IPMN is a disease of the middle age. It affects males slightly more often than females. IPMN is a mucin-producing neoplasm that arises from the epithelium of the pancreatic ducts and leads to ductal dilation (Fig. 3.3). Based on imaging [15] or gross pathologic examination, the location of ductal involvement can be categorized as main duct, branch duct, or a mixture of both; each category accounts for approximately one-third of resected IPMNs [16–18]. Clinically, this differentiation is an important distinction to make, because main duct (and mixed) IPMNs manifest a much greater risk for malignancy, and therefore, resection is usually advised, while branch duct IPMN can be followed if small, asymptomatic, and free of mural nodules and has no other worrisome features [15] (see Chap. 6). Main duct IPMN is seen most commonly in the head of the pancreas, though about a third of IPMNs arise in the body or tail of the organ; some proximal-based IPMNs produce diffuse duct ectasia involving the entire pancreas. Branch duct IPMN is most often found in the head or uncinate process of the pancreas, but with high-resolution imaging, other smaller branch duct IPMNs are often seen as well.

Microscopically, IPMNs are lined by mucin-producing cells which may be arranged in a flat layer but more often present as papillary projections. The epithelial cells may recapitulate a gastric foveolar, intestinal, pancreaticobiliary, or oncocytic lining (Fig. 3.4). The intestinal form of epithelium represents the most common type of epithelium seen in IPMNs. Intestinal-type IPMNs feature long, slender papillae lined by tall columnar cells with oval nuclei. MUC2 and CDX2 label the neoplastic cells. The intestinal-type IPMNs may be associated with malignant transformation; the cancers that arise in this setting are mucinous (colloid) carcinomas (Fig. 3.5). The gastric foveolar type of epithelium common in branch duct IPMNs has a much less risk of malignant transformation. This type of epithelium appears very bland with abundant mucin and regularly oriented, basal nuclei. These neoplastic cells express MUC5AC. The pancreatobiliary-type IPMN has complex papillae lined by cuboidal cells which stain positive for MUC1. This type of IMPN has the greatest risk for malignant transformation, and the cancer that arises in this background is a ductal adenocarcinoma. Lastly, the oncocytic type of epithelium is characterized by cells with abundant, granular eosinophilic cytoplasm, reflecting their large numbers of mitochondria. The neoplasm forms complex papillae or solid sheets with occasional admixed goblet cells.

The epithelium of all types of IPMN is classified histopathologically according to the degree of dysplasia [19, 20]. Briefly, low-grade dysplasia refers to retained nuclear polarity, minimal variation of nuclear shape, and slight nuclear enlargement. High-grade dysplasia is characterized by architectural complexity, loss of nuclear polarity, marked nuclear pleomorphism, and prominent irregularity (Fig. 3.6). Moderate dysplasia is intermediate between these two categories [20]. Such classification is important in prognosis and risk of associated invasive malignancy.

IPMNs must be sampled extensively, because approximately 30 % of them, most often main duct IPMN [21], are associated with an invasive component. The invasive component determines the prognosis, underscoring the need for a diligent search for foci of invasion. Microscopically, it can be challenging to distinguish invasion from intraductal spread of an IPMN into smaller branch ducts. The criteria for diagnosis of invasion include: perineural or angiolymphatic invasion, glands adjacent to muscular arteries or in peripancreatic fat, an infiltrative growth pattern, and variation in nuclear size of neoplastic cells with more than a 4:1 ratio between the largest and smallest tumor nuclei. Pools of mucin with floating neoplastic epithelial cells within the stroma are also diagnostic of invasion and must be distinguished from acellular extruded mucin.

While mutations in KRAS, GNAS, and RNF43 have been identified which support the diagnosis of IPMN, mutations in these genes are also seen in MCN which renders detection of these genetic alterations as markers of neoplasia but not specific for either diagnosis [13, 14].

Pancreatic SCNs tend to occur in the body or tail of the pancreas; and as with MCN, females predominate with a female to male ratio of 3:1. SCN is a benign neoplasm and should be treated as such. These tumors are well circumscribed and have a spongelike cut surface due to the presence of multiple small cysts (Fig. 3.7). Although macrocystic/oligocystic examples occur, they are exceedingly rare [22]. In about 30 % of SCNs, there is a characteristic pathognomonic radiologic appearance imparted by calcification of a central stellate scar [23, 24].

The microscopic appearance is also characteristic of SCN: a single layer of cuboidal cells with round, regular nuclei and a clear cytoplasm lining numerous small cystic spaces (Fig. 3.8). The cytoplasm of the cuboidal cells is clear due to glycogen, which can be confirmed by performing PAS stains with and without diastase digestion [25]. In rare instances, the epithelium can be attenuated focally, but other areas will show the expected microscopic findings. The sparse stroma between the cysts is mostly acellular, but islets of Langerhans and or pancreatic acini may be entrapped rarely in this stoma.

Macrocystic SCNs may be unilocular but are characteristically composed of larger and fewer cysts (measured in centimeters). The macrocystic SCN may not have a central stellate scar and may be less well circumscribed [26]. These variants should still be recognized readily on histopathologic exam because of the bland, clear, cuboidal epithelium lining the cysts. A solid variant of pancreatic SCN has been described (Fig. 3.9) [27]. The neoplastic cells of this variant are arranged in sheets or nests, a pattern that mimics the clear cell form of renal cell carcinoma or a neuroendocrine carcinoma; renal cell carcinoma, however, shows more nuclear atypia and expresses both vimentin and a wide-spectrum cytokeratin, while neuroendocrine carcinomas feature nuclei with a “salt and pepper” appearance to the chromatin and are strongly and diffusely positive for synaptophysin and chromogranin by immunohistochemistry. In contrast, pancreatic SCNs are positive for cytokeratins, MUC6, and inhibin, but SCNs do not express vimentin or the neuroendocrine marker chromogranin [22]. Synaptophysin may be focally positive in pancreatic SCN [28].