Intraductal Papillary Mucinous Tumors

Roberto Salvia1, Claudio Bassi1, Massimo Falconi1, Paola Serini1, Stefano Crippa1,
Paola Capelli2, Paolo Pederzoli1
Departments of 1Surgery and 2Pathology, University of Verona. Verona, Italy
Summary
The intraoperative management of the
margins of intraductal papillary mucinous
tumors (IPMNs) undergoing pancreatic
resection is crucial. The surgeon must
discontinue the resection whenever the
pancreatic margin is negative and, of course,
when a total pancreatectomy is indicated.
Nevertheless, a wide gray area exists. The real
surgical problems are represented by i)
IPMNs involving only a segment of the
pancreatic gland, thus necessitating
intraoperative histological examination of the
resection and the decision as to “when to stop
the resection”; ii) the intraoperative
management of those margins which are
neither clearly negative nor clearly positive;
iii) the actual indications either for surgery or
for follow-up in those patients affected by
peripheral IPMNs.
In the literature, negative resection margins
have a range of between 49 to 81% with a
pancreatic recurrence rate of from 0 to 25% in
follow-ups ranging from 6 months to 11 years
after the first operation.
In general, in this disease which mainly
involves the head and uncinate process of the
gland, decisions are a “balance” between the
patient and the disease. In fact, on the one
hand, there is the usual elderly patient with
possible comorbidities, symptoms and the
presence of diabetes; on the other hand, the
disease, which usually involves the head and
the uncinate process of the gland, tends to
grow along the duct and be potentially
malignant if carcinoma is not already present.
Described for the first time in 1982 as a
mucin producing neoplasm with dilatation of
the main duct and protruding papilla (the
Ohashi triad) [1], intraductal papillary
mucinous neoplasms of the pancreas (IPMNs)
have had a remarkable “epidemiological
explosion” in recent years [2, 3, 4, 5, 6].
The disease originates from the epithelium of
the pancreatic ducts and can evolve through
different biological stages ranging from mild
dysplasia to invasive carcinoma; the different
stages could be simultaneously present within
the same lesion [7]. Currently, most of the
Authors agree that evolution towards the
carcinoma stage is slow, but probably
inexorable [8, 9, 10].
In consideration of the improvement in
radiological imaging, IPMNs are diagnosed
with increasing frequency and at earlier
stages. It is remarkable that nowadays
pancreatic main duct dilatation of less than 1
cm and small cysts can be clearly identified
by MRCP instead of invasive diagnostic tools
such as ERCP [11].
If we trust in the potential malignancy of
IPMNs, the therapy of all the “ectasiae”
involving the main pancreatic duct should be
surgical resection.
Thus, the correct answer to the question
“IPMNs, at what point should we stop in the
operating theatre?” is only "if" a normal

Page 2
JOP. J Pancreas (Online) 2005; 6(1 Suppl.):112-117.
JOP. Journal of the Pancreas – http://www.joplink.net – Vol. 6, No. 1 Supplement – January 2005. [ISSN 1590-8577]
113
epithelium is shown at intraoperative frozen
section examination of the resection margin.
The presence of any positive resection margin
must push the surgeon to proceed with
pancreatic resection in order to achieve a
negative margin up to total pancreatectomy
when necessary. Actually, the first studies
reported in the literature consider surgery as
the only treatment for IPMNs [3, 12, 13].
At the end of the 90’s, IPMNs were divided
into two different groups: those with
involvement of the main pancreatic duct and
those with involvement of the side branch of
the ductal system [14, 15, 16].
In 1999, some authors [15, 16] showed for the
first time that “branch-duct” IPMNs may have
a less aggressive biological behavior as
compared to the main duct type thus
suggesting limited resection or, at least,
conservative surgical treatment.
Between 1999 and 2001 several studies
identified some radiological findings as
criteria in discriminating between benign and
malignant forms; in particular parameters
related to malignancy were well-characterized
[17, 18, 19, 20].
Not only radiological findings, but also
clinical, demographic and laboratory
parameters should be considered to
understand whenever a “wait and see” follow-
up is the best option for these patients.
A recent paper analyzed the databases from
Harvard University and the University of
Verona [6] in order to describe the clinical
characteristics and outcomes of a large
number of patients affected by IPMNs
involving the main pancreatic duct. A total of
140 patients were considered and the results
of the study showed interesting findings never
before described in a large series. First of all,
patients with malignant tumors were found to
be almost seven years older than those with
adenomas or borderline tumors. This
observation supports the evidence that the
neoplasm arises as benign and subsequently
becomes malignant, thus making it possible to
evaluate the median time required for this
progression.
Regarding clinical findings, a recent onset or
worsening of diabetes, steatorrhea and,
mainly, jaundice were significantly associated
with malignancy. On the contrary, patients
with benign IPMNs had a higher frequency of
abdominal pain and a longer duration of the
symptoms.
Further considerations lead us to carefully
consider the surgical option in IPMNs. Most
patients are elderly with a mean age of 65-70
years at diagnosis and they can be affected by
co-morbidity increasing the surgical risk. The
lesion mainly affects the head of the pancreas
and the uncinate process (60%) but the entire
gland may be involved. Therefore, in
agreement
with
this
finding,
pancreaticoduodenectomy is the most
common surgical procedure followed by total
pancreatectomy [5, 6, 21, 22, 23].
Moreover, as regards the concept of
transformation from benign neoplasm to
invasive carcinoma, studies involving a large
cohort of patients showed a “progression
time” ranging from 5 to 7 years [5, 6].
Even if there is still a lack of data regarding
non-surgical follow-up, this “wait and see”
policy may be suggested in asymptomatic
patients with branch IPMNs and absence of
any malignancy criteria together with high
operative risk.
Therefore, patients affected by peripheral
IPMNs without any malignant parameters
should be candidates for a strict clinical-
radiological “wait and see” follow-up.
In such instances, surgery is not indicated.
In the remaining patients, surgical resection is
still the treatment of choice.
Among those undergoing surgery, some
patients present a dilatation of the entire
ductal system of the gland with an
involvement of the main pancreatic duct and
side branches. Total pancreatectomy has to be
considered the main surgical option.
IPMNs involving only a segment of the
pancreatic gland represent the real challenge
for the surgeon. In these cases, an
intraoperative histological examination of the
resection margin is mandatory [2] in order to
answer the question “when to stop?”.
Because the extent of ductal involvement may
be difficult to determinate prior to surgery,
many authors have stressed the importance of

Page 3
JOP. J Pancreas (Online) 2005; 6(1 Suppl.):112-117.
JOP. Journal of the Pancreas – http://www.joplink.net – Vol. 6, No. 1 Supplement – January 2005. [ISSN 1590-8577]
114
obtaining a tumor-free surgical margin by
intraoperative frozen section pathological
examination [10, 12, 22, 24].
In a previous report from our institution, we
evaluated the resection margins in 49 patients
who had undergone a partial pancreatectomy
for IPMNs between 1988 and 1998. Forty-
seven percent of the 49 patients had negative
resection margins at pathological examination
while 18%, 22% and 2% had mild, moderate
and high-grade dysplasia, respectively.
Five patients (10%) presenting with invasive
IPMN had a de-epithelialized resection
margin.
In 4 of these patients there was local
recurrence of the tumor, and a fifth patient,
who
underwent
pylorus-preserving
pancreaticoduodenectomy, has had too short a
follow-up to be properly assessed. The
presence of de-epithelialization should
therefore be regarded as a "positive resection
margin" [2].
In our recent paper, reporting the Harvard-
Verona combined experience, the rate of
negative margins in the surgical specimen
was 58.5% [6].
The results of the intraoperative frozen
section analysis altered the surgical plan by
extending resection or leading to total
pancreatectomy in 29 patients.
Considering the long-term follow up of these
patients, recurrence in the remaining pancreas
occurred in 8 patients (7%). Only one of these
patients did not have invasive cancer in the
initial pathology. He underwent a Whipple
procedure for an adenoma and had a
pancreatic margin that was negative. Five
years later, he developed a recurrence and
underwent a complete pancreatectomy for a
carcinoma in situ in the distal pancreas.
The other 7 recurrences occurred in patients
who had presented invasive cancer. Two
patients presented recurrence within 6 months
and they also had liver metastases. Five
presented recurrence in the remnant between
28 and 67 months. Three of them underwent
further resection but subsequently developed
metastases and died; 2 are currently disease-
free after the re-resection.
None of the transection margins of these
patients showed invasive cancer: 2 borderline,
2 de-epithelialized and one was negative.
Chari et al. [25], in a series of 73 patients
with non-invasive IPMNs, performed partial
pancreatectomy in 60 cases and total
pancreatectomy in the remaining 13.
Considering patients who underwent partial
pancreatectomy, a negative or hyperplastic
resection margin was achieved in 58 cases
while mild or moderate dysplasia was found
in 2; recurrence was observed in 5 of 60
patients (8%) and, in all cases, the surgical
margin was negative after the initial resection.
Two recurrences were benign and 3 were
malignant (carcinoma in situ in one case and
invasive carcinoma in the remaining two).
Patients with benign recurrences presented
IPMN adenoma both at the first and at the
second surgical resection. Patients with
carcinoma in situ and invasive carcinoma had,
after initial surgery, a borderline tumor and
carcinoma in situ, respectively.
Sohn et al. [5] showed a recurrence of disease
in 9 of 136 (7%) patients with resected non-
invasive (n=84) or invasive (n=52) IPMNs.
Seven patients had an invasive IPMN after the
second surgery: 5 of them had carcinoma in
situ after initial surgery, with negative
resection margins in 3 cases, while the
remaining two had invasive carcinoma. One
patient operated on for an IPMN with
moderate dysplasia and a borderline resection
margin had a recurrence one year later and the
pathological examination showed the same
histological findings. The last patient, who
had an initial carcinoma in situ with a
negative resection margin, presented a
recurrence of the same neoplasm 11 years
later.
On the one hand, the presence of malignant
growth at the pancreatic resection margin
requires an extension of the surgical resection
up to a total pancreatectomy [10, 23, 26]; on
the other hand, in the case of microscopic
benign dysplastic lesions at the pancreatic
margin, the optimal surgical strategy remains
controversial.
Traverso et al. [22] and Sugiyama and Atomi

Page 4
JOP. J Pancreas (Online) 2005; 6(1 Suppl.):112-117.
JOP. Journal of the Pancreas – http://www.joplink.net – Vol. 6, No. 1 Supplement – January 2005. [ISSN 1590-8577]
115
[23] reported completion of total
pancreatectomy in 24% and 29% of their
patients, respectively. A significantly
different strategy was carried out by the
Erasme University Hospital group [3, 27].
These authors reported the presence of benign
dysplasia at the surgical margin in 57% of
their patients but none of those underwent
subsequent total pancreatectomy; it is
remarkable that only one patient experienced
a recurrence in the remnant gland 66 months
after distal pancreatectomy.
Since IPMNs are usually diffuse or
multicentric within the pancreatic gland, the
surgeon should ask himself if surgical margin
examination is the only factor to be
considered in determining the extent of the
resection.
For this reason, Gigot et al. [28] suggested
intraoperative endoscopic staged biopsies of
the main pancreatic duct as complementary
tools.
Finally, in patients with IPMNs undergoing
pylorus-preserving pancreaticoduodenectomy,
pancreo-gastric anastomosis may be more
indicated than pancreatico-jejunostomy.
Actually, this reconstructive technique allows
direct access to the pancreatic stump by
endoscopy during follow-up.
Chari et al. [25] showed that, in patients with
invasive IPMNs associated with a negative
resection margin, 50% of the recurrences
were identified by CT scan before clinical
symptoms developed. However, surveillance
CT scan is not necessary after total
pancreatectomy for noninvasive tumors,
because this operative approach seems to be
curative.
At the moment, it is unclear whether there is a
role for resection of isolated or distant
metastases in selected patients with
asymptomatic recurrence.
Recurrence after resection of non-invasive
IPMN may occurred because there is residual
dysplastic tissue at the surgical margins, due
to the fact that there is multifocal disease in
the remnant pancreas or because
metachronous lesions develop in the remnant
pancreas as a result of a neoplastic tendency
of the entire gland.
In conclusion, the question “at what point
should we stop the surgical treatment?” is
really difficult. The surgeon has to consider
the possibility of a “wait and see” follow-up
for the patient. When he decides on a surgical
approach, he has to be aware and inform the
patient about the high possibility of being
forced to extend the resection up to a total
pancreatectomy.
In the operating theatre, the aim of reaching a
negative resection margin is, in general a
“balance” between the disease and the patient.
In fact, on the one hand, there is the usual
elderly patient with possible comorbidities,
symptoms and the presence of diabetes; on
the other hand, the disease which usually
involves the head and the uncinate process of
the gland, tends to grow along the duct and be
potentially malignant if carcinoma is not
already present.
Keywords Surgical Procedures, Operative;
Neoplasms, Cystic, Mucinous, and Serous;
Pancreaticoduodenectomy; Pancreatectomy
Abbreviations IPMN: intraductal papillary
mucinous tumor
Correspondence
Roberto Salvia
Dipartimento di Scienze Chirurgiche e
Gastroenterologiche
Università degli Studi di Verona
Policlinico "GB Rossi"
P.le L.A. Scuro, 10
37134 Verona
t
References
1. Ohashi K, Murakami Y, Murayama M, Takekoshi
T, Ohta H, Ohashi I, et al. Four cases of mucus
secreting pancreatic cancer. Prog Dig Endoscopy 1982;
20:348-51.
2. Falconi M, Salvia R, Bassi C, Zamboni G,
Talamini G, Pederzoli P. Clinicopathological features
and treatment of intraductal papillary mucinous tumour

Page 5
JOP. J Pancreas (Online) 2005; 6(1 Suppl.):112-117.
JOP. Journal of the Pancreas – http://www.joplink.net – Vol. 6, No. 1 Supplement – January 2005. [ISSN 1590-8577]
116
of the pancreas. Br J Surg 2001; 88:376-81. [PMID
11260102]
3. Azar C, Van de Stadt J, Rickaert F, Deviere M,
Baize M, Kloppel G, et al. Intraductal papillary
mucinous tumours of the pancreas. Clinical and
therapeutic issues in 32 patients. Gut 1996; 39:457-64.
[PMID 8949654]
4. Kimura W. IHPBA in Tokyo, 2002: surgical
treatment of IPMT vs MCT: a Japanese experience. J
Hepatobiliary Pancreat Surg 2003; 10:156-62. [PMID
14505149]
5. Sohn TA, Yeo CJ, Cameron JL, Hruban RH,
Fukushima N, Campbell KA, Lillemoe KD. Intraductal
papillary mucinous neoplasms of the pancreas: an
updated experience. Ann Surg 2004; 239:788-97.
[PMID 15166958]
6. Salvia R, Fernandez-del Castillo C, Bassi C,
Thayer SP, Falconi M, Mantovani W, et al. Main-duct
intraductal papillary mucinous neoplasms of the
pancreas: clinical predictors of malignancy and long-
term survival following resection. Ann Surg 2004;
239:678-85. [PMID 15082972]
7. Kloeppel G SE, Longnecker DS, Capella C, Sobin
LH. Histological typing of tumours of the esocrine
pancreas. World Health Organization International
Histological Classification of Tumours. 1996;
Berlin:Springer-Verlag.
8. Brat DJ, Lillemoe KD, Yeo CJ, Warfield PB,
Hruban RH. Progression of pancreatic intraductal
neoplasias to infiltrating adenocarcinoma of the
pancreas. Am J Surg Pathol 1998; 22:163-9. [PMID
9500216]
9. Longnecker DS. Observations on the etiology and
pathogenesis of intraductal papillary-mucinous
neoplasms of the pancreas. Hepatogastroenterology
1998; 45:1973-80. [PMID 9951850]
10. Rivera JA, Fernandez-del Castillo C, Pins M,
Compton CC, Lewandrowski KB, Rattner DW,
Warshaw AL. Pancreatic mucinous ductal ectasia and
intraductal papillary neoplasms. A single malignant
clinicopathologic entity. Ann Surg 1997; 225:637-44.
[PMID 9230804]
11. Procacci C. Intraductal papillary mucinous tumors:
imaging. In: Imaging of the Pancreas. Procacci C,
Megibow A, eds. New York. NY, USA: Springer-
Verlag, 2003:97-137. [ISBN 3-540-42742-2]
12. Loftus EV Jr, Olivares-Pakzad BA, Batts KP,
Adkins MC, Stephens DH, Sarr MG, DiMagno EP.
Intraductal papillary-mucinous tumors of the pancreas:
clinicopathologic features, outcome, and nomenclature.
Members of the Pancreas Clinic, and Pancreatic
Surgeons of Mayo Clinic. Gastroenterology 1996;
110:1909-18. [PMID 8964418]
13. Shyr YM, Su CH, Tsay SH, Lui WY. Mucin-
producing neoplasms of the pancreas. Intraductal
papillary and mucinous cystic neoplasms. Ann Surg
1996; 223:141-6. [PMID 8597507]
14. Nakagohri T, Kenmochi T, Kainuma O, Tokoro Y,
Asano T. Intraductal papillary mucinous tumors of the
pancreas. Am J Surg 1999; 178:344-7. [PMID
10587197]
15. Kobari M, Egawa S, Shibuya K, Shimamura H,
Sunamura M, Takeda K, et al. Intraductal papillary
mucinous tumors of the pancreas comprise 2 clinical
subtypes: differences in clinical characteristics and
surgical management. Arch Surg 1999; 134:1131-6.
[PMID 10522860]
16. Terris B, Ponsot P, Paye F, Hammel P, Sauvanet
A, Molas G, et al. Intraductal papillary mucinous
tumors of the pancreas confined to secondary ducts
show less aggressive pathologic features as compared
with those involving the main pancreatic duct. Am J
Surg Pathol 2000; 24:1372-7. [PMID 11023098]
17. Taouli B, Vilgrain V, Vullierme MP, Terris B,
Denys A, Sauvanet A, et al. Intraductal papillary
mucinous tumors of the pancreas: helical CT with
histopathologic correlation. Radiology 2000; 217:757-
64. [PMID 11110940]
18. Wakabayashi T, Kawaura Y, Morimoto H,
Watanabe K, Toya D, Asada Y, et al. Clinical
management of intraductal papillary mucinous tumors
of the pancreas based on imaging findings. Pancreas
2001; 22:370-7. [PMID 11345137]
19. Silas AM, Morrin MM, Raptopoulos V, Keogan
MT. Intraductal papillary mucinous tumors of the
pancreas. AJR Am J Roentgenol 2001; 176:179-85.
[PMID 11133563]
20. Lim JH, Lee G, Oh YL. Radiologic spectrum of
intraductal papillary mucinous tumor of the pancreas.
Radiographics 2001; 21:323-37. [PMID 11259696]
21. Sohn TA, Yeo CJ, Cameron JL, Iacobuzio-
Donahue CA, Hruban RH, Lillemoe KD. Intraductal
papillary mucinous neoplasms of the pancreas: an
increasingly recognized clinicopathologic entity. Ann
Surg 2001; 234:313-21. [PMID 11524584]
22. Traverso LW, Peralta EA, Ryan JA Jr, Kozarek
RA. Intraductal neoplasms of the pancreas. Am J Surg
1998; 175:426-32. [PMID 9600293]
23. Sugiyama M, Atomi Y. Intraductal papillary
mucinous tumors of the pancreas: imaging studies and
treatment strategies. Ann Surg 1998; 228:685-91.
[PMID 9833807]
24. Navarro F, Michel J, Bauret P, Ramos J, Blanc P,
Fabre JM, et al. Management of intraductal papillary
mucinous tumours of the pancreas. Eur J Surg 1999;
165:43-8. [PMID 10069633]

Page 6
JOP. J Pancreas (Online) 2005; 6(1 Suppl.):112-117.
JOP. Journal of the Pancreas – http://www.joplink.net – Vol. 6, No. 1 Supplement – January 2005. [ISSN 1590-8577]
117
25. Chari ST, Yadav D, Smyrk TC, DiMagno EP,
Miller LJ, Raimondo M, et al. Study of recurrence after
surgical resection of intraductal papillary mucinous
neoplasm of the pancreas. Gastroenterology 2002;
123:1500-7. [PMID 12404225]
26. Fernandez-del Castillo C, Warshaw AL. Cystic
tumours of the pancreas. Surg Clin North Am 1995;
75:1001-16. [PMID 7660245]
27. Van de Stadt J, Closset J, Gelin M. Intraductal
papillary mucinous tumors (IPMT). Ann Surg 1999;
230:828-9. [PMID 10615940]
28. Gigot JF, Deprez P, Sempoux C, Descamps C,
Metairie S, Glineur D, Gianello P. Surgical
management of intraductal papillary mucinous tumors
of the pancreas: the role of routine frozen section of the
surgical margin, intraoperative endoscopic staged
biopsies of the Wirsung duct, and pancreaticogastric
anastomosis. Arch Surg 2001; 136:1256-62. [PMID
1169596

There are no products listed under this category.