Ductal and Lobular Neoplasia
Ian O. Ellis
City Hospital, NHS Trust
The existing classification systems for ductal and lobular epithelial poliferative lesions of the
breast use conventional morphological criteria to identify an epithelial hyperplastic process commonly
termed ductal hyperplasia of usual type, occurring at one end of a possible spectrum of epithelial
proliferative disease. High grade ductal carcinoma in situ (DCIS) is placed at the opposite pole.
Intermediary forms include intermediate and low grade forms of DCIS and the putative precursor lesion for
low grade DCIS in the form of atypical ductal hyperplasia (ADH). Lobular neoplastic lesions (atypical
lobular hyperplasia and lobular carcinoma in situ) are believed to form a parallel spectrum of disease.
The latter is recognized to carry a significant but bilateral risk for subsequent development of
carcinoma particularly when associated with a family history of breast cancer although this varies with
time.1 The distinctions between these entities are based on evidence derived from many studies
carried out over the last 20 or more years but which have acquired great attention following publication
of the studies by David Page and co-workers.2 They have been supported by other more recent studies,
in particular the results derived from the Nurses' Health Study.3, 4
The fact that this classification system (ADH through to high grade DCIS) has been accepted
internationally reflects the relative consistency of data emerging from the various studies with respect
to risk of subsequent development of invasive breast cancer. Perhaps more significantly, it indicates
that such evidence supports the compelling hypothesis that some forms of breast carcinoma may arise not
only from established forms of DCIS, but that these lesions may arise from epithelial proliferation
recognized as ADH and possibly from more common forms of usual hyperplasia. This concept, however
appealing, has limitations. Some forms of carcinoma in situ and invasive carcinoma, possibly the
majority, do not appear to be associated with such lesions and appear to arise de-novo or from as yet
unknown precursor lesions. In addition, ADH was recognized initially based on exclusion rather than
positive criteria, i.e. recognition of some but not all features of DCIS and lack of the characteristics
of usual type epithelial hyperplasia.5
Although having found great favor as a concept backed by evidence from long term follow-up studies,
the major problem with recognition of these entities has been the difficulty in achieving acceptable
levels of concordance or consistency in diagnosis between pathologists. Various strategies have emerged
to try and improve reliable recognition, including revision of the criteria, providing a more positive
basis for future recognition, education and emphasis of the use of one system by all for diagnostic
classification and also the use of lesion size.6 Despite the adoption of such principles, reliable
classification around the boundaries of ADH remains elusive in most,7, 8 although not all,9
This problem with reproducibility of diagnosis is unlikely to be resolved by the adoption of
alternative systems or nomenclature based on the same diagnostic criteria. For example, the mammary
intraepithelial neoplasia, ductal type (MIN) system (8) (or ductal intraepithelial neoplasia (DIN))
proposed by Tavassoli 10, 11 has some attraction in that it uses a terminology which has been adopted
in other organ systems. Unfortunately the MIN system retains the existing diagnostic boundaries and
requires the same problematic distinction between intraductal hyperplasia of usual type, ADH, low grade
DCIS, intermediate grade DCIS and high grade DCIS. It thus in essence promotes a change in terminology
without any change of diagnostic criteria or conceptual basis. In addition this particular proposal also
includes a hyperplastic process, ductal epithelial hyperplasia of usual type in a classification of
"neoplasia". For these reasons some feel that this classification is unlikely to stand the test of time
as it cannot inherently improve on interobserver reproducibility and provides no additional evidence on
which to promote a "new" classification system.
One further potential problem exists when using a simple system such as the existing methods or indeed
the MIN system in the breast. We currently recognize a wide morphological diversity of breast malignant
tumor, both in situ and invasive. This diversity is most probably a consequence of a range of underlying
different pathogenic mechanisms and pathways. These may have some common origins, overlap or be entirely
distinct with separate pathogenetic origins. Neoplastic processes in other organ systems such as the
cervix appear to be far less genetically and morphologically diverse and as a consequence lend themselves
to a unifying concept of intraepithelial neoplasia based on morphology. We believe that adaptation of
such simplicity, although appealing, is unlikely to be successful due to the morphological and presumably
genetic complexity of the breast neoplastic processes. We would suggest that specific
clinico-pathological entities should be identified through an understanding of their genetic basis and
that these distinct entities could then be further sub-classified using a grading system if they exhibit
morphological variation or by alteration of further influential genes.
The classification of DCIS has been a very topical subject in recent years stimulating consensus
conferences amongst pathologists, clinicians and radiologists in the USA, Europe and Australia 12-14
The origin of this interest has been the increased frequency of detection of DCIS, and in
particular localized DCIS, due to the uptake of mammography since the 1970's.15 These lesions have
allowed the adoption of conservative surgical management techniques and have led to a search for
predictive variables for local recurrence both as in situ and more significantly as invasive disease.16-20
Traditional histological classification of DCIS based on architecture appears to have limited value in
this role. Most of the improved histological classification systems are based on a three-tier grading or
differentiation system and use nuclear grade,21, 22 differentiation and polarity 23 and/or the
presence or absence of necrosis.24, 25 Mel Silverstein and colleagues have been particularly
innovative in promoting use of histological grade coupled with lesion size and excision margin distance
in the form of a prognostic index,26 and have shown significant predictive power for local recurrence.
However, although many of the various histological classification systems described appear predictive in
many of the studies published to date, questions still remain about diagnostic reproducibility between
pathologists and their long-term clinical relevance. At present there is limited data on reproducibility 27, 28, 19, 22
but these early studies do appear to show moderate to good levels of concordance for
many of the three-tier grading systems. It is however possible that the histological classification of
established DCIS may be irrelevant if viable surgical excision is achieved. Total ablation of DCIS by
mastectomy is generally accepted to be curative. Conservative surgical management, particularly with
"close" margins, is complicated by a significant risk of local recurrence which can be reduced (but not
negated) by adjuvant radiotherapy.29 Use of complete local excision aiming to achieve excision by
over 10 mm, coupled with diligent pathology examination of margins, can reduce the risk of local
recurrence,30 but to date no randomized control trials examining such surgical and pathological
techniques and comparing them with a less diligent approach combined with radiotherapy have been
The existing information on DCIS indicates that it is typically a unicentric lesion confined to a
single duct system which presumably could lend itself to complete surgical excision without the need for
complete mastectomy.31-33 The main problem however is our present lack of ability to map
disease extent pre-operative and thus plan the surgical procedure.33, 34 Current imaging techniques
do not provide sufficient accuracy to allow such tailored conservative surgery and most centres offer a
standardized technique resecting an area of calcification with a circumferential extended margin of
"normal" tissue of varying extent.
In many three-tier classification systems in pathology, pathologists have little difficulty in
recognizing the entities at either end of the spectra. Problems of concordance of classification are
generally found in the middle group and its boundaries. Two-tier classification systems could
potentially improve on reproducibility, but at present there is no clear agreement where such a boundary
should be and thus in two-tiered systems at present reproducibility remains poor.28 We feel that most
authorities would choose the boundary between low and intermediate grade DCIS rather than a boundary
between intermediate and high grade DCIS. In practice, however, the distinction around either boundary
is difficult. Most of the newly promoted classification systems use nuclear grade, some with necrosis as
an additional morphological feature, for this distinction. Nuclear grading is assisted in the latest
grading systems through reference to red cell size; low grade nuclei are identified as being less than or
equal to two red blood cells in size, intermediate and high grade nuclei being over two red cells in
area. In practice this size criteria is relatively restrictive and certainly in current UK practice
there are only a small proportion of cases of DCIS which fulfil these criteria for low grade designation.
It is for the above reasons that currently we retain the use of the standard terminology of usual
epithelial hyperplasia, ADH and DCIS, the latter sub-classified into three grades. However we feel that
recently generated data may offer a more appropriate and pragmatic approach to future classification
which could resolve the diagnostic dilemmas for pathologists and also provide a more rational basis for
There is a need for an improved and innovative classification system for epithelial proliferative
lesions and in situ malignancy of the breast. We feel strongly that there is little value in revising
the existing systems in view of their faults, as described above, unless or until it is possible to
devise a classification method which has biological and clinical relevance and which can be applied
consistently by pathologists. We suspect that such a system based on recognition of genetic lesions is
now emerging and it is tempting to draw comparisons with the developments in leukemia and lymphoma
classification over the last 10 years which recognize distinct clinico-pathological entities based on
fundamental genetic changes. Similar specific and diagnostically helpful genetic changes are being
identified in many soft tissue tumors.
It is unlikely that the basic pathological process of hyperplasia and neoplasia in the breast are
different from other organ systems. We feel that a fundamental distinction between hyperplasia and
neoplasia will remain in breast disease classification and serve as one distinct boundary. At present
this separation is based mainly on morphological criteria but in recent years additional features have
become recognized which could assist in achieving diagnostic reproducibility. We would propose that the
boundary between usual type ductal hyperplasia and neoplastic proliferation of the breast should be based
on recognition of a clonal cell process but not necessarily based on molecular investigations of
clonality. A clonal process, particularly of low grade cellular morphology, potentially can also broadly
be recognized by its uniformity of morphology and of phenotype such as cytokeratin expression or hormone
receptor expression. Although not widely recognized, some groups have demonstrated that usual epithelial
hyperplasia is morphologically and also phenotypically heterogeneous, being composed of a mixed cell
population arranged in a haphazard architectural structure and showing mixed / heterogeneous cytokeratin
and estrogen receptor (ER) expression.35 The finding of ER heterogeneity in this hyperplastic
condition is not surprising when one considers the focal expression seen in normal epithelium. In
contrast ADH and established low grade DCIS have not only a uniformity of cell type but also show
uniformity of cytokeratin, particularly cytokeratin 5 / 6, and estrogen receptor expression. High grade
DCIS is, however, frequently ER negative.36
The concept of in situ epithelial neoplasia exists in other organs such as cervix and prostate. The
concept of a progression from a benign to malignant neoplastic processes is well established in some
sites particularly in the colo-rectum, as the adenoma-carcinoma sequence. At present, in the breast one
could argue that the conceptual distinction between benign neoplasia and in situ malignancy has been
arbitrarily drawn at the boundary between ADH and low grade DCIS. Is this the appropriate boundary and
should we pursue the need for distinction between benign and malignant neoplasia? Indeed, is it
appropriate to distinguish between benign and malignant in situ neoplasia in the breast? Would it be
more appropriate to identify established neoplastic processes and then sub-classify these according to
their grade and extent; the former being related to risk of progression to invasive carcinoma, the latter
being used to direct the appropriate technique of ablative removal?
The molecular genetic studies of low grade DCIS and ADH using loss of heterozygosity (LOH) techniques
have demonstrated similar genetic lesions and, in informative cases, confirmatory evidence that these are
clonal processes and therefore fulfil the basic concept of a neoplastic process.37 The frequency of
LOH in cases of usual hyperplasia is much lower in most series and, although the finding of LOH in this
process is intriguing, suggests that it is appropriate to draw the boundary line between hyperplasia and
neoplasia between usual epithelial hyperplasia and ADH. The presence of LOH in some cases of usual
hyperplasia 38, 39 most probably indicates that clonal lesions may emerge from this hyperplastic
process. This is a well-recognized concept at other sites. These are not, however, morphological
distinct and have not reached autonomy and dominance over the otherwise hyperplastic process.
Equally exciting studies, in our view, are the very recently published work using comparative genomic
hybridization (CGH) to investigate DCIS of the breast. These have prompted the proposal of a
hypothetical model for the pathogenesis of DCIS, which recognizes genetic lesions associated with
particular morphological sub-types. Well-differentiated DCIS is associated with 16q and 17p loss whilst
tumors of intermediate and high grades often have allelic losses of significantly more chromosomal arms,
frequently including 1p, 1q, 6q, 9p, 11p, 11q, 13q, and 17q.40 High grade DCIS particularly has gains
at 17q but also 11q and 13q.41 Intermediate grade DCIS appears to include a combination of lesions
which show 16q loss but gains at other chromosomes particularly 1q and also cases which show gain at
11q13q, but lack the gain at 17q12 which is a feature of high grade DCIS.42 As in intraductal
proliferations (ADH and DCIS), atypical lobular hyperplasia and lobular carcinoma in situ similarly show
the same genetic mutations as each other with loss of material from 16p, 16q, 17p, and 22q and gain of
material from 6q.43
We believe that these studies may herald a new era in classification of breast disease. To date these
series have themselves analyzed groups based on nuclear grading criteria, but we would expect that
further refinement of genetic abnormalities will derive from analysis of distinct morphological types of
The benefits in routine clinical practice from following a simplified classification system such as
nuclear grade are a greater chance of achieving reproducibility of recognition between pathologists and
clinical relevance, particularly prediction of risk of local recurrence. The problem in terms of
classification development in the modern era is that they may over simplify. In the past pathologists
have recognized a range of morphologically distinct types of DCIS based on their architectural and
cytomorphological features; these include comedo, micropapillary, cribriform, small and large cell solid,
papillary, apocrine, signet ring, clear cell, hypersecretory and neuroendocrine DCIS and as well as
lobular carcinoma in situ (LCIS). Should we abandon recognition of these morphologically distinct
tumors? We believe that despite problems in achieving diagnostic reproducibility these morphological
types probably hold the key to understanding the underlying pathogenic mechanisms. We would not be
surprised to find distinct genetic lesions associated with each morphological sub-type and feel that
histopathologists may re-visit morphological sub-typing of DCIS in the near future.
We would make the following proposal with regard to future classifications of the these lesions:
1. The distinction of the boundary between hyperplasia and neoplasia in the breast should be
recognized on the basis of a dominant, uniform, clonal cell population using morphological,
immunophenotypical and molecular genetic information, if feasible. This is practicable at present and
pathologists can utilize immunohistochemistry facilities to detect heterogeneity in staining, for example
in ER reactivity.
2. Established clonal, neoplastic breast lesions (including lesions presently classified as ADH,
ALH, LCIS and DCIS) should be sub-categorized according to their specific molecular genetic basis. This
sub-categorization could routinely be based on morphological characteristics, but we would anticipate
that this would be supported by the expression or loss of phenotypic markers related to specific genetic
lesions. These genetically distinct in situ neoplasms could be further sub-categorized according to
additional genetic changes and the extent of the lesion.
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