Pancreatic Tumors, an Integrated Cyto/Histopathologic Approach
Mostafa Fraig, MD and David Lewin, MD
Pancreatic malignant tumors are one of the leading causes of cancer related deaths in the United
States and the incidence of these tumors continues to rise. Approximately 32,000 cases are diagnosed
every year and less than 5 percent of these patients survive beyond 5 years. The advent of new and
improved imaging modalities has increased the resolution and accuracy of detection, detecting
ever-smaller lesions. However, only 15 percent of cases are confined to the pancreas by the time of
presentation and amenable to surgical resection and possible cure.
The accessibility of the pancreas by different techniques has offered many options to evaluate and
biopsy pancreatic lesions. The integration of clinical and imaging findings along with the limited
material obtained by fine needle aspiration biopsy is paramount in reaching the correct diagnosis and
avoiding diagnostic pitfalls. Recently, EUS-guided FNAB has gained popularity in the
evaluation of pancreatic lesions. Collecting the pertinent clinical data is key to laying the foundation
for an accurate FNAB diagnosis. Among these are age, gender, history of alcohol abuse, history of
biliary obstruction and subsequent stent insertion, history of metabolic or hormonal level changes and
recent significant weight loss.
Incidence of various tumors in different age groups can be useful in the differential diagnosis of
pancreatic lesions. For example, pancreatoblastoma tends to occur in a very young population below the
age of 5 years. Younger adults in their 20s and 40s tend to have endocrine tumors and
solid-pseudopapillary neoplasms. On the other hand, older adults, in their 40s and 50s, are more likely
to present with chronic pancreatitis or some mucinous tumors. In a much older population, in the 60s and
70s, the tendency is towards malignant adenocarcinomas.
With regard to gender, solid-pseudo capillary neoplasms are nine times more common in females than in
males. Mucinous cystic lesions are almost exclusive to female patients. There is a slight increase of
incidence in male patients of chronic pancreatitis, pancreatic ductal carcinoma and acinar cell
In many instances the occurrence of chronic pancreatitis precedes that of ductal carcinoma by about
one or two decades. The most common cause of chronic pancreatitis is alcohol abuse. The most common
presentation of pancreatic head mass is an obstruction of either the biliary or pancreatic duct systems.
This may result in the dilation of both ducts resulting in "double duct sign", a radiographic term that
is useful in identifying an ill-defined mass in the head of the pancreas. A common procedure to relieve
biliary obstruction is to insert a stent to keep the duct system patent. This may result in severe
reactive atypia. For the unsuspecting pathologist this may result in cancer overdiagosis (a diagnostic
pitfall), especially if the endoscopist inadvertently introduces the needle in the area near the stent or
obtains biliary brushings from the same area.
Functioning islet cell tumors can result in abnormal levels of the produced hormone and associated
clinical manifestations. Multiple endocrine neoplasias (MEN) are well known sets of syndromes resulting
in tumors in multiple organ systems, including the pancreas. History of recent substantial weight loss
is usually associated with malignancy and such history could be helpful in cases where the findings are
suspicious but not diagnostic of malignancy.
The integration of endoscopic or radiological findings into the diagnostic algorithm may help in
sorting out diagnostic possibilities. For example, the finding of a solid versus a cystic lesion is very
helpful in reaching a more accurate diagnosis. The location of the lesion in the pancreas is also very
helpful. Certain tumors tend to occur in different locations, for example pancreatic endocrine tumors
tend to occur in the tail of the pancreas whereas pancreatic ductal adenocarcinoma tends to occur in the
head of the pancreas. Small well-defined masses are more consistent with pancreatic endocrine tumors,
whereas larger ones tend to represent ductal carcinoma or solid pseudopapillary neoplasms. Local
invasion (vascular or into adjacent organs) is a helpful sign of malignancy. Intraductal papillary
mucinous neoplasms tend to occur in the main ducts or in side branch duct causing proximal dilation of
the duct while still communicating with the duct system, a finding that can be appreciated with a variety
of imaging techniques. Additionally, endoscopically these lesions are described as having a patulous
ampulla of vater with abundant mucin extruding from the papilla. With cystic lesions, the quality of the
aspirated material (a serous fluid or thick mucin) is helpful in differentiating serous from mucinous
neoplasms. Additional laboratory studies (such as viscosity, amylase, and CEA level) on the aspirated
material can be performed to help in ascertaining the potential presence of malignancy in the lesion.
Management considerations may also be important with regard to the information the clinicians may need
from the pathologist. In the situation of a resectable lesion in a patient with an abnormal radiographic
finding, the need for a definitive diagnosis by cytology is less important than an unresectable patient.
The first patient is going to go to surgery unless there is an unexpected finding (lymphoma or metastatic
carcinoma). In this instance a suspicious or atypical result may be reasonable for the clinician.
However, an unresectable patient getting definitive chemo and radiation therapy or going on a clinical
trial will often require a definitive malignant diagnosis.
Cytologic Evaluation of the Pancreato-Biliary Tree
There are a number of different methods to evaluate the pancreato-biliary tree. These include
aspiration of biliary of pancreatic juice, duct brushing, intraductal biopsy, and fine needle
aspiration. The first three methods are typically performed during endoscopic retrograde
cholangiopancreatography (ERCP) and their clinical utility is limited (with diagnostic yields up to
50-60%). The mainstay of diagnosis in pancreatic lesions is fine needle aspiration (FNA). These can be
performed by a variety of methods including endoscopic ultrasound (EUS) guided, CT guided, ultrasound
guided, or intraoperative. In terms of sensitivity and diagnostic criteria, they are all similar.
EUS-Guided FNA Biopsy:
The introduction of EUS-guided FNA in the early '90s has increased in popularity as it offered many
advantages. The first type of EUS to be introduced was the radial array echoendoscope. This was
accomplished by attaching an ultrasound transducer to an endoscope. In the radial array, the ultrasound
transducer produces a 360-degree live image in a plane perpendicular to that of the endoscope. The
radial array is not suited for FNAB as the needle appears as a white dot as it crosses the ultrasound
field. Linear array is another type by which ultrasound imaging is created perpendicular to that of the
endoscopic axis. Using this type, the needle can be visualized hence as it is introduced into the
lesion. By having the ultrasound source close to the target lesion, higher resolution and accuracy could
be attained than by using CT. In reported sensitivity and specificity of EUS-guided FNA in the
literature ranged from lower '90s of the former and close or 100% percent for the latter.
The presence and availability of on-site evaluation of EUS or CT guided FNAB has proven to be crucial
to the success of the procedure. Numerous studies have indicated that there is a significant increase in
the diagnostic yield with 10-15 percent decrease in the "unsatisfactory specimen" rate. Subsequently,
this has proven to be cost effective when compared with the alternative of repeating the procedure or
resorting to surgical procedures. Another major advantage is the ability to triage specimens and obtain
materials for ancillary studies and obtain information during the procedure. This ultimately would lead
to less equivocal diagnoses and higher quality of care.
One potential pitfall is contamination from the GI landing tissue which can overshadow other
components obtained from the target lesion.
Normal Material Obtained Through EUS-Guided FNAB Procedure:
1- Mucin: This could represent either a
contamination from the GI tract or a component of a neoplastic process. The normal mucin is usually
thin, in small amounts, and is devoid of cells. On the other hand, thick viscous mucin and mixed with
macrophages and cellular debris should raise the possibility of a neoplastic process. Additional studies
of extracted mucin using a combination of PAS stain with diastase digestion and mucicarmine/Alcian blue
at pH 2.5. They could help in the distinction between neutral mucin from the stomach versus acidic mucin
from a mucinous lesion and the presence of intracytoplasmic mucin.
2- Small intestinal epithelium: Shows as flat sheets of uniform cells with
occasional goblet cells in between.
3- Pancreatic ductal cells: Appear as flat sheets with uniform cells having
round or oval nuclei equidistant from each other in the perfect honeycomb pattern.
4- Gastric epithelium: Usually present as sheets of foveolar epithelium
similar in appearance to "bubble wrap" with the nuclei situated basally to a clear cytoplasm when looked
at en face.
5- Pancreatic acinar cells: Usually appear as clusters of cells with
uniform nuclei and granular cytoplasm in an acinar pattern. They should be differentiated from endocrine
cells, which have a clear cytoplasm.
6- Other cells: These could potentially be present in the FNA specimens.
They include squamous cells from the esophagus, stromal cells from the GI wall, mesothelial cells and
Based on imaging studies, pancreatic lesions could present as either solid masses or cystic lesions.
This could constitute a basis for a diagnostic algorithm with distinctive entities included in clusters
for a differential diagnosis.
These would include pancreatic ductal carcinoma, chronic pancreatitis, pancreatic endocrine neoplasms
(PEN), solid-pseudopapillary tumor (SPT), pancreatoblastoma and acinar cell carcinoma. Metastatic
lesions should also be included in this differential, especially if there is any history of prior
Pancreatic ductal carcinoma:
This is the most common malignant tumor of the pancreas, constituting 85% of all pancreatic tumors.
It is more prevalent in older patients (typically in the 6th and 7th decades) in contrast to chronic
pancreatitis (which usually occurs a decade or two earlier). It is more common in males than in
females. The usual site of involvement is the head of the pancreas. On imaging it appears as a vague
lesion with loss of the usual acinar lobulation. Strictures of the biliary and/or pancreatic ducts are
common, resulting in irregular dilation of both ducts, a finding that is commonly known as "double duct
The aspirate is usually cellular and in high-grade lesions there is a necrotic background and variable
amount of mucin. The cells are in sheets, clusters and individual cells with significant pleomorphism,
high N/C ratio and cellular crowding and overlapping.
Well-differentiated adenocarcinoma poses the greatest diagnostic challenge as it's cytologic and
histologic features overlap with chronic pancreatitis. Several studies have shown that at least four
cytologic criteria are prevalent in the majority of these malignant cases. These include nuclear
enlargement (2.5 the size of red blood cells), anisonucleosis (4:1 rule), nuclear membrane irregularity
and the overlapping and cellular overcrowding resulting in three-dimensional clusters. Other additional
findings could include loss of cellular polarity, necrosis, nuclear hyperchromasia or parachromatin
clearing, brisk mitotic activity and macronucleoli. The latter group is less prevalent.
In patients who are resectable and good surgical candidates, the diagnoses of adenocarcinoma (or the
finding of a pancreatic head mass with atypical or suspicious cytology) will typically result in a
Whipple resection as this is the best hope for long term survival. The Whipple resection is a
pancreatoduodenectomy and the pathologist typically receives the head of the pancreas, duodenum +/-
stomach and gallbladder (which may or may not be attached to the primary specimen). Usually the surgeon
will request a frozen section of the pancreatic neck margin and bile duct margin. In reality the most
important margin is the uncinate or superior mesenteric margin as this is the region where most
recurrences occur. The surgeon typically does the best they can with this margin and do not usually ask
for frozen sections of this margin as it will not change what they do intraoperatively (they typically
can do no more). However this margin should be documented in the final report. Similar to cytology,
well-differentiated adenocarcinoma can mimic chronic pancreatitis. The useful features at frozen (and
permanent) section are: nuclear size variation greater than 4:1, incomplete gland lumens, intraluminal
necrosis, disorganized duct distribution (meaning ducts running within the intralobular septae),
perineural and vascular invasion.
A number of relatively rare adenocarcinoma variants are described (the vast majority of lesions are
- Mucinous noncystic adenocarcinoma (colloid carcinoma): These lesions are similar to colloid
carcinoma of the breast with epithelial cells floating in pools of mucin. The majority of them are
associated with intraductal papillary mucinous tumors and they appear to have a better survival.
- Signet-ring cell carcinoma: This is a very rare neoplasm with at least 50% signet ring cells. It
must be distinguished from metastatic breast or gastric carcinoma.
- Adenosquamous carcinoma: A tumor with at least 30% squamous component
- Undifferentiated (anaplastic) carcinoma: A very poorly differentiated carcinoma with either
pleomorphic large cell or spindle cell component. Often requires immunohistochemical stains to identify
the epithelial origin.
- Osteoclast-like giant cell tumor: An interesting tumor with benign osteoclast-like giant cells
(which stain with CD68) and undifferentiated epithelial or mesenchymal cells. Needs to be differentiated
from anaplastic carcinoma (which may have malignant giant cells). Has also been reported in association
with mucinous cystic tumors (IPMN and MCN)
Occurs in patients with history of alcohol abuse and early in the course of the disease can appear as
an ill-defined lobulated mass resulting in strictures and obstruction of the biliary and/or pancreatic
ducts with concomitant calcification. As the disease progresses, increased fibrosis and loss of acinar
cells could lead to the loss of lobulation and result in a picture mimicking that of invasive
adenocarcinoma. Focal chronic pancreatitis does occur. The overlap in clinical and radiologic features
leads to further evaluation and FNAB. This explains how most of cases of chronic pancreatitis undergo
The cytologic findings are variable depending on the level of fibrosis and degree of loss of acinar
cells. Fragments of fibrous tissue are usually obtained as well as a mixture of ductal cells and acinar
cells. Foamy histiocytes and multinucleated giant cells could also be seen. Ductal cells could be seen
admixed with inflammatory cells in areas where there is an active inflammation. One or two of the major
criteria for diagnosing well differentiated ductal adenocarcinoma may be encountered in a few clusters
but are usually not in many groups (<6 groups) and not in combination with other criteria for
malignancy. Histologically, there is loss of the normal acinar architecture with residual ducts and
islet cells. The lobular architecture is maintained (a very important histologic clue in differentiating
this from carcinoma).
Autoimmune pancreatitis can present radiographic and cytologic overlap with carcinoma, although the
histologic changes are very distinct from carcinoma. These lesions may present as a focal mass. At our
institution, a number of lesion lesions have been called atypical when aspirated. They appear to be a
part of a generalized autoimmune lesion and are associated with increased IgG4. The characteristic
histologic findings are an intense lymphoplasmacytic inflammatory infiltrate with a ductocentric and duct
destructive pattern. Additionally there is an obliterative phlebitis and occasional arteritis.
Pancreatic endocrine neoplasms (PEN):
These usually present as small well circumscribed lesions anywhere in the pancreas with slight
increase towards the tail. Incidence is equal between male and female patients. They could present with
manifestations of hyperfunctioning tumor resulting in hypersecretion of a given hormone. Diabetes
mellitus and peptic ulcers are two examples of increased secretion of insulin and gastrin, respectively.
Cytologic feature includes cellular smears, with what is called "tumor cellularity". There are usually
numerous sheets and clusters of uniform cells in addition to discohesive cells which have a plasmacytoid
appearance, in a clean background. There is occasional nuclear enlargement, which is known as
"neuroendocrine atypia". On Papaniclaou stain, the nuclei have stippled chromatin and inconspicuous
nucleoli. Histologically these lesions typically have a nested, trabecular or gyriform architecture.
They may be associated with sclerosis. Atypical cystic or intraductal lesions have been described.
Typically strong chromogranin or synaptophysin immunohistochemical staining is diagnostic. All of these
lesions are considered to have a malignant potential and unfortunately histologic examination will not
definitively distinguish benign from malignant. Tumor size (greater 2 cm), mitotic counts greater than 2
per 10 high power fields, vascular, peripancreatic, or perineural invasion all suggest a more aggressive
lesion. There is a poorly-differentiated endocrine carcinoma (similar to small cell carcinoma of the
lung) that has a very poor prognosis.
Solid-pseudopapillary neoplasm (SPN):
They usually present as well defined well-circumscribed masses in young women. They can attain larger
size and show cystic degeneration on imaging. These gross and radiographic features overlap with those
of PEN. Cytologically the smears are comprised by sheets of uniform cells with bland appearing nuclei
showing occasional nuclear grooves or indentation. The cytoplasm is scant and shows occasional
magenta-colored hyaline globules. The same globules could appear at the edges of some clusters or as
free material in the background. Histologically, these lesions can have a variable appearance. They may
be solid or have a degenerative pseudopapillary pattern. Cystic areas may be identified.
Characteristically there are often foam cells and cholesterol crystals (clefts) with foreign body giant
cells. These lesions are typically immunohistochemically positive for alpha-1-antitypsin and
chymotrypsin, CD 10, neuron-specific enolase and vimentin. These lesions have a low malignant potential
and similar to PEN histologic identification of malignant lesions may be difficult. Typically vascular
invasion, increased mitotic rates, and marked nuclear atypia suggest a more malignant behavior.
Acinar cell carcinoma:
These lesions are an epithelial malignancy with acinar cell differentiation and represent 1-2% of all
pancreatic neoplasms (which would seem odd as the majority of the pancreas is composed of acinar cells).
They typically occur in the same age group as usual ductal adenocarcinomas (60-70) and have a 2:1 male to
female ratio. They may be associated with a lipase hypersecretion syndrome with subcutaneous fat
necrosis, a peripheral eosinophilia and arthralgia. The tumors have overlapping features with PEN
(well-circumscribed and similar cytologic findings), it's major differential diagnosis. Helpful features
cytologically are more cohesive acinar groups and prominent nucleoli. Histologically, these lesions will
have a solid or acinar pattern. The acinar areas have a characteristic granular cytoplasm with apical
cytoplasmic eosinophilia (this can be enhanced with PAS stain). Immunohistochemically, these lesions
will be mostly negative with chromogranin and synaptophysin (although there will be admixed positive
endocrine cells, up to 10-20% of cells). They are positive for trypsin, cytokeratins (especially CAM
5.2) and alpha-1-antichymotrypsin. These lesions are aggressive tumors with a poor prognosis.
These are unusual tumors typically of infants (less than 4 years of age), although lesions in adults
have been described. It is a malignancy with an epithelial (acinar differentiation) and mesenchymal
component. Similar to the other solid neoplasms, this is often encapsulated, soft circumscribed tumor.
It may present with AFP elevation. The characteristic histologic and cytologic finding is scattered
squamoid nests. Immunohistochemical staining profile is very similar to acinar cell carcinoma.
The most common pancreatic cysts include pseudocyst, serous cysts and neoplastic mucinous cysts
(mucinous cystic neoplasm [MCN] and intraductal papillary mucinous neoplasm [IMPN]). Distinguishing
pseudocyst from other neoplastic cysts should be considered first as the clinical implications are vastly
different. Pseudocysts could be treated conservatively whereas neoplastic cysts would require surgical
It represents a collection of pancreatic secretion and necrotic debris within a confined cyst in the
pancreatic parenchyma or along the edges. The most common cause for the formation of pseudocyst is acute
pancreatitis secondary to alcohol abuse in most cases. Other causes for the formation of pseudocyst are
trauma, biliary disease and hereditary pancreatitis.
Pseudocysts are usually unilocular and vary in size. They can occur anywhere in the pancreas but
generally they tend to occur in tail. The presence of calcification around the edges within a thick
fibrous band could be appreciated on imaging studies.
The aspirated fluid is usually thin, dark with very few cells. The majority of the smear is comprised
by cellular debris, crystals, macrophages and inflammatory cells. Pseudocysts by definition lack an
epithelial lining. The histologic findings are similar to that of the cytology. The wall of these
lesions should be well sampled to exclude a mucinous lesion.
Analysis of the cyst fluid usually reveals high content of amylase and low level of CEA (<200
ng/dl). Pseudocysts lack any appreciable mucin content.
This is a benign neoplasm comprised by proliferation of microcysts lined by cuboidal glycogen-rich
cells and containing clear serous fluid. The radiologic images are characteristic with "soap bubble"
pattern. There could be a central scar with calcifications embedded within the scar. They are usually
will defined with small microcysts separated by delicate septa.
The cyst fluid is usually thin, clear or admixed with blood and contains only few clusters of cuboidal
cells with bland appearing nuclei and finally vacuolated cytoplasm. Mucin is not appreciated grossly or
on the smears. Chemical analysis of the cyst fluid usually shows low levels of amylase and CEA.
Periodic acid Schiff stain with and without diastase digestion will demonstrate the presence of glycogen
and rule out the presence of mucin.
Neoplastic mucinous cysts:
There are two main groups of diagnostic entities; mucinous cystic neoplasm (MCN) and intraductal
papillary mucinous neoplasm (IPMN). Within each group there is a spectrum of epithelial changes based on
the level of cytologic atypia and invasive and non-invasive lesions can be identified. Radiologically,
the main distinction between the two main diagnostic categories is presence or absence of communication
between the cystic lesion and the main duct. In the presence of such communication, IPMN is the most
likely diagnosis and no communication suggests MCN.
Mucinous cystic neoplasms (MCN):
These are comprised by mucin producing cells lining a cyst that is not in communication with the main
ductal system. They contain a subepithelial ovarian-like stroma that may or may not be sampled by FNAB.
They are almost exclusively seen in middle-aged women and their malignant counterparts usually appear a
decade or two later.
The aspirate usually contains abundant mucin with thick viscous consistency. It is usually admixed
with inflammatory cells, macrophages and few epithelial cells, which serve as a tip off for the nature of
mucin; contaminant or neoplastic. The cyst lining shows as sheets and small clusters of mucin producing
cells appearing as goblet cells with intracellular mucin overlying or indenting the nucleus. Mucin
stains using periodic acid Schiff with diastase digestion or mucicarmine/Alcian blue stain (at 2.5 pH)
should confirm the presence of intracellular mucin. One caveat however, is that negative staining for
mucin does not exclude the presence of MCN. CEA analysis of cyst fluid usually shows an elevated level.
Histologically the major differentiating feature between MCN and IPMN is the presence of an ovarian
stroma in MCN. This finding is essentially a requirement for this lesion. The ovarian stroma is
typically positive for estrogen and/or progesterone by Immunohistochemistry. There is some controversy
regarding the nomenclature for the non-invasive lesions. The WHO has suggested dividing these into
benign (adenoma), borderline (mild to moderate dysplasia) and carcinoma-in situ (high grade dysplasia),
with the later two having some malignant potential. The AFIP suggests calling all of these lesions
mucinous cystic neoplasms with all of them having a malignant potential. This is based on their study
that had a some subset of "benign" lesions recurring. The key element appears to be adequate sampling
of the lesion (a criticism of the AFIP study). In order to make the diagnosis of an invasive lesion,
atypical glands or single cells invading into the stroma should be identified.
Intraductal papillary mucinous neoplasm (IPMN):
As it has been mentioned before, IPMNs are a group of neoplastic dilated pancreatic ducts lined by
mucin producing cells in papillary configuration. These lesions can be divided into the main duct type
or side branch type (which is thought to behave in a more benign fashion). Most of these tumors occur in
the elderly with a peak around the age of 65. Their cystic nature and their communication with the main
duct should be appreciated on imaging studies (especially ERCP or MRCP) and is an important piece of
pertinent information that could be obtained prior or during the FNAB or duct brushing procedure.
Cytologically, these tumors present with abundant mucin and as either large fragments of tissue or
small clusters of cells having papillary fronds and bland cytologic features in case of benign tumors or
the ones with low-grade dysplasia. IPMNs with moderate to high grade dysplasia or invasion will present
with the cytologic criteria seen in well-differentiated or high-grade ductal carcinoma. These would
include cellular crowding and three dimensional clusters, loss of polarity, irregularity of the nuclear
contour and increase N/C ratios.
Chemical analysis of the cyst fluid will reveal an elevated level of CEA (>200ng/dl) and pancreatic
amylase, the latter is because of their communication with the main duct system.
These patients typically will be treated surgically, however non-surgical candidates and individuals
with side-branch lesions and/or bland cytology may be followed using a "watch and wait" protocol. For
those individuals who undergo surgery, evaluation of the pancreatic neck margin by frozen section is one
of the more important aspects. Moderate dysplasia or greater at the margin requires additional tissue if
possible. Mucinous hyperplasia and low grade dysplasia at the margin should be considered as a negative
Within the surgical specimen there is typically dilation of the pancreatic ducts. Histologically
these dilated ducts are filled with papillary epithelial projections varying degree of dysplasia. The
final diagnosis should reflect the highest grade of dysplasia. Identification of invasive carcinoma may
be difficult in these resections. Obvious infiltrative glands or presence of colloid carcinoma may be
present, however the dilatation of some small ducts filled with mucin and partially lined by a neoplastic
epithelial lining may be difficult to differentiate from invasive carcinoma. The distinction is
important, as presence of carcinoma suggests a high incidence of recurrence (90% at 3 years).
Histologically the distinction of pseudocyst, MCN, IPMN, and serous cystadenoma is relatively straight
forward. It is based on evaluation of the lining of the cyst: no epithelium in pseudocyst, serous
epithelium in serous cystadenoma, and a mucinous epithelium in MCN and IPMN. Presence or absence of an
ovarian stroma will differentiate between MCN and IPMN. With all of these lesions, adequate sampling
(which typically meaning embedding the entire lesion) is important for accurate diagnosis.
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