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429
Pathologic Findings from the National Surgical
Adjuvant Breast Project (NSABP) Eight-Year Update
of Protocol B-17
Intraductal Carcinoma
Edwin R. Fisher, M.D.1
James Dignam, Ph.D.2
Elizabeth Tan-Chiu, M.D.3
Joseph Costantino, Dr.P.H.2
Bernard Fisher, M.D.3
Soonmyung Paik, M.D.1
Norman Wolmark, M.D.3
for the National Surgical Adjuvant
Breast and Bowel Project (NSABP)
Collaborating Investigators
1
National Surgical Adjuvant Breast and Bowel
Project (NSABP) Pathology Center, Pittsburgh,
Pennsylvania.
2
National Surgical Adjuvant Breast and Bowel
Project (NSABP) Statistical Center, Pittsburgh,
Pennsylvania.
3
National Surgical Adjuvant Breast and Bowel
Project (NSABP) Operations Center, Pittsburgh,
Pennsylvania.
Supported by U.S. Public Health Services National
Cancer Institute Grants NCI -U10-CA-120270, NCIU10-CA-37377, and NCI-U10-CA-39086, and by
American Cancer Society Grant ACS-RC-13.
The following are the institutions (and principal
pathologists) who contributed 10 or more patients
to the study: Baptist Medical Center, Oklahoma
City, OK (S. Shrago); Boston University, Boston, MA
(D. Faller); British Columbia Cancer Agency, Vancouver, British Columbia, Canada (A. J. Worth);
Community Clinical Oncology Program (CCOP), Allegheny General Hospital, Pittsburgh, PA (R. J.
Hartsock); Alton Ochsner Medical Foundation, New
Orleans, LA (G. Farr); Columbia River Oncology
Program, Portland, OR (P. W. Kohnen); CCOP,
Marshfield Clinic, Marshfield, WI (C. Reyes); City of
Hope Medical Center, Duarte, CA (H. Battifora);
Good Samaritan Hospital,, Cincinnati, OH (T.
Wessler); Hartford Hospital, Hartford, CT (A. Ricci,
Jr.); Hotel-Dieu, Montreal, Quebec, Canada (Y.
Boivin); Jewish General Hospital, Montreal, Quebec, Canada (L. Begin, M. Brisson); Kaiser Perma-
© 1999 American Cancer Society
BACKGROUND. This report is an 8-year update of the authors’ previous findings
from National Surgical Adjuvant Breast Project (NSABP) Protocol B-17, which
relates to the influence of pathologic characteristics on the natural history and
treatment of intraductal carcinoma (DCIS).
METHODS. Nine pathologic features observed in a pathologic subset of 623 of 814
evaluable women enrolled in this randomized clinical trial were assessed for their
role in the prediction of second ipsilateral breast tumors (IBT), other events, and
selection of breast irradiation (XRT) following lumpectomy.
RESULTS. The frequency of subsequent IBT was reduced from 31% to 13% (P 5
0.0001) by XRT. The average annual hazard rates for IBT were reduced by XRT for
all pathologic features examined. Four characteristics were individually noted to be
significantly related to IBT, but only moderate-to-marked and absent-to-slight
comedo necrosis were found to be independent high and low risk predictors,
respectively, for such an event in patients of both treatment groups. XRT effected
a 7% absolute reduction at 8 years in the low risk group. Despite a relatively high
incidence ('40%) of IBT consisting of invasive cancer, mortality due to breast
carcinoma after DCIS for the entire cohort was found to be only 1.6% at 8 years.
CONCLUSIONS. The degree of comedo necrosis in patients with DCIS appears to be
sufficient for discriminating between high and low risks for IBT following lumpectomy for DCIS. Although margin status, unlike in our previous report, was found to
have only a slight or borderline influence on the frequency of IBT at 8 years,
excision of DCIS with free margins is advised. The low risk group exhibits a
statistically significant reduction of IBT from XRT. The decision to forgo XRT in the
treatment of this singular subset of patients would appear to depend on clinical
considerations and the input of informed patients rather than being standard
practice. [See editorial on pages 375–7, this issue.] Cancer 1999;86:429 –38.
© 1999 American Cancer Society.
KEYWORDS: breast, intraductal carcinoma, ductal carcinoma in situ, pathology,
treatment.
nente, Portland, OR (N. Olson); Medical College of
Wisconsin, Milwaukee, WI (D. Rothwell); Michigan
State University, East Lansing, MI (H. Bowman, R.
Edminister); Mt. Sinai Medical Center, Cleveland,
OH (R. Lash, G. Mendelsohn); Pennsylvania Hospital, Philadelphia, PA (M. Cunnane); St. Michael’s
Hospital, Toronto, Ontario, Canada (A. Chalvardjian); Tufts University/New England Medical Center, Boston, MA (H. Safaii); University of Hawaii,
Honolulu, HI (D. Hono); University of Michigan, Ann
Arbor, MI (H. A. Oberman); University of Pittsburgh,
Pittsburgh, PA (S. Yousem).
Address for reprints: Edwin R. Fisher, M.D., Allegheny University, Allegheny General Hospital, 5th
Floor, Continuing Care Center, 320 East North
Avenue, Pittsburgh, PA 15212.
Received August 14, 1998; revisions received October 26, 1998, and February 16, 1999; accepted
February 16, 1999.
430
CANCER August 1, 1999 / Volume 86 / Number 3
I
ncreased detection of ductal carcinoma in situ
(DCIS) continues to provoke a spate of reports concerning its pathologic features, natural history, and
treatment. In 1993, the initial 5-year clinical findings
from what we believe was the only prospectively randomized clinical trial addressing some of these issues,
Protocol B-17 of the National Surgical Adjuvant Breast
Project (NSABP), disclosed a significant reduction in
second ipsilateral breast tumors (IBT) in patients who
received local breast irradiation (XRT) following
lumpectomy, as opposed to those who were treated
with only the latter (16.4% vs. 7.0%).1 Parenthetically,
it should be noted that although “lumpectomy” is the
term used for the surgical procedure, in approximately
80% of the cohort no lump or nodule was appreciated
either clinically or pathologically. The beneficial effect
of XRT in reducing IBT has been observed to persist
into the eighth year of follow-up.2 It was not influenced by any mammographic characteristics of the
lesions that were examined.
Results of our attempt to identify pathologic discriminants predictive of IBT at 4-1/2 years in a pathologic subset of 573 of the 790 women evaluated in the
clinical report appeared in 1995.3 Several of the nine
pathologic features individually analyzed for their relation to IBT were found to be significant in this regard. However, when jointly evaluated, only the presence of moderate-to-marked comedo necrosis and
uncertain or involved margins of resection were found
to be independent high risk factors for such an event.
The highest hazard rates occurred in both treatment
arms when both high risk parameters were present,
and the lowest occurred when margins were free and
comedo necrosis was absent or slight. The difference
in average annual hazard rates between the two treatment arms for absent-to-slight comedo necrosis and
free margins was not great (1.97 vs. 1.18 per 100 patients). Although the difference in the relative frequency of IBT was 40%, the absolute difference was
only 3%. This suggested that patients whose tumors
exhibited such features might not require XRT following lumpectomy. However, the number of events were
too few to warrant such a proposal at that time, a view
subsequently expressed by others as well.4
The current report is an update describing 8 years
of our pathologic observations of the B-17 cohort of
patients with DCIS. The accumulation of a greater
number of events during the past several years
prompted us to perform these analyses.
METHODS
Details regarding patient selection, eligibility, study
design, randomization, stratification, follow-up procedures, and identification of endpoints for NSABP Pro-
tocol B-17 have been presented elsewhere.1,2 Patients
were randomly assigned to receive either XRT or no
further treatment after lumpectomy for “pure” DCIS.
Although initially all women underwent axillary lymph
node dissection, this procedure became optional and
was rarely performed after 2 years from the time the
protocol was activated because of the absence of
lymph node metastases as well as the historic rarity of
such an event among patients with DCIS. XRT consisted of 50 Gray (Gy) at a rate of 10 Gy per week for 5
weeks. A boost to the tumor bed with either external or
interstitial technique was not used, nor was lymph
node irradiation administered.
The recent clinical study of follow-up for 8 years
for B-17 recorded in 19982 was based on the evaluation of 814 patients instead of the 790 evaluated previously.1 This increase resulted from the addition of 24
patients from one institution who had been excluded
because of concerns about the quality of their data.
However, subsequent audits failed to confirm this suspicion. A central pathology review excluded 2 of the 24
patients from this study. The remaining 22, as well as
28 who had been excluded from our initial pathologic
analyses because slides representative of IBT had not
been submitted for central review, were added to the
original subset of 573 patients. Careful evaluation of
the surgical pathology reports and other information
that was subsequently supplied for these 28 cases
indicated that IBT did occur. Except for some instances in which data was regarded and tabulated as
unknown, all analyses were performed on 623 patients, or 77% of the entire B-17 cohort. Three hundred
three were treated by lumpectomy only and 320 by
lumpectomy and subsequent XRT. The findings in this
report are based on an average time since entry into
the study of 102 months.
The 9 tumor characteristics reviewed by NSABP
central pathologists are found in Table 1. These have
been described in detail previously.3, 5– 8 However, several characteristics that are not generally used by pathologists warrant brief explanation. In the context of
this study, the designation “multifocal” indicates the
presence of DCIS in sections prepared from more than
one block of the specimen. Tumor in only one block of
several was regarded as “unifocal.” If only one block
was available for evaluation, focality was considered
“unknown.” Comedo necrosis was assessed as an independent feature of DCIS rather than a representative feature of a specific histologic tumor type. When
this alteration occurred in more than one-third of
ducts exhibiting DCIS, it was subjectively graded as
“moderate/marked”; fewer or none were graded as
“absent/slight.”
Although the protocol required tumor margins to
Pathology of Intraductal Breast Carcinoma/Fisher et al.
431
TABLE 1
Average Annual Hazard Rates per 100 Patients and Rate Ratios of IBT According to Pathologic Characteristics and Treatment
Lumpectomy 1 XRT
Lumpectomy
IBT
Characteristic
Comedo necrosis
Abs/slight
Mod/marked
Histologic type
Cribriform
Solid
Other
Margins
Free
Uncertain/involved
Lymphoid infiltrate
Absent/slight
Moderate/marked
Nuclear grade
Good
Poor
Focality
Unifocal
Multifocal
Cancerization
Absent/slight
Moderate/marked
Stroma
Absent/slight
Moderate/marked
Tumor size (mm)
,10b
$10b
,5c
$5–10c
IBT
No.
No.
HR
No.
No.
HR
RRa
95% CI
P value
164
139
38
56
3.5
7.5
178
142
23
20
1.8
2.1
1.00
1.72
1.23–2.41
0.002
36
79
188
10
28
56
4.4
6.6
4.7
72
58
190
3
13
27
0.6
3.6
2.1
1.00
2.41
1.64
1.28–4.52
0.91–2.95
0.006
0.19
249
54
73
21
4.7
7.2
267
53
34
9
1.9
2.5
1.00
1.48
0.98–2.21
0.06
244
59
71
23
4.7
7.0
249
71
29
14
1.7
3.1
1.00
1.59
1.09–2.32
0.02
161
142
46
48
4.4
6.1
160
160
19
24
1.7
2.3
1.00
1.36
0.97–1.9
0.07
117
170
31
57
4.0
5.8
114
189
10
31
1.2
2.5
1.00
1.55
1.07–2.26
0.02
222
77
69
24
5.1
5.2
239
79
26
15
1.6
2.8
1.00
1.22
0.84–1.77
0.31
214
89
64
30
4.7
6.1
208
112
26
17
1.8
2.3
1.00
1.25
0.88–1.78
0.22
260
40
62
97
77
16
12
21
4.8
7.0
3.0
3.4
284
31
62
81
40
3
3
9
2.1
1.4
0.7
1.6
1.00
1.20
1.0
1.37
0.74–1.96
0.45
0.74–2.55
0.32
IBT: ipsilateral breast tumor; XRT: radiotherapy; HR: hazard rate; RR: rate ratio; CI: confidence interval.
a
Risk of IBT for patients with category of pathologic characteristics compared with reference (baseline 1.00) (e.g., relation of moderate/marked to absent/slight comedo necrosis adjusted for treatment).
b
Macroscopic estimates.
c
Based on 302 tumors microscopically ,10 mm.
be free, i.e., not transected, central review revealed
instances in which the tumor margin was violated. In
some instances in which the margins were not inked,
their status was regarded as uncertain because it could
not be determined whether transected tumor represented “tumor” or “patient” margin. Because a preliminary investigation disclosed residual tumor in
specimens from completion lumpectomies to be similar when margins were considered uncertain or involved and there were only a few examples of the
latter, they were combined and designated as “uncertain/involved.”
Tumor size was recorded from information provided by institutional pathologists on their pathology
reports. Approximately 80% were detected mammo-
graphically without any distinctly measurable lesion.
In these instances, it was stated in the reports that
blocks were obtained from areas indicated by a guide
wire or stain. Some examples were macroscopically
measurable, particularly when $1.0 cm. This size was
considered an appropriate cutoff, and consequently
tumors were described as either $1.0 cm or ,1.0 cm.
Lesions were also measured microscopically in 553
patients as described previously,7,8 without prior
knowledge of the macroscopic estimates. The microscopic size was represented by the greatest dimension
of tumor encountered in any of the slides examined.
This included intervening normal tissue or in situ cancer when several foci were encountered in the same
section. This mimicked the method for macroscopic
432
CANCER August 1, 1999 / Volume 86 / Number 3
mensuration. There was 94% agreement between
macroscopic and microscopic sizes for tumors ,1.0
cm but only 19% for those $1.0 cm. Accordingly,
microscopic sizes were used only to delineate tumors
,10 mm and macroscopic estimates for those $10
mm. As a result, only 302 of the 553 microscopic
measurements were utilized.
The site of IBT was obtained from pertinent clinical records and compared with that recorded for the
index tumor. Because some lesions appeared to be
“on the line” of two or more quadrants or in a subareolar location, it was considered most appropriate
to regard IBTs found in the same quadrant or close to
the site of the index cancer as being at the “same” site,
as opposed to IBTs that were distinctly in a remote
quadrant, which were designated as being at a “different” site.
Microscopic sections of material from IBT was
available for central review in 90% of instances. The
type of cancer, i.e., “pure” DCIS, invasive, or that
comprised of both elements, was noted. The histologic
type of DCIS when present in IBT was compared with
that of the index lesion and designated as “same” or
“different.”
Chi-square tests were utilized for comparisons of
selected characteristics of the pathologic subset of 623
patients and the clinical cohort of 814. A log rank test9
was performed to compare the patterns of disease
outcome in these two populations.
Frequency distributions for the nine pathologic
features were compared by treatment groups using
chi-square tests of association. Average annual IBT
rates according to pathologic features were computed
as ratios of the number of events to total person-years
of observation.10 Rates were also estimated for each
follow-up year through 8 years.
The Cox proportional hazards model was used to
evaluate further the prognostic significance of each
pathologic feature in relation to risk of IBT.11,12 Tests
of interactions of each factor with treatment were
conducted to detect a differential magnitude of the
treatment benefit for XRT according to pathologic features. Variables associated with IBT at a 5 0.10 or less
in univariate analyses were evaluated jointly to determine which were independently associated with the
risk of IBT. From these models, IBT rates and the
cumulative probability of IBT were computed for each
treatment group. This provided an estimate of the
effect of treatment within each risk group. The cumulative probability of IBT, taking into account competing risks, was determined using cumulative incidence
functions.13
There have been a number of classifications of
DCIS purported to define risk groups for IBT and to
have a possible impact on the treatment of DCIS. Two
popular schemes in particular were considered for
analysis with our data. One was described in 199514
and the other the following year15 by Silverstein et al.
Our material closely conformed to the three groups of
DCIS described in their earlier publication, which represented a pathologic classification. We found 218 patients whose tumors qualified as their Group 1 because of “non-high grade” nuclei (our good nuclear
grade) and no necrosis (our absent/slight comedo necrosis). One hundred three Group 2 cases also appeared to be characterized by “non-high grade” nuclei
but with necrosis (our good nuclear grade and moderate/marked comedo necrosis). Three hundred two
cases in Group 3 had “high grade nuclei”(our poor
nuclear grade) with or without comedo necrosis, as
defined by the authors.
The second and more recent classification, designated as the Van Nuys Prognostic Index (VNPI), is
more complicated and was difficult to adapt to our
material. Our patient population contained much
fewer tumors measuring .15 mm. Further, the degree
of freedom of the margins used in the VNPI was not
required in NSABP Protocol B-17. Because of this,
adaptation of our material to this scheme might have
been regarded as arbitrary, and such analyses were
not performed.
RESULTS
The frequency of such characteristics as age, race,
tumor size, presence of lobular carcinoma in situ,
method of detection (mammographic, clinical, or
both), and disease free survival at 8 years was comparable in the pathologic subset (623) and the cohort of
814 evaluated for the recent clinical report of NSABP
Protocol B-17 published in 1998.2 The distribution of
all pathologic features except histologic tumor type
was similar in the two treatment arms. The “pure”
cribriform type was frequent and the “pure” solid
form less so in the lumpectomy-and-XRT group than
in the lumpectomy-only arm.
The cumulative frequency of IBT was 137 (22%)
for all 623 patients. Ninety-four of 303 (31%) occurred
in the lumpectomy-only group and 43 of 320 (13%) in
those also receiving XRT. The average annual hazard
rate per 100 patients for the former was 5.10 and the
latter 1.97, resulting in a relative risk of 0.39 (95% CI,
0.27– 0.56). This represented a 61% relative reduction
in IBT for patients receiving XRT (log rank test,
P , 0.0001). The time of occurrence of IBT ranged
from 2 to 123 months (median time, 36 months) after
surgery. Forty-nine percent and 17% of all IBT occurred within the first 4 years in the lumpectomy-only
and lumpectomy-and-XRT groups, respectively. The
Pathology of Intraductal Breast Carcinoma/Fisher et al.
FIGURE 1.
The biennial frequency of ipsilateral breast tumors (IBTs) is
shown.
frequency of IBT in the lumpectomy-and-XRT group
was relatively constant throughout: 17% in the first 4
years and 12% in the later periods. Sixty-seven percent
of all invasive and 72% of all noninvasive IBTs occurred in the first 4 years (Fig. 1).
The average annual hazard rates for IBT were
lower for all 9 pathologic characteristics in the
lumpectomy-and-XRT group than in the lumpectomyonly group (Table 1). The relative risks for this event,
shown in Table 1, were adjusted for treatment; they
pertained to the pathologic characteristics and not the
effects of treatment. Only moderate/marked comedo
necrosis, solid tumor type, moderate/marked lymphoid infiltrate, and multifocality were found to be
significant predictors for IBT in both treatment
groups. Uncertain/involved margins and poor nuclear
grade were borderline (0.05 , P , 0.10). The absolute
reduction in IBT due to XRT for patients with free
margins was 16% and 22% when the margins were
uncertain/involved. Only comedo necrosis exhibited a
suggestion of a differential treatment effect or interaction; the degree of benefit from XRT was less when
comedo necrosis was absent/slight than when it was
moderate/marked. The relative reduction in IBT risk
resulting from XRT when comedo necrosis was absent/slight was 48%, compared with 70% when a moderate/marked degree was present (Table 2). The differences in treatment groups at 8 years were 7% for the
low risk group and 27% for the high risk group. Thus,
absent/slight comedo necrosis might be regarded as a
low risk predictor for IBT and moderate/marked
comedo necrosis as the converse.
433
Many of these pathologic features are interrelated.
Comedo necrosis was associated with solid tumor
type, multifocality, and nuclear grade. This latter was
also interrelated with solid tumor type. Multifocality
was more frequent among patients with positive margins.
When all nine pathologic features were examined
jointly for prognostic significance, only comedo necrosis remained as a significant predictor for IBT.
When other individual characteristics that exhibited
an increased risk for IBT (a 5 0.10 or less) were assessed jointly, tumor type and multifocality were
found to be only marginally associated with IBT
(0.05 , P , 0.10).
Including degrees of comedo necrosis and status
of margins into a model with treatment failed to reveal
any significant modification of the effect of the latter
(interaction P 5 0.42). After cross-classifying categories of two features and treatment, it was observed
that patients subjected to lumpectomy whose tumors
exhibited two favorable features, such as absent/slight
comedo necrosis and free margins, had the lowest
rates of IBT (3.0 per 100 patients per year), whereas
those with both unfavorable characteristics had the
highest (8.2 per 100 patients per year). Yet those with
moderate/marked comedo necrosis and free margins
exhibited the same incidence of IBT as the group with
both unfavorable features. The incidence was intermediate when margins were uncertain/involved and
comedo necrosis absent/slight. A benefit due to XRT
was observed in each risk group. Similar results were
obtained when either multifocality or tumor type were
cross-classified with comedo necrosis. The combination of multifocality, tumor type, and status of margins
each with comedo necrosis revealed only a marginally
greater risk for each pair than comedo necrosis alone
(0.05 , P , 0.10).
Classifying our data according to the 1995 Van
Nuys pathologic classification14 revealed that both of
their Groups 2 and 3 represented high risk categories
for IBT in patients treated with lumpectomy but not
lumpectomy and XRT. All three groups had a significant benefit from the latter (Table 3).
The frequency of first events is presented in Table
4. The most frequent of these, other than IBT, was the
occurrence of contralateral breast carcinoma (4.3%)
and second primary cancers (3.2%). These second primary cancers presented at a variety of sites, including
the colon, pancreas, lung, endometrium, uterine cervix, and thyroid. There was one instance of lymphoma. There were 36 deaths among patients of this
cohort, and they were equally distributed between the
two treatment arms. Ten of these were attributable to
breast carcinoma, four in the lumpectomy-only treat-
434
CANCER August 1, 1999 / Volume 86 / Number 3
TABLE 2
Average Annual Hazard Rates per 100 Patients, Rate Ratios, and Absolute Reductions of IBT According to Comedo Necrosis and Margin Status
Lympectomy 1 XRT
Lumpectomy only
IBT
Feature
Comedo necrosis
Absent/slight
Moderate/marked
Status margins
Free
Uncertain/involved
IBT
No.
No. (%)
HR
No.
No. (%)
HR
RRa
ARe
164
139
38 (23%)
56 (40%)
3.5
7.5
178
142
23 (13%)
20 (14%)
1.8
2.1
0.52
0.30
10
26
249
54
73 (29%)
21 (39%)
4.7
7.2
267
53
34 (13%)
9 (17%)
1.9
2.5
0.40
0.36
16
22
IBT: ipsilateral breast tumor; XRT: radiotherapy; HR: hazard rate; RR: rate ratio; ARe: absolute reduction.
a
Treatment comparison among patients with the degree of pathologic features indicated (e.g., 0.52 represents relative risk for lumpectomy 1 XRT/lumpectomy among patients with absent/slight comedo necrosis
only).
TABLE 3
Analysis of NSABP B-17 Pathologic Data According to the 1995 Van Nuys Pathologic Classification
Lumpectomy 1 XRT
Lumpectomy
IBT
IBT
Group
No.
No.
%
HRa
No.
No.
%
HRa
RRb
95% CI
1. NG* good 1 absent/slight necrosis
2. NG good 1 moderate/marked necrosis
3. NG poor 1 any degree of necrosis
105
56
142
25
21
48
24
38
34
3.5
6.4
6.1
113
47
160
12
7
24
11
15
15
1.5
2.2
2.3
0.42
0.35
0.38
0.21–0.83
0.15–0.81
0.24–0.63
XRT: radiotherapy; IBT: ipsilateral breast tumor; HR: hazard ratio; RR: risk ratio; CI: confidence interval.
a
Average annual hazard rate/100 patients.
b
Rate ratio (lumpectomy 1 XRT/lumpectomy) within the risk group.
ment arm and six in the lumpectomy-and-XRT arm.
Only two in each group had prior IBT. There were no
statistically significant differences in the incidences of
these events other than IBT in the two treatment arms.
Eighty-four (61%) of the 137 IBTs were “pure”
DCIS (Table 5). The remainder were either a combination of the latter and invasive cancer (26%) or
“pure” invasive cancer (13%). The presence of invasive
IBT was not specifically associated with any pathologic feature of the index DCIS. The relative and absolute reductions for the IBT comprised of invasive
cancer after XRT were not significantly different from
the reductions observed for all IBTs according to degree of comedo necrosis or margin status noted in
Table 2. The percentages of types of IBT were not
influenced by treatment. Seventy-six percent of all
IBTs were found to be at the same site as the index
DCIS. Although this difference was not statistically
significant, the invasive form of IBT occurred at different sites more frequently than the noninvasive type.
The DCIS component in 90% of IBTs was morpholog-
ically similar to that of the index lesion. The average
size of IBT containing invasive cancer was 1.3 cm
(range, 0.3– 4.5 cm). Fifty percent were #1.0 cm.
None of the 24 instances of DCIS that were independently associated with LCIS or noted to arise in
fibroadenoma (2) or that presented as intracystic DCIS
(6) have as yet been followed by an IBT.
DISCUSSION
The increase in the cumulative incidence of IBT in
both treatment arms at 8 years, shown in Figures 2
and 3, closely mimicked that observed in our recent
clinical report. We did not observe any increase in
these events, particularly in the lumpectomy-and-XRT
group, over later years of follow-up. These observations fail to support the notion that XRT might only
delay the occurrence of IBT following lumpectomy.16
A recent review concerning the pathology of DCIS
emphasized that tumor size, status of margins, and
histologic tumor type represent the most important
characteristics related to what the authors refer to as
Pathology of Intraductal Breast Carcinoma/Fisher et al.
435
TABLE 4
Frequency of Events after DCIS According to Treatment
Lumpectomy 1
XRT
Lumpectomy
First events
IBT
Other logoregional
Distant
Contralateral breast carcinoma
Second primary cancer
Deaths
Other causes
Breast carcinoma
All patients
No.
%
No.
%
No.
%
94
1
3
10
10
31.0
0.3
1.0
3.0
3.0
43
3
2
17
10
13.0
0.9
0.8
5.0
3.0
137
4
5
27
20
22
0.6
0.8
4.3
3.2
14
4a
2.0
1.0
12
6a
2.0
2.0
26
10
4.2
1.6
DCIS: ductal carcinoma in situ; XRT: radiotherapy; IBT: ipsilateral breast tumor.
a
Two had prior IBTs.
TABLE 5
Frequency of Types of IBT According to Treatment
Lumpectomy
Lumpectomy 1 XRT
All patients
Type
No.
%
No.
%
No.
%
Pure DCIS
DCIS 1 invasive
Pure invasive
57
26 37a
11
61
28 40
12
27
9 16
7
63
21 37
16
84
35 53
18
61
26 39
13
94
43
137
IBT: ipsilateral breast tumor; XRT: radiotherapy; DCIS: ductal carcinoma in situ.
a
Combined to represent invasive cancer.
the “control of DCIS” after conservation therapy.17
However, histologic type is rarely included in such
evaluations, and then generally refers only to comedo
and noncomedo types of DCIS. Most investigators
have thus far regarded comedo necrosis as an independent pathologic variable rather than a specific histologic type, a view expressed by us more than a
decade previously.4 The authors of the review also
indicate that most classifications of DCIS, of which we
have found at least eight,5,6,17–23 have utilized nuclear
differentiation, presence or absence of necrosis (apparently delineating between a comedo type and another ill-defined form simply referred to as “necrosis”), and growth pattern. In any event, nosologically,
these characteristics are presented individually or in
groups of varying numbers. Tumor size and status of
margins appear in only a few,6,19 and in those they are
also incorporated with other features, resulting in a
complex categorization. One group of investigators
expanded their classification within l year.5,6 This brief
overview reflects the lack of unanimity and consternation attendant with efforts to classify DCIS. This
difficulty is further compounded by the sparsity of
studies revealing their biologic significance vis-à-vis
the actual development of IBT as well as the natural
history and treatment of DCIS. Some of those that
have been correlated with IBT reveal contradictions.6,19 It is not surprising that a recent panel concerned with these issues failed to endorse any particular algorithm that might be predictive for IBT.24
Classifying our material according to the criteria
of the Van Nuys pathologic method described in 19955
failed to reveal complete agreement regarding predictive value for IBT or response to XRT in the 3 groups
they evaluated. When their method of stratification
was applied to our material, it revealed only two,
rather than three, predictive groups for IBT. Furthermore, XRT was found to be of benefit to all patient
subgroups (rather than just one, as noted by those
investigators14). Our findings also indicate that estimation of comedo necrosis alone might have provided
similar results in their analyses. This is in accord with
the association between comedo necrosis and nuclear
grade observed in this study. Yet only the former was
436
CANCER August 1, 1999 / Volume 86 / Number 3
FIGURE 2.
The cumulative incidence of ipsilateral breast tumors (IBTs) is
shown according to comedo necrosis and treatment.
FIGURE 3.
The cumulative incidence of ipsilateral breast tumors (IBTs) is
shown according to margin status and treatment.
found to be an independent predictor for IBT. The
basis of this dichotomy is unclear. However, the sample sizes utilized in the Van Nuys presentation were
relatively small, and some possibly important statistical analyses were either not available for review or not
performed.
Recent efforts to define the extent of free margins
necessary to minimize or prevent the development of
IBT without the administration of XRT might appear
to render moot both the simple and the complex
pathologic classifications purported for this purpose.
However, there is currently no unanimity regarding
the best way to demonstrate margin status, let alone
regarding how free it should be to accomplish this.25
Unfortunately, most information regarding an optimum extent of excision is derived from estimates of
residual disease in mastectomy specimens or in the
tissue of completion lumpectomies following removal
of DCIS. These have revealed residual disease ranging
from 19% to 43% for free margins ,1 mm,26,27 and an
optimum width for possibly avoiding IBT has been
variably suggested to be 5 mm28 or 10 mm.29 –31 There
were 243 two- and three-step procedures performed
in this study that allowed for estimation of residual
disease. The presence of the latter was found in 25% of
instances in which the margins were free, and there
was no quid pro quo relation between the detection of
residual disease in anatomic specimens and IBT, the
latter being much less than expected not only for DCIS
but also for invasive cancer.32 Further, IBT was not
found to be related to the various treatments administered to our cohort. It remains to be demonstrated
whether a 10 mm margin is sufficient or necessary for
the omission of XRT as prophylaxis against IBT.
Our own material offers no information concerning an optimum width, because this protocol, like
other NSABP protocols that utilize lumpectomy, requires only enough tissue to ensure complete removal
with a satisfactory cosmetic result. Pathologically,
margins are regarded as free when the tumor is not
transected, and no quantitative width is prescribed.
Yet, despite claims that the width of margins utilized
by the NSABP may be inadequate,27,33 the annual rate
of incidence of IBT ('4%) in our cohort of women
who did not receive XRT was almost identical to the
rates reported by others for nonrandomized studies in
which follow-up was even shorter, as was reported by
Marks and Prosnitz.4 Also, the rate of overall incidence
of IBT following lumpectomy and XRT was also similar
to the rates in 2 other studies, each of which contained
more than 100 cases and a 7-year follow-up period
(13% vs. 9%33 and 10%34).
Even more important in this regard, and unlike
our earlier pathologic analyses of protocol B-17,3 uncertain/involved or free margins were not independent high or low risk predictors of IBT at the eighth
year of follow-up; they were only borderline for this
latter period. The biologic implication of this inconsistency is unclear, but it may be related to the predominantly early appearance of IBT in our cohort. In
our experience, changes in the significance of prognostic discriminants occasionally occur, e.g., tumor
necrosis represents a prognostic indicator for invasive
cancer at 5 years but not at 10 years.35 Although margin status was found to be borderline as a predictor for
IBT, it does exhibit some additional but slight effect in
this regard when examined together with comedo necrosis. Despite this limited effect at 8 years, its early
importance signifies the need for histologically free
margins in the treatment of DCIS patients with
lumpectomy.
Tumor size is another important factor that might
be expected to be related to the extent of tumor excision and IBT. Indeed, one might consider one of the
important attributes of mammography to be its ability
Pathology of Intraductal Breast Carcinoma/Fisher et al.
to detect truly small (,10 mm) tumors, allowing for
wide excision without compromising cosmesis. Yet we
continue to fail to discern any significant or consistent
relation between tumor size and IBT, whether assessed macroscopically or microscopically with cutoff
points of 10 mm or even 5 mm. Furthermore, tumors
of all sizes according to our groupings exhibit a beneficial effect of XRT. This suggests that even very small
foci of DCIS may represent a marker of risk for subsequent IBT, in keeping with the recognized multifocality of DCIS (vide infra), as we have suggested previously.7,8 The appearance of the majority of IBTs at or
close to the site of the index cancer, as well as the
discovery that the histologic identity of the DCIS component of the IBT (when present) is the same as that of
the index cancer in 90% of instances, also confirms
our view that most IBTs following DCIS—as well as
some invasive cancers—represent residual disease or
incomplete removal of the index lesion.3,7,8 In this
light, IBT is not necessarily related to any surgical
inadequacy per se, but is instead more closely related
to the multifocal nature of DCIS (multiple foci of tumor within the same quadrant or close to the index
lesion32), which cannot be perceived at the time of
surgery.
One of the conundrums related to DCIS is the
origin and biologic nature of the invasive cancer,
which we have encountered in '40% of IBTs. Such
invasive cancers, found alone or with DCIS in some
IBTs, are conventionally considered to arise from preexisting DCIS. However, there is no unequivocal evidence to support such a contention. Our recognition
of a trend revealing a higher incidence of invasive IBT
at sites different from the index lesion strongly suggests that at least some may arise de novo or not
necessarily from preexisting DCIS. Despite the relatively high incidence of invasive cancer in IBT following DCIS, as well as in 11 of 21 (52%) of the contralateral breast carcinomas associated with ipsilateral
DCIS, we continue to find the rate of death related to
breast carcinoma to be exceedingly low; overall, it is
only 1.6% at 8 years. This event showed no predilection for either treatment group, and it was preceded
by an IBT in one-half of the deaths in the lumpectomy-only group and one-third of the deaths in the
lumpectomy-and-XRT group. One apparent reason for
this dichotomy in mortality may be the very good
prognosis associated with the small size of the recurrent invasive cancers detected in our material. Our
analyses continue to reveal an overall benefit for XRT
in reducing IBTs for all patients. In the low risk group,
the 59% relative risk reduction provided a 7% absolute
difference in IBT at 8 years. This estimate is more than
twice that noted in our previous pathologic report
437
concerning IBT at 4-1/2; years.3 The decision to forgo
XRT in the treatment of DCIS patients would now
appear to depend on clinical considerations, such as
patient age, health, and informed patient input, rather
than standard practice.
It is surprising that despite the long-standing recognition and importance of comedo necrosis in DCIS,
there is little or no consistent information concerning
its pathogenesis. It has been found to be associated
with cells exhibiting either high or low proliferative
rates.36 Its relation to the identification of such biologic markers as c-erb B-2, p 53, and hormone receptors is unclear.23,37 Although some32 have observed an
increased frequency of vascularity in its vicinity, suggesting a relation to angiogenesis factor,38 others have
not confirmed this observation.39 One might hypothesize that if comedo necrosis were related to a vascular
phenomenon, the contrary or vascular obliteration
would be a more likely cause. Recognition of “regressive” changes associated with comedo necrosis3,7–9
resulting in scars is in keeping with such a suggestion.
Yet the association of such a vascular change with
comedo necrosis has apparently not been noted.
Finally, as emphasized in our most recent clinical
report,2 there is no information provided in these
analyses to support the need for mastectomy among
patients with DCIS, at least among those who exhibit
the characteristics of the women who comprised this
cohort.
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