Invasive breast carcinoma - IARC

Intraductal proliferative lesions
F.A. Tavassoli
S.J. Schnitt
H. Hoefler W. Boecker
J. Rosai S.H. Heywang-Köbrunner
R. Holland F. Moinfar
I.O. Ellis
S.R. Lakhani
Definition
Intraductal proliferative lesions are a
g roup of cytologically and arc h i t e c t u r a l l y
diverse proliferations, typically originating
f rom the terminal duct-lobular unit and
confined to the mammary duct lobular
system. They are associated with an
i n c reased risk, albeit of greatly diff e re n t
magnitudes, for the subsequent development
of invasive carcinoma.
ICD-O codes
In the ICD-O classification, /2 is used
for in situ carcinomas. The code 8500/2
covers all grades of ductal carcinoma in
situ and ductal intraepithelial neoplasia,
grade 3.
Site of origin and route of lesion
progression
A vast majority of intraductal proliferative
lesions originate in the terminal duct-lobular
unit (TDLU) {3091}. A substantially
smaller proportion originates in larger
and lactiferous ducts.
Segmentally distributed, ductal carcinoma
in situ (DCIS) progression within the
duct system is from its origin in a TDLU
t o w a rd the nipple and into adjacent
branches of a given segment of the duct
system. The rare lesions that develop
within the lactiferous ducts may progress
toward the nipple resulting in Paget disease
or to the adjacent branches of a
reference duct {2089,2090,2093}.
Terminology
Intraductal proliferative lesions of the
breast have traditionally been divided
into three categories: usual ductal hyperplasia
(UDH), atypical ductal hyperplasia
(ADH) and ductal carcinoma in situ
(DCIS). It should be noted, however, that
the term "DCIS" encompasses a highly
heterogeneous group of lesions that differ
with regard to their mode of presentation,
histopathological features, biological
markers, and risk for progression to
invasive cancer. In most cases, the
histopathological distinction between different
types of intraductal proliferation
can be made on morphological grounds
alone, particularly with standardization of
histopathological criteria. However, even
then, the distinction between some of the
lesions (particularly between ADH and
some low grade forms of DCIS) remains
p roblematic. In addition, populationbased
mammography screening has
resulted in increased detection of lesions
that show cytological atypia with or without
intraluminal proliferation but do not
fulfil the diagnostic criteria for any of the
existing categories. Those lesions lacking
intraluminal projection have been
described in the past as clinging carcinoma
and more recently re f e r red to
under a variety of names including flat
epithelial atypia, atypical cystic lobules,
atypical columnar alteration with prominent
apical snouts and secretions.
Progression to invasive breast cancer
Clinical follow-up studies have indicated
that these intraductal proliferative lesions
a re associated with diff e rent levels of risk
for subsequent development of invasive
b reast cancer, that ranges from appro x i-
mately 1.5 times that of the re f e re n c e
population for UDH, to 4-5-fold (range,
2.4-13.0-fold) for ADH, and 8-10-fold for
DCIS {886}. Recent immunophenotypic
and molecular genetic studies have provided
new insights into these lesions indicating
that the long-held notion of a linear
p ro g ression from normal epithelium
t h rough hyperplasia, atypical hyperplasia
and carcinoma in situ to invasive cancer
is overly simplistic; the inter- re l a t i o n s h i p
between these various intraductal pro l i f-
erative lesions and invasive breast cancer
is far more complex. In brief, these data
have suggested that: (1) UDH shares few
similarities with most ADH, DCIS or invasive
cancer; (2) ADH shares many similarities
with low grade DCIS; (3) low grade
DCIS and high grade DCIS appear to re p-
resent genetically distinct disorders leading
to distinct forms of invasive bre a s t
c a rcinoma, further emphasizing their hete
rogeneity; and (4) at least some lesions
with flat epithelial atypia are neoplastic.
These data support the notion that ADH
and all forms of DCIS represent intraepithelial
neoplasias which in the WHO
classification of tumours of the digestive
system have been defined as ‘lesions
characterized by morphological changes
that include altered arc h i t e c t u re and
abnormalities in cytology and differentiation;
they result from clonal alterations in
genes and carry a predisposition, albeit
of variable magnitude, for invasion and
metastasis’ {1114}. The WHO Working
Group felt that UDH is not a significant
risk factor and that at the time of the
meeting, there was insufficient genetic
evidence to classify it as a precursor
lesion. However, a recent CGH study
suggests that a subset of UDH can be a
precursor of ADH {1037}.
Classification and grading
These emerging genetic data and the
increasingly frequent detection of ADH
and low grade DCIS by mammography
have raised important questions about
the manner in which intraductal proliferative
lesions are currently classified.
Although used by pathology laboratories
worldwide, the traditional classification
system suffers from high interobserver
variability, in particular, in distinguishing
between atypical ductal hyperplasia
(ADH) and some types of low grade ductal
carcinoma in situ (DCIS). Some members
of the Working Group proposed that
the traditional terminology be replaced
by ductal intraepithelial neoplasia (DIN),
reserving the term carcinoma for invasive
tumours. This would help to avoid the
possibility of overtreatment, particularly
in the framework of population-based
mammography screening programmes.
In several other organ sites, the shift in
terminology has already occurred e.g.
cervix (CIN), prostate (PIN) and in the
recent WHO classification of tumours of
the digestive system {1114}.
The majority of participants in the WHO
Working Group was in favour of maintaining
the traditional terminology which in
Table 1.11 is shown next to the corresponding
terms of the DIN classification.
For purposes of clinical management
and tumour registry coding, when the
Intraductal proliferative lesions
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