Table Of ContentP.M. Pour' Y. Konishi' G. Kloppel
D.S. Longnecker (Eds.)
Atlas ofE xocrine
Pancreatic Tumors
Morphology, Biology, and Diagnosis
with an International
Guide for Tumor Classification
A Publication of the International Pancreatic
Cancer Study Group (IPCSG)
With 363 Illustrations, 41 in Full Color
Springer-Verlag
Tokyo Berlin Heidelberg New York
London Paris Hong Kong
Barcelona Budapest
PARVIZ M. POUR, M.D.
The Eppley Institute for Research in Cancer; Department of Pathology
and Microbiology, University of Nebraska Medical Center, Omaha,
NE 68198-6805, USA
Y OICHI KONISHI, M.D.
Department of Oncological Pathology, Cancer Center, Nara Medical College,
Kashihara, N ara, 634 Japan
GUNTER KU)PPEL, M.D.
Department of Pathology, Academy HospitalJette, Free University of Bruss cis,
1090 Brussels, Belgium
DANIEL S. LONGNECKER, M.D.
Department of Pathology, Dartmouth Medical School, Hanover, NH 03756,
USA
ISBN-13:978-4-431-68313-1 e-ISBN-13:978-4-431-68311-7
DOl: 10.1007/978-4-431-68311-7
Printed on acid-free paper
Library of Congress Cataloging-in-Publication Data
Atlas of exocrine pancreatic tumors: morphology, biology, and diagnosis, with an inter
national guide for tumor classification/P.M. Pour ... [et aI.] (eds.). p. cm. Includes
bibliographical references and index. ISBN-13:978-4-431-68313-1
I. Pancreas-Tumors-Classification-Atlases-Con-
gresses. I. Pour, P.M. (Parviz M.), 1933- . [DNLM: I. Pancreatic Neoplasms
atlases. 2. Pancreatic Neoplasms-classification-congresses. WI 17 A87945 1994]
RC280.P25A87 1994, 616.99'437-dc20, DNLM/DLC, for Library of Congress
© Springer-Verlag Tokyo 1994
Softcover reprint ofthe hardcover I st edition 1994
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Background
The classification of tumors is important for understanding tumor histogenesis,
for predicting prognosis, for differential diagnosis, and for recommending
appropriate therapy. Since 1836, when pancreatic cancer was first described,
progress has been made in pancreatic cancer morphology, and a number of
classifications have been proposed. All of these classifications are mainly based
on morphological characteristics. Some are too detailed to be of practical use
while others are more pragmatic. Some of the inherent problems in the previous
classifications included difficulties in obtaining an adequate number of pan
creatic tumors for examination and insufficient clinical data and follow-up.
With the increasing incidence of pancreatic cancer in many parts of the world
during the past six decades, and with the availability of more tumors to patho
logists, advances have been made in pancreatic tumor studies. Classifications
by Cubilla and Fitzgerald and by Kloppel, which are generally similar, mostly
considered prominent morphological features and their histogenesis. These
pathology-oriented classifications, although complete, were not practical from
the standpoint of clinicians concerned with the prognosis of individual tumors.
The recent devclopment of sophisticated diagnostic instruments, awareness of
the increasing incidence of the disease by clinicians, increased governmental
funding of pancreatic cancer studies, improved follow-up procedures, develop
ment of various tumor markers, discovery of growth factors and their receptors,
and the use of flow cytometry, DNA analysis, and molecular biological tech
niques have all contributed to a significant advancement in understanding the
biology and morphogenesis of pancreatic neoplasms. The need for a revised
pancreatic cancer classification arose, in part, from greater collaboration
between pathologists, surgeons, clinicians, and basic researchers. The world
wide use of a single classification system would standardize data bases and
facilitate international comparisons of incidences and results of treatment.
In August 1990, members of the International Pancreatic Cancer Study
Group (IPCSG), which was established in 1987 to provide an international
forum for pancreatic cancer researchers, met in Nagasaki, Japan, to discuss the
existing problems of pancreatic tumor classification and biological characteris
tics of pancreatic cancer cells, and to propose a practical and clinically
useful classification system. Experts from different biomedical fields, including
pathologists, clinicians, surgeons, immunologists, and basic researchers, includ
ing molecular biologists, attended this meeting in which clinical, histomor
phological and biological data of pancreatic exocrine tumors, selected from
different institutions in the United States, Europe, and Japan, were reviewed
and discussed. The researchers agreed that some of the previously described
lesions, which were thought to represent an entity, are in reality a different
v
Background
phenotypical expression of a more common neoplasm. For example, the
"pleomorphic or giant cell type" in the classification of several authors is a
variant of ductal adenocarcinoma and has no prognostic significance. Another
example is the mixed duct-islet, duct-islet-acinar, and acinar-islet tumors
proposed by Cubilla and Fitzgerald and by Sommer and Meissner. Based on
several recent studies, more than 80% of exocrine pancreatic carcinomas
(ductal adenocarcinoma, mucinous cystic tumor, acinar cell carcinoma, and
pancreatoblastoma) contain endocrine cells, some in a pattern consistent with
the mixed exocrine-endocrine cell tumors and, therefore, their consideration as
an entity is debatable. However, because more well-differentiated ductal adeno
carcinomas contain endocrine cell clements than the poorly differentiated
variety, the presence of endocrine cells within the cancers may have a prognostic
value.
Accumulating observations have clarified the histogenesis of some tumors
that previously were thought to be of acinar cell origin or whose histogenesis
was unknown. Solid cystic tumors with favorable prognosis, thought by Kloppcl
to be of acinar cell origin, seem to originate from primitive primordial pancreatic
cells, with the tendency for differentiation into ductal, insular, and acinar cells.
The same is true for pancreaticoblastoma, which appears to present as a more
immature form of an embryonic tumor with a rather poor prognosis. Micro
adenocarcinoma, listed as a variant of ductal type carcinoma by Cubilla and
Fitzgerald, appears to be a variant of acinar cell eancer. Other tumors described
by Cubilla and Fitzgerald, such as oncocytic carcinoma, oncocytic carcinoid,
and ciliated cell carcinoma have not been observed by other investigators. A
more recent detailed and extended classification by some Japanese pathologists,
who differentiate cystic tumors on the basis of their connection to the pancreatic
ductal system, was considered to be of value for establishing pathogenesis but
unneeded for practical clinical classification and determination of prognosis.
Moreover, the clinical experience has revealed that intraductal tumors have a
better prognosis than others. An example is the intraductal papillary tumor
with excess mucin production. Many investigators have recognized the entity of
these tumors although it is still unclear whether these tumors were missed or
misdiagnosed in the past or whether their incidence has increased.
Much discussion surrounded intraductal lesions. It was recognized that the
prognosis of some of these lesions cannot be determined from the his to
morphological appearance, and, therefore, their designation as either an
adenoma or carcinoma was improper. It was agreed that until more is known
about these lesions, the designation of "tumors" should be given to them. This
rather ambiguous designation indicates the unpredictable nature of such neo
plasms. Additional morphologic phrases, such as "non-invasive" and
"invasive", reflects their "observed" biological behavior. However, this
distinction is subjective and relative. Costly serial sectioning and time
consuming histological examination mayor may not distinguish a potentially
malignant version (with invasion) from another prognostically more favorable
"non-invasive" counterpart. Future studies are needed to reveal markers useful
in predicting their biological behavior.
This subject highlighted another problem in establishing a unified clas
sification system-the lack of guidelines for preparation and processing of
specimen for histological diagnosis. Personal perception also confounds tumor
diagnosis. Some consider small papillary projections occurring in some cystic
tumors as papillary neoplasms, whereas others require a dominant papillary
structure as a prerequisite for lesions to be termed papillary tumors.
The distinction between the benign and malignant tumors is still muddled.
Although previous classifications considered cystic serous tumors (microcytic
adenoma) as benign, recent observations point to their malignant potential
inasmuch as a few adenocarcinomas with this histologic type have been
VI
Background
reported. Genetic alteration of pancreatic cancer cells seems to offer a partial
explanation, but the available biological and molecular biological data arc not
sufficient to form the basis of a clear-cut distinction between benign and
potentially malignant tumors. For example, although the c-Ki-ras mutation can
be used to distinguish normal from malignant cells, the pattern of mutation is
not useful in differentiating invasive from non-invasive adenocarcinoma. As
described in this atlas, the current results on tumor antigenicity, growth factors
and their receptors, chromosomal aberrations, and gene mutations have not
demonstrated a useful correlation that can be used to predict the prognosis of
the diseases. Consequently, we still rely on histopathological findings in
assessing the malignancy, grade of differentiation, and staging of pancreatic
cancer. It was also recognized that the patterns of tumor invasion and
metastases, and definition and characterization of preneoplastic lesions need
careful study. These data could help to better understand the biology of
pancreatic cancer.
The participants of the meeting considered the above problems and proposed
a revised classification presented in this atlas and also recommended practical
hints for tissue examination, fixation, and preparation for histological, immuno
logical, and molecular biological studies with the hope that such
standardization will facilitate common understanding.
These recommendations can guide pathologists, clinicians, and basic
researchers in developing standardized techniques for tumor examination that
will improve the understanding of the biology of pancreatic cancer. The
classification represents a step in developing a clinically useful system with
international acceptance. Further change and refinement of the classification on
the basis of new data should be anticipated.
Other inherent problems that need collaborative efforts for resolution relate
to the grading system of the tumors and their correlation with the prognosis.
Because the method of surgical resection (partial, total, curative), availability of
pancreatic and parapancreatic tissues for examination, and preoperative and
postoperative patient treatment arc all important factors in prognostic
considerations and survival, current data do not provide a reliable base to
determine which correlations exist and we await prospective studies.
The Editors
VII
THIRD SYMPOSIUM OF INTERNATIONAL PANCREATIC CANCER STUDY GROUP ~~
International Classificat,on of Pancreatic
L._._ _ ' ...........
Members of the International Pancreatic Cancer Study Group participating in
the classification of pancreatic cancer. Rear row (left to right): Akira Wada,
Tetsuo Hayakawa, Reinhard Klapdor, Akinori Ishihara, Takahiko Funabiki,
Yoshifumi Kawaharada, Akira Kuroda, Katsusuke Sataka, Tsukasa Tsunoda,
Martin Sarner, Eugene DiMagno, Toshio Morohoshi, Shigetoshi Matsuo,
Tsutoma Tomioka
Front row (left to right): Kohtaro Uchida, Hideo Harada, Hideo Ozaki, Ryoichi
Tsuchiya, Parviz M. Pour, Daniel S. Longnecker, Gunter Kloppel, Yoichi
Konishi, Yo Kato
VIII
Histological Classification
o/Exocrine
Pancreatic, Tumors
Benign
Serous cystadenoma
Tumors with uncertain malignant potential
Intraductal (papillary-mucinous) tumors
non-invasive (adenoma, severe dysplasia)
Mucinous cystic tumors
non-invasive (adenoma, severe dysplasia)
Solid (papillary)-cystic tumors
Malignant
Serous cystadenocarcinoma
Intraductal (papillary-mucinous) carcinoma (invasive)
Ductal adenocarcinoma
Mucinous cystadenocarcinoma
Mucinous noncystic carcinoma
Adenosquamous carcinoma
Squamous cell carcinoma
Anaplastic (undifferentiated) carcinoma
Acinar cell carcinoma
Pancrea tobIas toma
Small cell carcinoma
IX
Contents
Background. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . V
Classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IX
Contributors .............................................. XIII
Color Plates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. XV
Gross Anatomy of the Pancreas ............................ .
Microanatomy and Fine Structure of the Pancreas. . . . . . . . . . . . . 17
Serous Cystadenoma ..................................... 31
Intraductal Papillary Mucinous Tumors,
Non-Invasive and Invasive .............................. 43
Mucinous Cystic Tumors, Non-Invasive and Invasive. . . . . . . . . . 67
Solid Cystic Tumors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
Serous Cystadenocarcinoma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 101
Ductal Adenocarcinoma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 117
Mucinous (Noncystic) Adenocarcinoma, Including Signet-Ring
Carcinoma ........................................... , 155
Adenosquamous Cell Carcinoma ........................... 159
Squamous Cell Carcinoma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169
Anaplastic (Undifferentiated) Carcinoma. . . . . . . . . . . . . . . . . . .. 175
Acinar Cell Carcinoma ................................... , 185
Pancreatob1astoma ...................................... , 199
Small Cell Carcinoma .................................... , 207
Preneoplastic Lesions of the Exocrine Pancreas . . . . . . . . . . . . . . .. 211
Pathology of Metastatic Patterns of Pancreatic Cancer ......... , 221
Tumor Spread and the Factors Influencing Prognosis in Patients
with Resected Pancreatic Carcinoma ..................... , 237
Staging for Carcinoma of the Pancreas: Japanese Stage
Classification Compared to UICC Stage Classification. . . . . . .. 247
Molecular Biology ....................................... 257
Sampling Method for Pancreatic Tissue Examination .......... 265
Authors' Affiliations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 281
Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 285
XI
Contributors
Background ... P.M. POUR*, Y. KONISHI, G. KLOPPEL, D.S. LONGNECKER
Gross Anatomy of the Pancreas ... A. KURODA*, H. NAGAI
Microanatomy and Fine Structure of the Pancreas ... T. MOROHOSHI*,
D.E. BOCKMAN
Serous Cystadenoma. Microcystic Type ... T. FUNABIKI*, K. KAMEL Macrocystic
Type ... K.B. LEWANDROWSKI*
Intraductal Papillary Mucinous Tumors, Non-Invasive and Invasive. Mucin
Hypersecreting Tumors ... K. Y AMAO*, S. N AKAZAWA, M. FUJIMOTO,
M. YAMADA. Papillary Tumors ... S. MILCHGRUB*, J. ALBORES-SAA VEDRA
Mucinous Cystic Tumors, Non-Invasive and Invasive ... Y. WADA*
Solid Cystic Tumors ... K. YAMAGUCHI*, T. MOROHOSHI, G. ZAMBONI
Serous Cystadenocarcinoma ... T. FUNABIKI*, K. KAMEl
Ductal Adenocarcinoma ... P.M. POUR*, T. MOROHOSHI
Mucinous (Noncystic) Adenocarcinoma, Including Signet-Ring Carcinoma ...
A. YANAGISAWA*, Y. KATO, G. KLOPPEL
Adenosquamous Cell Carcinoma ... S. MATSUYA*, P.M. POUR
Squamous Cell Carcinoma ... S. MATSUYA*, P.M. POUR
Anaplastic (Undifferentiated) Carcinoma ... M. TSUTSUMI*, T. MOROHOSHI,
Y. KONISHI. Pleomorphic Giant Cell Carcinoma ... K.B. LEWANDROWSKI, W.H.
YONG. Mixed Pleomorphic, Osteoclastic Carcinoma ... B. GATT ESC HI * , V. PUGLIESE,
P.M. POUR
Acinar Cell Carcinoma ... A. ISHIHARA *
Pancreatoblastoma ... T. MOROHOSHI*, G. KLOPPEL
Small Cell Carcinoma ... G. KLOPPEL *
Preneoplastic Lesions of the Exocrine Pancreas ... D.S. LONGNECKER *,
G. KLOPPEL, P.M. POUR
Pathology of Metastatic Patterns of Pancreatic Cancer. General Metastatic Pat
terns ... K. KISHI*, T. UEHARA, T. IzUMO, M. KUROSUMI, S. HIROHASHI,
K. MUKAI. Lymphatic and Neural Invasion .. . T. NAGAKAwA*, M. KAYAHARA
Tumor Spread and the Factors Influencing Prognosis in Patients with Resected
Pancreatic Carcinoma ... M. Y AMAMOTO*, Y. SAITOH
* Asterisks indicate the principal authors; for their affiliations see back matter.
XIII
