50 ENCORE! Pancreas: Surgical Pathology and Cytopathology...

50 ENCORE! Pancreas: Surgical Pathology and Cytopathology of Pancreatic Neoplasms

N Adsay MD Michelle Reid MD

2011 Annual Meeting – Las Vegas, NV

AMERICAN SOCIETY FOR CLINICAL PATHOLOGY 33 W. Monroe, Ste. 1600

Chicago, IL 60603

50 ENCORE! Pancreas: Surgical Pathology and Cytopathology of Pancreatic Neoplasms With recent advances in imaging and interventional techniques and a dramatic decline in mortality and morbidity of pancreatic operations pancreatic resection specimens are now seen more often by surgical pathologists. Endoscopic ultrasound-guided fine needle aspiration has significantly increased the number of preoperative cytologic specimens reviewed by cytopathologists. Changes in terminology and classifications add to the new information one must now absorb. This session will provide an overview of challenges and practical clues in the diagnosis of pancreatobiliary specimens, with an algorithmic approach to differential diagnosis. Discussions will include: Pancreatic adenocarcinoma and its distinction from its mimics; Differential diagnosis of solid cellular/fleshy tumors of the pancreas; Clinicopathologic characteristics and biologic behavior of cystic tumors of the pancreas; Cytopathologic diagnosis of solid and cystic pancreatic lesions.

• Accurately differentiate problematic cases in surgical pathology of the pancreas, including solid-scirrhous lesions, solid/fleshy circumscribed lesions and cystic and traductal pancreatic tumors.

• Recognize the most common solid and cystic pancreatic lesions/tumors encountered on pancreatic fine needle aspiration; Evaluate the usefulness of ancillary studies in their cytologic diagnosis; Recognize key gastrointestinal contaminants in endoscopic tultrasound-guided pancreatic fine needle aspiration, that may lead to misdiagnosis on cytology.

• Distinguish and diagnose tumors of the ampulla, gallbladder and extrahepatic bile duct; Describe the grossing of pancreatoduodenectomy specimens.

FACULTY: N Adsay MD Michelle Reid MD Practicing Pathologists Surgical Pathology Surgical Pathology (GI, GU, Etc.) 3.0 CME/CMLE Credits Accreditation Statement: The American Society for Clinical Pathology (ASCP) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education (CME) for physicians. This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME). Credit Designation: The ASCP designates this enduring material for a maximum of 3 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity. ASCP continuing education activities are accepted by California, Florida, and many other states for relicensure of clinical laboratory personnel. ASCP designates these activities for the indicated number of Continuing Medical Laboratory Education (CMLE) credit hours. ASCP CMLE credit hours are acceptable to meet the continuing education requirements for the ASCP Board of Registry Certification Maintenance Program. All ASCP CMLE programs are conducted at intermediate to advanced levels of learning. Continuing medical education (CME) activities offered by ASCP are acceptable for the American Board of Pathology’s Maintenance of Certification Program.

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EUS‐Guided Fine Needle Aspiration and

Cytopathology of Cystic and Solid Lesions of the Pancreas

Michelle Reid, MDDepartment of PathologyEmory University Hospital

Atlanta, GA

NEEDLE ASPIRATION OF THE PANCREAS

– 1. Percutaneous fine needle aspiration (FNAB) • Performed by a radiologist

– 2. Endoscopic ultrasound‐guided (EUS) FNAB (# 1 technique)• Performed by a gastroenterologist

• An echoendoscope is placed g

• A. Trans‐abdominal ultrasound

• B. CT‐ guided» Better resolution of smaller lesions

p pagainst stomach/duodenum

• High‐resolution image obtained

INTRODUCTION

Endoscopic ultrasound‐guided (EUS) FNAB • Advantages:

– Most cost effective and sensitive diagnostic modality

– Higher resolution of sub‐centimeter (0.5 cm) lesions than CT

Real time visualization of needle during FNA– Real‐time visualization of needle during FNA

– Simultaneously diagnose and stage patients

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DIAGNOSIS OF PANCREATIC LESIONS

• Can be challenging ‐ SO WHY DO IT?• Because cytologic diagnosis affects surgical management

• Pseudocysts, serous cystadenoma, pancreatitis –NO SURGERY REQUIRED

• All other lesions/neoplasms –SURGERY REQUIRED

• Initial assessment of pancreatic lesions is radiologic – Lesions are either cystic, solid or mixed

ABRIDGED CLASSIFICATION OF SOLID AND CYSTIC PANCREATIC NEOPLASMS

Gross Configuration Neoplasms %

Solid Neoplasms

Ductal Adenocarcinoma 85%

Pancreatic Neuroendocrine Tumor 3‐4%

Acinar Cell Carcinoma 1‐2%

(Solid‐Pseudopapillary Neoplasm) 1‐2%

Pancreatoblastoma <1%

Cystic ‐True cysts Serous Cystadenoma 1‐2%Cystic ‐True cysts Serous Cystadenoma 1‐2%

Mucinous Cystic Neoplasm 1‐2%

Cystic ‐ Intraductal Intraductal Papillary Mucinous Neoplasm 3‐5%

Cystic ‐ DegenerativeSolid‐Pseudopapillary Neoplasm

(Ductal Adenocarcinoma, Acinar Cell Carcinoma, Pancreatic Neuroendocrine Tumor)

Entities in parentheses only rarely exhibit this gross configuration

Modified from Klimstra et al. Archives of Pathology and Laboratory Medicine 2009; 133(3):454‐64.

INTRODUCTION• FNA diagnosis of pancreatic lesions requires correlation of:

• Cytologic and clinical findings

• Radiologic findings

• Ancillary studies» Immunohistochemistryy

» Flow cytometry

» Cyst fluid analysis

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INTRODUCTIONAccuracy of FNAB

• Immediate cytologic assessment IS A MUST• Best performed by cytopathologist or cytotechnologist

• Reduces number of passes

• Reduces inadequate samples

• Saves time and money

Accuracy of Pancreatic FNAB• Sensitivity for detecting malignancy:

– 86% ‐ 98% for percutaneous FNAB – 75% ‐ 94% for EUS‐FNAB

• Specificity for both approaches 100% • False‐negative and false‐positive results occur• False negative results more common• False‐negative results more common

SAMPLE PREPARATION AND EVALUATION

• 1. Prepare air‐dried and alcohol‐fixed slidesA. Air‐dried slides

• Stain with a Romanowski stain– Diff‐Quik®

• Determine adequacy• Triage specimens

• Flow cytometry (if

• 2. Collect needle rinses for:– Cell blocks (place specimen in

95% alcohol or formalin) • Immunohistochemical stains

Flow cytometry (if lymphoma is suspected)

• Cyst fluid collection for analysis*

B. Alcohol‐fixed slides• Papanicolaou and hematoxylin

and eosin (H&E)

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Pancreatic Cyst Fluid Analysis1. Enzymes Pseudocyst or Non‐Neoplastic Cyst Neoplastic Cyst

amylase High low*

lipase High low

leukocyte esterase high low

2. Viscosity Non‐Mucinous Cyst Mucinous Cyst

viscosity < serum viscosity > serum

3. Tumor Markers Non‐Mucinous Cyst Mucinous Cyst

CEA Not elevated (<5ng/mL)

Elevated (>200ng/mL)(<5ng/mL) (>200ng/mL)

CA72‐4 not elevated elevated


CA125 not elevated elevated


4. Molecular Markers Negative for K‐rasmutationNegative for LOH mutation Low quantity/quality DNA

K‐rasmutation LOH mutation or

High quantity/quality DNACEA, carcinoembryonic antigen; CA, cancer antigen; LOH, loss of heterozygosity.

Modified from Weinstein L, Pancreas. In: Cytology. Diagnostic principles and clinical correlates. 3rd Ed. E. Cibas, B. Ducatman editors

Molecular Markers in Pancreatic Cyst Fluid Analysis

• RedPath Integrated Pathology developed a commercially available molecular kit for pancreatic cyst fluid and cell block analysis

• Called “PathFinderTG”

– Includes 3 tests• 1 k ras gene point mutation (on chromosome 12p12)• 1. k‐ras gene point mutation (on chromosome 12p12)

• 2. Loss of heterozygosity (LOH) analysis for mutations in ≥ 2 of 15 genomic loci

» 1 and 2 are considered high amplitude mutations if they involves > 75% of total DNA content

• 3. Measurement of DNA quantity and quality

Use of Immunohistochemical Stains in Diagnosis of Pancreatic Neoplasms

Table from Klimstra et al. Archives of Pathology and Laboratory Medicine 2009; 133(3):454-64.[14]

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REPORTING TERMINOLOGYSix diagnostic categories

• 1) Non‐diagnostic

• 2) Negative for malignancy

• 3) Atypical cells present

• 4) Suspicious for malignancy

• 5) Positive for malignant cells

• 6) Neoplastic cells present

Diagnostic Categories

1. Non‐diagnostic: • Material is unsatisfactory:

– Because of low cellularity

– Because it does not represent the site biopsied

2. Negative for malignancy: • Benign pancreatic epithelium

p


3. Atypical cells present:

• Atypia is mild• Background pancreatitis

common

4. Suspicious for malignancy:

• Atypia ≥moderate • Worrisome for malignancy but:

• Qualitatively insufficientcommon

• A COMMENT should be added

Qualitatively insufficient

• Quantitatively insufficient

for a definite diagnosis of malignancy

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5. Positive for malignant cells• Cells shows obvious malignant

features

6. Neoplastic cells present: • When the cells are obviously

“neoplastic” but not definitely benign or malignant

• e.g. Mucinous cystse.g. Mucinous cysts

Contaminants in Pancreatic FNAB• EUS‐FNAB introduces gastrointestinal (GI) tract contaminants

• GI tract contaminants include:– 1.Duodenal epithelium

– 2. Gastric epithelium

– 3. GI tract mucin

• Distinguishing GI contaminants from pancreatic ductal adenocarcinoma and neoplastic mucinous cysts can be challenging

CONTAMINANTS IN PANCREATIC FNAB

• Must know location of lesion to determine likely contaminant

• Lesions in head and uncinate process →duodenal epithelial pcontaminants

• Lesions in body/tail →gastric epithelial contaminants

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1. Duodenal Epithelial Contaminants

• Form flat honeycomb sheets with interspersed goblet cells

• Tissue edges have distinct brush border best seen atbrush border best seen at very high power

• Distinction from well differentiated ductal carcinoma or a neoplastic mucinous cyst can be difficult

Well Differentiated Ductal Adenocarcinoma vs

Duodenal Contaminants

Well differentiated ductal carcinoma ‐ note pleomorphism, overlapping cells and absence of brush border

Duodenal epithelium –note blanduniform cells with 2‐dimensional arrangement and brush border at edge of sheet

Duodenal Contaminants vs Mucinous Neoplasm

Goblet cells

Duodenal epithelium has 2‐dimensional honeycomb sheets with isolated goblet cells interspersed between benign columnar cellsThis helps to distinguish duodenal contaminants from a neoplastic mucinous cyst which has a pure population of mucin‐filled cells which are often

crowded together and overlapping

Duodenal epithelium Neoplastic mucinous cyst

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2. Gastric Epithelial Contaminants

Gastric epithelial mucin does not fill the entire cell but is confined to the superficial 1/3rd of the cellwhere it forms a distinct “mucin‐cup”

Gastric epithelium on cell block

2. Gastric Epithelial Contaminants

•It is even more challenging to distinguish gastric epithelium from mucinous cystic lesions•Note the distinct mucin “cups” in superficial 1/3rd of cell (on the left)

3. GI Tract Mucin

• GI tract mucin may also be seen in EUS‐FNAB

• Thin, watery and scant

• Not abundant or thick like mucin in cystic mucinous

Thin watery GI tract mucin

mucin in cystic mucinous neoplasms

• “Neoplastic” mucin may have tumor cells admixed

Thick colloid-like mucin in mucinous neoplasm

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Normal Exocrine Pancreas ‐ Acinar Cells

– Cells form acinar structures without distinct lumens– Cells are bland, pyramidal/triangular with low N/C ratio, granular (zymogen‐rich) cytoplasm, round nuclei, inconspicuous or prominent nucleoli

CYTOLOGY OF THE NORMAL EXOCRINE

PANCREAS

• Ductal cells– Form monolayer sheets

– Cells are evenly dispersed

– Well‐defined cell borders

Round nuclei with fine– Round nuclei with fine chromatin

– Inconspicuous or absent nucleoli

Ductal cells in honeycomb sheet

CYTOLOGY OF THE

NORMAL PANCREAS

Endocrine pancreas• Islet cells

– Rarely sampled on a FNA

– Form loose aggregates with ill‐defined cell bordersdefined cell borders

– Wispy cytoplasm

– Round nuclei

– Fine chromatin

– Nucleoli are absent or inconspicuous

Endocrine cells are small, monotonous with low N/C ratio and bland nuclei

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CYSTIC PANCREATIC LESIONS

CYSTIC PANCREATIC LESIONS• The majority are non‐neoplastic or benign

• Pancreatic pseudocysts account for the majority (75%)

• Lymphoepithelial cysts

• Serous cystadenoma

M i ti l• Mucinous cystic neoplasm

• Intraductal papillary mucinous neoplasm

• Solid neoplasms with cystic degeneration



Solid Neoplasms






Cystic True cysts Serous Cystadenoma 1 2%Cystic ‐True cysts Serous Cystadenoma 1‐2%






Modified from Klimstra et al. Archives of Pathology and Laboratory Medicine 2009; 133(3):454‐64.

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Serous cystadenoma

Solidpseudopapillaryneoplasm

Mucinous CysticNeoplasm

Intraductal

CYSTIC PANCREATIC LESIONS

Pseudocyst

papillarymucinous neoplasm

The primary goal of FNAB of cystic lesions is to distinguish low from

high‐risk pancreatic cystsg p y

• Low‐risk pancreatic cysts– Less likely to harbor malignancy

– Resected only if:• Symptomatic

• When definitive diagnosis

• High‐risk pancreatic cysts– Have a higher risk of high‐

grade dysplasia or malignancy – Managed surgically with

partial/total pancreatectomy

impossible

• Low‐risk pancreatic cysts– Pancreatic pseudocysts

– Serous cystadenomas

– Lymphoepithelial cysts

• High‐risk pancreatic cysts– Intraductal papillary mucinous

neoplasm (IPMN)– 30% harbor carcinoma

– Mucinous cystic neoplasm (MCN)

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CYSTIC LESIONS OF THE PANCREASSerous cystadenoma



Intraductal

LOW-RISK PANCREATIC CYSTS

Pseudocyst


Pancreatic Pseudocyst ‐ FNA

• Collection of amylase‐rich secretions, debris and blood

• Lacks a true epithelial lining

i ll l i h l d b i• Paucicellular smears with granular debris, macrophages, yellow bile/hematoidin pigment and fat necrosis

Pancreatic Pseudocyst

• Fluid is turbid/necrotic• NOT mucinous or gelatinous• Granular background debris• Inflammatory cells• Pigment is important for

diagnosisY ll i t

Cell blocks• Yellow pigment =

bile/hematoidin• Brown pigment =

hemosiderin

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Pancreatic Pseudocysts vs Mucinous Cystic Lesions

Pancreatic Pseudocysts• Fluid is turbid or necrotic• Mucicarmine negative • Amylase

Mucinous Cystic Lesions

• Fluid is gelatinous• Mucicarmine positive• Amylase y

• High (>250ng/mL) • CEA

• Low (<5ng/mL)

y– Low **

• CEA • High (> 200ng/mL)

Serous cystadenoma



Intraductal


Pseudocyst


Serous Cystadenoma

Cystic spaces lined by bland cuboidal or low columnar clear epithelial cells

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Serous Cystadenoma ‐ FNA

• Cyst fluid is usually thin and clear

• Aspirates are often hypocellular

• AE1/AE3 and CA19.9 are +, EMA is focally +

• Amylase and CEA levels are low• Amylase and CEA levels are low

• Mucicarmine negative

• Accuracy of diagnosis by imaging, cytology and chemical analysis is ONLY 20%**

Serous Cystadenoma

Sheets and clusters of cells with clear cytoplasm, defined borders, PAS+ cytoplasm


Lymphoepithelial cyst

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Lymphoepithelial Cyst ‐ FNA

• Has thick, white, cheesy fluid • Lined by mature squamous epithelium• Surrounded by dense lymphoid infiltrate +/‐ follicles• Smears have:

• Nucleated/anucleated squames• Nucleated/anucleated squames• Keratinous debris • Lymphocytes, histiocytes, giant cells

• Aspirates are usually DIAGNOSTIC • Accurate FNA diagnosis obviates the need for radical surgery– Cyst fluid has high CEA and amylase levels

Lymphoepithelial Cyst ‐ FNA

Anucleated squames Mature lymphocytes

Keratinous debris Cell block with gastric contaminants

HIGH‐RISK PANCREATIC CYSTS“NEOPLASTIC MUCINOUS CYSTS”

Mucinous CysticNeoplasmIntraductal

illpapillarymucinous neoplasm

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NEOPLASTIC MUCINOUS CYSTS

• Mucinous cystic neoplasm (MCN)– Primary mucin‐producing cystic neoplasm – Lined by bland mucin‐filled columnar cells– Has classical sub‐epithelial ovarian‐type ER+, PR + stroma

• Intraductal papillary mucinous neoplasm (IPMN)– Primary mucin‐producing cystic neoplasm – Arises from the main or branch pancreatic ducts– Lined by papillary mucinous epithelium with variable atypia

Key Differences Between the Two Cysts

• MCN– Large, circumscribed, solitary cystic

lesion– Not connected to the main pancreatic

duct or its branches – Because they are not connected to the

main pancreatic duct/branches amylase levels are usually low

– >90% arise in the tail

• IPMN – Diffuse ectasia involving the main

and/or branch pancreatic ducts– Always connected to the main

pancreatic duct or branches – Because they are connected to main

pancreatic duct amylase levels are highin cyst fluid

– >80% arise in the head of the pancreas – Most patients are perimenopausal

females between 40 ‐50 yrs– F : M 20:1 – Has sub‐epithelial ovarian‐type fibrous

stroma– Malignant features include:

• Size >3cm• Thick wall, peripheral calcifications• Intramural mass/nodules

– Most patients are older adults, over the age of 60

– M = F or are slight > females – No sub‐epithelial ovarian‐type stroma

present– Malignant features include:

• Size > 3cm• Dilated main pancreatic duct• Intramural mass/nodules

Cytologic Similarities

• Both IPMN and MCN have abundant thick mucin

• Difficult to express from needle

• Difficult to spread on the slide

• Smear cellularity is variable

Abundant thick colloid-like mucin

Diff‐Quik stainSmear cellularity is variable

• Higher the grade of dysplasia, the greater the cellularity

• Psammomatous calcifications may be seen in IPMN

Pap stain

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Similarities Between MCN and IPMN

Both contain sheets and clusters ofcolumnar cells with abundant intracytoplasmic mucin

Similarities between MCN and IPMN

The mucin fills the entire cytoplasm and displaces the nucleus peripherally – Note limited nuclear atypia in this example.


Nuclei are slightly pleomorphic with

Mucin +

coarse chromatin and prominent nucleoli

Macrophages may be present

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• Papillary clusters may be seen in IPMN but are not typical in MCN

• Nuclear and architectural atypia can be seen in both IPMN and MCN– Includes hypercellularity

– Nuclear crowding

– Loss of polarity

Papillary structure in an IPMN

Note nuclear atypia with nuclear Crowding and hyperchromasiap y

– Hyperchromasia, pleomorphism

– High N/C ratio and nucleoli

– Single epithelial cells in mucin

• Nuclear atypia is more often seen in IPMN than MCN

Crowding and hyperchromasia

Pancreatic Neoplastic Mucinous Cyst with High‐Grade Dysplasia

Interesting Case - Pancreatic Tail Cyst

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Diagnosis? – Adenocarcinoma (at least in situ) possibly arising in a neoplastic mucinous cyst

NEOPLASTIC MUCINOUS CYSTS• Necrosis, inflammation and

signet ring cells more common in high‐grade dysplasia/carcinoma

Note background mucin and necrosisy p /

• Best correlate of invasion in pancreatic mucinous cysts is necrosis

• Single highly atypical cells are also suggestive of malignancy

Signet ring cells Single atypical cells

Key Point In Daily Practice

Thick gelatinous mucin is DIAGNOSTIC of a l ti i t ifneoplastic mucinous cyst even if

diagnostic cells are not identified.- Correlation with imaging is required.

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PANCREATIC MUCIN‐PRODUCING CYSTS

• Definitive cytologic distinction between MCN and IPMN is discouraged

• The best diagnosis for such lesions is:• The best diagnosis for such lesions is:– “Neoplastic cells present.”

– “Neoplastic mucinous cyst”

– A comment should be made regarding the presence and grade of cytologic atypia/dysplasia

SOLID PANCREATIC LESIONS



Solid Neoplasms






Cystic True cysts Serous Cystadenoma 1 2%Cystic ‐True cysts Serous Cystadenoma 1‐2%






Modified from Klimstra et al. Archives of Pathology and LaboratoryMedicine 2009; 133(3):454‐64.

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Ductal Adenocarcinoma

• 60% ‐ 70% occur in the pancreatic head

• Well ‐ poorly differentiated

• Poorly differentiated carcinoma is straightforward

• Well and moderately differentiated carcinoma mayWell and moderately differentiated carcinoma may be difficult to distinguish from reactive ductal cells and GI tract contaminants

Poorly Differentiated Ductal Carcinoma

Poorly Differentiated Ductal Carcinoma

• Not a diagnostic challenge• 3‐dimensional groups

• 4‐fold anisonucleosis is characteristic

• Irregular nuclei

• High N/C ratio

• Macronucleoli

• Abnormal mitoses

• Necrosis

• Single intact tumor cells are critical

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Poorly Differentiated Ductal Adenocarcinoma

3-D crowded groups 4-fold anisonucleosis

Disorganized sheets with hyperchromatic cells with irregular nuclei

MALIGNANT BENIGN

Poorly Differentiated Ductal Adenocarcinoma

Well Differentiated Ductal Carcinoma

• Disorganized sheets similar to normal ductal cells

• Slight nuclear crowding

• “Drunken” honeycomb sheets

• Mild nuclear enlargement• Mild nuclear enlargement

• N/C ratio may remain low

• Anisonucleosis not as pronounced

• Normal pancreatic acini and endocrine cells are rare to absent

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Interesting Case ‐ FNAB Pancreatic Mass

Slightly “drunken” honeycomb sheet and cellular dissociation

Irregular nuclear contours, hypochromasiaand prominent nucleoli

An extremely bland-appearing well differentiated adenocarcinoma with voluminous foamy cytoplasm

Cells have abundant mucinous vacuoles and very bland almost benign cytologic appearance

Closer examination revealed single intact malignant cells with nuclear irregularity

Diagnosis?

Foamy Gland Variant of Well Differentiated Ductal Adenocarcinoma

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Foamy Gland Ductal Adenocarcinoma

Ductal Adenocarcinoma• Immunohistochemical markers:

– CK7, CK8, CK18, CK19

– CA 125

– DUPAN‐2 (pancreatic cancer‐associated antigen)

– Mucin glycoproteins are variably expressed • MUC1, 3, 4 and MUC5AC

• Molecular markers:– K‐rasmutation

– Loss of heterozygosity (LOH) mutation

– p53 mutation

Other Variants of DuctalCarcinomaCarcinoma

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Squamous Cell Carcinoma of Pancreas

• Extremely rare variant of pancreatic carcinoma• Incidence ranges from 0.5% ‐ 5%

• Only diagnose after metastasis has been excluded and after a glandular component has been excluded (i.e. adenosquamous carcinoma)

• Similar biologic behavior to ductal adenocarcinomag


Malignant squamous cells are admixed with benign pancreatic ductal cellsThis was a case of primary pancreatic squamous cell carcinoma


• Most cases represent metastases – From the lung, followed by

cervix then esophagus

• Correlation with clinical information is paramount to accurate diagnosis

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Osteoclastic‐ Giant Cell Carcinoma of Pancreas• Extremely rare primary malignant pancreatic tumor

• Associated with ductal adenocarcinoma (40% of cases)• May be focal or predominant

• Prognosis is controversial:• Some say not as dismal as ductal carcinoma

• Others say more aggressive than ductal carcinoma• Others say more aggressive than ductal carcinoma

• Mean survival ≤ 12 months – related to quantity of ductal carcinoma

Osteoclastic‐ Giant CellCarcinoma of Pancreas

• 3 cell types:– 1. Benign‐appearing osteoclast‐

like giant cells– CD68 +, Cytokeratin ‐

– 2 Pleomorphic giant carcinoma

3

2. Pleomorphic giant carcinoma cells

– CD68 ‐, Cytokeratin –– 3. Small ovoid‐spindle histiocyte‐

like carcinoma cells – CD68 +– Cytokeratin +/‐, EMA +/‐

– P53 +, ki‐67 +

1 2

Osteoclastic‐Giant Cell Carcinoma of Pancreas

Conventional ductal adenocarcinoma –same case Cell block with benign giant cells

Benign osteoclast‐like giant cellsAll 3 cell types are represented

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Mucinous “Colloid” Carcinoma of Pancreas

• Accounts for <1% of pancreatic malignancies

• Commonly associated with IPMN

• Clusters and singly dispersed malignant cells indispersed malignant cells in thick colloid‐like mucin

• Signet ring cells are present• Cytologic diagnosis is

straightforward

Mucinous “Colloid” Carcinoma of PancreasMucinous “Colloid” Carcinoma of Pancreas

Note clusters of slightly pleomorphic, hyperchromatic malignant cells in thick mucin

Chronic Pancreatitis• Can present as solid

pancreatic head lesion• Distinction from carcinoma

challenging on radiology• Reactive ductal cells may

be challengingLymphohistiocytic infiltrates

Stromal fragmentsFat necrosis

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Chronic Pancreatitis• Atypical reactive ductal cells can be confused with ductal carcinoma

• Distinction between the Reactive ductal cells2 may require immunohistochemistry

Reactive ductal cells

FNA: “Atypical Cells Present”Reactive Ductal Cells vs. Ductal Carcinoma

Note the sheet‐like arrangement, round nuclear contours and similarity between cells.

This is marked reactive atypia

Benign ductal cells – in honeycomb sheets

Drunken HoneycombSheet

Well differentiated ductal carcinomaAbnormal mitosis

Reactive ductal cells – in honeycomb sheetsWell differentiated ductal carcinoma

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Immunohistochemical Distinction between Adenocarcinoma,

Chronic Pancreatitis and GI Tract Contaminants

Atypical Ductal Cells

SMAD4 p53 CDX‐2

Ductal Adenocarcinoma ‐ + ‐Chronic pancreatitis + ‐ ‐GI tract contaminants + ‐ +SMAD4: Belongs to the SMAD family of cell signaling proteins: It is a homologue of the Drosophila protein: “Mothers against decapentaplegic“ and is also known as DPC4 (Deletion target in pancreatic carcinoma 4); CDX-2, caudal-related homeobox 2 .

Key Point In Daily Practice

• If atypical glandular cells are present and one cannot determine whether they are neoplastic or reactive the best diagnosis is:

• “Atypical cells present” with COMMENT– Correlate clinically and radiologically

Autoimmune Pancreatitis

• “Lymphoplasmacytic sclerosing pancreatitis”

• Can produce a mass effect in pancreas

• Associated with RA IBDAssociated with RA, IBD, primary sclerosing cholangitis

• ↑ serum IgG4 antibody• Antinuclear antibody (ANA) +

• Rheumatoid factor +

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Autoimmune Pancreatitis (AIP)

• Few reports on cytologic features

• Range from paucicellular to hypercellular aspirates

• Contain stromal fragments• Contain stromal fragments, lympho‐plasmacytic infiltrate, eosinophils

• Minimal ductal epithelium

• IgG4 immunostain is positive in plasma cells

Pancreatic Neuroendocrine Tumors• Range from well ‐ poorly differentiated

• Well differentiated pancreatic neuroendocrine tumor (Pan NET) is the most common

• Poorly differentiated neuroendocrine carcinomaPoorly differentiated neuroendocrine carcinoma (Pan NEC) is extremely rare

• Small cell carcinoma

• Large cell neuroendocrine carcinoma

Well DifferentiatedPancreatic Neuroendocrine Tumor– Hypercellular smears

– Uniform, dyscohesive cells

– Fragile, easily stripped cytoplasm

– Often have eccentric nuclei →plasmacytoid appearance

Well differentiated NET

Plasmacytoid cells– May resemble lymphocytes

– Classical “salt‐n‐pepper” chromatin on Pap/H&E stain

– Indistinct nucleoli usually

– May have prominent nucleoli– Variable nuclear atypia

Plasmacytoid cells

NET with prominent nucleoli

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Well Differentiated Pancreatic Neuroendocrine Tumor

D

Plasmacytoid cells

Pseudorosettes on cell block

Salt-n-pepper chromatin, small nucleoli

Prominent nucleoli and pseudoacini

Well Differentiated Pancreatic NET

Pseudorosettes are visible both on smear and cell block

Well Differentiated Pancreatic Neuroendocrine Tumor - Pleomorphic Variant

Single plasmacytoid cells and cells with focal degenerative “endocrine” atypia

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Pancreatic Neuroendocrine Tumor• Immunohistochemistry

• Positive for neuroendocrine

markers

– Synaptophysin, chromogranin, CD56,

CD57

• Positive for keratin, CAM5.2

Poorly Differentiated Pancreatic Neuroendocrine Carcinoma (NEC)

• Extremely rare

• Include small cell and large cell NEC

• Rule out metastasis before making this diagnosis

• Small cell carcinoma resembles small cell carcinoma of the lung– Molding, salt and pepper chromatin,

crush artifact

• Large cell NEC– Resembles poorly differentiated carcinoma

– Expresses neuroendocrine markers

Small cell carcinoma

Acinar Cell Carcinoma

Hypercellular smears Acinar formation and naked nuclei

Abundant granular cytoplasmCells have basophilic cytoplasm,Nuclei with fine to coarse chromatin,inconspicuous nucleoli

Normal pancreatic acini

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Acinar Cell Carcinoma

Prominent nucleoli may be seen Cell block with acinar groups and trabeculae

Acinar Cell Carcinoma• Tumor cells stain positively for:

– Pancytokeratin

– Pancreatic enzymes:• Lipase, trypsin, chymotrypsin, α 1 anti‐chymotrypsin, elastase and h h li A2phospholipase A2

• Do not confuse trypsin with α‐1‐antitrypsin

• α‐1‐ antitrypsin is not a very useful stain for acinar cells

• Because it also stains solid‐pseudopapillary neoplasm and pancreatic neuroendocrine tumors

Trypsin

Solid‐Pseudopapillary Neoplasm

Tumor cells form vague clefts or spaces lined by bland epithelial cells with intervening myxoid stroma, thin-walled vessels and vesicular, grooved nuclei

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– Rare low‐ grade solid and cystic pancreatic

– Usually arises in the pancreatic tail

– Almost exclusively in women (F:M 9:1)

– Third decade (mean age 28 years) or adolescence

– Cytologic features are distinctive

– Accurate diagnosis often made before resection


Monomorphic small cells with high N/C Complex branching papillae gratio, fine chromatin, nuclear grooves

g

Papillary fronds with central myxoid stroma (on Diff Quik stain) and blood vessel (H&E)

Solid-Pseudopapillary Neoplasm

Fibrovascular core

Vesicular nuclei with open, fine, powdery chromatin

Nuclear grooves

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• Immunohistochemistry is characteristic and diagnostic• Positive for vimentin:

• Frequently negative for cytokeratin

• Positive for:• Neuron specific enolase

• CD56 (variable)

• CD10

• β‐catenin (nuclear)

• Progesterone receptor

• α ‐1‐ antitrypsin is not helpful because it is positive in SPN, acinar cell carcinoma and pancreatic NETs

Pancreatic Neuroendocrine Tumor (NET) vs Solid‐Pseudopapillary Neoplasm (SPN)

NET SPN

Fine, open chromatinFibrovascular core Salt-n-pepper chromatin

Secondary Pancreatic Neoplasms• Various tumors may metastasize to the pancreas

• Lung (small cell and squamous cell carcinoma)

• Breast

• Kidney

L h• Lymphoma

• Less commonly:• Ovary, colon and stomach

• History of previous malignancy and immunohistochemistry are helpful in diagnosis

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SUMMARY ‐ PANCREATIC FNAB

– Cytologic evaluation of pancreatic lesions is complex

– Knowledge of types and location of the most common solid and cystic lesions is helpful in diagnosis

– Correlation with clinical, imaging data is paramount

– Cytopathologist /cytotechnologist’s presence during immediate evaluation improves adequacy and diagnostic yield

– Be mindful that chronic pancreatitis and GI tract contaminants (in EUS‐FNAB) may simulate carcinoma

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• 9. Brandt KR, Charboneau JW, Stephens DH, Welch TJ, Goellner JR. CT‐ and US‐guided biopsy of the pancreas. Radiology 1993;187(1):99‐104.• 10 David O Green L Reddy V Kluskens L Bitterman P Attal H Prinz R Gattuso P Pancreatic masses: a multi institutional study of 364 fine• 10. David O, Green L, Reddy V, Kluskens L, Bitterman P, Attal H, Prinz R, Gattuso P. Pancreatic masses: a multi‐institutional study of 364 fine‐

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ultrasound‐guided fine‐needle aspiration biopsy. Cancer 2008;114(2):102‐10.• 16. Jimenez‐Heffernan JA, Vicandi B, Lopez‐Ferrer P, Gonzalez‐Peramato P, Perez‐Campos A, Viguer JM. Fine needle aspiration cytology of

endocrine neoplasms of the pancreas. Morphologic and immunocytochemical findings in 20 cases. Acta Cytol 2004;48(3):295‐301.• 17. Gupta RK, Lallu S, Delahunt B. Fine‐needle aspiration cytology of metastatic clear‐cell renal carcinoma presenting as a solitary mass in the

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