2013 CA Mamario Intracanalicular

7/30/2019 2013 CA Mamario Intracanalicular

1/7

Ductal carcinoma in situ:current morphological andmolecular subtypesJohn P Brown

Sarah E Pinder

AbstractThe term ductal carcinoma in situ (DCIS) of the breast encapsulates a bio-

logically, morphologically, clinically and genetically heterogeneous group

of lesions. These have a wide spectrum of histological features but are

characterized by a non-invasive proliferation of malignant epithelial

cells confined to the parenchymal structures of the breast and thus con-

tained within basement membrane-bound structures. Analysis at the

molecular and genetic level has improved our understanding of these

entities as non-obligate precursors of invasive breast cancer. It is clear

that the linear progression model from normal epithelium through hyper-

plasia to atypical hyperplasia to DCIS to invasive breast cancer is inaccu-

rate. Here we examine current methods for classifying DCIS and some

recent molecular advances, including the impact of genetic profiling

and immunohistochemistry, upon our understanding of current patholog-

ical definitions of DCIS.

Keywords breast cancer; ductal carcinoma in situ (DCIS); histopa-

thology; immunohistochemistry; prognostic factors

Introduction

The incidence of DCIS has risen in the UK from 1 to 5% of lesions

detected prior to mammographic breast screening to approxi-

mately 20e25% of all breast lesions found in the screened pop-

ulation.1 Whilst detection of malignant lesions prior to invasion

is paramount, selecting the optimum treatment remains difficult

for both clinicians and patients, due to the inability to predict the

risk of development of invasive cancer and the likelihood of

recurrence for each individual lesion. Surgical options include

mastectomy or breast conserving surgery (BCS). BCS, with or

without radiotherapy, results in local recurrence rates of 7e9%

and 16e22% respectively.2 Some patients may potentially also

receive adjuvant hormone therapy, although this is not univer-

sally prescribed.

DCIS is generally regarded as a non-obligate precursor of

invasive breast cancer but the heterogeneous nature of the

disease complicates our understanding of its progression to

invasion and thus attempts at developing robust systems of

clinically relevant classification. However, it is clear that various

clinical and histopathological factors are predictive of a poorer

prognosis; the presence of narrow resection margins, high cyto-

nuclear grade, comedo necrosis and increased tumour size are

indicators, but not prerequisites, for local recurrence of disease.

Advances in molecular profiling have enhanced our under-standing of invasive breast cancer over the last decade, with

genomics identifying distinct molecular subtypes.3 Similar

translational progress in our understanding of DCIS remains

more elusive.

Clinical outcome and known prognostic factors in DCIS

DCIS rarely presents as a distinct clinical finding (other than

radiologically-detected calcification) and, in the majority of

cases, no palpable lesion or visual signs are present. There is,

however, evidence that symptomatic disease has a poorer prog-

nosis than screen-detected lesions.4 In the latter, the absence of

gross features makes surgical excision and further laboratory

assessment challenging. Insertion of one, or more, wires understereotactic or ultrasound guidance enables the surgeon to target

the appropriate areas of radiological calcifications for wide local

excision (WLE). Intraoperative radiological examination is then

employed to ensure all microcalcifications are removed, along

with a margin of uninvolved breast tissue. However, difficulty

arises in the underestimation by radiography of the extent of the

lesion, with as little as 50% being detected in cases of micro-

papillary or cribriform disease and even in cases of comedo/solid

DCIS only 85% may be identified.5 Results from the Sloane

project, the UK National Audit of Breast Screen-detected DCIS,

has reported that pre-surgical radiography underestimates the

size of 30% of DCIS cases undergoing BCS.6 It is therefore

particularly important to undertake detailed pathologicalsampling of the resection margins to identify any areas of

residual disease, even in the absence of calcification close to the

periphery of the specimen. The College of American Pathologists

protocol document outlines guidelines for handling and reporting

of DCIS specimens7 and includes methods for estimation of the

size of DCIS and width of margin, which are not described in

detail here. However, it should be noted that there is currently no

consensus on the width of uninvolved margins that defines

complete excision of DCIS. It is clear that margins less than 1

mm result in a greater incidence of local recurrence and that

residual disease is frequently present if further surgery is per-

formed. However, recommendations vary from complete

excision being defined as a 2 mm or more rim of tumour-freetissue in a wide local excision specimen, to other Cancer Units

where a 10 mm or greater margin of uninvolved breast tissue is

required for a case of DCIS to be considered completely

excised.1 Despite these controversies regarding optimum margin

width, and the fact that recurrence rates are higher after BCS than

mastectomy for DCIS, complete excision and a good cosmetic

result can be achieved with the former. The addition of post-

operative radiotherapy after BCS reduces the risk of local recur-

rence by approximately 50%4,8 and is widely recommended.

Although many clinicians believe this is not required for all small

low grade lesions, the identification of such cases in randomized

clinical trials has proven problematic.

John P Brown MPhil BSc (Hons) FIBMS Breast Pathology Research, Research

Oncology, Division of Cancer Studies, Kings College London, UK.

Conflict of interest: none.

Sarah E Pinder MBChB FRCPath Breast Pathology Research, Research

Oncology, Division of Cancer Studies, Kings College London, UK.

Conflict of interest: none.

MINI-SYMPOSIUM: THE BIOLOGICAL PHENOTYPE OF BREAST CANCER

DIAGNOSTIC HISTOPATHOLOGY 18:3 112 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.mpdhp.2012.01.001http://dx.doi.org/10.1016/j.mpdhp.2012.01.001


2/7

Histological classification of DCIS

Histopathologists have long recognized that DCIS varies in

microscopic appearance and have classified the disease in

a variety of ways. Categorization was formerly based upon the

architectural patterns of the lesion. Descriptive histology terms

such as comedo, cribriform (Figures 1 and 2), micropapillary

(Figure 3), solid (Figure 4), papillary or flat/clinging type

(Figure 5) provide some indication of extent and likely behaviour

of disease but are often present in combination, making repro-

ducible categorization difficult. Indeed lesions have been re-

ported to be of mixed architecture in 62% of cases.9 Despite this,

the architecture of the disease provides prognostic information;

in the UK DCIS I randomized clinical trial, assessing the benefits

of radiotherapy and of tamoxifen therapy, patients with a solid

morphology as the main architectural pattern of DCIS had

a 15.2% recurrence rate, compared to 14.3% of those with

micropapillary DCIS and only 7.3% of those with predominantly

cribriform DCIS had ipsilateral recurrence, as either DCIS or

invasive breast cancer.10

Cytonuclear grade of the malignant cells is typically less

variable within a case9 and has proven valuable, in some systems

in conjunction with the presence or absence of comedo necrosis,

as a means of differentiating lesions with a poorer prognosis.

Most current classification systems define DCIS as low grade,

intermediate grade or high grade based on cytonuclear features

(Table 1). Although rare, sometimes a DCIS lesion will exhibit

a range of nuclear features, when this occurs the classification is

according to the highest nuclear grade present.

High grade DCIS is characterized by large pleomorphic cells with

variation in size and shape and a lack of polarity (Figures 3e5).

Coarse chromatin, prominent nucleoli and mitoses are often

abundant. Nuclearoutlinestend to haveirregular contours and may

appear crenallated, with the enlarged nuclei being greater than two

and a half to three times the size oferythrocytes.

7

Highgrade DCIS isusually associated with centralcomedo-type necrosis (Figure 4)and

microcalcification within the central luminal debris.

Low grade DCIS is composed of more evenly spaced, uniform

cells (Figure 1). These have regular, round nuclei located cen-

trally with the cytoplasm. Nuclei are one to two times the size of

Figure 1 Cribriform architecture ductal carcinoma in situ of low cytonu-

clear grade, with secretions in sieve-like spaces.

Figure 2 DCIS of cribriform architecture with comedo-type necrosis, of

intermediate grade.

Figure 3 High grade DCIS of micropapillary architecture.

Figure 4 High grade, solid architecture, DCIS with focal comedo-type

necrosis.




3/7

erythrocytes.7

The malignant cells are typically arranged in wellordered patterns, showing polarity around cribriform or micro-

papillary structures. Mitotic figures are sparse. A solid architec-

ture to low grade DCIS is rare, but cribriform and micropapillary

patterns are common, often with both present within the same

lesion.

Classification of the intermediate grade can be challenging;

reproducibility of this categorization is not good.11 This is at least

in part due to the relatively poorly defined criteria for this cate-

gory, which intrinsically are those of exclusion of a diagnosis of

low grade and high grade disease. Cells of intermediate grade

DCIS exhibit moderate pleomorphism, lack the uniformity of

a low grade lesion but do not show the pleomorphism of high

grade DCIS (Figure 2). Occasional nucleoli may be present.Lesions can have a cribriform, solid or micropapillary architec-

ture with some polarization of cells. However, now the College of

American Pathologists guidelines recommend that the nuclear

size of intermediate grade DCIS is generally two to three times

the size of erythrocytes and this, more definite criteria is, in our

opinion, useful.7

In addition to the cytonuclear grade of DCIS, the Van Nuys

system of classification12 incorporates the absence or presence of

comedo-type necrosis into categorization of DCIS and, like

cytonuclear grade, has been shown to be of prognostic signifi-

cance. Of note, we do not consider comedo DCIS to represent

an architectural type, as comedo necrosis can be seen in asso-

ciation with a variety of growth patterns, including solid, crib-

riform (e.g. Figure 2) and micropapillary lesions, and thus we

report the architectural pattern and the presence or absence of,

and proportion of ducts with, comedo-type necrosis separately inour routine histological reports, as well as the cytonuclear grade.

Reassuringly, in studies that have compared the pure cytonuclear

grade with Van Nuys grading systems for categorization of DCIS,

little difference has been shown between clinical outcome of the

two classifications, suggesting that both approaches are equally

valid.10

Despite the value of DCIS cytonuclear grade in predicting local

recurrence of ipsilateral disease (DCIS or invasive breast cancer)

in randomized clinical trials such as the UK DCIS I trial, one of the

difficulties in routine application is that most (62%) of DCIS

detected in the UK is of high cytonuclear grade.13 A potential new

system for sub-categorization of this high grade group has been

described.10

This system was derived from review of cases in theUK DCIS trial, in which it was identified that high cytonuclear

grade DCIS without extensive comedo-type necrosis (


4/7

with variable, from negligible to low, risk of developing invasive

disease. Hyperplastic and atypical proliferations, such as usual

epithelial hyperplasia (UEH), columnar cell lesions (CCLs)

including flat epithelial atypia (FEA), and atypical ductal hyper-

plasia (ADH) represent a disparate group of entities that may

exhibit some of the features of DCIS and can mimic this lesion.

These entities are briefly included here to highlight possible

diagnostic pitfalls and to demonstrate the morphological andmolecular similarities with DCIS.

Usual epithelial hyperplasia (UEH) can be sub-categorized

into mild, moderate or florid forms but this entity is not associ-

ated with a significant risk of developing subsequent breast

cancer and so distinguishing degree of UEH is not considered

essential. Mild UEH extends no more than three or four cells

above the basement membrane (BM) whilst moderate UEH

extends five or more cells above the BM. Florid UEH is seen

when patterns such as streaming of the proliferating epithelial

cells, mild to moderate variation of nuclear shape and size and

slit-like lumina are present. It is this latter degree of UEH that can

be mistaken for DCIS by the unwary (Figure 6a).

Columnar cell lesions (CCLs) are formed from enlargedterminal duct lobular units, typically containing dilated acini

lined by columnar shaped epithelial cells. These lesions are

increasingly seen in image guided needle biopsies targeting

mammographic microcalcifications, as this is frequently present

within secretions in the luminal spaces. In 2003 Schnitt and

VincenteSalomon proposed a classification system consisting of

four categories: columnar cell change, columnar cell hyperplasia,

columnar cell change with atypia and columnar cell hyperplasia

with atypia.14 The later two categories were combined to a single

entity of flat epithelial atypia (FEA) in 2003 by the World Health

Organization (WHO) Working Group on the Pathology and

Genetics of Breast Tumours.15 Columnar cell change and

columnar cell hyperplasia are not considered to increase a risk ofbreast cancer development. FEA shows low grade cytological

atypia as seen in low grade DCIS but lacks architectural atypia in

the form of micropapillae, cribriform spaces or arches and

bridges. Molecular evidence indicates that FEA may be the

earliest morphological identification of neoplastic change in the

breast; when this process is seen in association with DCIS and/or

invasive carcinoma, a matched loss of heterozygosity (LOH) can

be seen. Common chromosomal alterations have been identified

on 16q, 11q and 3q which are absent in UEH, but are frequently

also seen ADH and DCIS.16,17

The morphology and cytological features of ADH are similar

to low grade DCIS but this is a microfocal lesion that is generally

confined to a single lobular unit. Specifically ADH does notinvolve two complete membrane-bound spaces. The nuclei in

ADH are uniform, small, regular and evenly spaced. As well as

the uniformity of cells, ADH forms rigid cellular bars and

secondary spaces, which are not seen in FEA.

The proliferating epithelial cells in FEA, ADH and low grade

DCIS are small, uniform and regularly spaced whilst in UEH they

show more variation in shape and orientation. Occasional cases

may cause diagnostic difficulty, particularly in distinguishing

intermediate grade DCIS from UEH (especially if the former is of

neuroendocrine type which may show streaming of cells and

oval rather than small round nuclei (Figure 7)), or if the UEH

bears necrosis (Figure 6a) or moderate numbers of mitoses.

Immunohistochemistry (IHC) shows uniform strong positivity

for oestrogen receptor (ER) and negative reactivity for basal

cytokeratins (e.g. Ck5 and Ck14) in FEA, ADH and low grade

DCIS, and can be helpful in difficult cases to distinguish theselesions from UEH. The latter shows a mosaic, heterogeneous

pattern, confirming the absence of a clonal population

(Figure 6b). There are no presently available markers to distin-

guish ADH from low grade DCIS and this distinction is largely

based on extent of the process.

Rare morphological subtypes

Several rarer morphological variants of DCIS exist, some of

which exhibit features that have potential for causing errors in

histological diagnosis. The clinical significance of the histological

features, and genetic aberrations, present in such lesions remains

poorly researched and are not understood. Apocrine DCIS is most

Figure 6 (a) Usual epithelial hyperplasia. Expanded ducts bear an

epithelial proliferation with central necrosis. The proliferation shows,

however, slit-like rather than well-defined punched out (cribriform)

spaces. (b) Cytokeratin 14 in the same case as (a) confirms that the

epithelial proliferation has a mosaic/heterogeneous pattern confirming an

absence of clonality.




5/7

commonly of high cytonuclear grade, and typically does notcause diagnostic difficulties, as the cells have eosinophilic,

granular cytoplasm, large nuclei and prominent nucleoli with

marked cytological atypia and central necrosis. However, lower

grades of apocrine DCIS often cause difficulties in diagnosis and

distinguishing these from atypical apocrine changes can be

extremely tricky. The overall size of the process, as well as the

degree of variation in nuclear size and nuclear features are

helpful in distinguishing these processes and the reader is

referred to reviews on this topic.18 Neuroendocrine DCIS

(Figure 7) is formed from polygonal and/or spindle shaped cells

that often have a granular cytoplasm. A pseudorosette architec-

ture and admixed solid papillary areas may be seen. Often

strongly uniformly positive for ER, as well as for neuroendocrinemarkers, this lesion should not be confused with epithelial

hyperplasia that has a similar streaming architecture. Some

consider flat DCIS to be one end of the spectrum of the columnar

cell lesions; it is of high cytonuclear grade and is distinguished

from FEA based on the degree of cytological atypia present. Other

rare forms of DCIS exist which are not covered in this article and

in general these are classified according to the cytonuclear grade

as little in known about the specific genetic changes, if any, in

such lesions.

Progression pathways in DCIS and breast carcinogenesis

models

Until recently, the accepted model for progression from normalbreast tissue to invasive breast cancer was that of a linear,

multistep progression of carcinogenesis, as described in other

organ systems. This hypothesis proposed that acquisition of

genetic mutations in the terminal duct lobular unit would give

rise to morphologically identifiable precursors starting with usual

epithelial hyperplasia, progressing to atypical ductal hyperplasia

and eventually low grade DCIS. This would be followed by

further in vivo mutagenic changes and epigenetic events that

caused progression to either high grade DCIS and then invasion,

or directly to invasion alone.

Although the molecular mechanisms involved in the initi-

ation of breast carcinogenesis have yet to be elucidated, there

is clinical and molecular evidence that DCIS is a precursor of

invasive cancer. The multi-linear step model can, however, be

updated to include FEA and ADH as non-obligate precursors

of low grade DCIS and/or low grade invasive breast

carcinoma, whilst UEH is a distinct entity which does not

appear to participate in breast cancer development or

progression.19

Of particular note, modern research techniques, includingchromosomal and array comparative genomic hybridization

(CGH & aCGH) studies have shown disparities between high

grade and low grade lesions.16,20 Both low grade DCIS and grade

1 invasive carcinomas are often diploid and have recurrent

deletions on chromosome 16q (approximately 70e80% of cases).

The unbalanced chromosomal translocation (der (16)t(1;16)/

der(1;16)) is found in invasive lobular carcinoma and the line

between low grade lobular and ductal lesions is also becoming

more blurred.16 Conversely, high grade DCIS exhibits deletions of

16q in less than 30% of cases, is usually aneuploid and has

increased numbers of genetic aberrations. Studies of high grade

DCIS show gains on 17q and 11q and 13q loss.20 In addition to

revealing different genomic abnormalities in low grade and highgrade DCIS, aCGH studies of matched DCIS and invasive lesions

have demonstrated clustering of lesions according to histological

grade rather than stage of progression, casting further doubt on

the historical linear model of UEH through to high grade DCIS.

The evidence is compelling that multiple pathways of breast

carcinogenesis exist.

Identification of a precursor for high grade DCIS remains

elusive, partially due to the multiple quantitative genomic events

evident in several studies. Bombonati17 suggests the possibility

of a subset of microglandular adenosis (MGA) being a precursor

to a group of triple negative (oestrogen receptor, progesterone

receptor and HER2 negative) high grade DCIS. MGA is, however,

a rare histological entity, and this is unlikely to be a commonpathway.

An alternative hypothesis, although not independent, from

the linear breast cancer progression model is the cancer stem cell

model. It proposes that stem cells, or their progeny, determine

initiation, survival and metastasis of a tumour. This small frac-

tion of malignant cells alone has endless proliferative potential

and gives rise to differentiated tumour cells, potentially

explaining the heterogeneity found in both DCIS and invasive

breast cancer. It has been proposed that normal breast epithelial

stem cells, or their progeny, undergo mutagenic changes result-

ing in a cancer stem cell, although the theory remains contro-

versial. In support, CD44 positive, ALDH positive, CD24 negative

cells have been shown to be capable of tumour initiation in xeno-transplantation models (reviewed in21). Further research is

continuing in the area of cancer stem cells in breast

carcinogenesis.

Similarly, epigenetic changes (alterations of gene expression

that cannot be attributed to variation in the DNA sequence), such

as hypermethylation of specific genes or epigenetic silencing, has

identified candidate genes responsible for adhesion, cell cycle

regulation, DNA repair, transformation, signal transduction and

tumour suppressor genes prior to evidence of DCIS in histological

sections. Epigenetic studies therefore have the potential to

enhance both risk assessment and provide a route for novel

diagnostic markers.

Figure 7 Neuroendocrine-type DCIS can mimic usual epithelial hyperplasia

with apparent streaming of aligned nuclei, which may be oval rather than

round.




6/7

Immunohistochemical profiling of DCIS

Gene expression profiling has revealed the presence of at least

three categories of invasive breast cancer. These categories,

luminal (A and B), HER2 and basal-like, exhibit different clinical

outcomes and are now widely used to describe subtypes of

invasive cancer. Whilst genomic studies using aCGH and whole

genome profiling are providing valuable insights into the path-

ways of breast carcinogenesis, use in the routine diagnosticsetting is limited by factors including cost, technical difficulties

and the availability of sufficient tissue. Subsequent analyses of

invasive breast cancers have shown a rough concordance of

molecular subtypes can be achieved using IHC.22 The possibility

of using immunohistochemistry (IHC) as a surrogate for the

genomic methods in examination of DCIS has also been explored

in several series.23e25 As with invasive cancer, the differential

expression of multiple markers or a panel of antibodies may give

a better prognostic indication than a single marker alone. Results

indicate that the morphological variants of DCIS express different

IHC markers and give further support to the concept that low and

high grade invasive carcinomas arise from different pathways

and do not represent a single entity. Tamimi et al founda difference in the IHC expression patterns between DCIS and

invasive carcinoma molecular grouping phenotypes.25 The

luminal A category was seen at a lower frequency in DCIS than

invasive tumours whilst the HER2 and luminal B groups had

a higher incidence in DCIS lesions. This supports the view that

not all invasive carcinomas arise directly from/through a DCIS

phase, and that FEA and other members of the low grade

neoplasia family contribute to invasive carcinoma without

necessarily passing through a stage recognized histologically as

DCIS.

Several researchers have identified a basal-like immunophe-

notype of some DCIS lesions23,24 using IHC, with ER, HER1

(EGFR), HER2 and basal cytokeratins (e.g. CK5/6) being the corepanel. There are, however, several caveats that should be applied

to the interpretation of IHC studies of DCIS (and invasive breast

cancer). Comparison is difficult due to the disparate nature of

cases in series, with some studies looking at pure DCIS whilst

others have examined DCIS in the presence of associated inva-

sive cancer. Even where cases of pure DCIS alone are assessed,

the other pathological and clinical features described above, such

as excision margin width, disease extent, treatment regimens and

length of follow up, vary, thus confounding comparative anal-

yses of clinical outcome. In addition, there is no clear consensus

with regard to choice and scoring criteria of antibodies that

define these molecular groups. Nevertheless, the application of

IHC panels as a method of classifying DCIS and invasive breastcarcinoma has significant appeal. The infrastructure in the

routine laboratory setting, the relative low cost and availability of

technical expertise are all positive attributes. However until

a general consensus on the antibodies to be examined and

defined scoring methods can be achieved, accurate and repro-

ducible classification will remain elusive.

DCIS in the screened population currently accounts for

approximately 20% of malignant breast lesions. As screening

methods advance this figure may increase. With greater research,

applying morphological, immunohistochemical, genomic,

epigenetic and molecular techniques, our understanding of the

precursors of invasive breast cancer has increased but also has

revealed an elevated complexity that was previously not envi-

sioned. It is no longer in doubt that a single multistep model of

invasive breast carcinogenesis is flawed and that DCIS can be

considered a group of heterogeneous lesions. High throughput

genomic analysis, coupled with proteomic research, may help

identify potential therapeutic targets as well as variants with

differing clinical outcomes but in order to fully comprehend the

processes involved in DCIS progression, a multifaceted approachis required. A

REFERENCES

1 Pinder SE. Ductal carcinoma in situ (DCIS): pathological features,

differential diagnosis, prognostic factors and specimen evaluation.

Mod Pathol 2010; 23(suppl 2): S8e13.

2 Polyak K. Molecular markers for the diagnosis and management of

ductal carcinoma in situ. J Natl Cancer Inst Monogr 2010; 2010:

210e3.

3 Perou CM, Srlie T, Eisen MB, et al. Molecular portraits of human

breast tumours. Nature 2000; 406: 747e

52.4 EORTC Breast Cancer Cooperative Group, EORTC Radiotherapy Group,

Bijker N, Meijnen P, Peterse JL, et al. Breast-conserving treatment

with or without radiotherapy in ductal carcinoma-in-situ: ten-year

results of European Organisation for Research and Treatment of

Cancer randomized phase III trial 10853-a study by the EORTC Breast

Cancer Cooperative Group and EORTC Radiotherapy Group. J Clin

Oncol 2006; 24: 3381e7.

5 Fitzgerald R. Pre-invasive disease: pathogenesis and clinical

management. Springer, ISBN 978-1-4419-6693-3; 2011.

6 Thomas J, Evans A, Macartney J, et al. Radiological and pathological

size estimations of pure ductal carcinoma in situ of the breast,

specimen handling and the influence on the success of breast

conservation surgery: a review of 2564 cases from the SloaneProject. Br J Cancer 2010; 102: 285e93.

7 Lester SC, Bose S, Chen YY, et al. Protocol for the examination of

specimens from patients with ductal carcinoma in situ of the breast.

Pathol Lab Med 2009; 133: 15e25.

8 UK Coordinating Committee on Cancer Research Ductal Carcinoma in

situ Working Party. Radiotherapy and tamoxifen in women with

completely excised ductal carcinoma in situ of the breast in the UK,

Australia, and New Zealand: randomised controlled trial. Lancet

2003; 362: 95e102.

9 Quinn CM, Ostrowski JL. Cytological and architectural heterogeneity in

ductal carcinoma in situ of the breast. J Clin Pathol 1997; 50: 596e9.

10 Pinder SE, Duggan C, Ellis IO, et al. A new pathological system for

grading DCIS with improved prediction of local recurrence: resultsfrom the UKCCCR/ANZ DCIS trial. Br J Cancer 2010; 103: 94e100.

11 Ellis IO, Coleman D, Wells C, et al. Impact of a national external

quality assessment scheme for breast pathology in the UK. J Clin

Pathol 2006; 59: 138e45.

12 Silverstein MJ, Poller DN, Waisman JR, et al. Prognostic classification

of breast ductal carcinoma-in-situ. Lancet1995; 345: 1154e7.

13 Thomas J, Hanby A, Pinder S, et al. Sloane Project Steering Group.

Implications of inconsistent measurement of ER status in non-

invasive breast cancer: a study of 1,684 cases from the Sloane

Project. Breast J 2008; 14: 33e8.

14 Schnitt SJ, Vincent-Salomon A. Columnar cell lesions of the breast.

Adv Anat Pathol 2003; 10: 113e24.




7/7

15 World Health Organization Classification of Tumours. In:

Tavassoli FA, Devilee P, eds. Pathology and genetics of tumours

of the breast and female genital organs. Lyon: IARC Press, 2003;

65e66.

16 Lopez-Garcia MA, Geyer FC, Lacroix-Triki M, Marchio C, Reis-Filho JS.

Breast cancer precursors revisited: molecular features and progres-

sion pathways. Histopathology2010; 57: 171e92.

17 Bombonati A, Sgroi DC. The molecular pathology of breast cancerprogression. J Pathol 2011; 223: 307e17.

18 OMalley FP, Bane A. An update on apocrine lesions of the breast.

Histopathology2008; 52: 3e10.

19 Boecker W, Moll R, Dervan P, et al. Usual ductal hyperplasia of the

breast is a committed stem (progenitor) cell lesion distinct from

atypical ductal hyperplasia and ductal carcinoma in situ. J Pathol

2002; 198: 458e67.

20 Buerger H, Otterbach F, Simon R, et al. Comparative genomic

hybridization of ductal carcinoma in situ of the breast-evidence of

multiple genetic pathways. J Pathol 1999; 187: 396e402.

21 OMalley FP, Pinder SE, Mulligan AM. Breast pathology: a volume in

the foundations in diagnostic pathology. Saunders Elsevier, ISBN

978-1-4377-1757-0; 2011.22 Abd El-Rehim DM, Ball G, Pinder SE, et al. High-throughput protein

expression analysis using tissue microarray technology of a large

well-characterised series identifies biologically distinct classes of

breast cancer confirming recent cDNA expression analyses. Int J

Cancer 2005; 116: 340e50.

23 Livasy CA, Perou CM, Karaca G, et al. Identification of a basal-like

subtype of breast ductal carcinoma in-situ. Hum Pathol 2007; 38:

197e204.

24 Dabbs DJ, Chivukula M, Carter G, Bhargava R. Basal phenotype of

ductal carcinoma in situ: recognition and immunohistologic profile.

Mod Pathol 2006; 19: 1506e

11.25 Tamimi RM, Baer HJ, Marotti J, et al. Comparison of molecular

phenotypes of ductal carcinoma in situ and invasive breast cancer.

Breast Cancer Res 2008; 10: R67.

Acknowledgement

The authors are grateful for financial support from the Break-

through Breast Cancer Research Unit at Kings College London, the

Department of Health via the National Institute for Health

Research (NIHR) comprehensive Biomedical Research Centre

award to Guys & St Thomas NHS Foundation Trust in partnershipwith Kings College London, and also the Cancer Research UK

Experimental Cancer Medicine Centre at Kings College London.



Documents

2013 CA Mamario Intracanalicular