Predictors of residual invasive disease after core needle biopsy diagnosis of ductal carcinoma in situ.

Abstract

Core needle biopsy (CNB) is used to sample both mammographically and ultrasound detected breast lesions. A diagnosis of ductal carcinoma in situ (DCIS) by CNB does not ensure the absence of invasive cancer upon surgical excision and as a result an upstaged patient may need to undergo additional surgery for axillary nodal evaluation. This study evaluates the accuracy of CNB in excluding invasive disease and the preoperative features that predict upstaging of DCIS to invasive breast cancer. Two hundred fifty-four patients over an 8-year period from 1994 to 2002 with a diagnosis of DCIS alone by CNB were retrospectively reviewed. Underestimation of invasive cancer by CNB was determined. Radiographic, pathologic, and surgical features of the cohort were compared using univariate and multivariate analysis. The mean age was 55 years (range 27-84) and mean follow-up was 25 months with one patient unavailable for follow-up. There were a total of six patient deaths, all of which were not disease-specific. A total of 21 out of 254 patients (8%) with DCIS by CNB were upstaged to invasive cancer following surgical excision. There was a significant inverse relationship between the number of core biopsies and the incidence of upstaging (p < 0.006) in that patients with fewer core samples were more likely to be upstaged at surgical pathology. No relationship was noted between the size of the core samples and the likelihood of upstaging (p > 0.4). Of 21 patients with invasion, all but two had comedonecrosis by CNB. Comedonecrosis by CNB significantly increased the likelihood of upstaging (p < 0.001). Of the 21 patients who were upstaged, 12 required subsequent surgery for nodal evaluation while nine had sentinel node biopsy at initial operation. Finally, upstaged patients were significantly more likely to have a positive margin (p < 0.008). Ductal carcinoma in situ with comedonecrosis on CNB can help to predict the possibility of invasion. Increasing the number of core biopsies reduced the likelihood of sampling error.

Full text

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ORIGINAL ARTICLE
Predictors of Residual Invasive Disease after Core
Needle Biopsy Diagnosis of Ductal Carcinoma In Situ
Lisa A. Rutstein, MD,* Ronald R. Johnson, MD,†William R. Poller, MD,
FACR,‡David Dabbs, MD,§Jan Groblewski, BS,–Tina Rakitt, BS,–Allan
Tsung, MD,** Thomas Kirchner, BA,††Jules Sumkin, DO,‡‡Donald Keenan,
MD, PhD,†Atilla Soran, MD, MPH,†Gretchen Ahrendt, MD,†and Jeffrey S.
Falk, MD,†
*Maine Medical Center, Portland, Maine 04102;†Department of Surgical Oncology, University of
Pittsburgh Medical Center, Magee-Womens Hospital, Pittsburgh, Pennsylvania;‡Allegheny General
Hospital, Cancer Center, Pittsburgh, Pennsylvania;§Department of Pathology, University of Pittsburgh
Medical Center, Magee-Womens Hospital, Pittsburgh, Pennsylvania;–Office of Student Affairs,
University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; **General Surgery Resident,
Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania;
††Department of Psychology, University of Pittsburgh, Pittsburgh, Pennsylvania;‡‡Department of
Radiology, University of Pittsburgh Medical Center, Magee-Womens Hospital, Pittsburgh,
Pennsylvania
n
lesions. A diagnosis of ductal carcinoma in situ (DCIS) by CNB does not ensure the absence of invasive cancer upon surgi-
cal excision and as a result an upstaged patient may need to undergo additional surgery for axillary nodal evaluation. This
study evaluates the accuracy of CNB in excluding invasive disease and the preoperative features that predict upstaging of
DCIS to invasive breast cancer. Two hundred fifty-four patients over an 8-year period from 1994 to 2002 with a diagnosis
of DCIS alone by CNB were retrospectively reviewed. Underestimation of invasive cancer by CNB was determined. Radio-
graphic, pathologic, and surgical features of the cohort were compared using univariate and multivariate analysis. The mean
age was 55 years (range 27–84) and mean follow-up was 25 months with one patient unavailable for follow-up. There were
a total of six patient deaths, all of which were not disease-specific. A total of 21 out of 254 patients (8%) with DCIS by CNB
were upstaged to invasive cancer following surgical excision. There was a significant inverse relationship between the num-
ber of core biopsies and the incidence of upstaging (p < 0.006) in that patients with fewer core samples were more likely to
be upstaged at surgical pathology. No relationship was noted between the size of the core samples and the likelihood of
upstaging (p > 0.4). Of 21 patients with invasion, all but two had comedonecrosis by CNB. Comedonecrosis by CNB signifi-
cantly increased the likelihood of upstaging (p < 0.001). Of the 21 patients who were upstaged, 12 required subsequent sur-
gery for nodal evaluation while nine had sentinel node biopsy at initial operation. Finally, upstaged patients were
significantly more likely to have a positive margin (p < 0.008). Ductal carcinoma in situ with comedonecrosis on CNB can
help to predict the possibility of invasion. Increasing the number of core biopsies reduced the likelihood of sampling error. n
Key Words:core needle biopsy, ductal carcinoma in situ, upstaging
Abstract: Core needle biopsy (CNB) is used to sample both mammographically and ultrasound detected breast
T
stage definitive surgery. Patients with noninvasive
breast cancer on CNB will need to return for axillary
he goal of percutaneous breast core needle biopsy
(CNB) is to allow accurate planning of a single
staging if unsuspected invasive disease is identified.
Therefore, it is critical to accurately identify invasive
disease if present. Prior to the utilization of CNB,
patients with a suspicious breast lesion on either a
mammogram or an ultrasound underwent an open
excisional breast biopsy. With the advent of CNB, a
histologic diagnosis can be achieved utilizing a min-
imally invasive approach for most cases. However, it
has been shown in prior studies that a CNB diagnosis
of ductal carcinoma in situ (DCIS) does not guarantee
Address correspondence and reprint requests to: Jeffrey S. Falk, MD,
Department of Surgical Oncology, University of Pittsburgh Medical Center,
Magee-Womens Hospital, 300 Halket Street Pittsburgh, Pennsylvania
15213, USA or e-mail: jfalk@mail.magee.edu
ª 2007 Blackwell Publishing, Inc., 1075-122X/07
The Breast Journal, Volume 13 Number 3, 2007 251–257

Page 2

the absence of invasive cancer. In reviewing the
current literature, on average, 20% of patients diag-
nosed by CNB with DCIS are upstaged to invasive
carcinoma following surgical excision (Table 1).
Patients who are understaged at CNB may need to
undergo additionalsurgical
increasing both risk and cost. Identifying factors asso-
ciated with a high probability of finding invasive can-
cer at the time of surgical excision would allow for
the patient to be offered axillary sentinel lymph node
biopsy at the time of their lumpectomy.
Over the 8-year study period, the total number of
CNB performed at our institution for all breast lesions
increased each year with the highest total, 1664 CNB
performed in 2002. In 2002, 877 (53%) CNB were
ultrasound guided and 787 (47%) were obtained by
mammography-guidedstereotactic CNB
Patient data were retrospectively reviewed to assess
the diagnostic ability of CNB. The aim of this study
was to identify patient, imaging, or pathology factors
which would predict upstaging to invasive breast car-
cinoma after a CNB diagnosis of DCIS.
procedures thereby
technique.
MATERIALS AND METHODS
A retrospective review of patients who presented to
Magee-Womens Hospital between 1994 and 2002, and
then had a CNB with a pathologic diagnosis of DCIS
was conducted. After University of Pittsburgh IRB study
approval, the data from 254 consecutive patients were
obtained from the Magee-Womens Hospital Breast
Tumor Registry, office charts, and hospital records.
All mammography was performed or reviewed at
our institution by dedicated, fellowship-trained breast
radiologists who performed additional imaging when
appropriate prior to performing all CNB at Magee.
All core specimens were read by inhouse dedicated
breast pathologist using both hematoxylin and eosin
staining and immunohistochemistry as indicated.
For mammographically detected lesions, 88% of the
CNB were performed using a 11-gauge Mammotome
stereotactic device (Ethicon, Cincinnati, OH). The most
often used protocol involved the acquisition of 12 indi-
vidual cores at biopsy and radiographs of the core spec-
imensto confirm thepresence
microcalcifications. For lesions amenable to ultra-
sound-guided biopsy, a handheld, spring-loaded 14-
gauge Bard core biopsy device was used. Typically, 3–5
cores were taken at the time of each ultrasound guided
CNB which accounted for 12% of the biopsies per-
formed at Magee-Womens Hospital for DCIS over the
study time period.
Multiple potential variables were assessed inclu-
ding: patient characteristics (age, history of breast
pathology, and laterality of disease); imaging charac-
teristics (presence of mass or calcification, biopsy tech-
ofthe targeted
Table 1. Reported Upstaging Rates 1994–2005
AuthorYearBiopsy TypeTotal Number of CasesTotal Number Upstaged at SurgeryPercent Upstaged
Jackman et al. (1)
Liberman et al. (24)
Acheson et al. (25)
Burbank (5)
Fuhrman et al. (3)
Liberman et al. (7)
Jackman et al. (26)
Liberman et al. (27)
Meyer et al. (28)
Won et al. (29)
Burak et al. (30)
Darling et al. (31)
1994
1995
1997
1997
1998
1998
1999
1999
1999
1999
2000
2000
S LCNB
SCNB
LCNB
Automated Needle
IG CNB
S 11-G VA
14-G S
S 11-G VA
LCNB
Automated Gun
S VA
Automated 14-G, 14-G directional VA,
and 11-G VA
SCNB
14-G LCNB
IG CNB
SCNB
CNB
CNB
11-G VA CNB
CNB
CNB
43
15
54
55
84
21
54
28
8
3
19
20
19
16
36
10
9
30
1
8
4
5
15
14
15
35
11
14
133
20
89
289
20
7
10
40
Lee et al. (32)
Jackman et al. (9)
King et al. (33)
Mendez et al. (34)
Wahedna et al. (35)
Renshaw (36)
Pandelidis et al. (37)
Yen et al. (23)
Rutstein et al.
Total
2000
2001
2001
2001
2001
2002
2003
2005
2003
5917
76
36
21
61
17
12
80
21
29
20
26
27
44
19
13
20
373
140
77
140
91
91
398
254
2508
8
491 20
CNB, core needle biopsy; LCNB, large core needle biopsy; SCNB, stereotactic core needle biopsy; VA, vacuum assisted; IG, Image-guided; S, stereotactic; G, gauge.
252 • rutstein et al.

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nique, stereotactic or ultrasound guidance, and size of
mammographic lesion[s]); and pathology characteris-
tics (number of core biopsies, size of core biopsies,
and core biopsy pathology (comedonecrosis versus
noncomedonecrosis), operative procedure, final surgi-
cal pathology, and margin status. All data points were
analyzed using the SAS statistical system. Contigency
tables were analyzed using the chi-squared and Fish-
er’s exact tests. Statistical significance was accepted if
the p-value was equal to or less than 0.05.
RESULTS
A total of 254 patients had a CNB revealing a patho-
logic diagnosis of DCIS without evidence of invasion.
The mean age of these patients was 55 years with a
range of 27–84 years of age. Of the 254 patient cohort,
only one patient was lost to follow-up. About 66% of
the patient population reported no history of prolifera-
tive breast lesions, atypia, or breast malignancy while
29% reported a prior diagnosis of either atypical ductal
hyperplasia or atypical lobular hyperplasia. One patient
had a history of LCIS and four patients (2%) had
undergone prior treatment for a diagnosis of DCIS.
The remaining nine patients (3%) had a history of
invasive carcinoma (Table 2). The initial imaging
abnormality detected was microcalcifications in 209
patients and a radiographic breast mass⁄nodule in 44
patients (Table 3). Mammographic stereotactic CNB
was utilized in 88% of the cohort while the remaining
12% of patients had an ultrasound-guided CNB. An
overview of surgical characteristics is presented in
Table 4. The majority of patients underwent segmen-
tal mastectomy (82% or 209 patients). The remainder
of the group underwent either a unilateral or bilateral
mastectomy (18%).
There were 137 (54%) of the 254 patients with
DCIS who had comedonecrosis at CNB. A total of 21
out of 254 patients (8%) with DCIS by CNB were
upstaged to invasive cancer and of these 21 patients,
19 had comedonecrosis at CNB. Six patients were
diagnosed with microinvasion and 15 patients were
found to have larger areas (>1 mm) of invasive disease
(Table 6). A pathologic finding of comedonecrosis on
CNB significantly increased the likelihood of up-
staging at surgical resection (p < 0.001).
Table 2. Demographic Characteristics of 254 Pati-
ents with DCIS
Characteristic Number of PatientsPercentage of Sample
Ethnicity
Caucasian
African-American
Unknown
History of proliferative
breast lesions
No history
Atypia
LCIS
DCIS
Invasive Cancer
Age
Mean (years)
Range (years)
24195
7
6
3
2
167
73
66
28
1
4
9
1
2
3
55 ± 11
27–84
Table 3. Diagnostic Characteristics
Characteristic Number of PatientsPercentage of Sample
Laterality
Right
Left
Both
Calcifications
Tumor mass
Without calcification
With calcification
Number of lesions
1
2
3
4
5
Core needle biopsy method
Stereotactic
Ultrasound
Unknown
Core pathology
Comedo
Noncomedo
Unknown
139
114
55
45
10
209 83
16
28
6
11
197
44
79
18
7
1
1
3
0
0
224
29
88
12
1
137
86
31
61
39
Table 4. Surgical Characteristics
Characteristic Number of PatientsPercentage of Sample
Type of operation
Segmentectomy
Mastectomy
Bilateral mastectomy
Pathology after surgical excision
DCIS
Microinvasion
Invasion
Other
Margin status
Negative
Positive
Unknown
Upstaging
None
Microinvasion
Invasion
209
39
82
15
63
226 89
62
6
3
15
7
227
24
90
10
3
23392
62
615
Predictors of Residual Invasive Disease after Core Needle Biopsy Diagnosis of Ductal Carcinoma In Situ • 253

Page 4

The number of core needle samples and the size of
the CNB samples were also examined. There were 200
patients (89%) who had between 1 and 12 core biopsy
specimens taken at CNB. Although the most common
practice at our institution when performing mammo-
graphic-guided stereotactic CNB is to obtain 12 core
specimens, it was at the radiologists’ discretion as to
how many cores were an adequate sampling of the
breast lesion being biopsied. When examining the 21
patients found to have invasive breast cancer, there was
a significant inverse relationship between the number of
core samples obtained and the risk of upstaging with less
core biopsies leading to a greater likelihood of upstaging
(p < 0.006). In particular, 11 of these 21 patients had
less than 12 cores, six had 12 cores, and only four
patients had more than 12 cores. The core specimen
sizes ranged from 11 to 14 gauge. The relationship
between core size and the incidence of upstaging did not
reach statistical significance in our series (p > 0.4).
Patients who presented with a radiographic mass as
compared with those with presenting with microcalci-
fications alone showed no significant difference in
upstaging (p > 0.6). Of the 21 patients who were
upstaged, 12 required subsequent surgery for nodal
evaluation while nine patients already had undergone
a sentinel node biopsy procedure at the time of their
initial operation.
A total of 24 patients (9%) had an initially positive
margin after pathologic analysis. The incidence of a
positive margin after surgical excision for the patients
who were upstaged was 5 of 21 patients (24%)
(Table 6) compared with 19 of 230 (8%) for those
who were not upstaged. Therefore, upstaged patients
were significantly more likely to have a positive mar-
gin (p < 0.008).
There were a total of six patient deaths, all of
which were not disease-specific. With respect to indi-
vidual patient outcomes, four patients had an ipsi-
lateral recurrence(2%)
contralateral breast cancer event (5%).
and12patients hada
DISCUSSION
Core needle biopsy has evolved as a minimally inva-
sive alternative to open surgical biopsy for the evalua-
tionof suspiciousbreast
mammography or ultrasound. A recognized limitation
of CNB is the possibility of a sampling error. The
ability to preoperatively differentiate those patients
with invasive breast cancer form those with non-
invasive disease allows for sentinel lymph node map-
ping and axillary staging to be performed at the time
of the initial surgical procedure. When the diagnosis
of DCIS was obtained by core needle biopsy, there
has always been some degree of understaging. Review
of the literature since 1994 demonstrates that up to
40% of patients with a core biopsy diagnosis of DCIS
will be found to have invasive carcinoma after com-
plete surgical excision and subsequently require a sec-
ond surgical procedure to evaluate the axilla (1–3).
Our study specifically examines 254 patients with an
initial histologic diagnosis of DCIS to assess both the
ability of CNB to exclude invasive disease as well as
to determine which preoperative factors might predict
the upstaging of DCIS to invasive carcinoma.
In our series, CNB predicted the absence of inva-
sion in 92% (233 of 254) of the cases. Our results
compared with other published work have shown
upstaging to range from 5% to 44%. This literature
review is summarized in Table 1 and shows a cumula-
tive mean upstaging rate of 20 percent.
Many breast cancers have both intraductal and
infiltrating components. It is not surprising that stereo-
tactic or ultrasound-guided CNB techniques may
result in small areas of invasion being missed given
that the total volume of tissue sampled by CNB is
smaller than that sampled surgically. It has been
argued that by increasing the number and⁄or size of
core samples (10 or more per lesion) a higher level of
diagnostic accuracy can be achieved (4). It was surpri-
sing in our data that larger core samples did not lead
to a decrease in upstaging following CNB. We expec-
lesionsdetected by
Table 5. Initial Margin Status and Diagnosis Change
Diagnosis ChangeNegative MarginPositive Margin
No upstaging
Microinvasion
Invasion
Microinvasion + Invasion
Total
211 19 (8%)
2
3
5 (24%)
4
12
16
Note: Frequency missing = 3; p = 0.03.
Table 6. Comedonecrosis and Diagnosis Change
Diagnosis ChangeComedonecrosis Noncomedonecrosis
No upstaging
Microinvasion
Invasion
Microinvasion + Invasion
Total
11885
51
1
2
14
19
Note: Frequency Missing = 31; p = 0.002.
254 • rutstein et al.

Page 5

ted less upstaging with larger core specimen size as a
result of the greater amount of tissue sampled when
compared with the smaller core sizes. Recent reports
of experience with the vacuum-assisted directional
probe for performing CNB have shown a higher
degree of concordance between the results of the core
biopsy specimens and the final surgical histopathologic
diagnosis in cases of pure DCIS (5,6). Liberman et al.
(7), and Heywang-Kobrunner et al. (8) have reported
their experiences with vacuum-assisted needle devices
and note a marked drop in their rates of upstaging
from noninvasive to invasive breast carcinoma due
largely to increased specimen volume. Jackman et al.
found that DCIS underestimation was 1.8 times more
likely with a large core device than with a vacuum-
assisted device, and 1.5 times more likely if the num-
ber of specimens obtained per lesion was 10 or fewer
compared with greater than 10 specimens (9).
Our results confirm a decreased incidence of up-
staging as the number of CNB increases. However,
although we did see a trend between increasing size of
core specimens and a lower rate of upstaging, this did
not reach statistical significance (p > 0.4). It is possible
that increasing the number of cores as opposed to
increasing the size of the cores is more likely to reduce
upstaging. This may be because different areas of a
breast lesion are sampled with the taking of more cores
as contrasted to the taking of greater volumes of tissue
at the same and fewer sites by increasing core size.
In patients undergoing screening mammography,
DCIS accounts for 15% to 20% of all detected can-
cers, yet it is seen in 40% to 50% of biopsies per-
formed for suspicious calcifications (10–12). The most
common presentation of DCIS is clustered microcalci-
fications. Other less common findings include presen-
tationasasoft tissue
calcifications or as a noncalcified abnormality (13,14).
In our series, 209 patients (82%) presented with
microcalcifications and 44 (17%) demonstrated a
tumor mass on initial evaluation.
Of the patients who presented with a tumor mass,
approximately two thirds had associated microcalcifi-
cations while the remaining one third had no calcifica-
tions detected. It was surprising to discover that no
differences were seen in the rate of upstaging follow-
ing CNB whether a patient presented with a mass or
microcalcifications(p > 0.6). Prior studies such as that
reported by Fuhrman et al. concluded that the pres-
ence of a mass on breast imaging was a significant
predictor for the presence of invasion (15).
masswith associated
Various histologic factors are reportedly associated
with a higher likelihood of occult invasion in associ-
ation with DCIS including high nuclear grade, comedo
subtype and large size (16–19). It is known that
comedonecrosis can be seen in lower nuclear grades as
well. Unfortunately, over the time period of this study,
nuclear grade was not routinely reported for all cases
ductal carcinoma in situ and as a result is not avail-
able. Comedonecrosis and⁄or high nuclear grade in
particular has been shown to be a significant marker
for microinvasion, local recurrence and progression to
invasive cancer (19–22). Patchefsky et al. (18) found
that 42% (eight of 19) of in situ tumors with comedo-
necrosis showed microinvasion. Fuhrman et al. (15)
found that more patients with a final diagnosis of
invasive cancer demonstrated high nuclear grade DCIS
(28% versus 14%) and comedo-type necrosis (44%
versus 31%) on core biopsy. Our results support the
finding that comedonecrosis when identified by CNB
significantly increased the likelihood of upstaging to
invasive cancer at surgical resection (p < 0.001). Of
21 patients with invasion, all but two had comedone-
crosis by CNB. The histologic finding of comedone-
crosis can therefore be used to help to identify
potential cases of invasive cancer likely to be under-
estimated as DCIS by core needle biopsy.
Our studyresults demonstrated
upstaged from DCIS to invasive cancer were signifi-
cantlymore likely to
(p < 0.008). The incidence of a positive margin was
24% for patients with invasive carcinoma compared
with 8% for those patients who were not upstaged.
In summary, this single institution, large series of
patients demonstrates the ability of image-guided CNB
to exclude invasive malignancy in greater than 90% of
patients with a diagnosis of DCIS after CNB. To poten-
tially avoid additional procedures, accurate staging at
CNB allows for the surgical management of the axilla
(sentinel node biopsy) at the time the lumpectomy is
initially performed. By analyzing the data of 254
women with DCIS by CNB, we have been able to iden-
tify factors which help to predict the upstaging of DCIS
to invasive carcinoma. DCIS with comedonecrosis by
CNB correlates with the finding of invasive carcinoma
in the final surgical specimen. We found that other fac-
tors thought to be predictive of occult invasion such as
mass versus calcification at presentation do not corre-
late with the presence of invasive tumor. In addition,
the acquisition of multiple core specimens optimizes
the chance that the pathologic findings in the core
thatpatients
haveapositive margin
Predictors of Residual Invasive Disease after Core Needle Biopsy Diagnosis of Ductal Carcinoma In Situ • 255

Page 6

biopsy specimens accurately reflect the pathologic pro-
cess in the breast. Our data suggest that a patient with
DCIS and comedonecrosis could be considered for sen-
tinel lymph node biopsy at the time of definitive sur-
gery. In addition to comedonecrosis, Yen et al. at
MD Anderson Cancer Center also found that young
age (less than 56), high grade DCIS, and mammo-
graphic DCIS > 4 cm may predict a higher likelihood
of upstaging at surgery (23). Future studies directed at
identifying patients at sufficient elevated risk for upsta-
ging following CNB would be reasonable to allow syn-
chronous axillary staging in that subset of patients.
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