The incidence of ductal carcinoma in situ (DCIS) has increased dramatically
since the advent of screening mammography in the 1980s. The age-adjusted
DCIS incidence rates increased 17.5% annually from 1983 to 1992. The
percentage of patients with DCIS treated with mastectomy has decreased
from 71% in 1983 to 44% in 1992. The percentage of patients with DCIS undergoing
lumpectomy and radiation in 1992 was 23.3% and lumpectomy only was 30.2%.
The clinical significance of DCIS detected by mammography is still uncertain.
It is unclear which patients will ultimately develop invasive disease.
Many investigators are concerned about the overdiagnosis and subsequent
overtreatment of these cases. However, this concern must be balanced against
the finding in one study of an actuarial local recurrence rate of 19% after
excision and radiation therapy, with 53% of the recurrences presenting
as invasive disease. Therefore, it is certain that a significant percentage
of DCIS lesions are obligate precursors to invasive disease and could potentially
affect the survival of the patient.
Different Classifications for DCIS
Drs. Silverstein and Lagios, in their thoughtful summary and discussion,
present a tool to help predict local recurrence in patients with DCIS and
therefore recommend local treatment. It has long been recognized that DCIS
is not one homogeneous disease. Therefore, there have been various suggestions
for new classifications of DCIS.
Poller et al suggested a simplified classification for DCIS based on
cellular proliferation and c-erbB-2 protein expression. This paper is
the basis for the current Van Nuys Pathologic Classification. The three
categories proposed by Poller et al were comedo DCIS, DCIS with necrosis
(non-pure comedo), and DCIS without necrosis. The cases of comedo DCIS
and DCIS with necrosis were associated with a higher S-phase and the presence
of c-erb-B2 protein. The current Van Nuys classification identifies three
factors that are felt to be important in predicting local recurrence: tumor
size, pathologic margins, and a pathologic classification using nuclear
grade and the presence or absence of necrosis.
Holland et al based their classification primarily on cytonuclear differentiation
and secondarily on architectural differentiation. These investigators
defined three categories. The first category consists of poorly differentiated
tumors with absent or minimal architectural differentiation and usually
with necrosis present. The most important characteristic feature is the
marked pleomorphic nuclei. The second category is well-differentiated DCIS,
usually with a cribriform, micropapillary, changing, and rarely solid pattern.
Necrosis is absent and mitoses are uncommon. The third group is intermediately
The strength of this classification is that cytonuclear features are
more often consistent in DCIS than is architectural pattern or necrosis.
However, as yet there is no correlation between this classification and
the biologic activity of DCIS.
In a study by Bobrow et al, two independent observers used the Holland
classification to reclassify 105 cases of DCIS. The poorly differentiated
group was associated with c-erb-B2 protein staining, a high proliferation
rate, p53 protein, and the absence of progesterone receptors. Well-differentiated
lesions had no c-erb-B2 or p53 present, proliferation was low in all cases,
and progesterone receptors were present in 95%. These findings may help
determine the biology of DCIS and may be used in the future to determine
How to Define a Free Margin?
The specific prognostic factors used in the Van Nuys Prognostic Index
(VNPI) include the measurement of tumor margins. When is a free margin
free? The answer is not so simple. Determination of negative pathologic
margins differs among groups reporting DCIS data. Solin et al defined negative
margins as tumor more than 2 mm from the inked margin. Margins were
determined by a retrospective review of patient records and were available
in only 47%. The NSABP defined negative margins as no transection of the
tumor. Of the 790 NSABP cases, 40% either were unavailable for central
pathologic review or had unknown margins.
In the Van Nuys series, all cases underwent central pathology review
by one pathologist. In their initial publications, Silverstein et al did
not rigorously define free margins.[7,8] However, in a subsequent publication,
the scoring system used an exact measurement of tumor-free areas, giving
each one a different score. This includes, as a best-case scenario,
a 10-mm or more margin.
The use of a 10-mm or more margin seems very logical based on the work
of Holland's group. They reported on the results of a three-dimensional
imaging study of DCIS in 60 mastectomy specimens. They found that continuous
and multifocal growth patterns are usual, and that multicentric tumors
(defined as a gap of 4 cm or more) are rare, occurring in only one case.
Poorly differentiated tumors more often had continuous growth, whereas
well-differentiated lesions had multifocal distribution. Therefore, reliability
of margin assessment varies with type. In all the cases reviewed, only
8% had a multifocal distribution with gaps more than 10 mm and 7% were
in well-differentiated tumors.
The conclusion that can be drawn from the work of Holland et al is that
90% of all DCIS can be removed surgically if a 1-cm margin is attainable.
Clearly, it is not always feasible to do this and obtain a good cosmetic
Which Factors Predict Local Recurrence?
The next question is, if all DCIS is removed, which prognostic factors
will predict local recurrence? The Van Nuys group suggests that it is patients
with high-nuclear-grade lesions (grade 3) who are most likely to develop
a recurrence, followed by those with grade 1 or 2 lesions with necrosis.
Their conclusion is based on a retrospective classification of patients,
which, as the authors point out, are a highly selected group. The patients
presented in the Van Nuys series received one of two different nonrandomized
treatments, either excision or excision followed by radiation therapy.
The multivariate analysis for prognostic factors predictive of recurrence
was significant for nuclear grade, tumor size, and margin width, and showed
a trend toward significance for the presence of necrosis.
The NSABP B-17 study reported that the presence of moderate or marked
comedo necrosis predicted for second ipsilateral breast tumors. Solin
et al found that no pathologic parameters were predictive of local failure
after radiation therapy. Ottesen et al found that tumor size 10 mm,
or more large nuclei, and comedo necrosis predicted for local recurrence
after excision of DCIS. These data would suggest that necrosis, indicative
of a high proliferative rate, and large nuclei with pleormorphism and prominent
nucleoli are associated with more aggressive local disease.
In conclusion, DCIS is a very heterogeneous disease. This is no doubt
the reason for such controversy, disagreement, and uncertainty over its
treatment. The Van Nuys classification attempts to simplify treatment decisions.
Intuitively, this classification and the treatment recommendations based
on it make good common sense. First, it is ideal to obtain clear margins
by 1 cm. If that is impossible, residual disease is likely, and thus, mastectomy
is the only treatment available to remove all the disease. This still does
not take into consideration the possibility that lesions may be biologically
"benign" and not likely to progress to invasive disease. If the
tumor is large, a good cosmetic result may not be likely with wide excision,
and therefore, mastectomy may be appropriate. If the tumor is small with
clear margins, excision alone may be adequate, except in high-grade cases.
There is still a question as to whether the local recurrence rate is
higher with high-grade cases compared to good nuclear grade. Treatment
options for high-nuclear grade lesions include radiation, with mastectomy
reserved for the treatment of the local recurrence (since disease will
not recur in a significant number of women), or mastectomy as primary local
treatment. In any case, as Drs. Silverstein and Lagios state, patients
should be informed of all the pros and cons of each treatment option.
The Van Nuys group appropriately points out that their data are retrospective.
Patients were selected for a certain local treatment based on the factors
felt to be important at that moment in time. Ideally, it is important to
test various local treatments in a prospective randomized trial with attention
to such details as margins, nuclear grade, and necrosis.
There are many ongoing European trials evaluating radiation after segmental
mastectomy in a large number of women with DCIS. Central pathologic
review of these studies could help clarify some of the unanswered questions.
Future trial results, such as those of the NSABP and the United Kingdom
trial evaluating the use of tamoxifen (Nolvadex) in DCIS, are eagerly awaited.
The elucidation of the biology of different subsets of DCIS will go
a long way toward clarifying treatment decisions. Also, prospective treatment
based on biologic markers of proliferation and aggressiveness will help
determine the appropriate treatments.
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