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In contrast to the relatively uniform pathology and the unyielding dismal outcome associated with infiltrating ductal adenocarcinoma of the pancreas, cystic lesions have a broad spectrum of gross and microscopic pathologies, and a range of clinical outcomes. The common cystic lesions of the pancreas are reviewed with emphasis on practical tips for distinguishing between the main entities.
With the increasing use and resolution of abdominal imaging, ever increasing numbers of cystic lesions of the pancreas are being discovered.1,2 For example, Pitt et al reviewed all computed tomography (CT) and magnetic resonance imaging (MRI) scans performed at the Medical College of Wisconsin on patients without pancreatitis between January 1995 through December 2002, and found that 1.2% of the 24 039 patients had pancreatic cysts.1 Similarly, Laffan et al recently reported that 2.6% of 2832 consecutive patients who underwent a contrast enhanced multidetector CT (MDCT) scanning of the abdomen and pelvis at the Johns Hopkins Hospital for a nonpancreatic indication had an asymptomatic pancreatic cyst.2 Clearly, a significant number of individuals have asymptomatic pancreatic cysts.
The most common symptomatic cystic lesion of the pancreas is the non-neoplastic pseudocyst.3 The common neoplastic cystic lesions include serous cystic neoplasm, mucinous cystic neoplasm, intraductal papillary mucinous neoplasm and solid-pseudopapillary neoplasm.4 In addition, usually solid lesions, such as pancreatic endocrine neoplasms, may undergo cystic degeneration. The most appropriate treatment and likely prognosis for patients with a cystic lesion of the pancreas differ greatly depending on the type of cyst. For example, pseudocysts are benign and often managed medically or simply drained, while mucinous cystic neoplasms can harbour an associated invasive carcinoma and are best treated by complete surgical resection.
The last two features, the nature of the epithelium and stroma, are best appreciated on biopsy or surgical resection, but the epithelium can be sampled by fine needle aspiration biopsy as well.10
The following sections will consider each of the most common cystic neoplasms in greater detail.
The serous cystadenoma is a benign neoplasm composed of uniform cuboidal epithelial glycogen-rich cells.4,12 The cells line numerous small cysts containing clear straw-coloured fluid.4,12 Synonyms include microcystic serous cystadenoma, glycogen-rich cystadenoma and microcystic adenoma.
Serous cystadenomas are slightly more common in women (female:male ratio 7:3) and the mean age at diagnosis is 65 years.4,12–14 Most serous cystic neoplasms are sporadic, but they can also arise in association with the von Hippel-Lindau (VHL) syndrome.15 Serous cystadenomas usually present clinically as large abdominal masses, and common symptoms include abdominal pain, early satiety, weight loss, dyspepsia, and nausea and vomiting.4,12–14 CT will reveal a well-demarcated mass composed of innumerable small cysts. The lesions often have a central stellate calcified scar, and when the pancreatic duct can be visualized, it is usually seen to drape around the mass.
Grossly, serous cystadenomas can involve any portion of the pancreas. Most are solitary and large (mean 6.0 cm). They are well-demarcated and composed of innumerable small (< 2 mm) thin-walled cysts filled with clear straw-coloured (serous) fluid (Fig. 1).4,12–14 As noted in the description of the radiographic appearance of these neoplasms, they often contain a calcified central stellate scar. Two less common variations on the gross appearance of serous cystadenomas deserve note. Serous neoplasms can rarely be solid (the solid variant) or macrocystic (the macrocystic variant).4 Synonyms for the macrocystic serous cystadenoma include oligocystic serous cystadenomas, serous oligocystic adenoma and ill-demarcated adenoma. Solid serous cystadenomas mimic well-differentiated endocrine neoplasms, and macrocystic serous cystadenomas mimic mucinous cystic neoplasms.
Microscopically the cysts of serous cystadenomas are lined by clear cuboidal cells with uniform round nuclei (Fig. 2).4,12–14 These cells can focally form microscopic papillae that project into the cysts, a finding that has no clinical significance. Stains for glycogen, such as the periodic acid-Schiff stain, can be used to highlight abundant intracytoplasmic glycogen.
The cells immunohistochemically label with antibodies to pancytokeratin (AE1/AE3), CAM5.2, epithelial membrane antigen (EMA), and for cytokeratins 7, 8, 18, and 19.4,12–14 Loss of heterozygosity on chromosome 3p25, the location of the VHL gene, is one of the most frequently identified molecular alterations.16
The vast majority of serous cystic neoplasms are entirely benign and patients are cured if the lesion is resected. Very rare examples of locally invasive, and even metastatic, serous cystic neoplasms have been reported.17 Serous cystic neoplasms that have metastasized are designated ‘serous cystadenocarcinoma’. Recently, Galanis et al suggested that the identification of locally aggressive disease in a resected neoplasm may indicate an increased likelihood of recurrence or metachronous metastasis.13
By definition, the mucinous cystic neoplasm has both a mucin-producing epithelium and an ovarian-type of stroma.4,11 The neoplastic epithelial cells line larger cysts (1–3 cm) containing mucous. These cysts do not communicate with the larger pancreatic ducts.
Mucinous cystic neoplasms arise in women much more commonly than in men (female:male ratio 20:1), and the mean age at diagnosis is 45 years.4–6,11 Symptoms are similar to those associated with serous cystic neoplasms and include abdominal pain, early satiety, weight loss, dyspepsia, and nausea and vomiting. Abdominal imaging, such as CT, demonstrates a mass composed of 1–3-cm cysts with thick walls.
Mucinous cystic neoplasms involve the tail of the pancreas more frequently than they do the head.4–6,11 Grossly, these neoplasms are usually solitary and well-demarcated. On cross-section the 1–3-cm cysts usually contain tenacious mucin, but some can contain degraded blood (Fig. 3). The walls of the cysts are thick (1–3 mm). Microscopically, by definition, the cysts are lined by columnar mucin-producing epithelial cells, and the stroma in the septa of the cysts resembles ovarian stroma with crowded spindle cells with thin cytoplasm (Fig. 4).4–6,11 Ovarian stroma is seen even in mucinous cystic neoplasms that arise in men. The epithelium can show varying degrees of dysplasia, and noninvasive mucinous cystic neoplasms can be divided into three grades: mucinous cystic neoplasm with low-grade dysplasia, mucinous cystic neoplasm with moderate dysplasia, and mucinous cystic neoplasm with high-grade dysplasia based on the degree of architectural and cytological atypia.4 A third of mucinous cystic neoplasms have an associated invasive carcinoma and, not surprisingly, these are designated mucinous cystic neoplasm with an associated invasive carcinoma.
The neoplastic cells label with antibodies to pan-cytokeratin, cytokeratins 7, 8, 18 and 19, CAM5.2 and carcinoembryonic antigen (CEA), while the stromal cells label with antibodies to vimentin, inhibin, progesterone receptors and oestrogen receptors.4,11 Activating point mutations in the KRAS2 oncogene and inactivation of the TP53 tumour suppressor gene have been reported in mucinous cystic neoplasms, particularly those with high-grade dysplasia.
The prognosis for patients with a surgically resected noninvasive mucinous cystic neoplasm is excellent. The vast majority of these patients are cured.4–6,11 Most examples of metastasizing ‘noninvasive mucinous cystic neoplasms’ reported in the literature were likely to be mucinous cystic neoplasms with an associated invasive carcinoma in which the invasive component was simply not sampled. Clearly extensive, if not complete, histological sampling of mucinous cystic neoplasms is advisable.
The best prognosticator for a patient with a mucinous cystic neoplasm is the presence or absence of an associated invasive carcinoma.4–6,11 If an invasive carcinoma is present, then the size of the invasive component, depth of invasion, resectabilty and stage all become useful prognosticators. The 5-year survival rate for patients with an invasive carcinoma arising in association with mucinous cystic neoplasm is 50%.
The intraductal papillary mucinous neoplasm, as the name so aptly describes, is a mucin-producing, usually papillary, epithelial neoplasm that arises in one of the larger pancreatic ducts.4,7,8 As is true for mucinous cystic neoplasms, about one-third of these are associated with an invasive carcinoma.
In contrast to mucinous cystic neoplasms, intraductal papillary mucinous neoplasms are more common in men than in women.4,7–9 The mean age at diagnosis is 65 years. Presenting symptoms typically include abdominal and back pain, anorexia, weight loss and recurrent episodes of pancreatitis.4,7–9 Abdominal imaging will reveal a cystic mass that communicates with one of the larger pancreatic ducts. The main pancreatic duct is often dilated. Features on imaging that suggest a malignancy include size > 3 cm, a mural nodule and dilatation of the main pancreatic duct.18–20 Mucin oozing from the ampulla of Vater is almost diagnostic of an intraductal papillary mucinous neoplasm on endoscopy.
In contrast to mucinous cystic neoplasms, intraductal papillary mucinous neoplasms involve the head more frequently than the tail of the gland, and intraductal papillary mucinous neoplasms are often multifocal.4,21 Grossly, on sectioning the pancreatic duct or one of its branches will be distended with thick mucin. Papillary projections into the lumen can be observed (Fig. 5). Those that involve the main pancreatic duct are designated ‘main-duct type’, while those that predominantly involve a branch duct are designated ‘branch-duct type’.
Microscopic examination typically reveals long thin intraductal papillae lined by mucin-producing columnar epithelial cells (Fig. 6).4,7–9 In contrast to mucinous cystic neoplasms, the stroma is composed of loose, relatively acellular, connective tissue. As is true for mucinous cystic neoplasms, the epithelium of intraductal papillary mucinous neoplasms can show varying degrees of dysplasia, and noninvasive intraductal papillary mucinous neoplasms can be divided into three grades based on the degree of architectural and cytological atypia. The three grades are intraductal papillary mucinous neoplasm with low-grade dysplasia, intraductal papillary mucinous neoplasm with moderate dysplasia, and intraductal papillary mucinous neoplasm with high-grade dysplasia (Fig. 7).4 A third of intraductal papillary mucinous neoplasms have an associated invasive carcinoma and, not surprisingly, these are designated intraductal papillary mucinous neoplasm with an associated invasive carcinoma. These invasive carcinomas are usually either colloid carcinomas or ductal carcinomas.4,22,23
Immunolabelling can be used to demonstrate the expression of cytokeratin, and intraductal papillary mucinous neoplasms label with antibodies to pancytokeratin (AE1/AE3), CAM5.2 and cytokeratins 7, 8, 18 and 19, and variably cytokeratin 20.4,7,24,25 They express CEA and those with ‘intestinal’ phenotype are strongly MUC2 positive.4,22 Intraductal papillary mucinous neoplasms with ‘pancreatobiliary’ histology may express MUC1 instead of MUC2.22 Activating point mutations in the KRAS2 oncogene and inactivation of the TP53 tumour suppressor gene have been reported in these neoplasms. The STK11/LKB1 gene is biallelically inactivated in a minority of cases.26 As is true for mucinous cystic neoplasms, the number of genetic alterations in intraductal papillary mucinous neoplasms typically increases with increasing degrees of dysplasia.
The single most important prognostic factor is the presence or absence of an associated invasive carcinoma.4,9,21 Unlike mucinous cystic neoplasms, however, patients with a surgically resected noninvasive papillary mucinous neoplasm still have to be carefully followed because of the real risk of multifocal disease.21 If an invasive carcinoma is present, then the size of the invasive component, resectabilty and stage are all useful prognosticators. The 5-year survival rate for patients with an invasive carcinoma arising in association with an intraductal papillary mucinous neoplasm is 40%.
Solid-pseudopapillary neoplasms are difficult to define because they do not have a recognizable direction of differentiation. Instead, these distinctive neoplasms are defined by their gross and morphological appearance as epithelial neoplasms composed of discohesive uniform cells that surround delicate blood vessels and form solid masses with frequent cystic degeneration and intracystic haemorrhage.4,27
Almost all solid-pseudopapillary neoplasms occur in women (female:male ratio 10:1), and the mean age at diagnosis is ~25 years.4,27 Patients usually present nonspecifically with abdominal pain, early satiety, weight loss, dyspepsia, and nausea and vomiting. Abdominal imaging will reveal a solid mass, a cystic mass or, more commonly, a solid and cystic mass.
Solid-pseudopapillary neoplasms can arise anywhere in the gland and they have a distinctive gross appearance. They typically form well-demarcated masses with solid areas and irregular foci containing friable necrotic material and haemorrhagic debris (Fig. 8).4,27
Microscopically they are composed of loosely cohesive uniform cells that cling to delicate capillaries (Fig 9 and Fig 10).4,27 The nuclei are uniform and oval, and typically have nuclear grooves. Eosinophilic hyaline globules, cholesterol clefts and multinucleated giant cells are also seen. Immunolabelling will reveal that the neoplastic cells express vimentin, α-1 antitrypsin, CD10, neuron-specific enolase and CD56.4,27 The expression of synaptophysin and cytokeratin (AE1/AE3, CAM5.2) is variable. Almost all harbour mutations in the β-catenin gene and, as a result, immunolabelling with antibodies to the β-catenin protein will show an abnormal nuclear pattern of labelling.28
Solid-pseudopapillary neoplasms are considered low-grade malignancies, and the prognosis for most patients is excellent. Only 10–15% metastasize and even metastases can be surgically resected with good outcome.4,27
In addition to the common cystic neoplasms discussed above, it should be noted that usually solid neoplasms, such as well-differentiated pancreatic endocrine neoplasms, can undergo cystic degeneration and present as a cystic mass. In addition, not all cystic lesions in the pancreas are neoplasms. Pseudocysts, paraduodenal wall cysts (‘groove pancreatitis’) and retention cysts all need to be considered in the differential diagnosis of a cyst in or adjacent to the pancreas.3
Cystic lesions of the pancreas are becoming more and more important. As the resolution of abdominal imaging improves, we are finding that as many as 3% of the population has a pancreatic cyst.1,2 Some of these cysts will be precursors to invasive pancreatic cancer, and these represent an opportunity to cure pancreatic neoplasia. On the other hand, many will be harmless non-neoplastic cysts, and many will be such early neoplasms that surgical intervention is not justified. The challenge of the coming decade will be to develop new techniques that can be used to distinguish between the many cysts that can involve the pancreas.
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Ralph H. Hruban, Department of Pathology and Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.
Noriyoshi Fukushima, Department of Pathology, The University of Tokyo, Tokyo, Japan.