Director of Endoscopic Ultrasound
Division of Gastroenterology and Hepatology
University of Virginia Medical Center
Charlottesville, Virginia
Section of Digestive Diseases and Nutrition
Department of Medicine
University of Oklahoma
Oklahoma City, Oklahoma
Pancreatic cysts are a biologically diverse group of lesions that have varying degrees of malignant potential. Due to the widespread use of cross-sectional imaging, these lesions are increasingly being detected incidentally.
Despite our growing armamentarium of tests, there is no perfect test for quantifying the malignant potential of pancreatic cysts. This creates challenges for clinicians and patients alike and underscores the importance of a multidisciplinary approach to pancreatic cysts.
It is estimated that pancreatic cysts are identified in approximately 3% of patients who undergo CT and up to 13.5% in older patients undergoing MRI.1,2 The management of pancreatic cysts requires accurate risk stratification for malignant potential based on the presence or absence of symptoms and high-risk features on imaging. This process of risk stratification often begins with a careful review of cross-sectional imaging and occasionally requires the use of additional testing, such as endoscopic ultrasound (EUS), with or without fine needle aspiration (FNA) for fluid analysis and/or cytology.
Classifying Pancreatic Cysts
Multiple classification schemes have been proposed to describe pancreatic cysts. Perhaps the most clinically relevant classification involves grouping cysts based on their malignant potential (Table 1). This classification creates 2 groups of cysts: inflammatory fluid collections and pancreatic cystic neoplasms (PCNs).
Determining whether a PCN is serous/nonmucinous or mucinous usually is the first step in risk stratification because mucinous cysts are considered premalignant. Mucinous cysts are lined by a columnar epithelium capable of producing mucus.4 When aspirated, these lesions will have viscous contents with a positive “string sign” (Figure 1), which has a specificity of 95%.5 In addition, fluid carcinoembryonic antigen (CEA) levels can be helpful in distinguishing mucinous and nonmucinous PCNs. CEA is secreted from columnar epithelial cells that are derived from the endoderm and line mucinous PCNs.6 The Cooperative Pancreatic Cyst study revealed that a CEA level cutoff of 192 ng/mL was the most accurate in differentiating mucinous from nonmucinous cysts.7 Therefore, the majority of guidelines use a cyst fluid CEA level of 192 ng/mL as a cutoff value, above which CEA is considered elevated, indicating the PCN is a mucinous lesion. Finally, an elevated pancreatic cyst fluid amylase level indicates a connection with the pancreatic duct and typically is noted in IPMNs and pseudocysts.
Pancreatic inflammatory fluid collections are not lined by an epithelium and are a result of local complications of acute pancreatitis. These are classified according to revised Atlanta classification and include acute peripancreatic fluid collections (APFCs), pancreatic pseudocysts, acute necrotic collections, and walled-off pancreatic necrosis.3 APFCs occur within 4 weeks of the onset of acute interstitial pancreatitis and do not have a definable wall. Pseudocysts are mature fluid collections that occur 4 weeks after the onset of interstitial pancreatitis and can be challenging to distinguish from PCNs.
PCNs, according to the World Health Organization histologic classification, are divided into 2 categories: serous (nonmucinous) and mucinous. Serous cystadenomas (SCAs) are the most common serous PCNs. These are benign cysts lined by glycogen-rich cuboidal cells that originate from pancreatic acinar cells. Other serous PCNs include solid serous adenoma, von Hippel-Lindau (VHL) syndrome–associated serous cystic neoplasm, and mixed serous-neuroendocrine neoplasm. Mucinous PCNs include mucinous cystic neoplasms (MCNs), intraductal papillary mucinous neoplasms (IPMNs), and solid pseudopapillary neoplasms (SPNs).
Case 1
A 38-year-old woman with a history of alcohol-related pancreatitis presents with postprandial abdominal pain, early satiety, and emesis. A CT scan revealed a 65- × 65-mm unilocular cystic structure at the level of the pancreatic head (Figure 2A). EUS confirmed a unilocular cyst at the pancreatic head (Figure 2B). The cyst had a mature wall and no internal debris or mass. There was clear communication with the pancreatic duct. FNA revealed thin brown fluid with an amylase level greater than 15,000 U/L and a CEA level less than 5 ng/mL. Cystoduodenostomy was performed, with complete resolution of the patient’s symptoms.
Case 1 Answer: Pancreatic Pseudocyst
Pseudocysts occur in the setting of pancreatitis. Clues on history include a discrete episode of pancreatitis (acute epigastric pain associated with nausea and vomiting, lipase or amylase levels 3 times the upper limit of normal, and imaging evidence of pancreatitis) and risk factors of pancreatitis (heavy alcohol use, gallstones, hypertriglyceridemia). Pseudocysts occur more than 4 weeks after the onset of interstitial pancreatitis. On imaging, they appear as an encapsulated unilocular collection of fluid with a well-defined inflammatory wall usually outside the pancreas, with minimal or no necrosis. Communication with the pancreatic duct usually is demonstrated. Although pseudocysts have no malignant potential, pancreatic cancer sometimes can present as acute pancreatitis, and a pseudocyst may develop in that setting. Therefore, EUS is recommended for patients over 40 years of age with acute pancreatitis without a clear cause.8 In cases of diagnostic uncertainty, EUS-FNA is useful. Fluid from pseudocysts is dark yellow or brown and has an elevated amylase level (>250 U/L) and a low CEA level (<5 ng/mL). Pseudocysts do not require surveillance but require drainage if they are symptomatic.
Case 2
A 74-year-old woman underwent CT for intermittent right upper quadrant discomfort. This revealed a 21- × 16- × 21-mm round cystic density in the body of the pancreas (Figure 3A). EUS revealed a 17- × 17-mm cystic lesion in the pancreatic body, which appeared microcystic in a honeycomb pattern (Figure 3B). FNA revealed rare clusters of bland epithelium. No mucin was seen.
Case 2 Answer: Serous Cystadenoma
SCAs have an exceedingly low (approximately 0.1%) likelihood of malignant transformation.9 These lesions are almost always asymptomatic and detected incidentally on imaging. They occur in the fifth to seventh decades of life and are more common in women. Rarely, larger SCAs can cause abdominal pain, pancreatitis, and bile duct and/or gastric outlet obstruction.10 On imaging, a classic SCA appears as a solitary, well-demarcated microcystic lesion with a honeycomb appearance. A central scar or “sunburst” calcified center is considered pathognomonic for SCA but is seen only in 20% to 30% of lesions. A macrocystic variant exists less commonly, and this can be difficult to distinguish from mucinous cystic lesions. Multifocal SCAs are associated with VHL syndrome and may include a neuroendocrine component. Pancreatic ductal communication is absent. SCAs usually can be diagnosed based on radiographic findings; however, EUS occasionally is needed if there is diagnostic uncertainty. The cyst aspirate is thin or serous (nonmucinous) and typically shows a low level of CEA (<5 ng/mL).11
Case 3
A 38-year-old woman with intermittent left upper quadrant discomfort and 1 episode of idiopathic acute pancreatitis is referred for assessment. She underwent MRI, which revealed a unilocular cyst at the level of the pancreatic tail (Figure 4A). EUS revealed a unilocular 48-mm cyst with a thick wall and floating mucin ball (Figure 4B). There was no communication with the main pancreatic duct. FNA revealed clear mucinous cyst fluid. The CEA level was 355 ng/mL and the amylase level was 25 U/L. Cytology revealed cuboidal mucinous cells without dysplasia. Molecular testing revealed mutated KRAS and wild-type GNAS. The patient was referred for distal pancreatectomy. Pathology revealed an MCN with extensive enzymatic fat necrosis but without dysplasia.
Case 3 Answer: MCN
MCNs present almost exclusively in women between 40 and 60 years of age. Radiographically, they usually appear as a septated cystic lesion in the body or tail of the pancreas, although unilocular lesions also are possible. Communication with the main pancreatic duct is absent. Eccentric calcifications may be present in 15% of cases.12 Fluid aspiration reveals viscous or mucinous fluid with a high level of CEA (>192 ng/mL). The risk for invasive cancer in patients with MCNs depends on the presence of concerning features on preoperative imaging. These include large size (>5 cm), a thickened or irregular cyst wall, an internal nodule or mass, and the presence of a calcified cyst wall. In a meta-analysis, small (<4 cm) asymptomatic MCNs without worrisome features on imaging were found to have a small (approximately 0.03%) risk for harboring invasive cancer.13 The management of MCNs requires a multidisciplinary approach. Surgical resection should be considered in large MCNs with high-risk features on imaging. Surveillance may be appropriate for smaller lesions without high-risk features. If resection is offered and the lesion is completely resected on pathology, postoperative surveillance usually is not required.
Case 4
A 61-year-old man with a history of hypertension and dyslipidemia undergoes a CT scan for workup of suspected nephrolithiasis. An incidental multilocular cystic lesion is noted at the level of the pancreatic head (Figure 5A). There is a suspected mural nodule/mass within the cyst. The main pancreatic duct is dilated to 12 mm. EUS is performed and confirms a multilocular cystic lesion at the level of the pancreatic head. The lesion communicates with the dilated main pancreatic duct. There is a focal mural nodule measuring 6 mm (Figure 5B). EUS-guided microforceps biopsy of the mural nodule was performed, revealing superficial fragments of intestinal-type papillary neoplasia with at least high-grade dysplasia. The patient was referred for surgical resection.
Case 4 Answer: IPMNs
The most common pancreatic cysts, IPMNs occur in men and women equally, typically presenting in patients over 60 years of age. IPMNs may involve the main duct (MD-IPMN), the branch ducts (BD-IPMN), or both (mixed-type IPMNs). MD-IPMNs appear radiographically as a diffusely or partially dilated main pancreatic duct filled with mucin. They are found predominantly in the pancreatic head but can involve any part of the pancreas. BD-IPMNs are characterized by dilation of side branches of the pancreatic duct. They often are seen in the pancreatic head or uncinate process.14 Cyst aspirate reveals mucinous fluid, and the CEA level is typically elevated (>192 ng/mL).
The risk for malignancy associated with IPMNs depends on the type. MD-IPMNs and mixed-type IPMNs have a higher risk for malignancy compared with BD-IPMNs; the elevated risk was up to 60% in surgical series of resected lesions, but selection bias is a significant limitation of these data.15 The risk for malignant transformation of BD-IPMNs is much lower. In a study of 1,404 consecutive patients with BD-IPMNs, the overall incidence rate of pancreatic carcinoma 5, 10, and 15 years after IPMN diagnosis was 3.3%, 6.6%, and 15%, respectively.16 Prospective studies are needed to define the malignant risk of these lesions more accurately.
Available guidelines recommend some form of long-term surveillance of patients with IPMNs.8,15,17,18 There are differences in surveillance intervals between the various guidelines, but most guidelines suggest that small cysts (<3 cm) in asymptomatic patients without any suspicious features may be observed with serial imaging because the risk for malignancy is low. The surveillance interval is based on the size of the cyst and varies between guidelines but generally is every 2 years for cysts under 1 cm, every year for cysts between 1 and 2 cm, and every 6 months for cysts between 2 and 3 cm. Patients with worrisome features (Table 2) should be referred to a multidisciplinary group for further evaluation and consideration of surgical resection. If surgical resection is offered, surveillance is required after resection because additional IPMNs may develop.
Table 2. Alarm Features For IPMNs |
Clinical |
---|
|
Radiographic |
|
CA 19-9, cancer antigen 19-9; IPMN, intraductal papillary mucinous neoplasms |
Case 5
A 55-year-old man with a history of diabetes and hypertension undergoes CT after being involved in a motor vehicle collision. This reveals an incidental unilocular cyst in the body of the pancreas cyst, with a thick wall and internal septations measuring 17 mm (Figure 6A). EUS reveals a hypoechoic lesion with distinct borders (Figure 6B). Cytology reveals small blue cells on Diff-Quik stain (Figure 6C). Immunohistochemistry is positive for chromogranin, which confirms the diagnosis of pancreatic neuroendocrine tumor (PNET) (Figure 6D). The patient underwent distal pancreatectomy.

Case 5 Answer: PNET With Cystic Degeneration
PNETs are rare lesions, with an incidence of fewer than 1 case per 100,000 individuals per year.19 Most PNETs are sporadic, but they can be associated with hereditary endocrinopathies, including multiple endocrine neoplasia type 1, VHL syndrome, neurofibromatosis type 1, and tuberous sclerosis.
PNETs occasionally undergo cystic degeneration. They usually present as a unilocular cyst with a prominent wall that is hyperenhancing on contrast CT. Cyst aspirate usually reveals blood-tinged fluid and fluid CEA is low.
Surgical resection is offered for functional (hormone-secreting) PNETs and PNETs larger than 2 cm. PNETs smaller than 1 cm generally can be followed radiographically. There is debate in the literature about the optimal management of PNETs measuring between 1 and 2 cm, and multidisciplinary discussion is advised in these cases.
Case 6
A 31-year-old woman without a significant medical history is evaluated for worsening postprandial left upper quadrant pain associated with early satiety. Ultrasounds showed an ill-defined cyst in the pancreas body, and an MRI revealed a heterogeneous lesion measuring 70 mm in diameter arising from the body of the pancreas, with both cystic and solid components (Figure 7A). Microcalcifications were present. EUS revealed a mixed solid/cystic lesion (Figure 7B), and EUS-FNA revealed thin, bloody aspirate. Immunohistochemistry stains for vimentin, alpha1-antitrypsin, and beta-catenin were positive. The patient was referred for distal pancreatectomy, and the final pathology confirmed an SPN without dysplasia.
Case 6 Answer: SPN
SPNs occur almost exclusively in women and usually present in the second to third decade. Radiographically, they appear as a solitary lesion with cystic and solid components. They can be located anywhere in the pancreas. Occasionally, calcifications are present.
Historically, the majority of patients with SPNs were symptomatic. However, incidental detection of SPNs is becoming more common with widespread use of cross-sectional imaging and now accounts for up to 50% of cases. Reported symptoms, in order of increasing frequency, are abdominal pain, nausea/vomiting, and weight loss. Other symptoms that occur less frequently include bowel obstruction, anemia, jaundice due to bile duct obstruction, and pancreatitis. Patients also may have a palpable mass, which is the most common presentation in children.20
The risk for malignancy in SPNs in estimated to be around 15%, based on data from 2 surgical series.20,21 Tumor size of at least 5 cm was associated with an increased risk for high-grade malignancy.20 Given that these lesions occur in younger individuals and have a malignant potential, surgical resection generally is offered.
Emerging Technologies
In recent years, new markers from EUS-guided fluid samples from PCNs and new technical modalities of tissue acquisition and assessment have emerged that could improve our ability to accurately diagnosis PCNs and understand their risk for malignant transformation. However, these are not currently recommended by any of the guidelines, so we discuss them only briefly.
Next-generation sequencing of PCN fluid: Newer DNA-based molecular analysis using next-generation sequencing has allowed for the identification of specific markers for PCNs. The technology of next-generation sequencing allows for parallel sequencing of millions or billions of DNA strands, which has enabled the rapid sequencing of entire genomes and exomes, including targeted sequencing studies. In a single-center prospective study, next-generation sequencing was used for to differentiate 102 surgically resected PCNs.22 The sensitivity and specificity of KRAS and/or GNAS mutations to differentiate mucinous from nonmucinous PCNs were 89% and 100%, respectively. Advanced neoplasia was identified by the additional mutation of TP53/PIK3CA/PTEN, with 79% sensitivity and 96% specificity.
Cyst fluid glucose level: Studies have shown pancreatic cyst fluid glucose levels to be lower in mucinous PCNs than in nonmucinous ones.23,24 A meta-analysis of 8 studies including 609 PCNs found that when comparing PCN fluid glucose with PCN fluid CEA, glucose had a higher sensitivity (91% vs 56%) and diagnostic accuracy (94% vs 85%) for detecting mucinous lesions, and there was no difference in specificity between the tests.25
Microbiopsy: Recently, a through-the-needle microforceps device (Moray micro forceps, US Endoscopy) was introduced for EUS-guided tissue sampling in PCNs. This single-use microforceps can be passed through the lumen of a standard 19-gauge EUS-FNA needle, allowing through-the-needle tissue biopsy for histologic sampling of PCNs. Use of microbiopsy forceps may increase the diagnosis yield, help differentiate nonmucinous from mucinous PCNs, and improve presurgical assessment of risk for malignancy.26-28
Needle-based confocal laser endomicroscopy: Needle-based confocal laser endomicroscopy (nCLE) enables the observation of the inner wall of the pancreatic cyst using EUS-FNA. A confocal laser endomicroscope is inserted through a 19-gauge EUS-guided needle. Intravenous injection of fluorescein is performed 30 seconds to 2 minutes before nCLE. A low-power laser scans and illuminates tissue within a pancreatic cyst in a single focal plane, allowing microscopic detail of the surface epithelium to be examined for characteristics distinguishing various pancreatic cyst types. The use of nCLE has been shown to increase accuracy of differentiation of PCNs.29
Conclusion
Although pancreatic cysts present a clinical challenge, familiarity with the different types of cysts and the ability to identify those with malignant potential are important. Pattern recognition taking into account demographics, imaging characteristics, and cyst content analysis is helpful. Although emerging technologies are promising to identify different cyst types, we are still far from having the perfect test.
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