C y s t i c Tum o r s o f t h e Pa ncre as: Imagin g and Management

Catherine E. Dewhurst, MB BCh, BAO, BMedSca, Koenraad J. Mortele, MDb,*

KEYWORDS
 Pancreas  Cystic lesions  Mucinous  MR imaging

Cystic tumors of the pancreas are a diverse group of lesions that vary from benign to premalignant to frankly malignant entities. There has been a 20-fold increase in the detection of cystic pancreatic lesions in the last 15 years, most notably by cross-sectional modalities such as computed tomography (CT) and magnetic resonance (MR) imaging.1 The true prevalence of pancreatic cystic lesions is unknown but has previously been reported to be in the range 2.4% to 16.0%, and they are detected more with increasing age.2,3 One study reported prevalence of incidental pancreatic cystic lesions on MR imaging to be in the order of 13.5% and showed

that the prevalence and cyst size also increased with age.4 These findings have been corroborated at autopsy with the prevalence of cystic lesions approaching 25%.5 Given that the prevalence of pancreatic cystic lesions is increasing because of increased detection by cross-sectional imaging, and that most cystic pancreatic lesions are neoplastic, accurate diagnosis via clinical information, radiological images, and endoscopic ultrasound (EUS) with cyst fluid analysis may play an important role.68 Most of these lesions, especially when large, have characteristic imaging features at radiology, and accurate differentiation between them is

Differential diagnosis of cystic pancreatic lesions Common Serous microcystic pancreatic adenoma Mucinous cystic tumor Intraductal papillary mucinous neoplasm (IPMN) Solid pseudopapillary tumor (SPT) Uncommon Cystic endocrine tumor Cystic metastases to the pancreas Cystic teratoma of the pancreas Pancreatic lymphangiomas/lymphoepithelial cyst of the pancreas

The authors have no conflicts of interest and nothing to disclose. a Division of Abdominal Imaging and MRI, Department of Radiology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02115, USA; b Abdominal Imaging and MRI, Division of Clinical MRI, Harvard Medical School, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Ansin 224, Boston, MA 02115, USA * Corresponding author. E-mail address: [email protected] Radiol Clin N Am 50 (2012) 467486 doi:10.1016/j.rcl.2012.03.001 0033-8389/12/$ see front matter 2012 Elsevier Inc. All rights reserved.

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Key Points: SEROUS MICROCYSTIC PANCREATIC ADENOMA  They are benign lesions and often discovered incidentally  80% are found in women, average age 60 years (grandmother lesion)  Increased incidence in von Hippel-Lindau disease  Solitary, large (>5 cm)  Well-circumscribed, but not encapsulated, lobulated lesion  Cysts more than 6 in number, measure less than 2 cm  Central stellate scar, calcifications centrally 30%

important to help guide future treatment and management.9,10 Nevertheless, smaller lesions may appear indeterminate and the management pathways of these may be confusing and variable. This article reviews the histopathologic features and common imaging findings for an array of cystic pancreatic neoplasms, including the common cystic tumors of the pancreas: serous microcystic adenoma, mucinous cystic tumor (MCT), IPMN, and SPT. Uncommon cystic tumors of the pancreas include cystic endocrine tumors, cystic metastases, cystic teratomas, and lymphangiomas. This article also provides comprehensive algorithms on how to manage the individual lesions, with recommendations on when to reimage patients.

COMMON CYSTIC TUMORS OF THE PANCREAS Serous Microcystic Adenoma

Serous microcystic adenoma is an uncommon tumor of the pancreas making up 1% to 2% of exocrine pancreatic tumors.11 Eighty percent of these occur in women more than 60 years old, hence the term grandmother lesion.12 Serous microcystic adenomas are benign and many are found incidentally. There is a slight predominance of occurrence in the pancreatic head, but they have been reported to occur throughout the pancreas. Atrophy of pancreatic tissue and dilatation of the pancreatic or biliary ductal systems proximal to the lesion are not commonly seen because of the tumors tendency to displace surrounding structures rather than invade them. The tumor tends not to cause many clinical symptoms, and so can become large before being detected. Mass effect, caused by larger tumors on surrounding structures, may lead to symptoms such as nausea or nonspecific abdominal discomfort.1113 Larger tumors (>4 cm) may grow fast (approximately 2 cm/y) and become symptomatic. Therefore, in some institutions, these larger lesions, albeit benign, are surgically removed. Hemorrhage has occasionally been reported either from the

tumor bleeding into itself or from the gastrointestinal system secondary to ulceration from stretching of the stomach or duodenum over the tumor.12 Whether this tumor occurs with an increased frequency in diabetics is still debated.11,12 There is also an increased incidence of serous microcystic adenoma in patients with von HippelLindau disease.12,14,15 Histopathologically, these lesions comprise multiple cysts (usually >6) measuring less than 2 cm and separated by thin septa lined by epithelial cells. The cysts are filled with serous fluid and the larger cysts are typically located peripherally, contributing to the lesions lobulated contour. Grossly, the tumor has been described as having the appearance of a cluster of grapes.1618 In 30% of cases, the cysts are arranged around a central fibrous scar in a sunburst pattern.19 These scars tend to have areas of coarse calcification in tumors that measure greater than 5 cm (Fig. 1).16

Fig. 1. Serous microcystic adenoma. Histopathologically, serous microcystic adenomas comprise multiple cysts (usually >6) measuring less than 2 cm , separated by thin septa lined by epithelial cells. The cysts are filled with serous fluid. Grossly, the tumor has been described as having the appearance of a cluster of grapes. In 30% of cases, the cysts are arranged around a central fibrous scar in a sunburst pattern.

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Ultrasound of a serous microcystic adenoma typically displays a well-circumscribed, lobulated lesion with decreased through-transmission. The fibrous portion of the lesion is hyperechoic, whereas the cystic portions are hypoechoic. In lesions in which the cysts are a few millimeters in size (microcysts), the tumor can have a solid appearance caused by innumerable interfaces. Areas of calcification appear hyperechoic with decreased through-transmission and posterior acoustic shadowing. On CT, serous microcystic adenomas most commonly have a lobular shape.1720 Because the tumor is primarily of water density on unenhanced CT scans, they appear hypodense. Calcifications, if present, are hyperdense and generally arranged in a stellate pattern centrally in the lesion (Fig. 2). After administration of iodinated contrast material, the fibrous portions of the lesion enhance. Serous microcystic adenomas are the only hypervascular cystic pancreatic tumors and, therefore, their enhancement pattern is an important distinguishing feature that differentiates them from other cystic neoplasms such as neuroendocrine tumors of the pancreas or hypervascular metastases. The characteristically described appearance, akin to a sponge or irregular honeycomb, is seen in only 20% of cases. Lesions with fewer fibrous septations may maintain fluid density, even after contrast administration. In lesions composed primarily of microscopic cysts, the lesions can have a solid appearance with more homogeneous enhancement after contrast administration.21 In these cases, as with all other cystic pancreatic neoplasms, MR imaging may be helpful to further characterize the lesion. On T2-weighted images, the cystic fluid-filled components are hyperintense relative to adjacent pancreatic parenchyma, and the fibrous components are hypointense. The cystic portions are classically hypointense on T1-weighted imaging, but may have areas of hyperintensity if there has been previous intracystic hemorrhage.22 The fibrous components are also hypointense on T1-weighted imaging. Any areas of calcification are hypointense on both T1-weighted and T2weighted imaging, if visible at all. After gadolinium infusion, enhancement of the fibrous septations may be seen on early and late phases of imaging, with persistent enhancement of the central scar on more delayed phases of imaging (Fig. 3). MR imaging has increased sensitivity in detecting fluid compared with CT because the fluid components of tumors composed primarily of microcysts may not be easily detected with CT. These lesions do not show significant restricted diffusion on diffusion-weighted imaging with T2 shine-through on the corresponding apparent diffusion coefficient (ADC) map.23 A small number of tumors have been described with similar histologic characteristics to serous microcystic adenoma, but with different gross appearances. These tumors all contain fewer than 6 cysts and the size of the cysts has usually been described as between 1 and 2 cm, but sometimes as large as 8 cm.18 The tumors lack a central scar, and the fibrous components may irregularly extend into the surrounding pancreatic parenchyma. Several names have been used to describe this variant: macrocystic serous cystadenoma, serous oligocystic adenoma, and ill-demarcated adenoma. Like their microcystic variant, they are benign, and do not necessitate surgical resection unless the size and/or location of the tumor causes symptoms, such as pain, pancreatitis, or jaundice (Fig. 4). Several small, retrospective reviews have attempted to define discriminating radiologic features of this lesion.17,19 A retrospective study containing 12 cases by Cohen-Scali and colleagues19 attained a specificity of 100% in differentiating the lesion from a mucinous cystic tumor by using a combination of any 3 of the following 4 findings on contrast-enhanced CT: location in the pancreatic head, wall thickness less than 2 mm, lobulated contour, and absence of wall enhancement. A retrospective study by Kim and colleagues17 containing 10 cases differentiated serous oligocystic adenoma from mucinous cystadenomas and intraductal papillary mucinous tumors using contrast-enhanced CT with a specificity of 90% if the lesion was either multicystic or

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Fig. 2. Serous microcystic adenoma. Axial, contrastenhanced, curved, reformatted CT image shows a lobulated, hypodense mass in the head of the pancreas composed of multiple small cysts with a central stellate scar containing calcifications and enhancement of the fibrous septations in a honeycomb pattern.

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Fig. 3. Serous microcystic adenoma. (A) Heavily T2-weighted image and (B) coronal two-dimensional (2D) magnetic resonance cholangiopancreatography (MRCP) image shows a lobulated cystic lesion in the body of the pancreas that is predominantly hyperintense to pancreatic parenchyma with associated thin, fibrous septations that are hypointense. After gadolinium administration (C), during the arterial phase of imaging, there is enhancement of the fibrous septations.

lobulated cystic with or without internal septations. However, although these studies found features that may help to differentiate these lesions, definite determination based on radiologic criteria alone cannot be made in all cases. Therefore, cyst fluid analysis is important in making distinctions for

this group of benign cystic lesions. For serous microcystic adenomas, cytology is positive in only 20% to 50% of cases for periodic acid-Schiff reaction, and cytokeratin AE1 and AE3. Hemosiderinladen macrophages are seen histologically in 43% of cases and therefore still do not provide

Fig. 4. Serous macrocystic (oligocystic) adenoma. (A) Curved reformatted CT image shows a lobulated lesion that is unilocular, measures greater than 2 cm, and shows no calcifications, mural nodules, or capsular enhancement. (B) Endoscopic retrograde cholangiopancreatography (ERCP) in the same patient shows external compression of the pancreatic duct by the cystic mass. The patient went to surgery and pathology revealed a serous macrocystic pancreatic adenoma.

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the high diagnostic accuracy necessary for diagnosis.24 The biochemical analysis of the fluid consists of a low amylase level (<250 IU/L), low carcinoembryonic antigen (CEA) (<5 ng/mL), and low carbohydrate antigen 19.9 (CA 19.9) (37 U/mL).25 important and differentiates this tumor from an IPMN, whose stromal elements are ductal in origin. The epithelial elements consist of tall columnar cells with abundant intracellular mucin. The cells can be arranged either in a single row or vertically, forming papillary or polypoid projections. Areas may have no columnar cells and only consist of atrophic epithelial cells. Importantly, the epithelium can have different configurations in different portions of the lesion, with portions of benignappearing epithelium being adjacent to areas of invasive carcinoma.32 This makes biopsy to determine benign versus invasive disease unreliable in virtually all cases. Coupled with the future potential for malignant conversion, all lesions are considered surgical. Ultrasound of a mucinous cystic tumor displays a well-circumscribed cystic mass in the pancreas. Depending on the size and composition, a lesion can have an irregular contour to the wall, septations, mural nodularity, and calcifications.33 However, because findings on ultrasound tend to overlap with those seen in other cystic tumors, further evaluation with either CT or MR imaging is necessary. On unenhanced CT studies, the cyst contents are of fluid density, and the lesions are usually well circumscribed with a smooth morphology. Curvilinear calcifications occur along the periphery of the lesion and are seen in 15% of cases.27,34 After administration of iodinated contrast material, enhancement of the fibrous cyst wall (capsule) along with enhancement of any septations or mural nodules can be depicted (Fig. 5).33 A retrospective study by Procacci and colleagues27 using both conventional and 2-phase helical CT scans in 52 patients with histologically proven mucinous cystic tumor found that, if a lesion contained wall or septal calcifications, septations, and a thick surrounding wall, the probability of malignancy was 94.5%. The probability of malignancy in lesions that

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Mucinous Cystic Tumor

Mucinous cystic tumors of the pancreas are rare, comprising approximately 2.5% of all exocrine pancreatic tumors.26 Lesions within this group include the benign mucinous cystadenoma (72%), borderline mucinous cystic tumor (10.5%), mucinous cystic tumor with carcinoma in situ (5.5%), and the most aggressive form, mucinous cystadenocarcinoma (12%).2730 It is not reassuring that mucinous cystadenomas occur more frequently than the other types because it has also been documented that any tumor within this group has the potential to transform into an invasive carcinoma.26 Therefore, all are considered surgical lesions.31 Mucinous cystic tumors occur 99.7% of the time in women.28,29 The mean age of occurrence is earlier than in serous adenomas, approximately age 50 years with a range from 20 to 82 years, and therefore the term mother lesion has been coined to describe them. There are only a few reported cases in men, with the mean age of presentation occurring significantly later in life, at approximately 70 years.26 The most common locations are the pancreatic body and tail. Mucinous cystic tumors are composed of a dominant cyst that is round or oval and is encapsulated. Series have differed in the average size of mucinous cystic tumors of the pancreas at diagnosis, with average sizes being quoted from 6 cm to 11 cm.31 Histologically, the stromal elements of the tumor are similar to ovarian stroma. This element is

Fig. 5. Mucinous cystic tumor. Axial unenhanced (A) and contrast-enhanced (B) CT images show a unilocular, wellcircumscribed, encapsulated cystic lesion in the tail of the pancreas. It has a smooth morphology.

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Key Points: MUCINOUS CYSTIC TUMOR  Premalignant or malignant lesions  Round or oval in shape  Nearly exclusively in middle-aged female patients (mother tumor)  Encapsulated  Rarely hemorrhage  Not communicating with the pancreatic duct  Predominant location in the body and tail of the pancreas  Contains ovarian stroma histologically

contained any 2 of the 3 features ranged from 56% to 73.8% depending on which 2 features were present. Overall, using these features to predict malignancy, readers ability to correctly characterize the lesions produced 81.3% sensitivity and 83.3% specificity, respectively. MR imaging shows a cystic lesion that is hyperintense to pancreatic parenchyma on T2-weighted imaging. The capsule is T2 hypointense. It may be hypointense, isointense, or slightly hyperintense to pancreas on fat-saturated T1-weighted imaging based on the proteinaceous content of the cyst. After gadolinium infusion, enhancement of the thick cyst wall is seen on more delayed phases of imaging because it is fibrous, with associated enhancing internal septations and areas of mural nodularity (Fig. 6).33 Atrophic changes in the gland with compensatory ductal dilatation, areas of decreased signal intensity on T1-weighted fat-saturated images, and heterogeneous and delayed enhancement after gadolinium administration may be seen in patients with concomitant obstructive pancreatitis. Calcifications, if visible, are hypointense on both T1-weighted and T2-weighted imaging. The use of diffusion-weighted imaging and corresponding ADC maps has been evaluated for assessment of the presence of mucin within these lesions. Mucin-producing tumors have a mean ADC value (b 5 1000) of 2.7 103

mm2/s versus pseudocyst of the pancreas and serous tumors having a mean ADC value of 3.2 103 mm2/s and 5.8 103 mm2/s, respectively. However, more recent studies have not been able to confirm these findings and the role of diffusion MR imaging in differentiating cystic pancreatic tumors based on ADC values remains controversial.3539 The prediction of malignancy with imaging and cyst fluid analysis now approaches a sensitivity of 57% to 94% and a specificity of 85% to 97%.40,41 Cytology is positive in 40% to 68% cases and mucinous cystic tumors stain positive for alcian blue and mucicarmine. Their fluid has a low amylase level (<250 I/L), high CEA (>800 ng/mL) and, when malignant, also a high CA 19.9 level.42,43

IPMN
IPMN are mucin-producing tumors arising from the epithelium of the pancreatic duct (main-duct type), its side branches (side-branch type), or both (combined type). They were first described as a distinct pancreatic neoplasm in 1982.36 Since that time, IPMN has been diagnosed with increasing frequency with the advent of high-resolution cross-sectional imaging techniques and thus has become a more recognized pathologic entity.

Key Points: IPMN  Composed morphologically of main-duct IPMN, side-branch IPMN, or combined-type IPMN  May be slow growing or aggressive  70% occur in men with an average age of 65 years (grandfather lesion)  Pleomorphic in contour  Only cystic lesion clearly communicating with the ducts  Spectrum from benign adenomas to frankly malignant carcinomas  Concern for malignancy if main duct diameter is >1 cm or if a side-branch lesion is >3 cm

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Fig. 6. Mucinous cystic tumor. Heavily T2-weighted image (A) shows a hyperintense cyst in the tail of the pancreas with a few internal septations. After gadolinium administration (B), there is enhancement of the fibrous wall with regions of internal septal enhancement and mural nodularity. Gross pathology specimen (C) assessment following distal pancreatectomy shows a mucinous cystadenocarcinoma.

In 1996, the lesion received formal recognition by the World Health Organization (WHO) as an intraductal papillary mucin-producing neoplasm, arising in the main pancreatic duct or its major branches.44 IPMNs have been noted to be variable in aggressiveness, from slow-growing, local lesions to invasive and metastatic tumors. This finding led to further categorization by the WHO in 2000; from least to most aggressive, the lesions are referred to as IPMN adenoma (mild dysplasia), IPMN borderline lesion (when moderate dysplasia is present), and intraductal papillary mucinous carcinoma.45 Carcinomas are further categorized into carcinoma in situ (high-grade dysplasia) and invasive carcinoma.46,47 IPMN typically presents in men (70%) and in the older age group, with a mean age of 65 years.45,47 Therefore, it has been called the grandfather lesion. Histologically, the tumor is characterized as intraductal with growth of mucin-producing columnar cells with differing degrees of atypia, supported by pancreatic parenchyma with fibroatrophic changes, and lack of the ovarianlike stroma typical of mucinous cystic tumors. Lesions are graded by the greatest degree of atypia present in the sample (Fig. 7).48

Imaging diagnosis of an IPMN is most dependent on identifying the relationship of the lesion to the pancreatic duct, especially in the case of side-branch lesions. These lesions distend the affected side branch with mucin, giving the

Fig. 7. IPMN. Histologically, the tumor is characterized as intraductal with growth of mucin-producing columnar cells with differing degrees of atypia (moderate dysplasia in this case), supported by pancreatic parenchyma with fibroatrophic changes, and lack of the ovarianlike stroma typical of mucinous cystic tumors. Lesions are graded by the greatest degree of atypia present in the sample.

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appearance of a pleomorphic cystic mass in the pancreas that communicates with the main pancreatic duct. Identifying this communication is important, because other neoplastic cystic lesions such as mucinous cystic tumors, serous microcystic adenomas, and SPT generally do not communicate with the pancreatic duct.15,4952 Ultrasound of IPMNs generally displays pancreatic duct dilatation in the case of a mainduct IPMN, or a well-circumscribed pleomorphic cystic mass in the pancreas in the case of a side-branch IPMN. Ultrasound does not generally show the communication with the main-duct of side-branch lesions. Depending on the size and composition of the lesion, other findings such as mural nodules, mucin globules, or septations may be visualized. However, ultrasound findings tend to be nonspecific and these lesions typically require imaging with other modalities for further evaluation. On CT, a side-branch IPMN appears most commonly as a hypodense, pleomorphic lesion in close proximity to the pancreatic duct.53 The classic location is in the uncinate process. The main pancreatic duct is usually not dilated. The communication between the lesion and the duct is best shown using curved planar reformatted images, and usually is not seen on axial imaging alone. The main pancreatic duct lesions are typified by diffuse or segmental dilatation of the duct (Figs. 8 and 9). A discrete lesion may or may not be visualized. Enhancement is generally only appreciated in lesions containing nodular foci. Assessing for enhancement is best performed by comparing the Hounsfield unit (HU) densities of the lesion before and after iodinated contrast administration to differentiate mucin globules, which are nonenhancing, from solid tumor, which enhances. Magnetic resonance cholangiopancreatography (MRCP) has the ability to provide noninvasive, multiplanar imaging of the pancreatic ductal system, and has similar accuracy to endoscopic retrograde cholangiopancreatography (ERCP) in identifying cystic lesions.54 Arakawa and colleagues53 also showed that findings made on MRCP correlate with findings at histopathology. The main pancreatic duct lesions are typified by dilatation of the entire duct (see Fig. 8). A discrete lesion may or may not be visualized in these patients. Therefore, main-duct IPMN should be entertained in the differential of patients with

Fig. 8. IPMN. Contrast-enhanced CT image (A) shows pancreatic ductal dilatation in the region of the body and tail of the pancreas with intraductal soft tissue nodules. MRCP image (B) confirms segmental dilatation of pancreatic duct. Distal pancreatectomy (C) shows invasive carcinoma arising in combined-duct IPMN.

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Fig. 9. IPMN. (A) Coronal reformatted CT image shows a small pleomorphic cystic lesion in the body of the pancreas, clearly communicating with the main pancreatic duct. MRCP image (B) confirms the communication (arrow), confirming the diagnosis of side-branch IPMN.

a dilated pancreatic duct without a visible obstructing lesion or stenosis, along with ampullary dysfunction. In these cases, an MRCP with secretin injection or ERCP may be helpful for further assessment. Side-branch lesions are pleomorphic and are hyperintense to pancreatic parenchyma on T2weighted imaging and hypointense on T1weighted imaging. The lesion is either in close proximity to, or in direct communication with, the main duct (see Fig. 9; Fig. 10). The relationship of the lesion and the main pancreatic duct is generally best shown on MRCP imaging. Combined-type lesions show dilatation of both the main duct and side branches. Enhancement of nodular components or areas of wall thickening (if present) are appreciated after gadolinium infusion (Fig. 11).

As discussed earlier, the histologic appearances of IPMNs range from adenomas (benign) to carcinomas (malignant), with carcinomas being further subdivided into in situ and invasive lesions. The ability to reliably diagnose malignant lesions is beneficial for presurgical planning and for predicting the prognosis of patients. Several studies in the radiologic literature have thus attempted to clarify specific CT and MR imaging features that would help differentiate invasive lesions from noninvasive ones. The risk of malignancy in main-duct IPMN is 63% at 5 years and, with isolated side-branch lesions, is 15% at 5 years. Risk factors for malignancy depicted on imaging include main duct width greater than 10 mm, increasing size of side-branch lesions, side-branch lesions larger than 3 cm, presence of calcifications, common

Fig. 10. Side-branch IPMN. MRCP image shows a pleomorphic lesion in the uncinate process of the pancreas, which is a classic location for a side-branch lesion. It is hyperintense relative to pancreatic parenchyma on T2weighted imaging (A) and, on the coronal 2D slab MRCP sequence (B), communication is seen between the side-branch lesion and the duct of Wirsung. Note presence of pancreas divisum.

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Fig. 11. IPMN. MRCP image (A) shows diffuse dilatation of the main pancreatic duct throughout the pancreas, greater in the head and neck compared with the body and tail of the pancreas, with associated side-branch dilatation. Fat-suppressed T1-weighted image following gadolinium administration (B) shows enhancement of a mural nodule in the duct in the pancreatic head. Postsurgical diagnosis was invasive carcinoma in combinedduct IPMN.

bile duct dilatation, thick septations, and/or mural nodules.48,53,5557 At this time, radiologic studies have not led to clearly defined criteria that reliably establish the presence of malignancy, and, even in areas of agreement between studies, differences in threshold values or the power of a finding to predict malignant disease is not well established. It is probably most helpful to have an awareness of findings that have been described in malignant disease, but not to rely too heavily on any single, specific factor in predicting the malignancy of a lesion. In general, main-duct lesions with a diameter greater than 1 cm are likely to be malignant, whereas most side-branch lesions less than 3 cm are likely benign. IPMN cyst fluid analysis is positive for acidSchiff reaction in 60% cases and for alcian blue and mucicarmine, just like mucinous cystic tumors. However, IPMNs have a high amylase level (>20,000 U/mL) because they communicate with the pancreatic duct, a high CEA level (>200 ng/mL), and a high CA 72.4 (>40 U/mL) when malignant.57 Treatment of IPMN, especially lesions involving the main pancreatic duct, is surgical resection. Preoperative imaging can both overestimate and underestimate the degree of involvement of the ductal system, and surgeons should be aware of this pitfall and be ready to modify the resection plan during surgery to ensure negative margins. In cases of invasive disease, regional lymph node dissection is also performed. The treatment of side-branch lesions without malignant features is controversial, especially asymptomatic lesions in the elderly or infirm, with increasing numbers of patients undergoing serial imaging without surgical intervention in the event of stable imaging

findings, especially if the lesion is less than 3 cm in size.

SPT
SPT, formerly known as solid and papillary epithelial neoplasm (SPEN), is a rare pancreatic tumor with less than 1000 cases described in the literature.58 SPT occurs almost exclusively in women (85%), with most being found in younger women (mean age 25 years; age range 867 years).59 Thus, the term daughter lesion has been coined to describe it among the cystic pancreatic tumors. Although some case series have reported that SPT is most commonly located in the tail of the pancreas and in patients of African and Asian descent,6062 other series have not confirmed these findings.63 The pathogenesis of SPT is uncertain, but abnormalities in primordial pancreatic stem cells have been implicated as the most likely source because of the lack of endocrine or exocrine differentiation of the tumor. SPT is usually a benign or a low-grade malignant tumor. The tumor is generally asymptomatic and, therefore, incidentally discovered in most cases. However, when it grows to a sufficient size, it may cause symptoms related to extrinsic compression on surrounding structures. It is usually solitary and large at presentation with an average size of 9.3 cm.64 SPT tends to displace surrounding vessels and organs rather than invade them, and only rarely has encasement of vessels and involvement of the mesentery been described.63 Rarely, dissemination has been described and, if present, is most commonly to the liver. Fifteen percent of cases are diagnosed as solid pseudopapillary carcinoma. These tumors are usually larger than

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Key Points: SPT  85% are seen in women; age at diagnosis approximately 25 years; termed the daughter lesion  Solitary large lesion, approx 9.3 cm at diagnosis  No race or location predilection  Well demarcated on imaging and has a capsule  Predominantly solid and cystic components but this is variable depending on the lesion  May have internal hemorrhage  Calcification seen in 30% of lesions

5 cm , are more commonly seen in men, and are associated with vascular invasion and metastatic disease. However if diagnosed and resected they have a 5-year survival of 96%.64 Ultrasound is generally not helpful in differentiating an SPT from other types of cystic pancreatic lesions. In cases in which patients underwent sonography, the presence of a large, diffusely echogenic, or complex mass that is well circumscribed in the upper abdomen was described, with or without through-transmission depending on the composition of the tumor, but findings suggesting a definitive diagnosis were not generally made, and further imaging was usually required.61 Tumors imaged with CT are generally described as well-demarcated, encapsulated, large, cystic, and solid masses. In cystic and solid tumors, the solid tissue components are generally noted at the periphery, with central areas of hemorrhage and cystic degeneration noted more centrally.6466 After contrast administration, the capsule and solid components enhance (Fig. 12).66 Casadei

and colleagues58 reported 2 tumors with calcifications, 1 with central calcifications, and 1 with both central and marginal calcifications. MR imaging also typically shows a well-defined mass that commonly has a heterogeneous appearance on both T1-weighted and T2-weighted imaging.66 Areas of hemorrhage appear hyperintense relative to pancreatic parenchyma on T1-weighted imaging, and hypointense on T2weighted imaging (Fig. 13). After gadolinium infusion, peripheral mild enhancement is typically noted during the arterial phase with progressive enhancement of the solid portions during the portal venous and delayed phases. A key diagnostic finding of SPT is the presence of a fibrous capsule that encompasses and surrounds the tumor. In a review of 19 cases, Cantisani and colleagues62 found that 18 contained a capsule that was hypointense on T1-weighted and T2weighted imaging, with earlier and more intense enhancement than the rest of the tumor during the arterial phase, and progressive blending in with the rest of the enhancing components during later phases.

Fig. 12. SPT. Contrast-enhanced CT image (A) shows a well-demarcated, encapsulated, hypodense lesion in the head of the pancreas; the solid components peripherally enhance and the more central cystic components do not. T2-weighted MR imaging (B) confirms the cystic nature of the mass and better illustrates the T2hypointense capsule. (Courtesy of Dr Jeff Mottola and Dr Dejana Radulovic, Winnipeg, MB, Canada.)

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Fig. 13. SPT. (A) Fat-saturated, unenhanced, T1-weighted image of the pancreas shows increased signal intensity in an encapsulated, well-demarcated lesion in the head of the pancreas. The increased signal intensity is consistent with hemorrhage. (B) The lesion is predominantly cystic and of increased signal intensity relative to pancreatic parenchyma on T2-weighted imaging. More solid components are noted peripherally in the lesion. Note is also made of a hypointense rim corresponding with the capsule. (C) MRCP coronal 2D lesion showing that this lesion does not communicate with the main pancreatic duct and there is no evidence for ductal obstruction. (D) After gadolinium administration, there is intense progressive enhancement of the fibrous capsule and peripheral solid components of the lesion.

Treatment of SPT has generally been surgical resection but enucleation procedures have been described, made possible by the fibrous capsule encompassing the tumor. Overall, patients with this tumor have excellent survival rates, including the rarer solid pseudopapillary carcinoma (15%), which has a 5-year survival of 96%.

UNCOMMON CYSTIC PANCREATIC TUMORS Cystic Endocrine Tumors

Endocrine tumors of the pancreas originate from the islet cells of the pancreas. As a group, they are rare, occurring at a rate of 1 case per million people per year.67,68 They are divided into 2 main groups: syndromic (also termed hyperfunctioning) and nonsyndromic (also termed nonhyperfunctioning).69 The cystic endocrine lesions tend to be larger than the solid lesions (8.4 cm vs 2.9 cm, respectively).70 They tend to be nonsyndromic (64%) and, of those that were syndromic, most tended

to be of the noninsulin-producing varieties.70 Seventy-five percent of these occur sporadically in the population but the remainder (25%) are associated with multiple endocrine neoplasia (MEN) type 1. On ultrasound, the cystic or necrotic portion appears anechoic with posterior through-transmission.71 In cases of cystic degeneration, there is a well-circumscribed, uniform wall, whereas, in cases of necrosis, the wall tends to be less uniform and more irregular. There are no reported ultrasound features that help to discriminate a cystic or necrotic endocrine tumor from other cystic or necrotic tumors of the pancreas. On CT, the cystic or necrotic portion is hypodense and of fluid density. The peripheral rim of tissue typically enhances more than the pancreatic parenchyma during the arterial and venous phases, although smaller lesions may blend with the surrounding parenchyma on the venous phase.71 Again, in lesions with necrosis, the

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Key Points: CYSTIC ENDOCRINE TUMORS  Rare, seen in middle-aged adults, no gender predilection  Usually found in body and tail of pancreas  75% sporadic, 25% associated with MEN type 1  Most cystic endocrine tumors are nonhyperfunctioning  May be encapsulated  Solid components are hypervascular  Irregular solid wall, thick nodular septations  Round to oval shape, not lobulated

peripheral rim of tissue tends to appear less uniform and more irregular than in lesions in which there is cystic degeneration. On MR imaging, the peripheral rim of tissue has a similar signal intensity pattern to a solid endocrine tumor, classically described as moderately hyperintense to pancreatic parenchyma on fatsaturated T2-weighted images, and hypointense on fat-saturated T1-weighted imaging.7274 When a capsule is present, it may appear as a T2hypointense rim. Hypervascular enhancement is expected after gadolinium infusion, although this is not present in all cases (Fig. 14).69,72,73 Dynamic acquisition of multiple contrast-enhanced images at different time points is recommended, especially for cystic or necrotic endocrine tumors, because the classic enhancement pattern helps to differentiate these lesions from other cystic tumors of the pancreas.74

The exception to this is renal cell carcinoma, in which cases of solitary metastatic disease to the pancreas have been described.76 However, even in these cases, there should be a lesion in the kidney or evidence of a previous partial or total nephrectomy

Cystic Teratoma
Cystic teratoma of the pancreas is an extremely rare tumor with fewer than 20 cases being reported in the literature. Patients can be asymptomatic, with incidental discovery, to symptomatic, with detection during work-ups for vague abdominal pain. As with teratomas from other locations in the body, they can form many different tissue types including bone, cartilage, hair follicles, teeth, and sebaceous glands. They are thought to develop from epithelial inclusions, secondary to arrest in migration of pleuripotential stem cells in the process of migrating to the gonads during development, and subsequent incorporation into the tissues making up the pancreas.77 Because the tissues comprising teratomas can be of any of the 3 germinal layers, there are different subtypes. Teratomas can be divided into mature and immature, with the mature subtype being further subdivided into solid and cystic (dermoid cyst).78 Because there are so few cases described in the literature, the imaging findings of these tumors are discussed in this article as a group. Pancreatic cystic teratomas appear well defined on ultrasound,79,80 but have been described as

Cystic Metastatic Disease

Some metastases present as cystic pancreatic masses. Although metastases to the pancreas are most commonly seen with renal cell carcinoma and lung carcinoma, necrotic metastases occur most often in cases of aggressive tumors such as sarcomas, melanomas, or ovarian carcinomas.75 Metastatic disease to the pancreas occurs most often through a hematogenous route, and is generally found late in the disease process. Because of this, foci of disease in multiple organs are to be expected in patients with metastatic pancreatic lesions (Fig. 15).

Key Points: CYSTIC METASTATIC DISEASE  Generally seen in the setting of diffuse metastatic disease: renal, lung, bowel, breast, prostate cancer  Purely cystic lesions seen in cases of melanoma and sarcoma  Multifocal or solitary

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Fig. 14. Cystic pancreatic endocrine tumor. Contrast-enhanced CT image (A) shows a round lesion in the tail of the pancreas that shows necrosis centrally. The peripheral solid components are hypervascular. Axial T-weighted imaging of the upper abdomen (B) shows a lesion that is hyperintense to pancreatic parenchyma on T2weighted imaging and (C) shows peripheral irregular enhancement after gadolinium on the arterial phase of imaging.

Fig. 15. Axial contrast-enhanced CT of the pancreas shows a cystic mass lesion in the tail of the pancreas. The central necrotic component of the tumor does not enhance. It is a solitary lesion. Findings at pathology were consistent with metastasis from the patients soft tissue sarcoma.

both predominantly echogenic79 and hypoechogenic.80 This is likely because of the variable amount of fat and sebum that may be found in different types of lesions. Lesions containing bone or tooth elements also have areas of acoustic shadowing.79 On CT, teratomas have also been described as well defined.80 The lesions are variable in appearance: low attenuation, multilocular, and cystic,80 soft tissue with fat elements and peripheral calcification,79 or purely soft tissue.80 Heterogeneous enhancement after contrast has been reported.79 Several case reports noted that, although the mass abutted vascular structures or the biliary or pancreatic ducts, there was no evidence of invasion or obstruction of these structures.79,80 Strasser and colleagues77 described the appearance of teratomas on MR imaging as hyperintense to pancreatic parenchyma and well defined on T2weighted imaging, with areas of loss of signal

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intensity on fat-saturated sequences consistent with bulk fat. They can have heterogeneous signal intensity on T1-weighted precontrast imaging, and there is variable heterogeneous enhancement after administration of gadolinium. Seki and colleagues80 described the findings of 2 cases at MRCP. One appeared predominately as a soft tissue mass with a small cystic area within it, and the other was predominately cystic, with a nodular filling defect. No communication, involvement, or dilatation of the biliary or pancreatic ducts was appreciated.

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Lymphangioma
Lymphangiomas are benign tumors usually found in the soft tissues of the neck and axilla in the pediatric population. Less than 1% occurs in the abdomen.81,82 Lymphangiomas are congenital malformations of the lymphatic system, and are classified as capillary, cavernous, or cystic.83 A review of the literature by Igarashi and colleagues82 found that the cystic type is the most common (17 cases), followed by the cavernous type (15 cases), and the capillary type (13 cases). They also found that the lesions occur more often in women by almost a 2:1 ratio (29:16). Although they are found in all parts of the pancreas, they arise most commonly in the body and tail (30/45). There is no age predilection.83 Lymphangiomas can grow to be large, becoming 20 cm or larger.83 Patients may be asymptomatic, have nonspecific general symptoms, have a palpable mass, or present with acute symptoms secondary to hemorrhage, infection, torsion, or rupture.83 Definitive diagnosis requires surgical excision and pathologic examination.83 Although benign, lymphangiomas can be locally invasive, but complete surgical excision is usually curative.82,83 Ultrasound typically shows a hypoechoic or anechoic cystic or multicystic lesion in the region of the pancreas.82,83 Hyperechoic masses have also been reported.83 On CT, multiple well-circumscribed cystic masses are noted in, abutting, or attached via a pedicle to the pancreas; thin septations with a variable enhancement pattern are seen after iodinated contrast injection.83 The cystic components are most often of fluid density, but, in cases of previous hemorrhage, the density may be higher. Phlebolithlike calcifications can occur in the dilated lymphatic spaces (Fig. 16).83 MR imaging also displays a well-circumscribed lesion. Because the lesion is predominantly cystic, the cystic portion of the lesion is hyperintense on T2-weighted images and hypointense on T1weighted images. In cases of previous hemorrhage or infection, this is reflected in decreased T2

Fig. 16. Lymphangioma. There is a large cystic lesion attached to the pancreas. The most common subtype of lymphangioma is cystic malformation. They show variable enhancement after contrast administration and there may be thin septations within it.

signal, and, in the case of hemorrhage, increased T1 signal. The capsule is hypointense on T1weighted and T2-weighted imaging, and is thin. Enhancement may or may not be found after gadolinium infusion.

(Lympho)Epithelial Cyst
Nonneoplastic epithelial cysts are seen in the following syndromes: von Hippel-Lindau disease, cystic fibrosis, hepatorenal polycystic disease, Meckel-Gruber syndrome, Saldino-Noonan syndrome, Jeune and Ivermark syndrome.84 On imaging, they can be indistinguishable from other cystic lesions of the pancreas. On CT imaging, the lesion is hypodense and has no capsule. Because it is entirely cystic, it does not have central enhancement (Fig. 17). On MR imaging, the lesion can be isointense or hypointense relative to pancreatic parenchyma

Fig. 17. Epithelial, nonneoplastic cysts in von HippelLindau disease. Axial contrast-enhanced CT image shows multiple cystic lesions throughout the pancreas.

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on T1-weighted imaging and hyperintense on T2-wighted imaging. There may be a thin rim of enhancement after gadolinium. Lymphoepithelial cysts (LECs) are rare cystic lesions of the pancreas. They usually measure less than 5 cm and are usually seen in men.8588 evaluation (cytology, CEA, CA 19.9, presence of mucin, molecular analysis). Based on the presence of mucin, dysplasia, or cancer, the patient undergoes resection. Nonmucinous, nondysplastic lesions may be followed with short-term repeat imaging. For an asymptomatic lesion that measures less than 3 cm, observation is the recommended management. For a symptomatic lesion less than 3 cm, we recommend further evaluation with EUS and FNA to evaluate the presence of mucin, CEA, and Ca 19.9 levels, cytology, and molecular analysis. The patient can then be managed with resection or observation depending on the FNA results.

MANAGEMENT OF CYSTIC PANCREATIC LESIONS Facts

Of all focal cystic pancreatic lesions detected incidentally on imaging, almost 75% to 90% of these lesions are stable at long-term follow-up. Of those that do progress, the mean time interval for significant growth (>20%) is longer than 2 years. The size of the lesion at first diagnosis is an important factor in determining the probability of malignancy. If a lesion measures less than 3 cm, then the likelihood of malignancy is less than 3%. It has also been shown that symptomatic focal cystic pancreatic lesions are also more likely to be malignant than nonsymptomatic lesions.89 Therefore, we designed an in-house algorithm for the management of cystic pancreatic lesions based on size of the lesion and presence of patient symptoms (Fig. 18). Although we recognize that this algorithm requires prospective validation in patients with long-term follow-up, it has the significant advantage that patients at our institution are now undergoing an agreed-on and systematic management approach, independent of the radiologist who reads the study.90 In general, symptomatic lesions larger than 3 cm usually go straight for resection. An asymptomatic lesion larger than 3 cm could be further evaluated first with fine-needle aspiration (FNA) and cyst fluid

Follow-up Guidelines
Focal cystic pancreatic lesions can be followed up on imaging to ensure stability by identifying the size and other features that may be associated with malignancy (Table 1). The detection of increasing cyst size, size larger than 3 cm, suspicious features, or development of symptoms related to the lesion should prompt the reader to recognize these as risk factors for malignant change in the lesion. As to which imaging modality is the most beneficial in follow-up of lesions less than 3 cm, MR imaging and EUS seem to be the most sensitive and specific in characterizing these lesions.91 EUS is an invasive technique and is usually reserved for when FNA is being considered. MR imaging has an accuracy of 60% to 98% in classifying lesions and a sensitivity for detection of 94.4%. Macari and colleagues92 showed that use of gadolinium chelates has minimal impact in follow-up of focal cystic pancreatic lesions; therefore, an express cystic pancreatic

Fig. 18. Algorithm displays our standardized in-house approach to cystic pancreatic lesions. Follow-up guidelines are described in Table 1.

Cystic Tumors of the Pancreas REFERENCES

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Table 1 Follow-up guidelines for focal pancreatic cystic lesions measuring less than 3 cm Lesion Size <1 cm

Recommended Follow-up

Every 2 y (2) for a total of 4 y; if still stable then stop 12 cm Every year for 2 y (2), then once after 2 y; if still stable then stop >2 cm but Every 6 mo for 1 y (2), then every <3 cm year for 3 y (3); if still stable then stop

follow-up protocol without gadolinium may be used. CT is not generally used for follow-up because of radiation consideration. Ultrasound (US), although inexpensive, risk free, and widely available, is typically not used routinely for smaller lesions or lesions located more distally in the body or the tail of the pancreas because these regions become obscured by overlying bowel gas. Moreover, they may be difficult to visualize because of patient body habitus, and US is operator dependent. MR imaging has been shown to be the most consistent imaging modality for follow-up of these lesions.92 Table 1 lists guidelines that can be used for the follow-up of focal cystic pancreatic lesions, taking into account lesion size. When the lesions size or appearance changes, the lesion has to be recategorized within the provided algorithm. If patients are not surgical candidates (eg, because of advanced age or comorbidities), following their cystic pancreatic lesions has minimal benefits.

SUMMARY
Cystic tumors of the pancreas represent a diverse group of pancreatic lesions, many of which have specific imaging findings that allow them to be differentiated. Accurate assessment of these lesions with US, CT, or MR imaging is important both to help guide treatment and prevent unnecessary surgical interventions. An accurate preoperative diagnosis can routinely be achieved with a combination of imaging and EUS with or without FNA. Although exact guidelines for management and follow-up of incidental and symptomatic cystic lesions in the pancreas vary widely from institution to institution, by understanding the pathology and clinical course of these lesions, only lesions with true malignant potential should be resected owing to the considerable morbidity and mortality associated with pancreatic surgery.

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