Journal Reading

2005-12-02
Presented by Dr.
 An Illustrated Consensus on the
Classification of Pancreatic Intraepithelial
Neoplasia and Intraductal Papillary
Mucinous Neoplasm

Original article

Hruban RH, Takaori K, Klimstra DS, Adsay NV,

Albores-Saavedra J, Biankin AV, Biankin SA,
Compton C, Fukushima N, Furukawa T, Goggins M,
Kato Y, Kloppel G, Longnecker DS, Luttges J, Maitra
A, Offerhaus GJ, Shimizu M, Yonezawa S.

Am J Surg Pathol. 2004 Aug;28(8):977-

87.
Introduction
Identification and treatment of pre-invasive
lesions in the ducts of the pancreas is important.
Noninvasive precursors:
(1) Pancreatic intraepithelial neoplasm (PanINs)
(2) Intraductal papillary mucinous neoplasm (IPMN)
(3) Mucinous cystic neoplasm
the first two lack the internationally accepted
nomenclature and diagnostic criteria.
Introduction

Pancreatic intraepithelial neoplasia (PanIN):

first proposed in 1994.
Developed at a National Cancer Institute
in 1999.
Progression model for pancreatic neoplasia:
a series of molecular analyses
Intraduction
Introduction
Introduction
Papillomatosis of pancreatic duct: case
report in 1936
A series of intraductal neoplasm of
pancreas: byOhhashi et al in 1982.
Intraductal papillary mucinous neoplasm
(IPMN): introduced by Sessa et al in 1994.
A progression model for IPMNs: a growing
body of molecular and clinical evidence.
Introduction
Introduction
Introduction

2002, Nagoyo, Japan: PanIN and IPMN

should be revised and clarified
2003, The Johns Hopkins Hospital:
(1) Characteristics of PanIN and IPMN
(2) Ambiguities in the previous classification systems
(3) Revised definition
General Feature of PanIN and
IPMN
PanIN/L-1A and PanIN-1B: common incidental
finding
Higher-grade PanIN: more often associated
with an invasive cancer.
(1) PanIN-1 lesions: 40% of adult pancreas
without cancer (PanIN-3 lesions are seen in
<5% of such pancreas)
(2) PanIN-3: 30%~50% of pancreas with invasive
ductal carcinoma.
General Feature of PanIN and
IPMN
Higher grade of PanIN: can be a precursors of
invasive carcinoma
(1) Same genetic alterations in invasive ductal
carcinoma and PanINs: KRAS2, TP53/p53,
CDKN2A/p16, and MADH4/SMAD4/DPC4 genes
(2) Continum of intraductal neoplastic progression:
greater numbers of genetic alteration in higher-
grade PanIN lesions.
General Feature of PanIN and
IPMN
IPMN:
(1) Typical radiographically identifiable ductal dilatation:
(a) Main duct type: main pancreatic ducts
(b) Branch duct type: secondary ducts
(c) Mixed type: both
(2) Associated with an invasive adenocarcinoma:
particular main duct type.
(a) Colloid (mucinous noncystic) carcinoma:
approximately one half
(b) Conventional tubular adenocarcinoma:
the most of remainder
General Feature of PanIN and
IPMN

IPMN: can be a precursors of invasive

carcinoma
(1)Same genetic alterations in conventional
ductal adenocarcinoma: KRAS2,
TP53/p53, and CDKN2A/p16 genes.
General Feature of PanIN and
IPMN
(2) Frequencies and stage of neoplastic progression : differ
from PanIN.
(a) CDKN2A/p16 gene, may be inactivated through
aberrant DNA methylation.
(b) IPMNs with carcinoma in situ: microsatellite
instability (-), high telomerase activity (+), and COX-2
expression (+).
(c) IPMNs: one third with inactived Peutz-Jeghers gene
STK11/LKB1 ( some patients with Peutz-Jeghers
syndrome develop IPMNs ).
(d) IPMNs: rare abnormalities in the MADH4/SMAD4/DPC4
gene, in contrast to ductal adenocarcinomas and PanIN-3
lesions.(~30%)
General Feature of PanIN and
IPMN
Surgical resection: treatment of choice for
most IPMNs
IPMNs resected before the development
of invasive carcinoma are highly curable.
The prognosis is worse once invasive
carcinoma develops: colloid type of
invasive carcinoma has better prognosis
than tubular type of invasive carcinoma.
General Feature of PanIN and
IPMN

Immunohistochemistry: MUC proteins

(1) MUC2 : expressed in many IPMNs.
General Feature of PanIN and
IPMN
PanINs and IPMNs share many fundamental
features:
(1) Intraductal growth
(2) Columnar, mucin- producing cells
(3) Flat or papillae
(4) A range of cytologic and architectural atypia
(5) Precursors to invasive adenocarcinoma
(6) Sequentially accumulate similar genetic
alterations with increasing cytoarchitectural atypia.
General Feature of PanIN and
IPMN

Sometimes, intraductal neoplasm may be

almost impossible to classify by
morphology alone.
(1) PanIN: typical arise in the smaller ducts,
may involve the large ducts
(2) IPMNs: usually involve the larger ducts,
may involve small ducts
General Feature of PanIN and
IPMN

Despite this overlap, there are abundant

data suggesting that PanINs and IPMNs
represent two separate classes of
intraductal neoplasia of pancreas.
General Feature of PanIN and
IPMN
Ambiguities in the Previous Classification
Systems

The size of involved duct:

(1) Size: the only factor used to distinguish between PanINs and
IPMNs in the previous classification system
(2) Some IPMNs involve the branch ducts and can be <1 cm, and still
other IPMNs extend into the smallest caliber pancreatic ducts
(3) Some PanINs can involve the main pancreatic duct and ducts
involved with PanINs can be large due to secondary dilatation from
an obstructing mass or stricture

New definitions were needed that encompass these possibilities.

Ambiguities in the Previous Classification
Systems

Measurement of involved duct: no specific

guidelines:
(1) The anatomic terms are particularly hard to
apply to histological sections.
(2) Extent of ductal dilatation often is difficult to
establish based on the diameter of the duct:
impossible to determine the original caliber of
an involved duct
Ambiguities in the Previous Classification
Systems

Reproducible criteria: the previous

classification system failed to provide to
distinguish between retention cysts and
IPMNs.
Cancerization of the duct: a histologic
finding to be distinguished from PanIN,
Ambiguities in the Previous Classification
Systems

Reactive change:
(1)Previous classification system : against
diagnosing PanIN in the setting of
inflammation
(2) Now recognized that PanIN lesions can,
and often do, occur in the setting of
chronic pancreatitis.
Ambiguities in the Previous Classification
Systems

Complex lesins: multiple lesions are present in a single

pancreas.
Limits of radiologic detection: the use of radiologic
detectability in the definitions of PanINs and IPMNs
should be abandoned
Ambiguities in the Previous Classification
Systems

It was recognized that the current grading

systems for PanINs (PanIN-1, PanIN-2,
and PanIN-3) and IPMNs (IPMN adenoma,
IPMN borderline, IPMN carcinoma in situ)
lack interobserver reproducibility.
A better consensus on the features
defining each grade is needed.
Ambiguities in the Previous Classification
Systems

It was acknowledged that different

histologic types of papillae may occur in
IPMNs and that criteria and designations
for each different type need to be better
defined.
Revised Definitions
Guidelines for Evaluation of PanINs

Size:
(1) <5mm: cross sectioned diameter: from
basement membrane to basement membrane.
(2) >5mm: carefully examination of multiple
sections of the pancreatic ducts
Neoplasms:
(1)Not mean to suggest the lesion need clinical
treatment.
(2) Clonal proliferation with alterations in cancer-
related genes.
Guidelines for Evaluation of PanINs

PanINs-1 and -2 :
(1)Typically incidental findings
(2)Unproved clinical significance.
PanIN-3:
(1)Thought to have clinical significance:
(a) Potential to progress to invasive carcinoma
(b) Information regarding progression is limited
Difference with IPMN: when PanIN involving the main pancreatic
duct
(1) Papillae in PanINs: usually are not as tall and complex as those in
IPMNs.
(2) Abundant luminal mucin production is a feature of IPMNs.
(3) MUC2 expression is a specific but relatively insensitive marker of an
IPMN and is generally not present in PanINs.
Guidelines for Evaluation of PanINs

If multiple distinct PanINs in a single

pancreas:
(1) Graded separately
(2) Many prefer to list the range and/or
the highest grade of PanIN present.
Guidelines for Evaluation of PanINs

Reactive epithelial changes from PanINs:

(1) A heterogeneous cell population
(2) Prominent nucleoli
(3) Intraepithelial inflammatory cells, particularly neutrophils
should all suggest a reactive process.

In general, it is agreed that one should be conservative

in categorizing a lesion as a PanIN in the setting of
inflammation.
Guidelines for Evaluation of PanINs

Cancerization of the ducts, and can occur either as

direct continuity of invasive carcinoma.
(1) These processes should be distinguished from PanIN-3.
(2) Suggest secondary ductal involvement:
(a) An abrupt transition from markedly atypical to
normal-appearing epithelium
(b) Continuity of the involved duct with invasive
carcinoma
Guidelines for Evaluation of IPMNs

Entirely submitted for histologic

examination:
The associated invasive cancer is the
most important determinant of prognosis
for patients with an IPMN.
Guidelines for Evaluation of IPMNs

Differential diagnosis of IPMNs:

(1) PanINs: If both PanINs and an IPMN are present in a single
pancreas, efforts should be made to separate these lesions using
the above-mentioned criteria.
(2) Mucinous cystic neoplasm:
(a) The presence of ovarian-type stroma
(b) The absence of ductal involvement
(3) Retention cysts:
(a) Flat, or at most very low papillary, epithelium.
(b) Epithelial atypia is minimal in retention cysts
(c) Usually unilocular.
Guidelines for Evaluation of IPMNs

Involvement what kind of ducts?

(1) Main duct type ? branch duct type? Or mixed type?
Branch duct-type IPMNs are usually confined to the
head/tail of the pancreas, they tend to occur at a
younger age, and they less often are associated with an
invasive cancer than main duct type IPMNs
(2) Efforts should be made, radiographically or at the time
of gross examination of resected specimens, to
determine if an IPMN involves the main pancreatic duct
or a branch duct.
Issues Requiring Further Study
Neoplasm ? Lesion? Hyperplasia?
(1) These entities with the modifying term lesion
(PanIN/L-1A) to acknowledge that the neoplastic nature
of many cases of PanIN-1A has not been
unambiguously established.
(2) Similarly, the Japanese classification system for IPMNs
includes Intraductal papillary mucinous tumor -
hyperplasiafor histologically low-grade structures
without atypia.
(3) Additional study is needed to identify reproducible
criteria to distinguish hyperplastic lesions from low-grade
neoplasms.
Issues Requiring Further Study
Reproducible criteria?
(1) Morphometric evidence that a two-tier system (low-
grade/high-grade) may be more reproducible.
(2) It was the consensus of the group that further genetic
and morphologic studies should be conducted to refine
the histologic grading of PanINs and IPMNs.
Issues Requiring Further Study
Histologic classification of IPMN:
(1) Morphologically, IPMNs may have a variety of different
cytoarchitectural features even in different regions of a single
neoplasm.
(2) Some separate IPMNs into clear-, dark-, and compact-cell types
based on the density of the cytoplasm and the shape of the
epithelial cells, and the expression patterns of MUC1, MUC2, and
MUC5AC
(3) It also has been proposed that IPMNs should be subdivided into
gastrointestinal, pancreaticobiliary, and oncocytic subtypes. It was
the consensus of the group that further clinical, genetic, and
morphologic studies are needed to refine the histologic classification
of IPMNs.
Issues Requiring Further Study
Finally, some of the group speculated on the interesting possibility
that some IPMNs may begin as PanINs that then progress along a
different pathway of neoplasia than conventional pancreatic ductal
adenocarcinoma.
Conclusion
IPMNs and PanINs are important precursors to invasive
adenocarcinoma of the pancreas. It is our hope that the
proposed revised definitions and diagnostic guidelines
presented will help advance the study of these lesions
such that genesis of pancreatic cancer will be elucidated
and that pancreatic cancer, one of the most dreadful
diseases of humankind, can one day be treated at the
preinvasive stage.