Dr. Ralph H. Hruban
Dr. Günter Klöppel
Case 1 -
Pancreatic Mucinous Cystadenoma
Dr. Benoît Terris
Service d'Anatomie Pathologique
Hôpital Cochin, Paris, France
A 22-year-old female with no significant past medical history was admitted for further evaluation of
anemia. She had no evidence of gastrointestinal bleeding such as hematemesis. On admission, she was
slightly pale and an abdominal mass was palpable. Laboratory examination confirmed the anemia
(haemoglobin 7.4g/dl, hematocrit 25;2% and MCV 85 fl). Upper gastrointestinal endoscopy revealed nodular
esophageal and gastric varices with red spots suggesting stigmata of bleeding. On abdominal CT, the tail
of the pancreas revealed a 10cm unilocular cystic lesion with irregular walls and septations. Mild
splenomegaly, obstruction of splenic vein and gastrooesophageal varices were also observed. A clinical
diagnosis of pancreatic cystadenocarcinoma was proposed. The patient underwent a distal pancreatectomy.
Macroscopically, the tail of pancreas was occupied by a 10cm cyst showing numerous septa and filled with
serosanguineous fluid. The inner lining of the cystic space did not show nodular masses.
The selected slide is of the cyst wall.
Case 1 - Figure 1
Microscopic examination of the wall of this cyst revels two main features permitting the diagnosis :
The pathologic diagnosis proposed is a pancreatic mucinous cystadenoma.
- Whereas large areas of extensive denudation are present, this cyst is lined focally by a single
layer of regular columnar cells. By definition, the presence of an epithelial lining defines a true
cystic pancreatic lesion. The epithelial lining is better preserved in small cysts included in the wall
than in the principal cyst. The columnar cells show basally orientated regular nuclei and abundant
eosinophilic cytoplasm with small amount of mucosecretion at the apical pole of cells. This
mucosecretion is better appreciated on Alcian Blue or PAS staining. There is no significant cytological
or architectural atypia. Moreover this cyst did not communicate with the main pancreatic duct.
- The epithelial lining is characteristically surrounded by a distinctive cellular stroma composed of
spindled-shaped cells resembling to an ovarian stroma. Although this stroma becomes partially or even
completely hyalinized in some areas, it is well observed particularly around the small cystic lesions
included in the wall. This stroma shows frequently evidence of luteinization consisting of epithelioid
cells with eosinophilic cytoplasm.
This patient's portal hypertension can be explained by the compression and obstruction of the splenic
vein by this benign cystic pancreatic lesion . Such case underlines that pre-operative
diagnosis between large compressing benign mucinous cystadenoma of the pancreas and advanced
cystadenocarcinoma can be difficult . Surgery must be considered whenever possible to
provide curative treatment.
Cystic Pancreatic Lesions
Cystic neoplasms of the pancreas are rare accounting for less than 10% of pancreatic neoplasms.
However, due to recent improvements in pancreatic imaging, an increasing number of cystic lesions are
identified both in asymptomatic and symptomatic patients. Diagnostic assessment and therapeutic
indications in patients with cystic lesions of the pancreas are often difficult. Cystic neoplasms
encompass a spectrum of tumors from neoplasms with indolent biological behaviour, to neoplasms with a
potential of more aggressive behaviour (premalignant), to frankly malignant neoplasms. Most often, they
can be cured by surgical resection in contrast to ductal adenocarcinomas .
Different classifications of cystic pancreatic neoplasms exist. Based on the presence or absence of
an epithelial or non epithelial cystic lining , we can distinguish:
- Cysts with no lining corresponding to pseudocysts. These unilocular cysts are the most common and
are often pancreatitis associated .
- Cysts with a true lining: Among them, serous cystadenomas, mucinous cystadenomas and intraductal
papillary mucinous neoplasms (IPMNs) represent the majority of these lesions in daily practice. Rare
acinar cystadenomas, lymphoeepithelial or retentional cysts and lymphangiomas can be encountered.
- Cysts secondary to degenerative or necrotic changes in neoplasms: This group comprises
solid-pseudopapillary neoplasms, endocrine neoplasia, rare ductal adenocarcinomas and mesenchymal tumors
and pancreatic metastasis .
Mucinous Cystic Neoplasms
Mucinous cystic neoplasms represent the most frequent cystic neoplasms occurring in pancreas. The
WHO subclassification of mucin-producing neoplasms of the pancreas includes two main categories :
mucinous cystic neoplasms (MCNs) and IPMNs . These two entities share numerous
histopathological features but differ respectively by the presence of a communication with the pancreatic
ductal system for IPMNs and a dense mesenchymal ovarian-like stroma for MCNs.
A major characteristic of these lesions is that they may demonstrate a wide histologic spectrum of
epithelial atypia within a single neoplasm. Based on the degree of atypia and the the presence or
absence of an invasive component, these cystic tumors are classified in benign (low-grade dysplasia,
adenomatous), moderate dysplasia (borderline), high-grade dysplasia (carcinoma in situ) and invasive
cancer. Both IPMNs and MCNs are known to progress from non-invasive low-grade dysplasia to invasive
carcinoma. As the prognosis depends on the presence of an invasive component, surgical resection of
mucinous cystic tumours should be entirely examined histologically, in order to avoid designating a
poorly sampled invasive carcinoma as a non-invasive neoplasm . The discrepancy among the
series concerning the frequency of invasive and non invasive form of these tumors is probably due to
differences in the pathological sampling.
1. Mucinous cystic neoplasms
MCNs which are found almost exclusively in women tend to occur most commonly in the tail or body of
the pancreas (90%). MCNs do not communicate with the pancreatic ductal system, are usually uni-locular,
may be rarely muli-locular
The neoplastic cysts are usually filled with
clear mucoid fluid. The wall of the cyst may be dense and fibrous with occasionally foci of
calcification and be confused with a pseudocyst. Histologically, MCNs are lined by tall mucinous
epithelial cells. Adequate sampling of MCN is important. A wide variation in epithelial cell shape may
be seen, ranging from flattened or low cuboidal to tall columnar. The chance of finding dysplastic or
invasive foci is greater in the thickened fibrotic walls and septae as well in intramural nodules
projecting into the cyst lumen. An invasive component is present in less of one third of MCN. The
invasive component corresponds usually to well or moderately differentiated adenocarcinomas. Mucinous
(colloid) carcinomas frequently seen in IPMNs are rarely observed in MCNs.
Characteristically, a dense stroma resembling ovarian stroma surrounds the epithelial cells. Although
this stroma becomes partially or even completely hyalinized, extensive sampling here again will almost
always show it. Because such stroma is now required in the current definition of MCNs, the proportion of
MCNs relative to IPMNs is declining in most series. There are two hypotheses on the origin of a neoplasm
in the pancreas with ovarian-type stroma. The first hypothesis is that these neoplasms arise from an
ectopic ovarian stroma. This is supported by the close proximity of the left primordial gonad to the
dorsal pancreas during the fifth week of gestation, possibly facilitating the transfer of cells. The
second hypothesis neoplasms is that the stroma represents an equivalent of periductal fetal mesenchyme,
the primitive mesenchyme seen around the pancreatic and hepatic ducts in the developing fetus
. This last hypothesis could similarly explain mucinous cystadenoma occurring in the
hepatobiliary tract. Regardless of its origin, it is clear that female sex hormones might have had a
role in the pathogenesis of this neoplasm. This stroma which is often admixed with luteal-type cells
(40% of cases) is hormone sensitive expressing in more than 50% of cases progesterone receptors and
alpha-inhibin . Rare observations of an undifferentiated carcinoma with sometimes osteoclast
giant cells or sarcomatous transformation have been reported .
Accurate prognosis of MCNs depends of the presence and the extent of an invasive component as
non-invasive lesions follow a benign course after surgical resection. It is important to evaluate the
depth of invasion as the prognosis appears worth for tumors showing a peritumoral invasion than those
limited to the cyst wall . The 5-year survival rate of patients with invasive mucinous
cystadenocarcinomas is 30%. It remains better than patients with typical infiltrating ductal
adenocarcinomas highlighting the importance to distinguish these two entities.
2. Intraductal papillary mucinous neoplasms
IPMNs are the neoplasms most frequently misdiagnosed as MCNs. In several pancreatic referral
centers, IPMNs are now more frequent than MCNs due to a better clinical and pathological diagnosis of the
former and the requirement of an ovarian stroma for the diagnosis of the later  . A
consensus definition of IPMN has been recently proposed as follows: "a grossly visible non-invasive,
mucin-producing, predominantly papillary, or rarely flat, epithelial neoplasm arising from the main
pancreatic duct or branch ducts, with varying degrees of duct dilatation. IPMN usually produce a lesion
> 1 cm in diameter and include a variety of cell types with a spectrum of cytologic and architectural
atypia"  . In contrast to MCN, IPMN occurs equally in men and women, usually in the seventh
decade of life and most often is found in the head of the pancreas (75% of cases). Different
classifications of IPMN exist:
Rare related entities of IPMN have been described: the intraductal oncocytic papillary neoplasms
 and the intraductal tubular adenoma or pyloric gland adenoma  .
- IPMN can be subdivided into main duct and branch duct types depending on the location of the lesion in the
main pancreatic duct or the branch ducts, respectively 
In both locations, the involvement may be relatively continuous along the
duct with diffuse dilatation or segmental ectasia with a local cystic appearance. Multifocal involvement
characterized by skip lesions occur. Grossly they may be alterations in surrounding pancreatic
parenchyma attributed to pancreatitis which is due to mucinous obstruction of the duct system. Any solid
or firm areas should be sampled in order to rule out invasive adenocarcinoma.
- Like MCN, several grades according to the cytological and architectural atypia of the proliferating epithelium may be
encountered  : Non-invasive IPMNs can be categorized into mild dysplasia (adenoma), moderate
dysplasia (borderline), and marked dysplaia (carcinoma in situ). An
associated invasive carcinoma is seen in 30% of the cases and it can show either a ductal (tubular) or a
mucinous (colloid) phenotype. Invasion may be especially difficult to identify in some tumors. Presence
of extra ductal acellular mucin pools are often observed and do not necessarily indicate an invasive form
of IPMN. In such situations, presence of viable neoplastic cells within lake of mucus is needed to
establish definitive tissue invasion.
- IPMN may also been sub-classified according to the differentiation of epithelial cells and the related expression of MUC antigens
: the intestinal phenotype composed of macropapillae, similar to those in colonic villous
adenomas, producing large amount of mucus (MUC2+, MUC1-), the pancreatobiliary type showing
micropapillae (MUC1+, MUC2-) and the gastric foveolar type with few or no cellular atypia (MUC1-, MUC2-,
MUC5AC+). Interestingly, the type of invasion is correlated to phenotype of intraductal proliferation :
a colloid invasive pattern for the intestinal phenotype and a conventional ductal invasive pattern for
the pancreaticobiliary type
Clinical recognition of IPMN is difficult and be confused with chronic pancreatitis or other cystic
lesions. Invasive component may not be distinguish by imaging studies. Currently, the only treatment of
non-invasive IPMN is surgical resection. The extent of resection that is necessary is usually determined
by histological examination of the margins on frozen sections. Like MCN, the prognosis of IMPN is highly
correlated to the presence or absence of an invasive component. The type of invasion plays probably also
a role with a better prognosis of the colloid pattern as compared to the conventional ductal form
 . However, overall five year survival rate remains higher in patients with malignant
invasive IPMN compared with those with pancreatic ductal adenocarcinoma.
3. Differential diagnosis :
As we have seen, several clinical and pathological characteristics can be used to distinguish MCNs
and IPMNs (table 1). They are easily differentiated from other non mucinous cystic tumors as serous
cystadenomas. It may be more difficult to distinguish :
- MCN from pseudocyst when the epithelium of the MCN
is totally denuded and the ovarian stroma largely hyalinized, and from retentional cysts.
- IPMN from pancreatic intraepithelial neoplasia
(PanIN) due to the similarities of the tumoral epithelium in some cases. However, PanIns are incidental
and microscopic findings. They do not form macroscopic and/or radiologic detectable mass and usually
involved ducts <5mm in diameter .
Table 1: Clinical and pathological characteristics of Mucinous Cystic
Neoplasms and Intraductal Papillary Mucinous Neoplasms.
| ||Mucinous cystadenoma neoplasms ||Intraductal papillary mucinous neoplasms|
|Average age ||50 ||65|
|Gender ||Female +++ (>95%) ||Male / Female : 60 / 40|
|Specific endoscopic finding ||None ||Mucin extrusion from ampulla|
|Endoscopic and radiological findings ||Macrocystic lesions with small cysts inside the wall ||Mucin extrusion from ampulla|
Macrocystic and microcystic lesions
|Pancreatic location ||Tail : 90% ||Head : 70%|
|Histological findings ||
- Ovarian stroma
- No ductal communication
- Epithelium showing frequently a pancreaticobiliary type
- Ductal communication
- Epithelium showing frequently an intestinal phenotype with abundant mucosecretion
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