Tumors of the Pancreas

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Chapter 40

Tumors of the Pancreas

David S. Klimstra

N. Volkan Adsay


The diagnosis of pancreatic neoplasms requires differentiation of invasive ductal adenocarcinoma from its mimics and preoperative evaluation of cystic lesions. Solid, cellular pancreatic neoplasms present a different type of diagnostic challenge. The relative inaccessibility of the pancreas and the potential complications from substantial biopsies means that small tissue samples (i.e., core biopsies or fine-needle aspirations) are often the only specimens available for diagnosis.

Research has helped to clarify the diagnostic features of many pancreatic tumors, including cystic and intraductal neoplasms, neuroendocrine tumors, acinar cell neoplasms, and rare variants of ductal adenocarcinoma. An accurate diagnosis is usually possible, particularly when ancillary diagnostic and radiographic tests are used. The use of sensitive imaging techniques, such as spiral computed tomography (CT), endoscopic ultrasound, and magnetic resonance cholangiopancreatography (MRCP), has increased detection of less common types of pancreatic tumors. Advances in surgical techniques and improvements in postoperative care have rendered pancreatectomy a relatively commonplace operation, with markedly decreased rates of mortality and morbidity associated with pancreatic tumors and tumor-like lesions.


The past few decades have witnessed the characterization of several previously unrecognized types of pancreatic neoplasms and tumor-like lesions (e.g., autoimmune pancreatitis). The classification of pancreatic tumors and delineation of the mechanisms of pancreatic neoplasia changed somewhat with the publication of the 2010 World Health Organization (WHO) classification.1 The current classification, which is outlined in Box 40.1,1,2 is based on three features: the lines of cellular differentiation reflected in the neoplasm,3 the gross configuration of the tumor (i.e., solid, cystic, or intraductal), and for an important subgroup of potentially noninvasive neoplasms, the degree of dysplasia (i.e., low, intermediate, or high grade).

Box 40.1

Classification of Pancreatic Neoplasms

Invasive ductal adenocarcinoma

Tubular (conventional) adenocarcinoma

Colloid (mucinous noncystic) carcinoma

Medullary carcinoma

Adenosquamous carcinoma

Signet ring cell carcinoma

Hepatoid carcinoma

Undifferentiated carcinoma

Anaplastic (giant cell) carcinoma

Sarcomatoid carcinoma


Undifferentiated carcinoma with osteoclast-like giant cells

Mixed ductal-neuroendocrine carcinoma

Pancreatic intraepithelial neoplasia (PanIN)

PanIN-1A and PanIN-1B



Serous neoplasms

Microcystic serous cystadenoma

Macrocystic serous cystadenoma

Solid serous adenoma

Serous cystadenocarcinoma

Mucinous cystic neoplasms

Mucinous cystic neoplasm with low-grade dysplasia (mucinous cystadenoma)

Mucinous cystic neoplasm with intermediate-grade dysplasia

Mucinous cystic neoplasm with high-grade dysplasia (carcinoma in situ)

Mucinous cystic neoplasm with an associated invasive carcinoma

Intraductal neoplasms

Intraductal papillary mucinous neoplasms

Intraductal papillary mucinous neoplasm with low-grade dysplasia

Intraductal papillary mucinous neoplasm with intermediate-grade dysplasia

Intraductal papillary mucinous neoplasm with high-grade dysplasia (carcinoma in situ)

Intraductal papillary mucinous neoplasm with an associated invasive carcinoma

Intraductal oncocytic-papillary neoplasm

Intraductal tubulopapillary neoplasms

Intraductal tubulopapillary neoplasm with an associated invasive carcinoma

Acinar cell neoplasms

Acinar cell cystadenoma

Acinar cell carcinoma

Acinar cell cystadenocarcinoma

Mixed acinar-neuroendocrine carcinoma

Mixed acinar-ductal carcinoma

Mixed acinar-neuroendocrine-ductal carcinoma


Pancreatic neuroendocrine neoplasms

Neuroendocrine microadenoma

Well-differentiated PanNET, functional






Well-differentiated PanNET, nonfunctional


Not otherwise specified

Poorly differentiated neuroendocrine carcinoma

Small cell carcinoma

Large cell neuroendocrine carcinoma

Solid pseudopapillary neoplasm

Mesenchymal neoplasms


Secondary neoplasms

PanNET, Pancreatic neuroendocrine tumor; PPoma, pancreatic polypeptide–secreting tumor; VIPoma, tumor secreting vasoactive intestinal polypeptide.

The line of differentiation refers to the cellular phenotype of the neoplasm.4 Most pancreatic tumors recapitulate one or more of the normal epithelial cell lines of the pancreas: ductal, acinar, or neuroendocrine (Fig. 40.1). The defining pathologic features of each of these normal cell types are reflected to various degrees in their corresponding neoplasms (Table 40.1).

Ductal differentiation in pancreatic neoplasia is defined as recapitulation of the characteristics of normal ducts (i.e., gland or tubule formation and mucin production). Mucin can be demonstrated histochemically with stains, such as periodic acid–Schiff (PAS), mucicarmine, or high-iron diamine and Alcian blue, and it is regarded as a hallmark of ductal differentiation in the pancreas, although it is not invariably identified in ductal-type neoplasms.

Many immunohistochemical markers of ductal differentiation, such as cancer antigen (CA) 19-9, carcinoembryonic antigen (CEA), tumor-associated glycoprotein 72 (TAG72 [clone B72.3]), the gastrointestinal cancer–associated protein DUPAN2, and cell surface–associated mucin 1 protein (MUC1), detect mucin-related antigens or oncoproteins.5,6 Mutations at codon 12 of the KRAS gene are common (>90%) in ductal adenocarcinomas and in many related carcinomas and ductal-type preinvasive neoplasms. Because KRAS mutations are unusual in nonductal neoplasms, they may be considered evidence of ductal differentiation in certain situations. Expression of specific keratin subtypes, including cytokeratins 7 and 19 (CK7 and CK19), is characteristic of ductal neoplasms but is not lineage specific.

Neuroendocrine differentiation is defined as the production of peptide hormones or bioamines by tumor cells.3 Well-differentiated pancreatic neuroendocrine tumors (PanNETs) often have an organoid growth pattern and a characteristic appearance of the nuclear chromatin. Neuroendocrine differentiation is documented mainly by immunohistochemistry. The general neuroendocrine markers, chromogranin and synaptophysin, are considered the most specific. Other neuroendocrine markers include neuron-specific enolase (NSE), β-1,3-glucuronyltransferase 1 (B3GAT1, formerly called Leu-7 or CD57), and neural cell adhesion molecule 1 (NCAM1 or CD56), but their specificity has been questioned, and they are no longer recommended for the diagnostic confirmation of neuroendocrine differentiation.7 Production of specific peptides or bioamines may be demonstrable in certain PanNETs, but it is not necessary diagnostically. Electron microscopy may be used to identify dense-core secretory granules, but this technique has been largely supplanted by immunohistochemistry.

Despite the preponderance of acinar cells among the epithelial elements of the pancreas, pancreatic neoplasms with acinar differentiation are uncommon.3 In addition to having characteristic light microscopic features, acinar cell neoplasms produce zymogen granules containing pancreatic enzymes that can be detected by immunohistochemistry. Antibodies directed against trypsin and chymotrypsin are the most widely used, and lipase, elastase, and a few others can be detected.8 Zymogen granules can be demonstrated with the PAS stain in combination with diastase (d-PAS), which typically reveals small, positively staining cytoplasmic granules. Zymogen granules also can be visualized ultrastructurally. A second type, the irregular fibrillary granule, is considered a highly specific ultrastructural feature of acinar cell neoplasms.8

Many primary tumors of the pancreas have a characteristic radiographic and gross appearance. Most can be divided into primarily solid or primarily cystic categories (Table 40.2). Several types of tumors are inherently cystic, with each locule lined by neoplastic epithelial cells. Others develop a cystic change through a process of degeneration or necrosis, or both. This feature is characteristic of some entities, but it may also occur in typically solid tumor types. Intraductal tumors often appear cystic because of massive dilation of the native pancreatic ducts.


Although most pancreatic tumors can be divided into frankly benign or malignant categories, the concept of borderline malignant potential was applied to certain families of pancreatic tumors that showed a spectrum of dysplasia,520 such as intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms that demonstrate intermediate-grade dysplasia. It was later recognized that most neoplasms in the borderline category (which lack invasive carcinoma) have a benign clinical course similar to that of tumors with low-grade dysplasia. The most recent Armed Forces Institute of Pathology (AFIP) fascicle on tumors of the pancreas and the 2010 WHO classification proposed eliminating the borderline category in favor of a system that uses the degree (grade) of dysplasia (see Box 40.1).1,2

Ductal Adenocarcinoma and Variants

The ductal system of the pancreas, which is responsible for carrying acinar secretions to the duodenum, is not the most abundant epithelial component of the organ. However, most pancreatic neoplasms (>90%) have a ductal origin, and 80% to 90% of these lesions are invasive ductal adenocarcinomas.9 The term pancreatic cancer is used synonymously with ductal adenocarcinoma, despite the fact that many other carcinoma types arise in this organ. This type of neoplasm is responsible for the dismal prognosis of pancreatic cancer, and the diagnosis of ductal adenocarcinoma remains problematic for pathologists.

Ductal-type pancreatic carcinomas are separated into three general categories:

Carcinomas in the third category often have an associated conventional ductal adenocarcinoma component, which provides evidence in favor of their ductal origin.

Invasive Ductal Adenocarcinoma

Clinical Features

Invasive ductal adenocarcinoma (i.e., conventional ductal adenocarcinoma, tubular adenocarcinoma) is the most common type of pancreatic neoplasm and is one of the most fatal of all human cancers. In the United States, there were 43,900 new cases and 37,400 deaths in 2012, and the number of new cases appears to have risen over the past decade. The age-adjusted incidence rate is 12.3 cases per 100,000 persons.10 Pancreatic cancer is the fourth leading cause of death from cancer.

Patients are usually between the ages of 60 and 80 years at diagnosis; occurrence in patients younger than 40 years is unusual.11 At clinical presentation, patients usually have jaundice (caused by invasion and obstruction of the common bile duct) when the carcinoma is in the head of the gland, or they may have nonspecific symptoms such as back pain and weight loss.12

The cause of ductal adenocarcinoma is complex and probably multifactorial. Smoking and high intake of dietary saturated fat are considered risk factors.1316 Whether acquired chronic pancreatitis and diabetes mellitus constitute risk factors is a subject of ongoing debate, although patients with hereditary chronic pancreatitis and tropical calcifying pancreatitis are considered at increased risk.1720

Most ductal adenocarcinomas are sporadic, but approximately 10% of pancreatic cancer cases are familial. The genetic basis for 80% of familial cases is unknown, but the risk is increased by heritable genetic syndromes such as hereditary breast cancer syndrome (resulting from mutations in BRCA2 or, less commonly, BRCA1), familial atypical multiple mole–melanoma (FAMMM) syndrome (resulting from mutations in CDKN2A [p16], a tumor suppressor gene), Peutz-Jeghers syndrome (resulting from STK11 [LKB1] mutations), familial pancreatitis (resulting from PRSS1 mutations), hereditary nonpolyposis colorectal cancer (HNPCC) syndrome (resulting from mutations in DNA mismatch repair genes), and Fanconi anemia (resulting from FANCC and FANCG mutations).2128 Some families also carry germline mutations in PALB2 and ATM.2931 IPMNs also appear to develop in patients with familial pancreatic carcinoma at an increased frequency.32,33

More than 75% of ductal adenocarcinomas are solid tumors, and 60% to 70% develop in the head of the pancreas.34 Possibly because of the lack of a capsule surrounding the pancreas, ductal adenocarcinomas typically involve surrounding structures, especially the common bile duct, duodenum, and peripancreatic soft tissues, even when the tumors are relatively small. Ductal adenocarcinomas that develop in the tail of the pancreas may spread to surrounding organs (i.e., spleen, kidney, stomach, and colon) when they are still relatively small.436 If a solid pancreatic tumor is larger than 5 cm in its greatest dimension and is still resectable, it is unlikely to represent a ductal adenocarcinoma.

Almost 80% of ductal adenocarcinomas are unresectable at the time of diagnosis,35 largely because of encasement of major mesenteric vessels36 or metastases to the liver, peritoneum, or other distant sites. Many ductal adenocarcinomas disseminate very early in the course of disease, although some data suggest that the subset of cases lacking mutations in SMAD4 (formerly DPC4) remains more localized to the pancreas and adjacent structures.37

Pathologic Features

Grossly, most ductal adenocarcinomas are solid, firm, infiltrative tumors (Fig. 40.2) with ill-defined borders. The cut surface is often gritty or slightly gelatinous.38,39 Less commonly, gross areas of necrosis may be seen. It is often difficult to distinguish carcinoma from adjacent areas of fibrosing chronic pancreatitis.

For tumors in the head of the gland, direct invasion of the common bile duct and duodenum is common. The major pancreatic ducts coursing through the carcinoma are usually narrowed or even completely obliterated. Recognition that the center of the tumor is located in the head of the pancreas helps to distinguish pancreatic ductal adenocarcinomas from primary carcinomas of the common bile duct, duodenum, or ampulla of Vater. Some ductal adenocarcinomas exhibit cystic changes due to necrosis with cystic degeneration, as a result of cystic dilation of obstructed ducts (i.e., retention cyst formation), or because of cystic dilation of the neoplastic glands (i.e., large duct pattern).40 In some cases, invasive ductal adenocarcinomas may be associated with a preexisting benign cystic or intraductal neoplasm, such as a mucinous cystic neoplasm or an IPMN.

Microscopically, in its conventional form, ductal adenocarcinoma is characterized by a proliferation of small tubular structures lined by cuboidal mucinous cells in abundant desmoplastic stroma (Fig. 40.3).41 In well-differentiated ductal adenocarcinomas, the growth pattern and cytologic appearance of the cells may be deceptively benign, closely mimicking non-neoplastic ductules characteristic of chronic pancreatitis (Fig. 40.4). Malignant glands usually replace the normal lobular arrangement of benign ducts with haphazardly arranged tubules. The cells that line malignant glands typically form a single regular layer, but stratification and irregular papillae may be prominent in some cases.

The cytoplasm of the tumor cells may be abundant and usually contains mucin; clear cell change is also common. The nuclei may retain a basal orientation in the cells, but loss of polarity in some of the glands is typical. The nuclei vary in size, shape, and intracellular location between cells in each gland (Fig. 40.5). A variation in size of more than fourfold between adjacent nuclei suggests carcinoma.

Perineural invasion and vascular invasion are common and diagnostically useful, although these features often are not detected in core-needle biopsies. In some cases, tumor cells infiltrate adjacent normal islets. Invasion into peripancreatic adipose tissue is also common. The finding of an immediate juxtaposition of a gland with adipocytes without intervening stroma (i.e., naked glands in fat) is a strong sign of malignancy.42 Another helpful feature in the differential diagnosis of benign from malignant glands is the finding of glands situated adjacent to muscular blood vessels, because normal pancreatic ducts are usually separated from large blood vessels by a considerable amount of acinar parenchyma.43,44 However, this feature is less helpful when the pancreas is profoundly atrophic.

In poorly differentiated ductal adenocarcinomas, the neoplastic glands are usually admixed with small clusters of cells with ill-formed lumina, pleomorphic nuclei, and abundant mitotic figures (Fig. 40.6). It is common for ductal adenocarcinomas to exhibit a mixture of well-formed glands along with individual cells or solid clusters.

The periphery of ductal adenocarcinomas is often indistinct, and neoplastic glands may be found well beyond the apparent gross extent of the tumor. The finding of isolated glands in otherwise normal peripancreatic adipose tissue several millimeters from the nearest edge of the carcinoma confounds the evaluation of the soft tissue margins.42 Invasion of preexisting epithelial structures, such as the common bile duct, duodenal mucosa, blood vessels, or native pancreatic ducts, can result in colonization of the basement membrane of the invaded structure,45 which may simulate a preinvasive neoplasm, such as a duodenal adenoma or pancreatic intraepithelial neoplasia (PanIN). Continuity of intraductal neoplastic cells with frankly invasive elements supports an interpretation of colonization.

The current grading system for pancreatic ductal adenocarcinoma (i.e., Klöppel’s grading scheme endorsed by the WHO) entails evaluation of glandular differentiation, mucin production, mitoses, and nuclear atypia.46 This scheme correlates well with prognosis but is cumbersome and not widely used. Another proposal advocates assigning two scores to the two most prevalent patterns, mirroring Gleason grading for prostate carcinoma. This system is more independently significant in predicting outcome.47 The American Joint Committee on Cancer (AJCC) staging parameters for ductal adenocarcinoma are outlined in Table 40.3.48

Chronic pancreatitis (i.e., interstitial fibrosis, atrophy, and modestly dense inflammation) is often seen in the pancreatic tissue adjacent to ductal adenocarcinomas. Differentiating chronic pancreatitis from carcinoma is discussed later (see Differential Diagnosis). The lining of native pancreatic ducts may show proliferative changes (i.e., PanINs). Squamous, transitional, intestinal, and, rarely, oncocytic49 metaplasia may be seen in the non-neoplastic ducts.50

Ancillary Diagnostic Tests and Molecular Properties

Mucin histochemistry and immunohistochemical markers of ductal differentiation (i.e., glycoproteins) invariably show at least focal positivity in typical ductal adenocarcinomas. Staining for CK7, CK8, CK18, and CK19 and epithelial membrane antigen (EMA) is usually positive. CK20 is detected in about 25% of cases, and its expression is usually less widespread and intense than that of CK7. The exception to this cytokeratin expression pattern is colloid carcinoma, in which CK20 expression is strong and diffuse (discussed later).51,52 Immunohistochemical markers of glycoproteins that are often detectable in ductal adenocarcinoma include CA 19-9, CEA, TAG72, CA 125, and DUPAN2. Of these, CEA, TAG72, and CA 125 are regarded as tumor-associated glycoproteins that are not significantly expressed in normal ductal cells and are expressed only to a limited degree in low-grade PanIN.53

Cell surface–associated mucin proteins are expressed in various degrees in different types of ductal neoplasms. Most conventional ductal adenocarcinomas express MUC1, MUC3, MUC4, and MUC5AC.51,5457 In contrast, MUC2 is not expressed in ductal adenocarcinomas other than those with intestinal differentiation, such as colloid carcinoma. MUC6, a marker of pyloric gland differentiation, is expressed in 35% of ductal adenocarcinomas.58

Stains for chromogranin or synaptophysin may demonstrate a minor neuroendocrine cell component associated with the neoplastic glands. Some neuroendocrine cells are non-neoplastic islet cells entrapped in the tumor, because ductal adenocarcinomas have a propensity to invade islets. However, neoplastic neuroendocrine cells also occur in ductal adenocarcinomas.59,60

The molecular alterations in ductal carcinomas have been studied extensively in the past decade. A comprehensive genomic analysis of more than 20,000 genes disclosed that most cases have primarily point mutations, which average 63 per tumor.61 Twelve core signaling pathways were altered in 67% to 100% of the tumors. The most commonly mutated genes include KRAS, CDKN2A (formerly called p16, INK4A, or CDKN), TP53, and SMAD4.62,63 Mutations in codon 12 of the KRAS oncogene are detected in more than 90% of ductal adenocarcinomas, and TP53 mutation occurs in 50%. Most ductal adenocarcinomas also harbor abnormalities in CDKN2A because of mutation or hypermethylation of the promoter region of DNA.64 Loss of SMAD4 expression is found in 55% of invasive ductal adenocarcinomas.65,66 Although many other molecular abnormalities occur in ductal adenocarcinoma,64 this constellation of genetic changes is characteristic and distinguishes ductal adenocarcinomas from pancreatic neoplasms of other cell lineages.

Other pathways commonly altered include apoptosis, regulation of the G1/S phase transition, hedgehog signaling, DNA damage control, cell adhesion, integrin signaling, MAPK8 (JNK) signaling, control of invasion, GTPase signaling, transforming growth factor-β (TGF-β) signaling, and NOTCH signaling.61 Mutations in mismatch repair genes, BRCA2, STK11, BRAF, TGFBR2, and MAP2K4 are less common, but some of them underlie the hereditary cases of pancreatic ductal carcinoma.63

Analysis of gene expression has revealed other overexpressed molecules (e.g., fascin, mesothelin, claudin 4, S100AP, S100A6, S100P) in ductal adenocarcinomas. Some have been used as potential immunohistochemical markers to help distinguish reactive (non-neoplastic) glands from carcinoma.6773 Strong immunoexpression of TP53 or complete loss of SMAD4 expression can be used to support a diagnosis of carcinoma, although both markers lack a high degree of sensitivity.

Differential Diagnosis

The main diagnostic consideration for conventional ductal adenocarcinoma is the distinction of a well-differentiated carcinoma from benign ductules in areas of atrophic chronic pancreatitis.2,74 Ductal adenocarcinoma may appear deceptively benign, and ductules in chronic pancreatitis may appear infiltrative.

On low-power examination, ductules in areas of chronic pancreatitis retain the original lobular configuration of the normal pancreas, because they represent the residual intralobular ductules remaining after the loss of acinar elements during atrophy. Each lobular cluster of ductules contains a central, larger, branched, slightly dilated duct surrounded by small, round ductules (Fig. 40.7). The stroma in each lobule often is less dense than that between lobules. In contrast, invasive glands lack a lobular growth pattern and are usually distributed more haphazardly (see Fig. 40.7). The contours of individual glands also are usually irregular and angulated. Some glands may be incomplete, with epithelium lining only part of the neoplastic lumen and stroma lining the rest.

Cytologically, nuclear enlargement, nuclear contour irregularities, and loss of nuclear polarity are important clues to a diagnosis of carcinoma. Variations in size and shape and an intracellular location between adjacent nuclei in individual glands indicate malignancy. The finding of a nucleus-to-cytoplasm ratio of 4 : 1 is considered highly suspicious for carcinoma. Dense acidophilic cytoplasm is more common in carcinomas than in benign conditions.

Unlike other sites where reactive stromal cells may display significant nuclear atypia, pleomorphism and bizarre nuclei are uncommon in the stroma of inflammatory conditions of the pancreas. Individual atypical cells in the stroma of the pancreas are much more likely to be cancer cells, especially if they contain dense acidophilic cytoplasm. The finding of atypical glands in abnormal locations is also helpful. For instance, perineural or vascular invasion, invasion of the duodenal muscularis propria, invasion of stroma closely adjacent to a muscular vessel,43,44 and immediate juxtaposition of glands to adipocytes42 are features considered to be almost 100% diagnostic of carcinoma (Fig. 40.8).

FIGURE 40.8 

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