal elements; in these cases, positive staining for ER or PR can help identify these diagnostic elements.

Molecular features Both MCNs and IPMNs have molecular alterations that overlap with those of conventional infiltrating ductal adenocarcinomas, including mutations in codon 12 of the KRAS oncogene and in the TP53 tumor suppressor gene.24,37,64-68 Similar to the gradual accumulation of these and other genetic abnormalities that occurs with the progression of PanIN to infiltrating carcinoma, MCNs and IPMNs accumulate more genetic abnormalities with higher grades of dysplasia.69-72 Inactivation of the SMAD4/DPC4 tumor suppressor gene is uncommon in noninvasive MCNs and IPMNs,67,73 and MCN-associated invasive carcinomas appear to lose SMAD4/DPC4 with any significant frequency (50%).74 Conversely, inactivation of the p16/CDKN2A or p14 genes, another common genetic change in conventional ductal adenocarcinoma, occurs in approximately 50% of IPMNs (usually via promoter methylation) but is uncommon in MCNs.75,76 Despite these differences in molecular alterations, there are no distinguishing molecular phenotypes of MCNs or IPMNs that have diagnostic utility.3

Distinction from other cystic lesions There are other cystic lesions of the pancreas that can be confused for both IPMNs and MCNs. Serous cystic neoplasms are relatively common in the pancreas.4,5 The classic microcystic serous cystadenoma has a very distinctive radiographic and gross appearance when large: there are small (microscopic up to 1.0 cm) cysts and a central stellate fibrous scar. However, smaller examples may not be obviously microcystic by imaging techniques. More confusing is the macrocystic serous cystadenoma, in which the individual locules usually measure more than 1.0 cm. These neoplasms closely resemble branch duct IPMNs, although they lack the peripheral capsule of MCNs and are often less well demarcated. All serous neoplasms are lined by a flattened cuboidal epithelium with clear, glycogen-rich cytoplasm and round, hyperchromatic nuclei. The absence of mucin is very helpful in the distinction from MCNs and IPMNs. Ductal retention cysts are generally unilocular but can resemble MCNs and IPMNs.5,77 Retention cysts are not

Seminars in Diagnostic Pathology, Vol 22, No 4 neoplastic and generally are lined by normal-appearing ductal epithelium. However, PanIN secondarily involves some retention cysts, and the mucinous epithelial lining can be nearly indistinguishable from the lining of an IPMN.77 However, there are no papillae in retention cysts, and the ovarian-like stroma of MCNs is absent. Other cystic lesions can simulate MCNs or IPMNs radiographically, but the histological features are highly distinctive. These include lymphoepithelial cysts, cystic endocrine neoplasms, acinar cell cystadenomas and cystadenocarcinomas, and dermoid cysts.4,5 The problem of distinguishing pseudocysts from MCNs has been previously addressed (above).

Clinical management issues Because MCNs and IPMNs are preinvasive neoplasms with the potential for the development of infiltrating carcinoma, many clinical management issues are similar. In both, foci of high grade dysplasia or carcinoma may be focal, and extensive histological examination of the completely resected neoplasm is needed to exclude the presence of carcinoma. Thus, many experts espouse total resection, and once resected, the prognosis of both is similar and depends on the presence and extent of any invasive carcinoma. So why emphasize the distinction of MCNs from IPMNs? One major reason is that MCNs are very discrete cysts that can generally be completely encompassed by a distal pancreatectomy. IPMNs, in contrast, may extend for variable distances along the pancreatic ducts, and their microscopic extent may exceed their gross appearance.55 Conservative surgical resection often leaves some mucinous epithelium within the ducts at the cut pancreatic margins, and the issue of extent of resection, management of the positive margin, and appropriate follow-up after subtotal pancreatectomy all are problematic.52,78 Incidental foci of PanIN commonly involve the pancreatic ducts away from MCNs and IPMNs.77,79 In the case of MCNs, it is easy to determine that mucinous papillary epithelium in a duct outside the gross neoplasm is a separate focus of PanIN, but in IPMNs, the distinction of incidental foci of PanIN from intraductal extension of the IPMN can be very challenging77 and introduces additional issues into the surgical management of these neoplasms. In addition, as improved imaging technology allows for the detection of smaller and smaller cystic lesions, small branch duct IPMNs are being increasing identified, and it is no longer clear that all such lesions require immediate surgical intervention.80 Thus, the issue of preoperative assessment of the extent of dysplasia or presence of invasive carcinoma is becoming increasingly pressing. These issues are much less problematic in the case of MCNs, although their preoperative distinction from distally located IPMNs remains challenging.

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Cytology, frozen sections, and histological sampling The distinction of MCNs from IPMNs on the basis of a biopsy or aspiration cytology specimen is difficult, unless the clinical and radiographic information strongly points to one specific diagnosis (see above). Fine needle aspiration (FNA) smears from both lesions yield a mucinous background containing sheets of well differentiated ductal epithelium with abundant mucinous cytoplasm, and there may also be more cytoarchitecturally atypical elements depending on the degree of dysplasia.81-83 If well-formed papillary structures are present, a diagnosis of IPMN may be favored, but it is generally not possible to be definitive.84-86 The cellular stroma of MCNs is rarely demonstrated in FNA smears. Despite these limitations, the utility of FNA for cystic lesions lies in the ability to separate the mucinous neoplasms from other cystic lesions, with the potential to identify high grade dysplasia or carcinoma (although cytology often underestimates the degree of dysplasia), since both MCNs and IPMNs are usually treated surgically. Frozen sections maybe performed for diagnostic purposes or to explore the possibility of an invasive carcinoma component.78 If the entire lesion has been resected, the gross evaluation may be very helpful in separating these entities (see above), although a frozen section would be required to confirm the presence of a mucinous lining. There should be careful examination of the gross to identify solid or firm regions that may harbor more highly dysplastic epithelium or invasive carcinoma. Sections from the cystic regions usually show ovarian-like stroma if the neoplasm is an MCN. In the case of IPMNs, it may be more difficult to establish the intraductal nature of the neoplasm based on a single frozen section, but the presence of small ductules surrounding the cystic spaces, well-formed papillae, or an intestinal phenotype all favor the diagnosis of IPMN. Once the diagnosis of IPMN is established, evaluation of the cut pancreatic margin is important54 (the pancreatic margin is rarely an issue with MCNs). In addition to excluding the presence of any invasive carcinoma at the margin, it is often requested to examine the ducts for extension of the intraductal neoplasm. There are varying opinions among surgeons about how to handle the positive surgical margin when dealing with a purely intraductal neoplasm,33,52,54 and the potential to identify incidental foci of PanIN in sections from the margin complicates the interpretation. It is recommended to report the presence of mucinous epithelium along with the grade of dysplasia to help the surgeon decide how much (if any) additional pancreas to resect. Because foci of invasive carcinoma can be very focal in both MCNs and IPMNs, it is very important that these neoplasms be extensively sampled for histology, and some authors have advocated complete submission of the entire gross lesion.8 Indeed, it appears that reports describing metastases from MCNs and IPMNs that appeared to lack invasive carcinoma included cases with inadequate sampling. That being said, the prospect of com-

327 pletely submitting a cystic neoplasm that can measure 20 cm or more is daunting. Initial sectioning should focus on firm, fleshy, or mucoid areas, especially those within the wall of MCNs or not clearly intraluminal in IPMNs, as these are the most likely to harbor invasive carcinoma. If the neoplasm is small enough to submit completely in 20 to 30 blocks, it is reasonable to do so. Then, if no invasive carcinoma is found, an excellent prognosis can be anticipated (barring recurrence of an IPMN elsewhere in the pancreas). If the neoplasm were so large that the pathologist deems it impractical to submit it completely, then it would be unwise to use a diagnostic term that projects complete benignity, such as mucinous cystadenoma or intraductal papillary mucinous adenoma.

Conclusions Although there are many histological similarities and biological parallels between MCNs and IPMNs, careful attention to the clinical and radiographic findings, the gross appearance, and the characteristic histological features will allow the distinction of these two cystic, mucin-producing neoplasms of the pancreas in most instances. More accurate separation of these entities is allowing better determination of their unique clinical, pathological, and molecular features and will help to better define prognostic determinants.87

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