Pancreatic Cysts - mainweb-v.musc.edu - 04 - EU… · 6 FNA • Only way to look inside the cyst • Procures cyst fluid for analysis • May produce sufficient cells for CB • Requires

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Multidisciplinary and Multimodal Approach

To the Pre-Operative Diagnosis

of Pancreatic Cysts

Martha Bishop Pitman, M.D.Director of Cytopathology

Massachusetts General Hospital

Professor of Pathology

Harvard Medical School

Boston, MA

Pancreatic Cysts

• 1.2% of the general population

• 7-8% of the elderly

• 10% of pancreatic neoplasms

• Benign, premalignant and malignant

• Most patients are asymptomatic

• Management conundrum

• Accurate diagnosis requires a multidisciplinary

and multimodal team approach

Pancreatic Cysts• Differential Diagnosis

– Pseudocyst

– Lymphoepithelial cyst

– Serous cyst

– Mucinous cyst

• (MCN and IPMN)

– Cystic degeneration of

typically solid tumors

• PanNET

• SPN

• other

– Other more rare cysts

radiologyassistant.nl

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Management Options

• Surgical

– Distal pancreatectomy

– Middle pancreatectomy

– Pancreatoduodenectomy (Whipple)

• Medical

– Drain

– Ablate

• Observation

Surgical procedures

WhippleMiddle

pancreatectomy

Distal

pancreatectomyOther

Frequency, (%) 368, (43.2%) 63, (7.4%) 373, (43.8%) 47, (5.5%)

Complications (%) 40% 49.2% 36.4% 32.4%

Pancreatic fistula 12.5% 35.5% 18.2% 8.8%

Delayed gastric

emptying6.5% 0% 0.3% 0%

Other major

complication12.9% 12.7% 12.6% 11.8%

Median length of stay,

days8 days 6 days 6 days 8 days

Operative mortality, n 2 0 1 1

MCN MD

IPMN

BD

IPMN SCA CNET SPN

n 199 180 146 137 62 29

Malignant (%) 10.3% 33.7% 13.7% 0.0% 10.7% 0.0%

Outcome

3-year survival (%) 94.0% 83.0% 88.0% 97.0% 98.0% 100.0%

5-year survival (%) 90.0% 78.0% 80.0% 90.0% 98.0% 100.0%

Outcomes

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International Consensus Guidelines for Management of IPMN

and MCN

(Tanaka, et.al. Pancreatology. 2006; 6:17)

The International Consensus Guidelines 2012 for the Management of IPMN and MCN of the PancreasTanaka M, Fernandez del-Castillo C, Adsay V, Chari S, Falconi M, Jang J-Y, Levy P, Pitman MB, Schmidt MC, Shimizu M, Wolfgang CL, Yamaguchi K, Yamao K.Pancreatology, 2012 May-Jun;12(3):183-97.

• High Risk Stigmata Surgery if clinically feasible– Obstructive jaundice in a patient with a cyst in the pancreatic head

– Enhancing solid component of the cyst

– Main pancreatic duct dilatation ≥10mm

• Worrisome Features EUS-FNA– Cyst ≥ 3cm

– Thickened/enhancing cyst walls

– Main duct 5-9mm

– Non-enhancing mural nodule

– Abrupt change in MPD size with distal pancreatic atrophy

• EUS-FNA Susp/Pos cytology Surgery

Current Recommendations• Surgery-optional

– PCT

– LEC

– SCA

– IPMN-LGD

– IPMN-IGD??.

• Surgery-recommended

– MCN, all grades

– IPMN-HGD

– IPMN-invasive

– Cystic PanNET

– SPN

– Cystic Acinar Cell Ca.

– Cystic PDAC

Cytology is a critical test in cyst classification for management.

Decision to operate is based on surgical risk versus malignancy risk.

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Pancreatic Cysts: CT

Benign to Worrisome imaging

Worrisome to High-risk imaging

unilocular

multilocular

complex

Benign imagingSimple cysts PCT BD-IPMN w/ LGD MCN w/ LGD

SCA BD-IPMN w/ LGD

MCN w/ inv. Ca. IPMN w/ inv. Ca.

Small or non-enhancing MN: IPMN with HGD

SPNcPanNET

MCN Pseudocyst IPMN

Cohen-Scali F et al. Radiolgy 2003

Khurana B et al. AJR 2003

Kim S et al. AJR 2006

Challenges in Cyst Characterization:

Morphologic Overlap

EUS Recommended(2012 guidelines)

• Worrisome Imaging

– Cyst > 3cm

– Thickened/enhanced

cyst walls

– MPD 5-9 mm

– Nonenhancing mural

nodule

– Abrupt change in

caliber of MPD with

distal atrophy

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Nonspecific EUS Imaging

• Broad differential

diagnosis:

– Mucinous

• BD-IPMN

• MCN

– Nonmucinous

• Macrocystic SCA

• Lymphangioma

– Benign

– Malignant (≥HGD)

Small Cysts with “Benign” Imaging

are not all low-grade• Fritz S, Klauss M, Bergmann F, et al. Small (Sendai negative) branch-duct IPMNs: not harmless. Ann Surg.

Aug 2012;256(2):313-320.

• Wong J, Weber J, B AC, et al. High-Grade Dysplasia and Adenocarcinoma Are Frequent in Side-Branch Intraductal Papillary Mucinous Neoplasm Measuring Less than 3 cm on Endoscopic Ultrasound. J Gastrointest Surg. Jan 2013;17(1):78-85.

• Pelaez-Luna M, Chari ST, Smyrk TC, et al. Do consensus indications for resection in branch duct intraductal papillary mucinous neoplasm predict malignancy? A study of 147 patients. Am J Gastroenterol. Aug 2007;102(8):1759-1764.

• Pitman, M. B., P. J. Michaels, et al. (2008). "Cytological and cyst fluid analysis of small ≤3 cm) branch duct intraductal papillary mucinous neoplasms adds value to patient management decisions." Pancreatology8(3): 277-284.

• Tang RS, Weinberg B, Dawson DW, et al. Evaluation of the guidelines for management of pancreatic branch-duct intraductal papillary mucinous neoplasm. Clin Gastroenterol Hepatol. Jul 2008;6(7):815-819; quiz 719.

• Woo SM, Ryu JK, Lee SH, Yoon WJ, Kim YT, Yoon YB. Branch duct intraductal papillary mucinous neoplasms in a retrospective series of 190 patients. Br J Surg. Apr 2009;96(4):405-411.

EUS-guided FNA• Technique of choice

• Controversial

• Not used in Japan

and much of Korea

• Requires significant

experience for

quality aspiration

and interpretation

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FNA

• Only way to look inside the cyst

• Procures cyst fluid for analysis

• May produce sufficient cells for CB

• Requires training for both the endoscopist

performing the FNA and the pathologist

interpreting the sample

• EUS-FNA is safe

Peritoneal Seeding in Intraductal Papillary Mucinous Neoplasm of the

Pancreas Patients Who Underwent Endoscopic Ultrasound-Guided Fine-

Needle Aspiration: The PIPE StudyYoon WJ, Dagilar ES, Fernandez-del Castillo C, Pitman MB, Brugge WR. Peritoneal Seeding in Intraductal Papillary Mucinous Neoplasm of the

Pancreas Patients WHO Underwent Endoscopic Ultrasound-Guided Fine-Needle Aspiration; Results of the PIPE Study.

Endoscopy. 2014;46(5):382-7

Table 1. Characteristics of patients with IPMN with pre-operative EUS-FNA (EUS-FNA

Group) and patients with no pre-operative tissue sampling (No Sampling Group)

EUS-FNA Group No Sampling Group p value

Number of patients 61 68 -

Sex (male : female) 32 : 29 32 : 36 0.540*

Age at surgery, y† 68 (39 – 83) 66 (37 – 89) 0.790

‡

Follow-up period after

surgery, mo†

66.7 (6.0–161.4) 58.6 (7.6–155.2) 0.843‡

Pancreatic head

involvement, no. (%)

38 (62.3) 41 (60.3) 0.816*

Main duct involvement,

no. (%)

28 (45.9) 37 (54.4) 0.334*

Invasive IPMN, no. (%) 11 (18.0) 19 (27.9) 0.184*

Peritoneal seeding, no.

(%)

1 (1.6) 3 (4.4) 0.621§

Quality FNA

Quality specimenSpecimen representative of the lesion

Proper tissue triage and preparation

Quality interpretationKnowledge of pancreatic pathology

Experience of interpreter

Team approach to diagnosis

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HARVARDMEDICAL SCHOOL

MASSACHUSETTS GENERALPHYSICIANS ORGANIZATION

Two basic questions for Cyst analysis

1) Is the cyst mucinous or non-mucinous?

2) Is the cyst low-grade or high-grade?

Mucinous HGA

IPMN with LGD

GI duplication

cyst

Non-neoplastic

Mucinous cyst

Cystic PanNET

Cystic Acinar

Cell carcinoma

SPN

IPMN/MCN with HGD

IPMN/MCN with

Invasive carcinoma

Cystic PDAC

IPMN with IGD

PCT

LEC

SCA

Surgery

MCN

with

LGD



Cytological Preparations

• Cysts• Direct smears

• If fluid thick enough

• Fresh undiluted cyst fluid

• CEA; Amylase• Molecular • Cytology

• Cytospin• Cellblock

No-ROSE

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Pancreatic Cyst Fluid Triage



Include Secondary Pathology

CEA by cyst fluid analysis

1

10

100

1000

10000

100000

1000000

Serous Inflammatory Mucinous Borderline Malignant

192 ng/ml

CFA cut-off levels lab and study dependent(van der Waaij, et. al. Cystfluid analysis in the differential diagnosis of pancreatic cystic lesions: a pooled

analysis. Gastrointes Endosc. 2005; 62:383)

CEA >800ng/ml

Neoplastic mucinous cysts

CEA <5ng/mlSerous cystadenoma

Pseudocyst

Amylase <250 U/L

Not a pseudocyst

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CEA and Amylase: Key Points

• Elevated CEA (≥ 192 ng/ml) supports a mucinous cyst• Does not distinguish IPMN from MCN

• Level does not correlate with malignancy

• Rare FP: PCT, GI duplication cyst, LEC

• Amylase levels• Elevated in the 1000’s for most PCT

• Low amylase level tends to exclude a PCT

• Level does not distinguish IPMN from MCN



Molecular Tests • KRAS

• Mutation(s) support a neoplastic mucinous cyst• Does not distinguish IPMN and MCN

• Does not correlate with grade

• GNAS

• Mutation supports IPMN over MCN• Does not correlate with grade

• RNF43• Mutation supports a mucinous cyst

• Does not distinguish IPMN and MCN

• 3p deletions• 3p25, VHL gene, supports SCA

• Other 3p deletions also noted in SCA

• CTNNB1 (beta-catenin) deletion• Mutation(s) support SPN

• TP53, CDKN2A loss SMAD4 loss support a HR cyst



• NGS supported the imaging impression in 78% but changed it in 12%

• NGS defined a cyst as mucinous in 48% of cysts with a non-elevated CEA

• KRAS and/or GNAS mutations supported a diagnosis of IPMN in 71% of cases without an elevated CEA

• KRAS mutation reclassified 19% of cysts non-neoplastic by imaging and with low CEA

Impact of Next-Generation Sequencing on the

Clinical Impression of Pancreatic Cysts

1Massachusetts General Hospital, Department of Pathology, Boston, MA, United States | 2Massachusetts General Hospital, Department of Medicine,

Boston, MA, United States | 3Massachusetts General Hospital, Department of Surgery, Boston, MA, United

Martin Jones, MBBS1*, Zongli Zheng, MD, PhD1*, Jessica Wang, MD1, Emily Albanese1, Abdurrahman Kadayifci, MD2, Dora Dias-

Santagata, PhD1, Long Le, MD1, William R. Brugge, MD2, Carlos Fernandez-del Castillo, MD3, Mari Mino-Kenudson1, MD, A. John

Iafrate, MD, PhD1 ,̂ and Martha Pitman, MD1 ̂States | *Co-first authors | ^Co-senior authors

Gastrointest Endosc. 2016 Jan; 83(1):140-8.

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Cytology Interpretation• Multimodal Approach

– Clinical Information• Patient age and gender

• Symptoms

• Past medical history

– Radiological Information• Location of mass in the pancreas (and thus organ traversed for

EUS)

• Mass characteristics– Solid or cystic

» Size, contours, invasion

» Cyst structure: uni- or multilocular; thick/thin wall, Ca++, nodule/mass in the wall

» Gross cyst contents: thick, viscous, thin, water, clear, brown

– Ancillary tests: CEA, amylase, molecular analysis

Communication within the Care

Team is Critical to Success

EUS-FNA Requisition Form

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Recommended Standardized

Reporting Terminology• Nondiagnostic

• Negative– AP, CP, AIP, LEC, PCT, Splenule

• Atypical

• Suspicious

• Neoplastic– Benign: SCA

– Other: MCN, IPMN, PanNET SPN

• Positive/Malignant– PDAC, ACC, PBL, lymphomas, metastases

Pitman MB, Centeno BA. Ali SZ, Genevay M, Stelow E, Mino-Kenudson M, Fernandez-del Castillo C, Schmidt CM, Brugge WR, and Layfield L.

Standardized Terminology and Nomenclature for Pancreatobiliary Cytology: The Papanicolaou Society of Cytopathology Guidelines for

Pancreatobiliary Cytology. Diagn Cytopathol, 2014.; 42(4):338-350

Complex Cysts

(solid and cystic)

High-Risk Imaging

Clinical

Rare but may represent up

to 6% of all pancreatic

neoplasms and 24% of

resected cysts

89% in young women,

mean age ~ 28 years

1/3 in head, 1/3 in body

and 1/3 in tail

Radiology

shows large solid and

cystic neoplasm

Image: AFIP Pancreas fascicle 2007

Secondarily Cystic Solid Neoplasms:

SPN

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Classic Cytology

SPN

Papillary branching

Myxoid stroma

Clinging cells and single cells

Euchromatin

Oval, indented, grooved nuclei

Perinuclear vacuoles/globules

Cytohistology: CB

SPN

Beta-catenin

Secondarily Cystic Solid Neoplasms:

cPanNET

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Cystic PanNETs

• ~10% of PanNETS

• Half are completely cystic and half are solid

and cystic

• Most are nonfunctioning

• If clinically suspected, serum chromogranin A

(CgA) levels may support the diagnosis when

elevated (sensitivity ~70%)– False positive CgA levels have been reported in patients taking proton pump

inhibitors, renal or liver failure and untreated hypertension.

– Elevated serum pancreatic polypeptide increases sensitivity to 93%

Imaging Features

• Thick cyst wall is a clue

• Pseudocysts also have a thick wall, but almost all of these patients have a history of pancreatitis

• MCN have a thick wall, but these cysts are septated and almost all are in women

• SPN are solid and cystic, but these tumors are almost always in young women

• IPMNs and MCNs can be solid and cystic when malignant

Cystic Pancreatic Neuroendocrine Tumors:

The Value of Cytology in Pre-Operative Diagnosis Vicente Morales-Oyarvide MD, Won Jae Yoon, MD2, Thun Ingkakul MD, David G Forcione MD, Brenna Casey, MD, William R Brugge MD,

Carlos Fernández-del Castillo MD, and Martha B Pitman MD

Cancer Cytopathology. 2014; 122:435-444..

N Diagnostic Suspicious HR

Benign or

indeterminate

Cytology 35 71% 77% 86% 5%

EUS 34 38% 47% 56% 15%

Key: EUS, endoscopic ultrasound; HR, high-risk

TABLE 2. Accuracy of Cytology and EUS for the Diagnosis of Cystic Pancreatic Neuroendocrine Tumors

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Cystic pancreatic neuroendocrine tumors:

endoscopic ultrasound and fine-needle aspiration characteristics.

Yoon WJ, Daglilar ES, Pitman MB, Brugge WR.

Endoscopy. 2013;45(3):189-94.

Table 3. Comparison of CPanNet patients and mucinous cyst patients

CPanNet (n=15)* Mucinous cyst (n=15)

† P value

‡

Sex (male : female) 9 : 6 9 : 6 1.000§

Age, y, median (range) 57 (34 – 80) 57 (33 – 79) 0.950∥

Cyst diameter, mm,

median (range)

29 (16 – 70) 23 (8 – 90) 0.110∥

Wall thickness (thick :

thin)

10 : 5 2 : 13 0.003§

Septation (yes :no) 6 : 9 9 : 6 0.273§

Associated mass lesions

(yes : no)

8 : 7 4 : 11 0.136§

Cyst fluid CEA level,

ng/mL, median (range)

1.1 (0.3 – 500) 400 (2.8 – 6661) <0.001∥

Diagnostic cytology

(n, %)

11 (73.3)# 3 (20.0)

** 0.003

§

Cystic PanNETS• Imaging Nonspecific

– Thick cyst wall

– Solid and cystic

• Cytology is THE

diagnostic test

– CEA low

– Amylase low

– KRAS/GNAS negative

• Cells usually diagnostic

when present

Cystic Pancreatic Neuroendocrine Tumors: The

Value of Cytology in Pre-Operative Diagnosis

Vicente Morales-Oyarvide MD1, Won Jae Yoon,

MD2, Thun Ingkakul MD1, David G Forcione

MD3, Brenna Casey, MD3, William R Brugge

MD3, Carlos Fernández-del Castillo MD1,

Martha B Pitman MD4

Cancer Cytopathology, 2014; 122:435-444.

PanNET Cytohistology: CB

SynaptophysincPanNET

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Grading GEP NETs(WHO, ENETS)

GRADE MITOSES KI-67

1 < 2 AND <3%

2 2-20 OR 3-20%

3 >20 OR >20%

Korean Journal of Pathology 2013; 47(3): 227-237

Tumor CarcinomaTumor

Multilocular Cyst

Serous Cystadenoma

Clinical

Benign, slow growing neoplasm

women>>men, mean age 7th decade

Associated with VHL with deletion of

3p25 in most cases

Often asymptomatic, but can

hemorrhage and cause pain

Radiology

circumscribed, multi-lobulated

Microcystic with fibrous septae,

central scar, calcifications in ~30-

40%

Histology

“glycogen-rich”

dPAS+ cuboidal

epithelium

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Serous Cystadenoma: Variants

Unilocular and Macrocystic

SCA

Serous Cystadenoma

• Cuboidal non-mucinous

epithelial cells

• Hemosiderin-laden

macrophages in a clean

or bloody, non-

pseudocyst like

background

• CEA and amylase low

• NO KRAS/GNAS

• 3p deletions support

diagnosis

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Cytohistology: CB

SCA

PAS/DPAS

Neoplastic Mucinous Cysts

MCN IPMN

Non-Complex Cyst

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Pancreatic PseudocystClinical

Associated with

pancreatitis, trauma,

surgery (almost always)

RadiologyUnilocular, non-

septated

Thick walled

No mural nodule

HistologyCyst lining of

histiocytes and

inflammatory

cells

Pancreatic Pseudocystcytology

• cyst debris with blood, proteinaceous material and yellow

hematoidin-like pigment

• variable inflammation

• NO cyst lining epithelium (beware of contamination, mucin

and epithelium)

•CEA low; amylase usually in the 1000’s; no KRAS or GNAS

cytospin smear

•Clinical

• F:M=20:1

• Most are benign

• Prognosis excellent for non-

invasive completely resected

tumors

•Resection recommended despite

grade

•Radiology

•body and tail (90%)

•do not communicate with the

pancreatic ductal system

•thick walled (Ca++ in 20%)

•thin or thick septa

Mucinous Cystic Neoplasm

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•Not associated with the pancreatic ducts

•Lined by mucinous, generally non-papillary epithelium

•Subepithelial “ovarian-like stroma” required

•Atypia may be very heterogeneous; invasion may be very focal,

so the entire cyst should be submitted for histology

Mucinous Cystic Neoplasm is not an

Aggressive Entity(Crippa, et.al. Annals of Surgery 2008; 247:571-579

• Collaborative study between MGH and University

of Verona

• 163 patients with MCN, strictly defined

Non-invasive

Invasive


• Difficult to distinguish from IPMN on cytology alone

• Ovarian-type stroma typically not seen

• Cyst lining denudation produces cyst aspirate resembling PCT

• CEA

• Amylase

• KRAS +/GNAS-

LGD

INV

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Intraductal Papillary Mucinuos Neoplasm

Intra-ductal Branch duct IPMN Combined disease

IPMN

•Main duct type

•Diagnosed clinically

•Dilated main pancreatic duct

(definition varies, but >5mm)

•Pancreatic head mostly, but

occur all through the pancreas

•Intestinal type lining most

common

•60% have HGD

•45% have invasive carcinoma

•Symptoms common but 25%

asymptomatic

•Treatment-resection

AFIP 4th Series Fascicle

IPMN• Branch Duct Type

• Most often in head/uncinate

• 1/3 with multiple cysts

• Supports clinical dx

• Most patients asymptomatic

• Imaging: “bunch of grapes”; single cyst may not be diagnostic for BD-IPMN unless visualized connection to the MPD

• Most lined by gastric type epithelium

• Most low grade

• Treatment-depends….


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•Variously papillary mucinous epithelium of variable

cell type and heterogenous atypia

•No association with ovarian-like stroma under the

epithelium


IPMN

Gastric (null) Type Cells: Most BD-IPMN MUC 5AC+, MUC 6+, MUC1-, MUC2-, Usually LGD CDX2-


Intestinal Type Cells: Most Main Duct-IPMN MUC 5AC+, MUC 6 weak, MUC1-, Moderate/Intermediate-grade dysplasia MUC2+, CDX2+


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Pancreatobiliary Type: Less common type MUC 5AC+, MUC 6 focal, High grade dysplasia MUC1+, MUC2-, CDX2-

Shi and Hruban. Human Pathol 2011.epub 20 July 2011

Oncocytic Type: Uncommon type MUC 5AC goblet cells+, MUC1-, MUC2

High grade dysplasia goblet cells+, MUC 6 + , CDX2-


HGD/Carcinoma

Intraductal Papillary Mucinous Neoplasm of the Pancreas:

Cytologic Analysis and Correlation with Histologic GradePJ Michaels, EF Brachtel, BC Bounds, WR Brugge, and MB Pitman

(Cancer Cytopathol 2006; 108:174-179.)

Low grade dysplasia Moderate dysplasia

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1) Gross examination

2) CEA (best test)

3) Cytology

4) Molecular mutations


1) Cytology!!



Gross Cyst Fluid

Mucinous cyst fluid Non-mucinous cyst fluid

Acellular thick, colloid-like mucin is NOT non-diagnostic!

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MASSACHUSETTS GENERALPHYSICIANS ORGANIZATION Mucin with LBC processing



Mucinous Epithelium



Ancillary Tests for Mucinous Etiology

• CEA ≥ 192 ng/ml

• Genetic mutations

• KRAS (IPMN or MCN)

• GNAS (IPMN)

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1) Gross examination

2) CEA (best test)

3) Cytology


1) Cytology!!



Diagnostic Morphology of Carcinoma

Already invasive- prognosis decreases ~50%



Ideal World- Recognize HGD

with accuracy

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Atypical Epithelial Cells

Morphological Overlap with AEC

Histologically Confirmed LGD-IGD



Grading Epithelial Atypia in EUS-FNA of Intraductal Papillary Mucinous Neoplasms:

An international interobserver concordance study Martha B Pitman MD1, Barbara A Centeno MD2, Muriel Genevay MD3,

Ricardo Fonseca, MD4 and Mari Mino-Kenudson MD1.Cancer Cytopathology 2013;121(12):729-736.

Table 3. Kappa Coefficient for Two-Tiered Cytological Grading of Branch-Duct IPMN

Cyst Fluids

Grade

Four

Reviewers

Randolph's

Multirater

Kappa

Two

Reviewers*

Cohen's

Kappa

0-2, 3-4 54% 0.45 87% 0.74

0-1, 2-4 52% 0.44 88% 0.71

* Two most experienced reviewers

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Cytological Criteria of High-Grade Epithelial Atypia in the Cyst Fluid of Pancreatic Intraductal Papillary

Mucinous NeoplasmsMartha B. Pitman, MD, Barbara A. Centeno, MD, Ebubekir S. Daglilar, MD,

William R. Brugge, MD, and Mari Mino-Kenudson, MDCancer Cytopathology 2014;122(1):40-47.

HGA is most accurately identified in mucinous cyst fluids by:

1. an increased N/C ratio,

2. an abnormal chromatin pattern

3. background necrosis

Reference duodenal enterocyte Low-grade High-grade



Risk of Malignancy in Pancreatic Cysts with High-Grade Atypical CytologyRaza S Hoda1, Ronald Arpin1, Matthew W Rosenbaum1 and Martha B Pitman1

1Department of Pathology, Massachusetts General Hospital, Boston, MA, United States

METHODSBACKGROUND

RESULTS

1. de Jong K et al. High prevalence of pancreatic cysts detected by screening

magnetic resonance imaging examinations. Clin Gastroenterol Hepatol. 2010;8:806-11.

2. de Oliveira PB et al. Prevalence of incidental pancreatic cysts on 3 tesla magnetic

resonance. PLoS One. 2015;10:e0121317.

3. Ketwaroo GA, Mortele KJ, Sawhney MS. Pancreatic Cystic Neoplasms: An Update.

Gastroenterol Clin North Am. 2016;45:67-81.

Cytologic criteria for highgrade atypia (HGA) of IPMNs were recently reported by the Papanicolaou Society of Cytopathology (see Table 1). Our aims include:

•Evaluation of the risk of malignancy in PCF cytology with HGA

•Evaluation of the overall ability of PCF cytology to predict high-risk or malignant cysts

The incidence of pancreatic cysts is rising, with the increasing use of high-resolution imaging techniques. Reported incidences on imaging studies of asymptomatic patients range from <1% to 24%.1-3 This group of cysts is comprised of a variety of entities, ranging from pseudocysts to invasive adenocarcinomas. Intraductal papillary mucinous neoplasms (IPMNs) may present as such and demonstrate a variable disease course, depending on its histologic appearance. Given the rising incidence of these lesions and varied natural histories,

accurate diagnosis though endoscopic ultrasound guided fine needle aspiration (EUS-FNA) of pancreatic cyst fluid (PCF) can help guide management.

• High-risk cytology is both sensitive and specific for identifying malignant pancreatic cysts

• High grade atypia on PCF cytology is associated with a high risk of malignancy (89%)

OBJECTIVES

CONCLUSIONS

REFERENCES

Table 1. Cytologic criteria for HGA for IPMN4

• Abnormal chromatin pattern

• Increased nuclear:cytoplasmic ratio

• Background cellular necrosis

• Nuclear membrane irregularities

• Small cell size compared to 12µ enterocyte

All patients who underwent EUS-FNA for a pancreatic cyst at

Massachusetts General Hospital from June 2015 to July 2016 were

evaluated. Clinical data, cytologic diagnoses and surgical outcomes

were documented. High-risk imaging characteristics included an

enhanced solid component, main pancreatic duct dilatation ≥1cm, and

a cystic lesion in the head of the pancreas in a patient with obstructive

jaundice. Worrisome imaging features were cysts ≥3cm in size, main

pancreatic duct size of 5-9mm, abrupt change in the main pancreatic

duct caliber with distal pancreatic atrophy, enhanced, thickened cyst

wall, non-enhanced mural nodule, and lymphadenopathy. High-risk

cytologic findings included an IPMN with HGA, neuroendocrine tumors

(NET), and adenocarcinoma. Malignant histologic features included

mucinous cysts with high-grade dysplasia (HGD), NET, and

adenocarcinoma. The risk of malignancy was determined by the

histologic outcomes.

Table 2. Pancreatic Cysts with Histologic Followup.

Imaging Classification

Cytologic Diagnosis

Histologic Diagnosis

High Risk Adenocarcinoma Adenocarcinoma

Worrisome Adenocarcinoma Adenocarcinoma

Worrisome Adenocarcinoma Adenocarcinoma

Worrisome MC with HGA Adenocarcinoma

Low Risk IPMN with HGA Adenocarcinoma

Worrisome NET NET

High Risk IPMN with HGA IPMN with HGD

High Risk IPMN with HGA IPMN with HGD

Worrisome MC with HGA IPMN with IGD

Worrisome MC without HGA IPMN with IGD

Worrisome MC without HGA IPMN with LGD

Worrisome Non-mucinous cyst MCN, denuded

Worrisome Serous cystadenoma Serous cystadenoma

Worrisome Non-mucinous cyst Endometriotic cyst

Abbreviations: HGD, high-grade dysplasia; IGD, intermediate-grade dysplasia; LGD, low-grade dysplasia; MC, mucinous cyst; MCN, mucinous cystic neoplasm

90 PCFs from 80 patients were evaluated. Our patients were 54% women and ranged from 20 to 91 years old (mean = 66). 14 patients had follow-up histology (see Table 2). 10 PCFs (11%) had high-risk cytology, of which 9 had followup histology. The absence of HGA or worse was noted in 80 PCF samples from 70 patients, of which 5 had followup histology, all with no malignant features. One patient was thought to have a low-risk cyst by radiology, which was later found to be harboring adenocarcinoma. High-risk cytology was 100% sensitive

and 83% specific for malignancy. All cysts with HGA were resected with one falsepositive of an IPMN with intermediategrade dysplasia (IGD). The risk of malignancy with HGA cytology was 89%.

Figure 1. Radiologic and cytologic findings of high-grade atypia.

Benign/Low Grade Glandular Epithelium

High-Grade Atypical Epithelial Cells in Pancreatic Mucinous Cysts are a More Accurate Predictor of Malignancy than “Positive” CytologyMartha Bishop Pitman M.D, et.al. (Cancer Cytopath 2010)

28

High Grade Atypical Glandular Epithelium

High-Grade Atypical Epithelial Cells in Pancreatic Mucinous Cysts are a More Accurate Predictor of Malignancy than “Positive” CytologyMartha Bishop Pitman M.D, et.al. ( Cancer Cytopath 2010)



Cytohistology: CB

IPMN-HGA IPMN-LGA



Ancillary Tests: IPMN/MCN

• IHC insufficiently specific to be diagnostic of grade in premalignant cysts

• SMAD4 may be helpful for dx of PDAC-loss of nuclear staining

29



Moray™ Micro-forceps biopsy



Platform PresentationMorayTM Micro Forceps Biopsy Improves the Diagnosis of Specific Pancreatic CystsM. Lisa Zhang, Ronald N. Arpin, William R. Brugge, David Forcione, Osman Yuksel, Omer Basar, Martha B. Pitman

MGH, Harvard Medical School [in press, Cancer Cytopathology]

19 gauge needle



PCF (%) MFB (%) P

Diagnostic Yield 35 (72.9) 36 (75.0) 0.818

Mucinous Diagnosis 29 (61.8) 28 (58.8) 0.949

High-risk Detection 3 (6.3) 2 (4.2) 0.670

Specific Diagnosis 9 (18.8) 24 (50.0) <0.001

Cytology 26 (89.7)Extracellular mucin 13 (44.8)

Mucinous epithelium 20 (69.0)

Both 8 (27.6)

CEA > 192 ng/ml 13 (44.8)Molecular

(KRAS/GNAS)

19 (65.5)

Comparison of Pancreatic Cyst Fluid Analysis and MorayTM Micro Forceps

Biopsy for the Diagnosis of Mucinous Cysts

Mucinous Non-mucinous

P

669.5 12.4 0.003

30



# Cases (%)PCF

IPMN with low-grade atypia

(LGA)

6 (12.5)1

Adenocarcinoma 1 (2.1)2

Serous cystadenoma 2 (4.2)3

MFBIPMN with low-grade dysplasia

(LGD)

18 (37.5)

Mucinous cystic neoplasm 1 (2.1)Adenocarcinoma 1 (2.1)Serous cystadenoma 3 (6.3)Acinar cell cystadenoma 1 (2.1)

1 All cases diagnosed by GNAS mutation (IPMN) and cytology (LGA).2 Diagnosed by cytology alone.3 One case diagnosed by cytology alone and one case diagnosed by 3p25 mutation.

Specific Cysts Diagnosed by Pancreatic Cyst Fluid Analysis and MorayTM

Micro Forceps Biopsy



IPMN-LGD MCN-LGD

SCA IPMN-invasive carcinoma



Nonmucinous epithelial cells with prominent nucleoli in acinar cell cystadenoma, Pap stain, 60x

Acinar cell cystadenoma, H&E, 40x Acinar cell cystadenoma, Trypsin, 40x

Chen AL et al. Diagn Cytopathol.

2017

31



PCF Analysis and Histology discordanceSCA by

PCF

Fibrous

tissue only

by MFB

HGA by PCF

Low-grade

mucinous

epithelium in

CF patient- ?

Neoplasia

vs.

obstruction

NGS 3p25 deletion

NGS KRAS and GNAS mutation

Example Case65 year old female with incidental pancreatic cyst

• CEA 357 ng/ml

• Amylase 11,203 U/L

• NGS pending

• Neoplastic:Other

• Mucinous cyst with

HGA consistent with

BD-IPMN with at least

HGD

Low-risk “Sendai negative” High-grade epithelial atypia

Histology follow-up

IPMN with HGD

32

Acknowledgements

• Dr. Carlos Fernandez-del Castillo

• Dr. Dushyant Sahani

• Dr. Bill Brugge

• Dr. Mari Mino-Kenudson

• Dr. Ralph Hruban

• Dr. David Klimstra

• Dr. Lester Layfield

Documents

Pancreatic Cysts - mainweb-v.musc.edu - 04 - EU… · 6 FNA • Only way to look inside the cyst • Procures cyst fluid for analysis • May produce sufficient cells for CB • Requires