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Intraepithelial neoplasms (PanIN) and intraductal
papillary-mucinous neoplasms (IPMN) of the pancreas as precursor
lesions of pancreatic carcinoma.Med
Klin (Munich). 2007 Feb
15;102(2):127-35.
Due to the
fatal prognosis of pancreatic carcinoma, great efforts have been
made to investigate precursor lesions of invasive neoplasia during
the last few years. Pancreatic intraepithelial neoplasias (PanIN)
have been recognized as precursor lesions of ductal adenocarcinoma,
and are classified into different grades from PanIN-1A, -1B, -2, to
-3. Molecular analyses have helped to define a progression model for
pancreatic neoplasia. The most important step seems to be the
occurrence of a PanIN-3 lesion defining a high risk of malignant
transformation. As in PanINs, different types of intraductal
papillary-mucinous neoplasms (IPMN) can be discriminated ranging
from benign to invasive lesions. Becoming invasive, some of these
tumors appear as ductal adenocarcinoma, others as colloid carcinoma
with a much better prognosis. In this review, the characteristics of
these two precursor lesions and their genetic alterations are
summarized.
Molecular
genetics of pancreatic intraepithelial neoplasia.J
Hepatobiliary Pancreat Surg.
2007;14(3):224-32.
BACKGROUND:
Recent evidence suggests that noninvasive precursor lesions,
classified as pancreatic intraepithelial neoplasia (PanIN), can
progress to invasive pancreatic cancer. This review will discuss the
major genetic alterations in PanIN lesions. METHODS: A comprehensive
review of the literature was performed in order to find studies on
the molecular profile of human PanIN lesions. In addition, recent
publications on genetically engineered mouse models of preinvasive
neoplasia and pancreatic cancers were reviewed. RESULTS: PanINs
demonstrate abnormalities at the genomic (DNA), transcriptomic
(RNA), and proteomic levels, and there is a progressive accumulation
of molecular alterations that accompany the histological progression
from low-grade PanIN-1A to high-grade PanIN-3 lesions. Molecular
changes in PanINs can be classified as "early" (KRAS2 mutations,
telomere shortening, p21(WAF1/CIP1) up-regulation, etc.),
"intermediate" (cyclin D1 up-regulation, expression of proliferation
antigens, etc.), or "late" (BRCA2 and TP53 mutations,
DPC4/SMAD4/MADH4 inactivation, etc.). All the genetic changes
observed in PanINs are also found in invasive ductal adenocarcinomas,
where they usually occur at a higher frequency. Genetically
engineered mice expressing mutant Kras in the pancreas, with or
without additional genetic alterations, provide a unique in vivo
platform to study the pancreatic cancer progression model.
CONCLUSIONS: Molecular studies have been instrumental in
establishing that PanIN lesions are the noninvasive precursors for
invasive ductal adenocarcinomas. The availability of molecular date
provides the basis for designing rational early detection strategies
and therapeutic intervention trials before pancreatic neoplasms
invade, with the intention of alleviating the dismal prognosis
associated with this disease.
Precursors
to pancreatic cancer.Tidsskr
Nor Laegeforen. 2006 Mar 23; 126(7):
905-8.
BACKGROUND:
Pancreatic adenocarcinoma is a relatively frequent cancer with an
extremely poor prognosis. Until recently, the natural history of
pancreatic adenocarcinoma has not been possible to study, but the
identification of precursor lesions (pancreatic intraepithelial
neoplasia, PanIN) has lead to a better understanding of the stepwise
morphological and genetic alterations involved in the development of
invasive adenocarcinoma. MATERIAL AND METHODS: Relevant literature
from the period of 1996-2005 was found by searching the Medline
database, combining the terms "pancreas", "cancer", "PanIN" and "neoplasia".
Principal original and review papers were extracted and used as
background for a presentation of the PanIN cancer progression model.
RESULTS AND INTERPRETATION: PanINs are established as designation of
histological precursor lesions to pancreatic adenocarcinoma. PanIN
grade I to III represent stepwise morphological alterations in the
pancreatic ductal epithelium, from early neoplasia (PanIN I and II),
via carcinoma in situ (PanIN III) to the development of invasive
ductal adenocarcinoma. This model allows for the investigation of
sequential molecular changes such as activation of oncogenes and
inactivation of tumour suppressor genes. Increased knowledge about
pancreatic carcinogenesis may pave the way for prevention
strategies, early detection, and new treatment options, thus
ultimately improving the prognosis of the patients.
Current
topics on precursors to pancreatic cancer.
Adv Med Sci. 2006;51:23-30.
Prognosis of
invasive pancreatic ductal adenocarcinoma is bleak and the vast
majority of patients with pancreatic cancer die of their disease.
The detection and treatment of the non-invasive precursor lesions of
pancreatic cancer offer the opportunity to cure this devastating
disease and therefore great efforts are being made to identify the
precursors to pancreatic cancer. Several distinct precursor lesions
have been identified. Mucinous cystic neoplasms (MCNs), intraductal
papillary mucinous neoplasms (IPMNs), and pancreatic intraepithelial
neoplasias (PanINs) all harbor varying degrees of dysplasia and
stepwise accumulation of genetic alterations, suggesting progression
of these lesions from benign toward malignant neoplasms. MCNs have a
characteristic ovarian-type stroma. About one-third of MCNs are
associated with invasive carcinoma of ductal phenotype. IPMNs are
recently established clinical entity with characteristic features of
mucin hypersecretion and duct dilatation. Some IPMNs are associated
with invasive carcinoma and IPMNs are recognized precursors to
pancreatic cancer. PanINs are microscopic proliferative lesions
arising from any parts of the pancreatic duct system. Low grade
PanINs are commonly found in pancreatic ducts of elder individuals,
while high grade PanINs, previously called carcinoma in situ/severe
ductal dysplasia, may eventually give rise to invasive pancreatic
cancer. Appropriate clinical managements are requisite for patients
with MCNs, IPMNs and PanINs. Further investigation of these
precursor lesions is expected to reduce the mortality from
pancreatic cancer.
Histopathological diagnosis of pancreatic intraepithelial neoplasia
and intraductal papillary-mucinous neoplasms: interobserver
agreement.
Pancreas. 2005 Nov;31(4):344-9.
OBJECTIVES:
The goal of this study was to evaluate the consistency of
distinction between pancreatic intraepithelial neoplasia (PanIN) and
intraductal papillary-mucinous neoplasms (IPMN) and the hypothesis
that guidelines for their distinction might be inadequate. METHODS:
A group of 93 pancreas specimens from surgical resections or
autopsies that contained lesions consistent with histopathological
diagnoses of PanIN-1A, PanIN-1B, PanIN-2, or IPMN (adenoma or
borderline) was collected. The classification of these neoplasms by
6 pathologists, 2 from Europe, 2 from Japan, and 2 from the United
States, was compared. The pathologists initially used guidelines
current in their practice and then reviewed 47 of the 93 specimens a
second time using new consensus definitions and guidelines for PanIN
and IPMN that were developed in 2003. RESULTS: The initial
comparison showed frequent disagreement regarding both category and
grade of the lesions. Agreement was greater for category than grade.
In the second review, agreement among the 6 reviewers improved,
remaining higher for category, although disagreements persisted for
both category and grade. CONCLUSIONS: We conclude that the new
definitions of PanIN and IPMN improve the consistency in classifying
these lesions, but additional work is needed to further improve the
reproducibility of their classification.
Precursors
to invasive pancreatic cancer.Adv
Anat Pathol. 2005 Mar;12(2): 81-91.
Pancreatic
cancer, once invasive, is almost uniformly fatal. In order to
alleviate the dismal prognosis associated with this disease, it is
imperative that pancreatic cancer be recognized and treated prior to
invasion. Understanding the morphology and biology of precursor
lesions of invasive pancreatic cancer has therefore become an issue
of paramount importance. In the last decade, significant progress
has been in the recognition and appropriate classification of these
precursor lesions, and the current review will focus on our
state-of-the-art knowledge on this topic. Mucinous cystic neoplasms
(MCNs), intraductal papillary mucinous neoplasms (IPMNs), and
pancreatic intraepithelial neoplasia (PanIN) encompass the three
known morphologically distinct precursors to invasive pancreatic
cancer. In addition to discussion of the "classic" precursor
entities, this review will also address some of the recent
diagnostic controversies for these lesions, in particular features
that distinguish IPMNs from PanIN lesions. Finally, the potential
clinical impact of recognizing these precursor lesions in the
context of early detection of pancreatic cancer will be discussed.
Proliferative activity in pancreatic intraepithelial neoplasias of
chronic pancreatitis resection specimens: detection of a high-risk
lesion.
Neoplasma. 2004;51(5):400-4.
Patients
with chronic pancreatitis have a markedly increased risk of
pancreatic cancer compared with general population. Mechanism of the
increased risk is not completely known. The current progression
model for pancreatic ductal adenocarcinoma proposes the progression
from normal ductal epithelium through a series of lesions called
pancreatic intraepithelial neoplasias (PanINs) to invasive cancer.
These lesions are frequently seen in chronic pancreatitis tissue.
Proliferative activity in PanINs of chronic pancreatitis tissue has
not been separately studied using the current nomenclature. Our
study included 36 chronic pancreatitis resection specimens. A total
number of 106 PanINs found within 32 resection specimens was
histologically graded and then immunolabeled using a monoclonal
antibody against Ki-67 that is expressed in dividing cells. The
Ki-67 labeling indices in the increasing grades of PanINs were
counted with following results: PanIN-1A, 0.77%; PanIN-1B, 3.26%;
PanIN-2, 14.68%; and PanIN-3, 25.4%. The difference in Ki-67
labeling indices among these types of lesions was statistically
significant (p<0.001, t-test). These results correlate with known
genetic alterations found in chronic pancreatitis, especially with
p16 inactivation that was recently described in PanINs arising in
patients with chronic pancreatitis. Moreover, our findings support
the currently accepted pancreatic progression model and Ki-67
immunohistochemistry might represent an efficient tool for an
identification of a high-risk lesion.
Intraepithelial neoplasm of the pancreas.Orv
Hetil. 2004 Jan 4;145(1):19-23.
INTRODUCTION: Intraductal lesions occurring in the vicinity of the
pancreatic cancer had been recognized and described almost 50 years
ago, but their relation to the malignant tumor has remained rather
speculative until recently. Moreover, researchers employed several
dozens of terminologies preventing the comparison between the
results of different groups. AIM: The paper reviews the development
of term "pancreatic intraepithelial neoplasia" (PanIN) and describes
its pathological characteristics. METHODS: Data collected from the
world literature and from own material. RESULTS: Introduction of the
term PanIN was based on the accumulated data from molecular studies
suggesting that these preneoplastic alterations are most likely
precursor lesions of the ductal adenocarcinoma rather than
hyperplastic changes. PanIN-1A, PanIN-1B, PanIN-2, PanIN-3 represent
consecutive steps towards the malignant phenotype but they all share
a common histological finding: an intact basement membrane around
them. CONCLUSIONS: It is highly desirable that this standardized
nomenclature be uniformly applied in the histopathological reports
of pancreatic specimens.
Pancreatic
intraepithelial neoplasia.Pancreas.
2004 Apr;28(3):257-62.
Great
efforts have been devoted to detecting preinvasive precursors to
ductal carcinoma of the pancreas in the hope of improving the
currently bleak prognosis of invasive pancreatic cancer. Intensive
investigations of the pancreas have led to the recognition of
intraductal papillary mucinous neoplasms (IPMNs) and the detection
of preinvasive precursors to conventional ductal carcinoma. The
pancreatic intraepithelial neoplasia (PanIN) nomenclature for
precursor lesions of ductal carcinoma was developed at the
"Pancreatic Cancer Think Tank" held in the United States in 1999.
However, some reports of precursor lesions have suggested that these
definitions do not encompass the full spectrum of precursors of
ductal carcinoma, and these issues were the subject of the "Forum on
Carcinoma In Situ of the Pancreas" held in Japan in 2002. After this
forum, it became clear that the existing definitions of PanINs
needed to be revised and expanded. Both participants of the
Pancreatic Cancer Think Tank and the Forum gathered together at a
meeting on precursor lesions of pancreatic cancer in 2003, and an
international consensus on the diagnostic criteria for PanINs and
IPMNs was created. We describe herein the current understanding of
precursor lesions of pancreatic cancer.
An
illustrated consensus on the classification of pancreatic
intraepithelial neoplasia and intraductal papillary mucinous
neoplasms.
Am J Surg Pathol.
2004;28(8):977-87.
Invasive
pancreatic ductal adenocarcinoma is an almost uniformly fatal
disease. Several distinct noninvasive precursor lesions can give
rise to invasive adenocarcinoma of the pancreas, and the prevention,
detection, and treatment of these noninvasive lesions offers the
potential to cure early pancreatic cancers. Noninvasive precursors
of invasive ductal adenocarcinoma of the pancreas include pancreatic
intraepithelial neoplasias (PanINs), intraductal papillary mucinous
neoplasms (IPMNs), and mucinous cystic neoplasms. Diagnostic
criteria, including a distinct ovarian-type stroma, and a consistent
nomenclature are well established for mucinous cystic neoplasms. By
contrast, consistent nomenclatures and diagnostic criteria have been
more difficult to establish for PanINs and IPMNs. Because both
PanINs and IPMNs consist of intraductal neoplastic proliferations of
columnar, mucin-containing cells with a variable degree of papilla
formation, the distinction between these two classes of precursor
lesions remains problematic. Thus, considerable ambiguities still
exist in the classification of noninvasive neoplasms in the
pancreatic ducts. A meeting of international experts on precursor
lesions of pancreatic cancer was held at The Johns Hopkins Hospital
from August 18 to 19, 2003. The purpose of this meeting was to
define an international acceptable set of diagnostic criteria for
PanINs and IPMNs and to address a number of ambiguities that exist
in the previously reported classification systems for these
neoplasms. We present a consensus classification of the precursor
lesions in the pancreatic ducts, PanINs and IPMNs.
Pancreatic
intraepithelial neoplasia in association with intraductal papillary
mucinous neoplasms of the pancreas: implications for disease
progression and recurrence.Am
J Surg Pathol. 2004;28(9):1184-92.
The
development of pancreatic cancer (PC) several years after curative
resection for noninvasive intraductal papillary mucinous neoplasm (IPMN)
and the presence of PC distant from IPMN suggest that PC may develop
independently of the IPMN. Here, we identified pancreatic
intraepithelial neoplasia (PanIN) lesions, the putative precursors
of PC, in the ducts of pancreata resected for IPMN and assessed the
frequency of molecular aberrations common to PanIN and PC, within
these lesions. The protein expression of p53, p21(WAF1/CIP1), cyclin
D1, p16(INK4A) and DPC4/Smad4 were examined by immunohistochemistry
in 267 PanIN lesions from a cohort of 23 patients with IPMN.
Overexpression of p21(WAF1/CIP1) was present in PanIN-1A and -1B
lesions and increased in frequency in PanIN-2 and PanIN-3.
Overexpression of p53 and cyclin D1, and loss of p16(INK4A)
expression were detected in PanIN-2 and PanIN-3 lesions. Loss of
DPC4/Smad4 expression occurred only in the PanIN-3 lesions. PanIN
lesions that were more dysplastic than the coincident IPMN were
identified in 5 of 12 patients, and 2 of these contained a greater
number of aberrations in protein expression than the IPMN. PanIN
lesions seen in association with IPMN demonstrate molecular and
histologic changes identical to PanIN lesions found in association
with PC and, in some cases, are more advanced than the associated
IPMN. These data suggest that PanIN lesions found in the ducts of a
pancreas with IPMN may be relevant to the development of PC either
coincident with IPMN or in the remnant pancreas after curative
resection of IPMN.
Clinicopathological features of pancreatic intraepithelial
neoplasias and their relationship to intraductal papillary-mucinous
tumors.J
Hepatobiliary Pancreat Surg.
2003;10(2):125-36.
Pancreatic
intraepithelial neoplasia (PanIN) is a recently proposed
nomenclature for putative precursor lesions of pancreatic cancer,
which are designated as PanIN-1 through -3 according to their
increasing grade of dysplasia. A stepwise progression model of
PanINs has been proposed, and multistep genetic alterations in
PanINs are being investigated. PanIN-1A and PanIN-1B may remain
unchanged for a long period. PanIN-3 potentially progresses toward
invasive ductal carcinoma (IDC), and there are several case reports
suggesting such progression. In these reported patients, PanIN-3 was
found in specimens from partial pancreatectomies, and IDC manifested
in the pancreatic remnant 17 months to 29 years after the surgery.
We describe herein a patient with PanIN-3, in whom IDC manifested in
the distal remnant pancreas 69 months after segmental pancreatectomy.
Of the reported cases, including the present one, four of the
patients were male and three were female, and the age at the first
operation ranged from 46 to 70 years. Intraductal papillary-mucinous
tumor (IPMT) is an entity that is distinct from PanIN. However,
IPMTs of small size resemble PanINs morphologically. Loss of Dpc4
expression has been reported in the invasive component of IPMT, as
well as in PanIN-3 and IDC. Analysis of mucin expression patterns
has been reported, suggesting that, in practice, MUC1-positive
MUC2-negative IPMTs may not be distinguishable from PanINs. There
may be overlapping lesions between PanINs and IPMTs. Should the
paradigm of the ductal origin of IDC be accepted, PanINs and a
fraction of IPMTs would represent precursors of IDC.
Premalignant
conditions of the pancreas.
Pathology. 2002;34(6):504-17.
Premalignant
conditions of the pancreas include benign tumours of the pancreas,
intraepithelial neoplasia arising within pancreatic ducts, and
tumours of the neuroendocrine cells of the pancreas. In addition,
there is a variety of rare genetic conditions that predispose to
pancreatic exocrine malignancies such as Peutz-Jeghers syndrome,
hereditary non-polyposis colorectal cancer syndrome, familial
pancreatitis, germline BRCA2 mutations, and pancreatic endocrine
malignancies such as type 1 neurofibromatosis (von Recklinghausen's
disease) and multiple endocrine neoplasia type 1. More controversial
is the concept of chronic pancreatitis and diabetes mellitus as
conditions that increase the risk of pancreatic cancer. However,
there is no doubt that smoking is a potentiating factor for
pancreatic cancer, especially in people who have familial/genetic
risk factors. This review will include the recently proposed new
nomenclature and classification system for intraepithelial neoplasia
in the pancreatic ducts, an overview of the various familial
syndromes that are associated with an increased risk of pancreatic
tumours, the surveillance programmes that have been introduced to
monitor such families, and methods for early diagnosis.
Neoplastic
intraepithelial lesions of pancreatic ducts: new entities.Ann
Pathol. 2002 Oct;22(5):357-66.
Intraductal
neoplastic lesions of the pancreas have been the focus of recent
efforts aiming to better characterize several entities. Beside
reactive papillary hyperplastic lesion of pancreatic ducts whose
limits and significance are unclear, two different entities,
intraductal papillary mucinous neoplasm (IPMN) with its variant
intraductal oncocytic papillary neoplasm, and pancreatic
intraepithelial neoplasia (PanIN), the precursors of pancreatic
adenocarcinoma have been recognized. Each has been carefully
described at the microscopic level with classification into several
grades of dysplasia. IPMNs are intraductal, papillary, often diffuse
and mucus hypersecreting neoplastic lesions. Mucin accumulation
gives to the lesion a cystic pattern. Treatment is surgical
resection of the whole lesion. Intraductal oncocytic papillary
neoplasm is a rare variant of IPMN. The prognosis of IPMN is
globally favorable, but these tumors display the risk of malignant
transformation into a mucinous or a tubular pancreatic
adenocarcinoma. Although IPMN can induce symptoms, PanIN are silent
and always discovered at the vicinity of an invasive adenocarcinoma.
The usefulness and the reproducibility of the classification of
PanIN remain to be determined. PanIN classification might resume the
different successive steps of molecular genetic or epigenetic events
associated with the development of a pancreatic carcinoma.
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