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. 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. 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.

The cause of ductal adenocarcinoma is complex and probably multifactorial. Smoking and high intake of dietary saturated fat are considered risk factors. 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.

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). Some families also carry germline mutations in PALB2 and ATM . IPMNs also appear to develop in patients with familial pancreatic carcinoma at an increased frequency.

More than 75% of ductal adenocarcinomas are solid tumors, and 60% to 70% develop in the head of the pancreas. 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. 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, largely because of encasement of major mesenteric vessels 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.

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. Less commonly, gross areas of necrosis may be seen. It is often difficult to distinguish carcinoma from adjacent areas of fibrosing chronic pancreatitis.

Gross appearance of ductal adenocarcinoma. The solid, white to yellow, and ill-defined tumor occupies much of the head of the gland.

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). 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 ). 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.

Ductal adenocarcinoma consists of various sizes of well-formed glands surrounded by abundant desmoplastic stroma.

Some infiltrating cases of well-differentiated ductal adenocarcinoma consist of remarkably well-formed glands and exhibit minimal cytologic atypia, mimicking benign ductules.

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.

In a moderately differentiated ductal adenocarcinoma, the nuclei show variations in size, shape, and location within the cells.

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. 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. 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 poorly differentiated ductal adenocarcinoma exhibits minimal gland formation, instead growing as clusters and individual cells with marked cytologic atypia.

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. 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, 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. 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. The American Joint Committee on Cancer (AJCC) staging parameters for ductal adenocarcinoma are outlined in Table 40.3 .

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, oncocytic metaplasia may be seen in the non-neoplastic ducts.

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). 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.

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. 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.

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.

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. 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 . 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. Loss of SMAD4 expression is found in 55% of invasive ductal adenocarcinomas. Although many other molecular abnormalities occur in ductal adenocarcinoma, 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 G ₁ /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. 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.

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. 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. 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.

Comparison of atrophic chronic pancreatitis and well-differentiated ductal adenocarcinoma. In these low-power images, the example of chronic pancreatitis (A) shows retention of the lobular architecture of the gland, with larger, dilated central ducts surrounded by smaller, round ductules. The stroma separating each lobule is somewhat denser than the intralobular stroma. In contrast, adenocarcinoma (B) shows a haphazard arrangement of neoplastic glands and lacks a lobular configuration.

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, and immediate juxtaposition of glands to adipocytes are features considered to be almost 100% diagnostic of carcinoma ( Fig. 40.8 ).

Diagnostic findings for ductal adenocarcinoma. A, Perineural invasion is virtually diagnostic of invasive carcinoma, provided the epithelial structures are gland forming. B, Immediate juxtaposition of glands to adipocytes is a very helpful finding.

Invasive ductal adenocarcinoma should be differentiated from noninvasive PanIN, which can be challenging because high-grade PanIN displays most of the cytologic abnormalities of invasive carcinoma. Evaluation of the number, distribution, and location of the individual glandular units in relation to the lobular architecture helps to make this pathologic distinction. Desmoplastic stroma and irregularity of ductal contours are characteristic features of invasive carcinoma. Because pancreatic ducts do not contain a basal or myoepithelial cell layer and because many of the abnormalities of invasive carcinoma are also found in high-grade PanINs, there are no immunohistochemical stains that can reliably determine whether a specific atypical gland is invasive. When the differential diagnosis for a core-needle biopsy specimen includes high-grade PanIN and invasive carcinoma, it is worth considering that high-grade PanIN is rarely encountered in the absence of invasive carcinoma somewhere in the gland, especially when there is a pancreatic mass.

Another potential pitfall in the differential diagnosis of ductal adenocarcinoma is aggregation of islets in atrophic chronic pancreatitis ( Fig. 40.9 ). Clustered islets may form small, irregular nests or cords of cells that have an infiltrative appearance. Occasionally, these islet cells are situated around small nerve fibers, simulating perineural invasion by carcinoma. However, the uniformity of cells, round nuclei, lack of glandular lumina, and neuroendocrine-type chromatin point to a benign reactive process. Immunolabeling for neuroendocrine markers (i.e., chromogranin and synaptophysin) can be helpful in problematic cases.

Pancreatic atrophy with aggregation of islets. The neuroendocrine cells exhibit a trabecular configuration, suggesting origination from the diffuse islets located in the posterior head of the pancreas. The pseudoinfiltrative nature of these neuroendocrine cells may simulate an invasive carcinoma.

Adenocarcinomas of other organs can resemble pancreatic ductal adenocarcinoma, especially carcinomas arising in the biliary tree or upper gastrointestinal tract. Metastases to the pancreas from sites such as the lung, breast, or gynecologic organs can be mistaken for pancreatic primaries, but more commonly, a pancreatic primary is considered for metastases to the peritoneum, the liver, or other organs.

Although the previously described immunophenotype and molecular profile of pancreatic ducal adenocarcinoma is characteristic, it is not sufficiently specific to be useful to distinguish pancreatic primaries from adenocarcinomas of other sites. Coexpression of CK7, CK19, CEA, CA 19-9, TAG72 and CA 125 can occur in multiple primary adenocarcinomas, and the lack of expression of lung markers (e.g., thyroid transcription factor 1 [TTF-1], napsin A) or hormone receptors does not exclude origin in the lung, breast, or gynecologic tract. Clinical and radiographic correlation is often needed to define the primary site in these cases.

Natural History

The prognosis of patients with pancreatic ductal adenocarcinoma is dismal. The overall 5-year survival rate is less than 5%, and the median survival time after diagnosis is approximately 9 months.

Surgical resection is considered the best hope for long-term survival. However, only approximately 20% of ductal adenocarcinomas are resectable at the time of diagnosis; the remainder are locally advanced (mostly invading neighboring large mesenteric vessels) or metastatic (usually to the liver or peritoneum). In addition to high-resolution CT scanning, laparoscopy is increasingly used to identify radiographically occult metastatic disease before laparotomy.

Postresection survival has not improved significantly during the past several decades. The median survival time of patients after resection is 12 to 18 months, with a reported 5-year survival rate as high as 20%, although patients may still die of their disease after 5 years. . The survival rate beyond 8 years is approximately 3%. Some authorities advocate adjuvant therapy (i.e., chemotherapy and radiation) after surgery. Cases that are unresectable are usually treated with chemotherapy. Current chemotherapy protocols include mainly gemcitabine or 5-fluorouracil, often in combination with other agents.

Foamy Gland Pattern

The foamy gland pattern represents a subtle, well-differentiated carcinoma that mimics benign glands with low-grade PanIN. This variant is characterized by infiltrating, well-formed glands lined by columnar cells that contain abundant, pale cytoplasm, resembling PanIN-1. The nuclei are typically well polarized but wrinkled in appearance, with indentations caused by the cytoplasmic contents ( Fig. 40.10 ).

Ductal adenocarcinoma with a foamy gland pattern. The tumor exhibits well-formed ductal structures, simulating a low-grade intraductal proliferation. It has abundant, foamy cytoplasm with a thick apical cytoplasmic condensation. Nuclear abnormalities are subtle.

The most characteristic features that help to distinguish this variant from low-grade PanIN are a foamy, microvesicular, pale cytoplasm with vesicles that are small, fine, and evenly sized and an apical chromophilic condensation of the cytoplasm that forms a thin, well-delineated band reminiscent of a brush border. Although the apical condensation is strongly positive for mucin markers, the microvesicular component of the cytoplasm is typically negative (in contrast to ducts involved by PanIN-1 that are often PAS positive). This staining pattern parallels that of small, nonmucinous, intralobular ducts, which contain apical mucin granules that do not form a distinct band, but rather demonstrate a gradual acquisition. The tumor protein TP53 is often abnormally expressed in the nuclei of these malignant glands.

Large Duct Pattern

Occasionally, invasive tubular adenocarcinomas have a microcystic appearance because of ectasia of infiltrating neoplastic glands ( Fig. 40.11 ). For unclear reasons, this phenomenon may be particularly pronounced in regions of the tumor that infiltrate the muscularis propria of the duodenum. Although microcystic glands may be detected grossly, the cystic change is usually not pronounced enough to be detected radiographically. The cytologic appearance of the epithelium may be deceptively bland.

Ductal adenocarcinoma with a large duct pattern. The invasive neoplastic glands are ectatic, resembling dilated native ducts, but the configuration is irregular, and smaller, more typical infiltrating glands also are identified.

Patients with tumors that have a large duct pattern have only a slightly higher survival rate than patients with conventional ductal adenocarcinoma. Cystic dilation of an invasive gland should be distinguished from a noninvasive component of a mucinous cystic neoplasm or intraductal neoplasm, both of which have a much better prognosis.

Features that favor large, duct–type adenocarcinomas are clustering of glands, irregularity of the contour of the ducts, and a desmoplastic stroma. Tumor cells often contain intraluminal necrotic debris with neutrophils.

Vacuolated Pattern

Lesions with a vacuolated pattern have a gland-in-gland architecture in which tumor cells form cribriform nests punctuated by many large vacuoles (i.e., microcysts) that contain cellular debris and mucin ( Fig. 40.12 ). The vacuoles appear to form by the merging of multiple intracytoplasmic lumina. Focally, vacuolated cells have the morphologic features of adipocytes or signet ring cells. This pattern may be helpful in the differential diagnosis of metastatic tumors of unknown origin because it is seen only rarely in other types of adenocarcinoma.

Ductal carcinoma with a vacuolated pattern. Solid nests of cells are punctuated by multiple, large, empty vacuoles.

Lobular Carcinoma–like Pattern

Occasionally, ductal adenocarcinoma may display a pattern of growth similar to that of mammary lobular carcinoma. Instead of forming tubules, the tumor cells form cords and may have a single-file arrangement ( Fig. 40.13 ). Targetoid patterns and individual cell infiltration, often with signet ring cell formation, may be seen. This growth pattern may mimic diffuse-type gastric adenocarcinoma and is often associated with conventional tubular-type ductal adenocarcinoma elsewhere in the tumor.

Ductal carcinoma with a lobular, carcinoma-like pattern. Small neoplastic cells are arranged in thin cords without lumen formation, resembling mammary lobular carcinoma.

Solid Nested Pattern

Poorly differentiated pancreatic ductal adenocarcinomas may infiltrate in a nested pattern without prominent gland formation, mimicking a neuroendocrine neoplasm or squamous cell carcinoma ( Fig. 40.14 ). However, most of these cases contain foci of typical ductal adenocarcinoma.

Ductal carcinoma with a solid, nested pattern. Large cells have pleomorphic nuclei and abundant eosinophilic cytoplasm.

In some cases, the cells display abundant acidophilic cytoplasm and single, prominent nucleoli. This pattern creates a picture reminiscent of a hepatocellular carcinoma (i.e., hepatoid pattern) or an oncocytic neoplasm. However, the immunohistochemical staining pattern is different from that of hepatocellular carcinoma. In some cases, cells with a nested pattern have clear cytoplasm, resembling renal cell carcinoma. Some authorities refer to this variant as clear cell carcinoma .

Micropapillary Pattern

Some poorly differentiated ductal adenocarcinomas exhibit a micropapillary pattern, with solid clusters of cells suspended in lacunar spaces ( Fig. 40.15 ). Neutrophils infiltrate regions in a micropapillary pattern. As in other anatomic locations, pancreatic carcinomas with a micropapillary pattern are particularly aggressive.

Ductal carcinoma with a micropapillary pattern. Clusters of tumor cells are suspended in the lacunar spaces.

Colloid Carcinoma

Colloid carcinoma is a type of pancreatic ductal carcinoma clinically and biologically distinct from the others discussed earlier. Whereas those tumor types are clinically aggressive, colloid carcinomas have a more protracted clinical course. Colloid carcinoma (i.e., mucinous noncystic carcinoma) is characterized by stromal pools of mucin-containing, scant, malignant epithelial cells arranged as strips; stellate or cribriform clusters; small, round tubules; or individual signet ring cells ( Fig. 40.16 ). Colloid carcinomas are usually associated with an IPMN or a mucinous cystic neoplasm.

The colloid carcinoma (i.e., mucinous noncystic carcinoma) is composed of large stromal mucin lakes in which are suspended relatively scanty strips and clusters of cells. Individual cells have a signet ring configuration.

Data suggest that colloid carcinomas have a more favorable clinical course than conventional, ductal-type invasive carcinomas. In one report, the 5-year survival rate for resected cases of colloid carcinoma was 55%, compared with 12% to 15% for conventional ductal adenocarcinomas. Some patients died of thromboembolic complications. In the same study, all patients who died had a history of an incisional biopsy, which raises the possibility that disruption of the integrity of the tumor may cause dissemination of these highly mucinous lesions.

Colloid carcinomas share intestinal differentiation (i.e., expression of CK20, MUC2, and CDX2) with intestinal-type IPMNs. Although these tumors harbor molecular abnormalities similar to those of conventional ductal adenocarcinoma (i.e., mutations in KRAS and TP53 ), the defects occur less frequently in colloid carcinomas. Loss of SMAD4 expression never occurs in colloid carcinomas.

Medullary Carcinoma

Similar to medullary carcinomas in the breast and large intestine, medullary carcinoma of the pancreas is defined as a tumor with a syncytial pattern of growth of poorly differentiated epithelial cells with pushing borders, which is mostly devoid of a desmoplastic reaction but often accompanied by an inflammatory infiltrate ( Fig. 40.17 ). Experience with these tumors is limited, and their natural history and prognosis are poorly understood. However, they do not appear to be significantly different from conventional ductal adenocarcinomas.

The medullary carcinoma is poorly differentiated, lacks gland formation, and has a pushing growth pattern at the periphery. The tumor cells are large and appear syncytial. A lymphocytic infiltrate can be seen between tumor cells.

In contrast to conventional ductal adenocarcinoma, some medullary carcinomas are associated with genetic alterations commonly seen in medullary carcinomas of the colon (i.e., microsatellite instability), and the rate of KRAS mutations is very low. Some patients have a personal or family history of colon cancer, which raises the possibility of an associated inherited cancer syndrome.

Squamous Cell Carcinoma and Adenosquamous Carcinoma

Squamous cell and adenosquamous carcinomas constitute approximately 2% of all pancreatic cancers. They are more prevalent in the tail of the pancreas. The clinical outcome of these tumors is similar to that of conventional ductal adenocarcinoma or possibly worse.

Some cases have the appearance of an adenoacanthoma (i.e., adenocarcinoma with benign-appearing squamous elements), whereas others may have a combination of adenocarcinoma with a well-differentiated keratinizing squamous cell carcinoma, poorly differentiated squamous carcinoma without keratinization, or basaloid squamous cell carcinoma. Because small foci of squamous differentiation may occur in ductal adenocarcinomas, an arbitrary squamous component of 30% has been proposed for a carcinoma to be regarded as adenosquamous. Pure squamous cell carcinoma (without a glandular component) is rare. Most cases contain a glandular component (e.g., adenosquamous carcinoma) on careful histologic examination ( Fig. 40.18 ), and any amount of glandular differentiation is sufficient for a predominantly squamous carcinoma to be regarded as adenosquamous.

The adenosquamous carcinoma contains neoplastic glands resembling conventional ductal adenocarcinoma and large nests of cells with squamous differentiation.

Hepatoid Carcinoma

Rarely, pancreatic carcinomas may have bona fide hepatocellular differentiation. Hepatoid carcinomas have a solid, nested, or trabecular architecture and are composed of polygonal cells with granular eosinophilic cytoplasm, centrally located nuclei, and prominent nucleoli. Bile pigment may be identified.

Staining for hepatocellular differentiation is typically positive, including hepatocyte paraffin 1 (HepPar1), polyclonal CEA (canalicular), and CD10 (canalicular). α-Fetoprotein (AFP) also may be expressed in these tumors. The differential diagnosis of hepatoid carcinoma includes acinar cell carcinoma and pancreatoblastoma, both of which can express AFP, and intraductal oncocytic papillary neoplasm, which consistently stains for HepPar1 but is not thought to possess true hepatocellular differentiation.

Undifferentiated Carcinoma

Similar to other organs, the pancreas may give rise to a family of neoplasms that show little or no morphologic evidence of epithelial differentiation. In theory, undifferentiated carcinomas may arise from any of the epithelial cell lines in the pancreas. However, most undifferentiated carcinomas are thought to represent ductal neoplasms. In some instances, evidence for a ductal origin stems from the finding of a ductal adenocarcinoma component in an otherwise undifferentiated carcinoma. Oncogenic mutations in genes typical of ductal carcinomas (e.g., KRAS ) have been identified in some undifferentiated carcinomas.

The histologic types of undifferentiated carcinomas include spindle cell (sarcomatoid) carcinoma, carcinosarcoma, anaplastic giant cell carcinoma, and undifferentiated carcinoma with osteoclast-like giant cells. The histologic features of the first three of these tumors overlap; the sarcomatoid components consist of anaplastic giant cells or spindle cells ( Fig. 40.19 ) and sometimes contain heterologous stromal differentiation (e.g., bone, cartilage, and skeletal muscle). The designation carcinosarcoma is used when a tumor contains a separate glandular component, which results in a biphasic appearance. In some cases, the undifferentiated elements retain immunohistochemical positivity for epithelial markers, such as keratin or EMA. Others lack evidence of epithelial differentiation even at the immunohistochemical and ultrastructural levels. If these tumors lack an associated glandular component, they are indistinguishable from undifferentiated sarcoma. Cases with differentiation along a definable mesenchymal line may be classified as primary sarcomas of the pancreas, even though they may have originated from an epithelial precursor.

Patterns of undifferentiated carcinoma include anaplastic giant cell carcinoma (A), in which enormous tumor cells grow in solid sheets and have markedly atypical nuclei, and carcinosarcoma (B), in which the tumor exhibits a biphasic pattern of glandular epithelium and sarcomatoid elements.

With the possible exception of undifferentiated carcinoma with osteoclast-like giant cells, the prognosis for undifferentiated carcinomas is poor, possibly worse than that for conventional ductal adenocarcinoma.

Undifferentiated Carcinoma with Osteoclast-like Giant Cells

Undifferentiated carcinoma with osteoclast-like giant cells shares histologic features with certain poorly differentiated neoplasms of other epithelial organs, sarcomas, and melanoma. In all these situations, undifferentiated neoplasms contain a combination of neoplastic, plump spindle cells and non-neoplastic osteoclast-like giant cells. In the pancreas, many undifferentiated carcinomas with osteoclast-like giant cells contain a separate glandular component or are associated with a preinvasive neoplasm, such as a mucinous cystic neoplasm or PanIN. The neoplastic elements are usually moderately to markedly atypical, noncohesive, and somewhat epithelioid. Various numbers of osteoclast-like giant cells, with many nuclei showing only mild nuclear atypia ( Fig. 40.20 ), are typically scattered randomly among the neoplastic elements. A component of mononuclear histiocytic cells can be identified in these tumors.

A, The undifferentiated carcinoma with osteoclastic giant cells (i.e., osteoclastic giant cell carcinoma) contains neoplastic, undifferentiated cells that vary from epithelioid to spindle shapes, mixed with various numbers of non-neoplastic, multinucleated osteoclasts. B, Immunohistochemical staining for CD68 demonstrates the histiocytic nature of the osteoclast-like giant cells.

Some cases also contain anaplastic giant tumor cells in addition to osteoclast-like giant cells. The osteoclast-like cells have phagocytic capability and may contain neoplastic cells engulfed in the cytoplasm. The giant cells have a histiocytic origin as demonstrated by positive immunohistochemical staining for CD68 (see Fig. 40.20, B ) and other histiocytic markers, as are the mononuclear histiocytic cells. Anaplastic giant cells and mononuclear neoplastic cells are usually undifferentiated at the immunohistochemical level, and keratin expression often is restricted to only an associated glandular component. Oncogenic mutations in KRAS have been detected in the neoplastic elements of undifferentiated carcinomas with osteoclast-like giant cells.

Some cases have a less aggressive clinical course than expected, but undifferentiated carcinomas with osteoclast-like giant cells are not an indolent type of neoplasm. Most patients die of the disease within 2 years of diagnosis.

Clinical Features

Serous cystic neoplasms are the most common type of true cystic neoplasms of the pancreas, which means that the cysts are lined by a continuous layer of neoplastic epithelium rather than being degenerative or representing dilated pancreatic ducts. Because serous cystadenomas are usually microcystic, the term microcystic adenoma is a synonym, although a macrocystic (oligocystic) type of serous cystadenoma also occurs.

Microcystic serous cystadenomas are composed of numerous small cysts (>1 mm to 1 cm in diameter) that ultimately form a large (up to ≤25 cm), well-delineated tumor mass. These cystadenomas arise mostly in the body or tail of the pancreas and occur predominantly in women (female-to-male ratio of 3 : 1). The mean age of patients at diagnosis is 66 years.

Cysts (often multiple) that appear histologically similar may develop in patients with von Hippel-Lindau syndrome, although most patients with microcystic serous cystadenomas have no other associated diseases. However, this association provides some insight into the molecular biology of the neoplasm. Other concurrent pancreatic tumors described in patients with microcystic serous cystadenomas include ductal adenocarcinoma and PanNETs.

Pathologic Features

Grossly, microcystic serous cystadenomas are usually circumscribed and often contain a central, stellate, fibrous scar. The innumerable cysts produce a gross appearance resembling that of a sponge ( Fig. 40.22 ). In some regions, the cysts may be so small that the tumor appears solid. Degenerative changes, including hemorrhage and macrocystic degeneration, may be prominent in some cases, mimicking the gross appearance of a pseudocyst.

Gross appearance of a microcystic serous cystadenoma. The lesion is well circumscribed and composed of small cysts measuring less than 1 cm in the greatest dimension and separated by thin, translucent septa.

Microscopically, the cysts of microcystic serous cystadenomas are lined by a single layer of flat to cuboidal cells with clear cytoplasm, well-defined cytoplasmic borders, and small, round nuclei with dense, homogeneous chromatin ( Fig. 40.23 ). Cytoplasmic clearing results from accumulation of glycogen; mucin is not usually found in the tumors. In rare cases, the cells are more columnar and contain acidophilic, granular cytoplasm. Blunt papillary projections may be found focally, but well-formed or complex papillae are unusual. Underlying the epithelium is a continuous layer of capillary-sized vessels with plump endothelial cells. The stroma between cysts is hyalinized and may contain entrapped islets. These cytologic features are characteristic of microcystic serous cystadenomas and less common types of serous tumors of the pancreas, such as macrocystic serous cystadenoma and solid serous adenoma.

Microcystic serous cystadenoma. A, At low power, each small cyst is lined by a flattened layer of epithelium. B, Cytologically, the lining cells show clear cytoplasm and small, uniform, hyperchromatic nuclei.

Macrocystic serous cystadenomas occur more commonly in men than women. The boundaries of the tumor are often ill defined, the individual locules are 1 cm to several centimeters in diameter, and a central scar is usually absent ( Fig. 40.24 ). Microscopically, the cyst lining is identical to that of the microcystic type, with glycogen-rich, clear cells arranged in a single, flat layer without nuclear atypia or mucin production ( Fig. 40.25 ).

Gross appearance of a macrocystic serous cystadenoma. The cysts are much larger than those of the microcystic counterpart.

Macrocystic serous cystadenoma. Despite the large size of the cysts, the lining epithelium is identical to that of microcystic serous cystadenomas. The clear cells have round, hyperchromatic nuclei.

Solid serous adenomas show a complete absence of cystic change. This tumor type is composed of back-to-back, small glands with cytologic features that are otherwise typical of a serous neoplasm ( Fig. 40.26 ).

In the solid serous adenoma, there is no cyst formation. Back-to-back glands exhibit the same cytologic features as the cystic members of the serous tumor family.

Histologically and immunophenotypically, all types of serous neoplasms appear to recapitulate centroacinar cells. For instance, they express low-molecular-weight keratins (in addition to broad-spectrum keratins), EMA, inhibin, and MLANA (MART1). Human melanoma black 45 (HMB-45) staining is typically negative in these tumors. Staining results for ductal mucin markers (i.e., TAG72, MUC1, CA 19-9, and CEA) are negative or only focally positive, although MUC6 is usually positive. Molecular genetic alterations include mutations of the von Hippel-Lindau tumor suppressor gene ( VHL on chromosome 3p25.3) and allelic losses on chromosome 10q. As is true of other neoplasms arising in patients with von Hippel-Lindau syndrome, serous neoplasms express carbonic anhydrase IX (CA9), hypoxia-inducible factor 1α (HIF-1α), vascular endothelial growth factor (VEGF), and SLC2A1 (previously called GLUT1). Overexpression of the glucose transporter SLC2A1 may help to explain the accumulation of cytoplasmic glycogen in serous tumors that causes the cytoplasmic clearing. Genetic abnormalities typical of ductal adenocarcinoma (e.g., mutations of KRAS and TP53 ) have not been identified in serous tumors nor have mutations in GNAS or RNF43 , which are found in other cystic or intraductal pancreatic neoplasms.

Differential Diagnosis

The differential diagnosis of serous neoplasms includes other cystic tumors of the pancreas (see Differential Diagnosis of Cystic and Intraductal Lesions ). The clear cell nature of the cytoplasm raises the possibility of metastatic renal cell carcinoma, a tumor that may involve the pancreas as the sole site of metastasis, may reveal a cystic change, and is common in patients with von Hippel-Lindau syndrome. Solid and acinar regions and prominent nuclear atypia combined with a more pronounced sinusoidal vascular pattern favor a diagnosis of renal cell carcinoma. Lymphangiomas also resemble serous cystic neoplasms, particularly when the latter have an attenuated epithelial lining. Lymphangiomas typically occur in peripancreatic tissue rather than in the pancreas, and they contain lymphoid aggregates between the cystic spaces. In difficult cases, immunohistochemical staining can help to demonstrate the endothelial nature of the lining and the absence of keratin in lymphangiomas.

Natural History

Most serous tumors of the pancreas are benign, and serous cystadenocarcinoma of the pancreas is rare. Malignancy is defined as metastasis. Primary and metastatic serous cystadenocarcinomas usually exhibit the microscopic features of microcystic serous cystadenomas, with an absence of cytoarchitectural atypia or other morphologic findings suggesting malignancy. Some authorities have questioned the malignant potential of these rare cases and have suggested instead that they develop as a form of parasitic growth of a benign neoplasm or as a manifestation of multicentricity. In the absence of demonstrable metastases, any typical serous neoplasm should be considered benign. If a definitive diagnosis can be achieved preoperatively and the tumor is asymptomatic, treatment by clinical observation and follow-up is considered a viable option.

Another type of malignancy has been reported for serous neoplasms. In rare cases, a cytologically obvious carcinoma may arise in a microcystic serous cystadenoma (i.e., carcinoma eg microcystic adenoma). The carcinomas in these cases are composed of nests or clusters of clear cells, and some have large, cytoplasmic vacuoles, producing a sievelike pattern. The nuclei are enlarged and atypical relative to the residual benign serous elements, and increased mitotic activity and necrosis may be seen. The biologic behavior of these rare cases has not been defined.

Clinical Features

Similar to their serous counterparts, mucinous cystic neoplasms are true cystic neoplasms of the pancreas. In contrast to most serous cystadenomas, mucinous cystic neoplasms are consistently macrocystic, and when defined strictly, they have very distinctive clinicopathologic characteristics. They are seen almost exclusively in women (with rare examples documented in men) in the fifth to sixth decades of life (mean age, 50 years). The tumor usually is located in the tail of the pancreas. Presenting symptoms are nonspecific and are usually the result of the effects of an enlarging mass.

Pathologic Features

Macroscopically, mucinous cystic neoplasms are typically single, multilocular cysts surrounded by a thick, fibrotic capsule ( Fig. 40.27 ). The mean diameter of most mucinous cystic neoplasms is greater than 10 cm. Unless there is fistula formation, these tumors do not communicate with the pancreatic ductal system. The septa between cysts are usually thin and may have velvety papillations; some appear trabeculated and thickened. The cyst contents are often mucoid, but some may have a watery consistency. Solid areas in the cysts or the peripheral capsule should be sampled extensively, because these areas may harbor an invasive carcinoma component. Degenerative changes with hemorrhage may occur, simulating the gross appearance of a pseudocyst.

Gross appearance of a mucinous cystic neoplasm. The circumscribed tumor involves the tail of the pancreas and contains numerous, large (1- to 5-cm) cysts. The septa are fibrotic and show no gross evidence of solid tumor nodules in this example.

Histologically, pancreatic mucinous cystic neoplasms are similar to ovarian mucinous neoplasms ( Fig. 40.28 ). The lining epithelium consists of tall, columnar cells with abundant apical mucin, although cuboidal cells that lack obvious mucin may be seen in some cases or may predominate ( Fig. 40.29 ). Examination sometimes reveals intestinal-type epithelium with goblet cells, but the villiform papillae resemble those of colonic villous adenomas, which are typical of intestinal-type IPMNs, are very unusual in mucinous cystic neoplasms. Neuroendocrine cells and Paneth cells may be detected. The epithelium may display a wide range of cytologic atypia. Some mucinous cystic neoplasms may be largely bland in appearance, containing mostly uniform, basally oriented nuclei and displaying minimal architectural complexity, whereas other tumors exhibit abundant papillary formations, pseudostratified hyperchromatic nuclei, and a cribriform architecture. Severe epithelial atypia may be focal, and numerous sections may be required to properly and thoroughly evaluate these neoplasms ( Fig. 40.30 ).

At low power, the mucinous cystic neoplasm is surrounded by a thick, fibrous capsule. The large cysts are lined by mucinous epithelium, and the stroma of the septa is hypercellular.

At higher magnification, the epithelial lining of the mucinous cystic neoplasm is composed of tall, columnar, mucin-containing cells. In this region, there is no significant nuclear atypia, loss of polarity, or architectural complexity (i.e., mucinous cystic neoplasm with low-grade dysplasia). The subepithelial stroma is hypercellular, resembling the stroma of the ovary.

In a mucinous cystic neoplasm, high-grade dysplasia may be focal, with an abrupt transition from bland mucinous epithelium. In this case, there is marked nuclear atypia and complete loss of polarity but no invasive carcinoma (i.e., mucinous cystic neoplasm with high-grade dysplasia).

The resemblance of pancreatic mucinous cystic neoplasms to ovarian tumors extends to a distinctive subepithelial, hypercellular, spindle cell stroma (i.e., ovarian-like stroma). This type of stroma is a diagnostic prerequisite for mucinous cystic neoplasms and is found at least focally in all bona fide examples of this neoplasm. Most contemporary authorities require it to establish a diagnosis of mucinous cystic neoplasm. In addition to spindle cell elements, the stroma often contains nests of epithelioid cells, which suggests luteinization ( Fig. 40.31 ). Occasionally, large, circumscribed regions of stromal hyalinization may resemble corpora albicantia. The stromal cells frequently express estrogen and progesterone receptors, inhibin, and MLANA (recognized by the A103 monoclonal antibody); inhibin and MLANA are intensely expressed in epithelioid, lutea-like cells (see Fig. 40.31, B ). A plausible explanation for ovarian-like stroma in mucinous cystic neoplasms has not been offered, but because the fetal pancreas contains similar hypercellular stroma surrounding developing pancreatic ducts, some authorities have suggested that the stroma of mucinous cystic neoplasms represents recapitulation of the fetal periductal mesenchyme.

Stroma of a mucinous cystic neoplasm. A, In addition to the hypercellular spindle cell component, there may be clusters of epithelioid cells resembling the luteinized stroma of the ovary. B, Immunohistochemical staining for inhibin is positive in the epithelioid cell nests.

The epithelium of mucinous cystic neoplasms expresses keratin and glycoprotein markers, such as CEA and CA 19-9. MUC5AC is expressed diffusely, whereas the MUC2 antibody typically stains only scattered goblet cells. MUC1 usually is detected only in invasive carcinomas that arise in mucinous cystic neoplasms. Other than in goblet cells, intestinal differentiation is not commonly found. For instance, staining for CK20 and CDX2 is usually negative in these tumors.

Invasive carcinoma may develop in mucinous cystic neoplasms. This is a concern in cases with marked cellular atypia, because the invasive component may be focal and grossly inapparent. Solid areas of the tumor and the interface with adjacent tissues should be sampled generously and carefully. Invasive carcinoma arising in a mucinous cystic neoplasm usually resembles conventional pancreatic ductal adenocarcinoma. However, other types, such as sarcomatoid carcinoma, or undifferentiated carcinoma with osteoclast-like giant cells, may occur ( Fig. 40.32 ). Although colloid carcinomas often are associated with IPMNs, they develop rarely in mucinous cystic neoplasms. Reports of apparent sarcomatous transformation of the cellular subepithelial stroma exist, although genetic analysis of these cases found that the sarcomatoid elements were of epithelial derivation and probably represented sarcomatoid carcinoma rather than true sarcoma.

Within a septum of a mucinous cystic neoplasm with invasive carcinoma, there is a component of undifferentiated anaplastic giant cell carcinoma, which is one of several types of invasive carcinoma that may arise in these tumors.

According to the 2007 Armed Forces Institute of Pathology (AFIP) fascicle on the pancreas and the 2010 WHO classification, the degree of dysplasia in mucinous cystic neoplasms should be graded as low, intermediate, or high based on the most severely dysplastic region, and the presence or absence of invasive carcinoma should be reported. Cases with low-grade dysplasia have minimal cytoarchitectural atypia of the lining epithelium. These tumors are also designated as mucinous cystadenoma , but extensive or complete tissue sectioning of the tumor should be performed to confirm this diagnosis. Mucinous cystic neoplasms with intermediate-grade dysplasia have a loss of nuclear polarity, moderate atypia, and mild architectural complexity. Mucinous cystic neoplasms with high-grade dysplasia (i.e., mucinous cystadenocarcinoma in situ) have marked cytologic atypia, mitotic figures, and larger, irregular, and hyperchromatic nuclei, usually accompanied by significant architectural complexity. Cases of mucinous cystic neoplasm with an associated invasive carcinoma are also called invasive mucinous cystadenocarcinoma .

The histologic type of invasive carcinoma should be reported, and the extent of intratumoral or extratumoral invasion should be determined. Unfortunately, the clinical relevance of this classification system is a matter of debate. Some investigators have reported recurrence or metastasis from tumors that lacked an obvious invasive carcinoma or significant cellular atypia. These investigators suggested that even benign-appearing mucinous cystadenomas have latent malignant potential. Others have suggested that rare metastasis from otherwise benign-appearing tumors may be explained on the basis of incomplete surgical removal or inadequate tissue sampling of the primary tumor and failure to identify an invasive component. Studies in which mucinous cystic neoplasms have been thoroughly sectioned have found no recurrences in cases that lack invasive carcinoma at the time of resection. Minimally invasive carcinoma confined to the stroma of the cyst septa is usually cured by surgery, provided the specimen has been thoroughly evaluated microscopically to ensure that the extent of invasive carcinoma is limited.

DNA ploidy analysis may correlate with prognosis. Overall, the rate of malignancy in mucinous cystic neoplasms is approximately 10%. It has been suggested that invasive carcinomas that arise in mucinous cystic neoplasms may be less aggressive than conventional pancreatic ductal adenocarcinomas. Nevertheless, surgical resection is recommended for all patients with a mucinous cystic neoplasm.

Molecular analysis of mucinous cystic neoplasms has disclosed mutations or promoter methylation in many of the genes known to be abnormal in ductal adenocarcinomas, including KRAS , TP53 , SMAD4 , and CDKN2A . Approximately one half of mucinous cystic neoplasms have mutations in RNF43 , which codes for a protein with intrinsic E3 ubiquitin ligase activity that is also mutated in IPMNs but not in ductal adenocarcinomas. GNAS mutations are not found in mucinous cystic neoplasms, in contrast to IPMNs.

Differential Diagnosis

The differential diagnosis of mucinous cystic neoplasms of the pancreas is discussed later (see Differential Diagnosis of Cystic and Intraductal Lesions ). Mucinous cystic neoplasms sometimes develop extensive denudation of the lining epithelium, with the stroma showing hemorrhage, fibrosis, and inflammation. Biopsy specimens from these regions of the tumor resemble pseudocysts.

Recognition of the clinical setting (e.g., young woman, no history of pancreatitis or other cause for a pseudocyst, otherwise normal-appearing pancreas) can help to direct the pathologist to examine other regions of the cyst to find the characteristic mucinous lining. Elements of ovarian-like stroma may persist in denuded areas. Immunohistochemical demonstration of hormone receptors in stroma cells supports a diagnosis of mucinous cystic neoplasm. The term mucinous cystadenocarcinoma should not be used for a ductal adenocarcinoma that shows ectatic glands (i.e., large duct pattern), unless there is evidence that the tumor arose in a preexisting mucinous cystic neoplasm.

Some cystic lesions of the pancreas have a mucinous lining that resembles a mucinous cystic neoplasm, but they lack evidence of cellular, ovarian-like stroma. Most lesions represent a branch duct–type IPMN or retention cyst with superimposed PanIN. Because the stromal component is regarded as critical for the diagnosis of a mucinous cystic neoplasm, this designation should be made with great caution in its absence.

Cystic Change in Ductal Adenocarcinoma

Cystic change in ductal adenocarcinoma is uncommon and may occur by three mechanisms. A large, radiographically detectable cyst may develop as a result of central necrosis of the tumor. Diagnosis can be clinically challenging, but residual carcinoma at the periphery of the cystic cavity is usually recognizable histologically. In other cases, a ductal adenocarcinoma can produce cystic dilation of distally located obstructed ducts, which results in one or more ductal retention cysts that can be misinterpreted as the main disease process on imaging or gross pathologic evaluation. In the large duct (microcystic) pattern of ductal adenocarcinoma, infiltrating tubular units are cystically dilated and may achieve a size large enough to be visible to the naked eye. Cystic glands may appear to be noninvasive, mimicking foci of PanIN or IPMN, especially when the cystic change occurs in the pancreatic parenchyma.

Cystic Pancreatic Neuroendocrine Tumor

A cystic PanNET rarely occurs. It usually consists of a single, unilocular cyst that occupies most of the tumor. Cysts that develop in well-differentiated PanNETs are usually centrally located and solitary, and they are typically lined by a cuff of well-preserved tumor with overlying fibrin ( Fig. 40.33 ). The cyst cavity is typically filled with clear fluid instead of necrotic debris.

In a pancreatic neuroendocrine tumor with central cystic degeneration, a rim of viable tumor covered by fibrin is seen between the fibrotic capsule and the central region of cystic change.

Most cystic changes in PanNETs are degenerative, although in some cases, the cyst is partially lined by non-neoplastic ductal epithelium, suggesting the cyst may occur because of dilation of a duct surrounded by the neoplasm. Some cysts may grow as large as 25 cm. A pathologic diagnosis of cystic neuroendocrine tumor is facilitated by careful attention to the cytologic features of the tumor cells.

Cystic Acinar Neoplasms

Acinar cell cystadenoma and acinar cell cystadenocarcinoma are discussed later (see Cystic Acinar Cell Neoplasms ).

Squamous Cysts of Pancreatic Duct

Squamous cysts of pancreatic duct have an average diameter of 2.5 cm and arise in adults. They are lined by flat epithelium composed of squamoid or transitional cells that can be simple or stratified. Keratinization is not found. The cells in the basal layers express tumor protein p63 (TP63), and the cells bordering the cyst lumen are positive for MUC1 and MUC6. These cysts appear to be dilated pancreatic ducts with squamous (multilayered) metaplasia.

Dermoid Cysts

Dermoid cysts (i.e., mature cystic teratomas) are rare in the pancreatic region. They have been reported in patients in the second to third decade of life and are morphologically similar to teratomas that develop in other sites of the body.

Epidermoid Cysts in the Intrapancreatic Accessory Spleen

Epidermoid cysts in the intrapancreatic accessory spleen are rare lesions that are seen mainly in patients in the second to third decade of life. They occur almost exclusively in the tail of the pancreas, a location where accessory splenic tissue is most often found. These cysts are lined by attenuated squamous cells surrounded by normal-appearing splenic tissue.

Paraampullary Duodenal Wall Cysts

Paraampullary duodenal wall cysts occur as a consequence of chronic fibrosing inflammation in the periampullary region between the duodenum and the distal common bile duct. Accessory pancreatic ducts may form the cysts in the duodenal wall and underlying pancreas, mimicking duodenal duplication. The cyst wall is lined partially by ductal epithelium and partly by inflammation and granulation tissue, and it is surrounded by hypercellular spindle cells with smooth muscle features that are possibly derived from the muscularis propria of the duodenum. The process is closely related to so-called groove pancreatitis (i.e., paraduodenal pancreatitis).

Retention Cysts

Retention cysts are unilocular cysts that result from obstruction of a pancreatic duct. They are usually lined by normal-appearing ductal epithelium without prominent cytoplasmic mucin. Superimposed PanIN may be found in some retention cysts. Retention cysts with low-grade PanIN closely resemble gastric-type branch duct IPMNs, which can have minimal papilla formation in the most cystic regions of the neoplasm. The distinction between these two entities is largely semantic. Features favoring a diagnosis of IPMN include papilla formation, multiple cysts, specialized (intestinal or oncocytic) epithelium, and lack of non-neoplastic ductal epithelium lining part of the cystic duct.

Other Cysts

Other rare cysts that can occur in the pancreas include parasitic cysts, endometriotic cysts, and congenital foregut (intestinal-type) cysts.

Clinical Features

IPMNs are grossly and radiographically visible tumors characterized by an intraductal proliferation of mucin-producing cells that usually are arranged in a papillary pattern. The tumors typically are associated with intraluminal mucin accumulation and cystic dilation of the ducts, which may be localized or involve the entire ductal system. Mucin spillage into the duodenum through the ampulla of Vater is an endoscopic finding that is virtually diagnostic of IPMN.

Depending on the location of the primary process and subsequent mechanical changes in the pancreatic ducts, IPMNs may manifest as multilocular cystic masses or abundant papillary nodules. Papilla formation may be a microscopic or macroscopic finding; the latter appear as large, nodular masses in dilated ducts. The various patterns that can occur in IPMNs led to a wide variety of designations for this group of tumors before unification under the term IPMN . Previous terms include mucinous duct ectasia (i.e., ductectatic mucinous cystadenoma), mucin-producing tumor, villous adenoma of the pancreatic duct, and intraductal papillary tumor.

IPMNs account for approximately 5% of all pancreatic neoplasms, although they are being reported in increasing numbers and may be more common than previously recognized. Patients with IPMNs are usually in the seventh to eighth decades of life and have nonspecific symptoms. Some patients have a history of pancreatitis. IPMNs in younger, asymptomatic patients are often detected incidentally during abdominal imaging performed for other indications.

Endoscopic findings (e.g., mucin extrusion through the ampulla of Vater) and radiographic findings (e.g., ectasia of the ducts) are diagnostic features. Approximately 80% of IPMNs occur in the head of the pancreas. Based on the extent of involvement of the ductal system, IPMNs are classified as main duct and branch duct types (discussed later).

Pathologic Features

Careful macroscopic examination is imperative to document the intraductal nature of the tumor. The extent of ductal dilation and the amount of gross papilla formation vary between cases and regionally in individual cases ( Fig. 40.35 ). The tumor can primarily involve the major pancreatic duct (i.e., main duct type). However, other cases are limited to involvement of the secondary ducts (i.e., branch duct type), particularly in the uncinate process and in the body and tail of the pancreas. Branch duct IPMNs may appear as multiple, separate, small cysts grossly and radiographically because of the tortuous nature of the dilated ducts. In these cases, connection to the ductal system may be difficult to demonstrate grossly.

Gross appearance of an intraductal papillary mucinous neoplasm. The pancreatic ducts are significantly dilated. A, In some examples, gross papilla formation is obvious, with extensive involvement of the main pancreatic ducts and cystic dilation of branch ducts. B, In other examples, intraductal papillae are inconspicuous, and the lesion appears as a cystic dilation of branch ducts.

Preoperative designation of IPMNs as main duct or branch duct types is clinically important because the main duct type has a greater likelihood of harboring high-grade dysplasia or invasive carcinoma. Small (<3 cm) branch duct IPMNs may not require surgical resection if they lack other worrisome findings such as mural nodules and interval growth during follow-up.

IPMNs may be localized or multicentric, or rarely, the entire ductal system of the organ may be involved. Thorough sampling of the specimen is necessary for detection of an invasive carcinoma, which is found in approximately 35% of cases.

Microscopically, mucinous cells with various degrees of atypia line the cystically dilated ducts of these tumors ( Fig. 40.36 ). Three papillary patterns have been described. The intestinal type (35% of cases) is morphologically similar to villous adenomas of the gastrointestinal tract ; the gastric type (50% of cases) is characterized by cells that resemble the foveolar epithelium of the stomach ; and the pancreatobiliary type (15% of cases) has more complex papillae composed of cuboidal cells ( Fig. 40.37 ).

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