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Simple Mucinous Cyst of the Pancreas: Review and Update.


Mucinous pancreatic cystic lesions are generally considered to be precursor lesions of pancreatic adenocarcinoma owing to their common association or coexistence with cancer. (1) The only 2 mucinous pancreatic cystic neoplasms recognized by the World Health Organization (WHO) are intraductal papillary mucinous neoplasm (IPMN) and mucinous cystic neoplasm (MCN), (2) each of which has a risk for malignant transformation. Depending on subtype, about 10% to 68% of these mucinous cysts are reported to be associated with invasive adenocarcinoma. (3,4) Although the management of branch duct-type IPMNs is controversial, most MCNs and IPMNs involving the main pancreatic duct are managed with surgical resection.

With the increasing use of imaging modalities, there is an increasing prevalence of pancreatic cysts, including mucinous cysts. Notably, some of the mucinous cysts that are identified do not fit perfectly into either the IPMN or MCN diagnostic categories. Among these other types of mucinous cyst is the "simple mucinous cyst." This review provides a timely update of simple mucinous cyst, with a focus on the evolution of its nomenclature, definition, classification, and its diagnostic and molecular features. We will also discuss whether the "simple mucinous cyst" is truly a distinct entity or a variant of other mucinous cystic lesions and whether it has malignant potential like the other mucinous pancreatic cysts.

Two German pathologists, Kosmahl and Kloppel, and their colleagues (5) in 2002 were the first to describe this type of mucinous cyst in the English-language literature. They described a series of 5 cases, and later an additional 4 cases, of pancreatic cystic lesions that "differ from all categories described so far." (5,6) These lesions lacked communication with the pancreatic duct and showed no evidence of recurrence or malignant transformation after resection during a mean follow-up time of 2 years. Therefore, Kosmahl et al (5) suggested that "they may represent a nonneoplastic cystic change of the pancreas" and proposed the term mucinous nonneoplastic cyst for these lesions. The photomicrographs of these cystic lesions are identical to what is now referred to as "simple mucinous cyst" (Figure 1, A).

Goh et al (7) in 2005 reported another possible case of "mucinous nonneoplastic cyst." The histologic features were similar to those described by Kosmahl et al, (5) but magnetic resonance imaging showed that this cyst communicated with the main pancreatic duct, which had not been reported previously. Although these findings raised the possibility of IPMN or a retention cyst, the lack of characteristic papillary architecture and evidence of ductal obstruction made IPMN and retention cyst less likely.

A group of pathologists at Northwestern University (Chicago, Illinois) later looked at the apomucin and molecular phenotypes of 15 "mucinous nonneoplastic cysts." (8,9) The authors found that mucinous nonneoplastic cysts have a distinct apomucin immunoprofile as compared to IPMNs. Polymerase chain reaction-based clonality analysis using the HUMARA gene indicated that mucinous nonneoplastic cysts were polyclonal and suggested the nonneoplastic nature of these cysts. (8) However, a more recent study of the same 15 cysts from the same group identified KRAS mutations or loss of heterozygosity of tumor suppressor genes in about 27% (4 of 15) of the cases. These findings again raised questions about the true nature of these lesions (9); however, no follow-up clinical data were presented. Another study from Nadig et al (10) in 2012 analyzed 7 cases of mucinous nonneoplastic cysts and found a slightly different apomucin immunoprofile than did Cao et al, (8) but the 2 studies used antibodies from different companies. In addition, the study by Nadig et al (10) suggested that these cysts behaved in a benign manner because there was no recurrence during a mean follow-up of 44 months, the longest follow-up period reported in the literature to date.

In 2015, the Baltimore Consensus Meeting for Neoplastic Precursor Lesions in the Pancreas published a revised classification system and recommended to rename these macroscopic cysts with flat mucinous lining as simple mucinous cyst. (11) This name was intended to clearly separate these cysts from IPMNs and MCNs owing to their overall benign behavior, but also to acknowledge their unclear pathogenesis and progression. Most recently, the largest single study of 39 cases of simple mucinous cyst with morphologic, immunohistochemical, and molecular studies was reported by Krasinskas et al (12) who again challenged the benign nature of simple mucinous cyst because of the presence of KRAS mutations and focal high-grade dysplasia. However, no clinical follow-up data were presented. This review provides a summary of clinical, histopathologic, and molecular features of a total of 71 previously reported cases of simple mucinous cyst.


Simple mucinous cysts have been identified in 2.0% to 3.4% (7 of 347 to 15 of 436) of pancreatic resections, 2.2% to 6.7% (9 of 418 to 7 of 104) of pancreatic cyst resections, and 7.6% to 10.3% (9 of 118 to 7 of 68) of mucinous cyst resections. (6,8,10) From a total of 71 cases reported so far in the literature, (5-8,10,12) simple mucinous cysts occur more commonly in females (2.8:1 female to male ratio) with a mean age at diagnosis of 64 years (range, 20-88 years) (Table 1). About half (49%, 29 of 59) of the patients are asymptomatic and the other half presented with abdominal pain (34%, 20 of 59), jaundice (7%, 4 of 59), or other symptoms. These cysts occur with roughly equal frequency in the pancreatic head/neck/uncinate and body/tail (Table 1). Their size ranges from 1 to 12 cm (2.5-cm average diameter). By consensus, a cyst must be greater than 1 cm in size to fulfill the diagnostic criteria of simple mucinous cyst. Therefore, a case of a 0.3-cm "mucinous nonneoplastic cyst" reported by Assifi et al (13) was not included in our analysis. Radiologically, the cysts are either unilocular (59%, 34 of 58) or multilocular (41%, 24 of 58) and only 7% of the cysts communicate with pancreatic duct (4 of 58). Cytology findings of simple mucinous cysts ranged from negative, to atypical, to suggestive of adenocarcinoma (Table 1). Zhu et al (14) looked at the cytomorphology of simple mucinous cysts from fine-needle aspiration specimens and found that all of the cases contained flat "honeycomb" sheets/nests of cuboidal or columnar cells without significant cytologic atypia, and only rare cases showed papillary, acinar, 3-dimensional cluster or single-cell architecture. Some samples had goblet cells or cells with vacuolated cytoplasm. (14) When cyst fluid carcinoembryonic antigen (CEA) was measured, it was elevated in most samples with a mean cyst fluid CEA level of 6797 ng/mL (range, 11-64 000 ng/mL). Consequently, simple mucinous cysts clinically and radiographically mimic the more aggressive mucinous neoplasms, IPMN and MCN, and frequently receive aggressive surgical treatment.


According to the Baltimore Consensus Meeting, simple mucinous cysts are defined as macroscopic cysts that are greater than 1 cm in size with gastric-type flat mucinous lining and minimal cytologic atypia without ovarian-type stroma. (11) Grossly, they can be either unilocular or multilocular with mostly clear or serous fluid. (12) Approximately a third of the cysts contain mucinous fluid and a few contain serosanguinous or brown/green thick fluid. All cysts have a smooth lining with no or minimal focal papillary excrescence. (12) With rare exceptions, the cysts do not communicate with pancreatic duct and are not associated with ductal obstruction. Microscopically, the cysts are lined by a flat single layer of mucinous columnar epithelial cells or attenuated cuboidal epithelial cells with no or minimal cytologic atypia (Figure 1, A and B). Most mucinous epithelial cells resemble gastric-type mucinous epithelial cells with low-grade dysplasia, mimicking low-grade pancreatic intraepithelial neoplasia (PanIN). However, focal high-grade dysplasia has been reported in rare cases (8%, 3 of 39). (12) There is no or minimal papillary architecture of the epithelial lining, which distinguishes these cysts from IPMNs. The cysts are distinguished from MCNs or lymphoepithelial cysts in that they are often surrounded by a paucicellular fibrous wall with no ovarian-type stroma or lymphoid band (Figure 1, B). In addition, degenerative changes, including hyalinization, myxoid stroma, hemorrhage, calcification, and macrophage clusters or granulation-like tissue, are common in the cyst wall (67%, 26 of 39; Figure 1, C through F). (5,12) Low-grade PanIN or, rarely, highgrade PanIN, atrophy, periductal fibrosis, squamous metaplasia, or acinar-ductal metaplasia have been seen in the adjacent pancreatic parenchyma.

The differential diagnosis of simple mucinous cysts of the pancreas comprises 3 main entities that often have overlapping clinical and histopathologic features: neoplastic mucinous cysts, such as IPMN and MCN, and nonneoplastic entities such as retention cysts. Clinically, MCNs usually present at an earlier age than simple mucinous cysts or IPMNs (Table 2). Mucinous cystic neoplasms occur almost exclusively in women (20:1 female to male ratio). Simple mucinous cysts have a female predominance and IPMNs have a male predominance, but each type of lesion can be seen in either sex. Also, MCNs are located predominantly in the pancreatic body/tail, in contrast to IPMNs, which are most commonly located in the head of the pancreas, or simple mucinous cysts, which occur with roughly equal frequency in the body/tail and head/neck. All 3 entities often have highly elevated CEA levels in cyst fluid, but IPMNs can also have elevated cyst fluid amylase levels owing to their communication with the pancreatic duct. Both IPMNs and MCNs are considered premalignant neoplasms and are associated with invasive carcinoma; however, no invasive carcinoma has been reported with simple mucinous cysts to date. Histopathologically, most simple mucinous cysts have no or minimal cytologic atypia, whereas IPMNs and MCNs have various grades of dysplasia (Table 3). A diagnostic feature of MCNs is the characteristic ovarian-type stroma in the subepithelial area (Figure 2, A and B), which is absent in simple mucinous cysts. Intraductal papillary mucinous neoplasms often have a prominent papillary epithelial architecture, which is typically not seen in simple mucinous cysts or MCNs. However, some IPMNs, especially gastrictype IPMNs with only low-grade dysplasia, can have minimal papillary formation (Figure 2, C and D), which makes them diagnostically challenging to distinguish from simple mucinous cysts. In this context, the overall lowpower histologic architecture of the cyst, the presence of various grades of dysplasia, communication with pancreatic duct, and other clinical features would help to differentiate IPMNs and simple mucinous cysts. Finally, the distinction between a retention cyst and a simple mucinous cyst is largely dependent on clinical features including imaging and gross findings because retention cysts result from duct obstruction and both entities share similar histopathologic findings.


Immunohistochemically, simple mucinous cysts generally have a gastric phenotype. They are often positive for MUC5AC (90%, 55 of 61) and MUC6 (74%, 29 of 39), and mostly negative for MUC2 (only 8%, 5 of 61 with focal staining; Table 4). (5,6,8,10,12) Approximately one-third of the simple mucinous cysts have MUC1 positivity (35%, 11 of 31). In addition, all simple mucinous cysts are positive for cytokeratin 7 (100%, 39 of 39). In contrast, IPMNs are often MUC2 positive (71%, 12 of 17) in addition to being MUC5AC positive (100%, 17 of 17) and mostly MUC1 negative (focal weak MUC1 staining in 18%, 3 of 17). (8) Therefore, in challenging cases, immunohistochemical mucin profiles could be helpful in establishing a diagnosis.


Molecular findings with simple mucinous cysts have been inconsistent. The first molecular study in 2010 used a polymerase chain reaction-based clonality analysis with the HUMARA gene and showed that, in 4 of 6 cases, microdissected mucinous cystic epithelial cells were polymorphic, suggesting a nonneoplastic process. (8) However, these findings contrast with more recent results from molecular studies using DNA sequencing and loss of heterozygosity analysis. (9,12) Among the 42 cases that were sequenced in either the mucinous epithelium or the cyst fluid, KRAS mutations were detected in 40% (17 of 42) of the cases. In 4 cases, the same KRAS mutation was identified in both the cyst fluid and cyst lining. (12) Interestingly, in 3 cases, KRAS mutations were only identified in the cyst fluid, but not in the cyst lining. In addition, loss of heterozygosity at 10q (PTEN) or 17q (ubiquitin E3 ligase ring finger 43, RNF43) was identified in 2 cases. (9) Of note, 2 cases with communication to pancreatic ducts, 1 with focal papillary architecture, and 3 cases with focal high-grade dysplasia were included in 1 of the studies, (12) which does not entirely fulfill the diagnostic criteria of simple mucinous cyst according to the recommendations from the Baltimore Consensus Meeting. (11) Nevertheless, the presence of KRAS mutation and loss of heterozygosity of tumor suppressor genes in a fraction of these cases raises concern for a neoplastic process. Interestingly, none of these cysts had accumulated more than a single mutation, whereas sequencing of IPMNs reveals about 26 mutations per neoplasm, with mutations in KRAS, GNAS, and RNF43 observed most frequently. (15) These findings suggest that simple mucinous cyst may represent the earliest lesion in a premalignant to malignant progression spectrum.


The originally termed mucinous nonneoplastic cyst has undergone a recent nomenclature change and is now referred to as a simple mucinous cyst according to the 2014 Baltimore Consensus Meeting recommendation. Simple mucinous cyst denotes a pancreatic cyst that is greater than 1 cm in size and lined by flat gastric-type mucinous epithelium without significant atypia and without ovarian-type stroma. The malignant potential of simple mucinous cysts is still debatable. Recent molecular studies support a neoplastic process at the lowest spectrum of the neoplastic progression, but these cysts generally exhibit benign behavior without recurrence or malignant transformation. Nevertheless, there are only a few studies of simple mucinous cysts with a very low number of cases and short follow-up periods. Accurate diagnosis of simple mucinous cysts is critical to distinguish them from other mucinous pancreatic cysts, to ensure future cohort studies with large samples and prolonged follow-up periods, and to determine their biologic behavior and implications for prognosis.

Note: Illustration(s) are not available due to copyright restrictions.


(1.) Hruban RH, Takaori K, Canto M, et al. Clinical importance of precursor lesions in the pancreas. J Hepatobiliary Pancreat Surg. 2007; 14(3):255-263.

(2.) Luttges J. What's new: the 2010 WHO classification for tumours of the pancreas [article in German]. Pathologe. 2011; 32(suppl 2):332-336.

(3.) Talukdar R, Nageshwar Reddy D. Treatment of pancreatic cystic neoplasm: surgery or conservative? Clin Gastroenterol Hepatol. 2014; 12(1):145-1 51.

(4.) Koh YX, Zheng HL, Chok AY, et al. Systematic review and meta-analysis of the spectrum and outcomes of different histologic subtypes of noninvasive and invasive intraductal papillary mucinous neoplasms. Surgery. 2015; 157(3):496-509.

(5.) Kosmahl M, Egawa N, Schroder S, Carneiro F, Luttges J, Kloppel G. Mucinous nonneoplastic cyst of the pancreas: a novel nonneoplastic cystic change? Mod Pathol. 2002; 15(2):154-158.

(6.) 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):168-178.

(7.) Goh BK, Tan YM, Tan PH, Ooi LL. Mucinous nonneoplastic cyst of the pancreas: a truly novel pathological entity? World J Gastroenterol. 2005; 11(13): 2045-2047.

(8.) Cao W, Adley BP, Liao J, et al. Mucinous nonneoplastic cyst of the pancreas: apomucin phenotype distinguishes this entity from intraductal papillary mucinous neoplasm. Hum Pathol. 2010; 41(4):513-521.

(9.) Zhu B, Finkelstein SD, Feng G, Keswani RN, Lin X. Molecular analysis of mucinous nonneoplastic cyst of the pancreas. Hum Pathol. 2016; 55:159-163.

(10.) Nadig SN, Pedrosa I, Goldsmith JD, Callery MP, Vollmer CM. Clinical implications of mucinous nonneoplastic cysts of the pancreas. Pancreas. 2012; 41(3):441-446.

(11.) Basturk O, Hong SM, Wood LD, et al. A revised classification system and recommendations from the Baltimore Consensus Meeting for Neoplastic Precursor Lesions in the Pancreas. Am J Surg Pathol. 2015; 39(12):1730-1741.

(12.) 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.

(13.) Assifi MM, Nguyen PD, Agrawal N, et al. Non-neoplastic epithelial cysts of the pancreas: a rare, benign entity. J Gastrointest Surg. 2014; 18(3):523-531.

(14.) Zhu B, Keswani RN, Lin X. Fine needle aspiration cytomorphology of mucinous nonneoplastic cyst of the pancreas. Pancreas. 2013; 42(1):27-31.

(15.) Amato E, Molin Md, Mafficini A, et al. Targeted next-generation sequencing of cancer genes dissects the molecular profiles of intraductal papillary neoplasms of the pancreas. J Pathol. 2014; 233(3):217-227.

Shula Schechter, MD; Jiaqi Shi, MD, PhD

Accepted for publication May 22, 2017.

From the Department of Pathology, University of Michigan, Ann Arbor.

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

Presented in part at the New Frontiers in Pathology meeting; October 13-15, 2016;Ann Arbor, Michigan.

Reprints: Jiaqi Shi, MD, PhD, Department of Pathology, University of Michigan, 5231C Med Sci I, 1301 Catherine St, Ann Arbor, MI 48109 (email:

Caption: Figure 1. Simple mucinous cyst. A, Classic appearance with single layer of flat mucinous epithelium without papillary architecture and fibrous cyst wall; no ovarian-type stroma. B, Higher magnification showing gastric-type flat mucinous lining with no cytologic atypia or papillary architecture and dense fibrous cyst wall. C through F, Degenerative changes, including hyalinization (C), myxoid changes (D), hemorrhage (E), and histiocytic aggregates (F) in the cyst wall are common (hematoxylin-eosin, original magnifications X20 [A], X200 [B], X100 [C through E], and X400 [F]).

Caption: Figure 2. Mucinous cystic neoplasm and gastric-type intraductal papillary mucinous neoplasm (IPMN). A and B, Mucinous cystic neoplasm with a single layer of flat mucinous epithelium with low-grade dysplasia and the characteristic ovarian-type stroma. C and D, IPMN with gastric-type mucinous epithelium and low-grade dysplasia (hematoxylin-eosin, original magnifications X20 [A and C] and X200 [B and D]).
Table 1. Clinicopathologic Characteristics of
Previously Reported Simple Mucinous Cysts

                             No. (%)          No. of Cases With
                                            Available Information

Age, y                                             71
  Mean (range)            64 (20-88)
Sex, male:female            1:2.8                  71
Presenting symptom                                 59
  Abdominal pain           20 (34)
  Jaundice                  4 (7)
  Other symptoms            6 (10)
  Asymptomatic             29 (49)
Distribution                                       68
  Body/tail                36 (53)
  Head/neck/uncinate       32 (47)
Size, cm                                           57
  Mean (range)           2.5 (1.0-12)
Radiologic findings                                58
  Unilocular cyst          34 (59)
  Multilocular cyst        24 (41)
  Communication             4 (7)
    with duct
Cyst fluid CEA, mean   6797 (11-64 000)            34
  (range), ng/mL
Cytology diagnosis                                 15
  Negative                  5 (33)
  Atypical                  4 (27)
  Suspicious                4 (27)
  Other                     2 (13)

Abbreviation: CEA, carcinoembryonic antigen.

Table 2. Clinical Comparison Among Pancreatic Mucinous Cysts

                                         SMC          IPMN

Age, decade                           6th-7th      6th-7th
Sex, F:M                              2.8:1        1:2
Location, body and tail, % (No.)      53 (36/68)   29 (41/140)
CEA                                   High         High
Amylase                               Low          Elevated
Pancreatic duct communication         No           Yes
Associated with invasive carcinoma    No           Yes


Age, decade                           4th-5th
Sex, F:M                              20:1
Location, body and tail, % (No.)      96 (125/130)
CEA                                   High
Amylase                               Low
Pancreatic duct communication         No
Associated with invasive carcinoma    Yes

Abbreviations: CEA, carcinoembryonic antigen; IPMN, intraductal
papillary mucinous neoplasm; MCN, mucinous cystic neoplasm; SMC,
simple mucinous cyst.

Table 3. Histopathology and Molecular Comparison Between Mucinous
Pancreatic Cysts

                            SMC                 IPMN

Cytologic atypia   No significant atypia   Low-high grade
Epithelium         Flat                    Papillary
Ovarian stroma     No                      No
KRAS mutation, %   13-55                   47-82
GNAS mutation, %   Unknown                 41-66


Cytologic atypia   Low-high grade
Epithelium         Flat or papillary
Ovarian stroma     Yes
KRAS mutation, %   20-73
GNAS mutation, %   No

Abbreviations: IPMN, intraductal papillary mucinous neoplasm; MCN,
mucinous cystic neoplasm; SMC, simple mucinous cyst.

Table 4. Immunohistochemical Features of Simple
Mucinous Cyst of Pancreas

                   No. (%)      No. of Cases

Cytokeratin 7   39(100)              39
MUC5AC          55 (90)              61
MUC1            11 (35)              31
MUC2             5 (focal, 8)        61
MUC6            29 (74)              39
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Author:Schechter, Shula; Shi, Jiaqi
Publication:Archives of Pathology & Laboratory Medicine
Article Type:Report
Date:Oct 1, 2017
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