The Pancreas

The Pancreas

Dengfeng Cao

Hanlin L. Wang

  • I. NORMAL ANATOMY. The pancreas is located in the retroperitoneum. In adults, the pancreas measures 15 to 20 cm in length and weighs 85 to 120 g. The pancreas is divided into four parts: the head (including the uncinate process), neck, body, and tail. The vascular supply to pancreas is from branches of celiac trunk and superior mesenteric arteries. The lymph nodes draining the pancreas consist of two major systems: those ringing the pancreas, and those near the aorta from the level of celiac trunk to the origin of the superior mesenteric artery. Microscopically, the pancreas consists of lobules that include both exocrine and endocrine components.

    The vast majority of the exocrine component is the acinar epithelium. The acinar cells are large and polarized, with basally situated nuclei; the apical cytoplasm is eosinophilic due to the presence of abundant zymogen granules, whereas the basal portion is basophilic and contains abundant rough endoplasmic reticulum. The second component of the exocrine pancreas is the duct system that begins with the centroacinar cells. The centroacinar cells then drain into intercalated ducts, intralobular ducts, interlobular ducts, and then into the main pancreatic duct of Wirsung and the accessory duct of Santorini. The duct system is lined by cuboidal to low columnar cells with no visible cytoplasmic mucin by hematoxylin and eosin (H&E) staining.

    The endocrine component, constituting 1% to 2% of the pancreas in adults, is composed of islets of Langerhans and extrainsular endocrine cells scattered among the acini and ducts. The islets of Langerhans contain four major cell types: insulin-secreting β cells (60% to 70%), glucagon-secreting α cells (15% to 20%), somatostatin-secreting δ cells, and pancreatic polypeptide-secreting PP cells.


    • A. Biopsy, fine needle aspiration, and brushing cytology specimens may be obtained percutaneously, intraoperatively, or via endoscopic retrograde cholangiopancre-atography (ERCP). Needle core biopsies should be immediately fixed in 10% formalin. The number and the length, or length range, of the biopsies should be recorded. Documentation of the number and length is important to ensure that the biopsies are adequately represented on the slides. Three H&E-stained slides from each block are prepared for microscopic examination. Aspiration smears are processed with alcohol fixation for Papanicolaou staining or air dried for Diff-Quik staining. Brushings are handled by routine liquid-based cytology methods.

    • B. Distal pancreatectomy specimens consist of the pancreatic tail (usually with attached spleen) and a portion of the pancreatic body. After orientation, each organ should be measured separately. An externally visible mass or lesion should be documented for its size, extent, and location. The proximal and peripancreatic margins should be inked. Before sectioning through the pancreas, the proximal margin is typically taken either as a shave margin or as a series of perpendicular sections, depending on the location of tumor. The method of sectioning the pancreas depends on personal preference. One method is to bivalve the pancreas using a probe in the main duct as a guide; another method is to section the pancreas in a breadloaf fashion. The size and characteristics of any lesions (masses or cysts), along with their relationship to the main duct, spleen, and peripancreatic soft tissue resection margins should be documented. If the
      lesion is cystic, the cyst contents and the cysts relationship to the main duct should be also documented.

      Sections from the lesion should include samples that demonstrate the relation of the lesion to margins and uninvolved pancreas. If the pancreatic lesion is cystic and small, it should be submitted in its entirety. For large lesions (e.g., >5 cm), at least one section per centimeter is recommended, which should focus on thickened, solid, or irregular areas. One or more perpendicular sections from the inked posterior (retroperitoneal) soft tissue margin should be submitted. One to two representative sections from the spleen are sufficient unless gross abnormalities are detected. Finally, the peripancreatic and splenic hilar soft tissue is searched for lymph nodes; all identified lymph nodes should be submitted in their entirety for microscopic examination.

    • C. The Whipple procedure, performed for tumors of the pancreatic head, common bile duct, ampullary, or periampullary region, involves excision of a composite specimen usually consisting of the pancreatic head, a portion of the common bile duct, the duodenum, the distal stomach, and the gallbladder. After orientation, the dimension of each organ should be measured. The various surgical margins of the pancreas (pancreatic neck, posterior, portal vein groove, and uncinate) should be inked with different colors in the operating room with the surgeon’s aid; frozen section evaluation of the pancreatic neck and bile duct margins is almost always requested intraoperatively. The stomach is opened along the greater curvature and the duodenum is opened along the aspect opposite the pancreas to avoid the ampulla. The pancreas can be sectioned along the plane defined by the pancreatic duct and bile duct using probes as a guide, or cut perpendicularly. The size, location, and nature of the tumor are recorded, as is the relation of the tumor to the margins. If the tumor is cystic, the cyst contents and the relationship of the cyst to the main duct should be documented. The specimen is then pinned out and fixed in 10% formalin before grossing. In general, one section per centimeter of the tumor is submitted; if the tumor is an intraductal papillary mucinous neoplasm (IPMN) or mucinous cystic neoplasm (MCN), and is noninvasive in the initial sections, it is necessary to return to the gross specimen and submit the entire lesion to ensure that invasive tumor is not missed. Additional sections should demonstrate the relation of the tumor to the various margins of excision, uninvolved pancreas, ducts, ampulla, duodenum, and soft tissue; one section from the proximal gastric resection margin, and one from distal duodenal resection margin should also be submitted. One section from the uninvolved pancreas and one from uninvolved ampulla are also submitted if not already sampled in the tumor sections. All identified lymph nodes in the soft tissue should be submitted for microscopic examination; there is no need to separate the nodes into groups because they are all considered regional. Microscopic examination of a minimum of 10 to 15 nodes has been recommended for Whipple specimens.


    • A. Acute pancreatitis is an inflammatory process in which pancreatic enzymes autodigest the gland. It is most commonly associated with biliary tract disease (such as gallstones) and alcohol abuse. The pancreas is swollen and edematous, and hemorrhagic in more severe cases. Chalky white fat necrosis may be evident. Histologically, mild pancreatitis is characterized by interstitial edema and leukocytic infiltration; the pancreatic parenchyma may be well preserved, with only limited necrosis. In severe cases, extensive necrosis and hemorrhage are seen (e-Fig. 17.1).* Calcification and secondary infection may occur.

    • B. Chronic pancreatitis is an inflammatory process characterized by irreversible destruction of the exocrine component with acinar atrophy, mixed inflammatory cell infiltrates, and fibrosis with relative sparing of the islets of Langerhans (e-Fig. 17.2). Dilatation of the pancreatic ducts with proteinaceous, often calcified, secretions is characteristic. In later stages, the endocrine component may also be destroyed.

      • 1. Etiology. Most cases are associated with chronic alcohol abuse. Other etiologies include bile duct and pancreatic duct obstruction (due to lithiasis), hyperlipidemia, hyperparathyroidism, autoimmune disorders, and hereditary chronic pancreatitis [due to germline mutations in cationic trypsinogen (PRSS1), cystic fibrosis transmembrane conductance regulator (CFTR), chymotrypsin C, calcium-sensing receptor, and anionic trypsin (PRSS2)] (Dig Dis. 2010;28:324).

      • 2. Autoimmune pancreatitis (AIP) is a distinct type of chronic pancreatitis frequently associated with systemic autoimmune diseases, including inflammatory bowel disease and primary sclerosing cholangitis. AIP may mimic pancreatic cancer radiographically and endoscopically when it presents as a mass lesion in the pancreatic head and/or with strictures of the pancreatic and common bile ducts. Histologically, AIP shares many features of conventional chronic pancreatitis, but is distinguished by a dense lymphoplasmacytic infiltrate, particularly in the periductal region (e-Fig. 17.3), and obliterative phlebitis (e-Fig. 17.4). In addition to various autoantibodies, selective elevation of serum immunoglobulin G4 (IgG4) level helps establish the diagnosis (Arch Pathol Lab Med. 2005;129:1148; J Gastroenterol. 2006;41:613). The number of IgG4 plasma cells in the pancreas is typically >10 per high-power field (HPF), and >50 per HPF is highly specific for the diagnosis (Adv Anat Pathol. 2010;17:303). Patients often respond well to steroid therapy.

        A recent study has suggested that AIP can be further divided into type 1 and type 2 diseases (Am J Surg Pathol. 2011;35:26). Type 1 AIP is the pancreatic manifestation of IgG4-related systemic disease, whereas type 2 is confined to the pancreas; the serum IgG4 level is higher in patients with type 1 disease than in patients with type 2 disease. Pathologically, type 1 and type 2 AIPs share periductal inflammation, however, interlobular inflammation and fibrosis is unique to type 1, and obliterative phlebitis is much more common in type 1 than type 2 (91% vs. 6%). The number of IgG4-positive plasma cells in the pancreas is much higher in type 1 disease than type 2 disease (>50 per HPF in 88% and 7% of type 1 and 2 diseases, respectively; >10 in 100% type 1 and 50% type 2 diseases, respectively). On the other hand, ductular/lobular abscesses and ductal ulceration are much more common in type 2 than type 1 AIP.

  • IV. CYSTIC LESIONS AND TUMORS OF THE PANCREAS. Cystic lesions of the pancreas include non-neoplastic and neoplastic types. The former mainly include pseudocyst, lymphoepithelial cyst, ductal retention cyst, mucinous non-neoplastic cyst, and paraampullary duodenal wall cyst (groove pancreatitis). Neoplastic cystic lesions include serous cystic neoplasm, MCN, IPMN, intraductal tubulopapillary neoplasm (ITPN), solid pseudopapillary neoplasm, and cystic acinar neoplasm. Pancreatic neuroendocrine tumors (islet cell tumors) can also be cystic.

    • A. Nonneoplastic cystic lesions

      • 1. Pseudocyst is the most common cystic lesion of the pancreas and usually develops as a result of pancreatitis or trauma. About two-third of pseudocysts are located in the tail. The cyst is lined by granulation or fibrous tissue without an epithelial lining, with a wall thickness ranging from several millimeters to several centimeters (e-Fig. 17.5).

      • 2. Lymphoepithelial cyst is usually lined by squamous epithelium, typically keratinized, with abundant underlying lymphocytes that occasionally form germinal centers (e-Fig. 17.6). The lining epithelium may be of other types such as flat, cuboidal, or transitional. Rarely sebaceous and mucinous cells may be also seen in the wall, but skin adnexal structures are not found.

      • 3. Ductal retention cyst (also named simple cyst) is caused by obstruction. Microscopically, it is a unilocular cyst lined by a layer of simple epithelium. When the lining epithelium becomes mucinous, it is termed a mucinous nonneoplastic cyst.

      • 4. Paraampullary duodenal wall cyst (groove pancreatitis, cystic dystrophy of the duodenal wall, paraduodenal pancreatitis) is located within the “groove” between the head of the organ, the duodenum, and the common bile duct (Hepatogastroenterology. 1982;29:198). It most likely arises from the submucosal pancreatic tissue associated with remnants of the minor papilla, and is caused by obstruction of the minor papilla. It causes segmental chronic pancreatitis affecting the groove area (hence the name groove pancreatitis). Microscopically, it consists of dilated ductal structures within the duodenal wall; the lining of the ducts is often partially denuded and may contain mucinous epithelium and reactive changes (e-Fig. 17.7). The cyst wall is composed of inflamed fibrous tissue containing lymphocytes, plasma cells, and neutrophils, and the adjacent pancreatic tissue shows atrophy, fat necrosis, and fibrosis.

    • B. Neoplastic cystic lesions

      • 1. Serous cystadenoma is a benign cystic neoplasm usually found in the body or tail of the pancreas in elderly patients. The vast majority is sporadic but the lesion can be associated with the von Hippel-Lindau syndrome. It is usually multilocular (microcystic cystadenoma), but occasionally unilocular, oligocystic (macrocystic), or even solid. Grossly, the tumor has a spongy appearance with a stellate central scar (e-Fig. 17.8) with cysts that are filled with clear serous fluid. Microscopically, the individual cysts are lined by a single layer of flat to cuboidal epithelial cells, with pale to clear glycogen-rich cytoplasm (e-Fig. 17.9). Focally papillary structures lined with clear cells may be seen. Immunohistochemically, the lining cells are positive for cytokeratin and in most cases are also positive for α-inhibin and MUC6 (Am J Surg Pathol. 2004;28:339). The solid variant can mimic metastatic clear-cell renal cell carcinoma (e-Fig. 17.10).

        Serous cystadenocarcinoma is exceedingly rare in the pancreas and is morphologically indistinguishable from serous cystadenoma. The diagnosis is established by the presence of distal metastasis, but vascular invasion and invasion into adjacent structures have been observed.

      • 2. MCN tends to occur in the tail or body of the pancreas, predominantly in women about 50 years of age with a female to male ratio of 20:1. The neoplasm is a solitary, multilocular (rarely unilocular) cystic mass filled with mucin (e-Fig. 17.11) or mucin admixed with necrotic material. The cysts do not communicate with the ductal system. The cyst lining, which may be partially denuded, consists of tall columnar mucin-producing cells with characteristic underlying ovarian-type stroma (e-Fig. 17.12). The ovarian-type stroma surrounding the cysts is the defining feature of MCN and is useful for distinguishing MCN from IPMN (Table 17.1). The stromal cells are frequently positive for estrogen and progesterone receptors and inhibin, and can be luteinized.

        On the basis of the cytologic and architectural features of the lining epithelium, noninvasive MCN can be divided into three categories: MCN with lowgrade dysplasia (mucinous cystadenoma) (e-Fig. 17.13), MCN with moderate or intermediate grade dysplasia (borderline MCN) (e-Fig. 17.14), and MCN
        with high-grade or severe dysplasia (carcinoma in situ, noninvasive mucinous cystic adenocarcinoma). Severe dysplasia is characterized by papillary, cribriform, branching, and budding growth patterns; marked nuclear stratification and atypia; mucin depletion; and frequent mitosis (e-Fig. 17.15). Up to one-third of MCNs have an associated invasive carcinoma that commonly is of ductal type and forms tubules and duct-like structures (e-Fig. 17.16). Other rare types of invasive carcinoma arising in association with MCN have also been reported including adenosquamous carcinoma, undifferentiated carcinoma, and undifferentiated carcinoma with osteoclast-like giant cells. The prognosis for noninvasive MCN is excellent and surgical resection is curative for almost all patients. The prognosis for those lesions with an invasive component is determined by the extent of invasive carcinoma, stage, and resectability (Am J Surg Pathol. 1999;23:410).

        TABLE 17.1 Distinction Between Intraductal Papillary Mucinous Neoplasm (IPMN) and Mucinous Cystic Neoplasm (MCN)




        Patient population

        Older women and men

        Predominantly middle-aged women

        Location in pancreas


        Tail or body

        Communication with ductal system



        Ovarian-type stroma



      • 3. IPMN is defined as a grossly visible (≥1 cm) epithelial tumor arising in the main pancreatic duct (main duct IPMN) or its branches (branch-duct-type IPMN). IPMN is typically seen in the head of the pancreas but it may diffusely involve the whole organ. Branch-duct-type IPMN tends to involve the uncinate process. Symptomatic patients often have a main-duct-type IPMN, whereas most of the branch-duct-type IPMNs are detected incidentally. Histologically, the neoplastic epithelium typically forms papillary fronds lined by mucin-producing columnar cells (e-Fig. 17.17). On the basis of the degree of architectural and cytologic atypia, IPMN can be divided into four categories: IPMN with low-grade dysplasia, IPMN with intermediate-grade dysplasia, IPMN with high-grade dysplasia, and IPMN with an associated invasive carcinoma. Four types of mucinous epithelium can be seen: gastric type, intestinal type, pancreatobiliary, and oncocytic (intraductal oncocytic papillary neoplasm, e-Fig. 17.18). These four types of epithelium show distinct mucin profiles by immunohistochemical staining (gastric-type MUC1+ variable/MUC2-/MUC6+ variable; intestinal-type MUC1-/MUC2+/MUC6-; pancreatobiliary MUC1+/MUC2-/MUC6+ weak; oncocytic-type MUC1- variable/MUC2-/MUC6+) (Am J Surg Pathol. 2010;34:364).

        The major determining prognostic factor for surgically resected IPMNs is whether there is an associated invasive carcinoma, which is seen in approximately one-third of cases, since IPMNs without an associated invasive carcinoma are often cured by surgery. Two types of invasive carcinomas are seen: colloid (e-Fig. 17.19) and conventional ductal (e-Fig. 17.20); the former typically arises in association with intestinal-type IPMNs, whereas the latter is associated with pancreatobiliary-type, oncocytic-type, or intestinal-type IPMNs. The invasive carcinoma may be focal, and therefore IPMNs should be extensively (or, ideally, completely) submitted for histologic examination. Patients with an invasive carcinoma arising in association with an IPMN, except those with an advanced stage invasive carcinoma, usually do better than those with a ductal carcinoma not associated with IPMN. In addition,
        patients with an invasive colloid carcinoma arising in association with an IPMN have a better prognosis than those with an invasive conventional ductal carcinoma arising in association with an IPMN (Ann Surg. 2001;234:313; Ann Surg. 2004;239:400).

      • 4. ITPN is a grossly visible solid nodular tumor obstructing the duct system (Am J Surg Pathol. 2009;33:1164). Architecturally, the tumor forms tubulopapillary structures composed of cell with little cytoplasmic mucin (e-Fig. 17.21). The cells uniformly show high-grade dysplasia, and some cases have associated invasive carcinoma. ITPNs do not harbor KRAS or BRAF mutations. Expression of DPC4 is retained in most cases.

      • 5. Intraductal tubular adenoma, pyloric gland type, is an uncommon tumor consisting of pyloric-type glandular structures with mild to moderate atypia (Am J Surg Pathol. 2005;29:607) (e-Fig. 17.22). Intraductal tubular carcinoma is characterized by high-grade cytology and can have an associated invasive carcinoma component (Anticancer Res. 2010;30:4435). Some authors consider intraductal tubular carcinoma as part of the spectrum of ITPN (Am J Surg Pathol. 2009;33:1164).

      • 6. Cystic acinar cell cystadenoma is an extremely rare unilocular or multilocular cystic mass lined by a single layer of cells cytologically resembling acinar cells. In acinar cell cystadenocarcinoma, the cysts are lined by layers of cells that exhibit more cytologic atypia with easily identifiable mitotic figures.

      • 7. Cystic pancreatic neuroendocrine tumors are probably more common than previously recognized. In one study, 17% of the pancreatic neuroendocrine tumors were cystic (one-third purely cystic and two-thirds were partially cystic) (J Am Coll Surg. 2008;206:1154).

  • V. SOLID TUMORS OF THE EXOCRINE PANCREAS. The current World Health Organization (WHO) histologic classification of tumors of the exocrine pancreas is given in Table 17.2. The 2010 American Joint Committee on Cancer (AJCC) tumor, node, metastasis (TNM) staging schema is given in Table 17.3.

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Oct 20, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on The Pancreas

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