Ductal adenocarcinomas tend to infiltrate into vascular, lymphatic, and perineural spaces. At the time

of resection, most ductal carcinomas have already metastasized to regional lymph nodes. In addition to

the lymph nodes, PDAC frequently metastasize to the liver (80%), peritoneum (60%), lungs and pleurae

(50% to 70%), and adrenal glands (25%). They also can directly invade the duodenum, stomach,

transverse mesocolon, colon, spleen, and adrenal glands.

1 The histologic examination of a pancreas resected for cancer frequently reveals the presence of

precursor lesions in the pancreatic ducts and ductules adjacent to the cancer. This suggests that much

like colon cancer, which arises from benign adenomas, pancreatic cancer may also demonstrate

progression to malignant from benign precursor lesions. These precursor lesions are referred to as

pancreatic intraepithelial neoplasia (PanIN). Briefly, PanIN-1A and PanIN-1B are proliferative lesions

without remarkable nuclear abnormality that have a flat and papillary architecture, respectively. PanIN3 is associated with severe architectural and cytonuclear abnormalities, but invasion through the

basement membrane is absent. The older term for PanIN-3 includes carcinoma in situ (CIS). PanIN-2 is

an intermediate category between PanIN-1 and PanIN-3 and is associated with a moderate degree of

architectural and cytonuclear abnormality.7 Several lines of evidence suggest that PanINs are precursors

of infiltrating pancreatic cancer: PanINs are often found in association with ductal adenocarcinomas,

three-dimensional mapping techniques that demonstrated a stepwise transformation from mild dysplasia

to severe dysplasia in pancreatic duct lesions, and PanINs demonstrate some of the same genetic

changes seen in infiltrating adenocarcinomas, most notably activating point mutations in codon 12 of Kras and mutations in the p16 and p53 tumor-suppressor genes.

Figure 55-2. Microscopic appearance of ductal adenocarcinoma of the head of the pancreas demonstrating glands from an

adenocarcinoma embedded in a fibrous matrix.

Adenosquamous Carcinomas

Adenosquamous carcinoma is a rare variant of ductal adenocarcinoma that shows both glandular and

squamous differentiation. This variant appears to be more common in patients who have undergone

previous chemoradiation therapy. The biologic behavior of adenosquamous carcinoma appears to be

similar to that of ductal adenocarcinoma, with similar rates of perineural invasion, lymph node

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metastases, and dissemination.

Acinar Cell Carcinomas

Acinar cell carcinomas account for only 1% of pancreatic exocrine tumors. Acinar tumors are typically

smooth, fleshy, lobulated, hemorrhagic, or necrotic. Histologically, they form acini, and the cells

display an eosinophilic, granular cytoplasm. Immunohistochemical staining demonstrates expression of

trypsin, lipase, chymotrypsin, or amylase. These tumors are more common in males with a male-tofemale predominance of approximately 3:1. The age of diagnosis is usually in the fifth to seventh

decades. These tumors tend to be larger than ductal adenocarcinomas, often being larger than 10 cm.

Although data are limited, it appears that patients with acinar cell carcinoma have a slightly better

prognosis than patients with ductal carcinoma.8 Therefore, surgical resection is the treatment of choice.

Giant Cell Carcinomas

Giant cell carcinomas account for less than 1% of nonendocrine pancreatic cancers. They tend to be

large, with average diameters greater than 15 cm. Microscopically, they contain large, uninucleated or

multinucleated tumor cells, many of which are pleomorphic. The nuclei contain prominent nucleoli and

numerous mitotic figures. Giant cell carcinomas are associated with a poorer prognosis than ductal

adenocarcinomas. There is a variant of giant cell carcinoma termed giant cell carcinoma with osteoclastlike giant cells. These lesions tend to be well circumscribed with nonpleomorphic giant cells and are less

aggressive than standard giant cell carcinomas.

Pancreatoblastoma

Pancreatoblastomas occur primarily in children ages 1 to 15 years. Pancreatoblastomas contain both

epithelial and mesenchymal elements. The epithelial component appears to arise from acinar cells. The

tumors are typically larger than 10 cm and often contain areas of degeneration and hemorrhage. The

prognosis appears to be more favorable than that for typical ductal adenocarcinoma if the tumor can be

resected.

Cystic Epithelial Tumors

Cystic neoplasms also arise from the exocrine pancreas. Cystic neoplasms are less common than ductal

adenocarcinomas, tend to occur in women, and are evenly distributed throughout the gland. Many

pancreatic and peripancreatic cysts are actually benign inflammatory pseudocysts. It is important to

identify cystic neoplasms because their management is very different from that of nonneoplastic cysts.

With advancements in imaging technology, cystic lesions of the pancreas are being detected with

increased frequency. With routine application of cross-sectional imaging to early diagnostic processes in

medicine, pancreatic cysts are often detected incidentally.9 Although many of these lesions are small

and asymptomatic, they can have malignant potential. Therefore, the management of these patients is

complex, and knowledge of pancreatic cyst natural history and predictors of neoplasia are important.

Serous Cystic Neoplasms

Serous cysts are epithelial neoplasms composed of uniform cuboidal glycogen-rich cells that usually

form numerous small cysts containing serous fluid. Serous cystadenomas or microcystic adenomas are

more common in women than in men (3:1 preponderance). These tumors can vary from a few

centimeters to more than 10 cm in size. Twenty-five percent to 30% of patients are asymptomatic;

however, most patients present with symptoms such as abdominal or epigastric pain, dyspepsia, nausea,

or vomiting. Serous cystadenomas can be located anywhere in the pancreas – head, body, or tail – and

usually do not communicate with the pancreatic ducts. Plain computed tomography (CT) shows a

honeycomb pattern of microlacunae, with thin septa separating different segments. Serous cystic

neoplasms can have a sunburst pattern of central calcification, which is seen in 10% to 30% of cases.

Grossly, they appear as spongy, well-circumscribed, multiloculated cysts. Microscopically, they consist

of a layer of simple cuboidal cells separated by dense fibrous bands. Most serous cystic neoplasms are

benign, although malignant behavior has been reported rarely (<1% with metastases to the liver or

peripancreatic lymph nodes). Symptomatic cysts or cysts that cannot be differentiated from other

potentially malignant cysts should undergo surgical excision.

Mucinous Cystic Neoplasms

Mucinous cystic neoplasms (MCNs) are neoplasms composed of mucin-producing epithelial cells

associated with an ovarian-type of stroma. These cysts usually do not communicate with the larger

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pancreatic ducts. MCNs are relatively uncommon but account for almost 30% of all cystic neoplasms.

The mean age at diagnosis is between 40 and 50 years. MCNs are more common in women with a

female-to-male ratio of 9:1. Most patients with MCNs present with vague abdominal symptoms that

include epigastric pain or a sense of abdominal fullness. The majority (70% to 90%) of MCNs arises in

the body or tail of the pancreas, and only a minority (10% to 30%) involves the head of the gland.

Microscopically, the cysts are lined by tall columnar mucin-producing epithelium. These columnar cells

have basal nuclei and abundant intracytoplasmic apical mucin and can form flat sheets or papillae. The

walls of the cysts contain a very distinctive “ovarian-type” stroma. This stroma is composed of densely

packed spindle cells with sparse cytoplasm and uniform elongated nuclei. All MCNs are considered to be

premalignant lesions and should be completely resected to prevent progression to malignancy.

Invasive mucinous cystadenocarcinomas are MCNs associated with an invasive carcinoma, whereas

noninvasive mucinous neoplasms can be categorized into MCNs with low-grade dysplasia (adenoma),

MCNs with moderate dysplasia (borderline) neoplasms, and MCNs with high-grade dysplasia (carcinoma

in situ) based on the degree of architectural and cytologic atypia of the epithelial cells. In surgical series

between 15% and 30% of all MCNs are associated with invasive carcinoma. Patients with mucinous

cystadenocarcinomas tend to be 5 to 10 years older than patients with benign MCNs. The extent of

invasive and in situ carcinomas in MCNs can be very focal. Therefore, a benign diagnosis cannot be

established on biopsy alone and the lesions should be completely resected. The prognosis for patients

with resected benign or borderline tumors is excellent. Patients with mucinous cystadenocarcinoma tend

to do better than patients with ductal adenocarcinoma, with a 5-year survival of approximately 50%.

Intraductal Papillary-Mucinous Neoplasms

Intraductal papillary-mucinous neoplasms (IPMNs) are intraductal mucin-producing neoplasms with tall,

columnar, mucin-containing epithelium with or without papillary projections. These neoplasms

extensively involve the main pancreatic ducts and/or major side branches. In addition, IPMNs lack the

ovarian stroma characteristic of MCNs. Similar to the well-defined adenoma–carcinoma sequence in

PDAC (PanIN to invasive ductal carcinoma), IPMNs seem to follow a similar pattern progressing from

IPMN with low-grade dysplasia to invasive carcinoma. Microscopically, they consist of papillary

projections lined by columnar mucin-secreting cells. They show varying degrees of cellular atypia. The

noninvasive IPMNs are graded on the basis of greatest degree of dysplasia and classified into low-grade,

moderate-grade, and high-grade dysplasia or carcinoma in situ. Invasive IPMNs are either colloid or

tubular, with the latter having a worse prognosis. The mean age of patients with invasive carcinoma is

approximately 5 years older than patients with noninvasive IPMNs suggesting an approximately 5-year

lag period for progression to malignancy. Further histologic subtyping of epithelial differentiation is

based on the cell lineage, the morphology of the papillae, and the immunophenotype, and includes

classification into intestinal, gastric, pancreaticobiliary, and oncocytic subtypes.

IPMNs are subclassified as main- and branch-duct types and as a mixed type that contains elements of

both. Main-duct IPMN is characterized by involvement of the duct of Wirsung, which is dilated to more

than 1 cm in diameter. Branch-duct IPMN originates in the side branches of the pancreatic ductal system

and appears as a multilobular cystic lesion communicating with a nondilated main pancreatic duct.

Typically, branch-duct IPMN occurs in the uncinate process–head of the gland, but it can also be seen in

the neck and distal pancreas. If the main duct is dilated with synchronous involvement of the branch

ducts, it is described as a mixed IPMN.

IPMNs are usually found in individuals in their 60s to 80s. Some patients may experience symptoms

that include: abdominal pain, steatorrhea, weight loss, jaundice, diabetes, and chronic pancreatitis. A

substantial number of these lesions are also detected as incidental findings on cross-sectional imaging

studies performed for other indications. IPMNs appear to be more common in the head, neck, and

uncinate process of the pancreas but can be found diffusely throughout the whole gland. CT scans will

typically reveal a cystic mass in the head of the pancreas that appears to communicate with the

pancreatic ductal system. On endoscopy, mucin can be seen oozing from the ampulla of Vater.

Endoscopic retrograde cholangiopancreatography (ERCP) can be used to confirm that the cysts

communicate with the pancreatic ducts.

MCNs are the main entity to consider in the differential diagnosis of IPMNs (Table 55-5). Two

morphologic features distinguish IPMNs from MCNs: IPMNs communicate with ducts, mucinous cysts do

not; IPMNs also lack an ovarian stroma that is present in mucinous cysts. In addition, mucinous cysts

are usually seen in the tail of the pancreas and occur in middle-aged women, whereas IPMNs are found

in the head of the pancreas and occur in older individuals of either sex.

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