Pathology and Molecular Biology of Pre-invasive Breast Lesions
Moderator: Werner Boecker
Section 3 -
Pathology Work-up of DCIS Specimens
Thomas Decker, Muenster , Germany
Daniel Faverly, Brussels , Belgium
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The aim of this presentation is to highlight the importance of
pathological examination of surgical specimens in all types of DCIS. With respect to pathological
work-up, DCIS is a challenge for the surgical pathologist. Firstly, identifying the lesions is
difficult. They are macroscopically nonpalpable and invisible and, therefore, as a rule, detected due to
microcalcifications at mammography. Secondly, breast-conserving therapy (BCT) is a serious option in
DCIS. However, the therapeutic decision to proceed with BCT depends on a number of pathologic features.
There is no doubt that all the information contained in the pathology report primarily depends on the
correct sampling of specimens. This requires optimal macroscopic work-up and sampling of surgical
specimens. Microscopic identification of the radiological target lesion is a prerequisite. The data
obtained is of decisive importance for planning further clinical management. Inadequate evaluation of
surgical specimens can lead to both over and under-treatment. Only by providing all clinically relevant
data can the pathologist meet his commitments as a member of a multidisciplinary breast team.
Principles of Distribution of DCIS in the Breast
Knowledge of the lobar architecture of the mammary gland is a prerequisite for understanding DCIS. In
1975 Wellings et al. were able to show by means of extensive submacroscopic examinations of
196 breasts with DCIS  that, with few exceptions, DCIS takes its origin from the
terminal duct lobular unit (TDLU), starting with distension of the ductular structures and unfolding of
lobules by the proliferating tumor cells. Further expansion then leads to involvement of the
extralobular ductal system. Thus, the neoplasia spreads within the pre-existing ductal lobular system.
It follows that the very architecture of the mammary ductal system is one of the key factors that
determine the varied distribution patterns observed in these tumors
system forms segments from the nipple to the periphery, which appear to be pyramid-shaped: the base
lying in the periphery of the breast with its peak pointing towards the nipple .
Using computer-assisted three-dimensional reconstruction, Ohtake and coworkers were able to show that
the various segments are of different size and usually overlapping in their parenchymal structures
. Therefore, these segments do not follow the geometry of the artificial system of
quadrants. Furthermore, an analysis of complete galactograms of 85breasts  disclosed
that 37% of segments are aligned in an outer subcutaneous layer, 41% in an inner layer
beneath this, and 22% are aligned centrally. This explains why segmentectomy usually contains
several independent segments .
Size and intraglandular extension of DCIS
Due to the complex architecture of breast tissue only three-dimensional analysis will yield realistic
DCIS extension patterns
Based on the technique of Wellings mentioned above, the
Nijmegen group developed an original stereomicroscopic method for investigating the mammary gland. It
enabled reconstruction of the glandular tree with its lobes, segments and lobules and, in addition,
correlation of 3D-findings with conventional 2D-histology as well as detailed radiograms of specimen
slices (Fig. 1).
Thus, data from two such studies has provided evidence that DCIS most frequently occurs within the
In contrast, DCIS foci are only rarely fo und in clearly separate
segments  (Fig. 2).
Findings by Ohtake and coworkers who examined the intraductal growth of DCIS components in invasive
carcinomas  also indicate that a total of 81.3% of DCIS showed some type of
intraductal expansion towards the nipple; and that tumors obviously also spread in a retrograde fashion
into the periphery of segments. In addition, Ohtake et al. established so-called network models and
determined the maximum angle of the segment of DCIS growth from the mamillary pole towards the periphery
. In all cases cone or pyramid-like shapes with a broad base towards the periphery were
found. Furthermore, overlap of ductal lobular systems from different segments could be detected, as well
as connecting anastomoses at different levels of the ductal system.
Given such growth patterns, even DCIS sizes of up to 100mm could be explained in terms of
unicentric lesions with continuous segmental growth via connecting channels between different segments.
Although the literature on DCIS sizes (including those treated with mastectomy) is limited, large lesions
seem to account for a considerable number of cases. Holland and coworkers found that 51% (42/82)
of DCIS lesions were more than 50mm in diameter 11. In the course of the CMP-CHIREC
study undertaken by Faverly et al. a full histological revision of 80 consecutive surgical specimens with
DCIS was performed (unpublished data). All patients had previously been subjected to a vacuum-assisted
biopsy, and none of them had any radiological contraindication for BCT. The mean size of DCIS was 24.4
mm, 37 % of the lesions did not show any residual tumor after the vacuum-assisted biopsy, whereas 63 %
did and were larger than 10 mm. In 36 % of all patients the diameter of DCIS was larger than 30 mm.
This data was confirmed by the Berlin-Buch experience: The following data on the sizes of 411DCIS
is derived from excision and re-excision specimens as well as from (primary or secondary) mastectomy
specimens. About 27.2% of DCIS were smaller than 15mm in diameter, while 16.3% were
16–40mm and 56.4% were 40mm or larger (Table 1).
*1993–2002 Berlin-Buch Breast Center, including all DCIS patients irrespective of therapy.
Table 1: Pathological assessment of size in 411 patients*
|0-15 mm ||15-40 mm ||>40 mm ||Total|
|112 (27.2%) ||67 (16.3%) ||232 (56.4%) ||411 (100%)|
In more than half of the DCIS cases (56%: 232/411), the lesions were fo und to be larger than
40mm. For results of both groups see Fig. 3.
Multifocality and multicentricity
In DCIS cases treated by breast-conserving therapy discontinuous growth may cause serious clinical
problems. DCIS foci discontinuous to the main lesion may remain in the breast as residual tumors and
cause local recurrence. In order to estimate the risk of such recurrence, it is essential to consider
DCIS expansion patterns and the likelihood of distant foci elsewhere in the breast.
Unfortunately, due to the use of inconsistent definitions, the data in the literature concerning the
incidence of multicentricity of DCIS ranges from 0to 78%
multicentricity as the presence of two or more separate foci in the breast more than 40mm apart.
Holland et al. detected only a single case in a total of 60 mastectomy specimens containing two foci of
completely isolated DCIS that fulfilled the above criteria (Fig. 4). In 232mastectomy specimens of
DCIS patients of the Berlin-Buch Breast Unit, we found two cases with multicentric foci that were more
than 45mm apart. Multicentric DCIS as defined above, therefore, seems to be the exception.
Furthermore, this conclusion is supported by data showing that local recurrence after breast-conserving
therapy usually occurs within the area of previous surgery and that bilateral DCIS is extremely rare
In another study 60cases of DCIS were analyzed with a combination of radiological and
pathological techniques in a three-dimensional approach
In 50% of
cases only continuous growth expansion was fo und, while the other half displayed discontinuities (gaps)
in their intraductal growth. When the distances between discontinuous DCIS areas were measured, their
length was less than 5mm in 63%, and less than 10mm in 83% of cases. In total,
only 8% of DCIS cases showed discontinuities between DCIS foci of more than 10mm.
Furthermore, Faverly and coworkers fo und a correlation between the respective grade of a given DCIS and
the frequency and size of gaps between foci. While 90% of poorly differentiated DCIS (high-grade)
showed no gaps at all, 70% of well-differentiated (low-grade) DCIS did. In addition, the gaps were
shorter in poorly differentiated lesions, while intermediate and well-differentiated DCIS displayed
larger gaps. All gaps of more than 10mm were found in the latter group. The only case of
multicentric DCIS with a distance of more than 40mm between foci was a well-differentiated DCIS.
In summary, based on the architecture of the ductal lobular tree, the expansion of DCIS can be seen to
start within the terminal ductal lobular unit (TDLU) and extend in different directions, preferentially
towards the nipple. Therefore, DCIS growth occurs within one segment due to the anatomic lobar units of
the mamillary gland. However, DCIS can involve several lobes or segments via intersegmental anastomoses
and thus affect a larger area of breast tissue.
Examination of Excision Specimens
As a rule, DCIS grade, the type of calcification associated, and its correlation with mammography are
nowadays determined preoperatively using minimally invasive biopsy techniques (MIB). Therefore the vast
majority of excision specimens in modern breast medicine are performed for therapeutic reasons as
segmental resections after MIB, rather than for diagnostic reasons.
These specimens are generally larger than diagnostic excisions or the "lumpectomies" of earlier times.
Complete processing of such specimens may be ideal but seems to us impossible in daily practice. Anyway,
in DCIS cases the pathologist is f undamentally confronted with three tasks: the lesion must be fo und
and classified, the size of the lesion must be determined and, finally, resection margins must be
assessed. There is no doubt that all the information contained in the pathology report primarily depends
on the correct sampling of specimens. The following protocol for "systematic and guided" work-up of DCIS
operational specimens is based on the principles of distribution of DCIS in the breast as demonstrated in
the first part of our presentation. This systematic pathological examination of the excision specimen
considers the segmental architecture of the ductal-lobular system, and it is immediately obvious that the
ducts of the segment contained in a given specimen are generally oriented along virtual lines between the
nipple and the periphery. In addition the associated microcalcifications are used as guidance for
In order to examine DCIS lesions appropriately, the pathologist needs the support of radiologists and
surgeons: Before he can determine the histological type of DCIS, the lesion has to be found within the
specimen. As mammographic microcalcifications are the primary indication of DCIS, the mammographic
report and images as well as the specimen radiograph are needed to identify the target lesion. For
determining the size of DCIS lesions and for margin assessment an intact surgical specimen is required.
Cuts and tears in the specimen can impede reliable diagnosis, while fragmentation renders it virtually
impossible. Immediately after removing the surgical specimen the surgeon should mark the mamillary
margin of resection. The pectoral fascia should be removed in such a way that the dorsal resection
margin is formed by the fascia. The external surface of this dorsal (fascial) resection margin should be
marked with blue dye. Ideally, the surgeon then places the excision specimen on a foil with a schematic
drawing of the breast outlines. Alternatively the surgeon can mark the surface of the six margins with
sutures of different lengths, colors or materials to ensure proper orientation.
After performing specimen radiography the microcalcification area is marked with several pins. This
marking for the pathologist is done independently of the preoperative marking for the surgeon.
Systematic and guided examination
The systematic pathological examination of the excision specimen has to consider the ductal-lobular
extension and segmental growth of the DCIS with special emphasis on resection margins. Generally, the
ducts run from the nipple to the peripheral resection margin. If the specimen is sliced perpendicularly
to the mamillary-peripheral axis, it is quite obvious that most ducts will be cross-sectioned, which
increases the chance of recognizing as many ducts as possible within the histological slide (Fig. 5). To
be able to identify non-visible DCIS detected as a result of mammographic calcifications, the pathologist
must be guided, for example, by pins marking the microcalcification area observed in the specimen
Measurement of Specimens
The measurement of the specimen's dimensions – the lengths of the mamillary-peripheral axis and the
dorsal-ventral extension – is essential for later reconstruction of the size of a DCIS and should
therefore be the first step in examination.
Marking of margins
Marking the surface of excision tissue is essential for microscopic identification of the original
resection margins. This can be done by painting the specimen's surface with marker substances that
adhere to the tissue during fixation, dehydration, embedding, cutting and staining and must also be
visible at microscopy. Various substances such as ink, gelatin, dyes, latex (correction fluid) or silver
nitrate can be used. If marking of the surface is done by the surgeon before specimen radiography,
radio-opaque substances (latex, silver nitrate) should be avoided. As a rule, all these materials adhere
better to fresh than to fixed tissue. To avoid seeping of the marking substance into crevices of the
surface, the specimen should not be dipped. Rather, the surface marker should be applied carefully with
a small brush or a cotton applicator. It is possible to mark different margins by using different colors
for recognition on the microscopic slide.
The specimen should be serially sectioned from the mamillary pole to the periphery of the segment.
Care should be taken to slice the tissue thinly (about 4mm). Slice radiographs (in addition to the
radiograph of the intact specimen) provide an even more precise orientation by identifying individual
slices that contain microcalcifications.
It is obvious that tissue samples with microcalcifications (as incidentally macroscopically suspicious
findings) must be examined. In our protocol, all slices with microcalcifications identified by slice
radiography must be embedded completely for histological examination. Due to the discrepancy between the
size of areas of microcalcification and of the histologically detected DCIS, we also embed the
corresponding tissue of the neighboring slices. Furthermore, assessment of the resection margins of all
of these slices is mandatory. Finally, the two first mamillary as well as the two last peripheral slices
are embedded for assessment of 10mm margins in these directions (Fig.5).This means that
slices of the nipple and peripheral margins are therefore embedded tangentially for processing. Two
cassettes for the mamillary slice and four to six cassettes for the peripheral slice are usually
required. The other resection margins are contained in the slices cut perpendicular to the long axis of
the resection specimen. We also include the dorsal and ventral margins in the examination when the
pectoral fascia is removed. This is indispensable for three-dimensional size determination and for
quality control of the surgical techniques. Both three-dimensional reconstruction of the lesion and
exact information about the direction of an involved margin require recognition of the original location
of every tissue block. Since the color of the surface marking substance is not sufficient for this
purpose, we use a coding system to designate the original slice location of the excision specimen
examined: the serially sectioned slices are labeled by ascending numbers from mamillary to peripheral
slice. Abbreviations are used to designate the direction of the margin (ma = mamillar, p = peripheral,
cra = cranial, cau = caudal, d = dorsal, v = ventral, m = medial and l = lateral). For example, the code
39004/06-3-cau would indicate patient number 39004 from year 2006, with tissue of the third slice
containing the caudal resection margin.
Analysis of pathological data of 299 DCIS excision specimens
We analyzed 299excision specimens of patients with DCIS worked up pathologically according to
the protocol described above between 1993 and 2003. Of the primary excision specimens,
254of299 showed DCIS exactly at the resection line or within the 10mm margin. In each
of these cases a second operation was carried out, if possible as a re-excision. In cases with an
unfavorable relation of the lesion to breast size we advised patients to undergo mastectomy. In more
than 85% of cases (254/299) residual DCIS could be detected in the re-operation specimen. (Table
Table 2: Residual tumor after involved margins* in primary excisions in 299 DCIS patients
| ||Re-excision ||Mastectomy (%) ||Total|
|Residual tumor ||142 ||67 ||209 (82.3 %)|
|Tumor-free ||45 ||0 ||45 (17.7 %)|
|Total ||187 ||67 ||254 (100.0 %)|
If one compares the results the difference between re-excisions and mastectomies is rather striking:
whereas there were 17.7 % tumor-free re-excisions, secondary mastectomies were never tumor-free. This
can be attributed to the fact that whenever a decision in favor of mastectomy was made, it did not solely
depend on the margin status, but other factors as well (see below).
Width of Tumor-free Margins
The tumor-free margin of the surgical specimen in BCT correlates with the risk of residual tumor and
the frequency of recurrence
The concept of local recurrence developing from
remaining DCIS in situ is based on this correlation, which has been demonstrated in numerous studies.
Nevertheless, opinions differ as to the optimal minimal distance, and there is no generally accepted
standard for determining this parameter. Not until the 1980s when breast-conserving therapy was
introduced for DCIS was special attention paid to resection margins. The NSABP B-17 protocol only
stipulated that the DCIS must not be transected . This requirement was certainly
insufficient: patients whose DCIS had been treated by excision without radiotherapy suffered a local
recurrence rate of 43% . Tumor-free margins suggested by other experts were equally
small: Lagios 
und Silverstein  originally chose 1mm, Solin 2mm . However, as
early as 1994 Silverstein documented that a margin of 1mm was insufficient .
Residual tumor was found in 45% of mastectomy and re-excision specimens in these cases. Holland
and coworkers were able to prove in 1985 that 1mm wide resection margins involved a high risk in
view of the large amounts of residual tumor tissue . Therefore they proposed leaving a
rim of normal glandular tissue between tumor and resection line as a criterion for a safer excision.
Subsequent studies by Faverly and co-workers from the same working group provided an explanation for this
finding: discontinuities in the intraductal neoplastic growth . The most important
finding relating to the debate on histological minimal distances is that only in 8% of all DCIS
cases gaps of more than 10mm occur. Theoretically, excision with a tumor-free margin of 10mm
should remove DCIS with a probability of 90%. This pathomorphological data corresponds with the
clinical results presented by the Van Nuys group in 1996 , the Nottingham group in 1997
and the combined Children's Hospital and Van Nuys study in 1997 [(32)]. In DCIS
excisions with larger than 10mm-wide, tumor-free margins the rate of local recurrence ranged from 8
to 6%, or was even as low as 5%. Correspondingly, local recurrence rates are higher in cases
with shorter minimal distances to the resection margins. Nevertheless, several studies have yielded
results that are in glaring contrast, among them the prospectively randomized NSABP B-17 study. This
study revealed hardly any, or no correlation between the width of the histological tumor-free margins and
residual tumor or the risk of recurrence . Recent data published by the Boston
group  shows a 5-year local recurrence rate of 12 % in cases of non-high grade DCIS excised
with 10 mm free margins. Discrepancies among this data may be chiefly attributed to three reasons:
Our experience with excisions of 299 DCIS is that all cases with complete primary excision as well as
all re-excision specimens with 5mm wide tumor-free margins showed even 10mm wide DCIS-free
zones along the resection margins.
techniques used to examine resection margins;
- Variations in the extent of margin assessment; and
- Varying minimum requirements regarding the tumor-free margin.
We were not able to establish any differences in the rate of residual tumor between the group with
direct involvement of margins and those with tumor-free margins of 1mm or 1–5mm.
Most of the 142DCIS cases (85%) that contained tumor within the 10mm margins of the
segmental excisions and residual tumor in re-excision specimens showed involvement of more than one of
the margins (in several directions). In cases with residual tumor the mamillary resection margin was far
more often involved (87%) than all the other five. We consider findings of tumor tissue within a
10mm margin along the resection line (under standardized conditions of systematic and specimen
radiograph-oriented slicing) to be an indicator of residual tumor in the breast. The probability of
residual tumor increases with the number of affected resection lines as well as with involvement of the
margin facing the nipple.
Size of DCIS
As DCIS is considered an obligate precursor lesion of invasive breast carcinoma, the aim of
breast-conserving therapy should be complete removal of the lesions. Naturally, the size of the DCIS
largely determines the success of such an approach. The greater the extent of the DCIS the larger the
excision has to be. Many studies have been performed regarding the relationship between DCIS and
specimen size, resection margin findings and recurrence risk
available data on the influence DCIS size on treatment outcome is poor, mainly because of methodological
problems, inconsistencies in study design, and the influence of patient selection.
Complete excision of the lesion was almost never achieved in patients with DCIS of more than
40mm in diameter. With very few exceptions, these large DCIS showed involvement of another
quadrant or of the central portion of the gland. Due to the poor anatomical
definition of the central portion of the mammary gland this analysis was restricted to a retroareolar
area up to 25mm from the nipple. In cases where a lesion was mammographically detected in an
overlapping area of two quadrants, only one quadrant was evaluated. Ninety-eight percent of the DCIS with diameters larger than 40mm were also
larger than 60mm. In these cases, even in women with larger breasts, re-excisions were not
successful and mastectomies had to be performed. Therefore, we consider a maximum diameter of 40mm
to be the upper limit for BCT,independent of breast size.
Residual Tumor Risk Evaluation
DCIS size, resection margin findings and evidence of residual tumor are closely related. The
frequency of DCIS within 10mm margins increases with the total size of the DCIS: 100% of the DCIS of less than 15mm in diameter showed 10mm free
margins. This could only be achieved after re-excision of nearly half of DCIS with diameters of
16–40mm. In contrast, we were unable to excise DCIS larger than 40mm in diameter with
10mm tumor-free margins. Moreover, in DCIS of 40mm or more, detection of tumor within the
10mm margin with involvement of the mamillary resection margin indicates that the lesion cannot be
removed completely by BCT. We could not find any correlation between grade (or comedo necrosis) and
residual tumor risk.
By combining margin findings (distance and number of margins involved) and size the pathologist is
able to estimate different risks of residual tumor. Figs. 6A-C show three examples for residual tumor
risk estimation: A )Low residual tumor risk: Margin >10mm, lesion size <16mm. B)
Intermediate residual tumor risk: Margin <5mm, only one margin involved, mamillary margin not
involved, lesion size 16–40mm. This combination indicates a reasonable risk of residual tumor;
nevertheless there is a good chance that breast conservation by completing re-excision will be
successful. C) Highest residual tumor risk. Margin <5mm, multiple margins involved (mamillary
margin included), lesion size >40mm. This combination indicates a very high risk of residual
tumor; there is no chance of completely excising the DCIS. The patient should be advised to undergo
mastectomy with reconstruction.
Biologically, DCIS is considered to be an 'early' lesion without invasion and metastasizing potential.
Nevertheless, DCIS is not necessarily a 'small' lesion – it can involve a considerable area of the
glandular body. Size is the most important limiting factor for BCT, because there is a close relation
between DCIS size and resection margin findings: the larger the DCIS, the greater the risk for involved
resection margins. DCIS larger than 40mm in diameter in the primary excision specimen almost
always show involved resection margins. Here the resection margin findings are more than just an
indication for re-excision. DCIS of more than 40mm with involved resection margins under 5mm
always extend into the retromamillary central glandular body and/or other quadrants of the gland and are
therefore in total much larger. Starting at 40mm, size becomes the essential risk marker for
residual tumor. The complete removal of such lesions can only be achieved by (subcutaneous or
skin-sparing) mastectomy. In contrast, in our experience, small DCIS with diameters of less than
40mm can be excised completely with 10mm-wide free resection margins if preoperative planning
is performed according to our protocol  (Fig. 7).
One of the most interesting questions of modern practical management of DCIS is the quantitative
analysis of vacuum-assisted biopsies to estimate risk factors such as size and correlation with
microcalcification before the surgical intervention.
Finally, questions of individualized therapy within BCT are currently a topic of discussion. Which
patients do not need additional radiotherapy? Which patients really benefit from additional tamoxifen
therapy? Any attempt to answer these questions must be based on prospective pathological data. In
addition to the histopathological classification and biological markers, data on size and quantity of the
lesions is und oubtedly of importance, especially with reference to resection margins.
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