Pancreatic Cystic Neoplasms: Diagnosis and Management

Pancreatic cystic lesions are being detected with increasing frequency, at least partly because of the increased use of cross-sectional imaging for the evaluation of abdominal complaints or screening for other conditions. Image-based studies report prevalences of pancreatic cystic lesions ranging from 1.2% to 19.6%. In a study of 1064 pancreatic cystic neoplasm (PCN) patients pathologically confirmed over a 12.5-year period, 108 (10.5%) of the patients had pancreatic lesions that were detected while undergoing workup for other diseases.

PCNs are reported to account for up to 60% of all pancreatic cystic lesions, followed by injury-related and inflammation-related cysts (30%). PCNs include intraductal papillary mucinous neoplasm (IPMN), mucinous cystic neoplasm (MCN), serous cystic neoplasm (SCN), solid-pseudopapillary neoplasm (SPN), cystic neuroendocrine neoplasm, ductal adenocarcinoma with cystic degeneration, and acinar-cell cystic neoplasm. The proportion of PCNs varies with population. In the Western Hemisphere, SCNs account for 32% to 39%, MCNs for 10% to 45%, IPMNs for 21% to 33%, and SPNs for less than 10% of all PCNs. A nationwide survey from Korea reports the proportions of PCN which are composed of IPMNs (41.0%), MCNs (25.2%), SPNs (18.3%), SCNs (15.2%), and others (0.3%).

The Major Pancreatic Cystic Neoplasms

The 4 major types of PCNs are IPMN, MCN, SCN, and SPN. Distinguishing among the 4 most common types of cysts is important, since the management varies with each type of cyst.

Intraductal Papillary Mucinous Neoplasms

IPMNs are defined as intraductal grossly visible (typically ≥1.0 cm) epithelial neoplasms of mucin-producing cells, arising in the main pancreatic duct or its branches. The first report was 4 cases with the triad of mucus secretion, main pancreatic duct dilatation, and a swollen duodenal papilla. Since then, the number of IPMN cases reported has been increasing significantly. This may be due to a true increase in the incidence, improvement in the understanding of IPMN, and/or increased use of cross-sectional imaging in clinical practice.

IPMNs are usually diagnosed in the elderly, often diagnosed in the seventh decade of life. There is a slight male preponderance. Although the true incidence of IPMN is unknown, IPMNs are reported to be the most common PCN. IPMN accounts for approximately 1% to 3% of pancreatic exocrine neoplasms and 20% to 50% of all PCNs. Most patients diagnosed with IPMN are asymptomatic and are usually incidentally diagnosed. Symptomatic patients present with abdominal pain, pancreatitis, weight loss, diabetes mellitus, and jaundice.

The World Health Organization (WHO) classification of tumors of the pancreas, including IPMN, was modified in 2010. In the 2000 WHO classification, IPMNs were separated according to the degree of dysplasia into intraductal papillary mucinous adenoma; intraductal papillary mucinous neoplasm with moderate dysplasia; intraductal papillary mucinous carcinoma, noninvasive; and intraductal papillary mucinous carcinoma, invasive. In the 2010 WHO classification, IPMNs were classified into IPMN with low- or intermediate-grade dysplasia (which includes the former intraductal papillary mucinous adenoma and intraductal papillary mucinous neoplasm with moderate dysplasia), IPMN with high-grade dysplasia (which is equivalent to the intraductal papillary mucinous carcinoma, noninvasive), and IPMN with an associated invasive carcinoma (changed from intraductal papillary mucinous carcinoma, invasive).

Macroscopically, depending on the pancreatic ductal system involved, IPMNs are classified as either main-duct IPMN (MD-IPMN), branch-duct (BD-IPMN), or combined-type IPMN. The clinicopathologic behavior of combined-type IPMN is similar to that of MD-IPMN. Intraductal proliferation of columnar mucin-producing cells is the main histologic characteristics of IPMN. The neoplastic epithelium may show diverse architecture and cytology. Four subtypes of IPMNs have been characterized: gastric, intestinal, pancreatobiliary, and oncocytic. In a recent report, the 4 subtypes of IPMNs were associated with significant differences in survival. Patients with gastric-type IPMN had the best prognosis, whereas those with pancreatobiliary type had the worst prognosis.

Most IPMNs are diagnosed incidentally. Even symptomatic patients present with nonspecific symptoms such as abdominal pain, malaise, nausea/vomiting, and weight loss. In patients with an associated invasive carcinoma, symptoms and signs of pancreatic ductal adenocarcinoma such as weight loss, diabetes mellitus, and/or painless jaundice may be observed.

Routine blood tests, such as complete blood count, liver function test, amylase, and lipase, are usually within normal limits or show nonspecific changes. Serum CA 19-9 and carcinoembryonic antigen (CEA) are generally not of diagnostic value. However, there is a report that serum CA 19-9 was elevated in 74% of patients with invasive IPMN and in 14% of patients with noninvasive IPMN. Furthermore, it is reported that 80% of patients with invasive IPMN had elevated serum levels of CA 19-9 and/or CEA, compared with 18% of patients with noninvasive IPMN.

Endoscopic retrograde cholangiopancreatography (ERCP) was the standard diagnostic tool for IPMN in the past. In MD-IPMN, the hallmark finding is a diffusely dilated main pancreatic duct with filling defects correlating to mucinous filling or papillary tumors.

For BD-IPMN, the affected branch ducts are cystically dilated and communicate with the main pancreatic duct. In some occasions, the cystic side branch ducts do not fill with contrast due to mucus plugging. In some cases, duodenoscopy during ERCP reveals a patulous duodenal papilla and mucin extrusion through the orifice.

The use of ERCP for the diagnosis of IPMN is limited by its invasiveness and risk of complications. In some cases, visualization of the entire pancreatic duct system is not possible because of copious amount of mucin. However, ERCP offers the advantages of cytologic sampling and intervention. In addition, it may serve as a platform for developing endoscopic technologies.

Endoscopic ultrasonography (EUS) is being increasingly used to differentiate the types of IPMNs ( Fig. 1 ). EUS demonstrates a detailed morphologic analysis of pancreatic cystic lesions, guides fine-needle aspiration (FNA), and provides fluid for subsequent cyst fluid analysis such as cytology, CEA, and DNA analysis. Furthermore, EUS may play a role in the treatment of IPMN, such as the intracystic injection of ethanol or ethanol/paclitaxel for cyst ablation. EUS findings associated with malignancy in IPMN patients include marked dilatation of the main pancreatic duct (≥10 mm) in MD-IPMN and large tumors (>40 mm) with irregular septa in BD-IPMN; mural nodule greater than 10 mm in height was associated with malignancy in both MD-IPMN and BD-IPMN. The drawbacks of EUS include operator dependence and the inability to differentiate between malignancy and areas of focal inflammation that infiltrate pancreatic parenchyma and mimic malignancy. Cyst fluid analysis often demonstrates a high concentration of CEA, reflecting the presence of a mucinous epithelium. A cut-off CEA level of 192 ng/mL has the sensitivity of 73%, specificity of 84%, and accuracy of 79% for differentiating mucinous from nonmucinous pancreatic cystic lesions. However, cyst fluid CEA differentiates neither malignant mucinous cysts from benign mucinous cysts nor malignant IPMNs from benign IPMNs. Cyst fluid cytology is rarely sufficiently diagnostic to distinguish IPMN from MCN; the result is a generic cytology report of a “mucinous cyst.” The reported sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of EUS-FNA for malignant IPMN were 75%, 91%, 79%, 89%, and 86%.

Computed tomography (CT) and magnetic resonance imaging (MRI)/magnetic resonance cholangiopancreatography (MRCP) are used to describe the anatomic location of the IPMNs, the relationship between the lesion with surrounding organs and vessels, and the presence of distant metastasis ( Fig. 2 ). MD-IPMNs show diffuse or focal involvement of the main pancreatic duct. BD-IPMNs appear as either a cyst or a cluster of cysts, usually located in the head, particularly in the uncinate process. BD-IPMNs may be multifocal. In a report of 145 resected cases of BD-IPMN, multifocality was observed in 14.5% of patients. In another report of 190 patients with radiologically and/or histologically diagnosed BD-IPMN, 27.4% of the patients had multifocal disease. MRCP has been reported to be superior to CT in detecting ductal communication in BD-IPMN. However, with advances in multidetector CT, imaging details of CT including visualization of ductal communication have improved similar to those of MRI/MRCP.