Pancreatic cysts are increasingly detected on imaging studies. Accurate determination of the cyst type is important to provide appropriate care for the patients. It is also very clear that not one single modality can provide adequate diagnostic information. A multidisciplinary approach is the key to the diagnosis of pancreatic cysts. In this setting, the role of ancillary testing, which includes biochemical testing (carcinoembryonic antigen and amylase levels in the cyst), molecular testing (e.g., KRAS, GNAS, VHL, and CTNB1), and/or immunohistochemical tests are very important to obtain an accurate diagnosis. This review will discuss helpful ancillary tests in common pancreatic cyst neoplasms and how to approach the diagnosis of pancreatic cysts.

1.
Brugge
WR
.
Pancreatic fine needle aspiration: to do or not to do?
JOP
.
2004
Jul
;
5
(
4
):
282
8
.
[PubMed]
1590-8577
2.
Jhala
NC
,
Jhala
DN
,
Chhieng
DC
,
Eloubeidi
MA
,
Eltoum
IA
.
Endoscopic ultrasound-guided fine-needle aspiration. A cytopathologist’s perspective
.
Am J Clin Pathol
.
2003
Sep
;
120
(
3
):
351
67
.
[PubMed]
0002-9173
3.
Pitman
MB
,
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
Dec
;
18
(
6
):
331
47
.
[PubMed]
0956-5507
4.
Jais
B
,
Rebours
V
,
Malleo
G
,
Salvia
R
,
Fontana
M
,
Maggino
L
, et al
Serous cystic neoplasm of the pancreas: a multinational study of 2622 patients under the auspices of the International Association of Pancreatology and European Pancreatic Club (European Study Group on Cystic Tumors of the Pancreas)
.
Gut
.
2016
Feb
;
65
(
2
):
305
12
.
[PubMed]
0017-5749
5.
Reid
MD
,
Choi
H
,
Balci
S
,
Akkas
G
,
Adsay
V
.
Serous cystic neoplasms of the pancreas: clinicopathologic and molecular characteristics
.
Semin Diagn Pathol
.
2014
Nov
;
31
(
6
):
475
83
.
[PubMed]
0740-2570
6.
Ahmad
NA
,
Kochman
ML
,
Brensinger
C
,
Brugge
WR
,
Faigel
DO
,
Gress
FG
, et al
Interobserver agreement among endosonographers for the diagnosis of neoplastic versus non-neoplastic pancreatic cystic lesions
.
Gastrointest Endosc
.
2003
Jul
;
58
(
1
):
59
64
.
[PubMed]
0016-5107
7.
Belsley
NA
,
Pitman
MB
,
Lauwers
GY
,
Brugge
WR
,
Deshpande
V
.
Serous cystadenoma of the pancreas: limitations and pitfalls of endoscopic ultrasound-guided fine-needle aspiration biopsy
.
Cancer
.
2008
Apr
;
114
(
2
):
102
10
.
[PubMed]
0008-543X
8.
Lal
A
,
Bourtsos
EP
,
DeFrias
DV
,
Nemcek
AA
,
Nayar
R
.
Microcystic adenoma of the pancreas: clinical, radiologic, and cytologic features
.
Cancer
.
2004
Oct
;
102
(
5
):
288
94
.
[PubMed]
0008-543X
9.
Lastra
R
,
Jhala
D
,
Ahmad
N
,
Jhala
N
.
Brunner glands: A major pitfall in assessing endoscopic ultrasound guided fine needle aspiration samples ofthe pancreas
.
Pathol Case Rev
.
2015
;
20
(
4
):
182
5
. 1082-9784
10.
Collins
BT
.
Serous cystadenoma of the pancreas with endoscopic ultrasound fine needle aspiration biopsy and surgical correlation
.
Acta Cytol
.
2013
;
57
(
3
):
241
51
.
[PubMed]
0001-5547
11.
Lilo
MT
,
VandenBussche
CJ
,
Allison
DB
,
Lennon
AM
,
Younes
BK
,
Hruban
RH
, et al
Serous Cystadenoma of the Pancreas: Potentials and Pitfalls of a Preoperative Cytopathologic Diagnosis
.
Acta Cytol
.
2017
;
61
(
1
):
27
33
.
[PubMed]
0001-5547
12.
Lewandrowski
KB
,
Southern
JF
,
Pins
MR
,
Compton
CC
,
Warshaw
AL
.
Cyst fluid analysis in the differential diagnosis of pancreatic cysts. A comparison of pseudocysts, serous cystadenomas, mucinous cystic neoplasms, and mucinous cystadenocarcinoma
.
Ann Surg
.
1993
Jan
;
217
(
1
):
41
7
.
[PubMed]
0003-4932
13.
Cizginer
S
,
Turner
BG
,
Bilge
AR
,
Karaca
C
,
Pitman
MB
,
Brugge
WR
.
Cyst fluid carcinoembryonic antigen is an accurate diagnostic marker of pancreatic mucinous cysts
.
Pancreas
.
2011
Oct
;
40
(
7
):
1024
8
.
[PubMed]
0885-3177
14.
Brugge
WR
,
Lewandrowski
K
,
Lee-Lewandrowski
E
,
Centeno
BA
,
Szydlo
T
,
Regan
S
, et al
Diagnosis of pancreatic cystic neoplasms: a report of the cooperative pancreatic cyst study
.
Gastroenterology
.
2004
May
;
126
(
5
):
1330
6
.
[PubMed]
0016-5085
15.
Salomao
M
,
Remotti
H
,
Allendorf
JD
,
Poneros
JM
,
Sethi
A
,
Gonda
TA
, et al
Fine-needle aspirations of pancreatic serous cystadenomas: improving diagnostic yield with cell blocks and α-inhibin immunohistochemistry
.
Cancer Cytopathol
.
2014
Jan
;
122
(
1
):
33
9
.
[PubMed]
1934-662X
16.
Wu
J
,
Jiao
Y
,
Dal Molin
M
,
Maitra
A
,
de Wilde
RF
,
Wood
LD
, et al
Whole-exome sequencing of neoplastic cysts of the pancreas reveals recurrent mutations in components of ubiquitin-dependent pathways
.
Proc Natl Acad Sci USA
.
2011
Dec
;
108
(
52
):
21188
93
.
[PubMed]
0027-8424
17.
Basturk
O
,
Hong
SM
,
Wood
LD
,
Adsay
NV
,
Albores-Saavedra
J
,
Biankin
AV
, et al;
Baltimore Consensus Meeting
.
A Revised Classification System and Recommendations From the Baltimore Consensus Meeting for Neoplastic Precursor Lesions in the Pancreas
.
Am J Surg Pathol
.
2015
Dec
;
39
(
12
):
1730
41
.
[PubMed]
0147-5185
18.
Emerson
RE
,
Randolph
ML
,
Cramer
HM
.
Endoscopic ultrasound-guided fine-needle aspiration cytology diagnosis of intraductal papillary mucinous neoplasm of the pancreas is highly predictive of pancreatic neoplasia
.
Diagn Cytopathol
.
2006
Jul
;
34
(
7
):
457
62
.
[PubMed]
8755-1039
19.
Zhai
J
,
Sarkar
R
,
Ylagan
L
.
Pancreatic mucinous lesions: a retrospective analysis with cytohistological correlation
.
Diagn Cytopathol
.
2006
Nov
;
34
(
11
):
724
30
.
[PubMed]
8755-1039
20.
Michaels
PJ
,
Brachtel
EF
,
Bounds
BC
,
Brugge
WR
,
Pitman
MB
.
Intraductal papillary mucinous neoplasm of the pancreas: cytologic features predict histologic grade
.
Cancer
.
2006
Jun
;
108
(
3
):
163
73
.
[PubMed]
0008-543X
21.
Pitman
MB
,
Michaels
PJ
,
Deshpande
V
,
Brugge
WR
,
Bounds
BC
.
Cytological and cyst fluid analysis of small ([{LT}] or =3 cm) branch duct intraductal papillary mucinous neoplasms adds value to patient management decisions
.
Pancreatology
.
2008
;
8
(
3
):
277
84
.
[PubMed]
1424-3903
22.
Genevay
M
,
Mino-Kenudson
M
,
Yaeger
K
,
Konstantinidis
IT
,
Ferrone
CR
,
Thayer
S
, et al
Cytology adds value to imaging studies for risk assessment of malignancy in pancreatic mucinous cysts
.
Ann Surg
.
2011
Dec
;
254
(
6
):
977
83
.
[PubMed]
0003-4932
23.
Pitman
MB
,
Centeno
BA
,
Daglilar
ES
,
Brugge
WR
,
Mino-Kenudson
M
.
Cytological criteria of high-grade epithelial atypia in the cyst fluid of pancreatic intraductal papillary mucinous neoplasms
.
Cancer Cytopathol
.
2014
Jan
;
122
(
1
):
40
7
.
[PubMed]
1934-662X
24.
Sigel
CS
,
Edelweiss
M
,
Tong
LC
,
Magda
J
,
Oen
H
,
Sigel
KM
, et al
Low interobserver agreement in cytology grading of mucinous pancreatic neoplasms
.
Cancer Cytopathol
.
2014
.
[PubMed]
1934-662X
25.
Park
WG
,
Mascarenhas
R
,
Palaez-Luna
M
,
Smyrk
TC
,
O’Kane
D
,
Clain
JE
, et al
Diagnostic performance of cyst fluid carcinoembryonic antigen and amylase in histologically confirmed pancreatic cysts
.
Pancreas
.
2011
Jan
;
40
(
1
):
42
5
.
[PubMed]
0885-3177
26.
van der Waaij
LA
,
van Dullemen
HM
,
Porte
RJ
.
Cyst fluid analysis in the differential diagnosis of pancreatic cystic lesions: a pooled analysis
.
Gastrointest Endosc
.
2005
Sep
;
62
(
3
):
383
9
.
[PubMed]
0016-5107
27.
Jin
D
,
Small
AJ
,
Vollmer
CM
,
Jhala
N
,
Furth
EE
,
Ginnsberg
G
, et al
A lower cyst fluid CEA cut-off increases diangostic accuracy in identifying mucinous pancreatic cystic lesions.
Journal of the Pancreas.
2015
;
16
(
3
):
271
7
.
28.
Layfield
LJ
,
Ehya
H
,
Filie
AC
,
Hruban
RH
,
Jhala
N
,
Joseph
L
, et al;
Papanicolaou Society of Cytopathology
.
Utilization of ancillary studies in the cytologic diagnosis of biliary and pancreatic lesions: the Papanicolaou Society of Cytopathology guidelines for pancreatobiliary cytology
.
Diagn Cytopathol
.
2014
Apr
;
42
(
4
):
351
62
.
[PubMed]
8755-1039
29.
Frank
R
,
Li
S
,
Ahmad
NA
,
Sepulveda
AR
,
Jhala
NC
.
Mesothelin expression in pancreatic mucinous cysts
.
Am J Clin Pathol
.
2014
Sep
;
142
(
3
):
313
9
.
[PubMed]
0002-9173
30.
Khalid
A
,
McGrath
KM
,
Zahid
M
,
Wilson
M
,
Brody
D
,
Swalsky
P
, et al
The role of pancreatic cyst fluid molecular analysis in predicting cyst pathology
.
Clin Gastroenterol Hepatol
.
2005
Oct
;
3
(
10
):
967
73
.
[PubMed]
1542-3565
31.
Schoedel
KE
,
Finkelstein
SD
,
Ohori
NP
.
K-Ras and microsatellite marker analysis of fine-needle aspirates from intraductal papillary mucinous neoplasms of the pancreas
.
Diagn Cytopathol
.
2006
Sep
;
34
(
9
):
605
8
.
[PubMed]
8755-1039
32.
Wu
J
,
Matthaei
H
,
Maitra
A
,
Dal Molin
M
,
Wood
LD
,
Eshleman
JR
, et al
Recurrent GNAS mutations define an unexpected pathway for pancreatic cyst development
.
Sci Transl Med
.
2011
Jul
;
3
(
92
):
92ra66
.
[PubMed]
1946-6234
33.
Kadayifci
A
,
Atar
M
,
Wang
JL
,
Forcione
DG
,
Casey
BW
,
Pitman
MB
, et al
Value of adding GNAS testing to pancreatic cyst fluid KRAS and carcinoembryonic antigen analysis for the diagnosis of intraductal papillary mucinous neoplasms
.
Dig Endosc
.
2017
Jan
;
29
(
1
):
111
7
.
[PubMed]
0915-5635
34.
Springer
S
,
Wang
Y
,
Dal Molin
M
,
Masica
DL
,
Jiao
Y
,
Kinde
I
, et al
A combination of molecular markers and clinical features improve the classification of pancreatic cysts
.
Gastroenterology
.
2015
Nov
;
149
(
6
):
1501
10
.
[PubMed]
0016-5085
35.
Rosenbaum
MW
,
Jones
M
,
Dudley
JC
,
Le
LP
,
Iafrate
AJ
,
Pitman
MB
.
Next-generation sequencing adds value to the preoperative diagnosis of pancreatic cysts
.
Cancer Cytopathol
.
2017
Jan
;
125
(
1
):
41
7
.
[PubMed]
1934-662X
36.
Faias
S
,
Duarte
M
,
Albuquerque
C
,
da Silva
JP
,
Fonseca
R
,
Roque
R
, et al
Clinical Impact of KRAS and GNAS Analysis Added to CEA and Cytology in Pancreatic Cystic Fluid Obtained by EUS-FNA
.
Dig Dis Sci
.
2018
Sep
;
63
(
9
):
2351
61
.
[PubMed]
0163-2116
37.
Liu
X
,
Rauch
TM
,
Siegal
GP
,
Jhala
N
.
Solid-pseudopapillary neoplasm of the pancreas: three cases with a literature review
.
Appl Immunohistochem Mol Morphol
.
2006
Dec
;
14
(
4
):
445
53
.
[PubMed]
1541-2016
38.
Jhala
N
,
Siegal
GP
,
Jhala
D
.
Large, clear cytoplasmic vacuolation: an under-recognized cytologic clue to distinguish solid pseudopapillary neoplasms of the pancreas from pancreatic endocrine neoplasms on fine-needle aspiration
.
Cancer
.
2008
Aug
;
114
(
4
):
249
54
.
[PubMed]
0008-543X
39.
Jhala
N
,
Siegal
GP
,
Jhala
D
.
Fine Needle Aspiration: A powerful modality in preoperative diangosis of solid pseudopapillary neoplasm of the pancreas
.
Pathol Case Rev
.
2007
;
12
(
4
):
170
6
. 1082-9784
40.
Canberk
S
,
Elcin
BB
,
Uludokumaci
A
,
Uygun
N
,
Gulsen
F
.
Clear cell variant of solid pseudopapillary neoplasm of pancreas diagnosed by fine needle aspiration: A case report and review of the literature
.
Cytojournal
.
2013
Dec
;
10
(
1
):
26
.
[PubMed]
1742-6413
41.
Zhao
P
,
deBrito
P
,
Ozdemirli
M
,
Sidawy
MK
.
Solid-pseudopapillary neoplasm of the pancreas: awareness of unusual clinical presentations and morphology of the clear cell variant can prevent diagnostic errors
.
Diagn Cytopathol
.
2013
Oct
;
41
(
10
):
889
95
.
[PubMed]
8755-1039
42.
Burford
H
,
Baloch
Z
,
Liu
X
,
Jhala
D
,
Siegal
GP
,
Jhala
N
.
E-cadherin/beta-catenin and CD10: a limited immunohistochemical panel to distinguish pancreatic endocrine neoplasm from solid pseudopapillary neoplasm of the pancreas on endoscopic ultrasound-guided fine-needle aspirates of the pancreas
.
Am J Clin Pathol
.
2009
Dec
;
132
(
6
):
831
9
.
[PubMed]
0002-9173
43.
Tanigawa
M
,
Nakayama
M
,
Taira
T
,
Hattori
S
,
Mihara
Y
,
Kondo
R
, et al
Insulinoma-associated protein 1 (INSM1) is a useful marker for pancreatic neuroendocrine tumor
.
Med Mol Morphol
.
2018
Mar
;
51
(
1
):
32
40
.
[PubMed]
1860-1480
44.
Woo
CG
,
Choi
SY
,
Kwak
JJ
,
Chin
S
,
Kim
HK
.
Clear cell neuroendocrine tumor of the pancreas in von Hippel-Lindau disease: a case report and literature review
.
Neuro Endocrinol Lett
.
2017
May
;
38
(
2
):
83
6
.
[PubMed]
0172-780X
45.
Albores-Saavedra
J
.
Acinar cystadenoma of the pancreas: a previously undescribed tumor
.
Ann Diagn Pathol
.
2002
Apr
;
6
(
2
):
113
5
.
[PubMed]
1092-9134
46.
Singhi
AD
,
Norwood
S
,
Liu
TC
,
Sharma
R
,
Wolfgang
CL
,
Schulick
RD
, et al
Acinar cell cystadenoma of the pancreas: a benign neoplasm or non-neoplastic ballooning of acinar and ductal epithelium?
Am J Surg Pathol
.
2013
Sep
;
37
(
9
):
1329
35
.
[PubMed]
0147-5185
47.
Zamboni
G
,
Terris
B
,
Scarpa
A
,
Kosmahl
M
,
Capelli
P
,
Klimstra
DS
, et al
Acinar cell cystadenoma of the pancreas: a new entity?
Am J Surg Pathol
.
2002
Jun
;
26
(
6
):
698
704
.
[PubMed]
0147-5185
48.
Khor
TS
,
Badizadegan
K
,
Ferrone
C
,
Fernández-del Castillo
C
,
Desai
GS
,
Saenz
A
, et al
Acinar cystadenoma of the pancreas: a clinicopathologic study of 10 cases including multilocular lesions with mural nodules
.
Am J Surg Pathol
.
2012
Nov
;
36
(
11
):
1579
91
.
[PubMed]
0147-5185
49.
Yergiyev
O
,
Krishnamurti
U
,
Mohanty
A
,
Thakkar
S
,
Gurram
K
,
Silverman
JF
.
Fine needle aspiration cytology of acinar cell cystadenoma of the pancreas
.
Acta Cytol
.
2014
;
58
(
3
):
297
302
.
[PubMed]
0001-5547
50.
Cosgrove
N
,
DiPalma
J
,
Katz
D
,
Kowalski
T
.
A Rare Case of Acinar Cell Cystadenoma in a 14-Year-Old Adolescent: A Case Report
.
Case Rep Pancreat Cancer
.
2016
Jan
;
2
(
1
):
3
5
.
[PubMed]
2379-9897
51.
Jhala
N
,
Jhala
D
. Cytology primer for endosnographers 4TH ed
2019
.
52.
Tanaka
M
,
Fernández-Del Castillo
C
,
Kamisawa
T
,
Jang
JY
,
Levy
P
,
Ohtsuka
T
, et al
Revisions of international consensus Fukuoka guidelines for the management of IPMN of the pancreas
.
Pancreatology
.
2017
Sep - Oct
;
17
(
5
):
738
53
.
[PubMed]
1424-3903
53.
Zhang
ML
,
Arpin
RN
,
Brugge
WR
,
Forcione
DG
,
Basar
O
,
Pitman
MB
.
Moray micro forceps biopsy improves the diagnosis of specific pancreatic cysts
.
Cancer Cytopathol
.
2018
Jun
;
126
(
6
):
414
20
.
[PubMed]
1934-662X
54.
Basar
O
,
Yuksel
O
,
Yang
DJ
,
Samarasena
J
,
Forcione
D
,
DiMaio
CJ
, et al
Feasibility and safety of microforceps biopsy in the diagnosis of pancreatic cysts
.
Gastrointest Endosc
.
2018
Jul
;
88
(
1
):
79
86
.
[PubMed]
0016-5107
55.
Lévy
P
,
Rebours
V
.
The Role of Endoscopic Ultrasound in the Diagnosis of Cystic Lesions of the Pancreas
.
Visc Med
.
2018
Jul
;
34
(
3
):
192
6
.
[PubMed]
2297-4725
56.
Kadayifci
A
,
Atar
M
,
Basar
O
,
Forcione
DG
,
Brugge
WR
.
Needle-Based Confocal Laser Endomicroscopy for Evaluation of Cystic Neoplasms of the Pancreas
.
Dig Dis Sci
.
2017
May
;
62
(
5
):
1346
53
.
[PubMed]
0163-2116
57.
Lee
LS
,
Andersen
DK
,
Ashida
R
,
Brugge
WR
,
Canto
MI
,
Chang
KJ
, et al
EUS and related technologies for the diagnosis and treatment of pancreatic disease: research gaps and opportunities-Summary of a National Institute of Diabetes and Digestive and Kidney Diseases workshop
.
Gastrointest Endosc
.
2017
Nov
;
86
(
5
):
768
78
.
[PubMed]
0016-5107
58.
Rhim
AD
,
Thege
FI
,
Santana
SM
,
Lannin
TB
,
Saha
TN
,
Tsai
S
, et al
Detection of circulating pancreas epithelial cells in patients with pancreatic cystic lesions
.
Gastroenterology
.
2014
Mar
;
146
(
3
):
647
51
.
[PubMed]
0016-5085
59.
Jones
M
,
Zheng
Z
,
Wang
J
,
Dudley
J
,
Albanese
E
,
Kadayifci
A
, et al
Impact of next-generation sequencing on the clinical diagnosis of pancreatic cysts
.
Gastrointest Endosc
.
2016
Jan
;
83
(
1
):
140
8
.
[PubMed]
0016-5107
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.