Context.—

Pancreatic cystic lesions are increasingly diagnosed. Among other criteria, they are often distinguished in mucinous versus nonmucinous cysts. Mucinous pancreatic cystic lesions have received increasing attention, especially those known as precursors of pancreatic ductal adenocarcinoma. However, the group of nonmucinous cystic lesions of the pancreas includes numerous entities that may pose a diagnostic challenge. Their accurate diagnosis and classification are crucial for adequate patient management.

Objective.—

To review the spectrum of nonmucinous cystic lesions of the pancreas, taking into consideration their epidemiology and typical clinical context, their characteristic gross morphology and histomorphology, as well as their immunohistochemical and molecular profile.

Data Sources.—

Literature was searched and reviewed with MEDLINE via PubMed. Macroscopic and microscopic images were obtained from the archives of the Institute of Pathology, Heinrich Heine University and University Hospital of Duesseldorf, Germany.

Conclusions.—

Nonmucinous cysts of the pancreas comprise numerous, mostly rare entities displaying different biological behaviors. The most frequent are serous cystic neoplasms, solid-pseudopapillary neoplasms, cystic neuroendocrine tumors, and pancreatitis-associated pseudocysts. Accurate diagnosis can be achieved if characteristic clinical context, histomorphology, and immunoprofile are taken into account.

Cystic lesions of the pancreas represent a heterogeneous spectrum of entities. They are classified according to various criteria (eg, benign versus malignant, neoplastic versus nonneoplastic, or epithelial versus nonepithelial lesions), but one of the most common distinctions made is between mucinous and nonmucinous cysts.1 

Cystic neoplasms of the pancreas with mucinous differentiation, such as intraductal papillary-mucinous neoplasms (IPMNs) or mucinous cyst neoplasms (MCNs), are among the most frequent pancreatic cystic lesions in resection specimens24  and are well known owing to their role as precursor lesions of pancreatic ductal adenocarcinoma.5,6 

However, the role of nonmucinous pancreatic cystic lesions extends further than being merely rare differential diagnoses. Nonmucinous cysts of the pancreas include a broad spectrum of lesions, ranging from fully benign, nonneoplastic changes to malignant neoplasms (Table 1). Whereas some lesions do not need any treatment and may be left in place unless they cause discomfort or symptoms, others may need surveillance or even surgical resection. After surgical resection, the subsequent clinical management, as well as mode and interval of follow-up, requires accurate classification. A correct diagnosis of nonmucinous pancreatic cyst is therefore mandatory for optimal patient treatment.

Table 1

Overview of Nonmucinous Cystic Neoplasms of the Pancreas

Overview of Nonmucinous Cystic Neoplasms of the Pancreas
Overview of Nonmucinous Cystic Neoplasms of the Pancreas

In an older series of 418 cystic lesions of the pancreas, which included consultation cases, chronic pancreatitis-associated pseudocysts and retention cysts were the most common nonneoplastic entities, whereas IPMNs, MCNs, solid-pseudopapillary neoplasms (SPNs), cystic neuroendocrine tumors (cNETs), and cystic variants of ductal adenocarcinoma were the most common neoplastic lesions.7  However, a more recent surgical series demonstrated that a shift in the frequency of resected cystic lesions has occurred: benign lesions such as pseudocysts are significantly less frequently resected than in older times.4  Accordingly, in addition to IPMNs and MCNs, 3 nonmucinous cystic lesions belong to the most frequently resected cystic lesions of the pancreas. These are serous cystic neoplasms (SCNs), which make up about 16% of resected cystic tumors, SPNs, and cNETs, both representing about 5% of pancreatic cysts in resection specimens (Figure 1).24 

Figure 1

Overview of resected cystic lesions of the pancreas.24  While mucinous lesions (intraductal papillary mucinous neoplasms [IPMNs; approximately 45%] and mucinous cystic neoplasms [MCNs; approximately 16%]) make up most of the resected cystic pancreatic lesions, serous cystic neoplasms (SCNs; approximately 16%), cystic neuroendocrine tumors (cNETs; approximately 5%), and solid-pseudopapillary neoplasms (SPNs; approximately 3%) represent the most frequently resected nonmucinous lesions of the pancreas.

Figure 1

Overview of resected cystic lesions of the pancreas.24  While mucinous lesions (intraductal papillary mucinous neoplasms [IPMNs; approximately 45%] and mucinous cystic neoplasms [MCNs; approximately 16%]) make up most of the resected cystic pancreatic lesions, serous cystic neoplasms (SCNs; approximately 16%), cystic neuroendocrine tumors (cNETs; approximately 5%), and solid-pseudopapillary neoplasms (SPNs; approximately 3%) represent the most frequently resected nonmucinous lesions of the pancreas.

Close modal

Serous cystic neoplasms are more common in females than in males (female to male ratio: 3:1) and slightly more common in the pancreatic body and tail than in the pancreatic head (body/tail to head ratio: 1.6:1).8  The mean age at diagnosis is 58 years (range, 16–99 years).9  Serous cystic neoplasms range in size from 0.2 to 18 cm (mean size, 4.2 cm).8  Although many patients (approximately 40%) are asymptomatic, symptoms related to an abdominal mass, such as abdominal pain, nausea, and vomiting, may be present.8,10 

Three macroscopic subtypes of SCN have been described (Table 2). The most common subtype, the microcystic serous cystadenoma (45%–77%), usually presents as a well-circumscribed lesion with spongelike or honeycomb-like cut surface consisting of numerous small cysts with smooth inner surface; sometimes, a stellate central star is present (Figure 2, A),8,9  representing a characteristic aspect at imaging.11  The macrocystic (oligocystic) subtype (21%–32% of cases), also termed serous oligocystic and ill-demarcated adenoma,12  consists of fewer (1–10), larger cysts; is often less well demarcated; and usually lacks a central scar.8,9  The solid serous adenoma (2%–5% of cases) is the rarest macroscopic subtype of SCN.8,9 

Table 2

Overview of Serous Cystic Neoplasms of the Pancreas

Overview of Serous Cystic Neoplasms of the Pancreas
Overview of Serous Cystic Neoplasms of the Pancreas
Figure 2

Serous cystic neoplasm (SCN). A, Resection specimen of microcystic SCN of the pancreatic head shows a well-demarcated tumor with numerous small cysts on cut surface and a central white scar. B, At microscopy, simple cysts filled with serous fluid can be appreciated. C, Upon higher magnification, a 1-layered flattened to cuboidal epithelium lining the collagen-rich septa is visible. D, Epithelial cells of SCN are usually immunoreactive for MUC6. E, CD31 immunohistochemistry highlights the capillary network of SCN (hematoxylin-eosin, original magnifications ×25 [B] and ×50 [C]; original magnifications ×50 [D] and ×200 [E]).

Figure 2

Serous cystic neoplasm (SCN). A, Resection specimen of microcystic SCN of the pancreatic head shows a well-demarcated tumor with numerous small cysts on cut surface and a central white scar. B, At microscopy, simple cysts filled with serous fluid can be appreciated. C, Upon higher magnification, a 1-layered flattened to cuboidal epithelium lining the collagen-rich septa is visible. D, Epithelial cells of SCN are usually immunoreactive for MUC6. E, CD31 immunohistochemistry highlights the capillary network of SCN (hematoxylin-eosin, original magnifications ×25 [B] and ×50 [C]; original magnifications ×50 [D] and ×200 [E]).

Close modal

At microscopic examination, microcystic and macrocystic variants of SCN are characterized by thin fibrous septa usually lined by single-layered flat or cuboidal serous epithelia with glycogen-rich clear cytoplasm and round nuclei with dense homogeneous chromatin,8  although sometimes, small papillary projections can be seen (Figure 2, B and C). Recently, a case of SCN with focal complex papillary architecture causing the appearance of mural nodules at imaging and suggesting the presence of an associated neuroendocrine tumor (NET) was described.13  Owing to the high glycogen content, periodic acid–Schiff staining was positive in the cytoplasm of the tumor cells. Nuclear atypia was not encountered. Immunoreactivity of epithelial cells for MUC1, MUC6, α-inhibin, neuron-specific enolase, and cytokeratins (7, 8, 18, 19) can be demonstrated (Figure 2, D).14  Positivity for MUC1 and MUC6 suggests that SCN may arise from centroacinar cells.14  Serous cystic neoplasms possess a dense epithelial capillary network, which can be highlighted by immunohistochemistry using vascular markers like CD31 (Figure 2). This is related to the activation of the hypoxia-inducing factor α (HIFα)–dependent pathway in SCN with subsequent upregulation of its target genes, such as the vascular endothelial growth factor, due to the frequent mutation of the von Hippel–Lindau gene (VHL) observed in these neoplasms (see below).15 

Solid serous adenomas microscopically display numerous nests and/or back-to-back tubules with no or only exceedingly small lumina, while the cells otherwise share the characteristics of other SCN variants.8,9 

Serous cystic neoplasms belong to the spectrum of pancreatic lesions observed in patients affected by VHL syndrome, which is characterized by a frequent involvement of the pancreas in up to 87% of patients.16  Macroscopically and microscopically, VHL-associated SCNs share the same morphology as sporadic SCN cases, but they sometimes involve the whole pancreas in a patchy or diffuse pattern (in the latter case also called diffuse serous cystadenoma).17  In addition, they are sometimes associated with other lesions, such as NETs and simple cysts.18 

The preoperative diagnosis of SCN is challenging owing to the scarcity of tumor cells usually present in endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) material. In these cases, the immunohistochemical visualization of the above-described dense capillary network can be useful to reach diagnosis (Figure 2, E).15  The presence of alterations of the VHL gene both in sporadic and in VHL syndrome–associated SCN can be useful if molecular analysis of cyst fluid is performed.19,20  On the other hand, diagnosis of microcystic SCN in resection specimens is usually straightforward owing to the characteristic gross and microscopic morphology. The macro-oligocystic variant has no distinctive features at imaging and is therefore often misdiagnosed. For example, in the study of Reid et al,8  only 1 of 40 macrocystic SCNs was diagnosed correctly; most cases were interpreted as MCN or IPMN. After resection, diagnosis is usually easily made according to the abovementioned histologic and immunohistochemical features. Important histologic differential diagnoses of the rare solid serous adenoma include the so-called PEComa (perivascular epithelioid cell tumor), clear-cell neuroendocrine neoplasm, and metastases of clear-cell renal cancer. Immunohistochemistry is helpful in these cases for correct interpretation.

Serous cystic neoplasms are usually benign and, subsequently, prognosis is excellent. Malignant transformation of SCN (“serous cystadenocarcinoma”) has been reported but is exceedingly rare. Therefore, the World Health Organization (WHO) requires unequivocal distant metastasis (ie, to the liver) for this diagnosis.9,21  Interestingly, most reported cases of serous cystadenocarcinoma show bland cytologic features similar to those of serous cystadenoma. However, a case with distinct carcinomatous features (ie, signet-ring–like cells, solid areas) has been reported and termed carcinoma ex microcystic adenoma.22 

Solid-pseudopapillary neoplasms are rare tumors of the pancreas, which account for less than 3% of all pancreatic tumors and about 5% of all resected cystic pancreatic tumors.7  They typically occur in younger females (female to male ratio: approximately 9:1; mean age, 28 years).23  A slight preference for the pancreatic tail has been reported, but SPNs can be found in all parts of the pancreas.23  Solid-pseudopapillary neoplasms usually present as large, well-demarcated tumors (mean diameter, 5.9 cm; range, 1.4–20 cm).24  The most common symptom in patients with SPN is abdominal pain or discomfort, but more than one-third of all tumors are incidentally detected in asymptomatic patients.23 

On cut surface, SPNs appear heterogeneous, containing solid areas, areas of hemorrhage and necrosis, and pseudocystic spaces due to degenerative changes (Figure 3, A). Therefore, SPNs are not true cysts, and the extent of the cystic areas of the lesion varies among cases.

Figure 3

Solid-pseudopapillary neoplasm (SPN). A, Resection specimen of an SPN. Owing to hemorrhage, the cut surface appears red. In the center, pseudocystic degenerative changes are visible. B, Pseudocystic spaces of SPNs are filled with pseudopapillae lined by poorly cohesive monotonous cells. C, SPNs may also contain solid areas. Cytoplasmic hyaline globules may be appreciated (arrows). D, Cells of SPN show cytoplasmic and nuclear expression of β-catenin in immunohistochemical stain. E, CD10 is strongly expressed by SPN (hematoxylin-eosin, original magnification ×200 [B and C]; original magnification ×200 [D and E]).

Figure 3

Solid-pseudopapillary neoplasm (SPN). A, Resection specimen of an SPN. Owing to hemorrhage, the cut surface appears red. In the center, pseudocystic degenerative changes are visible. B, Pseudocystic spaces of SPNs are filled with pseudopapillae lined by poorly cohesive monotonous cells. C, SPNs may also contain solid areas. Cytoplasmic hyaline globules may be appreciated (arrows). D, Cells of SPN show cytoplasmic and nuclear expression of β-catenin in immunohistochemical stain. E, CD10 is strongly expressed by SPN (hematoxylin-eosin, original magnification ×200 [B and C]; original magnification ×200 [D and E]).

Close modal

Upon histopathologic evaluation, the solid areas of SPN consist of clusters of poorly cohesive monotonous cells, which may mimic neuroendocrine neoplasms or acinar cell carcinomas. The cell clusters or nests are separated by fibrovascular bands. Pseudocystic spaces contain the eponymous pseudopapillary projections (Figure 3, B). No mucin or glycogen can be found in the cytoplasm of SPNs, but hyaline globules may be appreciated, highlighted by periodic acid–Schiff staining after diastase digestion (Figure 3, C). Nuclei are usually round or oval and may be grooved. By immunohistochemistry, SPNs show distinct positivity for β-catenin both in the cytoplasm and the nucleus, as well as positivity for vimentin, CD10, cyclin D1, and progesterone receptor (Figure 3, D and E). They may display weak and focal expression of cytokeratins and synaptophysin expression, but are negative for chromogranin, an important feature in the distinction from NET. Newer immunohistochemical markers for SPN include LEF1 (lymphoid enhancer-binding factor 1), TFE3 (transcription factor E3), and CD200,2527  although only LEF1 can be used to distinguish them from NET.

On a molecular level, SPNs are characterized by somatic activating mutations of CTNNB1 in exon 3 (approximately 90% of cases),28,29  which can be used as a reliable marker if molecular cyst fluid analysis is performed in the preoperative setting. The mutation results in an abnormal accumulation of β-catenin in the nucleus and the subsequent activation of the Wnt/β-catenin signaling pathway. A “multi-omics” profiling study of SPNs confirmed that these neoplasms are driven by the abovementioned CTNNB1 hotspot mutation, resulting in increased expression of genes coding for proteins involved in the Wnt/β-catenin pathway.30 

The WHO has classified SPN as a tumor with low malignant potential.21  About 9% to 15% of SPNs show distant metastasis, especially in the liver, but also in the peritoneum or the lung.23  However, even in metastatic settings, SPNs have an excellent prognosis with a 5-year survival rate of up to 97%, provided that complete surgical resection is achieved.23  As metastases may occur late, a long follow-up period, at least longer than 5 years, after resection is necessary.31  Efforts have been made to identify factors indicative of poor prognosis and recurrence of SPN. So far, components of undifferentiated carcinoma in histology, unresectable tumors, and metastases within 36 months of the initial diagnosis have been suggested as negative prognostic factors.32,33  Some data suggest that SPNs in male patients may also harbor poorer prognosis than those in female patients,34  but this finding has not been confirmed by others.31  A newer study using whole-exome sequencing of matched SPNs and their metastases has revealed a possible role of epigenetic modulators such as KDM6A and BAP1 in metastatic disease.35 

Neuroendocrine tumors with cystic features (cNETs) comprise 6% to 27% of all NETs of the pancreas (13% in a recent meta-analysis).36,37  Approximately 90% of the tumors are sporadic, while 10% arise in the context of multiple endocrine neoplasia type 1 (MEN1).37  While most cNETs are nonfunctioning, insulinomas are the most frequent type among functioning cNETs.37 

Upon macroscopic evaluation, cNETs often present as unilocular cystic tumors filled with serous fluid, but multilocular lesions with hemorrhagic cyst content have also been described.38  Histologically, cNETs consist of monotonous eosinophilic cells with round nuclei, virtually only distinguishable from solid NETs of the pancreas by the presence of cystic areas (Figure 4, A through F). While they also generally share the same immunophenotype with their noncystic counterparts, cNETs frequently show glucagon expression, though this is not linked to glucagonoma syndrome.38  Cystic neuroendocrine tumors usually have a lower proliferative index (Ki-67) and histologic grade than non-cNETs. However, survival for patients with cNET of the pancreas seems rather similar to the survival of those with solid pancreatic NET.36,39  EUS-FNA diagnosis is simple in specimens of adequate cellularity, owing to the characteristic histologic appearance and the typical immune profile (Figure 4).

Figure 4

Cystic neuroendocrine tumor (cNET). A, Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) specimen of a cNET with high cellularity, containing clusters of monomorphic cells. B, Synaptophysin immunohistochemistry of the EUS-FNA specimen confirms the neuroendocrine nature of the lesion. C, Ki-67 staining of the EUS-FNA specimen reveals low proliferative index. D, Histopathology of a resection specimen of a cNET shows a cystic lesion with a fibrous capsule lined by trabeculae and nests of monomorphic cells with round monomorphic nuclei. E and F, Chromogranin A (E) and synaptophysin (F) immunohistochemical stains (hematoxylin-eosin, original magnifications ×200 [A] and ×100 [D]; original magnifications ×200 [B and C] and ×100 [E and F]).

Figure 4

Cystic neuroendocrine tumor (cNET). A, Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) specimen of a cNET with high cellularity, containing clusters of monomorphic cells. B, Synaptophysin immunohistochemistry of the EUS-FNA specimen confirms the neuroendocrine nature of the lesion. C, Ki-67 staining of the EUS-FNA specimen reveals low proliferative index. D, Histopathology of a resection specimen of a cNET shows a cystic lesion with a fibrous capsule lined by trabeculae and nests of monomorphic cells with round monomorphic nuclei. E and F, Chromogranin A (E) and synaptophysin (F) immunohistochemical stains (hematoxylin-eosin, original magnifications ×200 [A] and ×100 [D]; original magnifications ×200 [B and C] and ×100 [E and F]).

Close modal

There is a variety of other nonmucinous cystic lesions of the pancreas, many of which are nonneoplastic. They include inflammatory lesions, such as pancreatitis-associated pseudocysts and parasitic cysts; developmental and congenital lesions, such as foregut cysts, dermoid cysts, endometrial cysts, duodenal duplication cysts, and possibly, lymphoepithelial cysts and lesions at least partially resulting from obstruction, such as retention cysts and acinar cystic transformation. Another group consists of cystic variants of benign (eg, cystic schwannoma) or malignant tumors (eg, cystic acinar cell carcinoma, cystic sarcomas) as well as primarily cystic neoplasms, such as lymphangiomas. Finally, aside from the abovementioned simple cysts in patients with VHL syndrome, pancreatic cysts have also been described in the context of various other congenital conditions, for example, in patients with autosomal-dominant polycystic kidney disease.40  Most of these lesions are very rare, apart from pancreatitis-associated pseudocysts, which actually represent one of the most common cystic pancreatic lesions.41  In the following section, some of the abovementioned rare lesions will be described in detail.

Inflammatory Cysts

Pancreatitis-Associated Pseudocysts

Pancreatitis-associated pseudocysts are common complications of pancreatitis. While pseudocysts may also occur in the course of acute pancreatitis, the incidence of pseudocysts is especially high in cases of chronic pancreatitis (20%–40%), most commonly in the alcohol-induced or paraduodenal (“groove”) type.42  Pseudocysts are usually unilocular cavities filled with dark, cloudy fluid containing pancreatic enzymes and debris, lined by a wall of granulation tissue and ultimately thick fibrous tissue. The pseudocyst wall may contain macrophages and other inflammatory cells but lacks any epithelial lining. Pancreatic pseudocysts are thought to be the result of localized necrosis and autodigestion of pancreatic parenchyma, possibly due to leakage of pancreatic juice during the course of chronic pancreatitis.43 

Parasitic Cysts

Parasitic cysts of the pancreas are another rare example of inflammatory pancreatic cysts. They occur mostly in regions endemic for Echinococcus species. An infection with the helminth Echinococcus granulosus or Echinococcus multilocularis, for which humans are an accidental host, results in the formation of hydatid cysts. These cysts contain the worm's immature form (protoscolices) and are most commonly located in the liver or lung, but may also occur in other organs, such as the pancreas. Their reported incidence in the pancreas is 0.14% to 2%.44  Macroscopically, hydatid cysts are typically large unilocular cysts, but can also contain “daughter cysts.” Upon microscopy, the cyst wall consists of fibrous and hyaline laminated acellular material on the outer side and an inner germinative layer containing brood capsules with protoscolices (Figure 5, A and B). The surrounding parenchyma commonly shows chronic inflammatory and sometimes a granulomatous reaction with numerous eosinophils.

Figure 5

Other nonmucinous cystic lesions of the pancreas. A, Histomorphology of hydatid cyst with fibrous outer capsule and inner hyaline laminated cyst wall component. B, Periodic acid–Schiff staining highlights the laminated aspect of the inner cyst wall. Protoscolices are not visible in this histophotograph. C, Histomorphologic aspect of lymphoepithelial cyst of the pancreas. The cystic lesion is filled with keratinous material (right) and lined by stratified squamous epithelium without atypia, with underlying lymphatic parenchyma containing lymph follicles. On the left, adjacent normal pancreatic parenchyma can be seen. D, Acinar cell cystic transformation consisting of multiple cysts lined by flattened epithelium, embedded in fibrotic pancreas parenchyma. E and F, The epithelial cells of acinar cell cystic transformation stain positively for cytokeratin 7 (E) and trypsin (F) (hematoxylin-eosin, original magnifications ×50 [A and C] and ×100 [D]; original magnification ×100 [B, E, and F]).

Figure 5

Other nonmucinous cystic lesions of the pancreas. A, Histomorphology of hydatid cyst with fibrous outer capsule and inner hyaline laminated cyst wall component. B, Periodic acid–Schiff staining highlights the laminated aspect of the inner cyst wall. Protoscolices are not visible in this histophotograph. C, Histomorphologic aspect of lymphoepithelial cyst of the pancreas. The cystic lesion is filled with keratinous material (right) and lined by stratified squamous epithelium without atypia, with underlying lymphatic parenchyma containing lymph follicles. On the left, adjacent normal pancreatic parenchyma can be seen. D, Acinar cell cystic transformation consisting of multiple cysts lined by flattened epithelium, embedded in fibrotic pancreas parenchyma. E and F, The epithelial cells of acinar cell cystic transformation stain positively for cytokeratin 7 (E) and trypsin (F) (hematoxylin-eosin, original magnifications ×50 [A and C] and ×100 [D]; original magnification ×100 [B, E, and F]).

Close modal

Congenital and Developmental Cysts

Lymphoepithelial Cysts and Other Squamous Cysts

Lymphoepithelial cysts of the pancreas are very rare, and only about 100 cases have been reported so far.45  They typically occur in middle-aged males (median age at diagnosis, 55 years; range, 21–74 years; male to female ratio: approximately 4:1) and show a slight preference for the body and tail region of the pancreas.46,47  On gross examination, lymphoepithelial cysts present as pancreatic or often peripancreatic well-defined unilocular or multilocular cystic lesions with smooth glistening surface and may be filled with keratin.46  Their size ranges considerably (range, 1.5–16 cm; mean diameter, 4 cm).47  Upon histologic evaluation, pancreatic lymphoepithelial cysts are lined by mature stratified squamous epithelium without atypia. Underneath the epithelium, mature lymphoid tissue with lymph follicles containing organoid germinal centers can be found (Figure 5, C).46  Despite these distinct features on histology, the diagnosis of lymphoepithelial cysts of the pancreas may present a challenge in smaller biopsy samples or cytologic material. While the presence of squamous epithelium or keratin debris is common, EUS-FNA specimens may contain only limited lymphocytes, and contaminants, such as intestinal epithelia, may be present.48  In addition, the cyst fluid of lymphoepithelial cysts is often milky and may contain elevated carcinoembryonic antigen (CEA) levels, which can lead to misdiagnosis as mucinous cystic neoplasm.45,48 

The etiology and pathogenesis of pancreatic lymphoepithelial cysts are unclear and several theories exist, including development from ectopic epithelia in pancreatic lymph nodes, origin from dilated pancreatic ducts with squamous metaplasia surrounded by inflammatory lymphatic tissue and misplaced branchial clefts.46  So far, no case of malignant transformation of lymphoepithelial cysts of the pancreas has been described.

Cystic mature teratomas are differential diagnoses of lymphoepithelial cysts of the pancreas, although these are exceedingly rare and only about 30 cases have been described in the pancreas to date.49  In contrast to lymphoepithelial cysts, these lesions contain not only squamous, but also respiratory/mucinous epithelia as well as skin appendages and less prominent lymphoid tissue. Other differential diagnoses are squamoid cysts of pancreatic ducts. These cysts are lined by flat to stratified nonkeratinizing squamous epithelium and are suggested to be a type of metaplastic retention cyst owing to the presence of intraluminal acinar secretions. However, evidence of obstruction has not been found in the cases described in literature.50 

Foregut Cysts

Cysts derived from the foregut may rarely occur in the pancreas owing to abnormal sequestration of a foregut segment during embryogenesis.51  Only about 15 cases of pancreatic foregut cysts have been described so far.52  Foregut cysts are usually lined by cytologically bland cuboidal or columnar epithelium including ciliated cells and sometimes goblet cells, although variants with squamous epithelium or mixed epithelium exist as well.51,53,54  The cyst wall may contain respiratory glands, cartilage, and smooth muscle.51,53,54  By immunohistochemistry, the ciliated epithelia of foregut cysts are positive for cytokeratin 7, CEA, and CA 19-9.51,53,54  Malignant transformation of a ciliated foregut cyst is only described in a single case of a hepatic ciliated foregut cyst, but not in the pancreas.53 

Cysts Related to Obstruction

Retention Cysts

Retention cysts are usually single unilocular cysts lined by cytologically bland, 1-layered cuboidal epithelium lacking significant mucin, and are a result of pancreatic duct obstruction, for example, due to calculi or fibrosis in the context of chronic pancreatitis, but also due to obstructive neoplastic processes. Pancreatic intraepithelial neoplasias (PanINs) may develop in retention cysts, rendering them mucinous cysts.55 

Acinar Cell Cystic Transformation

Acinar cell cystic transformation of the pancreas is a lesion of currently uncertain etiology. While it has been referred to as acinar cell cystadenoma in the past, doubts have arisen considering its neoplastic nature, as 2 independent studies56,57  have found evidence of polyclonality. Therefore, the lesion has now been termed acinar cell cystic transformation and its pathogenesis is thought to include dilation due to obstructive changes, at least in some cases.21  Acinar cystic transformation shows a slight preference for female patients (female to male ratio: 2.3:1); the age at diagnosis ranges widely in studies (range, 16–66 years; mean age, approximately 50 years).58,59  Acinar cell cystic transformation is characterized by cystic transformation that can either include parts of the pancreas or the whole organ in a multifocal or diffuse pattern.21  It can therefore vary in size considerably and either result in unspecific abdominal symptoms, such as pain or discomfort, or be found incidentally in asymptomatic patients. Macroscopically, acinar cell cystic transformation appears as unilocular or multilocular cysts rarely connected to the pancreatic duct system, and usually with a thin, smooth cyst wall. Microscopically, cysts are lined by bland-appearing, flat, acinar, or ductal epithelium (Figure 5, D). Mucinous and/or squamous differentiation may be seen as well. Immunohistochemistry shows positivity of the lining epithelium for cytokeratins 7, 8, 18 and 19; MUC1; MUC6; and trypsin (Figure 5, E and F).59  Cases of malignancy in acinar cell cystic transformation have not been described.

Nonmucinous pancreatic cysts include numerous entities, ranging from fully benign lesions to aggressive neoplasms, therefore implicating profoundly different treatment approaches. However, they often have overlapping clinical and imaging features, a fact that renders preoperative diagnosis, apart from few exceptions, quite challenging. A correct postoperative histopathologic assessment is of utmost importance to predict prognosis and further tailor patients' management.

1.
Adsay
NV.
Cystic lesions of the pancreas
.
Mod Pathol
.
2007
;
20
(suppl 1)
:
S71
S93
.
2.
Valsangkar
NP,
Morales-Oyarvide
V,
Thayer
SP,
et al
851 resected cystic tumors of the pancreas: a 33-year experience at the Massachusetts General Hospital
.
Surgery
.
2012
;
152
(3 suppl 1)
:
S4
S12
.
3.
Kleeff
J,
Michalski
C,
Kong
B,
et al
Surgery for cystic pancreatic lesions in the post-Sendai era: a single institution experience
.
HPB Surg
.
2015
;
2015
:
847837
.
4.
Gaujoux
S,
Brennan
MF,
Gonen
M,
et al
Cystic lesions of the pancreas: changes in the presentation and management of 1,424 patients at a single institution over a 15-year time period [discussion in J Am Coll Surg. 2011;212(4):600–603]
.
J Am Coll Surg.
2011
;
212
(4)
:
590
600
.
5.
Esposito
I,
Segler
A,
Steiger
K,
Kloppel
G.
Pathology, genetics and precursors of human and experimental pancreatic neoplasms: an update
.
Pancreatology
.
2015
;
15
(6)
:
598
610
.
6.
Kloppel
G,
Basturk
O,
Schlitter
AM,
Konukiewitz
B,
Esposito
I.
Intraductal neoplasms of the pancreas
.
Semin Diagn Pathol
.
2014
;
31
(6)
:
452
466
.
7.
Kosmahl
M,
Pauser
U,
Peters
K,
et al
Cystic neoplasms of the pancreas and tumor-like lesions with cystic features: a review of 418 cases and a classification proposal
.
Virchows Arch
.
2004
;
445
(2)
:
16
178
.
8.
Reid
MD,
Choi
HJ,
Memis
B,
et al
Serous neoplasms of the pancreas: a clinicopathologic analysis of 193 cases and literature review with new insights on macrocystic and solid variants and critical reappraisal of so-called “serous cystadenocarcinoma”
.
Am J Surg Pathol
.
2015
;
39
(12)
:
1597
1610
.
9.
Jais
B,
Rebours
V,
Malleo
G,
et al
Serous cystic neoplasm of the pancreas: a multinational study of 2622 patients under the auspices of the International Association of Pancreatology and European Pancreatic Club (European Study Group on Cystic Tumors of the Pancreas)
.
Gut
.
2016
;
65
(2)
:
305
312
.
10.
Colonna
J,
Plaza
JA,
Frankel
WL,
Yearsley
M,
Bloomston
M,
Marsh
WL.
Serous cystadenoma of the pancreas: clinical and pathological features in 33 patients
.
Pancreatology
.
2008
;
8
(2)
:
135
141
.
11.
Ishigami
K,
Nishie
A,
Asayama
Y,
et al
Imaging pitfalls of pancreatic serous cystic neoplasm and its potential mimickers
.
World J Radiol
.
2014
;
6
(3)
:
36
47
.
12.
Egawa
N,
Maillet
B,
Klöppel
G,
Schröder
S,
Mukai
K.
Serous oligocystic and ill-demarcated adenoma of the pancreas: a variant of serous cystic adenoma
.
Virchows Arch
.
1994
;
424
(1)
:
13
17
.
13.
Tracht
J,
Reid
MD,
Hissong
E,
et al
Serous cystadenoma of the pancreas with complex florid papillary architecture: a case report and review of the literature
.
Int J Surg Pathol
.
2019
;
27
(8)
:
907
911
.
14.
Kosmahl
M,
Wagner
J,
Peters
K,
Sipos
B,
Kloppel
G.
Serous cystic neoplasms of the pancreas: an immunohistochemical analysis revealing alpha-inhibin, neuron-specific enolase, and MUC6 as new markers
.
Am J Surg Pathol
.
2004
;
28
(3)
:
339
346
.
15.
Thirabanjasak
D,
Basturk
O,
Altinel
D,
Cheng
JD,
Adsay
NV.
Is serous cystadenoma of the pancreas a model of clear-cell-associated angiogenesis and tumorigenesis?
Pancreatology
.
2009
;
9
(1)
:
182
188
.
16.
Park
TY,
Lee
SK,
Park
JS,
et al
Clinical features of pancreatic involvement in von Hippel-Lindau disease: a retrospective study of 55 cases in a single center
.
Scand J Gastroenterol
.
2015
;
50
(3)
:
360
367
.
17.
Agarwal
N,
Kumar
S,
Dass
J,
Arora
VK,
Rathi
V.
Diffuse pancreatic serous cystadenoma associated with neuroendocrine carcinoma: a case report and review of literature
.
JOP
.
2009
;
10
(1)
:
55
58
.
18.
Blandamura
S,
Parenti
A,
Famengo
B,
et al
Three cases of pancreatic serous cystadenoma and endocrine tumour
.
J Clin Pathol
.
2007
;
60
(3)
:
278
282
.
19.
Wu
J,
Jiao
Y,
Dal Molin
M,
et al
Whole-exome sequencing of neoplastic cysts of the pancreas reveals recurrent mutations in components of ubiquitin-dependent pathways
.
Proc Natl Acad Sci U S A
.
2011
;
108
(52)
:
21188
21193
.
20.
Singhi
AD,
McGrath
K,
Brand
RE,
et al
Preoperative next-generation sequencing of pancreatic cyst fluid is highly accurate in cyst classification and detection of advanced neoplasia
.
Gut
.
2018
;
67
(12)
:
2131
2141
.
21.
WHO Classification of Tumours Editorial Board.
Digestive System Tumours. 5th ed
.
Lyon, France
:
IARC Press;
2019
.
World Health Organization Classification of Tumours; vol 1.
22.
Zhu
H,
Qin
L,
Zhong
M,
et al
Carcinoma ex microcystic adenoma of the pancreas: a report of a novel form of malignancy in serous neoplasms
.
Am J Surg Pathol
.
2012
;
36
(2)
:
305
310
.
23.
Law
JK,
Ahmed
A,
Singh
VK,
et al
A systematic review of solid-pseudopapillary neoplasms: are these rare lesions?
Pancreas
.
2014
;
43
(3)
:
331
337
.
24.
Butte
JM,
Brennan
MF,
Gonen
M,
et al
Solid pseudopapillary tumors of the pancreas: clinical features, surgical outcomes, and long-term survival in 45 consecutive patients from a single center
.
J Gastrointest Surg
.
2011
;
15
(2)
:
350
357
.
25.
Singhi
AD,
Lilo
M,
Hruban
RH,
Cressman
KL,
Fuhrer
K,
Seethala
RR.
Overexpression of lymphoid enhancer-binding factor 1 (LEF1) in solid-pseudopapillary neoplasms of the pancreas
.
Mod Pathol
.
2014
;
27
(10)
:
1355
1363
.
26.
Jiang
Y,
Xie
J,
Wang
B,
Mu
Y,
Liu
P.
TFE3 is a diagnostic marker for solid pseudopapillary neoplasms of the pancreas
.
Hum Pathol
.
2018
;
81
:
166
175
.
27.
Lawlor
RT,
Daprà
V,
Girolami
I,
et al
CD200 expression is a feature of solid pseudopapillary neoplasms of the pancreas
.
Virchows Arch
.
2019
;
474
(1)
:
105
109
.
28.
Tanaka
Y,
Kato
K,
Notohara
K,
et al
Frequent beta-catenin mutation and cytoplasmic/nuclear accumulation in pancreatic solid-pseudopapillary neoplasm
.
Cancer Res
.
2001
;
61
(23)
:
8401
8404
.
29.
Abraham
SC,
Klimstra
DS,
Wilentz
RE,
et al
Solid-pseudopapillary tumors of the pancreas are genetically distinct from pancreatic ductal adenocarcinomas and almost always harbor beta-catenin mutations
.
Am J Pathol
.
2002
;
160
(4)
:
1361
1369
.
30.
Selenica
P,
Raj
N,
Kumar
R,
et al
Solid pseudopapillary neoplasms of the pancreas are dependent on the Wnt pathway
.
Mol Oncol
.
2019
;
13
(8)
:
1684
1692
.
31.
Gao
H,
Gao
Y,
Yin
L,
et al
Risk factors of the recurrences of pancreatic solid pseudopapillary tumors: a systematic review and meta-analysis
.
J Cancer
.
2018
;
9
(11)
:
1905
1914
.
32.
Tang
LH,
Aydin
H,
Brennan
MF,
Klimstra
DS.
Clinically aggressive solid pseudopapillary tumors of the pancreas: a report of two cases with components of undifferentiated carcinoma and a comparative clinicopathologic analysis of 34 conventional cases
.
Am J Surg Pathol
.
2005
;
29
(4)
:
512
519
.
33.
Hao
EIU,
Hwang
HK,
Yoon
DS,
Lee
WJ,
Kang
CM.
Aggressiveness of solid pseudopapillary neoplasm of the pancreas: a literature review and meta-analysis
.
Medicine (Baltimore)
.
2018
;
97
(49)
:
e13147
.
34.
Machado
MC,
Machado
MA,
Bacchella
T,
Jukemura
J,
Almeida
JL,
Cunha
JE.
Solid pseudopapillary neoplasm of the pancreas: distinct patterns of onset, diagnosis, and prognosis for male versus female patients
.
Surgery
.
2008
;
143
(1)
:
29
34
.
35.
Amato
E,
Mafficini
A,
Hirabayashi
K,
et al
Molecular alterations associated with metastases of solid pseudopapillary neoplasms of the pancreas
.
J Pathol
.
2019
;
247
(1)
:
123
134
.
36.
Carr
RA,
Bletsis
P,
Roch
AM,
et al
Cystic pancreatic neuroendocrine tumors: a more favorable lesion?
Pancreatology
.
2019
;
19
(2)
:
372
376
.
37.
Hurtado-Pardo
L,
Cienfuegos
JA,
Ruiz-Canela
M,
Panadero
P,
Benito
A,
Hernández Lizoain
JL.
Cystic pancreatic neuroendocrine tumors (cPNETs): a systematic review and meta-analysis of case series
.
Rev Esp Enferm Dig
.
2017
;
109
(11)
:
778
787
.
38.
Konukiewitz
B,
Enosawa
T,
Kloppel
G.
Glucagon expression in cystic pancreatic neuroendocrine neoplasms: an immunohistochemical analysis
.
Virchows Arch
.
2011
;
458
(1)
:
47
53
.
39.
Nakashima
Y,
Ohtsuka
T,
Nakamura
S,
et al
Clinicopathological characteristics of non-functioning cystic pancreatic neuroendocrine tumors
.
Pancreatology
.
2019
;
19
(1)
:
50
56
.
40.
Silverman
JF,
Prichard
J,
Regueiro
MD.
Fine needle aspiration cytology of a pancreatic cyst in a patient with autosomal dominant polycystic kidney disease: a case report
.
Acta Cytol
.
2001
;
45
(3)
:
415
419
.
41.
Klöppel
G.
Pseudocysts and other non-neoplastic cysts of the pancreas
.
Semin Diagn Pathol
.
2000
;
17
(1)
:
7
15
.
42.
Kleeff
J,
Whitcomb
DC,
Shimosegawa
T,
et al
Chronic pancreatitis
.
Nat Rev Dis Primers
.
2017
;
3
:
17060
.
43.
Kloppel
G,
Maillet
B.
Pseudocysts in chronic pancreatitis: a morphological analysis of 57 resection specimens and 9 autopsy pancreata
.
Pancreas
.
1991
;
6
(3)
:
266
274
.
44.
Shah
OJ,
Robbani
I,
Zargar
SA,
et al
Hydatid cyst of the pancreas: an experience with six cases
.
JOP
.
2010
;
11
(6)
:
575
581
.
45.
Arumugam
P,
Fletcher
N,
Kyriakides
C,
Mears
L,
Kocher
HM.
Lymphoepithelial cyst of the pancreas
.
Case Rep Gastroenterol
.
2016
;
10
(1)
:
181
192
.
46.
Adsay
NV,
Hasteh
F,
Cheng
JD,
et al
Lymphoepithelial cysts of the pancreas: a report of 12 cases and a review of the literature
.
Mod Pathol
.
2002
;
15
(5)
:
492
501
.
47.
Groot
VP,
Thakker
SS,
Gemenetzis
G,
et al
Lessons learned from 29 lymphoepithelial cysts of the pancreas: institutional experience and review of the literature
.
HPB (Oxford)
.
2018
;
20
(7)
:
612
620
.
48.
Nasr
J,
Sanders
M,
Fasanella
K,
Khalid
A,
McGrath
K.
Lymphoepithelial cysts of the pancreas: an EUS case series
.
Gastrointest Endosc
.
2008
;
68
(1)
:
170
173
.
49.
Degrate
L,
Misani
M,
Mauri
G,
et al
Mature cystic teratoma of the pancreas: case report and review of the literature of a rare pancreatic cystic lesion
.
JOP
.
2012
;
13
(1)
:
66
72
.
50.
Othman
M,
Basturk
O,
Groisman
G,
Krasinskas
A,
Adsay
NV.
Squamoid cyst of pancreatic ducts: a distinct type of cystic lesion in the pancreas
.
Am J Surg Pathol
.
2007
;
31
(2)
:
291
297
.
51.
Woon
CS,
Pambuccian
SE,
Lai
R,
Jessurun
J,
Gulbahce
HE.
Ciliated foregut cyst of pancreas: cytologic findings on endoscopic ultrasound-guided fine-needle aspiration
.
Diagn Cytopathol
.
2007
;
35
(7)
:
433
438
.
52.
Gomez Mateo Mdel
C,
Munoz Forner
E,
Sabater Orti
L,
Ferrandez Izquierdo
A.
Foregut cystic malformations in the pancreas: are definitions clearly established?
JOP
.
2011
;
12
(4)
:
420
424
.
53.
Sharma
S,
Dean
AG,
Corn
A,
et al
Ciliated hepatic foregut cyst: an increasingly diagnosed condition
.
Hepatobiliary Pancreat Dis Int
.
2008
;
7
(6)
:
581
589
.
54.
Dua
KS,
Vijayapal
AS,
Kengis
J,
Shidham
VB.
Ciliated foregut cyst of the pancreas: preoperative diagnosis using endoscopic ultrasound guided fine needle aspiration cytology—case report with a review of the literature
.
Cytojournal
.
2009
;
6
:
22
.
55.
Krasinskas
AM,
Oakley
GJ,
Bagci
P,
et al
“Simple mucinous cyst” of the pancreas: a clinicopathologic analysis of 39 examples of a diagnostically challenging entity distinct from intraductal papillary mucinous neoplasms and mucinous cystic neoplasms
.
Am J Surg Pathol
.
2017
;
41
(1)
:
121
127
.
56.
Singhi
AD,
Norwood
S,
Liu
TC,
et al
Acinar cell cystadenoma of the pancreas: a benign neoplasm or non-neoplastic ballooning of acinar and ductal epithelium?
Am J Surg Pathol
.
2013
;
37
(9)
:
1329
1335
.
57.
Bergmann
F,
Aulmann
S,
Welsch
T,
et al
Molecular analysis of pancreatic acinar cell cystadenomas: evidence of a non-neoplastic nature
.
Oncol Lett
.
2014
;
8
(2)
:
852
858
.
58.
Khor
TS,
Badizadegan
K,
Ferrone
C,
et al
Acinar cystadenoma of the pancreas: a clinicopathologic study of 10 cases including multilocular lesions with mural nodules
.
Am J Surg Pathol
.
2012
;
36
(11)
:
1579
1591
.
59.
Zamboni
G,
Terris
B,
Scarpa
A,
et al
Acinar cell cystadenoma of the pancreas: a new entity?
Am J Surg Pathol
.
2002
;
26
(6)
:
698
704
.

Competing Interests

The authors have no relevant financial interest in the products or companies described in this article.

Author notes

Presented in part at the Companion Meeting of the Pancreatobiliary Pathology Society at the United States and Canadian Academy of Pathology Annual Meeting; February 29, 2020; Los Angeles, California.