Final Draft Terminology Document 5 1 12

7/30/2019 Final Draft Terminology Document 5 1 12

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Committee 3: Diagnostic TerminologyMembers:1) Martha Pitman, MD (Chair) Cytopathologist MGH, HMS

2) Barbara A. Centeno, MD Cytopathologist H. Lee Moffitt Cancer Center

and Research Institute, Tampa , FL

3) Lester Layfield, MD Cytopathologist University of Utah

4) Muriel Genevay, MD Cytopathologist - Hospital de Pathologie Clinique,

Geneva, Switzerland

5) Syed Ali, MD Cytopathologist Johns Hopkins Medical Center

6) C. Max Schmidt, MD Surgeon Indiana University

7) Carlos Fernandez-del Castillo, MD Surgeon- MGH, HMS

8) William Brugge, MD Gastroenterologist MGH, HMS

9) Volkan Adsay, MD Surgical Pathologist Emory University Hospital

10) David Klimstra, MD Surgical Pathologist Memorial Sloan Kettering

Proposed Terminology Scheme for Pancreatobiliary Cytology

Background

Early detection of cancer whether it is malignancy of the ductal, acinar, or

neuroendocrine system is the key to survival for patients. With the increased use ofEUS and FNA for the evaluation of pancreatobiliary lesions, coupled with our

improved understanding of premalignant lesions and the evolving management

algorithm for patients with pancreatic cysts, it is clear that cytopathologists play a veryimportant role in the diagnosis and management of patients with pancreatic mass or

cystic lesions and pancreatobiliary strictures.

The indication for FNA is the evaluation of a solid or cystic mass lesion.EUS guided FNA of the pancreas is a technically difficult procedure and yields

aspirates that are diagnostically challenging. Thus, the sensitivity of this procedure isvariable, averaging 80% but ranging from 60% to 100% Sensitivity of the procedure

can increase overtime, reflecting increasing experience with this technique. Thespecificity of diagnosis in the setting of a solid pancreatic mass is greater than 90%.

The adequacy and sensitivity rates are generally higher when rapid onsite assessment

is performed. It is difficult to compare the sensitivity of FNA among studies becauseof the wide variability in factors such as needle size, operator experience, and

radiological equipment. Additionally, the atypical and suspicious categories have been


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variably interpreted as negative or positive for the purposes of statistical analysis. The

inaccuracies of pancreatic FNA are primarily due to false negative reports. The

sensitivity for cystic neoplasms is lower than that for solid neoplasms largely due tothe low cellularity of most of these cystic lesions and the lack of clear criteria for

interpretation.

The most frequent indication for biliary brushing is the presence of a strictureor obstruction of the biliary tree. Endobiliary brushing is currently the preferred

method of sampling the biliary system in cases of stricture or obstruction, since the

preparation is usually rich in cells and cell preservation can be excellent if thespecimen is fixed immediately and the cells are spared preparation artifact Prospective

studies document a higher level of sensitivity of biliary brushings over exfoliative

cytology for the detection of biliary carcinoma. Furthermore, the sensitivity of

bile duct brushings has been shown to increase after repeated attempts In fact theprobability of a patient having a carcinoma is less than 6% after three negative

brushings. Predictors of positive yield include older age, mass size>1 cm, and

stricture length of >1 cm.

Most false negative interpretations occur from sampling error, which occursmost often when the tumor does not invade biliary mucosa, or when tumor cells are

entrapped in sclerotic desmoplastic stroma. Poor visualization of the area by theendoscopist may also negatively impact sampling. Interpretation errors (17%) and

technical errors (17%) are the second most frequent causes of false negative results.

Most interpretation errors result from under-interpretation of adenocarcinoma due tothe difficulty of distinguishing adenocarcinoma from reactive changes, often due to the

underlying disease process or the result of an indwelling stent. Poor sample fixation

and preparation also contribute to under-interpretation of adenocarcinoma . A

necrotic or inflammatory background may obscure malignant cells and may be yetanother factor contributing to under-diagnosis. The converse is also true: reactive

changes can mimic adenocarcinoma, and lead to a false positive interpretation.

Degeneration of malignant cells is also a source of false negatives. False positivescommonly result from over-interpretation of reactive and degenerative changes.

Another important pitfall are dysplastic but non-invasive neoplasms of the

ampulla or bile ducts.A standardized nomenclature system that provides intra- and

interdepartmental guidance for diagnosis that correlates with management

recommendations is imperative for both FNA of pancreatic masses and cysts and

brushing cytology of pancreatobiliary strictures. Below is a proposed terminologyscheme with 6 categories including a category Neoplastic that is divided into clearly

benign neoplasms and other neoplasms with less definitive biologic behavior

predictable by cytological features.

I. Nondiagnostic

Insufficient cellular material for diagnosisII. Negative

Pancreatitis-acute, chronic, autoimmune

Pseudocyst

Lymphoepithelial cyst


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Spenule/accessory spleen

III. Atypical

Mild-moderate cellular atypia, NOSMucinous ductal epithelium with and mild-moderate nuclear atypia

IV. Neoplastic

BenignSerous cystadenoma

Mature teratoma

SchwannomaOther

Pancreatic neuroendocrine tumor

Solid-pseudopapillary neoplasm

Mucinous cyst (IPMN or MCN), not otherwise specified(NOS), e.g. only thick, colloid-like mucin or elevated

CEA or positiveKRAS, if known

Mucinous cyst (IPMN or MCN) with low-grade

atypia/dysplasiaMucinous cyst (IPMN or MCN) with high-grade

atypia/dysplasiaGIST

V. Suspicious

Severe cellular atypia, suspicious for invasive ductal carcinomaor other high-grade malignant neoplasm, or

Solid cellular smear pattern without diagnostic cytological features or tissue

available for confirmatory immunohistochemistry supportive of a specific neoplasmsuch as PanNET or SPN.

VI. Positive/MalignantAdenocarcinoma of the pancreatobiliary ducts, and variants

Acinar cell carcinoma

High-grade neuroendocrine carcinoma (small andlarge cell type)

Pancreatoblastoma

Lymphoma

Metastases

Category I. Non-Diagnostic

Background:

Non-diagnostic specimens may be due to technical or sampling issues that

preclude the pathologist from providing any useful information from the biopsy

relative to the lesion sampled. The clinical and imaging context should be taken into

consideration. The absence of "epithelial cells" in the sample does not necessarily

make a specimen non-diagnostic. For example, pseudocyst fluid or a mucinous cyst


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with only thick colloid-like mucin, or a cyst with elevated CEA, both findings

sufficient to support an interpretation of a mucinous cyst.

Definition:

A non-diagnostic cytology specimen is one that provides no diagnostic or

useful information about the lesion sampled. Any cellular atypia precludes a non-

diagnostic report.

Cytological Criteria: Non-Diagnostic

Preparation artifact precludes evaluation of the cellular component

Obscuring artifact precludes evaluation of the cellular component

Gastrointestinal epithelium only

Normal pancreatic tissue elements in the setting of a clearly defined

solid or cystic mass by imaging

Acellular aspirates of a solid mass or pancreatobiliary brushing

Acellular aspirate of a cyst without evidence of a mucinous etiology

such as thick colloid-like mucus, elevated CEA orKRASmutation (See

Section IV)

Category II. Negative

Background:

A negative cytology sample is synonymous with the absence of malignancy

and any cellular atypia. A negative cytology interpretation without a diagnosis of aspecific condition such as chronic pancreatitis or pseudocyst is not synonymous with a

benign lesion. A descriptive negative interpretation implies that the sample is

adequately cellular and that no cytological atypia is identified in the cells evaluated.

This includes the presence of normal pancreatic tissue in the appropriate clinical

setting such a vague fullness on imaging and no distinct mass lesion. The false

negative rate of an FNA of a solid mass lesion averages 15%, and in the setting of a


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clinically and radiologically suspicious mass with a presumed diagnosis of ductal

adenocarcinoma, such an aspirate is presumed to be a false negative sample. The false

negative rate for aspirates of cystic lesions is as high as 60% due to acellular or

scantily cellular samples, in addition to the lack of experience in interpreting these

lesions outside of major academic hospital settings. The false negative rate for the

interpretation of pancreatobiliary brushing samples is also high due to the difficulty in

obtaining diagnostic tissue that is often subepithelial or entrapped in desmoplastic

stroma, coupled with the high threshold for a malignant interpretation due to the

typical clinical setting of inflammation and/or biliary stenting.

Definition:

A negative cytology sample is one that contains adequate cellular and/or

extracellular tissue to evaluate or define a non-neoplastic lesion that is identified onimaging.

Cytological Criteria: Benign Pancreatobiliary Tissue

Acinar epithelium:

o High cellularity

o polygonal cells with basal nuclei and apical granular cytoplasm present

mostly in grape-like acinar structures singly or attached to connective tissue

fragments; cellularity may be high

o single cells may be present

o nucleoli may be inconspicuous or quite prominent

o naked acinar cell nuclei are few

Ductal epithelium:

o flat, honeycombed sheets of non-mucinous glandular epithelial cells in

an evenly spaced, lattice-like arrangement with

round to oval uniform, evenly spaced nuclei

smooth nuclear membranes, even chromatin and inconspicuous nucleoli

o orderly, polarized picket-fence arranged cells with


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basal nuclei

non-mucinous columnar cytoplasm

o Even chromatin or open vesicular chromatin with small nucleoli

indicative of reactive changes or repair

o goblet cells are rare

o mitoses are absent or rare and normal

Islet cells:

o generally not recognized

o May be present in small clusters of small uniform polygonal cells in a

background of acinar and/or ductal epithelial cells

Bile in biliary brushing specimens

Cytologic criteria - Gastrointestinal Contaminants

o Duodendal epithelium

o Large, flat sheet of non-mucinous, evenly spaced epithelial cells with

o Scattered goblet cells [fried egg appearance on Papanicolaou stain]

o Interspersed lymphocytes

o Brush border on luminal edge of cytoplasm

o Gastric epithelium

o Small groups of mucinous, evenly spaced epithelial cells with

o Apical cytoplasmic mucin

o No goblet cells, lymphocytes or brush border

Cytological Criteria: Acute Pancreatitis


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Dominance of neutrophils, fragments of granulation

tissue and

aggregates of necrotic fat and foamy macrophages.

Granulation tissue is composed of reactive fibroblastsendothelial cells and inflammatory cells. The endothelial cells frequently form

interconnecting tubular (capillary) structures.

In later stages of acute pancreatitis, increasing numbers

of lymphocytes and plasma cells are seen.

The amount of epithelial tissue present is variable and

necrotic ductal and acinar epithelial groups may be present.

Atypia of the epithelial component is usually minimal

and mitotic activity is generally restricted to the granulation tissue component.

Cytological Criteria: Chronic Pancreatitis

Variable cellularity, often scanty, but may be highly cellular in early

stages.

Chronic inflammatory cells as well as ductal, acinar and islet cell

epithelium, but the acinar component decreases with late stages

Fragments of fibrous tissue that may appear disorganized with spindle

cells running in irregular interlacing groups. Within these tissue fragments, little

inflammation is apparent and mitotic figures are not seen.

Cell debris (necrotic fat) and calcifications, but no coagulative cellular

necrosis

Islet cells, singly and even intact islets of Langerhans that are tightly

cohesive with well-delineated tissue fragment edges.

Ductal epithelium in sheets and clusters with reactive nuclear changes+/- some loss of the normal honeycomb monolayer sheet-like pattern, but no

significant nuclear atypia

Ductal epithelium may show squamous metaplasia resulting in an

appearance of squamous eddies.


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Cytological Criteria: Autoimmune Pancreatitis

Pure cytomorphologic analysis cannot definitively diagnose

autoimmune pancreatitis but may be sufficient to suggest the diagnosis with the

findings below. Flow cytometric analysis for IgG4 may be helpful in confirming the

diagnosis

Ductal epithelial cells are few to absent but, when present, may show

reactive changes and significant atypia; AIP is a source of significant false positive

cytological interpretations

Conspicuous background of single lymphocytes and/or plasma cells

may or may not be present

Stromal fragments with high cellularity of mixed inflammatory cells,

possibly acinar cells, sometimes obscured by smearing artifact

Cytological Criteria: Pseudocyst

Mixed inflammatory cells, mostly lymphocytes and histiocytes

Cellular debris with red blood cells, granular necrotic debris and yellow

pigment , crystalline debris and calcifications

Hemosiderin-laden macrophages

No serous or mucinous cyst lining epithelium

Contaminating epithelium from GI tract common, and from the

pancreas, occasional

Fragments of granulation tissue and fibrous tissue uncommon

Cytological Criteria: Lymphoepithelial Cyst

Abundant anucleated squamous cells and sheets of benign squamous

epithelium

Small mature lymphocytes, may be prominent or sparse +/- histiocytes

Plate glass-like cholesterol crystals may be present


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Cytological Criteria: Splenule/Accessory Spleen

Bloody background

Platelet aggregates dispersed among tissue fragments composed of

lymphocytes and endothelial cells.

Lymphoid population dominates the smears but is without germinal

centers and tingible body macrophages as in a reactive node

Lymphoglandular bodies

Dendritic cells (CD8+)

Category III. Atypical

Background:

The interpretation category Atypical represents an ill-defined category with

significant interobserver variability often stemming from varying experience in

interpreting pancreatic cytology. Also contributing to this interpretation are samples

with scant cellularity, poor cellular preservation, and an inflammatory background.

This interpretation is used when a cytological specimen contains cellular or

extracellular tissue that is beyond recognizable normal tissue components or reactivechanges that can comfortably be interpreted as such and thus leading to a negative

interpretation. An atypical interpretation does raise the possibility of a neoplasm, but

the cytological findings are insufficient to be suspicious for a high-grade neoplasm.

Conservative interpretation of diagnostic samples is not uncommon due to the

significance of the surgical intervention, often a pancreaticoduodenectomy.

Abundant cytoplasmic mucin in pancreatic ducts is an abnormal finding and

indicates a neoplastic change. The differential diagnosis for glandular epithelium with

mucinous cytoplasm includes pancreatic intraepithelial neoplasia (PanIN), intraductal

biliary neoplasia, intraductal papillary mucinous neoplasm, mucinous cystic neoplasmand adenocarcinoma. PanIN is not an entity recognized by imaging but it may be a

source of atypia in aspirates of solid masses. Gastric epithelial contaminant is another

source of mucin containing epithelium that may be confused with ductal epithelium

with mucinous metaplasia. Of note, gastric epithelium may demonstrate some of the

changes of pancreatic neoplasia, such as nuclear grooves and inclusions, and subtle

crowding. Duodenal enterocytes are nonmucinous with a brush border, and, in


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addition to this feature, can be recognized by the presence of scattered goblet cells and

intraepithelial lymphocytes.

Premalignant lesions of the bile ducts have historically been called biliary

dysplasia or atypical biliary epithelium. A new consensus classification of Biliary

Intraepithelial Neoplasia (BilIN),was published in 2007. This proposal classified BilINinto a three grade classification scheme, similar to that used in other organs such as the

pancreas and prostate. The lesions were derived from patients suffering from primary

sclerosing cholangitis, choledochal cyst or hepatolithiasis. The histopathological

criteria are similar as for other intraepithelial lesions, but the cytopathological criteria

of these lesions have not been defined. However, it can be assumed that their

cytological features will be similar to what has been described as dysplasia in the

biliary tract with grade 1 and 2 lesions causing atypia on bile duct brushings,

previously referred to as low grade dysplasia .

Definition:

The category of atypical should only be applied when there are cells present

with cytoplasmic, nuclear, or architectural features that are not consistent with normal

or reactive cellular components of the pancreas or bile ducts, and are insufficient to

classify them as a neoplasm or suspicious for a high grade malignancy. The findings

do not explain a lesion identified on imaging studies. Follow-up evaluation is

warranted.

Cytological Criteria: Atypical

Architectural

o Mild disorder of honeycomb pattern with mild nuclear crowding, and

touching of the nuclei

o Pseudostratification of nuclei in on-edge groups with maintenance of polarity

o Papillary clusters

o Range of atypia without two distinct groups of ductal cells


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o Non-ductal cells (acinar, endocrine, or extra-pancreatic) that are not normal

appearing in architecture or morphology but are insufficient in quality or quantity to be

suspicious for or diagnostic of a neoplasm

Nuclear

o Mild anisonucleosis of ductal cells (less than 4 fold; generally 2-fold or less)

o Nuclear elongation

o Mild to moderate nuclear hyperchromasia

o Hypochromasia with subtle nuclear membrane abnormalities

o Prominent nucleoli

o

Occasional degenerative changes with nuclear pyknosis and karyorrhexis

o Mitotic activity may be visible, but mitotic figures are few and symmetrical

Cytoplasmic

o Cytoplasmic mucin in ductal type cells

o Hard, keratinous cytoplasm (not oral or esophageal contamination)

o Mild increase in nuclear to cytoplasmic ratio of ductal type cells

Category IV. Neoplastic

IVA. Neoplastic: Benign

Background

A common benign neoplasm of the pancreas is the serous cystadenoma.

Histologically, serous neoplasms consist of fine fibrous septae surrounded by

cuboidal, glycogen-rich cells without atypia. Fibrous septa include numerous small

capillary structures. This dense vascularization explains the often hemorrhagic aspectof the cyst fluid as well as the presence of numerous hemosiderin-laden macrophages

on cytological preparations. Such macrophages can be observed in up to 63% of cases,

whereas they are almost always absent in mucinous cystic neoplasms. Macrophagescan, however, only be considered as a surrogate marker of serous cystic neoplasm and

cannot be used as a definitive cytological criterion. When coupled with cytological

analysis, and with appropriate clinical and imaging features, biological analysis ofCEA level, typically less than 5 ng/ml, and amylase levels, typically also very low,


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support the diagnosis. Caution must be used because some mucinous cysts have very

low CEA levels, and conversely, serous neoplasms can, albeit rarely, present with

elevated CEA levels. Other benign neoplasms in the pancreas such as cystic teratomaand schwannoma are extremely rare.

Definition: Neoplastic: Benign

This interpretation category connotes the presence of a cytological specimen

sufficiently cellular and representative, with or without the context of clinical,imaging, and ancillary studies, to be diagnostic of a benign neoplasm.

Cytological Criteria: Serous Cystadenoma

Paucicellular to acellular specimens

Clear to bloody background

No extracellular mucin [except for occasional GI contamination]

Uniform non-mucinous, cuboidal cells in small clusters that form a flat

sheet or small groups

Round, central to slightly eccentric nuclei with a smooth nuclear contour,

evenly dispersed chromatin and indistinct nucleolus.

Scant but visible granular to clear, sometimes finely vacuolated cytoplasm.

PAS and PAS-D positivity of the cytoplasm, confirming the glycogeniccontent [rare to have sufficient cells to make a cellblock for this]

Absence of necrosis, atypia or mitoses

Cytologic Criteria: Cystic Teratoma

The content of the cyst cavity will vary depending on the nature of the

epithelium layering the cyst wall

Variable cellularity

Sebaceous elements, keratinous debris, respiratory epithelium

Nucleated squamous cells that are often accompanied by keratinous

debris

High grade to malignant component should not be identified for

inclusion in this category


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Cytologic Criteria: Schwannoma

Hypocellular or moderately cellular samples

Large, cohesive tissue fragments.

Scattered or closely packed tumor spindle cells with poorly defined cell

borders.

Nuclear palisading.

Wavy, ovoid nuclei with a fine chromatin pattern.

Fibrillary to myxoid stroma.

Mitoses are typically absent.

IIIB. Neoplastic: Other

Background

Not all neoplasms of the pancreas can be categorized as definitively benignor malignant. Aside from the clearly malignant neoplasms like conventional pancreatic

ductal adenocarcinoma and the definitively benign neoplasms like serous cystadenoma,

there are neoplasms (Other) that are either preinvasive (IPMN and MCN with low,intermediate or high grade dysplasia) or of low-grade malignant behavior based on pre-

operative cytological parameters. The cytological features of these neoplasms do not

correlate with biological behavior (PanNET and SPN). The same is also true for biliary tract

counterparts of these lesions which are now termed intraductal papillary neoplasms of thebile ducts (IPN-B), although previously also called intraductal papillary mucinous

neoplasms or papillomatosis or papillary cholangiocarcinomas

All of these pancreatic tumors are clearly neoplastic and the standard cytological

categories of atypical and suspicious for malignancy are categories that connote an

indeterminate interpretation that does not provide for a definitive cytological interpretationof the neoplasm which would lead to appropriate patient management and preclude the need

for a repeat diagnostic procedure.

Definition:Neoplastic: Other

This interpretation category defines a neoplasm that is either premalignant

such as IPNB, IPMN or MCN with low, intermediate or high grade dysplasia, or asolid-cellular neoplasm such as well-differentiated PanNET or SPN. While mucinous

epithelium in biliary brushing specimens may indeed represent a neoplastic change,


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given the lack of evidence-based literature on the cytology, histology and management

of these lesions, low-grade mucinous change of biliary epithelium will remain in the

atypical rather than neoplastic category.

Pancreatic Neuroendocrine Tumor

To be consistent with the new 2010 WHO, the current preferred nomenclature ispancreatic neuroendocrine tumor (PanNET). Synonyms include pancreatic endocrine tumor

(PET), pancreatic endocrine neoplasm (PEN) and well-differentiated endocrine carcinoma.

With the WHO-2010 the term neuroendocrine carcinoma without the preface well-differentiated, however, infers either high-grade large cell neuroendocrine carcinoma or

small cell carcinoma. The cytological interpretation of PanNET infers a well-differentiated

proliferation of the pancreatic endocrine cells creating a mass lesion greater than 0.5 cm that

may or may not be functional by producing inappropriate levels of various hormones, andthat may or may not demonstrate aggressive features on histological examination. However,

it is now widely accepted that PanNETs are all malignant neoplasms, albeit very slow

growing, and even curable, if caught at an early stage.

Cytological Criteria: Pancreatic Neuroendocrine Tumor

Moderately to highly cellular smears; scant cellularity is common withcystic degeneration

Mostly non-cohesive single cells with or without small to medium sized

groups or rosettes and clusters of cells

+/- vascular network and/or bloody background

Monotonous population of small to medium sized polygonal epithelial

cells

Nuclei are usually bland and uniform, but can be quite atypical and

may display significant pleomorphism (endocrine atypia)

Cells have round nuclei and generally visibly coarse, stippled, evenlydistributed ("salt and pepper") chromatin pattern

Nucleoli are usually inconspicuous but occasionally quite prominent

Stripped naked nuclei are not uncommon

Cytoplasm is relatively scant, and usually dense and eccentric yielding

a plasmacytoid appearance (this feature is best appreciated in single cells)

Rare variants produce cells with clear, vacuolated cytoplasm or

oncocytic cytoplasm

Mitotic figures and necrosis are absent to rare

Solid-Pseudopapillary Neoplasm

Solid-pseudopapillary neoplasm (SPN) is a solid, secondarily cystic low-grade epithelial neoplasm with established clonal mutations in cancer-associated genes

and an ability to metastasize. They typically occur in young females and demonstrate a

variably solid and cystic appearance on imaging. Like PanNET, it is a parenchymal-rich, stromal-poor proliferation of monotonous cells that belie prediction of the


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biological behavior. Although this neoplasm, like PanNET, is considered a low-grade

malignancy, it is included in this category to distinguish it from PDAC.

Cytologic Criteria: Solid-Pseudopapillary Neoplasm

Cellular smear pattern composed of small, uniform cells in cohesive,

often branching and papillary cell clusters

Background may be clean or filled with hemorrhagic cyst debris ladenwith foamy histiocytes and multinucleated giant cells

Small clusters and single neoplastic cells in the background

Individual cells are homogeneous in appearance with littleanisonucleosis

Nuclei are round to oval with smooth to slightly indented or grooved

nuclear membranes

Delicate fibrovascular cores with myxoid stroma (Romanowsky stains:

magenta colored, metachromatic material; PAS positive, diastase resistant) Zone of cytoplasm often separates the nuclei of the neoplastic cells

from the fibrovascular cores

Even and finely granular chromatin

Inconspicuous nucleoli

Cytoplasm is scant to moderate, non-granular to finely granular, andmay contain a small perinuclear vacuole or intracytoplasmic hyaline globule

No to rare mitotic activity

Neoplastic Mucinous Cysts of the Pancreas (Intraductal papillary

mucinous neoplasm (IPMN) and Mucinous cystic neoplasm (MCN))

The two primary neoplastic mucinous cysts of the pancreas include IPMN

and MCN. Understanding the clinical and imaging features of IPMN and MCN is vital

to the interpretation of the cytological specimen. Given that the cytological features ofthese two mucinous cysts are usually indistinguishable for all practical purposes, the

cytological features will be presented together. The pathologist should correlate the

clinical and imaging features to suggest the most likely specific diagnosis.

Management guidelines have evolved over time and have become muchmore conservative given the prevalence of incidental, asymptomatic cysts identified in

the general population and especially in the elderly. MCN, although mostly low grade,

are usually identified in young to middle-aged women in the body or tail of thepancreas that can be relatively easily removed with a distal pancreatectomy alleviating

the need for expensive, life-long surveillance. Main duct and combined type IPMNs

are all removed due to the inherent high risk of malignancy. Branch-duct IPMNs aremore often than not low-grade neoplasms identified in the pancreatic head of the

elderly with co-morbid conditions making pancreaticoduodenectomy a high-risk

procedure greater than the risk of the cyst progressing to malignancy. If a cyst is

mucinous and there is no evidence of high-grade dysplasia or carcinoma, then


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conservative management is reasonable. The difficult position for the pathologist then

becomes grading the epithelium of the cyst. It is quite difficult in other organ systems

even on histology to stratify grades into 4 tiers: low, moderate, and severe dysplasiaand carcinoma. This difficulty is exponential when interpreting just a few cells that

have been degenerating in cyst fluid and that may be associated with GI

contamination. A high threshold for malignancy is in order. That being said,recognition of atypical epithelial cells and the distinction from low grade dysplasia is

vitally important to recognizing a cyst with high grade atypia that likely corresponds to

a cyst with at least moderate dysplasia and in a high proportion of cases, high-gradedysplasia or worse. Resection prior to invasion provides the patient with the best

prognosis, and high risk imaging features such as a markedly dilated main pancreatic

duct or a mural nodule in a cyst that lead to resection are very often signs of an

invasive neoplasm. As such, aspiration of cysts without these features provides thebest opportunity to detect early carcinoma.

Intraductal papillary mucinous neoplasm

IPMNs are primarily intraductal proliferations of ductal epithelium creating amacroscopic lesion resulting in ductal dilatation, cyst formation and/or a mass lesion.

Intraductal tubulopapillary neoplasms are included with IPMN as this neoplasm is notonly rare, but would be indistinguishable from most IPMN on cytology. Invasion of

the duct or cyst occurs in about one third of resected IPMN, and is most common in

IPMN of the main pancreatic duct. There are three main types of IPMN :1. Main-duct IPMN: Generally associated with diffuse dilatation of the main

pancreatic duct of any part or the entire pancreas. The definition of dilatation is

variable in the literature. The 2006 Sendai guidelines define it as >6mm, but the new

2012 guidelines define it as 10mm or greater with > 5mm being worrisome.Visualization of mucin extruding from the ampulla on EUS or ERCP is

pathognomonic. The epithelial cell type most often associated with main duct IPMN is

intestinal type epithelium (MUC 5AC, MUC 2 and CDX2+) which, by definition, is atleast intermediate (moderate) dysplasia. Invasive carcinomas most often arising from

intestinal type IPMN are colloid carcinomas.

2. Branch-Duct IPMN: Cysts adjacent to a non-dilated main pancreatic duct,most often in the uncinate process, but occurring throughout the pancreas in one or

more locations. Imaging features generally depict a thin-walled unilocular cyst that

may or may not demonstrate a connection to the pancreatic ductal system. Small

"raspberry-like" multiloculated cysts are also typical of BD-IPMN. The cyst lining ismost often gastric-foveolar in type, and, although most are low grade, this epithelial

cell type can display intermediate and high-grade dysplasia. Invasive carcinomas

arising from these cysts tend to be tubular type and have a prognosis similar toconventional pancreatic adenocarcinoma.

3. Combined-type IPMN: Neoplasia involving both the main and branch

ducts of the pancreas typically represented on imaging by a dilated main pancreaticduct with one or more branch-duct cysts.

Two other epithelial cell types may be seen in IPMN. Pancreatobiliary

epithelium is relatively uncommon and, by definition, is equivalent to high-grade

dysplasia. Oncocytic epithelium is the least common epithelial cell type, and is also


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considered high-grade. Oncocytic type epithelium is distinguished by the moderate

amounts of dense, granular, oncocytic cytoplasm. While low-grade gastric-foveolar

type epithelium is recognizable, it may not be distinguishable from gastric epithelialcontamination in transgastric biopsies. It is generally not possible nor is it important to

distinguish the epithelial cell types with intermediate to high-grade dysplasia.

Cyst Fluid Analysis

Analysis of the cyst fluid from pancreatic cysts is invaluable in accurate

classification of the cyst as mucinous or non-mucinous. It is well established thatalthough each lab should establish their own cut-off value, that, CEA levels of ~200

ng/ml is strongly supportive of a neoplastic mucinous cyst. A low CEA level does not

exclude a mucinous etiology. In addition, CEA levels do not distinguish between

benign and malignant cysts. Amylase levels of cyst fluid are helpful in supportingthe interpretation of a pseudocyst as such fluids typically have amylase levels in the

thousands, but amylase levels do not distinguish between IPMN and MCN. Serous

cystadenomas tend to have both low CEA and amylase levels as do cystic pancreatic

neuroendocrine tumors.

Molecular Analysis

KRAStesting may supplement CEA as the detection ofKRASsupports a

mucinous etiology. Although the combination ofKRAS, LOH and quality and

quantity of DNA correlates with malignancy, aKRASmutation in and of itself is notspecific for malignancy. A recent study of pancreatic cyst fluid has shown that

detection ofGNASsupports a specific interpretation of IPMN, but does not distinguish

pre-malignant from malignant (invasive) IPMN. See the report of Committee 5 for a

more detailed discussion of ancillary testing.

Mucinous Cystic Neoplasm (MCN)

MCN of the pancreas is typically a multiloculated, mucin-producing

epithelial neoplasm with subepithelial ovarian-type stroma that in almost all cases doesnot communicate with the pancreatic ductal system and in almost all cases occurs in

women. Like IPMN, these neoplasms are stratified by the degree of cytological and

architectural atypia into low-grade, intermediate-grade and high-grade dysplastic, pre-

malignant (non-invasive neoplasms) and invasive carcinomas (invasive mucinouscystadenocarcinoma). The invasive carcinomas are usually tubular type, but rare

carcinomas such as undifferentiated carcinoma with osteoclast-type giant cells may

also be seen. . A similar neoplasm occurs in the biliary tract. The cytological featureswill be similar to its pancreatic counterpart.

Approach to the Cytological Analysis of Pancreatic Cysts

The cytopathologists approach to the interpretation of a pancreatic cyst

should be to address two basic questions. 1: Is the cyst mucinous or non-mucinous;

and 2: Is the cyst high-grade or not? Malignant is defined as unequivocal features of


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adenocarcinoma (See section on Positive for Malignant Cells). Atypia less than overtly

malignant is included in this category of Neoplastic: Other.

To answer the first question of a mucinous etiology, the first clue may comefrom the gastroenterologist who describes thick, viscous or white, sticky fluid upon

aspiration. This type of fluid is generally thick enough to make a direct smear. Thinner

fluids are best processed as a cytospin in order to capture all of the cells and topreserve the characteristics of the cyst fluid. Placing the cyst fluid in a preservative

attenuates the viscosity of the fluid and may make thin mucin difficult or impossible to

appreciate. Contamination of the specimen with mucin from the gastrointestinal tractis also a consideration. Thick, colloid-like mucin is neoplastic (with rare exception

such as in a gastrointestinal duplication cyst), and mucin with evidence of cellular cyst

debris also supports origin from the cyst and not the GI tract. Conversely, thin

mucous with naked grooved nuclei evoke GI contamination. Special stains for mucinmay be helpful but should be interpreted with caution. A mucicarmine or Alcian blue

positive thin film of a cytospin or thick wavy wisps of mucoid fluid that stains

positively without significant GI epithelial contamination are stain outcomes that

support a mucinous etiology. Negative mucin stains do not exclude a mucinous cyst.CEA elevation or detection of aKRASmutation may be necessary to support a

mucinous etiology, but, a non-elevated CEA or absentKRASmutation does notexclude a mucinous cyst.

To answer the second question of high-grade, an evaluation of the epithelial

component is required. The criteria for overt malignancy are outline below. Less thanovert malignancy is interpreted as either low grade or high-grade atypia as the

accuracy in distinguishing intermediate (moderate) from high-grade dysplasia is

difficult if not impossible, and the criteria to do so with any accuracy has not been

established. GI contaminating epithelium needs to be recognized as such (see criteriaunder category I)

Both mucin production and epithelial cells are not required for the diagnosis

of a mucinous cyst. The aspirates of some mucinous cysts are acellular but are clearlymucinous from the visible thick, colloid-like extracellular mucin, elevated CEA or

KRAS mutation. Similarly, a cyst fluid with high-grade mucinous epithelial dysplasia

or carcinoma may not demonstrate extracellular mucin or an elevated CEA.

Approach to The Cytological Evaluation of Biliary Tract Cysts

The approach to evaluating cysts arising in the biliary tract has not beenas formally studied as those of the pancreas. However, it can be surmised that IPN-B

and MCN-B will have similar cytological features on aspiration. The role of ancillary

studies in these cysts, such as measurement of CEA, is not established.

Cytological Criteria: Mucinous Cysts

Mucin Production Established

o Thick, colloid-like extracellular mucin

Cellular or inflammatory debris within the mucin


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o Thin mucin covering the slide confirmed with

Special stains for mucin (mucicarmine or alcian blue pH2.5)

OR

Elevated CEA (192 ng/ml is ~ 85% accurate)

OR

KRASmutation

And/OR

Neoplastic Epithelial Cells identified

o Low grade mucinous epithelium ,e.g. low-grade atypia (gastrointestinal

epithelium or low grade to intermediate grade dysplasia)

scant cellularity

single cells, small clusters and flat sheets of bland glandular epithelialcells

cytoplasmic mucin visible on routine light microscopy nuclei round and regular with even chromatin and inconspicuous to

occasionally prominent nucleoli

honeycomb sheet or on edge with basally located nuclei and apical

cytoplasmic compartment

the cells may be indistinguishable from gastric contamination

few to small single cells or groups with bland nuclei, no nuclear

membrane abnormalities but increased N/C ratio +/- cytoplasmic vacuoles

muciphages (foamy histocytes)

o High grade epithelium, e.g. high-grade atypia (at least high-grade

dysplasia/carcinoma in-situ, but quality and quantity of atypia is insufficient for

diagnosis of adenocarcinoma) Scant to high cellularity

Epithelial cells that have lost the benign features of low grade dysplasia

Small to large clusters and single cells

2-4 cell tight buds of cells

3-dimensional architecture

papillary arrangement (supports IPMN)

single cells

High nuclear to cytoplasmic ratio

Variable amounts of cytoplasm with and without visible mucin or

vacuoles Nuclear membrane irregularity mild to moderate

Coarse chromatin

Variable nucleoli

Cyst fluid with necrosis or acute inflammation scant to moderate

.

Intraductal Papillary Neoplasm of the Bile Ducts (IPN-B)


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Intraductal papillary neoplasm of the bile ducts shares many clinical and

pathological features with IPMN of the pancreas (IPMN-P). It is a neoplastic

proliferation growing within the bile ducts composed of a papillary proliferation ofmucin containing neoplastic cells that may occur anywhere in the ductal system. It

progresses from low, to high grade and eventually invasive carcinoma, just as IPMN-P

does. Gastric, pancreatobiliary, intestinal and oncocytic types subtypes have beendescribed, but show a different distribution than observed in IPMN-P. These are more

likely to be sampled by brushing cytology than by fine needle aspiration. When they

present as cystic masses, they may be aspirated, and the cytological features ofaspiration cytology will be similar to those of IPMN-P. The cytological features of

brushing cytology for IPN-B are described here. While there are no prospective or

retrospective reports, these features are extrapolated from the histopathological

features and are similar to what is encountered in brushing cytology of IPMN-P.

Cytology

Groups with crowding and overlapping Papillary formations, or columnar cells seen on edge

Elongated nuclei in lower grade dysplasia

Larger, vesicular nuclei in higher grade dysplasia

Mucinous cytoplasm which may vary in appearance depending on the

degree of differentiation

Oncocytic cytoplasm in the oncocytic variant

Gastrointestinal Stromal Tumor (GIST)

GISTs are very rare as a primary pancreatic neoplasm (extra-gastrointestinalstroma tumor, EGIST), however, they commonly occur in a peripancreatic location such asthe omentum, mesentery, duodenum and stomach, thus mimicking a primary pancreatic

neoplasm at times. GIST are spindle cell or epithelioid mesenchymal neoplasms with

differentiation along the lines of the interstitial cell of Cajal that usually expression c-kitprotein (CD117) and DOG1 by immunohistochemistry. There is variable expression of

alpha-smooth muscle actin and CD34, and essentially no reactivity for desmin. As with all

spindle cell lesions, procuring cell-blocks on such specimens will facilitate a definitivediagnosis.

Cytological Criteria: Gastrointestinal Stromal Tumor

Spindle cell proliferation with

o cellularity scant to moderate

o possible hemorrhagic background

o uniform ovoid nuclei with tapered ends

o palisading nuclei,

o delicate cytoplasmic processes with indistinct cell borders


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o perinuclear vacuoles not usually identified

o very rare mitoses possible

Epithelioid cell proliferation with

o cellularity scant to moderate

o polygonal cells of small to medium size Round, usually bland nuclei

Even chromatin (not stippled and coarse like a neuroendocrine tumor)

Variable nucleoli

Visible cytoplasm that may be dense or contain perinuclear vacuoles

IV. Suspicious for Malignancy

Background

The cytological interpretation category of suspicious for malignancy

generally refers to pancreatic adenocarcinoma, but may be used with any malignantneoplasm. Suspicious for is NOT diagnostic of, and clinical and radiological

information must be correlated with the suspicious cytological findings to justify

surgical intervention. Like the atypical interpretation category, suspicious formalignancy suffers from significant interobserver variability often stemming from

varying experience of the pathologist in interpreting pancreatic cytology. Due to the

high threshold of a malignant interpretation, and thus the low false positive rate of

pancreatic cytology, many samples are conservatively interpreted and may benefitfrom a second opinion by an experienced pancreatic cytopathologist to save the patient

the potential of a repeat diagnostic procedure.

Although the cytologic criteria for pancreatic adenocarcinomas,

neuroendocrine tumors, lymphomas, and metastases are well established (see below),cytologists are faced with three major challenges when dealing with fine needle

aspiration specimens of the pancreas.

The first challenge is the very high level of differentiation of certainpancreatic adenocarcinomas that may harbor very subtle cytologic abnormalities. The

second challenge is scant cellularity. Pancreatic adenocarcinoma induces a tumor-

associated sclerotic response that may contribute to this sparse cellularity. The third

problem that cytologists must address is gastrointestinal contamination that, when

substantial, may mask some scattered tumor cells, and when injured and reactive, maymimic carcinoma. When these challenges are faced in a single case, a definitive

diagnosis of malignancy may be impossible, but malignancy is probable. In thesecases, where the degree of suspicion for malignancy is high enough to require

therapeutic intervention, one may classify the lesion as suspicious for malignancy

(SFM). This category has a very high positive predictive value for malignancy. TheSFM diagnosis must be correlated with clinical symptoms and imaging characteristics.

When a patient has a high clinical suspicion of pancreatic cancer and a pancreatic mass


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on imaging studies, the diagnosis of suspicious most likely indicates the presence of

cancer. AIP should be a clinical consideration as it is a well-known pitfall mimicker of

PDAC clinically, radiologically and cytologically. The distinction between a positivediagnosis and an SFM diagnosis is based on both quantitative and qualitative criteria.

Suspicious cases represent 5 to 12% of published cases, but most studies focus on

pancreatic adenocarcinoma, so the number of cases that are considered as suspiciousfor pancreatic neuroendocrine tumors, acinar cell carcinomas or lymphomas is very

difficult to establish. In this section, we will present the criteria for all of these tumors.

In the context of endocrine or acinar cell tumors, the diagnosis of SFM is mainly usedwhen, due to technical issues, one cannot definitively confirm the nature of the cells

with ancillary techniques such as immunohistochemistry.

Definition

A specimen is SFM when some but an insufficient number of the typical

features of a specific low grade malignant or high grade malignant neoplasm are

present, mainly pancreatic adenocarcinoma. The cytological features raise a strongsuspicion for malignancy, but the findings are qualitatively and/or quantitatively

insufficient for a conclusive diagnosis. The morphologic features must be sufficientlyatypical that malignancy is considered more probable than not.

Criteria: Suspicious for adenocarcinoma

Clusters of epithelial cells present with typical cytological

abnormalities of well-differentiated adenocarcinoma, but some clusters do not displaythese abnormalities

And/or the number of clusters presenting such abnormalities is too low

(


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Moderate to high cellularity

cells organized in loosely cohesive clusters and/or acini resembling

normal pancreatic parenchyma

monomorphic population of medium to large cells with abundant,

granular eosinophilic cytoplasm

mild anisonucleosis or three-dimensionality of cell clusters nucleus is round with finely granular chromatin

nucleoli are either not prominent raising doubt about the acinar origin,

or nucleoli are centrally located and of normal or slightly larger size and calibersimilar to normal acini

Large, cherry-red nucleoli in a few polygonal cells

Criteria: Suspicious for Non-Hodgkin lymphoma

monomorphous, small- to intermediate-sized lymphocytes (low-gradelymphoma)

monomorphous or polymorphous, large cells (high grade lymphoma)

lymphoglandular bodies in the background

no tissue available to confirm clonality

Criteria: Suspicious for malignancy, not otherwise specified

Numerous other malignancies may involve pancreatic parenchyma, including

metastases and sarcomas. In these cases, insufficient malignant cells are present forconclusive diagnosis of malignancy and for classification of tumor type with ancillary

testing. Cells are present in the specimen, but require further investigation.

Category VI. Positive or Malignant

Background

Since 9 of 10 malignancies in the pancreas are conventional PDAC, the "positive"

or "malignant" category is often related to this category. Low grade malignancies such as

well-differentiated PanNET and SPN are included in the Neoplastic: Other category. Other

high grade malignancies are also included here such as acinar cell carcinoma, PBLlymphoma and metastasis.

Definition

A group of neoplasms that unequivocally display malignant cytologic

characteristics and include pancreatic ductal adenocarcinoma (PDAC) and its variants,cholangiocarcinoma, acinar cell carcinoma, poorly-differentiated neuroendocrine carcinoma

(small cell or large cell NEC carcinoma), pancreatoblastoma, lymphomas, sarcomas and

metastases to the pancreas.

Pancreatic Ductal Adenocarcinoma


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Pancreatic ductal adenocarcinoma(PDAC) is a malignant invasive gland (duct)

forming epithelial neoplasm typically composed of classic tubular glands, but, in variants,

with other morphologically diverse epithelial morphologies. Pancreatic ductaladenocarcinoma, or infiltrating ductal adenocarcinoma, is the most common primary cancer

of the pancreas which accounts for 8590% of all pancreatic malignancies. As in other

organ-based cancers most patients are in their 60s and above; PDAC is quite uncommon inpatients younger than 40 years of age. Pancreatic cancer is a one of the most lethal

malignancies of human body with an extremely poor prognosis. It is considered the fourth

leading cause of cancer death in the US and is estimated to cause 227, 000 deaths per yearworldwide. The incidence and overall mortality caused by pancreatic cancer has been

gradually rising. An estimated 20% of pancreatic cancers are caused by cigarette smoking .

Other major risk factors include family history and familial syndromes, chronic pancreatitis,

advancing age, male gender, diabetes mellitus, and obesity Typical presenting symptoms ofpancreatic cancer include vague abdominal or mid-back pain, obstructive jaundice, weight

loss and new-onset diabetes mellitus. Most if not all, early-stage pancreatic cancers are often

clinically asymptomatic, and only become apparent after invasion of the tumor into the

surrounding tissues or metastases to distant organs. A clinical/radiologic or pathologicdiagnosis is usually rendered late when the cancer is unresectable. Overall survival is better

for patients with locally advanced disease (median 915 months) than for those withmetastatic disease (36 months).

Cytologic Criteria

Well-differentiated PDAC

Variable cellularity with predominance of one cell type, i.e., ductal cells

Cohesive small to medium-sized sheets of cells with smooth borders, andrarely single cells

Three-dimensional fragments

Moderate nuclear enlargement with high N/C ratios, cellular crowding andoverlap

Loss of nuclear polarity, often pale nuclei with chromatin clearing and/or

clumping, nuclear membrane irregularity with clefts and notches

Lack of prominent nucleoli

Mild to moderate anisonucleosis (typically more than 4 to 1 in the same

gland/duct)

Rare mitoses

Uncommon necrosis

Moderately-differentiated PDAC

Above features with addition of one or more of the following

Larger cellular sheets/fragments with increased amount of single cells

More extensive cellular pleomorphism

Marked anisonucleosis and occasional prominent nucleoli


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More crowded three-dimensional or syncytial tissue fragments

Poorly-differentiated PDAC

Extreme pleomorphism, with almost total lack of glandular differentiation

Larger loosely cohesive syncytial tissue fragments

Significant populations of single large malignant cells

High N/C ratio, nuclei with coarse dark chromatin and often macro nucleoli

Occasional bizarre nuclei with triangular shapes and/or multinucleated cells

Mitoses and karyorrhexis

Prominent necrosis

Other Invasive Carcinomas of Pancreatobiliary Origin

Cholangiocarcinoma

The diagnostic criteria for invasive cholangiocarcinoma are the same as for PDACon fine needle aspiration samples. Published diagnostic criteria for adenocarcinoma in a bile

duct brushing specimen demonstrate variable predictive values Features associated with

adenocarcinoma include: three dimensional cell clusters with marked nuclear crowding andloss of polarity, nuclear molding, papillary groups, cell-in-cell groups, cellular dyshesion,

nuclear pleomorphism with nuclear membrane and chromatin irregularities, increased

nuclear to cytoplasmic ratio, vacuolated or dense squamoid cytoplasm, atypical mitoticfigures and background necrosis. , In the analysis by Renshaw et al, a consensus evaluation

of loss of polarity had a sensitivity of 36% and a specificity of 97% for the diagnosis ofadenocarcinoma. The sensitivity and specificity of a consensus diagnosis of bloody

background was 15% and 88% respectively. Finally, the sensitivity and specificity for thecombination of nuclear molding, chromatin clumping, increased nuclear cytoplasmic ratio,

loss of honeycomb pattern, enlarged nuclei, bloody background and cell and cell

arrangement was 36% and 95% respectively. An overall assessment for the presence ofmalignancy may be best in these samples.

Major diagnostic pitfalls in the evaluation of bile duct brushings include obscuringof malignant epithelium by overlying benign epithelium , insufficient sampling,

degeneration due to bile or duodenal contents, primary sclerosing cholangitis and atypical

squamous metaplasia due to bile duct stones and stents. Correlation of the cytologicalfindings with the clinical findings may help, as a biliary stricture is more likely to be

malignant in older male patients who are symptomatic and do not have a history of stones

Criteria

Architectural


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o Marked cellular dyshesion demonstrated by poorly cohesive groups and /or

atypical single cells

o Three dimensional cell clusters with marked nuclear crowding

o Loss of polarity

o Nuclear molding

o Papillary groupso Syncytial groups

o Cell-in-cell groups

Nuclear

o Large pleomorphic nuclei

o Nuclear membrane irregularities, such as elongation, or blunting

o Abnormal chromatin distribution

o Atypical mitotic figures

o Four fold or greater variation in nuclear size

Cytoplasmic

o

vacuolated, squamous or dense cytoplasm

Background

o Necrotic debris

o Bloody background with degenerated debris

Colloid carcinoma

A carcinoma of ductal differentiation showing abundant extracellular mucinproduction, with at least 80% of the tumor on histology demonstrating large pools of

extracellular mucin and cuboidal epithelial cells floating in the mucin. This uncommon

variant accounts for 1-3% of PDAC and majority arise in association with intraductalpapillary mucinous neoplasm (IPMN), intestinal type. Gender and age distribution is similar

to PDAC; however, the prognosis appears to be significantly better.

Cytologic Criteria

Variable cellularity

Abundant clean mucin

Strips and small three-dimensional fragments of cuboidal epithelium withovert malignant features

High N/C ratios, round nuclei, fine chromatin, prominent nucleoli

A subpopulation of signet ring cells maybe present

Typically no necrosis

Inflammatory debris and calcifications may be present

Medullary Carcinoma

A carcinoma characterized by poor histologic differentiation, syncytial growth

pattern, pushing borders, and an intense lymphoplasmacytic response. Medullary carcinomais characterized by a special genetic profile with 69% of these tumors displaying wild-type

k-ras genes and 22% of these tumors have microsatellite instability (MSI).


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Cytologic Criteria

Hypercellular

Mostly large syncytial sheets, few single cells

Monotonous cells with round nuclei, high N/C ratios, macronucleoli Variable amount of lymphocytes in the smear background

Adenosquamous Carcinoma

A variant of PDAC with glandular and squamous components ranging from

extensive glandular differentiation with focal squamous differentiation to predominantly

squamous differentiation. A rare subtype with relative frequency of 3-4% and relativelypoorer prognosis compared to the conventional PDAC.

Cytologic Criteria

Cytomorphologic characteristics of well, moderately or poorly differentiatedductal adenocarcinoma

Focal or confluent squamous differentiation keratinized squamous cells;singly, in tissue fragments and/or fragments of high grade non-keratinizing basaloid type

cells

Focal to extensive necrosis, often cystic background

Undifferentiated Carcinoma with Osteoclast-like Giant Cells

Often admixed with ordinary PDAC, this tumor is a distinctive type of sarcomatoidcarcinoma with the striking and unique cytohistologic features characterized by a prominent

component of reactive osteoclast-like giant cells in a background of spindle cells. Often

seen in association with IPMN or MCN, these tumors may also arise with in-situ andinvasive PDAC.

Cytologic Criteria

Hypercellular smears, composed predominantly of dispersed isolated single

cells, or loosely cohesive cell groups

Round to spindled, often pleomorphic and high-grade malignant cells

Nuclei are hyperchromatic, often with prominent nucleoli

A second population of multinucleated osteoclast-type giant cells (reactive

histiocytes) scattered throughout the smear, often containing as many as 3050 nuclei

An associated component of IPMN, MCN or PDAC may be present

Often accompanied by hemorrhage and hemosiderin

Anaplastic Carcinoma

A rare variant of pancreatic ductal adenocarcinoma composed of large,

undifferentiated, markedly pleomorphic cells. Also known as undifferentiated carcinoma


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this tumor is rare with a relative frequency of 2-7% and may show small foci of poorly-

differentiated PDAC.

Cytologic Criteria

Usually cellular, predominantly single cells

Extreme pleomorphism with marked anisonucleosis and bizarre, often

multinucleated giant cells

Hyperchromasia, macronucleoli

No ductal or acinar differentiation

Abundant abnormal mitoses

Extensive necrosis

Acinar Cell Carcinoma

A rare malignant epithelial neoplasm with predominantly exocrine acinar

differentiation. A rare primary malignancy, predominantly seen in older Caucasian men(mean age, 62 years). The presenting symptoms are usually nonspecific, and jaundice is

often not present. Hypersecretory syndrome is present in only 16% of the patients. Asignificant proportion of the cases have neuroendocrine component or scattered

neuroendocrine cells. Approximately 50% of the patients have metastatic disease atpresentation, often restricted to the regional lymph nodes and liver. The prognosis appears

to be significantly better than ordinary PDACs.

Cytologic Criteria

Usually hypercellular, mostly small to mid-sized cellular fragments and few

single cells

Prominent acinar formations without lobular arrangements (in well-

differentiated tumors that can be confused with rosettes of a PanNET), rare syncytia

Uniform population of cells larger than ductal carcinoma, minimalpleomorphism

Finely granular to denser cytoplasm, granularity is often basophilic

Mildly increased N/C ratios, single round to oval nucleus which areeccentrically placed, coarse chromatin, single prominent nucleoli, focal anisonucleosis

Significant anisonucleosis in high-grade tumors

Numerous bare stripped off nuclei, rare intranuclear inclusions

Rare necrosis

Poorly-differentiated Neuroendocrine Carcinoma (Small Cell Carcinoma or

Large Cell Neuroendocrine Carcinoma)A high-grade neuroendocrine carcinoma, cytoarchitecturally and

clinicopathologically exhibit features indistinguishable from its pulmonary (and extra

pulmonary) counterparts. This accounts for less than 1% of all primary pancreatic cancersand 2-3% of PanNETs. Primary small cell carcinoma is extremely rare in pancreas and

possibility of metastatic lung carcinoma should always be excluded first. Small cell

carcinoma has an extremely poor prognosis and usually displays an extensive peripancreaticinvasion. Chemotherapy remains the only mode of therapy.


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Cytologic Criteria

Hypercellular, with mostly single cells or loosely cohesive cell groups

Barely discernible cell cytoplasm with mostly bare round to oval nuclei

Nuclei display hyperchromasia, finely granular chromatin, lack of nucleoli,nuclear molding and crush artifact

Abundant mitoses and karyorrhexis and often necrosis

Pancreatoblastoma

A rare neoplasm, primarily of childhood, characterized by acinar differentiation,

endocrine differentiation and distinctive squamoid nests. Also known as infantile pancreaticcarcinoma, this is an extremely rare pancreatic tumor in childhood, comprising 0.5% of

pancreatic non-endocrine tumors with rare occurrence in adults. Pancreatoblastoma tend to

be less aggressive in infants and children compared to adults. The cancer has been

associated with alterations in the Wnt signaling pathway and chromosome 11p loss of

heterozygosity (LOH), Beckwith-Wiedemann syndrome and familial adenomatouspolyposis. Alpha-fetoprotein may be elevated in up to 68% of patients with

pancreatoblastoma.

Cytologic Criteria

Hypercellular smears

Tissue fragments of varying sizes with solid sheets, three dimensional

loosely cohesive epithelial groups, abundant stromal tissue

Primitive spindled mesenchymal tissue (rare focal cartilage formation)

Epithelial component with mostly acinar formations, nests and organoid

patterns Epithelial cells appear cuboidal with central nuclei, indistinct nucleoli, and

clear cytoplasm

Spindle-shaped, elongated and triangular-shaped epithelial cells

Cells in the acinar formations had a slightly elongated columnar shape with

more abundant delicate cytoplasm and basally-placed nuclei and prominent

Focally, the large epithelial cells formed swirling eddies consistent with

squamoid corpuscles (mostly cell block)

Non-Hodgkin Lymphoma

Hematopoietic malignancies in the pancreas are rare and usually involve the

pancreas secondarily. Pancreatic lymphomas are most commonly non-Hodgkins lymphoma

that can clinically mimic pancreatic adenocarcinoma. One of the advantages to FNAevaluation is that pre-operative diagnosis of lymphoma can preclude unnecessary surgery.

Primary pancreatic lymphomas are most commonly large B-cell lymphomas. While the

cytomorphological features may suggest lymphoid differentiation, there may be overlapping

features with other neoplasms that produce a solid cellular smear pattern. Ancillary tests


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such as flow cytometry and immunohistochemistry are typically necessary for diagnosis and

especially for subclassification.

Metastatic tumors

Secondary neoplasms involving the pancreas are rare, and pancreatic

involvement as the sole site of metastasis is even more uncommon. The common neoplasms

that metastasize to the pancreas include melanoma, and carcinomas from the lung,colorectum and breast. Direct extension from cancer of the stomach, duodenum,

gallbladder, liver and retroperitoneum may also occur.

Renal cell carcinoma is notorious for giving rise to a late solitary metastasis, even

decades following nephrectomy. Renal cell carcinoma is also the most likely malignancy tometastasize to the pancreas and mimic a primary neoplasm. The cytological findings of

metastatic renal cell carcinoma are similar to those seen in the kidney with bland polygonal

cells, round slightly eccentric nuclei, prominent nucleoli and vacuolated cytoplasm.

Distinction from clear cell or lipid rich neuroendocrine tumor is warranted as themorphology of these two neoplasms may be indistinguishable.


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References

1. Tanaka M, Chari S, Adsay V, et al. International consensus guidelines for

management of intraductal papillary mucinous neoplasms and mucinous cystic

neoplasms of the pancreas. Pancreatology 2006; 6(1-2): 17-32.2. Tanaka M, Fernandez-del Castillo C, Adsay V, et al. International consensus

guidelines 2012 for the management of IPMN and MCN of the pancreas.

Pancreatology in press.3. Mallery JS, Centeno BA, Hahn P, et al. Pancreatic tissue sampling guided by EUS,

CT/US, and surgery: a comparison of sensitivity and specificity. Gastrointestinal

Endoscopy 2002; 56(2): 218-224.

4. Chang KJ. Endoscopic Ultrasound-guided fine needle aspiration in the diagnosis andstaging of pancreatic tumors. Gastrointestinal Endoscopy Clinics of North America

1995; 5(4): 723-734.

5. Erickson RA, Sayage-Rabie L, and Avots-Avotins A. Clinical utility of endoscopic

ultrasound-guided fine needle aspiration. Acta Cytologica 1997; 41(6): 1647-1653.6. Faigel DO, Ginsberg GG, Bentz JS, et al. Endoscopic ultrasound-guided real-time

fine-needle aspiration biopsy of the pancreas in cancer patients with pancreaticlesions. Journal of Clinical Oncology 1997; 15(4): 1439-1443.

7. Bhutani MS, Hawes RH, Baron PL, et al. Endoscopic ultrasound guided fine needle

aspiration of malignant pancreatic. Endoscopy 1997; 29(9): 854-8.8. Bentz JS, Kochman ML, Faigel DO, et al. Endoscopic ultrasound-guided real-time

fine-needle aspiration: clinicopathologic features of 60 patients. Diagnostic

Cytopathology 1998; 18(2): 98-109.

9. Suits J, Frazee R, and Erickson RA. Endoscopic ultrasound and fine needleaspiration for the evaluation of pancreatic masses. Arch Surg 1999; 134(6): 639-42;

discussion 642-3.

10. Williams DB, Sahai AV, Aabakken L, et al. Endoscopic ultrasound guided fineneedle aspiration biopsy: A large single centre experience. Gut 1999; 44: 720-726.

11. Sahai AV, Schembre D, Stevens PD, et al. A multicenter U.S. experience with EUS-

guided fine-needle aspiration using the Olympus GF-UM30P echoendoscope: safetyand effectiveness. Gastrointest Endosc 1999; 50(6): 792-6.

12. Erickson RA, Sayage-Rabie L, and Beissner RS. Factors predicting the number of

EUS-guided fine-needle passes for diagnosis of pancreatic malignancies.

Gastrointest Endosc 2000; 51(2): 184-90.13. Ylagan LR, Edmundowicz S, Kasal K, et al. Endoscopic ultrasound guided fine-

needle aspiration cytology of pancreatic carcinoma: a 3-year experience and review

of the literature. Cancer 2002; 96(6): 362-9.14. Shin HJ, Lahoti S, and Sneige N. Endoscopic ultrasound-guided fine-needle

aspiration in 179 cases: the M. D. Anderson Cancer Center experience. Cancer 2002;

96(3): 174-80.15. Eloubeidi MA, Jhala D, Chhieng DC, et al. Yield of endoscopic ultrasound-guided

fine-needle aspiration biopsy in patients with suspected pancreatic carcinoma.

Cancer 2003; 99(5): 285-92.


32/36


33/36

32. Kurzawinski TR, Deery A, Dooley JS, et al. A prospective study of biliary cytology

in 100 patients with bile duct strictures. Hepatology 1993; 18(6): 1399-403.

33. Bardales RH, Stanley MW, Simpson DD, et al. Diagnostic value of brush cytologyin the diagnosis of duodenal, biliary, and ampullary neoplasms. Am J Clin Pathol

1998; 109(5): 540-8.

34. Siddiqui MT, Gokaslan ST, Saboorian MH, et al. Comparison of ThinPrep andconventional smears in detecting carcinoma in bile duct brushings. Cancer 2003;

99(4): 205-10.

35. Oh HC, Kim MH, Hwang CY, et al. Cystic lesions of the pancreas: challengingissues in clinical practice. Am J Gastroenterol 2008; 103(1): 229-39; quiz 228, 240.

36. Brugge WR, Lewandrowski K, Lee-Lewandrowski E, et al. Diagnosis of pancreatic

cystic neoplasms: a report of the cooperative pancreatic cyst study. Gastroenterology

2004; 126(5): 1330-6.37. Belsley NA, Pitman MB, Lauwers GY, et al. Serous cystadenoma of the pancreas:

limitations and pitfalls of endoscopic ultrasound-guided fine-needle aspiration

biopsy. Cancer 2008; 114(2): 102-10.

38. Payne M, Staerkel G, and Gong Y. Indeterminate diagnosis in fine-needle aspirationof the pancreas: reasons and clinical implications. Diagn Cytopathol 2009; 37(1): 21-

9.39. Jarboe EA and Layfield LJ. Cytologic features of pancreatic intraepithelial neoplasia

and pancreatitis: potential pitfalls in the diagnosis of pancreatic ductal carcinoma.

Diagn Cytopathol 2011; 39(8): 575-81.40. Nagle J, Wilbur DC, and Pitman MD. The cytomorphology of gastric and duodenal

epithelium and reactivity to B72.3: A baseline for comparison to pancreatic

neoplasms aspirated by EUS-FNAB. Diagn Cytopathol 2005; 33: 381-6.

41. Nawgiri RS, Nagle JA, Wilbur DC, et al. Cytomorphology and B72.3 labeling ofbenign and malignant ductal epithelium in pancreatic lesions compared to

gastrointestinal epithelium. Diagn Cytopathol 2007; 35(5): 300-5.

42. Zen Y, Adsay NV, Bardadin K, et al. Biliary intraepithelial neoplasia: aninternational interobserver agreement study and proposal for diagnostic criteria. Mod

Pathol 2007; 20(6): 701-9.

43. Lee JG, Leung JW, Baillie J, et al. Benign, dysplastic, or malignant-making sense ofendoscopic bile duct brush cytology: results in 149 consecutive patients. American

Journal of Gastroenterology 1995; 90(5): 722-726.

44. van der Waaij LA, van Dullemen HM, and Porte RJ. Cyst fluid analysis in the

differential diagnosis of pancreatic cystic lesions: a pooled analysis. GastrointestEndosc 2005; 62(3): 383-9.

45. Cizginer S, Turner B, Bilge AR, et al. Cyst Fluid Carcinoembryonic Antigen Is an

Accurate Diagnostic Marker of Pancreatic Mucinous Cysts. Pancreas 2011.46. Hruban RH, Bolfetta P, Hiraoka N, et al. Tumours of the pancreas, in WHO

Classification of Tumours of the Digestive System, F.T. Bosman, et al., Editors.

2010, IARC: Lyon. 279.47. Crippa S, Fernandez-Del Castillo C, Salvia R, et al. Mucin-producing neoplasms of

the pancreas: an analysis of distinguishing clinical and epidemiologic characteristics.

Clin Gastroenterol Hepatol 2010; 8(2): 213-9.


34/36

48. Crippa S, Salvia R, Warshaw AL, et al. Mucinous cystic neoplasm of the pancreas is

not an aggressive entity: lessons from 163 resected patients. Ann Surg 2008; 247(4):

571-9.49. Hruban RH, Pitman MB, and Klimstra DS. Tumors of the Pancreas. Atlas of Tumor

Pathology, 4th series, fascicle 6. 2007, Washington, D.C.: American Registry of

Pathology; Armed Forces Institutes of Pathology.50. Pitman MB and Deshpande V. Endoscopic ultrasound-guided fine needle aspiration

cytology of the pancreas: a morphological and multimodal approach to the diagnosis

of solid and cystic mass lesions. Cytopathology 2007; 18(6): 331-47.51. Pitman MB, Genevay M, Yaeger K, et al. High-grade atypical epithelial cells in

pancreatic mucinous cysts are a more accurate predictor of malignancy than

"positive" cytology. Cancer Cytopathol 2010; 118: 434-40.

52. Pitman MB, Michaels PJ, Deshpande V, et al. Cytological and cyst fluid analysis ofsmall (< 3 cm) branch duct intraductal papillary mucinous neoplasms adds value to

patient management decisions. Pancreatology 2008; 8: 277-284.

53. Adsay NV. Cystic neoplasia of the pancreas: pathology and biology. J Gastrointest

Surg 2008; 12(3): 401-4.54. Adsay NV, Longnecker DS, and Klimstra DS. Pancreatic tumors with cystic

dilatation of the ducts: Intraductal papillary mucinous neoplasms and intraductaloncocytic papillary neoplasms. Semin Diagn Pathol 2000; 17: 16-31.

55. Adsay NV, Merati K, Basturk O, et al. Pathologically and biologically distinct types

of epithelium in intraductal papillary mucinous neoplasms: delineation of an"intestinal" pathway of carcinogenesis in the pancreas. Am J Surg Pathol 2004;

28(7): 839-48.

56. Hruban RH, Takaori K, Klimstra DS, et al. An illustrated consensus on the

classification of pancreatic intraepithelial neoplasia and intraductal papillarymucinous neoplasms. American Journal of Surgical Pathology 2004; 28(8): 977-87.

57. Adsay NV, Pierson C, Sarkar F, et al. Colloid (mucinous noncystic) carcinoma of

the pancreas. American Journal of Surgical Pathology 2001; 25(1): 26-42.58. Mino-Kenudson M, Fernandez-Del Castillo C, Baba Y, et al. Prognosis of invasive

intraductal papillary mucinous neoplasm depends on histological and precursor

epithelial subtypes. Gut 2011; 60(12): 1712-20.59. Moparty B, Pitman MB, and Brugge WR. Pancreatic cyst fluid amylase is not a

marker to differentiate IPMN from MCN. Gastrointestinal Endoscopy 2007; 65(5):

AB303.

60. Ryu JK, Woo SM, Hwang JH, et al. Cyst fluid analysis for the differential diagnosisof pancreatic cysts. Diagn Cytopathol 2004; 31(2): 100-5.

61. O'Toole D, Palazzo L, Hammel P, et al. Macrocystic pancreatic cystadenoma: The

role of EUS and cyst fluid analysis in distinguishing mucinous and serous lesions.Gastrointestinal Endoscopy 2004; 59(7): 823-9.

62. Khalid A, Zahid M, Finkelstein SD, et al. Pancreatic cyst fluid DNA analysis in

evaluating pancreatic cysts: a report of the PANDA study. Gastrointest Endosc 2009;69(6): 1095-102.

63. Shen J, Brugge WR, Dimaio CJ, et al. Molecular analysis of pancreatic cyst fluid: a

comparative analysis with current practice of diagnosis. Cancer Cytopathol 2009;

117(3): 217-27.


35/36

64. Wu J, Matthaei H, Maitra A, et al. Recurrent GNAS mutations define an unexpected

pathway for pancreatic cyst development. Sci Transl Med 2011; 3(92): 92ra66.

65. Lau SK, Lewandrowski KB, Brugge WR, et al. Diagnostic significance of mucin infine needle aspiration samples of pancreatic cysts. Modern Pathology 2000; 13(3):

48A.

66. Layfield LJ and Cramer H. Fine-needle aspiration cytology of intraductal papillary-mucinous tumors: A retrospective analysis. Diagnostic Cytopathology 2005; 32(1):

16-20.

67. Kloek JJ, van der Gaag NA, Erdogan D, et al. A comparative study of intraductalpapillary neoplasia of the biliary tract and pancreas. Hum Pathol 2011; 42(6): 824-

32.

68. Barton JG, Barrett DA, Maricevich MA, et al. Intraductal papillary mucinous

neoplasm of the biliary tract: a real disease? HPB (Oxford) 2009; 11(8): 684-91.69. Ando N, Goto H, Niwa Y, et al. The diagnosis of GI stromal tumors with EUS-

guided fine needle aspiration with immunohistochemical analysis. Gastrointest

Endosc 2002; 55(1): 37-43.

70. Reith JD, Goldblum JR, Lyles RH, et al. Extragastrointestinal (soft tissue) stromaltumors: an analysis of 48 cases with emphasis on histologic predictors of outcome.

Modern Pathology 2000; 13(5): 577-585.71. Willmore-Payne C, Layfield LJ, and Holden JA. c-KIT mutation analysis for

diagnosis of gastrointestinal stromal tumors in fine needle aspiration specimens.

Cancer 2005; 105(3): 165-70.72. Lin F and Staerkel GA. Cytologic criteria for well differentiated adenocarcinoma of

the pancreas in fine-needle aspiration biopsy specimens. Cancer 2003; 99(1): 44-50.

73. Robins DB, Katz RL, Evans DB, et al. Fine needle aspiration of the pancreas. In

quest of accuracy. Acta Cytologica 1995; 39(1): 1-10.74. Cohen MB, Wittchow RJ, Johlin FC, et al. Brush cytology of the extrahepatic biliary

tract: comparison of cytologic features of adenocarcinoma and benign biliary

strictures. Mod Pathol 1995; 8: 498-502.75. Nakajima T, Tajima Y, Sugano I, et al. Multivariate statistical analysis of bile

cytology. Acta Cytol 1994; 38(1): 51-5.

76. Renshaw AA, Madge R, Jiroutek M, et al. Bile duct brushing cytology. Statisticalanalysis of proposed diagnostic criteria. Am J Clin Pathol 1998; 110: 635-640.

77. Layfield LJ and Cramer H. Primary sclerosing cholangitis as a cause of false positive

bile duct brushing cytology: report of two cases. Diagn Cytopathol 2005; 32(2): 119-

24.78. Adsay NV, Pierson C, Sarkar F, et al. Colloid (mucinous noncystic) carcinoma of

the pancreas. Am J Surg Pathol 2001; 25(1): 26-42.

79. Nakata K, Ohuchida K, Aishima S, et al. Invasive carcinoma derived from intestinal-type intraductal papillary mucinous neoplasm is associated with minimal invasion,

colloid carcinoma, and less invasive behavior, leading to a better prognosis. Pancreas

2011; 40(4): 581-7.80. Yopp AC, Katabi N, Janakos M, et al. Invasive carcinoma arising in intraductal

papillary mucinous neoplasms of the pancreas: a matched control study with

conventional pancreatic ductal adenocarcinoma. Ann Surg 2011; 253(5): 968-74.


36/36

81. Furukawa T, Hatori T, Fujita I, et al. Prognostic relevance of morphological types of

intraductal papillary mucinous neoplasms of the pancreas. Gut 2011; 60(4): 509-16.

82. Yopp AC and Allen PJ. Prognosis of invasive intraductal papillary mucinousneoplasms of the pancreas. World J Gastrointest Surg 2010; 2(10): 359-62.

83. Kitagami H, Kondo S, Hirano S, et al. Acinar cell carcinoma of the pancreas: clinical

analysis of 115 patients from Pancreatic Cancer Registry of Japan Pancreas Society.Pancreas 2007; 35(1): 42-6.

84. Hartwig W, Denneberg M, Bergmann F, et al. Acinar cell carcinoma of the pancreas:

is resection justified even in limited metastatic disease? Am J Surg 2011; 202(1): 23-7.

85. Suzuki A, Sakaguchi T, Morita Y, et al. Long-term survival after a repetitive

surgical approach in a patient with acinar cell carcinoma of the pancreas and

recurrent liver metastases: report of a case. Surg Today 2010; 40(7): 679-83.86. Matos JM, Schmidt CM, Turrini O, et al. Pancreatic acinar cell carcinoma: a multi-

institutional study. J Gastrointest Surg 2009; 13(8): 1495-502.

87. Schmidt CM, Matos JM, Bentrem DJ, et al. Acinar cell carcinoma of the pancreas in

the United States: prognostic factors and comparison to ductal adenocarcinoma. JGastrointest Surg 2008; 12(12): 2078-86.

88. Seth AK, Argani P, Campbell KA, et al. Acinar cell carcinoma of the pancreas: aninstitutional series of resected patients and review of the current literature. J

Gastrointest Surg 2008; 12(6): 1061-7.

89. Basturk O, Zamboni G, Klimstra DS, et al. Intraductal and papillary variants ofacinar cell carcinomas: a new addition to the challenging differential diagnosis of

intraductal neoplasms. Am J Surg Pathol 2007; 31(3): 363-70.

90. Volmar KE, Routbort MJ, Jones CK, et al. Primary pancreatic lymphoma evaluated

by fine-needle aspiration: findings in 14 cases. Am J Clin Pathol 2004; 121: 898-903.

91. Thompson LD and Heffess CS. Renal cell carcinoma to the pancreas in surgical

pathology material. Cancer 2000; 89(5): 1076-88.

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