Journal of Surgical Oncology 2013;108:207–212

When Mastectomy Is Needed: Is the Nipple-Sparing Procedure a

New Standard With Very Few Contraindications?

LUCIO FORTUNATO, MD,1* ANDREA LORETI, MD,1 RENATO ANDRICH, MD,1

LEOPOLDO COSTARELLI, MD,2 MOSTAFÀ AMINI, MD,2 MASSIMO FARINA, MD,1
ELENA SANTINI, MD,3 AND CARLO E. VITELLI, MD1
1
Breast Unit, Department of Surgery, San Giovanni-Addolorata Hospital, Rome, Italy
2
Department of Pathology, San Giovanni-Addolorata Hospital, Rome, Italy
3
Department of Radiology, San Giovanni-Addolorata Hospital, Rome, Italy

Background and Objectives: Nipple‐sparing mastectomy (NSM) improves cosmetic results after mastectomy. As most consider advanced tumors,
or tumors near the nipple–areola complex (NAC), as a contraindication for this type of surgery, we challenged this hypothesis.
Methods: One hundred thirty‐eight NSM were performed in 121 consecutive patients. In 122 procedures for cancer, patients were included if there
was no evidence of NAC proximity (<1 cm), and if the retro‐areolar margin was negative, even for locally advanced tumors or after neoadjuvant
chemotherapy.
Results: Total NAC necrosis occurred in six cases (4.3%). Additionally, NAC was removed after histological exam of the retro‐areolar tissue in 19
cases (16% of cancer patients). Among 93 cases whose tumor‐to‐NAC distance was recorded, NAC was removed in 11/31 cases (35%) if the
distance was 1 cm, and in 8/62 cases (12.9%) if it was more than 1 cm (P ¼ 0.01). NAC was removed more frequently in the first half of the study
(17/69 vs. 8/69: P ¼ 0.05). At a median follow‐up of 26 months for the cancer patient group, there was only one local recurrence (outside the NAC).
Conclusions: Our experience adds evidence that NSM is safe, if the retro‐areolar resection margin is clear and maximal surgical clearance is
performed.
J. Surg. Oncol. 2013;108:207–212. ß 2013 Wiley Periodicals, Inc.

KEY WORDS: breast cancer; mastectomy; nipple‐sparing mastectomy; total skin‐sparing mastectomy; breast
reconstruction

INTRODUCTION
Although conservative breast surgery has been demonstrated
equivalent to mastectomy in six prospective randomized trials around
the world [1], the latter is still needed in more than 25% of patients
because of multifocality, inability to obtain negative resection margins,
or patient’s preference.
Toth and Lappert initially described in 1991 a skin sparing approach,
combining immediate breast reconstruction after mastectomy to
improve cosmetic results [2]. A meta‐analysis of nine studies involving
3,739 patients has recently shown that local recurrences are equivalent to
non‐skin–sparing mastectomies [3]. Furthermore, it is now well
recognized that immediate breast reconstruction has no negative impact
on prognosis or local recurrence rates [4], and that, rather, it improves
recovery, quality of life, and body image [5].
Mastectomy for breast cancer has traditionally included resection of
the nipple–areola complex (NAC) for fear that this area may harbor
occult tumor cells. Only a decade ago, a literature survey concluded that
a nipple‐sparing mastectomy (NSM) should not be advocated, since up
to 58% of specimens may show nipple involvement [6]. Since then,
several additional reports [7–10] have examined the incidence of occult
NAC involvement, and the majority of larger series report an incidence
of 5–12%, showing that this event is infrequent in modern clinical series.
When the NAC is preserved during mastectomy, patients report
improved satisfaction, body image, and psychological adjustment
[11,12]. On the other hand, occult nipple involvement is difficult to
diagnose, as it occurs as ductal carcinoma in situ (DCIS) in
approximately two‐thirds of cases [13]. For this reason, NSM has so
far been considered controversial by most, and the oncological safety of
this approach remains to be fully demonstrated.
Predictive models and algorithms for occult nipple involvement have
been developed [14,15]. However, while it is clear that small and
peripheral cancers have a negligible risk of nipple involvement, the true
question is whether NSM can be safely offered today to a large group of
patients who are candidates for mastectomy, in order to improve
cosmetic outcome.
We present our experience with NSM in one institution, and present a
large cohort of patients so treated whose main exclusion criteria was
absence of radiologic or clinical tumor involvement of the NAC, and
absence of histologically proved cancer at serial examination of the
retro‐areolar breast tissue.
PATIENTS AND METHODS
This was a retrospective review of a prospectively maintained
database. According to an institutionally approved written protocol of
our Breast Unit, all patients necessitating mastectomy, without clinical
evidence of the NAC invasion or retraction, and with a minimum of 1 cm
clinical–radiological distance of the tumor from the NAC, were
considered eligible.
The decision to attempt an NSM was taken after careful and
multidisciplinary analysis of the radiological findings for each patient,
Grant sponsor: Fondazione Prometeus, ONLUS
*Correspondence to: Lucio Fortunato, MD, Breast Unit, San Giovanni‐
Addolorata Hospital, Via Amba‐Aradam 8, 00187 Rome, Italy. Fax: þ39‐06‐
7705‐5549. E‐mail: lfortunato@hsangiovanni.roma.it
Received 12 May 2013; Accepted 09 July 2013
DOI 10.1002/jso.23390
Published online 1 August 2013 in Wiley Online Library
(wileyonlinelibrary.com).

© 2013 Wiley Periodicals, Inc.

208 Fortunato et al.
which always included, since 2009, mammography, sonogram, and MRI
for all cancer cases.
Candidates were preferentially young and interested in improved
cosmetic outcome. Large and ptotic breasts were not considered suitable
for this technique, as additional problems are raised by NSM in this
setting. While at the beginning we were quite prudent regarding
indications for NSM, since 2009 we have adopted a liberal policy of
considering this operation for all patients with a minimal tumor–NAC
distance of 1 cm, in the absence of clinical involvement of the NAC,
Paget disease, bloody discharge, or inflammatory carcinoma of the
breast. Therefore, according to our institutionally approved written
protocols, no exclusions were made according to tumor histology (ductal
vs. lobular), advanced tumor stage and nodal status, neoadjuvant
chemotherapy, presence or absence of in situ disease in the breast.
Generally, we used a radial lateral or an italic S incision, paying
attention not to compromise the peri‐areolar blood supply. Skin flaps were
carefully raised, with electrocautery at low setting, at the level of the
Cooper’s ligaments and avoiding excessive counter traction. Warm saline
compresses were applied to the skin during periodic rest times. Attention
was paid to dissect the retro‐areolar breast tissue and to maintain a 2–3 mm
retro‐areolar thickness to assure maximal surgical clearance. In the last
2 years of the study, we often used hydrodissection of the areola to ease
the complete removal of the glandular tissue behind the NAC [16].
An intra‐operative serial histological exam of the retro‐areolar tissue
was performed after marking the retro‐areolar area with a single stay
suture. After inking the retro‐areolar margin, a 5‐mm‐thick transverse
core was removed, and 4–5 sagittal sections obtained, conventionally
numbered from medial to lateral. Sections were stained with Toluidine
blue and hematoxylin–eosin (Fig. 1).
Immediate breast reconstruction was performed in conjunction with
our plastic surgery team by insertion of a sub‐muscle tissue expander or
prosthesis.
Fig. 1. Protocol for intra‐operative examination of the retro‐areolar breast margin.
Journal of Surgical Oncology
Cosmetic results were anonymously judged by the patients, refer to
the score issued at the time of last follow‐up, and were evaluated
according to an intention‐to‐treat analysis.
All patients signed a specifically designed informed consent
for NSM. Prospectively collected data included smoking habits,
breast size, type of surgery, reason for surgery, histological and
immunohistochemistry data, presence or absence of ductal or lobular in
situ neoplasia, tumor–NAC distance, complications of surgery, adjuvant
or neoadjuvant therapies, and disease status at the latest visit. Tumors
were classified as multifocal or multicentric if there was such
histological evidence.
The study was conducted according to the principles laid down in the
Declaration of Helsinki.
Statistical analysis was performed with a statistical package. Chi‐
squared or Fisher exact test were used to compare categorical variables.
Significance was defined as 2‐tail P < 0.05.
RESULTS
One hundred thirty‐eight NSM were performed in 121 consecutive
patients (17 cases bilateral) from 2003 to 2012, and were retrospectively
analyzed. Of 138 cases, 124 were performed in the period 2009–2012.
During this latter interval, 1,216 breast cancer cases were surgically
treated by our team and 354 mastectomies performed (29%). Among
these, 124 NSM were attempted (35%).
Patients’ characteristics are described in Table I. While the majority
of cases were performed for multifocal/multicentric cancers (n ¼ 83;
60%), NSM was performed for locally advanced disease (n ¼ 30; 22%),
contralateral (n ¼ 4; 3%) or ipsilateral relapsing breast cancer (n ¼ 2;
1.5%), personal choice (n ¼ 3; 2%), or prophylaxis in high‐risk patients
(n ¼ 16; 11.5%).
 Is Nipple‐Sparing Mastectomy a New Standard? 209
TABLE I. Patients’ and Tumors’ Characteristics initial expander (1/23 vs. 5/115). Two of six patients with NAC necrosis
lost the permanent device, one patient had the prostheses removed for
Characteristics n (%) or (range)
insertion on an expander, while in three other patients simple
Median age (year) 46 26–71 debridement and skin closure sufficed.
Tumor size (cm) 2.0 0–4–10 Intra‐operative or post‐operative NAC removal was performed for
Histology cancer near the retro‐areolar margin, distance less than 2 mm from the
Ductal 71/122 58% ink of the sagittal sections obtained according to our described protocol,
Lobular 21/122 17% in 16 and 3 cases, respectively (16% of cancer cases). There was no
DCIS 20/122 16% association between several examined risk factors of the primary tumor,
Phyllodes 4/122 3% or the presence of locally advanced tumor undergoing neoadjuvant
Other 6/122 5%
chemotherapy, and the need for NAC resection for documented
Stage
I 35/98 36%
insufficient (<2 mm) retro‐areolar margins (Table III).
II 44/98 45% The closest distance between the NAC and the tumor according to the
III 19/98 19% best clinical and radiological assessment (including mammography,
Positive nodal status 41/98 41% sonogram, and MRI) was available in 93/122 cases. In 31 of these (33%),
Hormone receptorsþ 83/98 88% the tumor was located at a minimum distance of 1 cm from the NAC,
Grade 3 43/98 33% either at the time of primary surgery or before initiation of neoadjuvant
Her2‐neuþ 9/98 7.5% treatment. Within our sample group, NAC was removed for evidence of
Lymphovascular invasion 9/98 9% cancer in the retro‐areolar tissue in 11/31 cases (35%) if tumor‐to‐NAC
Neoadjuvant chemotherapy 29/98 30%
distance was 1 cm, and in 8/62 cancer (12.9%) if this was more than 1 cm
Adjuvant chemotherapy 43/98 44%
Radiotherapy 19/98 19%
(P ¼ 0.01). NAC was more frequently removed, for inadequate margins
Presence of multifocal LIN/DIN 91/122 75% or full thickness necrosis, in the first half of the study (17/69 vs. 8/69:
P ¼ 0.05), although the two groups were comparable in terms of
patients’ and tumors’ characteristics.
In 11/19 NAC removed, there was histological evidence of residual
NAC events are described in Table II. Six additional patients (4%) cancer found at definitive examination (58%).
suffered partial necrosis of the mastectomy skin flaps, occasionally In three cases, the intra‐operative examination was falsely positive,
requiring operative debridement. showing intraductal proliferative lesions at 1 mm from the inked margin.
Nipple necrosis or skin desquamation (Fig. 2) occurred in 7/34 The first was a papillary lesion, classified as intraductal papilloma at the
patients with smoking history (21%) vs. 18/104 without (17%) definitive histological exam. The other two were classified as flat
(P ¼ 0.6), and in 5/46 patients with small‐sized breasts (cup size 1–2; epithelial atypia at intra‐operative examination, and later as columnar
11%), vs. 20/92 patients whose breast was medium‐sized or large (cup change by immunohistochemistry.
size 3–5; 22%; P ¼ 0.1). One‐stage reconstruction with final implant was Sensitivity and specificity of intra‐operative examination were 81%
not related to skin necrosis as compared with two‐stage procedure with and 97%, respectively, while the negative predictive value was 97%.

TABLE II. NAC Events

Journal of Surgical Oncology

210 Fortunato et al.

Fig. 2. Post‐operative picture of partial skin necrosis/desquamation Fig. 3. Post‐operative picture of a patient after nipple sparing
with later complete recovery. mastectomy and immediate breast reconstruction with an implant.

In 97 patients operated for cancer, the NAC was not removed because in diameter, hormonal responsive, NEU negative, high‐grade cancer
final margins of resection were considered adequate, nor full thickness located at 1 cm from the NAC in the lateral portion of the breast, staged
necrosis occurred. Among them, 16 cases showed presence of tumor ypT1cN1a, 9 months after the surgical procedure. At that time the NAC
cells in the retro‐areolar tissue at 2 mm from the inked margin, was removed intra‐operatively for presence of DCIS in the retro‐areolar
including seven cases of DCIS, four cases of in situ ductal neoplasia type tissue. She developed a single 5‐mm invasive subcutaneous relapse
1A or 1B, three of in situ lobular neoplasia, and two of invasive lobular outside the NAC area, in the superior portion of the breast.
cancer. These cases were discussed at the multidisciplinary conference Six additional patients developed systemic relapses (three, bone
and patients were counseled to observation, including four women who metastases only; one, bone and liver; one, liver only; one, brain only),
received post‐operative radiotherapy because the retro‐areolar margins one patient a contralateral cancer, and one patient died.
were considered close.
Breast reconstruction was performed with immediate prostheses DISCUSSION
(n ¼ 113), tissue‐expanders (n ¼ 23), or with prostheses and autologous
flaps (n ¼ 2). We present our experience with NSM in a consecutive cohort of
Loss of the devise due to infection or skin/NAC necrosis with major patients whose indication for mastectomy was cancer in the vast majority
exposure occurred in six cases. Capsular contracture was reported in 19 of cases.
cases and it was classified as Baker II or III in seven of them. Our patients often presented not only with multifocal or multicentric
In 9/114 cases, patients reported some sensation of the NAC in the tumors but also with loco‐regionally advanced cancers, as evidenced by
first month after surgery (8%), while this occurred in 19/114 cases at the fact that two‐thirds of them were Stage II or III, three quarters
6 months post‐operatively (17%), although typically described as received neoadjuvant or adjuvant chemotherapy, and some were
minimal or partial. counseled to undergo radiotherapy. Over 10% of breast cancer
Patients scored cosmetic outcome as excellent (n ¼ 46; 33%) (Fig. 3), patients in our breast unit underwent NSM over the last 4‐year
good (n ¼ 72; 52%), fair (n ¼ 14; 10%), or insufficient (n ¼ 6; 3%) at the period; conversely, NSM accounted for over one‐third of mastectomies
time of last follow‐up. performed during the same time interval, and these data testify that we
Median follow‐up was 28 months for the whole group, and 26 months adopted a more liberal attitude than usually described.
for cancer patients. One patient was lost to follow‐up. We acknowledge the fact that patient selection for NSM can be a
Only one loco‐regional recurrence was recorded, so far, in a 41‐year‐ difficult task, because both the surgeon and the patient are faced with the
old woman after completion of neoadjuvant chemotherapy for a 3.5 cm desire of improved cosmetic outcome and the fear of occult NAC disease
and relapse. However, our data indicate that NSM can be considered
when mastectomy is needed for cancer, even in advanced cases, and that:
TABLE III. Correlation With Intra‐Operative or Post‐Operative Removal (1) pre‐operative assessment; (2) intra‐operative histological confirmation
of NAC of retro‐areolar resection with negative margins ( 2 mm); (3) accurate
surgical technique to leave a very thin retro‐areolar skin flap; may be the
Present (%) Absent (%) P‐value
key factors for oncological safety in this setting. Therefore, we believe that
Multifocality/multicentricity 12/83 (14) 7/30 (23) NS patients should not be precluded NSM solely on the basis of set arbitrary
DCIS histology 2/20 (10) 17/98 (17) NS risk factors, such as primary tumor diameter or tumor‐to‐NAC distance.
High‐grade tumors 9/43 (21) 12/55 (22) NS One‐third of our patients whose this information was recorded had breast
Hormone receptorþ 16/83 (19) 1/15 (7) NS cancers at 1 cm from the NAC, and we managed to leave the NAC in
C‐Erb‐B2þ 2/9 (22) 17/91 (19) NS roughly two‐thirds of cases in this setting.
LVIþ 2/9 (22) 16/91 (18) NS Clinical and radiological assessment are predictors of NAC
Neoadjuvant chemotherapy 7/32 (22) 12/106 (11) 0.1
involvement in patients with breast cancer, and when both factors are
Tumor–NAC distance 1 cm 11/31 (35) 8/62 (13) 0.01
First half of study 17/69 (25) 8/69 (12) 0.05
absent the negative predictive value is 93–94% for mammography
[15,17], and 100% for MRI when the cut‐off was set at 10 mm [15].

Journal of Surgical Oncology


On the other hand, analysis of the retro‐areolar margin has been
reported to have a sensitivity of 80% and a negative predictive value of
96%, showing that this can be the main parameter to assess the safety of
NSM [13]. Therefore, as clinical assessment may play a more limited
role in excluding patients from the potential benefits of NSM, analysis of
the retro‐areolar margin maximizes the number of patients who are
potentially free from occult nipple involvement [9]. Our experience is
confirmatory.
It is arguable whether all cases with microscopic evidence of cancer
in the retro‐areolar tissue near the margin mandate, today, removal of the
NAC, and there is debate on what is considered an acceptable resection
margin. Our experience demonstrates that roughly one‐half of these
NACs show histological evidence of microscopic cancer involvement.
Some may argue that these cases might have been treated with post‐
operative radiation with the reasonable target of obtaining good local
control. However, in a recent report on 98 NSM cases with false‐
negative frozen sections or close margin the 5‐year incidence of loco‐
regional and NAC recurrence was 11.2% and 2.4%, respectively, after
delivery of intra‐operative radiotherapy, and in situ carcinoma as a
primary tumor was a significant predictor of NAC event [18].
In our experience, patients operated after neoadjuvant chemotherapy
were not at higher risk for intra‐ or post‐operative NAC removal. This is
an interesting finding as some patients presented initially with tumors
quite near the NAC that showed major regression after systemic therapy
allowing consideration for NSM. Whether NSM can be used in this
setting is still unproven, but it represents an additional field of interest
and we should consider recruiting patients interested in this approach.
We have shown that despite adopting, with time, a more liberal
attitude to consider NSM for patients undergoing mastectomy, NAC
removal decreased in the second half of the study, possibly as a
consequence of our increased confidence with the procedure and
standardization of the technique. In the second half of the study, more
than 90% of patients undergoing NSM retained their NAC.
Nipple necrosis remains a major concern for patients undergoing
NSM. Our complete NAC necrosis rate of 4.3% is within the range of
what was reported in a recent review [19]. While in some studies age,
smoking habits, type of surgical incision, and flap thickness were
associated with a high incidence of skin necrosis [20], this has not been
confirmed in a recent report [21], and it is well possible that surgical
technique, different reconstruction techniques, intra‐operative radiation
may all play a role in this regard.
Several experiences with NSM have been published in literature, so
far, and loco‐regional recurrences have ranged between 1% and
24% [19]. Many studies are represented by small series with a limited
follow‐up, but most agree on low recurrence rates. Although the one
experience describing a very high loco‐regional failure in non‐irradiated
patients is a large study with long‐term follow‐up [22], it raises the doubt
that not all operations (performed between 1988 and 1994) were radical
by today’s standards, and that a thick flap beneath the NAC and the skin
must be avoided if one wishes to maintain acceptable local recurrence
rates without having to rely on radiation therapy. As maximal skin and
NAC preservation is desirable in patients with breast cancer undergoing
mastectomy, special technical considerations need to be addressed by
the surgical team, because the risk of leaving some glandular tissue
behind can be as high 10% if skin flaps are more than 5 mm thick [23].
Similar considerations can probably be made for the retro‐areolar flap in
order to leave a very small number of ducts, therefore limiting the
potential for relapse.
Others have employed different strategies, and routinely deliver
electron beam intra‐operative radiation therapy (ELIOT) to the NAC. At
the European Institute of Oncology 861 patients were so treated and a
local relapse was reported in 4.2% of patients at a median follow‐up of
47 months [24]. Patients with tumors showing DCIS, or invasive ductal
carcinoma with extensive in situ component, negative hormonal
receptors, high pathological grade, and overexpression of HER2/neu,
Journal of Surgical Oncology
Is Nipple‐Sparing Mastectomy a New Standard? 211
tended to be significantly associated with local recurrence. In case of
DCIS, these authors report a local recurrence in the breast and in the
NAC of 4.9% and 2.9%, respectively. Routine delivery of ELIOT at the
time of NSM to sterilize eventual foci of residual cancer is appealing, but
while it is clearly unnecessary in the majority of cases, it should not be
used as an excuse to leave an unnecessary amount of breast tissue behind
the nipple for fear of necrosis.
Several recent experiences have contributed to raise interest around
NSM.
Boneti et al. [25] compared 227 SSM with 281 NSM performed for
293 patients and concluded that the latter is oncologically safe with
superior cosmesis, and can be offered to patients with Stage I and II
breast cancer and those who have been down staged with neoadjuvant
chemotherapy.
The Memorial Sloan‐Kettering group [26] reported on 353 NSM
procedures performed over a 10‐year period, 157 of whom were
therapeutic (45%). NAC was removed in 3% of patients for cancer at the
margin of resection. The NAC was dissected with a 5‐mm flap and no
radiotherapy was employed. No local recurrences were reported.
However, this study represented only a selected group of patients,
comprising 3.9% of all mastectomies performed in that institution over
the same period of time, while in our experience we elected to offer the
procedure to roughly one‐third of the patients undergoing mastectomy in
the last 4‐year period.
At the University of California at San Francisco [27], 657 procedures
were performed, mainly for cancer, in a high‐risk cohort, 49% of whom
received neoadjuvant chemotherapy, with a loco‐regional recurrence
rate of 2% and no NAC recurrences at 28 months of median follow‐up.
At the John Wayne Cancer Center [28], 99 patients were treated with
149 NSM procedures over an 11‐year period. Fourteen percent of NAC
were removed because of a positive sub‐areolar biopsy result, 6% were
removed for necrosis, while 3% of patients experienced a recurrence in
the breast at a median follow‐up of 5 years.
Our study has some limitations. First, the median follow‐up of our
patients is short, and while only one local relapse was recorded so far, we
certainly expect more loco‐regional recurrence in the future. Therefore,
our findings will have to be confirmed by studies with longer follow‐up.
Second, our group of patients is quite heterogeneous, and the
retrospective nature of the study, albeit from a prospectively
maintained database, may include bias. Third, cosmetic scores were
judged by patients and were not assessed using a standardized validated
instrument, such as Breast‐Q, which analyzes satisfaction and well being
after reconstruction [29]. We are in the process of re‐evaluating this
aspect, which will be the focus of a specific project.
However, we believe that the originality of our clinical setting adds
significant interest to this topic. As oncological need to remove the skin
envelope or the NAC has never been proved, arbitrary‐specific
indications for NSM, including distance from the NAC, tumor
diameter or clinical stage, should be challenged if no cancer if found
near the margin of resection. This is not dissimilar from what we all do
every day in breast conservation surgery.
Eligible patients can retain their NAC in at least 80% of cases even if
non‐restrictive indications are implemented, and this represents a step‐
forward in the surgical treatment of breast cancer.
ACKNOWLEDGMENT
This work was supported by Fondazione Prometeus, ONLUS, for the
development of research and training in oncology.
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