MEDICAL RADIOLOGY

Diagnostic Imaging
Editors:
A. L. Baert, Leuven
K. Sartor, Heidelberg
Springer
Berlin
Heidelberg
New York
Hong Kong
London
Milan
Paris
Tokyo
c. Procacci . A. J. Megibow (Eds.)

Imaging
of the Pancreas
Cystic and Rare Tumors
With Contributions by
C. Bassi· R. Bettini· C. Biasiutti . G. Bogina . A. Brighenti . P. Capelli· G. Carbognin
L. Casetti . E Cirillo· D. Coser . E. Della Chiara· M. Falconi· M. Ferdeghini . M. Ferrari
E Fornasa . I. R. Francis· I. Frigerio . A. Fuini . A. Guarise . W. Mantovani . G. Martignoni
A. J. Megibow· E. Molinari· T. Oweity· N. Pagnotta· P. Pederzoli· A. Pesci . E. Petrella
C. Procacci· R. Salvia· A. Scarpa· G. Schenal· M. Tapparelli· R.E Thoeni· S. Vasori
S. Venturini· A. B. West· G. Zamboni

Foreword by
A.L. Baert

With 238 Figures in 598 Separate Illustrations, 130 in Color and 17 Tables

' " Springer

CARLO PROCACCI, MD
Professor, Istituto di Radiologia
Dipartimento di Scienze Morfologico-Biomediche
Universita degli Studi di Verona
Policlinico "Giambattista Rossi"
P.zza L.A. Scuro 10
37134 Verona
Italy

ALEC J. MEG !BOW, MD, MPH, FACR

Professor of Radiology
NYU School of Medicine
Department of Radiology
560 First Avenue
New York, NY 10016
USA

MEDICAL RADIOLOGY' Diagnostic Imaging and Radiation Oncology

Series Editors: A. L. Baert . L. W. Brady· H.-P. Heilmann· M. Molls· K. Sartor
Continuation of
Handbuch der medizinischen Radiologie
Encyclopedia of Medical Radiology

ISBN-13978-3-642-63942-5 Springer-Verlag Berlin Heidelberg New York

Library of Congress Cataloging-in-Publication Data

Imaging of the pancreas: cystic and rare tumors / C. Procacci, A. J. Megibow (eds.) ;
with contributions by C. Bassi ... [et al.] ;foreword by A. L. Baert.
p. ; cm. -- (Medical radiology)
Includes bibliographical references and index.
ISBN- 13 978-3-642-63942-5 (alk.paper)
1. Pancreas--Tumors--Imaging. 2. Pancreas--Cysts--Imaging. I. Procacci, C. (Carlo),
1950- II. Megibow, Alec J. III. Bassi, C (Claudio) IV. Series.
[DNLM: 1. Pancreatic Neoplasms--diagnosis. 2. Carcinoma. 3. Diagnostic
Imaging--methods. 4. Pancreatic Neoplasms--pathology. WI 810 131 2003]
RC280.P25 1434 2003
616.99'2370757--dc21 2002026896

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Foreword

The pathology of the pancreas, which was a "hidden" retroperitoneal organ for many years,
can now be marvelously depicted by the modern sectional imaging techniques. As a result
great progress has been achieved during the past decade in the diagnosis and differential
diagnosis of pancreatic tumors.
Among the tumors of the pancreas the so-called rare tumors need to be well known by
radiologists because they pose challenging problems for differential diagnosis and for clini-
cal management. This is particularly true because these tumors are frequently discovered
incidentally.
This volume covers comprehensively all aspects of cystic tumors , intraductal cystic
tumors, endocrine tumors, rare tumors and secondary tumors of the pancreas and features
numerous superb illustrations. It really provides a wealth of information on a relatively less
well known area of the digestive system.
The book has been prepared and edited by two outstanding abdominal radiologists, Alec
Megibow and Carlo Procacci, both widely known internationally for their many brilliant
contributions to the scientific literature on pancreatic imaging. The other contributors come
also from both sides of the Atlantic and were invited to provide chapters because of their
exceptional expertise and experience.
I would like to congratulate the editors and the authors most sincerely for their efforts,
which have resulted in a volume exceptional both in its contents and in its presentation. I am
confident that this outstanding book will meet with great interest not only from general and
abdominal radiologists but also from gastroenterologists and abdominal surgeons. I believe
that it will encounter the same success with readers as previous volumes published in this
series.

Leuven ALBERT 1. BAERT

Preface

The availability and the widespread diffusion of ever more sophisticated radiological instru-
ments has significantly improved radiologists' ability to image pancreatic diseases. Imaging
studies now playa decisive role not only in the diagnosis, but also in the therapy of pancreatic
disorders. However, our improved ability to image diseases has brought new challenges in
understanding the nature and significance of our findings. The technological improvements
require radiologists to update and revise their current imaging techniques and integrate new
information from novel imaging procedures. To attempt to aid this process, we undertook a
project dedicated to pancreatic diseases. At the conclusion of this writing, we expect a four-
volume set encompassing imaging findings in pancreatic diseases.
For the first volume, we purposefully chose cystic and rare tumors of the pancreas. These
tumors are becoming more frequently observed and less well understood. Not surprisingly,
these lesions have been the focus of a burst ofliterature from many sources. Researchers and
physicians are beginning to accept a more uniform classification scheme by which the lesions
can be more accurately compared in terms of their biologic and clinical behavior. This infor-
mation will lead to a more uniform approach to therapy.
Subsequent volumes will focus on pancreatitis, acute and chronic (volume 2); ductal
carcinoma (volume 3); and imaging techniques (volume 4). We chose to place the volume
on techniques at the end of the series so that, at completion, the series will reflect the most
current imaging protocols and procedures.
With this book, we hope to attract the attention not only of radiologists, but also of pathol-
ogists, gastroenterologists and surgeons. In order to meet this goal, a complete description
of the clinical aspects, the therapeutic options and the pathological characteristics of these
tumors precedes all of the imaging chapters. This model integration between the clinical,
pathologic and imaging analyses reflects the collaborations which characterize the New York
University and Verona teams, both of which have been researching pancreatic imaging and
pathology for many years. Furthermore, this book boldly attempts to demonstrate how dif-
ferent authors, working on different continents, achieve consensus and thereby add to the
knowledge of those interested in this pathology.
Presently the second volume, dedicated to inflammatory diseases of the pancreas, is in
preparation.
We would like to thank the Editor-in -Chief, Prof. Albert Baert, for his valuable suggestions,
and Ursula N. Davis of Springer-Verlag for her constant and patient collaboration. We would
also like to sincerely thank all the authors for their extremely hard work in preparing their
contributions.
Last, but certainly not least, special thanks to our families and collaborators for all their
encouragement and support.

Verona CARLO PROCACCI

New York ALEC J. MEGIBOW
Contents

Cystic Tumors ............................................................. .

Clinical Manifestations and Therapeutic Management

CLAUDIO BASSI, ENRICO MOLINARI, MASSIMO FALCONI, and PAOLO PEDERZOLI 3

2 Pathology of Cystic Tumors

GIUSEPPE ZAMBONI, PAOLA CAPELLI, ANNA PESCI, and ANTONIETTA BRIGHENTI .. 9

3 Serous Cystic Tumors

GIOVANNI CARBOGNIN, MARGHERITA TAPPARELLI, ENRICO PETRELLA,
ARNALDO FUINI, and CARLO PROCACCI ..................................... 31

4 Mucinous Cystic Tumors

CARLO BIASIUTTI, FRANCESCA FORNASA, SILVIA VENTURINI,
NICOLETTA PAGNOTTA, GIACOMO SCHENAL, and CARLO PROCACCI 57

Intraductal Cystic Tumors .................................................... 75

5 Clinical Manifestations and Therapeutic Management

ROBERTO SALVIA, MASSIMO FALCONI, LUCA CASETTI, WILLIAM MANTOVANI,
ISABELLA FRIGERIO, and PAOLO PEDERZOLI ................................. 77

6 Pathology of Intraductal Cystic Tumors

GIUSEPPE ZAMBONI, PAOLA CAPELLI, GIACOMO BOGINA, ANNA PESCI,
and ANTONIETTA BRIGHENTI .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85

7 Intraductal Papillary Mucinous Tumors: Imaging

CARLO PROCACCI, GIACOMO SCHENAL, EMILIANO DELLA CHIARA,
ARNALDO FUINI, and ALESSANDRO GUARISE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97

Endocrine Thmors .......................................................... 139

8 Clinical Manifestations and Therapeutic Management

of Hyperfunctioning Endocrine Tumors
FERNANDO CIRILLO, MASSIMO FALCONI, and ROSSELLA BETTINI ............... 141

9 Clinical Manifestations and Therapeutic Management

of Hyperfunctioning Endocrine Tumors
MASSIMO FALCONI, ROSELLA BETTINI, CLAUDIO BASSI, ROBERTO SALVIA,
and PAOLO PEDERZOLI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 153
10 Pathology
PAOLA CAPELLI, GIUSEPPE ZAMBONI,ANNA PESCI, GUIDO MARTIGNONI,
and ALDO SCARPA. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 161

11 Endocrine Hyperfunctioning Tumors

RUEDI F. THOENI ......................................................... 177

12 Nonhyperfunctioning Endocrine Tumors

CARLO PROCACCI, MARCO FERDEGHINI, ALESSANDRO GUARISE, SIMONE VASORI,
DANIELA COSER, and MAURO FERRARI ...................................... 197

Rare Tumors ................................................................ 217

13 Rare Solid Tumors: Clinical Manifestations and Pathology

THAIRA OWElTY and A. BRIAN WEST ....................................... 219

14 Unusual Pancreatic Neoplasms: Imaging

ALEC J. MEGIBOW and ISAAC R. FRANCIS .................................... 249

Secondary Tumors .......................................................... 267

15 Secondary Tumors: Clinical Manifestations and Pathology

THAIRA OWElTY and A. BRIAN WEST ....................................... 269

16 Secondary Pancreatic Tumors: Imaging

ALEC J. MEGIBOW ........................................................ 277

Subject Index ............................................................... 289

List of Contributors .......................................................... 297

Cystic Tumors
1 Clinical Manifestations and Therapeutic Management
C. BASSI, E. MOLINARI, M. FALCONI, and P. PEDERZOLI

CONTENTS prevalence in imaging, led by ultrasound, may be the

main reason for the increased detection of pancreatic
1.1 Introduction 3 cystic tumors (BASSI et al. 2001).
1.2 Clinical Data 3 In this chapter, we shall analyze the clinical and
1.2.1 Clinical History and Lifestyle 3
1.2.2 Symptoms 4
laboratory data presented by patients suffering
1.3 Laboratory 5 from cystic tumors of the pancreas and then go on
1.3.1 Hemo-Chemistry Routine 5 to discuss their prognostic significance and further
1.3.2 Markers 5 management.
1.4 Index of Suspicion from Clinical Data 5
1.5 From Assessment to Management 5
1.5.1 Diagnostic Suspicion 5
1.5.2 Definite Diagnosis 6
1.5.2.1 Operable Patients 6 1.2
1.5.2.2 Inoperable Patients 7 Clinical Data
1.5.2.3 Follow-Up 7
References 7
1.2.1
Clinical History and Lifestyle

The most impressive epidemiological data regarding

1.1
Introduction
Cystic tumors of the pancreas were first observed in
1830 (BECOURT and BECOURT 1830). Even so, there
still remain many unanswered questions as to their
identification, classification, staging, history, and
treatment (TALAMINI et al. 1992). Modern under-
standing of these tumors stems from the work of
CAMPAGNO and OERTEL (1978). These pathologists
first grouped these lesions into mucinous-macro-
cystic and serous-micro cystic type. More recent
classifications are based on the appearance of the
epithelium (KUJPPEL et al. 1996) or as microcystic
and oligocystic variants (LEWANDROWSKI et al. 1992;
EGAWA et al. 1994).
Nowadays, in virtually all but the most remote
countries worldwide, every patient presenting with
abdominal symptoms will undergo ultrasound
imaging due to its wide availability and low cost. The
C. BASSI, MD; E. MOLINARI, MD; M. FALCONI, MD;
P. PEDERZOLI, MD
Surgical-Gastroenterological Department, Hospital 'G .B. Rossi',
University of Verona, 37134 Verona, Italy
peripheral cystic tumors of the pancreas is their nota-
bly more frequent occurrence in women (ratio of 4:
1). In fact, in our series of serous cystic tumors (SCT),
87% are women (BASSI et al. 2002), while almost all
peripheral mucinous cystic tumors (MCT), benign
or malignant, are found in women (ZAMBONI et al.
1999; PEDERZOLI et al. 2000). Frequently, peripheral
mucinous tumors display ovarian-like stroma in the
rim of the lesion at histology. The presence of ovar-
ian-like stroma is thought to represent a common
pathway between the pancreatic peripheral muci-
nous tumor and its counterpart in the hepatobiliary
system, ovary, and retroperitoneum (ZAMBONI et al.
1999). However, there are no epidemiological data
available that might suggest any correlation in this
sense between the tumor's appearance, menarche,
irregular menstruation, pregnancy, estro-progesto-
gen treatment, etc. The female predilection is not
true for intraductal papillary mucinous tumor.
The patient age range is very large, with an aver-
age age which seems to vary depending on the type
and malignancy of the neoplasm. The average age for
serous forms is around 50 years, while the mucinous
variant mainly affects patients in their 60s. Patients
presenting with malignant mucinous tumors tend to
4 C. Bassi et al.
be older, suggesting the possible progression of the
tumor over time from initial benignity to variable
degrees of malignancy (BASSI et al. 2001; TALAMINI
et al. 1992; ZAMBONI et al. 1999; PEDERZOLI et al.
2000; LE BORGNE 1998; YANG et al. 1994; WARSHAW
et al. 1990).
Serous cysts are reported to be associated
with other neoplasms and chronic diseases; how-
ever, the only established association is with von
Hippel-Lindau disease (PYKE et al. 1992). A review
of 55 patients with von Hippel-Lindau disease
shows the presence of serous pancreatic cysts in
15% (NEUMANN et al. 1991). The diagnosis of von
Hippel-Lindau disease must always be considered
when multiple pancreatic cysts are found in an
asymptomatic patient without clinical suspicion of
pancreatitis. Imaging and clinical evaluation of the
central nervous system, eyeball, kidneys, adrenal
gland, and epididymis should be incorporated into
the work-up (GIRELLI et al. 1997). The presence of
symptoms related to the larger pancreatic lesions will
require a careful evaluation of the type of treatment,
with particular attention given to the most conserva-
tive attitude, which will be dealt with in more detail
later (BASSI et al. 2002). Lastly, the mainly autosomal
hereditary nature of the syndrome will require an
accurate report of the family case history data and
genetic screening of the patient's relatives, on the
basis of which method and time for follow-up can be
planned so as to make an early diagnosis, especially
of renal neoplasm which is, at the moment, the main
risk and mortality factor in these patients.
1.2.2
Symptoms
The most common clinical complaint is some degree
of abdominal pain or discomfort. Other frequent
symptoms are weight loss, palpable mass, post-
prandial fullness, nausea, and vomiting. Onset with
jaundice, acute pancreatitis, or bleeding is rare. Lastly,
the percentage of patients discovered incidentally is
constantly increasing.
In truth, both symptomatic cases and the percent-
age of incidental findings appear to vary depending
on the benign or malignant nature of the tumor.
In two American series (WARSHAW et al. 1990;
PYKE et al. 1992),40% and one-third of all patients,
respectively, were asymptomatic, but when study-
ing the mucinous and the serous tumors separately,
the percentage increases to 50% in the former and
decreases to 20% in the latter. Malignant mucinous
tumors are more frequently symptomatic (dyspep-
sia, pain, weight loss, and jaundice) compared with
their benign counterparts. Tables 1.1 and 1.2 show
the symptoms reported in a series of 85 patients
undergoing surgical resection of serous (n=44) or
mucinous (n=41) cystic pancreatic tumors (BASSI et
al. 2001,2002).
Considering all the tumors surgically or medically
treated, 46% of patients were asymptomatic: 56%
serous tumor and 28% mucinous tumor. In the latter,
symptoms referable to the malignant behavior of the
tumor (anorexia and weight loss) were more fre-
quent, especially in mucinous cystadenocarcinoma
(Table 1.3).
The precise pathophysiological basis for an individ-
ual patient's complaint is almost impossible because
the symptoms are so nonspecific. Even when present,
the clinical symptoms often do not warrant immediate
concern; therefore, it is not uncommon that, in retro-
spect, the onset of symptoms occurred years (about a
year and a half in the case of serous tumors) before
the diagnosis (TALAMINI et al. 1992; YANG et al. 1994;
WARSHAW et al. 1990; BASSI et al. 2002).
The most common symptom is abdominal pain,
but in reality, only about 35% of patients suffer-
ing from symptomatic serous and mucinous cystic
Table 1.1. Symptoms of patients affected with serous cystic
tumors of the pancreas, surgically treated (n=44)
Paina 33 (75%)
Anorexia and dyspepsia 7 (15.9%)
Weight loss and dyspepsia 6 (13.6%)
Obstruction of upper GI tractb 3 (6.8%)
a Five patients (11.3%) suffered from pain associated with
dyspepsia
b One case with associated jaundice
Table 1.2. Symptoms in patients with mucinous cystic tumors
of the pancreas, surgically treated (n=41)
Pain 41 (lOO%)
Weight loss and dyspepsia 14 (34%)
Anorexia and dyspepsia 3 (7.3%)
Jaundice 1 (2.5%)
Table 1.3. Symptoms of patients with mucinous cystadenocar-
cinoma, surgically treated (n=40)
Pain 22 (55%)
Weight loss and dyspepsia 25 (62.5%)
Anorexia and dyspepsia 21 (52.5%)
Jaundice 5 (12.5%)
Clinical Manifestations and Therapeutic Management
tumors experience a pain complex (such as radia-
tion to the flanks) which would suggest a possible
pancreatic etiology (BASSI et al. 2002; EGAWA et al.
1994). Moreover, the clinical picture does not always
correlate to the location and dimension of the neo-
plasia. Therefore, the presence of 'pancreatic-type
pain' is associated with a negative prognosis. Many
patients presenting with radiating pain will prove to
have invasive cystadenocarcinoma infiltrating the
retroperitoneum. When such pain is accompanied by
symptoms like weight loss, anorexia, and jaundice, it
is obvious why the suspicion of malignancy becomes
necessarily high.
1.3
Laboratory
1.3.1
Hemo-Chemistry Routine
Routine laboratory tests are only helpful in the work-
up and staging of pancreatic cystic neoplasia in terms
of further confirmation of the advanced stages of
malignant pathologies which have generally already
been clinically and radiologically documented. Dia-
betes is not thought to have a prognostic significance
in peripheral tumors.
1.3.2
Markers
Unfortunately, serous tumor markers are neither
diagnostic nor indicative of the biological behav-
ior of the lesion. However, aspiration of the fluid
content of the cyst may provide significant informa-
tion (LEWANDROWSKI et al. 1993, 1995; GUPTA and
ALANSARI 1994). To gather these data and plan the
surgical treatment, it is necessary to perform a fine
needle aspiration biopsy (FNAB) to evaluate the
chemical nature of the cyst content and to elucidate
the presence of dysplastic or neoplastic cells. The
question is whether this approach is justifiable in all
cases of pancreatic cystic lesions or whether it should
only be performed on patients selected on the basis
of the lesion's clinical and radiological characteristics
(see Section 1.5.1 Diagnostic Suspicion).
The absolute concentrations of serum markers
found within the fluid content of cystic masses is
variable (Ca 19-9, CEA, Ca 125). The presence of
newer markers, such as CA 72-4, may offer greater
5
predictive value in discriminating between benign
or malignant cystic masses. When the cyst content
displays elevated Ca 19-9 and/or CEA levels and an
elevated CA 72-4, the lesion should be assumed to
be a malignant neoplasm and resected if possible
(HAMMEL et al. 1998; SPERTI et al. 1996). However, at
least at the time of this writing, the presence and value
of intracystic tumor markers should be considered in
the context of the patient's clinical presentation and
results of radiological studies (SAND et al. 1996).
It is hoped that molecular findings will further
improve specificity, but this is still in the experimen-
tal stages.
1.4
Index of Suspicion from Clinical Data
By what has been previously stated, it is evident how
the index of suspicion for pancreatic cystic tumor is
severely limited based on available clinical and labo-
ratory data. Only with imaging correlation can the
pancreas be implicated as the source of the patient's
complaint.
Only in very particular cases, such as an already
diagnosed von Hippel-Lindau syndrome associated
with specific pancreatic symptoms, can a suspicion
of pancreas-related disease be suggested from the
clinical findings alone.
The appearance of specific pancreatic symptoms
associated with neoplastic marker positiveness, like
Ca 19-9, as can be determined in the case of invasive
and/or metastatic cystadenocarcinoma, more easily
leads to the suspicion of the more common advanced
ductal adenocarcinoma. Thus, without the help of
imaging, every suspicion of a cystic tumor cannot
reasonably be assumed.
1.5
From Assessment to Management
1.5.1
Diagnostic Suspicion
Although there are rare exceptions, SCTs almost always
demonstrate a benign biological and clinical course
(GEORGE et al. 1989; KAMEl et aI. 1991; YOSHIMI et al.
1992;ABE et aI. 1998; WIDMAIER et al.1996).Mucinous
tumors are either already malignant at diagnosis or
will degenerate in time (BASSI et al. 2001).
6 C. Bassi et al.
Diagnosis of tumor type is predominantly based
on the radiological findings since, as discussed
above, the lack of specificity of the clinical picture is
not helpful. The discovery by imaging, usually ultra-
sound, of a finding that could suggest a large cystic
lesion in the pancreatic area is frequently the starting
point. The patient should therefore be investigated in
greater detail as regards the case history, clinical and
morphological data to indicate which of the different
radiological examinations should be carried out (CT,
MR, MRCP, and ERCP).
Another possible step is an image-guided FNAB
either with ultrasound or CT guidance. In our opin-
ion, this procedure should not be carried out as a
matter of routine for all cases of cystic pancreatic
lesions, but only in selected patients. Information
gained from cytologic analysis of the cyst's content
can undoubtedly be invaluable when positive. The
inability to confirm malignancy cytologically does
not rule out its presence, and further investigations
are necessary. Another aspect arguing against the
generalized use of FNAB is the aforementioned
lack of diagnostic reliability of serum markers. The
procedure is best used for the detection of elevated
isoamylase levels in distinguishing a pancreatitis-
related fluid collection from a cystic neoplasm.
Neither the intracystic Ca 19-9 nor CEA is of any
help in distinguishing between serous and mucinous
cystadenomas (LEWANDROWSKI et al. 1993, 1995;
GUPTA and ALANSARI 1994). The appearance of the
aspirate - fluid and transparent on the one hand,
and dense, streaky, and/or hemorrhagic on the other
- clearly distinguishes between the serous and muci-
nous forms. In the latter, a high concentration of Ca
19-9 and CEA is indicative of possible malignancy,
making it appears that these findings, associated
with a high viscosity and a reliable cytologic result,
represent a definite final diagnosis of the disease.
This procedure seems to be applicable in those
patients whose radiological data suggest the suspi-
cion of a mucinous form when they are not suitable
for surgical resection due to their clinical condition.
It is better to proceed with the operation on the other
patients, bearing in mind the absolute necessity of
giving the pathologist the entire lesion so that a
complete analysis of the epithelium of the internal
covering of the cyst can be carried out. On the one
hand, the intracavity pressure can strip whole areas,
making them unsuitable for a reliable diagnosis, and
on the other, there is the possibility that the malig-
nant degeneration has a focal character, thus sparing
extensive areas of epithelium.
1.5.2
Definite Diagnosis
Generally speaking, the biological behavior of cystic
tumors of the pancreas leaves little room for the
conservative management, making three progres-
sive steps in their work-up and staging mandatory:
confirmation of the intraglandular origin of the
neoplasia; exclusion of an inflammatory cause, i.e.,
pseudocyst; identification of a surgical indication for
actual or potential malignancy (LE BORGNE 1998).
This last concept could be better expressed as the
correct identification of clearly benign serous tumors
and, therefore, the only clear indication for conserva-
tive management (BASSI et al. 2001). If it cannot be
identified with absolute certainty in the diagnostic
work-up, laparotomy is the next inevitable step
even for serous tumors discovered casually during
the course of a definitive and complete histological
diagnosis. Resection, moreover, represents the only
therapy possible in symptomatic cases except when
the risk of resection is unacceptable, and a digestive
bypass is performed to decompress the cyst (TALA-
MINI et al. 1992; YANG et al. 1994; GRIESHOP et al.
1994).
1.5.2.1
Operable Patients
Suspected or established malignancy, persistent
symptomatology, and diagnostic confirmation rep-
resent the principal surgical indications. The serial
demonstration by imaging of volumetric growth of
asymptomatic serous forms could be added (BASSI
et al. 2001; GRIESHOP et al. 1994; LE BORGNE 1998;
PYKE et al. 1992; TALAMINI et al. 1992; WARSHAW et
al. 1990).
Once an indication has been established, the sur-
gical approach will be based on the site and nature
of the lesion. In patients with suspect, potential, and
clear malignancy, the standard rules of oncology
with resections from the left or widened pancreato-
duodenectomies together with a lymphadenectomy
are followed (LE BORGNE 1998; PYKE et al. 1992;
PEDERZOLI et al. 2000).
In the possibly benign forms, particularly in
young patients, more conservative approaches to the
pancreatic parenchyma are also possible, for example
intermediate resection and cephalic resection pre-
serving the duodenum; laparoscopic resection is also
possible for small (diameter less than 4 cm) lesions of
the tail (PEDERZOLI et al. 2000).
Clinical Manifestations and Therapeutic Management
1.5.2.2
Inoperable Patients
Concerning the symptomatic tumors, the patient
who cannot be operated on due to the local diffu-
sion of the disease or co-morbidity could undergo
digestive or biliary bypass. When tumors of any
nature appear clinically with obstructive symptoms,
whether digestive or biliary, and are not suitable for
traditional surgical correction, the endoscopic or
radiological alternatives commonly carried out in
nonresectable cases of ductal adenocarcinoma will
be opted for.
It is also compulsory with these patients to per-
form a cytology by aspiration of the primitive lesion
or, if in stage IV, of the hepatic metastases, especially
when a neo-adjuvant therapy is possible.
1.5.2.3
Follow-Up
The vast majority of patients undergoing radical
resection for cystic tumors report relief of symptoms
in the postoperative period.
As far as the mucinous forms are concerned, to
obtain long-term survival, a distinction must be
made between the invasive and noninvasive types.
The former, with peri tumoral infiltration outside
the cystic wall, has a survival rate of 5 years like that
of ductal pancreatic carcinoma, for less than 20% of
patients. Some 40% of patients with only cystic wall
invasion are still alive after 5 years, while all those
who underwent radical surgical resection, with or
without focal malignancy but only at the intratu-
moral level, are alive and well (ZAMBONI et al. 1999).
These considerations once again suggest how the
management of cystic lesions of the pancreas must
take on a totally aggressive attitude as the only guar-
antee of radical curative treatment in a large percent-
age of patients. It is obvious that given the difficult
staging and the risky treatment in terms of surgical
morbidity and mortality, it is better that such an
approach be performed only in specialized centers
with a vast amount of reference volumes of activity.
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Egawa N, Maillet B, Schroder S, Mukai K, Kloppel G (1994)
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Kloppel G, Solcia E, Longnecker DS, Capella C, Sobin LH (1996)
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2 Pathology of Cystic Tumors
G. ZAMBONI, P. CAPELLI, A. PEsel, and A. BRIGHENTI

CONTENTS techniques, such as ultrasonography (US) and com-

puted tom6graphy (CT). They have been encountered
2.1 Introduction 9
in 1.4% of all abdominal CT scans (PARIENTY et al.
2.2 Serous Cystadenomas 10
2.2.1 Macroscopy 10 1980), in 10% of all pancreatic cysts (HODGKINSON
2.2.2 Microscopy 11 et al. 1978; WARSHAW et al. 1990) and in 1%-7.1% of
2.2.3 Differential Diagnosis 12 all pancreatic neoplasms (CUBILLA and FITZGERALD
2.2.4 Treatment and Outcome 14 1984; MOROHOSHI et al. 1983).
2.3 Mucinous Cystic Neoplasms 14
Although all pancreatic neoplasia, including
2.3.1 Macroscopy 15
2.3.2 Microscopy 16 ductal adenocarcinoma, may clinically appear as a
2.3.3 Pathogenesis --17 cystic lesion due to degenerative changes in a solid
2.3.4 Differential Diagnosis 18 tumor (ADSAY et al. 2000b), the most typical cystic
2.3.5 Treatment and Outcome 19 neoplasms of the pancreas are cysts lined by differ-
2.4 Solid Pseudopapillary Tumor 20
ent epithelium. Two decades ago, the classification of
2.5 Acinar Cell Cystic Tumors 23
2.5.1 Acinar Cell Cystadenoma 23 cystic tumors of the pancreas seemed straightforward,
2.5.2 Acinar Cell Cystadenocarcinoma 24 and two lesions were distinguishable: micro cystic or
2.6 Other Cystic Tumors 25 glycogen-rich adenomas (also called serous cystic),
References 25 with an excellent prognosis and only minimal risk
of malignant transformation, and mucinous cystic
neoplasms (MCNs), which encompass a broad spec-
trum of morphological changes and showed 'overt' or
2.1 'latent' malignancy (COMPAGNO and OERTEL 1978b;
I ntrod uction COMPAGNO et al. 1979; GIBSON and SOBIN 1978).
It must be stressed that the main diagnostic cri-
The category of cystic lesions of the pancreas includes terion is the morphology of the epithelium, whereas
cystic formations of differing morphology, pathogen- the shape and volume of cysts are of no importance
esis, and biology. Although these lesions are uncom- (KU'lPPEL et aL 1996). The spectrum of pancreatic
mon compared with solid tumors of the pancreas, tumors with cystic features is broad and includes
they constitute an important group of lesions with serous micro cystic or oligocystic (macro cystic ) tumor
distinctive clinical and pathological features. The (COMPAGNO and OERTEL 1978a; EGAWA et al. 1994;
therapeutic approach and the prognosis differ sub- LEWANDROWSKI et al. 1992), MCNs (SOLCIA et al.
stantially, depending on the specific diagnosis (ADSAY 1997; ZAMBONI et al. 2000), acinar cell cystadenoma
et al. 2000b). An incorrect diagnosis may therefore (ZAMBONI et al. 2002), acinar cell cystadenocarci-
result in inappropriate therapy, leading for instance noma (CANTRELL et al. 1981; STAMM et al. 1987},solid
to incomplete removal of a tumor that requires total pseudopapillary tumor with cystic degeneration (i.e.,
resection to prevent malignant degeneration (SACHS et solid cystic tumor) (KU'lPPEL et al. 1991; MATSUNOU
al. 1989; WARSHAW and RUTLEDGE 1987). The current et al. 1990), and endocrine tumor with cystic degen-
interest in identifying cystic pancreatic lesions arises eration (IACONO et al. 1992). Nonneoplastic cysts,
from their easier recognition with modern imaging such as congenital cysts (KLOPPEL 2000), single true
cysts (HOWARD 1989), lymphoepithelial cysts (ADSAY
et al. 2000), enterogenous cysts (PILCHER et al. 1982),
G. ZAMBONI, MD; P. CAPELLI, MD; A. PEsel, MD;
A. BRIGHENTI, MD and endometrial cysts (MARCHEVSKY et al. 1984), are
Department of Pathology, University of Verona, Strada Le extremely rare, but an exact estimation of their true
Grazie 8,37134 Verona, Italy prevalence is so far not available.
10
The World Health Organization (WHO) clas-
sification of exocrine pancreatic tumors (KU)PPEL
et al. 1996) is used in this chapter to classify cystic
neoplasms. It divides neoplasms on the basis of their
histological type and biological behavior into benign
tumors, borderline tumors, and malignant tumors.
2.2
Serous Cystadenomas
Serous cystadenomas are cystic tumors formed by
glycogen-rich, periodic acid-Schiff (PAS)-positive
epithelial cells which produce serous fluid. They have
frequently been reported as micro cystic or glycogen-
rich cystadenomas. They differ from the mucinous
neoplasms of the pancreas, both MCNs and intra-
ductal papillary mucinous neoplasms (IPMNs),
which are potentially or overtly malignant. The
absence of atypia and the indolent course are the two
most important characteristics of this tumor. Serous
tumors are classified in the WHO classification into
serous cystadenoma (SCA), the vast majority of cases
being clearly benign, and serous cystadenocarcinoma
(SCAC), with only a few reported cases. SCAs are sub-
classified according to the macroscopic variation of
the cysts into serous micro cystic adenoma and serous
oligocystic or macro cystic adenoma.
SCAs, which account for 1%-2% of all exocrine
neoplasms, occur more often in women at an aver-
age age of 66 years (KU:>PPEL et al. 1996). About one-
third of patients are asymptomatic, and the tumors
are discovered incidentally. Two-thirds of patients
complain of symptoms related to local mass effects,
such as abdominal pain, nausea, and vomiting; in
some cases, the mass can be palpable.
Clinically, they can be sporadic or associated
with von Hippel-Lindau syndrome (VHL). Pancre-
atic involvement is frequent in VHL, occurring in
60%-80% of patients. In these patients, the pancreatic
lesions are diffuse or multifocal (HORTON et al. 1976)
and frequently associated with cysts in other organs
(liver, lung, kidney, spleen, epididymis) (GIRELLI et al.
1997). There is genetic evidence supporting the role of
the VHL gene, located at chromosome 3p25.5, in SCA
tumorigenesis, in both VHL-associated and sporadic
pancreatic SCAs (VORTMEYER et al. 1997). In a study
by our group (MOORE et al. 2001), we demonstrated
the involvement of chromosomal arms 3p in 40% of
our SCAs and VHL gene involvement in a subset of
sporadic cases. Loss of chromosome lOq was the most
frequent event in SCAs (50% of patients). No muta-
G. Zamboni et al.
tions were found in either K-ras or p53. No patient
showed micro satellite instability of the type seen in
mismatch repair-deficient tumors.
SCAs may coexist either with other pancreatic
tumors or with extrapancreatic neoplasms. In the
pancreas, SCAs were found to be associated with
both ductal adenocarcinoma (MONTAG et al. 1990)
and endocrine tumor (KEEL et al. 1996).
A precise histogenesis has not been established.
Ultrastructural analogies with normal pancreatic
centro acinar cells have been demonstrated (LAITIO
et al. 1974), as well as the presence of abundant intra-
cytoplasmic glycogen in fetal centro acinar cells, which
is almost absent in normal adult centroacinar cells
(LAITIO et al. 1974).
SCAs in our series represent 2% of all pancreatic
tumors and 44% of cystic tumors. We observed a
marked female predominance and a mean age (57
years) which was higher than that of benign MCNs
(47 years) and almost identical to that of malignant
MCNs (55 years). Topographically, the body-tail
location was similar in frequency to the pancreatic
head. Two patients had diffuse pancreatic multi cystic
lesions associated with VHL syndrome. None of the
lesions in our 61 patients exhibited malignant behav-
ior; nevertheless, a diffuse involvement of the entire
pancreas was observed later in 3 patients. One patient
died of concomitant pancreatic ductal carcinoma.
2.2.1
Macroscopy
SCAs frequently appear as a well-circumscribed,
round, cystic mass filled with clear watery fluid and
with bulging edges (Fig. 2.1). The lesions range in
Fig. 2.1. Serous cystadenoma. Cut section showing a well-cir-
cumscribed, round mass with bulging edges
Pathology of Cystic Tumors 11

diameter from 1 to 25 cm (average 6-11 cm). This

broad size range encompasses large lesions which
are often symptomatic and small lesions incidentally
found in pancreas resected for other reasons or dis-
covered during radiological study for unrelated prob-
lems. They are usually single, but in some cases they
can be multifocal or characterized by contiguous and
confluent tumors, which can rarely extend to involve
the entire parenchyma. seAs show no communication
with the pancreatic ducts.
Macroscopically, they are subdivided according to
the number and dimensions of the individuallocules
into two subtypes: micro cystic and macro cystic.
a

1. Microcystic or classic type (KU)PPEL et al. 1996):

The tumors appear as relatively well-circumscribed
lesions with multilobular margins. On cut section,
they are sponge-like, formed by innumerable cysts
which range from 1 to 5 mm in diameter, larger ones
(up to 1-2 cm) being rarer and frequentlyperipher-
ally located. The cysts are filled with a clear, watery
fluid. Typically, they have a central stellate scar made
up of white, fibrous nodules with peripheral fibrous
bands (Fig. 2.2). The scar frequently shows calcium
deposits, the pathological basis of the typical 'sun-
burst' pattern of calcification seen on radiological
studies. In our series of 61 patients, the microcystic
b
variant was seen in the large majority of cases (38
patients, 64%); 31 patients were women and 7 men, Fig. 2.2a,b. Serous cystadenoma, micro cystic type. a Gross
with an average age of 61 years. appearance showing a well-circumscribed tumor made up
of innumerable small cysts, with central scar and peripheral
fibrous bands. b Whole-mount macrosections showing the
2. Macrocystic or oligo cystic type (EGAWA et al. 1994; small cysts and the central fibrous scar
LEWANDROWSKI et al. 1992): These tumors, charac-
terized by a small number oflocules, are less demar-
cated than the micro cystic variant due to the pres- The macro cystic subtype, which frequently contains
ence of cysts extending into the adjacent pancreatic hemorrhagic fluid and calcifications, is seldom dif-
parenchyma. The cyst fluid may vary from classic ferentiated preoperatively from either pseudocyst or
clear and watery to bloody and brown. The cut sur- mucinous cystic tumors and may occasionally be con-
face shows the presence of a countable number of fused with these entities microscopically (LEWAND-
cysts (oligocystic: Fig. 2.3a) or sometimes a single ROWSKI et al. 1992). The final pathological diagnosis
cyst (unilocular: Fig. 2.3b) with a variable diameter may necessitate extensive sampling of the cyst wall,
of 2-15 cm. The oligo cystic variant characteristically because epithelial denudation occurs frequently. The
lacks a central scar and usually has ill-defined tumor correct diagnosis of macro cystic serous adenoma is of
growth, whereas the multilocular variant may show the utmost importance, since surgical resection may
a central scar (Fig. 2.3c). In our series, 21 patients not be necessary in patients at high surgical risk.
(36%) had unilocular or multilocular macro cysts,
ranging in dimension from 2 to 7 cm. This subtype
was far more common in women (20 women and 1 2.2.2
man); the average age was 50 years. Fourteen lesions Microscopy
could be considered 'pure', whereas 7 had a mixture
of micro- and macrolocules. The patients with 'pure' Microscopically, the micro cystic and macro cystic
macro cystic types were younger than those with the types are indistinguishable and show the typical
'mixed' types: 43 vs 51 years. cuboidal to almost flat serous epithelium charac-
 12 G. Zamboni et al.

terized by clear cytoplasm and round nuclei with

inconspicuous nucleoli. Neither cytologic atypia
nor mitotic activity is found in either type. Intra-
cellular glycogen is characteristic of this neoplasm
(diastase-sensitive PAS-positive deposits) (Fig. 2.4).
Intracellular mucins are not present. Occasional
cases may show the presence of intracystic tufting
of the epithelium with the formation of true papil-
lae (Fig. 2.5). In some cases and in focal areas, the
cytoplasm may be eosinophilic and granular. The
neoplastic stroma is highly vascular, creating a fine
supporting network. The septa separating the larger
cysts are hyalinized and contain hemosiderin-laden
macrophages and sometimes entrapped islets of
Langerhans and exocrine acini. Central fibrous scar
formed by hyalinized tissue is present in the major-
ity of micro cystic types, frequently associated with
calcification. Although the micro cystic variant is
usually more sharply demarcated, both types lack a
well-formed fibrous pseudocapsule.
Serous adenomas with identical cytological fea-
tures and immunohistochemical profile without cystic
locules and characterized by an exclusively solid pat-
tern of growth are reported as solid serous adenomas
(PEREZ-ORDONEZ et al. 1996; COMPTON 2000) (Fig.2.6).
They are usually small lesions, measuring 2-4 cm at
the most and are made up of small acini lined by typi-
cal serous cells.
b

c
Fig. 2.3a-c. Serous cystadenoma, oligo cystic or macrocystic
type. Whole-mount macrosections showing an ill-defined
lesion made up of a few large cysts extending into the pan-
creatic parenchyma (a), unilocular lesion with a thick fibrous
pseudo capsule (b), and multilocular tumor with central fibrous
scar adjacent to the duct of Wirsung (c)

Fig. 2.4a,b. Serous cystadenoma. Typical histological appear-

ance of lining epithelium, composed of cuboidal cells with
clear cytoplasm (a), filled with PAS-positive glycogen (b) b
Pathology of Cystic Tumors 13

honeycomb appearance, is almost always correctly

identified at preoperative imaging. In these cases,
the pathologist is asked to confirm a radiologic
diagnosis. Serous micro cystic adenoma has to be
differentiated from solid-pseudopapillary tumor of
the pancreas (ZAMBONI et al. 1993), from endocrine
tumor with clear cells, and from metastatic clear-cell
carcinoma of the kidney. An interesting differential
diagnosis is with a clear-cell 'sugar' tumor of the
pancreas (ZAMBONI et al. 1996), an extremely rare
tumor belonging to the family of lesions character-
ized by the presence of perivascular epithelioid cells
(PEC) and described in mUltiple organs and sites
Fig. 2.5. Serous cystadenoma. Small intracystic papillary
(PEA et al. 1991, 1996; BONETTI et al. 1992, 1994).
structures
The latter is characteristically HMB45-positive and
cytokeratin -negative.
The preoperative radiological differential diagno-
sis of the macro cystic or oligo cystic variant of serous
adenoma with pseudo cysts and mucinous cystic
neoplasms is at the moment extremely difficult. In
fact, these two lesions frequently appear as either
oligo cystic or unilocular cysts.
Fine needle aspiration biopsy under ultrasound
guidance for cytological and biochemical analysis
may help in the differential diagnosis (YOUNG et al.
1991). The cytological smears are characterized by
sparse cellularity in a background devoid of debris
and, most importantly, of mucus. The neoplastic
cells, individually dispersed or rarely aggregated in
a flat sheet with a honeycomb pattern, have a mono-
Fig. 2.6. Serous cystadenoma, solid type. Whole-mount macro- morphic appearance with poorly defined cytoplasm
section showing a small lesion, measuring 2 cm at its largest, and small, round, oval nuclei. PAS staining performed
made up of small, packed acini with and without diastase shows abundant cytoplas-
mic glycogen and the absence of mucins. Frequently,
histiocytes and hemosiderin-laden macrophages are
Immunohistochemically, the epithelium shows present. Immunohistochemical staining for cyto-
diffuse cytoplasmic staining for low-molecular- keratin and antimacrophage markers can help in
weight cytokeratins (CK 7,8, 18 and 19) and diffuse the diagnosis (Fig. 2.7). The sensitivity of cytologi-
membrane staining using antibodies against epithe- cal examination is only about 50%-60% because of
lial membrane antigen (EMA) (SOLCIA et al. 1997; inadequate sampling, with an absence of diagnostic
ALPERT et al. 1988; ALBORES-SAAVEDRA et al. 1990). epithelial components or poor cellular preserva-
The neoplastic cells may focally express CA 19-9 and tion (CARLSON et al. 1998; CENTENO et al. 1994;
B72.3 (ISHIKAWA et al. 1998) but are CEA-negative LAUCIRICA et al. 1992).
(SOLCIA et al. 1997). Endocrine and acinar cell dif- The biochemical and immunological analysis of
ferentiation is not found (SOLCIA et al. 1997). the cystic fluid may assist in the differential diag-
nosis with mucinous tumors and pseudo cysts. The
cystic fluid of serous adenoma does not have the
2.2.3 high levels of either enzymes (amylase and lipase)
Differential Diagnosis or tumor markers (CEA, CA 19.9, CA 125) observed
in pseudo cysts and mucinous tumors, respectively
The differential diagnosis of SCAs differs according (LEWANDROWSKI et al. 1993; COMPTON 2000).
to the two morphological subtypes. The microcys- The pathological differential diagnosis with
tic variant, which has a typical macroscopic solid lymphangiomas is quite easy morphologically due to
 14
a b
Fig.2.7a,b. Serous cystadenoma. a Fine needle aspiration biopsy specimen showing sparse cellularity with epithelial-like cells mixed
with macrophages with foamy cytoplasm; b immunohistochemical stain for cytokeratins 8, 18, 19 in the neoplastic cells
the presence of flat cells lacking glycogen and immu-
noreactivity for factor VIII and cytokeratins (SOLCIA
et al. 1997).
2.2.4
Treatment and Outcome
Surgical resection is only necessary when the
tumors are symptomatic and the benefits of the
operation outweigh the risk (SOLCIA et al. 1997) or
to prevent the development of complications such
as erosion into adjacent organs, hemorrhage, and
biliary and gastrointestinal obstruction. Resection
may be contraindicated in elderly or asymptomatic
patients, and follow-up examination can be accept-
able (COMPAGNO and OERTEL 1978a; WARSHAW et al.
1990; HODGKINSON et al. 1978).
The prognosis of both microcystic and macrocys-
tic types of serous cystadenoma is excellent. How-
ever, there are rare exceptions in which there is local
destructive growth with progressive involvement of
the entire pancreas and the slight risk of malignant
transformation. In a recent review of SCAC of the pan-
creas' Compton found 11 reported cases (COMPTON
2000). However, the interpretation of these neoplasms
as malignant is not so clear. In fact, they show the
features of aggressive growth with perineural and
perivascular invasion, involvement of regional lymph
nodes and adjacent organs, such as the stomach and
liver. Surgical resection in all cases proved to be cura-
tive, however; not one patient died of disease (GEORGE
et al. 1989; ABE et al. 1998; KAMEl et al. 1992; OHTA
et al. 1993; YOSHIMI et al. 1992; ZIRINSKY et al. 1984;
FRIEDMAN 1990; WIDMAIER et al. 1996; ALPERT et al.
1988; FUJII et al. 1998; COMPTON 2000).
G. Zamboni et al.
2.3
Mucinous Cystic Neoplasms
These cystic tumors, occurring almost exclusively
in women, are formed of epithelial cells producing
mucin, supported by ovarian-type stroma, showing
no communication with the pancreatic ductal system
(Fig. 2.8). According to the grade of epithelial dys-
plasia, they may be classified into adenoma, border-
line tumor, and carcinoma, noninvasive or invasive
(KU:'>PPEL et al. 1996; ZAMBONI et al. 2000).
In 1978, Compagno and Oertel (COMPAGNO and
OERTEL 1978b) reported their experience with 41
patients with MCN. They defined these tumors as
cystic masses containing mucin-producing colum-
nar epithelium supported by 'ovarian-like stroma'
and emphasized that all MCNs of the pancreas must
be considered and treated as potentially malignant,
regardless of their epithelial differentiation. They
therefore discouraged the use of the terms 'cyst-
adenoma' and 'cystadenocarcinoma' and instead
proposed the term 'mucinous cystic neoplasm with
overt or latent malignancy'. Although their work
resulted in the appropriate therapy for MCNs, i.e.,
complete resection instead of a drainage procedure,
it prevented a more individualized approach to the
tumors, such as that developed for MCN s of the ovary
(RUTGERS and SCULLY 1988; BOSTWICK et al. 1986).
However, a cystic structure and the presence of
mucin-secreting epithelium are not sufficient to clas-
sify a neoplasm as an MCN (COMPAGNO and OERTEL
1978b; FURUKAWA et al. 1992; YAMADA et al. 1991),
because IPMNs with duct ectasia and mucin hyper-
secretion (YAMADA et al. 1991; RICKAERT et al. 1991)
also show these features. While most cystic tumors
are easily differentiated from each other, distinguish-
 Pathology of Cystic Tumors
a b
Fig.2.8a,b. Mucinous cystic tumor. A round cystic lesion in the tail of the pancreas. The pancreatic duct, which does not com-
municate with the cyst lumen, has been opened (a); pancreatography of the resected specimen shows no connection between
the pancreatic ducts and the cystic tumor (b)
ing MCNs from the duct ectatic variant of IPMN
may be difficult. This histological similarity has led
some pathologists to interpret MCN and IPMN as
a single entity (ITAI et al. 1986). A clear distinction
between these two tumors therefore requires precise
definitions: (1) MCN has unilocular or multilocular
cysts with no or minimal connection with the main
pancreatic duct, lined by mucin -secreting epithelium
supported by ovarian type stroma (YAMADA et al.
1991); (2) IPMN is characterized by dilatation of the
main and/or branch ducts, mucinous epithelium with
mucus hyperproduction, and intraductal growth
(RICKAERT et al. 1991; MOROHOSHI et al. 1989).
MCN is still considered a rare lesion, represent-
ing approximately 2%-5.7% of all exocrine pancre-
atic tumors (SOLCIA et al. 1997; THOMPSON et al.
1999; WILENTZ et al. 1999,2000). These figures may
be biased because of the change in the diagnostic
criteria over the years and the probable over-rep-
resentation of MCNs in pathology files due to their
high resectability rate compared with that of ductal
adenocarcinoma (ZAMBONI et al. 2000).
It is evident from all reports on MCNs that the
neoplasms are much more common in women than
in men (SOLCIA et al. 1997; THOMPSON et al. 1999;
WILENTZ et al. 1999) or occur almost exclusively in
women (ZAMBONI et al. 1999). It is likely that many of
the cases reported in men in the early literature were
IPMNs (COMPAGNO and OERTEL 1978b). The peak
age occurs in the fifth decade (range 20-82 years,
mean 49 years) (SOLCIA et al. 1997). The clinical
presentation depends on the size of the tumor. Small
tumors are generally found incidentally, whereas
larger tumors produce symptoms which are usually
derived from compression of adjacent structures and
are often accompanied by a palpable abdominal mass
(SOLCIA et al. 1997).
15
We reviewed the anatomic and clinical features of
our panel of 56 mucinous cystic tumors (ZAMBONI
et al. 1999). All patients were women, ranging in age
from 18 to 78 years (mean 48.2 years). The 56 MCNs
included 22 mucinous cystic adenomas (MCAs), 12
mucinous cystic borderline neoplasms (MCBs), and
22 mucinous cystic carcinomas (MCCs). Sixteen of
the MCCs were invasive. The difference between the
mean ages of MCC patients (54.2 years) and patients
with MCA and MCB (44.7 years) was statistically sig-
nificant (p<0.04).
2.3.1
Macroscopy
The vast majority of lesions occur in the body-tail
of the pancreas (COMPAGNO and OERTEL 1978b;
THOMPSON et al. 1999; WILENTZ et al. 1999; YAMADA
et al. 1991; ZAMBONI et al. 1999). The head is only
rarely involved, with a predilection for mucinous
cystadenocarcinomas (THOMPSON et al. 1999; ZAM-
BONI et al. 1999).
MCNs appear as a round mass with a smooth sur-
face and a fibrous pseudo capsule of variable thick-
ness and with frequent calcifications. The diameter
of the tumor ranges from 2 to 35 cm, with an average
between 6 and 10 cm. The cut section shows either
unilocular or multilocular tumor with cystic spaces
ranging from a few millimeters to several centime-
ters in diameter, containing either thick mucin or a
mixture of mucin and hemorrhagic-necrotic mate-
rial. The internal surface of unilocular tumors is
usually smooth and glistening (Fig. 2.9), whereas the
multilocular tumors often show papillary projections
and mural nodules (Fig. 2.10). There is no significant
difference in size among the different categories of
16
Fig. 2.9. Mucinous cystic tumor. Benign unilocular tumor with
smooth and glistening internal surface
MCN, whereas the malignancy of the tumors cor-
relates significantly with the presence of papillary
projections and/or mural nodules and multilocu-
larity (ZAMBONI et al. 1999). As a rule, there is no
communication between the tumor and the duct of
Wirsung or the secondary ducts, but exceptions have
been reported (YAMADA et al. 1991).
2.3.2
Microscopy
MCNs show two distinct components: an inner
epithelial layer and an outer densely cellular layer
of 'ovarian-like' stroma (Fig. 2.11). The epithelium
frequently displays areas with pseudopyloric, gastric
foveolar, small-intestinal, colonic, and squamous
Fig. 2.11. Mucinous cystic adenoma. Cyst wall lined with
mildly dysplastic columnar epithelium supported by 'ovar-
ian-like' stroma
G. Zamboni et al.
Fig. 2.10. Mucinous cystic tumor. Malignant tumor with mul-
tiple, solid, nodular areas
differentiation. About half of the tumors contain
scattered argyrophil and argentaffin endocrine
cells at the base of the columnar cells (ALB ORES-
SAAVEDRA et al. 1987; COMPAGNO and OERTEL
1978b; YAMAGUCHI and ENJOJI 1987). The spectrum
of differentiation ranges from histologically benign
columnar epithelium to severely atypical epithelium.
MCNs are classified according to the degree of epi-
thelial dysplasia into the following different types, as
suggested by the WHO.
Mucinous cystadenomas (MCA) show only mild
epithelial dysplasia characterized by a slight increase
in the size of the basally located nuclei and the
absence of mitoses.
Mucinous cystic neoplasms of borderline malignant
potential (MCB) exhibit moderate dysplasia, charac-
terized by papillary projections or crypt -like invagina-
tions, and cellular pseudostratification with crowding
of atypical nuclei with rare mitoses (Fig. 2.12).
Mucinous cystadenocarcinomas (MCC) have
severe dysplasia/carcinoma-in-situ changes which
usually occur focally and may only be detected after
careful search of multiple sections from different
regions of the tumor. The epithelial cells, which often
form papillae with irregular branching and budding,
show nuclear stratification, severe nuclear atypia, and
frequent mitoses. The presence of carcinomatous
stromal invasion characterizes the invasive mucinous
cystadenocarcinoma. The invasive component usu-
ally resembles the common ductal adenocarcinoma
(Fig. 2.13). However, MCCs with invasive adeno-
squamous carcinoma, osteoclast-like giant cells, or
choriocarcinoma have been reported (COMPAGNO
and OERTEL 1978b; POSEN 1981; REGO et al. 1991;
Pathology of Cystic Tumors
ZAMBONI et al. 1999; MOLBERG et al. 1998; WESTRA
et al. 1998). Occasionally, MCNs have mural nodules
with a sarcomatous stroma or an associated sarcoma
(WENIG et al. 1997; THOMPSON et al. 1999; ZAMBONI
etal.1999).
In the series we reported in 1999, the invasive
carcinomatous foci of 16 MCCs were limited to the
intratumoral septa in 3 cases (19%), to the tumor wall
in 5 cases (31 %), of which 3 were at the site of a previ-
ous cystojejunostomy, and in 8 cases (50%) there was
peri tumoral extension. The 7 grossly visible mural
nodules were undifferentiated carcinoma (1), adeno-
squamous carcinomas (2), osteoclast-like giant-cell
tumors (2), malignant sarcoma (1), and reactive
inflammatory process (1) (ZAMBONI et al. 1999).
The epithelial cells show immunoreactivity to
epithelial markers including EMA, CEA, cytokeratins
7,8,18 and 19, to gastric-type mucin markers (PGII
and M1), and to the pancreatic-type mucin marker
DUPAN-2. Noninvasive MCNs are positive for
MUC5AC and DPC4 and negative for MUCl, whereas
the carcinomatous invasive component is DPC4-neg-
ative and MUCl-positive (LUTTGES et al. 2002).
The ovarian-like stroma, composed of densely
packed, spindle-shaped cells with round or elongated
nuclei and sparse cytoplasm, frequently exhibits a
variable degree ofluteinization (Fig. 2.14a). The stro-
mal cells are positive for vim entin, smooth-muscle
actin, and desmin (focally), progesterone receptors
Fig. 2.12. Mucinous cystic neoplasm of borderline malignant
potential. Papillary projections lined with moderately dysplas-
tic epithelium
17
Fig. 2.13. Mucinous cystadenocarcinoma. Cyst wall with tubu-
lar-type invasive carcinoma within the intratumoral stroma
(bottom)
(PR) (Fig. 2.14b), and estrogen receptors (ER). The
luteinized cells stain for alpha-inhibin (Fig. 2.14c)
(ZAMBONI et al. 1999).
2.3.3
Pathogenesis
Pancreatic MCNs are exclusively, or almost exclusively,
limited to women (WARSHAW et al. 1990; COMPAGNO
and OERTEL 1978b; YAMAGUCHI and ENJOJI 1987;
ALBORES-SAAVEDRA et al. 1987), a feature that they
share with their counterparts in the liver (AKWARI et
al. 1990; WHEELER and EDMONDSON 1985) and retro-
peritoneum (TENTI et al. 1994). All these mucinous
cystic tumors can be considered a biphasic tumor
with the same pattern of cell lineage differentiation
in both the epithelium and the stroma. The stromal
component stains for PR, ER (CZERNOBILSKY et al.
1989; ZAMBONI et al. 1994), and inhibin, indicating
stromal luteinization (ZAMBONI et al. 1999). Stro-
mal luteinization was found in a similar percentage
in ovarian MCNs (SCULLY 1979; ROME et al. 1981;
FLEMMING et al. 1996). The demonstration of inhibin
in ovarian (FLEMMING et al. 1996; ZHENG et al. 1997)
and in pancreatic MCNs is of special interest, because
inhibin has proved to be a sensitive serum marker for
ovarian tumors, including MCNs (HEALY et al. 1993).
Inhibin may therefore also serve as a tumor marker
for pancreatic MCNs. These findings indicate a strik-
ing resemblance between pancreatic, hepatobiliary,
retroperitoneal, and ovarian MCNs, which suggests
a common pathway of tumor development. The pos-
sible derivation of the stromal component of MCNs
 18
a " b
c progesterone receptors (b) and inhibin (c)
from the ovarian primordium is supported by its
morphology, tendency to undergo luteinization, and
immunophenotypic features. One possibility is that
there may be ectopic ovarian stroma in the pancreas
(particularly in the tail), along the biliary tree, and in
the retroperitoneum, which may release hormones
and growth factors, causing endodermally derived
epithelium in its vicinity to proliferate and form cystic
tumors. It is important to note that the left primordial
gonad and the dorsal pancreatic anlage, which gives
rise to the pancreatic body and tail and a small part
of the pancreatic head, lie side by side at an early
stage (4th to 5th week) of development (NISHIMURA
1983; TUCHMANN-DuPLESSIS 1968). Theoretically,
therefore, during that period, primordial ovarian cells
could easily become incorporated into the pancreas,
explaining the predilection of MeN for the body-tail
region of the pancreas. The development ofhepatobili-
ary MeN may be due to a similar process because the
hepatobiliary anlage is also found in close proximity
to the right genital ridge. The hepatobiliary anlage,
on the other hand, separates the ventral pancreatic
anlage from the genital ridge, since it buds off from
the duodenum between the ventral and dorsal anlage
G. Zamboni et al.
--
,-
• •
;.--
Fig. 2.14a-c. Mucinous cystic neoplasm. Ovarian-type stroma
with luteinized cells, characterized by clear cytoplasm, large
nuclei with evident nucleoli (a), showing immunostaining for
of the pancreas. This could explain the fact that the
pancreatic head is only rarely involved by MeN. The
occurrence of retroperitoneal MeN can easily be
related to the localization of the genital ridges.
2.3.4
Differential Diagnosis
The differential diagnosis of MeN is usually easy
from serous cystadenoma, mucinous noncystic carci-
noma, acinar cystadenocarcinoma, solid -pseudopap-
illary tumor, and cystic endocrine tumor because of
the lack of mucin-producing columnar epithelium.
It may be more difficult to distinguish MeN from a
pancreatic pseudocyst (SACHS et al. 1989; WARSHAW
and RUTLEDGE 1987; REMINE et al. 1987; TALAMINI
et al. 1992). In our series, approximately 10% of the
patients were initially treated by cystojejunostomy,
suggesting that they were mistaken for a pseudocyst.
Differentiating a pseudocyst from MeN may not only
be a clinical problem but also a morphological one,
since in MeN, due to degenerative processes, the
tumor epithelium may be denuded and the contents
Pathology of Cystic Tumors
hemorrhagic. The necessity of appropriate sampling
for making the correct diagnosis must be emphasized
(COMPAGNO and OERTEL 1978b).
The best approach to obtain an exact preoperative
diagnosis is the combined evaluation of all available
clinical, serological, radiological, and cytological find-
ings. An increase in the peripheral blood serum tumor
markers CEA or CA 19-9 or high cyst fluid levels of
CEA, CA-19-9, TAG-72, CA-15-3,or the mucin-like car-
cinoma-associated antigen, together with a low amylase
level, is suggestive of MCN. The highest levels of these
markers are seen in cystadenocarcinoma (YAMAGUCHI
and ENJOJI 1987; ALLES et al. 1994; LEWANDROWSKI et
al. 1993; RUBIN et al. 1994; SPERTI et al. 1997).
Fine needle aspiration biopsy can be performed
percutaneously with CT or US guidance or intraop-
eratively. The latter appears to be a valid alternative
to the classic surgical biopsy that can cause com-
plications such as fistulas and protracted bleeding
(BLANDAMURA et al. 1995). Aspirates are charac-
terized by the presence of background mucin and
columnar cells, with a clear and vacuolated cyto-
plasm, arranged in sheets and in papillae (Fig. 2.15).
Significant cytological atypia is absent in many cases.
The disordered arrangement of cells, with nuclear
crowding and overlapping, the presence of single
cells, large nuclei with distinct nucleoli, irregular
chromatin distribution, and marked variations in
size and shape are the most important cytologic fea-
tures of mucinous cystadenocarcinoma (LAUCIRICA
et al. 1992; YOUNG et al. 1991; SCHWERK 1981). Fine
needle aspiration biopsy is used to confirm the pres-
ence of malignancy and prevent unnecessary surgery
in unresectable cases.
Fig. 2.15. Mucinous cystic tumor. Fine needle aspiration
biopsy specimen showing moderately atypical aggregates of
cells in a mucinous background
19
2.3.5
Treatment and Outcome
The treatment of choice is complete surgical resec-
tion, with the lesion being examined histologically
in its entirety to avoid designating an invasive MCN
incorrectly as an adenoma, borderline tumor, or in-
situ carcinoma (WILENTZ et al. 2000). Internal (cyst-
enteric anastomosis) or external drainage of the cystic
tumors has to be avoided, since there are many well-
documented cases of apparent histologically benign
mucinous cystic tumors which have recurred after
drainage procedures as invasive cystadenocarcinomas
(CAMPELL and CRUICKSHANK 1962; COMPAGNO and
OERTEL 1978b; HODGKINSON et al. 1978; ZAMBONI
et al. 1994) (Fig. 2.16). The prognosis of a mucinous
cystadenoma, borderline tumor, and mucinous cyst-
adenocarcinoma without invasion, regardless of the
degree of cellular atypia, is excellent if the tumor can
be completely removed (Fig. 2.17) (ZAMBONI et al.
1999; COMPAGNO and OERTEL 1978b; CORBALLY et
al. 1989; DIDOLKAR et al. 1975; HODGKINSON et al.
1978; WARSHAW et al. 1990). However, in a minor-
ity of cases, recurrence and metastasis have been
reported after a curative resection of a noninvasive
MCN (ALB ORES-SAAVEDRA et al. 1987; COMPAGNO
and OERTEL 1978b; WARREN and HARDY 1968;
THOMPSON et al. 1999; WILENTZ et al. 1999). In con-
nection with this problem, we would like to emphasize
the necessity of appropriate sampling for making the
correct diagnosis (ZAMBONI et al. 1999). The chance
of finding carcinomatous foci is greater in the grossly
conspicuous areas than in flat and thin portions of the
cystic wall. It is worth noting that all cases of invasive
MCC usually show foci with MCB and MCA changes.
Fig. 2.16. Mucinous cystadenocarcinoma. A large cystic lesion,
treated 11 years previously with cystojejunostomy due to an
incorrect diagnosis of inflammatory pseudocyst, with malig-
nant progression into invasive cystadenocarcinoma
 20 G. Zamboni et a1.

a b

Fig. 2.17a,b. Mucinous cystadenocarcinoma. a Cut section of the tumor characterized by multiloculated cyst and'irregular solid
areas, with a thick, fibrous pseudo capsule. b Whole-mount section showing multilocular cystic spaces with multiple papillary
projections, but no invasion into the thick fibrous pseudocapsule

It is conceivable that limited tumor sampling might
be the reason why in these rare cases in which metas-
tases were observed, the original resection specimen
was thought to be noninvasive.
The prognosis of invasive mucinous cystadeno-
carcinoma depends on the extent of tumor invasion.
Tumor recurrence and tumor-related death correlate
with tumor wall and peritumoral invasion (ZAMBONI
et al. 1999) (Fig. 2.18). Patients over than 50 years old
have been shown to have a poorer survival rate.
Tumor ploidy and S-phase fraction may predict
survival in patients with MeN. Aneuploid neoplasms
with a high S-phase had a worse prognosis than
patients with diploid tumors with a low S-phase
(SOUTHERN etal. 1996; THOMPSON et al.1999; FLEJOU
et al. 1996; BRENIN et al. 1995). Other variables such
Fig. 2.18. Mucinous cystadenocarcinoma. Cut section of malig-
nant cystadenocarcinoma showing gelatinous carcinomatous
infiltration of the pseudocapsule (top, right)
as site, tumor size, macroscopic appearance, grade of
differentiation, presence/absence/luteinization of the
stroma, and p53 positivity have no prognostic signifi-
cance (ZAMBONI et al. 1999).
2.4
Solid Pseudopapillary Tumor
Solid pseudopapillary tumor (SPT) of the pancreas
is a distinctive low-grade malignancy that primarily
occurs in girls and young women (KLOPPEL et al.1981;
ZAMBONI et al. 1993) and is composed of monomor-
phous, small cells. It has been referred to as solid-cystic
tumor or papillary-cystic tumor. It has been reported
rarely in older women (LIEBER et al. 1987) and men
(KLOPPEL et al. 1991; LIEBER et al. 1987) and at extra-
pancreatic sites (KLOPPEL et al. 1991; ISHIKAWA et al.
1990; KIM et al. 1990). SPTs represent less than 1% of
all pancreatic tumors. In our series, they represented
11.5% of all cystic tumors; 15 occurred in women
(average age 31 years, range 14-69 years) and 1 in a
male adolescent (14 years old), with a predilection for
the head of the pancreas (12 cases).
Macroscopically, SPTs are frequently large, round,
well-circumscribed masses and show variable pro-
portions of solid and cystic areas filled with hem-
orrhagic fluid and necrotic debris (Fig. 2.19a,b). At
the extreme ends of the spectrum of macroscopic
appearances, some cases can be exclusively solid
(usually the smaller lesions), whereas others (usu-
Pathology of Cystic Tumors
C L-_ _
Fig. 2.19a-c. Solid pseudopapillary tumor. Cut sections of
predominantly solid (a), mixed solid and cystic (b), and pre-
dominantly cystic tumors (c)
ally the larger tumors) may be entirely cystic, and the
lesion easily mistaken for a pseudocyst (Fig. 2.19c).
Some tumors may present a fibrous pseudo capsule
with focal calcifications (KU)PPEL et al. 2000).
Microscopically, the tumors are composed of
a mixture of solid and cystic areas, usually sur-
rounded by a fibrous capsule (Fig. 2.20). The tumor
cells, forming solid areas or lining pseudopapillae,
are monomorphous, with round to oval nuclei and
eosinophilic, granular cytoplasm (Fig. 2.21a). PAS-
21
Fig. 2.20. Solid pseudopapillary tumor. Whole-mount macro-
section of a large, predominantly cystic lesion. The tumor shows
extensive hemorrhagic changes; the viable neoplastic compo-
nent is limited to a small semicircular area (middle, left)
posItive globules, stromal myxoid degeneration,
necrotic changes with foam cells, and hemorrhage
are characteristically present (Fig. 2.21b). Mitotic
figures are virtually absent, with a low proliferative
fraction (Ki-67 index <2%).
Clinically and radiologically, the differential diag-
nosis of endocrine tumors vs exclusively solid SPTs
that lack degenerative changes cannot be resolved.
Sometimes this may also be difficult during patho-
logical examination. Immunohistochemical studies
help to distinguish the two lesions. SPTs are positive
for neuron-specific enolase, CD56, CDI0, vimentin,
a-I-antitrypsin, and a-l-antichymotrypsin, whereas
the immunoreactivity for a broad spectrum of keratin
markers is usually negative (MOROHOSHI et al. 1989;
KU)PPEL et al. 1991; ZAMBONI et al. 1993; NOTOHARA
et al. 2000; KOSMAHL et al. 2000) (Fig. 2.22). Recently,
immunohistochemical positivity for p-catenin has
been reported (Fig. 2.23) (TANAKA et al. 2001). SPTs
have not shown the molecular changes reported in
ductal adenocarcinomas, such as p53, Ki-ras, DPC-4,
and p16 (KLIMSTRA et al. 2000).
A preoperative diagnosis may be obtained using
fine needle aspiration biopsy under ultrasound guid-
ance (ZAMBONI et al. 1993; PELOSI et al. 1995). The
cytological smears are highly cellular and character-
ized by the presence of mildly atypical, monomor-
phous cells, with scanty eosinophilic cytoplasm and
round, oval nuclei with grooves and finely granular
chromatin. Branching papillae, formed by delicate
central fibrovascular stalks covered by one or more
layers of tumor cells, are frequently observed together
with irregular clusters, acinar structures, and individ-
ual dissociated cells (Fig. 2.24). Eosinophilic, hyaline
 22 G. Zamboni et al.

a ......~........1000 b

Fig. 2.21a,b. Solid pseudopapillary tumor. a Pseudopapillary structures with fibrovascular cores lined by small monomorphic
cells. b Solid area showing foam cells and hemorrhage

Fig. 2.22. Solid pseudopapillary tumor. Exclusively solid tumor, without degenerative changes (H&E: second section from the left),
showing negative immunoreactivity for cytokeratins 8, 18, 19 (first section) and intense positivity for vimentin (third section)
and neuron-specific enolase (NSE) (fourth section)

globules and numerous foam cells may also be pres-

Fig. 2.23. Solid pseudopapillary tumor. Cytoplasmic and
nuclear ~-catenin immunostaining in the neoplastic cells
(left); slight membranous positivity is present in the normal
pancreatic tissue (right)
ent. The most important differential diagnosis is from
nonfunctioning islet cell tumors (IACONO et al. 1992),
pancreatoblastoma (CUBILLA and FITZGERALD 1984),
and acinar cell tumor (KUMSTRA et al. 1992).
Although the histogenesis remains obscure, the
immunohistochemical and ultrastructural findings,
demonstrating a prevalence of ductular cells with
minimal acinar and endocrine differentiation, favor
the hypothesis of a ductular cell origin with divergent
differentiation (MATSUNOU et al. 1990). The pathoge-
netic role of sex hormones is suggested by the predi-
lection of SPT for young, fertile women. Controversial
data have been provided for the presence of progester-
one receptors (PR) and/or estrogen receptors (ER) in
SPT (CARBONE et al. 1989; WRBA et al. 1988; KOSMAHL
et al. 2000). We reported the immunohistochemical
detection of PR in the large majority of neoplastic
Pathology of Cystic Tumors
Fig. 2.24. Solid pseudopapillary tumor. Fine needle aspiration
biopsy showing branching papillae, formed by delicate, cen-
tral, fibrovascular stalks covered by monomorphic cells with
eosinophilic cytoplasm and round nuclei
cells in ten patients with SPT, whereas no ER-posi-
tivity was found (ZAMBONI et al. 1993). This finding
supports the hypothesis of a possible pathogenetic
role of progesterone in SPT, regardless of the patient's
age and sex. However, it is not possible to exclude that
it simply represents an epiphenomenon, if one consid-
ers that PR is also expressed in pancreatic endocrine
tumors (VIALE et al. 1992) as well as in normal islets
(DOGLIONI et al. 1990).
SPT has to be regarded as a carcinoma with
low malignant potential and a favorable clinical
course, although invasion of vital structures and
metastases have been reported (CAPPELLARI et al.
1990; MATsuNou et al. 1990; SCLAFANI et al. 1991;
NISHIHARA et al. 1993; KLIMSTRA et al. 2000). More
than 95% of patients with SPT limited to the pancreas
are cured by complete surgical resection (KLIMSTRA
et al. 2000). Only a few patients have died of metas-
tasizing tumor (COMPAGNO et al. 1979; MATSUNOU et
al. 1990; Ky et al. 1998).
2.5
Acinar Cell Cystic Tumors
Acinar cell carcinomas are tumors with evidence
of pancreatic enzyme production by the neoplastic
cells (SOLCIA et al. 1997). The vast majority are solid
tumors (KLIMSTRA et al. 1992). The cystic variant of
these tumors has only rarely been reported. We can
now consider two categories of lesions: acinar cell
cystadenocarcinoma and the newly reported acinar
cell cystadenoma.
23
2.5.1
Acinar Cell Cystadenoma
We recently described the detailed clinicopathologi-
cal features of ten patients with acinar cell cystad-
enoma (ACA), a previously unrecognized type of
cystic pancreatic lesion, which is characterized by
acinar cell differentiation of the lining cells, absence
of distinct cellular atypia, focal or diffuse involvement
of the pancreas, and a good prognosis (ZAMBONI et
al. 2002). In our ten patients, ACAs showed no clear
age predilection; the patients' age ranged from 16 to
66 years. There was, however, a female predilection:
seven women and three men, with the largest lesions
occurring in women. There was no clear preferential
localization within the pancreas. Though the largest
cysts had developed in the head of the pancreas, the
remaining cysts also involved the body and tail of
the gland, and in one case, the entire pancreas was
affected. All patients remained alive and well during
a follow-up period of up to 84 months.
Macroscopically, the lesions show a well-circum-
scribed cystic pattern with a thin, fibrous pseudo capsule
(Fig. 2.25), which in some cases can be thick and pres-
ent with calcification. On cut section, they were either
unilocular (with a diameter between 0.5 and 10 em)
or multilocular, with the largest diameter being 7.5 em.
In all cases, the internal surface was smooth and shiny,
with no solid areas or papillary projections. The cysts
contained serous fluid.
Microscopically, the cysts were lined by a single
layer of cuboidal or columnar cells with little tendency
to pseudostratification or crowding (Fig. 2.26a). Their
cytoplasm was typical for acinar cells, with deeply
eosinophilic granules in the apical part and basophilic
Fig. 2.25. Acinar cell cystadenoma. Intraoperative picture
showing a large, multilocular cystic lesion in the body of the
pancreas
24
staining at the base of the cells. In addition, the apical
cytoplasm showed characteristic PAS-positivity which
was diastase-resistant. The nuclei were basally located,
uniform, and normochromic with small but evident
nucleoli; atypia was very mild or absent. Mitoses were
extremely rare. The cysts were usually connected with
small clusters of acinar cells forming acini that opened
into the cystic lumen. These acini were often dilated
and had the appearance of tubular complexes. Intra-
cystic club-like pseudopapillae with a fibrous stalk
were a distinctive feature (Fig. 2.26b). In some cases,
the cysts contained eosinophilic secretions.
Immunohistochemically, the epithelial cells stained
positively with at least one of the acinar markers:
trypsin (Fig. 2.27), chymotrypsin, and lipase. All but
one of the cases stained positively for pancreatic stone
protein (PSP). The eosinophilic secretions also stained
for trypsin and PSP. The neuroendocrine markers
chromogranin A and synaptophysin were negative in
Fig. 2.26a,b. Acinar cell cystadenoma. Portion of cyst lined
by columnar cells with acinar differentiation. Note the small
acini connected to the lining cells (a); cyst showing a collar of
dilated acinar structures opening into the lumen, with club-
like pseudopapillae (b)
G. Zamboni et al.
all cases. All seven stained cases were positive for the
cytokeratin markers CAM 5.2 (cytokeratins 8, 18, 19),
KLl (cytokeratins 1,2,5,6,7,8,11,14,16,17,18), and
cytokeratin 7. The proliferative fraction was very small
in all cases, with a Ki-67 index <1%. No case showed
nuclear positivity for the p53 tumor suppressor gene.
Although at present a nonneoplastic nature
cannot be completely excluded, we refer to this tumor
as acinar cell cystadenoma (and suggest that it might
represent the benign counterpart of the well-recog-
nized acinar cell cystadenocarcinoma (CANTRELL
et al. 1981; ISHIZAKI et al. 1995; JOUBERT et al. 1998;
STAMM et al. 1987).
2.5.2
Acinar Cell Cystadenocarcinoma
Rare examples of cystic acinar cell carcinoma have
been reported as 'acinar cell cystadenocarcinomas'
(CANTRELL et al. 1981; STAMM et al. 1987; JOUBERT
et al. 1998; ISHIZAKI et al. 1995). The patients are
frequently men, with a mean age of 50-60 years.
Macroscopically, these neoplasms are large masses
with diameters up to 35 cm containing multiple cysts,
with a diameter ranging from a few millimeters to
many centimeters. Hemorrhage and necrosis have
been reported (KLIMSTRA et al. 2000). Microscopi-
cally, the tumors are composed of multiple cysts of
varying sizes, mixed with tubular and solid areas. The
lining cells show the typical acinar differentiation, the
cytoplasm filled with deeply eosinophilic granules in
the apex and with basophilic staining at the base. The
.,
Fig. 2.27. Acinar cell cystadenoma. Immunohistochemical
expression of the pancreatic enzyme trypsin in the lining
epithelium
Pathology of Cystic Tumors
cells composing cystic acinar cell carcinomas show
clear signs of atypia and many mitoses; necrosis is
frequently found.
The prognosis of reported cases was poor and
similar to that of the solid counterpart; metastases
were evident either at the time of diagnosis or within
a few months of surgery (KLIMSTRA et al. 2000).
2.6
Other Cystic Tumors
This category includes very rare lesions, which
account for less than 5% of our cystic tumors.
Cystic endocrine tumor is an endocrine tumor char-
acterized by solid growth with massive degenerative
changes, which may be confused with other cystic neo-
plasms. The preoperative diagnosis may be solved with
fine needle aspiration biopsy showing the characteris-
tic cytological features (AOSAY and KLIMSTRA 2000).
The diagnosis may be confirmed by the immunohisto-
chemical demonstration of endocrine markers such as
chromogranin A and synaptophysin and the detection
of hormone production (IACONO et al. 1992).
Lymphoepithelial cyst is a benign, uncommon
lesion characterized by mature squamous epithe-
lium associated with lymphoid tissue (AOSAY et al.
2000a; IACONO et al. 1996). They are more common
in men, the mean age of the patients being 56 years
(AOSAY et al. 2000a). Macroscopically, they may
occur predominantly as extrapancreatic lesions and
in any case are well demarcated from the surround-
ing pancreatic parenchyma. They can be either mul-
tilocular (60% of cases) or unilocular (40% of cases);
their mean diameter is 4.7 cm. The cyst wall is usually
thin, and the inner surface of the cysts is smooth or
finely granular. Microscopically, the cysts are lined
by stratified squamous epithelium mixed with flat or
cuboidal epithelium. The cyst wall and the septa are
filled with dense lymphoid tissue composed of CD3-
positive T-cells, frequently associated with germinal
centers formed by B-cells. The differential diagnosis
is essentially from serous cystadenoma and mature
teratoma. They have no malignant potential.
Mature teratoma is a benign, extragonadal germ-
cell tumor with mature tissues derived from all three
germ layers (AOSAY et al. 2000a; IACONO et al. 1993).
They have no gender predominance; the mean age of
the patients is 29 years. Macroscopically, they have
both solid and cystic areas, with frequent calcifica-
tion. Microscopically, the cystic spaces are lined by
squamous epithelium, mixed with respiratory and
25
columnar epithelium. Suppurative inflammation is
frequently found. They have no malignant potential.
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3 Serous Cystic Tumors
G. CARBOGNIN, M. TAPPARELLI, E. PETRELLA, A. FUINI, and C. PROCACCI

CONTENTS (GEORGE et al. 1989; SOYER et al. 1994; KLOPPEL et

al. 1996; WIDMAIER et al. 1996; ABE et al. 1998; ERI-
3.1 Introduction 31 GUCHI et al. 1998; Wu et al. 1999). Authors are still
3.2 Imaging 32 not in complete agreement about the therapeutic
3.2.1 Transabdominal US 32
3.2.2 Computed Tomography 33 management of SCT. Reports are divided in the sur-
3.2.2.1 General Principles of Technique 33 gical literature between those who advocate resec-
3.2.2.2 CT Findings 34 tion in all cases (PADOVANI et al. 1991; TALAMINI
3.2.3 Magnetic Resonance Imaging 41 et al. 1992; NAGEL et al. 2000; Box and DOUGLAS
3.2.3.1 Technique 41 2000; SHEENAN et al. 2000) and those who accept
3.2.3.2 MR Findings 42
3.2.4 Other Imaging Modalities 44 the imaging diagnosis of SCT, allowing the lesions
3.2.4.1 Plain Radiographs 44 to be followed (ISELIN et al. 1993; SARR et al. 2001).
3.2.4.2 Contrast Examination Conservative management is favored in patients with
of the Upper Gastrointestinal Tract 44 large masses who are asymptomatic; elderly patients
3.2.4.3 Angiography 44 or those who may be poor surgical candidates; lesions
3.2.4.4 Endoscopic Retrograde
Cholangiopancreatography 46 in the pancreatic head where the morbidity and mor-
3.2.4.5 Endoscopic US 49 tality associated with pancreaticoduodenectomy may
3.3 Differential Diagnosis 50 be higher than the presence of the untreated lesion;
References 53 and above all, those small tumors which occasionally
show up in otherwise completely healthy or young
patients (KIMURA and MAKUUCHI 1999). COMPAGNO
and OERTEL (l978a, b) originally observed the ana-
3.1 tomic-pathological appearance of SCT. Their studies
Introduction characterized the morphology of all cystic lesions
containing serous fluid as 'micro cystic'. This unique
The serous cystic tumor (SCT) of the pancreas is morphology narrows down the differential diagno-
most often incidentally detected when an imaging sis of pancreatic masses with this appearance. This
study is performed for clinical symptoms which may classification has been further expanded by the
or may not be directly related to the pancreas. Once identification of an oligo cystic type (KLOPPEL et al.
detected, accurate characterization of a pancreatic 1996; SOLCIA et al. 1997), resulting in a considerable
mass as an SCT is of primary importance since this increase in differential diagnosis problems.
tumor is benign, unlike all the other cystic tumors As stated above, these lesions are detected acciden-
of the pancreas. There are no more than 10 reports tally during ultrasound (US), computed tomography
of serous cystadenocarcinoma in the world literature (CT) or magnetic resonance (MR) imaging. The other
conventional radiological investigations (plain film
G. CARBOGNIN, MD; M. TAPPARELLI, MD; E. PETRELLA, MD; of the abdomen, barium study of the upper gastroin-
C. PROCACCI, MD testinal tract, angiography, etc.) have no application
Istituto di Radiologia, Dipartimento di Scienze Morfologico- in the study of this lesion. Endoscopic ultrasound
Biomediche, Universita degli Studi di Verona, Policlinico
(EUS) or endoscopic retrograde cholangiopancrea-
'Giambattista Rossi', P.zza L.A. Scuro 10,37134 Verona, Italy
A. FUINI,MD tography (ERCP) may be utilized in certain cases
Servizio di Gastroenterologia, Ospedale Civile Maggiore, P.le when the previously mentioned imaging methods do
Stefani, 1,37124 Verona, Italy not suggest a conclusive diagnosis.
 32 G. Carbognin et al.

3.2 ticular features (obesity, meteorism). The successful

Imaging
3.2.1
Transabdominal US
US investigations have significantly contributed to
the increase in the number of seT observations
due to its widespread use in clinical practice. Only
in a minority of cases do us investigations identify
the lesion following a request to clarify the cause of
symptoms, even if they are nonspecific (epigastric
pain, vomiting, weight loss, jaundice), supported by
a mass of conspicuous size. Identification usually
occurs completely by chance, especially where small
tumors are concerned (PROCACCI et al.I997,2001a,b;
MATHIEU et al. 1989). The false-negative rate of us
in identifying seT is low; recognition of a small seT
can be missed either because its site is more difficult
to explore (tail) and/or because of the patient's par-
identification of seT with us is solely based on the
unique morphological characteristics of the tumor.
The microcystic type SeT can be easily classified
when the us investigations show a mass which usu-
ally has a multilobulated border, no posterior acoustic
enhancement, and an internal 'honeycomb' architec-
ture (Fig. 3.1a) due to the presence of multiple septa
which delimit small «2 cm diameter) cystic spaces
(WOLFMAN et al. 1982; VILGRAIN et al. 1987; JOHNSON
etal.1988;BuCK and HAYES 1990;PADOVANI etal.1991;
YANG et al. 1994; FUGAZZOLA et al. 1991; PROCACCI et
al. 1997, 2001a,b). More frequently, the multiplicity of
the interfaces results in a predominantly echogenic
mass in which cystic spaces (Fig. 3.1b) can be recog-
nized (BUCK and HAYES 1990; PADOVANI et al. 1991).
Often, together with the micro cysts, larger cystic
spaces (>2 cm diameter) can be found at the periphery
of the lesion, resulting in a mixed pattern (Fig. 3.1c),
with a micro cystic or mainly solid, central portion and

a b

c d

Fig. 3.1a-d. Microcystic serous cystic tumor (SCT) (ultrasound, US evaluation). a Multilobulated mass with multiple internal
cystic spaces, delimitated by septations, giving the tumor a 'honeycomb' appearance. b Mass with solid appearance (calipers)
with a mainly echogenic texture; minute transonic cystic spaces are recognizable within. c Mixed appearance tumor (micro-
cystic and macrocystic): large cysts (>2 em in diameter: asterisk) are distinguishable at the periphery of the tumor. d Large
echogenic mass, with solid appearance. Calcifications appear like hyperechoic spots with posterior shadowing (arrows). L, liver;
ICV, inferior caval vein; A, aorta; P, pancreas; K, kidney
 Serous Cystic Tumors
peripheral macro cysts (PROCACCI et al. 1997,2001b).
The macrocysts can grow as large as 8-10 cm in dia-
meter, making it difficult to recognize the true nature
of the tumor. Sometimes, in more 10%-30% of cases
(PADOVANI et al. 1991; TORRESAN et al. 1997; COMP-
TON 2000; PROCACCI et al. 2001b), there can be hyper-
echogenic spots with posterior shadowing (Fig. 3.1d),
due to the presence of calcifications within the septa.
Less frequently, when there is a calcified scar, large
hyperechogenic spots can be found in the center. SCT
is more frequently located in the pancreatic head, and
the gland is usually normal upstream. In extreme
cases, dilation of either the duct ofWirsung or the bili-
ary tree can be found due to obstruction by the mass.
The micro cystic appearance is also seen in the
serous cystadenoma which accompanies von Hippel-
Lindau disease. In this case the tumor is multicentric
or diffusely involves and enlarges the pancreas. Typical
of SCT, these masses also display a multilobulated out-
line and an inhomogeneous echotexture secondary to
the coexistence of cystic and solid areas, and frequent
hyperechoic spots due to the calcifications (CHOYKE
et al. 1995; HES and FELDBERG 1999). In patients with
von Hippel-Lindau disease, it is necessary to perform
renal US to exclude clear-cell carcinoma.
There are two reasons why US may fail to charac-
terize a pancreatic mass accurately as an SCT. First,
in the presence of a 'sponge-like' mass, the tumor can
manifest a homogenously echogenic aspect (Fig. 3.2)
with sharp borders, just like a solid tumor (JOHNSON
et al. 1988; BUCK and HAYES 1990; PADOVANI et al.
1991; PROCACCI et al. 1997, 2001a,b), because the
multiplicity of the small cysts and thick fibrous
stroma produce innumerable acoustic interfaces
yielding the false impression that the lesion is solid.
a b
Fig. 3.2a,b. Microcystic SCT (US evaluation). Two cases. In the oblique subcostal (a) and axial (b) scans, a sharply demarcated,
uniformly hyperechoic mass, mimicking a solid tumor, can be seen. In the first case (a) the mass is compressing the biliary duct
( CBD) which appears dilated upstream. L, liver; K, kidney
33
Second, in the case of a mixed tumor (a micro cystic
center and peripheral macrocysts), the macro cystic
component can conceal the micro cysts with the con-
sequent misdiagnosis of a unilocular or multilocular
macro cystic mass.
The macrocystic type SCT, whether unilocular or
multilocular (Fig. 3.3), is easily detectable even when
its dimensions are small. It appears as a sharply
marginated, hypoechoic mass with the transmission
characteristics of a cyst. There may be sparse, thin,
central septa (MORI et al. 1995; GOUHIRI et al. 1999;
PROCACCI et al. 1997, 2001a,b; KANETO et al. 2000).
In this case, the possibility of a differential diagnosis
from the other cystic masses of the pancreas is lower
(GOUHIRI et al. 1999; PROCACCI et al. 1997,2001a,b).
3.2.2
Computed Tomography
The most reliable method of detecting and char-
acterizing SCT is intravenous contrast-enhanced
computed tomography (CT). Characterization
will probably be further improved as experience
with multidetector-row CT (MDCT) accumulates
(FISHMAN et al. 2000; NINO-MuRCIA et al. 2001).
3.2.2.1
General Principles of Technique
As stated above, most SCT are detected accidentally
during CT examinations for other or nonspecific
diagnoses. In most cases, proper characterization of
the mass will require an additional dedicated pan-
creatic study. Regardless of the type of scanner one
 34
a b
Fig. 3.3a,b. Oligo cystic SCT (US evaluation). Two cases. a Ovoid, transonic, unilocular mass occupying the body of the pancreas.
Note relation to the aorta (A) and the inferior vena cava (ICV). b Large, transonic, multilocular mass in the pancreatic head
with lobulated contours and thick septum (arrow)
uses, the imaging protocol must ensure the following:
distension of the stomach and the duodenum with
oral contrast or, preferably, with water; appropri-
ately delivered intravenous (IV) contrast medium,
administered by power injector (automatic), so that
scanning can occur during a phase in which there
is maximal pancreatic parenchymal enhancement;
and finally, acquisition with collimation of less than
3mm.
3.2.2.1.1
Single Detector CT
Single detector CT examination starts with a pre-
contrast (unenhanced) acquisition, indispensable
for detecting calcifications or hemorrhage within
the tumor (ITAI et al. 1988; SaYER et al. 1994;
COMPTON 2000; PROCACCI et al. 1997, 2001a,b). Fol-
lowing this, 120-150 ml of iodinated contrast agent
is administered at a minimal rate of 3 mlls. A second
acquisition is then initially performed after 30-35 s
delay (the pancreatic phase), and a third one after
70-80 s delay (venous phase). In the pancreatic phase
acquisition, a slice thickness of 3 mm coupled with
a reconstruction interval of 2 mm is used, and the
images are acquired from the porta hepatis through
the transverse duodenum. In the venous phase, a
slice thickness of 5-7 mm is used coupled with a
reconstruction interval of 4-6 mm at a pitch of 1.5
from the diaphragm to the lower pole of the kidneys.
In approximately 10%-15% of cases, after 120 s, a
further acquisition, limited to the pancreatic area, is
performed with the aim of better demonstrating the
enhancement of the internal septations (PROCACCI
et al. 1999, 2001b).
G. Carbognin et al.
3.2.2.1.2
Multidetector-row CT
Multidetector-row CT substantially increases the
diagnostic information available from the CT study.
MDCT offers significantly increased diagnostic
information from a single CT examination. This
includes the ability to create an arterial and venous
map of the pancreatic area (FISHMAN et al. 2000) and
the ability to view the data in high quality 3D, improv-
ing our understanding of the relation of the mass to
surrounding structures (NINO-MuRCIA et al. 2001).
Pancreatic imaging with MDCT is performed in a
similar fashion to SCT; the major difference is that one
must choose both an acquisition collimation and a dis-
play collimation. Two acquisitions are utilized, the first
(pancreatic phase) is acquired 34-40 s following the IV
injection oflow osmolality contrast medium at a rate of
not less than 3 mlls. The scan range is prescribed in an
identical fashion to that in Section 3.2.2.1.1. We utilize
a 4x 1 mm detector row configuration and create 3-mm
slices for image analysis. Additionally, we retain the
volume of slices and use them on the workstation for
3D evaluation. The second acquisition (venous phase)
uses a 4x2.5 mm detector configuration. This scan is
prescribed from the top of the diaphragm through the
iliac crests. This scan begins approximately 70-80 s fol-
lowing the initiation of the injection. From this acquisi-
tion, 5- to 7-mm slices can be created for viewing.
3.2.2.2
CTFindings
The CT appearance of SCT depends upon two factors:
the macroscopic features (microcystic or macro cystic
 Serous Cystic Tumors 35

structure) of the mass and the time of data acquisition
as it relates to the contrast injection (unenhanced, pan-
creatic or venous) during which the mass is examined.
3.2.2.2.1
Microcystic SeT
On unenhanced images, the tumor displays mass effect
or a simple deformation of the contour of the gland.
The lesion has multilobulated borders and a homoge-
neous density, slightly superior to that of water, and
appears isodense or slightly hypodense compared
with the pancreatic parenchyma (Figs. 3.4a, 3.Sa, 3.6a).
Sometimes, by reducing the width of the image
window, it is possible to demonstrate the septum and/
or the central fibrous scar (Fig. 3.5c). When calcification
is present, it is almost always central (Figs. 3.7a, 3.8a)
(ITAl et al. 1982,1988; WOLFMAN et al. 1982; VlLGRAlN
et al. 1987; JOHNSON et al. 1988; SOYER et al. 1994; YANG
et al. 1994; LE BORGNE et al. 1999; PROCACCl et al. 1999;
CURRY et al. 2000). These calcifications are punctate or
globular (Figs. 3.7a, 3.8a), as opposed to the lamellar
calcifications seen in the mucinous cystic tumors. It is
sometimes possible to find a large calcification with
a rounded or 'star-shape' morphology, situated in the
central scar(s) (Fig. 3.9a). Usually, the scar is visible in
the larger masses since it forms later on (HEALY et al.
1994). The presence of central calcifications in corre-
spondence with septa or scars is an important finding
as it definitively characterizes the mass as SCT (WAR-
SHAW et al. 1990; SOYER et al. 1994; CURRY et al. 2000).
Unfortunately, this pattern of calcification is seen in, at
most, 30% of cases (WARSHAW et al. 1990; COMPTON
2000). The presence of macro cysts at the periphery
are usually not recognized on the precontrast images
(Fig.3.6a).
Maximal visualization of the septa and therefore the
greatest opportunity to correctly characterize the mass

a b

c d

Fig. 3.4a-d. Microcystic SCT (CT evaluation). a Non-contrast: bulky, lobulated mass with homogeneous density, slightly superior to
that of water. b Pancreatic phase: 'honeycomb' appearance of the mass due to the presence of multiple enhancing septa. c, d Portal
venous and late phases: the septa appear isodense compared to the gland; the 'honeycomb' aspect is, however, clearly recognizable
 36 G. Carbognin et al.

a b

c d

Fig. 3.5a-d. Microcystic SCT (CT evaluation). a, b First case. Non-contrast phase (a), the sharply bordered lesion has homo-
geneous density. In the pancreatic phase (b), the radial orientation of hyperdense septa is recognizable, originating from the
central fibrous scar to the margins of the neoplasm. c, d Second case. On the un enhanced images viewed with a narrow window
(c), it is possible to demonstrate the septa and the central fibrous scar. In the contrast-enhanced pancreatic phase (d), the septa
coming from the central scar can be seen more clearly

a b

Fig. 3.6a,b. Microcystic SCT (CT evaluation). a On non-contrast enhanced images, the tumor has a homogeneous density, and
the peripheral macro cysts are not distinguishable from the micro cystic nucleus. b In the pancreatic phase, the peripheral mac-
rocysts and the micro cystic nucleus are readily demonstrated
 Serous Cystic Tumors 37

c d

Fig. 3.7a-d. Microcystic SCT (CT evaluation). a On non-contrast enhanced images, the mass appears homogeneously attenuat-
ing. Small calcifications are scattered around the peripheral portions (but not the wall) of the tumor. b In the pancreatic phase,
hyperdense septa create a sponge-like pattern where an inhomogeneous solid center and multiple peripheral cysts can be
identified. c In the portal venous phase, the mass maintains its central solid appearance with peripheral cysts. d In the delayed
phase, the marked enhancement of the large central fibrous scar is highlighted

occurs during the pancreatic phase (see 3.2.2.1.112).
The 'honeycomb' appearance so characteristic of this
mass is best seen during this phase (Fig. 3.4b). In larger
tumors it is possible to demonstrate the radial orien-
tation of the septa (Figs. 3.5b, 3.9b) emanating from
the central scar and extending towards the margins
of the lesion (JOHNSON et al. 1988; ITAI et al. 1988,
PADOVANI et al. 1991; SOYER et al. 1994; PROCACCI et
al. 1997; LUNDSTEDT and DAWISKIBA 2000; ZIRINSKY
et al. 1984). The mass may appear as inhomogeneously
hyperdense due to the combination of the vascular-
ized septa and the interspersed micro cysts (Fig. 3.7b).
Peripheral macrocysts related to the central micro-
cystic nucleus may have diameters that vary from 2
to 10 em (Figs. 3.6b, 3.7b, 3.8b) and are even more
easily recognizable (PROCACCI et al. 1997). In this
pancreatic phase, the intense enhancement of the
septa can obscure calcifications, thereby adding value
to the precontrast or unenhanced images. When thin
«5 mm) slices are obtained in the pancreatic phase,
it is possible to evaluate the tumor's relationships to
adjacent structures more accurately. The SCT, depend-
ing on its size, can compress surrounding viscera. It is
also possible to document the mass effect on adjacent
vessels. It is quite unusual to find occlusion or throm-
bosis which, in association with the collateral circula-
tion, is more common in pseudo cysts or malignant
cystic tumors. In extreme cases, it is possible to find
biliary obstruction in the presence of a large mass in
the pancreatic head. However, even large SCT rarely
involve the duct ofWirsung. When this happens, how-
ever rarely, the differential diagnosis may be difficult
as far as intraductal tumors of the collateral ducts are
concerned (Fig. 3.1O).
In the venous phase, the tumor appears isodense
compared to the gland; the 'honeycomb' aspect is
 38 G. Carbognin et al.

a b

c d

Fig. 3.8a-d. Microcystic SCT (CT evaluation). a Non-contrast enhanced images reveal a multilobulated mass with large calcifica-
tions. b In the pancreatic phase, the mixed aspect of the tumor is recognizable with a large micro cystic area and a peripheral
macrocyst. c, d In the venous (c) and late (d) phases, no significant variations are evident

a b

Fig. 3.9a,b. Microcystic SCT (CT evaluation). a On noncontrast enhanced image, the mass appears homogeneous with a slightly
higher density to that of water and with a large central calcification. b In the pancreatic phase, septa radiating from the central
scar are recognizable
 Serous Cystic Tumors 39

..

t~~
, ". . )~.,
c d

Fig. 3.lOa-d. Microcystic SCT (CT evaluation). a-c Axial scans, obtained in the craniocaudal direction during the pancreatic
phase, show dilation of the duct ofWirsung, stopping at the uncinate process. A small lesion (c) is seen, which has a micro cystic
architecture and a small stellate central calcification. d MRCP confirms the dilation of the duct of Wirsung and the micro cystic
lesion in the pancreatic head

easily visualized (Figs. 3.4c, 3.5d, 3.7c, 3.8c), and any
calcifications are identifiable due to the lower density
of the septa. In this phase and in later acquisitions,
when the tumor is sponge-like, the cystic component
may be difficult to recognize (Fig. 3.11) (ITAI et al.
1988; BUCK and HAYES 1990; PROCACCI et al. 1997;
COMPTON 2000). The diagnosis is, however, easier if
larger cysts are present at the periphery (Fig. 3.7c).
The study of the tumor during a delayed phase
related to the contrast injection (Figs. 3.4d, 3.7d,
3.8d) could simulate a unilocular macro cystic tumor
because of the nonrecognition of septa, indistin-
guishable from the liquid content of the cyst (BUCK
and HAYES 1990; PROCACCI et al. 1997).
Serous cystadenomas seen in patients with von
Hippel-Lindau disease have a unique appearance.
The pancreas appears enlarged due to the variable
presence of multiple cystic formations of varying
sizes. Some of these contain calcification and infre-
quently may be solid (CHOYKE et al. 1995; PROCACCI
et al. 1997, 2001a; HES and FELDBERG 1999). Other
organs, especially the kidneys, are more commonly
involved. The diagnosis is made easier by the diffuse
involvement of the gland, the coexistence of lesions
in other organs and, above all, by familial history
(Fig. 3.12).
SCT has been reported to coexist with other
tumors. This rare occurrence has been described
between the micro cystic form of SCT and the endo-
crine tumor (HERESBACH et al. 1993; KEEL et al. 1996;
TUNG et al. 2001). For this reason, the structure of the
lesion should be accurately evaluated, so as to exclude
the presence of solid components, which would indi-
cate an associated tumor.
 40 G. Carbognin et al.

a b

Fig. 3.11a,b. Microcystic SCT (CT evaluation). a, b Axial scans, obtained in the craniocaudal direction in the portal venous phase,
show a neoplasm with homogeneously solid density, within the limits of the pancreatic parenchyma. The lack of pancreatic
phase images disguises the presence of septa and leads to misdiagnosis

a b

C L-_""";'--_ d

Fig. 3.12a-d. Von Hippel-Lindau disease (CT evaluation). a, b First case. In the venous phase there is a diffuse enlargement of
the entire pancreas. The parenchyma has been replaced by multiple, water-density masses of variable dimensions. The larg-
est (asterisk in b) is in the head. c, d Second case (brother of the previous patient). In the portal venous phase, the gland has
increased in size and contains multiple cystic formations of uniform dimensions. There are also liquid and solid lesions in the
kidneys, the largest being in the right kidney
 Serous Cystic Tumors 41

3.2.2.2.2 3.2.3
Oligo cystic SeT Magnetic Resonance Imaging

Oligo cystic SCT, as already highlighted by many
authors (LEWANDROWSKl et al. 1992; MORl et al. 1995;
PROCACCl et al. 1997, 2001a,b; GOUHlRl et al. 1999;
KANETO et al. 2000; COMPTON 2000),is indistinguish-
able from other macro cystic masses of the pancreas,
primarily the mucinous cystic tumor. On CT, one
detects the presence of a unilocular or multilocu-
lar cystic mass, usually with thin walls and deeply
embedded 1n the pancreatic gland (PROCACCl et al.
1997,1999, 2001a; GOUHIRl et al. 1999). Calcifications
are not frequent as in the micro cystic variety. In the
pancreatic or venous phases of contrast enhance-
ment, both the walls and the scant, thin central
septations, when present, are highlighted (Fig. 3.13).
When immediate surgical treatment is not con-
sidered appropriate, it is advisable to proceed
with needle aspiration under US or CT guidance
(LEWANDROWSKl et al. 1993; CARLSON et al. 1998;
HAMMEL 2000; SPERTl et al. 2000).
MR is assuming an increasingly important role in
characterizing cystic tumors, particularly SCT, since
the multiplicity of the sequences gives greater and
more accurate information about the structure of
the lesion, most particularly the presence of septa.
Furthermore, the use of magnetic resonance chol-
angiopancreatography (MRCP) gives a better evalu-
ation of the relationship of the cystic mass to the
main pancreatic duct, which can be decisive in the
differential diagnosis between SCT and intraductal
papillary mucinous tumor (IPMT) of the collateral
ducts.
3.2.3.1
Technique
Multiple MR sequences can provide a comprehensive
evaluation of the pancreatic mass, its internal struc-
ture and enhancement characteristics. Most studies

a b

c d

Fig. 3.13a-d. Oligocystic SCT (CT evaluation). a, b First case. The axial scans obtained in the craniocaudal direction during the
pancreatic phase show a unilocular cystic mass with multilobulated borders. c, d Second case. At CT (c) in the portal venous phase,
there is a large cystic lesion of the pancreatic head with a central scar and radially oriented thin septa. Contrast injection into the
duct ofWirsung of the resected specimen (splenopancreatectomy (d) shows that the large cyst of the pancreatic head does not com-
municate with the main duct, which appears merely displaced, while the collateral ducts are displaced in a basket-like fashion
 42 G. Carbognin et al.

require several sequences from which this informa- 3.2.3.2

tion can be extracted.
Initially, T2-weighted fast or turbo-spin-echo
(TSE) images are obtained, which in suspected
micro cystic SCT are immediately followed by
MRCP. The information obtainable from these ini-
tial sequences is often enough to make a conclusive
diagnosis. If necessary, contrast-enhanced imaging
utilizing intravenous gadolinium-DTPA (Gd-DTPA)
is carried out. In this case, whenever possible, it is
better to use spoiled gradient refocused echo (GRE)
3D sequences with fat suppression. First, precontrast
images are acquired both in-phase and opposed-
phase. Then acquisitions in the pancreatic, venous
and late phases are obtained after the rapid bolus IV
injection of Gd-DTPA (MERGO et al. 1997; PROCACCI
et al. 1997; KANEMATSU et al. 2000). The advantage of
3D sequences is to offer, for each acquisition, the pos-
sibility of analyzing the enhancement of the paren-
chyma and, at the same time, of obtaining the lesion's
vascular map with postprocessing, which aids in
surgical planning for the larger masses.
MRFindings
3.2.3.2.1
Microcystic SeT
With GRE Tl-weighted images the lesion is easily
demonstrated and appears typically hypointense
compared with the adjacent parenchyma (Figs. 3.14a,
3.15a). The mass displays a homogeneous signal
since the septa and calcifications are not identifi-
able (PROCACCI et al. 1997, 2001a). Extremely rarely,
hyperintense hemorrhagic foci within the mass may
be detected (MERGO et al. 1997).
The T2-weighted TSE images are almost always
decisive in diagnosing SCT since the contrast reso-
lution afforded by MR can easily demonstrate the
small amounts of fluid interspersed within the
dense septa of the 'sponge-like' mass or, conversely,
will show the thin septa within the fluid of more
typical adenomas (Figs. 3.14b, 3.15b, 3.16a,b, 3.17a,b)
(NISHIHARA et al. 1996; MERGO et al. 1997; PROCACCI

c d

Fig. 3.14a-d. Microcystic SCT (MR evaluation). a Tl W SE sequence: the lesion appears homogeneously hypointense towards the
surrounding parenchyma. Septa and calcifications are not recognizable. b T2W SE sequence: the mass is hyperintense because
of the liquid content while the septa appear hypointense. c, d In the pancreatic (c) and venous (d) phases, there is enhancement
of the walls and the septa, giving the mass its 'honeycomb' aspect
a b

Fig. 3.1Sa-d. Microcystic SCT (MR evaluation; same patient as in Fig. 3.8). a Opposed phase, unenhanced TI W GRE sequence:
a homogeneously hypointense mass is located in the body of the pancreas. b T2W TSE sequence: the mass has a microcystic
architecture with septa radiating from the large central scar. A peripheral macrocyst, characterized by a higher signal than the
micro cysts, is evident. c, d Gd-DTPA-enhanced fat-suppressed TIW GRE sequence: in the pancreatic (c) and venous (d) phases
there is a progressive enhancement of the walls and septa, resulting in the typically 'honeycomb' appearance of the mass. The
peripheral macrocyst is easily identified. The large central calcification is not seen (see Fig. 3.8)

et al. 1997, 2001a,b). MR has a disadvantage in that it
is insensitive to calcification. In the case of SCT with a
mixed micro cystic and macro cystic architecture, the
homogeneously hyperintense peripheral macro cysts
and the central nucleus of microcysts are perfectly
recognizable (Figs. 3.15b, 3.17a,b). In this event, the
signal intensity of the peripheral macrocysts will be
higher than that of the central micro cystic nucleus
(PROCACCI et al. 1997). In the T2-weighted image
sequence, significant replacement of the pancreatic
gland is immediately demonstrated in von Hippel-
Lindau disease, particularly the multiple cystic areas
that replace most of the parenchyma (Fig. 3.18).
MRCP must be carried out routinely in the study
of these tumors (Figs. 3.lOd, 3.16c, 3.17c,d) since it
can contribute to distinguishing micro cystic SCT
from intraductal tumors of the collateral ducts,
which often have a septate appearance as well. MRCP
images should be obtained in the coronal plane,
according to multiple rotation angles, as well as the
axial plane to best detect dilatation of the duct of
Wirsung or the presence or absence of a communica-
tion duct between the cystic mass and the main duct
(Fig. 3.17c,d). The normality of the duct of Wirsung
and the lack of a communication duct can exclude the
presence of IPMT of the collateral ducts and allow for
a certain diagnosis of SCT (YAMAGUCHI et al. 1998;
DUPAS and LE BORGNE 2000).
In the contrast-enhanced phase, the MR findings
are essentially equivalent to CT. The mass will be
hypo intense in the pre contrast phase; enhancement
of both the septa and the walls is seen in the postcon-
trast pancreatic phase, at which time the 'honeycomb'
or 'sponge-like' patterns become evident (Figs. 3.14c,
3.15c) (MERGO et al. 1997; PROCACCI et al. 2001a,b).
In the venous phase the 'honeycomb' appearance is
even more easily recognizable (Figs. 3.14d, 3.15d,
3.19), while the mass with the 'sponge-like' aspect can
sometimes appear solid which, theoretically, could
lead to the misdiagnosis of a solid tumor. However,
with the T2-weighted image sequences this mistake
need not be made. Unfortunately, it is not possible to
find calcifications in any of these phases. The identifi-
cation of possible peripheral macro cysts is, however,
44 G. Carbognin et al.

Fig. 3.16a-d. Microcystic SCT (MR evaluation). T2W half-Fourier single-shot turbo-spin-echo (HASTE) sequence obtained in the axial
(a) and coronal (b) planes: a small, multilobulated lesion can be seen with a micro cystic aspect and a small, hypointense, central scar.
e MRCP highlights the normal duct of Wirsung overlaid by the small mass, making it impossible to establish the presence or absence
of communication between the two structures. d Only ERCP is able to exclude the communication between the main duct and the
cystic mass, allowing for a definite diagnosis of microcystic SCT. Only a small imprint (arrow) is recognizable on the ductal wall

easy (Fig. 3.1Sd). If a GRE 3D sequence is performed
in the same pancreatic and venous phases, postpro-
cessing can provide an accurate vascular map of the
pancreatic area, identifying phenomena of compres-
sion, more rarely occlusive, of the peripancreatic
vascular structures.
3.2.3.2.2
Oligocystic SeT
The oligocystic form has a nonspecific MR aspect with
characteristics analogous to those demonstrated by CT
(Fig. 3.20). Once again, calcifications eventually present
are not distinguishable (PROCACCI et al. 1997).
3.2.4
Other Imaging Modalities
3.2.4.1
Plain Radiographs
When the masses are sufficiently large, plain film
examination of the abdomen will demonstrate a soft-
tissue mass in the epigastric region, with a displace-
ment of gas-filled hollow viscera. Punctate, globular,
or rarely lamellar calcifications can be revealed in
the region of the pancreas (MATHIEU et al. 1989;
VILGRAIN et al. 1999; FRIEDMAN et al. 1983).
3.2.4.2
Contrast Examination
of the Upper Gastrointestinal Tract
SCT, more commonly situated in the head, can pro-
duce a widening of the duodenal loop, and the rare
positioning in the body-tail can impress the stomach
or the colon (MATHIEU et al. 1989; VILGRAIN et al.
1999). These findings are incidentally noted during
barium studies of the digestive tracts, in which pan-
creatic disease is not suspected as the cause of the
patient's symptoms.
3.2.4.3
Angiography
Angiography has often been used in the study of
cystic masses of the pancreas since it is able to distin-
guish hypervascular lesions, almost always benign,
from hypovascular ones, which are malignant or
 Serous Cystic Tumors 4S

a b

c d

Fig. 3.17a-d. Microcystic SCT (MR evaluation). a, b T2W HASTE sequences obtained in the craniocaudal direction reveal a lesion
of the pancreatic body. The mass gently displaces the duct ofWirsung. The lesion has a mixed micro cystic and macro cystic appear-
ance. The macro cystic component has a higher signal intensity than the micro cystic one. c, d At MRCP the mass overlies the main
duct in the coronal plane (c), while in the axial (d) plane, the absence of a communicating duct between the lesion and the main
duct leads to a diagnosis of serous cystadenoma

Fig. 3.18a,b. Von Hippel-Lindau disease (MR evaluation; same patient as in Fig. 3.12c,d). In the T2W TSE images obtained in
a craniocaudal direction, the pancreatic gland is notably increased in volume and replaced by multiple cystic formations; the
duct of Wirsung is not dilated. There are also lesions with analogous signal behavior in the right kidney (b)
 46 G. Carbognin et ai.

a b

Fig. 3.19a,b. Microcystic SCT (MR evaluation). After the administration of Gd-DTPA on both the axial (a) and coronal (b) II W
GRE scans, a large mass of the body-tail with the typical 'honeycomb' aspect is evident

a b

Fig. 3.20a,b. Oligo cystic SCT (MR evaluation). In the IIW (a) and T2W (b) images obtained in the axial plane, the mass shows
a unilocular macrocystic aspect. Typical internal septations are not evident in this variety of path-proven SCT

potentially so (WARTER et al. 1981). In fact, in the
case of a micro cystic tumor, selective arteriography
of the celiac trunk and the superior mesenteric artery
demonstrates the presence of a hypervascular mass
with dilated afferent arteries, neo-vascularization
and 'blush' capillaries (Fig. 3.21). The hypervascu-
larization is due to the extended capillary network
present in the septa (WARTER et al. 1981; WARSHAW
and RUTLEDGE 1987; BUCK and HAYES 1990). Signs of
vascular encasement are, however, not recognizable
(FRIEDMAN et al. 1983; ITAI et al. 1988). In the arterial
phase, radiolucent areas, equal to or less than 2 em,
are recognizable around the mass (Fig. 3.21a). In the
parenchymal phase, the intense enhancement of the
septa, especially in the sponge-like form, renders the
mass uniformly dense (Fig. 3.21b). The intense and
homogeneous enhancement of the lesion can some-
times lead to the misdiagnosis of a hypervascular
solid tumor (a nonfunctioning endocrine tumor, for
example). In the presence of a tumor with a micro-
cystic nucleus surrounded by macrocysts, arteriog-
raphy can document the intense enhancement of the
micro cystic hypervascularization and the 'basket-
like' imprint by the non-vascularized macro cysts on
the vessels at the periphery (Fig. 3.22).
Oligo cystic SCT inevitably has a nonspecific
angiographic appearance, showing up as an avascu-
lar mass with possible smooth displacement of arte-
rial and venous peripancreatic vessels (Fig. 3.23), an
appearance identical to mucinous cystic tumor.
3.2.4.4
Endoscopic Retrograde Choiangiopancreatography
ERCP has occasionally been used in the study of
cystic tumors with the aim of characterizing the
 Serous Cystic Tumors 47

a b

Fig. 3.2Ia,b. Microcystic SCT (angiographic evaluation). a Selective injection into the superior mesenteric artery shows the
presence of a large hypervascular mass in the pancreatic head. There is a capillary 'blush', around which the afferent arteries
appear dilated. The enhancement is inhomogeneous due to the presence of radiolucent areas inside the mass. In the portal
phase (b) the intense enhancement persists with imprinting on the veins

a b

Fig. 3.22a,b. Microcystic SCT. a CT evaluation: in the portal venous phase, a mass with a micro cystic nucleus outlined by mac-
rocysts is recognizable. b Angiographic evaluation: in the arterial phase, selective arteriography of the celiac trunk shows the
intense enhancement of the micro cystic nucleus and the basket-like dislocation of the branches of the pancreatic arches by the
non -vascularized macro cysts

lesion. In reality, in the presence of a SCT, the ERCP
examination is invariably normal (WARSHAW and
RUTLEDGE 1987). Only in the larger lesions is it pos-
sible to find a non-specific mass effect on the duct of
Wirsung which otherwise retains its regular caliber
and morphology (Fig. 3.24). An obstruction in the
main duct, relatively common in malignant cystic
tumors, is extremely rare in SCT (FRIEDMAN et al.
1983; GAZELLE et al. 1993). More recently, having
clarified the morphological characteristics of the
collateral duct IPMT, whose appearance is analo-
gous to SCT, particularly in small masses, ERCP is
justified for the differential diagnosis (Fig. 3.16d).
In fact, this is the only method able to confirm the
absence of communication between the cystic mass
and the main pancreatic duct, allowing for a definite
diagnosis of microcystic SCT (PROCACCI et al. 1996,
2001b). There is only one reported case of a micro-
 48 G. Carbognin et al.

a b

c d

Fig. 3.23a-d. Oligo cystic SCT. a CT evaluation: in the venous phase, a bi-lobed, macrocystic lesion is recognizable in the pancre-
atic tail. b-d Angiographic evaluation: in the arterial (b), venous (c) and delayed (d) phases, as shown by CT, a non enhancing
area is visible in the pancreatic tail (asterisk) at the site of the lesion

Fig. 3.24a,b. Oligo cystic SCT. a CT evaluation: in the late phase, a large, unilocular cystic mass is recognizable in the pancreatic
body. b ERCP evaluation: it is possible to distinguish the mass effect (arrows) on the duct of Wirsung that has an otherwise
regular caliber and morphology
 Serous Cystic Tumors
cystic adenoma communicating with the collateral
duct at ERCP (DELCENSERIE et al. 1988).
3.2.4.5
Endoscopic US
EUS can be used in the study of cystic masses of the
pancreas with the aim of characterizing the lesion
when this has not been done by cross-sectional imag-
ing. In fact, this technique's contrast and spatial reso-
lution are particularly high (ARIYAMA et al. 1998).
It is certainly not only superior to transabdominal
US, but to other cross-sectional imaging methods as
well (ARIYAMA et al. 1998). In the classic micro cystic
forms, which may falsely appear solid, EUS can visu-
alize the micro cysts (smaller than 2 mm) within the
mass (NAPOLEON et al. 1993; PALAZZO et al. 1999)
(Fig. 3.25). In our personal experience and that of
other authors, EUS has proved particularly useful in
studying small lesions since it can demonstrate the
micro cystic architecture and help clarify the nature
of a cystic pancreatic mass (Fig. 3.26). In the presence
of cystic lesions smaller than 2 cm, EUS becomes an
essential examination because the morphological
definition and classification have a high accuracy
(KoITO et al. 1997,2001). Even the small serous cys-
toadenomas demonstrate an internal structure similar
to that typical honeycomb (BRUGGE 2000) (Fig. 3.27).
The relationship between the small tumor and the
pancreatic duct can also be evaluated with greater
accuracy so as to exclude (SCT) or demonstrate
(branch duct IPMT) the presence of a communica-
a b
Fig. 3.25a,b. Microcystic SCT (EUS evaluation). a Large lesion, adjacent to the duodenal wall. Within the apparently solid struc-
ture, multiple cystic lesions are appreciable. b Different case: multiple micro cysts are visible within the smalliesion(arrow).
PV, portal vein
49
tion duct. Definitive evaluation of the communication
with the pancreatic duct is not possible in every case.
Recently, it was suggested that EUS should be used
in the study of unilocular or multilocular macrocys-
tic masses as the more accurate structural analysis,
even where large masses are concerned, would allow
visualization of the parietal microcysts which are
otherwise not distinguishable with other imaging
techniques. SCTs that manifest with an apparent
oligo cystic aspect in other investigations can also be
characterized if small micro cystic foci are present
(LEVY et al. 1995; PALAZZO et al. 1999; KANETO et
al. 2000). Nevertheless, there remains a percentage of
macro cystic lesions with unilocular appearance and
totally anechoic texture where EUS fails to demon-
strate the presence of peripheral micro cysts within or
just close to the wall. In this case, a diagnosis of nature
based only on morphological criteria is feasible in
no more than 50% (LEVY et al. 1995; MALLERY et al.
1998), while the differential diagnosis from a branch
duct IPMT appearing as an unilocular cyst is hardly
feasible (PALAZZO et al. 1999; VALETTE et al. 2001). In
the specific case of unilocular lesions, needle aspira-
tion under endosonographic guidance (FNA) may be
of help. The sample is taken in a more precise way
than that obtained under transabdominal guidance
and with a smaller risk of dissemination (PALAZZO et
al. 1999; BHUTANI et al. 1997; SUITS et al. 1999).
The cytologic examination, the biochemical
analysis of the fluid and the dosage of the tumoral
markers (CEA, CA 19-9, CA 72-4, Ki-ras gene muta-
tions, etc.) can contribute to improving the diagno-
 50
a b
c of a micro cystic SCT
sis. In particular, CEA is useful for discriminating
between mucinous and nonmucinous lesions (LEVY
et al. 1995; MALLERY et al. 1998; BRUGGE et al. 2001).
A lower titer of CEA, the absence of mucin, the pres-
ence of typical glycogen-rich, PAS-positive cells and
the absence of malignant cells lead to the diagnosis of
serous cystadenoma.
3.3
Differential Diagnosis
In light of what has been reported in the previous sec-
tion, whichever diagnostic method is used, the differ-
ential diagnosis problems that SCT poses for imaging
depend on whether the micro cystic or the oligocystic
form is being considered. US and/or CT, which are
the more commonly used imaging techniques in the
study of SCT, give three possible diagnoses.
In the majority of cases, these methods are able to
document the micro cystic, 'honeycomb' or 'sponge-
G. Carbognin et al.
Fig. 3.26a-c. Microcystic SCT. a Transabdominal US evalu-
ation: small cystic and apparently unilocular lesion in the
head of the pancreas. b CT evaluation: the unilocular aspect
of the lesion is confirmed. c EUS evaluation: the lesion has
lobulated contours and central septa which allows recognition
like' aspect of the lesion. Finding a mass with these
characteristics in the pancreatic head in a woman,
especially when the pancreatic gland upstream of the
lesion appears normal with no dilation of the duct
of Wirsung, and central calcification when present
(in 10%-30% of cases according to COMPTON 2000)
results in a definite diagnosis of SCT. In this case, there
is no need for further diagnostic investigation since
the therapeutic choice, especially in advocating radi-
cal surgery, will be made on the basis of the clinical
picture and the patient'S general condition. The diag-
nosis of SCT can also be considered definite when the
lesion shows a mixed aspect with macro cysts (more
than 3 cm in diameter) situated on the periphery
of the micro cystic nucleus. If surgical intervention
is decided against, the lesion must be monitored.
The development of a serous cystadenoma is vari-
able since the mass in some patients can remain
unchanged for many years (Fig. 3.28), while in others
a progressive growth is recorded (Box and DOUGLAS
2000) and, in relation to the appearance of signs of
compression on the adjacent structures, may justify
 Serous Cystic Tumors 51

a b

c d

Fig. 3.27a-d. Microcystic SCT (EUS evaluation). a Small lesion of the pancreatic body (arrow), with honeycomb architecture.
b Different case: middle-sized lesion with multiple septa and small peripheral cystic areas (white arrows). c Another case: small
lesion, composed of micro cysts separated by thin septa. Changing the scan angle (d), the same lesion shows microscopic septa
and a peripheral cystic area. PV, portal vein; SV, splenic vein; SMV, superior mesenteric vein

a b

Fig. 3.28a,b. Follow-up of micro cystic SCT (CT evaluation). The mass with a typical microcystic appearance (a) does not show
significant morphological or dimensional variations in the follow-up performed 2 years after the initial scan (b)
 52 G. Carbognin et al.

late, but inevitable, radical surgery (Figs. 3.29, 3.30).
In some cases the volume may spontaneously
decrease, and eventual macro cysts, situated on the
periphery of the micro cystic nucleus, may even dis-
appear (Fig. 3.31).
Despite demonstrating a micro cystic aspect, the
correct diagnosis of the lesion is less certain when-
ever the mass is found in a male patient, whether
located in the uncinate process and/or associated
with dilation of the duct of Wirsung (Fig. 3.10). In
this event, in fact, the differential diagnosis of branch
ducts IPMT may be more appropriate.
To make a differential diagnosis, the primary aim of
imaging is to demonstrate the presence or absence of
a communicating duct between the mass and the duct
of Wirsung. MRCP could be used for this purpose, but
the diagnosis can only be considered definite when
the absence of a communication duct between the
mass and the main duct is shown. This can be done by
acquiring multiple plane images (Fig. 3.17). However,
when the lesion is superimposed upon or adjacent to
the duct of Wirsung (Figs. 3.lOd, 3.16a-c), it is neces-
sary, even today, to carry out an ERCP (Fig. 3.16d).
For various reasons, the tumor can appear as a
solid mass with US or CT (Figs. 3.2, 3.11), resulting
in misdiagnosis. In particular, and above all with CT,
the bright enhancement of the tumor can lead to the
misdiagnosis of a non-functioning endocrine tumor.

a b

Fig. 3.29a,b. Follow-up of micro cystic SCT (US evaluation). The mass located in the tail of the pancreas has a typical micro-
cystic aspect and shows significant growth after 5 years. At the second follow-up (b) the compressing effect on the splenic vein
(arrows) is more evident. At surgery, benign micro cystic SCT was diagnosed

a b

Fig.3.30a,b. Follow-up of microcystic SCT (CT evaluation). The lesion with a micro cystic structure located in the tail of the
pancreas (a) shows conspicuous growth at the second follow-up (b) carried out after 3 years. At surgery, benign microcystic
SCT was diagnosed
 Serous Cystic Tumors
a b
Fig. 3.31a,b. Follow-up of micro cystic SCT (CT evaluation). In the second follow-up done after 28 months, the mass has changed
aspect in that the macrocyst, recognizable on the previous study (asterisk in a), has been reabsorbed (b)
In some cases the use of both techniques can correct
the reciprocal errors; in others, in order to resolve the
diagnostic doubt, it is necessary to turn to MR which,
mostly thanks to T2-weighted image sequences, is
always able to recognize the micro cystic aspect of
the lesion.
The diagnosis is necessarily non-specific when
the SCT has a unilocular or multilocular macro cystic
aspect (Figs. 3.3, 3.13, 3.20, 3.24), analogous to that
of many other cystic lesions of the pancreas. In the
past, in the cases examined with conventional CT,
such misclassification was due to not recognizing
central septations which were easily demonstrated
by US or MR. At present, the macro cystic lesion seen
with all imaging modalities is related to an oligocys-
tic SCT. Proper characterization of this mass may be
impossible: the only technique able to supply supple-
mentary information seems to be EUS, which can
demonstrate the micro cystic aspect of rather small
lesions (Figs. 3.25, 3.26) or the presence of parietal
microcysts around a macrocystic mass. Thanks to
such findings, not obtainable with the other methods,
it is possible to correctly classify the lesion. In the
majority of these cases, unfortunately the diagnosis
is still non-specific; needle aspiration of the lesion
is also not always able to supply decisive elements
for characterizing the lesion. Therefore, the smaller
lesions, particularly in elderly patients, are followed
up, while the inevitable final step for the others is
surgical intervention.
53
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4 Mucinous Cystic Tumors
C. BIASIUTTI, F. FORNASA, S. VENTURINI, N. PAGNOTTA, G. SCHENAL, and C. PROCACCI

CONTENTS of epithelial abnormality coexisting in the same

tumor (ZAMBONI et al. 1999; SARR et al. 2000), MCT
4.1 Introduction 57 will display a more uniform epithelial profile within
4.2 Imaging 57 the same lesion. However, most authorities believe
4.2.1 Transabdominal US 57
4.2.2 Computed Tomography 60
that MCT is, at best, a premalignant lesion, and there-
4.2.3 Magnetic Resonance Imaging 64 fore it is important to distinguish it from other cystic
4.2.4 Other Imaging Modalities 64 tumors of the pancreas. A complicating factor is that
4.2.4.1 Plain Films 64 because many are benign adenomas when resected,
4.2.4.2 Contrast Examination it is also desirable to be able to define features char-
of the Upper Gastrointestinal Tract 69
4.2.4.3 Angiography 69 acterizing either a benign or malignant tumor to aid
4.2.4.4 Endoscopic Retrograde in establishing the prognosis and to help in choosing
Cholangiopancreatography 69 the appropriate therapy (PROCACCI et al. 2001b).
4.2.4.5 Endoscopic US 70 In the majority of cases, an MCT is identified acci-
4.3 Prognostic Evaluation 71 dentally during radiological examinations carried
4.4 Differential Diagnosis 71
References 72
out for other clinical indications not directly refer-
able to the pancreas. Therefore, the roles of imaging
include identifying, characterizing, and classifying
a given lesion as MCT and, when appropriate, sug-
gesting a differential diagnosis. Today, ultrasound
4.1 (US), computed tomography (CT), and magnetic
Introduction resonance imaging (MR) are the three imaging pro-
cedures called upon to answer these questions. There
The mucinous cystic tumor (MCT) was first clas- is no role for radiological examinations, such as plain
sified by OERTEL and COMPAGNO as 'macro cystic film of the abdomen, upper gastrointestinal tract
cystadenoma/cystadenocarcinoma' to differentiate examination, or angiography. ERCP, endoscopic US
it from the microcystic serous cystic tumor (SCT) (EUS), and fine needle aspiration biopsy (FNAB) may
(COMPAGNO and OERTEL 1978). Subsequently, a provide definitive ancillary information (FUGAZZOLA
further subdivision between peripheral MCT and etal.1991).
intraductal papillary mucinous tumor (IPMT) was
made. Although both of these lesions are lined with
a mucin-secreting epithelium, the clinical and mac-
roscopic pathological characteristics are completely 4.2
different (SHYR et al. 1996). The WHO classification Imaging
of 1996 distinguishes MCT from IPMT. While IPMT
may display four different grades, from adenoma 4.2.1
through low-grade/high-grade dysplasia to invasive Transabdominal US
carcinoma in accordance with the degree of epithelial
dysplasia (WILENTZ et al. 2000), with different grades The increasing use of US in recent years has certainly
contributed to the rise in the number of diagnoses
of MCT. Moreover, the technological refinements in
C. BIASIUTTI, MD; F. FORNASA, MD; S. VENTURINI, MD; N.
PAGNOTTA, MD; G. SCHENAL, MD; C. PROCACCI, MD US in the last decade have improved pancreatic US
Istituto di Radiologia, Policlinico Universitario 'GB Rossi', P.le evaluation even in obese patients or those with large
L.A. Scuro, 10,37134 Verona, Italy amounts of intestinal gas.
 58 C. Biasiutti et al.

MCT displays two characteristic imaging patterns
on all cross-sectional modalities (ALGARD et al. 1986;
JOHNSON et al. 1988; FUGAZZOLA et al. 1991). The
macro cystic multilocular pattern is the most common
variety of MCT. Although it is not pathognomonic
(SPERTI et al. 1993), this variety is frequently located
in the body-tail, appearing as a rounded, sharply
defined mass with a variably thickened wall (BASTID
et al. 1989; BUETOW et ai. 1998). Centrally located thin
septa delimit wide cystic spaces (FRIEDMAN et al.
1983; FUGAZZOLA et al. 1991). The lesion has a multi-
locular, hypoechoic appearance displaying increased
through transmission (Fig. 4.1a) (ALGARD et al. 1986;
BUETOW et al. 1998). The cyst content can have vari-
able acoustic characteristics within the same mass,
related to the amount of mucin within any of the
locules (Fig. 4.1 b) (FRIEDMAN et al. 1983). Scattered
echoes can be recognized in the dependent portion
of the cyst (Fig. 4.1c), indicative of prior hemorrhage
(BUETOW et al. 1998). In calcified lesions, hyperechoic
lamellar foci will be present in the peripheral por-
tions of the tumor (Fig. 4.1d) (WOLFMAN et al. 1982;
FUGAZZOLA et al. 1991; FERNANDEZ DEL CASTILLO
and WARSHAW 1995; SCOTT et al. 2000). Larger cal-
cifications produce the expected shadowing. With
US examinations using tissue harmonics, exquisitely
thin peripheral septa will frequently be recognized.
The importance of recognizing septa as a diagnostic
feature of MCT cannot be overemphasized. Careful
attention to technique and examining the pancreas
from multiple orientations aid in the localization of
these septa (FRIEDMAN et al. 1983). The thickness of

a b

c d

Fig. 4.1a-d. Macrocystic multilocular mucinous cystic tumor (MeT) (US evaluation). a A fluid-containing mass with sharp bor-
ders; there are thin septa (arrows) within the cystic space. The increased through transmission results in acoustic enhancement
of the posterior wall (asterisk). b Multilocular cystic formation with thin wall. The cystic space on the left is more echo genic
due to the greater amount of mucin (arrow). c Multilocular cystic formation with hemorrhagic debris; fine echoes are seen in
the dependent portion of the mass (arrows), a sign of previous hemorrhage. d Multilocular cystic formation with a calcification
(arrow) along one of the septa results in posterior shadowing (asterisk)
 Mucinous Cystic Tumors 59

the septa, like that of the marginal capsule, is vari-
able, from 2 mm to over 1 cm (Fig. 4.2) (ALGARD et
al. 1986). When the wall is thicker, it is more common
to find papillary proliferations originating from the
wall or its septa. The thick septa and/or papillary pro-
liferations are often proof of the malignant degenera-
tion of the MeT (WOLFMAN et al. 1982; BUETOW et
al. 1998).
The macrocystic unilocular pattern is less
common and rather less specific than the multiloc-
ular one, in that it simulates any pancreatic cystic
mass (BUETOW et al. 1998; SCOTT et al. 2000). The
tumor shows up as a hypoechoic, sharply circum-
scribed mass with enhanced through transmission.
If the walls are smooth and thin (Fig. 4.3a), differen-
tiation between this lesion and other cystic masses,
including pseudocyst, cannot be made easily
(SPERTI et al. 1993; BUETOW et al. 1998). Smaller
lesions often have this appearance. It should be
emphasized that if one encounters a unilocular
mass with a thick irregular wall, MeT should be
the primary diagnostic consideration (Fig. 4.3b)
(SCOTT et al. 2000). There can sometimes be intra-
mural hyperechoic foci along the thick wall which
are due to calcifications. A thick wall and periph-
eral calcifications are ominous signs of malignant
degeneration. The content of the unilocular MeT
may be inhomogeneous due to the presence of
low-level echoes, producing a fluid-fluid level in the
dependent portion of the lesion. These are presum-
ably the result of episodes of recent hemorrhage
into the mass (BUETOW et al. 1998).

a b

Fig. 4.2a,b. Macrocystic multilocular MCT (US evaluation). Two large lesions with clear content and peripheral septa. The septa
thickness is variable, being either thin (long arrow in a) or thick (short arrow in b). Thick septa raise the suspicion of malignant
degeneration of the lesion

Fig.4.3a,b. Macrocystic unilocular MCT (US evaluation). Unilocular, thin-walled, fluid-containing intrapancreatic mass. In (a),
because of no other findings, the appearance is nonspecific, and a diagnosis cannot be made. In (b), however, the suspicion
of MCT can be more confidently raised due to the presence of mural vegetation (arrow). These mural elements also suggest
malignant degeneration
60 C. Biasiutti et al.

4.2.2
Computed Tomography

Thin-section helical/spiral CT is the primary modal-

ity for detecting and characterizing MCT. Multislice
CT offers significant improvements over single-slice
techniques. This is due to the ability to acquire thin-
section data and evaluate the images in any viewing
plane. The use of thin sections allows better delin-
eation of structural findings (septa, calcifications)
which, located in the superior or inferior poles of
the mass, can sometimes go unrecognized in axial
a
scans. The technique for studying these masses
either by single or multislice CT is identical to that
described in Chapter 3.2.2.1. The reader is referred
to this discussion.
The macrocystic multilocular pattern is best
demonstrated following IV contrast enhancement,
although careful attention should be paid to unen-
hanced images if they are obtained (BUETOW et al.
1998; PROCACCI et al. 2001a). On unenhanced images,
the tumor is easily identifiable (Figs. 4.4a, 4.5a, 4.6a,b,
4.7a). In this phase, the wall and the septa are identifi-
able only when they are thick or when there are lamel-
lar calcifications (BUETOW et al. 1998; CURRY et al.
2000; PROCACCI et al. 2001a; SARR et al. 2001). Precon- b
trast unenhanced images are particularly helpful for
documenting calcifications (Fig. 4.5a). In this phase,
variability in the density of the cyst contents is easily
recognizable (Figs. 4.5a, 4.6a,b). The variability is the
result of either greater or lesser quantities of mucin
or fluid-fluid levels resulting from prior hemorrhage
(ITAI and OHTOMO 1996; BUETOW et al. 1998).
Analysis of enhanced images during the pancre-
atic phase, the time during which the gland is maxi-
mally enhanced, reveals that the walls and the septa
appear to display a slightly lower attenuation value
compared with the densely enhanced surrounding
pancreatic parenchyma because of the fibrous tissue
composition and minimal vascularization (Figs. 4.4b,
c
4.5b, 4.6c,d, 4.7b) (SOYER et al. 1994). The outer wall
and the septa have a similar thickness (Figs. 4.4, 4.5). Fig. 4.4a-c. Macrocystic multilocular MCT (CT evaluation).
The septa are gently curved and can extend across a Unenhanced image: a large, thin-walled mass containing septa
the diameter of the tumor or bridge adjacent regions (arrows) expands the pancreatic tail and displaces the stomach
of the same wall. It is sometimes possible to recog- anteriorly. b Pancreatic phase image: notable enhancement of
the pancreatic parenchyma with respect to the mass. c Venous
nize small peripheral cysts located on, or sometimes
phase image: the septa become even more apparent
within, the wall (Fig. 4.8). When present in malignant
lesions, papillary projections or nodules can be
detected in the pancreatic phase of enhancement of the wall (FuGAZZOLA et al. 1991; PROCACCI et al.
(Figs. 4.6c, 4.7b, 4.8a) (ITAI et al. 1982; BUETOW et al. 2001a; SARR et al. 2001). Differential densities within
1998; CURRY et al. 2000; Ros et al. 2000). In mucinous the mass are less evident following contrast enhance-
cystadenocarcinoma, there can also be extracapsular ment (Fig. 4.5a,b). The combined use of thin sections
extension of the lesion as well as nodular thickening for optimal enhancement of peripancreatic vessels
a
a

Fig. 4.5a-c. Macrocystic multilocular MCT (CT evaluation). c

a Unenhanced image: large mass in the body-tail of the pancreas
with a mural (peripheral) calcification along the anterior wall
(arrow). Thin septa delimit different cystic compartments. The
variable attenuation within the loculations results from prior
hemorrhage into the largest one (asterisk). b Pancreatic phase
image: although the enhancement of the surrounding pancreas
makes localization apparent, the mural calcification is more dif-
ficult to detect. The septa are well seen. c Venous phase image:
progressive enhancement of the septa which have become hyper-
dense (short arrows) compared with the pancreatic parenchyma

Fig. 4.6a-d. Macrocystic multilocular MCT (CT evaluation). a,

b Unenhanced images: a large mass almost totally replaces the
pancreatic gland. The lesion contains multiple septa delimiting
cystic spaces with various attenuation resulting from prior hem-
orrhage. c, d Pancreatic phase image: enhancing mural nodules
d
(arrow) can be distinguished from hemorrhagic debris
 62 C. Biasiutti et al.

Fig.4.7a-c. Macrocystic multilocular MCT (CT evaluation).

a Unenhanced image: a large, partially cystic mass in the
body-tail of the pancreas with prominent solid component
and thick septa. b Pancreatic phase image: early enhancement
of the solid components. The mass displaces the splenic vein
(arrows). c Venous phase image: progressive enhancement of
the capsule delimits the mass from the pancreatic gland. The

..
splenic vein is displaced, but not infiltrated, by the mass

Fig. 4.8a,b. Macrocystic multilocular MCT (CT evaluation).

Pancreatic phase image. A bi-lobate mass in the pancreatic
body-tail with thick septa and thick walls. Nodules (arrow in a)
are present along the wall and the septal margins. Small cystic
formations (arrowheads in a and b) are visible. The mass com-
presses and displaces the stomach anteriorly (asterisk) and the
c descending colon (C) posterolaterally
 Mucinous Cystic Tumors 63

provides data sets which can accurately depict the
tumor's relationships with the peripancreatic vessels.
MeT will displace and compress surrounding arter-
ies; frank encasement is unusual. Venous thrombosis
may occur resulting from local mass effect, but this
phenomenon is also unusual (Figs. 4.6c, 4. 7b) (SOYER
et al. 1994). The relationships of the tumor with the
pancreatic duct and/or the common bile duct can
also be depicted in both axial scans and reconstruc-
tions. Similar to SeT, the MeT will compress or dis-
place the ducts without frank invasion (WARSHAW
et al. 1990; STEPHENS 1997; PROCACCI et al. 2001a).
The compression rarely results in duct obstruction
despite the large size of the lesions (MARTIN et al.
1998). Reconstructed thin section images can effec-
tively show the relationship of the mass to the sur-
rounding GI tract (Figs. 4.4-4.8).
Delayed enhancement of the tumor wall and septa
may be observed in the venous phase. This is a direct
result of the presence of fibrous tissue within the wall
and stroma. This phenomenon results in increased
conspicuity of the tumor margin against the pancreatic
parenchyma (Figs. 4.4c, 4.5c, 4.7c). The other findings
are identical to those obtained in the pancreatic phase.
Venous phase images are primarily used to survey the
entire abdomen and pelvis for extrapancreatic foci of
disease. The most frequent locations of metastases are
within the peritoneum (JOHNSON et al. 1988) and liver
(SHAMSI et al. 1993; BUETOW et al. 1998).
The macrocystic unilocular pattern is easily con-
fused with other cystic pancreatic masses (Fig. 4.9).
The demonstration of a thick irregular wall, calcifica-
tions (Fig. 4.9c), and/or parietal nodules (Fig. 4.9d)
allows a diagnosis of MeT (MARTIN et al. 1998; ITOH
et al. 1992; ITAI et al. 1982). When these findings are
absent, and when the tumor appears as an unilocular
cystic mass with a thin wall (Fig. 4.9a,b), MeT is no
longer distinguishable from other cystic masses of

c d

Fig. 4.9a-d. Macrocystic unilocular MCT. a, b Pancreatic phase images: two different patients display thin-walled unilocular
cystic lesions within the pancreatic parenchyma: the characteristics of the mass do not allow for classification. c, d Venous
phase images: two different cases. The presence of calcifications (arrow in c) within the wall of an unilocular cystic mass of
the pancreas, even though it is a nonspecific finding, is suspicious of MCT. Similarly, the demonstration of the thick wall with
nodules (arrowhead in d) leads to the diagnosis of MCT
64
the pancreas, even pseudocyst (JOHNSON et al. 1988;
FUGAZZOLA et al. 1991; SOYER et al. 1994; BUETOW
et al. 1998; CURRY et al. 2000). In this case, it may be
necessary to perform a fine needle aspiration biopsy
of the lesion. Increasing experience with MDCT
promises that architectural features may be better
recognized (Fig. 4.10).
4.2.3
Magnetic Resonance Imaging
Current MR technology provides acquisition times
of sufficiently short duration to allow breathhold
dynamic contrast-enhanced study of the pancreas
and the ability to acquire data in 3D (MINAMI et al.
1989; THOENI and BLANKENBERG 1993; KEHAGIAS
et al. 2000). The addition of MRCP provides further
imaging with the ability to visualize the pancreatic
duct (KoITO et al. 1998; MERA et al. 1999; ALBERT et
al. 2000; MEGIBOW et al. 2001a).
The overall MR evaluation consists of a series of
acquisitions performed prior to and following IV
contrast administration. On precontrast Tl-weighted
GRE images (optimally performed with fat suppres-
sion), lesions displaying the macrocystic multilocular
pattern (Figs. 4.11, 4.12) appear as rounded, sharply
circumscribed masses mainly located in the body-
tail (MINAMI et al. 1989; ITo et al. 2001). The con-
tent is homogeneous and hypointense (Fig. 4.11b).
Thick mucin or foci of hemorrhage may increase
the signal (Fig. 4.12b) (MINAMI et al. 1989; Ros et
al. 2000; PROCACCI et al. 2001a; ITO et al. 2001). On
this sequence, the central septa and the calcifications
are almost always unrecognizable. Identification of a
thick wall and of peripheral mural nodularity is dif-
ficult (Fig. 4.13a).
T2 characteristics may be rapidly visualized
by so-called 'turbo' or 'fast spin-echo' techniques,
such as rapid acquisition relaxation enhancement
(RARE) or half-Fourier single-shot turbo spin-echo
(HASTE). The predominantly fluid content of these
masses renders them bright on all T2-weighted
images. The presence, characteristics, and distribu-
tion of internal septa are best appreciated with these
images (Figs. 4.10c-f, 4.11a, 4.12a). Calcifications are
not appreciated unless they are large. The intracystic
fluid is slightly hypointense compared with the pure
water signal which might arise from the gallbladder.
The decrease in signal is directly related to the mucin
composition or the presence of hemorrhagic foci
(MEGIBOW et al. 2001a) (Fig. 4.12a). The sequence
allows for accurate examination of the septa and
C. Biasiutti et al.
the papillary projections (Fig. 4.10c-f). T2-weighted
images (highly sensitive to fluid) are optimal for
viewing the duct of Wirsung (Fig. 4.10c,d). When
the mass clearly appears isolated from the duct of
Wirsung, thereby excluding the possibility of an
intraductal tumor, further examination with MRCP
is superfluous (KoITO et al. 1998; MERA et al. 1999;
DUPAs and LE BORGNE 2000).
Following intravenous contrast administration
(Gd-DTPA), the pancreas can be examined in an
identical fashion as with CT, i.e., a pancreatic and
venous phase (Figs. 4.11c,d,4.12c,d, 4.13b). Enhance-
ment produced by contrast medium administration
makes it much easier to recognize the lesion's cap-
sule and the septa, as well as any mural excrescence
or vegetation when compared with the unenhanced
scan (MERGO et al. 1997; BUETOW et al. 1998;
PROCACCI et al. 2001a). Maximal enhancement of
septa is observed in the venous phase (Figs. 4.11d,
4.12d, 4.13b). Data acquisition in the coronal plane
aids in the recognition of these anatomic elements
(Fig. 4.13b). Obviously, if a 3D sequence is used, the
best reconstruction planes can be determined at the
workstation during postprocessing. Unfortunately,
the recognition of calcification is not improved with
IV contrast (MERGO et al. 1997; BUETOW et al. 1998;
PROCACCI et al. 2001a). 3D postprocessing provides
vascular maps of the peripancreatic vessels, which
aids in surgical planning.
The macrocystic unilocular pattern as studied by
MR is also problematic in that septa may go unrec-
ognized. The lack of septa documentation will result
in a broad differential diagnosis of the cystic mass
(Fig. 4.14), unless the presence of a thick wall and,
above all, parietal nodules leads to the suspicion of
MCT (Fig. 4.15).
4.2.4
Other Imaging Modalities
4.2.4.1
Plain Films
There is no primary use for plain films in the study
of MCT. As with large SCT, a soft-tissue mass can be
demonstrated, which may displace gas-distended
hollow organs (DE LIMA et al. 1999). Calcifications
appear at the periphery of the lesion (Fig. 4.16)
(FRIEDMAN et al. 1983; BUETOW et al. 1998; SARR et
al. 2001). It is important to remember that other cystic
masses, including pseudocyst and cystic endocrine
tumor, can demonstrate the same calcifications.
 Mucinous Cystic Tumors 65

Fig. 4. lOa-f. Macrocystic multilocular MCT. a, b Venous phase images. CT evaluation of a unilocular mass of the pancreatic tail.
In the scan (a) there is a thin septum, which is not visible inferiorly (b). c, d Axial HASTE T2W images: a hyperintense mass is
recognizable, containing a single, thin, hypointense septum (black arrow in c) and thick irregular walls. The duct of Wirsung
appears normal downstream; dilation of some collateral branches is appreciable in the tail. e, f Coronal HASTE T2W images:
the ability to acquire images in a variety of planes leads to the demonstration of multiple thin septa (black arrowheads), lead-
ing the diagnosis towards MCT
 66 C. Biasiutti et al.

a
__ ~~ __ a

d ~U~ ."'C'''Ol J. al~;':) a .lCl.l51l;;, '-l\)u.\... JBQ\)\) 11J l.U~ UVUY-lau

pancreas with a thick, sharply marginated wall. Multiple septa

are visible within the lesion. b-d Axial GRE Tl W images. On
the unenhanced image (b), the content of the mass is homoge-
neously hypo intense, and the septa are faintly visible. Follow-
ing intravenous gadolinium, the septa are better seen during
the pancreatic phase (c) . In the portal venous phase (d), wall
enhancement is demonstrated; also, the enhanced internal
septa stand out from the hypointensity of the mucin
 Mucinous Cystic Tumors 67

Fig. 4.12a-d. Macrocystic multilocular MCT. a Axial SE T2W

image demonstrates a large, multiloculated lesion in the
pancreatic body-tail. The signal from the mass is variable,
related to the presence of different mucin composition and
hemorrhagic components: on T2W images, mucin (asterisk) is
hyperintense, and hemorrhagic content is responsible for the
decreased signal in the larger portion of the cyst. b Axial SE
II W image at the same level as (a). Demonstration of the dif-
ferent components of the lesion: one (asterisk) is hypointense
compared with the other. A thick, slightly hypointense wall is
appreciable at the periphery of the mass. c, d Axial GRE II W
images in the pancreatic (c) and venous (d) phases following
IV gadolinium. Moderate enhancement of the wall and the
septa are better seen during the venous phase
OIl

Fig. 4.14a-c. Macrocystic unilocular MCT. a Axial GRE T2W

Fig.4.13a,b. Macrocystic multilocular MCT. Coronal GRE II W
images. a In the precontrast phase, a large, rounded lesion is
demonstrated in the pancreatic body. The lesion appears het-
erogeneous due to the presence of filling defects within. b In
the portal venous phase following IV gadolinium, enhance-
ment of the filling defects and the wall is demonstrated
image reveals a unilocular, sharply marginated, cystic mass in
the pancreatic tail. b, c Axial GRE 3D II W FS images. Unen-
hanced image (b), the lesion appears homogeneously hypoin-
tense. In the pancreatic phase following IV gadolinium (c),
the lesion persists as hypointense. No filling defects or septa
are visible within. A specific diagnosis of MCT is impossible
in this case by imaging alone
 68 C. Biasiutti et al.

a
a

b b
Fig. 4.15a,b. Macrocystic unilocular MCT. Axial GRE TlW FS
images. a Unenhanced image: a unilocular, slightly hyperintense
mass is present in the pancreatic tail. A papillary proliferation
originates from the nondependent portion of the lesion. b In the
venous phase, the thick wall is enhanced, as well as the papillary
projection: these findings lead to the diagnosis of MCT

Fig. 4.16a-c. Macrocystic multilocular MCT. a Plain film:

incidental finding of thin, curvilinear calcifications delimiting
a right upper quadrant ovoid mass; a second linear calcifica-
tion is oriented transversely (arrow). b, c CT evaluation: portal
venous phase. CT confirms the presence of a cystic lesion of the
pancreatic head with mural calcifications (arrow in b) and the
presence of multiple, thin, calcified septa (arrow in c)
 Mucinous Cystic Tumors 69

4.2.4.2 one. In the more advanced malignant forms, how-

Contrast Examination of the Upper Gastrointestinal
Tract
The findings obtained in the presence of MCT
(displacement/imprinting of the digestive tract) are
all nonspecific and analogous to those found with
other pancreatic tumors. Again, these findings are
incidental during the search for other pathologies.
4.2.4.3
Angiography
Angiography was used to distinguish MCT (nonvas-
cular) from SCT (richly vascularized) (FRIEDMAN
et al. 1983; PINSON et al. 1990; BUETOW et al. 1998).
Obviously, it is not possible with angiography to dis-
tinguish the multilocular form from the unilocular
ever, it is possible to demonstrate encasement of the
peripancreatic vessels (BUETOW et al. 1998). There is
no role for diagnostic angiography today. Improving
3D capabilities from cross-sectional imaging may
obviate the need to obtain angiograms for 'surgical
planning'.
4.2.4.4
Endoscopic Retrograde Cholangiopancreatography
ERCP is used when the location of the lesion (unci-
nate process) and/or its relationships with the duct
ofWirsung raises the suspicion of a collateral branch
IPMT (SHYR et al. 1996). ERCP is able to document
whether there is a communication between the cystic
formation and the duct (Fig. 4.17) (PINSON et al. 1990;
OBARA et al. 1991; SHIMA et al. 2000).

a b

c d

Fig. 4. 17a-d. Macrocystic unilocular MCT. a A rounded, sharply marginated, hypodense lesion embedded in the pancreatic tail
without septa or calcifications is detected. In the more caudal scan (b), the lesion appears to be adjacent to the duct ofWirsung.
Determination of possible communication is difficult. cHASTE T2W image obtained after the intravenous administration of
secretin in the parasagittal plane confirms the mass near the duct of Wirsung, which has a normal caliber. The presence of
communication is still questionable. d ERCP reveals the normal duct ofWirsung and fails to demonstrate communication with
the mass, excluding the possibility of an intraductal tumor of the collateral ducts
 70 C. Biasiutti et al.

4.2.4.5 municating duct with the duct of Wirsung) (KoITO

Endoscopic US
EUS, with superior spatial resolution compared
with transabdominal US (KoITO et al. 1997), is
helpful in classifying those masses when it has not
been possible to make a diagnosis with the exami-
nations carried out up to that point (KoITO et al.
1997; ARIYAMA et al. 1998). The most important
contribution of EUS is particularly in the study
of small cystic lesions of the pancreas (Fig. 4.18),
(ARIYAMA et al. 1998). When faced with a long list
of differential diagnostic possibilities of a small,
cystic, pancreatic mass, EUS can distinguish MCT
(macro cystic multilocular or unilocular pattern)
from SCT (microcystic appearance) and from the
collateral branch IPMT (demonstration of the com-
et al. 1997; GRESS et al. 2000). Furthermore,EUS aids
in the recognition of slight thickening or parietal
vegetation (Fig. 4.18a-c) aiding in accurate classifi-
cation (INUI et al. 1998; BRUGGE 2000).
When confronted with a large, unilocular cystic
mass, EUS can demonstrate thin septa or nodulation,
leading the diagnosis in the direction of a possible
MCT (INUI et al. 1998; BRUGGE 2000).
Last but not least, in nonspecific cases, the pos-
sibility of classification by means of fine-needle
aspiration (FNA) under endosonographic guidance
should be pointed out (Fig. 4.18d) (BRUGGE 2000;
BRUGGE et al. 2001; GRESS et al. 2000). The malignant
cells at cytology, the presence of mucin, or a high
titer of CEA, all contribute to the diagnosis of MCT
(LEWANDROWSKI et al. 1993).

a c

b d

Fig. 4.1Sa-d. Macrocystic unilocular MCT (EUS evaluation). a A unilocular cyst with a thick wall and hyperechoic mural nodules. b,
c Second case, different planes: a cyst with a thick wall and one single, thick, hyperechoic septum (arrow). d Fine-needle aspiration
(FNA) of a unilocular pancreatic cyst. The needle is visible inside the cyst (courtesy of Prof. G. Caletti, University of Bologna)
Mucinous Cystic Tumors 71

4.3 3. The unilocular mass with thick wall demands sur-

Prognostic Evaluation gical intervention when calcifications and/or pari-
etal nodulations are present because these have a
The potential or overtly malignant nature of MCT high likelihood of malignancy. When only a thick
makes surgical resection appropriate when a mass wall is present, however, there could be justifica-
with a macrocystic multilocular appearance is identi- tion enough to avoid intervention and proceed to
fied. Although this approach may lead to the resec- follow-up, as in point 2 (SACHS et al. 1989).
tion of a benign mass such as an oligo cystic SCT, 4. The unilocular mass with thin wall is absolutely
the overwhelming majority will be MCT (JOHNSON nonspecific, and if it is an MCT, it has a very high
et al. 1988; SPERTI et al. 1993; SOYER et al. 1994; possibility of being benign. In this case, follow-up
BUETOW et al. 1998; LUNDSTEDT and DAWISKIBA or further diagnostic investigations, including an
2000; PROCACCI et al. 2001b). Many patients with FNAB, should be carried out (SACHS et al. 1989;
MCT will be older and carry a high surgical risk. CARLSON et al. 1998).
Therefore, it is important to try and glean prognostic
information from the imaging procedure (ISELIN et
al. 1993; LE BORGNE et al. 1999; BAGDASARIAN and
FUHRMAN 2000; PROCACCI et al. 2001b). 4.4
MCT, unilocular or multilocular, appears with Differential Diagnosis
rather variable degrees of wall and septal thickness
and the presence or absence of parietal nodulations The macrocystic multilocular pattern is considered
and/or calcifications. A thick wall, thick septa, parietal typical but not pathognomonic. A mass with these
nodules, and, above all, calcifications are considered to characteristics in an adult woman, especially when
be the best predictors of the malignant nature of MCT it is located in the body-tail, is almost certainly
(ZAMBONI et al. 1999; SHIMA et al. 2000; PROCACCI et MCT. As already said, mural calcifications and thick
al. 2001b). It has been shown that when the three signs septa lead to the prediction of the malignant nature
are present (calcifications, thick wall, and thick septa), of the lesion (PROCACCI et al. 2001 b). Oligo cystic
the probability of a malignant MCT is 95%. When SCT, solid pseudopapillary tumor (cystic variant),
fewer than three signs are present, the probability of cystic endocrine tumor, and necrotic metastases can
malignancy decreases until it almost cancels itself out have an identical appearance (JOHNSON et al. 1988;
when there are no calcifications and septa, and the wall FUGAZZOLA et al. 1991; SOYER et al. 1994; HAMMEL
is thin. Therefore, CT is the primary imaging modal- and BERNADES 1996; BUETOW et al. 1998; CURRY et
ity for these patients because calcifications cannot be al. 2000). In this case, the clinical history and the
visualized with MR. On CT, four classes of lesion can laboratory data are critical for an accurate diagnosis
be distinguished, each requiring a different therapeu- (PINSON et al. 1990).
tic approach (PROCACCI et al. 2001b): Oligocystic SCT, accounting for less than 3% of
1. The macrocystic multilocular mass with thick SCT, has an appearance identical to benign MCT
wall, thick septa, and calcifications has the high- (Fig. 4.19a) (LUNDSTEDT and DAWISKIBA 2000;
est probability of being a malignant MCT. Imme- PROCACCI et al. 2001a). These lesions will never have
diate surgical resection is indicated if possible a thick wall, thick septa, or calcifications. This lesion
(BUETOW et al. 1998). is almost never correctly diagnosed preoperatively.
2. The macro cystic multilocular mass with thin wall Cystic solid pseudopapillary tumor results from pre-
and thin septa, without calcifications is strongly vious necrosis and hemorrhage within the tumor. On
indicative of MCT, but the probability of malig- US, these lesions show a finely hyperechoic appearance.
nancy is low. In this case, surgical resection without On unenhanced CT, the cyst contents may be hyper-
performing an FNAB is advised for young and/or dense. On MR, depending on the degree of necrosis
healthy patients because even though the lesion and the extent of hemorrhage, the signal will appear
at the time of resection may appear benign, most high on II-weighted and low or high on T2-weighted
authorities feel these are premalignant lesions. In sequences (PROCACCI et al. 2001a). Most lesions dis-
older and/or clinically compromised patients, a play a complex alternating pattern combining solid
high -risk operation could be avoided by careful (neoplastic) and fluid components (Fig. 4.19b).
follow-up. If the presence of the mass produces The endocrine cystic tumor also owes its appear-
symptoms from local compression of adjacent ance to previous necrosis and hemorrhage. Similarly
viscera, surgical resection is appropriate. to the solid pseudopapillary tumor, calcification and
 72
a
b and calcifications, not only the mucinous nature can
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lesion displays a thin wall and small calcification (arrow).
b Solid pseudo-papillary tumor, portal venous phase CT
evaluation. In the axial image, both the hypodense (fluid) and
hyperdense (solid) components are appreciable. c Endocrine
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A thin septum along with a small calcification (black arrow)
are visible within the lesion
C. Biasiutti et al.
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Intraductal Cystic Tumors
5 Clinical Manifestations and Therapeutic Management
R. SALVIA, M. FALCONI, L. CASETTI, W. MANTOVANI, I. FRIGERIO, and P. PEDERZOLI

CONTENTS The tumor originates from the main duct or

peripheral ducts and can involve the whole pancre-
5.1 Introduction 77 atic gland, having different histological grades within
5.2 Clinical Data 78 the same tumor.
5.2.1 Sex and Age 78
5.2.2 Habits 78 The disease originates from the epithelium of the
5.2.3 Pain and Previous Diagnosis pancreatic ducts and can evolve through all stages
of Acute Pancreatitis 78 from slight dysplasia to carcinoma. Currently, most
5.2.4 Weight Loss 79 researchers agree that their evolution towards the
5.2.5 Asthenia 79 carcinoma stage is slow, but probably inexorable
5.2.6 Diabetes 79
5.2.7 Jaundice 79 (BRAT et al. 1998; FURUKAWA et al. 1994; KLOPPEL
5.2.8 Clinical Evaluation Summary 80 1996; LONGNECKER 1998; OBARA et al. 1993; RIVERA
5.3 Laboratory Findings 80 et al. 1997; SOLCIA 1997; YAMAGUCHI et al. 1996;
5.4 Clinical Aspects in Differential Diagnosis 80 Z'GRAGGEN et al. 1997).
5.4.1 Chronic Pancreatitis 80 At the beginning, the major clinical problem
5.4.2 Serous Cystadenoma 80
5.4.3 Mucinous Cystic Tumor 81 was to recognize IPMT and to differentiate it from
5.5 From Assessment to Management 81 chronic pancreatitis (CP). The majority of undiag-
5.5.1 Surgical Therapy 82 nosed IPMTs are, in fact, wrongly interpreted as CPo
5.5.2 Follow-Up 82 Increased awareness of these tumors has decreased
References 83 the number of incorrect diagnoses. Nowadays, pre-
operative recognition of the histological grading of
these tumors is desirable (YAMAGUCHI et al. 1996).
The need for this is related to a series of consid-
5.1 erations concerning the patients and the disease:
Introduction the only therapeutic option considered in the lit-
erature for the treatment of these tumors is partial
Intraductal papillary mucinous tumors (IPMTs) of or total surgical resection of the pancreatic gland
the pancreas are a relatively new entity among cystic (CUILLERIER et al. 1998; PARTENSKY et al. 1996;
tumors. Described for the first time in 1982 as neo- RIVERA et al. 1997; SIECH et al. 1999; SUGIYAMA
plasms with mucin hyperproduction, dilatation of the and ATOM! 1998; TRAVERSO 1998), but this option
duct ofWirsung, and protruding papilla (the Ohhashi applies to patients who are generally elderly (65-70
triad) (OHHASHI 1982), they have undergone a true years old) with multiple medical problems. However,
epidemiological explosion in recent years (AZAR et patients with a malignant tumor certainly benefit
al. 1996; FALCONI et al. 2001; NAVARRO et al. 1999; from partial or total pancreatic resection. There is
OHHASHI 1982; SHIMA et al. 2000; SUGIYAMA and little justification for the risks and costs of surgery in
ATOMI 1999; TAOUL! et al. 2000; TRAVERSO 1998). high-risk patients harboring a benign tumor, which
could simply be followed up.
Collaboration between the clinician and radiolo-
gist, therefore, focuses on two aspects: diagnosis of
R. SALVIA, MD; M. FALCONI, MD; 1. CASE TTl, MD;
W. MANTOVANI, MD; 1. FRIGERIO, MD; P. PEDERZOLI, MD the disease and evaluation of the clinical and radio-
Surgical-Gastroenterological Department, Hospital 'G .B. Rossi', logical data that might be helpful in the assessment of
University of Verona, 37124 Verona, Italy the stage of the disease before surgery.
78 R. Salvia et al.

S.2 of patients suffering from IPMT reported alcohol

Clinical Data
The parameters considered in the literature for the
diagnosis of IPMT that can discriminate between the
benign or malignant neoplasia are (Table 5.1): demo-
graphic data, daily habits, clinical history, symptoms,
laboratory findings, and, of course, radiological find-
ings (CUILLERIER et al. 1998; SUGIYAMA and ATOMI
1998; TRAVERSO 1998; YAMAGUCHI et al. 1996,2000).
5.2.1
Sex and Age
The patients suffering from this tumor are in their
60s and 70s; there is an equal distribution of men
and women (YAMAGUCHI et al. 2000; YAMAO et al.
2000). In personal experience (Table 5.1), the aver-
age age of IPMT patients was 64 years, with an equal
distribution between the sexes (M:F=l:1) (FALCONI
et al. 2001). This is in distinction to patients with CP,
where there is a marked male predominance, and
the average age at diagnosis is 42 years (CAVALLINI
et al. 1998).
5.2.2
Habits
Evaluation of the alcohol and tobacco intake is
important in terms of the differential diagnosis in
patients with CPo Traverso points out how only 12%
abuse which, according to the author, would also be
a predictive factor of malignancy (TRAVERSO 1998).
On the contrary, alcohol abuse is almost constant
in patients with CPo Smoking does not seem to be
a discriminating factor. In personal experience,
42% of patients suffering from IPMT were smokers
(FALCONI et al. 2001).
5.2.3
Pain and Previous Diagnosis
of Acute Pancreatitis
Recurrent pain is certainly the most common of
symptoms and is described by many authors as
'pancreatitis-like' (AZAR et al. 1996; NAVARRO et al.
1999; WARSHAW 1991). The painful symptomatology
is generally referred to as continuous, related to meals,
localized in the upper area of the abdomen, radiating
to the back. Well-investigated symptoms like those
described above suffice to focus clinical suspicion on
the pancreas. The percentage of patients complaining
of pain is higher when those with a previous history
of acute pancreatitis are also taken into consideration.
The pain from IPMT and from acute pancreatitis have
the same origin: the hyperproduction of mucin is
responsible for hindering the outflow of pancreatic
juices (WARSHAW 1991). An episode of acute pancre-
atitis in the case history can make it more difficult to
distinguish an IPMT of the peripheral ducts from a
pseudocyst. However, in personal experience, an epi-
sode of acute pancreatitis which was severe enough

Table 5.1. Main demographic and clinical characteristics of 88 patients suffering from surgically resected intraductal papillary
mucinous tumors (IPMTs; personal series) (IPMA/B, intraductal papillary mucinous adenoma and borderline; IPMC/IC, intra-
ductal papillary mucinous carcinoma and invasive carcinoma; AP, acute pancreatitis; CP, chronic pancreatitis)
Characteristic Total IPMA/B (n=47) IPMC/IC (n=41) p
Sex (M/F) 47/41 28119 19122 NS
Average age (years) 62.7 62.4 63.0 NS
Average alcohol intake (g/day) 38 35.4 40.6 NS
Smokers (no. of patients) 41 (46.6%) 23 18 NS
Symptoms:"
Recurrence of painful attacks 58 (66%) 34 (72.3) 24 (58.5) NS
Weight loss 37 (42%) 18 (38.3) 19 (47.5) NS
Asthenia 14 (16%) 3 (6.4) 11 (26.8) 0.02
Fever 5 (5.6%) o (0) 5 (12.2) 0.02
Onset or worsening of diabetes 10 (11.4%) 1 (2.1) 9 (22) 0.003
Jaundice 11 (12.5%) 1 (2.1) 10 (24.4) 0.002
Incidental diagnosis 14 (16%) 9 (19) 5 (12.2) NS
Previous diagnosis of AP 17 (19%) 11 (23.4) 6 (14.6) NS
Previous diagnosis of CP 8 (9%) 6 (12.8) 2 (5) NS
Previous diagnosis of pseudocyst 6 (6.8%) 4 (8.5) 2 (5) NS

"Patient with more symptoms

Clinical Manifestations and Therapeutic Management 79

to potentially develop a pseudocyst occurred in less 5.2.6

than 2% of all patients with IPMTs observed. Diabetes

The sudden onset of diabetes almost always leads

5.2.4
Weight Loss
Another frequent symptom is weight loss (AZAR et al.
1996; RICKAERT et al. 1991), which is found in 42% of
patients in a personal series. Weight loss might have
two different physiopathological mechanisms related
to the stage of the disease. In the early phases, the
hyperproduction of mucin obstructs normal pancre-
atic secretion, causing the pain related to meals. Thus,
just as with CP, the patients stop eating in order to
avoid pain, with subsequent weight loss (CAVALLINI et
al. 1996; WARSHAW 1991). In the advanced stage of the
disease, the weight loss is more likely due to the produc-
tion of neoplastic factors responsible for cachexia.
Weight loss is common to all neoplastic patholo-
gies and should therefore be considered nonspecific.
Persistent weight loss arouses the suspicion of the
malignancy of the tumor.
to the suspicion of ductal adenocarcinoma. Some
11 % of patients suffering from IPMT have diabetes,
almost all in the advanced stages of the disease (AZAR
et al. 1996; FALCONI et al. 2001; KIMURA et al. 1996;
KOBARI et al. 1999; LOFTUS et al. 1996; NAVARRO et
al. 1999; PARTENSKY et al. 1996; PAYE et al. 1999;
RICKAERT et al. 1991; SUGIYAMA and ATOMI 1998;
TAOULI et al. 2000). In personal experience, too, the
recent onset of diabetes or its worsening within a year
from diagnosis of an IPMT more frequently occurred
with advanced tumors (p<0.005). Other authors do
not confirm this correlation between diabetes and the
advanced stage of the disease (TRAVERSO 1998). The
symptom, when present, therefore has a double value:
suspicion of the neoplasm and its malignancy.
5.2.7
Jaundice

Jaundice, like diabetes, plays an important role in

5.2.5
Asthenia
Asthenia is usually associated with weight loss, but
it is difficult to interpret, as it is subject to the char-
acter and mood of the patient. In fact, the majority
of authors do not describe the symptom. In personal
experience, it was present in 16% of patients.
It is interesting to point out that this symptom
was more frequent in those patients with advanced
disease (p<0.05).
being a typical symptom of pancreatic head dis-
eases. The frequency of this symptom varies from
5% to 50% of IPMTs (Table 5.2) in the literature
(CUILLERIER et al. 1998; ITAI et al. 1987; ITOH et al.
1992; KIMURA et al. 1996; OBARA et al. 1991; OHTA
1992; PAYE et al. 1999; RAIJMAN et al. 1994; SUGIYAMA
and ATOMI 1998; UEHARA et al. 1994; YAMAGUCHI
and TANAKA 1991). Jaundice is a sign of the tumor
in its advanced stages (Table 5.1), as confirmed by
many authors (ITAI et al. 1987; MILCHGRUB et al.
1992; TRAVERSO 1998).

Table 5.2. Symptoms reported by the principal authors, review of the literature

Publication No. of Pancreatitis Abdominal Weight Diabetes Jaundice Other

cases (% ) pain (%) loss (%) (%) (% ) (% )

TRAVERSO (1998) 33 75 82 36 27 9
RICKAERT et al. (1991) 8 60 87 50 25
LOFTUS et al. (1996) 14 15 73 27
KIMURA et al. (1996) 222 41 52 11 19 18
CUILLERIER et al. (1998) 41 24 7 7 14
PARTENSKY et al. (1996) 54 12 36 24 18 9 2
SUGIYAMA and ATOMI (1998) 41 51 44 7 22 10
PAYE et al. (1999) 41 19 34 37 20 5 7
FALCONI et al. (2001) 63 35 66 42 11 12 16
NAVARRO et al. (1999) 111 29 11 2
SIECH et al. (1999) 8 33 100
TAOUL! et al. (2000) 36 56 41 19
AZAR et al. (1996) 32 42 44 50 37 6
KOBARI et al. (1999) 30 100 54
80 R. Salvia et al.

5.2.8
Clinical Evaluation Summary
In conclusion, an incidental diagnosis of IPMT occurs
in 30%-35% of patients, the majority of whom are
symptomatic (PARTENSKY et al. 1996; CUILLERIER et
al. 1998; PAYE et al. 1999; SHIMA et al. 2000). These
symptoms, characterized by recurrent abdominal pain
correlated to meals, weight loss, diabetes, jaundice,
previous diagnosis of acute pancreatitis (Table 5.2),
lead to the suspicion of pancreatic pathology. Demo-
graphic data (sex, age) and lifestyle habits may con-
tribute to the differential diagnosis between IPMT
and chronic pancreatitis, while the presence of jaun-
dice and diabetes, with the diagnosis already made,
are indications of the malignancy of the lesion.
et al. 1996). In other series, the M:F ratio is, however,
only slightly higher than one (YAMAGUCHI et al. 2000;
YAMAO et al. 2000). Patients with CP (mean age 42
years) are about 20 years younger on average than
those with IPMT (mean age 64 years) (CAVALLINI et
al. 1996; FALCONI et al. 2001). A protracted clinical
history could indicate an inflammatory pathology,
but this is only a hypothesis, given that the natural
history of IPMT is not yet completely known (BARBE
et al. 1997; OBARA et al. 1993).
Lastly, there are symptoms that do not lead to any
kind of discrimination, like nicotine abuse, abdomi-
nal pain correlated to meals, the onset of diabetes,
and obstructive jaundice, as they are present in both
diseases.

5.4.2
Serous Cystadenoma
5.3
Laboratory Findings The differential diagnosis between serous cyst-
adenoma and IPMT is difficult and particularly
The laboratory does not contribute in any way to
the diagnosis of IPMT. No blood tests, even tumoral
markers, are specific for these tumors (ALONSO
Table 5.3. Principal laboratory data reported in the two
CASADO et al. 2000; AZAR et al. 1996; OBARA et al. groups of benign and malignant IPMTs (mean values), per-
1993; UEHARA et al. 1997). sonal series
Once the diagnosis of IPMT has been obtained,
Parameter Benign Malignant p
elevated blood glucose, alkaline phosphatase (ALP), (n=47) (n=41)
alanine aminotransferase (ALT), and gamma-glu-
Glycemia (mg/dl) 101.1 121 0.003
tamyl transferase (GGT) are more common with
Albuminemia (gil) 42 40.6 NS
malignant tumors (Tables 5.3,5.4). Total bilirubin (mg/dl) 0.7 1.2 NS
Direct bilirubin (mg/dl) 0.3 0.7 NS
AST (U/I) aspartate aminotrans- 23.6 30.2 NS
ferase
ALT (U/I) alanine aminotrans- 25.7 61.3 0.004
5.4 ferase
Clinical Aspects in Differential Diagnosis LDH (UIl) lactate dehydrogenase 141 l31.3 NS
ALP (U/I) alkaline phosphatase 76.6 171.5 0.006
The problems in the differential diagnosis of IPMT GGT (U/I) gamma-glutamyl 27.2 88.9 0.007
vary according to the tumor's site of growth. IPMTs transferase
Serous amylase (UIl) 242.8 122.3 NS
of the main duct can, in fact, simulate CP, while neo-
Urinary amylase (U/I) 994 473 NS
plasms involving the secondary ducts, 'branch side C-reactive protein (mg/I) 9.8 9.3 NS
IPMTs', should be differentiated from cystic tumors
(FUKUKURA et al. 2000).
Table 5.4. Principal neoplastic markers reported in the two
groups of benign and malignant IPMTs (mean values), per-
sonal series
5.4.1
Chronic Pancreatitis Marker Benign Malignant p
(n=47) (n=41)

In the differential diagnosis between IPMT and CP, CEA (ng/ml) carcinoembryonic antigen 4.8 3.4 NS
some demographic and clinical data can be helpful. Ca 19-9 (U/ml) 23.9 145.1 NS
In personal experience, the vast majority of patients Ca 15.3 (U/ml) 19 16.3 NS
Ca 125 (U/ml) 9.7 12.8 NS
with CP are male, with a M:F ratio of 6:1 (CAVALLINI
Clinical Manifestations and Therapeutic Management
important since the former is almost always benign.
In fact, malignancy has been described in only a few
isolated cases (ABE et al. 1998; KAMEl et al. 1991;
WIDMAIER et al. 1996; YOSHIMI et al. 1992). Patients
with a histological diagnosis of serous cystadenoma,
when asymptomatic, can be followed up without
surgical intervention.
Serous cystadenoma is definitely more common in
women (F:M=6.7: 1) with an average age of 51.8 years,
10 years younger than those with IPMT. The tumor
is mainly located in the head of the pancreas. In
personal experience, about 45% of serous cystad-
enomas were located within the pancreatic head
and neck, 27% in the body, and 28% in the tail. The
demographic characteristics, the case history, and the
habits do not lead to differentiation between the two
types of tumor. The presence of symptoms, mainly
jaundice, diabetes, and 'pancreatitis-like' pain, may
indicate IPMT since almost all serous cystadenomas
(75%) were discovered incidentally, due to their lack
of symptoms. This hypothesis is confirmed in the
literature (GRIESHOP et al. 1994), while the behavior
of IPMT, with only 16% incidental diagnosis, can be
considered the opposite.
5.4.3
Mucinous Cystic Tumor
The differences in the clinical presentation between
IPMT and mucinous cystic tumor are less important
because, due to the potential malignancy of these
neoplasms, surgical treatment is indicated in both
cases.
Mucinous cystic tumor occurs almost exclusively
in women of around 45 years of age. The average age
is higher when the neoplasm takes on malignant
characteristics. The topography of the neoplasm can
be useful for the differential diagnosis since IPMT is
frequently located in the uncinate process, while the
mucinous cystic tumor more commonly involves the
body-tail. In some series, there is a 93% incidence of
tumors in the tail (ZAMBONI et al. 1999).
Moreover, it is necessary to point out that
IPMT is almost always symptomatic, and in those
cases involving the main duct, it can simulate CP,
while the mucinous cystic tumor is almost always
asymptomatic. It is obvious that all of this clinical
information is helpful in the diagnosis, which is
based essentially on imaging findings. It is there-
fore essential that, at the time of investigation, the
radiologist is aware of all appropriate history and
clinical information.
81
5.5
From Assessment to Management
Once the diagnosis of IPMT has been made with the
contribution of imaging, the clinician will need fur-
ther information before going on to therapy.
In relation to the site, several authors have sug-
gested classifying these lesions into two groups:
IPMTs of the main duct and IPMTs of the peripheral
ducts (FURUKAWA et al. 1994; KOBARI et al. 1999;
NAKAGOHRI et al. 1999; TERRIS et al. 2000).
All the authors agree on the appropriateness of sur-
gery( assumingaresectablesituation,see Section5.5.1)
for main duct tumors, due to the high malignancy
rate of this group.
On the other hand, the therapeutic choice for
branch duct IPMTs is more debatable. The literature,
like personal experience, confirms that tumors aris-
ing from the peripheral ducts are less aggressive. It
is assumed that branch duct IPMTs are a different
entity, or that diagnosis was made earlier in the
tumor group originating in the periphery. This latter
hypothesis, however, would contrast with the finding
that IPMTs of the peripheral ducts are less symptom-
atic and that their diagnosis is more often incidental
and therefore late.
The parameters recently suggested in the evalua-
tion of these neoplasms are the dimensions, the pres-
ence or absence of papillary growth, and the thick-
ness of the walls of the cystic lesion (LIM et al. 2001;
SILAS et aI. 2001; TAOUL! et al. 2000; WAKABAYASHI
et al. 2001).
As can be seen in Table 5.5, in our experience, the
aggressive behavior of these neoplasms was justified
by 31% (9/29) of peripheral IPMTs being identified
as carcinomas at the final histological examination,
17.2% (5/29) of which showed signs of invasion. The
finding of intraductal carcinomas among the branch
side IPMTs has also been reported by some authors
(KOBARI et al. 1999, NAKAGOHRI et al. 1999), while
being excluded by others (TERRIS et al. 2000).
It is, in any case, right to point out that invasive
carcinomas are always characterized by thick walls
and endoluminal papillary growth, while only carci-
Table 5.5. Anatomopathological findings in 88 resected IPMTs,
distinguished according to site of origin, personal series
Tumor Central Peripheral
Adenoma (20) 5 (25%) 15 (75%)
Borderline (27) 22 (81.5%) 5 (18.5%)
Noninvasive carcinoma (11) 7 (63.6%) 4 (36.4%)
Invasive carcinoma (30) 25 (83.3%) 5 (16.7%)
82
noma in situ can have small dimensions, thin walls,
and no endoluminal vegetation. However, despite the
histological diagnosis, the behavior of the tumor may
be quite different. For this reason, despite the differ-
ent opinions, in clinical practice, a peripheral lesion
with a diameter of less than 3 cm, thin walls, and no
papillary growth in an elderly, asymptomatic patient
can be followed up (KOBARI et al. 1999; NAKAGOHRI
et al. 1999; TAOULI et al. 2000; TERRIS et al. 2000).
5.5.1
Surgical Therapy
Before performing surgery, it is necessary to consider
operability, which is different to resectability. In fact,
operability indicates whether or not it is possible to
carry out surgery in terms of the patient's general
clinical condition. When these conditions are partic-
ularly poor, surgical resection may not be advisable.
Operability criteria are made strictly on the basis of
a clinical evaluation.
The clinician will obviously ask the radiologist for
information on resectability. For IPMTs, as for ductal
adenocarcinomas, at the more common cephalic
location, encasement of the vascular structures adja-
cent to the gland, in particular the splenomesenteric-
portal confluence, but also the superior mesenteric
artery and the celiac trunk, is a contraindication of
resectability for tumors in the head of the pancreas.
Tumors located within the body-tail sites can be
resected even when infiltration of the splenic artery
and vein has occurred, since the spleno-pancreatec-
tomy involves the tying of both vessels. Possible
evaluation can be made of how much the macro-
scopic infiltration influences the prognosis of these
neoplasms. The differential diagnosis between IPMT
and ductal adenocarcinoma of the body-tail involv-
ing the splenic vessels is important since the latter
has a low indication of resectability and, in any case, a
poor prognosis. On the contrary, IPMTs, even if infil-
trating, should be resected; they are not sensitive to
chemotherapy or radiotherapy, leaving no alternative
treatment to surgical intervention (KLOPPEL 1998).
The presence of hepatic metastases precludes
resectability. In our experience, the latter event only
appeared in 2% of patients. This is clearly different
from patients with ductal adenocarcinomas, 50% of
whom are affected by hepatic metastases at diagno-
sis. The prognosis of infiltrating IPMTs depends on
the histological type of infiltration (FUKUSHIMA et
al. 1997). Patients with the tubular type of infiltration
have a poor prognosis similar to ductal adenocarci-
R. Salvia et al.
noma, unlike patients with muconodular infiltration,
who have a considerably better prognosis.
Once the resectability has been assessed, the clini-
cian needs to know the site of the neoplasm in order
to decide on the type of surgical resection. Again, from
personal data (Table 5.6) and the literature, we see
that 70% of IPMTs are located in the head of the pan-
creas (SHIMA et al. 2000; SUGIYAMA and ATOMI 1998;
TAOULI et al. 2000). In personal experience, no IPMT
was found in the body-tail, while this site is indicated
in 0% to 14.3% of peripheral IPMTs in the literature
(NAKAGOHRI et al. 1999; TERRIS et al. 2000).
Table 5.6. Anatomical location and site of origin of 88 resected
IPMTs, personal series
Part of pancreas Central Peripheral
Head (60) (68.2%) 33 (55%) 27 (45%)
Neck (11) (12.5%) 9 (82%) 2 (18%)
Body-tail (14) (15.9%) 14 (100%) o (0)
Diffuse (3) (3.4%) 3 (100%) 0(0)
Indications for surgery can also arise from the
occurrence of complications, as in those patients
considered nonresectable but symptomatic of
obstructive jaundice or obstruction of the alimentary
tract. In these cases, the surgeon is forced to oper-
ate and perform a biliodigestive and/or alimentary
bypass. This is why it is necessary to know radiologi-
cally if there is any obstruction of the main biliary
duct and/or alimentary tract.
Faced with a resectable lesion, the best interven-
tion is pancreoduodenectomy for cephalic IPMTs
and splenopancreatectomy for those with a body-tail
location (ALONSO CASADO et al. 2000; FALCONI et al.
2001; KOBARI et al. 1999; SUGIYAMA and ATOMI 1998;
TERRIS et al. 2000). Limited or atypical resections,
as some authors suggest (SCIAUDONE et al. 2000;
TAKEYOSHI et al. 1999; TERRIS et al. 2000), involve a
greater risk oflocal recurrence (FALCONI et al. 2001).
Intraoperatively, it is crucial to ensure that a nega-
tive margin for dysplasia is found, even if it leads to
total pancreatectomy. In this case, considering the
patient's age and general condition, the surgeon may
decide not to perform a total pancreatectomy if low
or moderate dysplasia is present on the edge of the
section (FALCONI et al. 2001).
5.5.2
FollOW-Up
At the moment, the data in literature and from
personal experience are not sufficient to consider
Clinical Manifestations and Therapeutic Management
follow-up as a standard choice for these patients
because of the potentially malignant nature of these
tumors. Nevertheless, small lesions of the pancreatic
head, originating from the branch ducts, with no
past history of diabetes or jaundice, without risk
factors, and in the absence of radiological signs of
malignancy can be strictly followed up, as some
authors advise (KIMURA and MAKUUCHI 1999;
YAMAO et al. 2000).
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6 Pathology of Intraductal Cystic Tumors
G. ZAMBONI, P. CAPELLI, G. BOGINA, A. PESCI, and A. BRIGHENTI
CONTENTS
6.1 Introduction 85
6.2 Macroscopic Examination 85
6.3 Microscopic Examination 88
6.4 Immunohistochemical and Molecular
Characteristics 90
6.5 Preoperative and Intraoperative
Pathological Diagnosis 91
6.6 Differential Diagnosis 93
6.7 Prognosis 93
References 93
6.1
Introduction
In recent years, increasing attention has been paid
to intraductal papillary mucinous tumors (IPMTs)
because of their clinical picture, favorable prognosis,
unclear nature, and potential relationship with ductal
adenocarcinoma. While the diagnosis of IPMTs has
improved considerably over the past few years (AZAR
et al. 1996; LOFTUS et al. 1996; SESSA et al. 1994), the
nature of these neoplasms, their pathogenesis, and their
relationship to ductal adenocarcinoma and its variants,
specifically mucinous noncystic carcinoma (MNCC),
are still largely unknown (LONGNECKER 1998).
In the past, this entity has been reported under
different names, reflecting either the various authors'
specialty (radiology, gastroenterology, endoscopy, sur-
gery, pathology) or the different features of the tumors
(KLOPPEL 1998). Mucous-secreting cancer (OHASHI et
al. 1982), mucin-producing tumor (OBARA et al. 1991;
YAMADA et al. 1991), mucus-hypersecreting tumor
(FURUKAWA et al. 1992), intraductal mucin-hyperse-
creting neoplasm (RICKAERT et al. 1991), ductectatic
mucinous cystadenoma (ITAI et al. 1986), intraductal
G. ZAMBONI, MD; P. CAPELLI, MD; A. BRIGHENTI, MD
Department of Pathology University of Verona, Verona, Italy
G. BOGINA, MD; A. PESCI, MD
Ospedale S.Cuore-Don Calabria, Verona, Italy
papillary neoplasms (MOROHOSHI et al. 1989), dif-
fuse intraductal papillary adenocarcinoma (CONLEY
et al. 1987), villous adenoma of the main pancreatic
duct (PAYAN et al. 1990), villous adenomatosis of duct
of Wirsung (BRESLER et al. 1992) are among these
names.
Apart from their macroscopically heterogeneous
appearance, all these tumors can be regarded as a
single clinicopathological entity. The revised WHO
classification of exocrine pancreatic neoplasms
(KU)PPEL et al. 1996), reported in the Armed Forces
Institute of Pathology (AFIP) fascicle (SOLCIA et al.
1997), suggests the term intraductal papillary muci-
nous tumor (IPMT), calling attention to a possible
adenoma-carcinoma sequence; the transition from
benign to malignant epithelium, which can be seen
in a single IPMT, with identifiable adenomatous, bor-
derline, and malignant components is morphological
evidence of tumor progression.
The pathologic hallmarks of IPMT are: (1) diffuse
or segmental dilatation of the main and/or branch
pancreatic ducts, with no mechanical strictures, (2)
intraductal growth of the mucin-producing epithelial
lining cells, with a 'flat' or 'papillary-villous' appear-
ance, (3) protrusion and dilatation of the major and/
or minor papilla of Vater, with mucous excretion.
To be classified as an IPMT, a neoplasm must
involve the main pancreatic duct and/or major
branches and should be grossly or radiologically
visible (TERRIS et al. 2000). If it is not, it would be
better classified as a pancreatic intraepithelial neo-
plasia (PanIN), a proliferative epithelial lesion that
typically involves the smaller pancreatic ducts and
ductules (HRUBAN et al. 2001; Fig. 6.1).
6.2
Macroscopic Examination
The macroscopic examination of the surgical speci-
men should document the intraductal origin and
growth of the lesion, the distribution and type of
86
Fig. 6.1. Pancreatic intraepithelial neoplasia of the pancreas
(PanIN). Branch duct and small branches with microscopic
alteration, previously unidentified at both imaging and macro-
scopic examination, characterized by papillary formation
tumor, and search for an invasive carcinoma com-
ponent.
Macroscopically, two main types can be distin-
guished: the ductectatic mucin-hypersecreting vari-
ant in which the dilated main duct or branch ducts
are filled with tenacious mucin, and the cyst lining
is flat and smooth (Fig. 6.2), and the papillary-villous
variant, characterized by soft and friable, nodular or
papillary proliferation associated with mucous mate-
rial within the dilated pancreatic duct (Fig. 6.3). The
polypoid proliferations, together with mucin plugs, are
responsible for the typical filling defects seen at endo-
scopic retrograde cholangiopancreatography (ERCP).
IPMT may also be divided into main duct and
branch duct types. The main duct type involves the
main duct, either in a diffuse or segmental manner.
Fig. 6.2. IPMT ductectatic mucin-hypersecreting type. A cystically
dilated branch duct of the uncinate process is filled with sticky
mucus. The lesion communicates with the main pancreatic duct
G. Zamboni et al.
The large majority of cases arises in the main pancre-
atic duct of the head of the pancreas and progresses
in a retrograde direction over a variable length with
frequent extension into the branch ducts (Fig. 6.4).
Extension of the IPMT to the major and/or minor
papilla creates the typical protrusion into the duode-
num, which can be seen either at endoscopy or at US
and CT. The patulous orifice is observed in 50%-60%
of cases (Fig. 6.5). Unfortunately, it is present only in
the advanced stages of disease, being present in 73%
of patients with either in situ carcinoma or invasive
carcinoma as opposed to 39% of patients with hyper-
plasia and adenoma (HARA et al. 2002). In advanced
cases, IPMT may form fistulas with adjacent organs.
According to the study of 36 patients with IPMTs with
fistulae (KOBAYASHI et al. 1993), the organs involved
were the stomach (17%), duodenum (64%), and bile
duct (56%). When the tumor creates a biliopancre-
atic fistula, it is important to differentiate a primary
fistula from neoplastic invasion of the bile duct
(KURIHARA et al. 2000). In fact, half of the patients
with fistulae retain the basic characteristics of IPMT
with no carcinomatous invasion around the fistula.
Mechanical pressure due to the tumor's expansion
and/or thick mucus 'bursting' into the bile duct are
the proposed pathophysiologic mechanisms in this
subset of patients. The other half appeared with foci
of invasive colloid carcinoma in the stroma around
the fistula. Local recurrence and diffuse peritoneal
carcinomatosis have been reported (KURIHARA et al.
2000). The pancreatic acinar parenchyma surround-
ing the central type IPMT is frequently replaced by
fibrous tissue, related to local chronic pancreatitis
resulting from long-lasting duct obstruction.
Fig. 6.3. IPMT papillary-villous type. Duodenopancreatectomy
specimen showing a nodular, papillary proliferation within a
dilated duct of Wirsung with extension to the duct of Santorini,
associated with a scirrhous carcinomatous area involving the
head of the pancreas and infiltrating the terminal bile duct
 Pathology of Intraductal Cystic Tumors
Fig. 6.4. IPMT main duct type. Total pancreatectomy showing
an advanced stage of the disease with diffuse dilatation of the
main duct and the duct of Santorini with multiple gelatinous
areas in the head and tail of the pancreas
Fig. 6.5. IPMT main duct and branch duct type. Whole-mount
macro section showing papillary proliferations involving the
main and branch ducts of the head of the pancreas with exten-
sion to the intraduodenal portion of the main duct and to the
ampulla of Vater
a h----------------------------------- b
Fig.6.6a,b. IPMT branch duct type. A grape-like aspect with protrusion from the outer part of the uncinate process of the
pancreas (a); on section, the main cyst measured 2 cm in diameter at its largest point (b)
87
IPMTs of the branch ducts arise anywhere within
the pancreas, although the head and neck of the pan-
creas and the uncinate process are the more common
locations. They often have a grape-like appearance
and may protrude from the outer part of the pancre-
atic parenchyma (Fig. 6.6). Cystic dilatation ranges
from 3 mm to 50-60 mm. The cystic changes in this
subtype can sometimes be so extensive that they may
be confused with mucinous cystic tumor. The main
criterion for distinguishing the two lesions is that in
IPMT the cysts communicate with the duct system
(Fig. 6.7), whereas mucinous cystic tumors do not.
The adjacent pancreatic parenchyma in the branch-
type IPMT is usually normal.
Searching for invasive carcinomatous components
in IPMTs is extremely important for many reasons.
The presence of carcinomatous invasion is considered
the most important predictive factor for survival and
disease recurrence along with the presence of lymph
node metastases (CUILLERIER et al. 2000). Although
carcinomatous invasion is reported in 30%-50% of
patients (KLOPPEL 1998; FUKUSHIMA et al. 2001;
GIGOT et al. 2001; ADSAY et al. 2002; SUGIURA et al.
2002; SOHN et al. 2001; CUILLERIER et al. 2000), the
sensitivity of imaging in preoperatively identifying
invasive cases is less than 80% (CUILLERIER et al.
2000). IPMTs with carcinomatous transformation are
frequently found in the main duct type, characterized
by marked longitudinal extension and involvement of
secondary ducts (Fig. 6.4), but can also be observed
in variable proportion in the peripheral branch duct
type. The macroscopic findings, which correlate with
the carcinomatous nature of the lesions, are thick
ductal walls and endoluminal papillary or nodular
vegetations. In the muconodular or colloid type
carcinoma, the invasive component is constituted
by multiple, well-circumscribed, gelatinous nodules,
which can be confined to the pancreatic parenchyma
 88 G. Zamboni et al.

a b

Fig.6.7a,b. IPMT branch duct type of the uncinate process. a A mucus-filled cystic lesion of the uncinate process; the probe
indicates the bile duct. b Whole-mount macro section of the lesion showing a connection with the main duct, the presence of
sticky mucus, and a smooth internal surface of the cyst

or extend into the peripancreatic adipose tissue, with
or without lymph node involvement. Identification of
the tubular type carcinoma within an IPMT depends
on the extension of the carcinomatous foci. Grossly,
they appear as a firm mass with ill-defined margins,
merging imperceptibly with the surrounding pan-
creatic parenchyma, like common ductal carcinomas
of the pancreas. This macroscopic appearance may
be difficult to differentiate from the fibrous scars of
chronic pancreatitis.
findings (FURUKAWA et al. 1997; KOITO et al. 2001).
The combination of these two new diagnostic pre-
operative techniques is highly sensitive in differenti-
ating between benign and malignant IPMTs (HARA
et al. 2002). The presence or absence of protruding
lesions, their morphology, height, and the presence or
absence of tumor vessels in the protrusions are useful
features for the differential diagnosis (Fig. 6.9). The
visualization by POPS of villous or vegetative types
of growth and the presence of tumor vessels correlate
with malignancy, as well as the presence of lesions
protruding more than 4 mm on mus.

6.3
Microscopic Examination

Microscopically, the epithelial component lining the

ectatic main duct or the cystically dilated branch
ducts is represented by tall mucin-producing colum-
nar cells, but lacks the 'ovarian-type' stroma seen in
mucinous cystic tumors (MCTs) (Fig. 6.8). This
epithelium frequently forms papillary projections
and shows dysplastic modifications. The papillary
proliferations may consist of microscopic folds, usu-
ally lined by slightly atypical columnar cells, or florid
branching papillae measuring up to several centi-
meters. The latter prevalently show intestinal-type
epithelial lining, similar to villous adenoma of the
large bowel, or may rarely appear with a pancreato-
biliary-type epithelium, which is less mucinous than
the former and is more likely to be highly dysplastic
(ADSAY et al. 2002). The pathological features of the
papillary proliferations constitute the anatomical
basis for the interpretation of peroral pancreatoscopy
(POPS) and intraductal ultrasonography (mUS) Fig. 6.8. IPMT with tall columnar epithelium and mild atypia
Pathology of Intraductal Cystic Tumors 89

Fig. 6.9. IPMT with micropapillary proliferations of the epithe-

liallining, showing fibrous stalks with small vessels

Individual IPMTs, or sometimes within the single

lesion, show a spectrum of changes with the preva-
lence in some areas of ductal ectasia and the presence
Fig. 6.10. IPMT with diffuse involvement of central and
of papillary proliferations in contiguous areas. The peripheral ducts, with ductal ectasia and papillary prolifera-
lesions, either the central or the peripheral types, are tion, with no tumoral pseudocapsule
usually poorly circumscribed and without a fibrous
capsule delimitating them from the parenchyma.
However, the large, dilated ducts may have a fibrous
wall (Fig. 6.10).
Recently, an oncocytic variant of IPMT was iden-
tified (ADSAY et al. 1996). The clinical-pathological
features seem to be similar to those of the classical
type, with a slight prevalence in elderly, male patients
and the pancreatic head. The tumors have mucin-
filled cysts containing nodular papillary projections
lined by cells with abundant granular eosinophilic
cytoplasm (Fig. 6.11) (oncocytic cells rich in mito-
chondria), mixed with both goblet and mucin-con-
taining cells. Characteristically, these oncocytic cells
show intracytoplasmic lumina (Fig. 6.12). Most of
them were noninvasive carcinomas; one case showed
focal microinvasion, and another displayed wide-
spread invasive carcinoma.
IPMTs are classified on the basis of the greatest
degree of dysplasia, according to the WHO classifica-
tion, into adenoma, borderline tumor, and carcinoma Fig. 6.11. IPMT oncocytic type. Presence of papillary prolifera-
(KLOPPEL et al. 1996). tions, lined by cells with finely granular cytoplasm and nuclei
Intraductal papillary-mucinous adenoma is char- with prominent nucleoli
acterized by tall columnar mucin-producing cells with
mild dysplasia and the absence of mitosis (Fig. 6.8); changes with the presence of irregular branching
borderline intraductal papillary-mucinous tumor is papillae or cribriform growth. The epithelial cells
characterized by papillary projections, cellular pseu- show nuclear stratification, severe nuclear atypia, and
do stratification with crowding of moderately atypical frequent mitosis. Because of the great variability within
and hyperchromatic nuclei (Fig. 6.13); intraductal a tumor, it is important to emphasize the necessity of
papillary-mucinous carcinoma has severe dysplastic extensive tumor sampling in order to make the correct
 90
Fig. 6.12. IPMT oncocytic type. Oncocytic cells showing intra-
cytoplasmic lumina
a Although IPMTs represent an extremely interest-
b pared with ductal carcinoma. Mutations in the p53
Fig. 6.13a,b. IPMT borderline. a Intestinal-type papillae,
morphologically similar to those in colonic villous adenoma.
b Papillary projections characterized by cellular pseudostrati-
fication with crowding of moderately atypical and hyperchro-
matic nuclei; mitosis is observed
G. Zamboni et al.
diagnosis and assess the presence of tumor invasion,
giving special emphasis to papillary or nodular prolif-
erations and sclerotic areas.
Carcinomatous stromal invasion by invasive IPMT
is characterized by the presence of mucin-filled cystic
spaces, partially lined by atypical cells and containing
floating mucus-secreting cell nuclei (Fig. 6.14). This
pattern of invasion, which has been called'muconodu-
lar' (YAMADA et al. 1991), assumes the appearance of
MNCC (SOLCIA et al.1997; KLOPPEL et al. 1996) or col-
loid carcinoma (ADSAY et al. 200l). The overwhelming
majority of colloid carcinomas in the pancreas arises
from pre-existing IPMTs. When colloid tumors of the
pancreas have been extensively sampled, pre-existing
IPMTs were found in all cases (SEIDEL et al. 2002),
whereas with less extensive pathological sampling,
ADSAY et al. reported 59% of association with IPMTs
(ADSAY et al. 2001). The finding of a colloid carcinoma
in the pancreas should prompt the pathologist to
search for an IPMT. On the contrary, the presence of
a glandular component, which characterizes the'tubu-
lar' pattern (similar to the usual ductal carcinoma), is
rarely encountered (YAMADA et al. 1991). The 'tubular'
type carcinoma within an IPMT is characterized by
the presence of malignant glands, similar to those of
common ductal carcinoma (Fig. 6.15).
6.4
Immunohistochemical and Molecular
Characteristics
ing system for studying tumor progression in the
pancreas, very little is known about their molecular
abnormalities. HER-2neu overexpression has been
found in about 75% of cases (SESSA et al. 1994). K-ras
mutation has been reported in 30%-80% of IPMTs
(SESSA et al. 1994; TADA et al. 1991; Z'GRAGGEN et
al. 1997; YANAGISAWA et al. 1991). Independent and
different K-ras mutations have been identified in
IPMTs, suggesting a field cancerization and giving
a molecular basis for the risk of synchronous and!
or metachronous tumors (IzAwA et al. 200l). The
retention of tumor suppressor functions in IPMTs
may explain their more favorable prognosis com-
tumor-suppressor gene were detected in only 8%
of cases (SESSA et al. 1994). Recently, a 25% rate of
inactivation of the STKll!LKBl tumor-suppressor
gene responsible for Peutz-Jeghers syndrome has
been reported (SATO et al. 200l). This gene, which is
Pathology of Intraductal Cystic Tumors 91

a _____...-.. b

Fig. 6.14a,b. IPMT with 'muconodular' carcinomatous transformation. a Whole-mount macro section of duodenopancreatec-
tomy showing a diffuse ductal ectasia of the head of the pancreas and multiple nodular gelatinous areas. b Histologically, the
mucin-filled cystic spaces are partially lined by atypical cells and contain floating mucus-secreting cells

involved in growth suppression activity, also associ-

ates with p53 in apoptosis control.
Depending on their mucin expression profiles, one
common (MUC2-positive) and two rarer (MUCl/
MUC2 and MUC1) types of IPMTs (LUTTGES et al.
2001) can be identified. The MUC2-positive IPMTs
typically form papillary structures. When invasive,
all MUC2-positive IPMTs assume the appearance
of a MNCC. The IPMTs showing focal MUC1/MUC2
expression are characterized by oncocytic histology.
The third group seems to be related to ductal carci-
noma because of its MUC1 positivity in the absence
of, or very slight, MUC2 staining and due to the prev-
alence of the 'tubular' pattern of their invasive carci-
nomatous component. This assumption is supported
Fig. 6.15. IPMT with 'tubular' carcinomatous transforma-
by the DPC4 findings. DPC4 is a tumor-suppressor tion. Tubular-type carcinoma is characterized by infiltrating,
gene on chromosome 18q, which mediates the effect irregular tubular structures, similar to those of ordinary
of TGF-beta signaling, resulting in growth inhibi- ductal carcinoma
tion (DAr et al. 1998). While DPC4 is consistently
expressed in the MUC2 and MUCl/MUC2 types of
IMPTs, both in the intraductal and in the muconodu- 6.S
lar carcinomatous component, 50% of the MUC1- Preoperative and Intraoperative
positive IPMTs and the 'tubular' invasive carcinomas Pathological Diagnosis
show the loss of DPC4/SMAD4 expression (LUTTGES
et al. 2001; IACOBUZIO-DoNAHUE et al. 2000).A simi- A preoperative pathological diagnosis of IPMT
lar proportion of deletion (55%) has been reported in is possible with both cytology and histology. The
conventional ductal carcinomas (HAHN et al. 1996). cytological examination of the intraductal material
As DPC4 expression in conventional carcinoma cor- collected during the endoscopic examination (ERCP)
relates with longer survival (WrLENTz et al. 2000), reveals the presence of abundant extracellular mucin
it is possible to hypothesize that the prolonged and with a floating epithelial component, either in singly
indolent clinical course of IPMT compared with dispersed cells or in a sheet-like arrangement. While
conventional ductal carcinomas may be related in it is possible to subdivide low-grade and high-grade
part to the persistent expression of DPC4 in IPMTs tumors, it is not possible to predict the invasiveness
(IACOBUZIO-DoNAHUE et al. 2000). of the tumor. The examination of K-ras mutation
92 G. Zamboni et a1.

from pancreatic juice, in association with cytologi-

cal examination, proved to be useful, although the
accuracy rate is low (HARA et al. 2002; TADA et al.
1991; YANAGISAWA et al. 1991). The histological
diagnosis can be performed on biopsy material
obtained from the major/minor papilla or directly
from the main duct during a pancreatoscopy. The
disadvantage of histology is that a single localized
biopsy may not accurately reflect the region of the
severest dysplasia.
As positive resection margins and postoperative a
recurrence have been reported in up to 50% of patients
(SHO et al. 1998; FALCONI et al. 2001; AZAR et al. 1996;
RIVERA et al. 1997; TRAVERSO et al. 1998; SHO et al.
1998), the determination of tumor-free resection lines
is extremely important. It is crucial for the surgeon to
assess the intraductal spread of the disease in order to
achieve a total resection. Preoperative imaging, com-
puted tomography (CT), magnetic resonance imaging
(MRI), endoscopic ultrasonography (EUS), and ERCP
do not provide accurate information, failing to pre-
dict neoplasm extension in more than 20% of cases
(CUILLERIER et al. 2000). Partial pancreatic resection
b
should be guided by intra-operative frozen section
examination until disease-free margins are obtained.
Pathologists face many difficulties. One of these is the
differential diagnosis between papillary hyperplasia
and low-grade dysplasia; the pathologist should report
only the moderate to high-grade dysplasia. A second
problem is represented by the extensive inflammatory
reaction with epithelial denudation, which is frequently
found in association with dilatation of the main duct.
The mere absence of dysplastic epithelium in these
cases is not sufficient to define a negative margin. We
experienced two stump recurrences in such cases (Fig.
6.16). Another important point to stress is that careful
attention must be paid to epithelial changes of the small,
peripheral ducts, since the tumor may develop over a
c
wide area in the branches (NAGASAKA and NAKASHIMA
2001). In fact, a tumor component with low-grade dys- Fig. 6.16a-c. IPMT with stump recurrence. a The resected jeju-
plasia remaining in the resected margins may explain nopancreatostomy showing a gelatinous enlargement of the
the high percentage oflocal tumor recurrence in IPMTs. anastomotic area. b A whole-mount macro section showing
the pancreatic stump with multiple areas of colloid carcinoma
For this reason, a negative margin in IPMT patients cor- involving the anastomotic area. c The resection margin of the
responds only to a normal ductal epithelium. Recently, previous duodenopancreatectomy showing a central duct of
the importance of using intraoperative annular array Wirsung with extensive inflammatory reaction and epithelial
US (KANAZUMI et al. 2001), intraductal ultrasonogra- denudation; some branch ducts were dilated and filled with
phy (GIGOT et al. 2001), and pancreatoscopy (HARA et mucus, but lacked evident cellular atypia
al. 2002) has been emphasized to highlight the small
intraluminal proliferations of the duct ofWirsung, lead- This approach seems particularly effective for detecting
ing to biopsy and frozen section examination. In the longitudinal spread of the disease and the multicentric
series reported by HARA et al., a postoperative recur- micropapillary lesions which are not macroscopically
rence was observed in only one patient, and the 3-year visible, and for improving the postoperative outcome
cumulative survival rate was 93% (HARA et al. 2002). (GIGOT et al. 2001; HARA et al. 2002).
Pathology of Intraductal Cystic Tumors
The use of pancreatogastric anastomosis in patients
with IPMT treated with pancreatoduodenectomy
improves the long-term oncological follow-up. This
reconstructive technique gives direct access to the
pancreatic stump by endoscopy during the follow-up,
allowing direct opacification of the pancreatic duct,
sampling of the pancreatic juice for cytological exami-
nation, and ductal mapping with multiple biopsies for
histological examination (NAVARRO et al. 1999; GIGOT
et al. 2001).
6.6
Differential Diagnosis
The differential diagnosis of IPMT is MCT, chronic
pancreatitis with ductal papillary hyperplasia, and
ductal adenocarcinoma. It is quite easy to differ-
entiate IPMT from most cystic lesions, but dis-
tinguishing the 'ductectatic mucin-hypersecreting
variant' of IPMT from MCT may be difficult. This
histological similarity has led some pathologists to
interpret MCT and IPMT as a single entity (ITAI
et al. 1986). A clear distinction between these two
tumors therefore requires precise definitions: the
growth within the pancreatic duct system (dem-
onstrated on ERCP, MRCP with macroscopic and
microscopic confirmation) and the absence of a
subepithelial ovarian-type stroma typically pres-
ent in MCT (ZAMBONI et al. 1999). The differential
diagnosis with chronic pancreatitis may be difficult
in the early stages of IPMT, in which the only histo-
logical modifications are the papillary hyperplasia
and a mild dilatation of the pancreatic duct system
(BASTID et al. 1991). Such a misdiagnosis causes
delay in administering the appropriate therapy
and may favor carcinomatous transformation. The
diagnosis of ductal adenocarcinoma is usually easy
because only a solid mass is present. There may
be some problems with ductal carcinoma associ-
ated with marked ductal ectasia (secondary to the
obstruction) or with a relevant intraductal compo-
nent, which is, however, detected only at a micro-
scopic level (ADSAY and KLIMSTRA 2000).
6.7
Prognosis
Although IPMTs are generally considered slow-grow-
ing tumors, approximately 30%-50% of cases may
93
become invasive and metastasize (KLOPPEL 1998;
FUKUSHIMA et al. 2001; GIGOT et al. 2001; ADSAY
et al. 2002; SUGIURA et al. 2002; SOHN et al. 2001;
CUILLERIER et al. 2000), and the 5-year survival rate
for all patients with IPMT ranges from 50% to 80%
(SOHN et al. 2001; ADSAY et al. 2002; KANAZUMI et
al. 2001; CUILLERIER et al. 2000). The prognosis of
IPMTs depends on the presence of carcinomatous
invasion at the time of resection (KANAZUMI et al.
2001; KIMURA et al. 1998). Therefore, a careful dis-
section and a complete submission of the resected
specimen are mandatory to search for the presence
of microscopically invasive carcinoma. The type
of carcinomatous invasion seems to be significant
since 'colloid' -type carcinoma (Fig. 6.14) has a more
favorable prognosis than 'tubular' -type carcinoma.
However, patients with 'tubular'-type invasive carci-
noma (Fig. 6.15) follow a better course than patients
with conventional ductal carcinoma (ADSAY et al.
2002). The prognosis is also influenced by the type
of surgery (total pancreatectomy vs partial pancre-
atectomy; FUKUSHIMA et al. 2001; SEIDEL et al. 2002;
CUILLERIER et al. 2000). Extrapancreatic invasion,
lymph node metastases, venous invasion, and peri-
neural invasion, although less frequent than in ductal
carcinoma (SOHN et al. 2001), are all indicators of a
poor prognosis (FUKUSHIMA et al. 2001; CUILLERIER
et al. 2000; SUGIYAMA and ATOMI 1998).
Among the IPMTs with a good prognosis are those
originating in the branch ducts instead of the main
duct (TERRIS et al. 2000). However, there is no com-
plete agreement: in situ and invasive carcinoma have
been reported in branch duct type IPMTs (YAMADA
et al. 1991; FALCONI et al. 2001; KANAZUMI et al.
2001; FUKUSHIMA et al. 2001; KOBARI et al. 1999;
NAKAGOHRI et al. 1999). The dimension of the lesion
(greater than 3 cm), luminal vegetations, the thick-
ness of the walls, and a dilated main pancreatic duct
are currently considered as negative prognostic fac-
tors and suggest surgical resection (WAKABAYASHI et
al. 2001; LIM et al. 2001).
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Kloppel G (1999) Mucinous cystic tumors of the pancreas:
clinicopathological features, prognosis, and relationship
to other mucinous cystic tumors. Am J Surg Pathol 23:
410-422
Z'Graggen K, Rivera JA, Compton CC, Pins M, Werner J,
Fernandez-del Castillo C, Rattner DW, Lewandrowski KB,
Rustgi AK, Warshaw AL (1997) Prevalence of activating
K-ras mutations in the evolutionary stages of neoplasia
in intraductal papillary mucinous tumors of the pancreas.
Ann Surg 226:491-498; discussion 498-500
7 Intraductal Papillary Mucinous Tumors: Imaging
C. PROCACCI, G. SCHENAL, E. DELLA CHIARA, A. FUINI, and A. GUARISE

CONTENTS al. 1986,1987; BASTID et al. 1991; YAMADA et al. 1991;

OBARA et al. 1993a,b; YANAGISAWA et al. 1993; RAT-
7.1 Introduction 97 TNER and PINS 1994; RAIJMAN et al. 1994). In 1997,
7.2 IPMT of the Main Duct 98 the tumor was classified with other cystic tumors of
7.2.1 Transabdominal US 98
7.2.2 Computed Tomography 101 the pancreas, and the name of 'intraductal papillary
7.2.3 Magnetic Resonance Imaging 106 mucinous tumor' was proposed as the proper term
7.2.4 Endoscopic Retrograde referring to these lesions. The name emphasizes the
Cholangiopancreatography 11 0 neoplasm's intraductal location, the macroscopic
7.2.5 Endoscopic US 111
papillary architecture, and the abnormal production
7.3 IPMT of the Collateral Ducts 113
7.3.1 Transabdominal US 113 of mucin (SOLCIA et al. 1997; WADE et al. 1997).
7.3.2 Computed Tomography 114 Reports of this neoplasm have been few for many
7.3.3 Magnetic Resonance Imaging 116 years because the lesion has often been misdiagnosed
7.3.4 Endoscopic Retrograde as chronic pancreatitis when its origin is in the main
Cholangiopancreatography 120 duct (AGOSTINI et al. 1989; AZAR et al. 1996; TENNER
7.3.5 Endoscopic US 122
7.4 IPMT of the Mixed Type 123 et al. 1996; PROCACCI et al. 1999; CASADO et al. 2000)
7.5 Differential Diagnosis 124 or has often been included in the mucinous cystic
7.6 Biological Behavior and Recurrences 129 tumor group when its origin is in the collateral ducts
References 135 (arising from the parenchyma as opposed to the
duct epithelium) with which it shares its histologi-
cal characteristics (OHTA et al. 1992; TENNER et al.
1996; SOLCIA et al. 1997; SUGIYAMA et al. 1997). In
7.1 the past 10 years, however, recognition of this neo-
Introduction plasm has increased such that it can be considered
the most frequently occurring cystic tumor of the
The first description of the radiological appearance pancreas. Furthermore, the literature underestimates
of intraductal papillary mucinous tumors (IPMTs) the prevalence of the tumor because not all cases
dates back to 1982 when OHHASHI and co-authors are reported (PROCACCI et al. 1999,2001; LIM et al.
(OHHASHI et al. 1982) described the lesion on endo- 2001). The widespread use of imaging techniques,
scopic retrograde cholangiopancreatography (ERCP). particularly US and CT, and the greater familiarity
Since then, this tumor has been called many different with the typical imaging findings is the most sig-
names: mucinous ductal ectasia, ductectatic muci- nificant reason that the lesion is being recognized
nous cystic tumor, mucinous villous adenomatosis, increasingly often (OHTA et al. 1992; YANAGISAWA et
intraductal mucin-hypersecreting neoplasm (ITAI et al. 1993; KOBAYASHI et al. 1995).
IPMT develops exclusively from the epithelial lining
of pancreatic ducts. The macroscopic characteristics
C. PROCACCI, MD; G. SCHENAL, MD; E. DELLA CHIARA, MD
Istituto di Radiologia, Dipartimento di Scienze Morfologico- and the corresponding appearance at imaging vary sig-
Biomediche, Universita degli Studi di Verona, Policlinico nificantly depending on whether the tumor is located
'Giambattista Rossi', P.zza L.A. Scuro lO, 37134 Verona, Italy in the main duct, the collateral ducts, or both (ITAI et
A. FUINI,MD al. 1986, 1987; MOROHOSHI et al. 1989; FURUKAWA et
Servizio di Gastroenterologia, Ospedale Civile Maggiore, P.le
al. 1992; PROCACCI et al. 1996, 1999). The radiologist's
Stefani, 1,37124 Verona, Italy
A. GUARISE, MD job is to recognize the lesion as soon as possible, to
Servizio di Radiologia, Ospedale S. Cuore-Don Calabria, Via D. give an evaluation of its extent, and whenever possible,
Sempreboni, 37024 Negrar, Italy to express a judgment on its biological behavior. The
 98
tumors can vary histologically from hyperplasia to
invasive carcinoma and are classified by the Armed
Forces Institute of Pathology (AFIP) in the 'benign',
'borderline', and 'malignant' categories. Frequently,
multiple forms of epithelial change are present in the
same lesion (FURUKAWA et al. 1992). The prognosis
of this tumor is significantly more favorable than that
of a ductal adenocarcinoma (MOROHOSHI et al. 1989;
TENNER et al. 1996; LOFTUS et al. 1996; WADE et al.
1997; CELLIER et al. 1998; PROCACCI et al. 1999; YAMAO
et al. 2000; KANEKO et al. 2001). Even patients with the
malignant form who are adequately treated by surgery
can have a significant long-term survival (RAIJMAN
et al. 1994; MADURA et al. 1997; CASADO et al. 2000).
When, however, there is the least suspicion of a benign
lesion, the management of this tumor need not be sur-
gical, and the choice of follow-up can be opted for.
The imaging findings of each of the three tumor
forms (tumor of the main duct, of the collateral
branches, and of both) will be discussed individu-
ally. Following this, the differential diagnoses will be
presented. In the conclusion, the potential of imaging
in defining the biological behavior of these tumors
and the problems encountered at follow-up will be
analyzed.
7.2
IPMT of the Main Duct
Main duct IPMT presents as segmental (early) or
diffuse (late) dilatation of the main pancreatic duct.
Segmental IPMT is the most difficult to diagnose
(Fig. 7.1a). Once the entire duct becomes diffusely
a b
Fig. 7.1a,b. Intraductal papillary mucinous tumor (IPMT) of the main duct. a Segmental lesion: ectasia of the main duct, involv-
ing a portion of the main duct. b Diffuse form: cystic ectasia of the collateral ducts is associated with dilatation of the entire
main duct. The dilated papilla protrudes into the duodenal lumen
C. Procacci et al.
involved (Fig. 7.1b), it is difficult to distinguish the
dilatation from chronic pancreatitis (AGOSTINI et al.
1989; AZAR et al. 1996; TENNER et al. 1996; PROCACCI
et al. 1999). The prompt diagnosis of IPMT of the
main duct is of paramount importance, because
when these tumors involve the main duct to any
degree, they must be considered malignant. Patients
should be immediately evaluated for possible surgical
resection, which unfortunately, in the more advanced
stages, can advocate a total pancreatectomy (TENNER
et al. 1996; KOBARI et al. 1999; LIM et al. 2001).
7.2.1
Transabdominal US
The primary objective of transabdominal US is to iden-
tify the lesion; once an abnormally dilated pancreatic
duct is identified, the differential diagnostic consider-
ations are limited (PAVONE et al. 1997; LIM et al. 2001;
KANEKO et al. 2001; SILAS et al. 2001). The major limi-
tation with the US examination is that excessive bowel
gas can limit a complete visualization of the pancreas
in about 25% of patients (PAVONE et al. 1997).
Dilation of the main duct is usually demonstrated
(ITAI et al. 1987; MADURA et al. 1997; WADE et al. 1997;
KANEKO et al. 2001). In the segmental form, the dila-
tion can be in the pancreatic head (Fig. 7.2a) or, less
frequently, in the tail (Fig. 7.2b) (PROCACCI et al. 1999).
Suspicion of segmental IPMT is mostly based on the
absence of an obstructing mass and the absence of
a history of episodes of acute pancreatitis that could
lead to the suspicion of a postinflammatory stenosis
(DABEZIES et al. 1990). The pancreatic parenchyma usu-
ally has normal thickness, as long as there is no cystic
 Intraductal Papillary Mucinous Tumors: Imaging 99

a b

c d

e f

Fig.7.2a-f. IPMT of the main duct, segmental type (a, b) and diffuse type (c-f) (US evaluation). a Segmental dilation of the
main duct in the pancreatic head is shown in the axial scan. The content is inhomogeneously hyperechoic due to the presence
of mucin. b Another patient. Cystic ectasia of the distal tract of the duct of Wirsung is shown in the axial scan; within, there are
some hyperechoic formations attributed to mucin deposits and papillary proliferations. c, d Axial image shows marked dilation
of the main duct (calipers in c); both the Santorini and Wirsung ducts (arrows in d) are dilated. e, fDifferent patient. Dilation of
the duct of Wirsung in the body-tail is shown in the axial scans and cystic ectasia of the portion of the duct in the pancreatic
head within which echoic formations (arrows) can be seen, presumably due to papillary growth
 100 C. Procacci et al.

dilatation of the duct, with resulting adjacent parenchy-
mal atrophy (PROCACCI et al. 1999). The duct's cystic
transformation (Fig. 7.2b) has sometimes been reported
in the tail (KANEKO et al. 2001; LIM et al. 2001).
In the diffuse form, the whole duct is dilated
(Fig. 7.2c,d), to a greater or lesser degree, depend-
ing on the time of onset of the neoplasm (PROCACCI
et al. 1999). In this event, cystic ectasia of the duct
is likely, more commonly in the head of the gland,
associated with mild dilation of the tract upstream
(Fig. 7.2e,f). Obviously, in this case, it is difficult to
establish whether the whole duct is affected by the
neoplasm or if the cephalic tract neoplasm is associ-
ated with the dilation of the tract upstream simply
due to obstruction.
Parenchymal atrophy is usually proportional to the
ductal dilation (OBARA et al. 1993a). When the mark-
edly dilated duct is bordered by a thick, echogenic
wall (Fig. 7.2a) displaying luminal irregularity, malig-
nant degeneration of the tumor can be presumed. In
this case, usually the neoplastic layer is indistinguish-
able from the residual, infiltrated parenchyma.
With transabdominal US, it is not possible to docu-
ment the dilated, protruding duodenal papilla seen
frequently at endoscopy (PROCACCI et al. 1999). It is
easy to recognize cystic ectasia of the collateral ducts
which appears in the form of small, multiple, anechoic
structures located near the main duct or, more com-
monly, grouped in bunches in the uncinate process
(Fig. 7.3a,b) (KANEKO et al. 2001).
The content of the dilated main or collateral ducts
is usually transonic but can be inhomogeneous
because of the frequent presence of echogenic areas
located in the sloping portion of the duct or near
the walls (Fig. 7.2) (TAKI et al. 1997). It is not always
possible to establish with US if these echo genic
formations are produced by mucin globules or by
papillary proliferations (KANEKO et al. 2001). The

a b

c d

Fig. 7.3a-d. IPMT of the main duct (US evaluation) a, b In the axial scans, dilation of the main duct (calipers in a) is demon-
strated with transonic content and cystic ectasia of the collateral ducts of the uncinate process (calipers in b). c, d Another
patient. Significant dilatation of the entire main duct in which intensely echoic formations are seen in the dependent position
(asterisk in c), attributed to mucin and other less echoic formations (arrows in c, d) attributed to papillary growths
 Intraductal Papillary Mucinous Tumors: Imaging 101

papillary growths, however, tend to be less echogenic
than mucin (Fig. 7.3c,d); these growths have a height
of between 1.5 and 21 mm, with an average value of
6.7 mm (FUKUSHIMA et al. 1997; KANEKO et a1. 2001).
Rarely, one can differentiate luminal projections
from mucin by varying the patient's position: mucin
can be seen to vary in position within the duct, while
the papillary projections remain fixed (KANEKO et a1.
2001). In some cases, the large volumes of mucinous
concretions within the ductal content can render
the appearance of the dilated duct echogenic, and
because the dilated ductal lumen is not distinguish-
able from the adjacent parenchyma, the entire lesion
may go undiagnosed (PROCACCI et a1. 1996). Careful
attention to 'gain' settings is necessary so that this
error may be avoided. Sometimes the echogenicity of
these intraductal mucinous formations can be par-
ticularly high in relation to the deposits of calcium
within them (ITAI et a1. 1987; PROCACCI et a1. 1996);
nonetheless, the posterior shadow is not appreciable.
7.2.2
Computed Tomography
CT has contributed significantly to the improved
recognition of IPMT, even surpassing ERCP as the
primary imaging test for diagnosis. CT recognition
has improved with the advent of helical/spiral data
acquisition (FUKUKURA et a1. 2000; TAOUL! et a1.
2000). It is presumed that a further significant diag-
nostic improvement will be gained from using the
multislice technique.
Patients with known or suspected IPMT should be
studied utilizing a dedicated pancreatic technique.
The details of this technique are elaborated in Sec-
tion 3.2.2.1 and the following.
On non-IV contrast images, it is possible to evalu-
ate the gland's morphology, identifying the localized
increase in gland size due to the cystic ectasia of
the main duct or of the collateral ducts (FUKUKURA
et a1. 2000). In this phase, if the duodenal lumen
has been distended using an oral radiopaque con-
trast medium, it may be possible to recognize the
hypo dense protruding papilla (Fig. 7.4a) (PROCACCI
et a1. 1999; FUKuKuRA et al. 2000). If water is used
to identify the duodenal lumen, this feature may
not be recognized at this stage of the examination.
Calcifications may be most apparent on non-IV
contrast-enhanced images. Calcification located at
the margin of the duct with the parenchyma may be
due to superimposed chronic pancreatitis (Fig. 7.5)
(PROCACCI et al. 1996), whereas those located centrally
result from deposits of calcium within the mucin glob-
ules (Fig. 7.6) (TAOUL! et al. 2000).
On IV contrast-enhanced images, the lesion is
better outlined against the bright background of
contrast-enhanced parenchyma (ITOH et a1. 1992).
In this phase, it is possible to define the parenchymal
thickness and the extent of the parenchymal atrophy
(ITAI et a1. 1987; RICKAERT et a1. 1991; ITOH et a1.
1992; PROCACCI et a1. 1996). The main duct, vari-
ably dilated, appears distinctly hypodense compared
with the glandular tissue (Figs. 7.5, 7.7-7.9). Careful
inspection reveals that the lumen is seldom homoge-
neous (Fig. 7.7), since mucin deposits and/or papil-

a b

Fig.7.4a,b. IPMT of the main duct (CT evaluation) a On non-IV contrast images, modest enlargement of the pancreatic head
and a large defect (arrow) in the duodenal lumen, opacified by diluted oral contrast (Gastrografin), representing a dilated major
papilla are demonstrated. b On IV contrast-enhanced images, significant ectasia of the main duct is shown in direct continuity
with the dilated papilla protruding into the duodenal lumen that, in this phase, is distended by the hypodense contents (water)
 102 C. Procacci et a1.

a b

c d

Fig. 7.5a-d. IPMT of the main duct (CT evaluation). Axial scans, carried out in a craniocaudal direction with IV contrast, reveal
mild ectasia of the duct of Wirsung in the body-tail (a) and cystic ectasia of the duct within the pancreatic head (b-d). The
major papilla (arrowhead) and minor papilla (arrow) bulge into the duodenal lumen. Multiple parenchymal calcifications are
present, presumably secondary to chronic obstructive pancreatitis

lary proliferations can be revealed, characterized

Fig. 7.6. IPMT of the main duct (CT evaluation). The axial
scan, carried out with delayed IV contrast-enhanced images,
demonstrates marked cystic-type dilatation of the main duct
in the body-tail, with significant atrophy of the parenchyma
surrounding the lesion. Within the duct, there are multiple
amorphous calcifications, presumably located in the mucin
deposits
by higher density {Fig. 7.8} {FUKUKURA et al. 2000}.
Nonenhancing mucin deposits can therefore be dis-
tinguished from contrast-enhancing papillary prolif-
erations. Alternatively, CT can differentiate between
mucin and papillary proliferations by changing the
patient's position (KANEKO et al. 2001; PROCACCI et
al. 2001).
Pancreatic ductal dilation is accompanied by a
proportional thinning and atrophy of the parenchyma
{Figs. 7.7, 7.8}. Parenchymal calcifications may appear
in long-standing cases (ITAI et al. 1987; RICKAERT et al.
1991; ITOH et al. 1992; PROCACCI et al. 1996; SUGIYAMA
and ATOMI 1999). Whenever significant ductal dilation
with normal or even increased parenchymal thickness
is present, one must assume malignant degeneration
of the tumor {Fig. 7.9}. The suspicion of malignancy
is also supported by the presence of multiple papillary
proliferations {Fig. 7.8}. Even if a tumor in its advanced
stages invades the pancreatic parenchyma, the cystic
component remains recognizable {Fig. 7.9}, which
 Intraductal Papillary Mucinous Tumors: Imaging 103

_ _ ___ d
c

e f

Fig.7.7a-f. IPMT of the main duct (CT evaluation). a, b First patient. Significant dilation of the distal duct of Wirsung with
protrusion of the dilated papilla (arrow in b) into the duodenum (d). The duct ofWirsung is not recognizable in the body-tail.
c-f Different patient. Significant dilatation of the main duct in the portion between the pancreatic neck (arrow in c) and the
papilla which, dilated, protrudes into the duodenal lumen (arrow in e); there is coexisting cystic ectasia of the collateral ducts
of the uncinate process (arrows in f)
a b

c d
Fig. 7.8a-d. IPMT of the main duct (CT evaluation). In the IV contrast-enhanced images obtained in the craniocaudal direc-
tion, significant dilatation of the duct of Wirsung and dilation of the papilla (long arrow in d) is present. Marked parenchymal
atrophy is also present. Multiple small formations are recognizable originating on the ductal walls (small arrows) , corresponding
to papillary proliferations

a b

Fig.7.9a,b. IPMT of the main duct (CT evaluation). Modest dilatation of the duct of Wirsung in the body-tail. Thick-walled,
cystic dilation of the duct in the head of the gland is also appreciable
 Intraductal Papillary Mucinous Tumors: Imaging 105

makes it possible to distinguish IPMT of the main
duct from the classic ductal adenocarcinoma (ITOH
et al. 1992). The component which invades the paren-
chyma will demonstrate greater enhancement than
the atrophic and fibrotic parenchyma that delimits its
exterior (ITOH et al. 1992).
In the segmental form, the CT picture is more often
nonspecific (TAOULI et al. 2000; PROCACCI et al. 2001),
since only the segmental ductal dilation can be docu-
mented, even when there is no significant parenchymal
atrophy (Fig. 7.10). Segmental IPMT seldom appears
with cystic dilation of the main duct; one will see a
cystic mass most commonly in the tail (Fig. 7.11). In this
case, in order to avoid the risk of misdiagnosing a muci-
nous cystic tumor, one must demonstrate that the cyst
communicates with the duct ofWirsung (Fig. 7.11a).
With the diffuse form, the diagnosis of IPMT is
certainly much easier because, in addition to the
above-mentioned findings (ductal dilation with
mucin deposits or papillary proliferations: Fig. 7.8),
there are another two helpful findings. First, cystic
ectasia of the collateral ducts is more or less con-
stant, even if modest, above all in the uncinate
process (Fig. 7.70. Second, dilation of the major
and/or minor papillae (Figs. 7.7e, 7.8d, 7.12c,d),
which protrude into the duodenal lumen (FuKu-
KURA et al. 2000), is seen more frequently than in
the segmental form (Figs. 7.5, 7.7b). On IV con-
trast-enhanced images, when the duodenal lumen
has been distended with water, the papilla, with
a hypo dense content, is perfectly distinguishable
from the intraluminal content thanks to the intense
enhancement of the walls (Fig. 7.4b). If, however,
the duodenal lumen has been distended with radi-
opaque contrast medium, the papilla will appear as
a hypodense intraluminal mass (Fig. 7.4a).

a _ """-_ _ b

Fig. 7.10a,b. IPMT of the main duct (CT evaluation). a Initial examination shows modest dilatation of the main duct in the tail.
b At a second examination 10 years later, there is more pronounced dilatation of the duct of Wirsung

a b

Fig. 7. 11 a,b. IPMT of the main duct (CT evaluation). Cystic dilatation of the proximal portion of the duct ofWirsung; the cyst
appears to be in continuity with the main duct in the body (a). There is a small mural nodule in the posterior wall of the cystic
formation (arrow in b)
 106 C. Procacci et a1.

a b

c _ ..._ __
d

Fig. 7.12a-d. IPMT of the main duct (CT evaluation). IV contrast-enhanced scans carried out in the craniocaudal direction
reveal marked dilation of the main duct with adjacent parenchymal atrophy, most evident in the pancreatic neck (a). There is
coexisting dilation of both minor (arrowhead in c) and major (arrow in d) papillae, both of which protrude into the duodenal
lumen (d)

7.2.3 T2-weighted half-Fourier single-shot turbo spin-echo

Magnetic Resonance Imaging
Current magnetic resonance (MR) technology, with
the use of fast, breathhold sequences and the possibil-
ity of obtaining visualization of the biliary and pan-
creatic ducts, has significantly increased its clinical
utility (SUGIYAMA et al. 1997; SUGIYAMA and ATOMI
1998; SUGIYAMA et al. 1998a; ARAKAWA et al. 2000).
MR study of pancreatic diseases requires the utiliza-
tion of un enhanced and IV gadolinium -enhanced gra-
dient recalled echo (GRE) Tl-weighted fat-suppressed
(FS) sequences, and fast T2-weighted sequences. Added
to these are magnetic resonance cholangiopancreatog-
raphy (MRCP) renderings obtained either with a long
echo train, single-shot thick slab technique or a heavily
(HASTE) acquisition. The latter is performed in mul-
tiple planes including axial and coronal (ONAYA et al.
1998; ARAKAWA et al. 2000). The oral administration of
superparamagnetic contrast medium greatly improves
MRCP quality. The intravenous administration of
gadolinium during the GRE Tl-weighted sequences,
with a timing analogous to that of the CT IV contrast
phases, improves contrast resolution in the pancreas
and allows for preoperative planning by the ability to
create MR angiographic renderings.
The unenhanced GRE Tl-weighted sequences give
the first indication of the extent (segmental or diffuse)
of duct involvement. With segmental IPMT, it is pos-
sible to demonstrate the typical hypo intense image of
the dilated duct (Fig. 7.13a). Without IV gadolinium,
 Intraductal Papillary Mucinous Tumors: Imaging 107

a b

c d

Fig. 7. 13a-d. IPMT of the main duct (MR evaluation). a On this noncontrast opposed-phase GRE Tl-weighted image, there is a
marked hypointense signal within the pancreatic tail. b, c On images acquired in the craniocaudal direction utilizing a HASTE
T2-weighted sequence, segmental dilatation of the duct of Wirsung with adjacent parenchymal atrophy is demonstrated. Cystic
ectasia of a collateral duct is also present (arrow in b). d MRCP confirms the segmental dilation of the caudal portion of the
duct of Wirsung and the cystic ectasia of a collateral duct (arrow)

the signal of the lumen is not significantly different
from that of the adjacent pancreatic tissue, unless fat
suppression is employed (Fig. 7.14a,b). In the diffuse
form, the gland atrophies so that it is often impossible
to distinguish the thin and hypo intense parenchyma
from the dilated duct lumen with the same signal,
especially if there are mucin and/or papillary pro-
liferations inside the main duct (Fig. 7.15a). Unlike
with CT, it is not possible to document the presence
of calcifications.
The HASTE T2-weighted sequences are acquired
with a 4-mm slice thickness in both the axial and
coronal planes. These images are vital in diagnosing
IPMT, since they provide an accurate evaluation of
the duct and its contents (IRIE et al. 2000; ARAKAWA
et al. 2000). The segmental or diffuse dilation
(Figs. 7.13b,c, 7.14c,d, 7.16a) of the main duct and
the possible coexistence of cystic ectasia of the
collateral ducts are visible (SUGIYAMA et al. 1998;
ARAKAWA et al. 2000). The dilation of the major
and/or minor papilla, protruding into the duodenal
lumen, can also be seen (LIM et al. 2001). Moreover,
with these sequences it is possible to recognize
papillary proliferations within the dilated ducts
(Figs. 7.15b, 7.17), which appear hypointense com-
pared with the intraductal mucin (IRIE et al. 2000).
The nondependent location of these intraluminal
defects confirms their neoplastic nature. The maxi-
mum resolution is obtained with HASTE sequences,
where identification of the tiniest intraluminal
defects can be made, which are sometimes underes-
timated with MRCP (IRIE et al. 2000). MRCP, carried
out with breath-holding and thick slabs, supplies an
accurate demonstration of the pancreaticobiliary
ducts, revealing the location and the extent of the
main duct dilation (Figs. 7.13d, 7.14e, 7.16b) and the
associated collateral ducts dilation (ARAKAWA et al.
2000). It also allows for the recognition of dilatation
of the duodenal papilla. Documentation of possible
intraluminal defects is less accurate. Both small pap-
 108
c d
e common bile duct is slightly and regularly dilated
illary proliferations and mucin deposits located within
a dilated duct can, in fact, be hidden by volume aver-
aging within the hyperintense signal within the thick
slab image. The use of diffusion-weighted echo-planar
imaging has been proposed to differentiate the mucin
from the pancreatic juice (YAMASHITA et al. 1998), but
not all the authors agree on that (IRIE et al. 2002).
C. Procacci et al.
Fig. 7.14a-e. rPMT of the main duct (MR evaluation). a, b Axial
non contrast GRE FS II-weighted image reveals segmental
dilatation of the duct of Wirsung in the head and neck of the
pancreas. Decreased signal is apparent within the dilated duct
compared with the parenchyma. There is also modest dilation
of the common bile duct (arrow in b). c, d Axial HASTE T2-
weighted images (same region as a, b): the above-mentioned
findings are confirmed. Within the common bile duct, a
fluid-fluid level image is recognizable due to the presence of
layering sludge (arrow in d). e MRCP confirms the segmental
dilatation of the duct ofWirsung with associated cystic ectasia
of the collateral branches in the uncinate process (arrow). The
The GRE Tl-weighted sequences, carried out in
the IV contrast phase, allow for the analysis of the
enhancement and preservation of the pancreatic
parenchyma (Fig. 7.16c,d). Just like with spiral CT in
the IV contrast phase, it is even possible to recognize
the presence of hard, neoplastic rind and/or papillary
proliferations, which show intense enhancement.
 Intraductal Papillary Mucinous Tumors: Imaging 109

a b

Fig. 7.15a,b. IPMT of the main duct (MR evaluation). a Axial noncontrast opposed-phase GRE Tl-weighted image. The pan-
creas appears homogeneously hypointense. b Axial SE T2-weighted image. The duct of Wirsung appears markedly dilated with
significant parenchymal atrophy. Within it, large hypointense filling defects attributed to papillary growths are seen

a b

c d

Fig. 7.16a-d. IPMT of the main duct (MR evaluation). a The axial HASTE T2-weighted image shows dilatation of the duct of
Wirsung in the body-tail, with cystic ectasia oflocal collateral ducts (arrows). The dilatation of the duct ofWirsung is segmental:
the duct in the head of the gland is normal. b MRCP confirms the segmental dilatation of the proximal segment of the duct of
Wirsung with cystic ectasia of the collateral ducts. c, d In the gadolinium-enhanced GRE Tl-weighted sequence, carried out in
the arterial (nonfat-suppressed: c) and venous (fat-suppressed: d) phases, the pancreatic duct is clearly hypointense compared
with the parenchyma, which shows normal enhancement
110 C. Procacci et al.

into the duodenum, because of the patulous papillary

orifice (CROSS 1980; ITAI et al. 1987). In some cases,
an adequate pancreatogram can be obtained using
a balloon occlusion technique within the papillary
orifice (ITAI et al. 1987; OBARA et al. 1993a,b). Finally,
incomplete opacification of the ductal tree (Fig. 7.18)
can be caused by the obstructing mucin deposits
(TENNER et al. 1996; PAVONE et al. 1997; SUGIYAMA et
al. 1998a; YAMAGUCHI et al. 1999). These limitations
notwithstanding, ERCP provides optimal demonstra-
tion of the main pancreatic duct and precise docu-
mentation of segmental or diffuse dilatation (Figs.
7.19-7.21), and reveals the presence of ectasia within
the collateral branches (Fig. 7.19b) (FUKUKURA
Fig. 7.17. IPMT of the main duct (MR evaluation). The coro- et al. 2000). Further specific findings of IPMT are
nal heavily T2-weighted image highlights cystic dilatation of intraluminal filling defects resulting from mucinous
the main duct (asterisk), which appears to be surrounded by
ectatic collateral ducts. On the main duct walls, there are small, deposits or neoplastic papillary proliferations. Mucin
multiple, hypointense nodules attributed to papillary growths. deposits appear as elongated and amorphous intra-
A stone is present in the gallbladder luminal filling defects (Figs. 7.18, 7.19), isolated from
the ductal walls because of the interposition of the
contrast medium which, due to the injection pres-
sure, can mobilize them. On the contrary, the papil-
7.2.4 lary growths arise from the ductal walls, appearing
Endoscopic Retrograde as multilobulated, more constant defects within the
Cholangiopancreatography contrast-enhanced lumen (Fig. 7.21).
In case of doubt, it is possible not only to carry out
In 1982, OHHASHI and co-workers reported the first aspiration of the pancreatic juice and the subsequent
description of IPMT based on findings at ERCP cytological tests, but also to biopsy the ductal walls
(OHHASHI et al. 1982). ERCP remains today the 'gold or the papillary proliferations directly (BLOCK et al.
standard' imaging modality in studying IPMT. For
many years, its use was considered indispensable
in diagnosing this pathology (RAIJMAN et al. 1994;
RATTNER and PINS 1994; TENNER et al. 1996; LIM et
al. 2001). Today, its role is diminished because of the
increasing recognition of this entity on noninvasive
cross-sectional imaging, in particular MRCP. The
information that can be gained is twofold: endo-
scopic and radiographic (PAVONE et al. 1997).
The definitive diagnosis is established endoscopi-
cally by first recognizing the dilated papillae protrud-
ing into the lumen (PAVONE et al. 1997; FUKUKURA et
al. 2000) and, second, the abundant mucin pouring
from the patulous papillary orifice into the duodenal
lumen (DABEZIES et al. 1990; TENNER et al. 1996;
PAVONE et al. 1997; FUKUKURA et al. 2000). The secre-
tion of large quantities of mucin is typical of malig-
nant tumors (OBARA et al. 1993a; NAKAGOHRI et al.
1999). In more advanced stages, it is even possible
to find the opening of fistulous tracts which reach
the duodenal lumen from the common bile duct or
Fig. 7.18. IPMT of the main duct (ERCP evaluation). Opacifica-
from the main pancreatic duct. Opacification of the tion of the distal portion of the markedly dilated duct of Wir-
pancreatic duct is not always easy to accomplish, sung, with a voluminous amorphous filling defect attributed
especially when there is reflux of contrast medium to mucin. Normal-sized common bile duct (arrows)
 Intraductal Papillary Mucinous Tumors: Imaging III

a ~----~------------~.. b

Fig. 7.19a,b. IPMT of the main duct (ERCP evaluation). a Segmental IPMT within the distal duct of Wirsung associated with
cystic dilatation and a voluminous filling defect (arrow). The main duct appears regularly dilated upstream. b Segmental IPMT
of the proximal portion of the main duct, which appears markedly dilated, with cystic ectasia of the collateral ducts, within which
small filling defects, attributed to mucin deposits (arrows), are highlighted. The remaining ductal segments appear normal

1996; SHIMA et al. 2000). However, biopsy can lead to

a misdiagnosis of benignity (HURWITZ et al. 2001).

7.2.5
Endoscopic US

This technique is mostly used in the study of IPMT

Fig. 7.20. IPMT of the main duct (intraoperative pancreato-
gram). Opacification by means of direct injection into the duct
of Wirsung shows its cystic dilatation in the head and body
with mild dilatation in the tail
Fig. 7.21. IPMT of the main duct (pancreatogram on surgical
specimen: total pancreatectomy). The same patient as in Fig. 7.15.
Opacification by means of direct injection into the duct of Wir-
sung confirms its dilation along with the irregular contour of the
walls due to the presence of multiple papillary growths
of the collateral ducts when cross-sectional imaging
has not resolved the problem of differential diagnosis
with other cystic masses of the pancreas. When seg-
mental or diffuse ectasia of the main duct has been
identified by other imaging modalities, but the ques-
tion of pancreatitis versus neoplasm remains uncer-
tain, EUS may be valuable. However, the number of
nonspecific diagnoses is declining due to the increas-
ing awareness of the imaging features of this tumor.
The high resolution of EUS, related to the contiguity
of the probe with the structure under examination,
can lead to the finding of the smallest useful elements
for diagnosis (FUKUSHIMA et al. 1997; NAKAGOHRI
et al. 1999). Dilation of the main duct in these cases
has usually already been demonstrated; but it is pos-
sible to find the small cystic ectasia of the collateral
branches and the presence of intensely echogenic
mucin deposits and/or small hyperechoic papil-
lary proliferations within the main duct (Fig. 7.22)
(PAVONE et al. 1997; YAMAGUCHI et al. 1999). Thick-
ening and irregularities of the walls and hyperechoic
parietal septations or nodules correspond to areas
of malignant transformation. The presence of mucin,
in the form of hyperechoic aggregates or filaments,
within the lumen of the cystically dilated branches is
also well shown (Fig. 7.23) (SUGIYAMA et al. 1998b;
 112 C. Procacci et al.

a b

Fig. 7.22a,b. IPMT of the main duct (EUS evaluation). a Significant dilatation of the duct of Wirsung (W), starting from the
papilla. The ectatic hypoechoic collateral branches (black arrows) are visible. b Marked dilatation of the pancreatic duct (W)
in the body-tail, associated with atrophy of the adjacent parenchyma. The content of the duct is hyperechoic due to intraductal
mucin. PV, portal vein; SV, splenic vein; SMV, superior mesenteric vein

a b

Fig. 7.23a-c. IPMT of the main duct (EUS evaluation). a The

cephalic portion of the pancreatic duct at the ampullary orifice
into the duodenum (black arrow) is distended and contains
mural irregularities with small nodules (white arrow). b
Same image as a, magnified. Both the papillary projections
(white arrow) and the main duct opening into the duodenal
lumen (black arrow) are better visualized. c Different patient.
Distended main pancreatic duct within which a hyperechoic
nodule is appreciable (white arrow). PV, portal vein; SMV,
c superior mesenteric vein
 Intraductal Papillary Mucinous Tumors: Imaging
ARIYAMA et al. 1998). EUS has been used to evalu-
ate the longitudinal extent of the neoplastic portion
of the main duct, useful for defining the therapeutic
approach of these forms (CELLIER et al. 1998). Find-
ings which closely correlate to the probability of
malignancy include a duct of Wirsung more than 10
mm in diameter in main duct lesions, or alternatively,
the presence of cystic lesions larger than 40 mm, con-
taining septa or nodules greater than 10 mm in size
(KuBo et al. 2001).
The introduction of high frequency miniprobes
(15-20 MHz) has made it possible to extend EUS
by actually performing intraductal US examination
(intraductal ultrasonography, IDUS). This technique
is particularly useful in studying some IPMTs of the
main duct since the introduction of a miniprobe into
the papilla of Vater during the ERCP examination
is made easier. With IDUS, the identification of all
the aforementioned alterations is enhanced. Conse-
quently, papillary projections, mural nodules, and
extraductal proliferations with parenchymal inva-
sion, suggestive of a carcinomatous transformation,
are better visualized (FURUKAWA et al. 1997; MUKAI
et al. 1998; YAMAO et al. 2001; KOITO et al. 2001). The
association of EUS and IDUS seems to increase the
accuracy in the diagnosis and staging of the invasive
forms (KoITO et al. 2001).
Performing an endoscopically directed fine- needle
aspiration biopsy (FNAB) can refine the differential
diagnostic possibilities either by collecting muci-
nous fluid, if this is not practicable by the retrograde
approach, or by carrying out multiple biopsies of all
the focal lesions protruding into the ductal lumen
or infiltrating the wall towards the parenchyma
(BRUGGE 2000).
a b
Fig.7.24a,b. Microcystic IPMT of the collateral ducts (US and CT evaluations). The US (a) and CT (b) axial scans highlight
confluent cystic structures occupying the pancreatic head
113
7.3
IPMT of the Collateral Ducts
IPMTs of the collateral ducts are more easily identifi-
able than those of the main duct since they always
appear with a mass effect. The considerable increase in
reports of this tumor, recorded over the past few years,
is due to the ever more frequent casual finding of the
lesion with noninvasive imaging techniques like US
and CT (YANAGISAWA et al. 1993; CELLIER et al. 1998;
LIM et al. 2001). The lesion, when limited to the col-
lateral ducts, is almost always asymptomatic; clinical
symptoms related to this tumor often occur following
the secondary involvement of the main duct and are
identical to those reported for main duct IPMTs.
7.3.1
Transabdominal US
The lesion has multilobulated outlines and a tran-
sonic texture at US investigation (LIM et al. 2001).
Identification is facilitated by the fact that the tumor
is most commonly found in the head or the uncinate
process (Figs. 7.24a, 7.25a, 7.26a, 7.27a) and less com-
monly in the body and tail (DABEZIES et al. 1990; LIM
et al. 2001). With current sonographic technology, a
skilled operator should be able to identify lesions
with a diameter of 1-2 cm (LIM et al. 2001). The lesion
can have a 'honeycomb' micro cystic or an unilocular
or multilocular macro cystic architecture (Figs. 7.24a,
7.25a, 7.26a, 7.27a) (KANEKO et al. 2001; LIM et al.
2001). Despite the multiplicity of the septa, the micro-
cystic form never appears as a solid echoic mass, as
happens with a 'sponge-like' SCT. The diagnosis of
 114
b c
IPMT is further insured by finding intraluminal
defects (Fig. 7.27a) that can appear with an intensely
echoic texture in the presence of mucin deposits or
with a hypoechoic texture, originating on the ductal
wall in the case of papillary proliferations (KANEKO
et al. 2001; LIM et al. 2001).
With US, it is difficult to demonstrate the com-
municating duct between the tumor and the main
pancreatic duct; for this reason, the differential
diagnosis between collateral branch IPMT and
either a serous cystadenoma ('honeycomb' micro-
cystic aspect: Figs. 7.24a, 7.25a, 7.26a) or mucinous
cystic tumor (unilocular or multilocular macrocys-
tic aspect: Fig. 7.27a) may be impossible. US is, how-
ever, particularly sensitive in documenting possible
associated dilation, both segmental and diffuse, of
the main duct.
Finding a lesion with the above-mentioned charac-
teristics near the uncinate process in a male patient,
especially without symptoms, must lead to the suspi-
cion of IPMT (DABEZIES et al. 1990). However, if the
lesion is found in a woman, is not located in the unci-
nate process, does not have a communicating duct, and
is not associated with dilation of the main duct, other
C. Procacci et al.
Fig. 7.25a-c. Microcystic rPMT of the collateral ducts (US and
CT evaluations). In the longitudinal US (a) and axial CT (b, c)
scans, a small, ovoid mass with cystic architecture is visualized
in the uncinate process
cystic tumors of the pancreas should be considered
in the differential diagnosis. Therefore, the primary
role of transabdominal US is the identification of the
lesions, rather than their classification.
7.3.2
Computed Tomography
The recognition of IPMT by computed tomography
(CT) has been responsible for reducing the ERCP
evaluation of this lesion. Spiral and now multi slice CT
techniques have allowed the pancreas to be evaluated
with thinner sections (improving resolution), with
optimal contrast enhancement (facilitating recogni-
tion of smaller lesions), and in 3D (refining the ability
of the procedure to determine whether or not a cyst
communicates with the main duct) (FUKUKURA et
al. 2000). For this reason, it is particularly useful to
acquire scans at a slice thickness of 3 mm on single-
slice systems or 1-1.25 mm with multislice systems.
In the non-IV contrast phase, IPMT of the col-
lateral ducts is recognizable when, depending on
its size, it is able to produce a localized mass effect
 Intraductal Papillary Mucinous Tumors: Imaging
c
Fig. 7.26a-d. Microcystic IPMT of the collateral ducts (US and CT evaluations). In the US (a) and axial CT (b-d) images obtained
following IV contrast enhancement, a fluid-containing lesion is identified in the pancreatic head, made up of microcysts and
macrocysts
within the gland. The lesion will appear isodense
or slightly hypodense compared with the adjacent
un enhanced parenchyma (Figs. 7.28a, b, 7.29a). Cal-
cifications are rare but could be located in the septa
or within mucin deposits. They are more often found
in larger tumors. Ductal calcifications may occur as
a result of chronic pancreatitis resulting from long-
standing obstruction of the duct of Wirsung by the
downstream tumor.
In the pancreatic IV contrast phase (PROCACCI et
al. 1996), the difference between a low attenuation
tumor and the normal parenchyma is highlighted
(Figs. 7.24b, 7.25b,c, 7.26b-d, 7.27b-d). Optimal
enhancement of the pancreatic parenchyma is
obtained in the pancreatic phase (see Section 3.2.2.1
115
and following) (Figs. 7.28 c, d, 7.29b). It is important
to assess the thickness of the wall and septa: the rec-
ognition of increased thickness is a useful indicator
of malignancy. On the other hand, thin wall and septa
do not exclude malignancy. With CT studies, it is still
difficult to distinguish mucin deposits from papil-
lary proliferations unless the latter are not located
in a nondependent position. Varying the patient's
position can be useful for differentiating mobile
mucin from fixed neoplastic elements. With IV con-
trast-enhanced spiral or multislice techniques, it is
possible to demonstrate the considerable enhance-
ment of the papillary proliferations which, unlike
the mucin deposits, will demonstrate an increase in
Hounsfield value. When the communicating duct is
 116 C. Procacci et al.

a b

c d

Fig. 7.27a-d. Macrocystic IPMT of the collateral ducts (US and CT evaluations). a In the axial transabdominal US, a large,
sharply marginated mass can be seen in the pancreatic head. The complex echo pattern results from the presence of papillary
proliferations and mucin deposits. b-d Axial IV contrast-enhanced CT images reveal a large, unilocular mass in the uncinate
process. Multiple nodules are seen along the wall, the central portion containing inhomogeneous fluid

not visible, the differential diagnosis between IPMT
and other cystic masses of the pancreas is difficult
(Fig. 7.27b-d). IPMT of the collateral ducts more
often, but not necessarily, has a unifocal character.
In fact, there are situations in which multiple lesions,
even of small dimensions, involve the whole pancre-
atic gland (Fig. 7.30). At other times, there can be a
dual location at both the uncinate process and the tail
(NAKAGOHRI et al. 1999).
Following IV contrast administration, the main
duct, which can either be quite normal or have some
degree of segmental or diffuse dilation (Fig. 7.28c), is
recognizable (SUGIYAMA and ATOMI 1998). This last
finding certainly contributes to the diagnosis of IPMT.
In the delayed IV contrast phases, the difference in
density between the lesion and the pancreatic paren-
chyma is less obvious because the enhancement of
the pancreatic parenchyma approaches the baseline.
However, the greater density of the septa, due to the
slower enhancement, makes it easier to demonstrate
the internal architecture of the tumor (Figs. 7.24b,
7.25b, c, 7.26b-d, 7.28e, f, 7.29c).
7.3.3
Magnetic Resonance Imaging
The study protocol is the same as described above for
IPMT of the main duct. However, in this case, par-
ticular attention should be paid to the obliteration of
signal coming from the liquid content of the stomach
and duodenum by the use of an oral contrast agent.
 Intraductal Papillary Mucinous Tumors: Imaging 117

a b

c d

e f

Fig. 7.28a-f. IPMT of the collateral ducts (CT evaluation). a, b In the noncontrast images, there is a mild increase in the size of
the pancreatic head. c, d On the pancreatic phase IV contrast-enhanced images, there is intense enhancement of the head (c),
revealing an enlarged duct of Wirsung. Downstream (d), a multilobulated cystic lesion can be recognized. e, f In the venous
phase, the multilocular architecture of the cystic mass is more evident due to the greater enhancement of the septa
 118 C. Procacci et a1.

a b

Fig. 7.29a-c. IPMT of the collateral ducts (CT evaluation). a

On the non contrast image, there is a multilobulated lesion,
slightly hypodense compared with the surrounding pancreatic
tissue. b Following IV contrast enhancement, in the pancreatic
phase the lesion is contrasted against the intensely enhancing
parenchyma. c In the venous phase, the central and thin septa
c are seen

a b

Fig. 7.30a,b. Multicentric IPMT of the collateral ducts (CT evaluation). Multiple hypodense lesions with clear outlines can be
seen throughout the gland (asterisks in a); the largest is located in the uncinate process (asterisk in b)
 Intraductal Papillary Mucinous Tumors: Imaging 119

a b

______ .~~ .. ~~ ___________ ~ d

Fig. 7.31a-d. IPMT of the collateral ducts (MR evaluation). a In the axial unenhanced GRE FS Tl-weighted image, a tubular
lesion, hypointense compared with the pancreatic parenchyma, can be seen located in the uncinate process. b HASTE T2-
weighted sequence: the lesion is homogeneously hyperintense; the multilobulated contour and the communication with the
main duct (arrow) are more easily recognizable. c, d Gd-DTPA-enhanced, Tl-weighted GRE images obtained in the pancreatic
and venous phases show the intense enhancement of the parenchyma delimiting the tumor. The duct of Wirsung is identifiable
in the head of the pancreas (arrow)

During the MRCP study, it is also necessary to use
multiple acquisition planes to attempt to document
the presence or absence of a communication between
the lesion and the main duct. Unfortunately, at the
time of this writing, there is no 3D MRCP acquisi-
tion technique.
In the GRE FS Tl-weighted sequence, the lesion,
despite its size and structural characteristics, appears
hypo intense compared with the normal pancreatic
parenchyma (Fig. 7.31a). It is impossible to define the
microcystic or macro cystic architecture of the tumor.
The pancreatic signal is brightest when the images
are obtained with an 'opposed-phase' protocol.
On the T2-weighted HASTE sequence, the lesion
always appears hyperintense with a macro cystic or
micro cystic architecture (Figs. 7.31b, 7.32a-c, 7.33a-d).
The signal intensity is proportional to the size of the
cystic space. The septa are hypointense, as are the
mural papillary proliferations; mucin is indistin-
guishable from the pancreatic juice. Further, with this
sequence, it is possible to evaluate the relationships
between the lesion and the duct ofWirsung (Figs. 7.31 b,
7.32a-c), particularly in the axial section (ARAKAWA et
al. 2000). The demonstration of the status of the main
duct is facilitated (ARAKAWA et al. 2000). This particu-
lar sequence is felt to have the highest sensitivity for
detecting these lesions (Fig. 7.33a-d). Therefore, T2-
weighted HASTE sequences are indispensable in the
MR evaluation of these lesions.
Long echo-train, thick slab MRCP acquisitions
are not to be omitted from the study of these tumors
(SUGIYAMA et al. 1998a; IRIE et al. 2000). This tech-
120 C. Procacci et al.

......._ _ ~_ ;.J_ ..._ _ _.......... b

Fig.7.32a-d. rPMT of the collateral ducts (MR evaluation). a-c HASTE T2-weighted axial scans show a tubular hyperintense
lesion with central septa communicating with (arrow) the main duct (arrowhead in a); the latter appears moderately dilated
upstream. The tumor is located in the posterior portion of the head. d MRCP confirms the presence of a multilobulated cystic
lesion in the pancreatic head, partially superimposed over the enlarged duct of Wirsung

nique gives a complete map of the pancreatic duct
and the lesions, whether single or multiple (Figs.
7.32d, 7.33e,f), that surround it (ARAKAWA et al.
2000). Carrying out multiple acquisitions in dif-
ferent spatial planes contributes to the recognition
of the communicating duct (ONAYA et al. 1998). In
the larger masses, the papillary proliferations are
sometimes obscured due to volume averaging effects
related to the thick slab acquisition.
MR investigations, especially when performed for
monitoring a previously found lesion, are made up
exclusively of the previously mentioned sequences.
The use of IV contrast medium (gadolinium-DTPA)
is useful once a diagnosis of IPMT has been obtained
to predict the biological behavior of the lesion (IRIE
et al. 2000). In fact, as with CT, the presence of thick
walls and septa (Fig. 7.31c,d) testifies to the malig-
nant nature of the tumor, while thin septa do not
exclude malignant transformation of the lesion.
7.3.4
Endoscopic Retrograde
Cholangiopancreatography
ERCP still represents the 'gold standard' of IPMT
diagnosis even today, although MRCP has recently
replaced a good deal of its diagnostic role. Having
 Intraductal Papillary Mucinous Tumors: Imaging 121

c _~_--'-=-' " d

e f

Fig. 7.33a-f. Multicentric IPMT of the collateral ducts (MR evaluation). a-c On axial HASTE T2-weighted scans, small cystic
formation in the pancreatic tail (black arrow in a) and a dominant mass with micro cystic architecture in the pancreatic head
can be seen; the duct of Wirsung in the pancreatic head is moderately dilated. d In the coronal plane, the caudal extension and
the micro cystic aspect of the larger lesion are confirmed as well as the modest dilatation of both the common bile duct and
the duct of Wirsung. e, f MRCP examination, carried out in the coronal (e) and axial (f) planes, confirms the aforementioned
cystic lesions and the mild dilation of both the duct of Wirsung and the common bile duct
 122
said that, in doubtful cases (SUGIYAMA and ATOMI
1998) and, above all, just before surgical resection,
this technique is still utilized. The opacification of
the lesion, especially when the pancreatic duct is
normal, is almost always possible (Figs. 7.34, 7.35a)
unless a mucin deposit obstructs the orifice of the
communicating duct and the lesion does not fill (LIM
et al. 2001; SUGIYAMA and ATOMI 1998; OBARA et al.
1993a). ERCP shows, like the other imaging modali-
ties, the micro cystic or macro cystic architecture of
the mass, along with the aforementioned mucin
deposits or intraluminal growths (OBARA et al.
1993a,b; SUGIYAMA and ATOMI 1998; LIM et al. 2001).
The distension of the duct of Wirsung, even when
the size is normal, can make recognition of intra-
Fig. 7.34. IPMT of the collateral ducts (ERCP evaluation). The
duct of Wirsung is dilated in the head of the pancreas; on its
right side an ovoid, cystic lesion (asterisk) opacities, oriented
parallel to the duct of Wirsung
a b
Fig. 7.35a,b. IPMT of the collateral ducts (ERCP and CT evaluations). a Cystic ectasia of two collateral branches in the pancreatic
head is shown (arrows). b CT axial scan shows the two cystic lesions (arrows) located near the enlarged duct ofWirsung
C. Procacci et al.
luminal defects easier, which significantly modify
the therapeutic strategy of these lesions (LIM et al.
2001). Finally, ERCP is able to document a multicen-
tric IPMT of the collateral ducts even if its sensitivity
seems to be inferior to that of MRCP in the dem-
onstration of single lesions (SUGIYAMA and ATOMI
1998; NAKAGOHRI et al. 1999; IRIE et al. 2000).
7.3.5
Endoscopic US
EUS is only occasionally used in the study of IPMT
of the collateral ducts since other imaging modalities,
especially MRCP, are able to characterize the lesion
more often than not. The advantage of this technique
is its accurate definition of the architecture of the
lesion (Fig. 7.36), where even the thinnest septa,
mucin deposits, and small papillary proliferations
can be seen (OBARA et al.1993a; SUGIYAMA et al.1997,
1998b; SUGIYAMA and ATOMI 1998). Furthermore, it
is sometimes possible to recognize the communicat-
ing duct. The cystic IPMTs can have a wide range of
morphological variations, particularly if located in
the uncinate process. They cause problems of differ-
ential diagnosis at EUS when they are confused with
other cystic tumors, especially when they present as a
unilocular cyst. Cysts with this appearance are found
when the IPMT is in an advanced stage and there is
a higher probability of malignancy.
When the results of the imaging studies are
inconclusive, lesions located in the head or uncinate
process can be further analyzed by transduodenal
FNA with analysis of the aspirated liquid, cytologic
 Intraductal Papillary Mucinous Tumors: Imaging
a b
Fig.7.36a,b. IPMT of the collateral ducts (EUS evaluation). Cystic ectasia of a collateral branch in the uncinate process with
hyperechoic mucin globs on the inside (arrows). A magnified view (b) shows the mucin aggregate better (arrows). Ao, aorta;
SMV, superior mesenteric vein
analysis, and assay for tumor markers (BRUGGE 2000;
GRESS et al. 2000; BOUNDS and BRUGGE 2001;AITHAL
et al. 2001).
7.4
IPMT of the Mixed Type
The mixed form deserves a separate classification.
When tumors involve both the collateral as well as
the main duct, the clinical picture is severer, and
the patients will present with a symptom complex
which is not seen in the previously mentioned forms.
Because both duct systems are involved, the site of
origin (e.g., main duct into collateral duct or collat-
eral duct into main duct) cannot be discerned.
At transabdominal US, it is possible to recognize
the dilation of the duct of Wirsung associated with
the cystic ectasia of the collateral ducts (Fig. 7.3 7a,b).
In some cases, it is possible to distinguish the main
duct from the collateral ducts. In others, there might
be one large mass that occupies the pancreatic head
inside of which cystic spaces can be seen, whose
origin is difficult to establish (Fig. 7.38a,b). Dilation
of the common bile duct is often found secondary to
compression or direct involvement by the mass. It is
more difficult to establish the lesion's relationship
with the duodenum. Within the dilated ducts, it is
common to find deposits of hyperechoic mucin or
hypoechoic papillary proliferations (Fig. 7.39a). With
123
power Doppler, it is possible to demonstrate the flow
within the papillary proliferations (Fig. 7.39b,c). In
the more advanced stages of the disease, it is pos-
sible to find peripancreatic adenopathy or malignant
ascites.
CT examination documents the multiplicity of
collateral ductal ectasia associated with the dilation
of the main duct (Fig. 7.37c,d). The gland can increase
in volume, particularly in the head. There is compres-
sion of the duodenal lumen (Figs. 7.38c-f, 7.40, 7.41)
and/or papillae protrusion into it (Figs. 7.38f, 7.41b).
Mucin deposits can always be recognized in these
advanced tumors. The neoplastic rind around it
(Fig. 7.41a) or the large papillary proliferations (Fig.
7.42a,b) are commonly demonstrated as signs of
malignant degeneration of the tumor. It can happen,
however, that the multiple lesions, despite their large
size, have thin walls. They can protrude towards the
peritoneal cavity or the retroperitoneal space with
the possible appearance of ascites, due to peritoneal
carcinomatosis. In this case, mucin deposits are
sometimes visible as they are well delimited com-
pared with the ascitic fluid (Fig. 7.41), surrounded by
a thin, dense rim. It is possible to recognize adenopa-
thy while hepatic metastases are uncommon.
MR, especially with the use of intravenous contrast
medium (gadolinium), gives the same information as
CT with the added benefit of MRCP renderings of the
ductal tree and its contents (Figs. 7.42c,d, 7.43, 7.44).
The utilization of ERCP or EUS in studying this
advanced form of IPMT is not often necessary
 124 C. Procacci et a!.

a b

c d

Fig. 7.37a-d. IPMT of the mixed type (US and CT evaluations). In the oblique subcostal (a) and axial (b) scans, a small, fluid-
containing lesion with micro cystic architecture is visible in the pancreatic neck (arrow) with dilation of the duct of Wirsung
upstream (caliper). c, d In the axial, IV contrast-enhanced CT images, the corresponding cystic lesion with microcystic archi-
tecture can be found in the pancreatic neck with dilation of the duct of Wirsung upstream

because useful information, not only for diagnosis
but also for the therapeutic decision-making, has
already been gained through noninvasive techniques.
Obviously, whenever there is the tiniest suspicion of
the nature of the lesion being different (chronic
obstructive pancreatitis), it is advisable to perform
an ERCP. This technique gives an optimal endoscopic
evaluation of the papillae and the possible fistulous
tracts with mucin leakage. Complete opacification of
the ducts is difficult because of the patulous orifice
of the papilla and the dilution and obstruction of the
contrast by the thick mucin.
7.5
Differential Diagnosis
The problems of differential diagnosis of IPMT
depend on whether the main duct form or the col-
lateral duct form is being examined. Mixed type
lesions, on the other hand, are easily characterized
by imaging modality.
With main duct IPMTs, the greatest difficulty in
classification arises in the presence of the segmen-
tal form. When the involvement is minimal, US or
CT will reveal only a simple ectasia of the affected
portion of the main duct (Fig. 7.10). Supporting
findings (ectasia of the collateral branches, papil-
lary proliferations, mucin deposits) will not easily
be recognized. MRCP is more helpful and shows the
continuity between the normal duct and the dilated
segment. In this case, the most important aim of
imaging is to show that there is no postinflammatory
or neoplastic stenosis responsible for the segmental
dilation of the main duct. MRCP is able to demon-
strate the absence of a stenotic segment of the duct
of Wirsung, but ERCP is, undoubtedly, the modality
which gives the most specific results and the only one
able to demonstrate, with certainty, the patency of the
 Intraductal Papillary Mucinous Tumors: Imaging 125

a b

c d

e f

Fig. 7.38a-f. IPMT of the mixed type (US and CT evaluations). a, b In the axial US scans, there is marked ectasia of the main
duct (caliper) and a large lesion of mixed content (solid and fluid) in the head (calipers). c-f In the IV contrast-enhanced CT
scans, marked ectasia of the duct of Wirsung and a predominantly cystic mass in the head of the pancreas are visible. Some of
the cystic spaces show papillary growths within (arrows in d, e). f Conspicuous dilation of the major papilla is present (asterisk)
which bulges into the duodenal lumen
 126 C. Procacci et al.

a b

Fig. 7.39a-c. IPMT of the mixed type (US evaluation). High-

lighted in the US axial scan (a), cystic ectasia of the main
duct within which numerous papillary growths can be seen,
especially along the posterior wall (arrows). With power Dop-
pler (b, c), arterial flow within the stalk of the largest papillary
c growth is seen

a b

Fig.7.40a,b. IPMT of the mixed type (CT evaluation). IV contrast-enhanced CT images in the craniocaudal direction reveal
diffuse enlargement of the entire pancreatic gland, especially in the head, which deforms the inferior vena cava. The significant
dilation of the main duct and the cystic ectasia of the collateral ducts are clearly recognizable
 Intraductal Papillary Mucinous Tumors: Imaging 127

a b

Fig. 7.41a,b. IPMT of the mixed type (CT evaluation). In the CT carried out following IV contrast administration, marked ectasia
of the main duct with multiple solid parietal growths is shown. There is also dilation of the major papilla which protrudes into
the duodenal lumen and cystic ectasia of the collateral ducts of the uncinate process. Moreover, ascites is recognizable, within
which there are omental masses (asterisks) with soft-tissue attenuation

a b

c d

Fig. 7.42a-d. IPMT of the mixed type (CT and MR evaluations). a, b CT scans carried out in the venous phase demonstrate ectasia
of the duct of Wirsung, with cystic appearance in the cephalic portion. Multiple hypodense parietal nodules are recognizable.
c, d In the MR scans, acquired with HASTE T2-weighted sequence, the significant ectasia of the main duct and the collateral
ducts are confirmed. Furthermore, the multiple hypointense parietal nodules are also demonstrated
 128 C. Procacci et al.

a b

Fig. 7.43a-c. IPMT of the mixed type (MR evaluation). Same

patient as in Fig. 4.39. Conspicuous dilation of the duct of
Wirsung with parenchymal atrophy is present. In the body,
two papillary projections originating from the posterior wall
are highlighted (arrows), which are slightly hyperintense in
non-IV contrast images (GRE FS II WI in a), hypointense in
c T2 (b), and hyperintense after contrast medium (c)

a b

_ _ _..... d
c

Fig. 7.44a-d. IPMT of the mixed type (MR evaluation). The axial GRE FS II-weighted venous phase-enhanced images docu-
ment dilation of the main duct and the collateral ducts, within which multiple hypointense parietal nodules are recognizable.
Dilation of the papilla (arrow in d) which protrudes into the duodenal lumen is also appreciable
Intraductal Papillary Mucinous Tumors: Imaging
main duct over its entire extent. Further, ERCP may
occasionally demonstrate intraluminal filling defects
(mucin or papillary proliferations). Therefore, US, CT
or MR demonstration of the segmental dilation of the
duct ofWirsung (Fig. 7.10), especially when noted in
a patient with no previous pancreatic clinical history,
must lead to the suspicion of the possible presence of
segmental main duct IPMT. ERCP is recommended in
these cases for the optimal depiction of ductal anat-
omy (PAVONE et al. 1997; YAMAGUCHI et al. 1999).
The segmental involvement of the main duct can
more rarely appear as a cystic dilation (Figs. 7.3a,
b, 7.11b). In these cases, the lesion will be misdiag-
nosed as an extraductal cystic mass, particularly a
mucinous cystic tumor (FUKUKURA et al. 2000). In
the past, some reports of mucinous cystic tumor,
in male patients, might really have represented seg-
mental IPMTs with cystic ectasia of the main duct
(PAVONE et al. 1997). The communication of the
cystic ally dilated segment with the normal duct can
be suspected with CT (Fig. 7.11b) and, above all, with
MRCP, but without doubt, it can only be confirmed at
ERCP (PAVONE et al. 1997).
In the diffuse form, the diagnosis of IPMT of the
main duct is easier. In this case, other signs, such as
cystic ectasia of the collateral branches and the dila-
tion of the papillae protruding into the duodenal
lumen, are present in association with the previously
mentioned findings of mucin deposits and papillary
proliferations (PAVONE et al. 1997). These signs are
not always visible, however (Fig. 7.45). Furthermore,
there may also be findings typically associated with
chronic obstructive pancreatitis, in particular calci-
fications. For this reason, it is sometimes difficult to
differentiate the diffuse form of main duct IPMT and
chronic pancreatitis with US, CT, and conventional
MR (CASADO et al. 2000). The diagnostic difficulties
are also related to the clinical picture of main duct
IPMTs which may be identical to those of relapsing
acute or chronic pancreatitis (TRAVERSO et al. 1998;
NAVARRO et al. 1999; TIBAYAN et al. 2000).
In our personal experience, there have been cases
of main duct IPMT mistakenly interpreted as chronic
obstructive pancreatitis and submitted to surgi-
cal intervention (pancreatojejunostomy: Fig. 7.46),
which were correctly diagnosed several years later
because of the significant progression of the disease.
There have also been cases where the radiological
signs useful for the diagnosis were present in radio-
logical examinations, especially CT, carried out up to
10 years previously (Fig. 7.47). The misdiagnoses of
chronic pancreatitis were done mainly in the 1990s
when IPMT of the main duct was not very well
129
known. More recently, the opposite error has been
made, that is chronic obstructive or cystic fibrosis
correlated pancreatitis has mistakenly been labeled as
IPMT and submitted to surgical resection (Fig. 7.48).
Because of all these considerations, whenever a diag-
nosis of IPMT of the main duct or chronic obstructive
pancreatitis leads to the decision to proceed to surgi-
cal resection or derivative surgery, it is imperative to
establish the diagnosis by means of an endoscopic
biopsy, analysis of pancreatic juice (for mucin or
amylase), or during surgery with immediate frozen
section reporting.
Collateral branches IPMTs, easily recognizable as
a cystic mass of the pancreas, may be mistaken for
cystic tumors which do not arise from the walls of
the pancreatic ducts The diagnosis, despite the size
of the tumor, is definitively established when the
communication with the main duct is documented
(FUKUKURA et al. 2000). This goal is difficult to
reach with US but easier with CT (FUKUKURA et
al. 2000). Demonstrating such continuity is easier
when the main duct is dilated near the lesion. If the
communication is not visible, IPMT cannot be dif-
ferentiated with certainty from serous cystadenoma
(when of micro cystic architecture), mucinous cystic
tumor, retention cysts, or lymphangioma (when of
macro cystic unilocular or multilocular architecture)
(PAVONE et al. 1997; GRIFFITH et al. 1998). In this
case, MRCP can significantly aid in establishing the
correct diagnosis providing that acquisitions are
taken along multiple spatial planes (FUKUKURA et
al. 2000). While the failure to recognize the com-
munication does not exclude this tumor, ERCP may
be necessary to find it. If even this investigation fails
to provide a conclusive diagnosis, the use of biopsy
of the lesion utilizing EUS guidance may be defini-
tive. It has been suggested to limit needle aspirations
by means of an endoscope so as to lower the risk of
mucin and neoplastic dissemination along the tract
(DABEZIES et al. 1990; PAVONE et al. 1997).
7.6
Biological Behavior and Recurrences
The difficulty in the therapeutic management of
intraductal tumors derives from the wide range of
epithelial changes manifested by this neoplasm, rang-
ing from simple hyperplasia to aggressive carcinoma.
It is not uncommon to find all grades of epithelial
change in the same lesion. Therefore, imaging is
required not only to identify and characterize the
 130 C. Procacci et al.

c .....'--_ _ _
d

e f

Fig. 7.4Sa-f. IPMT of the mixed type (CT evaluation). The craniocaudal scans, taken in the craniocaudal direction, show a cystic
lesion (asterisk in a) of the pancreatic tail and uniform dilation of the duct of Wirsung up to the papilla

lesion, but also to make an assessment of its biologi-
cal behavior. Pathological correlation has shown that
there are considerable differences between the main
duct and collateral duct forms (TERRIS et al. 2000).
IPMT of the main duct, whether segmental of
diffuse, must be considered a malignant tumor, and
surgical resection is recommended (SUGIYAMA and
ATOMI 1998; YAMAGUCHI et al. 1999; KOBARI et al.
1999; NAKAGOHRI et al. 1999; TERRIS et al. 2000; IRIE
et al. 2000; WAKABAYASHI et al. 2001). Any sized pap-
illary proliferations (Figs. 7.42, 7.43) and/or a thick
rind with irregular contour delimiting the dilated
duct (Figs. 7.41, 7.44) are always signs of malignant
degeneration of the tumor (SUGIYAMA et al. 1997;
SUGIYAMA and ATOMI 1998; YAMAGUCHI et al. 1999;
IRIE et al. 2000; TAOULI et al. 2000; LIM et al. 2001;
 Intraductal Papillary Mucinous Tumors: Imaging 131

a b

c d

Fig.7.46a-d. IPMT of the mixed type (CT and ERCP evaluations). a-c CT scans, carried out in the IV contrast-enhanced phase,
reveal cystic dilation (asterisk) of the duct of Wirsung in the head and neck of the pancreas. d ERCP confirms the cystic dila-
tion of the duct within the head (asterisk). This patient had undergone previous pancreatojejunostomy (arrow), and contrast
material opacifies the jejunal loop

WAKABAYASHI et al. 2001). Moreover, marked dila-
tion of the main duct and protrusion of the dilated
papillae into the duodenum (Figs. 7.4, 7.5, 7.8, 7.12)
are almost always indicative of malignant behavior
(LIM et al. 2001). In the absence of these findings, it
is still impossible to exclude the presence of foci of
malignant degeneration (carcinoma in situ) (SUGI-
YAMA and ATOMI 1998; IRIE et al. 2000).
The definition of the biological behavior of IPMT
of the collateral ducts is of notable clinical importance
since the occurrence of benign tumors is rather high,
and it is theoretically possible to avoid surgical inter-
vention and follow these lesions with serial imaging
studies. It should be remembered that IPMT of the
collateral ducts is often multicentric (NAKAGOHRI
et al. 1999), involving the entire gland so that only
a total pancreatectomy would guarantee its surgical
resection.
Some authors think that the size of the lesion in
the collateral ducts is a useful parameter for defin-
ing the biological behavior of the tumor, considering
lesions greater than 3 cm as suspicious for malignant
degeneration (SUGIYAMA and ATOMI 1998; KIMURA
and MAKUUCHI 1999; IRIE et al. 2000; WAKABAYASHI
et al. 2001). In reality, it is possible to find very large
cystic masses with thin walls where only the presence
of hyperplasia is later documented. Finding thick
walls and/or septa and, above all, the presence of
papillary growths (Fig. 7.27) is certainly much more
reliable for assessing malignancy.
Unfortunately, even with small lesions, the absence
of the above-mentioned signs cannot justify the defi-
nite diagnosis of a benign tumor since microscopic
foci of malignant epithelium may be present in any
given lesion (AGOSTINI et al. 1989). However, it has
been shown that these lesions grow very slowly, with
no significant variation in the majority of cases, even
after a number of years (KAWARADA et al. 1992;
OBARA et al. 1993a; BARBE et al. 1998; MEGIBOW et
al. 2001; WAKABAYASHI et al. 2001). Therefore, in the
 132 C. Procacci et al.

3 b

c d

e f

Fig.7.47a-f. rPMT of the mixed type (CT evaluation). 3-d Contrast-enhanced CT scans in the venous phase demonstrate mild
dilation of the duct of Wirsung in the pancreatic body-tail, and significant, cystic-like dilation of the duct in the neck and head
of the pancreas. Additionally, protrusion of the dilated papilla into the duodenum (arrow in d) can be seen. Papillary growths
and mucin deposits are present within the dilated ducts. e, f The same investigation, carried out 10 years previously in the
same patient, documented the initial ectasia only in the cephalic portion of main duct and collateral branches within the head
(arrows in f)
 Intraductal Papillary Mucinous Tumors: Imaging l33

a b

c d

e f

Fig.7.48a-f. Chronic pancreatitis secondary to cystic fibrosis, erroneously diagnosed as main duct IPMT (CT and MR evalua-
tions). a, b CT scans carried out on non-IV contrast images (a) and in IV contrast-enhanced images in the pancreatic phase (b)
demonstrate dilation of the entire main duct. Multiple, nonenhancing, solid deposits (arrows in a, b) located in the dependent
portion are present. c-d Axial HASTE T2-weighted MR images reveal dilatation of the duct of Wirsung with parenchymal
atrophy. Numerous, markedly hypointense deposits are also present. e MRCP confirms the diffuse dilation of the main duct
and the multiple defects. f On the specimen (total pancreatectomy), the dilated main duct is occupied by multiple amorphous
calcifications
 134 C. Procacci et al.

a _ _ ........ b

c d

e f

Fig.7.49a-f. rPMT of the mixed type (CT evaluation). a-c CT scans performed during the contrast-enhanced venous phase
show cystic-like segmental dilation of the duct of Wirsung in the pancreatic body (asterisk in a) with modest upstream dilata-
tion; the pancreatic head is normal. d-f The follow-up examination carried out after 5 years, following intermediate resection,
demonstrates significant atrophy of the pancreatic tail and neoplastic transformation of the duct of Wirsung with the dilated
papilla protruding into the duodenum (arrow)
Intraductal Papillary Mucinous Tumors: Imaging
presence of a cystic lesion presumably originating in
the collateral ducts with benign characteristics and
in an elderly patient, it is possible to avoid surgical
intervention and monitor the lesion with US or CT
(KIMURA and MAKUUCHI 1999; YAMAO et al. 2000).
But when the lesion appears in a young patient and
there is diagnostic doubt as to its nature, it is better
to carry out an immediate ERCP. Once the IPMT has
been confirmed, thanks to the demonstration of its
communication with the main duct, according to
some authors it is better to proceed immediately to
surgical resection (SUG IYAMA and ATOMI 1998; SIECH
et al. 1999; VAN DE STADT et al. 1999; YAMAGUCHI et
al. 1999; TIBAYAN et al. 2000; FALCONI et al. 2001).
Others favor a varied approach and accept follow-up
in selected cases (SHO et al. 1998; TAKEYOSHI et al.
1999; NAKAGOHRI et al. 1999; SCIAUDONE et al. 2000;
YAMAO et al. 2000; CASADO et al. 2000; WAKABAYASHI
et al. 2001). Watchful monitoring is particularly
advisable in the case of cystic lesions smaller than
2.5 cm in diameter with a normal main duct, since it
has been documented that these lesions are normally
benign and grow very slowly. Resection is, however,
preferable when the main duct is dilated, partial
resection being an option when there is segmental
ductal involvement. Unfortunately, in the presence of
diffuse dilation of the main duct, whether primary
or associated with a collateral duct tumor, it is not
possible to define, by imaging, the true intraductal
extension of the neoplasm. For this reason, a total
pancreatectomy should be performed. As an alterna-
tive, it is possible to initially resect the more highly
involved part of the gland, extending the resection
distally or proximally until the margins at frozen sec-
tion are free of tumor (SUGIYAMA and ATOMI 1998;
CUILLERIER et al. 2000). Unfortunately, this method
does not exclude 'skip lesions' from which tumor may
recur several years following resection (Fig. 7.49)
(CUILLERIER et al. 2000).
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Endocrine Tumors
8 Clinical Manifestations and
Therapeutic Management
of Hyperfunctioning Endocrine Tumors
F. CIRILLO, M. FALCONI, and R. BETTINI

CONTENTS 8.1
Introduction
8.1 Introduction 141
8.2 Clinical Data 142
8.2.1 Epidemiological Data A significant percentage of neuroendocrine malig-
and Benign/Malignant Ratio 142 nancies of the gastrointestinal tract arise within
8.2.1.1 Insulinoma 142 the pancreas. From a clinical point of view, pan-
8.2.1.2 Gastrinoma 142 creatic endocrine tumors can be divided into two
8.2.1.3 VIPoma 142 types: nonfunctional (nonsecreting, 'inactive') and
8.2.1.4 Glucagonoma 142
8.2.1.5 Somatostatinoma 143 functional (secreting, 'active'). Functional secreting
8.2.1.6 Other Tumors 143 neuroendocrine tumors are capable of producing
8.2.2 Hormonal Pathophysiology and secreting hormone substances that can evoke
and Clinical Symptoms 144 physiological effects producing well-known symp-
8.2.2.1 Insulinoma 144 toms and signs. Typically, these include flushing and
8.2.2.2 Gastrinoma 144
8.2.2.3 VIPoma 145
chronic diarrhea seen in carcinoid syndrome; hypo-
8.2.2.4 Glucagonoma 145 glycemic crisis in insulin om a; diabetes mellitus and
8.2.2.5 Somatostatinoma 146 necrolytic erythema associated with glucagonoma;
8.2.3 Laboratory Data and Evocative Tests 146 erosive gastritis sometimes associated with diarrhea
8.2.3.1 Insulinoma 146 in the case of gastrinoma.
8.2.3.2 Gastrinoma 147
8.2.3.3 VIPoma 147
The occurrence of pancreatic tumors can be spo-
8.2.3.4 Glucagonoma 147 radic or hereditary and prevalent in individuals with
8.2.3.5 Somatostatinoma 147 a positive family history of hormonal disorders.
8.3 Therapeutic Strategy 148 The increase in the number of diagnosed cases of
8.3.1 Insulinoma 148 digestive endocrine tumors over the past few years is
8.3.2 Gastrinoma 148
8.3.3 VIPoma 149 a result of increased awareness by clinicians, imagers
8.3.4 Glucagonoma 149 and pathologists (CHIT! et al. 2000; ERIKSSON et al.
8.3.5 Somatostatinoma 149 2000a), the routine availability of serum hormone
References 150 assays (ERIKSSON et al. 2000b; SEREGNI et al. 2000),
and improved treatment options (ARNOLD et al.
1996; OBERG 2000).
A recent complete pathological overview of all
these digestive tumors has enabled pathologists
F. CIRILLO, MD to distinguish between well-differentiated tumors
Department of General Surgery II, 'Istituti Ospitalieri' Hos- and endocrine carcinoma with different grades of
pital, Cremona and Post-Graduate School of Endocrinology malignancy (SOLCIA et al. 2000). The combination of
and Metabolic Diseases, Viale Concordia, 1, University of
the old prognostic criteria (tissue type, grading, and
Parma, 26100 Cremona, Italy
M. FALCONI, MD size) with new parameters, e.g., the tumor's biological
Department of Surgical, Gastroenterological Endocrine and activity, angio-invasion, cell mitotic and proliferative
Pancreatic Unit, Hospital 'GB Rossi', University of Verona, index, is crucial for a correct diagnostic and prog-
37134 Verona, Italy nostic assessment.
R. BETTINI, MD
The aim of this chapter is to focus on all these
Department of Surgical, Gastroenterological Endocrine and
Pancreatic Unit, Hospital 'GB Rossi', University of Verona, aspects of functional endocrine tumors arising in
37134 Verona, Italy the pancreas.
142
8.2
Clinical Data
8.2.1
Epidemiological Data
and Benign/Malignant Ratio
The most frequent pancreatic functioning endocrine
tumors are insulinomas (representing 17% of cases),
gastrinomas (9% occurrence rate), while VIPomas,
glucagonomas, and somatostatinomas account for
less than 2%, respectively (CIRILLO 2001). Other,
rarer forms of tumor are those involving an ectopic
production of hormones such as adrenocortical tro-
phic hormone (ACTH), calcitonin, (growth-releasing
factor (GRF), and parathormone. Table 8.1 summa-
rizes all the main features of these tumors, which are
better specified in the individual sections below.
8.2.1.1
Insulinoma
At this writing, approximately 4000 cases of insu-
linoma have been reported. Insulinoma represents
the most common islet-cell tumor with an incidence
of 11100,000 cases yearly. Men are affected half as
often as women, and 20%-30% of patients report a
positive family history of diabetes mellitus. The peak
incidence is between the 4th and 5th decade of life.
Most insulinomas (85%) are single lesions. Child-
hood insulinomas, however, are multiple lesions
predominantly located in the head of the pancreas
and are known as nesidioblastosis. This entity is
recognized in the presence of focal or diffused b-cell
hyperplasia. The symptoms related to this entity can
be managed with pharmaceutical treatment. Extra-
pancreatic insulinomas are observed rarely (only
0.5% of cases).
The rate of malignancy among insulinomas
reaches 10% and should be suspected in cases
where the symptoms are recent and are accompa-
nied by high plasma levels of insulin or pro-insulin.
Malignant tumors usually have larger dimensions
(diameter in excess of 2.5 cm), and metastases may
already be present at the time of diagnosis (KLOPPEL
and HEITZ 1990). In 5%-10% of cases, there is a posi-
tive family history (MERREL 1988).
8.2.1.2
Gastrinoma
The incidence of gastrinomas is approximately II
500,000. Over 2500 cases have been described so far
F. Cirillo et al.
in the literature, 72% of the primary tumors were
located in the pancreas. Localization in the gastroin-
testinal tract (duodenum, liver biliary ducts, jejunum,
omentum) is less common, and other extragastroin-
testinallocations (such as the parathyroid, kidneys,
ovaries, bone, lung, spleen, and skin) are even more
uncommon (DE BELLIS et al. 1988,1990; PERCOPO et
al. 1990a; SANTINI et al. 1991). On average, patients
are in their 40s at the time of diagnosis, while 2%-
5% of tumors are diagnosed in childhood. Men are
more frequently affected than women (63%-7l %)
(SANTINI et al. 1991; SOLCIA et al. 1993; CIRILLO
2001).
Malignant pancreatic gastrinoma is present in
70% of cases (SOLCIA et al. 1993); symptomatic dis-
ease is associated with a high incidence of metastases.
Pancreatic gastrinoma more frequently presents with
nodal metastases than does duodenal gastrinoma
(39% vs 28%), while the difference is slight for hepatic
metastases (27% vs 3%) (SOLCIA et al. 1993). In 50%
of patients, gastrinomas represent a hereditary dis-
ease (JENSEN et al. 1983; PIPELEERS-MARICHAL et al.
1993). In such cases, the parathyroid glands are more
frequently involved (80.2%), followed by hypophysis
(19.5%) (CIRILLO 2001).
8.2.1.3
VIPoma
Over 250 cases of VIPoma have been reported in
the literature. The average age at onset is 50 years. It
affects women more often than men. Some 80% of
VIPomas are single lesions with a diameter ranging
from 1 to 7 cm (a 20 cm nodule was reported in one
case) (STINNER and ROTHMUND 1992).
Pancreatic VIPomas are localized in 80% of
patients, and 50% of them are malignant; 10%
of tumors are localized elsewhere in the adrenal
cortex, retroperitoneum, and neck. In childhood, the
observation of elevated plasma levels of vasoactive
intestinal polypeptide (VIP) is usually indicative of
neuroblastoma.
8.2.1.4
Glucagonoma
The number of documented cases of glucagonoma is
247 (CASADEI et al. 1999). However, the nonspecific
nature of many of its symptoms suggests that this
disease may have a higher incidence (estimated at
around 0.2/100,000/year) (WHIPPLE and FRANTZ
1935). The average age at onset is approximately
65 years (range 19-84 years), and 75% of cases
Clinical Manifestations and Therapeutic Management of Hyperfunctioning Endocrine Tumors 143

Table 8.1. Main features of pancreatic hyperfunctioning endocrine tumors

Name a Incidence M/F Age Tumor location Size Malignant Associated Symptoms
(cases/ (years) (em) (%) with
million pop. MEN I
per year) (%)

Insulinoma 10 112 40-60 Pancreas 99.5% 0.12-S 10 5-10 Whipple syndrome (fasting
(beta cells, (head 50%, hypoglycemia attacks,
insulin) tail 50%); glycemia <40 mg/dl during
extrapancreatic attacks, remission of symp-
0.5% toms following food intake);
neuropsychiatric symptoms;
tachycardia; obesity
Gastrinoma 2 5/3 40 Pancreas SS%; O.I-IS 70 20-25 Zollinger-Ellison syndrome
(G cells, duodenum 13%; (pancreas); (peptic ulcer 93%, diarrhea
gastrin) other sites 2% 38 40%, steatorrhea 30%)
(duodenum)

VIPoma (VIP) 0.05-0.2 3/5 45-55 Pancreas 90%; 0.6-20 SO Verner Morrison syndrome
extrapancreatic (diarrhea 90%, electrolyte
(adrenal cortex, imbalance 50%-70%, hyper-
retroperitoneum, glycemia 50%, flushing
neck) 10% 20%)
Glucagonoma 0.2 111 45-70 Pancreas 3-35 65 Diabetes 90%; necrolytic
(alpha cells, (head 12%, erythema 70%; diarrhea
glucagon) body 38%, 20%
tail 50%)
Somato- Rare 111 40-50 Pancreas 35%; 2-10 70
statinoma extrapancreatic: (pancreas) Diabetes; gallstones;
(delta cells, duodenum 52%, SO diarrhea/steatorrhea
somatostatin) other 13% (duodenum)

aIn parentheses: type of cells and peptide secreted

have been diagnosed in individuals between 45 and
70 years of age (GUILLAUSSEAU et al. 1995). No gen-
der differences have been noted (BODEN et al. 1977;
PRINZ et al. 1981). Only rarely has it been possible
to observe hereditary forms of glucagonoma with
contemporary elevation of different peptides such
as insulin, gastrin, somatostatin, VIP, and pancreatic
polypeptide (PP) (OHNEDA et al. 1979).
Glucagonomas are indeed malignant in 60%-70% of
cases. Most metastases involve the liver, other possible
locations being the vertebrae, adrenal cortex, and nodes.
In 50%-77% of cases, the primary tumor is located
in the pancreatic tail and may reach a large diam-
eter. Lastly, most glucagonomas are functional tumors
(BODEN 1987; MOZELL et al. 1990; NORTON 1994).
8.2.1.5
Somatostatinoma
This tumor most frequently affects individuals in
their 40s and 50s with no particular gender pre-
dominance. Somatostatinomas more frequently arise
in the duodenum than in the pancreas (51.6% and
34.7%, respectively). The rate of malignancy varies
depending on the primary location of the tumor: 70%
in the pancreas, 50% in the duodenum, and practi-
cally all rare somatostatinomas located outside of the
gastrointestinal tract (NEGRO and PERCOPO 1988;
CIRILLO 2001).
8.2.1.6
Other Tumors
Several other types of functional tumors have been
described in the literature even though they occur
infrequently. The only reliable epidemiological data
concern carcinoids located in the pancreas, of which
43 cases between 1838 (one year before Merling's
description of intestinal carcinoid) and 1998 have
been reported. They account for 0.5% of all gastro-
enteropancreatic neuroendocrine tumors. This rare
variety mainly involves the pancreatic head and
tail, while 29.2% of cases presented with multiple
localizations.
144
The patients affected were all men in their 50s. The
carcinoid syndrome was present in 64.3% of cases,
and in 88.4% the tumor proved to be malignant, with
metastases present at the moment of diagnosis in the
great majority of cases.
8.2.2
Hormonal Pathophysiology
and Clinical Symptoms
8.2.2.1
Insulinoma
The term insulinoma defines a tumor originating
from the B-cells of the pancreas. This tumor was
first described by NICHOLLS in 1902 (NICHOLLS
1902; WHIPPLE et al. 1935). However, the detailed
description of this pathology is credited to WHIPPLE
(WHIPPLE and FRANTZ 1935). He described a triad of
clinical symptoms characteristic of the insulinoma
syndrome: hypoglycemic attacks during fasting,
glycemia levels of less than 40 mg/dl during attacks,
and a rapid remission of symptoms following food
consumption. Hypoglycemia is a frequent symptom
of insulinoma with the typical neuropsychiatric, car-
diovascular, and digestive implications.
Neuropsychiatric symptoms are present in 80%
of cases and may be triggered by fasting or physical
exercise. Harrington defined them as 'funny turns'
in order to underline the extreme variability of
behavior that these symptoms cause (HARRINGTON
1983). Manifestations may include neurovegetative
disorder (such as nausea, vomiting, dizziness,
asthenia, diplopia), automatism, psychomotor
agitation, epileptic-type attacks, paresis, paraly-
sis, irritability, disorientation, and torpor and, in
some cases, may result in coma secondary to a
sharp decline in glycemic levels. These symptoms
may be preceded by a perceptive aura (FILIPI and
HIGGINS 1973; STEFANINI et al. 1974; PERCOPO et
al. 1990b). In 7% of cases, there may be permanent
brain damage.
Cardiovascular manifestations may include
tachycardia, extrasystoles, atrial fibrillation, angina,
sweating, and pallor. These symptoms, present in
approximately 10%-15% of patients, are secondary
to the liberation of adrenaline during marked hypo-
glycemic episodes.
Hunger pains mainly represent the gastrointes-
tinal symptoms (4%-8% of cases). Patients with
insulinoma thus become polyphagic and, in the long
term, obese.
F. Cirillo et al.
As a result, these patients may be erroneously
considered as psychiatric, cardiopathic, or epileptic
individuals and be treated as such, even for long
periods of time.
8.2.2.2
Gastrinoma
The term gastrinoma refers to a type of pancreatic
tumor originating from a cellular population called
G-cells. This tumor is responsible for the pathological
production of gastrin, the hormone capable of stimu-
lating acid secretion in the stomach.
This tumor and the associated clinical symptoms
were first reported by ZOLLINGER and ELLISON in
1955 (GREGORY et al. 1960; ZOLLINGER et al. 1980).
Several years later, Gregory succeeded in isolating
gastrin, the peptide responsible for the clinical symp-
toms, from the tumor cells (GREGORY et al. 1960). The
presence of hypergastrinemia, resulting in a second-
ary hypersecretion of chloridric acid, constitutes the
Zollinger-Ellison syndrome.
The specific symptoms of gastrinomas are ab-
dominal pain (>75%) and diarrhea (50%).
In 93% of cases, the abdominal pain can be related
to the presence of ulcer disease (JENSEN 1996), to an
increase in bowel movements in 14%, and to neo-
plastic infiltration of the nerves in 2.4% (JENSEN et al.
1983). In 25% of patients, abdominal pain is the only
symptom (JENSEN and GARDNER 1993). Peptic ulcers
are located in the proximal portion of the duodenum
in 75% of cases and less frequently in the distal part
of the stomach. Location in the distal part of the
duodenum or the proximal portion of the jejunum is,
however, quite rare. The esophagus may be involved
in 35% of cases, with possible complications such as
perforation, neoplastic transformation, or Barrett
esophagus.
The diarrhea, initially of an intermittent nature,
is associated with steatorrhea in a third of patients,
and in 7% it is the only clinical manifestation in the
absence of ulcer disease. Four different pathophysi-
ological theories have been put forward to explain
the presence of diarrhea and steatorrhea in patients
affected by gastrinoma:
- the increased gastric secretion reduces the
intestinal absorption; the presence of hypergas-
trinemia induces a reduction in the absorption
of water and electrolytes in the gut. Indeed, the
increased secretion of chloridric acid induces the
conversion of pepsinogen into pepsin, the action
of which alters the permeability of the intestinal
mucosa;
Clinical Manifestations and Therapeutic Management of Hyperfunctioning Endocrine Tumors
- the lowering of the duodenal pH results in the
inactivation of the pancreatic lipases and the
precipitation of biliary acids, thus making fat
absorption difficult;
- the nonabsorbed fatty acids stimulate the secretive
activity of the colon;
- an additional cause of diarrhea could be the
hypersecretion of other enteric hormones that
have a stimulating effect on the motility and
secretive activity of the gastrointestinal tract.
The alteration of the gastrointestinal motility
is another factor which plays a significant role in
the pathogenesis of diarrhea in patients with gas-
trinoma. It has, in fact, been demonstrated that the
gastric emptying in these individuals is possibly
accelerated because the receptors are not able to
regulate the gastroduodenal peristalsis.
Furthermore, 7% of all gastrin om as are clinically
silent. In these cases, the onset of disease may take
a different course, appearing as a result of digestive
disturbances or compressive disease. Gastrointes-
tinal hemorrhages have been described in 46% of
patients, intestinal occlusion in 20%, and perforation
in 6% (DE BELLIS et al. 1990).
Gastrinomas may be present in 0.1 %-1 % of all
patients suffering from peptic ulcer disease. How-
ever, the diagnosis may not be immediate (the period
of latency may extend for up to 6 years) (JENSEN and
GARDNER 1993). This is partly due to the fact that the
abdominal pain might not be recognized as a symp-
tom of gastrinoma and also to the indiscriminate use
of antisecretive drugs able to mask the clinical man-
ifestations of these tumors, particularly in the initial
phases (ZOLLINGER et al. 1980; DE BELLIS et al. 1988).
Such a late diagnosis may account for the frequent
observation of metastases at the time of diagnosis
(50%-60% of cases).
Therefore, the diagnosis of a gastrinoma should
always be suspected in patients with the following: (1)
multiple ulcerations of the upper digestive tract resis-
tant to pharmacological treatment or recurring quickly
after targeted surgical treatment; (2) secretive diarrhea
of unknown origin; (3) highly positive family history of
peptic ulcer disease; (4) a positive individual or family
history of parathyroid and/or hypophysial tumors; (5)
acid hypersecretion and/or hypergastrinemia.
8.2.2.3
VIPoma
In 1958, VERNER and MORRISON described two
patients with a syndrome characterized by diarrhea,
145
hypokalemia, hypochlorhydria, and consequently
metabolic acidosis (VERNER and MORRISON 1958,
1974). MARKS applied the acronym WDHA to this
syndrome (watery diarrhea hypokalemia hypochlor-
hydria) (STINNER and ROTHMUND 1992).
This syndrome has also been defined as 'pan-
creatic cholera'. This name is inappropriate when the
disease arises in locations other than the pancreas.
The observation of elevated plasma levels of vasoac-
tive intestinal peptide (VIP) gave rise to the currently
used term - VIPoma.
The VIPoma syndrome is mainly characterized by
the presence of profuse and progressively worsening
watery diarrhea (l-61!day). Electrolyte imbalances
are secondary to the diarrhea and may result in
lethargy, muscular asthenia, cardiac conduction dis-
orders, weight loss, abdominal pain, and dyspepsia.
Flushing may be present in 20% of cases and, more
rarely, acute tubular necrosis.
During its initial phases, the Verner-Morrison
syndrome may be confused with other forms of
diarrhea of bacterial, viral, or parasitic origin or with
ulcerative diseases (such as ulcerative colitis and
Crohn disease). The differential diagnosis should
also be made in the face of other endocrine diar-
rheogenic tumors.
8.2.2.4
Glucagonoma
Glucagon, secreted by the alpha-cells of the pan-
creatic islets, is a hormone which plays a fundamental
role in the metabolism of sugars. An inappropriate
secretion of glucagon gives rise to a syndrome first
described by BECKER in 1942 (BECKER et al. 1942),
with manifestations involving the skin, such as
Wilkinson migrant necrolytic erythema (WILKINSON
1973), angular stomatitis, chelitis, atrophic glossitis,
and, more rarely, purpura.
The pathogenesis of the cutaneous lesions is prob-
ably multifactorial. The reduced concentration of
alanine and glutamine amino acids in the blood may
be one of its causes, thus excluding a direct relation
between the occurrence of skin disease and elevated
plasma concentrations of glucagon (NORTON et al.
1979).
Apart from the skin lesions, this syndrome is char-
acterized by a marked loss of weight, normochromic
normocytic anemia, reduced plasma concentrations of
alanine, glutamine, essential fatty acids, and zinc, all due
to the catabolic effect of glucagon. Some 20% of patients
have diarrhea, which may be caused by the hypersecre-
tion of other enteric hormones besides glucagon.
146
In other cases, constipation may be present, the
gravity of which may reach the stage of intestinal
subocclusion; glucagon is indeed a powerful inhibitor
of intestinal motility.
Other symptoms reported include neurological
alterations probably due to the action of a circu-
lating factor capable of inducing encephalomyelitis.
Thrombophlebitis and pulmonary embolism, whose
elevated frequency justifies the use of prophylactic
treatment, may be among the manifestations with
unclear pathogenesis.
8.2.2.S
Somatostatinoma
Somatostatin is a hormone primarily isolated from
the pituitary as a metabolic regulator of the growth
hormone. Somatostatin is synthesized in the delta-
cells present in the pancreas and throughout the
entire gastrointestinal tract (SOLCIA et al. 1993).
The first observation of a tumor with a pre-
dominant secretion of somatostatin dates back to
1977 and was reported by LARSSON et al. (1977). This
tumor can be either functional or asymptomatic. In
the latter case, the diagnosis can be secondary to the
occurrence of biliary obstruction due to the frequent
localization of the tumor in the pancreatic ampulla.
When biologically active, this tumor is characterized
by the presence of a syndrome of extremely variable
clinical symptoms, which reflect the entire range of
the pharmacological actions of somatostatin.
Acquired diabetes is present, even if modest, due to
the inhibitory effect of somatostatin on both insulin
and glucagon. Biliary stasis may occur secondary to
the reduced function of the gallbladder, which subse-
quently results in the formation of stones (8l.5%).
The altered biliary and intestinal motility, in asso-
ciation with the reduced pancreatic secretion, causes
diarrhea and steatorrhea (77.8%). In several cases,
hypochromic anemia (55.5%), weight loss (43%),
and hypo- or achlorhydria (29.6%) may be present
(NEGRO and PERCOPO 1988).
The classic triad (diabetes/gallstones/diarrhea-
steatorrhea) can, in some cases, be accompanied by
clinical symptoms secondary to the production of
other enteric hormones. Such variability of the clin-
ical presentation may also be due to the secretion of
atypical derivatives of somatostatin characterized by
different biological actions.
The simultaneous occurrence of somatostatinoma,
pheochromocytoma, and neurofibromatosis of von
Recklinghausen is the cause of a rare polyendo-
crinopathy.
F. Cirillo et al.
D-cells have been reported to be involved in
other digestive endocrine tumors, too (such as
gastrinomas and insulinomas), even if no clear
somatostatinoma-related syndrome is present
(WHEELER et al. 1986).
In the majority of cases, the diagnosis of
somatostatinoma is retrospective, mostly due to
the nonspecific clinical presentation. In other cases,
the tumor may be recognized incidentally during
an intervention to remove gallstones, or follow-
ing other investigations for disorders that are part
of the complications of the primary or metastatic
lesion (such as hemorrhage, abdominal pain, and
jaundice). In such cases, the tumors may reveal sig-
nificant growth (over 5 cm in diameter) and distant
metastases in almost 74% of patients (MOZELL et al.
1990; DELCORE and FRIESEN 1994; NORTON 1994).
In 75% of patients, the tumor may induce the secre-
tion of other hormones (such as calcitonin, PP, glu-
cagon ACTH), which may account for the variable
clinical presentation.
8.2.3
Laboratory Data and Evocative Tests
8.2.3.1
Insulinoma
The laboratory diagnosis of insulinom a is based on
the determination of alterations in serum glucose
and insulin levels measured at baseline or during
attacks. It is especially important to carry out a con-
temporary measurement of both serum glucose and
insulin under fasting conditions. The diagnostic test
of choice is the fasting glucose tolerance test, with
insulin and C-peptide levels taken every 6 h from
the onset of symptoms. Patients in whom the serum
glucose/insulin ratio is less than or equal to 1 should
be suspected of having insulinoma.
Most insulinomas can produce an insulin pre-
cursor known as pro-insulin. The determination
of the levels of this metabolite and of C-peptide, a
by-product of the conversion process of pro-insu-
lin to insulin, may further facilitate the diagnosis
of this type of tumor (DELCORE and FRIESEN 1994;
NORTON 1994). It should be stressed, however, that
10%-25% of patients with insulinoma may have
a normal level of pro-insulin and also that a high
concentration of this metabolite may be observed
in otherwise healthy obese individuals (GRANT
1993).
Clinical Manifestations and Therapeutic Management of Hyperfunctioning Endocrine Tumors 147

The measurement of C-peptide plasma levels may 8.2.3.3

be extremely useful in those patients who do not have VIPoma
overt hypoglycemia under fasting conditions.
In addition to the above alterations, patients with In 75% of patients, hypercalcemia combined with
insulinoma may also have an elevated level of chori- hypophosphatemia is also present, probably due to
onic gonadotropin (HCG) (KAHN et al. 1977; OBERG the presence of associated hyperparathyroidism. The
and WIDE 1981). hormones secreted by the tumor may themselves
The use of pharmacological loading tests (using induce hypercalcemia.
tolbutamide calcium, glucagon, or leucine) has been Approximately half of the patients with VIPoma
discontinued due to the high percentage of false pos- have hyperglycemia due to reduced glucose tol-
itives and their potential risks. On the contrary, those erance. Hypo-achlorhydria is present in 40% of
dynamic tests still practiced (long-term fasting and patients, flushing in 20%.
administration of exogenous insulin) tend to high- Patients with VIPoma have extremely elevated
light the increase in the glucose/insulin ratio under plasma concentrations of VIP (in different molecular
specific conditions. forms). Other diarrheogenic substances, such
as secretin, pancreatic polypeptide (PP), gastric
8.2.3.2 inhibitory polypeptide (GIP), prostaglandin E2,
Gastrinoma and peptide histidine isoleucine (PHI), may also be
increased (BLOOM et al. 1983).
All patients with gastrinoma have markedly elevated
serum gastrin levels (exceeding 1000 pg/ml), estab- 8.2.3.4
lishing the diagnosis. It must be remembered that Glucagonoma
serum gastrin may be elevated in other diseases, and
therefore, more refined laboratory tests may be applied The existence of glucagonoma should always be
to make a specific diagnosis. suspected when diabetic patients display the typical
Elevated basal acid output (BAO) indicates a rash. The diagnosis is confirmed by the observa-
pathologic hypersecretion (>15 mEq/h) in 85% of tion of elevated plasma levels of glucagon. Other
patients. This observation is significant in the diag- conditions characterized by high glucagon blood
nosis of gastrinoma only when the serum gastrin concentration are chronic renal failure, chronic liver
level exceeds 1000 pg/ml. However, patients with disease, Cushing syndrome, prolonged fasting, and
gastrinoma with BAO values of less than 5 mEq/h acute pancreatitis. Loading tests (using arginine
have been described. In the absence of serum gas- tolbutamide calcium or calcitonin) may be useful
trin levels> 1000 pg/ml, a BAO/MAO (maximal acid in diagnosing doubtful cases. The continuous oral
output) relationship >0.6 is not pathognomonic of or parenteral administration of somatostatin and
gastrinoma. glucose further facilitates the diagnosis.
Loading tests may be of help in the differential
diagnosis of patients with gastrin levels ranging from 8.2.3.5
100 to 1000 pg/ml, gastric pH <2.5, and clinical symp- Somatostatinoma
toms suggestive, but not specific, of gastrinoma. The
loading test using secretin is currently considered the Low, reduced plasma concentrations of growth
most reliable as regards sensitivity and specificity. hormone and glucagon, together with the reduced
In 90% of patients with gastrin om a, the adminis- sensitivity of blood insulin levels to exogenous glu-
tration of secretin induces a rapid (within 2 min) cose treatment, may steer the clinician towards the
and massive (>200 pg/ml) increase of gastrin blood diagnosis of somatostatinoma. Other dynamic tests
concentration, which returns to the pretest level after (tolbutamide calcium-pentagastrin secretin) may be
30 min (MCGUIGAN and WOLFE 1980). This test will useful in dubious cases. However, a definitive diag-
be positive in 87% of patients with serum gastrin lev- nosis can be formulated when the plasma concen-
els varying between 100 and 1000 pg/ml. In patients trations of somatostatin exceed 100 pmolll.
with achlorhydria with pH levels> 2.5, false positives In 75% of patients, the tumor may induce the
may be encountered (FELMAN et al. 1987). secretion of other hormones (such as calcitonin, PP,
Other commonly employed loading tests are those glucagon, ACTH), which may account for a variable
using bombesin, glucagon, calcium, and standard clinical presentation.
proteic meal.
148
8.3
Therapeutic Strategy
The object of the therapy is, whenever possible, pri-
marily cure. If this aim cannot be achieved, then the
clinician must at least try to manage the symptoms
of endocrine hyperfunction, since these are some-
times so incapacitating that they seriously affect the
patient's quality of life (NORTON 1994). When sur-
gery is radical, it is able to achieve both objectives. As
regards the therapeutic strategy of these neoplasms,
this is still the first option to consider. This is also true
for those cases where, when the clinical and labora-
tory diagnosis is certain, the radiologist is not able
to identify the disease. Where radical resection is not
possible, the surgeon has more options. Debulking
increases the possibility of reducing the symptoms
and may be an option because of the slow growth
of many of these lesions. Nevertheless, the surgeon
should not forget, especially when controlling the
symptoms, that different therapeutic choices also
exist (analogues, diazoxide, interferon, proton pump
inhibitors, etc.). The therapeutic strategy should be
dealt with according to the particular aspects of each
type of tumor.
8.3.1
Insulinoma
The presence of characteristic clinical symptoms
and the positive results of valid laboratory tests
make the diagnosis of insulinoma definite even
when the tumor is still hidden in 10%-20% of
patients despite significant improvement in imag-
ing. In this situation, a rigorous surgical procedure
leads to the identification of a tumor (GIANELLO et
al. 1988; ZEIGER et al. 1993; ROTHMUND 1994). In
any case, the surgeon must perform a wide exposure
to make the entire gland accessible to palpation.
The whole parenchyma should be studied with the
help of an intraoperative ultrasound using a 10 or
7.5 MHz probe (KLOTTER et al. 1987; GRANT et al.
1988; NORTON et al. 1988; BOTTGER et al. 1990). In
this way, small lesions can be seen, which gives an
important advantage over mere palpation, especially
when the neoplasm is in the head of the pancreas
(NORTON 1999).
Whenever localization is impossible, even during
surgery, reports in the literature state that 'blind
resection' can be carried out only when the 'venous
sampling' is definitely positive in 'regionalizing' the
lesion (NORTON 1994) and when medical therapy
F. Cirillo et aI.
cannot control the clinical symptoms satisfactorily
(DOHERTY et al. 1991; VINIK et al. 1991; MILLER
1993).
Surgical treatment of benign insulinom as may be
limited to the simple excision of the mass (if single)
or to the resection of a pancreatic segment (usually
caudal). Malignant insulinomas on the contrary
require a more extensive and radical treatment. Such
aggressive resection involves all the metastatic local-
izations and ensures an improvement in the quality
of life. In fact, a partial or incomplete removal of
the tumor does not allow adequate control of the
hypoglycemia (possible in approximately 20% of
patients).
In metastatic disease, diazoxide and somatostatin
analogues are considered. Octreotide controls symp-
toms well in 25%-30% of patients but only at a high
dosage (VERSCHOOR et al. 1986).
8.3.2
Gastrinoma
Gastrinomas, too, can also be clinically diagnosed
without definite identification of the site of the dis-
ease. A correct intraoperative examination leads to
the identification of 95% of those gastrinomas not
seen at imaging. Aside from careful exploration and
palpation of the pancreatic parenchyma, a thorough
study of the entire peritoneal cavity should be done,
since there is also the possibility of disease in the
extrapancreatic area. Small gastrin om as located in
the submucosa of the duodenal wall can be found by
trans-illumination or by longitudinal duodenectomy
of about 3 cm for a correct palpation of the entire
mucosal surface, even of the medial wall. Norton
recently pointed out that a duodenectomy for gastri-
nomas in this site is the best solution (NORTON 1999)
as it is able to identify small gastrinomas that were
'missed' at palpation, intraoperative ultrasound, and
trans-illumination. Intraoperative ultrasound shows
91 % of gastrinomas located in the pancreas and
about 30% of the duodenal ones (NORTON 1995). In
all, this procedure is able to identify from 64% to 92%
of lesions (NORTON et al. 1992).
If at the end of the staging procedures no lesion
has been identified, the surgeon should not turn to a
'blind resection' or a total gastrectomy. It should not
be forgotten that, with proton pump inhibitors, med-
ical therapy today is able to control symptoms in the
majority of patients.
The therapeutic approach to gastrinoma has
changed radically since the advent of synthetic
Clinical Manifestations and Therapeutic Management of Hyperfunctioning Endocrine Tumors
antisecretive molecules. The increasingly accurate
topographic diagnosis has led to the definitive
suspension of the once abused gastrectomy. These
changes created the opportunity for better-targeted
interventions, which vary from a simple excision in
cases of a single and well-delineated benign pancre-
atic lesion to the more articulated intervention of
pancreatic surgery. The best intervention is debatable
since the authors who propose surgical enucleation
as a first choice report that only 51 % of patients are
clear of disease immediately following surgery. Their
choice is due to the fact that the survival rate is still
94% after 10 years (NORTON et al. 1999). According to
other authors (IMAMURA et al. 1989; DELCORE and
FRIESEN 1992; UDELSMAN et al. 1993; STADIL 1995;
PHAN et al. 1998; THODIYIL et al. 2000), this opinion
is not altogether correct since, in experienced cen-
ters, the mortality rate following a pancreaticodu-
odenectomy is less than 2% and guarantees greater
radicality.
In the past, the 5-year survival rate of patients
with gastrinoma was approximately 69% in patients
undergoing radical surgery and 38% in patients with
advanced disease. The respective survival rates at
10 years were 62% and 27% (ELLISON et al. 1987).
Norton's more recent results indicate how an even
earlier diagnosis followed by an adequate surgical
and pharmacological treatment could improve the
survival of these patients and reduce the number of
neoplastic complications (NORTON et al. 1999).A sig-
nificant number of patients (25%) tend, in any case,
to develop distant and mainly skeletal metastases
(30% with liver metastases), which further impair
the patient's prognosis (BARTON et al. 1986; NORTON
and JENSEN 1991; ZAYENE et al. 1997).
Long-term treatment of gastric acid hyperse-
cretion involves antisecretory molecules like Hz-
antagonists (ranitidine) or proton pump inhibitors
(in particular omeprazole) and somatostatin ana-
logues (octreotide, lanreotide). Omeprazole provides
for a good control of symptoms with a dosage vary-
ing from 40 to 160 mg daily (METz and JENSEN 1995).
The other pump inhibitors, such as pantoprazole,
lansoprazole, and rabeprazole, show different char-
acteristics of efficacy and potency. Octreotide, even
in low doses, seems able to control gastrin secretion
in order to reduce the daily antisecretory therapy.
Proglumide prostaglandin analogues and anticho-
linergic molecules show a low antisecretory activity
in association with many side effects.
149
8.3.3
VIPoma
Given the presence of invalidating symptoms, sur-
gery is the first treatment and is often indicated
when there are also metastases (AKERSTROM 1992;
STINNER and ROTHMUND 1992; GRANT 1993; OBERG
1996; WIEDENMANN et al. 1998). Treatment with
somatostatin analogues is able to reduce diarrhea
by regularizing the electrolyte imbalance. Shrinkage
of metastases was observed in a few cases (CLEMENTS
and ELIAS 1986).
8.3.4
Glucagonoma
Due to the nonspecific clinical presentation, this
tumor is normally diagnosed late, when metastases
are already present. To date, surgical treatment is
considered the only effective approach, giving satis-
factory results in approximately one-third of patients
(HIGGINS et al. 1979). Surgical intervention will con-
sist of the most radical pancreatic resection possible
depending on the location of the lesion within the
pancreas. Moreover, the surgeon is perfectly justi-
fied in performing debulking interventions, even
repeatable ones, in the attempt to control particularly
incapacitating clinical symptoms. For these patients,
the preoperative use of somatostatin analogues can
be helpful in controlling clinical symptoms (AKER-
STROM 1992; STINNER and ROTHMUND 1992; GRANT
1993; OBERG 1996; WIEDENMANN et al. 1998).
Chemotherapy may produce a response in a num-
ber of patients without prolonging survival (KESS-
INGER et al. 1983; MOERTEL et al. 1992; DELCORE and
FRIESEN 1994). There is evidence of partial remission
after treatment with somatostatin analogues and with
interferon (SILLER et al. 1994; STROHM 1996). In any
case, metastasis recurrence is extremely frequent.
8.3.S
Somatostatinoma
As already described for VIPomas and
somatostatinomas, the surgical approach must be
as aggressive as possible, justifying the association
of pancreatic demolition, even with vascular recon-
struction, to extensive debulking of eventual hepatic
metastases (AKERSTROM 1992; STINNER and ROTH-
MUND 1992; GRANT 1993; OBERG 1996; WIEDENMANN
et al. 1998). Nevertheless, given the typically virulent
150
development of this tumor, the survival rate 1 year
after diagnosis is approximately 48%, whatever the
treatment (HARRIS et al. 1987; KONOMI et al. 1990).
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9 Clinical Manifestations and Therapeutic Management
of Nonfunctioning Endocrine Tumors
M. FALCONI, R. BETTINI, C. BASSI, R. SALVIA, and P. PEDERZOLI

CONTENTS use of diagnostic testing, and improved characteriza-

tion of pancreatic neoplasms by pathologists rather
9.1 Introduction 153 than to a real epidemiological increase (YEO et al.
9.2 Clinical Data 153 1993; SALEH et al. 1996; DI STASI et al. 1998). The
9.2.1 Clinical History, Habits and Heredity 153
9.2.2 Symptoms 154 cyto-/histological definition of the endocrine origin
9.3 Laboratory 154 of these tumors is indispensable for establishing the
9.4 Clinical Data 155 correct therapy and the prognosis, which are very
9.5 From Assessment to Management 155 different from those of the more common ductal
9.5.1 Diagnostic Suspicion 155 adenocarcinoma.
9.5.2 Definite Diagnosis 156
9.5.2.1 Surgically Treatable Patients 156
9.5.2.2 Patients Suitable for Debulking
and Multidisciplinary Approach 157
9.5.2.3 Nonresectable Patients 9.2
and Nonsurgical Therapies 157 Clinical Data
9.6 Follow-up 158
References 158
9.2.1
Clinical History, Habits and Heredity

These neoplasms are usually diagnosed in patients

9.1
Introduction
Nonfunctioning endocrine tumors arise from pan-
creatic insular cells. Sharing the same histological
and immunohistochemical features as functioning
endocrine tumors, they are characterized by the
lack of clinical symptoms due to hormonal hyper-
production (AKERSTROM 1992; STINNER et al. 1992;
OBERG 1996; WIEDENMANN et al. 1998; AZIMUDDIN
and CHAMBERLAIN 2001; RIGAUD et al. 2001).
In the different reported series, their percentage
varies from 15% to 52% of pancreatic endocrine
lesions (PHAN et al. 1998). These tumors have been
increasingly observed (Fig. 9.1) over the last few
years (THOMPSON 1988; YEO et al. 1993; FALCONI et
al. 1999; FALCONI 2000). This finding seems to be
related more to greater clinical awareness, increasing
in their 50s and 60s with a ratio of 1:1 for men
and women (THOMPSON 1988; EVANS et al. 1993;
MADURA et al. 1997; PHAN et al. 1998; MATTHEWS et
al. 2000). The neoplasm can be idiopathic or detected
as part of the multiple endocrine neoplasia (MEN 1)
syndrome or, more rarely, of the von Hippel-Lindau
syndrome. MEN 1 syndrome is an autosomal domi-
nant disease with a variable degree of penetration in
which tumors can develop in different organs. Almost
all patients have parathyroid hyperplasia. The diag-
nosis of primary hyperparathyroidism often leads to,
or precedes, the diagnosis of other neoplasms. Fewer
than 50% of patients also develop pituitary tumors

M. FALCONI, MDj R. BETTINI, MDj C. BASSI,MDj R. SALVIA,MDj 84--'85 86-'87 88-'89 90-'91 92-'93 94-'95 96-'97 98-'99 00-'01

P. PEDERZOLI, MD
Surgical-Gastroenterological Department, Endocrine and Fig. 9.1. Yearly distribution of functioning and nonfunctioning
Pancreatic Unit, Hospital 'G.B. Rossi', University of Verona, pancreatic endocrine tumors observed between 1984 and 2001
37134 Verona, Italy in personal experience
154 M. Falconi et al.

(usually prolactinomas), while about 75% develop
concurrent islet-cell tumors of different types. Non-
functioning tumors represent only 20% of these
(NORTON 1994). In patients with MEN 1 syndrome,
the pancreatic tumors are recognized at an average
age of 25 years (WIEDENMANN et al. 1998).
As far as the influence of nonessential factors such
as alcohol or coffee abuse and cigarette smoking is
concerned, there is no evidence of any correlation
between them and the occurrence of these neo-
plasms.
9.2.2
Symptoms
By definition, there are no clinical symptoms related
to hormonal hyperproduction in nonfunctioning
endocrine lesions. In 10%-15% of patients, the
diagnosis is made following characterization of an
incidentally detected pancreatic mass (KENT et al.
1981). In these cases, imaging is usually carried out
for nonspecific dyspeptic symptoms or the presence
of a palpable mass. Alternatively, the patient may be
referred to the radiologist for symptoms related to
infiltration or local compression of adjacent struc-
tures by the tumor or its metastases. Pain is, in fact,
the most common symptom reported, occurring in
60% of patients, followed by nausea, vomiting, and
jaundice. A greater frequency of cephalic tumors
(Table 9.1) is reported in the literature (DIAL et
al. 1985; ECKHAUSER et al. 1986). Pain, weight loss,
symptoms of exocrine and/or endocrine pancreatic
insufficiency (steatorrhea and diabetes mellitus), and
asthenia are often expressions of advanced disease.
Other rarely reported symptoms are those due to
recurrent pancreatitis or gastrointestinal bleeding.
In endocrine tumors, there is a discrepancy
between the extent of the disease and the usually
limited symptoms. This is probably due to their low
biological aggressiveness and slow growth. It should
be noted that the symptom complex is virtually iden-
tical to that of ductal adenocarcinoma.
Table 9.2 summarizes the symptoms and their fre-
quency in the main series reported in the literature.
9.3
Laboratory
Traditional routine laboratory analysis is useful when
the tumor has caused an obstruction at the biliary
duct level or when there is a massive replacement
of hepatic parenchyma with subsequent cholestasis
and/or tissue necrosis.

Table 9.1. Location of nonfunctioning endocrine tumors in the different series (NA, not available)

Location Personal BARTSCH PHAN Lo EVANS THOMPSON KENT

experience (2000) et al. (2000) et al. (1998) et al. (1996) et al. (1993) (1988) et al. (1981)
(n=115) (n=18) (n=58) (n=34) (n=73) (n=27) (n=25)

Head/neck/uncus 56% 61 % 50% 47% 59% Predominantly 56%

Body/tail 44% 39% 17% 47% 41 % NA 12%
Multicentric NA 19% 6% 0 NA 12%

Table 9.2. Clinical presentation in the different series (NA, not available)

Complaints/Symptoms Personal MATTHEWS BARTSCH KENT MADURA PHAN

experience (2000) (2000) (2000) (1981) (1997) (1988)
(n=115) (n=28) (n=18) (n=25) (n=14) (n=58)

Incidental diagnosis 22.4% NA 11% 16% NA NA

Abdominal pain 60.3% 67.9% 72% 36% 57% 56%
Nausea/vomiting 10.3% 35.7% 11% NA 43% 21%
Weight loss 31% 32.1 % 39% NA 50% 46%
Anorexia 16.3% 21.4% 33% NA NA 14%
Jaundice 11.2% 21.4% 22% 28% 50% 35%
Malaise NA 14.3% NA NA 21% 7%
Pancreatitis NA 7.1 % 11% NA NA NA
Abdominal mass 6.9% 7.1% 17% 2% NA NA
Gastrointestinal 4.3% 3.6% 5.5% NA NA NA
bleeding/acute abdomen
New onset diabetes NA NA NA NA 14% NA
Clinical Manifestations and Therapeutic Management of Nonfunctioning Endocrine Tumors 155

Nonfunctioning endocrine tumors are frequently 9.4

associated with elevated chromogranin A values. This
is a glycoprotein contained in intracellular granules of
the insular cells. Chromogranin A is, in fact, the most
sensitive of the markers for nonfunctioning endocrine
tumors (68%) and simultaneously shows good speci-
ficity (86%) (FERRARI et al. 1999). However, in 19%
of nonselected patients, the chromogranin A value is
high even with no endocrine tumor. The correlation
between the marker value and the size of the tumor
is not certain (SCHURMANN et al. 1992; BAUDIN et al.
1998; FERRARI et al. 1999; GOEBEL et al. 1999). Lastly,
the marker can be useful in identifying recurrence and
as a marker of successful therapy, although the value
is limited in patients being treated with somatostatin
analogues (STIVANELLO et al. 2001).
The neuronspecific enolase (NSE) has no sig-
nificant role at present in defining endocrine tumors.
Although it shows an analogous specificity to chro-
mogranin A, the sensitivity is inferior (33%) (FER-
RARI et al. 1999). Nevertheless, it would seem that the
high levels of this marker are associated with a poor
cellular differentiation (BAUDIN et al. 1998).
Pancreatic polypeptide (PP) is elevated in about
60% of pancreatic endocrine tumors. Fractions of
beta- and alpha-subunits of human chorionic gonad-
otropin (HCG) may also be useful, as they seem to
be correlated to a worse prognosis, even though only
20%-30% of patients show an increase of the serum
levels (ERIKSSON et al. 1990a, 2000).
Some hormones, characteristic of the functional
types, can also have higher values in the blood and
be used as markers, even if they do not produce a
clinical syndrome.
Furthermore, in patients suffering from MEN 1
syndrome, some authors have suggested the use of
the 'meal stimulatory test' for PP as a method of early
diagnosis (CIRILLO 2001; LANGER et al. 2001).
Clinical Data
Generally speaking, once a pancreatic mass has been
identified, the suspicion of a nonfunctioning endo-
crine neoplasm arises when the biological behavior
of the tumor is 'non aggressive'. Despite the fact that
a nonfunctioning endocrine tumor is diagnosed in
a high percentage of patients in the advanced stages
of the disease (Table 9.3), the patient rarely shows
significant symptoms. The absence of a hormonal
clinical syndrome allows these tumors to grow unde-
tected, and therefore they are larger and present with
a greater frequency of hepatic metastases than the
functioning types. In personal experience, the per-
centage of hepatic metastases at diagnosis was 33%
compared with 16% for functioning types. Moreover,
on average, the dimension of the primary neoplasm
at diagnosis is 32 mm (Table 9.3) compared with 15
mm for functioning ones. Despite the larger tumor
size and aggressive appearance, the patients rarely
appear to be suffering from metastatic cancer.
9.5
From Assessment to Management
9.S.1
Diagnostic Suspicion
Nowadays, cyto/histological confirmation of the clin-
ical suspicion of nonfunctioning endocrine tumor is
possible with fine needle aspiration biopsy of both
the primary pancreatic mass and hepatic metastases
(SALEH et al. 1996; DI STASI et al. 1998). This proce-
dure does not predict tumor resectability. The cyto-
logical and/or histological confirmation, however, is

Table 9.3. Biological behavior and main surgical and pathological features in the different series (NA, not available)
Personal BARTSCH PHAN Lo EVANS THOMPSON KENT
experience (2000) et al. (2000) et al. (1998) et al. (1996) et al. (1993) (1988) et al. (1981)
(n=1l5) (n=18) (n=58) (n=34) (n=73) (n=27) (n=25)

Diameter of primary tumor:

Median (cm) 3.2 5.0 4.0 NA NA NA NA
Range (cm) 0.5-14 3-10 0.5-5
Malignant at diagnosis 69% 83% 60% 84%" 60% NA NA
Resectable 62%b 83% 79.3% 53% 43.8% 51% 60%
Curative resection 50.4%b 62% NA 35% 26% 37% 48%
Operative mortality 0.8% 16.6% NA 2% 0 3% 8%
" Distant metastases: 63%; locoregional metastases: 34%
b All patients included
156
mandatory for the future therapeutic strategy when
the disease is either locally advanced or metastatic.
In fact, the diagnosis of pancreatic endocrine tumor
gives the clinician a choice of therapeutic options.
Surgical resection is still justifiable for advanced
forms, and if this cannot be performed, palliative
surgery can be carried out. Furthermore, in cases of
nonresectability, evaluation of the histological differ-
entiation and the Ki-67 cellular mitotic index leads
to the choice of therapy.
9.5.2
Definite Diagnosis
The therapeutic approach for a patient with a non-
functioning pancreatic endocrine tumor is often
multidisciplinary. Nevertheless, surgery, when pos-
sible, is the only possibility for cure and is, even today,
the first therapeutic option to consider (OBERG 1996).
From a management point of view, then, it would
seem useful to distinguish those patients eligible for
surgical resection from those who are not.
9.5.2.1
Surgically Treatable Patients
Compared with ductal carcinomas, these neoplasms
have a very high rate of resectability. This varies, in
the different series, from 26% to 62% (KENT et al.
1981; DIAL et al. 1985; THOMPSON 1988; BARTSCH et
al. 2000). Such a high resectability rate does not mean,
however, that surgical resection always corresponds
to radical surgery, whose incidence is, in fact, lower
(Table 9.3).
In the presence of nonfunctioning endocrine
tumor, the surgeon must try to completely resect all
of the visible tumor mass along with total debulking
of all visible intra- and extrapancreatic disease.
Surgical resection is indicated in all cases where
the disease appears to be 'limited' to the pancreas.
However, some have shown that a survival benefit
can be gained by radical resection of the tumor and
surrounding structures (stomach, colon, kidney,
adrenal gland) or by further vascular resection (DIAL
et al. 1985; DELCORE and FRIESEN 1994; MADURA
et al. 1997; BARTSCH et al. 2000; MATTHEWS et al.
2000). In 1985, DIAL did not exclude resection of the
involved portal vein (DIAL et al. 1985). More recently,
EVANS suggested the possible segmental resection
of the portal-mesenteric vein confluence (EVANS et
al. 1993). Involvement of the superior mesenteric
artery and the celiac trunk by endocrine tumors
M. Falconi et al.
is less common compared with ductal carcinoma
(EELKEMA et al. 1984; MADURA et al. 1997) and, in
any case, does not exclude the possibility of radical
resection. The choice of procedure will depend on
each individual case.
The possible surgical options are: limited resec-
tion (enucleation or middle pancreatectomy) and
conventional resection (pancreoduodenectomy or
distal pancreatectomy with or without spleen preser-
vation). In general, limited resection has the advan-
tage of preserving the largest possible part of the
pancreatic parenchyma, but it is less 'sure' in onco-
logical terms. This can usually be performed in those
cases where the lesions are single, well-localized, of
limited size «4 em in diameter), and do not involve
or are at a 'sufficient' distance from the pancreatic
duct (PARK et al. 1998). Nevertheless, conventional
resection, depending on the site, appears to be the
most standard procedure (DELCORE and FRIESEN
1992; UDELSMAN et al. 1993; NORTON 1994; PHAN et
al. 1998; JORDAN 1999).
The long-term results vary in accordance with
the histological grade of the lesion as determined
by microscopic pathology. Table 9.4 summarizes
the survival percentage of the main surgical series
published in the literature. Generally, for endocrine
tumors presently defined as benign by the World
Health Organization (WHO) 2000 classification
(SOLCIA 2000), the survival rate after radical surgery
is 100%. This rate decreases in patients resected for
endocrine carcinoma (PHAN et al. 1998). During
follow-up, 66% of patients show recurrence of the
disease, usually within the liver (CHAMBERLAIN et al.
2000; PEDERZOLI et al. 1999).
As for the synchronous or metachronous metasta-
ses, whenever a resection must leave no residual dis-
ease, hepatic resection should be performed (DAN-
FORTH et al. 1984; NORTON et al. 1986; McENTEE et
al. 1990; CARTY et al. 1992). Contemporary resection
of the primary tumor and all the hepatic metastases
or the removal of subsequent ones does not, in fact,
seem to be an unfavorable prognostic factor (CHEN et
al. 1998; CHAMBERLAIN et al. 2000).
Unfortunately, in 90% of patients, the liver metas-
tases are multifocal or bilateral (MATTHEWS et al.
2000), making radical surgery impossible. In fact,
fewer than 18% of patients have a localized disease
(unilobar or less than 75% involvement of the hepatic
parenchyma) which can be considered for resection
with intent of cure (CHAMBERLAIN et al. 2000).
This approach leads to good results, with the pres-
ent survival rate of 76% at 5 years (CHEN et al. 1998).
The survival rate seems to be directly related to the
Clinical Manifestations and Therapeutic Management of Nonfunctioning Endocrine Tumors
Table 9.4. The 2-, 5-, and 10-year survival rates for different surgical series (NA, not available)
Survival Personal BARTSCH PHAN
experience (2000) et al. (2000) et al. (1998)
(n=1l5) (n=18) (n=58)
2-year 85% NA 79%
5-year 70% 65% 52%
lO-year 45% 49% 42%
level of hepatic involvement (SOREIDE et al. 1992;
QUE et al. 1995; CHEN et al. 1998; FUJII et al. 1999).
9.5.2.2
Patients Suitable for Debulking
and Multidisciplinary Approach
In some clinical situations, the information gained
from preoperative examinations or during a lapa-
rotomy does not give a reasonably sure prediction of
achieving total surgical removal of all sites of disease.
In these cases, resection would leave a macroscopic
residual disease (R2) due to the presence of'signifi-
cant and massive' local infiltration (vessels, organs,
retroperitoneum) and/or not completely resectable
hepatic metastases.
In this case, many surgeons have suggested deb-
ulking with follow-up treatment of residual disease
with locoregional therapies. It should be remem-
bered that, to be therapeutically successful, the deb-
ulking must reduce the mass by at least 90%, which
is seldom possible. Debulking has further been sug-
gested as a preventive method against complications
related to local growth of the tumor, such as recur-
rent pancreatitis, biliary or intestinal occlusion, and
gastrointestinal bleeding.
In truth, surgical resection does not appear justi-
fiable in all cases of locally incompletely resectable
disease. In fact, existing data do not justify a local
partial resection of the mass, fearing fragmentation
with subsequent dissemination of the tumor in the
peritoneal cavity. Moreover, the vascularity of these
neoplasms introduces a high risk of bleeding, and
palliation of the symptoms secondary to the mass
is only temporary, since local relapse is the rule.
Furthermore, the survival rate of unresected patients
with locally advanced disease remains at 44% at 5
years (EVANS et al. 1993).
Debulking can, however, play a role if intended
as a total resection of the primary tumor, even in
the presence of residual hepatic metastatic disease
(PEDERZOLI et al. 1999). Even when the metastatic
residue is more than 10%, resection of the primary
tumor will help avoid symptoms related to com-
157
EVANS THOMPSON KENT
et al (1993) (1988) et al. (1981)
(n=73) (n=27) (n=25)
NA 58% at 3 years 60% at 3 years
50% NA 44%
NA NA NA
pression of adjacent viscera. The disease can be
'restricted' to the liver, thus facilitating subsequent
appropriate therapies.
The palliative resection of the residual hepatic
metastases after radical resection of the primary
tumor has limited applications, as it does not lead to
a significant increase in the survival rate (FALCONI et
al. 1999; CHAMBERLAIN et al. 2000).
In nonfunctioning lesions, where less than 90% of
the tumor is resectable and there are no symptoms of
locoregional compression, catheter embolization is
the best treatment (CHAMBERLAIN et al. 2000).
As an alternative to traditional surgical tech-
niques for the treatment of residual hepatic dis-
ease, embolization and chemo-embolization may
be proposed (MARLINK et al. 1990; NESOVIC et al.
1992; MAVLIGIT et al. 1993; RUSZNIEWSKI et al. 1993;
CLOUSE et al. 1994; ERIKSSON et al. 1998; FALCONI
et al. 1999). Ligation of the hepatic artery alone is
not enough because a collateral circulation quickly
appears (WIEDENMANN et al. 1998). At present, the
first results with dia-thermo-ablation are beginning
to emerge (OBERG 1999,2000). The experience with
this technique and its practice is currently limited to
a few centers.
Indications for hepatic transplant are also experi-
mental. The criteria for patient selection include:
patients under 60 years old, nonresectable hepatic
metastases, no extrahepatic abdominal tumor, and
failure of conventional therapies. Rapid growth of
the tumor as an indication for transplant is con-
troversial (LANG et al. 1997; FRILLING et al. 1998).
Data on patients selected according to the above
indications show a global survival rate at 5 years of
36%, with 17% of survivors completely disease-free.
Unfortunately, the postoperative mortality is 30% (LE
TREUT et al. 1997).
9.5.2.3
Nonresectable Patients and Nonsurgical Therapies
Those patients unsuitable for surgical resection and
with symptoms of compression of ducts and/or vis-
cera related to the mass are candidates for palliative
158
surgical therapy. Because these patients live longer
than those with adenocarcinoma of the pancreas,
surgical bypass is preferred. Biliary enteric bypass
can be combined with gastric drainage procedures
to prevent duodenal obstruction (SPEER et al. 1987;
ANDERSEN et al. 1989; WELVAART 1992). Although
endoscopic palliative treatment is available, the
longer life expectancy results in multiple procedures
to replace the endoprostheses (DELCORE and FRI-
ESEN 1994; PEDERZOLI et al. 1999).
Medical therapy is indicated for those patients
suffering from nonresectable, nondebulkable dis-
ease. Somatostatin analogues (octreotide, lanreotide)
associated or unassociated with interferon are first
line agents. The presence of somatostatin receptors,
imaged with indium-lll-pentrotide (octreoscan)
scintigraphy, correlates with response to treatment.
Treatment with somatostatin analogues leads to con-
trol of the tumor in at least 20% of patients suffering
from metastatic gastro-entero-pancreatic neuroen-
docrine tumor (ARNOLD et al. 1996). The antitumor
activity can be increased by association with alpha-
interferon, which inhibits the transitory growth of
the tumor by 67% (FRANK et al. 1999).
Chemotherapy is reserved for cases of progressive
disease, when the tumor is anaplastic. The optimal
regimen employs streptozocin (STZ) associated with
either 5-fluorouracil (5-FU) or doxorubicin (MOER-
TEL et al. 1980,1982). The rate of objective response is
around 50% for both combinations, and the response
duration is about 2 years (ERIKSSON et al. 1990b;
ERIKSSON and OBERG 1993). For those patients with
rapid growth anaplastic forms, treatment with cispla-
tin (CDDP) + etoposide (VPI6) seems to give better
results at the moment (67% of objective response;
MOERTEL et al. 1991).
Although gastrointestinal endocrine tumors
have classically been considered as radioresistant,
radiometabolic therapy-based trials with iodine-
131-metaiodobenzylguanidine (l3l I-MIBG) or with
yttrium-90-1,4,7,10-tetra-azacyclododecane tetra-
acetic acid eOY-DOTA) are underway at present. The
results, however, are preliminary.
9.6
Follow-up
Follow-up monitoring of the success of surgical or
medical therapy is based on clinical, laboratory, and
imaging examinations. Appropriate follow-up inter-
vals are not standardized; the tumor growth is usually
M. Falconi et al.
slow, and the therapeutic programs adopted are quite
different. In general, the follow- up intervals should be
closer during the initial phase following diagnosis,
when therapeutic variations occur, or whenever the
disease shows progression.
The following outline seems to be rational and
common, mainly based on clinical experience.
- Patients treated with radical surgery but with
unfavorable histological and prognostic factors
cannot be considered cured of disease and should
be followed up every 4-6 months. On the basis
of the WHO 2000 classification (SOLCIA 2000),
negative prognostic factors include: presence of
a mass larger than 2 cm, a mitotic index greater
than 2%, and/or the presence of vascular or
microscopic neural invasion.
- Patients with favorable prognostic factors should
be followed up every 12 months.
- Patients with metastatic endocrine tumor should
be followed up every 4 months in order to detect
any eventual progression of the disease.
- Patients with residual disease after surgery should
be followed up at the same regular intervals.
With further experience accrued over the years,
these outlines will be re-evaluated. In light of the
previously recently revised histopathological classi-
fication, results from many series will become easier
to interpret and compare.
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10 Pathology
P. CAPELLI, G. ZAMBONI, A. PESCI, G. MARTIGNONI, and A. SCARPA

CONTENTS types have preferred sites (SOLCIA et al. 1997). They

originate from multipotent cells which have retained
10.1 Introduction 161 the ability to proliferate and differentiate into various
10.2 General Features 161 endocrine cell types and to produce several types of
10.2.1 Cytology 162
10.2.2 Macroscopic Features 162 hormones, both 'eutopic' and 'ectopic' in respect of
10.2.3 Histologic Features 163 those normally produced by this organ (CARNEY
10.3 Ancillary Methods for 1976; HEITZ et al. 1982; KLOPPEL and HEITZ 1988;
Histopathological Evaluation 166 PHILIPPE et al. 1988; SOLCIA et al. 1989,2000).
10.3.1 Immunohistochemistry 166 From the clinical point of view, PET are subdi-
10.3.2 Histochemistry 168
10.3.3 Electron Microscopy 168 vided into functioning and nonfunctioning endo-
10.4 Functioning Endocrine Tumors 168 crine tumors depending on whether or not they are
10.4.1 Insulinomas 168 accompanied by a clinical syndrome caused by the
10.4.2 Gastrinomas 168 hormone produced. The majority of well-differenti-
10.4.3 Glucagonomas 169 ated endocrine tumors of the pancreas are function-
10.4.4 VIPomas 169
10.4.5 Somatostatinomas 169
ing (SOLCIA et a1.1997).
10.4.6 Functioning Endocrine Tumors Sporadic PET are mostly solitary, while the heredi-
Producing Ectopic Hormones 169 tary ones are multifocal, such as those associated with
10.5 Nonfunctioning Endocrine Tumors 169 multiple endocrine neoplasia type I (MEN I) (BRANDI
10.6 Endocrine Tumors in MEN I Syndrome 170 et al. 1987; CHANDRASEKHARAPPA et al. 1997; DUH
10.7 Criteria of Malignancy
and Tumor Classification 170
et al. 1987; HESSMAN et al. 1998; LARSSON et al. 1988;
10.8 Differential Diagnosis 171 MOORE et al. 2001a; PADBERG et al. 1995; ROSAI et al.
References 172 1972; SAMAAN et al. 1989). In accordance with the
recent World Health Organization (WHO) classifica-
tion, PET are classified into well differentiated and
poorly differentiated tumors (SOLCIA et al. 2000).
10.1 While the poorly differentiated tumors are invariably
Introduction malignant and are therefore known as poorly differ-
entiated endocrine carcinomas, the behavior of the
Pancreatic endocrine tumors (PET) are either benign well differentiated tumors, which are more common,
or malignant epithelial tumors with endocrine differ- is unpredictable. A well differentiated tumor is defined
entiation characterized, in the majority of cases, by a as a malignant, well differentiated endocrine carci-
low grade of histological aggressiveness. noma only when invasion of the neighboring tissue
These tumors are rare, representing about 1%-2% and/or metastases are also present.
of all pancreatic tumors. They occur with similar fre-
quency in male and female adults and can be located
in any part of the pancreas, although the different
10.2
General Features
P. CAPELLI, MD; G. MARTIGNONI, MD; A. SCARPA, MD
Istituto di Anatomia Patologica, Policlinico Universitario 'G.B.
In the majority of patients, the cytological-histologi-
Rossi', P.le L.A. Scuro, 10,37134 Verona, Italy
G. ZAMBONI, MD; A. PESCI, MD cal characteristics are enough to suggest an endocrine
Servizio di Anatomia Patologica, Ospedale S. Cuore-Don Cal- origin. There is a well-defined spatial ratio between
abria, Via D. Sempreboni, 37024 Negrar, Italy the tumor cells and the rich vascular network and
162
the rather uniform appearance of the majority of the
cells. The endocrine functionality is demonstrated by
immunohistochemical methods.
10.2.1
Cytology
Examination of cytological material obtained by
image-guided fine needle aspiration biopsy (FNAB)
is a technique increasingly utilized for the diagnosis
of a pancreatic mass. The material obtained is usually
extremely cellular. At low magnification, the morpho-
logical picture is characterized by the presence of
small to medium-sized, monomorphic cells, which
are homogeneously distributed and poorly cohesive.
The cells usually have a round or oval, central or
outlying nucleus (superficially resembling plasma
cells). The nucleus has finely distributed chromatin
with a 'salt and pepper' pattern (with tiny clumps of
dense heterochromatin scattered through the nuclei)
and displays an inconspicuous nucleolus. Cytoplasm
is often slight, homogeneously eosinophilic and only
rarely finely granular (Fig. 10.1).
Although most cases have these features, atypical
cytological aspects can be found, which can make
the diagnosis difficult. The tumor cells can assume
particular features or arrange themselves in a pattern
similar to other pancreatic cell types. The presence
of a conspicuous nucleolus associated with a finely
granular cytoplasm simulates acinar cell carcinoma
(KLIMSTRA et al. 1992).
Fig. 10.1. Endocrine tumor: fine needle aspiration biopsy.
Extremely cellular aspirate composed of uniform, small to
medium-sized, poorly cohesive cells with eosinophilic cyto-
plasm, rounded nucleus, 'salt and pepper' chromatin, and
inconspicuous nucleolus. Some cells resemble plasma cells
P. Capelli et al.
The cellular elements can show particular fea-
tures: oncocytic-like appearance, clear cytoplasm,
a prominent pleomorphic fused appearance, lead-
ing to a wide range of differential diagnoses such
as common ductal adenocarcinoma, rare anaplastic
carcinoma, mesenchymal or metastatic tumors. The
presence of papillary-like structures characterized
by a thin stromal core with a vessel in the center or
by acinar-like structures simulates solid pseudopap-
illary tumor (KLIMSTRA et al. 2000) and acinar cell
carcinoma (KLIMSTRA et al. 1992).
The amount of neoplastic cells obtained with
FNAB can also be low because of the presence of a
large fibrous component of the tumor. Sometimes,
the cytological smear contains a large quantity of
amorphous material, eosinophilic to hematoxylin-
eosin and polychromatic with Papanicolaou staining,
similar to amyloid. In this case, the rare neoplastic
cells must be looked for very carefully.
Cytological evaluation of the malignant potential
of endocrine tumors, with the exception of the most
poorly differentiated carcinomas, is not reliable. In
fact, there are no definite criteria able to identify
potentially aggressive tumors. A high nucleus-cyto-
plasmic ratio, nucleus characterized by thickened
chromatin and sometimes with clearer areas against
the nuclear membrane, the presence of frequent
signs of apoptosis with a background of cellular
debris have negative prognostic significance. The
presence of single or rare cells with notable pleomor-
phism, gigantic nucleus, and intranuclear cytoplas-
matic pseudoinclusions is not a sign of malignancy
(SOLCIA et al. 1997).
10.2.2
Macroscopic Features
The majority of PET is a single lesion with a rounded
or multilobulated border and sharp demarcation
from the surrounding parenchyma, despite the lack
of a pseudo capsule. Most masses are between 1 and 5
cm in diameter, but larger masses are not uncommon.
These characteristics indicate an expansive pattern
of growth which differs from the infiltrative pattern
of a ductal adenocarcinoma (Figs. 10.2, 10.3).
PETs usually have a solid appearance; cystic degen-
erative areas are rare; however, cystic PETs are well
described (DAVTYAN et al. 1990; LIGNEAU et al. 2001;
WARSHAW et al. 1990). When present, the preoperative
diagnosis (SOLCIA et al. 1997) compared with a solid
pseudopapillary tumor and other cystic masses may
be impossible (Fig. lOA).
Pathology
Fig. 10.2. Endocrine tumor: Whipple resection specimen. Endo-
crine tumor of the head of the pancreas. Cut surface shows a
solid, well-circumscribed, whitish tumor compressing the
common bile duct (arrow)
Fig. 10.3. Endocrine tumor: left-side pancreatectomy specimen.
Endocrine tumor of the body of the pancreas. Cut surface shows
a solid, intrapancreatic tumor, well circumscribed compared
with the surrounding parenchyma, brownish in color
The color and the consistency depend on the
amount of stroma and the degree of vascularization.
The color varies from brown to reddish, and the con-
sistency in most cases is higher than the surrounding
pancreatic parenchyma. In rare cases, these masses
appear considerably hemorrhagic, with a purple to
bluish color and soft consistency. Sometimes, however,
the fibrosis is considerable, giving a firm consistency
and a whitish color. There may be necrotic and hem-
orrhagic foci, especially in malignant masses, which
appear as yellowish or brownish areas with a soft
consistency. Nonfunctioning PETs are usually large;
insulinomas are among the smallest (Fig. 1O.5).
Sometimes, a PET may demonstrate the features of
a malignant tumor: ill-defined margins, infiltration
of the perivisceral adipose tissue, mainly as satellite
nodules, infiltration of the duodenal wall, common
bile duct, spleen, or large vessels. Involvement of the
163
Fig. 10.4. Endocrine cystic tumor. Whole-mount macrosection
of an endocrine tumor with pseudo capsule and cystic change
Fig. 10.5. Insulinoma. Enucleation of an intrapancreatic endo-
crine tumor. The tumor nodule appears well-circumscribed,
has a homogeneous aspect and an intense red, hemorrhagic
color
splenic vessels with vascular thrombosis can cause
splenic infarcts (Fig. 1O.6).
Sometimes the tumor reaches a remarkable size,
even tens of centimeters, and infiltrates the walls of
the neighboring organs, forming ulcers responsible
for significant digestive bleeding and anemia.
The presence of multiple lesions should lead to
the suspicion of pancreatic involvement with MEN
I (BRANDI et al. 1987; SAMAAN et al. 1989). Multiple
insulinomas may be present in 7.5%-13% of patients,
and gastrinomas in up to 30% (SOLCIA et al. 1997).
10.2.3
Histologic Features
In the majority of cases, the histological appearance
of the tumor is enough to suggest an endocrine
164
Fig. 10.6. Endocrine carcinoma. The tumor completely occu-
pies the tail of the pancreas, infiltrates the peripancreatic adi-
pose tissue and the splenic capsule. Cut surface of the spleen
shows signs of embolization of the splenic vessels
ongm because the majority are well-differenti-
ated tumors (Fig. 10.7). These are characterized by
a homogeneous cellularity, composed of small to
medium-sized elements, similar in shape and size,
which can occasionally have an irregular shape with a
voluminous nucleus and frequent cytoplasmic inclu-
sions. Three main growth patterns can be observed:
(1) trabecular pattern (Fig. 10.8a) with cords and
ribbons, frequent in benign tumors where the cells
are lengthened, the main axis perpendicular to that
of the trabecula, and the nucleus polarized; (2) glan-
dular-like or acinar pattern (Fig. 10.8b) comprising
acini and tubules, often containing secreted material;
Fig. 10.7. Endocrine tumor. Endocrine tumors are typically
composed of small to medium-sized cells with uniform,
round, or oval, central or outlying nuclei, and eosinophilic
and granular cytoplasm
P. Capelli et al.
(3) solid-nodular ('insular') pattern, typical of malig-
nant tumors (Fig. 10.8c), where the fibrous stroma of
the mass delineates cohesive groups of cells, resulting
in the characteristic nodular or insular appearance
(MUKAI et al. 1982; SOLCIA et al. 1997). Although one
pattern is generally prevalent, there may be different
growth patterns within the same tumor. Reports of
a papillary growth pattern (Fig. 10.8d) or rare cases
with mucus (TOMITA et al. 1981), hyaline periodic
acid-Schiff (PAS)-positive globules, cells with clear
(Fig. 10.9a; GUARDA et al. 1983; HOANG et al. 2001),
vacuolated (ORDONEZ and SILVA 1997), or oxyphilic
cytoplasm (Fig. 10.9b; GOTCHALL et al. 1987; RADI
et al. 1985) can be observed, but these forms are
extremely unusual.
The hyperdense radiological appearance is related
to the rich vascularization, which characterizes the
large majority of these lesions (Fig. 10. lOa). Only
rare cases show prevalent wide bands of sclerohya-
line stroma, sometimes with calcified foci. When the
sclerosis is widespread, the cells can appear to float in
this fibrous tissue (Fig. 10.1 Ob). Calcifications, either
as large deposits or as psammoma bodies, are rare.
The presence of amyloid, as deposits of extracellu-
lar, amorphous, eosinophilic material, is frequently
observed in insulinomas.
Since these tumors grow slowly, normal pancreatic
structures such as ducts and islets can be entrapped
within the tumor.
Infiltration of local structures characterizes malig-
nant forms and should be identified by histological
examination. Infiltration is not always evident from
macroscopic examination and therefore should be
looked for with care. Generally, there are foci of
tumoral infiltration of the muscular tunic of the duo-
denum, the choledochal wall, or lymph node metasta-
ses; evaluation of perivisceral adipose tissue infiltra-
tion can be more difficult especially when the tumor
has expansive growth margins and a pseudocapsule.
In very rare cases, solid and wide areas with
poorly differentiated, small cells with hyperchro-
mic nucleus and little cytoplasm characterize the
tumor. The mitotic activity is generally high because
of widespread apoptosis; necrotic areas can some-
times be very large, with an appearance known as a
'geographic map' (Fig. 10.11). In this case, the tumor
is poorly differentiated, similar to a small-cell pul-
monary carcinoma, and requires the use of immu-
nohistochemical methods to identify its endocrine
differentiation.
It should be remembered from the latter that the
tumor's histological aspect alone does not lead to any
conclusions about its functional state or the type of
 Pathology 165

a b

Fig. 1O.8a-d. Endocrine tumors growth pattern: trabecular pattern (a), microglandular pattern (b), solid-nodular pattern (c),
unusual papillary pattern (d)

a b

Fig. 10.9a,b. Endocrine tumors, unusual cell types: cells with clear cytoplasm (a), oncocytic cells with deeply eosinophilic
cytoplasm (b)
 166 P. Capelli et al.

Fig.lO.lOa,b. Endocrine tumors, the stroma: richly vascularized stroma (a), fibrous stroma (b)

a
Fig. 10.11a,b. Poorly differentiated endocrine carcinoma. a Tumor with solid pattern made up of atypical, small cells with high
nucleus-cytoplasm ratio, poor, scanty cytoplasm, and frequent mitosis. b Abundant necrosis is present

hormone produced. There are two exceptions: the
presence of stroma with amyloid deposits indica-
tive of insulin om a, and a glandular-like growth pat-
tern with psammoma bodies seen in periampullary
somatostatinoma.
10.3
Ancillary Methods for Histopathological
Evaluation
10.3.1
Immunohistochemistry
The immunohistochemical method is extremely
useful both for the diagnosis of endocrine tumors
and for their classification.
Endocrine differentiation of the tumor can be
highlighted by immunophenotype markers common
to the cells of the endocrine system (BORDI et al.
1979): neurospecific enolase (NSE) (SCHMECHEL et
al. 1978), protein gene product (PGP) 9.5 (RODE et
al. 1985), synaptophysin (GOULD et al. 1987), and
chromogranins A, B, and C (HAGN et al. 1986; LLOYD
et al. 1984). It is important to subdivide these into
cytoplasmic markers, cytosolic and microvesicular,
and granular.
NSE and PGP 9.5 are cytoplasmic proteins, while
synaptophysin belongs to the complex family of
proteins of small vesicle membrane. The staining
intensity does not depend on the granular secre-
tion or the type of hormone produced (BaRD! et al.
1979). The staining due to antibodies that recognize
neurosecretory granules depends on the granule
content of the cells. Positivity for chromogranin
 Pathology
A is the same as the identification of granules by
silver impregnation methods (coloring according
to Grimelius).
Generic endocrine markers are most important
when used for confirming the diagnosis, especially
with poorly differentiated tumors. Nevertheless,
highly specific granular markers are only faintly
positive or completely negative in poorly differenti-
ated tumors. Therefore, with these tumors, it would
be better to use cytoplasmic markers, which persist
in the neoplastic cells. Synaptophysin has a higher
level of specificity compared with NSE.
As well as endocrine differentiation markers,
these tumors are positive for cytokeratins 8, 18,
and 19 (HOEFLER et al. 1986; HOORENS et al. 1998)
(Fig. 10.12).
There are also specific antibodies for the nor-
mally produced pancreatic hormones or hormones
of ectopic origin, which can be used in classifying
endocrine tumors because of their pathogenetic or
prognostic role (i.e., alpha-chain of human chorionic
gonadotropin; KAHN et al. 1977; OBERG and WIDE
a b
167
1981). The hormone produced and responsible for
the clinical syndrome can be highlighted (HEITZ et
al. 1982; SOLCIA et al. 1997). The staining intensity
or the number of positive cells does not correlate
with the severity of the symptoms. Moreover, the
cells may not demonstrate positivity for any hor-
mones because of their hormonal overproduction.
This classification is used in the differentiated forms,
whereas hormone production is never seen in poorly
differentiated endocrine carcinomas. The type of
hormone produced may be useful for the prognosis
(SOLCIA et al. 2000) and for the early recognition of
relapse or metastases.
Finally, the proliferation index (Ki -67), p53, human
chorionic gonadotropin, and the progesterone recep-
tor obtained with immunohistochemical methods
have shown prognostic significance in PETs (KAHN
et al. 1997; OBERG and WIDE 1981; PELOSI et al. 1996;
VIALE et al. 1992). The cells of these tumors are,
however, negative for the markers which identify the
enzymes produced by the exocrine pancreas, such as
trypsin, amylase, and lipase.
Fig.l0.12a-c. Endocrine tumor, immunohistochemistry: cyto-
keratin (a), chromogranin (b), and PGP 9.5 (c) positivity
168
10.3.2
Histochemistry
The use of specific histochemical stains for endocrine
cells has almost been completely replaced by immuno-
histochemical markers. Grimelius silver staining was
particularly diffuse; its role in identifying neurosecre-
tory cytoplasmic granules is analogous to that of the
immunohistochemical expression of chromogranin A.
Mucus staining (mucicarmine, PAS) is generally
negative, although mucus droplets can be identified
inside a glandular or ductal type pattern. Glycogen,
identified by PAS and PAS-diastasis, is usually absent.
Sometimes hyaline PAS-positive globules may be
identified inside or outside the cells (generally alpha-
I-antitrypsin positive).
Congo red staining and the subsequent observa-
tion under polarized light confirm the possible pres-
ence of amyloid.
10.3.3
Electron Microscopy
Electron microscopy has long been used to show the
neuroendocrine differentiation of the tumors since
the cells contain electron-dense secretory granules,
which are similar to those of islet cells. The neurose-
cretory granules can vary in shape and size according
to the specific hormone that they store. This method
has been largely replaced by immunohistochemistry,
at least at the diagnostic level.
10.4
Functioning Endocrine Tumors
These are tumors with an associated clinical syn-
drome, and they represent the large majority of
clinically significant PETs.
The different types of hormones or cells have a
different potential in producing symptoms that are
relevant from a clinical point of view. For example,
most patients with insulin-producing tumors develop
the insulinoma syndrome even when their tumor
is smaller than 1 em, while only a small percentage
of patients with glucagon-producing tumors, usu-
ally very large, develop the glucagonoma syndrome
(BORDI et al. 1979; KLOPPEL et al. 1986; RUTTMAN et
al. 1980). In the latter case, a more voluminous mass or
a longer clinical course is probably necessary to pro-
duce symptoms, with the consequent selection of cells
P. Capelli et al.
with a higher growth potential. This could explain why
most glucagon-producing tumors resulting in gluca-
gonoma syndrome are malignant in contrast to, for
example, insulinomas. The majority of glucagon-pro-
ducing tumors without syndrome are micro adenomas
discovered by chance.
Insulinomas, glucagonomas, and VIPomas have a
preference for the body-tail, while gastrinomas are
mainly found in the head of the pancreas. Tumors in
the body-tail preferably spread through blood ves-
sels, while pancreatic gastrinomas spread along the
lymphatic route.
10.4.1
Insulinomas
Insulinomas are the most common functioning PET
and are, after gastrinomas, the tumors which are
most frequently found in patients with MEN I. The
clinical signs and symptoms are a direct result of
insulin -mediated hypoglycemia.
The tumors are exclusively located in the pancreas
and can be distributed throughout this organ. Most
insulinomas are benign (85%-99%), single, and less
than 2.5 em in size (LIU et al. 1985; STEFANINI et al.
1974). Malignant insulinomas are generally larger
than 3 em, and about a third of them have metastases
at the time of diagnosis. In 2%-7% of patients, insu-
linomas are multiple, synchronous or metachronous,
and 6% of patients have MEN I syndrome (DONOW
et al. 1990).
Immunohistochemically, well-differentiated insu-
linomas with a trabecular-type growth pattern are
characterized by considerable insulin positivity (at the
lower pole of the cell; ROTH et al. 1992). By contrast,
insulinomas with a solid pattern show no positiv-
ity at all or only a very slight positivity. In 5% of the
insulinom as, amyloid may be present in the stroma.
In the pancreatic parenchyma around the tumor, the
islet content of immunoreactive insulin cells may
be decreased; this probably represents an adaptive
response by the beta-cells to the prolonged hypoglyce-
mia (BANI SACCHI et al. 1989).
10.4.2
Gastrinomas
This is the second most common endocrine tumor
of the pancreas. Most gastrinomas are located inside
the anatomic region between the head of the pan-
creas, the common bile duct, and the first and second
Pathology
portion of the duodenum, known as the 'gastrinoma
triangle' (STABILE et al. 1984).
The excessive production of gastrin leads to the
onset of Zollinger-Ellison syndrome. This syndrome
may be sporadic or a manifestation of MEN I. About
50%-70% of gastrinomas associated with the spo-
radic form of Zollinger-Ellison syndrome are found
in the pancreas, especially in the head, while the rest
are mainly found in the duodenum (DONOW et al.
1991). Single gastrinomas have a diameter of 2 cm or
more in the pancreas and usually of 1 cm or less when
in the duodenum (DONOW et al. 1991; STAMM et al.
1986; THOMPSON et al. 1989). Most of the gastrino-
mas associated with MEN I are found in the duode-
num (PIPELEERS-MARICHAL et al.1990). In this case,
they are usually smaller than 1 cm, multicentric, and
difficult to identify. Pancreatic gastrinomas in MEN
I are rare (KLOPPEL et al. 1986; VELLA et al. 1988),
although the pancreas of these patients can be the
site of multiple endocrine tumors, which rarely pro-
duce appreciable amounts of gastrin (KLOPPEL et al.
1986; PIPELEERS-MARICHAL et al. 1990).
At diagnosis, about 60% of gastrinomas already
have metastases in the peripancreatic lymph nodes
and less frequently in the liver (DELCORE et al. 1988;
STABILE and PASSARO 1985).
Histologically, gastrinomas show a solid, trabecular
or pseudoglandular-type growth pattern, and immu-
nohistochemically almost all cases are gastrin positive,
particularly in the forms with a trabecular growth pat-
tern. In about 50% of cases, there is even positivity for
other hormones (PP, glucagon, insulin).
10.4.3
Glucagonomas
These are malignant tumors in over 60% of patients
(RUTTMAN et al. 1980). The size at diagnosis varies
between 2 and 3.5 cm, and they are generally located
in the distal portion of the pancreas. Tumors char-
acterized by glucagon-positive cells with no clinical
symptoms are mostly benign and are either found by
chance at autopsy or are small tumors in the course of
MEN I syndrome (BORD! et al. 1979; KLOPPEL et al.
1986; RUTTMAN et al. 1980). Immunohistochemically,
glucagonomas often show weak glucagon positivity,
while there may be numerous PP cells.
The excessive amount of glucagon in the blood
results in a clinical syndrome characterized by
migrant necrolytic erythema, slight intolerance to
glucose, depression, and a tendency to develop deep
venous thrombosis (MALLINSON et al. 1974).
169
10.4.4
VIPomas
Most VIPomas arise in the pancreas and are malig-
nant 80% of the time. They are usually large, solitary
tumors with an average diameter at diagnosis of 4-5
cm and are often located in the tail of the pancreas
(BLOOM et al. 1973; SOLCIA et al. 1997; VERNER and
MORRISON 1974).
The overproduction of VIP (vasoactive intestinal
polypeptide), demonstrated immunohistochemi-
cally, causes watery diarrhea, hypokalemia, and
achlorhydria (BLOOM et al. 1973; HEITZ et al. 1982;
VERNER and MORRISON 1974).
10.4.5
Somatostatinomas
These are rare and generally malignant endocrine
tumors of the pancreas. Only pancreatic somatostati-
nomas can be responsible for a hormonal syndrome.
Histologically, they can be characterized by the pres-
ence of calcifications with the features of psammoma
bodies (SOLCIA et al. 1997; VINIK et al. 1987). The most
common site of extrapancreatic somatostatinoma is
the second portion of the duodenum around the
papilla of Vater, and some are associated with neuro-
fibromatosis type 1 (Von Recklinghausen syndrome)
and pheochromocytomas (STAMM et al. 1986).
10.4.6
Functioning Endocrine Tumors
Producing Ectopic Hormones
This is a group of tumors associated with syndromes
caused by ectopic hormones. They appear as large
masses and are malignant. Their microscopic pat-
terns are usually the same as in other PETs. They
can produce adrenocorticotropic hormone (ACTH;
Cushing's syndrome), serotonin (atypical carcinoid
syndrome), growth hormone releasing factor (acro-
megaly), or parathyroid hormone (PTH)-like hor-
mones (paraneoplastic hypercalcemia).
10.5
Nonfunctioning Endocrine Tumors
These are endocrine tumors not associated with any
particular clinical syndrome. However, hormone
170
positivity can be shown on tissue with immunohis-
tochemical methods. This functional 'silence' can be
due to: (1) the production and/or release of an insuf-
ficient amount of hormone; (2) the rapid degradation
of the hormone; (3) the processing of a hormone
which is unable to produce a definite clinical picture,
as is the case with PPomas; (4) the production of a
functionally inactive hormone.
The symptoms are mostly linked to the presence of
metastases or the mass effect. At surgery, they appear
as large masses, usually with a diameter greater than
5 cm, and are malignant in the majority of cases
(ECKHAUSER et al.1986; SOLCIA et al.I997). However,
there are also small nonfunctioning tumors, discov-
ered by chance and generally benign.
There is no difference in the growth pattern
between endocrine functioning and nonfunctioning
tumors.
About 10% of tumors have absent secretory
granules; this is reflected in the absence or slight
positivity of chromogranin, while the positivity of
other differentiation markers, such as NSE, synapto-
physin, and PGP 9.5, is preserved. Among nonfunc-
tioning endocrine tumors, which are chromogranin
A-positive and therefore have secreting granules, PP
is the hormone which is more frequently identified
(TOMITA et al. 1983), followed by glucagon and soma-
tostatin (KLOPPEL and HEITZ 1988).
10.6
Endocrine Tumors in MEN I Syndrome
The pancreatic involvement in MEN I syndrome is
characterized by a diffuse micro adenomatosis in
association with one or several macrotumors (more
than 0.5 cm in diameter) (KLOPPEL et al. 1986; KOM-
MINOTH et al. 1998; PADBERG et al. 1995).
Histologically, the majority of these small
tumors shows a characteristic trabecular pattern
and can have a fibrous capsule. Immunohisto-
chemical positivity for more than one hormone is
typical, even though one hormone usually prevails
(PP»glucagon>insulin; KLOPPEL et al. 1986). In
patients with MEN I and hypoglycemic syndrome,
only one of the macrotumors generally produces
insulin (DONOW et al. 1990; KLOPPEL et al. 1986)
despite the presence of multiple endocrine tumors. In
patients with MEN I and Zollinger-Ellison syndrome
(about 60% of the patients with MEN 1), gastrino-
mas are often located in the proximal portion of the
duodenum, are less than 1 cm in diameter, and are
P. Capelli et al.
multifocal. The pancreas is usually characterized by
the presence of multiple endocrine tumors of vari-
ous sizes, which produce different hormones (PIPEL-
EERS-MARICHAL et al. 1990). In patients with MEN
I, the Verner-Morrison syndrome, glucagon om a
syndrome, or acromegaly is very rare (KLOPPEL et al.
1986; 001 et a1.l985; STACPOOLE et al. 1981; WARNER
et al. 1983).
10.7
Criteria of Malignancy
and Tumor Classification
Invasion of the adjacent organs and/or the pres-
ence of metastases within the lymph nodes, liver, or
other organs are unequivocal criteria of malignancy
(Fig. 10.13). With the exception of poorly differenti-
ated tumors characterized by anaplastic cells (like
small-cell carcinoma), the traditional histopathologic
criteria of malignancy are poor predictors of the
biological behavior of PETs. They are usually well-
differentiated and, at the time of diagnosis, display
neither metastases nor macroscopic invasion of the
adjacent organs, making prediction of their biologi-
cal behavior difficult. Metastases may appear years
after the operation. Numerous studies have been car-
ried out to determine the predictive value of several
indicators. The parameters considered are the size of
the tumor, microscopic identification of vascular inva-
sion, perineural invasion, mitosis, necrosis, expression
of some immunophenotypic markers, and evaluation
of the DNA content.
These studies demonstrate that the only reliable
histological marker of malignancy is invasion of the
blood vessels. Lymphatic vascular invasion, high pro-
liferative activity (Ki 67>2%-5%), high mitotic index
(>2 per 10HPF),and the presence of tumoral necrosis
(LA ROSA et aI. 1996; PELOSI et al. 1996,1997; RIGAUD
et al. 2001) are presumptively correlated to malignant
behavior. Another prognostic factor seems to be the
size of the tumor. Well-differentiated endocrine non-
functioning tumors that are larger than 4 cm have a
greater risk of relapse and metastases (LA ROSA et al.
1996); for functioning tumors, the cut-off is smaller
(2 cm) (DONOW et al. 1990).
On the whole, well-differentiated endocrine
tumors smaller than 2 cm are benign.
Ploidy (RIGAUD et al. 2001 ),expression of oncogenes/
tumor suppressor genes (HOFLER et al. 1988; CHUNG et
al. 1997; BEGHELLI et al. 1998; MISSIAGLIA et al. 2002;
SCARPA et al. 2002), expression of progesterone recep-
 Pathology
a b
tors (PELOSI et al. 1996; VIALE et al. 1992), and the pres-
ence of alpha-human chorionic gonadotropin (HCG)
(KAHN et al. 1977; OBERG and WIDE 1981; RUSCHOFF et
al. 1993; SOLCIA et al. 2000), although important, seem
to be ofless prognostic value.
The possible presence or absence of a clinical syn-
drome also seems to have a predictive value, with a
likelihood of metastases reaching 10% for clinically
silent tumors discovered by chance and insulinomas,
and up to 60%-90% for glucagon om as, somatostatin-
omas, VIPomas, gastrinomas, tumors associated with
ectopic hormone production, and symptomatic non-
functioning endocrine tumors (SOLCIA et al. 1997).
The poor survival rate of non functioning endo-
crine tumors compared with functioning ones
should probably be considered secondary to the
advanced stage at diagnosis.
A new classification of PET has recently been
published by the World Health Organization (WHO)
(SOLCIA et al. 2000), based on a consensus of 12
leading pathologists. This classification takes into
account the clinical and pathological features in an
171
Fig. 10.13a-c. Endocrine carcinoma: vascular invasion (a),
lymph node (b) and hepatic metastases (c)
attempt to define the outcome of such lesions better.
In this classification, PETs have been subdivided
into distinct categories according to their biological
behavior, considering the level of histological differ-
entiation, eventual hormone secretion, size and other
parameters taken as prognostic indicators, such as
angio-invasion, number of mitoses, and the prolif-
eration index (Table 10.1).
10.8
Differential Diagnosis
The diagnosis of PET is usually made with conven-
tional histology and confirmed by the immuno-
histochemical identification of endocrine markers.
Problems of differential diagnosis may arise in
some patients with chronic pancreatitis with massive
endocrine hyperplasia and may occur with exocrine
tumors of the pancreas, nonepithelial tumors, or
pancreatic metastases.
172 P. Capelli et al.

Table 10.1. Clinicopathological correlations of endocrine tumors of the pancreas (Functioning, associated with pertinent clinical
syndrome of endocrine hyperfunction; Nonfunctioning, not associated with pertinent clinical syndrome, irrespective of hormone
detection in blood or tumor tissue)
Well-differentiated endocrine tumor
1.1 Benign behavior: confined to the pancreas, non-angioinvasive, <2 cm in sizea, £2 mitoses, and £2 Ki 67-positive cells/lO HPF
1.1.1 Functioning insulinoma
1.1.2 Nonfunctioning
1.2 Uncertain behavior: confined to the pancreas, +2 cm in size, >2% Ki 67-positive cells/lO HPF, or angioinvasive
1.2.1 Functioning gastrinoma, insulinoma, VIPoma, glucagonoma, somatostatinoma, or inappropriate syndromeb tumor
1.2.2 Nonfunctioning
2 Well-differentiated endocrine carcinoma
2.1 Low-grade malignant with gross local invasion and/or metastases
2.1.1 Functioning gastrinoma, insulinoma, VIPoma, glucagonoma, somatostatinoma, or inappropriate syndromeb tumor
2.1.2 Nonfunctioning
3 Poorly differentiated endocrine small-cell carcinoma, high grade malignant

a <2 cm in size implies close to 100% probability of benign behavior, <3 cm corresponds to 90% probability
b Inappropriate hormone syndromes: Cushing (ACTH), acromegaly or gigantism (GRH), hypercalcemia, etc.

Endocrine hyperplasia may be observed in the
course of obstructive or nonobstructive chronic
pancreatitis. In this case, endocrine elements are
grouped in vaguely insular structures characterized
by the persistence and normal distribution of all
four cell types normally present in the pancreatic
islet. Moreover, the microadenomas generally show
signs of fibrosis or intratumoral sclerosis, unlike the
hyperplastic insulae.
The exocrine tumors that can be confused with
endocrine tumors are the solid pseudopapillary
tumor (KLIMSTRA et al. 2000) and less frequently
the acinar cell carcinoma (KLIMSTRA et al. 1992).
The solid pseudopapillary tumor mimics an endo-
crine neoplasm when it is solid and lacks regressive
phenomena usually seen in this tumor. Immuno-
histochemically, the cells show diffuse positivity for
vimentin, neuron-specific enolase, focal but intense
alpha-l antitrypsin positivity, and generally appear
negative for cytokeratin and other endocrine mark-
ers (KLIMSTRA et al. 2000).
The distinction between endocrine tumors and
acinar cell carcinomas is very important because of
the latter's worse prognosis. An acinar cell carcinoma
with a solid-trabecular pattern, without an acinar
pattern, may be confused with an endocrine tumor.
The presence of rare acinar structures and cells with
abundant PAS-positive granular cytoplasm, together
with a large nucleus with a prominent nucleolus, are
suggestive of acinar differentiation. Confirmation is
obtained by the immunophenotypic demonstration
of pancreatic enzyme positivity (trypsin, lipase,
amylase) and the absence of endocrine differentia-
tion markers (KLIMSTRA et al. 1992).
Immunohistochemical investigations playa fun-
damental role in resolving the problems of differ-
ential diagnosis with other tumors. The presence of
endocrine markers solves the differential diagnosis
with poorly differentiated ductal adenocarcinoma;
differential diagnosis with a malignant, small- or
large-cell lymphoma is solved with the presence of
lymphoid markers. Differential diagnosis for the rare
fused cell forms must be made with mesenchymal
tumors of low-level malignancy, such as gastroin-
testinal stromal tumor, highlighted by mesenchymal
markers. Among the pancreatic metastases which can
mimic an endocrine tumor are the clear-cell carcino-
mas of the kidney, small-cell carcinoma of the lung,
and endocrine carcinoma originating in the ileum.
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11 Endocrine Hyperfunctioning Tumors
R. F. THOENI

CONTENTS 11.1
Introduction
ILl Introduction 177
11.2 Imaging of the Pancreas with CT 177 Radiologic imaging tests for suspected endocrine
11.2.1 Techniques 177
11.2.2 Appearance of the Pancreas on CT 179 hyperfunctioning tumors of the pancreas are usually
11.3 Imaging of the Pancreas with MR Imaging 179 performed to localize a lesion rather than to prove
1l.3.1 Spin-Echo Sequences 179 its existence. This is due to the fact that these lesions
1l.3.2 Fast MR Imaging 179 produce specific symptoms, and therefore the clini-
1l.3.2.1 Fast Spin-Echo and cal presentation, together with the laboratory tests,
Single-Shot Fast Spin-Echo Sequences 179
11.3.2.2 Gradient-Echo Sequences 180 is diagnostic of the disease. The role of radiologic
11.3.3 Appearance of the Pancreas on MR Imaging 180 imaging lies in determining the exact location of the
11.4 Imaging of the Pancreas with Ultrasound 181 neoplasm within the pancreas and/or outside of the
11.4.1 Endoscopic Ultrasound of the Pancreas 181 pancreas in cases with ectopic locations. Multiple
11.4.2 Intraoperative Ultrasound of the Pancreas 182 imaging techniques can be employed for detecting
11.4.3 Appearance of the Pancreas on Ultrasound 182
1l.S Somatostatin -Receptor these lesions as they are often quite small. We shall
Imaging of the Pancreas 182 describe the various techniques available in the
11.5.1 Techniques of armamentarium of imaging tests for assessing these
Somatostatin-Receptor Imaging 182 rare lesions and outline the specific features as well
11.5.2 Appearance of the Pancreas as the results with each one. Finally, we shall assess
on Somatostatin-Receptor Imaging 184
11.6 Other Radiologic Diagnostic Tests 184 the effectiveness and role of imaging for these hyper-
11.6.1 Arteriography of the Pancreas 184 functioning pancreatic tumors.
11.6.2 Portal Venous Sampling 184
11.6.3 Arterial Stimulation and Venous Sampling 185
11.7 Features and Results of Imaging Hyperfunctioning
Endocrine Tumors of the Pancreas 185
11.7.1 Insulinoma 185 11.2
11.7.2 Gastrinoma 188 Imaging of the Pancreas with (T
11.7.3 VIPoma 189
11.7.4 Glucagonoma 190 11.2.1
11.7.5 Somatostatinoma 191 Techniques
11.7.6 Other Hyperfunctioning Endocrine Tumors 192
11.8 Role of Imaging for Hyperfunctioning
Endocrine Tumors 193 Multirow helical computed tomography (CT) pro-
References 193 vides high image resolution, excellent contrast
enhancement, and very short examination times and
therefore is considered the primary imaging method
for the pancreas. In order to assess the pancreatic
parenchyma accurately by CT, intravenous iodinated
contrast material should be used. Initially, regardless
of the protocol employed, the patient is scanned
without an intravenous contrast agent in order to
determine where the pancreas is located.
R. F. THOEN!, MD
Professor of Radiology, University of California San Francisco, The protocol varies depending on the question at
Department of Radiology, Box 0628, San Francisco, hand. If the clinical question is to screen the pancreas,
CA 94143-0628, USA a single-phase protocol can be sufficient. However, for
178
diagnosing and staging a suspected hyperfunctioning
endocrine tumor (islet cell tumor) of the pancreas, a
dual-phase helical CT should be performed because
these masses are predominantly hypervascular. This
protocol is similar to that commonly used for the
staging of pancreatic adenocarcinoma (TABUCHI et
al. 1999; BOLAND et al. 1999). Hypervascular tumors
are neoplasms that enhance significantly in the arte-
rial phase and appear as conspicuous high-density
lesions (IGLESIAS et al. 2001; STAFFORD JOHNSON et al.
1998). In the portal venous phase, these tumors may
be isodense to the remaining pancreatic parenchyma
(HOLLETT et al. 1995) and therefore could be missed,
particularly if they are small. Large lesions can be par-
tially hypo dense in this phase. A dual-phase protocol
is also needed for the liver as hepatic metastases have
the same enhancement characteristics as the primary
hypervascular tumor.
Using a single-row detector scanner and a dual-
phase helical CT protocol of the pancreas, we initi-
ate scanning with a 20 s delay. We obtain scans with
3-5 mm slice thickness through the pancreas starting
at the bottom (level of third portion of duodenum)
and extending cranially to the dome of the liver.
Contrast material is administered as a rapid bolus
(150 ml delivered at a rate of 3-4 mlls). We then
repeat this series at 55-65 s and start at the dome of
the diaphragm and continue through the pancreas
and the remainder of the abdomen. Scans through
the pancreas should be obtained in one breathhold
with a second breathhold for the rest of the liver, and
finally another one for the entire abdomen. The first
phase in the pancreas serves to define the arterial
anatomy and to detect hypervascular lesions in the
pancreas and liver, and the second phase serves to
define hypovascular lesions and parenchyma in the
pancreas, liver, and the rest of the abdomen.
With the multislice or multirow helical CT scanner,
a dual- or triple-phase study is used (McNULTY et al.
2001). The prospective slice thickness is thin (e.g., 2.5
mm on a GE LightSpeed scanner; General Electric,
Milwaukee, WI). For a dual-phase protocol, the first
scan series is obtained through the pancreas with a
scan delay of 40 s and a high pitch (e.g.,6:1) (Fig.ll.l).
The injection rate is increased to 4-5 mlls. The second
scan series is obtained from the diaphragm to the
symphysis with a scan delay of 60 s, a slice thickness of
3.75 mm, and a pitch of 6:1 or 3:1. With a triple-phase
protocol, scan series with a scan delay of 20, 40, and
60 s are obtained. The triple-phase protocol has the
advantage of demonstrating a hypervascular lesion
on late arterial images (40 s) if the early (20 s) arterial
phase did not demonstrate an enhancing lesion due to
R. F. Thoeni
low cardiac output or impaired bolus technique. Alter-
natively, some type of bolus tracking technique can be
used to optimize timing of the bolus.
Whenever possible, oral contrast material should
be administered to avoid confusion of nonopacified
bowel loops with intraperitoneal fluid collections and
to more clearly define the boundaries of the normal
and neoplastic pancreatic parenchyma. In our institu-
tion, the first cup of contrast material (500 ml of 2%
iodinated contrast agent) is given 45 min before the
examination together with an oral tablet of metoclo-
pramide (Reglan, 10 mg,AH Robins, Philadelphia, PA)
to facilitate filling of the distal small bowel and right
colon (THOENI and FILSON 1988). The same amount
of contrast agent is given 30 min before the start of the
CT examination, which fills the proximal ileum and
jejunum. Finally, a cup of water is administered imme-
diately before scanning to assure optimal filling of the
stomach and duodenum with a low-contrast medium
for better definition of the gastric and duodenal wall.
With the advent of helical CT, 3D reconstruction of
the celiac axis, superior mesenteric artery, and supe-
rior mesenteric vein and their branches has become
possible and has the potential of increasing the accu-
racy for staging pancreatic neoplasms (HONG and
FREENY 1999). Usually, any vascular findings can be
identified on axial images, but surgeons often prefer
the 3D display for surgical planning. It reduces the
number of images that need to be assessed. For the
best results, curvilinear reconstructions should be
used. If needed, 3D images of the pancreatic and bili-
ary duct can also be obtained (ZEMAN et al. 1995).
Fig. 11.1. Arterial phase of a dual-phase computed tomogra-
phy (CT). The late arterial phase shows an enhancing lesion in
the body of the pancreas measuring 1 cm in diameter (arrows).
The clinical picture suggested an insulin om a, and the lesion
was surgically removed. L, liver; SP, spleen
Endocrine Hyperfunctioning Tumors
11.2.2
Appearance of the Pancreas on CT
In the early or late arterial phase, hyperfunctioning
endocrine tumors of the pancreas appear as hyper-
vascular masses that are round or oval in shape.
Rapid washout is usually seen in the portal venous
phase. In lesions measuring 2 em or less, enhance-
ment is usually homogeneous, but larger lesions may
appear heterogeneous. Larger lesions tend to have
areas of necrosis that can be quite large depending
on the overall size of the lesion. Hepatic metastases
appear similar to the primary lesion in the pancreas.
Secondary phenomena such as bile duct dilation or
vascular compromise may occasionally be seen.
11.3
Imaging of the Pancreas with MR Imaging
Currently, magnetic resonance (MR) imaging is not
as widely used as CT for imaging hyperfunctioning
endocrine tumors of the pancreas. This is in part
due to the speed of the CT examination and its
excellent image resolution and in part due to the
ease with which reformations and reconstructions
in multiple planes can be obtained with multirow
helical CT. Nevertheless, results with MR imaging
of the pancreas are getting better. Intravenous
contrast material and fast Tl-weighted as well as
T2-weighted sequences with breathholding have
improved MRI results in the pancreas. In addition,
MR cholangiopancreatography (MRCP) permits
accurate assessment of the biliary and pancreatic
ducts. Presently in the USA, only gadopentetate
dimeglumine is approved for clinical use in assess-
ing the pancreas; it acts similarly to iodinated con-
trast material for CT. Some reports indicate that
mangafodipir trisodium (Teslascan, Mangafodipir
or Mn-DPDP, Amersham Health AS, Princeton, NJ)
also enhances the pancreatic tissue and postulate
that this enhancement could be used for demon-
strating pancreatic pathology better (GEHL et al.
1993). More work is needed in this area.
11.3.1
Spin-Echo Sequences
Imaging of the pancreas is performed with Tl-
and T2-weighted sequences (TSCHOLAKOFF et al.
1987). For a long time, only spin-echo sequences
179
were available, which were relatively slow (4-6 min
for Tl-weighted and 13-16 min for T2-weighted
sequences). Artifacts from breathing often degraded
these sequences. Fat suppression proved to be helpful
in eliminating some of the ghosting artifacts from
respiration produced by the high signal intensity
of fat on spin-echo sequences. For fat-suppression
techniques, the triglycerides in an image volume
are initially excited and the resulting transverse
magnetization of lipids dephased through a spoiling
gradient pulse (MITCHELL et al. 1991). The remain-
ing water magnetization is then excited to obtain
an image dominated by water. Because in spin-echo
techniques most signals are obtained from fat, sup-
pression of this signal allows the receiver-gain to be
increased and the dynamic range to be improved.
Differences between tissues can thus be enhanced.
This latter effect is used for imaging the pancreas
with Tl-weighted breathhold sequences. For the
pancreas, fat suppression appears to be more useful
for imaging with Tl- than with T2-weighted series
(THOENI et al. 2001). Therefore at UCSF, we use fat
suppression only for Tl-weighted sequences. With
the introduction of fast spin-echo, single-shot fast
spin-echo, and gradient-recalled echo sequences,
faster imaging and breathhold techniques became
available that improved results.
11.3.2
Fast MR Imaging
11.3.2.1
Fast Spin-Echo and Single-Shot Fast Spin-Echo
Sequences
Fast spin-echo (FSE) and single-shot fast spin-
echo (ssFSE) sequences are the main scan series
used currently for imaging the pancreas with
T2-weighting (OUTWATER and MITCHELL 1996).
These fast sequences offer the advantage of rapid
scanning with reduced or absent ghosting artifacts
from breathing. FSE is a fast scanning method that
uses spin-echoes and altered k-space filling. It is
designed to provide long TR/long TE images in scan
times that are about four to six times shorter than
those obtained with conventional spin-echo tech-
niques. For example, with FSE, using a TR of 4000
ms and a TE of -100 ms, 18 slices can be obtained
during quiet breathing in 4.0 - 4.5 min depending
on the gradient performance and coils used. This
technique is now mostly used with respiratory
triggering, which further reduces artifacts from
180
breathing. ssFSE sequences are obtained with a
single 90 deg excitation pulse, and k-space filling is
achieved through fast data sampling by using high
receiver bandwidth and rapid switching of gradi-
ents. These breathhold sequences typically have
an infinite TR, a TE of 90-180 ms and last about
15-25 s. With axial and coronal ssFSE, images of
high quality can be obtained during breathhold-
ing. For the MRCP portion of the study, coronal
and oblique coronal sequences without and with
fat suppression are employed. Sequences without
fat suppression provide a tomographic effect and
permit the evaluation of structures other than the
bright, fluid-filled ducts. Usually, the exact site and
cause of an obstruction are readily visible. On fat-
suppressed images with their cholangiographic
effect, the location of the obstruction, but not the
actual cause, is apparent.
77.3.2.2
Gradient-Echo Sequences
In recent years, gradient-echo sequences with breath-
holding have gained in popularity because of their
markedly reduced imaging time and associated
reduced motion artifacts. Gradient recalled echo
sequences (GRE) demonstrate lower tissue contrast
and, therefore, fat suppression, and administration of
an intravenous bolus of gadopentetate dimeglumine
is often needed for better definition of a mass in the
pancreas (GABATA et al. 1994). This is more appli-
cable to pancreas adenocarcinoma than to endocrine
tumors of the pancreas. These sequences offer strong
Tl-weighting, good temporal resolution for dynamic
studies, and absence of respiratory artifacts. Rapid
bolus technique and short scan delays produce
improved tissue contrast between the non enhanced
or minimally enhanced pancreatic parenchyma
and the markedly enhanced hyperfunctioning islet
cell tumors. However, the imaging window for the
pancreas using gadolinium is very narrow (less
than 1.5 min and optimal for the arterial phase only
between 20 and 35 s) due to the rapid enhancement
and washout effect of this compound in the pancreas
as well as in hypervascular metastases to the liver.
Similar to contrast-enhanced helical CT, enhance-
ment with gadolinium should be obtained in the
arterial (scan delay 20 s) or late arterial (40 s) phase
(SEMELKA et al. 1993; THOEN! et al. 2000). Mn-DPDP
has been shown to increase the signal intensity of the
pancreas and to improve the conspicuity of focal pan-
creatic lesions (DIEHL et al. 1999; GEHL et al.1993).Itis
assumed that this enhancement represents an uptake
R. F. Thoeni
of the contrast agent by the pancreatic tissue and
may possibly be caused by liberation of manganese
from the complex. The exact mechanism is unknown.
The advantage of this contrast agent is the fact that
the imaging window is much wider, and therefore, it
appears more practical than gadopentetate if further
studies confirm its usefulness. However, studies with
Mn-DPDP published thus far have only addressed its
use in patients with pancreatic adenocarcinoma.
11.3.3
Appearance of the Pancreas on MR Imaging
On Tl-weighted images, the pancreas has medium
signal intensity, similar to or slightly less than that of
liver and lower than that of the fat surrounding the
pancreas. Fat is particularly helpful in the area of the
tail where the dark signal intensity of the pancreas is
contrasted against the signal intensity of fat. For the
best visualization of the pancreas on Tl-weighted
sequences, fat suppression (see previous paragraphs)
should be used. In this fashion, the pancreas assumes
a bright signal intensity that facilitates the detection
of pathology (Fig. ll.2a). On T2-weighted images,
the pancreas again demonstrates a signal intensity
similar to that of the liver. T2-weighted images are
usually obtained without fat suppression for better
definition of the remaining structures in the abdo-
men (Fig. ll.2b). The low signal intensity of the
splenic, mesenteric, and portal veins can be used as
landmarks to identify the pancreas, and distension
of the stomach and duodenum with water can help
to define the head of the pancreas. In patients with
fatty involution of the pancreas, the signal intensity
of this organ increases according to the amount of fat
present within the parenchyma. However, on fat-sup-
pressed sequences, the pancreatic bed appears as an
area of very low signal intensity. The surface of the
normal pancreas is smooth or lobulated depending
on the amount of fatty involution.
The pancreatic duct appears as a low-signal inten-
sity tubular structure on Tl-weighted sequences
and as a high-signal intensity structure on heavily
T2-weighted scan series (Fig. ll.2c). During MRCP,
heavy T2-weighting and fat suppression provide a
cholangiogram effect where the pancreatic and bili-
ary ducts appear similar to the images obtained with
endoscopic retrograde cholangiopancreatography
(ERCP). On MRCP images without fat suppression,
both the bright duct and the dark parenchyma of the
pancreas are well visualized against a background of
relatively bright fat.
 Endocrine Hyperfunctioning Tumors
a b
Fig. 11.2a-c. Magnetic resonance (MR) image of an insuli-
noma. a Tl-weighted gradient recalled echo sequence with fat
suppression shows a low-signal intensity lesion in the head of
the pancreas (arrows) representing an insulinoma. A, aorta. b
T2-weighted fast spin-echo sequence demonstrates the lesion
(arrows) as a small high-signal intensity mass. L, liver. c T2-
weighted single-shot fast spin-echo sequence in the coronal
plane shows the same lesion (arrows). Note the normal main
pancreatic duct (PD). L, liver; ST, stomach
11.4
Imaging of the Pancreas with Ultrasound
Correct interpretation of imaging and sampling
methods depends on the expertise and skills of the
radiologist performing these procedures. This is
particularly true for modalities such as ultrasound
(transabdominal, endoscopic, or intraoperative
ultrasound) or vascular procedures (arteriography,
portal venous sampling, or arterial stimulation and
venous sampling) where the performance is highly
operator-dependent. Even if one of these procedures
is highly recommended, it serves little purpose if
performed without the requisite expertise. Such
limitations obviously become significant only in
cases where the pancreatic lesion is small or when
an appropriate differential diagnosis is needed.
Transabdominal ultrasound is only successful when
a pancreatic lesion is large enough to be visualized
and if the patient's body habitus or gas in bowel
does not prevent a complete examination of the
pancreas (HESSEL et al. 1982). When the presence of
a hyperfunctioning endocrine tumor of the pancreas
181
c
is suspected clinically, a more focused examination
with endoscopic ultrasound is usually more appro-
priate if an ultrasonographic examination is desired
(ROSCH et al. 1991). However, one has to bear in mind
that a complete evaluation of the abdomen is better
obtained with CT in these cases.
11.4.1
Endoscopic Ultrasound of the Pancreas
Patients undergoing endoscopic ultrasound are
asked to fast starting at midnight of the night before
the procedure. After the usual preprocedural inter-
view, the relevant patient history and informed con-
sent are obtained. Intravenous access is established,
and following routine pre-endoscopic procedures,
the patient is sedated for the examination and vital
signs monitored.
The actual endoscopic procedure is divided
into three parts. Initially, a preliminary endoscopic
examination of the upper gastrointestinal tract is
performed, and any abnormalities are noted. Then
182
the endoscopic examination is carried out. The
conventional endoscope is removed and the endo-
sonographic scope is introduced with a water-filled
balloon in place at its tip. The scope is advanced as
far into the duodenum as possible, and the duode-
num, ampulla, and pancreas are visualized while the
instrument is slowly withdrawn into the duodenum
and stomach. At times, difficulty can be encountered
in entering the duodenum, if peristalsis is excessive
or because of poor patient compliance. Muscle relax-
ant and increased sedation may be needed. Ultraso-
no graphic images of the various portions of the pan-
creas obtained with the high-frequency probe can
be recorded (SCHUMACHER et al. 1996). If necessary,
biopsies are performed through a conventional endo-
scope if a mass is present (GRESS et al. 2002).At times,
it may not be possible to completely evaluate the tail
of the pancreas if it is located beyond the reach of the
endosonography probe (HAYAKAWA et al. 2000).
11.4.2
Intraoperative Ultrasound of the Pancreas
Similar to endoscopic ultrasound, intraoperative
ultrasound (lOUS) permits placement of the ultra-
sonographic probe very close to the area of interest,
unimpeded by fat, bone, or gas. Because of the short
distance of the probe from the pancreas, a high-
frequency transducer (7.5 or 10 MHz) can be used
which provides images with much greater spatial
resolution than those obtainable in a transabdominal
ultrasound study.
For IOUS, the pancreas is exposed, the head
mobilized, and the lesser sac opened. The peritoneal
cavity is then filled with warm saline. The transducer
is enclosed in a sterile plastic sheath or drape and
the pancreas scanned in transverse and longitudinal
planes. Scanning is performed with the transducer
held approximately 1 cm from the surface of the pan-
creas. This permits the visualization of superficial
lesions (GUNTHER et al. 1985).
11.4.3
Appearance of the Pancreas on Ultrasound
The normal dimensions of the pancreas are difficult
to establish and vary significantly among patients.
Some authors have accepted 3.5 cm as the maximal
normal diameter of the head and tail of the pancreas,
with smaller dimensions for the body (DE GRAAFF et
al. 1978; HABER et al. 1976). Measurements obtained
R. F. Thoeni
in a single plane should be viewed with great cau-
tion, as anatomic variations of the pancreas are
considerable. Commonly, the texture of the body of
the pancreas and the overlying left lobe of the liver
are compared. The fibrous pancreas usually shows
higher echogenicity than the liver. However, in many
instances, the texture of these two organs is identical.
Numerous factors may influence the appearance of
the pancreas including the state of hydration, fatty
involution, or fasting. Also, in many instances, the
liver is not normal, which renders a comparison
of the pancreas to the liver even more difficult.
While vessels such as the splenic vein can be used
as landmarks, it is often impossible to distinguish
the contour of the gland from surrounding tissues
in the retroperitoneum. Also, the depth of penetra-
tion is limited with ultrasound, and retroperitoneal
extension of disease such as invasive tumor cannot
be accurately assessed.
11.5
Somatostatin-Receptor Imaging
of the Pancreas
11.5.1
Techniques of Somatostatin-Receptor Imaging
Somatostatin is a 14-amino-acid peptide hormone
found on many cells of neuroendocrine origin. It
acts as a neurotransmitter in the central nervous
system. Hormonally, it inhibits the release of growth
hormone, insulin, glucagon, and gastrin when it
binds to cells. Somatostatin receptors have been
demonstrated on the surface of human tumor cells
which includes cells with amine precursor uptake
and decarboxylation (APUD) properties such as pitu-
itary tumors, endocrine pancreatic tumors (REUBI
et al. 1990), carcinoids, paragangliomas, small-cell
lung cancers, medullary thyroid carcinomas, and
pheochromocytomas. Other non-APUD cells may
also bear somatostatin receptors, such as activated
lymphocytes, astrocytomas, and some breast carci-
noma. Animal studies have shown that somatostatin
analogues may inhibit the growth of many of these
tumors in vivo.
Analogues of somatostatin were developed because
human somatostatin has a very short half-life in
circulation (2-3 min) and is easily broken down
by endogenous peptidases (RENS-DoMIANO and
REISINE 1992). The analogues preserved two impor-
tant molecular features of somatostatin: its cyclic form
Endocrine Hyperfunctioning Tumors 183

and the four amino acids involved in the binding to pheochromocytoma) compared 1-123-Tyr3-octreo-
the receptor. One somatostatin analogue that has been tide and [In-111-DTPA-D-Phel]-octreotide scans and
studied extensively in vitro and in vivo is octreotide demonstrated a more rapid clearance of the former
(Sandostatin, Novartis Pharmaceuticals, East Hanover, (KRENNING et al. 1992). However, the iodine-labeled
N.J.). It also has been used as hormonal treatment in compound had a higher background because of deg-
patients with carcinoid syndrome. radation products and a higher intestinal background
Using a radiolabeled somatostatin analogue, because of biliary excretion. There appeared to be an
octreotide, tumors with somatostatin receptors can overall higher sensitivity of the indium-labeled com-
be detected by scintigraphy or positron emission pound in this small series. While results with indium-
tomography (PET) (KRENNING et al. 1992; LAM- 111-pentetreotide appear promising, insufficient data
BERTS et al. 1990). The incidence of somatostatin are currently available to conclusively compute the
receptors in hyperfunctioning endocrine tumors sensitivity, specificity, or accuracy (ELLISON et al.
of the pancreas was shown by in vivo scintigra- 1997; SCHIRMER et al. 1995). For the accurate inter-
phy with octreotide to be 100% for gastrinomas, pretation of the images, the normal tracer distribution
61% for insulinomas, 100% for glucagonomas, and needs to be understood, and knowledge of lesions
89% for unclassified APUDomas (REUBI et al. 1990; that are expected to accumulate the tracer is essential.
WEINEL et al. 1993). The numbers are generally More recently, other radioisotopes including Cu-64
slightly higher for in vitro receptor status. Failure to have been used for PET imaging and comparison to
demonstrate somatostatin receptors in some insuli-
nomas may be due to the existence of somatostatin
receptor subclasses that show high affinity binding
sites for native somatostatin but not for octreotide.
Somatostatin analogues also may be used therapeu-
tically to ablate lesions with somatostatin receptors
through radiation (UGUR et al. 2002). This method
is somewhat limited because many endocrine
tumors are quite small and located deep within the
abdomen.
In vivo studies with the radioiodinated (1-123)
derivative of octreotide have demonstrated the
visualization of somatostatin receptor-positive
tumors within minutes after the administration
of the tracer. However, 1-123 is expensive, not uni-
versally available, time consuming to prepare, has
a short half-life which does not allow for delayed
imaging, and its marked biliary excretion can
render interpretation of abdominal images dif-
ficult due to the large amounts of tracer in the
bowel. To avoid these problems, [In-ll1-DTPA-
D-Phe1]-octreotide was prepared (BAKKER et al.
1991; KRENNING et al. 1992). It was found to have a
high affinity for somatostatin receptors and similar
biological properties to octreotide. The compound,
also called OctreoScan, is easily labeled with In -Ill
(Fig. 11.3). Since this radiotracer is mainly elimi- Fig. 11.3. In-111-octreotide study of gastrinoma. The views
on the left demonstrate standard SPECT slice images in axial,
nated via the kidneys, intra-abdominal evaluation anteroposterior, and coronal planes. A lesion (thick arrows)
of somatostatin-receptor positive tumors could be is visualized adjacent to the upper pole of the kidney (thin
performed (DUNCAN et al. 1997). Usually, indium- arrows) on the right side. The anterior view of the whole body
111-0ctreoscan planar and SPECT images are on the right again shows the lesion (thick arrows) that proved
obtained at 4, 24, and 48 h following the injection of during endoscopic surgery to be located along the upper
common bile duct close to the origin of the cystic duct. CT
6.3 mCi of Octreoscan. and MRI did not visualize the gastrinoma. The patient has
One small series involving 6 patients (small-cell been symptom-free since the procedure. B, bladder (courtesy
lung cancer, gastrinoma, insulinoma, carcinoid, and of Dr. Robert Lull, SFGH Nuclear Medicine Services)
 184 R. F. Thoeni

In -111-diethylenetriaminepenta-acetic acid (DTPA)- 11.6

D-Phel-octreotide showed favorable results (ANDER-
SON et al. 2001; DECRISTOFORO et al. 2000). However,
the small number of patients examined again does not
allow for definite conclusions.
Somatostatin-receptor imaging can be a useful
technique for the diagnosis of many tumors of
neuroendocrine and non-neuroendocrine origin.
A positive finding may be predictive of the abil-
ity of octreotide to suppress the neuroendocrine
tumors. A lack of human antibody response allows
for repeated administration, and the entire body can
be imaged. Based on somatostatin-receptor imaging,
patient management decisions are more informed,
the therapy selection optimized based on tumor
biochemistry, and the success of the therapy readily
monitored.
11.5.2
Appearance of the Pancreas on Somatostatin-
Receptor Imaging
An 1-123-Tyr3-octreotide or In-111-pentetreotide
scintigram typically obtained at 4 and 24 h after
injection shows areas of increased tracer localization
in a hyperfunctioning endocrine mass or masses of
the pancreas. Other abnormal foci of uptake may be
present throughout the liver, adrenal gland, lymph
nodes, or bone consistent with metastases. Lesions
located adjacent to the liver and spleen may be
missed because of the adjacent normal uptake.
Other Radiologic Diagnostic Tests
11.6.1
Arteriography of the Pancreas
Before noninvasive cross-sectional imaging methods
were introduced, arteriography was the principal
technique for localizing these hypervascular endo-
crine tumors of the pancreas. This technique includes
selective arteriography of the proper or common
hepatic artery, the gastroduodenal, splenic, superior
mesenteric, and at times the dorsal pancreatic artery.
The arteriographic appearance of all islet cell tumors
is similar. It is not possible to distinguish a functioning
from a nonfunctioning tumor or one type of function-
ing tumor from another. The marked hypervascularity
and intense homogeneous staining permit the distinc-
tion of these types of tumors from other tumors such
as pancreatic adenocarcinoma (DOPPMAN et al. 1990)
(Fig. 11.4). Neovascularity and venous involvement
can often be demonstrated in larger lesions. The lower
limit of detectability of functioning islet cell tumors by
arteriography is 5 mm (GUNTHER et al. 1985).
11.6.2
Portal Venous Sampling
Portal venous sampling (PVS), also called pancreatic
venous sampling or transhepatic venous sampling,
involves catheterization of the portal vein using a

a b

Fig. 11.4a,b. Arteriography of a glucagonoma. aArteriogram demonstrates a large enhancing lesion in the tail of the pancreas
(arrows). The clinical picture and surgery proved the presence of a glucagonoma. SA, splenic artery. Same patient as Fig. 11.11 a.
b The venous phase of the same patient shows a persistent blush (arrows). SV, splenic vein; PV, portal vein (courtesy of Dr.
Ernie Ring, UCSF)
Endocrine Hyperfunctioning Tumors
transhepatic approach and is not an imaging study
(VINIK et al. 1990). The branches of the extrahepatic
portal venous system are selectively catheterized and
blood samples obtained. The hormone concentration
in each sample is plotted on a diagram of the portal
venous system. The sample with the highest concen-
tration comes from the vein that drains the area of the
tumor. The sensitivity of the procedure depends only
on hormone output by the tumor and not on the tumor
size (VINIK et al. 1991). An extrapancreatic location of
tumor such as seen in gastrinomas renders this test less
reliable for cure as the exact location of the tumor(s)
may not be established. This method requires thor-
ough knowledge of the anatomy of the portal venous
system. It also carries the disadvantages of being time
consuming, necessitating the administration of large
amounts of contrast material, exposure to a significant
radiation dose for patient and radiologist, and risk of
serious complications (MILLER et al. 1992).
11.6.3
Arterial Stimulation and Venous Sampling
For this method, the tumor is stimulated to secrete
hormones by a drug called secretagogue, and samples
are obtained from the right and left hepatic veins
(DOPPMAN et al. 1990; IMAMURA et al. 1989). This
technique is done in conjunction with pancreatic
arteriography. Venous samples are obtained at 0.5,
1, and 2 min after each injection of secretagogue.
If the hormone concentration increases twofold, the
arterial supply to the tumor can be identified and
therefore the region where the tumor is located. If the
hormone concentration increases after the drug has
been injected into the proper hepatic artery, the pres-
ence of hepatic metastases can be diagnosed. This
technique is easier to perform than PVS and can be
done at the same time as the arteriogram, thereby
avoiding an additional invasive procedure. Also, the
complication rate with this technique is lower than
with PVS. Today, this test is only used when morpho-
logic studies are negative (PEREIRA et al. 1998).
11.7
Features and Results of Imaging
Hyperfunctioning Endocrine Tumors
of the Pancreas
Among the islet cell tumors of the pancreas, insulin-
oma is the most common endocrine tumor, followed
185
by gastrinoma, glucagonoma, VIPoma, somatostati-
noma, and other rarely encountered secretory tumors
of the pancreas. In functioning adenomas, the clinical
data and laboratory tests often permit an accurate
clinical diagnosis, but in most cases, cross-sectional
imaging can localize the tumor in the pancreas.
Thus, radiography confirms a clinically suspected
lesion and can guide the surgeon to the appropriate
location for tumor resection. Localization by imaging
and treatment of patients with multiple endocrine
adenomatosis (MEA) or multiple endocrine neo-
plasia (MEN) are more difficult, and even venous
sampling does not always reveal the location of
additional tumors if the primary site is found in the
pancreas. In MEN, islet cell tumors may be ectopic in
location, such as in the duodenal or gastric wall, may
be multiple, and tend to be malignant. Many hyper-
functioning endocrine tumors of the pancreas may
be associated with MEN. MEN type I is an inherited
disease with an autosomal dominant trait and high
penetrance. It is a rare disease, and neoplasms involve
the pancreas, adrenal cortex, parathyroid, thyroid,
and pituitary glands. The symptomatology depends
on the organs involved.
11.7.1
Insulinoma
Insulinomas are generally small, measuring less than
2 cm in diameter. This is due to the fact than even
small tumors produce sufficient amounts of insulin to
cause symptomatic hypoglycemia. Larger lesions or
calcifications in the tumor mass suggest malignancy.
Most insulin om as are solitary lesions, and 90%-95%
are benign. In the rare instance of malignant degen-
eration of an insulinoma, the appearance of liver
metastases is similar to that of the primary tumor,
and this feature is shared by all hyperfunctioning islet
tumors. The likelihood of having multiple tumors in
the pancreas is significantly increased in patients
with MEN type I, and presentation at a young age
should suggest this syndrome. Patients with a spo-
radic insulinom a are predominantly women (60%)
and present in their fifth or sixth decade.
On CT, these hypervascular tumors appear as
brightly enhancing, round to oval masses that dem-
onstrate rapid washout on the portal venous phase
(Fig. 11.5). Over two-thirds are located to the left of
the superior mesenteric artery (HOWARD et al. 1990).
On MR imaging, islet cell tumors of the pancreas are
oflow signal intensity on Tl-weighted fat-suppressed
images and of high signal intensity on T2-weighted
 186 R. F. Thoeni

a b

Fig. ll.5a,b. CT of an insulinoma. a A 1.5 cm lesion is seen in the neck of the pancreas which reveals marked enhancement
(black arrows) in the arterial phase. Of incidental note is a lesion in the medial segment of the left hepatic lobe with some
peripheral enhancement (white arrow). b The portal venous phase demonstrates rapid washout of the lesion (black arrows).
The liver lesion (white arrow) now demonstrates features of a hemangioma

images (LIESSE et al. 1992; MOORE et al. 1995). Occa-
sionally, an insulinoma can be of dark signal intensity
on T2-weighted sequences due to the presence of
fibrous stroma (MORI et al. 1996) (Fig. 11.6a,b). This
was seen in 3 of 20 patients in our study (THOENI
et al. 2000). Some of the insulinomas show marked
enhancement with gadolinium throughout the lesion,
and some may demonstrate ring-like peripheral
enhancement (KRAUS and Ros 1994). The presence of
fibrous tissue diminishes the degree of enhancement
with gadolinium (Fig. 11.6c).
Transabdominal ultrasound and endoscopic
ultrasound visualize the islet cell tumor as a rela-
tively hypo echoic area compared with the adjacent
pancreas, with smooth and at times slightly irregular
margins that are well defined. Intraoperative ultra-
sound can be used to confirm lesions identified prior
to surgery and detect small lesions that eluded detec-
tion on other imaging studies. Octreotide studies
demonstrate a hyperfunctioning endocrine tumor as
a focal area of hyperactivity. On an arteriogram, insu-
linomas appear as a round, intensely staining tumor
without visible vessels and with smooth borders. This
appearance is seen in functioning and nonfunction-
ing tumors, and from the arteriogram it cannot be
predicted what hormones the tumor is secreting.
Neovascularity and portal vein invasion indicate that
the tumor is malignant.
Based on results available from the literature, the
sensitivity of nonhelical CT for determining the pres-
ence of an insulinoma ranges from 28% to 79%, with
a mean of 38% (PAVONE et al. 1993; ASPESTRAND et
al. 1993). Single-row helical CT and more recently
multirow helical CT have markedly improved the
detection of these small lesions compared with
conventional CT. This is due to faster scanning times
with earlier scan delays, super-thin slices and con-
centrated bolus techniques that demonstrate these
lesions well. This has been shown anecdotally in a
small series of patients, but presently no data in a
large group are available in the literature to prove
this point (VAN HOE et al. 1995; CHUNG et al. 1997;
KING et al. 1998). One of those studies demonstrated
a sensitivity of 82% (VAN HOE et al. 1995).
We collected a series of 20 patients with small
functioning adenomas which were missed by ultra-
sonography and CT but readily detected by Tl-
weighted fat-suppression sequences (THOENI et al.
2000). In our study, we achieved a MRI sensitivity of
85% for detecting functioning islet cell tumors of 2
cm or less in diameter, which is similar to the sensi-
tivity achieved by invasive procedures and is superior
to most of the MRI results reported in the literature.
Some MRI series reported a sensitivity of 100%,
but the number of patients examined was small
(SEMELKA et al. 1993). It is very likely that MRI would
detect lesions larger than 2 cm with a sensitivity of
greater than 85%. While the specificity and positive
predictive value of MRI in our study were excellent
(each 100%), the negative predictive value was only
73%. However, these values should be viewed with
caution, as the number of patients without tumors
(n=8) was relatively small in our series.
The superior MRI results in our study are based on
improved sequence design and better gradients and
coils which enable faster imaging sequences, higher
 Endocrine Hyperfunctioning Tumors 187

c _ __ ~

Fig.l1.6a-d. MR of an insulinoma. a Fat-suppressed Tl-weighted sequence demonstrates a low-signal intensity lesion (arrows)
in the body of the pancreas. ST, stomach (reprinted with permission from THOEN! et al. 2001). b The fast spin-echo sequence
demonstrates the same lesion as a low-signal intensity mass (arrows). The lack of bright signal is due to the fact that fibrous
stroma was present within the lesion. (Reprinted with permission from THOEN! et al. 2001). c Gadolinium-enhanced Tl-
weighted sequence demonstrates some enhancement (arrows) but not as pronounced as in Fig. ll.S due to the fibrous ele-
ments in the lesion. P, pancreas. d Insulinoma. The surgical specimen showed a well-defined lesion (arrows) in the body of the
pancreas. The patient has remained symptom-free since surgery

signal-to-noise ratios, and superior imaging of early
gadolinium enhancement. The fact that the two read-
ers agreed on the diagnosis in 82% of cases (K=0.61)
shows that the detection of hyperfunctioning endo-
crine tumors of the pancreas measuring <2 cm in
diameter is reliably achieved by MRI. Nevertheless,
errors in diagnosis occurred slightly more often with
the less experienced reader. It appears likely that MRI
results in these patients are superior when a seasoned
radiologist with special expertise in abdominal MR
imaging evaluates the images.
The sensitivity of transabdominal ultrasound for
detecting insulinomas has been reported to range
from 19% to 60%, with a mean of 46% (GUNTHER
et al. 1985; DOHERTY et al. 1991; MORI et al. 1996).
Endoscopic ultrasound provides excellent results
in the head of the pancreas (sensitivity 83%), but
poor evaluation of the tail of the pancreas (sensitiv-
ity 38%), because of its distance from the stomach
(SCHUMACHER et al. 1996). Therefore, it is of limited
use in this area. Another study that assessed the
use of the various imaging methods for detecting
insulinomas and gastrin om as found a sensitivity
of 90% for endoscopic ultrasound and insulinomas
(ZIMMER et al. 1995). This compares to a sensitivity
of only 20% for transabdominal ultrasound. For insu-
linomas, angiography is reported to reach a sensitiv-
ity between 59% and 80%, while venous sampling
reaches sensitivities between 77% and 94%, with
results slightly better for gastrinomas (GUNTHER et
al. 1985; DOHERTY et al. 1991; FRUCHT et al. 1989;
PISEGNA et al. 1993).
At the present time, insufficient data are available to
determine whether somatostatin-receptor localization
188
of islet cell tumors with l11In-octreotide scintigraphy
is a reliable method. Accurate numbers for hyper-
functioning endocrine tumors of the pancreas are
difficult to obtain from the various published studies
on radiolabeled somatostatin analogue scintigraphy.
These reports usually investigate the sensitivity of this
method in a wide variety of neuroendocrine tumors
including carcinoid, medullary carcinoma of the
thyroid gland, small-cell lung cancer, and neuroblas-
tomas. Preliminary data in 24 patients with biologic
and/or histologic evidence of a neuroendocrine tumor
showed that lllIn-octreotide scintigraphy was positive
in 23, but prospective surgical proof could be obtained
in only 8 of these patients (CORLETO et al. 1996). In
another study of 28 patients with carcinoid and islet
cell tumors, 22 of 28 were positive, and 3 were negative
(KVOLS et al. 1993). False-positive and false-negative
results have been reported with this method (WESTLIN
et al. 1993; ZIMMER et al. 1995). In one study that listed
results for the various types of neuroendocrine tumors
separately, the sensitivity of somatostatin-receptor
scintigraphy for insulinomas was only 10% (ZIMMER
et al. 1995).
Therefore, at present it appears that multirow heli-
cal CT and MRI are the best techniques for diagnos-
ing small pancreatic insulinom as, but optimal CT
and MRI techniques and state-of-the-art equipment
need to be used. In cases where CT, MRI, and EUS fail
to demonstrate a lesion, radio labeled somatostatin
analogue scintigraphy or arteriography could be
used to localize a lesion. However, for insulinomas,
somatostatin-receptor scintigraphy has not proven
to be sufficiently reliable. Arteriography and venous
sampling are infrequently used today because of the
invasiveness, the long procedure time, the special
expertise needed for performance, and the higher
cost of these tests. It is advisable to use intraopera-
tive ultrasound at the time of surgical resection (Fig.
11.6d) for the confirmation of lesions in patients with
a strong clinical suspicion and negative results from
cross-sectional images and scintigraphy and/or to
find additional tumors. Intraoperative ultrasound
is particularly important in patients with multiple
lesions and MEN as under these conditions, ectopic
tumors that may be multiple are quite frequent and
difficult to find with CT or MRI.
11.7.2
Gastrinoma
Gastrinomas are usually larger than insulin omas (~.2
cm), multiple in 60%, malignant in 60%-65%, and
R. F. Thoeni
associated with MEN type I in 20%-60%. Approxi-
mately 50% of patients with gastrinom a have metas-
tases at the time of diagnosis. Most of these tumors
are found in the so-called gastrin om a triangle
formed medially by the junction of head and neck of
the pancreas, inferiorly by the second and third por-
tion of the duodenum, and superiorly by the junction
of the cystic duct and the common bile duct. These
tumors are slow growing and have a better prognosis
than pancreatic adenocarcinoma.
Gastrinomas are hypervascular tumors that are
best visualized with thin sections (FRUCHT et al.
1989; TJON et al. 1989) and a dual-phase CT protocol
using an arterial and portal venous phase (PISEGNA
et al. 1993) similar to the technique used for insuli-
nomas. Most studies addressed the use of nonhelical
CT with a mean of over 38% for gastrinomas (ROSSI
et al. 1989). Because of their larger size, helical CT
generally readily detects gastrinomas. However, ecto-
pic locations are more challenging. Metastases to the
liver tend to have a similar appearance to the primary
tumor (DEBRAY et al. 2001) (Fig. 11.7). For gastrino-
mas, some reports have shown MRI sensitivities of
20%-62% (PISEGNA 1993; FRucHT et al.1989; TJON et
al. 1989). In one study, somatostatin-receptor scintig-
raphy showed a sensitivity of 100% for gastrinomas
(ZIMMER et al. 1995), whereas EUS was 90%, and CT,
MRI, and transabdominal US combined were only
30%. The scintigraphic sensitivity for gastrinomas
was much higher than that for insulinomas (see
above). Scintigraphy was also useful in distinguish-
ing hyperfunctioning endocrine tumors metastatic
to the liver from hepatic hemangiomas, with an accu-
racy of 96% (TERMANINI et al. 1997). Overall, EUS
was shown to be cost -effective when compared with a
control group employing venous sampling (BANSAL
et al. 1999). Results with angiography vary greatly. In
some studies, arteriography in patients with gastri-
nomas was reported to achieve a sensitivity of about
65% (FRUCHT et al. 1989; WISE et al. 1989). At the
NIH, 86% of gastrinomas were correctly identified
with angiography, with a specificity of 100% (MATON
et al. 1987) (Fig. 11.8), but a later study of patients suf-
fering from gastrin om as without and with metastases
revealed a sensitivity of only 41 % (GIBRIL et al. 1996).
In the same study, the sensitivity for CT and US was
64% and for MR and angiography, 77% (GIBRIL et al.
1996). In Maton's study (MATON et al. 1987), angiog-
raphy for extrahepatic gastrinomas had a specificity
of 94% and a sensitivity of 68%, a positive predictive
value of 97%, and a negative predictive value of 53%.
Comparison of CT and angiography revealed that
for hepatic metastases, CT demonstrated 72% and
 Endocrine Hyperfunctioning Tumors 189

a b

Fig. 1l.7a,b. CT of a gastrinoma. a A large enhancing lesion (white arrows) is seen in the head and body of the pancreas. The
common bile duct (CB) is dilated. Multiple liver metastases (black arrows) were present at the time of diagnosis. b In the portal
venous phase, the enhancement pattern of the hepatic metastases (arrows) changes. While in the arterial phase the entire lesion
opacifies, more enhancement is present in the periphery. In the portal venous phase, a reversal has occurred that is typical for
hypervascular metastases to the liver. SP, spleen

a _ _ _ _ _--';;:: b

Fig. 11.8a,b. Angiogram of a gastrinoma. a Arteriogram shows a large enhancing lesion (arrows) in the head of the pancreas
artery (courtesy of Dr. Ernie Ring, UCSF). b The venous phase demonstrates a persistent blush (arrows) in the area of the
pancreatic mass artery (courtesy of Dr. Ernie Ring, UCSF). SP, spleen

angiography 89% of tumors, and the combination of
the two techniques detected all tumors with no false-
positive results.
From the available data on imaging of gastrino-
mas, it again appears that CT or MRI (Fig. 11.9) and
endoscopic ultrasound are the primary imaging
modalities. Both CT and MRI have the advantage of
staging the entire abdomen and pelvis, which is not
possible with the limited depth penetration of endo-
scopic ultrasound. In equivocal or negative cases
with a high clinical suspicion, somatostatin-receptor
scintigraphy is very effective in assessing the primary
tumor in the pancreas or ectopic sites (Fig. 11.3) and
metastatic lesions to the liver. Based on the improved
results with cross-sectional imaging and scintigra-
phy, invasive techniques are not currently recom-
mended for this purpose.
11.7.3
VIPoma
The tumor is usually larger than 3 cm in diameter
and malignant in 60% or more (KLOPPEL and HEITZ
1988; ROTHMUND et al. 1991; JAFFE 1987). Over two-
thirds of the tumors are located in the body and tail
of the pancreas (JAFFE 1987). Occasionally, tumors
producing the same symptomatology are located
 190 R. F. Thoeni

a b

Fig. 11.9a,b. MRI of a gastrinoma. a On a Tl-weighted sequence, a large mass oflow-signal intensity (arrows) is seen in the head of
the pancreas. b A fat-suppressed T2-weighted sequence demonstrates the same lesion with high signal intensity (arrows). L, liver

in the adrenal gland, retroperitoneum, sympathetic
chain, lung, and intestinal carcinoids (KLOPPEL and
HEITZ 1988; JAFFE 1987). Rarely, these tumors are
associated with MEN type I (KREJS 1987).
Related to the fact that VIPomas are quite rare, sta-
tistical data on the use of imaging are not available.
Case reports or series with all types of hyperfunc-
tioning endocrine tumors mixed together have been
published. CT, MR, angiography, and somatostatin-
receptor scintigraphy have been used to localize the
primary lesion and to identify metastases (SOFKA
et al. 1997; MORTELE et al. 2001; THOMASON et al.
2000). On MRI, metastatic lesions to the liver may
show intense peripheral enhancement similar to the
appearance of primary and metastatic lesions on CT
(Fig. 11.10). A combination of CT or MRI with soma-
tostatin-receptor scintigraphy currently appears to
be the most effective presurgical assessment.
11.7.4
Glucagonoma
Glucagonomas are intrapancreatic and mostly occur
in the head and neck of the pancreas. The tumor
occurs slightly more often in women and is seen at
a mean age of 55 years (BLOOM and POLAK 1987). In
rare instances, the tumor can cause obstructive pan-
creatitis (PECH et al. 2000). The tumor is malignant
in about 60%, and the 5-year survival is 50%. When

a b

Fig. 11.10a,b. CT of a VIPoma. a In the arterial phase, a markedly enhancing mass (white arrows) is present in the head of the
pancreas. Multiple liver metastases (black arrows) with a pattern similar to the primary tumor are also seen. b The portal venous
phase at a slightly higher level demonstrates that the mass also involves the body of the pancreas (white arrows). The washout
effect is similar for the pancreatic lesion and the hepatic metastases (black arrows)
 Endocrine Hyperfunctioning Tumors
the tumor becomes symptomatic, its size usually
exceeds 5 cm, it is invasive and has metastasized
to the regional lymph nodes (Fig. 11.1 1). Tumors
measuring 3 cm or less are often seen as incidental
findings.
CT, MR, angiography, EUS, and F-18-fluorodeoxy-
glucose positron emission tomography (PET) have
been used with success, but all reports included only
anecdotal references to this type of tumor, largely
due to its rarity (SOLIVETTI et al. 2001; PHAN et al.
1998; ANDERSON et al. 2000; FERNANDEZ-REPRESA
et al. 2000; NISHIGUCHI et al. 2001). PET has been
used more recently as a reliable tool to localize the
primary pancreatic mass and its metastases to the
liver (FERNANDEZ-REPRESA et al. 2000; NISHIGU-
CHI et al. 2001). Somatostatin analogue (octreotide)
a (2-1O cm in diameter), and 75% occur in the head of
Fig. 11.11a,b. CT of a metastatic glucagonoma. a The patient is
status postresection of a glucagonoma in the tail and body of
the pancreas as demonstrated by the surgical clips (large white
arrow). Metastases to the liver (small white arrow) and a lymph
node (black arrow) are present. Note the dilation of the con-
trast -filled jejunal loops (arrowheads) that is due to excessive
glucagon in the circulation. b At a lower level, retroperitoneal
lymphadenopathy (black arrows) and multiple, dilated small-
bowel loops (arrowheads) without wall thickening are evident
191
imaging serves as an adjuvant to conventional imag-
ing (JOHNSON et al. 2000). Current therapeutic appli-
cations of octreotide focus on stabilization of the
disease in tumors expressing somatostatin receptors,
and tumor destruction using beta-emitting isotopes.
11.7.5
Somatostatinoma
Somatostatinomas are usually solitary lesions and
tend to be aggressive, with over 70% presenting
with metastases, particularly if the primary tumor is
larger than 2 cm (GOWER and FABRI 1990; TANAKA
et al. 2000) (Fig. 11.12). This tumor is usually located
within the pancreas, but it may also arise from the
small bowel, the duodenal ampulla, or periampullary
mucosa. In men, the tumor is more frequently seen
in the duodenum, and in women more often in the
pancreas (PATEL et al. 1983). When the small bowel
is involved, the neoplasm is usually a carcinoid that
consists almost completely of somatostatin-contain-
ing cells but produces little somatostatin. If the neo-
plasm is outside the pancreas, it tends to be smaller
(0.5-4 cm). This is probably related to the fact that
it produces symptoms such as jaundice, bleeding,
and ulceration and therefore is discovered early. The
tumor occurs in the fourth to sixth decades of life,
and the prognosis is poor, with an average survival
time of only 1-2 years. The tumor tends to be large
the pancreas (HOWARD et al. 1990).
Fig. 11.12. CT of a somatostatinoma. A very large, enhanc-
ing mass with areas of necrosis is demonstrated (large white
arrows) that involves most of the pancreas. Encasement of the
splenic artery (small white arrows) is also seen. An enhancing
liver metastasis (black arrows) is noted in this female patient
with a very aggressive lesion
192
The radiologic features of somatostatinomas
resemble those of other neuroendocrine tumors.
EUS, CT, MRI, angiography, and somatostatin-recep-
tor imaging have been used (ANDERSON et al. 2000;
SEMELKA et al. 2000; TJON et al. 1994; SCHILLACI et
al. 1997). All studies reported only a few cases or
included somatostatinomas in their series of neu-
roendocrine tumors. Lesions in the pancreas and
liver are usually well shown. However, radiological
techniques often fail to demonstrate tumors in the
duodenum but may show obstruction of pancreatic
or biliary ducts as indirect evidence. The diagnosis
in cases of duodenal localization can be established
by endoscopic techniques including biopsy (Guo et
al. 2001).
11.7.6
Other Hyperfunctioning Endocrine Tumors
There are some other hyperfunctioning endocrine
tumors of the pancreas worth mentioning that pro-
duce an endocrine syndrome, but they are very rare.
For each of them, no more than about 20 cases have
ever been reported. Nonfunctioning endocrine tumors
belong to the group of islet cell tumors of the pancreas
that are clinically not associated with a specific endo-
crine syndrome. Some of them have been reported
to be positive on immunohistochemistry for various
ectopic hormones (VUOLTEENAHO et al. 1990). These
tumors will be discussed in another chapter.
Corticotropinoma may secrete several different
hormones. ACTH-producing pancreatic islet cell
tumors are found in 4%-16% of patients with ecto-
pic ACTH syndrome. Corticotropinoma may also
secrete melanocyte-stimulating hormone (MSH),
corticotropin-releasing hormone (CRH), gastrin, or
insulin (FRIESEN 1982). ACTHomas must be distin-
guished from MEN type I that consists of an islet cell
tumor and an ACTH-secreting pituitary adenoma.
Corticotropin om as are large, malignant, and invari-
ably present with metastases at the time of the initial
diagnosis (DOPPMAN et al. 1989) (Fig.lLl3).
GRFoma secretes a growth hormone-releasing
factor, and patients with this tumor may develop
acromegaly (RIVIER et al. 1982; THORNER et al. 1982;
BERGER et al. 1984) (Table 12.1). Similar to corti-
cotropinoma, this tumor is large (>6 em) and has
metastasized at the time of diagnosis in over 30%
(JENSEN and NORTON 1991; SOLCIA et al. 1990). In
33% of these patients, MEN type I is present (TAKA-
HASHI et al. 1988), and 40% also have Zollinger-Elli-
son syndrome (see gastrinoma above).
R. F. Thoeni
Very rarely, a parathyrinoma may be present in
patients with an islet cell tumor and hypercalcemia,
but usually these patients have MEN type I with a
parathyroid adenoma. Parathyrinomas secrete a
parathyroid hormone (PTH)-like protein (KLOPPEL
and HEITZ 1988; FRIESEN 1982; BRESSLER et al. 1991).
The pancreatic tumor is almost always metastatic to
the liver at the time of diagnosis. Only 3 cases have
been reported so far (SOLCIA et al. 1990).
Some endocrine tumors of the pancreas can
secrete serotonin and produce the typical features
of a carcinoid tumor. These tumors may be benign
or have features of a carcinoma with poorly differ-
entiated cells. Over 50% of patients with this tumor
present with the carcinoid syndrome, but it is often
atypical. Patients tend to suffer from severer flash-
ing, hypotension, periorbital edema, and increased
lacrimation (FRIESEN 1982). Liver metastases do not
need to be present for the syndrome to occur. Nev-
ertheless, almost 90% of patients with the syndrome
have liver metastases (SOLCIA et al. 1990). Small
tumors are likely to be homogeneous and hypervas-
cular, whereas larger tumors are heterogeneous and
hypovascular, with areas of cystic degeneration and
necrosis (DAHAN et al. 2001).
Like all the other hyperfunctioning endocrine
tumors, these rare tumors demonstrate the features of
a hypervascular mass without or with metastases. CT
and MRI are used initially. EUS can be used for the pri-
mary tumor but cannot assess the frequent presence of
liver metastases. PET and somatostatin-receptor imag-
ing are also useful. Angiography and venous sampling
are rarely employed today for these rare lesions.
Fig. 11.13. CT of an ACTHoma. A very large, heterogeneously
enhancing mass (white arrows) is seen in the pancreas. The
biliary ducts (white arrowheads) are dilated due to compres-
sion by the pancreatic mass. Diffuse metastatic disease (black
arrows) is shown in the liver
Endocrine Hyperfunctioning Tumors
11.8
Role of Imaging for Hyperfunctioning
Endocrine Tumors
Hyperfunctioning endocrine tumors of the pancreas
represent a challenge to the radiologist. Earlier reports
have shown that up to 27% of patients have tumors not
detected preoperatively. Helical CT and MR with fast
imaging and short breathhold techniques have mark-
edly improved the preoperative results. Endoscopic
ultrasound often achieves sensitivities that approach
90%-95%, but lesions in the tail of the pancreas are
less well seen, and complete assessment of metastatic
disease cannot be achieved with this technique. Extra-
pancreatic islet cell tumors that are small and located
in the duodenal wall or other ectopic locations are
the tumors least likely to be detected preoperatively
by any of the radiographic techniques, and even
intraoperative ultrasonography fails to detect some
of these lesions. Overall, arteriography and venous
sampling are infrequently used today, even for these
difficult cases, because of the inherent technical
problems associated with the test and the higher cost.
More recently, somatostatin-receptor scintigraphy
and PET have been used to establish or confirm the
presence of ectopic lesions or small masses that were
only suspected on CT or MRI and to improve results
in assessing metastatic disease. However, while soma-
tostatin-receptor scintigraphy is superb in evaluating
patients with gastrinomas, it is not sensitive in patients
with insulinomas. Except in patients with insulinomas,
these two low-resolution techniques should be used as
adjuvant to the other imaging techniques. A combi-
nation of intraoperative palpation and intraoperative
ultrasonography was found to achieve the best results
due to the complementary nature of these two tech-
niques during surgery. Somatostatin-receptor tech-
niques can be used to treat and monitor the success
of treatment in patients with hyperfunctioning tumors
of the pancreas (UGUR et al. 2002).
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12 Nonhyperfunctioning Endocrine Tumors
C. PROCACCI, M. FERDEGHINI, A. GUARISE, s. VASORI, D. COSER, and M. FERRARI
CONTENTS
12.1 Introduction 197
12.2 Imaging 197
12.2.1 Transabdominal Ultrasound 197
12.2.2 Computed Tomography 199
12.2.3 Magnetic Resonance Imaging 206
12.2.4 Nuclear Medicine 209
12.3 Differential Diagnosis 213
12.4 Diagnostic Strategy 214
References 214
12.1
Introduction
Endocrine tumors of the pancreas are easily distin-
guishable from other pancreatic neoplasms when
specific clinical syndromes related to hypersecre-
tion of gastroenteropancreatic pep tides are present
(KITAJIMA et al. 1998). Imaging can identify the
single or multiple lesions that produce these clinical
findings. Unfortunately, this is not always possible
because of the small dimensions and the frequent
extrapancreatic location of the lesions. Sometimes
endocrine tumors can produce peptides but not in
sufficient amounts to result in a specific clinical syn-
drome. These lesions are called nonhyperfunction-
ing endocrine tumors (NHFET). From a pathological
point of view, these tumors are indistinguishable from
hyperfunctioning ones. Their size is usually larger
because of the delay in the diagnosis (KITAJIMA et al.
1998). For the same reason, signs of malignancy, such
C. PROCACCI, MD; M. FERDEGHINI, MD; S. VASORI, MD;
D. COSER, MD; M. FERRARI, MD
Istituto di Radiologia, Dipartimento di Scienze Morfologico-
Biomediche, Universita degli Studi di Verona, Policlinico
'Giambattista Rossi', P.zza L.A. Scuro 10,37134 Verona, Italy
A. GUARISE, MD
Servizio di Radiologia, Ospedale S. Cuore-Don Calabria, Via D.
Sempreboni, 37024 Negrar, Italy
as loco regional infiltration and/or distant metastases,
are more common at presentation.
The radiologist's task when faced with these
lesions is to avoid a misdiagnosis of ductal adeno-
carcinoma and, if possible, to suggest a NHFET. A
correct diagnosis influences the therapeutic strategy
and prognosis, which are significantly different from
those of ductal adenocarcinoma and other pancre-
atic neoplasms. Moreover, imaging must determine
whether it is resectable or not, by visualizing signs
such as vascular invasion and hepatic metastases. In
these cases, the alternative to surgery is chemother-
apyor treatment with somatostatin analogues.
12.2
Imaging
12.2.1
Transabdominal Ultrasound
Until recently, the characterization of endocrine
tumors with ultrasound (US) was limited due to its
inability to detect the hypervascularization of the
lesion, a decisive parameter. Recently, new contrast
agents, consisting of microbubbles (i.e. Sonovue,
Bracco, Milan, Italy) allow for dynamic studies by
US of pancreatic masses during contrast medium
administration. The early and intense enhance-
ment and the slow washout from hypervascularized
tumors can be documented by monitoring the mass
(Fig. 12.1). US findings are completely in agreement
with those of CT. OSHIKAWA et al. (2002) have recently
reported the value of dynamic US using pulse-inver-
sion harmonic imaging after the administration of
Levovist (D-Galactose, Schering-Berlin, Germany) in
the characterization of pancreatic tumors, including
three cases of endocrine tumors. In all three masses,
the contrast-enhanced US examination correlated well
with the spiral CT findings, showing a strong enhance-
ment in two cases and a moderate enhancement in one
(OSHIKAWA et al. 2002). Our initial evaluation of con-
 198 C. Procacci et al.

a b

c d

Fig. l2.la-d. Contrast-enhanced ultrasound (CEUS) of nonhyperfunctioning endocrine tumor (NHFET). a Unenhanced base-
line US shows a large, sharply outlined, inhomogeneous, hypoechoic mass at the pancreatic head with small internal lamellar
calcifications (arrow). The pancreatic gland appears atrophic upstream with dilatation of the main pancreatic duct (arrowheads).
b Enhanced US after microbubble injection in the arterial phase shows an intense enhancement of the lesion, appearing inhomo-
geneously hyperechoic due to the presence of small internal necrotic areas (arrows). c Enhanced US in the venous phase seconds
after contrast medium injection shows the persistent enhancement of the pancreatic mass. d Persistent weak enhancement of
the lesion in the delayed phase because of contrast medium microbubble 'stagnation' in the tumor circulation is seen

trast-enhanced ultrasound (CEUS) agrees with what
others have said, that the contrast seems to have great
potential. In fact, we have been able to identify and
characterize all the tumors, making a correct evalu-
ation of the locoregional diffusion and the hepatic
metastases at the same time. CEUS increases the
diagnostic specificity but not the sensitivity because
contrast medium administration currently is only
performed if the lesion has already been identified
during a basic ultrasound examination (FURUKAWA
et al. 1998). However, should the sensitivity of CEUS
become analogous to that of the other techniques, it
could be performed when the basic study is negative
in order to identify even the smallest lesions.
A small NHFET, which is quite rare, appears as a
well-circumscribed nodule embedded in the pancre-
atic gland and is clearly hypoechoic when compared
with the normal tissue (Fig. 12.2a). This feature is also
common to hyperfunctioning tumors (FUGAZZOLA et
al. 1990; FURUKAWA et al. 1998). The tumor can rarely
appear isoechoic compared to the normal gland. This
can occur in younger subjects, where the normal
gland is typically less echoic (Fig. 12.3). Occasionally,
the tumor can have a sonolucent appearance with
enhanced posterior wall reflections when it contains
fluid (KATO et al.2000).MostNHFETarelarge (Fig.12.1)
at presentation. The mass has a well-defined, multilob-
ulated border, with compression of the adjacent struc-
tures (digestive tract, vessels, etc.). Necrosis and hem-
orrhage appear as central hypoechoic areas (Fig. 12.4)
(FUGAZZOLA et al. 1990; FURUKAWA et al. 1998). The
lesion grows by expanding rather than encasing, and
therefore the common bile duct and main pancreatic
duct are frequently normal. Encasement of the arterial
vessels, thrombosis, or neoplastic involvement of the
portal venous system may be present in association
with large masses. Peritumoral lymphadenopathy is
rare, while metastatic disease in the liver occurs in
30% of cases (OGAWA et al. 2000). The US appearance
of the liver metastases is variable. Hyperechoic nodules
or 'target-like' appearances strongly suggest the endo-
crine nature of the primary tumor. In other cases, they
show a nonspecific hypo echoic pattern (FUGAZZOLA
et al.I990).
 Nonhyperfunctioning Endocrine Tumors 199

a b

Fig. 12.2a,b. Small NHFET, US evaluation. a Unenhanced US shows a well-outlined, small, hypoechoic lesion (circled) in the
pancreatic body. b Axial CT scan in arterial phase after contrast medium administration confirms the small hyperdense lesion
(circled) in the pancreatic body

12.2.2
Computed Tomography

The contribution of CT in identifying and char-

Fig. 12.3. US of small NHFET in a young patient. Basic US
shows a well-outlined lesion in the pancreatic head (arrow),
displaying slight difference in echogenicity with respect to the
normal parenchyma
acterizing NHFET is almost always decisive, when
the properly timed spiral or multi slice scanners are
used. The short scanning time optimizes the dynamic
study of the pancreas after iodinated contrast mate-
rial administration and results in demonstration of
the typical enhancement of these tumors (BUETOW et
al. 1997; STAFFORD-JOHNSON et al.1998; ICHIKAWA et
al. 2000; ZEMAN et al. 1995; PROCACCI et al. 2001).
Larger tumors that distort the morphology of the
gland can be demonstrated before contrast medium
administration (Figs. 12.5a, 12.6a, 12.7a) (MURASE et
al. 2000). The mass usually develops along the major
axis of the gland (Figs. 12.5a, 12.6a); less frequently,
it has a rounded morphology and radial growth
(Fig. 12.7a). Sometimes dilation of the main duct and
atrophy of the parenchyma can be seen upstream of

a b

Fig. 12.4a,b. Color-Doppler US of NHFET. a Unenhanced US shows a large, hypoechoic mass in the pancreatic body with a
central, small, anechoic area (arrow). b Color-Doppler baseline US with pulse repetition frequency set at low flow of the lesion
demonstrates vessels within the lesion
 200 C. Procacci et al.

a b

c d

Fig. 12.Sa-d. NHFET, CT evaluation. a Before iodinated contrast medium administration, the pancreatic neck appears larger in
volume compared with the remaining pancreatic parenchyma. The gastric antrum (asterisk) is displaced by the neoplasm. The
main duct is considerably dilated upstream (arrows). b, c During the pancreatic phase of contrast enhancement, the hyper-
vascularized tumor is visible, showing the same density as the renal cortex. There are hypodense necrotic gaps (black arrow)
within it. The gland is atrophic in the body-tail; the dilation of the main duct is more evident in this phase (arrows). A small
hyperdense metastasis (arrowhead) is evident in the right liver lobe (c). d In the venous phase, both the tumor and the liver
metastasis are almost isodense with the liver parenchyma

the lesion (Fig. Sa). Globular or lamellar calcifications
may be present (Fig. 12.7a). The latter are more likely
to be found on the edge of a necrotic or cystic area
(FVGAZZOLA et al.1990). The stomach and duodenum
may appear compressed by the tumor (Fig. 12.5a),
but frank invasion into adjacent viscera is rare.
Enlargement of the liver, with irregular contours, sig-
nals diffuse metastatic involvement (Fig. 12.8a). The
lesions are slightly hypo dense, compared with the
normal parenchyma (Fig. 12.7a), appearing hyper-
dense only in fatty liver (Fig. 12.8a). Calcifications are
often present.
There are controversial opinions in the literature
about the best dynamic phase, since some authors
(STAFFORD-JOHNSON et al. 1998; HOLLETT et al.
1995) claim that they obtain the highest enhance-
ment of the pancreatic gland, and therefore of the
tumor, during the early arterial phase (20-25 s scan
delay). According to others (Lv et al. 1996), the pan-
creatic phase (40-60 s scan delay) is more appropri-
ate to show the vascularization of the lesion. However,
the majority of authors confirm that a preliminary
examination before contrast administration and a
dual-phase acquisition (arterial or pancreatic and
venous) during the dynamic study are needed (VAN
HOE et al. 1995; ICHIKAWA et al. 2000; STAFFORD-
JOHNSON et al. 1998).
In the pancreatic phase, which is our personal
preference, the hypervascularized tumor shows
intense enhancement, similar to that of the spleen
or the renal cortex, definitely greater than that of the
liver parenchyma (Figs. 12.5b,c, 12.6b,c, 12.7b, 12.8c,d,
12.9,12.10,12.11, 12.12a,b, 12.13a,b). The lesion is also
denser than the pancreatic parenchyma, especially if
obstruction of the main duct has resulted in chronic
obstructive pancreatitis upstream of the lesion. In
 Nonhyperfunctioning Endocrine Tumors 201

a b

Fig. 12.6a-c. Typical NHFET, CT evaluation. a Before contrast

enhancement, the body of the pancreas has a slightly globular
appearance with convex posterior margins. A small, irregular,
hyperdense hepatic lesion is recognizable. b, c During the pan-
creatic phase following IV contrast administration, the tumor
is confirmed developing along the major axis of the pancreas.
It displays a slightly higher enhancement to the adjacent
parenchyma. The tumor displaces the splenic vessels. Metas-
c tasis shows the same density as the primary tumor

a b

Fig. 12.7a,b. NHFET with peripheral calcifications, CT evaluation. a Unenhanced scan shows small calcifications (arrow) along
the edge of the round mass in the tail of the pancreas. In the right hepatic lobe, there is a large, hypodense tumor. b During the
pancreatic phase, intense and inhomogeneous enhancement of the pancreatic mass is evident. The hepatic mass shows intense
and inhomogeneous enhancement, confirming its metastatic nature. Rich collateral networks are due to the compression of
the splenic vein by the mass
 202 C. Procacci et al.

a b

c d

Fig. 12.8a-d. NHFET with diffuse metastatic involvement of the liver, CT evaluation. a Unenhanced scan reveals an increase
in liver volume from the presence of metastases. These appear slightly hyperdense due to the fatty liver. b In the pancreatic
phase, the multiple metastases show marginal enhancement with large, central, necrotic areas. c, d In the same pancreatic phase,
the primary tumor at the head of the pancreas shows inhomogeneous enhancement; the superior mesenteric vein (arrow) is
embedded by the tumor

a b

Fig. 12.9a,b. NHFET with mixed appearance, CT evaluation. a In the pancreatic phase, the mass of the head of the pancreas
shows homogeneous and intense enhancement. b In the same phase, a hypo dense cystic component can be seen in the inferior
portion of the mass
 Nonhyperfunctioning Endocrine Tumors 203

a b

Fig. 12.10a,b. NHFET with vascular encasement, CT evaluation. a In the pancreatic phase, the large mass of the head and body
of the pancreas appears hyperdense. The obstruction of the hepatic artery (long arrow) and the encasement of the splenic
artery (arrowheads) are evident. b The occlusion of the splenic vein is demonstrated indirectly by the rich collateral network
(arrowheads) through the gastroepiploic veins

a b

Fig. 12.11a,b. NHFET with vascular encasement, CT evaluation. In the pancreatic phase, the large, inhomogeneously hyperdense
mass originating from the pancreatic body obstructs and obliterates the splenic vein, with resulting large collateral network
(arrows). The tumor displaces the stomach

this phase, necrotic areas or cystic degeneration,
if present, are characterized by clear hypodensity
compared with the hypervascularized neoplastic
tissue (Figs. 12.5b,c, 12.7b, 12.9b, 12.11, 12.12b). Due
to the intense enhancement of the tumor, its contours
and real dimensions are defined (CHUNG et al.1997).
At the same time, the tumor's relationship with the
adjacent vascular structures are better depicted. The
expansive growth and the considerable size of the
tumor account for the compression of the vascular
structures (Figs. 12.6b,c, 12.7b). Due to the unpredict-
able growth of the tumor, some arterial vessels, like
the superior mesenteric artery or the celiac axis, can
be encased within the neoplastic mass (Fig. 12.10).
The encasement (STAFFORD-JOHNSON et al. 1998) is
better recognizable in the three-dimensional recon-
struction of the peripancreatic vessels (CHUNG et
al. 1997). A rich collateral venous network bypasses
the obstructed or thrombosed peripancreatic veins
(Figs. 12.10b, 12.11). Neoplastic invasion into the
 204 C. Procacci et al.

a b

c d

Fig. l2.l2a-d. Typical NHFET with metastasis, CT evaluation. a, b In the pancreatic phase, the primary pancreatic tumor
and the liver metastasis show intense and inhomogeneous enhancement. Central necrotic areas are present in both lesions.
c, d During the venous phase, the lesions have 'washed out'. The presence of hypodense central necrotic gaps can be better
appreciated (asterisk in d). The tumor causes obstruction of the main duct, which is dilated at the body-tail (arrows); despite
the considerable size, the primary tumor has well-defined margins, only displacing the stomach and the superior mesenteric
artery (arrowhead in a and b)

spleno-mesenteric-portal tree is seldom found.
When present, the neoplastic thrombus has the same
density as the mass from which it derives, so it dis-
plays a slightly lower density than the vascular lumen
(Fig. 12.13a,b).
In the pancreatic phase, the hepatic metasta-
ses have the same density as the primary tumor
(STAFFORD-JOHNSON et al. 1998; DEBRAY et al. 2001)
(Figs. 12.7b, 12.12a,b). The homogeneous or inho-
mogeneous (target-like metastases) hyperdensity is
even more evident because of the low density of the
hepatic parenchyma (Fig. 12.8b).
The previously described features, essential for the
diagnosis of NHFET, are present in 70% of patients
(FUGAZZOLA et al. 1990; PROCACCI et al. 2001). In the
other 30%, the pattern is nonspecific (Fig. 12.14) or
similar to that of ductal adenocarcinoma (Fig. 12.15a)
(VAN HOE et al. 1995; KEOGAN et al. 1997) since the
tumor is clearly hypo dense compared with the spleen
or the renal cortex. When the mass is large and well-
circumscribed, a ductal adenocarcinoma can be
excluded, but the problem of differential diagnosis
from other rare solid tumors still remains. Small
tumors, especially those with infiltrating growth,
mimic ductal adenocarcinoma. The liver metastases
show in virtually all cases the same enhancement as
the primary tumor (Fig. 12.15), also similar to ductal
adenocarcinoma.
 Nonhyperfunctioning Endocrine Tumors 205

a b

c d

Fig. 12. 13a-d. NHFET with tumor thrombus in the portal vein, CT evaluation. a, b In the pancreatic phase, the portal mesenteric
axis is filled with a large neoplastic thrombus (arrowheads), which is in continuity with the primary tumor of the pancreatic
body (asterisk). c, d In the venous phase, both the neoplastic thrombus and the tumor have the same density

. .'

•.
( . '1

4 1
••. ~
..
.~ '.'

.: .

·~. ~·~~I
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l40
'l:;J
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a O.7~ b

Fig. 12.14a,b. Atypical NHFET, CT evaluation. In the pancreatic phase the normal parenchyma of the head (asterisk) appears
hyperdense compared with the tumor located at the uncinate process. The superior mesenteric vein (long arrow) is imprinted
and displaced

In the venous phase, there is a quick washout from
the hypervascularized tumor, whose density is anal-
ogous to that of the normal pancreatic parenchyma
(Figs. 12.5d, 12.12d, 12.13c,d). Possible calcifications,
necrotic or cystic areas are recognizable in the mass
(Fig. 12.12d). Some investigators reported that endo-
crine tumors, appearing as iso-attenuated in pan-
creatic phase CT images, are sometimes detected in
the portal venous phase (VAN HOE et al. 1995). The
late enhancement of the tumor is common when the
206
a b
Fig. 12.1Sa,b. Atypical NHFET, CT evaluation. The mass in the tail of the pancreas remains hypodense in both the pancreatic
(a) and late (b) phases. This enhancement pattern is indistinguishable from ductal adenocarcinoma. The multiple hepatic
metastases show the same low enhancement
extensive necrosis results in a slower washout from
the mass, due to the reduced vascularization (KoITO
et al. 1997).
In the venous phase, the tumor's contour and its
relationship with the surrounding arteries are less
conspicuous, due to the rapid washout of contrast
from the mass. During this phase, the relationship with
the peripancreatic veins can be accurately evaluated
because the tumor thrombus is optimally displayed
(Fig. 12.13c,d). The collateral network is also easily rec-
ognizable. The venous phase is less sensitive in depict-
ing the typically hypervascular hepatic metastases, as
they become isodense or hypodense compared with
the hepatic parenchyma (Fig. 12.12c,d). Sometimes
only the larger lesions that displace portal branches or
lesions with the 'target -like' appearance can be seen in
this phase. Those masses which are relatively hypovas-
cular tumors remain hypo dense in the venous phase,
as do their hepatic metastases (Fig. 12.1Sb).
12.2.3
Magnetic Resonance Imaging
Magnetic resonance (MR) imaging gives similar
information concerning NHFET to that displayed
by CT scanning. MR can be used for the character-
ization and evaluation of the extent (Fig. 12.16) of
masses previously detected with US. The advantages
of MR over CT include higher contrast resolution
and therefore higher sensitivity of the dynamic con-
trast-enhanced MR study for detecting endocrine
C. Procacci et al.
tumors (SEMELKA and ASCHER 1993; PAVONE et al.
1993; ANGELI et al. 1997). With current MR imag-
ing technology, the entire liver may be covered in a
breathhold or by single-shot techniques, allowing the
improved detection of hepatic metastases.
The elevated MR contrast resolution leads to the
identification of very small primary tumors, which
appear hypointense in comparison with the normal
parenchyma on Tl-weighted sequences (Figs. 12.16a,
12.17a, 12.1Sa, 12.19a). This difference in signal is fur-
ther exaggerated when fat-suppressed Tl sequences
are used with or without intravenous gadolinium
(Fig. 12.17a,b). Some authors have pointed out that
gadolinium may actually decrease the ability to
recognize the lesion (OWEN et al. 2001). The typical
features of primary non-hyperfunctioning islet cell
tumors include a large pancreatic mass of low signal
intensity (less than or equal to the normal pancreas)
on Tl-weighted images (Figs. 12.16a, 12.17a,b, 12.1Sa,
12.19a) and of intermediate to high intensity on T2-
weighted images (Figs. 12.16b, 12.17c, 12.1Sb, 12.19b).
In a minority of patients, the mass may contain
necrosis or hemorrhage, and is usually hyperintense
on Tl-weighted images (CARLSON et al.1993).
Cystic changes within islet-cell tumors are more
common than previously thought. Cystic islet-cell
tumors are usually unilocular lesions with hypoin-
tense contents on Tl-weighted and hyperintense
contents on T2-weighted images (BUETOW et al.
1997) and a wall of variable thickness (BUETOW et
al. 1997). The appearance is identical to other cystic
tumors of the pancreas, so that a definitive diagnosis
 Nonhyperfunctioning Endocrine Tumors 207

a b

c d

Fig.12.16a-f. NHFET, MR evaluation. a, bTl gradient recalled echo with fat saturation (GRE FS) and T2 short time inversion
recovery (STIR) sequences: an ovoid mass growing along the major axis of the body and tail of the pancreas; it is slightly
hypointense compared with the normal parenchyma on TlW (a) and hyperintense on T2W (b). The hepatic metastases also
appear hypointense on TlW and slightly hyperintense on T2W. c, d Gadolinium (Gd)-DTPA opposed phase Tl GRE sequence
(venous phase) in axial (c) and coronal (d) planes: the mass demonstrates inhomogeneous enhancement in relation to the
presence of hypointense necrotic areas within it (arrow). The hepatic metastases are not recognizable. Accessory spleen at the
splenic hilum (arrowheads). e, f In the 3D angio-MR reconstructions, the celiac trunk with its branches and the mesenteric
artery show normal patency
208
can only be obtained by histological examination of
the specimen.
The signal intensity and the morphological char-
acteristics detected without intravenous gadolinium
administration can only lead to the suspicion of
NHFET, and not to a specific diagnosis. Moreover,
some islet tumors may have a low signal on T2-
weighted images due to the presence of abundant
fibrous tissue (OWEN et al. 2001), and therefore, they
are indistinguishable from a ductal carcinoma. These
characteristics could justify the usefulness of gado-
linium-enhanced Tl-weighted images obtained 5-10
min following injection in detecting some endocrine
tumors. In fact, according to IcHIKAWA, up to 35%
of scirrhous NHFET at histopathological examina-
tion show this delayed enhancement (IcHIKAWA et
a1.2000)
Nowadays, it is possible to carry out breathhold
dynamic studies of the abdomen, as with CT, but with
a higher contrast resolution. The findings are the
same: the hypervascularized NHFET show the high-
C. Procacci et a1.
Fig. 12.17a-c. NHFET, MR evaluation. The mass of the pan-
creatic head is not recognizable with certainty in the II GRE
sequence in phase (a), while it is clearly evident on II GRE
using FS (b). The lesion typically appears slightly hyperintense
in the turbo spin-echo T2-weighted sequence (c)
est enhancement in the pancreatic phase (Fig. 12.18c)
and remain hyperintense (Figs. 12.16c,d, 12.19c) even
in the venous phase (STAFFORD-JOHNSON et al. 1998;
OWEN et al. 2001). Persistent hyperintensity is found
mainly in the larger lesions (Fig. 12.19c), where the
neoplastic thrombosis of the draining veins results in
retention of contrast medium (STAFFORD-JOHNSON
et al. 1998). According to KOITO et al., the delayed
enhancement correlates with malignancy (KoITO
et al. 1997). Sometimes, if quite large, these tumors
have central necrotic areas that remain hypointense
on Tl-weighted images even after contrast medium
administration.
The best dynamic phase for studying endocrine
tumors is still being debated. Some authors argue
that the pancreatic phase is superior, similar to the
experience with CT, while others prefer the delayed
(5-10 min) Tl GRE sequence after contrast medium
administration in order to demonstrate also the late
enhancement of tumors with an abundant scirrhous
component (ICHIKAWA et al. 2000). All (DEBRAY et al.
 Nonhyperfunctioning Endocrine Tumors 209

a b

c d

Fig.12.I8a-d. NHFET, MR evaluation. a, b II GRE in-phase sequence and T2 half-Fourier single-shot turbo spin-echo (HASTE)
images show a large, solid mass within the head of the pancreas displaying expansive growth with well-defined margins. The
mass is hypointense on II W image (a) and slightly hyperintense on HASTE (b). The HASTE sequence highlights the impressions
on the digestive tract. c On Gd-DPTA-enhanced, fat-suppressed, TI GRE sequence, the mass demonstrates marked enhancement
in the pancreatic phase. d At MRCP, the mass causes compression of the main duct, which is dilated upstream

2001; OWEN et al. 2001) agree on greater sensitivity
during the pancreatic phase in identifying hypervas-
cularized hepatic metastases (Fig. 12.20). Metastases
rarely contain necrotic and hemorrhagic areas or
calcifications (DEBRAY et al. 2001). Because there is
no radiation risk, a multiphasic MR examination can
be safely performed.
Using the 3D acquired Tl-weighted sequence, it
is possible to obtain a vascular map of the lesion,
together with information about its signal and
enhancement characteristics (MR angiography:
Figs. 12.16e,f, 12.1ge,f). Recently, some authors
(PETERSEIN et al. 2000) described the usefulness of
Gd-BOPTA where both the dynamic study and the
late study can be carried out. In the delayed examina-
tion (after 2 h), small metastases that other sequences
may have failed to demonstrate can be depicted as
small,hypointense nodules (Fig. 12.20). This particu-
lar capability of MR can be useful especially during
the follow-up of these patients.
12.2.4
Nuclear Medicine
The first time that receptor scintigraphy was applied
to the study of endocrine tumors was in 1987 with
the synthesis of 1231_Tyr3-octreotide, the radiola-
beled counterpart of the octapeptide somatostatin
analogue octreotide. Octreotide possesses a high
affinity for somatostatin receptor subtype 2 (also for
subtypes 3 and 5) and an appropriate serum half-life
(KRENNING et al. 1992). Nevertheless, hepatobiliary
and intestinal excretion of this radiopharmaceutical
 210 C. Procacci et al.

a b

c d

Fig. 12.19a-f. NHFET, MR evaluation: 'all in one' technique. Tl GRE FS and T2 HASTE sequences show a large, round tumor of
the body of the pancreas, hypointense on TlW (a) and inhomogeneously hyperintense on HASTE (b); a hypointense fibrous
component (arrowheads) is present. c Gd-DPTA enhanced Tl GRE FS sequence: in the late phase, the mass remains inhomo-
geneously enhanced. d On MRCP, the main duct is not recognizable in the body-tail due to compression by the mass. e The
arterial MR angiogram reveals regular patency of the celiac trunk and the superior mesenteric artery, which appear displaced
with a typical 'basket' pattern. f In the portal MR angiogram, compression and possible infiltration of the mesenteric-portal
confluence (arrows) can be seen
 Nonhyperfunctioning Endocrine Tumors 211

a b

c d

Fig. 12.20a-e. Hypervascularized hepatic metastasis (MR

evaluation with gadolinium BOPTA, Multihance, Bracco,
Milan, Italy). Tl GRE FS and T2 STIR sequences: a tiny focus
of altered signal (arrow), hypointense on Tl W (a) and slightly
hyperintense on T2W (b) is recognizable. Gd-DPTA-enhanced
Tl GRE FS sequence reveals the lesion only in the arterial
phase (c), becoming isointense (arrows) with the liver in the
venous phase (d). e On a 2-h delayed image, the hypointense
e metastasis is again evident

affected the quality of the study of the abdomen. This
is overcome with D-Phel-octreotide peptide. When
chelated with DTPA, and labeled with lllIn (>95%),
the agent is mainly excreted by the kidneys ellln-
pentetreotide, Octreoscan, Mallinckrodt Medical,
Petten, The Netherlands). The long half-life of lllIn
allows for an accurate study of the lesion up to 48 h
after the injection. The basis for receptor scintigra-
phy is receptor-mediated internalization and lyso-
some entrapment of a radiolabeled peptide within
high affinity receptors, which are overexpressed on
the cell membranes of many tumors, especially of
endocrine origin.
After intravenous administration of 10 Ilg of pep-
tide labeled with at least 200 MBq of III In, images can
be acquired with planar and single photon emission
computed tomography (SPECT) technique after
4, 24, and/or 48 h, with a wide field-of-view tomo-
graphic gamma-camera equipped with medium
energy collimators. In addition to octreotide scan-
 212
ning, positron emission tomography (PET) utilizing
e
18F-Iabeled ftuorodeoxyglucose 8FDG) is used to
identify areas with high anaerobic metabolism, pres-
ent in less differentiated endocrine tumors. These
anaplastic tumors tend not to express somatostatin
receptors and, therefore, are not visible on octreotide
scintigraphy (SRS). Somatostatin analogues labeled
with other positron-emitting isotopes (86Y_DOTA_
Tyr3-octreotide, 68Ga-DFO-octreotide, 64CU_ TETA-
octreotide) can give more detailed images than
IllIn Octreoscan scintigraphy. Furthermore, unusual
metabolic pathways, such as serotonin precursors in
carcinoids, can also be explored by PET with IIC_5_
HTP (5-hydroxytriptophane) (ERIKSSON et al. 2000).
The majority of pancreatic endocrine tumors can
be visualized by means of IIIIn-Octreoscan scintigra-
phy. Nuclear medicine techniques have a well-defined
role in localizing functioning endocrine tumors
(especially gastrinomas), particularly when small or
where other imaging methods have failed. However,
there are no reported studies comparing the different
imaging techniques in pancreatic NHFET.
The European Multicenter Trial (KRENNING et al.
1994) studied 350 patients who were submitted to
both somatostatin-receptor scintigraphy (SRS) and
conventional radiological investigations. The overall
sensitivity was 80% for SRS and 88% for the other
methods. Octreoscan scintigraphy identified 49 of
8
h
a
Fig.12.21a-c. Receptor scintigraphy with Octreoscan. a Planar image, 24 h post-injection: tracer uptake seen within
the pancreatic head. b SPECT image, transaxial projection, 4 h post-injection: intense uptake at the level of the
superior pole of the right kidney. c SPECT image, coronal projection, 4 h post-injection: intense uptake within the
pancreatic head
C. Procacci et al.
the 60 NHFET of the pancreas. Conventional investi-
gations, in contrast, could identify correctly 100% of
the positive lesions at scintigraphy and demonstrated
the primary in another nine patients, in whom SRS
was negative. Our personal experience matches
those of the literature: the sensitivity of scintigraphy
for lesions expressing somatostatin receptors was
95.6%, while CT and MR sensitivity for pancreatic
masses was 100%. SRS therefore has a high sensitiv-
ity with the possibility of also identifying small-sized
lesions (1-1.5 cm) (Fig. 12.21). False-negative scans
result from a paucity of somatostatin receptors on
an individual tumor. When studying NHFET, IIIIn_
Octreoscan scintigraphy is not indicated for the
identification but for the characterization of lesions.
In fact, in masses with uncertain or nonspecific fea-
tures on conventional imaging, scintigraphic uptake
leads to a clear diagnosis of endocrine tumor.
The most significant contribution of receptor scin-
tigraphy definitely lies in the possibility of staging
endocrine tumors. This is due to its high sensitivity
and, particularly, in the possibility to perform a 'total
body' exploration (Fig. 12.22).
In the identification of hepatic metastases, CHIT!
reports 90% sensitivity for SRS, slightly higher than
that of CT (78%) and US (88%), with a similar speci-
ficity (CHIT! et al. 1998). The sensitivity was even
greater for other soft-tissue lesions (90% with SRS vs
c
Nonhyperfunctioning Endocrine Tumors 213

a b c d

Fig.12.22a-d. Receptor scintigraphy with Octreoscan. a Planar image, anterior projection, 24 h post-injection: marked uptake
within the pancreatic region which corresponds to a 6 cm diameter pancreatic mass found with CT; hepatic lesions not found
on MR. b Planar image, anterior projection, 24 h post-injection uptake within the pancreatic region; large liver metastasis, bone
lesions. Planar images, anterior (c) and posterior (d) projections, 24 h post-injection: pancreatic lesion, mediastinal lymph
nodes, multiple bone metastases

66% with CT and 47% with US). In Chiti's large case
study (131 patients), which included both function-
ing and nonhyperfunctioning tumors, Octreoscan
altered the therapy choice in 21%. The sensitivity
of SRS was also high in revealing bone metastases,
superior to that of bone scintigraphy (LEBTAHI et
al. 1999), and metastases in other sites (FRILLING
et al. 1998). Metastases taking up the radiopeptide
can be treated with cold somatostatin analogues or
by radiometabolic therapy using analogues radiola-
beled with beta-emitting isotopes. Nonfunctioning
metastases by nuclear scan, however, need different
treatments, often palliative (chemoembolization,
chemotherapy). The long clinical history of non-
hyperfunctioning tumors accounts for their late
diagnosis and, therefore, for the frequent presence
of metastases at diagnosis. For this reason, NM can
be of critical importance for the characterization and
staging of these tumors, leading to optimization of
the subsequent therapeutic choice.
If NM techniques demonstrate the overexpression
of somatostatin receptors in the tumor at diagnosis,
the high sensitivity of this technique justifies its use
in the follow-up, for a rapid demonstration of relapse
and/or metastases. Further studies will focus on the
diagnostic value of 18FDG-PET in rapidly progress-
ing, poorly differentiated endocrine tumors.
12.3
Differential Diagnosis
The problems of the differential diagnosis between
NHFET and the other pancreatic masses vary accord-
ing to the macroscopic aspect of the tumor and its
vascularity.
The solid, hypervascularized variant is more easily
categorized due to its conspicuous enhancement after
contrast medium administration on CT, MR, and,
more recently, CEUS. The definite contours and expan-
sive growth pattern with the consequent compressive
effect on the peripancreatic vessels and viscera con-
tribute to the diagnosis. Arterial encasement and
venous thrombosis are rarely found. The characteriza-
tion of these tumors is facilitated by the frequent pres-
ence of hypervascularized hepatic metastases. These
findings lead only to a suspicion of this type of tumor,
214
as the diagnosis is not certain since other neoplasms
can show the same characteristics.
Acinar carcinoma, in its solid variant, can be well-
vascularized and thus may, in the pancreatic phase,
mimic an endocrine tumor. It should be pointed out
that also from a histological point of view, it is dif-
ficult to distinguish the endocrine or acinar nature
of the mass.
Ductal adenocarcinoma, in rare cases character-
ized by a poor endotumoral fibrous stromal com-
ponent, can appear hyperintense in the pancreatic
phase. Misdiagnosis can occur even when there are
clear signs of peripancreatic vessel infiltration, if the
mass is very large.
Finally, hypervascularized pancreatic metastases,
especially from renal tumors, must be taken into
account, since they can have the same pattern. Usu-
ally, the problem of differential diagnosis is extremely
uncommon, since synchronous or metachronous
metastases always arise in a well-known history of a
primary renal carcinoma. Moreover, pancreatic metas-
tases, which can appear many years after the identifi-
cation of the primary tumor, are frequently multiple.
The solid, hypovascularized variant can never be
categorized by imaging, as it shows the same aspects
as other solid pancreatic tumors. If an infiltrating
growth pattern and/or hypovascularized hepatic
metastases are already present, misdiagnosis of a
ductal adenocarcinoma is almost unavoidable. When
the tumor, however, has expansive growth and well-
defined contours, especially in women, a solid pseu-
dopapillary tumor can be wrongly diagnosed.
There is no possibility of primarily diagnosing
the cystic variant by imaging, since it has the same
aspects as the mucinous cystic tumor (macro cystic
multilocular aspect) or the solid pseudopapillary
tumor in its cystic variant (mixed solid and liquid
aspect) or a completely nonspecific pattern (macro-
cystic unilocular aspect).
For these reasons, fine needle aspiration of all solid
hypervascularized or hypovascularized pancreatic
masses is strongly recommended in order to achieve
a definite diagnosis. The cystic variant, however, can
be characterized only by histological examination of
the specimen.
12.4
Diagnostic Strategy
NHFET are mainly found by chance when patients
present with nonspecific symptoms (palpable mass,
C. Procacci et al.
dyspepsia, etc.). The diagnosis is usually late, and
either US or CT will be the first method to suggest
the diagnosis. The most significant aim of imaging
is characterization of the lesion, which is performed
by CT or MR after contrast medium administration,
demonstrating the high enhancement in the lesion.
Since CT and MR findings are virtually identical,
a choice has to be made as to which method to
adopt. Therefore, characterization could be made
by CEUS, but further studies are needed to deter-
mine the effective accuracy of this technique. At
the moment, the routine use of nuclear medicine
does not seem to be advisable. However, since a
definite characterization is not objectively possible
with imaging, fine needle biopsy is always required
before treatment.
The prognosis of these tumors is much better
than that of ductal adenocarcinomas, and therefore
a surgical attempt integrated with chemotherapy is
indicated, even in the more advanced stages of the
disease. For this reason, accurate staging of the tumor
can be obtained with CT or MR. Nuclear medicine
could improve the staging, being able to identify
distant metastases. lllIn-Octreoscan scintigraphy
is more accurate than bone scintigraphy in demon-
strating bone metastases.
Nuclear medicine investigation is essential to
assess the possibility of utilizing treatment with
somatostatin analogues, either cold or radiolabeled.
The presence of somatostatin receptor subtype 2 is
promising for the possible success of the treatment.
Finally, in the follow-up of these tumors, due to the
further advantage of identifying distant metastases,
nuclear medicine techniques are advisable, given the
actual difficulty of CT and MR in distinguishing scar
tissue from the residual or relapsing tumor, especially
in operated patients.
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Rare Tumors
13 Rare Solid Tumors:
Clinical Manifestations and Pathology
T. OWElTY and A. B. WEST

CONTENTS 13.5.1 Teratoma 233

13.5.2 Choriocarcinoma 233
13.1 Introduction 219 13.6 Mesenchymal Tumors 233
13.2 Tumors Peculiar to the Pancreas 220 13.6.1 Lymphovascular Tumors 233
13.2.1 Pancreatoblastoma 220 13.6.1.1 Lymphangioma 233
13.2.1.1 Epidemiology 220 13.6.1.2 Hemangioma 234
13.2.1.2 Clinical Features 220 13.6.1.3 Hemangioendothelioma 234
13.2.1.3 Pathology 220 13.6.1.4 Other Lymphovascular Tumors 234
13.2.1.4 Differential Diagnosis 222 13.6.2 Adipose Tissue Tumors 234
13.2.1.5 Molecular/Genetic Alterations 222 13.6.3 Myogenic Tumors 234
13.2.1.6 Natural History and Prognosis 222 13.6.3.1 Leiomyoma 234
13.2.2 Acinar Cell Carcinoma 223 13.6.3.2 Leiomyosarcoma 234
13.2.2.1 Clinical Features 223 13.6.4 Neurogenic Tumors 236
13.2.2.2 Pathology 223 13.6.4.1 Schwannoma 236
13.2.2.3 Differential Diagnosis 225 13.6.4.2 Primitive Neuroectodermal Tumor 236
13.2.2.4 Prognosis and Treatment 226 13.6.5 Other Mesenchymal Tumors 237
13.2.3 Mixed Acinar-Endocrine Carcinoma 226 13.7 Solid Tumor-like Lesions of the Pancreas 237
13.2.3.1 Clinical Features 226 13.7.1 Heterotopic (Ectopic) Spleen 237
13.2.3.2 Pathology 226 13.7.2 Hamartoma 237
13.2.3.3 Prognosis 227 13.7.3 Pseudolipomatous Hypertrophy 238
13.2.4 Solid Pseudopapillary Tumor 227 13.7.4 Inflammatory Pseudotumors 238
13.2.4.1 Pathology 227 13.7.5 Pseudolymphoma 239
13.2.4.2 Treatment and Prognosis 227 13.7.6 Chronic Pancreatitis 239
13.2.5 Osteoclast-like Giant-Cell Tumor 227 13.7.7 Miscellaneous Inflammatory Tumor-like
13.2.5.1 Clinical Picture 227 Masses 241
13.2.5.2 Pathology 227 References 241
13.2.5.3 Treatment and Prognosis 229
13.3 Other Epithelial Tumors 230
13.3.1 Clear-Cell Carcinoma 230
13.3.1.1 Pathology 230
13.3.1.2 Prognosis 230 13.1
13.3.1.3 Differential Diagnosis 230 Introduction
13.3.2 Oncocytic Tumors 230
13.3.2.1 Pathology 231
13.3.2.2 Prognosis 231 The rare solid tumors that arise in the pancreas
13.3.3 Minor Epithelial Tumors 231 can be divided conveniently into two major groups:
13.4 Lymphomas 232 those that are unique to the pancreas and those that
13.4.1 Incidence and Epidemiology 232 are found also in other locations. The former group
13.4.2 Clinical Manifestations 232 includes pancreatoblastoma, pancreatic acinar cell
13.4.3 Pathology 232
13.4.4 Treatment and Prognosis 232 carcinoma, mixed acinar-endocrine cell carcinoma,
13.5 Germ-Cell Tumors 233 solid-pseudopapillary tumor, and osteoclast-like
giant-cell tumor. These tumors are the major focus of
this chapter. The latter group includes some clear-cell
T. OWElTY, MD carcinomas, oncocytic tumors, lymphomas, germ -cell
Assistant Professor, Department of Pathology, New York Uni- tumors, and mesenchymal tumors. These entities are
versity, 560 First Avenue (TH461), New York, NY 10016, USA familiar because of their more common occurrence
A.B. WEST, MD, FRCPath
Professor and Director of Anatomic Pathology, Department
in other sites, and they are considered here in large
of Pathology, New York University Medical Center, 560 First part because of their importance in the differential
Avenue (TH461), NewYork,NY lO016, USA diagnosis. The literature relating to many of these
220
lesions arising in the pancreas is scant and composed
chiefly of case reports, in the absence of reports of
series. A third group of entities is also considered
here because of their importance in the differential
diagnosis of solid pancreatic masses: These are the
tumor-like lesions such as ectopic spleen, inflamma-
tory pseudotumor, and chronic pancreatitis.
13.2
Tumors Peculiar to the Pancreas
13.2.1
Pancreatoblastoma
13.2.1.1
Epidemiology
Although rare, this histologically distinct pancre-
atic neoplasm represents the most common malig-
nant pancreatic tumor in childhood. The reported
incidence among all pancreatic malignancies in
the Memorial Sloan-Kettering series was 0.16%
(CUBILLA and FITZGERALD 1984). First described by
BECKER in 1957, it was referred to as infantile pancre-
atic carcinoma until the term pancreatoblastoma was
introduced by HORIE in 1977 (BECKER 1957; FRABLE
et al. 1971; HORIE et al. 1977).
Almost half of the reported cases have been in
Asians (KLIMSTRA et al. 1995; CHUN et al. 1997). The
majority occur in the first decade of life, with a mean
age of 4.1 years and a slight male predominance.
Occasional cases have been reported in teenagers
(IMAMURA et al. 1998) and adults (18-56 years)
(HOORENS et al. 1994; DUNN and LONGNECKER 1995;
KLIMSTRA et al. 1995; LEVEY and BANNER 1996;
ROBIN et al. 1997). Pancreatoblastoma may be con-
genital and is sometimes associated with Beckwith-
Wiedemann syndrome (KOH et a1.l986; POTTS et al.
1986; DRUT and JONES 1988).
13.2.1.2
Clinical Features
Clinical symptoms are nonspecific and are usually
referable to the presence of an abdominal mass,
although pain, weight loss, diarrhea, and obstructive
jaundice are present occasionally (FRABLE et al. 1971;
GRIFFIN et al.1987; KLIMSTRA et al.1995; CHUN et al.
1997). Elevation of alpha-fetoprotein (AFP) occurs in
up to 68% of patients (KLIMSTRA et al. 1995; KOHDA
et al. 2000). No evidence of hormone secretion has
T. Oweity and A. B. West
been reported, except for one patient with Cushing's
syndrome with inappropriate antidiuretic hormone
(SIADH) (PASSMORE et al. 1988).
13.2.1.3
Pathology
The pathology of pancreatoblastomas has been
reviewed in detail by KLIMSTRA et al. (1995).
Macroscopic Features. Pancreatoblastomas are usu-
ally well-demarcated to encapsulated, although gross
extension into the adjacent pancreas or surrounding
tissue does occur. The reported diameter ranges from
1.5 to over 20 em (mean 10.6 em). There is no predi-
lection to a particular location in the pancreas. The
cut surfaces are yellow to tan, soft to firm, with promi-
nent lobulation (Fig. 13.1a). Areas of hemorrhage
and necrosis can be seen, and calcifications may be
prominent (KLIMSTRA et al. 1995; CHUN et al. 1997;
KOHDA et al. 2000). Cystic change occurs occasionally,
particularly in patients with Beckwith-Wiedemann
syndrome (PASSMORE et al. 1988; KLIMSTRA et al.
1995; KOHDA et al. 2000).
Microscopic Features. Although the tumors are usu-
ally partially surrounded by a fibrous capsule, there
is often invasion into the surrounding pancreatic,
duodenal, or peripancreatic tissue. Vascular and
perineural invasion are common.
On microscopic examination, pancreatoblastomas
usually appear lobulated with an organoid pattern
and consist of mixed epithelial and mesenchymal
components. The epithelial component exhibits
three different patterns in variable proportions: solid
sheets, acinar formations, and squamoid corpuscles
(Fig. 13.1b). The cells in the solid and acinar areas
are similar cytologically, with round nuclei and
finely granular cytoplasm. The nuclear chromatin
is clumped, and the cytoplasmic borders are usu-
ally better defined in the acinar areas than in the
solid areas. Occasional mild pleomorphism and an
increased nuclear-to-cytoplasmic ratio may occur in
the solid areas. Mitoses vary from rare to abundant.
Squamoid corpuscles are present in every case and
range in size from a few cells to geographic areas.
They vary from ill defined to sharply defined clusters
with a whorling pattern, and may show keratiniza-
tion. The nuclei in these areas are larger (often with
central clearing), and the cytoplasm is more eosino-
philic. In most cases, these squamoid corpuscles are
plentiful, but occasionally they require more than
 Rare Solid Tumors: Clinical Manifestations and Pathology
a
Fig. 13. 1a,b. Pancreatoblastoma. a The tumor has a fleshy,
tan, lobulated cut surface with focal areas of hemorrhage
and degeneration. The spleen is at the right. The patient was
a 6-year-old boy. At surgery, metastases were present in the
peritoneum and lungs. b The tumor cells display focal acinar
arrangements, solid areas, squamoid corpuscles, and a mes-
enchymal component that is present around the epithelial
clusters (H&E). Photograph in a by courtesy of Dr KATHLEEN
PATTERSON and Dr MIGUEL REYES-MUGICA. Case in b cour-
tesy of Dr DAVID KLIMSTRA
one histologic section to find them. Ductal structures
are usually inconspicuous, with a rare case showing
abundant apical cytoplasm and ectatic lumens with
tall columnar lining cells containing intracellular
mucin. Occasionally, the growth pattern is more dif-
fuse than organoid, with increased pleomorphism,
larger nuclei, higher nuclear-to-cytoplasmic ratios
and necrosis, and without squamoid corpuscles. The
stromal component varies in quantity and appear-
ance. It may be scant and fibrotic, particularly in
adults, but usually it is composed of broad bands
that are hypercellular, especially in infants. The
stromal cells generally resemble plump fibroblasts
with the nuclei arranged parallel to the long axis of
the band. Although hypercellular, they do not gener-
221
ally appear neoplastic; occasionally, they may show
more nuclear atypia with architectural disarray and
even chondroid or osteoid metaplasia (CUBILLA and
FITZGERALD 1984; KLIMSTRA et al. 1995).
Histochemical and Immunohistochemical Features.
Periodic acid-Schiff (PAS}-positive, diastase-resistant
granules can be seen in the acinar cells and squamoid
corpuscles. Mucicarmine positivity is detectable in
more than half of the patients (BUCHINO et al. 1984;
OHAKI et al. 1987; MOROHOSHI et al. 1987; KLIMS-
TRA et al. 1995). Pancreatoblastomas are thought to
originate from totipotent stem cells capable of dif-
ferentiating towards all three major cell types of the
adult pancreas: acinar, endocrine, and ductal, with
acinar differentiation being the one most consis-
tently present. These lines of differentiation can be
detected by routine light microscopy, by histochemi-
cal and immunohistochemical stains, and by electron
microscopy. The tumor cells usually express trypsin,
chymotrypsin, alpha-I-antitrypsin, and lipase, and
are also positive for cytokeratin (OHAKI et al. 1987;
MOROHOSHI et al. 1987; KISSANE 1994; KLIMSTRA et
al. 1995). Occasionally, a proportion of the cells will
stain for neuroendocrine markers such as neuron-
specific enolase (NSE), synaptophysin, and chromo-
granin, usually as scattered clusters or single cells
(KLIMSTRA et al. 1995; IMAMuRA et al. 1998). Rarely,
some cells may stain for pancreatic hormones such as
glucagon, (KLIMSTRA et al.1995) and insulin (IMAM-
URA et al.1998) or for nonpancreatic hormones (TSH,
FSH) (HuA et al. 1996). Ductal differentiation is evi-
dent on routine histology and by mucicarmine stain-
ing, which usually highlights the luminal surfaces of
the acinar/glandular structures with rare intracyto-
plasmic positivity. Carcinoembryonic antigen (CEA)
positivity is also commonly encountered and may
be seen in the squamous corpuscles, while CA 19.9
or DUPAN-2 staining may occur focally in scattered
clusters of cells. Double immunostaining for trypsin
and chromogranin reveals an intimate admixture of
the two cell types with rare cells expressing both pro-
teins. Staining for p53 is usually negative (KLIMSTRA
et al. 1995).
Ultrastructural Findings. Acinar differentiation
can be seen by demonstrating polygonal cells with
easily identifiable desmosomes, abundant rough
endoplasmic reticulum, and Golgi complexes, form-
ing acinar/glandular structures with a surrounding
basement membrane, and luminal spaces exhibiting
apical tight junctions and blunt microvilli. Homog-
enous, electron-dense, 400-800 nm, zymogen-like
222
granules are seen in variable numbers and distribu-
tion, but are most numerous in the apical cytoplasm
(FRABLE et al. 1971; BUCHINO et al. 1984; KLIMSTRA
et al. 1995). Occasional, irregular, elongated, fibril-
lary granules, mucin-like granules, and dense-core,
125-215 nm, neuroendocrine-like granules may be
present. However, none of the cells contain more
than one specific granule type (BUCHINO et al. 1984;
KLIMSTRA et al. 1995).
Cytology. Fine needle aspirates of pancreatoblastoma
have rarely been described (SILVERMAN et al. 1990;
HENKE et al. 2001). The smears are cellular, with large
clusters of cells and occasional single cells. The cells are
intermediate to large in size, round to spindle-shaped,
some with a moderate amount of granular cytoplasm
and others with a high nuclear-to-cytoplasmic ratio,
scant cytoplasm, and centrally placed nuclei. The chro-
matin is finely granular, with frequent inconspicuous
nucleoli. Mesenchymal fragments vary from rare to
abundant in the background. Squamoid corpuscles
have not been identified with certainty in smears,
but sections of cell blocks show the characteristic
histological features of solid, focally acinar cellular
arrangements and squamoid corpuscles with inter-
vening, small, round to spindle cells and scant stroma.
Ultrastructural preparations and immunohistochemi-
cal stains help to confirm the diagnosis.
13.2.1.4
Differential Diagnosis
Acinar cell carcinoma may be difficult to differenti-
ate from pancreatoblastoma histologically, but usu-
ally occurs in adults and rarely in children, contrary
to pancreatoblastoma. Squamoid corpuscles are the
most distinctive morphologic feature of pancreato-
blastoma, as both tumors otherwise show acinar
differentiation and may show some degree of neu-
roendocrine marker positivity. Mixed acinar-endo-
crine tumors are also distinguished by the lack of
squamoid corpuscles. Solid-pseudopapillary tumor
usually shows papillary-pseudopapillary arrange-
ments and is positive for vimentin but negative
for cytokeratin, in contrast to pancreatoblastoma.
Although this tumor may occur at a younger age,
it usually presents in the teenage years or later, and
in women. Neuroendocrine/islet-cell tumors may
occur in childhood. They are usually functional, and
the age of onset is the second decade (KOHDA et al.
2000). They lack acinar differentiation and squamoid
corpuscles, and are usually more diffusely positive
for general neuroendocrine markers or specific hor-
T. Oweity and A. B. West
mones. Ductal adenocarcinomas are extremely rare
in childhood and lack the characteristic acinar and
squamoid areas.
In general, pancreatoblastoma is the most likely
diagnosis in a child presenting with a pancreatic
mass in the first decade of life without clinical hor-
monal abnormalities, particularly when the tumor is
hypervascular, encapsulated, with calcifications and
necrosis, and associated with raised alpha-fetopro-
tein (KOHDA et al. 2000).
13.2.1.5
Molecular/Genetic Alterations
ABRAHAM et al. (2001) analyzed nine pancreato-
blastomas for alterations that are usually found in
pancreatic ductal adenocarcinomas (K-ras oncogene
and p53 and DPC 4 tumor suppressor genes) and
for mutations common to other embryonic malig-
nancies [somatic alterations in the adenomatous
polyposis coli (APC) /beta-catenin pathway and
chromosome l1p]. Allelic loss on chromosome l1p
was the most common genetic alteration, present in
8 of the reviewed cases (89%). Molecular alterations
in the APC/beta-catenin pathway were detected in
6 cases (67%). No alterations in the K-ras gene or
p53 expression were detected. Loss of DPC 4 protein
expression was seen in 2 cases. These findings prove
the distinctive genetic nature of pancreatoblastoma,
which appears to be closer to hepatoblastoma in
pathogenesis than to ductal adenocarcinomas of
the pancreas. Other abnormalities, including those
involving chromosome 1, have been reported in
2 cases (WILEY et al. 1995; NAGASHIMA et al. 1999).
In a separate study, KERR et al. (2002) confirmed the
loss of heterozygosity for chromosome 11 p.
13.2.1.6
Natural History and Prognosis
Pancreatoblastomas are malignant neoplasms with
frequent local invasion, recurrence, and metastases.
Lymph nodes, liver, and lung are the most common
sites of metastasis (KLIMSTRA et al. 1995; CHUN
et al. 1997; IMAMURA et al. 1998). Of the patients
reviewed by KLIMSTRA et al. (1995), 35% presented
with metastases, and some patients developed them
subsequently. In this series, 42% of the patients died
of disease within 3.5 years of presentation, with a
mean survival of 17 months. The prognosis in adults
appears worse than in children.
The treatment of choice for pancreatoblastoma
is complete surgical resection; resection of hepatic
Rare Solid Tumors: Clinical Manifestations and Pathology
metastases is sometimes performed also (KUMSTRA
et al. 1995; MURAKAMI et al. 1996; BENOIST et al.
2001). Neoadjuvant and postoperative chemotherapy
have been applied with good results, with radiation
for unresectable local recurrences (GRIFFIN et al.
1987; KUMSTRA et al. 1995; MURAKAMI et al. 1996;
IMAMURA et al. 1998). Serum alpha -fetoprotein, when
elevated, is helpful in monitoring patients following
surgery (KUMSTRA et al. 1995; CHUN et al. 1997;
OGAWA et al. 2000). The prognosis is generally favor-
able in resectable cases, and a substantial number of
patients have survived long enough to be considered
cured (KUMSTRA et al. 1995; IMAMURA et al. 1998;
OWAGA et al. 2000; BENOIST et al. 2001; DEFACHELLES
et al. 2001).
13.2.2
Acinar Cell Carcinoma
Acinar cell carcinomas are rare tumors of the exo-
crine pancreas with evidence of acinar cell differenti-
ation and occasional endocrine components (SOLCIA
et al. 1997). The majority are solid lesions and will
be covered in this chapter. Cystic variants, includ-
ing acinar cell cystadenocarcinoma and acinar cell
cystadenoma, are discussed in the chapter on cystic
tumors. Acinar cell carcinoma accounts for 1%-2% of
all primary nonendocrine pancreatic tumors (MoRO-
HOSHI et al. 1983; CUBILLA and FITZGERALD 1984;
CHEN et al. 1985).
13.2.2.1
Clinical Features
Acinar cell carcinomas can occur at any age (range
3-90 years), but they are more common during
the 5th through the 7th decades of life. They are
very rare in children, with few examples recorded
in the literature (OSBORNE et al. 1977; LACK et al.
1983; MOROHOSHI et al. 1987; KUMSTRA et al. 1992;
HOORENS et al. 1993). Male predominance was noted
in two series (KLIMSTRA et al. 1992; HOORENS et al.
1993). Although the majority of cases in KUMSTRA'S
series affected Caucasian patients, overall, no racial
predominance has been noted (ORDONEZ 2001;
SOLCIA et al. 1997).
Symptoms at presentation are nonspecific and
related to local expansion or metastases (CUBILLA
and FITZGERALD 1984). The ones most commonly
described are abdominal pain, loss of weight and
appetite, and vomiting. Jaundice is rare. Some
patients (16% in KUMSTRA'S series) present with a
syndrome characterized by polyarthralgia, dis semi-
223
nated (mostly subcutaneous) fat necrosis, and occa-
sionally fever with peripheral eosinophilia (GOOD et
al. 1976; KLIMSTRA et al. 1992). These features are
mostly associated with, and probably related to, high
serum lipase (KUMSTRA et al. 1992) or trypsin (VAN
KLAVEREN et al. 1990), while alpha-amylase is rarely
elevated (GOOD et al. 1976). An increase in serum
lipase, amylase, or elastase-l without concomitant
symptoms has been reported (ISHIHARA et al. 1989).
With rare exceptions (HORlE et al. 1984), serum CEA
and CA 19.9 are normal, and there are reported
cases of elevated alpha-fetoprotein (ITOH et al. 1992;
KAWAMOTO et al. 1992). Cases associated with hypo-
glycemia (MIZUTA et al. 1998), myeloma-like cast
nephropathy (REDUCKA et al. 1988), and thrombotic
endocarditis (WEBB 1977) have been described.
13.2.2.2
Pathology
Macroscopic Features. There is no clear preferential
localization in the pancreas, although more are found
in the head. The tumor is usually large, ranging in
diameter from 2 to 30 em (mean 10 em) and occasion-
ally appears attached to, rather than arising within, the
pancreas. It consists of well circumscribed to partially
encapsulated masses. The cut surface is soft to friable,
yellow to red, separated into lobules by fine fibrous
strands, and often showing necrosis and hemorrhage
and rarely focal cystic change (Fig. 13.2a). Invasion of
adjacent organs is seen in some cases (MOROHOSHI et
al. 1987; KUMSTRA et al. 1992; HOORENS et al. 1993).
Microscopic Features. Most acinar cell carcinomas
appear well circumscribed at low power and often sur-
rounded by a partial or complete capsule, but nearly all
show evidence of at least focal capsular invasion, with
broad nodules of tumor invading into adjacent tissue.
Broad fibrous bands divide the tumors into lobules
that are markedly cellular with scant stroma. A vari-
ety of growth patterns may be seen, most commonly
mixed, including acinar, solid, glandular, and trabecu-
lar patterns (KUMSTRA et al. 1992) (Fig. 13.2b).
The acinar pattern is the most characteristic pat-
tern of growth. It is present at least focally in most
tumors. It consists of cells growing in well-formed
acini, having frequently identifiable small lumina
with sharp borders. The solid pattern of growth is
also common, with sheets and cords of cells sepa-
rated by a thin fibrovascular stroma. Less commonly,
a glandular pattern is seen, probably reflecting
dilated acinar structures, with eosinophilic secretory
 224 T. Oweity and A. B. West

material within the lumen. A trabecular pattern with
double rows of cells is infrequently seen. The cells
of acinar cell carcinomas are cuboidal or columnar
with eosinophilic granular cytoplasm, which is most
abundant in the acinar areas, while scant in the solid
areas (Fig. l3.2c). The nuclei are usually uniform,
normochromatic, round to oval, with rare pleomor-
phism which occurs most often in the solid areas. In
acinar areas, the nuclei are polarized basally, result-
ing in a palisading pattern bordering the stroma or
the capsule. The nuclei are usually centrally located
in the solid areas. Single, small, prominent nucleoli
are commonly seen, centrally or peripherally. Mitotic
counts are variable between different tumors and dif-
ferent areas, ranging from none to more than 50110
high power fields, and occasionally atypical forms are
present (KLIMSTRA et al. 1992; ORDONEZ 2001).
Histochemical Stains. Periodic acid-Schiff (PAS)
staining after diastase digestion (PASD) character-
istically demonstrates variably positive cytoplasmic
granules which are best seen in the apical cytoplasm
of cells in the acinar areas. Occasionally, PAS-positive
material is seen in the glandular/acinar lumina, and
rarely mucin, although no intracytoplasmic mucin is
present. Butyrase stains, which define lipase activity,
are positive in more than 70% of cases (KLIMSTRA
et al. 1992).
Immunostains. A variety of pancreatic enzymes are
expressed in acinar cell carcinomas and may be
detected immunohistochemically. Trypsin is the one
most commonly expressed, occurring in up to 97% of
patients, and the one most useful in making a diag-

a b

c .... -...:;_~_

Fig. l3.2a-d. Acinar cell carcinoma. a The tumor is circumscribed and solid with a tan to red cut surface and foci of hemor-
rhage. b The tumor cells are arranged in solid masses with scattered acini, most conspicuous here at the top right of the field.
A duct or dilated acinar structure is seen on the left (H&E, low power). c The acini are lined by cuboidal cells with granular,
eosinophilic apical cytoplasm and uniform round nuclei, some with small prominent nucleoli (H&E, high power). d The cells
are arranged singly and in acinar groups, with eosinophilic cytoplasm, uniform round nuclei, and small punctate nucleoli (fine-
needle aspirate, H&E). Case courtesy of Dr PETER ILLEI
Rare Solid Tumors: Clinical Manifestations and Pathology
nosis (MOROHOSHI et al. 1987; KUMSTRA et al. 1992;
ORDONEZ 2001). Lipase has been reported to occur
in 85% of patients, chymotrypsin in 66%, and amy-
lase inl4% (ORDONEZ 2001). In general, enzymes are
more frequently recognized in areas of tumor having
an acinar growth pattern and are frequently local-
ized to the apical cytoplasm (KUMSTRA et al. 1992).
Alpha -I-antitrypsin and alpha-l-antichymotrypsin
are expressed by some acinar cell carcinomas, but
they appear to be neither sensitive nor specific as they
also occur in other pancreatic and extrapancreatic
tumors (ORDONEZ and MANNING 1984; LEADER et al.
1987; MOROHOSHI et al. 1987; KUMSTRA et al. 1992;
NOJIMA et al. 1992).
Acinar cell carcinomas react with the broad-spec-
trum anti-cytokeratin antibodies AEl! AE3 and CAM
5.2, and some express epithelial membrane antigen
(EMA). Markers expressed commonly by ductal
carcinoma, such as CEA and CA 19.9, may occasion-
ally be positive (KUMSTRA et al. 1992; HOORENS
et al. 1993). Vimentin staining in the tumor cells is
negative (ORDONEZ 2001). Alpha-fetoprotein (AFP)
expression, which is rare in pancreatic tumors other
than pancreatoblastoma, has been reported in some
cases (KUMSTRA et al.1992; HOORENS et al.1992) and
is occasionally associated with elevated serum AFP
levels (NOJIMA et al. 1992). Scattered, nondescript
endocrine cells expressing chromogranin A and syn-
aptophysin occur in about 40% of acinar cell carcino-
mas and occasionally may be shown to contain pan-
creatic hormones such as glucagon (KUMSTRA et al.
1992; HOORENS et al. 1993). Only rarely are exocrine
and endocrine markers demonstrable in the same
cells by double staining (HOORENS et al. 1993).
Electron Microscopy. Ultrastructural features of
acinar cell carcinomas resemble those of normal
acinar cells, particularly in the areas with acinar
patterns where the cells possess microvilli at the
apical surfaces with tight junctions and desmosomes
joining adjacent cells (KLIMSTRA et al. 1992). Abun-
dant rough endoplasmic reticulum, well developed
Golgi complexes, some mitochondria, and a few
lysosomes are seen, in addition to the characteristic
zymogen granules (CUBILLA and FITZGERALD 1984;
MOROHOSHI et al. 1987; DI SANT'AGNESE 1991;
KUMSTRA et al. 1992; HOORENS et al. 1993). These
electron-dense granules lack a halo between their
homogenous dark-staining contents and their limit-
ing membranes, and resemble zymogen granules of
the normal pancreas but with a wider size range (75
to > 1000 nm). They may be round, ovoid, fusiform, or
225
elongated in shape. Some have granular or flocculent
contents, while others are pleomorphic and may con-
tain fibrillary internal structures resembling zymo-
gen granules of fetal pancreas. They are commonly
oriented toward the lumen in the acinar areas and
are scanty in the solid areas (KUMSTRA et al. 1992;
TUCKER et al. 1994; ORDONEZ 2001).
Molecular Analysis. It appears that acinar cell carci-
noma is genetically distinct from ductal adenocarci-
noma. No overexpression of p53 protein or molecular
evidence of p53 mutation is seen (TERHUNE et al.
1998; HOORENS et al. 1993; ABRAHAM et al. 2002),
only rare cases show the characteristic ductal Ki-ras
mutation at codon 12 (HOORENS et al.1993; MOORE et
al. 2001),and no loss ofDPC4 or p16 is found (MOORE
et al. 2001). In contrast, allelic loss on chromosome
11 p occurs in up to 50% of patients, and molecular
alterations in the APC/ beta-catenin pathway are
present in approximately 25% of patients, genetic
alterations held in common with pancreatoblastoma
(ABRAHAM et al. 2002).
Cytology. Few reports describe the fine-needle
aspirate features of these tumors. Cytomorphologi-
cally, the smears show loose clusters or single cells
with granular eosinophilic cytoplasm and eccentric
nuclei with prominent nucleoli, some forming acinar
structures (ISHIHARA et al. 1989; LABATE et al. 1997)
(Fig. l3.2d).
13.2.2.3
Differential Diagnosis
The main tumors in the differential diagnosis are
ductal adenocarcinoma, endocrine tumors, solid-
pseudopapillary tumor, and pancreatoblastoma.
Ductal adenocarcinoma is easily separated from
acinar cell carcinoma (SOLCIA et al. 1997). Macro-
scopically, those tumors are usually firm, ill defined,
predominantly occurring in the head of the pancreas.
Histologically, they consist of duct-like glands embed-
ded in desmoplastic stroma. The cells stain for mucin
and for CEA and CA19.9 immunohistochemically.
They are usually negative for pancreatic enzymes
(MOROHOSHI et a1.1983; HOORENS et al.1993).
Endocrine tumors have a better prognosis than
acinar cell carcinoma, and it is important to distin-
guish them. This distinction may be difficult at the
light microscopic level when acinar cell carcinoma
displays a solid and trabecular pattern.
Histologic features favoring endocrine tumors
include: absence of foci of acinar differentiation,
226
more regular arrangement of the nuclei in the solid
areas, absence of intracellular PAS-positivity, and
more distinct demarcation from the surrounding
normal tissue along with denser, unevenly distrib-
uted fibrous stroma. Immunohistochemically, endo-
crine tumors are diffusely positive for markers such
as synaptophysin and chromogranin A, and negative
for pancreatic enzymes such as trypsin and lipase.
Ultrastructurally, they have typical dense core neuro-
secretory granules, 100-200 nm in diameter, and they
lack zymogen granules and acinar differentiation.
Solid-pseudopapillarytumors have a favorable prog-
nosis and a predilection for young women, although
they can occur at any age. Macroscopically, they often
show cystic degenerative changes, and microscopically,
they are characterized by a solid-pseudopapillary
pattern of growth with distinct fibrovascular myxoid
stroma and monomorphic cells, which have clear
to faintly eosinophilic cytoplasm and often nuclear
grooves. Immunohistochemically, these tumors are
positive for vimentin and negative for cytokeratin
CAM 5.2. They are also diffusely positive for NSE and
CDs6, with strong focal positivity for alpha-I-antitryp-
sin. They are usually negative for chromogranin and
mostly negative for pancreatic enzymes (MIETTINEN
et al.1987; MOROHOSHI et al.1987). They are discussed
in detail in the chapter on cystic tumors.
Pancreatoblastomas enter the differential diagnosis
with acinar cell carcinomas when they occur in adults
or when acinar cell carcinomas occur in children.
13.2.2.4
Prognosis and Treatment
Acinar cell carcinomas are aggressive tumors
that have a poor prognosis. More than half of the
patients present with metastases at the time of the
diagnosis, mostly to regional lymph nodes or liver,
with rare extraabdominal spread in advanced cases
(WEBB 1977; MOROHOSHI et al. 1987; KUMSTRA et
al. 1992; HOORENS et al. 1993). The reported overall
mean survival is 18 and 42 months in different series,
patients who are younger at presentation enjoying
longer survival periods, the longest reported survival
being 90 months (KUMSTRA et al. 1992; HOORENS
1993). Among all pathological parameters, only a
tumor diameter less than 10 cm was found to influ-
ence survival in KUMSTRA'S series (KUMSTRA et al.
1992). Along with surgical resection, radiation and
chemotherapy have a palliative role, with an occa-
sional good response to chemotherapy in patients
with liver metastases (VAN KLAVEREN et al. 1990;
KUMSTRA et al. 1992).
T. Oweity and A. B. West
13.2.3
Mixed Acinar-Endocrine Carcinoma
Although scattered endocrine cells may be seen in
up to 40% of acinar cell carcinomas (KUMSTRA et
al. 1992; HOORENS et al. 1993), truly mixed acinar-
endocrine tumors are extremely rare. They are
defined as tumors in which the acinar or endocrine
components are significant, constituting over 25%
(KUMSTRA et al. 1994) or 30%-50% of the tumor,
with the two cell populations intimately admixed
with each other (SOLCIA et al. 1997). Only rare cases
have been reported, and terms such as mixed acinar-
endocrine carcinoma (KUMSTRA et al. 1994), mixed
exocrine-endocrine tumor (HASSAN and GOGATE
1993), and acinar-endocrine cell tumor (UUCH et
al. 1982) have been used. These tumors provide fur-
ther evidence of the close histogenetic relationship
between the endocrine and exocrine components of
the pancreas. Their existence suggests that neoplastic
cells of the pancreas may have the potential for dual
differentiation, reflecting the common embryologic
origin of the endocrine and exocrine components
(KLOPPEL 2000).
13.2.3.1
Clinical Features
In the small series of five patients reported by
KUMSTRA, the tumors occurred in adult men and
women, age range 48-81 years (mean 68 years). None
presented with symptoms related to either enzyme or
hormone production (KUMSTRA et al. 1994).
13.2.3.2
Pathology
The tumors were fairly well circumscribed and histo-
logically very cellular, with various combinations of
solid, trabecular, acinar, and glandular growth pat-
terns, the solid pattern predominating. Only in one
patient were the endocrine and exocrine components
distinct under light microscopy, while in the others,
the cells were morphologically uniform with round
to oval nuclei and prominent nucleoli, with divergent
differentiation detected only immunohistochemically.
The cells contained diastase-resistant PAS-positive
granules and showed immunohistochemical positivity
for pancreatic enzymes (trypsin, chymotrypsin, and
focally lipase) and endocrine markers (chromogranin
and synaptophysin) with specific endocrine hormones
(glucagon, somatostatin, gastrin, vasoactive intestinal
polypeptide, VIP) found in two cases. Double immu-
Rare Solid Tumors: Clinical Manifestations and Pathology
no staining showed only one line of differentiation
(acinar or endocrine) in most cells, with few cells
showing both reactions (amphicrine).
Ultrastructurally, there was an admixture of cells
showing acinar and endocrine differentiation. Two
populations of granules were detected: neurosecre-
tory dense core type, 100-130 nm in diameter, and
zymogen granules, 250-525 nm in diameter. Many of
the cells showed intermediate features with frequent
variably sized granules of indeterminate type.
13.2.3.3
Prognosis
The prognosis appears to be similar to that of acinar
cell carcinoma. Four of the five patients developed
metastases within 1 year, and 2 died of their disease
(KUMSTRA et al. 1994).
13.2.4
Solid-Pseudopapillary Tumor
These uncommon tumors are frequently cystic and
are reviewed in greater detail in the chapter on cystic
tumors. First described by FRANTZ in 1959 (FRANTZ
1959), they are tumors of low malignant potential
that may occur at any age, but primarily affect young
women (KLOPPEL et al.1981). They have low metastatic
potential, metastases most commonly occurring in the
liver. They have been reported under various names
describing their variable gross and microscopic fea-
tures, which include: solid and cystic (KLOPPEL et al.
1981), papillary-cystic (BOOR and SWANSON 1979), and
solid and papillary (CUBILLA and FITZGERALD 1984).
The name solid-pseudopapillary tumor encompasses
the most characteristic histologic features: the solid
and pseudopapillary regions (SOLCIA et al. 1997).
13.2.4.1
Pathology
Macroscopically, the tumor varies from solid to
frequently cystic due to extensive hemorrhage and
degeneration (Fig. 13.3a).
Microscopically, it is characterized by uniform
cells, with often indented, hypo chromatic nuclei, and
clear to faintly eosinophilic cytoplasm, arranged in
solid and pseudopapillary patterns. In the latter, the
cells tend to degenerate away from the fibrovascular
stroma and gradually form cystic spaces with foamy
macrophages and cholesterol clefts (SOLCIA et al.
1997; KUMSTRA et al. 2000) (Fig. 13.3b). Immunohis-
227
to chemically, the tumor cells are positive for vimen-
tin (Fig. 13.3c), NSE, alpha-I-antitrypsin, CD10 and
CD56, and negative for cytokeratin.
Cytologically, fine-needle aspirate smears show
single cells and papillary fragments with fibrovas-
cular stroma, which appears metachromatic on Diff-
Quik stain, surrounded by cells with uniform, often
grooved nuclei, and wispy, ill-defined to eosinophilic
cytoplasm (WILSON et al.1992) (Fig. 13.3d-f).
13.2.4.2
Treatment and Prognosis
Surgery is the treatment of choice, and experience
with adjuvant therapy is limited. Complete resection
should be attempted, even if this requires resection
of metastases, as long-term survival can be achieved
even following the development of metastatic disease.
At a median follow-up of 8 years, only one recurrence
was seen in 18 patients who underwent complete
resection (MARTIN et al. 2002).
13.2.S
Osteoclast-like Giant-Cell Tumor
Also known as giant-cell tumor of the pancreas,
giant-cell carcinoma of the pancreas osteoid type,
giant-cell tumor (osteoclastic) of the pancreas, these
are rare tumors of the pancreas that simulate giant-
cell tumors of bone. First described by ROSAI in 1968,
they are defined histologically by the presence of
multinucleate osteoclast-like giant cells admixed with
proliferating oval to spindle-shaped, mononuclear
cells (ROSAI 1968).
13.2.5.1
Clinical Picture
The patients' age range is 3-82 years with a mean
age of 60 years. Women are more frequently affected
than men. The main symptoms are abdominal pain,
weight loss, jaundice, and a palpable mass (MANCI et
al. 1985; SOLCIA et al. 1997).
73.2.5.2
Pathology
Macroscopic Features. Most tumors appear in the
head of the pancreas and present as a large mass,
averaging 11 cm in diameter, with a rubbery, firm
consistency and a lobulated, white to yellow, focally
necrotic cut surface. Invasion into adjacent organs is
 228 T. Oweity and A. B. West

a b

c d

e f
Fig.13.3a-f. Solid-pseudopapillary tumor. a This tumor is mostly solid with a tan, granular surface, but some areas of degenera-
tion and cystic change (right and left). b The tumor cells are arranged around fibrovascular cores with a papillary appearance.
The cells away from the cores degenerate and falloff (H&E). c The tumor cells are diffusely positive for vimentin (brown),
highlighting the papillary arrangement (vimentin immunostain). d Papillary fragments have fibrovascular cores surrounded
by tumor cells, which are also present dissociated in the background (fine-needle aspirate, Papanicolaou stain, low power). e
The tumor cells are bland without significant atypia and with occasional nuclear grooves (fine-needle aspirate, Papanicolaou
stain, high power). f The fibrovascular cores appear metachromatic, with and without surrounding tumor cells (fine-needle
aspirate, Diff-Quik stain)
Rare Solid Tumors: Clinical Manifestations and Pathology
common, but metastases are found in only 50% of
patients (MANCI et al. 1985; SOLCIA et al. 1997).
Microscopic Features. The tumors are composed of
two populations of cells. The first population is a
proliferation of mononuclear cells of oval to spindle
shape, with pleomorphic-hyperchromatic nuclei,
distinct nucleoli, and faintly eosinophilic cytoplasm.
Mitoses can be abundant. The second distinctive
population is of multinucleate giant cells containing
abundant dense eosinophilic cytoplasm and 20 to
100 small, uniform nuclei with prominent nucleoli,
resembling osteoclasts (Fig. 13.4). In some of the
cases, pleomorphic, malignant-appearing, bizarre,
multinucleated giant cells may also be present
(LEWANDROWSKI et al. 1990; MULLICK and MOODY
1996; DECKARD-JANATPOUR et al. 1998).
Some osteoclast-like giant-cell tumors are associ-
ated with nearby areas of ductal hyperplasia or atypia
(GOLDBERG et al. 1991), others contain foci of ductal
adenocarcinoma (CUBILLA and FITZGERALD 1984),
and yet others lack neoplastic glands (ROSAI 1968;
SUSTER et al.1989; NEWBOULD et al.1992; WESTRA et al.
1998; MACHADO et al. 2001). A few have been reported
arising in the wall of a mucinous cystic neoplasm
(POSEN 1981; AOKI et al.1989; MENTES and YUCE 1993).
In some, foci of osteoid formation are present (CUBILLA
and FITZGERALD 1984; KAY and HARRISON 1969).
Electron Microscopy, Immunohistochemistry, and
Histogenesis. Conflicting results have been published
in the literature demonstrating epithelial and/or
mesenchymal features of this tumor and reflecting
the uncertainty about its histogenesis, which could
theoretically be explained by divergent differentiation
from a common precursor cell (LEWANDROWSKI et al.
1990). Epithelial acinar differentiation was suggested
initially by ROSAI (1968), based on the findings of
microvilli, desmosomes, and zymogen-like granules.
This was supported later by immunohistochemical
data showing positivity for epithelial markers such as
cytokeratin, epithelial membrane antigen (EMA), CEA,
and CA 19.9 (TREPETA et al.1981; BERENDT et al.1987;
NOJIMA et al. 1993; DECKARD-JANATPOUR et al. 1998;
IMAI et al. 1999; LEIGHTON and SHUN 2001). Mesen-
chymal differentiation was suggested by some reports
documenting positivity for vimentin in the absence
of keratin and of ultrastructural epithelial features in
the mononuclear and osteoclast-like cells (SUSTER et
al. 1989; LEWANDROWSKI et al. 1990; GOLDBERG et al.
1991; DWORAK et al. 1993; MACHADO et al. 2001). The
osteoclast-like giant cells have been found to stain
229
Fig. 13.4. Osteoclast-like giant-cell tumor. Osteoclast-like cells
with numerous nuclei are disposed among spindle-shaped
mononuclear cells with pleomorphic hyperchromatic nuclei
and occasional bizarre giant cells. The pigment is hemosiderin
(H&E). Case courtesy of Dr DIVA SALOMAO
as monohistocytic!mesenchymal cells for vimentin,
leukocyte common antigen (LCA), lysosomes, CD-68,
alpha-1-antichymotrypsin, and occasionally smooth
muscle actin, and mostly lack staining for epithelial
markers (LEWANDROWSKI et al. 1990; DECKARD-
JANATPOUR et al. 1998; SAKAI et al. 2000; MACHADO
et al. 2001), although the mononuclear and other
pleomorphic giant cells in the same tumors may show
epithelial differentiation (DECKARD-JANATPOUR et al.
1998; IMAI et al. 1999; SAKAI et al. 2000), suggesting
that osteoclast-like giant cells may represent a reactive
rather than a neoplastic component of the tumor.
Molecular Analysis. K-ras mutation involving codon
12.13 has been detected in osteoclast-like giant-cell
tumors, supporting a ductal origin (DECKARD-
JANATPOUR et al. 1998; IMAI et al. 1999; SAKAI et al.
2000). In some reports, these mutations were localized
specifically to the osteoclastic giant cells, suggesting
that this may be due to phagocytosis of mononuclear
tumor cells (WESTRA et al. 1998), while in another
report, the mutation was demonstrated to occur in
the other neoplastic cells but not in the osteoclastic
giant cells (SAKAI et al. 2000). Whether these cells are
neoplastic due to the fusion of mononuclear cells or
reactive is still a matter of debate.
13.2.5.3
Treatment and Prognosis
Complete surgical resection is the treatment of
choice; experience with radiotherapy or chemo-
230
therapy has not been reported (LEIGHTON and
SHUN 2001). Although many of these tumors have
been found to be aggressive with a behavior similar
to ductal adenocarcinoma and expected survival of
less than 1 year (DWORAK et al. 1993; LEIGHTON and
SHUN 2001), occasional cases with long survival (up
to 15 years) have been reported (JEFFREY et al. 1983;
CUBILLA and FITZGERALD 1984; DWORAK et al.1993;
MACHADO et al. 2001). Prolonged survival has been
related to a total absence of epithelial/ductal dif-
ferentiation on both routine light microscopy and
immunohistochemistry (MACHADO et al. 2001). This
probably reflects the presence of a spectrum of more
and less aggressive tumors displaying osteoclast-like
giant cells, including at one end the highly aggres-
sive pleomorphic giant-cell carcinoma (CUBILLA and
FITZGERALD 1984; MACHADO et al. 2001).
13.3
Other Epithelial Tumors
13.3.1
Clear-Cell Carcinoma
Focal clear-cell change is occasionally seen in ductal
or anaplastic pancreatic carcinomas (URBANSKI and
MEDLINE 1982), but tumors composed predomi-
nantly of clear cells are rare (CUBILLA and FITZGER-
ALD 1984; KANAI et al. 1987; LUTTGES et al. 1998).
13.3.1.1
Pathology
Macroscopically, these are solid tumors; microscopi-
cally, they consist of sheets and nests of cells with
slightly pleomorphic nuclei and clear glycogen-rich
cytoplasm. These tumors resemble the more com-
monly encountered clear-cell tumors of the kidney,
adrenals, and lung. No sinusoidal/vascular pattern,
necrosis, or distinct desmoplastic reaction are noted
(LUTTGES et al. 1998). Evidence of ductal origin has
been found in some cases, including intracytoplas-
mic mucin, elevated serum levels of CEA and CA 19.9,
and focal positive staining for CEA (CUBILLA and
FITZGERALD 1984; KANAI et al. 1987; LUTTGES et al.
1998). Additionally, an intraductal papillary compo-
nent was detected in the case described by LUTTGES
(LUTTGES et al. 1998). In that case, the tumor cells
showed positive staining for p53 and cytokeratins 7,
8, 18, and 19, but were negative for neuroendocrine
markers and vimentin. This, along with documenta-
T. Oweity and A. B. West
tion of a K-ras mutation at codon 12, which is seen
in more than 90% of pancreatic ductal carcinomas,
is further supporting evidence of a ductal phenotype
(LUTTGES et al. 1998).
13.3.1.2
Prognosis
The few reported cases of clear-cell carcinoma of the
pancreas have metastasized and behaved poorly, sim-
ilar to other pancreatic ductal carcinomas (CUBILLA
and FITZGERALD 1984; KANAI et al. 1987; LUTTGES
et al. 1998).
13.3.1.3
Differential Diagnosis
The first consideration on encountering a clear-cell
carcinoma in the pancreas is a metastasis from an
extrapancreatic primary tumor, particularly renal
cell carcinoma which has a tendency to develop
solitary late metastases (THOMPSON and HEFFESS
2000). The presence of an intraductal component
is helpful in excluding metastasis. Immunostaining
positivity for cytokeratins and CEA, and negativity
for vim en tin and for other renal cell carcinoma mark-
ers (RCC, CD 10) help in establishing the diagnosis of
primary pancreatic carcinoma, supported by clinical
and radiologic findings.
Other pancreatic neoplasms with clear-cell fea-
tures include endocrine tumors (GUARDA et al. 1983;
SOLCIA et al. 1997), solid-pseudopapillary tumor,
solid serous cystadenoma (PEREZ-ORDONEZ et al.
1996), and sugar tumor (ZAMBONI et al. 1996). The
last of these has been described only once in the
pancreas. Solid serous cystadenoma is negative for
CEA; sugar tumor (a mesenchymal tumor with epi-
thelioid cells characterized by an abundant vascular
sinusoidal network) is positive for vimentin and
HMB 45. Negativity for neuroendocrine markers
such as chromogranin and synaptophysin excludes
a neuroendocrine tumor, and negativity for NSE,
alpha-I-antitrypsin, and vimentin excludes solid-
pseudopapillary tumor.
13.3.2
Oncocytic Tumors
Tumors with oncocytic change in the pancreas are
otherwise well-defined entities such as endocrine
neoplasms (GOTCHALL et al. 1987; PACCHIONI et al.
1996), solid-pseudopapillary tumor (LEE et al. 1993),
Rare Solid Tumors: Clinical Manifestations and Pathology 231

or acinar cell carcinoma packed with zymogen gran- reported by NOZAWA et al. (1990) showed perineural!
ules (PAPOTTI et al. 1999). Pure oncocytic tumors in vascular invasion but lacked mitoses or nuclear pleo-
the pancreas are extremely rare (HUNTRAKOON morphism and was stable in size without metastases
1983; CHEN and BAIT HUN 1985; BONDE SON et al. at the 3-year follow-up.
1990; NOZAWA et al. 1990; SIRONI et al. 1991; ZERBI
et a1.1993). They are considered to be of ductal origin
(PAPOTTI et al. 1999). 13.3.3
Minor Epithelial Tumors
73.3.2.7
Pathology Other rare tumors have been described, most of
which represent variants of ductal carcinoma, e.g.,
Macroscopically, they may be large and encapsulated mucoepidermoid carcinoma (ONODA et al. 1995),
with a white-tan firm cut surface (Fig. 13.5a) and may ciliated carcinoma (SOMMERS and MEISSNER 1954;
exhibit cystic change (HUNTRAKOON 1983; NOZAWA MORINAGA et al. 1986), and carcinosarcoma (MILLIS
et al. 1990; THOMPSON et al. 1998). et al. 1994).
Microscopically, the tumor cells are large with
abundant, finely granular eosinophilic cytoplasm, and
uniform nuclei with prominent nucleoli (Fig. 13.5b).
The growth pattern is solid (HUNTRAKOON 1983;
NOZAWA et al. 1990), nested (CHEN and BAIT HUN
1985), or papillary (THOMPSON et al. 1998). Intra-
ductal papillary carcinomas with predominantly
oncocytic features have also been described (ADSAY
et al. 2000) where arborizing papillae lined by strati-
fied oncocytic cells may be confluent, forming large
sheets and imparting a pseudosolid pattern of
growth.
Ultrastructurally, the cells are packed with mito-
chondria but lack zymogen and neurosecretory
granules. Immunohistochemistry confirms the lack of
endocrine and acinar markers, and positivity for cyto-
keratin (CAM 5.2) and CEA further supports a ductal
origin (NOZAWA et al.1990; THOMPSON et al. 1998).
Cytologically, the cells obtained by fine-needle aspi- a
rates are uniform, epithelioid, clustered, disassociated,
or in papillary fragments. They have abundant well-
defined cytoplasm, which appears tan, gray-blue on
the May-Grunwald-Giemsa and Diff-Quik stains, and
granular eosinophilic on H&E stains. The nuclei are
eccentric, round, regular with single, prominent nucle-
oli (BONDESON et al. 1990; THOMPSON et al. 1998).
The differential diagnosis includes other acinar,
endocrine, and solid-pseudopapillary tumors of the
pancreas. It also includes extrapancreatic tumors
which are much more likely to have oncocytic features
such as those arising in the kidney or thyroid.

73.3.2.2
Prognosis
The behavior of oncocytic tumor is uncertain although
usually malignant (HUNTRAKOON 1983; SIRONI et al.
1991; ZERBI et al. 1993; THOMPSON et al. 1998). A case
Fig.13.5a,b. Oncocytic tumor. a The tumor has a yellowish-tan
cut surface with a central scar resembling renal oncocytoma.
b The tumor has a solid lobular architecture and is composed
of cells with abundant, granular, eosinophilic cytoplasm,
uniform nuclei, and prominent nucleoli (H&E). Photographs
courtesy of Dr RICHARD EISEN
232
13.4
Lymphomas
13.4.1
Incidence and Epidemiology
Although secondary involvement of the pancreas
is seen in more than 30% of patients with non-
Hodgkin's lymphoma (BEHRNS et al. 1994), primary
pancreatic lymphoma is rare, comprising less than
2% of extranodal non-Hodgkin's lymphomas, though
it is more common in HIV-positive patients (RADIN et
al. 1993; JONES et al. 1997). The diagnostic criteria for
primary pancreatic lymphoma include a predominant
pancreatic mass with gross involvement of only the
peripancreatic lymph nodes, in the absence of hepatic,
splenic, mediastinal, or superficial lymphadenopathy,
and along with a normal leukocyte count (BEHRNS et
al. 1994). Primary pancreatic lymphoma represents
1%-3% of pancreatic malignancies (REED et al. 1979;
MANSOUR et al. 1989; TUCHECK et al. 1993).
13.4.2
Clinical Manifestations
The patients' age range is 23-89 years (mean 56 years),
and this tumor is slightly more common in men than
women (MERKLE et al. 2000). Primary pancreatic lym-
phoma presents with nonspecific symptoms similar to
those of adenocarcinoma. The duration of symptoms
ranges from 2 days to 32 years (average 19 weeks). The
most common symptoms reported are: abdominal
pain (73%), weight loss (51 %),jaundice (42%), nausea
(34%), vomiting (18%), and fatigue (9%). Fever, chills,
and night sweats, symptoms classic of non-Hodgkin's
lymphoma elsewhere, are rarely reported (9%). The
only clinical presentation that suggests the possibility
of pancreatic lymphoma is a large, palpable pancre-
atic mass, homogenous on imaging, presenting with
abdominal pain and without jaundice, particularly
when lactate dehydrogenase (LDH) levels are elevated
(BOUVET et al. 1998; MERKEL et al. 2000).
13.4.3
Pathology
Resected primary pancreatic lymphomas appear
grossly as large, soft, nodular masses, ranging in size
from 4 to 14 cm, most commonly occurring in the
head of the organ (SATAKE et al.1991). The pancreatic
ductal system may be displaced but is not usually
destroyed (SOLCIA et al. 1997) (Fig. 13.6a).
T. Oweity and A. B. West
The diagnosis of lymphoma in most cases can be
established without surgery, using a percutaneous or
endoscopic, CT- or ultrasound -guided, fine- needle or
core biopsy (CARTER et al.1988; ROBBINS et al.1995).
Immediate assessment of the aspirate at the time of
the procedure is critical to ensure proper handling
of the specimen. When a preliminary diagnosis of
lymphoma is formed, sufficient sample for ancillary
studies should be obtained for confirmation. These
may include immunophenotyping by flow cytometry
or immunohistochemistry, and gene rearrangement
studies, particularly in certain rare cases of T-cell
lymphoma (KATZ et al. 1991; ROBBINS et al. 1995).
The majority of cases are of diffuse large-celllym-
phoma, predominantly of B-cell immunophenotype
(EZZAT et al. 1996;, BOUVET et al. 1998), although low
or intermediate grade tumors (small or mixed small
and large cells) have been reported in about 20% of
cases (PRAYER et al. 1992; KONIARIS et al. 2000), in
addition to occasional T-cell lymphomas (NISHIMURA
et al. 2002). The aspirate smears commonly show large,
atypical lymphocytes, distributed singly, in a back-
ground of lymphoglandular bodies, which represent
small fragments of cytoplasm that have detached from
lymphoid cells; these are specific for lymphoma and
cannot be seen on histology sections (BOUVET et al.
1998). Additional findings that support the diagnosis
of lymphoma include a monomorphic appearance of
the lymphoid cells (DEMAY 1996). The chromatin can
range from fine to coarse, with variable numbers and
prominence of nucleoli (Fig. 13.6b).
Cytologically, the differential diagnosis includes
undifferentiated carcinoma, particularly small-cell
carcinoma. The latter is more likely to show nuclear
molding, with a lack of lymphoglandular bodies. In
contrast to lymphomas, small-cell carcinomas are usu-
ally positive for keratin and some endocrine markers,
and negative for leukocyte common antigen (ACKER-
MAN et al.1976). Other rare tumors that may enter the
differential diagnosis include peripheral neuroecto-
dermal tumor (PNET), which should be considered
especially in children and can be distinguished by posi-
tivity for CD99 and negativity for leukocyte common
antigen (LUTTGES et al. 1997; MOVAHEDI-LANKARANI
et al. 2000), and desmoplastic small-cell tumor of the
abdomen.
13.4.4
Treatment and Prognosis
The primary treatment for pancreatic lymphoma is
combined chemotherapy with involved-field radio-
therapy, achieving cure rates of about 46% (KONIARIS
Rare Solid Tumors: Clinical Manifestations and Pathology 233

et al. 2000). The role of surgery is more controversial.

While some believe that the only role for surgery is in
establishing the diagnosis when percutaneous or endo-
scopic biopsies fail to do so (WEBB et al. 1989), others
recommend a more aggressive approach in resectable
cases (BEHRNS et al. 1994), suggesting a higher cure rate
for surgically treated patients (KONIARIS et al. 2000).

13.5
Germ-Cell Tumors

13.5.1 a
Teratoma

Intrapancreatic teratomas usually occur in patients

less than 25 years old (mean 20 years, median 11
years) (MESTER et al. 1990). Symptomatic patients
present generally with abdominal-lumbar pain and
have a palpable left upper quadrant mass. Radiologi-
cally and macroscopically, these tumors are charac-
terized by a solid-cystic appearance with a distinct
capsule (BOWEN et al. 1987). Hair, mucoid and fatty
areas, bone, or teeth are usually seen. Histologically,
teratomas consist of variably differentiated cells (usu-
ally well differentiated) from the three germ layers
including cartilage, bone, fat, teeth, and columnar or b
squamous epithelium, similar to mature teratomas
elsewhere. They likewise probably originate from Fig. 13.6a,b. Lymphoma. a Neoplastic lymphocytes diffusely
germ cells arrested in migration to the gonads early infiltrate and replace part of the pancreas (H&E, low power). b
The tumor is composed of a monomorphic population of dys-
in embryonic life (GONZALEZ-CRUSSI 1982).
cohesive lymphoid cells with prominent nucleoli (fine-needle
aspirate, ultrafast Papanicolaou stain)

13.5.2
Choriocarcinoma

Two cases of primary pancreatic choriocarcinoma
have been reported. Both tumors were cystic due to
necrosis and hemorrhage. They consisted microscop-
ically of typical choriocarcinoma, with undifferenti-
ated cytotrophoblastic cells and syncytiotrophoblast
which stained for HCG. They lacked gland forma-
tion and keratinization. Serum beta-HCG levels were
elevated, and dropped following the initiation of che-
motherapy (CHILDS et al. 1985; COSKUN et al. 1998).
(KLOPPEL and MAILLET 1989; FER ROZZI et al. 2000).
They derive from various connective tissue compo-
nents and can be classified according to their histo-
logic origin into lymphovascular, myogenic, fatty, or
neurogenic categories.
13.6.1
Lymphovascular Tumors

13.6
Mesenchymal Tumors
Mesenchymal tumors of the pancreas are rare,
accounting for 1%-2% of all pancreatic tumors
13.6.1.1
Lymphangioma
Lymphangiomas are rare benign tumors, of which
only a few cases have been reported in the literature.
In a review of 10 cases from the Endocrine Pathology
Registry of the Armed Forces Institute of Pathology,
234
8 cases occurred in female patients, two in males,
age range 2-61 years (mean 28.9 years) at initial
presentation (PAAL et al. 1998). Macroscopically, the
tumors were well circumscribed, and 6 occurred in
the tail of the pancreas. They can grow within the
parenchyma or can be connected to the organ by a
pedicle (FERROZZI et aI. 2000). They are multicystic,
containing serous or chylous fluid, and range in size
between 3 and 20 cm in greatest dimension (PAAL
et al. 1998). Histologically, lymphangiomas consist
of multilocular cystic spaces of various sizes rang-
ing from microscopic to as large as 10 cm, lined by
endothelial cells. The stroma contains smooth muscle
and mature lymphocytes. A thin capsule of fibrous
tissue is present (ABE et al. 1997). Calcifications are
rare (HANELIN and SCHIMMEL 1977). Immunohis-
tochemically, the lining endothelial cells stain posi-
tively for factor VIII-R antigen and CD-31, but are
CD-34 negative in all cases.
Lymphangiomas have an excellent prognosis. In
the series of PAAL et al. (1998), following surgery, all
patients were alive without disease with a median
follow-up of 7.2 years from diagnosis.
13.6.1.2
Hemangioma
Rare cases of hemangioma have been reported
(MANGIN et al. 1985). Most have a characteristic
radiological appearance and are easily diagnosed
(KOBAYASHI et al. 1991). Macroscopically, hemangio-
mas appear red, resembling a hematoma. Histologi-
cally, they consist of cavernous vascular spaces lined
by endothelial cells and filled with blood (KOBAYASHI
et al. 1991) and may be a cause of retroperitoneal or
intraabdominal hemorrhage.
13.6.1.3
Hemangioendothelioma
Few cases of hemangioendothelioma have been
reported, mainly in infants and children (HORIE et
al. 1985). Jaundice or pain was the presenting symp-
tom. Macroscopically, hemangioendotheliomas may
be poorly demarcated, white, and hard. Histologically,
the tumor cells infiltrate the pancreas, compressing
adjacent tissue. They are spindled or round, arranged
in rows and short strands in a fibrous stroma. Some
of the tumor cells line vascular channels and blood-
filled spaces, with moderate atypia and rare mitoses.
Focal fibrin thrombi are seen in the vascular spaces.
The cells stain positively for factor VIII (HoRIE et al.
1985). Although high cellularity and an infiltrative
T. Oweity and A. B. West
growth pattern may raise a suspicion of malignancy,
hemangioendotheliomas have a favorable prognosis
and spontaneous regression can be expected, even
without resection or treatment. Thus, a conservative
approach to treatment is generally recommended
(TUNELL 1976).
13.6.1.4
Other Lymphovascular Tumors
Other vascular tumors reported include hemangio-
pericytoma (BARDAXOGOU et al. 1995), which may
behave aggressively and metastasize, and angiosar-
coma (BANCU et al. 1971).
13.6.2
Adipose Tissue Tumors
In the pancreas, tumors of adipose tissue are
extremely rare (BIGARD et al. 1989; DI MAGGIO et al.
1996; BARUTCU et al. 2002). Lipomas consist of lob-
ules of mature adipose tissue surrounded by a thin
capsule presenting as a sharply defined mass. They
are usually recognized radiologically and should be
differentiated from localized lipomatosis which is
connected to the peripancreatic fat and does not have
a capsule (FERROZZI et al. 2000; BARUTCU et al. 2002),
and from the rare liposarcomas (ELLIOTT et al. 1980;
MILANO et al. 1988), fibrolipoma, and lipoblastoma.
13.6.3
Myogenic Tumors
13.6.3.1
Leiomyoma
Primary leiomyoma of the pancreas has occasionally
been described (NAKAMURA et al. 2000; BAKOLAS et
al. 2001). Radiologically and macroscopically, the
tumor has a sharp, well defined/encapsulated margin
without invasion of surrounding structures. It is com-
posed of bland, spindle-shaped, smooth muscle cells
in interweaving fascicles. However, the differential
diagnosis from leiomyosarcoma can be exceedingly
difficult (see below).
13.6.3.2
Leiomyosarcoma
Leiomyosarcomas of the pancreas primarily affect
adults in the 5th decade of life or older (mean age
Rare Solid Tumors: Clinical Manifestations and Pathology 235

53.6 years, range 14-80 years), with a nearly equal

male to female ratio (NESI et al. 2001). The present-
ing symptoms are nonspecific including abdominal
mass, pain, and weight loss. The tumors range in
size from 3 to 25 cm (median 11 cm), larger ones
frequently undergoing cystic degeneration and mim-
icking pancreatic pseudo cysts radiologically. The cut
surface is fleshy with variable areas of necrosis and
degeneration. Microscopically, the tumors have an
expansile growth pattern and may be encapsulated
and entrap residual normal pancreatic elements
(DE ALAVA et al. 1993; FERLAN-MARLoT et al. 2000;
MACHADO et al. 2000; NESI et al. 2001) (Fig. 13.7a).
The tumor cells are spindle-shaped, arranged in com- a
pact bundles and fascicles which may display herring
bone or storiform patterns in areas. The nuclei are
generally elongated, blunt ended, and cigar shaped,
surrounded by ill-defined eosinophilic cytoplasm
(Fig. 13.7b). Foci of round cells with an epithelioid
appearance may be present (FERLAN-MARLoT et al.
2000; NESI et al. 2001). Nuclear atypia and pleomor-
phism are variable depending on the grade of the
tumor: While these can be minimal in better differen-
tiated tumors (ISHIKAWA et al. 1981), they tend to be
prominent features in higher grade tumors with giant
and bizarre cells occasionally present (ZALATNAI et
al. 1998). Mitotic counts are variable also: Cases with
rare mitoses (0 to 1 per 10 high power fields) have b
been reported to metastasize, while mitotic counts of
more than 10 per 10 high power fields are associated
with an adverse outcome (ISHIKAWA et al. 1981; NESI
et al. 2001). Tumor necrosis is common.
Leiomyosarcomas are thought to originate from
smooth muscle cells of either the pancreatic ducts
or the intrapancreatic small vessels (ZALATNAI et al.
1998). The tumor cells are usually positive for actin
(muscle-specific actin and smooth muscle actin)
(Fig. 13.7c) with more variable staining for desmin,
consistent with a myogenic phenotype. This along
with positive vimentin staining and negative stain-
ing for epithelial markers (cytokeratins, EMA, CEA),
helps in excluding the more commonly encountered
sarcomatoid carcinoma, although focal keratin posi-
tivity in an otherwise typical leiomyosarcoma has
Fig. 13.7a-c. Leiomyosarcoma. a The tumor is cellular with an
been reported (SOLCIA et al. 1997). Ultrastructural expansile growth pattern (H&E, low power). b Spindle-shaped
studies are supportive of smooth muscle differentia- neoplastic cells exhibit pleomorphism and abundant mitoses
tion (ISHIKAWA et al. 1981; DE ALAVA et al. 1993). (H&E, high power). c The tumor cells express smooth muscle
The differential diagnosis of primary pancreatic actin (brown), supporting a myogenic phenotype (actin
immunostain). Case courtesy of Dr DIVA SALOMAO
leiomyosarcoma includes sarcomatoid carcinoma,
other poorly differentiated sarcomas, and leiomyo-
sarcoma metastatic from other organs. The clinical
and immunohistochemical features generally help
in making a definitive diagnosis. Distinguishing
236
leiomyoma from leiomyosarcoma is a more difficult
problem: However, since leiomyomas have been
very rarely reported in the pancreas, and as smooth
muscle tumors with as few as one mitosis per 10 high
power fields in a moderately cellular background
with minimal pleomorphism have been reported to
metastasize (ISHIKAwA et al. 1981), a diagnosis of
primary pancreatic leiomyoma should be made with
caution.
Although the number of reported cases is small,
leiomyosarcomas appear to be highly malignant,
usually pursuing an aggressive course. They are often
widely metastatic at the time of the presentation, par-
ticularly affecting the liver and sparing lymph nodes.
Surgical resection offers the best hope for prolonged
survival in localized cases (NESI et al. 2001).
13.6.4
Neurogenic Tumors
13.6.4.1
Schwannoma
Schwannomas (neurinomas, neurilemmomas) are
thought to derive from Schwann cells enveloping
peripheral nerves. They generally affect older adults
(average 60 years), with equal sex incidence, and are
often incidental findings (BROWN et al. 1998). The
most common presenting symptom is pain (ALMO
and TRAVERSO 2001). Some arise in a setting of Von
Recklinghausen's disease (WALSH and BRANDSPIGEL
1989; ALAMO and TRAVERSO 2001). Although the
majority of the reported cases have been benign, a
few malignant schwannomas (malignant peripheral
nerve sheaths tumors) have been reported (LUTT-
GES et al. 1997; MORITA et al. 1999), occasionally in
patients with Von Recklinghausen's disease. These
also tend to be cystic. Microscopically, they are often
poorly differentiated sarcomas in which the neural
phenotype may be difficult to demonstrate (BROWN
et al. 1998).
Schwannomas can be located in any part of
the pancreas (MORITA et al. 1999). They tend to
be encapsulated with a cystic cut surface, varying
from tan firm to yellow gelatinous depending on the
proportions of their cellular elements. They range
in diameter from 2 to 26 cm, average 7.4 cm. Histo-
logically, they are typical schwannomas, composed of
spindle cells with areas of cellular palisading (Antoni
A) and ofloose myxoid appearance (Antoni B). Peri-
vascular hyalinization may be prominent (Fig. 13.8).
The cells are immunoreactive for S-l 00 and vimentin
T. Oweity and A. B. West
and negative for epithelial and myogenic markers.
Electron microscopy shows long spaced collagen
(Luse bodies), numerous long, interdigitating cel-
lular processes, and abundant intercellular basement
membrane material (BROWN et al. 1998).
Surgical resection is the treatment of choice and
may involve enucleation for the benign tumors or
pancreatic resection. Preoperative or intraoperative
diagnosis aids in choosing the appropriate surgery
(MORITA et al. 1999). Following surgery, the progno-
sis is good, with no postoperative death reported.
13.6.4.2
Primitive Neuroectodermal Tumor
Primitive neuroectodermal tumors (PNETs, neu-
roepitheliomas) are very rare, small, round-cell
tumors that are part of the Ewing sarcoma family
of lesions. Patients range in age from 6 to 25 years
(mean 18 years) with an almost equal sex incidence
(BULCHMANN et al. 2000; MOVAHEDI-LANKARANI
et al. 2002). They usually present with jaundice or
abdominal pain.
These tumors are typically located in the head of
the pancreas and range in diameter from 3.5 to 9 cm.
Microscopically, they have the typical histology of
PNETs elsewhere and are composed of sheets and lob-
ules of small cells with round to oval nuclei and scant
cytoplasm. Nuclear molding may be prominent with a
mitotic rate of 3-5 per 10 high power fields. Infiltration
of peripancreatic soft tissue is a consistent finding. No
Homer-Wright rosettes are identified. Necrosis may be
present focally (MOVAHEDI-LANKARANI et al. 2002).
Immunohistochemically, there is strong cell mem-
Fig. 13.S. Schwannoma. The neoplastic spindle cells of this
tumor show prominent palisading. A hyalinized large vessel is
present on the left of the field (H&E,low power). Case courtesy
of Dr DIVA SALOMAO
Rare Solid Tumors: Clinical Manifestations and Pathology
brane positivity for CD-99, and most tumors are dif-
fusely positive for keratin AE-l/AE-3. NSE is positive
in the majority of patients, and focal chromogranin or
synaptophysin positivity may be seen. The tumor cells
are negative for desmin, actin, S-100 protein, insulin,
glucagon, and somatostatin. Ultrastructurally, they
display epithelial features including numerous desmo-
somes, and both neurosecretory granules and tonofila-
ments have been reported. Some 85% of patients show
the classic translocation t(11:22) (q24;q12), resulting
in the EWS-FLIl fusion gene.
The histologic differential diagnosis of PNET
includes all small, round-cell tumors such as lym-
phoblastic lymphoma, neuroblastoma, rhabdo-
myosarcoma, desmoplastic small round-cell tumor,
pancreatoblastoma, small-cell undifferentiated carci-
noma, and endocrine tumors. The pattern of positive
immunostaining for CD-99 (the MIC-2 gene product),
NSE, and keratin is characteristic and should confirm
the diagnosis. Although this profile may be seen in
desmoplastic small round-cell tumor, the latter is less
frequently positive for CD-99 and always positive for
desmin, in contrast to PNETs. Additionally, desmoplas-
tic small round-cell tumor displays the characteristic
t(11;22) translocation involving fusion of EWS gene
and WTl gene, different from the EWS-FLI 1 fusion
gene of PNETs. Small-cell undifferentiated carcinomas
appear in the adult population with a high mitotic rate
of more than 10 per high power field and karyorrhexis
similar to small-cell carcinomas of the lung. Endocrine
neoplasms of the pancreas usually display more diffuse
strong staining with synaptophysin or chromogranin
and may stain for islet-cell hormones and, unlike PNETs,
are predominantly tumors of adults. They display fine,
evenly distributed chromatin patterns and lack nuclear
molding. They also lack the EWS-FLI 1 fusion gene.
Neuroblastomas occur in young adults but lack the
characteristic translocation of PNETs. PNETs can be
distinguished from lymphoblastic lymphomas and
rhabdomyosarcomas by the lack of leukocyte common
antigen and muscle differentiation, respectively.
Although these tumors appear to be highly aggres-
sive, some patients treated surgically or with chemo-
therapy have a reported survival of up to 4 years.
13.6.5
Other Mesenchymal Tumors
Other miscellaneous mesenchymal tumors have been
reported such as solitary fibrous tumor (LUTTGES et
al. 1999) and the so-called malignant fibrous histio-
cytoma (PASCAL et al. 1989; BALEN et al. 1993).
237
13.7
Solid Tumor-like Lesions of the Pancreas
A variety of nonneoplastic conditions may present
with clinical and radiological features mimicking
pancreatic cancer.
13.7.1
Heterotopic (Ectopic) Spleen
Accessory spleens occur in about 10% of the popula-
tion. Most are located around the splenic hilum, but
in 16% of patients, they are located in the tail of the
pancreas (HAYWARD et al. 1992), and they rarely
occur in the head of the pancreas (LANDRY and
SARMA 1989). Although most of them are asymp-
tomatic, they may come to medical attention as a
hypervascular pancreatic mass which can mimic an
endocrine (islet-cell) tumor, metastasis, or pancreatic
carcinoma (SUZUKI et al. 1994; HARRIS et al. 1994;
CHUREI et al. 1998; BARAWI et al. 2000). Elevation
of CA19.9 and CEA serum levels has been reported
(CHUREI et al. 1998; LAUFFER et al. 1999).
Macroscopically, accessory spleens appear as well-
demarcated red masses, 0.5-4 em in size, usually in
the tail of the pancreas (SOLCIA et al. 1997). Micro-
scopically, they consist of lymphoid follicles and
splenic pulp. They may give rise to one or multiple
epidermal inclusion cysts which can mimic other
pancreatic neoplastic or nonneoplastic cysts (DAVID-
SON et al. 1980; TANG et al.1994; TSUTSUMI et al. 2000;
HORIBE et al. 2001; SONOMURA et al. 2002; YOKOMIZO
et al. 2002; FINK et al. 2002). These are usually lined
by keratinizing or nonkeratinizing squamous epi-
thelium, surrounded by splenic pulp tissue with a
fibrous capsule within the pancreatic parenchyma
(MOROHOSHI et al. 1991). They may be up to 15 em
in diameter (CHO! et al. 2000). The cystic part con-
tains yellow-white caseous material, and the solid
part appears red-brown granular, similar to splenic
parenchyma. No hair or skin appendages are seen.
13.7.2
Hamartoma
Pancreatic hamartomas are extremely rare lesions
consisting of normal pancreatic tissues in abnormal
relationship to one another. They may be solid or
cystic. In one case, in a premature infant with refrac-
tory hypoglycemia and hypocalcemia, the entire
pancreas consisted of non cystic ductal elements in
238
groups of varying sizes within connective tissue, with
a minority of well-organized islets and acinar tissue
(BURT et al. 1983). ANTHONY et al. (1977) described
pancreatic 'pseudotumors' in three patients com-
posed oflobulated connective tissue enclosing acinar
cells, endocrine cells, and dilated pancreatic ducts in
complete disarray, without malignant features. Large
multicystic pancreatic hamartomas, composed of
disorganized lobules of exocrine pancreatic acinar
tissue surrounding pancreatic ducts and cyst-like
spaces of variable diameter, lined by cuboidal to
columnar epithelial cells, admixed with clusters of
adipocytes and with diffusely scattered or clustered
islet cells, have been reported in an infant (FLAHERTY
and BENJAMIN 1992) and an adult (IZBICKI et al.
1994). Patients with Brunner's gland hamartoma
mimicking carcinoma of the head of the pancreas
have also been described (SKELLENGER et al. 1983).
13.7.3
Pseudolipomatous Hypertrophy
Pancreatic lipomatosis is uncommon as an isolated
abnormality, but it can be seen in a variety of con-
ditions such as chronic pancreatitis, obesity, aging,
cystic fibrosis, alcoholism, and Cushing's syndrome
(NAKAMURA et al.1979; PATEL et al.1980; THAM et al.
1991; ITAI et al. 1995; MATSUMOTO et al. 1995; KATZ
et al. 1999). It may be associated with pancreatic exo-
crine insufficiency (LOZANO et al.1988) and, particu-
larly when localized, may mimic pancreatic tumors,
especially lipoma (BARUTCU et al. 2002). However, as
opposed to lipoma, it is usually unencapsulated and
shows direct contact with the peripancreatic fat (ITAI
et al. 1995; KATZ et al. 1998; FERROZZI et al. 2000).
Grossly, the pancreas is moderately to markedly
enlarged, maintaining its usual shape. Histologi-
cally, the parenchyma consists of mature fatty tissue
separated by thin fibrous septa, containing isolated
clusters of normal islets (SOLCIA et al. 1997).
13.7.4
Inflammatory Pseudotumors
Inflammatory pseudotumors are tumor-like lesions
of uncertain pathogenesis, also known as plasma-
cell granuloma, inflammatory myofibroblastic tumor,
and inflammatory myofibrohistocystic proliferation
(Lm and CONSORTI 2000). Although the lung is the
most common site, these lesions occur in a variety
of extrapulmonary locations (COFFIN et al. 1995).
T. Oweity and A. B. West
Several cases isolated to the pancreas have been
described (JOHNSON et al. 1983; ABREBANEL et al.
1984; SCOTT et al. 1988; PALAZZO and CHANG 1993;
MORRIS-STIFF et al. 1998; SHANKAR et al. 1998;
PETTER et al. 1998), and a few have been described
in association with retroperitoneal fibrosis (CLARK
et al. 1988; CHUTAPUTTI et al. 1995). The most
common presentations are abdominal pain and bili-
ary obstruction secondary to local extension of the
lesion. Constitutional symptoms such as fever, weight
loss, and malaise have also been reported (PALLAZZO
and CHANG 1993),in addition to asymptomatic cases.
Hypergammaglobulinemia, anemia, and an elevated
sedimentation rate have also been reported in a child
(SCOTT et al. 1988). The age at presentation ranges
from 2.5 to 65 years (Lm and CONSORTI 2000), but
the majority present in childhood or early adulthood
(MCCLAIN et al. 2000). Given the radiologic similari-
ties to a malignant neoplasm, the low index of clinical
suspicion, and the variability of histologic appear-
ance, a misdiagnosis of malignancy may be readily
made (WALSH et al. 1998).
Macroscopically, the tumors are firm, poorly
circumscribed, yellow-white with indurated areas
(WREESMANN et al. 2001), or well-circumscribed,
nodular, gelatinous to firm, and mostly solid (WALSH
et al. 1998) but occasionally cystic (Lm and CON-
SORTI 2000), up to 12 cm in size.
Microscopically, these tumors are composed
of variable amounts of proliferating spindle cells,
admixed with a variety of inflammatory cells, pro-
ducing a wide spectrum of histopathologic appear-
ances. This has led to the diverse confusing nomen-
clature of this lesion.
Three basic histologic patterns have been recog-
nized in extrapulmonary inflammatory pseudotumor,
of which myofibroblasts are the main proliferating
cell (COFFIN et al. 1995). These include a myxoid
pattern with a loose arrangement of plump spindle
to stellate cells in a vascular, edematous background
resembling granulation tissue, containing a polymor-
phous inflammatory infiltrate. This pattern resembles
nodular fasciitis, and the stromal cells have vesicular
nuclei and abundant eosinophilic cytoplasm, reminis-
cent of rhabdomyoblasts but without cross-striations.
Numerous mitoses may be seen. The second pattern
is characterized by compact spindle cell proliferation
which may have a vascular arrangement or a storiform
pattern with areas of variable cellularity and variable
mitotic activity resembling a myogenic or fibrohistio-
cytic neoplasm. Plasma cells often predominate in the
background and may form aggregates. Lymphoid fol-
licles may be present, and growth into or around ves-
Rare Solid Tumors: Clinical Manifestations and Pathology
sels may be seen. Obliterative phlebitis and perineural
accentuation of inflammation have been described as
distinctive features of the entity (WREESMANN et al.
2001). The third histologic pattern is the least prolif-
erative, with extensive collagenous, sparsely cellular
areas resembling fibromatosis or myofibromatosis,
with scattered lymphocytes and plasma cells. Calcifi-
cation and ossifications may be seen. These three his-
tologic patterns may be equally represented in a single
tumor, or one or two may predominate.
The myofibroblastic nature of the proliferating
spindle cells is confirmed by diffuse immunoreactiv-
ity for vimentin, muscle-specific actin, and smooth
muscle actin with more variable and focal des min
positivity. Focal cytokeratin positivity occurs in up
to 35% of extrapulmonary myofibroblastic tumors
(COFFIN et al. 1995). The cells are negative for S-
100 protein and CI;! 35 (the follicular dendritic cell
marker), and the pl'asma cell infiltrate is polyclonal
(PALAZZO and CHANG 1993). Few B-Iymphocytes are
seen, but CD-4- and CD-8-positive T-Iymphocytes
are numerous (WALSH et al. 1998).
Electron Microscopy. Ultrastructural examination
shows spindle cells with abundant endoplasmic
reticulum, pinocytotic vesicles and subplasmalem-
mal plaques, and extracellular collagen. The dif-
ferential diagnosis includes a variety of spindle-cell
tumors, benign and malignant, and the diagnosis is
based on finding the characteristic myofibroblastic
proliferation with a mixed inflammatory back-
ground. Differentiation between this tumor and
inflammatory fibrosarcoma may be more difficult as
the two entities overlap, and they have been used syn-
onymously (MEIS and ENZINGER 1991), although no
cases of so-called inflammatory fibrosarcoma have
been described in the pancreas.
Etiology. The etiology of inflammatory pseudotumor
is unclear. Autoimmune mechanisms have been impli-
cated. This is supported by its association with reactive
hyperplastic lymphadenopathy (Voss et al. 1999), and
with other autoimmune diseases such as retroperito-
neal fibrosis (CHUTAPUTTI et al. 1995) and Sjogren's
syndrome (ECKSTEIN et al. 1995). Infectious causes
have also been proposed with emphasis on Epstein
Barr virus (EBV) in inflammatory pseudotumors of
other organs (ARBER et al. 1995), but this has been
found to be negative in the pancreatic cases tested
(WALSH et al. 1998).
Treatment and Prognosis. Most extrapulmonary
inflammatory pseudotumors are successfully man-
239
aged by surgical resection, and some associated
with retroperitoneal fibrosis have regressed with
the use of corticosteroids (CHUTAPUTTI et al. 1995).
Recurrence rates of up to 25% have been reported,
however (COFFIN et al. 1998). Cases of synchronous
or metachronous distant tumors with a similar his-
tology have been described, and it is uncertain if
these represent multifocal disease or distant metas-
tases (Voss et al. 1999). Cases of malignant trans-
formation have been described in recurrent tumors
(COFFIN et al. 1998). There are no distinguishing
pathologic features predictive of aggressive behav-
ior (COFFIN et al. 1998). Based on that, and as it is
difficult to distinguish this tumor from inflammatory
fibrosarcoma, the prognosis of this tumor should be
guarded. Long-term follow-up is mandatory because
recurrences and possibly distant tumors may develop
(WALSH et al. 1998).
13.7.5
Pseudolymphoma
Pseudolymphoma is characterized by a predomi-
nant nonneoplastic proliferation of lymphoid tissue.
Only rare cases have been reported in the pancreas
(NAKASHIRO et al. 1991; HATZITHEOKLITOS et al.
1994; PETTER et al. 1998), where it may be diffuse
or localized. One localized lesion presented with
obstructive jaundice and appeared grossly as a soft,
yellow nodule measuring 2 cm in size (NAKASHIRO
et al. 1991). Microscopically, it showed massive pro-
liferation of variably sized lymphoid follicles, not
closely packed, with prominent, well polarized ger-
minal centers, rimmed by a mantle of small round
lymphocytes, surrounded by variable amounts
of fibrous connective tissue in the interfollicular
areas. Tingible body macrophages and mitoses were
noted in the germinal centers, and plasma cells and
eosinophils were scattered in the interfollicular area.
The adjacent pancreatic parenchyma was generally
intact. Immunostaining revealed a polyclonal het-
erogeneous population of lymphocytes and plasma
cells. Another case mimicked lymphoplasmacytic
lymphoma (PETTER et al. 1998).
13.7.6
Chronic Pancreatitis
Chronic pancreatitis is the condition that most often
mimics pancreatic carcinoma clinically, radiologi-
cally, and even morphologically (SOLCIA et al. 1997).
240 T. Oweity and A. B. West

There are two major forms: chronic calcifying pan-
creatitis, the main type, and obstructive pancreatitis
(BARTHET et al.1999). In Western countries, it is most
commonly due to chronic alcoholism with a relapsing
acute autodigestive pancreatitis. Hereditary forms
and others related to malnutrition or autoimmune
origin have also been described (KLOPPEL 1999), the
last in association with other autoimmune diseases
such as primary sclerosing cholangitis, Sjogren's dis-
ease (MONTEFUSCO et al. 1984), multifocal idiopathic
fibrosclerosis (LEVEY and MATHAI 1988; CLARK et
al. 1988), and inflammatory bowel disease (BARTHET
et al. 1999). The diffuse atrophy and fibrosis of the
pancreas following obstruction of the main duct in
the head of pancreas by tumor, scar, or stone is called
chronic obstructive pancreatitis.
Macroscopically, in early chronic pancreatitis, the
gland is unevenly affected, with focal nodular or seg-
mental sclerosis and enlargement of the affected area.
The involved ducts may be distorted and occasion-
ally contain calculi. Pseudocysts may be present. In
the advanced stages, the entire pancreas is rock hard,
irregular, and shrunken. The main duct shows irregular
dilatation and distortion, usually impacted by calculi.
In chronic obstructive pancreatitis, there is marked
duct dilatation upstream of the stenotic or occluded
duct in the head of the pancreas. There is fibrotic
atrophy of the parenchyma, and no calculi are usually
seen. Microscopically, fibrosis progresses from inter-
lobular to intralobular distribution in the later stages,
against a background of lymphocytes, plasma cells,
and macrophages (Fig. 13.9a, b). The intralobular
ducts are distorted and focally ectatic, embedded in
fibrous tissue. The epithelium may show hyperplastic
changes initially and become atrophic later on, while
lacking significant cellular atypia. Eosinophilic pro-

Fig.13.9a-d. Chronic pancreatitis. a There is extensive destruction of pancreatic acini by chronic inflammation and replacement
by fibrosis. Surviving ducts are present on the right and left of the field (H&E, low power). b The inflammatory infiltrate consists
of plasma cells and lymphocytes, admixed with collagen bundles (H&E, high power). c Large blood vessels and nerve bundles are
usually seen, surrounded by marked inflammation (H&E, medium power). d In the late stage, only islets survive in the hyalinized
fibrous tissue. The lobular arrangement of the islets distinguishes this from an islet-cell tumor (H&E, medium power)
Rare Solid Tumors: Clinical Manifestations and Pathology
teinaceous material develops into plugs and calculi.
The fibrous tissue contains thick-walled arteries and
nerve trunks (Fig. 13.9c), and over time the inflam-
matory infiltrate becomes scantier, predominantly
lymphocytic, and periductal. In the late stages, the
pancreatic acini are replaced by fibrous tissue, and
only irregular, variably sized clusters of islet cells
remain (Fig. 13.9d), along with dilated interlobular
ducts. In obstructive chronic pancreatitis, the fibrotic
process is usually more evenly distributed and more
pronounced centrally around the pancreatic duct
rather than peripherally.
Differential Diagnosis. Chronic pancreatitis can be
mistaken on frozen sections and in small biopsies
for ductal adenocarcinoma. However, the lobular
arrangement of the remaining ducts, even when dis-
torted, is usually maintained, and significant atypia
is not seen. No perineural ductal invasion is present.
The remaining disorganized islets may be mistaken
for endocrine tumor, but they are usually arranged in
clusters and rarely show a diffuse irregular infiltration
of the fibrous tissue. The presence of calculi helps to
establish the diagnosis of chronic pancreatitis (SOLCIA
et al. 1997). It is important to remember that chronic
pancreatitis may coincide with ductal carcinoma.
13.7.7
Miscellaneous Inflammatory Tumor-like Masses
Tuberculosis (ALVAREZ et al. 1994), fungal infec-
tion (LUDWIG et al. 1999), and parasites (HUAROTO
SEDDA et al. 1989) have been reported to present
as pseudotumors. Sarcoidosis (MAHER et al. 1981)
and malakoplakia (ZUK et al. 1990) of the pancreas
have been described also. Noninflammatory lesions
presenting as tumors include traumatic neuroma
(GEDDY and VENABLES 1991), peripancreatic fat
necrosis (THURNHER et al. 2001), and pancreatic
artery aneurysm (ITOH et al. 2002).
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14 Unusual Pancreatic Neoplasms: Imaging
A. J. MEGIBOW and I. R. FRANCIS

CONTENTS 14.1
Introduction
14.1 Introduction 249
14.2 Solid-Pseudopapillary Tumor of the Pancreas 250
14.2.1 Clinical Considerations 250 'Unusual' pancreatic neoplasms can be thought of
14.2.2 Imaging Features 250 as a heterogeneous group of tumors that are infre-
14.2.3 Treatment and Prognosis 251 quently seen in any given individual clinical prac-
14.3 Primary Pancreatic Lymphoma 252 tice. Even large referral centers may see fewer than
14.3.1 Clinical Considerations 252 10 cases over a decade. There is no strict definition
14.3.2 Imaging Features 252
14.3.3 Treatment and Prognosis 252 as to what tumors comprise this group of neoplasms.
14.4 Adenosquamous Carcinoma 253 Probably the single most important reason why these
14.4.1 Clinical Considerations 253 lesions are being seen with any frequency is directly
14.4.2 Imaging Features 254 related to the widespread use of imaging (STEPHENS
14.4.3 Treatment and Prognosis 254 1997). These lesions display clinical, demographic,
14.5 Acinar Cell Carcinoma 254
14.5.1 Clinical Considerations 254 and imaging features that are sufficiently different
14.5.2 Imaging Features 255 from pancreatic adenocarcinoma, islet-cell neo-
14.5.3 Treatment and Prognosis 257 plasms, or cystic tumors that an 'unusual' histology
14.6 Osteoclast-like Giant-Cell Tumor 257 is anticipated when they are encountered on imaging
14.6.1 Clinical Considerations 257
studies.
14.6.2 Imaging Features 257
14.6.3 Treatment and Prognosis 257 Table 14.1 is derived from the Armed Forces Insti-
14.7 Pancreatoblastoma 258 tute of Pathology (AFIP) classification of pancreatic
14.7.1 Clinical Considerations 258 tumors and contains the histological type of those
14.7.2 Imaging Features 258 lesions which may be thought of as 'unusual' tumors
14.7.3 Treatment and Prognosis 258 of the exocrine pancreas (SOLCIA et al. 1997). The
14.8 Mesenchymal and Ectopic Tumors 258
14.8.1 Mesenchymal Tumors - Introduction 258 list as published in the AFIP fascicle is by no means
14.8.1.1 Mature Teratoma 259 complete. Omitted from the list are the secondary
14.8.1.2 Lymphangioma 260 tumors (considered in Chapter 17), the tumor-like
14.8.1.3 Pancreatic Lipoma 260 conditions of the pancreas (e.g., chronic pancreati-
14.8.1.4 Other Mesenchymal Tumors 260 tis), and several varieties of inflammatory cysts. No
14.8.2 Ectopic Tumors - Introduction 261
14.8.2.1 Intrapancreatic Accessory Spleen 262 consideration will be given to unusual tumor-like
References 263 conditions of the endocrine pancreas. Because of
the rare occurrence of these lesions, we are unable
to provide imaging examples of all of the entities
listed. This chapter will consider imaging features
of solid-pseudopapillary tumor, primary pancreatic
A. J. MEGIBOW, MD,MPH, FACR lymphoma, adenosquamous tumor, acinar cell carci-
Professor of Radiology, NYU Medical Center, New York, NY, noma, osteoclastic giant-cell tumor, pancreatoblas-
USA
1. R. FRANCIS, MD
toma, and mesenchymal tumors including mature
Professor of Radiology, University of Michigan School of Medi- teratoma, lymphangioma, lipoma, and heterotopic
cine, Ann Arbor, Michigan, USA spleen.
250 A. J. Megibow and I. R. Francis

Table 14.1. Entities from Armed Forces Institute of Pathology tumors. The term 'Frantz's tumor' refers to the initial
(AFIP) classification of pancreatic tumors (SOLCIA et al. 1997) description of this lesion in the 1959 AFIP classifica-
considered as 'unusual' tumors
tion (FRANTZ 1959). The term solid-pseudopapillary
Ductal adenocarcinoma variants tumor has been proposed as the single best term for
Mucinous noncystic adenocarcinoma this lesion in both the AFIP classification of 1997 and
Signet-ring-cell carcinoma the World Health Organization (WHO) classification
Adenosquamous carcinoma
Undifferentiated (anaplastic) carcinoma of 1996 (KLOPPEL et al. 1996).
Osteoclast-like giant-cell tumor The female predominance of this lesion is well
Acinar cell carcinoma documented. BUETOW et al. (1996) reviewed the
Acinar cell carcinoma variants AFIP experience, finding 53 female patients out of 56
Acinar cell cystadenocarcinoma (94.6%). MARTIN et al. (2002) reviewed the experi-
Mixed acinar-endocrine carcinoma
Pancreatoblastoma ence at Memorial Sloan-Kettering Cancer Center in
Solid-pseudopapillary tumor New York. documenting 20 female patients out of 24
Miscellaneous carcinomas (83.3%). The reason for the female predominance is
Oncocytic carcinoma unclear. Despite sophisticated pathologic, genetic,
Choriocarcinoma and immunohistochemical analysis, no consistent
Nonmucinous, glycogen-poor cystadenocarcinoma
Mature teratoma evidence of hormone receptors has been found.
Nonepithelial tumors The age of these patients is considerably less than
Benign soft-tissue tumors typically seen in patients with pancreatic adenocar-
Malignant soft-tissue tumors cinoma. Mean ages reported range from 25 years
Malignant lymphoma (range 10-74 years) (BUETOW et al. 1996), 27 years
Cysts
Congenital cyst (LAM et al. 1999),32 years (range 16-66 years) (YOON
Lymphoepithelial cyst et al. 2001), to 39 years (range 12-79 years) (MARTIN
Endometrial cyst et al. 2002). A few elderly patients are encountered in
Heterotopic pancreas all series. Individual case reports in patients as young
Heterotopic (ectopic) spleen as 10 years old also appear in the literature (YAG I et
Hamartoma and pseudotumor
Pseudolipomatous hypertrophy
al. 1994). Metastatic disease has been reported in an
Pseudolymphoma 11-year-old patient (HORISAWA et al. 1995), although
there is evidence that the tumor is more aggressive
in elderly patients based on the higher prevalence of
14.2 metastases and microscopic evidence of angio- and
Solid-Pseudopapillary Tumor perineural invasion (MATSUNOU and KONISHI 1990;
of the Pancreas PIATEK et al. 2000). These authors stress that even in
the presence of these markers of advanced disease,
14.2.1 the prognosis is extremely favorable.
Clinical Considerations

This neoplasm is considered as either a benign tumor 14.2.2

or a tumor with low malignant potential occurring
predominantly in young women (MAO et al. 1995;
MARTIN et al. 2002; YAMAGUCHI and TANAKA 2001).
A review of clinical experience with this tumor pub-
lished in 1999 documents 452 cases described in the
literature. Microscopic-based descriptions stress the
papillary features (hence the 'solid-papillary' nomen-
clature), whereas macroscopic-based descriptions
emphasize the gross pathologic appearance (hence
the 'solid-cystic' nomenclature). Therefore, it is not
surprising that this lesion has been referred to by a
variety of names including: benign or malignant pap-
illary neoplasms, papillary cystic tumors of the pan-
creas, papillary epithelial neoplasms, solid and papil-
lary epithelial neoplasms, solid and cystic acinar cell
Imaging Features
Because of their large size and heterogeneous
morphology, these lesions are easily recognized on
imaging studies. Most imaging descriptions of this
lesion are based on the computed tomography (CT)
appearance (Figs. 14.1, 14.3) On imaging studies, this
lesion appears as a round, encapsulated mass with
variable amounts of soft tissue and necrosis. The
appearance of the cystic regions suggests hemor-
rhage as the major factor in producing the necrosis
(CHO! et al. 1988; DONG et al. 1996). The lesions may
appear anywhere within the pancreas, although there
appears to be a slight predilection for the pancreatic
tail. When detected, lesions are often quite large:
Unusual Pancreatic Neoplasms: Imaging
Fig. 14.1. Solid-pseudopapillary pancreatic neoplasm. A large
mass is noted in the head of the pancreas. Note the well-defined
capsule. The mass contains a greater amount of soft-tissue atten-
uating (solid) tumor. Low attenuation necrotic regions are pres-
ent. Note the high attenuation material in the superior portion of
the mass (asterisks) compatible with hemorrhagic debris
Fig. 14.2. Solid-pseudopapillary pancreatic neoplasm in a 19-
year-old woman. A large mass is seen in the pancreatic head. A
well-defined capsule defines a predominantly fluid attenuating
mass. Several poorly defined densities of slightly higher atten-
uation are seen in the dependent portion. This mass could be
confused with a pseudocyst or cystic pancreatic neoplasm
mean sizes reported are 7.5 cm (YAMAGUCHI et al.
1990},9 cm (BUETOW et al. 1996), and 11 cm (MAO
et al. 1995).
The imaging appearances are cataloged as solid
(Fig. 14.1), partially or completely cystic (Figs. 14.2,
14.3). However, even in the 'solid' tumors, some
degree of cystic change and/or hemorrhagic degen-
eration (Fig. 14.1) can be identified (BUETOW et al.
251
Fig. 14.3. Solid-pseudopapillary pancreatic neoplasm. Low
attenuation lesion present in the pancreatic tail. The diagnosis
was suggested preoperatively based on the fact that the patient
was a 17-year-old woman
1996). A frequently described feature is a well devel-
oped capsule resulting in a sharply circumscribed
lesion. The cystic regions within the tumor contain
variable amounts of soft tissue and liquefaction. The
presence of blood products within the mass produces
hyperintense signal on Tl-weighted MR images
(SAVCI et al. 1996). Fluid-debris levels resulting from
prior hemorrhage (recognizable by MR) have been
noted (BUETOW et al. 1996). There is a conspicuous
absence of internal septations, which may aid in the
differential diagnosis from serous and mucinous
cystic tumors (CHOI et al. 1988). BUETOW and col-
leagues found calcifications in 16 of 56 (29%) patients
(BUETOW et al. 1996), with both central and rim calci-
fication being reported (DONG et al. 1996).
14.2.3
Treatment and Prognosis
The biological behavior of solid-pseudopapillary
tumor of the pancreas is variable. Most authors con-
sider these lesions to be low-grade malignancies and
suggest aggressive, curative resection when discov-
ered (YOON et al. 2001; ZINNER 1995). In a review of
292 cases reported in the world literature, 43 (14.7%)
were recognized as malignant (MAO et al. 1995). The
likelihood of malignancy increases with the patient's
age (MATSUNOU and KONISHI 1990). Despite malig-
nant epithelial changes and even the presence of
liver metastases, the long-term prognosis is good
252
for those patients in whom the total disease burden
can be resected (even with resectable extrapancre-
atic disease, the prognosis is excellent) (MARTIN et
al. 2002). Mean survival rates of 5.2 years are reported
following successful resection (YOON et al. 2001).
14.3
Primary Pancreatic Lymphoma
14.3.1
Clinical Considerations
Primary pancreatic lymphoma is an extremely rare
neoplasm. Eleven patients were seen at the M.D.
Anderson Cancer Center between 1980 and 1995
(BOUVET et al. 1998); 5 of a total of 1212 patients
with adult non-Hodgkin's lymphoma (NHL) were
seen at the King Faisal Specialist Hospital between
1987 and 1994 (EZZAT et al. 1996). Seven patients
with primary pancreatic lymphoma were treated at
the Loyola Medical Center between 1976 and 1991
(TUCHEK et al. 1993). Pancreatic involvement as part
of disseminated disease is more frequent but still
relatively unusual (BORROWDALE and STRONG 1994).
Involvement of the pancreas was present in 9 of 402
patients (2.2%) with NHL and 4.9% of all patients
presenting with pancreatic malignancies (9 of 182) at
the Johns Hopkins Medical Institutions between 1982
and 1986 (WEBB et al. 1989). There is one reported
case of non-cleaved small B-cell lymphoma in an
HIV-seropositive patient (JONES et al. 1997).
Patients present most commonly with abdominal
pain of a severity engendering an imaging examina-
tion, such as US, CT or MR, with CT scanning being
preferred in the USA and US in Europe and Asia. Labo-
ratory values are nonspecific. Lactate dehydrogenase
(LDH) levels may be elevated (BOUVET et al. 1998).
14.3.2
Imaging Features
The lesion presents most commonly as a focal mass
and less frequently as diffuse pancreatic enlarge-
ment. When the lesion presents as a focal mass,
there is little to distinguish it from primary ductal
adenocarcinoma (TEEFEY et al. 1986; VAN BEERS et
al. 1993). The mass is most frequently hypo dense and
slightly heterogeneous on dynamic CT (VAN BEERS
et al. 1993). They are usually quite large at presenta-
tion; reported sizes typically range between 5 and 7
A. J. Megibow and 1. R. Francis
cm in diameter (PRAYER et al. 1992; TEEFEY et al.
1986; VAN BEERS et al. 1993). The masses can extend
and infiltrate beyond the pancreas to encase major
peripancreatic vascular structures similar to ductal
adenocarcinoma (BOUVET et al. 1998). However, the
degree of pancreatic ductal dilatation is minimal,
even with ductal invasion. This lesser degree of
ductal dilatation in the presence of a bulky homo-
geneous tumor mass should suggest the possibility
of pancreatic lymphoma (Fig. 14.4). Alternatively,
diffuse infiltration and enlargement of the pancreas
without clinical signs of acute pancreatitis should
alert one to the possibility of pancreatic lymphoma
(Fig. 14.5). Finally, lymph node involvement below
the level of the renal veins, which can be seen in lym-
phoma, is unusual in ductal adenocarcinoma. These
findings may prompt fine needle aspiration biopsy
(FNAB) of the pancreatic mass to obtain a diagnosis
(MERKLE et al. 2000).
The classic ultrasound appearance of a lymphoma
anywhere in the body is that of a hypoechoic mass
with poor through transmission (KAUDE and JOYCE
1980). Therefore, pancreatic lymphoma can be poten-
tially confused with a pseudocyst, and thus color
Doppler may be useful to help distinguish between
these diagnostic possibilities (LEVIN et al. 1993). The
availability of high frequency, longer focal length US
probes has shown that, in fact, many lymphomatous
masses will display some degree of echogenicity.
US should be thought of as an index examination,
bringing the patient to the attention of the physician.
Diagnosis will be obtained by FNAB of the pancreas
or biopsy of peripheral lymph nodes. Some have
reported that endoscopic ultrasound (EUS) is useful
for detecting pancreatic lymphoma, and EUS-guided
biopsy can minimize sampling errors that can occur
when 'blind' open biopsies are performed (HAR-
RISON et al. 1999). Most oncologists prefer to use
conventional cross-sectional imaging techniques that
can survey the entire abdominal and pelvic cavities
(and thorax, if indicated).
14.3.3
Treatment and Prognosis
Primary pancreatic lymphoma has a significantly
better prognosis than adenocarcinoma. When che-
motherapy is instituted, complete remission can be
expected in the majority of patients (EZZAT et al.
1996; WEBB et al. 1989). Significant morbidity and
mortality are associated with postoperative com-
plications that occur when patients are operated on
 Unusual Pancreatic Neoplasms: Imaging 253

a b

c d

Fig.14.4a-d. Primary pancreatic lymphoma. a CT scan shows low attenuation mass in the pancreatic neck (arrow). The common
bile duct (CBD) is minimally enlarged. b Same patient, slightly more caudad level. A low attenuation mass is present in the
pancreatic head (arrow) . There is no pancreatic duct nor CBD dilatation. It would be difficult to exclude pancreatic ductal
adenocarcinoma on the basis of the CT appearance. c Arterial phase image from gadolinium-enhanced, Tl-weighted gradi-
ent recalled echo (GRE) sequence reveals the tumor as a hypointense mass in the pancreatic head. Compare with the brightly
enhanced pancreatic parenchyma. d Image at a level slightly caudad to c shows the hypointense mass against the brightly
enhanced pancreas. As in other images, note the lack of pancreatic and biliary dilatation. As on CT, it would be impossible to
differentiate this case from primary ductal adenocarcinoma. (Courtesy of Dr. Donald Hulnick, MD, Danbury, CT, USA)

for suspected adenocarcinoma of the pancreas, but
surgical pathology ultimately proves the lesion to be
pancreatic lymphoma (UEDA et al. 2000).
14.4
Adenosquamous Carcinoma
14.4.1
Clinical Considerations
Adenosquamous carcinoma of the pancreas is a rare
exocrine neoplasm, with distinctive histological fea-
tures characterized by the differentiation of both glan-
dular and squamous elements. Although few reports of
this lesion have appeared in the literature, all authors
agree that the lesion is highly aggressive, with a prog-
nosis actually worse than ductal adenocarcinoma.
The lesion is extremely rare, with 134 cases
reported between 1907 and 1999. The clinical symp-
toms are similar to those associated with ductal
adenocarcinoma (MADURA et al. 1999). A series of
25 patients from the AFIP collected between 1961 and
1994 represents the largest reported patient cohort.
The mean age was 65 years (range 28-82 years).
Weight loss and painless jaundice were the most fre-
quent symptoms. The head of the gland was the most
254
Fig. 14.5. Pancreatic lymphoma. Diffuse enlargement. Superfi-
cially analyzed, this image could be interpreted as acute pancre-
atitis. However, on the arterial phase image, there is no necrosis.
Note diffuse enhancement of the gland. The splenic vein is
engulfed, and the tumor extends to involve the left kidney
frequent site, and multiple areas were involved in 5
cases (KARDON et al. 2001).
No specific serum tests are available, but in one
report, marked elevation of serum CA 19-9 was
found. In one patient, the level was 354.8 Ulml, and
in the second 2010 Ulml (NABAE et al. 1998).
14.4.2
Imaging Features
Imaging studies cannot differentiate adenosqua-
mous carcinoma from ductal adenocarcinoma. The
most common presentation is that of a bulky mass
extending through multiple portions of the pancreas
(Fig. 14.6). The typical low attenuation associated with
squamous cancers is not evident in these tumors, and
they simulate ductal adenocarcinoma in that the
masses are predominantly lower in attenuation than
the normal pancreatic parenchyma. Masses may result
in upstream duct dilatation (Fig. 14.7}. Involvement of
the large peripancreatic veins, particularly the splenic
and portal veins, is characteristic, although arterial
invasion is not usually seen (KOMATSUDA et al. 2000;
MAKIYAMA et al. 1995). Tumoral calcification has been
reported as well (MAKIYAMA et al. 1995). As opposed
to other pancreatic tumors, adenosquamous cancers
appear to be Ga-67 avid (KuJI et al. 1997).
A. J. Megibow and 1. R. Francis
Fig. 14.6. Adenosquamous carcinoma of the pancreas. A bulky
mass occupies the body and tail of the pancreas. The mass
is heterogeneous but predominantly of low attenuation. The
lesion invades the splenic hilum. The splenic vein is encased,
and a prominent gastroepiploic collateral vein is present. A
metastasis is present in the greater omentum (arrow)
14.4.3
Treatment and Prognosis
As difficult as it is to imagine, the prognosis for patients
with adenosquamous carcinoma is significantly worse
than for patients with ductal carcinoma. In the AFIP
series, the average survival was 5.8 months (KARDON
et al. 2001). For 8 patients with this lesion, the cumula-
tive I-year survival was 21.4% compared with 42.1%
for patients with ductal adenocarcinoma (YAMAGU-
CHI and ENJOJI 1991). In a series of 6 patients seen at
Indiana University who underwent either pancreati-
co duodenectomy or distal pancreatectomy, only one
was alive 9 months after surgery with residual tumor
around the portal vein seen on follow-up imaging. It
is striking that all of the lesions were poorly differen-
tiated and 5 of 6 were locally metastatic to nodes or
contiguous structures (MADURA et al. 1999).
14.5
Acinar Cell Carcinoma
14.5.1
Clinical Considerations
Acinar cell carcinoma is a well described, albeit
rare pancreatic neoplasm, and accounts for 1% of
pancreatic exocrine neoplasms. The tumor occurs in
Unusual Pancreatic Neoplasms: Imaging
Fig. 14.7a,b. Adenosquamous tumor of pancreas. The upstream
pancreatic duct is dilated (a). The mass (arrow) is seen in (b).
This lesion is indistinguishable from adenocarcinoma
adults in the 5th-6th decades with white men being
predominantly affected and has been also reported
in children (KLIMSTRA et al. 1992). Clinical presen-
tations are nonspecific, and jaundice is rare even in
tumors within the pancreatic head.
A widely reported clinical syndrome manifested
by any or all of the symptoms including subcuta-
neous or interosseous fat necrosis, panniculitis,
polyarthralgias, and eosinophilia has been reported
(KUERER et al. 1997; MACMAHON et al. 1965; RADIN
et al. 1986). The syndrome occurs in association with
elevated serum lipase levels. Despite the widespread
knowledge of this association, this has been reported
in approximately 16% of cases (KLIMSTRA et al.
1992). CEA and or CA 19-9 levels may remain normal
(CHEN et al. 2001). Elevation of serum alpha-fetopro-
tein has been reported in tumors characterized by
acinar cell differentiation (CINGOLANI et al. 2000).
14.5.2
Imaging Features
The masses are usually large, encapsulated, and
heterogeneous as seen on CT (Figs. 14.8, 14.9a,b) or
US. US through transmission is good, and variably
255
sized hypoechoic regions suggesting necrosis may
be seen (RADIN et al. 1986). Dual-phase helical CT
with bolus contrast enhancement will demonstrate
the mass as hyperdense related to the pancreas
during the arterial phase and isodense in the portal
venous phase (Fig. 14.8). The brisk enhancement of
the tumor results in an imaging appearance which
mimics a neuroendocrine neoplasm (MUSTERT et al.
1998). Central low attenuation representing necrosis
and or hemorrhage may be visualized (Fig. 14.9a,b).
Punctate calcifications have been reported in a few
cases (LIM et al. 1990; RADIN et al. 1986). These
imaging features support the similarity of acinar cell
tumors to neuroendocrine tumors by light micros-
copy (ORDONEZ and MACKAY 2000). Peripancreatic
venous invasion is common with tumor thrombus
found growing into the portal and or splenic veins
(UEDA et al. 1996). The degree of thrombosis can
be so prominent that the splenoportal system can
appear enlarged. Recently, a single case of an acinar
tumor arising within a branch pancreatic duct, mim-
icking intraductal papillary mucinous tumor (IPMT),
was reported (FABRE et al. 2001).
On MRI, the lesion appears markedly hyperintense
on T2-weighted images (Fig. 14.9c) and hyperintense
on enhanced Tl-weighted images (Fig. 14.9d,e).After
the administration of mangafodopir trisodium (Mn-
DPDP; Teslascan; Nycomed, Amersham, Princeton,
NJ), the lesion enhances brightly. This brisk enhance-
ment is seen in functioning pancreatic parenchyma
and in functioning pancreatic tumors (SAHANI et al.
Fig. 14.8. Acinar cell carcinoma. Arterial phase CT image
reveals hyperdense mass in the pancreatic body. Low attenu-
ation clefts centrally presumably represent necrotic regions.
The similarity to neuroendocrine tumor is evident (© 1998
American Roentgen Ray Society, used with permission)
 256 A. J. Megibow and 1. R. Francis

a b

c d

Fig. 14.9a-e. Acinar cell carcinoma. a Noncontrast CT reveals

bulky mass in pancreatic head. There was no evidence of
biliary or pancreatic duct obstruction. b Same patient as in a.
Portions of the mass enhance during the arterial phase. Large
areas of low attenuation are consistent with necrosis andlor
hemorrhage. c Fat-suppressed T2-weighted MR reveals the
mass to be hyperintense. d Gadolinium-DTPA (Gd-DTPA)-
enhanced, fat-suppressed Tl-weighted GRE MR image in late
arterial phase. The contrast enhancement is more apparent
than on the CT scan. The necrotic region is clearly delineated.
e Contrast-enhanced, fat-suppressed, Tl-weighted GRE MR
image in portal venous phase. The mass enhances brightly.
e The characteristic capsule is evident as is the necrotic center
 Unusual Pancreatic Neoplasms: Imaging 257

2002). Mn-DPDP MR would therefore be useful in the
subset of acinar tumors which are 'functioning'.
14.5.3
Treatment and Prognosis
Acinar cell carcinoma is an aggressive lesion. Some
50% of patients present with metastases, which are
commonly seen in the liver, local lymph nodes or the
adjacent peripancreatic fat, while 25% of patients will
develop metastases while under treatment. Mean sur-
vival time in 28 cases reviewed by Klimstra and associ-
ates was 18 months, with 57% alive at 1 year and 26%
alive at 3 years. Survival was better in younger patients
with localized disease (KLIMSTRA et al. 1992), but sur-
vival times of longer than 6 years have been reported
in patients presenting with widespread metastatic
disease (KUOPIO et al. 1995). Surgery with attempted
removal of all of the tumor is the best chance for sur-
vival, but on the whole, the prognosis is similar to that
of ductal adenocarcinoma.
of osteoclast-like giant cells is extremely rare (ROSAI
1968; SCOTT et al. 1993). This tumor is characterized
as a malignant neoplasm of the pancreas contain-
ing osteoclast-like giant cells. The tumor has been
reported most frequently in the pancreas, but it also
occurs in the parotid, thyroid, skin, orbit, kidney, and
breast. Clinically, patients present with an abdominal
mass which immediately results in an imaging study
(SCOTT et al. 1993; LEIGHTON and SHUM 2001).
14.6.2
Imaging Features
These lesions present as large cystic masses with
focal hemorrhage or necrosis (LEIGHTON and SHUM
2001). The lesion has a predilection for local invasion
and lymph node metastases (GIL-GARCIA et al. 1992;
SHINDOH et al. 1998). The mass may contain septa with
multiple loculations with mural nodules simulating a
cystadenocarcinoma (Fig. 14.10). Without careful
scrutiny of the imaging findings, the mass could be
confused with a pseudocyst (OEHLER et al. 1997).

14.6 14.6.3
Osteoclast-like Giant-Cell Tumor Treatment and Prognosis

14.6.1 In all cases, resection should be attempted, but the

Clinical Considerations local invasiveness of the lesion may make total resec-
tion impossible. Assuming complete excision is pos-
While the presence of giant cells in ductal adenocar- sible and no lymph node metastases are present, no
cinoma is a frequent finding at histology, the presence benefit accrues in using adjuvant radiation. Although

a b

Fig. 14.10a,b. Osteoclast-like giant -cell tumor. A large, multiseptate mass is present in the pancreatic tail. Several soft-tissue
attenuation regions are present. b Same patient as in a. Note the irregularly thickened septa and the soft-tissue elements located
inferiorly within the tumor. This lesion is easily confused with mucinous cystic tumor. The septa and mural nodules should
eliminate pancreatic pseudocyst as a diagnostic consideration
258
there are reports of patients surviving up to 10 years
from the time of diagnosis, the overall prognosis is
poor with a median survival of 11 months, similar to
survival times with ductal adenocarcinoma (LEIGH-
TON and SHUM 2001).
14.7
Pancreatoblastoma
14.7.1
Clinical Considerations
Pancreatoblastoma is a malignant pancreatic neoplasm
that displays a bimodal peak frequency, occurring in
children (mean age 2.4 years) and, less frequently, in
adults (mean age 40 years). Boys are affected more fre-
quently than girls (KLIMSTRA et al. 1995; LEVEY and
BANNER 1996). The tumor is second in frequency to
solid-pseudopapillary pancreatic tumors in children
with pancreatic neoplasms (SHORTER et al. 2002).
Patients most frequently present with an abdominal
mass and consequent vomiting, constipation, or early
satiety. Pain, weight loss, and jaundice occur less fre-
quently (KLIMSTRA et al. 1995; ROEBUCK et al. 2001).
Patients with this neoplasm may demonstrate elevated
serum levels of alpha-fetoprotein (particularly when
there are liver metastases), alpha-I-antitrypsin, and
LDH levels. Elevated levels of adrenal corticotrophic
hormone (ACTH) are thought to be responsible for
the Cushing-like syndrome or the syndrome of inap-
propriate ADH secretion. The tumor has also been
associated with the Beckwith-Wiedemann syndrome
(ROEBUCK et al. 2001).
Pathologically, these encapsulated tumors contain
tissue closely resembling the fetal pancreas. Fre-
quently, one sees small areas of squamoid corpuscles
(MONTEMARANO et al. 2000; ROEBUCK et al. 2001)
14.7.2
Imaging Features
The imaging features of pancreatoblastoma are well
described. The masses are large (reported mean size
approximately 10 cm) and lobulated (LEE et al. 1996).
MONTEMARANO and colleagues reviewed the imaging
and surgical findings in 10 patients (age range 2-20
years; mean age 6.8years).Well-definedmargins (90f10)
correlated with the gross, morphologically evident
capsules (Fig. 14.11). The texture was heterogeneous
(9 of 10), and enhancement was seen in all tumors.
A. J. Megibow and 1. R. Francis
Other findings included calcification (2 of 10), biliary
and pancreatic ductal dilatation (1 of 10), and ascites
(3 of 10). Hepatic (2 patients) and pelvic (2 patients)
metastases were present in a small number of these
patients. Adenopathy (2 patients) and vascular invasion
(1 patient) which were seen at surgery and pathology
were not identified radiologically (MONTEMARANO et
al. 2000). The mass will be hypoechoic on US (ROE-
BUCK et al. 2001). Tumors had low to intermediate
signal intensity on Tl-weighted images and high signal
intensity on T2-weighted images (MONTEMARANO et
al. 2000). ROEBUCK and colleagues emphasized the pre-
dilection for origin in the body and tail of the pancreas,
with a tendency toward involvement of the entire gland.
Although one report comments on the frequency of
vascular invasion (GUPTA et al. 2000), most others
indicate that vascular invasion is, in fact, infrequent
(ROEBUCK et al. 2001).
14.7.3
Treatment and Prognosis
The biological behavior of the tumor is variable. The
tumor is thought to be slow growing because of the
frequency of presentation as a large mass. Metastases
occur in 36% of patients, most frequently in the liver
(KLIMSTRA et al. 1995). The best treatment option
appears to be complete surgical excision, and the
tumors in children appear to be more frequently
resectable than those in adults (SHORTER et al. 2002).
Recurrence rates are high, but survival is improved
by aggressive resection of the recurrent masses.
Unresectable disease has a poor prognosis (CHUN
et al. 1997). The role of adjuvant radiation and che-
motherapy has not been established (KLIMSTRA et
al. 1995; MONTEMARANO et al. 2000; ROEBUCK et al.
2001; SHORTER et al. 2002). When the tumor presents
in adults, the prognosis is significantly worse, with a
mean survival of 18 months (KLIMSTRA et al. 1995).
14.8
Mesenchymal and Ectopic Tumors
14.8.1
Mesenchymal Tumors - Introduction
Mesenchymal tissues, supporting connective tissue,
vessels, nerves, and lymphatics provide the stroma
for the specialized epithelial cells in all organs of the
body. These elements are derived from the meso-
 Unusual Pancreatic Neoplasms: Imaging 259

Fig. 14.1 la-d. Pancreatoblastoma in an adult man. a Gross specimen showing solid well-demarcated mass. b Microscopic section
of the tumor displays large nodules separated by thin fibrous strands similar to acinar cell carcinoma. c Contrast -enhanced CT
examination shows the mass appearing to be well-demarcated, hypodense, and nonhomogeneous. d Gd-DTPA-enhanced GRE
Tl-weighted MR image shows minimal enhancement

dermal cells in the embryo. Anyone of a number
of elements can give rise to a benign or malignant
neoplasm. It is estimated that these lesions account
for 1%-2% of all pancreatic neoplasms (FERROZZI
et al. 2000). This next section describes the imaging
findings in several of these lesions.
74.8.7.7
Mature Teratoma
These are extremely rare tumors arising from intra-
pancreatic embryonic rests. Fewer than 20 cases
have been described in the literature (FERNANDEZ-
CEBRIAN et al. 1998). The cases that appear to be true
dermoid cysts occur in a younger age group (mean
age 23 years, range 2-53 years), with no gender pre-
dominance. The cysts are lined with a squamous epi-
thelium, but mucinous epithelium, respiratory-type
mucosa, and sebaceous units are readily identifiable
in dermoid cysts, and they may contain hair (ADSAY
et al. 2000).
The imaging appearance of pancreatic teratoma is
similar to those seen elsewhere in the body (such as
in the adnexa) and is related to the amount of pre-
ponderant tissue within the teratoma. Fat with fat/
fluid levels are diagnostic (Fig. 14.12), and septations
 260
a _~a.....J b
Fig. 14.12a,b. Mature teratoma. a A fat density mass is seen in the pancreatic body. A soft-tissue nodule (arrow) is seen in the
inferior portion, adjacent to dense calcification. b A fat attenuation mass is seen in the pancreatic tail. The fat is not homoge-
neous, with lower attenuation at the superior portion of the mass
and calcifications have been reported (FERROZZI et
al. 2000; JACOBS and DINSMORE 1993).
74.8.7.2
Lymphangioma
Lymphangiomas are congenital abnormalities of
the lymphatics that occur predominantly in the
pancreatic head and neck, frequently in children
(KHANDELWAL et al. 1995). Abdominal sites account
for 1% of all lymphangiomas, with mesentery and
retroperitoneum (perirenal) accounting for the vast
majority (ABE et al. 1997). Pancreatic lymphan-
giomas are extremely rare (BISHOP and STEER 2001;
GRAY et al. 1998; VIOLA et al. 1997).
The clinical symptoms are nonspecific and include
abdominal pain and a palpable mass. All ages are
affected, and a female predominance is noted. Symp-
toms evolve slowly in adults but may present acutely
in children (KOENIG et al. 2001). The tumor is con-
sidered to arise from the pancreas if it is within the
parenchyma, adjacent to the gland, or attached by a
pedicle (PAAL et al. 1998).
At imaging, the tumor appears as a homogeneous
cystic mass (Fig. 14.13). Following IV contrast, there
may be mural enhancement and visualization of fine
septa. When pedunculated, the mass may appear as
a juxtapancreatic cyst. Local mass effect on adjacent
organs is present when the masses achieve a large
size. The masses are hypoechoic on US. MRI will
confirm a hyperintense cyst content on T2-weighted
sequences with low signal on Tl-weighted sequences.
The wall and the septa enhance following gadolinium
A. J. Megibow and I. R. Francis
injection (BISHOP and STEER 2001; GRAY et al. 1998;
KOENIG et al. 2001; PANDOLFO et al. 1985; VIOLA et al.
1997). The differential diagnosis includes mucinous
cystic tumor and pancreatic pseudocyst. Aspiration
of the cyst content may provide the diagnosis when
the fluid is chylous (PAAL et al. 1998).
Lymphangiomas are benign but can be locally inva-
sive. Complete surgical excision is curative. Incomplete
excision results in local recurrence (PAAL et al. 1998).
74.8.7.3
Pancreatic Lipoma
These are extraordinarily rare tumors. The first case
on CT was described in 1996 (DI MAGGIO et al. 1996).
They are identical to lipomas arising in other loca-
tions. Their capsule allows for relatively easy enucle-
ation (FERROZZI et al. 2000). The tumors are detected
as incidental findings on imaging studies performed
for other reasons. CT scans are diagnostic, show-
ing well-circumscribed masses within the pancreas
composed almost entirely of fat, with a few scattered
vessels or septa or both {Fig. 14.14) (KATZ et al. 1998).
The presence of a capsule allows for differentiation
from pancreatic fatty infiltration (JACOBS et al. 1994).
Conservative management is indicated.
74.8.7.4
Other Mesenchymal Tumors
As noted above, any connective tissue element can
give rise to a mesenchymal neoplasm. Schwannoma
may be characterized by two distinct architectural
 Unusual Pancreatic Neoplasms: Imaging 261

a b

Fig. 14.13a. Cystic lymphangioma, pancreatic tail. A low attenuation mass (M) grows between the pancreatic body (B) and the
tail (T). The features are nonspecific, and the differential diagnosis could be that of any 'macrocystic' pancreatic neoplasm or
a pseudocyst. b Cystic lymphangioma, pancreatic body. A unilocular cystic mass projects into the lesser sac from the ventral
portion of the pancreatic body

a b

Fig. 14.14a,b. Pancreatic lipoma: a sharply circumscribed, fat attenuation mass is present in the pancreatic head. The mass dis-
places adjacent parenchyma and does not alter the contour of the superior mesenteric vein as it travels adjacent to the mass

patterns: (a) the highly organized cellular Antoni-A
component and (b) the loose hypo cellular Antoni-
B component. The Antoni-A predominant tumor
is hypervascular, and tumors with this architecture
appear as hyperdense lesions with central necrosis
simulating islet-cell tumors. In those lesions with an
Antoni-B predominance, the lesion appears more
cystic. Neurofibromas in the pancreas are most often
seen in patients with neurofibromatosis as opposed
to isolated lesions. In these patients, there is a high
frequency of neurofibrosarcoma. Neurofibromas are
frequently low attenuating masses, probably related to
the lipid content of the Schwann cells composing them.
Larger, more heterogeneous lesions are more likely to
be malignant. Frequently, neurofibromas encase the
celiac axis, simulating locally invasive pancreatic ductal
adenocarcinoma (FERROZZI et al. 2000).
Sarcomas are extremely rare, accounting for 0.6%
of all pancreatic neoplasms. Malignant fibrous his-
tiocytoma, Kaposi sarcoma, and leiomyosarcoma
have been described. More frequently, the pancreas is
secondarily involved by invasion from the retroperi-
toneum or adjacent portion of the gastrointestinal
tract (FERROZZI et al. 2000).
14.8.2
Ectopic Tumors - Introduction
A variety of ectopic tissues may arise within the pan-
creas and locally grow to simulate a mass. When the
mass is composed of disordered normal tissue, it can
be defined as a hamartoma. In other cases, the mass
can be composed of tissues which are histologically
 262
identical to those seen within the normal organ, such
as endometrial rests.
14.8.2.1
Intrapancreatic Accessory Spleen
An accessory spleen is a common finding on CT
imaging. These are usually not even subjected to
further imaging because of their spherical shape
and attenuation identical to splenic tissue. Acces-
sory spleens are estimated to occur in 30% of autopsy
cases (SICA and REED 2000). They originate embryo-
logically from the dorsal mesentery of the stomach
and or pancreas (DODDS et al. 1990), or following
disruption of the spleen by surgery or trauma (sple-
nosis). Although intrapancreatic accessory spleen
is estimated to occur in 17% of cases of accessory
a b
c Dennis Balfe, MD, St. Louis, MO, USA)
A. J. Megibow and I. R. Francis
spleen (SICA and REED 2000), it is not seen in clinical
practice with this frequency.
When present on imaging, the lesion appears as a
well circumscribed mass with enhancement charac-
teristics paralleling the enhancement of the normal
spleen and can be confused for a hypervascular
pancreatic mass arising from the tail of the pancreas
(CHUREI et al. 1998; HARRIS et al. 1994; HAYWARD et
al. 1992). The mass may be most frequently confused
with islet-cell tumor or metastatic tumor such as
from renal cell cancer (Fig. 14.15). If the diagnosis
is considered, MR can be useful in confirming that
the lesion 'tracks' with splenic signal on a variety of
unenhanced and enhanced sequences (CHUREI et al.
1998). The diagnosis can be proven with scintigraphy
using 99ffiTc_sulfur colloid or lllIn-labeled damaged
red blood cells (SICA and REED 2000).
Fig.14.15a-c. Intrapancreatic accessory spleen. a Mass of soft-
tissue attenuation is present (arrow) in the splenic tail. b Arte-
rial phase imaging shows significant enhancement of the mass
(arrow). c The mass (arrow) continues to remain hyperdense.
Note the similar attenuation to the spleen. (Courtesy of Dr.
Unusual Pancreatic Neoplasms: Imaging
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Secondary Tumors
15 Secondary Tumors:
Clinical Manifestations and Pathology
T. OWElTY and A.B. WEST
CONTENTS
15.1 Introduction 269
15.2 Tumors Directly Invading
the Pancreas 269
15.3 Lymphomas and Leukemias 269
15.4 Tumors with Distant Metastases
to the Pancreas 271
15.4.1 Solitary Metastases 271
15.4.2 Metastatic Renal Cell Carcinoma 271
15.4.2.1 Clinical Features 271
15.4.2.2 Pathology 272
15.4.2.3 Differential Diagnosis 272
15.5 Role of Fine Needle Aspiration
Biopsy 273
References 275
15.1
Introduction
Secondary tumors of the pancreas are uncommon.
The reported incidence varies widely within dif-
ferent series. Autopsy series describe pancreatic
involvement in 3%-15% of patients with general-
ized malignancies, secondary tumors being nearly
four times as common as primary pancreatic malig-
nancies (WILLIS 1975; CUBILLA and FITZGERALD
1984). This most likely reflects the fact that pancre-
atic metastases from other organs are usually part of
widespread preterminal metastatic disease.
15.2
Tumors Directly Invading the Pancreas
Direct invasion of the pancreas by extension from
neighboring organs was the most common mode
of involvement by tumors of extrapancreatic origin
T. OWElTY, A.B. WEST
Department of Pathology, New York University, 560 First
Avenue (TH461), New York, NY 10016, USA
in Willis's study of 500 autopsies, whereas Cubilla
identified this route of involvement in 6% of autopsy
cases with secondary pancreatic tumors (WILLIS
1975; CUBILLA and FITZGERALD 1984). Some 17%
of secondary pancreatic tumors were directly inva-
sive in Nakamura's Japanese series (NAKAMURA
et al. 2001). While the first two series identified
carcinomas of the stomach and colon as the most
common directly invasive tumors of the pancreas,
no colonic cases were found in the Japanese series,
which identified extrahepatic bile duct carcinoma
and gastric carcinoma as the first and second most
common directly invasive tumors to the pancreas,
respectively.
Pathologically, it may be difficult to distinguish
primary pancreatic ductal carcinoma from invasive
gastrointestinal malignancies as both are adeno-
carcinomas that may display similar cytological!
architectural features and tumor markers (SESSA
et al. 1990). Finding in situ areas helps to estab-
lish the site of tumor origin (SOLCIA et al. 1997).
Extensive lymphatic invasion is a peculiar feature
of involvement by gastric signet-ring cell carci-
noma (Fig. 15.1). Positivity for cytokeratin 7 is more
likely seen in pancreatic carcinoma compared with
colorectal adenocarcinomas, which are frequently
negative (TOT 1999). In addition, morphologically,
colonic cancers tend to have more necrosis, mucin,
and tall columnar cells than primary pancreatic ade-
nocarcinoma (Fig. 15.2). Some patients with locally
advanced primary tumors invading the pancreas are
considered for surgical resection (HARRISON et al.
1997).
15.3
Lymphomas and Leukemias
Secondary involvement of the pancreas by advanced
Hodgkin's disease, non-Hodgkin's lymphoma, mul-
tiple myeloma, and granulocytic sarcoma is not
uncommon (BANKS et al. 1975; BELL et al. 1982;
 270 T. Oweity and A. B. West

a
Fig.lS.la, b. Gastric carcinoma directly invading the pancreas (H&E). a Signet-ring cell adenocarcinoma infiltrates the pancreas
(center) between residual islets (upper left) and pancreatic acini (lower right). b Lymphatic invasion in the pancreas is often a
prominent feature of gastric carcinoma

a
Fig.lS.2a, b. Cecal adenocarcinoma metastatic to the pancreas on fine needle aspiration biopsy. a Atypical intestinal-type
epithelium in a background of extensive necrosis (ultrafast Papanicolaou stain). b Tumor cells are columnar, with elongated
stratified nuclei (Diff-Quik)

EHRLICH et al. 1968; FISCHER et al. 1991; FRANTZ

1959; SATAKE et al. 1991; MWANDA and RAJAB 1999;
KAPLANSKI et al. 1994} and was noted in 1.9% of
all autopsies performed in the Memorial Hospital
series (CUBILLA and FITZGERALD 1984). They may
extend to the pancreas from the peripancreatic
lymph nodes. Leukemia, including chronic myelo-
cytic (CML), acute lymphocytic (ALL), chronic
lymphocytic (CLL), and acute myelocytic (AML)
forms, was present in 0.7% of the autopsies in
that series (CUBILLA and FITZGERALD 1984)
(Fig. 15.3}.

Fig. lS.3. Resected pancreatic mass in a patient with a long

history of CLL. Photograph shows eLL (bottom left) with large
cell transformation (top right) (H&E)
Secondary Tumors: Clinical Manifestations and Pathology
15.4
Tumors with Distant Metastases
to the Pancreas
When direct pancreatic invasion from carcinoma
of adjacent organs and systemic malignancies
(lymphomas/leukemias) are excluded, the truly
metastatic tumors to the pancreas usually arise
from the lung, breast, melanoma, colon, stomach,
ovary, or kidney (CUBILLA and FITZGERALD 1984;
WILLIS 1975). Moreover, when clinical series are
reviewed, rather than autopsy series, metastatic
tumors comprise only 2%-3% of pancreatic tumors
(ROLAND and VAN HEERDEN 1989; KLUGO et al. 1977;
STANKARD and KARL 1992).
The scarcity of premortem evidence of meta-
static disease probably relates to the lack of symp-
toms, or their nonspecific nature. Initial symptoms
include abdominal pain, weight loss, fatigue, anemia,
diarrhea, bleeding, jaundice, and the presence of a
mass lesion. Metastatic foci were discovered in the
pancreas in 14%-24% of asymptomatic patients
during radiographic follow-up for primary renal cell
carcinoma (THOMPSON and HEFFESS 2000). Intra-
pancreatic metastases can be identified by various
radiologic imaging studies. They can be solitary,
multifocal, or diffuse (MERKLE et al. 1998). Multi-
focal disease favors a metastatic malignancy over
primary pancreatic disease, although multifocal
pancreatic carcinoma occurs in up to 30% of cases
(WITTENBERG et al. 1982; MURR et al. 1994). With
improvement in cross-sectional imaging, more cases
of metastasis to the pancreas are being described. Of
1357 patients with solitary pancreatic masses, 2%
were found at exploration to be secondary rather
than primary pancreatic tumors (ROLAND and VAN
HEERDEN 1989).
15.4.1
Solitary Metastases
Of patients presenting with a pancreatic mass who
had a history of previous nonpancreatic malignancy,
42% had metastatic disease (WHITTINGTON et al.
1982). The most common sites of primary tumor
that present as solitary pancreatic lesions are: breast
(ODZAK et al. 2001), lung (JOHNSON et al. 1985),
and kidney. Other reported primary tumor sites
include stomach, ovary, melanoma (BRODISH and
McFADDEN 1993; SMITH et al. 1994), duodenum,
esophagus, uterus and salivary gland (ROLAND and
VAN HEERDEN 1989), prostate, liver, testis (ZUGEL et
27l
al. 1994), thyroid and bone (SWENSON et al. 1980;
SUGIMURA et al. 1991), medulloblastoma (KRouwER
et al. 1991), Merkel cell carcinoma (RUMANCIK et al.
1984), and soft-tissue sarcomas, including synovial
sarcoma, mesenchymal chondrosarcoma, and leio-
myosarcoma (YAMAMOTO et al. 2001; KOMATSU et
al. 1999; HOLMES and ALI 1997).
15.4.2
Metastatic Renal Cell Carcinoma
15.4.2.1
Clinical Features
The most commonly reported solitary metastasis
to the pancreas in recent series has been renal cell
carcinoma (ROBBINS et al. 1996; WHITTINGTON et al.
1982; HARRISON et al. 1997). Renal cell carcinoma can
recur at any time after nephrectomy. In the majority
of cases, pancreatic metastases occur early with a
tumor-free interval of often less than 1 year. How-
ever, late metastasis is not uncommon (KASSABIAN
et al. 2000): Among 15 patients reported by Robbins
to have renal cell carcinoma developing solitary
pancreatic metastases, the mean disease-free interval
was 11 years (ROBBINS et al. 1996), with the longest
reported interval being 32.7 years (THOMPSON and
HEFFESS 2000). The frequency of reports suggests a
recent increase in the detection of metastatic renal
cell carcinoma, perhaps reflecting an improvement
in cross-sectional imaging that has allowed for the
detection of indolent, discrete metastases in the pan-
creas which are characteristic of renal cell carcinoma.
These tumors are usually depicted as one or more,
well-defined, soft -tissue masses, with similar imaging
features to the primary renal cell carcinoma.
For isolated pancreatic metastases, an aggressive
surgical approach is recommended (Z'GRAGGEN et
al. 1998; ROBBINS et al. 1996). This is particularly
true for renal cell carcinoma metastases, for which
marked palliation or even potential cure is possible
with resection (STANKARD and KARL 1992; MELO et
al. 1992; SAHIN et al. 1998; JINGU et al. 1998; HIROTA
et al. 1996; HASHIMOTO et al. 1998; GHAVAMIAN et
al. 2000). In a Mayo clinic series of 23 patients with
metastatic renal cell carcinoma, approximately
4.6 years of palliation was achieved with surgery
(GHAVAMIAN et al. 2000). The grade of the metastatic
lesion correlated with the grade of the primary tumor
in most cases (96%). In the same series, survival was
shown to be worse with higher tumor grade (mean
41 months and 10 months in patients with grade
272
2 and 3 lesions, respectively). Other features that
may be associated with a favorable prognosis after
resection of renal cell carcinoma metastases include
a long interval between the primary tumor resec-
tion and the development of metastasis, evidence
of a solitary or isolated lesion in the pancreas, and
lack of clinical symptoms (THOMPSON and HEFFEss
2000). In the 21 surgical pathology cases from the
file of the Endocrine Registry of the Armed Forces
Institute of Pathology, the mean overall survival rate
from the date of nephrectomy was 19.8 years (range
0.7-39.6 years) with a 6.2 years mean overall survival
from the date of detection of pancreatic metastasis
(range 1 month to 21.8 years) (THOMPSON and HEF-
FESS 2000). This excellent prognosis for renal cell
carcinomas with solitary metastases, along with the
general lack of effective adjuvant therapy, empha-
sizes the necessity for complete resection of primary
and metastatic lesions when possible (KASSABIAN et
al. 2000; TOLIA and WHITMORE 1975).
15.4.2.2
Pathology
Of the 21 patients who underwent resection of
metastatic renal cell carcinoma in the pancreas
described by Thompson, 9 were women and 12 were
men, with an age varying between 47 and 67 years
(mean 64.4 years) (THOMPSON and HEFFESS 2000).
More patients presented with a solitary nodule in
the pancreas (12) than with multifocal disease (9).
The tumors occurred in the head of the pancreas
only (6), tail only (7), or randomly throughout the
pancreas, and ranged in size from 1.5 to 12 cm
(mean 4.0 cm). Macroscopically, the neoplasms were
usually well defined; the cut surfaces were brightly
yellow/orange to white-gray and sharply circum-
scribed. A few were partially necrotic, containing
cysts filled with hemorrhagic fluid. Microscopically,
although the neoplastic deposits were usually well
circumscribed or even encapsulated, tumor cells
were occasionally identified invading the surround-
ing pancreas. The predominant histologic pattern
was characterized by the presence of sheets, small
nests, and cords of neoplastic cells separated by a
prominent vascular stroma. The neoplastic deposits
were composed of polygonal or elongated cells with
clear cytoplasm, distinct cytoplasmic membranes,
and small, compact, eccentric nuclei showing mostly
minimal pleomorphism. Eosinophilic cytoplasm
was present focally in three cases. No papillary
features were detected. Hemorrhage was seen in all
cases, while necrosis and lymphoid infiltrates were
T. Oweity and A. B. West
uncommon. A sarcomatous pattern was seen in one
case. The cells showed variable amounts of glycogen.
No stainable mucin was found. Immunohistochemi-
cal staining showed about 50% of the cases to be
positive for cytokeratin (AE1/AE3) and epithelial
membrane antigen, while 9 of 21 cases were positive
for cytokeratin 7 (focally) and vimentin. Stains for
CA19-9 and CEA were negative. That for GP200AB-1,
a marker of distal kidney tubule, was positive in 9 of
21 cases, usually along the cell membrane and lumi-
nal border. The surrounding pancreas in the majority
of cases showed chronic pancreatitis. Of 21 patients
who had undergone pancreatic resections for meta-
static renal cell carcinoma, 17 had been treated ini-
tially by nephrectomy 1 week to 32.7 years before the
development of pancreatic metastases. In 4 patients,
the pancreatic mass was the initial manifestation of
the disease: a nephrectomy was performed 2 months
to 13.2 years after the diagnosis of metastatic clear-
cell carcinoma to the pancreas, which was not evident
by imaging during the interim (dormant).
There are several immunohistochemical features
that are helpful in differentiating renal cell carcinoma
from other neoplasms in the pancreas. Antibodies to
CD10 stain up to 89% of renal cell carcinomas (CHU
and ARBER 2000), while pancreatic carcinomas show
less frequent and more apical positivity. Renal Cell
Carcinoma Marker, a monoclonal antibody against a
normal human proximal tubular brush border anti-
gen, has also been found to be highly specific for renal
cell carcinomas (98% specificity), although not as
sensitive in metastases (67% sensitivity) (MCGREGOR
et al. 2001). Renal cell carcinoma also shows a positive
oil-red-O reaction and strong vimentin and GP200
immunoreactivity, accompanied by negative mucin,
cytokeratin 20, CEA, and CA19.9 staining (LUTTGES
et al. 1998; MURAISHI et al. 1996; KAUFMANN et al.
1996; ECHENIQUE and GRAHAM 1988; TOT 2002,
SHEAHAN et al. 1990; Loy et al. 1993).
15.4.2.3
Differential Diagnosis
The differential diagnosis of metastatic renal cell
carcinoma to the pancreas includes micro cystic
adenoma, clear cell adenocarcinoma, islet cell tumor,
and sugar tumor. Histologically, both metastatic
renal cell carcinoma and micro cystic adenoma can
have small, gland-like structures and a low nuclear:
cytoplasmic ratio with clear cytoplasm surrounding
nonatypical hyperchromatic nuclei. A rich vascular
pattern can be seen in both, but renal cell carcinoma
tends to form sheets of cells separated by fibrovas-
Secondary Tumors: Clinical Manifestations and Pathology
cular septa with a thin sinusoidal vascular pattern.
Microcystic adenomas generally have fibrotic bands
separating cells that are arranged around a larger
cyst-like lumen. Cytoplasmic glycogen is found in
both lesions. The cells of clear cell adenocarcinoma
of the pancreas have abundant clear cytoplasm sur-
rounding atypical nuclei, similar to those of renal cell
carcinoma although the latter's vascular sinusoidal
pattern is lacking (LUTTGES et al. 1998). Pancreatic
ductal tumors are usually negative for vimentin and
the renal cell carcinoma marker, but positive for cyto-
keratin. Some are positive for CEA or CA19.9. Clear-
cell islet-cell tumors are positive for chromogranin
and islet-cell hormones, while renal cell carcinoma is
negative for chromogranin (CUBILLA and FITZGER-
ALD 1984; SOLCIA et al. 1997). Sugar tumors of the
pancreas are extremely unusual: Although the sinu-
soidal pattern is present, the tumor cells are negative
for keratin and positive for HMB-45 (ZAMBONI et al.
1996) (Fig. 15.4).
Fig. 15.4a, h. Patient with a history of renal cell carcinoma,
presenting with a pancreatic mass (H&E). a Low power
view showing the fairly well circumscribed clear-cell tumor,
with pancreatic islets at the periphery. b Higher power view.
Cords of renal cell carcinoma cells displace the remaining
pancreatic islets. The cells have clear cytoplasm and irregular
nuclei (H&E)
273
15.5
Role of Fine Needle Aspiration Biopsy
As the preoperative distinction between primary and
secondary pancreatic neoplasms is almost impossible,
particularly in solitary masses, diagnostic biopsies are
commonly performed, especially in those patients with
a history of malignancy. Although a surgical biopsy of
the pancreatic tumor may be obtained in cases where
relief of obstructive symptoms mandates surgery, in
most other cases, fine needle aspiration (FNA) of the
pancreas (percutaneous or endoscopic) is the pro-
cedure of choice (BENNING et al. 1992; FRITSCHER-
RAVENS et al. 2001; DI STASI et al. 1998; LJUBICIC et
al. 1992; WILLIAMS et al. 1999; ERICKSON et al. 1997;
CARSON et al. 1995). This rapid, inexpensive, accurate,
and safe procedure with minimal complications can
have a decisive influence on the selection of appropri-
ate therapeutic strategies. Selected patients with iso-
lated pancreatic metastases from tumors of relatively
better prognosis can undergo resection, achieving a
5-year survival of as much as 35% (Z'GRAGGEN et
al. 1998), which is much better than that of primary
pancreatic carcinoma (HARRISON et al. 1997), while
other patients who might benefit from alternative
treatments such as chemotherapy or radiotherapy will
avoid superfluous surgery. When cytology reveals cells
that are unusual for the pancreas (e.g., lymphoid cells,
small cells, or squamous cells), a systemic or a second
malignancy, with pancreatic metastases, is still a dis-
tinct possibility (BENNING et al. 1992). The clinical his-
tory and a variety of immunohistochemical stains may
aid in establishing and refining this diagnosis. This
may include cytokeratins 7 and 20 in cases of adeno-
carcinoma, CD20 and CD3 in lymphoma (Fig. 15.5),
HMB-45 and S100 protein in melanoma (Fig. 15.6),
estrogen and progesterone receptors and gross cystic
disease fluid protein (GCDFP-15) in mammary carci-
noma, TTF-1 (thyroid transcription factor) in pulmo-
nary carcinoma, CD 10 and RCC (renal cell carcinoma
marker) in renal cell carcinoma (Table 15.1).
Table 15.1 lists the most characteristic immuno-
histochemical stains for each tumor as seen in the
majority of cases. However, the specificity and sensi-
tivity of these antibodies vary depending on the type
and differentiation of tumors and the type of com-
mercial antibodies used. They should be interpreted
in the context of the cytomorphological findings and
the clinical/radiological setting (Tot 1999,2000,2002;
Jang et al. 2001; Lagendijk et al. 1999; Castro et al.
2001; Sheahan et al. 1990; Loy et al. 1993; Clarkson
et al. 2001; Chu and Arber 2000; Moritani et al. 2002;
Kristiansen et al. 2002).
 274 T. Oweity and A. B. West

a a

Fig. 15.5a, b. Non-Hodgkin's lymphoma involving the pan-
creas on fine needle aspiration biopsy. a The tumor cells are
dissociated, with irregular chromatin and prominent nucleoli.
Lymphoglandular bodies (small, gray, circular structures char-
acteristic of lymphoid cells) are abundant in the background
(Diff-Quik stained smear). b The cells are positive (brown)
for the B-cell marker CD20 (immunoperoxidase with diami-
nobenzidine on a cell block section)
Fig. 15.6a, b. Malignant melanoma metastatic to the pan-
creas on fine needle aspiration biopsy. a The cells are char-
acteristically discohesive, binucleate or multinucleate, with
intranuclear cytoplasmic inclusions (ultrafast Papanicolaou
stained smear). b The tumor cells are immunoreactive for
HMB-45 (brown), confirming the diagnosis of melanoma
(immunoperoxidase with diaminobenzidine on cell block
section)

Table 15.1. Immunohistochemistry in differentiating primary pancreatic ductal carcinoma from metastases (+ positive in
majority of cases, - negative in majority of cases, ± positive or negative)
Tumor type CK-20 CK-7 CA19.9 CEA TTF-l GCDFP-15 ER SlOO/HMB-45 CDIO Vimentin

Pancreatic ductal ± + + + ±
adenocarcinoma
Colonic adeno- + + + ±
carcinoma
Gastric carcinoma ± ± + + ±
Pulmonary carcinoma - + ± ± + ±
Breast carcinoma + + +
Renal cell carcinoma +a +
Melanoma + ± +

aDiffuse positivity
 Secondary Tumors: Clinical Manifestations and Pathology
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16 Secondary Pancreatic Tumors: Imaging
A. J. MEGIBOW
CONTENTS
16.1 Introduction 277
16.2 Clinical Considerations 277
16.3 Imaging Features - Hematogenous Metastases 278
16.3.1 General Features 278
16.3.2 Renal Cell Carcinoma 278
16.3.3 Other Hematogenous Metastases 279
16.3.4 Complications and Treatment 283
16.4 Secondary Pancreatic Involvement
by Tumor in Adjacent Lymph Nodes 284
16.5 Secondary Pancreatic Involvement
by Tumors in Adjacent Organs 285
References 287
16.1
Introduction
The estimated prevalence of metastases to the pan-
creas at autopsy is between 3% and 10% (CUBILLA
and FITZGERALD 1980; SCATARIGE et al. 2001;
WILLIS 1973). Because pancreatic metastases occur
in patients with advanced disease, the presence of
the lesions themselves rarely cause 'pancreas related'
symptoms; rather, they are discovered during surveil-
lance imaging in oncology patients.
Beyond the detection of a pancreatic mass, the
imaging features are nonspecific. The diagnosis is
suspected when a pancreatic mass is detected in a
patient with a known primary tumor and confirmed
by biopsy. On imaging studies, pancreatic metas-
tases can appear as localized (50%-73% of cases),
multifocal masses (15%-44% of cases) or result in
diffuse enlargement of the gland (5%-10% of cases)
(MERKLE et al.1998; SCATARIGE et al. 2001). Enhance-
ment characteristics vary with the primary tumor.
The lesions may appear as solid masses, hyperdense
masses, cystic masses, or even diffusely infiltrate and
A. J. MEGIBOW, MD, MPH, FACR
Professor of Radiology, NYU School of Medicine, New York,
NY, USA
enlarge the pancreas - in other words they mimic
primary pancreatic neoplasms of a variety of mor-
phologic appearances. Because these masses signal
advanced disease, their presence is usually docu-
mented on a single imaging examination, almost
exclusively computed tomography (CT). Correlative
imaging is not available in most cases; therefore, as
distinct from other sections of this volume, the orga-
nization of the chapter will be based on pathology
instead of the imaging modality.
For the purposes of this discussion, we shall divide
the description of the imaging findings based on the
pathophysiologic mechanism by which the abnor-
mality may affect the pancreas. Three pathways by
which metastases can arrive at the pancreas include:
(1) hematogenous spread, (2) secondary involvement
of contiguous lymphoid tissue, (3) direct extension
from adjacent viscera.
16.2
Clinical Considerations
Autopsy studies reveal that metastases to the pan-
creas were found in 3% of 5000 patients (WILLIS
1973) and 10.6% of 2587 patients (CUBILLA and
FITZGERALD 1980). From these data, one might
conclude that pancreatic metastases should be seen
more frequently in an individual clinical practice.
Most imaging is performed at the time of diagnosis,
and pancreatic metastases often appear as a manifes-
tation of advanced disease. Conversely, the presence
of pancreatic metastases may be underestimated by
imaging studies. In 18/34 (53.8%) cases of autopsy-
confirmed metastatic tumors of the pancreas includ-
ing secondary malignant lymphoma, the pancreas
appeared abnormal on CT (8 diffuse enlargement, 9
localized mass, 1 multiple low attenuation nodules)
. In the remaining 16 patients, histologic investiga-
tion revealed that metastatic carcinoma resulted
in diffuse infiltration of the pancreatic lobules, not
macroscopically visualized by CT (MURANAKA et al.
278
1989). Although this study (from 1989) utilized less
sophisticated technology than is presently available,
it is evident that a significant number of cases may
go unrecognized.
KLEIN et al. (1998) reviewed a 10-year experience
in 66 patients seen at the Mayo Clinic between 1984
and 1994. Of these, 13 patients already had pancre-
atic metastases at the time of initial CT, whereas the
remainder developed them in the follow-up period
(range 2-295 months, mean 57.2 months). In more
than one-third of patients, the metastases appeared
after more than 60 months. The variability could be
correlated with the cell type of the primary neoplasm.
Patients with pancreatic metastases from renal cell
carcinoma (RCC) demonstrated the longest interval
between the detection of tumor and the development
of pancreatic metastases. In Klein's series, 85% of
patients with RCC who developed metastases mani-
fested the masses more than 60 months after diag-
nosis, followed by melanoma, breast cancer, and lung
cancers. In another series of 10 patients, the mean
time from nephrectomy for resection of the primary
tumor to re-operation for periampullary recurrence
in 10 patients with RCC was 9.8 years (median 8.5
years, range 0-28 years) (SOHN et al. 2001).
The pancreas is rarely the only site of metastatic
dissemination. In Klein's series, 45.5% of patients
had demonstrable extrapancreatic abdominal sites of
metastases. The most frequent sites were liver, lymph
nodes, and adrenal glands (KLEIN et al. 1998). In
another series, 19120 patients with pancreatic metas-
tases had lesions in other anatomic sites (FERROZZI et
al. 1997). When the pancreas is the sole site of metasta-
sis, differentiation from the primary pancreatic tumor
is difficult without tissue confirmation by biopsy. The
long-term survival of these patients is considerably
improved over those who might have primary pan-
creatic cancer, and therefore, in appropriate situations
(when imaging fails to define other foci of disease),
aggressive surgical therapy may provide survival ben-
efit (HASHIMOTO et al.1998; Z'GRAGGEN et al.1998).
Clinical symptoms directly and solely related
to the metastatic disease are unusual when the
tumor reaches the pancreas by hematogenous dis-
semination. Mild liver function test abnormalities
or hyperamylasemia may be observed. New onset
diabetes is rare (GHAVAMIAN et al. 2000). Acute pan-
creatitis may occur as a result of ductal obstruction
(McLATCHIE and IMRIE 1981). When the pancreas
is secondarily involved by adjacent invasive lymph-
adenopathy, there is a higher frequency of symptoms
such as biliary obstruction and bowel obstruction
(CHARNSANGAVEJ and WHITLEY 1993).
A. J. Megibow
16.3
Imaging Features - Hematogenous
Metastases
16.3.1
General Features
Virtually any primary neoplasm may metastasize to
the pancreas. However, from multiple reports, certain
cell types have a marked predilection to deposit in this
location. RCC and lung carcinoma are by far the most
commonly reported sources (FERROZZI et al. 1997;
KLEIN et al. 1998; RUMANCIK et al. 1984; SCATARIGE
et al. 2001). Other frequently reported primary lesions
include melanoma (BIANCA et al.1992), plasmacytoma
(MITCHELL and HILL 1985; RICE et al. 1981; TWOMEY
and KATZ 1983; WILSON et al. 1989), carcinoid tumor
(AKERSTROM 1996; VILLANUEVA et al.1994), and breast
cancer (MouNTNEY et al.1997). This list is by no means
complete; disparate sources such as hepatocellular car-
cinoma (TEXLER et al. 1998) and tonsillar carcinoma
(McLATCHIE and IMRIE 1981) have been reported.
As stated in Section 16.2, three broad morphologi-
cal patterns have been described: (1) solitary mass,
(2) multiple nodules; (3) diffuse micronodular pat-
tern with gland enlargement (KLEIN et al. 1998; SCA-
TARIGE et al. 2001). The metastases tend to mimic the
enhancement characteristics of the primary tumor
(FERROZZI et al.1997).
16.3.2
Renal Cell Carcinoma
In our initial publication (RUMANCIK et al. 1984), and
subsequently borne out in many series, RCC seems to
be the most common primary tumor to metastasize
to the pancreas (GHAVAMIAN et al. 2000; KLEIN et
al. 1998; RIVOIRE and VOIGLIO 1996; RUMANCIK et
al. 1984; WEERDENBURG and JURGENS 1984). A large
percentage of patients will harbor metastases in
other sites, most frequently the lungs. In an analysis
of 392 autopsy cases with metastatic RCC, 27% of
patients with metastatic renal cancer did not have
lung metastases, whereas 73% of cases without lung
metastases had no evidence of tumor elsewhere. In
84% of patients with lung metastases, there were
other metastases in the body. These observations
are concordant with the fact that the pancreas may
be secondarily seeded from other metastatic sites, so-
called 'metastatic cascades' (WEISS et al. 1988).
Most descriptions of the imaging features of these
lesions are derived from CT experience. RCC metas-
 Secondary Pancreatic Tumors: Imaging
tases to the pancreas are most frequently solitary
(Fig. 16.1), although multiple masses are not unusual
(Figs. 16.2, 16.3). Utilizing thin-section, bolus con-
trast-enhanced CT, the lesions rapidly enhance
during the arterial (25 s following injection) and
early portal phases to levels between 50 and 100 HU
over the normal pancreatic parenchymal enhance-
ment. On delayed (greater than 60 s) phase imaging,
this difference decreases to between 5 and 45 HU (NG
et al. 1999). The pattern of enhancement may show
preferential peripheral enhancement or be uniform
(GHAvAMIAN et al. 2000).
On magnetic resonance imaging (MRI), the lesions
are hypointense compared with normal pancreas
Fig. 16.1. Renal cell carcinoma (RCC) metastatic to pancreas. A
hyperdense (hypervascular) mass is present in the pancreatic
body. Note the upstream dilatation of the pancreatic duct.
Surgical clips and the position of the spleen are evidence of
prior left nephrectomy
Fig.16.2a. Multiple RCC metastases to the pancreas. There are multiple hyperdense nodules throughout the entire pancreatic paren-
chyma. Notice the primary tumor in the left kidney. b RCC metastatic to pancreas. Celiac axis angiogram of patient in a. The patient
presented with a nodule in her thyroid approximately 10 years prior to the CT examinations. The nodule was metastatic RCC
279
on Tl-weighted fat-suppressed SE images and high
in signal intensity on T2-weighted images. They
demonstrate rapid enhancement on the immediate
postgadolinium Tl-weighted gradient recalled echo
(GRE) images. Larger tumors peripherally enhance
due to central necrosis (KELEKIS et al. 1996; MERKLE
et al.1998).
Although studies have shown ultrasound (US)
(WERNECKE et al. 1986) to be capable of detecting
these lesions, most agree that transabdominal US is
inferior compared with CT or MRI (BISET et al. 1991).
In one series, the metastases appear as solitary or
multiple hypo echoic nodules (Fig. 16.3). US is most
useful in detecting complications such as biliary dila-
tation and pancreatitis (SATO et al. 2001). A new class
of intravenously administered ultrasound contrast
agents, stabilized microbubbles of sulfur hexafluo-
rine gas (Sonovue, Bracco Laboratories), have been
introduced which increase the echogenicity in hyper-
vascular masses (LEEN et al. 2002) (Fig. 16.4). While
frequently utilized in Europe, there is little US experi-
ence with these agents in abdominal imaging.
16.3.3
Other Hematogenous Metastases
As stated previously, any primary tumor could metas-
tasize to the pancreas. In our practice, melanoma and
lung cancer are the two most frequent sources. Mel-
anoma surpasses RCC in frequency in our practice
because our institution is a regional referral center
for patients with this disease.
Lung cancer (bronchogenic carcinoma) is the most
common malignant tumor in the USA, and therefore
 280 A. J. Megibow

a b

Fig. 16.3a,b. RCC metastatic to the pancreas. a Transabdominal ultrasound reveals a hypoechoic mass delimited by markers (+)
in the pancreatic body. b Solitary hyperdense mass is visualized during the arterial phase of helical/spiral CT scan

a b

Fig. 16.4a-c. RCC metastatic to pancreas. a Transabdominal

ultrasound reveals a sharply defined mass in the pancreatic
body (arrow) . SMA, superior mesenteric artery. b Ultrasound
following intravenous injection of Sonovue (stabilized micro-
bubbles of sulfur hexafiuorine gas) documents significant
increase in echogenicity within the lesion (arrow) and sug-
gests multiple smaller nodules. The increased echogenicity
correlated with a hypervascular lesion. c CT scan in arterial
phase shows typical hypervascular mass with several smaller
c nodules

one is not surprised that pancreatic metastases are
encountered in clinical practice. In Klein's series, bron-
chogenic carcinoma (small-cell and non-smaIl-cell
types) was the second most frequent source of metas-
tasis (15 of 66 patients) (KLEIN et al. 1998). There was
a slight predilection of metastases in small-cell cancer
(n=9) over non-smaIl-cell carcinoma (n=6). In other
series, bronchogenic carcinoma is the most common
source of metastatic disease (FERROZZI et al. 1997;
ROLAND and VAN HEERDEN 1989). In our experience,
lung cancer metastases exhibit anyone of the three
broad morphologic patterns enumerated previously
 Secondary Pancreatic Tumors: Imaging 281

(Fig. 16.5). Most of our cases have demonstrated low
attenuation masses, but the number is too few to make
a generalized statement (Fig. 16.6).
Melanoma metastases present with solitary or
multifocal lesions (Figs. 16.7, 16.8). In most cases,
extensive metastatic disease will be present in many
sites not commonly seen in primary adenocarcinoma,
although, unlike RCC, the pancreas has been reported
as the sole site of metastasis (BIANCA et al. 1992). Con-
trast enhancement will vary in relation to the size or the
treatment history of the individual patient. Melanoma
metastases demonstrate low signal on T2-weighted
images and rapid enhancement following intravenous
gadolinium administration (SOLOMONS et al. 2000).
The high signal on Tl-weighted images and low signal
on T2-weighted images result from the paramagnetic
effects of melanin (DEJORDY et al. 1992).
Pancreatic tumors with serotonin immunoreactiv-
ity may be classified as carcinoids and may result in an
unusual cause of the carcinoid syndrome (AKERSTROM
1996). In our practice, we have seen two patients with
carcinoid tumors in the pancreas, neither of whom
demonstrated carcinoid syndrome. In both, the pan-
creas was involved as part of multiorgan dissemina-
tion. In one, the lesion was barely visible on a CT scan
performed with 'pancreatic technique', but MR in this
patient showed the lesion to much greater advantage
(Fig. 16.9). We have seen pancreatic metastases in

a b

Fig.16.5a,b. Non-small-celliung cancer metastatic to pancreas. a There is a unifocallow attenuation mass in the pancreatic head.
The lesion is indistinguishable from other forms of cystic pancreatic tumors. b A fusiform low attenuation mass is present in
the pancreatic tail. The similarity in appearance to primary pancreatic adenocarcinoma is evident. Multiple hepatic metastases
are present as well

a b

Fig. 16.6a. Small-cell carcinoma metastatic to the pancreas. Multiple low attenuation masses are dispersed throughout the
pancreatic body. b Non-small-cell carcinoma metastatic to pancreas. Multiple nodules have coalesced to replace and enlarge
the entire gland. Notice the encasement of the splenic vein by the tumor. Vascular encasement is uncommon but reported in
patients with pancreatic metastases
 282 A. J. Megibow

a b

Fig. 16.7a. Metastatic melanoma, tail of pancreas. A mass is present in the pancreatic tail. Notice the hepatic metastases and the
subcutaneous lesions in the fat in the left posterior chest wall. b Melanoma metastatic to the pancreas: follow-up after chemo-
therapy. The lesion has diminished in size. There appears to be a decrease in attenuation possibly due to central necrosis as a
response to the therapy. Note the decrease in size of the hepatic metastasis in segment 2. The subcutaneous lesions persist

a .....
a

b b

Fig. 16.8a,b. Metastatic melanoma to pancreas:
mass in body of pancreas results in pancreatic
duct obstruction (b). Notice the adenopathy in
the porta hepatis (b)
Fig. 16.9a,b. Metastatic carcinoid to pancreas. a
There is a dilated main pancreatic duct to the mid-
body. A poorly visualized low attenuation region is
seen at the point of obstruction (arrow). b Gado-
linium (GD}-enhanced Tl-weighted fat-suppressed
image reveals extensive replacement of neck and
head of the gland. The extent of disease is more
clearly depicted than on CT. Notice the multiple
liver metastases shown on both studies
Secondary Pancreatic Tumors: Imaging 283

patients with hepatocellular carcinoma (Fig. 16.10)

and breast carcinoma (Fig. 16.11).
Scattered case reports of pancreatic masses in
patients with multiple myeloma or plasmacytoma
have appeared in the literature (MITCHELL and
HILL 1985; OLSON et al. 1993; SCHEIMAN et al. 1987).
Should a pancreatic mass develop in a patient with
these diagnoses, needle aspiration is recommended.
These lesions are responsive to chemotherapy and
may be temporarily palliated by biliary stenting
during the period of treatment.

16.3.4
Complications and Treatment

Metastatic masses in the pancreatic head can obstruct

both the common bile duct and the pancreatic duct,
resulting in a 'double-duct sign', an imaging feature
which potentially could be confused with primary
adenocarcinoma (Figs. 16.11, 16.12) (SMITH et al.
1994). We have seen two patients who developed
clinical acute pancreatitis related to ductal obstruc-
tion from pancreatic metastases. In one patient
with melanoma, a rapidly growing lesion within the
pancreatic body resulted in central cavitary necro-
sis, destruction of the main pancreatic duct, and the Fig. 16.11. Metastatic breast cancer to pancreas. Images reveal
rapid development of a pseudocyst (Fig. 16.13) asso- obstruction of the pancreatic duct and biliary tree by a hetero-
ciated with the rapidly growing tumor mass. geneous soft-tissue mass (asterisk) in the pancreatic head

Fig. 16.10. Metastatic hepatocellular carcinoma. A low attenu- Fig. 16.12. Metastatic lung carcinoma to pancreas. Dilated
ation mass with hyperdense rim is present in the pancreatic intrahepatic bile ducts and a portion of the dilated pancreatic
body (arrow). The lesion developed 2 years following the duct are visualized. The appearance is indistinguishable from
initial diagnosis primary adenocarcinoma or cystadenocarcinoma
 284 A. J. Megibow

c-----.
Fig. 16.13a-d. Central cavitary necrosis - metastatic melanoma. a A low attenuation mass grows across the main pancreatic
duct, resulting in minimal obstruction. b Scan 7 months later. The mass has grown and is associated with the development of
a unilocular fluid collection. c ERCP at same time of examination as b. There is disruption of the main pancreatic duct in the
d

region of the mass. The duct is not entirely destroyed, as evidenced by the filling of the upstream duct. d Contrast injected at
the site of duct disruption demonstrates extravasation into the tumor mass

Several reports have advocated aggressive surgical 16.4

treatment in selected cases. If en-bloc resection is pos-
sible, the median overall survival after metastatic dis-
ease to the pancreas has been reported to be 56 months
(PINGPANK et al. 2002). Others report 5-year survival
rates, in heterogeneous patient populations, ranging
between 17% and 24% (LE BORGNE et al. 2000; WOOD
et al. 2001). In one series of patients with RCC, aggres-
sive resection resulted in 5-year survival rates as high
as 75% (SOHN et al. 2001). All reports stress the proper
selection of patients - those with total resectable dis-
ease - as the criteria for this selection. Survival may be
improved in patients with multiple lesions as long as
the total tumor burden can be resected.
Secondary Pancreatic Involvement
by Tumor in Adjacent Lymph Nodes
Multiple lymph node groups cluster around the
pancreas. While they may harbor metastases from
primary pancreatic carcinoma, tumors of the gas-
trointestinal (GI) tract and lung can also spread
to these lymph nodes. Once a tumor is established
within these nodes, growth directly into the pancre-
atic parenchyma can occur, producing an imaging
picture identical to a primary pancreatic neoplasm.
Metastatic involvement in either the hepatoduode-
nal nodes or the peripancreatic nodes (EFREMIDIS
Secondary Pancreatic Tumors: Imaging
Fig. 16.14. Metastatic gastric carcinoma to peripancreatic
lymph nodes. A multiseptate mass is seen in the pancreatic
head. The lesion could easily be mistaken for a cystic pancre-
atic neoplasm. However, the extension into the porta hepatis
reveals the true identity
et al. 1999) may break through the lymph node(s)
and invade the pancreas. Peripancreatic lymph node
metastases from inframesocolic lesions follow the
distribution of regional lymph nodes, which follow
the vascular distributions of the major abdomi-
nal vessels and mesenteric supporting structures
(McDANIEL et al. 1993) (Fig. 16.14).
Tumors which predictably metastasize to these
lymph nodes include carcinomas of the esophagus,
stomach, duodenum, and right colon. Carcinoma of
the lung and melanoma are also frequent. Lymph
nodes cluster beneath the transverse duodenum and
are contiguous with the pancreas. These lymph nodes
may drain tumors at a considerable distance, most
frequently located in the cecum or ascending colon.
In 12 patients with ascending colon cancer and pan-
creatic metastases, excluding direct extension of the
tumor, 7 (58%) had obstruction of the bile duct and/
or pancreatic duct, 4 others had symptoms related
to the mass, including pain and gastrointestinal
obstruction. In 8 patients (67%), metastatic tumors
involved the pancreas as a focal mass; in the other 4
(33%), the masses were lobulated and engulfed the
285
Fig. 16.15. Gastric carcinoma invading the pancreas. A soft-
tissue mass (asterisk) extends from the posterior gastric wall
across the lesser sac. The residual, normally enhanced pan-
creas (p) is seen. Note the irregular margin of the advancing
tumor mass against the normally enhanced gland
pancreas and were indistinguishable from peripan-
creatic nodal disease (CHARNSANGAVEJ and WHIT-
LEY 1993). These observations have been made in
patients with other than colon cancer (Fig. 16.15).
Lymphoma can affect the peripancreatic nodes,
and this is usually easily recognized in the context of
other imaging findings in the individual patient. The
imaging findings of primary pancreatic lymphoma
will be considered elsewhere. Tuberculous peripan-
creatic nodes can invade the pancreas, simulating a
pancreatic mass (HULNICK et al. 1985).
16.5
Secondary Pancreatic Involvement
by Tumors in Adjacent Organs
The pancreas may be a site of secondary tumors
resulting from tumor extension across soft-tissue
supporting structures between it and adjacent vis-
cera. Most frequently, these tumors arise from the
stomach, gallbladder, and proximal colon. The spread
of tumor is directly through the serosa of the organ
and into the closely applied pancreas.
Primary tumors of the posterior wall of the stomach
(Fig. 16.16) or metastases to this portion of the stomach
(Fig. 16.17) can traverse the lesser sac and adhere to
and/or invade the pancreas. In 282 patients with gas-
 286 A. J. Megibow

a ..... b

Fig. 16.16a,b. Metastatic breast carcinoma to gastric antrum with secondary pancreatic invasion. a The antral wall is thickened
by a hypoattenuating soft-tissue mass (asterisks). b Scan slightly superior reveals a dilated main pancreatic duct (arrow) in the
tail and body

a b

Fig. 16.17a,b. Gallbladder cancer invading the pancreas. a The gallbladder is replaced by a soft-tissue mass. The mass extends across
the local fat and invades the gastric antrum. Note that the common bile duct is dilated. b The head of the pancreas is engulfed by
the extensive soft-tissue mass. Morrison's pouch is filled with tumor, and greater omental seeding is present as well

tric cancer invading adjacent organs, 150 (53.2%) had
tumors invading the pancreas. In cases of pancreas inva-
sion, the extent of lymph node metastasis was severer,
vascular involvement was more frequent, and the rate of
concomitant liver metastasis was higher. The prognosis
was better for patients treated with curative surgery and
pancreas resection. Pancreas-invasive gastric cancer
cells are likely to advance via lymphatic and vascular
routes (MAEHARA et al. 2000). Cross-sectional imaging
has performed poorly in detecting or excluding gastric
cancer extension into the pancreas (DAVIES et al. 1997;
TSUBURAYA et al. 1994). In the absence of irregularity
of the pancreatic surface, pancreatic invasion can be
excluded with certainty (BANBA et al.1998).
Gallbladder carcinoma can be locally invasive
and metastasize to regional lymph nodes along the
hepatoduodenalligament, which can also be a source
for invasion of the pancreas (EFREMIDIS et al. 1999).
The lesion can extend directly across the fat planes
between the gallbladder and biliary tree and pan-
creas. Secondary pancreatic involvement should be
suspected when the biliary tree is dilated below the
level of the cystic duct and/or pancreatic duct dilata-
tion is present.
Secondary Pancreatic Tumors: Imaging
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Subject Index

A Behavior 231
Accessory spleens 237 Beta-emitting isotopes 191
Acinar cell 23,221 Beta-HCG 233
- markers 24 Biliary (enteric) bypass 7, 158
Acinar cell carcinoma 22,162,214,222,224,255-257 - obstruction 37
Acinar cell cystadenocarcinoma 9,18,23,24,223 - stasis 146
Acinar differentiation 225 Biliary duct 238
Acinar growth pattern 225 Biochemical and immunological analysis 13
Acinar markers 231 Biological behavior 6,10,97,119,131,170,251,258
Acinar pattern 223 Biopsy 111
Acinar-endocrine cell tumor 226 Biphasic tumor 17
Acini 24 Blood products 251
Acoustic characteristics 58 Bone metastases 213
ACTH (adrenal corticotrophic hormone) 258 Breath-hold sequences 106,180
ACTH-producing pancreatic islet cell tumor 192 Brunner's gland hamartoma 238
Acute pancreatitis 78
Adenosquamous carcinoma 16,254
Adenosquamous tumor of pancreas 255 C
Adrenal corticotrophic hormone (ACTH) 258 C peptide 146
AFIP (Armed Forces Institute of Pathology) 249 CA 19.9 5,12,19,225,229,254,255
AFP (alpha-fetoprotein) 225 CA 72-4 5
Alanine aminotransferase (ALT) 80 CA 125 5,13
Alcohol abuse 78 Calcification/s 11,15,23,33-35,39,58,59,64, 7l, 101, 115, 129,
Alkaline phosphatase (ALP) 88 133,164,200,201,205,234,239,251,254,260
All-in-one technique 210 Calcifying pancreatitis, chronic 239
Alpha cells 145 Carcinoid 143, 191, 281
Alpha-fetoprotein (AFP) 225 Carcinoid syndrome 281
Alpha-inhibin 17 Carcinomatous invasion (in IPMT) 87,90
ALT (alanine aminotransferase) 80 Cardiovascular manifestations 144
Amine precursor uptake and decarboxylation (APUD) 182 CEA 5,12,17,19,50,70,225,229,255
Anaplastic pancreatic carcinoma 230 Cecal adenocarcinoma 270
Angiographic evaluation 48 Celiac axis 203
Angiography 69,187,188 Cellular palisading 236
Angiosarcoma 234 Central (fibrous) scar 11,12,35,37
Antoni-A component 261 Centro acinar cells 11
Antoni-B component 261 Cephalic resection 6
APUD (amine precursor uptake and decarboxylation) 182 CEUS (contrast-enhanced US) 198,213,214
Armed Forces Institute of Pathology (AFIP) classification 249 Chemo-embolization 157
Arteriogram 186 Chemotheraphy 158
Arteriography 46,184,188 Cholangiopancreatography (MRCP) 41,43,52,64,106,107,
Ascites 123, 127 119,124,129,133,209,210
Aspirate smears 232 - imaging (MR) 57
Asthenia 79,154 Choriocarcinoma 16
Chromogranin A 155
Chromosome 10q 10
B Chronic calcifying pancreatitis 239
B-cell 25, 144 Chronic pancreatitis (CP) 72,77,80,129,133
- hyperplasia 141 Clear cell adenocarcinoma 272,273
Basal acid output (BAO) 147 Clear cell carcinoma 33
Basket-like imprint/pattern 46,210 Clear cell change 230
Beckwith-Wiedemann syndrome 220,258 Clear cell 'sugar' tumor 13
290 Subject Index

Clinical information 81 Dorsal pancreatic anlage 18

Clinical presentation 15,81 Double-duct sign 283
- (ofNFET) 154 DPC4 91
Clinical symptoms 220, 260 Dual-phase acquisition (CT) 200
Collateral branches IPMT 69,70, 129 Dual-phase CT protocol 188
Collateral network 206 Dual-phase helical CT 255
Colloid carcinoma 90 Duct ectatic mucinous cystadenoma 85
Colonic cancer 269 - obstruction 63
Color-doppler (US) 199 Ductal adenocarcinoma 9, 15,214,222,225,253
Common bile duct 123 - dilation 100, 102
Communicating duct 43,49,70,114,115,119,122 Duodenal papilla 100
Compact spindle cell proliferation 238 Duodenectomy 148
Computed tomography (CT) 33,57,250 Dynamic phase (CT) 200,208
- dual-phase 178
- multirow helical 177
Congenital cysts 9 E
Contrast-enhanced US (CEUS) 198,213,214 EBV (Epstein Barr virus) 239
Conventional resection 156 Electron microscopy 225,229,239
Corticotropinoma 192 EMA (epithelial membrane antigen) 12,17,229
Corticotropin-releasing hormone (CRH) 192 En-bloc resection 284
CT (computed tomography) 177,186,188,193,250 Encasement (vascular) 203
- dual-phase helical 255 Endocrine cells 16
- dynamic 252 - cystic tumor 71
Cushing's syndrome 146,220,238 - insufficiency 154
Cushing-like syndrome 258 - markers 25,171
Cystic change/degeneration 203,206,231,235,251 - tumor 9,39,154
- ectasia 99-101,105,123 Endocrine hormone 226
- fibrosis 129,133 Endocrine tumors 225,230
- islet cell (endocrine) Tumor 18,25,64,206 Endoluminal papillary growth 81
- pancreatic lesions 9 - vegetation 81
- solid pseudopapillary tumor 71 Endometrial cysts 9
Cystic fibrosis 238 Endoscopic procedure 181
Cystic lymphangioma 261 Endoscopic Retrograde Cholangiopancreatography (ERCP)
Cystojejunostomy 18 46,52,57,122,123,124,129,180
Cytokeratin 17 - ultrasonography (EUS) 51,53,57,70,123,252
Cytokeratin markers 24 Endoscopic ultrasound (EUS) 51,53,57,70,123,186,187,252
Cytological smears 21 Endoscopically directed FNAB 70, 113
- evaluation 162 Endosonographic scope 182
Cytology 222,225 Enterogenous cysts 9
Enucleation 149
Epithelial markers 235
D Epithelial membrane antigen (EMA) 12, 17,229
3D reconstruction 178 Epstein Barr virus (EBV) 239
Debulking 157 Estrogen receptors (ER) 17,22
Delayed enhancement 63 Etiology 239
Demographic data 80 European Multicentric Trial 212
Derivative surgery 129 EUS (Endoscopic ultrasound) 51,53,57,70,123,186,187,252
Dermoid cyst, true 259 - guided biopsy 252
Diabetes 5,79, 146,278 Exocrine acini 12
- value of 79 Exocrine insufficiency 238
Diabetes mellitus 142 Extraductal proliferation 113
Diagnostic criterion (in cystic tumors) 9 Extra-pancreatic islet cell tumors 193
Diarrhea 144
Diarrheogenic substances 147
Differential diagnosis 21,22,25,31,33,80,204,213,231,232, F
235,237,240 F-18-fluorodeoxy-glucose positron emission tomography
Diff-Quik stain 231 (PET) 191,193
Diffuse intraductal papillary adenocarcinoma 85 Factor VIII 234
Diffusion-weighted echo-planar imaging 108 Fast sequences 179
Dilatation of the main duct (ofWirsung) 52,98,99,111,199 Fast T2-weighted sequences (FSE) 106
Dilated papilla 103 Fat 180
Display collimation 34 Fat necrosis 255
Distal pancreatectomy 156 Fat-suppressed TI-weighted images 56
Subject Index 291

Fat supression 180 HCG (human chorionic gonadotropin) 155

- techniques 179 Helical CT 193
Fatlfluid levels 259 Hemangiopericytoma 234
Fatty involution 180 Hemorrhage 24,34,58,59,64,71,198,220,250,255,272
Fatty liver 200 Hemorrhagic degeneration 251
Fibrolipoma 234 Hemosiderin-laden macrophages 12
Fibrosis 163 Hepatic metastases 7,82,123,149,155,185,204,206,209,212,
Fibrotic atrophy 239 213
Fibrous capsule 237 - transplant 157
Fibrous pancreas 182 Hepatobiliaryanlage 18
Fibrous pseudocapsule 15,23 High frequency miniprobes (EUS) 113
- tissue 63, 208 Histochemical stains 224
Fibrovascular stroma 227 Histogenesis 11,22,229
Findings (correlating to malignancy) 113 Histologic pattern 238,272
Fine-needle aspiration biopsy (FNAB) 5,6,13,19,21,57,64, Histological type 10
71,155,161,214,252,270 Hodgkin's disease 269
Fistulas (in IPMT) 86 Homer-Wright rosettes 236
Fistulous tract 11 0 Honeycomb (architecture) 32,37,43,49,50,113,114
Fluid -debris levels 251 Hormonal hyperproduction 154
Fluid-fluid level 59,60 Human chorionic gonadotropin (HCG) 155
FNAB 270 Hypervascular endocrine tumors 184
FNAB (Fine needle aspiration biopsy) 5,6,13,19,21,57,64, Hypervascular lesion 44
71,155,161,214,252,270 Hypervascular metastases 180
Follow-up 82,83 Hypervascularization 46, 197
Frantz's tumor 250 Hypervascularized tumor 200
Functional secreting neuroendocrine tumors 141 Hypoglicemia 144
Functioning endocrine tumors 212
Fungal infection 240

IDUS (intraductal ultrasonography) 88,92,113

G Image guided FNAB 6
Gadolinium-BOPTA 209,211 Imaging findings 98
Gallbladder carcinoma 286 Immunocytochemical method 166
Gamma-glutamyl transferase (GGT) 80 Immunohistochemical features 221,272
Gastric carcinoma 270 Immunoreactivity 17
Gastric signet-ring cell carcinoma 269 Immunostains 224
Gastric-type mucin markers (PGII and Ml) 17 Imunohistochemistry 229
Gastrin 192 Infantile pancreatic carcinoma 220
Gastrinoma 141,142,145,183,185,189,212 Inflammatory myofibroblastic tumor 238
Gastrinoma triangle 188 Inflammatory myofibrohistocystic proliferation 238
Gastrointestinal hemorrhages 145 In-octreotide scintigraphy 188
G-cells 144 Insulin 192
Genetic screening 4 Insulinoma 141,142,181,185,187
Germ cells 233 Intermediate resection 6
Germ-cell tumors 219 Intraductal component 230
GGT (gamma-glutamyl transferase) 80 Intraductal mucin-hypersecreting neoplasm 85
Giant-cell carcinoma 227 - carcinoma and invasive carcinoma, IPMC/IC 77,89
Giant-cell tumor 227 - ductectatic mucin-hypersecreting variant 86
Glandular-like or acinar pattern (of growth) 164 - IPMA/B 77,89
Glucagonoma 141,142,168,184,185 - IPMT of the main duct 80,81,86,130
Gradient recalled echo (GRE), Tl-weighted (FS) sequences - IPMT of the peripheral (branch)(collateral) ducts 43,81,87,
42,67,106,108,119,128,253,279 131
GRFoma 192 - oncocytic variant 89
Growth pattern 164,223,226 - operability 82
- papillary (mucinous) neoplasms (IPMNs) 14,15,85
- papillary-villous variant 86
H - pathological hallmarks of 85
Half Fourier single-shot turbo spin echo (HASTE) 64,106, - prognosis 93
107,119,209 - resectability 82
Hamartoma 261 - tumor, IPMT 41,57,77,80,85
Harmonic imaging 197 - types of infiltration 82
HASTE (Half Fourier single-shot turbo spin echo) 64, 106, Intraductal papillary carcinoma 231
107,119,209 Intraductal papillary mucinous tumor (rPMT) 255
292 Subject Index

Intraductal ultrasonography (lDUS) 88,92, 113 Macroscopic feature 34,220,223,227

Intraluminal (filling) defects 110,114,122,129 Magnetic resonance angiography 209
Intraoperative examination 146 Magnetic resonance (MR) 179
- ultrasound 148 Main duct IPMT 124
Intraoperative palpation 193 Major papilla 86,125,127
Intraoperative ultrasonography 193 Malignancy 16,208
Intraoperative ultrasound (lOUS) 182,188 - indications 115
Intrapancreatic embryonic rests 259 Malignant cystic tumors 37
Intrapancreatic metastases 271 - degeneration 6,59,100,102,130,131
Intrapancreatic teratoma 233 - potential 162
Invasive mucinous cystadenocarcinoma 16 Malignant degeneration 185
Iodine-labeled -compound 183 Malignant fibrous histiocytoma 237
IPMT (intraductal papillary mucinous tumor) 255 Malignant melanoma 274
Islet cell tumor 178,185,222,262,272 Management (therapeutic) 98,129,156
Islets of Langerhans 12 Mangafodopir trisodium (Mn-DPDP) 179,255
Markers 225
- of malignancy 170
Mature teratoma 25
Jaundice 79,223 May-Grunwald-Giemsa 231
MDCT (multislice (multidetector-row) CT) 33,34,60,64,114
Medical therapy 158
K Melanin 281
Kaposi sarcoma 261 Melanocyte-stimulating hormone (MSH) 192
Ki-67 21,155 Melanoma metastases 281
K-ras (mutation) 90,91,222 MEN - 1 (syndrome) 72,153-155,161,163
MEN type I 185,188,192
Mesenchymal tumors 219
L Metachronous metastases 214
Laboratory 80 Metastases 63,156
Lactate dehydrogenase (LDH) 232,252 - hepatic 178, 179
Leiomyoma, primary 234 - intrapancreatic 271
Leiomyosarcoma 235 - of the liver 226, 251
Lifestyle habits 80 - pancreatic 272,277,278
Lipoblastoma 234 Metastatic breast cancer to pancreas 283
Lipoma 234 Metastatic carcinoid to pancreas 282
Liposarcoma 234 Metastatic cascades 278
Liver mestastases 156, 185, 191, 192, 198, 204, 226, 251 Metastatic clear-cell carcinoma 13
Loading tests 147 Metastatic glucagonoma 191
Local (tumor) recurrence 82 Metastatic hepatocellular carcinoma 283
- in IPMT 92 Metastatic melanoma 282
Location ofNFET 154 Metastatic tumors of the pancreas 271
Lung cancer 279 Microcystic (or glicogen-rich) cystadenoma 10,57
- metastases 280 - appearance/architecture 33,49
Lymph node involvement 252 - (or classic) type (SCA)(SCT) 11,32,47
Lymph node metastases 87,257,286 - tumor 46
Lymphangioma/s 13,129,234 Microcystic adenoma 272,273
Lymphatic invasion 269 Microscopic features 227,229
Lymphoepithelial cyst/s 9,25 Minor papilla 86
Lymphoid infiltration 272 Mitotic activity 164
lymphoma 219,285 Mixed acinar-endocrine cell carcinoma 219
Lymphoplasmacytic lymphoma 239 Mixed appearance (ofNHFET) 202
- pattern 32
- tumor 33
M Mixed exocrine-endocrine tumors 226
Macrocystic cystadenoma/cystadenocarcinoma 57 MNCC (mucinous noncystic carcinoma) 18,85,90,91
- multilocular (appearance) pattern (MCT) 58,60,61,62,64, Mn-DPDP (mangafodopir trisodium) 180,255
71 Molecular analysis 225,229
- multilocular mass with thick wall 71 Morphological patterns 278
- multilocular mass with thin wall 71 MR(magnetic resonance) 179
- oligo cystic type (SCA) 11,33 MR (evaluation) 53,64,207
- unilocular pattern 59,63,64,72 - sequences 41
Macrocysts 11,37,43,46,50 MR cholangiopancreatography (MRCP) 179,180
Macroscopic characteristics 97 MRCP 179, 180
Subject Index 293

MRI 188,279 Obstructive jaundice 239

MSH (melanocyte-stimulating hormone) 192 Obstructive symptoms 7
Mucin 78,101,106,110,119 Octreoscan 158,183,211-214
- globules 100 Octreotide 183, 209
- hyperproduction 78 - scintigraphy (SRS) 212
- leakage 124 Ohhashi triad 77
- like carcinoma -associated antigen 19 Oligo cystic SCT 46,48, 7l
- plugs 86 Omental masses 127
- producing tumor 85 Oncocytic change 230
- secreting epithelium 14,15 Oncocytic tumor 219,231
Mucinous cystadenoma (MCA) 16,19 Operability 82
- cystadenocarcinoma (MCC) 4,16,19,60 Oral contrast (agent) 34,116
- cystic neoplasm of borderline malignant potential (MCB) - medium 101
16,19 Osteoclast-like giant cell tumor 16,219,227,229,257
- cystic neoplasms (MCN) 9,13-15,17-19 Ovarian (like) type stroma 3,14-17,88
- tumor, MCT 5,81,70,93,129,214
Mucinous cystic neoplasm 229
Mucinous cystic tumor 251,260 P
Mucinous neoplasms 10 Pain 78
Mucinous noncystic carcinoma (MNCC) 18,85,90,91 Pancreas, metastatic tumors 27l
Muconodular infiltration 82 Pancreatic acinar cell carcinoma 219
Mucous-hypersecreting tumor 85 Pancreatic carcinoma, primary 284
Mucous-secreting cancer 85 Pancreatic cholera 145
Multicentric (multifocal) IPMT 121,122 - endocrine tumor (PET) 161
Multilocular cystic mass 41 - insufficiency 154
Multiple endocrine adenomatosis (MEA) 185 - intraepithelial neoplasia (PanIN) 85
Multiple endocrine neoplasia (MEN) 161,185 - parenchyma 35,60,98
Multirow helical CT 186,188 - phase 60,115,200,208
- scanner 178 - polypeptide (PP) 155
Multislice (multidetector-row) CT (MDCT) 33,34,60,64,114 - secretion 146
Mural nodules 15,257 - signal (MR) 119
Myxoid apperance 236 - stone protein (PSP) 24
Myxoid pattern 238 - technique (CT) 101
- type pain 5
Pancreatic choriocarcinoma 233
N
Pancreatic ductal tumors 273
Necrosis 24, 7l, 179, 198,220,236,250,272,283
Pancreatic fatty infiltration 260
Neoplastic thrombus 204,205
Pancreatic hamartoma 238
Neovascularity 184,186
Pancreatic invasion, direct 271
Nesidioblastosis 142
Pancreatic lipoma 261
Neuroblastoma 142
Pancreatic lipomatosis 238
Neuroendocrine markers 230
Pancreatic lymphangioma 260
Neuroepithelioma 236
Pancreatic lymphoma 252,254
Neurofibroma 261
- primary 232,253
Neurofibromatosis of von Recklinghausen (type 1) 146,169
Pancreatic metastases 272,277,278
Neurological alterations 146
Pancreatic pseudo tumors 238
Neuron specific enolase (NSE) 21,155,221
Pancreatic technique 281
Neurovegetative disorders 144
Pancreatic teratoma 259
NHFET (nonhyperfunctioning endocrine tumor) 197
Pancreatic venous sampling 184
- atypical 205
Pancreaticoduodenectomy 31,156
NHL (non-Hodgkin'S lymphoma) 232,252,269,274
Pancreatitis-like pain 81
Nodular fasciitis 238
Pancreatoblastoma 22,219,222,226,259
Nodules 60
Pancreatogram 110
Non-functioning endocrine tumors (lesions) 52,154,155,
Pancreatojejunostomy 129
157,192
Pancreoduodenectomy 82
Nonfunctioning islet cell tumors 22
Papilla major 86
Non-Hodgkin's lymphoma (NHL) 232,252,269,274
- minor 86
Nonhyperfunctioning endocrine tumor (NHFET) 197
- patulous orifice of 86
Nuclear Medicine 214
Papillary cystic neoplasm (tumor) 20,250
Nuclear-to-cytoplasmic ratio 221,222
- growth 81,99,101,110,125,126,131
- projections 15,16,23,60
o - proliferations 59,68,88-90,101,102,104,106,108,110,111,
Obstrucitve pancreatitits 239 115,119,122
294
Papillary epithelial neoplasm 250
Parameters (in evaluating neoplasms)
Paraneoplastic hypercalcemia 169
Parathyrinoma 192
Parenchymal atrophy 100,101,104,106,128
- calcifications 102
- thickness 101,102
Parietal nodules 63
PAS (periodic acid-schiff) 10,12,224
Pathway 277
Patient's position 102, 115
Pattern of enhancement 279
Periodic acid-Schiff (PAS) (stain) 10,12,224
Peripancreatic fat necrosis 240
Peripancreatic veins 203,206
- vessels 60, 69
Peripheral cystic tumors 3
Peripheral eosinophilia 223
Peritoneal carcinomatosis 123
Peritumoral infiltration (extension) 7, 17
-lymphadenopathy 198
Perivascular epithelioid cells (PEC) 13
Peroral pancreatoscopy (POPS) 88
PET (F-18-fluorodeoxy-glucose positron emission tomogra-
phy) 191,293
Plain film (examination) 44,64
Plasma cell granuloma 238
Pleomorphic giant-cell carcinoma 230
PNETs 236
Portal vein invasion 186
Positron emission tomography (PET) 183,212
Posterior shadow/ing (US) 33,101
Power doppler 123,126
Predictors (of malignancy) 71
Premalignant lesion 57
Preoperative diagnosis 19,21
Primary hyperparathyroidism 153
Primary leiomyoma 234
Primary pancreatic carcinoma 284
Primary pancreatic lymphoma 232,253
Primordial gonad 18
Progesterone receptors (PR) 17,22
Prognosis 14,19,20,98,149,191,214
Prognostic criteria 71
Pro-insulin 146
Protruding papilla 77
Psammoma bodies 164
Pseudocysts 13,18,21,37,59,64,71,78,252,283
Pseudopapillae 21, 24
R - nodular (insular) pattern (of growth) 164
Radical resection (in functioning endocrine tumors) 148
Radiologicfeatures 192
Radiometabolic therapy 158,213
Rapid acquisition relaxation enhancement (RARE) 64
RCC (renal cell carcinoma) 271,278
- metastases 279
Receptor scintigraphy 209,211
Reconstruction interval (CT) 34
Recurrence 156
Recurrent pain 78
Renal cell carcinoma (RCC) 271,278
Subject Index
- markers 230,272
81 Resectability 82, 156
Resection 6, 7
Residual disease 157
Respiratory triggering 179
Retention cyst 129
Retroperitoneal fibrosis 238,239
Retroperitoneallymphadenopathy 191
Ring-like peripheral enhancement 186
Risk of misdiagnosing 105
S
Salt and pepper pattern 162
Sampling 19
Santorini (duct) 99
Sarcoidosis 240
Sarcoma 261
Schwann cells 236,261
Schwannoma 260
Scintigraphy 262
Scirrous tissue 208
Secondary pancreatic involvement 286
Secretagogue 185
Secretin 69
SegmentalIP11T 98,105,106,111,129
Selective arteriography 46
Sensitivity of transabdominal ultrasound 187
Septa/septations 60
Serous adenoma 12
Serous cystadenoma (SCA) 10,18,25,80,81,129
- cyst 4
- cystadenocarcinoma (SCAC) 10,31
Serous cystic tumor (SCT) 5,41,70
- micro cystic tumor (adenoma) 9,13
- oligocystic (macrocystic) tumor (adenoma) 9,10
Serum tumor markers 19
Signal intensity 208
Signs of malignancy 197
Single photon emission computed tomography (SPECT) 211
Single-row helical CT 186
Sjogren's syndrome 239
Skip lesions 135
Small cell carcinoma metastatic to the pancreas 281
Small-cell cancer 280
Solid and cystic acinar cell tumors 250
Solid and papillary cystic (epithelial) tumor 9,20
Solid and papillary epithelial neoplasm 250
Solid pseudopapillary pancreatic neoplasm 251
Solid pseudopapillary tumor (SPT) 9,13,18,20,21,162,214,
219,222,226,228,230
Solid serous adenoma 12
Solid serous cystadenoma 230
Solitary fibrous tumor 237
Somatostatin 191
Somatostatin analogue 149,158,183
- receptors 213, 214
Somatostatin receptors 182, 183
Somatostatin-receptor imaging 184
Somatostatin-receptor localization 187
Somatostatin-receptor scintigraphy 188,189,193
Somatostatinoma 143,147,185,191
Subject Index 295

Sonovue 279,280 Tubular type (of infiltration) 82

Spectrum of pancreatic tumors 9 Tumor
Spindle cell tumors 239 - hyperfunctioning endocrine 179
Spiral CT 60 - hypervascular 178
Splenic infarcts 163 Tumor thrombus 255
Splenopancreasectomy 82 Tumor type 6
Sponge-like (appearance) (mass) (SCT) 33,39,42,43,46,113 Tumoral markers 49
Squamoid corpuscules 220,258 Tumor-like lesions 220
Stromal luteinization 17 Type of infiltration 82
Structural findings 60
Sugar tumor 272,273
Superior mesenteric artery 203 U
Superparamagnetic contrast media 106 Ultrasonography (US) 57,197
Surgery 227 Ultrasound contrast agents 279
- indications 82 Ultrastructural findings 221
Surgical biopsy 273 Unilocular mass 59
Surgical indication 6 - with thick wall 71
- resection 7,14,71,98,129,156,157 - with thin wall 71
- treatment 149
Surgical resection 229,236
Survival rate 149,156,157 v
Suspicion of malignancy 102 Vascular encasement 46
Symptom complex 154 - resection 156
Symptoms 10,32,80,81,214,191,235 - thrombosis 163
Synchronous (metastases) 214 Vascular invasion 258
Syndrome of inappropriate ADH -secretion 258 Vasoactive intestinal polypeptide (VIP) 142,145,226
Venous involvement 184
Venous phase 63,189,206
T - sampling 148
Tl-weighted fat-suppression sequences 186 - thrombosis 63
Tl-weighted gradient recalled echo 253,279 Venous sampling 187,188
T2 short time inversion recovery (STIR) 207 Verner-Morrison Syndrome 145,170
TZ-W fast (turbo) spin-echo (TSE) 42 VHLgene 10
T2-weighted images 180,255 Villous adenoma of the main pancreatic duct 85
Target -like metastases 204 - adenomatosis of duct ofWirsung 85
Therapeutic management/option(s) 31,77 VIP (vasoactive intestinal polypeptide) 142, 145, 226
- approach 71 VIPoma 142,185,190
Thickness (of the septa/walls) 58,81 Von Hippel-Lindau disease 4,33,39,40,43,153
Three-dimensional reconstruction 203 - syndrome (VHL) 10
Tissue harmonics 58 Von Recklinghausen's disease 236
Total pancreatectomy 131,133
Trabecular pattern 164,168
Transabdominal ultrasonography (US) 123 W
Transabdominal ultrasound 181,186 Watchful monitoring 135
Transduodenal FNA 122 WDHA 144
Transhepatic venous sampling 184 Weight loss 79
Trans-illumination 148 WHO (World Health Organization) 250
Traumatic neuroma 240 - (2000) classification 10,89,156,158,161
Treatment 222,232 Wilkinson migrant necrolitic erythema 144
Treatment and prognosis 239
Triple-phase 178
Tuberculosis 240 Z
Tuberculous peripancreatic nodes 285 Zollinger-Ellison syndrome 144,168,192
List of Contributors

CLAUDIO BASSI, MD LUCA CASETTI, MD

Department of Surgical-Gastroenterological Department of Surgical-Gastroenterological
Endocrine and Pancreatic Unit Endocrine and Pancreatic Unit
Hospital "GB Rossi" Hospital "GB Rossi"
University of Verona University of Verona
37134 Verona 37134 Verona
Italy Italy

ROSSELLA BETTINI, MD FERNANDO CIRILLO, MD

Department of Surgical-Gastroenterological Department of General Surgery II

Endocrine and Pancreatic Unit "Istituti Ospitalieri"
Hospital "GB Rossi" Hospital- Cremona and Post-Graduate School
University of Verona of Endocrinology and Metabolic Diseases
37134 Verona Viale Concordia, 1
Italy 26100 Cremona
Italy
CARLO BIASIUTTI, MD
DANIELA COSER, MD
Istituto di Radiologia
Istituto di Radiologia
Policlinico Universitario "GB Rossi"
Policlinico Universitario "GB Rossi"
P.le LA Scuro, 10
P.le LA Scuro, 10
37134 Verona
37134 Verona
Italy
Italy

GIACOMO BOGINA,MD EMILIANO DELLA CHIARA, MD

Servizio di Anatomia Patologica Istituto di Radiologia
Ospedale S. Cuore-Don Calabria Policlinico Universitario "GB Rossi"
Via D. Sempreboni P.le LA Scuro, 10
37024 Negrar (VR) 37134 Verona
Italy Italy

ANTONIETTA BRIGHENTI, MD MASSIMO FALCONI, MD

Servizio di Anatomia Patologica Department of Surgical-Gastroenterological
Ospedale S. Cuore-Don Calabria Endocrine and Pancreatic Unit
Via D. Sempreboni Hospital "GB Rossi"
37024 Negrar (VR) University of Verona
Italy 37134 Verona
Italy
PAOLA CAPELLI, MD
MARCO FERDEGHINI, MD
Istituto di Anatomia Patologica Istituto di Radiologia
Policlinico Universitario "GB Rossi" Policlinico Universitario "GB Rossi"
P.le LA Scuro, 10 P.le LA Scuro, 10
37134 Verona 37134 Verona
Italy Italy

GIOVANNI CARBOGNIN, MD MAURO FERRARI, MD

Istituto di Radiologia Istituto di Radiologia
Policlinico Universitario "GB Rossi" Policlinico Universitario "GB Rossi"
P.le LA Scuro, 10 P.le LA Scuro, 10
37134 Verona 37134 Verona
Italy Italy
298 List of Contributors

FRANCESCA FORNASA, MD ENRICO MOLINARI, MD

Istituto di Radiologia Department of Surgical-Gastroenterological
Policlinico Universitario "GB Rossi" Endocrine and Pancreatic Unit
P.le LA Scuro, lO Hospital "GB Rossi"
37134 Verona University of Verona
Italy 37134 Verona
Italy
ISAAC R. FRANCIS, MD
Professor Radiology and Associate Chair for Research THAIRA OWElTY, MD
Department of Radiology Department of Pathology
University of Michigan Medical Center NYU School of Medicine
RmBID502 560 First Avenue (TH 461)
1500 East Medical Center Dr., Box 0300 New York, NY lO016
Ann Arbor, MI 48lO9 USA
USA

NICOLETTA PAGNOTTA, MD
ISABELLA FRIGERIO, MD Istituto di Radiologia
Department of Surgical-Gastroenterological Policlinico Universitario "GB Rossi"
Endocrine and Pancreatic Unit P.le LA Scuro, lO
Hospital "GB Rossi" 37134 Verona
University of Verona Italy
37134 Verona
Italy
PAOLO PEDERZOLI, MD
Dipartimento di Scienze Chirurgiche
ARNALDO FUINI, MD Policlinico Universitario "GB Rossi"
Servizio di Gastroenterologia P.le LA Scuro, 1
Ospedale Civile Maggiore 37134 Verona
P.le Stefani, 1
Italy
37124 Verona
Italy
ANNA PESCI, MD
Servizio di Anatomia Patologica
ALESSANDRO GUARISE, MD
Ospedale S. Cuore-Don Calabria
Servizio di Radiologia
Via D. Sempreboni
Ospedale S. Cuore-Don Calabria
37024 Negrar (VR)
Via D. Sempreboni
Italy
37024 Negrar (VR)
Italy
ENRICO PETRELLA, MD
WILLIAM MANTOVANI, MD Istituto di Radiologia
Policlinico Universitario "GB Rossi"
Department of Surgical-Gastroenterological
P.le LA Scuro, 10
Endocrine and Pancreatic Unit
37134 Verona
Hospital "GB Rossi"
Italy
University of Verona
37134 Verona
Italy CARLO PROCACCI, MD
Professor, Istituto di Radiologia
GUIDO MARTIGNONI, MD Dipartimento di Scienze Morfologico-Biomediche
Istituto di Anatomia Patologica Universita degli Studi di Verona
Policlinico Universitario "GB Rossi" Policlinico "Giambattista Rossi"
P.le LA Scuro, lO P.zza L. A. Scuro 10
37134 Verona 37134 Verona
Italy Italy

ALEC J. MEGIBOW, MD, MPH, FACR ROBERTO SALVIA, MD

Department of Radiology Department of Surgical-Gastroenterological
NYU School of Medicine Endocrine and Pancreatic Unit
Department of Radiology Hospital "GB Rossi"
560 First Avenue University of Verona
New York, NY 10016 37134 Verona
USA Italy
List of Contributors 299

ALDO SCARPA, MD SIMONE VASORI, MD

Istituto di Anatomia Patologica Istituto di Radiologia
Policlinico Universitario "GB Rossi" Policlinico Universitario "GB Rossi"
P.le LA Scuro, 10 P.le LA Scuro, 10
37134 Verona 37134 Verona
Italy Italy

SILVIA VENTURINI, MD
GIACOMO SCHENAL, MD Istituto di Radiologia
Istituto di Radiologia Policlinico Universitario "GB Rossi"
Policlinico Universitario "GB Rossi" P.le LA Scuro, 10
P.le LA Scuro, 10 37134 Verona
37134 Verona Italy
Italy
A. BRIAN WEST, MD, FRCPath
MARG HERITA TAPPARELLI, MD Professor and Director of Anatomic Pathology
NYU Medical Center
Istituto di Radiologia
Policlinico Universitario "GB Rossi" Department of Pathology
560 First Avenue, (TH 461)
P.le LA Scuro, 10
New York, NY 10016
37134 Verona
USA
Italy

GIUSEPPE ZAMBONI, MD
RUEDI F. THOENI, MD Universita di Verona
Professor of Radiology Servizio di Anatomia-Istologia Patologica
University of California San Francisco Ospedale S. Cuore-Don Calabria
Campus Box 0628 Via don Sempreboni, 5
San Francisco, CA 94143-0628 37024 Negrar-Verona
USA Italy
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Pediatric Chest Imaging
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Radiological Imaging ofthe Small Intestine
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Perinatal Imaging
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Radiological Imaging ofthe Neonatal Chest
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Radiology of Osteoporosis
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Interventional Radiology in Cancer
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Intracranial Vascular Malformations
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From Diagnostic Work-Up
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Imaging Pelvic Floor Disorders
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High Resolution Sonography
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Radiation Exposure and Occupational Risks
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Late Sequelae in Oncology
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Blood Perfusion and Microenvironment
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Radiation Therapy of Benign Diseases
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