Intraductal papillary mucinous neoplasms (IPMN) of the pancreas: clinico-pathologic results.

Abstract

intraductal papillary mucinous neoplasm (IPMN) shows a series of lesions which evolve from benign lesions -adenoma- to invasive carcinoma.
To analyze the clinical and pathological results of 15 patients diagnosed of IPMN, and surgically treated according to the guidelines of International Consensus Conference.
A retrospective analysis of 15 patients surgically treated between March 1993 and September 2009, according to the International Consensus recommendation. Demographic, diagnostic tools, surgical report, pathologic database and actuarial survival were analyzed with a follow-up from one and a half month through nine years.
6 Patients underwent pancreaticoduodenectomies, 4 total pancreatectomies, 2 body or central pancreatectomies, 2 partial pancreatectomies (enucleation) and 1 distal pancreatectomy. A morbidity of 46 and 0% hospital mortality were assessed, with a median length hospital stay of 10 days. In five cases, the IPMN was combined type (both main and branch pancreatic ducts involved) in four main duct-type and branch duct-type in the another six as well. Several atypia (IPMN carcinoma in situ) was observed in 2 patients and invasive carcinoma with negative lymph nodes was identified in 3 patients. A patient without invasive carcinoma died at 66 months of follow-up for pancreas adenocarcinoma. The actuarial survival up to recurrence or death was 105,133 months with a range of follow-up from 1 month and a half until 9 years.
IPMN main duct or mixed type warrants complete resection due to its incidence of invasive carcinoma or precursor lesions of malignancy as well. Due to its multifocal pattern, patients should be followed in long-term surveillance. The management of asymptomatic IPMN type branch less than 3 cm is controversial.

Full text

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ABSTRACT
Background:
(IPMN) shows a series of lesions which evolve from benign lesions
–adenoma– to invasive carcinoma.
Aim: to analyze the clinical and pathological results of 15 pa-
tients diagnosed of IPMN, and surgically treated according to the
guidelines of International Consensus Conference.
Material and methods: a retrospective analysis of 15 pa-
tients surgically treated between March 1993 and September
2009, according to the International Consensus recommenda-
tion. Demographic, diagnostic tools, surgical report, pathologic
database and actuarial survival were analyzed with a follow-up
from one and a half month through nine years.
Results: 6 patients underwent pancreaticoduodenectomies,
4 total pancreatectomies, 2 body or central pancreatectomies, 2 par-
tial pancreatectomies (enucleation) and 1 distal pancreatectomy.
A morbidity of 46 and 0% hospital mortality were assessed, with
a median length hospital stay of 10 days. In five cases, the IPMN
was combined type (both main and branch pancreatic ducts in-
volved) in four main duct-type and branch duct-type in the an-
other six as well. Several atypia (IPMN carcinoma in situ) was
observed in 2 patients and invasive carcinoma with negative
lymph nodes was identified in 3 patients. A patient without inva-
sive carcinoma died at 66 months of follow-up for pancreas ade-
nocarcinoma. The actuarial survival up to recurrence or death
was 105,133 months with a range of follow-up from 1 month
and a half until 9 years.
Conclusions: IPMN main duct or mixed type warrants com-
plete resection due to its incidence of invasive carcinoma or pre-
cursor lesions of malignancy as well. Due to its multifocal pattern,
patients should be followed in long-term surveillance. The man-
agement of asymptomatic IPMN type branch less than 3 cm is
controversial.
intraductalpapillarymucinousneoplasm
Key words: Intraductal papillary mucinous neoplasm. Prognosis
factors. Invasive carcinoma. Survival.
RESUMEN
Introducción: la neoplasia papilar mucinosa intraductal
(NPMI) del páncreas comprende una serie de lesiones que evolu-
cionan desde lesiones benignas (adenoma) hasta carcinoma ductal
invasivo.
Objetivo: analizar los resultados clínicos y patológicos de 15
pacientes diagnosticados de NPMI e intervenidos según las reco-
mendaciones de conferencia de consenso.
Material y métodos: análisis retrospectivo de 15 pacientes
con NPMI, intervenidos entre marzo de 1993 y septiembre de
2009; según pautas de conferencias de consenso internacionales.
Se recogieron datos demográficos, pruebas diagnósticas, tipo de
intervención, histopatología y supervivencia actuarial con un se-
guimiento entre mes y medio y nueve años.
Resultados: se realizaron 6 duodenopancreatectomías cefáli-
cas, 4 pancreatectomías totales, 2 pancreatectomías centrales,
2 pancreatectomías parciales y una pancreatectomía distal. Se re-
gistró una morbilidad del 40%, sin mortalidad operatoria, con una
estancia media de 10 días. En 5 casos la NPMI fue de tipo mixto,
en 4 afectaba al conducto pancreático y en los 6 restantes a ra-
mas accesorias. Dos pacientes presentaron carcinoma in situ y 3
carcinoma invasivo con ganglios negativos. Un paciente, sin carci-
noma invasivo, falleció a los 66 meses por adenocarcinoma de
páncreas. La supervivencia actuarial hasta recidiva o muerte fue
de 105,133 meses; con un rango de seguimiento entre mes y me-
dio y 9 años.
Conclusiones: la NPMI tipo ductal y mixto exige la resección
completa debido a la elevada incidencia de carcinoma invasivo o
de lesiones precursoras de malignidad. Por su carácter multifocal
los enfermos deben ser revisados a largo plazo. Existen controver-
sias en las NPMI tipo accesorio asintomáticas y menores de 3 cm.
Palabras clave: Neoplasia papilar mucinosa intraductal. Facto-
res pronósticos. Carcinoma invasivo. Supervivencia.
Intraductal papillary mucinous neoplasms (IPMN) of the
pancreas: clinico-pathologic results
J. A.-Cienfuegos1, F. Rotellar1, P. Martí-Cruchaga1, V. Valentí1, G. Zozaya1, A. Bueno1, N. Pedano1,
M. D. Lozano2, J. J. Sola2and F. Pardo1
1Departments of General Surgery and2Pathology. Clínica Universidad de Navarra. Pamplona, Navarra. Spain
1130-0108/2010/102/5/314-320
REVISTA ESPAÑOLA DE ENFERMEDADES DIGESTIVAS
Copyright © 2010 ARÁN EDICIONES, S. L.
REV ESP ENFERM DIG (Madrid)
Vol. 102. N.° 5, pp. 314-320, 2010
Received: 24-11-09.
Accepted: 09-02-10.
Correspondence: Javier A. Cienfuegos. Departamento de Cirugía General.
Clínica Universidad de Navarra. Avda. Pío XII, 36. 31008 Pamplona,
Navarra. Spain. e-mail: fjacien@unav.es
A.-Cienfuegos J, Rotellar F, Martí Cruchaga P, Valentí V, Zo-
zaya G, Bueno A, Pedano N, Lozano MD, Sola JJ, Pardo F. In-
traductal papillary mucinous neoplasms (IPMN) of the pancre-
as: clinico-pathologic results. Rev Esp Enferm Dig 2010; 102:
314-320.

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INTRODUCTION
Intraductal papillary mucinous neoplasm (IPMN) of
the pancreas encompasses a spectrum of histological and
clinical entities which have raised great attention in the
last decade (1-6).
The clinical series of IPMN was first described by
Ohhashi in 1982 and Sessa introduced the term of IPMN
in 1994 (7,8). The growing histopathological evidence
showing that 20-30% of the IPMN cases are multifocal
and that 5-10% of IPMN disease involve whole pancreat-
ic gland has raised multiple controversies regarding the
appropriate surgical treatment and interval follow-up of
these patients (1-5).
The most relevant features of IPMN include the pan-
creatic ducts involvement variants –main duct type, ac-
cessory branch type and mixed– and the sequential pro-
gression from early lesions as adenoma to in situ
carcinoma and invasive carcinoma. There is agreement in
considering IPMN as a precursor lesion of pancreatic car-
cinoma, specially the main duct type lesions (9-13).
Several consensus conferences have been held with
the aim of clarifying and establishing the diagnosis requi-
sites and therapeutic recommendations. The aim of this
study is to analyze the surgical outcomes of patients diag-
nosed of IPMN and the concordance of the pathological
findings and clinical data with the consensus conference
statements (14-16).
PATIENTS AND METHODS
Between March 1993 and September 2009, 38 patients
underwent pancreatic resection for pancreatic cystic tu-
mors. Fifteen of these 38 patients were resected and diag-
nosed of IPMN and were subject to further analysis.
A retrospective analysis of clinicopathologic data,
histopathology, disease free survival and recurrence pattern
was performed. The surgical indication was established in
multidisciplinary group based on the clinical parameters
and imaging techniques: computed tomography (CT), en-
doscopic ultrasonography (EUS) guided fine-needle aspira-
tion (FNA) and brush cytology, and magnetic resonance
cholangiopancreatography (MRCP) according to the men-
tioned conference guidelines. For the purposes of the study
aspirates interpreted as positive for malignancy or positive
for mucinous were considered positive for FNAresult.
In lesions located in the head, neck or uncinate process,
pancreaticoduodenectomy was performed (Krauss-Whip-
ple procedure). Cystic tumors limited to the neck and body
were treated with central pancreatectomy and distal pancre-
atectomy was carried out in tumors located in the tail of the
pancreas.
Total pancreatectomy was performed in patients with
diffuse involvement of the pancreatic duct. Frozen-sec-
tion evaluation of the pancreatic transection margin was
reported during the operation.
The IPMNs were diagnosed and classified according
to the World Health Organization (WHO) nomenclature
(17) and with the Osaka’s consensus conference held in
2004 (15). Tumors presenting ovarian like stroma were
excluded and diagnosed as mucinous adenoma (17).
The IPMN cases were classified in three categories:
main-duct type or branch-duct and mixed type as well,
depending on the pattern of ductal involvement. The
IPMN tumors were classified as non-invasive or invasive
according to the criteria published by WHO and later re-
viewed by Singh and Maitra (9,17).
The surgical margins were evaluated for evidence of
gross and microscopic disease according to the 2010 AJCC
(Cancer Staging Manual) (18). The positive transection
margin was defined as any neoplastic epithelium within
ducts. Specific information regarding the status of the
retroperitoneal margin, the node involvement, perineural
and vascular were reported in the pathological report.
Postoperative mortality was defined as death within
the same hospital stay or 30 days of surgery. Pancreatic
fistula was defined as output of any measurable volume
of fluid with an amylase content greater than three times
the serum amylase activity in the percutaneous drainage
(19). The site of first recurrence was defined as follows:
local indicates the pancreatic bed, regional indicates the
peritoneal cavity and distant metastases indicates the liv-
er, bone, lung or others organs of distant metastases. Sur-
vival curves were created by using the method of Kaplan-
Meier, with the SPSS program, version 15.0.
RESULTS
Table I summarizes the clinical characteristics of the
entire cohort. The incidence was similar in both genders
with and age range between 33 and 79 years (median age
63,2 years), confidence interval (CI): 95%; 55,95-70,44.
The presenting symptoms were, in general, vague, al-
though five patients presented specific symptoms as
jaundice, previous episodes of acute pancreatitis, fever
and constitutional syndrome.
Preoperative abdominal CT and EUS-guided FNA
were the most common imaging modalities. The FNA-
cytology was positive for mucinous tumor in 8 of 11 cas-
es (sensitivity 88.8%). In two patients the specimen ob-
tained was insufficient.
In 8 patients the tumor involved the head of the pan-
creas, in three the IPMN presented as diffuse pattern of
the main duct. In the remaining four patients, the IPMN
was limited to the uncinate process, two in body and the
tail of the pancreas as well. Six pancreaticoduodenec-
tomies, four pancreatectomies, two central pancreatec-
tomies, one distal pancreatectomy and two partial pancre-
atectomies were performed.
There was no operative mortality. Complications were re-
ported in six patients (40%); four developed collections in
the surgical “bed”. Three of them required transgastric
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316
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drainagethroughEUS.Apatientwhounderwentapartialre-
section developed a pancreatic fistula at 4 days of discharge,
being resolved with percutaneous drainage. Another one de-
veloped a delay gastric emptying. The mean hospital stay
was10days(range4-22).Therewasnotoperativemortality.
Five patients had mixed type of IPMN and three pre-
sented the main duct involvement pattern (Fig. 1). In the
remaining seven patients the IPMN presented side
branches type (Fig. 2). Among the 15 patients, three had
very low grade dysplasia (adenoma) at the pancreatic
transection margin (on frozen-section) analysis. No fur-
ther resection was performed in these patients.
In three patients pancreatic intraepithelial neoplasia
(“PanIN”) was assessed. Two of them presented the sub-
types PanIN-1A, with flat microscopic lesions (< 25 mm)
composed of columnar cells and minimal atypia and one
caseofPanIN-2withmoderateatypia.Twopatientspresent-
edhigh-gradedysplasia–insitucarcinoma–(cases6and10)
and another three patients (cases 1, 2 y 3) presented an inva-
sivecarcinomawithnegativenodesinthespecimen(Fig.3).
Two of them are alive with no evidence of recurrence at 8
and9yearsoffollow-up,meanwhiletheremainingpatientit
is free of disease at three years, having been resected of a
peritoneal recurrence at 15 months postsurgery.
One patient (case 4) died at 72 months after diagnosis
with multiple node involvement of a pancreatic adeno-
carcinoma. All patients were followed with a range be-
tween 1 month and 9 years, obtaining an actuarial sur-
vival of 105,133 months with a confidence index of 95%
(86,264-124,003) and a free-disease survival of 98.355
months (IC: 76,761-119,949). Kaplan-Meier survival
curve is depicted in figure 4.
DISCUSSION
The clinical series of IPMN was first described by
Ohhasi in 1982 (7,20). Sessa posteriously coined the term
of IPMN (8).
Fig. 1. IPMN specimen of total pancreatectomy showing the main pan-
creatic duct. A significant dilation from de joint of head and body with
cystic dilations containing mucinous in the tail.
Table I. Summary of clinic-pathological characteristics of 15 IPMN patient surgically treated
CaseAge/SexClinical presentationDiagnosisLocation and sizeSurgeryPathological findingsOutcome/follow up
1 79MSteatorrhea, weight lossEUS - FNA(+) - CTHead 3.5 cmPBMixed-type. Invasive ca.
Rx margin+. Low displasia
Excellent 9 y
2 67F Incidental findingEUS - FNA(+) - ERCPHead 2.5 cmPD Mixed-type. Invasive ca.Excellent 8 y
3 72M Astenia / anorexiaEUS - FNA(-) - CTHead 2.1 cm PDBranch-type. Rx margin+.
Low displasia
Excellent6.5 y
4 77M Abdominal pain, nausea, fever (38 ºC)EUS - FNA(+) - CTHead3 cm PD Mixed-type. Rx margin+.
Low displasia
† 5.5 y
5 77FAbdominal pain Diffuse 0.4 cmTP Main-type. PanIN-2Excellent4 y
6 73F Incidental findingEUS - FNA(+)Diffuse0.9 cm TPMixed-type. PanIN-1AExcellent4 m
758M Jaundice, weight lossEUS - FNA(+) Head5.5 cmTPMain-duct type. In situ carcinomaExcellent2.5 y
8
56F Incidental findingEUS - FNA(+)Body - tail1 cm DPBranch-type. PanIN-1A Excellent 2 y
9 33MRelapsing pancreatitisEUS - CTUncinate2.5 cm Partial P.Branch-typeExcellent 2 y
10 45F Lumbar painUS - MRCPBody0.5 cmCPBranch-type Excellent19 m
11 58M Diabetes, weight lossEUS Head2.6 cmPD Mixed-type.in situ carcinomaExcellent 1.5 m
12 56MIncidental findingEUSHead1.2 cmEnucleation Branch typeExcellent 4 y
1361F Acute pancreatitisCT - EUS - FNA(+)Diffuse2.5 cmTPMain-duct type. Invasive carcinomaPeriton. recurrence
Alive
3 y
1460MIncidental finding EUS - FNA(+) - MRCP Central1.7 cm CPMain-duct. Low dysplasiaExcellent2 y
15 76F Anomalies liver function paramet.EUS - FNA(+)Head1.2 cmPD Branch-typeExcellent5.5 y
EUS: endoscopic sonography; PD: pancreaticoduodenectomy; CT: computed tomography; TP: total pancreatectomy; FNA: fine-needle aspiration; PP: partial pancreatectomy;
MRCP: magnetic resonance cholangiopancreatography; CP: central pancreatectomy; ERCP: endoscopic retrograde cholangiopancreatography; DP: distal pancreatectomy.

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With occasion of a new classification of the exocrine
pancreatic tumor, in 1996 World Health Organization
(WHO), defined IPMN as the intraductal papillary
growth of mucin-producing columnar epithelia (17). This
classification and the revised WHO 2000’s classification
have disclosured previous misunderstanding and confus-
ing terms (5,6).
A significant number of reports on IPMN have been
published in the last decade, accounting between 8 to 20%
pancreatic resections in large-volume centers (22-24).
Among its specific characteristics are the different morpho-
logical pattern involvement of the duct –side branch duct
type and mixed form– and is considered as a premalignant
entity, having well documented the sequence from low dys-
plasia to in situ carcinoma, and invasive carcinoma as well.
Several focus of intraepithelial pancreatic neoplasia
(PanIN) have been reported in resected specimens and sub-
classified into different grades of cellular atypia (PanIN-1,
PanIN-2, PanIN-3). The PanIN-1 are classified on flat type
(PanIN-1A) and papillary type (PanIN-1B).
Several consensus conferences have been held and
guidelines recommendations have been published in or-
der to address the controversies regarding the diagnosis,
management and follow-up of IPMN (14-16).
Whereas our case series is limited, represents the sec-
ond largest in Spanish literature and depicts all the spec-
trum of IPMN ranging from the benign type –adenoma–
to invasive carcinoma. The demographic profile is simi-
lar to other series, presenting in advanced age (70-80
years); perhaps influencing a “nihilist” attitude regarding
the surgical treatment in this population.
The most frequent location was in the pancreatic head
(10 of 15 cases), and the presenting symptoms are similar
with other case series (3,21-25). In our series, four cases
with malignancy findings –in situ carcinoma or invasive
carcinoma– showed involvement of the main pancreatic
duct or a mixed type what is assessed in the majority of
authors (24,26-29).
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Fig. 3. Microscopic detail of the lesion depicted in figure 1. The main
duct is lining by a pseudostratificated epithelium with elongated nu-
clei, preservation of mucin secretion, mitosis corresponding with high-
grade dysplasia (superior H&E x 400). In the tail of the pancreas an in-
vasive colloid carcinoma with extracellular mucin pools with clusters of
malignant cells and stroma component reaction (inferior H&E x 200) is
observed (inferior view H&E x 200).
Fig. 2. Gross appearance of central pancreatectomy by IPMN type ac-
cessory branch. Pancreatic duct section shows a normal diameter with
smooth wall (superior imaging). The pancreas section shows an isola-
ted cystic cavity of 0.9 cm diameter without communication with the
main pancreatic duct.

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In this study, one patient died of loco-regional recur-
rence of a pancreatic adenocarcinoma at 66 months of
follow-up, who had a mixed type of duct involvement in
the specimen, the morphologic pattern with more inci-
dence of invasive lesions in large series (24,26-30). The
loco-regional relapsing or de novo tumor oscurred at five
years and a half after resection, which is the estimated
time (5-7 years) to develope the sequence from adenoma
tocarcinoma intheremanent
(9,11,12,24,27). Adsay at al, in a very similar series re-
ported two patients with non-invasive IPMN who died of
loco-regional recurrence of a pancreatic adenocarcinoma
65 months after surgical resection (21). One of our pa-
tients with an invasive carcinoma (case 13) developed lo-
calized peritoneal recurrence 15 months after total pan-
pancreatictissue
createctomy. The patient is alive and free of disease after
recurrence’s resection.
A multifocal IPMN disease has been published in
30% of the branch-duct type and 10% of recurrences
has been published in non-invasive disease after pan-
createctomies withnegative
Metachronous or synchronous adenocarcinoma of the
pancreas has been reported in 9.2% of 76 patients with
IPMN (33). Three of our patients showed low grade
dysplasia in the resection margin. There is agreement
that a completion pancreatectomy in not necessary be-
cause total pancreatectomy may have severe metabolic
consequences (11,15,16,32,34).
The remaining patients are free of disease with a fol-
low-up range between 6 months and 8 years. There was
not operative mortality and the 40% surgical morbidity is
according with published range of large experience acad-
emic centers (35,36). The median hospital stay was 10.06
days, (range 4-22 days). We have previously mentioned
that the invasive carcinoma incidence is more frequent in
the main duct type of IPMN (75%) than in the branch or
accessory duct type (25%) (15,24,30,42,43). These out-
comes justify the prospective study carried out by Salvia
in which they performed the follow-up of 89 patients
with branch-type IPMN, asymptomatic, size of the lesion
less than 3,5 cm and normal values of CA-19.9. In this
study five patients (6%) developed an increase in size
and underwent resection, without sings of malignization
(44,45). Similar results have been published by Tanno et
al. through the follow-up of 81 patients during 61 months
(46).
Based on this study –evidence grade 3– the guidelines
recommend the surveillance and follow-up for the lesions
with exclusively involvement of the accessory pancreatic
ducts, asymptomatic, less than 3 cm diameter and ab-
sence of nodules inside the lesion (15,44,47,48). The in-
terval between follow-up –high-resolution CT or EUS–
should not be longer than 6 months due to higher inci-
dence of metachronous pancreatic adenocarcinoma in the
remanent pancreatic tissue (49,50).
Based on previous published experience, we can con-
margins(31,32).
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Table II. Summary of reported outcomes of IPMN(*) surgically treated
Author Year# casesType IPMN (*)Margin (+) %Follow-up
X–: months
Loco-regional recurrence 5 year survival
Non invasiveInvasive OverallNon invasiveInvasiveNon invasive Invasive
Wada K (36) 2005100 7525 27%271.3% 42%100%46%
Raut CP (37)2006 35 2213 37% 610%30.7%100% 40%
White R (30)2007130 786029% 407.7% 87%
Nakagohri T (38)2007 824537-2820.7%78% 24%
Schnelldorfer T (25)200820814563 59%60 8%58% 94%31%
Nara S (39)2008104 5351-37.2 29.7%100%38%
Nagai K (40)
(*) IPMN: intraductal papillary mucinous neoplasm; X–: mean; Margin (+): involvement of pancreatic resection margin.
2008724230- 54100% 57.6%
1.0
0.8
0.6
0.4
0.2
0.0
0204060 80100 120
Survival analysis
Follow-up (months)
Disease specific survival
Fig. 4. Kaplan-Meer estimate of overall survival. The median overall sur-
vival was 105.133 months.
Supervivencia actuarial de 15 pacientes intervenidos de NPMI hasta re-
cidiva o fallecimiento. La supervivencia media es de 105,133 meses.

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clude that IPMN with main duct type pattern and mixed
type should be resected with intraoperative confirmation
of absence of invasive IPMN at the resection margin. An
80% survival at five years is estimated for the non-inva-
sive IPMN and 30% for the cases harboring an invasive
carcinoma. Table II shows the recent experience of large
series.
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