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Review Article
Pancreatic Cysts
Preoperative Diagnosis and Clinical Management
Martha Bishop Pitman, MD1; Kent Lewandrowski, MD1; Jian Shen, MD1; Dushyant Sahani, MD2; William Brugge, MD3;
and Carlos Fernandez-del Castillo, MD4
Preoperative diagnosis of pancreatic cysts benefits from integrating the clinical, radiological, and cytological features.
As patient management algorithms evolve to increasingly nonsurgical options, accuracy in distinguishing mucinous
from nonmucinous and benign from malignant mucinous cysts is important. This review focuses on pseudocysts,
serous cystadenomas, intraductal papillary mucinous neoplasms (IPMNs), and mucinous cystic neoplasms. Patients
with pseudocysts almost always present with pancreatitis and are usually medically managed. Radiological studies
reveal a unilocular cyst mostly in the pancreatic tail. Cyst fluid is thin, with high amylase but low carcinoembryonic
antigen (CEA) levels. DNA mutations are absent. Serous cystadenomas are benign and do not require resection.
Patients are usually asymptomatic and have microcystic or macrocystic masses anywhere in the pancreas. Cytology
is frequently nondiagnostic. CEA and amylase levels are low. DNA analysis may reveal loss of heterozygosity (LOH)
at 3p if associated with Von Hippel-Lindau disease. Neoplastic mucinous cysts are highly variable in their presentation. Most are resected. Mucinous cystic neoplasms typically arise in the body or tail of the pancreas of middle-aged
women and demonstrate a septated cyst without dilatation of the main pancreatic duct. Branch duct IPMNs are
more common in the pancreatic head of elderly men. Main duct dilatation correlates with main duct or combined
type IPMN. Both types of mucinous cysts produce variable amounts of mucin. Cytologically nonmalignant but atypical epithelial cells, even when scant, are an indication of a high risk for malignancy. High CEA level supports a mucinous cyst, as do KRAS mutation and good quality DNA levels. KRAS mutation and multiple LOH support malignancy.
C 2009 American Cancer Society.
Cancer (Cancer Cytopathol) 2010;118:1–13. V
KEYWORDS: pancreas, endoscopic ultrasound, fine-needle aspiration biopsy, endoscopic ultrasound fine-needle
aspiration, intraductal papillary mucinous neoplasm, mucinous cyst, pancreatic cysts, cyst fluid analysis,
carcinoembryonic antigen, molecular analysis, KRAS.
Cysts of the pancreas constitute a broad spectrum of entities from non-neoplastic to malignant cysts (Table 1). Until
the 1980s, cysts of the pancreas were thought to be relatively rare, but with the routine use of improved cross-sectional
imaging, there has been a dramatic increase in the detection of pancreatic cysts in general and asymptomatic cysts in
particular.1-8 It is now estimated that approximately 1.2% of general medical patients have a pancreatic cyst requiring
follow-up.4,9 Historically, all suspected neoplastic pancreatic cysts have been resected in good surgical candidates because
of the uncertainty in the biological behavior of mucinous cysts as well as the uncertainty in preoperative diagnosis.
Management algorithms have evolved, however, and nonsurgical treatment options are increasingly available because of
our improved understanding of the biological behavior of cystic neoplasms as well as our improved ability to accurately
diagnose these cysts preoperatively.8,10-20 Accurate preoperative diagnosis is essential for proper patient management, and
the pathologist plays a key role in the preoperative diagnosis. Despite the relatively low sensitivity and specificity of
cytology alone in this regard,21-23 when used in a multimodal approach, cytology plays an important role in patient
management decisions.11,12,24
We review our current multimodal approach to the preoperative diagnosis of pancreatic cysts at the Massachusetts
General Hospital, which includes clinical and radiological evaluation, cytology, cyst fluid chemical analysis for
Corresponding authors: Martha Bishop Pitman, MD, Department of Pathology, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114; Fax: (617)
724-6564; [email protected]
1
Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts; 2Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts; 3Department of Medicine, Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts; 4Department of Surgery, Massachusetts
General Hospital, Boston, Massachusetts
DOI: 10.1002/cncy.20059, Received: July 27, 2009; Revised: August 28, 2009; Accepted: September 1, 2009, Published online December 30, 2009 in Wiley
InterScience (www.interscience.wiley.com)
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Table 1. Cysts of the Pancreas
Non-neoplastic cysts
Pseudocyst
Retention cyst
Congenital cyst
Foregut cyst
Endometriotic cyst
Cystic nonepithelial neoplasms
Lymphangioma
Hemangioma
Primarily cystic epithelial neoplasms
Serous cystadenoma
Microcystic
Macrocystic
Mucinous cystic neoplasm
Mucinous
Mucinous
Mucinous
Mucinous
cystic
cystic
cystic
cystic
neoplasm
neoplasm
neoplasm
neoplasm
with
with
with
with
low-grade dysplasia
moderate dysplasia
high-grade dysplasia (CIS)
invasive carcinoma
Intraductal papillary mucinous neoplasm
Intraductal papillary
Intraductal papillary
Intraductal papillary
dysplasia (CIS)
Intraductal papillary
mucinous neoplasm with low-grade dysplasia
mucinous neoplasm with moderate dysplasia
mucinous neoplasm with high-grade
mucinous neoplasm with invasive carcinoma
Miscellaneous cysts
Lymphoepithelial cyst
Epidermoid cyst in intrapancreatic heterotopic spleen
Secondarily cystic solid neoplasms
Solid-pseudopapillary neoplasm
Ductal adenocarcinoma
Endocrine neoplasms
Acinar cell neoplasms
CIS indicates carcinoma in situ.
Modified from Hruban RH, Pitman MB, Klimstra DS. Tumors of the Pancreas. Atlas of Tumor Pathology. 4th Series. Fascicle 6. Washington, DC:
American Registry of Pathology, Armed Forces Institutes of Pathology;
2007.
carcinoembryonic antigen (CEA) and amylase, and in
select cases, molecular analysis. Although there are many
benign and malignant cysts in the pancreas to be aware of,
we focus on pseudocysts, serous cystadenomas (SCA), and
mucinous cysts (mucinous cystic neoplasms [MCN] and
intraductal papillary mucinous neoplasms [IPMNs]), as
these cysts represent the most commonly encountered
cysts in the pancreas.
Clinical Management
Patients with known pseudocysts are generally treated
medically with drainage.25 A history of acute or chronic
pancreatitis, or trauma, is almost always present.26 Serous
cystadenomas are benign neoplasms that can be monitored when small but are resected when large (>4 cm),
2
growing rapidly, or symptomatic.27 For patients with suspected mucinous cysts, treatment decisions may be based
on the presence or absence of symptoms, size of the cyst,
radiological features of the cyst, cytological and other parameters of cyst fluid analysis, patient age, and surgical
risk factors.14-16,20 Although both MCNs and IPMNs are
known to have malignant potential, and therefore have
historically all been resected, recent studies highlighting
slow growth and indolence of many of these neoplastic
mucinous cysts15,17 have led to increased use of nonsurgical alternatives, from close clinical follow-up to in situ
ablation.13,20,28-33
Main duct IPMNs, regardless of symptoms, cytology, or the presence of a mural nodule, are considered
high risk for malignancy, and are therefore all resected in
surgically fit candidates.8,34 For patients with suspected
branch duct IPMNs or MCNs, recent international consensus guidelines recommend surgical resection for
patients with mucinous cysts either >3 cm or smaller cysts
with high-risk features such as symptoms, positive cytology, or a mural nodule.14 We and others have shown,
however, that not all asymptomatic cysts <3 cm12,31,35 or
those with less than positive cytology are benign,11,24,28,31
and therefore have proposed aspiration and analysis of
fluid from most pancreatic cysts, especially those suspected of being mucinous cysts.20 The specific mode of
analysis depends on the fluid volume available.
Role of Imaging in Pancreas
Cyst Evaluation
Imaging plays a crucial role in both detection and characterization of pancreatic cysts. Identification of the cyst’s
morphologic details, such as internal septa, micro- or
macrocystic appearance, presence of a central scar, cyst
communication, cyst wall irregularity, mural nodules,
pancreatic duct dilation, and calcification, are essential to
categorize a cyst as a pathologic subtype and to stratify
risks for potential aggressive behavior.4,20,36 Recent
advances in computed tomography (CT), magnetic resonance imaging (MRI), and magnetic resonance cholangiopancreatography (MRCP) imaging techniques as well
as the postprocessing methods of the image have led to
high quality image acquisition and display in 2D or 3D
planes that have improved our ability to confidently recognize cyst features and make a reliable diagnosis. The
multidetector row CT is about 80% accurate for discriminating a nonmucinous from a mucinous cyst, and for predicting malignancy.20 MRI and MRCP have inherently
superior soft tissue contrast over CT that facilitates
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Update on Cysts of the Pancreas/Pitman et al
Table 2. Morphology of Pancreatic Cysts and Surgical Pathology Diagnoses
Unilocular
Microcystic
Macrocystic
Cyst With Solid Component
Pseudocyst
Retention cyst
IPMN
MCN
Unilocular SCA
SCA
IPMN
MCN
IPMN
SCA
Acinar cystadenoma
Lymphangioma
Lymphoepithelial cyst
MCN
IPMN
Solid-pseudopapillary neoplasm
Neuroendocrine neoplasm
Adenocarcinoma
Metastases
Acinar cell carcinoma
SCA indicates serous cystadenoma; MCN, mucinous cystic neoplasm; IPMN, intraductal papillary mucinous neoplasm.
recognition of subtle morphologic details not obvious on
CT, including small mural nodules, communication
between a branch duct cyst and the main duct, in the evaluation of IPMNs.20,37-39
Despite these advances in CT and MRI, reliable
image diagnosis of pancreatic cysts is not always possible
because of considerable morphological overlap in various
cyst subtypes, especially small (<3 cm) cysts. As such, a
classification system of cyst morphology has recently been
proposed for assessing the risk of malignancy.40 The 4 categories in this system are unilocular, microcystic, macrocystic, and cysts with a solid component (Table 2).
Unilocular cysts are those with thin walls and without internal septa, a solid component, or central cyst wall
calcification. Of this subtype, pseudocysts are the most
common, in which case the patient nearly always presents
with a clinical history of pancreatitis (Fig. 1). The diagnosis is supported by imaging findings of inflammation, atrophy, or calcification of pancreatic parenchyma, and
dilatation of and calculi in a typically thin-walled cyst.
Less commonly, unilocular cysts can be branch duct
IPMNs, SCAs, or lymphoepithelial cysts.
Benign SCAs are the only true microcystic lesions;
however, branch duct IPMNs can produce a raspberrylike microcystic appearance. Typically, SCAs demonstrate
a pattern of numerous tiny cysts that range from a few
millimeters up to 2 cm and show uniform lobulations. A
fibrous central scar is pathognomonic, but is only seen in
30% of multidetector row CT images. Macrocystic
lesions are larger (>2 cm in diameter) and yet have fewer
compartments than microcystic tumors. Microcystic neoplasms may appear solid, and when microcystic areas are
focal in an otherwise oligocystic serous cystadenoma,
there may be confusion with a high-risk mucinous cyst.
Mucinous cystic neoplasms are found predominantly
in young to middle-aged women, are well defined, exophytic lesions commonly located in the tail, and do not
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February 25, 2010
Figure 1. An axial computed tomography scan of a pseudocyst revealed a large, thin-walled unilocular cyst around the
head of the pancreas after pancreatitis.
communicate with the pancreatic duct. Branch duct IPMNs
are most often seen in older men. Whereas main pancreatic
duct IPMNs are morphologically distinct, branch duct or
combined IPMNs often show features similar to other macrocystic lesions. The presence of a channel of communication between the cyst and the main duct is highly suggestive
of a branch duct IPMN. Uncommon macrocystic lesions
include nonfunctioning neuroendocrine neoplasm, lymphangioma, and rare congenital malformations.
The presence of a solid mass or mural nodule in either unilocular or multilocular cysts, main pancreatic
duct dilatation >10 mm, thick septations, and biliary
obstruction are recognized features of malignancy
(Fig. 2).20,37 Both multidetector row CT and MRCP
are helpful in characterizing cystic pancreatic neoplasms
and, if performed appropriately, demonstrate comparable performance.39,41
In patients with small cysts (<3 cm) without suspicious features, where surgery is not considered the appropriate next step of management, imaging can be used as a
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Figure 2. An intraductal papillary mucinous neoplasm with
invasive carcinoma is shown. A mural nodule is a high-risk
feature of malignancy in a mucinous cyst.
surveillance tool to longitudinally follow lesions that
could progress to malignancy.
Endoscopic Ultrasound and Endoscopic
Ultrasound Fine-Needle Aspiration
The strength of endoscopic ultrasound (EUS) is its ability
to detect and aspirate small cystic lesions with a high level
of safety. EUS is very sensitive for detecting small cysts,
many of which are branch duct IPMNs, but imaging
alone is insufficient for differentiating between mucinous
and nonmucinous22 as well as between benign and malignant lesions.42 EUS assists in the detection of malignancy
arising from MCNs or IPMNs by demonstrating focal
nodules and invasive lesions, and guiding fine-needle aspiration (FNA) of suspicious lesions.43,44 The EUS criteria
for malignancy in IPMNs are: 1) main duct >10 mm, 2)
focal cystic lesion >3 cm, and 3) nodule >5 mm.45,46
EUS-FNA is performed with a linear echoendoscope
passed into the duodenum through the stomach. Pancreatic cystic lesions are readily seen as hypoechoic (dark)
lesions within the pancreatic parenchyma on EUS
(Fig. 3). FNA is usually performed with a 22-gauge needle
containing an occluding stylet. With the echoendoscope
transducer in close proximity to the cystic lesion, the
needle is guided in a perpendicular path to the wall of
the cyst. With 1 passage of the needle into the lumen of
the cyst, aspiration of cyst fluid is initiated with suction.
The cyst fluid is aspirated until the cyst collapses. Highly
viscous fluid may require a considerable amount of time
for evacuation of the cyst contents, and this is the first clue
that the cyst is likely mucinous. Focal nodules, thick
septations, and adjacent masses should be targeted for
aspiration and cytologic examination.
4
Figure 3. A mucinous cystic neoplasm with low-grade dysplasia is shown. This endoscopic ultrasound image depicts a
large cyst with thin septations in the pancreatic tail of a middle-aged woman. The aspiration needle is seen reflected
diagonally across the cyst cavity.
Allocation of cyst fluid should be based on the dominant clinical question (Fig. 4). When the clinical question
is whether the cyst is mucinous, cyst fluid CEA should
receive the highest priority for testing. Consideration of
molecular testing of the cyst fluid for KRAS or other mutations is entertained when the clinical and radiological
features strongly support a mucinous cyst without obvious
malignant features such as a mural nodule or invasion of
adjacent structures, and the clinical question is benign
versus malignant. Molecular testing should also be considered if the cyst fluid is too scant for CEA and likely
nondiagnostic cytology (<1 mL). There are few complications associated with cyst FNA, but intracystic bleeding
is the most common. Usually the bleeding stops spontaneously without sequel. Acute pancreatitis is a rare complication, but potentially serious.
Cyst Fluid Analysis
Chemical analysis of pancreatic cyst fluid has evolved
from an experimental evaluation of a long list of cancer
antigens, including CEA, CA 72-4, CA 125, CA 19-9,
and CA 15-3 to CEA alone, as it has been shown to be the
most accurate marker to date to distinguish nonmucinous
from mucinous cysts.23,47,48 CEA does not, however, distinguish benign from malignant mucinous neoplasms.23,49
It should be understood, however, that measurement of
CEA in cyst fluid has not been approved by the US Food
and Drug Administration (FDA), and therefore represents an off-label application in this setting. Furthermore,
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February 25, 2010
Update on Cysts of the Pancreas/Pitman et al
Figure 4. An algorithm for fluid triage from pancreatic cysts
answers the clinical questions of (A) mucinous versus neoplastic nonmucinous cysts and (B) benign versus malignant
mucinous cysts. CEA indicates carcinoembryonic antigen.
no commercially available CEA assays have been formally
validated for any of the cyst fluid matrices that may be
encountered in clinical practice. Published cyst fluid data
and cutoff values must therefore be viewed with caution,
because important validation parameters such as linearity,
precision, accuracy, and stability have not been reported.
Each cyst type represents a unique matrix that would need
to be independently validated. In addition, the handling
of cyst fluid submitted for CEA analysis is not standardized, with some laboratories receiving fluid undiluted,
and others diluted or placed in fixative such as Preservcyt
(Hologic, Inc, Marlborough, Mass) or Cytorich red (Becton-Dickinson, Burlington, NC). Approximately 1 mL of
fluid is needed for the CEA analysis. If samples are too
scant, too viscous to pipette, or inhomogeneous because
of mucin clumps in watery fluid, the cyst fluid can be
diluted with saline and/or vortexed to achieve homogeneity. The dilution factor must be accounted for in the final
CEA value reported. As such, it is best to let the laboratory
handle the fresh, undiluted fluid. Debris within the cyst
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February 25, 2010
fluid that may clog the pipette should be removed by centrifugation. Grossly bloody samples present a unique
problem, given that contaminating peripheral blood
dilutes the cyst fluid by an unknown dilution factor. This
is mostly a problem just below the cutoff value, as elevated
CEA levels still provide useful information.
Finally, it must be remembered that cyst fluid values
using different commercial assays may not yield equivalent results. Therefore, reported cutoff values are assay
specific, and it is inappropriate to apply a reported cutoff
value to an assay from a different manufacturer. That
being said, a cyst fluid CEA level of <192 ng/mL (at Massachusetts General Hospital) fails to support the presence
of a mucinous cyst, and values >192-200 ng/mL (at Massachusetts General Hospital) support the interpretation of
a mucinous cyst.23,48,50,51 A level >800 ng/mL is 98%
specific for a mucinous cyst using a meta-analysis of
pooled data from 12 studies at different institutions.47
Increasing the cutoff value of CEA for support of a mucinous cyst will have a negative effect on sensitivity. In this
same meta-analysis, levels <5 ng/mL were 98% specific
for a serous cystadenoma.47
Amylase is also a helpful marker, as amylase is typically very high, usually in the thousands and almost never
<250 ng/mL in pseudocysts,47 but is low in serous
cysts.23,47 Although it would seem to make sense that
high amylase levels would be consistently found in
IPMNs, in contrast to MSNs, because of the connectivity
to the pancreatic ductal system, this has not proven to be
true in our experience.52 Like CEA, measurement of amylase or lipase in pancreatic cyst fluids has never been formally validated or approved by the FDA. Comments
concerning technical problems for amylase measurement
are similar to those described for CEA. As a final caveat,
amylase values may be particularly useful when elevated to
rule out the possibility that the cyst in question may be a
nonpancreatic cyst.
Molecular Analysis of Cyst Fluid
The molecular testing of cyst fluid has increased over the
past few years because of the availability of a commercially
available test (PathFinderTG, RedPath Integrated Pathology, Pittsburgh, Pa) coupled with increasingly small
amounts of cyst fluid too scant for chemical analysis or
diagnostically useful cytology.
Similar to pancreatic ductal adenocarcinoma, molecular alterations in neoplastic mucinous cysts of the pancreas have also demonstrated multistep genetic changes
involving early KRAS mutation, followed by p53
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mutation, and loss of p16 and SMAD4.53-58 Detection of
these underlying molecular changes using cyst fluid DNA
derived from exfoliated epithelial cells in a small volume
of fluid has become a focus of active research. The group
from the University of Pittsburgh subjected cyst fluid
obtained from EUS-guided FNA to DNA extraction followed by polymerase chain reaction amplification.59,60
DNA quantity/quality, KRAS-2 gene mutation in the first
exon, and loss of heterozygosity (LOH) using microsatellite markers closely linked to a broad panel of genomic
loci associated with tumor suppressor genes including
p53, p16, PTEN, APC, CDKN2A, CMM, MCC, and
VHL, were analyzed and compared with histology.59,60
Their early studies showed that increased levels of DNA,
the presence of KRAS mutation, or 2 loci of allelic
imbalance (loss of heterozygosity) was each associated
more significantly with a mucinous neoplasm, whereas a
high amplitude of mutations, more specifically the
sequence of KRAS-2 gene mutation followed by allelic
loss, was predictive of malignancy.59,60 These results initiated the commercialized testing developed by this group
(PathFinderTG, RedPath Integrated Pathology).
The use of this specific commercially available molecular analysis is controversial, however. Recent studies
have demonstrated that the overall performance of molecular analysis was inferior to CEA analysis in predicting
mucinous cysts, although KRAS mutation did show
higher specificity, and the concordance of CEA level with
increased DNA level, KRAS mutation, or 2 allelic
imbalances appeared to be poor (kappa ¼ 0.1-0.3).61
Interestingly, however, in the same study by Sawhney
et al,61 the authors showed that although an elevated CEA
level (82%) showed higher sensitivity than molecular
analysis (77%), the combination of CEA and molecular
analysis achieved 100% sensitivity, suggesting that CEA
and molecular data may be complimentary rather than
concordant.
When using a multimodal approach to diagnosis
that includes clinical information, CEA level, EUS features, and cytology to render a clinical consensus diagnosis
instead of CEA level alone, we found good concordance
between the clinical consensus and molecular diagnosis in
the categories of nonmucinous, benign mucinous, and
malignant mucinous cysts, with an overall kappa statistic
of 0.816.62 A recently published multi-institutional prospective study (PANDA study),63 the largest study so far,
included 113 cysts with histologic follow-up and found
that among the 3 changes, including DNA level, KRAS
mutation, and 2 loci of allelic loss, KRAS mutation
6
showed the highest odds ratio (20.9) and specificity
(96%), but a low sensitivity (45%), for mucinous cysts.
The specific sequence of KRAS mutation followed by
allelic imbalance detected in cyst fluid was shown to be
specifically associated with mucinous cysts and malignancy, although the sensitivity is again suboptimal.63 In
addition to a CEA cutoff value of 192 ng/mL, the presence of a KRAS mutation identified additional mucinous
cysts and improved the sensitivity of CEA from 64% to
82% for combination of CEA and KRAS while maintaining the specificity at 83%. Data from the PANDA study,
in conjunction with others,61-63 highlight the importance
of interpreting information from molecular analysis in the
context of the clinical and radiological information as well
as cyst fluid analysis for maximizing the sensitivity and accuracy for the diagnosis of mucinous cysts.
The current commercially available molecular analysis is by a single commercial laboratory (RedPath Integrated Pathology), and it is unknown whether these
results can be reliably reproduced in other laboratories.
Most of the published studies have limited sample size
and population bias, because the study cohort often consists of a higher number of patients with malignant cysts
than expected because of the availability of histologic follow-up. A longer observation period and accumulation of
molecular data are needed to draw a definitive conclusion
about the clinical utility of molecular analysis of pancreatic cyst fluid in the future. Nevertheless, the current data
at least allow us to conclude that cyst fluid analysis for
DNA level, KRAS mutation, and allelic imbalances cannot
replace other clinical ancillary tests such as CEA or cytology at the present time; rather, this molecular analysis
adds additional information to the complex preoperative
diagnostic puzzle. Given the increasingly small cysts that
are detected resulting in small sample sizes inadequate for
optimal cytology or CEA analysis (<1 mL) in many cases,
the promise of information from analyzing such a small
amount of cyst fluid (200 lL) may be sufficient to warrant
this ancillary test despite the expense. In cysts with sufficient aspirate volumes for cytology and CEA analysis, the
value-added benefit of molecular analysis is yet to be
determined.
Cytological Features of Pancreatic Cysts
The most important job for the pathologist is to distinguish pseudocysts that can be medically managed from
neoplastic cysts that may require resection. The second
most important distinction for the pathologist to make is
between a serous cyst and a mucinous cyst. Distinguishing
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February 25, 2010
Update on Cysts of the Pancreas/Pitman et al
lesional cells and fluid from gastrointestinal contamination is vital to making an accurate interpretation. In addition, as we have emphasized in this review, it is important
for the pathologist not to interpret the cytology specimen
in a vacuum, but to make an interpretation with the
knowledge of the clinical history, radiological features,
and any ancillary tests, especially cyst fluid analysis of
CEA and amylase. Understanding and incorporating
these factors into the interpretation of the cytomorphologic findings guides the pathologist into making a more
meaningful report for the various clinicians in charge of
patient management decisions. Ancillary tests, such as
special stains, immunohistochemical tests, and molecular
tests, are part of the final pathology report for virtually all
pathology specimens, and pancreatic cyst fluid should not
be different. Below, the 4 major cysts of the pancreas are
discussed using a multimodal approach.
Figure 5. A pseudocyst is shown. It is a granular and proteinaceous cyst fluid without cyst-lining cells that may contain
histiocytes, inflammation, hemosiderin, and flecks of hematoidin pigment (Cytospin; Papanicolaou stain, high power).
Pseudocyst
Fluid from a cyst in the clinical setting of pancreatitis and/
or alcohol abuse, or with a history of trauma, should place
pseudocyst at the top of the differential diagnosis at the
time of slide examination. Caution is needed, however,
because patients with IPMNs, and to a lesser degree
MCNs and SCAs, can present clinically with pancreatitis.15,27,64 The cyst fluid aspirated from an uncomplicated
pseudocyst is generally thin and nonmucoid, and is frequently discolored (not white). An infected pseudocyst,
however, may produce purulent, mucoid-appearing fluid.
The cells present in the fluid may include acute and
chronic inflammatory cells, histiocytes, and hemosiderinladen or foamy macrophages, and by definition should
not contain any cyst lining epithelial cells. The background is often granular and proteinaceous, and may contain flecks of hematoidin pigment (Fig. 5).65 Not all
pseudocysts have a characteristic ‘‘dirty’’ proteinaceous
background, and the cyst contents may appear rather clear
with only scattered histiocytes, which may appear epithelioid and can be mistaken for epithelial cells.66 Gastrointestinal epithelial and mucin contamination, particularly
from the stomach, can lead to a misdiagnosis of a mucinous cyst.65,67,68 Special stains for mucin that show only
scant amounts of mucin-positive fluid should not be
interpreted as evidence of a mucinous neoplasm, as this
finding may well represent gastrointestinal contamination. Cyst fluid analysis with an elevated amylase in the
thousands and low CEA level (<192 ng/mL) supports the
interpretation of a pseudocyst.23,47,65 Molecular analysis
should not reveal KRAS mutation or LOH.62,63
Serous Cystadenoma
Patients are typically asymptomatic without a history of
pancreatitis.27 Distinction of a serous from a mucinous
cyst is not always straightforward. Despite the more solid
than cystic composition of the typical microcystic serous
cystadenoma, obtaining diagnostic tissue with EUS-FNA
is difficult.69-72 Oligocystic and unilocular variants of serous cystadenoma also occur, mimicking branch duct
IPMN and MCNs.20,39 Aspirated fluid is thin and clear
or thin and bloody and typically of very scant volume.
Intact cells are few, and the scant glycogenated cytoplasm
is very delicate, is often destroyed or distorted with smearing.69,70 Many cases are interpreted as nondiagnostic
because of insufficient cellularity. Intact cell clusters are
composed of bland cuboidal cells with round central to
slightly eccentric nuclei and scant finely vacuolated but
nonmucinous cytoplasm (Fig. 6). Epithelial cells present
on a cellblock preparation or unstained cytospins can be
evaluated with histological stains for periodic acid-Schiff
(PAS) and PAS with diastase to confirm the presence of
cytoplasmic glycogen. In our experience, there is rarely
sufficient cyst fluid for cellblock preparation or additional
cytospin preparations for such testing. We have noted
that hemosiderin-laden macrophages may be a clue to the
diagnosis when present in a clean, nonproteinaceous background.69 By using the multimodal approach, even if it is
not technically considered diagnostic from a pure cytological point of view, these cells in the setting of a microcystic
or septated (rarely unilocular) cyst in the body/tail of the
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Figure 6. A serous cystadenoma is shown, demonstrating
bland cuboidal cells with round central to slightly eccentric
nuclei and scant finely vacuolated but nonmucinous cytoplasm (direct smear; Papanicolaou stain, high power).
Figure 7. Thick and viscous cyst fluid from either an intraductal papillary mucinous neoplasm or a mucinous cystic neoplasm is reflected on the slide as a thick sheet of colloid-like
mucin that often covers much of the slide (direct smear; Papanicolaou stain, low power).
pancreas with a low CEA (<5 ng/mL) and amylase level
(<250 U/L) are sufficient to be consistent with an interpretation of a serous cystadenoma. Molecular analysis
may reveal LOH at 3p25, as serous cystadenomas are associated with von Hippel-Lindau syndrome.73 KRAS mutation or multiple LOH should not be detected.62,63
much of the slide (Fig. 7). Mucin contamination from the
gastrointestinal tract will not be of this quality or quantity,
and special stains for mucin and CEA analysis are not
needed to confirm this type of cyst fluid as mucin. Degenerated inflammatory cells and histiocytes within the
mucin provide added support that the mucin is from the
cyst.83 This type of mucin is sufficient in and of itself even
if acellular to make a diagnosis of a neoplastic mucinous
cyst.12,74,79
Approximately 50% of neoplastic mucinous cysts
lack such obvious extracellular mucin in our experience.
Extracellular mucin may appear as focally thick clumps or
thin wisps, and as focal or diffuse thin background mucin
not easily observed on routine preparations. Mucin stains
can be difficult to interpret because gastrointestinal contamination may introduce wisps of mucin into the specimen, so care must be taken not to interpret any wisp of
mucin-positive material as indicative of a mucinous cyst.
Scattered wavy clumps or a uniform film of mucin as well
as intracytoplasmic mucin accentuated with either Alcian
blue or mucicarmine help to identify thin mucin and distinguish it from fibrin and protein (Fig. 8). Liquid-based
cytology attenuates the appearance of mucin even more,
and is not a recommended mode of cyst fluid processing.
In most cases, CEA analysis is particularly helpful in these
situations, as an elevated level >192 ng/mL (at Massachusetts General Hospital) supports the interpretation of thin
or scant extracellular mucin as originating from a mucinous cyst.
MCNs and IPMNs: Neoplastic Mucinous Cysts
The cellularity of cyst fluid is rarely sufficient or characteristic enough to distinguish the 2 mucinous cysts, typically
resulting in a generic cytology report of a mucinous cyst.
Given that the cytological features of the 2 mucinous cysts
are similar with respect to the grade of dysplasia, as well as
the diagnostic features of carcinoma resulting in similar
patient management decisions, these neoplastic mucinous
cysts will be discussed together.
Aspiration of a neoplastic mucinous cyst produces
highly variable amounts of extracellular mucin and cyst
lining epithelium.12,21,74-81 Cytology may underestimate
the final histologic grade of neoplastic mucinous cyst,
given that the cyst lining is quite heterogeneous, and the
degree of epithelial atypia may not be representative of the
highest degree of atypia of the cyst on histology.12,79,82
Aside from the clinical suspicion of a neoplastic
mucinous cyst, the presence of a mucinous cyst is often
confirmed at the time of aspiration when thick, viscous
mucus is grossly appreciated by the aspirator. Direct
smears of this thick and viscous cyst fluid are reflected on
the slide as thick sheets of colloid-like mucin that covers
8
Cancer Cytopathology
February 25, 2010
Update on Cysts of the Pancreas/Pitman et al
Figure 8. An Alcian blue stain highlights scant, thin extracellular and intracellular mucin (direct smear; Alcian blue histochemical stain, high power).
Figure 9. Contaminating gastric epithelium may be impossible to distinguish from lesional epithelium of low-grade mucinous cysts (direct smear; Papanicolaou stain, high power).
Screening the cytology preparations for an epithelial
component is critical to accurate interpretation of the risk
of malignancy.11,12,79 Neoplastic mucinous cysts with
low-grade dysplasia (adenomas) are difficult to diagnose,
because of scantily cellular aspirates that rarely produce
epithelial cells confidently interpreted as arising from the
cyst. For branch duct IPMNs most commonly lined by
gastric-foveolar type epithelial cells, a transgastric EUSFNA may introduce contaminating gastric epithelium
impossible to distinguish from lesional epithelium
(Fig. 9). Fortunately, most branch duct IPMNs are
Cancer Cytopathology
February 25, 2010
Figure 10. A mucinous cystic neoplasm with low-grade dysplasia is shown. A small strip of glandular epithelial cells demonstrates cytoplasmic mucin filling the entire cytoplasmic
compartment (Cytospin; Papanicolaou stain, high power).
located in the pancreatic head, and are accessed by a transduodenal approach, allowing for an easier distinction
between duodenal contaminating epithelium and lesional
epithelium. MCNs are much more common in the body
and tail of the pancreas; however, so distinguishing the epithelium of a MCN adenoma and gastric epithelium
remains a challenge. One should not expect a benign
MCN adenoma to shed much epithelium into the cyst
lining, a fact that is exploited in the molecular analysis of
the cyst fluid, resulting in low DNA quantity and quality.62,63 The presence of few single cells, small clusters,
and small strips of bland glandular epithelial cells that
demonstrate cytoplasmic mucin filling the entire cytoplasmic compartment favors lesional epithelium in contrast to
columnar epithelium with a uniform apical mucin cup
typical of gastric epithelium (Fig. 10).67
Atypical epithelial cells are most critical to recognize, as we have shown that these cells even when very
scant correlate with an increased risk of malignancy.12,62,79 A neoplastic mucinous cyst with a cyst lining of moderate or higher dysplasia may produce atypical
epithelial cells in small, tight, bud-like clusters or singly
with increased nuclear to cytoplasmic ratio, irregular nuclear membranes, and cytoplasm with or without mucin
(Fig. 11). Crowded groups of cells with open chromatin,
irregular nuclear membranes and nucleoli, and necrosis
support the interpretation of carcinoma both in cyst fluid
and in solid mass lesions.79,84-86 Small atypical epithelial
cells with necrosis are also a suspicious finding (Fig. 12).
9
Review Article
Conclusions
In the optimal patient management algorithm, an asymptomatic patient with a noninvasive mucinous cyst could
be conservatively managed. We advocate a multimodal
approach using cytology, CEA, and molecular analysis in
selective cases and emphasize the importance of the cytologist in the preoperative diagnosis of pancreatic cysts.
CONFLICT OF INTEREST DISCLOSURES
The authors made no disclosures.
REFERENCES
Figure 11. An intraductal papillary mucinous neoplasm with
moderate dysplasia is shown. A small cluster of atypical epithelial cells in a small, tight, bud-like cluster demonstrates an
increased nuclear-to-cytoplasmic ratio, irregular nuclear
membranes, and cytoplasm with a small mucin vacuole
(direct smear; Papanicolaou stain, high power).
Figure 12. An intraductal papillary mucinous neoplasm with
invasive carcinoma is shown. Atypical epithelial cells and
background necrosis support the interpretation of carcinoma,
usually invasive carcinoma (direct smear; Papanicolaou stain,
high power).
Such atypical cells are not those expected from benign epithelium from the stomach or duodenum.67,68 Accurate
distinction between carcinoma in situ and invasive carcinoma has not been extensively investigated. In our experience, background cellular, coagulative-type necrosis (not
just a few degenerated cells in mucin) distinguished noninvasive from invasive tumors.79
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