The n e w e ng l a n d j o u r na l
case records of the massachusetts general hospital
From the Department of Surgery, Memo-
rial Sloan-Kettering Cancer Center, and
the Department of Surgery, Weill Cornell
Medical College — both in New York
(M.M.); and the Departments of Surgery
(J.M.W.), Radiology (P.E.F.), and Patholo-
gy (J.H.E.), Massachusetts General Hos-
pital; and the Departments of Surgery
(J.M.W.), Radiology (P.E.F.), and Pathol-
ogy (J.H.E.), Harvard Medical School —
both in Boston.
N Engl J Med 2013;368:1046-53.
DOI: 10.1056/NEJMcpc1214221
Copyright © 2013 Massachusetts Medical Society.
1046
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of m e dic i n e
Founded by Richard C. Cabot
Nancy Lee Harris, m.d., Editor Eric S. Rosenberg, m.d., Editor
Jo-Anne O. Shepard, m.d., Associate Editor Alice M. Cort, m.d., Associate Editor
Sally H. Ebeling, Assistant Editor Emily K. McDonald, Assistant Editor
Case 8-2013: A 48-Year-Old Woman
with Carcinoma In Situ of the Breast
Monica Morrow, M.D., Jonathan M. Winograd, M.D., Phoebe E. Freer, M.D.,
and John H. Eichhorn, M.D.
PR E SEN TAT ION OF C A SE
Dr. Michele A. Gadd (Surgical Oncology): A 48-year-old woman was seen in the outpa-
tient cancer center of this hospital because of carcinoma in situ of the left breast.
Eighteen days earlier, routine annual combination digital mammography and
tomosynthesis (three-dimensional mammography) of both breasts revealed hetero-
geneously dense breasts, with focal asymmetry in the left breast, seen only on the
tomosynthesis image. Nine days later, dedicated mammography of the left breast
without tomosynthesis did not reveal the lesion. Ultrasonography of the left breast
revealed a hypoechoic area of architectural distortion at the 12 o’clock position,
which was correlated with the finding on tomosynthesis. The next day, an ultra-
sound-guided core biopsy of the solid mass in the left breast was performed and
a clip placed. Pathological examination of the specimen revealed carcinoma in situ
with mixed ductal and lobular features. The tumor cells were positive for estrogen-
receptor and progesterone-receptor proteins.
On evaluation in the cancer center, the patient reported general good health.
She did not have pain in the breast, discharge from the breast, a palpable mass on
breast self-examination, or swelling of the arm. Menarche had occurred at 13 years
of age. She had a long history of painful menses; the pain had been attributed to
endometriosis. Her first pregnancy, at 27 years of age, ended in a miscarriage that
was followed by dilation and curettage; subsequent pregnancies at 28 and 31 years
of age resulted in term births, the first vaginal and the second by cesarean section.
She had mitral-valve prolapse and occasional migraine headaches. She had taken
oral contraceptives for 5 years in the past. Medications included acetaminophen,
as well as tablets containing a combination of acetaminophen, aspirin, and caf-
feine as needed for headaches. She was allergic to penicillin and bee stings; they
caused anaphylaxis, for which epinephrine by autoinjector was prescribed. She was
married, lived with her husband and children, and worked in health care. She
drank approximately one alcoholic beverage per month and did not smoke or use
illicit drugs. Her mother and two sisters had hypertension; her mother had had
lung cancer at 81 years of age; her father had diabetes mellitus and, in his 60s, had
had melanoma; a brother had skin cancer; a maternal cousin had had breast cancer
at 45 years of age and had tested negative for BRCA1 and BRCA2 mutations; her
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 case records of the massachusetts gener al hospital

A B C D

Figure 1. Breast Imaging.

The mediolateral-oblique screening mammogram of the left breast (Panel A) shows dense breast tissue that is other-
wise normal, with no evidence of carcinoma. The corresponding tomosynthesis study (Panel B), obtained at a slice
thickness of 1 mm through the central aspect of the breast at the same time and in the same compression as the
mammogram, shows a suspicious 2-cm region of architectural distortion in the superior breast (encircled area). A
selected slice at a thickness of 1 mm through the superior left breast in the craniocaudal plane on tomosynthesis
(Panel C) also shows the suspicious 2-cm area of architectural distortion (encircled area). A spot-compression image
(Panel D) of the same area, obtained with traditional (two-dimensional) mammography during the diagnostic workup,
does not show the lesion.

maternal grandmother died at 66 years of age of
a stroke; and her maternal great-grandmother
died of uterine cancer at 60 years of age.
On examination, the breasts were symmetric,
with no palpable masses and no abnormalities of
the nipples. The remainder of the physical ex-
amination was normal.
Two weeks later, needle localization of the
lesion in the left breast was performed, followed
by lumpectomy of the lesion. Pathological exami-
nation of the specimen revealed carcinoma in situ
with mixed ductal and lobular features, extending
to the margins, in 6 of 10 blocks and spanning at
least 1.2 cm.
One month later, the patient was seen in the
multidisciplinary breast cancer clinic of this hospi-
tal. Additional management decisions were made.
DI AGNOS T IC IM AGING
Dr. Phoebe E. Freer: We have been performing tomo-
synthesis at this hospital clinically since March
2011, a month after the technique was approved
by the Food and Drug Administration for clinical
use in the United States. This patient’s screening
examination involved a combination of mammog-
raphy and tomosynthesis. In this technique, the
two sets of images are obtained in the same com-
pression and each view takes an additional 4 sec-
onds; for the patient, the experience is nearly
identical to that of mammography alone. For to-
mosynthesis, the breast is compressed in the
same plane as in standard mammography, and
15 low-dose radiographic images are obtained in
a series of different angles along an arc through
the breast; the images are then reconstructed into
a series of thin slices (at a thickness of 1 mm) in
the same plane as that on a standard mammo-
gram. In a combination mammographic and to-
mosynthesis examination, the tomosynthesis is
immediately followed by standard mammogra-
phy, with the breast in the same compression.
Tomosynthesis, by definition, tackles the problem
of overlapping breast tissue that occurs in mam-
mography. As compared with mammography,
tomosynthesis has been shown to decrease the
false positive rate while increasing the cancer-
detection rate.1-6
The patient’s standard digital mammogram
(Fig. 1A) shows heterogeneously dense tissue and
is unchanged from previous examinations, with
no evidence of carcinoma. There are diffuse cal-

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 The n e w e ng l a n d j o u r na l of m e dic i n e

superiorly (Fig. 1B) and on a craniocaudal image

A
centrally (Fig. 1C). This large, suspicious area of
architectural distortion is not seen on either the
screening mammogram or on subsequent diag-
nostic spot-compression images obtained by stan-
dard digital mammography (Fig. 1D), because
the overlapping dense breast tissue obscures the
abnormality on mammography. An ultrasound
examination showed a suspicious hypoechoic
mass at the 12 o’clock position in the left breast,
which correlated with the suspicious tomosyn-
thesis finding.

B PATHOL O GIC A L DISCUSSION

Dr. John H. Eichhorn: Interpretation of the core-

biopsy specimen was challenging because of the
complexity of the cellular proliferation and the
character of its constituent cells. There was florid
sclerosing adenosis (Fig. 2A), which harbored nu-
merous calcifications and contained many acini
with expansive groups of neoplastic cells (Fig. 2B).
These cells had larger nuclei and more copious
cytoplasm than the non-neoplastic cells. They
were cohesive in some areas, with visibly apposed
cellular membranes, but dyshesive elsewhere. Im-
C munostaining for E-cadherin, an adhesion mole-
cule not expressed in lobular neoplasia, was pos-
itive on some but not all of the neoplastic-cell
membranes and variable in its intensity and tex-
ture. This pattern could be considered to indicate
mixed lobular and ductal differentiation, but I
interpret it as indicating ductal differentiation
with progressive loss of E-cadherin expression.
The tumor cells were positive for estrogen and
progesterone receptors on immunohistochemical
analysis.
The excised specimen showed many more neo-
plastic cells, spanning a 1.5 cm area, which ne-
Figure 2. Specimens from Breast Biopsy and Excision.
cessitated the use of immunoperoxidase studies
The biopsy specimen shows florid sclerosing adenosis,
with calcifications (Panel A, hematoxylin and eosin). It for myoepithelial markers to distinguish carci-
also shows carcinoma in situ (Panel B and inset, hema- noma in situ populating sclerosing adenosis from
toxylin and eosin), involving sclerosing adenosis. The invasive carcinoma (Fig. 2C). I used a panel of
excision specimen shows extensive carcinoma in situ antibodies to myoepithelial cells (p63, calponin,
(Panel C, hematoxylin and eosin), involving sclerosing
and myosin heavy chain) because of their differ-
adenosis. Immunoperoxidase staining for calponin
(inset) highlights myoepithelial cells that define acinar ent and complementary staining characteristics.
boundaries and show that the lesion is not invasive. Calponin and myosin are seen in the cytoplasm
of myoepithelial cells and other cells, whereas
p63, a nuclear antigen with greater specificity,
cifications bilaterally. However, on the tomosyn- often gives an impression of discontinuity of
thesis images, a 2-cm area of architectural dis- expression around acini and ducts. The results
tortion is seen on a mediolateral-oblique image showed complete envelopment of the adenotic

1048 n engl j med 368;11 nejm.org march 14, 2013

The New England Journal of Medicine

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Copyright © 2013 Massachusetts Medical Society. All rights reserved.
 case records of the massachusetts gener al hospital
acini involved by the tumor cells (Fig. 2C, inset),
providing no evidence of stromal invasion and
establishing a diagnosis of low-grade carcinoma
in situ. The excision had four separate shaved
margins, and two of them, “superior” and “infe-
rior,” had tumor at the final margins.
Discussion of M A NAGEMEN T
Dr. Monica Morrow: This patient has ductal carci-
noma in situ (DCIS), with positive margins after
lumpectomy. Treatment options include mastec-
tomy with or without reconstruction, reexcision
and radiotherapy, or reexcision alone. Tamoxifen
may be added to any of these treatments.
Mastectomy is an extremely effective treatment
for DCIS, with local recurrence in 1.4% of pa-
tients in a large meta-analysis.7 The use of skin-
sparing mastectomy to facilitate immediate breast
reconstruction has not been compared with con-
ventional mastectomy in prospective randomized
trials. However, retrospective studies do not sug-
gest an increase in local recurrence rates, and
skin-sparing mastectomy is a standard approach
in patients undergoing immediate reconstruc-
tion.8,9 The use of nipple-sparing mastectomy is
more controversial, particularly in patients with
DCIS, such as this one. Occult nipple involvement
is reported in up to 58% of patients with breast
cancer, and distance from the primary tumor to
the nipple is the best predictor of involvement.10
Nipple-sparing mastectomy is contraindicated in
patients with subareolar or extensive DCIS. In pa-
tients with localized DCIS in the periphery of the
breast, such as this patient, nipple-sparing mas-
tectomy is an acceptable option.
Although mastectomy is an effective method
of managing DCIS, it is not necessary for a pa-
tient with localized DCIS, such as this one. Good
outcomes have been reported after treatment of
localized DCIS with lumpectomy alone or lumpec-
tomy and radiotherapy.11-14 The use of radio-
therapy reduced the 10-year rate of local recur-
rence from 28.1% to 12.9% across all ages and
tumor grades.15 Efforts to identify patients who
do not need radiotherapy have focused on those
with very small areas of DCIS, usually of low or
intermediate grade. The rate of local recurrence
among patients with high-grade DCIS with a
median size of only 7 mm was 18% in a multi-
institutional prospective study,16 suggesting that
excision alone is a poor choice in such cases.
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This patient does not have high-grade DCIS, but
the DCIS is considerably larger than the very
small lesions that have been successfully treated
with excision alone. Furthermore, she is only 48
years of age. An age under 50 years is a risk fac-
tor for local recurrence, and for these reasons I
would favor the use of radiotherapy.15
The use of tamoxifen reduces local recurrence
by about 5%,12 but it has not been shown to reduce
mortality rates. Among patients with estrogen-
receptor–positive tumors, the use of tamoxifen
reduced the hazard ratio of breast cancer events
at 10 years to 0.58, although most of the benefit
was a reduction in contralateral cancers.17 In dis-
cussing treatment options with this patient, it is
important to convey that although the risk of
another breast-cancer event is higher after breast-
conserving approaches than after mastectomy,
her risk of death from breast cancer is extreme-
ly low. After 15 years of follow-up after breast-
conserving therapy in two randomized trials,
breast-cancer–specific mortality ranged from
2.3% to 4.7%, and all-cause mortality ranged
from 14.4% to 17.1%.14
If this patient chooses breast-conserving sur-
gery, she will require reexcision to obtain clear
margins, since there is a higher rate of local
recurrence in patients with positive margins.18
There appears to be no need for margins greater
than 2 mm in patients treated with radiotherapy.
The need for reexcision is greater in patients
with DCIS than in those with invasive cancer
(31% vs. 19% in one study).19 Preoperative mag-
netic resonance imaging (MRI) has been shown
neither to increase the likelihood of negative mar-
gins with the initial excision nor to decrease the
number of women who attempt breast conserva-
tion and require conversion to mastectomy.20-23
If this patient were to choose breast conserva-
tion, she would not require staging of the axil-
lary lymph nodes. DCIS does not metastasize,
and sentinel-node biopsy is undertaken because
of the risk of invasive carcinoma in unsampled
tissue after a diagnosis of DCIS on examination
of needle-biopsy specimens. Since this patient
has already undergone excision of most of the
lesion, the risk of invasive cancer in unsampled
tissue is low, and if invasive cancer is found, a
sentinel-node biopsy can be performed as a sub-
sequent procedure. This approach spares patients
with pure DCIS the side effects associated with
a sentinel-node biopsy. The only time sentinel-
1049
 The n e w e ng l a n d j o u r na l
node biopsy is routinely indicated in patients
with DCIS is when mastectomy is performed.24
In summary, in this patient with localized
DCIS, the risk of death from breast cancer is
low, regardless of the treatment she chooses.
Patient preference plays an important role in the
choice of therapy, and greater patient involve-
ment in decision making is associated with
higher mastectomy rates.25 Patients are also in-
creasingly opting for contralateral prophylactic
mastectomy. In a large population-based study
of women with unilateral DCIS, the risk of can-
cer in the second breast was 6.0%, 8.7%, and
10.6% at 10, 15, and 20 years of follow-up, respec-
tively.26 The low risk of cancer makes it extremely
unlikely that contralateral prophylactic mastecto-
my will prolong life. The use of tamoxifen re-
duces the risk of contralateral cancer by ap-
proximately 50%14 and is an alternative to con-
tralateral prophylactic mastectomy.
In this patient, I would favor reexcision and
radiotherapy as an approach with a high likeli-
hood of local control and low morbidity. The ad-
dition of tamoxifen is an option but not a neces-
sity; it would further reduce the risk of future
breast cancer events.
Dr. Gadd: The patient met with surgical, medi-
cal, and radiation oncologists in a multidisci-
plinary clinic to discuss treatment options. Re-
excision was recommended to achieve negative
margins. Mastectomy was discussed as an alter-
native. The use of adjuvant radiation therapy af-
ter reexcision and the use of tamoxifen were also
discussed. After considering her options for sev-
eral weeks, the patient indicated that she was
leaning toward mastectomy and requested con-
sultation with a plastic surgeon.
Dr. Jonathan M. Winograd: As a plastic surgeon
who typically consults with patients after they
have settled on an oncologic treatment plan, my
role is to inform patients about the options for
reconstruction and the associated risks and to
give my opinion on the best option for an aes-
thetic reconstruction within the confines of the
oncologic plan. Since this patient was consider-
ing bilateral mastectomies, her options included
reconstruction, with either autogenous tissue or
implants, performed as either a single-stage or a
two-stage procedure.
Despite the obvious convenience to the patient
of a single-stage reconstruction, a two-stage pro-
cedure with a tissue expander followed by an
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of m e dic i n e
implant has been preferred. A single-stage pro-
cedure was associated in the past with technical
difficulties and an unacceptably high complica-
tion rate, including capsular contracture and
unsatisfactory cosmetic results.27 However, the
availability of acellular dermal matrix28,29 now
allows for the immediate creation of an internal
support for the implant as an inferior and lat-
eral extension of the pectoralis major muscle. As
a result, the single-stage implant reconstruction
is simpler and more reliable than it used to be,
leading to its increasing use.
This patient was considering a single-stage
procedure; however, even in the best candidates,
it can be more risky than the two-stage proce-
dure. The weight and size of the implant pro-
duces tension on the skin of the breast before
the incision has healed. The presence of two
foreign bodies — the implant and the acellular
dermal matrix — may increase the risk of infec-
tion and associated implant loss. Some studies
have shown an increase in total postoperative
complications in patients in whom acellular der-
mal matrix was used in the reconstruction,30,31
and others have shown complication rates simi-
lar to those of the two-stage procedure.27,32
In deciding whether this patient should have a
single-stage implant reconstruction, we need to
consider the risk factors for complications. Preop-
erative or postoperative irradiation is a risk fac-
tor.27,32 Large breasts (bra-cup size, D or larger)
and increased ptosis of the breast (grade 2 or
more on a scale of 1 to 4, with grade 4 indicat-
ing the most severe ptosis) are risk factors for a
poor cosmetic result because of the difficulty in
managing the excess skin and in creating an ade-
quate breast shape with the use of a round implant
in a previously oval breast.32 Finally, poor viability
of the mastectomy flaps may lead to implant loss
after single-stage reconstruction. The best can-
didates for immediate reconstruction, therefore,
are patients with enough healthy, well-perfused
skin to accommodate an implant immediately
after mastectomy but without a large amount of
excess skin or an elongated breast shape.
This patient had D-cup-size breasts, grade 2
ptosis of the left breast, and grade 3 ptosis of
the right breast. She had no other health prob-
lems. She had not received radiotherapy, and it
was unlikely that she would need irradiation
after mastectomy. Thus, she was a candidate for
bilateral single-stage implant reconstruction.
 case records of the massachusetts gener al hospital
Dr. Gadd: After meeting with Dr. Winograd, the
patient remained undecided. After a second meet-
ing with me, she eventually decided that she was
most comfortable proceeding with bilateral mas-
tectomies and immediate single-stage implant
reconstructions. She thought that this procedure
would provide the best cosmetic result and, most
important, would alleviate worries that she had
about the occurrence of another breast cancer in
the future. Because of the large breast size and
the degree of ptosis, I elected not to perform a
nipple-sparing mastectomy, which would have
limited any ability to remove excess skin from the
breast and would have resulted in nipple malpo-
sition.33 I performed a skin-sparing mastectomy,
which allowed for tailoring of the excess skin
and the creation of an aesthetic breast shape. Dr.
Winograd then performed immediate bilateral
implant reconstructions with acellular dermal
matrix and 500-ml silicone gel implants, with a
very acceptable cosmetic result.
The patient had no complications from the
procedure and is happy with the results. She was
also happy to be the subject of this clinicopatho-
logical conference and hopes that her experience
with both early detection and the choice of treat-
ment will be helpful to other patients. She will
undergo annual examinations.
The Patient: After the lumpectomy with positive
margins, I was presented with the options of re-
excision and radiation with tamoxifen or mastec-
tomy and reconstruction. Discussions with oncol-
ogists and surgeons provided data on treatment
outcomes and recurrence risks, and conversations
with breast-cancer survivors and their families
about diagnosis, treatment, outcome, and recur-
rence were helpful. The recommendation that I use
tamoxifen if I had chosen breast preservation
would have been a concern, given my history of
endometriosis and my family history of uterine
cancer and stroke, and led me to reevaluate re-
excision. The possibility of recurrence in the other
breast contributed to my decision for bilateral
treatment. I feel that breast-cancer management
should be individualized, with all personal fac-
tors and risks considered. I hope that this case
report will remind physicians of the need to em-
power their patients to learn the variety of
treatment options and risks and to engage the
support of their caregivers, so that they have the
strength and confidence to make personalized
and educated decisions about their health care.
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Dr. Eichhorn: A focus of residual tumor was
found in the specimen from the left mastectomy,
spanning 0.4 cm, and there were two negative
ipsilateral sentinel lymph nodes. The contralat-
eral breast showed extensive sclerosing adenosis
but no neoplasia.
Dr. Morrow: This patient’s choice of mastecto-
my rather than breast conservation is not unusu-
al, but it is probably not justified by either the
risk of contralateral cancer or the likelihood that
contralateral prophylactic mastectomy will have
an effect on survival. For someone between 45 and
55 years of age at diagnosis, such as this patient,
the risk of a contralateral breast cancer during the
next 15 years is only approximately 9%.26 In pa-
tients with DCIS, all-cause mortality significantly
exceeds breast-cancer–specific mortality,34 so
the likelihood that a contralateral prophylactic
mastectomy will prolong this patient’s life is
very small.
Patients who opt for contralateral prophylactic
mastectomy are typically young, white women
with insurance and with a family history of breast
cancer (although not necessarily in a first-degree
relative).35,36 A high level of anxiety regarding
breast cancer is associated with rates of contra-
lateral prophylactic mastectomy that are as high
as those seen among women with two first-
degree relatives with breast cancer or known
BRCA mutations.37 Contralateral prophylactic
mastectomy is an extremely expensive, resource-
intensive way of treating anxiety, and we need to
find better ways of communicating the lack of
benefit of this procedure to patients.
A Physician: Every case has an anxiety compo-
nent. Patients often get second, third, and fourth
opinions. Very anxious patients can take 6 to
8 weeks before deciding on surgery. What is the
timeline before you see an effect of disease pro-
gression, in terms of starting treatment?
Dr. Morrow: In DCIS, time is one thing we are
not worried about, because the natural history of
DCIS is very prolonged and progression to inva-
sive cancer in a matter of weeks would be very
unusual.
A Physician: When should you do a sentinel-
node biopsy on the unaffected breast?
Dr. Gadd: At our institution, some think that
sentinel-node biopsy is a very low-risk procedure
and will perform it on the unaffected breast.
Others believe that if a breast MRI scan is com-
pletely normal within 6 months before surgery,
1051
 The n e w e ng l a n d j o u r na l of m e dic i n e

a sentinel-node biopsy of the contralateral breast
is not necessary.
Dr. Morrow: In approximately 4% of cases of
breast cancer, occult cancer is found in the con-
tralateral breast, and one half of those cases are
diagnosed as DCIS. A negative MRI in a patient
at high risk for breast cancer or a negative mam-
mogram in a patient at lower risk indicates an
extremely small likelihood of nodal metastases.
I perform a sentinel-node biopsy on the contra-
lateral breast only if an imaging abnormality is
present for which a biopsy has not already been
performed.
A Physician: In this case, the lesion was not seen
on conventional imaging. Does that affect your
counseling of a patient toward breast-conserving
treatment or mastectomy?
Dr. Morrow: The question always comes up: Can
you detect local recurrence with mammography
in someone whose initial cancer was occult?
Many years ago, long before MRI or even ultra-
sound screening, I studied whether the success
of breast conservation differed among women
with mammographically occult cancers and among
those with mammographically visible cancers,
and I found that it did not.38 In a more recent
study, the local recurrence rate did not differ
between mammographically occult cancers and
mammographically evident cancers, and 68% of
the local recurrences were mammographically
visible,39 suggesting that failure to visualize the
initial cancer mammographically is not an indi-
cation for mastectomy.
A NAT OMIC A L DI AGNOSIS
Ductal carcinoma in situ of the breast.
This case was discussed at the Harvard Medical School post-
graduate course Advances in Cancer Management for the
Surgeon, directed by Michele A. Gadd, M.D., and James C.
Cusack, M.D.
No potential conflict of interest relevant to this article was re-
ported.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
We thank Dr. Michele Gadd for assistance with the organiza-
tion of the conference; and the patient for her willingness to be
the subject of the conference.

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