Case 5 -
Intraductal Papillary Mucinous Neoplasm
Martha Bishop Pitman
Harvard Medical School and Massachusetts General Hospital
Click on each slide thumbnail image for an enlarged view
A 75 year old alcoholic woman presented with abdominal pain. Ultrasound revealed a 4 cm
multiloculated cystic mass in the head of the pancreas connected with a dilated pancreatic duct. The
cyst had thick septations and there was no apparent wall mass. An endoscopic ultrasound guided biopsy
was performed. 30cc of viscous mucoid fluid was aspirated and sent for cytological evaluation and cyst
fluid analysis. A cytospin slide was prepared and stained with a Papanicolaou stain.
Case 5 - Figure 1 - The smear background displayed thick "colloid-type" mucin containing scattered epithelial cells, inflammatory cells and histiocytes (Low power, Papanicolaou stain).
Case 5 - Figure 2 - Some of the epithelial cells were in small, cohesive sheets with small round uniform nuclei and ample clear to vacuolated cytoplasm consistent with "adenoma" type epithelium (Medium power, Papanicolaou stain).
Case 5 - Figure 3 - Other epithelial cells were single and resembled high grade cervical dysplasia with atypical convoluted and hyperchromatic nuclei and a high nuclear to cytoplasmic ratio consistent with at least borderline malignancy(High power, Papanicolaou stain).
The specimen background contained thick viscous, colloid-like mucin. Histiocytes and a few
inflammatory cells were also present in the mucin, but an acute inflammatory, bloody or bile stained
debris field was not present. Glandular epithelial cells were seen singly, in small flat groups, and one
large monolayered sheet was present. Some cells were degenerated and necrotic but many viable cells
demonstrated atypia. Single small cells displayed features of high-grade dysplasia, similar to what you
would see in high-grade dysplasia of the cervix. A large sheet of cells showed nuclear crowding,
chromatin clearing, mildly irregular nuclear membranes and nuclear grooves
Cytological Diagnosis: Neoplastic mucinous cyst with at least moderate
dysplasia (borderline malignancy) consistent with IPMN. Invasion cannot be determined from this
A Whipple procedure removed the pancreatic head that demonstrated a multiloculated cystic mass in
continuity with the pancreatic duct. Histologically the cysts were lined by papillary mucinous glandular
epithelium with variable atypia ranging from totally bland (adenoma-like) to moderate dysplasia
(borderline malignancy) and focally with atypia consistent with carcinoma in-situ. The pancreatic duct
and a major branch were involved. No subepithelial ovarian-like stroma was present. Unequivocal
invasion of the cyst wall was not identified.
Intraductal papillary mucinous neoplasm (combined type), predominantly with moderate dysplasia
(borderline malignancy) but with focal intraductal carcinoma.
Although the history of alcoholism raised the clinical differential diagnosis of a pseudocyst, the
aspiration of thick, viscous mucoid fluid and cytologically, the presence of thick colloid type
background mucin defines the cyst as a mucinous cyst. Although an obstructed duct and retention cyst can
contain mucin, these causes of a mucinous cyst are relatively rare, neither likely to be 4 cm in size.
GI contamination can be in the form of both mucin and epithelium, but GI mucin is not so abundant as to
cover the slide like colloid (see discussion below). The presence of the dysplastic epithelial cells is
a feature of at least borderline malignancy. The cytology alone defines a neoplastic mucinous cyst of at
least borderline malignancy. The cyst fluid CEA of 850 ng/ml support that interpretation, and the
cytology combined with the clinical and radiological findings allows for an interpretation of "consistent
Neoplastic mucinous cysts include two distinct neoplasms: intraductal pancreatic mucinous neoplasm
(IPMN) and mucinous cystic neoplasm (MCN).
Intraductal papillary mucinous neoplasm (IPMN)
These tumors represent a defined clinicopathological entity composed of a typically papillary
intraductal epithelial proliferation showing a spectrum of atypia ranging from benign to malignant.
IPMN, a.k.a. mucinous cystadenoma or cystadenocarcinoma, papillary adenomas, villous adenomas,
intraductal mucin-hypersecreting neoplasm, papillary cystadenoma and cyst adenocarcinoma, and
mucin-producing tumor or carcinoma, was first recognized as a distinct entity by Ohhashi, et.al. in 1982,
and since then this entity has been increasingly recognized. It is now estimated that IPMNs account for
3 to 5% of all pancreatic neoplasms, and 20% of cystic neoplasms of the pancreas.
These neoplasms occur primarily in elderly patients, are more common in men in most studies, although
at MGH there is a female predominance, and they occur primarily in the head and body of the pancreas. By
definition, these cysts connect with the pancreatic ducts. There are three subtypes: main duct, side
branch and combined. The main pancreatic duct may be markedly dilated, and may contain multiple cysts,
usually > 1cm and typically between 3 and 5cm, that may involve the entire length of the main
pancreatic duct, segments of the main pancreatic duct or branches of the pancreatic duct. Endoscopy may
show a dilated and patulous Ampulla extruding mucin a feature which is virtually pathognomonic for IPMN.
Histologically, the WHO categorizes the tumors according to the worst degree of atypia of the lining
epithelium that may be very heterogenous:
Intraductal papillary mucinous adenomas are lined by benign columnar mucinous epithelium.
Intraductal papillary mucinous neoplasms with moderate dysplasia (synonymous with the term
borderline neoplasm) show greater degrees of epithelial atypia characterized by pseudostratification of
the cells, loss of mucin due to increased nuclear to cytoplasmic ratio and increased architectural
complexity, e.g. tufting, cellular buds.
Intraductal papillary mucinous carcinomas are neoplasms with in-situ carcinoma lining the villi
and with no evidence of invasion of the cyst wall. The architectural complexity and cytological atypia
are more severe than borderline tumors.
Invasive papillary mucinous carcinomas are defined by a carcinoma breaching the integrity of
the cyst wall. The invasive carcinoma is usually colloid type or mucinous noncystic carcinoma
(50%) or tubular type (50%) and is seen in approximately 35% of cases. The presence or absence
of an invasive carcinoma is the single most important prognosticator for patients with IPMN. An
associated solid or gelatinous cyst wall nodule should suggest the presence of an invasive
carcinoma. Small invasive carcinomas can arise focally in a large IPMN, even in the absence of
a grossly defined stromal mass, and as such all IPMNs should be carefully examined and
Mucinous cystic neoplasm
Mucinous cystic neoplasms account for approximately 5-6% of primary pancreatic neoplasm. They occur
predominantly in middle-aged (40-50 year old) females in the body and tail of the pancreas. These
neoplasms typically do not connect with the pancreatic duct which is not dilated. The cysts are
lined by tall, columnar, mucin-producing epithelium that may be studded with neuroendocrine or Paneth
cells. An ovarian-type stroma underlies the epithelium in most MCN. The W.H.O. has classified these
neoplasms according to the degree of atypia of the cyst lining epithelium as:
Mucinous cystadenoma: A cystic mucinous neoplasm lacking atypia of the lining epithelium
Mucinous cystic neoplasm with moderate dysplasia (borderline): neoplasms showing dysplastic
epithelial changes such as papillary infoldings, cellular stratification, crowding of nuclei and
Mucinous cystadenocarcinoma: Tumors in which the cyst lining is malignant. These may be
further subclassified into invasive or non-invasive. Approximately one third of MCN will have an
invasive component. Most of the invasive carcinomas are of the conventional tubular type, but
undifferentiated carcinomas with osteoclastic-type giant cells and other rare malignancies including
choriocarcinoma and sarcoma have been reported. Proper subclassification of MCN is frequently not
accurate by cytology or biopsy alone. Due to the heterogeneity of the cyst lining epithelium and abrupt
transition from benign to dysplastic to carcinoma, complete histological examination is warranted.
Cytology of Neoplastic Mucinous Cysts
The pre-operative diagnosis of pancreatic cysts is generally dependent on cytology that is
increasingly being performed by EUS-FNAB. The cytological features frequently cannot distinguish these
two entities and distinction requires clinical and radiological correlation.
The required cytological components for a specific diagnosis of a neoplastic mucinous cyst in general
| Abundant, thick colloid-like mucin.|
| Glandular epithelium +/- visible cytoplasmic mucin and +/- varying degrees of atypia. The cytoplasmic mucin is less apparent in borderline and in-situ neoplasms.|
The first clue that the cyst is mucinous is often at the time of aspiration of cyst fluid if the fluid
is mucoid and viscous and does not readily pass into the needle, as in this case. Not all neoplastic
mucinous cysts will demonstrate this however. Mucin that appears as a thick layer in the background of
the smears and often contains histiocytes and cellular debris, is a feature that is helpful in
distinguishing neoplastic mucin from GI contamination. Since not all neoplastic mucinous cysts will
demonstrate abundant and obvious extracellular mucin, however, special mucin stains and cyst fluid
analysis should be done in all cases that produce enough fluid for these ancillary tests.
The degree of atypia in the epithelial groups in the cytology sample will depend upon the
differentiation of the part of the neoplasm sampled.
Adenomas: The glandular cells are arranged in flat sheets or as single cells and show a minimal
amount of nuclear atypia. Nuclear grooves and inclusions may be seen.
Borderline: The nuclei become larger with more hyperchromasia and some mitotic activity. The
architecture of the groups becomes more complex, and shows cellular groups with crowding and overlapping
of the nuclei. Small tight clusters of high N:C ratio cells may be all that is present. Inflammation is
commonly present in the background.
Intraductal carcinoma: Sheets of cells with features of well-differentiated adenocarcinoma,
single malignant cells and mitoses are characteristic. Well-differentiated adenocarcinoma cells display
pale nuclear chromatin similar to thyroid papillary carcinoma, nuclear grooves, irregular nuclear
membranes, odd nuclear shape, subtle nuclear crowding and focal loss of nuclear polarity. Necrosis and
inflammation are more often present than in lower grade neoplasms.
Invasive carcinoma: The presence of invasion cannot be determined from the aspiration of a cyst
alone. However, aspiration of a solid area in the cyst wall, when visualized by radiological guidance
may prove diagnostic of adenocarcinoma when the cyst fluid is not.
The most important question to answer when evaluating a cystic mass in the pancreas is: Is it a
pseudocyst or not? That determination will decide the need for resection in most cases. Pseudocysts are
the most clinically relevant since they are the most common, and most misdiagnoses occur when neoplasms
are misdiagnosed as these benign, inflammatory cysts. Pseudocysts occur following bouts of acute
pancreatitis from any cause when autodigested, necrotic parenchyma is walled off by an inflammatory
response forming a cystic lesion composed of a fibrous wall and inflammation without an epithelial cyst
lining. Alcoholism with pancreatitis is a common clinical setting. Aspiration of a pseudocyst typically
retrieves an abundant amount of dark brown, turbid fluid. Cytological preparations are characterized by
granular background debris and blood, occasionally bile or hematoidin pigment- but not mucin- and by an
inflammatory cell population composed predominantly of histiocytes, which may contain hemosiderin, and
neutrophils. The cyst fluid lacks cyst lining epithelial cells, but normal or metaplastic pancreatic
epithelium, acini, islet cells, fibroblasts, gastrointestinal epithelium or mesothelial cells may all be
Gastrointestinal (GI) epithelium is a consistent, and occasionally abundant, contaminant in aspirates
obtained with EUS FNAB. When abundant, the cellularity of the smear, combined with the architectural
features and subtle nuclear abnormalities may lead to a false positive diagnosis, either well
differentiated adenocarcinoma in the case of solid masses and neoplastic mucinous cyst with the
aspiration of cystic masses. This latter differential diagnosis is the most difficult. Quality of the
background mucin and its contents and evaluation of cellular architecture and nuclear features of the
epithelium are helpful in most cases but not all (Nagle and Pitman, unpublished data). Thick
colloid-like mucin defines neoplastic mucin and is not GI contamination, as discussed above. Scant to
moderate amounts of thick and thin mucin on a slide could be either GI contamination or neoplastic cyst
contents. Duodenal epithelium usually appears as large folded sheets of uniformly distributed round
regular nuclei with smooth nuclear membranes and inconspicuous nucleoli. Goblet cells are a helpful
distinguishing feature. A luminal edge may also be present demonstrating non-mucinous epithelium
(barring the presence of foveolar metaplasia in peptic injury). Gastric epithelium is often present in
smaller cell clusters and sheets and may well appear mucinous, but usually as a small apical cup of mucin
rather than diffusely involving the cytoplasm. When you consider that adenomas of either type of
neoplastic mucinous cyst are not likely to yield a highly cellular aspirate just by the histology of the
cyst (IPMN>> MCN), and this has been our experience, then any smear containing abundant glandular
epithelium is likely GI contamination.
Cyst Fluid Analysis
Cyst fluid analysis is helpful in many cases. CEA and amylase are the two markers routinely performed
on aspirated cyst fluid at MGH. Other tumor markers have been studied. Pseudocysts are characterized by
high amylase (usually greater than 5,000 U/L) and low CEA (<200 ng/l). Neoplastic mucinous cysts
generally have a high CEA (>200 ng/ml). The amylase will be low in MCN and high in IPMN given the
continuity of the cyst with the ductal system for IPMN. A recent study in our department showed that
cyst fluid CEA levels > 500 ng/ml and/or CA19.9 levels > 5000 U/ml strongly
supported a diagnosis of a malignant pancreatic mucinous cyst, and that a CEA > 500 ng/ml and a
CA125 > 50 U/ml in the context of a pancreatic mucinous cyst suggests a diagnosis of an IPMN
(Michaels and Pitman, unpublished data). Although CEA remains the single best predictor of cyst type, it
may be helpful to continue to analyze cyst fluid for these other markers.
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