Pathologic Evaluation and Reporting of Intraductal ... · Branch Versus Main Duct IPMN:...

ORIGINAL ARTICLE

Pathologic Evaluation and Reporting of Intraductal PapillaryMucinous Neoplasms of the Pancreas and Other Tumoral

Intraepithelial Neoplasms of Pancreatobiliary Tract

Recommendations of Verona Consensus Meeting

Volkan Adsay, MD,� Mari Mino-Kenudson, MD,y Toru Furukawa, MD, PhD,z Olca Basturk, MD,§

Giuseppe Zamboni, MD,� Giovanni Marchegiani, MD,jj Claudio Bassi, MD,�� Roberto Salvia, MD, PhD,��

Giuseppe Malleo, MD,�� Salvatore Paiella, MD,�� Christopher L. Wolfgang, MD, PhD,yyHanno Matthaei, MD,zz G. Johan Offerhaus, MD, PhD,§§ Mustapha Adham, MD, PhD,��

Marco J. Bruno, MD, PhD,jjjj Michelle D. Reid, MD,� Alyssa Krasinskas, MD,� Gunter Kloppel, MD,��

Nobuyuki Ohike, MD, PhD,yyy Takuma Tajiri, MD, PhD,zzz Kee-Taek Jang, MD, PhD,§§§

Juan Carlos Roa, MD,�� Peter Allen, MD,jjjjjj Carlos Fernandez-del Castillo, MD,��

Jin-Young Jang, MD, PhD,yyyy David S. Klimstra, MD,§ and Ralph H. Hruban, MDzzzz; on behalf of the

Members of the Verona Consensus Meeting, 2013

Background: There are no established guidelines for pathologic diagnosis/

reporting of intraductal papillary mucinous neoplasms (IPMNs).

Design: An international multidisciplinary group, brought together by the

Verona Pancreas Group in Italy–2013, was tasked to devise recommen-

dations.

Results: (1) Crucial to rule out invasive carcinoma with extensive (if not

complete) sampling. (2) Invasive component is to be documented in a full

synoptic report including its size, type, grade, and stage. (3) The term

‘‘minimally invasive’’ should be avoided; instead, invasion size with stage

and substaging of T1 (1a, b, c; �0.5, >0.5–�1, >1 cm) is to be documented.

(4) Largest diameter of the invasion, not the distance from the nearest duct, is

to be used. (5) A category of ‘‘indeterminate/(suspicious) for invasion’’ is

acceptable for rare cases. (6) The term ‘‘malignant’’ IPMN should be avoided.

(7) The highest grade of dysplasia in the non-invasive component is to be

documented separately. (8) Lesion size is to be correlated with imaging

Copyright © 2015 Wolters Kluw

From the �Department of Pathology, Emory University School of Medicine andWinship Cancer Institute, Atlanta, GA; yDepartment of Pathology, Massachu-setts General Hospital, Boston, MA; zDepartment of Pathology, Tokyo Wom-en’s Medical University, Tokyo, Japan; §Department of Pathology, MemorialSloan Kettering Cancer Center, New York, NY; �Department of Pathology,University of Verona, Verona, Italy; jjDepartment of Surgery, MassachusettsGeneral Hospital, Boston, MA;

��Department of Surgery, University of Verona,

Verona, Italy; yyDepartment of Surgery, Sol Goldman Pancreatic CancerResearch Center, Johns Hopkins University School of Medicine, Baltimore,MD; zzDepartments of Surgery, University of Bonn, Bonn, Germany;§§Departments of Pathology, University Medical Center Utrecht, Utrecht,The Netherlands; ��Department of Surgery, Edouard Herriot Hospital,HCL, Lyon, France; jjjjDepartment of Gastroenterology and Hepatology,Erasmus University Medical Center, Rotterdam, The Netherlands;��Departments of Pathology, Technical University, Munich, Germany;yyyDepartment of Pathology, Showa University Fujigaoka Hospital, Yoko-hama, Japan; zzzDepartment of Pathology, Tokai University Hachioji Hospital,Tokyo, Japan; §§§Department of Pathology, Samsung Medical Center, Sung-kyunkwan University School of Medicine, Seoul, Republic of Korea;��Department of Pathology, Pontificia Universidad Catolica de Chile, San-tiago, Chile; jjjjjjDepartment of Surgery, Memorial Sloan Kettering CancerCenter, New York, NY;

��Department of Surgery, Massachusetts General

Hospital, Boston, MA; yyyyDepartment of Surgery, Seoul National UniversityHospital, Seoul, Korea; and zzzzDepartment of Pathology, Sol GoldmanPancreatic Cancer Research Center, Johns Hopkins University School ofMedicine, Baltimore, MD.

Members of Verona Consensus Meeting are William Brugge, Boston, MA; AjayMaker, Chicago, IL; Anne Marie Lennon, Baltimore, MD; Aldo Scarpa,

162 | www.annalsofsurgery.com

findings in cysts with rupture. (9) The main duct diameter and, if possible, its

involvement are to be documented; however, it is not required to provide main

versus branch duct classification in the resected tumor. (10) Subtyping as

gastric/intestinal/pancreatobiliary/oncocytic/mixed is of value. (11) Frozen

section is to be performed highly selectively, with appreciation of its short-

comings. (12) These principles also apply to other similar tumoral intra-

epithelial neoplasms (mucinous cystic neoplasms, intra-ampullary, and intra-

biliary/cholecystic).

Conclusions: These recommendations will ensure proper communication of

salient tumor characteristics to the management teams, accurate comparison

of data between analyses, and development of more effective management

algorithms.

Keywords: intraductal, IPMN, mucinous, neoplasm, pancreas, papillary

(Ann Surg 2016;263:162–177)

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Verona, Italy; Silvia Carrara, Milan, Italy; Luca Frulloni, Verona, Italy; NigelJamieson, Glasgow, Scotland, UK; Mario Pelaez-Luna, Mexico City, Mexico;Masao Tanaka, Fukuoka, Japan; Takao Ohtsuka, Fukuoka, Japan; John Neo-ptolemos, Liverpool, UK; Chris Halloran, Liverpool, UK; Mohammed AbuHilal, Southampton, UK; Horacio Asbun, Jacksonville, FL; Louis Buscail,Toulouse, France; Riccardo Manfredi, Verona, Italy; Satoshi Tanno, Asahi-kawa, Japan; Sun-Wee Kim, Seoul, Republic of Korea; Vinciane Rebours,Paris, France; Alain Sauvanet, Paris, France; Ajith K Siriwardena, Manchester,UK; Giovanni Butturini, Verona, Italy; Charles Vollmer, Philadelphia, PA; JensWerner, Munich, Germany; Richard Schulick, Denver, CO; Kevin Conlon,Dublin, Ireland; Laureano Fernandez-Cruz, Barcelona, Spain; Christos Der-venis, Athens, Greece; Maximilian Bockhorn, Hamburg, Germany; AlessandroZerbi, Milan, Italy; Isabella Frigerio, Peschiera del Garda, Italy; Attila Olah,Gyor, Hungary; Miroslav Milicevic, Belgrade, Serbia; Roberto Coppola,Rome, Italy; Markus W. Buechler, Heidelberg, Germany; Thilo Hackert,Heidelberg, Germany; Werner Hartwig, Munich, Germany; Beat Gloor, Berne,Switzerland; Helmut Friess, Munich, Germany; Jakob Izbicki, Hamburg,Germany, Maximilian Bockhorn, Hamburg, Germany; Laurents Stassen, Maas-tricht, The Netherlands; Dirk J. Gouma, Amsterdam, The Netherlands; MarcoDel Chiaro, Stockholm, Sweden; Shailesh Shrikhande, Mumbai, Maharashtra,India; Clement Imrie, Glasgow, Scotland, UK; Sebastien Gaujoux, Paris,France; Guido Alsfasser, Rostock, Germany.

Disclosure: The authors declare no conflicts of interest.Reprints: Volkan Adsay, MD, Anatomic Pathology, Emory University, 1364 Clifton

Rd NE, Room H-180B, Atlanta, GA 30322. E-mail: [email protected] � 2015 Wolters Kluwer Health, Inc. All rights reserved.ISSN: 0003-4932/14/26105-0821DOI: 10.1097/SLA.0000000000001173

Annals of Surgery � Volume 263, Number 1, January 2016

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Annals of Surgery � Volume 263, Number 1, January 2016 Verona IPMN Reporting Recommendations

he term intraductal papillary mucinous neoplasm (IPMN) was
T created in 1994 by Kloppel and colleagues1 to embrace entitiespreviously reported in the literature under a plethora of designations,including duct-ectatic mucinous cystic neoplasms,2,3 mucin-pro-ducing tumors,4–6 intraductal papillary neoplasms,7 papillaryadenocarcinomas, villous adenomas,8 and others. Since then muchhas been learned about the nature and behavior of these distinctiveneoplasms; however, many of the diagnostic criteria and manage-ment protocols remain challenging to apply and some are highlycontroversial.
The challenges also extend to, and often stem from, a lack ofuniform criteria in the pathologic evaluation, terminology, andparameters to be reported. In fact, the absence of a uniform approachin pathology may be partly responsible for the obstacles to bettercharacterization of these tumors. For example, the terms ‘‘malignantIPMN’’9–28 and ‘‘minimally invasive IPMN’’29–39 have been highlyvariably defined in the literature, creating great confusion in under-standing the behavior of different stages of this entity and leading tomajor contradictions in establishing uniform management protocolsfor patients.

In April 2013, an international meeting was convened inVerona, Italy, under the leadership and organization of VeronaPancreas Group. The pathology team of this consensus meetingwas tasked with assessing the current state and possible improve-ments in the pathologic evaluation of terminology and documen-tation of IPMNs, and determination of clinically relevant parametersfor the management of these tumors. Accordingly, through literatureanalysis and interdisciplinary discussions with various experts bothamong the participants of the meeting and outside of the meeting, thisgroup developed consensus on refined definitions and basic guide-lines for the pathologic evaluation and reporting of IPMNs, which arediscussed in detail in this article.

METHODS

A pathology team was created in 2012 in preparation for theconsensus meeting to be held in Verona, Italy, in April 2013, underthe leadership of Verona Pancreas Group. This team group consistedof an interdisciplinary team of participants who are experts in thepathologic evaluation of branch duct IPMNs, including pathologists,surgeons, radiologists, and gastroenterologist (V.A., M.M.K., T.F.,G.Z., C.L.W., H.M., J.O., M.A., and M.J.B.). The team was taskedwith determining the state of pathologic diagnosis of IPMNs.

Premeeting analysis of the literature was performed especiallyfocusing on the pathologic assessment of IPMNs, and a list ofdiscussion points was created by participation of all the teammembers. During this preparation, it was noticed that wide disparitiesin pathologic evaluation, terminology, and reporting of IPMNsexisted. These disparities were presented in Verona in a generalsession, followed by active discussions conducted with the participa-tion of the entire consensus meeting membership. Further discus-sions were held in breakout sessions. The results of these discussionswere collated and presented again on the last day of the meeting.

After the meeting, further analyses were performed as taskedduring the consensus meeting. These included the analysis of institu-tional databases for the parameters in question and investigation ofpathology reports on IPMN (performed in the community and inexpert institutions). Evaluation of these pathology reports revealedthat crucial pieces of information were missing from the vastmajority of these reports, even in institutions where IPMN surgeryis performed routinely.

In establishing the clinically relevant pathologic parameters,consultation with other experts from various disciplines who had notparticipated in the consensus meeting was also sought.


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Separately, another international consensus meeting was heldon the topic of pancreatic intraepithelial neoplasia (includingIPMNs) at The Johns Hopkins University School of Medicine, ledby Drs Ralph Hruban and David Klimstra, under the auspices of theSol Goldman Pancreatic Cancer Research Center of The JohnsHopkins University in June 2014. Some of the parameters and salientissues were also discussed during this meeting. Although the pro-ceedings of this meeting are the subject of another study,40 theconclusions presented later are in accordance with the conclusionsof that latter meeting.

RESULTS/DISCUSSION

DefinitionIntraductal papillary mucinous neoplasms41–44 are pathologi-

cally defined as mass-forming preinvasive neoplasms (tumoral intra-epithelial neoplasms) that grow within the ducts of the pancreas.41–44

In the World Health Organization 2010 (WHO-2010) classifi-cation,45 to distinguish IPMNs from incidental microcysts and largepancreatic intraepithelial neoplasms (PanINs), IPMNs were requiredto be more than 1 cm in diameter.45

With the current definitions,41,42,44,45 IPMNs encompass aspectrum of lesions ranging from those that are very innocuous-appearing (what used to be called ‘‘hyperplasia’’) to those that arefull-blown intramucosal carcinomatous lesions (those used to bedesignated as ‘‘papillary adenocarcinoma’’).41,42,44,45

This spectrum, previously classified as ‘‘hyperplasia -adenoma - borderline - in situ carcinoma - invasive carcinoma’’,46

and later as ‘‘low-grade dysplasia - intermediate-grade dysplasia -high-grade dysplasia - invasive carcinoma’’43 is now recategorized as‘‘low-grade dysplasia - high-grade dysplasia - invasive carcinoma’’per the Baltimore consensus manuscript, December 2015.40 As such,IPMNs represent adenoma-carcinoma sequence.

Intraductal papillary mucinous neoplasms have different cyto-logic types classified as gastric, intestinal, pancreatobiliary, andoncocytic (Tables 1 and 2), and it has been shown that not onlythese cell types have different morphologic and immunohistochem-ical phenotypes, but also some have different genetic drivers47–56

(see subtypes section for details).Intraductal papillary mucinous neoplasms can progress to

invasive carcinoma of different types (ductal/tubular45,57–62 andcolloid/muconodular52,63–66) and of variable extent (Table 1). Theinvasive component of these tumors ought to be regarded anddocumented separately (see invasive carcinoma section for details).

Branch Versus Main Duct IPMN: Documentation ofMain Pancreatic Duct Findings Pathologically

The classification of IPMNs as branch (Fig. 1) versus mainduct (Fig. 2) type is of utmost importance in assessing the risk ofcarcinoma during the preoperative management of patients with anIPMN41,42,67–75; however, once the tumor is resected, naturally, thisseparation loses virtually all of its clinical value and is superseded atthat point by the absence or presence of an associated invasivecarcinoma.41,42,76,77 Furthermore, recent pathology studies haveshown that the main duct not infrequently shows some degree ofinvolvement even in the IPMNs that were classical branch duct typeby imaging. More importantly, those IPMNs with minimal involve-ment of the main duct, defined as ‘‘non-circumferential main ductinvolvement, limited in a few histologic sections’’ were very similarto branch duct cases and were different from main duct IPMNs, byboth clinicopathologic features and clinical outcome.78 Con-sequently, for pathologic reporting, it is advised to make an attemptto document the widest diameter of the main duct, and also the extent


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TABLE 1. Pancreatic Resection for Invasive CarcinomasArising in Association With Intraductal Neoplasms

Tumor type� Invasive carcinoma arising in association with an intraductal

papillary mucinous neoplasm (IPMN)� Invasive carcinoma arising in association with an intraductal

tubulopapillary neoplasm (ITPN)� Invasive carcinoma arising in association with mucinous cystic

neoplasm (MCN)� __________________________________

Invasive carcinoma type� Tubular� Colloid� __________________________________

Grade of invasive carcinoma� Well differentiated� Moderately differentiated� Poorly differentiated� _________________________________

Location of invasive carcinoma� Head of the pancreas� Body of the pancreas� Tail of the pancreas� Unknown� _________________________________

Size of invasive carcinoma� Unifocal, – cm in greatest dimension� Multifocal

Estimated size of all foci in aggregate: – cmSize of the largest

focus: – cm _________________________________Extrapancreatic invasion� Not identified� Peripancreatic soft tissue� Common bile duct� Duodenal wall (including the mucosa)� Ampulla of Vater� Spleen� Major vessel: __________� Other organs: _____________________� _________________________________

Vascular invasion� Not identified� Suspected� Identified� _________________________________

Perineural invasion� Not identified� Identified� _________________________________

Connectivity of preinvasive and invasive components (if documentable)� Invasive carcinoma is connected to the preinvasive component

(‘‘invasive carcinoma derived from IPMN’’)� Invasive carcinoma is – cm away from the IPMN (‘‘invasive

carcinoma concomitant with IPMN’’)� _________________________________

Size of intraductal/preinvasive neoplasm� – cm, as measured grossly/microscopically� – cm, measured clinically (thin-walled cyst, partial rupture before

pathologic measurement)� _________________________________

Maximum diameter of the main duct (if identified)� – cm� Could not be determined�_________________________________

Gross papillary nodules (in the preinvasive component)� Not seen� Present, largest nodule – cm� _________________________________

TABLE 1. (Continued)

Intraductal/preinvasive neoplasm cell type� Gastric� Intestinal� Oncocytic� Pancreatobiliary� Mixed� Other� _________________________________

Grade of intraductal/preinvasive neoplasm� Low grade� High grade� _________________________________

Adjacent pancreas� Unremarkable� Atrophy—mild, moderate, severe� Fibrosis—mild, moderate, severe� Inflammation—mild, moderate, severe� _________________________________

Neck (pancreatic duct) margin� Negative� Indeterminate for dysplasia� Positive for dysplasia, of – grade� Positive for suspect invasion� Positive for invasive carcinoma� _________________________________

Retroperitoneal (SMA/uncinate) margin� Negative� Indeterminate for dysplasia� Positive for dysplasia, of – grade� Positive for suspect invasion� Positive for invasive carcinoma� _________________________________

CBD margin� Negative� Indeterminate for dysplasia� Positive for dysplasia, of – grade� Positive for suspect invasion� Positive for invasive carcinoma� _________________________________

Other organs� Stomach is unremarkable� Stomach exhibits __________________� Duodenum is unremarkable� Duodenum exhibits _______________� Spleen is unremarkable� Spleen exhibits ___________________� _________________________________

Lymph nodes� Number of lymph nodes examined: ____� Number of lymph nodes with metastasis:_______� Perinodal extension

o Presento Absent

� _________________________________Staging

pT1 Invasive carcinoma is limited to the pancreas and �2 cmin greatest dimensionT1a: �0.5 cmT1b: >0.5 cm; �1 cmT1c: >1 cm; �2 cm

pT2 Invasive carcinoma is limited to the pancreas and >2 cm ingreatest dimension

pT3 Tumor extends beyond the pancreas but without involvement of theceliac axis or the superior mesenteric artery

pT4 Tumor involves the celiac axis or the superior mesenteric artery(unresectable primary tumor)

pN0 No regional lymph node metastasispN1 Regional lymph node metastasis

(Continued)

Adsay et al Annals of Surgery � Volume 263, Number 1, January 2016

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TABLE 2. Pancreatic Resection for Preinvasive Neoplasms

Intraductal/preinvasive neoplasm type� Intraductal papillary mucinous neoplasm (IPMN)� Intraductal tubulopapillary neoplasm (ITPN)� Mucinous cystic neoplasm (MCN)� __________________________________

Grade of invasive carcinoma� Low grade� High grade (Tis)� __________________________________

Extent of high grade dysplasia (Tis)� Focal (<25% of neoplasm)� Substantial (25%–75%)� Diffuse (>75%)� __________________________________

Invasion� No invasion is identified� Indeterminate (suspicious) for invasion

o Suspect focus – centimetero Suspect focus composed of – (mucin, tubules, other).

� (If there is definite invasion, please see synoptic form for invasivecarcinomas arising in association with IPMN).� __________________________________

Predominant cell type� Gastric� Intestinal� Oncocytic� Pancreatobiliary� Mixed� Other� __________________________________

Location� Head of the pancreas� Body of the pancreas� Tail of the pancreas� Undetermined� __________________________________

Size of preinvasive neoplasm� – cm, as measured grossly/microscopically� – cm, measured clinically (thin-walled cyst, partial rupture before

pathologic measurement)� __________________________________

Gross papillary nodules� Not seen� Present, largest nodule – cm� __________________________________

Multifocality� Unifocal, multilocular

Overall size:Size of the largest loculi:

� MultifocalNumbers of the foci:Size of the largest focus:

� __________________________________Maximum diameter of the main duct (if identified)� – cm� Could not be determined� __________________________________

Adjacent pancreas� Unremarkable� Atrophy—mild, moderate, severe� Fibrosis—mild, moderate, severe� Inflammation—mild, moderate, severe� __________________________________

Neck (pancreatic duct) margin� Negative� Indeterminate for dysplasia� Positive for dysplasia, of – grade

� Positive for suspect invasion

TABLE 2. (Continued)� __________________________________

Retroperitoneal (SMA/uncinate) margin� Negative� Indeterminate for dysplasia� Positive for dysplasia, of – grade� Positive for suspect invasion� __________________________________

CBD margin� Negative� Indeterminate for dysplasia� Positive for dysplasia, of – grade� Positive for suspect invasion� __________________________________

Other organs/findings� Stomach is unremarkable.� Stomach exhibits ____________________� Duodenum is unremarkable� Duodenum exhibits __________________� Spleen is unremarkable� Spleen exhibits _____________________� __________________________________

Lymph nodes� All – lymph nodes are negative for tumor (if there is tumor in lymph

nodes, please see form for invasive carcinomas arising inassociation with IPMN).� _______________________________

Tumor sampling:� The tumor was submitted entirely for microscopic examination

in – blocks.Overall sampling:� The uninvolved pancreas was submitted entirely for microscopic

examination in – blocks.� The uninvolved pancreas was submitted representatively for

microscopic examination in – blocks.

(Continued)



of involvement of main duct by abnormal epithelium, if possible;however, it is not required for pathologists to make a specificdistinction between the 2 groups.79–85

Measuring Overall Tumor SizeSize of an IPMN at the time of diagnosis and its growth over

time is an important criterion in the preoperative management ofIPMNs,12,41,42,70,86–89 although its significance becomes less inresected specimens. Regardless, every attempt should be made toaccurately determine the size of the lesion in the pathology report.This not only may be important for assessment of future risk but alsoserves as a feedback for radiologists to hone their skills.

There are, however, challenges in measuring the size of cysticlesions. Some IPMNs have very thin-walled cysts that can rupturebetween the time of specimen resection and measurement in thegross room due to manipulation, dissection, or for tumor bankingpurposes, which leads to shrinkage of the lesion. Therefore, for suchthin-walled cystic IPMNs the true size needs to be determined byclose correlation with the imaging findings, and in fact, if the sizemeasured in the gross room is smaller, then the clinical measurementis to be included in the pathology report. For these reasons, it isrecommended that the size of the lesion be documented along withthe mode of measurement as, for example, ‘‘Overall size of IPMN:3 cm, as measured clinically (cyst ruptured during processing).’’

Documenting the gross size of any solid component can beuseful as invasive carcinomas are often solid and the size is prog-nostically significant for invasive cancers. These also often corre-spond to ‘‘mural nodules’’ detected by imaging preoperatively. Forcases with a solid component, florid papillary nodules or invasive



FIGURE 1. A branch duct IPMN manifesting as a cyst withoutany significant dilation of the main pancreatic duct. Papillaformation is not evident grossly.

FIGURE 2. A main duct IPMN involving the entire pancreaticduct (star), filled with friable papillary projections and stickymucin. Note the adjacent normal common bile duct (CBD).


areas, imaging studies may underestimate or miscalculate the overalltumor size, and thus gross and microscopic evaluation is crucial fordetermining the size in such cases. If there is a discrepancy with theclinically measured size, an attempt can be made to explain thisdiscrepancy in a comment.

In the physical measurement of the cysts in the gross room,certain issues ought to be kept in mind. For unifocal but multilocularlesions, it is preferable to document the overall size of the collectionof locules along with the size of the largest locule. If a papillarylesion is present, it too can be measured. For multifocal lesions, thesize of the largest focus should be documented, as can the sizes of thesmaller lesions if it is clinically indicated.

Every attempt should be made to also measure the diameter ofthe main pancreatic duct. This requires proper identification of themain duct, which can be altered because of tumor, and may provedifficult to trace in a significant proportion of the cases. However, ifthe main duct is identifiable, then its diameter in the widest focusought to be documented. Most importantly, the size of the invasivecomponent, if present, should be carefully and separately docu-mented. This is discussed in detail in the Invasive Carcinoma sectiongiven later.

Invasive Carcinoma: Evaluation and Reporting

SignificanceThe most important determinant of outcome in the manage-

ment of patients with IPMN is whether an associated invasive



carcinoma is present or not.43,45,60,88,90–93 Recent studies haveuniformly shown that the vast majority of completely resectednon-invasive IPMNs have a very positive outcome, with a 5-yearsurvival of more than 90%,60,88,94 whereas half of those with anassociated invasive carcinoma die from their disease.32,33,58,77,95–98

SamplingAn invasive carcinoma arising in association with an IPMN

can be definitely excluded only with thorough evaluation of not onlythe entire lesion but also the uninvolved pancreas as well, because theneighboring pancreas often shows peritumoral abnormalities andmay harbor subtle invasive carcinomas. In fact, the aggressivebehavior of tumor reported in some patients with a ‘‘non-invasiveIPMN’’ may be due to ‘‘missed’’ invasive carcinomas in under-sampled IPMNs.43 Some invasive carcinomas also arise away fromthe lesion, and that is why it is important to regard the entirespecimen as suspect for invasive carcinoma, perform thorough grossexamination, and liberal sampling of even seemingly normal pan-creas.

Typing of Associated Invasive CarcinomaDifferent histologic types of invasive carcinoma can arise

from IPMNs, and these histologic types are associated with markedlydifferent prognostic and biologic properties.52,63,65,66,99–101 Abouthalf of the invasive carcinomas that arise in association with an IPMNare ordinary tubular (ductal) adenocarcinoma (Fig. 3A), character-ized by infiltrating small to medium tubular units separated byabundant stroma.45,61 This type often arises from either gastric orpancreatobiliary type IPMN and seems to have an aggressive behav-ior, although its prognosis may not be as poor as for ordinary PDACs,because of either early stage detection and/or different molecular/biologic characteristics (although it is often morphologically indis-tinguishable from ordinary PDACs).32,33,58,95–98

The other half of the invasive carcinomas that arise in associ-ation with IPMNs are colloid carcinomas (Fig. 3B), characterized bymuconodular type invasion (nodules of stromal mucin that containrelatively scant clusters of carcinoma cells). Colloid carcinomastypically arise from the intestinal type IPMN and are seldom, ifever, seen in association with other IPMN subtypes or with mucinous



FIGURE 3. Ductal (tubular) type invasivecarcinoma arising in IPMN (left) is virtuallyindistinguishable from ordinary pancre-atic ductal adenocarcinomas, character-ized by atypical cells forming irregular,often complex, tubular or glandular struc-tures, usually accompanied by densestroma. In contrasts, colloid carcinoma(right) is characterized by the muconod-ular pattern composed of distinct pools ofmucin that contain scanty clusters of car-cinoma cells, floating within the mucin(hematoxylin and eosin stain).


cystic neoplasms.66,102,103 Patients with colloid carcinomas have asignificantly better prognosis than do patients with tubular carci-nomas.52,63,64,66,99,101 Furthermore, both colloid carcinoma and itscommon precursor, intestinal type IPMN, are characterized byintestinal type differentiation markers—diffuse and strong expres-sion of the intestinal epithelial marker, MUC2, and, the intestinaldifferentiation marker, CDX2—neither of which is expressed sub-stantially in any other tumor type in the pancreas.51–53,104–106 Theserender colloid carcinomas a potential candidate for a differentmanagement approach and thus accentuate the importance of itsrecognition and proper documentation in the pathology reports.

Rarely, other invasive carcinoma types can arise in associationwith IPMNs, such as oncocytic,56 sarcomatoid/undifferentiated(some with osteoclast-like giant cells), medullary, or neuroendocrinecarcinomas.107,108 These also ought to be recognized and reportedaccordingly. Some carcinomas are of mixed type.109,110

Grading of Invasive CarcinomaThe histologic grade of invasive carcinoma ought to be given

separately from the grading of the non-invasive component. Fortubular/ductal carcinomas, the principles employed in grading ofordinary PDACs can be employed.111 There are different gradingschemes with their corresponding challenges, which are beyond thescope of this article. Readers are referred to appropriate litera-ture.112–115

For the grading of colloid type carcinoma, there are currentlyno guidelines. Most colloid carcinomas are by default well differ-entiated. However, some mucinous carcinomas in the pancreasexhibit significantly more prominent cellularity, cytologic atypia,and cells clinging to the stroma. These tend to be more aggressiveneoplasms. In such cases, the possibility of a non–colloid typemucinous carcinoma arising from the ampulla such as mucinoussignet ring carcinoma or mixed mucinous-intestinal carcinoma, or apancreatic ductal adenocarcinoma with excessive mucin productionought to be considered.109,110,116

Size of Invasive CarcinomaAs in any other cancer types, the size (and stage) of the

invasive carcinoma is one of the most important prognostic



parameters in IPMNs.32,37,57,98 Unfortunately, many studies havefailed to analyze this as a separate parameter. In fact, our review ofthe literature highlighted the unfortunate fact that the size of overalltumor (with non-invasive and invasive components lumped together)is often used interchangeably with the size of the invasive carcinoma.

The consensus at the Verona meeting was that it is imperativeto measure the size of invasive carcinoma as accurately as possible,and, if this cannot be achieved (because of fragmented sampling ormultifocality), then, to at least give an estimation of the invasion size.The invasive component should be staged, independent of the non-invasive component, as in any other cancer (see the discussion belowon staging).

If the invasive carcinoma is unifocal, the recommendation is tomeasure the largest diameter of the invasive focus, as is done for anyinvasive carcinoma in this organ and in other solid organs. Analternate possibility of measuring the ‘‘depth’’ from the nearest ductwas discussed but dismissed because it is often impossible todetermine where the nearest duct is located in 2-dimensionalhistologic sections.

For multifocal tumors,117 it is recommended that both thediameter of the largest one and the overall estimated size of all foci inaggregate be provided in the comment of the report (Table 1). As inother organs such as the breast, it is not yet clear as to which one ofthese better reflects the tumor burden and thus is to be taken as themain tumor size.115,118,119

Indeterminate (Suspicious) for InvasionBecause of the complexity of the intraductal lesions and their

common extension into the neighboring smaller ductules, non-inva-sive IPMNs often show remarkable architectural complexity with apseudoinvasive appearance. This is especially striking in main ductlesions (of the intestinal type) where atrophy and fibrosis of thesurrounding pancreatic parenchyma can be prominent, further accen-tuating the pseudoinvasive pattern. Prior biopsy site changes andinflammation also contribute to and accentuate this challenge.Separately, rupture of the ducts can lead to extrusion of mucin intothe stroma. This acellular mucin is not invasive carcinoma, but insome instances it can be very difficult to distinguish from trueinvasive colloid carcinoma (Fig. 4). As a result, in some cases, it



FIGURE 4. In IPMNs, rupture of the ducts can lead to extrusion ofmucin into the stroma, which can be difficult to distinguish fromtrue invasive colloid carcinoma (hematoxylin and eosin stain).


may be extremely difficult to determine whether a focus is invasive orpseudoinvasive. For such cases, the diagnosis of ‘‘indeterminate forinvasion’’ may have to be rendered. This would correspond to the‘‘suspicious for invasion’’ category of the Vienna classification ofreporting gastrointestinal malignancies.120 It is not yet known theclinical implications and behavior of such cases of IPMNs; however,it is certain that some cases cannot be classified definitively asinvasive versus non-invasive and thus this category is a necessaryone. In such cases, the estimated size of a suspect focus should beprovided in a comment.

Staging of Invasive Carcinoma; Proposed RefinedDefinition of ‘‘Minimally Invasive’’ as pT1 and T1a, b,and c

As for any invasive cancer, it is required to stage invasivecarcinomas arising from (or in association with) IPMNs.45 A sig-nificant proportion of the invasive carcinomas discovered in IPMNsis small and has been termed ‘‘minimally invasive.’’ However, thisterm is vague, nonspecific, and potentially misleading because it hasbeen used highly variably in the literature: In some studies, alsoincluding ‘‘indeterminate’’ cases,30–40,121–123 in others,32–37 theterm minimally invasive was reserved for cases with minute invasivefoci, whereas in others,121–123 the term was defined as a carcinomahaving invaded slightly beyond the duct wall, and yet in still others,as T1 cancers, and in yet others, for invasion not appreciated grosslybut discovered on microscopic examination. Thus, it is recommendedthat the term ‘‘minimally invasive’’ be abandoned and replaced byproper documentation of the size of invasive carcinoma and its properstaging. It has been proposed to substage these small carcinomas aspT1a, if 0.5 cm or less; pT1b, if more than 0.5 and 1.0 or less, and aspT1c, if more than 1.0 and 2.0 cm or less, although this classificationneeds to be validated in large-scale (multi-institutional) studies.41

In staging of IPMNs with more overt invasive carcinomas, it isrecommended that the Union for International Cancer Control/American Joint Committee on Cancer (UICC/AJCC) staging proto-col be employed.115 Unfortunately, numerous studies have disclosedthat the current T-stage protocol lack linear prognostic correlationdue to the irreproducibility and pathologic inapplicability ofill-defined parameters like ‘‘peripancreatic soft tissue involve-ment,’’124–126 or ‘‘common bile duct involvement’’ (as to whichpart of the common bile duct is to be considered).127,128 For thesereasons, a protocol that replaces these parameters with tumor size as



the main defining parameter for pT3 (in the current system, pT1 andT2 are already defined by size) is being considered.129 Until thischange is formally adopted, however, it is recommended that both thesize of invasive carcinoma and the current AJCC/UICC stage bedocumented.115

Invasive Carcinoma ‘‘Derived From’’ or ‘‘ConcomitantWith’’ IPMN

There is emerging evidence that there may be some biologicand prognostic differences between carcinomas ‘‘derived from’’(arising in the area of) IPMN and those that are ‘‘concomitant’’(not contiguous with) IPMN.98,130 Therefore, it is recommended thatevery attempt be made to document the relationship of invasivecarcinoma to the IPMN. For this purpose, it is recommended thatsections be taken to verify the continuity (or discontinuity) of theinvasive carcinoma with the IPMN. Considering that tumors andcarcinomas can grow in a dumb-bell fashion or with skip areas,examination of the entire tissue and assurance of the discontinuitybetween the invasion and IPMN have to be documented before a casecan be classified as ‘‘concomitant’’ rather than primarily arising inIPMN. Many current grossing/sampling protocols used in the Westmay fall short in being convincing in this regard. Therefore, thisdistinction may not be achievable in every case.

Evaluation of Invasive Carcinomas for AdjunctParameters

Invasive carcinomas in IPMN cases ought to be evaluated, inaddition to staging, for adjunct parameters that are typically requiredin cancer synoptic reporting such as those recommended by theCollege of American Pathologists. These include grade, perineuralinvasion, vascular invasion, and optionally also for budding.131

Invasion to neighboring organs ought to be documented as well(Tables 1 and 2).

N-stageIt is imperative that the lymph node status be documented

properly in IPMNs, regardless of whether invasion is detected or not.There have been cases in which the identification of lymph nodemetastasis has led to a more careful investigation of the IPMN andultimate detection of invasive carcinoma in an otherwise seeminglynon-invasive IPMN.132 It is recommended that a minimum of 12lymph nodes be identified in a pancreatoduodenectomy specimen asrecommended by American College of Surgeons,133,134 and if this isnot achieved, additional sampling should be performed in an attemptto identify more lymph nodes, and this should be clarified in acomment. Certain grossing approaches such as the ‘‘orange-peeling’’method may facilitate a more complete harvesting of lymph nodes.79

For assessment and documentation of lymph nodes, routineprotocols in the AJCC/UICC guidelines115 are to be followed.Accordingly, a direct invasion to a lymph node is regarded aslymph node metastasis, although the prognostic135 and scientificmerit of this is being debated. For pancreatic cancers, the number oflymph nodes involved also seems to be a significant prognosticatorand for this reason substaging of node-positive cases as N1 and N2has been proposed.136 Similarly, lymph node ratio may also haveprognostic significance but is currently not applicable in dailypractice. For these reasons, it is recommended to document thenumber of lymph nodes involved, as in any other oncologic path-ology report.

Definition of ‘‘Malignant IPMN’’In the literature, the term ‘‘malignant’’ has been used highly

variably, and this has led to major confusion in assessing the behaviorand significance of IPMNs: In some studies, the term malignant




IPMN was used in reference to clinical behavior to refer only to thosecases with metastasis and mortality. In other studies, both high-gradedysplasia (carcinoma in situ) and invasive carcinomas were regarded as‘‘malignant,’’9–20 whereas, in other studies, only the cases with anassociated invasive carcinoma were classified as ‘‘malignant.’’21–28

Considering that only invasive cases have the ability to exhibit truemalignant behavior (uncontrollable growth, destruction, and meta-stasis), the latter definition was determined at the Verona meeting to bethe most accurate. Nevertheless, to avoid confusion, and in accordancewith routine oncologic pathology practice in other organs, it wasrecommended that the term ‘‘malignant IPMN’’ should not be used,and instead, clarification is provided as to whether it is invasive.

Grading of IPMNThe degree of cytoarchitectural atypia (dysplasia) in IPMNs,

previously graded as low, intermediate, and high,41,42,44,45,51,52,137 isnow classified as low and high per Baltimore consensus with the highgrade also encompassing the cases regarded as ‘‘carcinoma in situ’’.The main reason for this new dichotomous approach was to avoidovertreatment for the cases that were previously called low orintermediate grade dysplasia.40 However, it should be noted herethat, in many parts of the world the word ‘‘carcinoma in situ’’ is stillemployed for the most advanced forms of high-grade dysplasia. Ifthis is preferred, then it is also crucial that this is clarified explicitly as‘‘non-invasive carcinoma.’’


FIGURE 5. (A) Gastric type IPMN shows relatively simple and typicaat their base in the cyst wall. The epithelial lining is highly similar to ga villous growth pattern and reveals pseudostratified columnar cellstype IPMN reveals arborizing papillae lined by 2 to 5 layers of cubnucleoli and intraepithelial lumina. (D) Pancreatobiliary type IPconfigurations with delicate fibrovascular cores and is composed of(hematoxylin and eosin stain).


In a given case, the final grade of IPMN is based on thehighest-grade focus, no matter how small. In cases with high-gradedysplasia (‘‘carcinoma in situ’’), it is advisable to document theextent of this as focal (<25% of the tumor), substantial (25%–75%),or diffuse (>75%) (synoptic 2), although the clinical and behavioralrelevance of this has not yet been established.

IPMN SubtypesThe category of IPMN had been created as an umbrella entity

to encompass all tumoral intraepithelial neoplasms (intraductalmass-forming neoplasms) with a predominantly papillary architec-ture involving the large ducts of the pancreas.44,45,52 It has nowbecome clear that the 4 cell lineages (Fig. 5) that occur in thepapillary components of IPMNs may represent different carcinoge-netic pathways with significant differences in their clinicopathologicassociations, cancer progression rates, immunophenotype, and mol-ecular characteristics.33,36,45,47,63,88,138–140

Most branch duct IPMNs prove to be of gastric type,50,51

characterized by papilla lining that is highly similar to gastricfoveolar epithelium. Although invasive carcinoma is less commonlyassociated with gastric IPMNs than it is with the other IPMN types,once it occurs, it is typically of the tubular/ductal type with aggres-sive behavior akin to the ordinary PDAC.63,137,141,142

Intestinal type IPMNs are similar to colonic adenomas, dis-tinguished by villous architecture and pale basophilic mucin that is


lly short papillae and often have pyloric-like glandular elementsastric foveolar epithelium. (B) Intestinal type IPMN typically haswith a basophilic appearance and apical mucin. (C) Oncocytic

oidal cells with oncocytic cytoplasm and prominent, eccentricMN has complex arborizing and interconnecting papillarycuboidal cells with enlarged nuclei and little mucin production



typically diffusely positive for MUC2, in addition to expression ofCDX2 (transcription factor of intestinal programming).51,52,143 Intes-tinal type IPMNs are typically main duct type and fairly extensive51–

53,104–106,144 and are more likely to harbor GNAS mutations than arethe other types of IPMN.145–147 Invasive carcinoma is identified in athird of intestinal IPMNs resected, and these invasive foci often proveto be of colloid type52,66 with surprisingly protracted clinicalcourse.52,63,64,66,101

Oncocytic IPMNs, previously called intraductal oncocyticpapillary neoplasms,54,56 typically present as complex, large multi-locular cystic lesions rather than the typical IPMN presentation ofductal dilatation or mucin extrusion from the ampulla. They arecharacteristically complex, arborizing, with florid proliferation ofoncocytic cells that have a relatively monotonous appearance.54–56

Despite their large size and striking complexity, invasive carcinomais surprisingly rare in these tumors and, if seen, is usually verylimited in quantity. The prognosis seems to be relatively indolent aswell. Mutations in KRAS and GNAS, which are common in otherIPMNs, are seldom detected in this group.148,149

Intraductal papillary mucinous neoplasms that have cuboidalcells with high-grade cytology and that do not have the characteristicsof the intestinal or oncocytic types are designated as pancreatobiliary.52

Many of these may represent high-grade transformation of gastric typeIPMN; however, some have a distinctive pattern and morphology thatsupports a separate lineage. It is also this pattern that has overlappingfeatures with intraductal tubulopapillary neoplasms.150–156

It is acknowledged that in some cases (about 15%), there areoverlapping features, and it is not possible to place a given tumor intoany one category, in which case the term ‘‘mixed’’ is to be employed,with an explanatory note in the comment section.

Definition and Delineation of IPMN From ItsMimickers

Large PanINsGastric type IPMNs have significant morphologic and molecu-

lar overlaps with PanINs. IPMNs are defined by their ‘‘tumoral’’ nature(formation of clinically or grossly visible cystic and papillary nodulesthat are typically >1 cm) and PanINs are incidental/microscopic(<0.5 cm) forms of dysplasia (intraepithelial neoplasia), but otherwisethey have very similar pathologic characteristics.44,45 To provide anumerical value to this distinction, the size criterion of 1 cm isgenerally employed. For cysts between 1 cm and 0.5 cm that are linedby gastric-like mucinous epithelium, the term ‘‘incipient IPMN’’ hasbeen proposed as an option.157,158 For intestinal and oncocytic lesions,this differential is largely a moot point, because these are classified asIPMN, irrespective of size, although it is exceedingly uncommon forthem to be discovered when less than 1 cm.157

Simple Mucinous Cysts (Cystic Mucinous Duct Lesions)Cysts larger than 1 cm lined by mucinous epithelium but

without overt papillary configuration and without any ovarian typestroma create a challenging entity to classify. Previously, the term‘‘mucinous non-neoplastic cyst’’ has been recommended for suchlesions,159–161 but considering that mucinous change in the pancreasis now equated with the earliest form of neoplastic transformation,this name is no longer practical. Because many of these lesions do notshow any signs of obstruction or any other abnormality in theremaining pancreas, they cannot be exactly regarded as retentioncysts either. Of note, these seem to be mega-cystic versions of PanIN-1A (also known as ‘‘mucinous duct lesion’’), and thus, the term cysticmucinous duct lesion was also proposed.162 However, the trueidentity and the best name to assign to this entity require furtheranalysis and discussions.



Retention Cysts: Secondary Dilatation of the DuctsMass lesions (and other obstructive factors) can lead to

secondary dilatation of the pancreatic ducts, and when these acquiremucinous epithelium, they can be difficult to distinguish fromIPMNs. Lack of florid papillary elements and their round openlumina and the location of the lesions (commonly located in theperiphery of the main mass) may help differentiate these fromtrue IPMNs. In addition, they often have at least focal cuboidallining.43

Occasionally, the main pancreatic duct is also dilated signifi-cantly because of an obstructive process. Recently, minute neuro-endocrine tumors arising on the duct wall (especially from serotonincells) are coming to clinical attention and may clinically mimic anIPMN as they can cause significant ductal dilatation.163,164 Moreimportantly, on rare occasions, small PDACs can lead to markeddilatation of the main duct, again clinically mimicking an IPMN. Inthese cases, the obstructive carcinoma can be missed.

Similar Tumoral Intraepithelial NeoplasmsIntraductal tubular/tubulopapillary neoplasms are very close

kindreds of IPMNs, to an extent that some have proposed to regardthem as a variant of IPMN. However, because they lack 2 of thecharacteristic features of IPMN that even have been incorporatedinto the name,153 significant mucin production and papilla forma-tion, this entity was kept separate from IPMN in the WHO-2010classification.45 Intraductal tubulopapillary neoplasms are composedof non-mucinous (or minimally mucinous) cells, which grow ina predominantly tubular pattern with minimal papilla forma-tion.45,150,155,156

In the areas lacking the ovarian-type stroma, mucinous cysticneoplasms can appear identical to branch duct IPMNs, and in theareas with florid papilla formation, they are very similar to pan-creatobiliary type IPMNs.102,165,166

Adenomas and non-invasive papillary neoplasms growingwithin the ampulla, which have recently been proposed to be unifiedunder the heading of intra-ampullary papillary tubular neoplasms,can also be virtually identical to IPMNs, especially when they showextension into the pancreatic ducts.167 If taken out of context,intraductal papillary neoplasms of the bile ducts are also indistin-guishable from IPMNs.168 Proper grossing, dissection, and sampling(with identifiers of the location of each tissue sampled) are crucial inmaking the distinction between these entities, because withoutknowledge of the specific location of a given lesion, these can beindistinguishable at microscopic level. For the appropriate grossingprotocols, the readers are referred to other detailed texts.79 It shouldalso be noted here that some intestinal type IPMNs show fistulousextension into adjacent organs169 that can mimic tumors of thosesecondary sites.

Large Duct-type Invasive AdenocarcinomasSome invasive ductal adenocarcinomas of the pancreas are

composed of larger dilated ducts, rather than the more classical smalltubular pattern. These are often well-differentiated and may exhibitabortive papillary elements, such that, when taken in isolation, manyof the invasive glandular units can closely mimic IPMNs. These largeduct-type invasive adenocarcinomas can be distinguished fromIPMNs by the highly irregular contours of the ducts, relatively flatepithelial lining, open, round lumen formation (rather than thecompressed ducts with undulating contours), and the presence ofnecrotic, granular debris in their lumen.170–172 The distinction ofthese invasive carcinomas from non-invasive IPMNs is of utmostsignificance because both the outcome and pathogenesis are vastlydifferent. In fact, some of the rapidly progressive IPMNs in somestudies may belong to this category.




Congenital, Duplication, Enteric, and ParaduodenalWall Cysts

A variety of cysts close to duodenal wall can clinically mimicIPMNs. In fact, when these cysts develop papillary carcinomatouschanges, they can be indistinguishable from IPMNs.173 Some con-genital, duplication, or enteric cysts can be recognized by thepresence of a muscular wall, which can be very helpful. Some alsohave focal ciliated epithelium that is not seen in IPMNs.

Para-ampullary duodenal wall cysts that occur as a con-sequence of paraduodenal (groove) pancreatitis often have partialmucinous lining, because they arise from preferential injury ofpancreatic tissue on the wall of the duodenum (‘‘cystic dystrophyof heterotopic pancreas’’).174–177 These can be confused withIPMNs.

Coincidental Tumors and Uninvolved PancreasIn a patient with IPMN, it is important to analyze the unin-

volved parts of the specimen. As discussed previously, it is now wellestablished that IPMNs can be multifocal,117,178 and furthermore,concomitant invasive carcinomas can be encountered far away fromthe main IPMN lesions.98,179–182 Although neuroendocrine tumorscan occur synchronously with IPMNs, it is much more common tosee a non-neoplastic aggregation of the islets of Langerhans secon-dary to long-standing duct obstruction.183–186 This latter findingshould not be overdiagnosed as ‘‘islet cell hyperplasia,’’ or as aneuroendocrine neoplasm.

It should also be kept in mind that many patients with IPMNshave metachronous and synchronous tumors in other organs particu-larly the colon, and some of these can be present in the resectionspecimen, including the ampulla and duodenum.187–192

It is also advisable to document the changes in the uninvolvedportions of the pancreas. Peritumoral pancreatitis is very commonlyencountered in main duct IPMNs as a consequence of the localeffects of the tumor, and it would be preferable not to designate theseas chronic pancreatitis, because chronic pancreatitis is a specificdisease entity, defined by a constellation of findings at the clinicallevel.193–195 It may be more appropriate to be descriptive about thesechronic changes as atrophy, inflammation, and others.

Sampling of seemingly uninvolved pancreas can also revealsubtle, grossly unapparent obstructive lesions that lead to ‘‘pseudo-IPMN.’’163

Frozen Section EvaluationAfter discussions at both the Verona and Johns Hopkins

consensus meetings, where different opinions were raised initially,it was finally widely agreed that if routine frozen section of theprimary tumor is performed, it should be done with the understandingthat both high-grade dysplasia and invasive carcinoma, which are themain targets of a frozen section, are typically focal and often grosslynot distinguishable from lower-grade portions of the lesion, andtherefore cannot be confidently excluded in a frozen section setting.Thus, discrepancy is commonly observed between frozen section andpermanent findings. Even if such a focus of high-grade dysplasia and/or carcinoma is present, histologic interpretation can be difficultbecause of the freezing artifact, the small size of the focus, andconsidering that the pathologic assessment of IPMNs is alreadydifficult even in properly obtained sections. Freezing of tissue oftenleads to adverse alterations in the specimen that may hamper the finaldiagnostic evaluation in permanent sections, especially consideringthat the focus of concern is often small and may disappear aswell.196–199

Evaluation of margins by frozen sections may be indicated insome cases of IPMNs.94,200–203 When evaluating the margins, theconcerns described previously would have to be considered. The



main task for the pathologist is to determine whether there is high-grade dysplasia or invasive carcinoma, because it is believed thatthese require more aggressive management with consideration of theperformance of more extensive surgery, including total pancreatec-tomy. The current data indicate that the presence of low-gradedysplasia do not require any further surgery provided that thereare no other lesions clinically (and intraoperatively) in the remainingpancreas.204 This approach also pertains to incidental low-gradePanINs at a margin. Low-grade PanINs are often encountered ingeneral population205 and thus also in pancreata with IPMNs (see thetext for mimickers of IPMN). Although intestinal and oncocytic typeIPMNs are easy to distinguish from PanINs, gastric IPMNs (andcystic components of intestinal and oncocytic IPMNs, which alsooften have gastric type epithelium) are virtually indistinguishablefrom PanINs. For this reason, it is recommended that low-gradegastric like epithelium in pancreatic margins be reported as ‘‘Nohigh-grade dysplasia or invasive carcinoma is identified; low-grademucinous epithelium is present (low-grade PanIN or low-gradeIPMN).’’ Current data indicate that these findings by themselvesdo not justify further resection.40,206,207

One challenging finding in frozen sections for margins is theinflamed ducts with denuded epithelium, especially if the duct isdilated.208 These should be reported as ‘‘denuded epithelium, cannotassess for neoplastic process.’’ At this point, clinical and operativejudgment may have to be used in determining the course of action,and the presence or absence of a lesion in the remaining pancreasmay be an important factor in this decision.

In terms of indications to obtain frozen sections, it should alsobe kept in mind that a frozen section should be performed only if itmight change the course of the operation. Because such criteria aremostly surgical, the specific situations that it might be needed arebeyond the scope of this study and require further discussions.

Reporting of Cytology SpecimensThere are different opinions on the value of fine needle

aspiration (FNA) in the diagnosis of IPMNs. In Japan, this is mostlyavoided because of concerns about tumor seeding or biopsy-relatedcomplications. In the United States, however, endoscopic-ultra-sound-guided FNA biopsy is widely utilized in the diagnosticalgorithm of IPMNs,209–211 especially those with undetermined risk,such as branch duct IPMNs with indeterminate features, or in patientsin whom surgery is contraindicated.

The findings of FNA biopsy ought to be interpreted in thecontext of the clinical findings, and with close communicationbetween the radiologist, clinical management team, and cytopathol-ogists.212–217 Otherwise, results can be misleading. For example, inthe right context, the presence of thick mucin alone may be sufficientfor a diagnosis of IPMN, even if it is relatively acellular.

Most branch duct IPMNs (and the cystic component of otherIPMN types) have a lining that is indistinguishable from that ofnormal gastric epithelium.45 For this reason, the presence of gastrictype epithelium on FNA smears from a pancreatic cyst should bereported as ‘‘gastric type epithelium, cannot exclude gastric con-tamination or a low-grade gastric type IPMN.’’ If present, parietalcells may help make this distinction.

It is important to note that foci of invasive carcinoma are oftensmall and the ‘‘invasive/carcinomatous’’ cells are less likely to beshed into the cyst fluid. Therefore, unless the solid areas containingthese invasive elements are sampled separately, invasive carcinomacan easily be missed by FNA. The same is also true for microfocalhigh-grade dysplasia. Conversely, reactive ductal epithelium can bemistaken as ‘‘carcinomatous’’ changes. For these reasons, theresults of FNA should be evaluated with the clinical findings inmind.




It is also often impossible to distinguish the cells of high-gradedysplasia from those of invasive carcinoma. For these cases, thediagnosis of ‘‘high-grade atypia, possible carcinomatous change inIPMN’’ is recommended, with the understanding that ‘‘high-gradeatypia’’ is an all-encompassing term that incorporates features ofboth ‘‘high-grade dysplasia’’ and ‘‘invasive carcinoma,’’ which arecytologically inseparable and both require resection. It should benoted here that the diagnosis of ‘‘high-grade atypia’’ is to be usedonly in FNA specimens (not in surgical biopsies or resections), andeven in FNAs, it must be followed by a comment indicating that thisdiagnosis conveys a suspicion of carcinomatous transformation butcannot distinguish between in situ or invasive carcinoma, becausethis distinction is typically not possible in cytologic specimens.

Intraductal papillary mucinous neoplasms and mucinouscystic neoplasms are indistinguishable on FNA.216 This is becausethe subepithelial ovarian stroma of mucinous cystic neoplasm isoften not sampled or recognizable on smears or cell block. For thisreason, in cytologic specimens deemed to represent one of theseentities, the term ‘‘mucinous neoplastic cyst’’ is preferred, with aqualifying comment indicating that these 2 differentials are included.Once a cyst is determined to be a mucinous neoplastic cyst, it isimportant to determine the presence and grade of cytologic atypia(low- vs high-grade atypia) in all cases, so as to better stratify riskof invasion.

Reporting Principles for IPMN Are Also Applicablefor Other Tumoral Intraepithelial Neoplasms of thePancreatobiliary Tract

Although the main task of the consensus group was to focus onpancreatic IPMNs, further detailed elaborations have led to theconclusion that IPMNs are indeed the prototype of a group of closelyrelated lesions that occur in various aspects of the pancreatobiliarytract, and that many of the principles discussed previously regardingpathologic evaluation and reporting would be highly applicable tothese similar tumors, namely tumoral intraepithelial neoplasmsas well.

Mucinous cystic neoplasms (of the pancreas and hepatobiliarytract),41,42,218,219 intraductal tubular/tubulopapillary neoplasms (ofthe pancreas and bile ducts),150–156 ‘‘adenomas’’ and ‘‘papillaryneoplasms’’ growing within the ampulla (recently proposed to becollected under the heading of intra-ampullary papillary tubularneoplasm with an approach similar to IPMNs),167 and ‘‘adenomas,’’and ‘‘intracystic papillary neoplasms’’ of the gallbladder (recentlyproposed to be unified under a title of intracholecystic papillarytubular neoplasms),220 all share various important characteristicswith IPMN. All are mass-forming non-invasive neoplasms that showa spectrum of neoplastic transformation; that is, adenoma-carcinomasequence, with the intramucosal/intraepithelial spectrum ranging fromhyperplastic-like gastric epithelium to full-blown intramucosal/intra-epithelial carcinomatous changes that used to be referred as ‘‘papillaryadenocarcinomas.’’ All of these entities also exhibit cell lineagesidentified in IPMNs (gastric, intestinal, pancreatobiliary, oncocytic,and mixed). The grading scheme and terminology for these tumors aremostly adopted from those used for IPMNs. Furthermore, they can beassociated with invasive carcinoma of various types. All the reportingprinciples discussed previously (grading, staging, typing, separatereporting of invasive carcinoma, and staging of invasive carcinoma)are also applicable to these tumors.

CONCLUSIONS

Proper, consistent evaluation and thorough documentation ofpathologic characteristics of the neoplasms and application ofuniform terminology are crucial for both the management of patients



with IPMNs and further unraveling of many puzzles of this entity andother similar tumoral intraepithelial neoplasms of the pancreatobili-ary tract.

ACKNOWLEDGMENTSThe authors thank Rhonda Everett for her assistance in the

preparation of the manuscript and Allyne Manzo and LorraineBiedrzycki for assistance with the figures.

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