Surgical Oncology 29 (2019) 126–133
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Surgical Oncology
journal homepage: www.elsevier.com/locate/suronc
Residual glandular tissue (RGT) in BRCA1/2 germline mutation carriers
with unilateral and bilateral prophylactic mastectomies
T
Olga Grinsteina,1, Barbara Kruga,∗,1, Martin Hellmicb, Florian Siedeka, Wolfram Malterd,
Christina Burkea, Rita Schmutzlerc, David Maintza, Kerstin Rhiemc
a
Department of Diagnostic and Interventional Radiology, University Hospital of Cologne, Germany
Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), University of Cologne, Faculty of Medicine and University Hospital of Cologne,
Germany
b
Institute of Medical Statistics and Bioinformatics, University of Cologne, Germany
d
Breast Center, Department of Gynaecology and Obstetrics, University Hospital of Cologne, Germany
c
A R T I C LE I N FO
A B S T R A C T
Keywords:
Residual glandular tissue
Breast magnetic resonance imaging
Breast cancer
BRCA1
BRCA2
Prophylactic mastectomy
Background: Prophylactic mastectomy (PME) is increasingly performed in women carrying deleterious BRCA1
and BRCA2 germline mutations. The oncologic risk resulting from residual fibroglandular tissue (RGT) is unknown.
Methods: All women who had received a mastectomy and at least one postoperative breast MRI, between 2006
and 2016 were extracted from the register of the Center for Hereditary Breast and Ovarian Cancer Cologne
(CHBOC). The index MRI was evaluated in terms of basic clinical data and the morphological criteria of RGT.
The RGT volume was measured in diameter and was semi-automatically evaluated using software.
Results: We identified 169 women carrying BRCA1/2 mutations who underwent prophylactic and curative
mastectomy: a total of 338 breasts. RGT was found in 128 of the 338 breasts (37.9%). 68 of the 128 breasts
(53.1%) were related to bilateral PME, 37 (28.9%) to unilateral PME and 23 (18.0%) to curative mastectomy.
RGT was predominantly unifocal and located in the retroareolar breast region. RGT was observed more often
after bilateral PME (p < 0.0001). In this subgroup, the nipple-sparing mastectomy dominated (108 of 136,
79.4%), in contrast to 23 standard mastectomies (23 of 94, 24.5%) in the subgroup of curative mastectomy
(23%). There was a trend towards higher amounts of RGT in surgical units with fewer mastectomies performed.
During follow-up, two breast cancers were detected after bilateral and unilateral PME, respectively.
Conclusions: Our results suggest that the indication for surgery and in particular the selected surgical procedure
affect the surgical outcome with respect to RGT. Oncological safety should not be neglected, especially in the
high-risk group of BRCA1/2 mutation carriers.
1. Purpose
The risk of developing breast cancer by the age of 80 is estimated to
be 44% to 79% for BRCA1 mutation carriers and 18%–77% for BRCA2
mutation carriers [1,2]. The risk of developing metachronous contralateral breast cancer is also increased depending on the mutated gene
and the age of the patient at diagnosis [3,4]. BRCA1 mutation carriers
have a 30% higher mortality rate compared to patients with BRCA1
negative and sporadic breast cancer [5]. BRCA2 mutation carriers have
a 29% poorer breast cancer specific survival compared to BRCA2 negative breast cancer patients [5].
The relevance of structured, image-based surveillance is undisputed
in the light of this background [6–10]. The German Consortium for
Hereditary Breast and Ovarian Cancer (GC-HBOC), founded in 1996 by
the German Cancer Aid, today comprises 19 specialized university
centers throughout Germany. Since 2005 it has offered women at risk of
breast cancer not only a detailed consultation with risk calculation and
genetic testing but also a structured image-based surveillance program
which includes an annual breast MRI [11,12]. As an alternative to
participating in this image-based surveillance program, bilateral prophylactic mastectomy (PME) in healthy BRCA1/2 mutation carriers and
unilateral PME in BRCA1/2 mutation carriers with history of contralateral breast cancer represent potential risk reducing options
[13,14]. Women undergoing bilateral PME in the GC-HBOC program
∗
Corresponding author. Department of Diagnostic and Interventional Radiology, University Hospital of Cologne, Kerpener Straße 62, 50924, Cologne, Germany.
E-mail address: Barbara.krug@uk-koeln.de (B. Krug).
1
contributed equally.
https://doi.org/10.1016/j.suronc.2019.04.009
Received 25 October 2018; Received in revised form 21 March 2019; Accepted 29 April 2019
0960-7404/ © 2019 Elsevier Ltd. All rights reserved.
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O. Grinstein, et al.
mastectomy and the first one after were included in the evaluations.
The image documentation and follow-up were taken from the Picture
Archiving and Communication System (PACS) of the University
Hospital (ImpaxEE®, AGFA Healthcare, NV, Mortsel, Belgium).
have at least one breast MRI following the surgical procedure in order
to ensure that there is no relevant residual glandular tissue (RGT) remaining warranting further MRI surveillance. The nipple-areola complex (NAC) is preserved in the majority of PME for aesthetic reasons
primarily, whereas in skin-sparing mastectomies, mainly carried out for
curative indications, the glandular tissue and the NAC are removed
leaving only the skin and a thin layer of subcutaneous fat and tissue to
maintain vascularization [15,16]. The results published to date show a
significant risk reduction for breast cancer in PME using different surgical techniques in the high-risk group of BRCA1 and BRCA2 mutation
carriers [17–19]. Contralateral PME after unilateral breast cancer has
also been associated with a significant risk reduction for metachronous
breast cancer [13,18]. Contrarily, the analysis of breast cancer mortality rates did not indicate a benefit after PME compared to women
who had not undergone PME [13,18]. Initial data published by
Heemskerk-Gerritsen BAM et al., in 2015 suggest a survival benefit
after contralateral PME [13]. There is currently a lack of long-term
studies, which provide a sound evaluation of oncological safety concerning PME.
The risk of developing breast cancer after PME is influenced significantly by the remaining RGT. Currently, there exist only few data on
the detection rates of RGT with predominantly histopathological approaches, small patient numbers ranging between 27 and 90 patients
and detection rates of RGT between 5% and 61% [20–23].
The aims of this study were
2.3. MR examination techniques
Between 2006 and 2014, breast MRIs were performed using an open
whole-body MRI scanner of 1.0 T main magnetic field strength
(Panorama 1.0, Philips Healthcare, Best, The Netherlands) and using a
whole-body MRI scanner of 1.5 T main magnetic field strength (Achieva
1.5, Philips Healthcare) with dedicated 4-channel and 7-channel breast
coils. Since 2015 all breast MRIs have been acquired using whole-body
MRI scanners of 1.5 T or 3.0 T magnetic field strength (Ingenia 1.5 and
Ingenia 3.0, Philips Healthcare) with 16-channel breast coils. In addition, diffusion imaging was introduced into the standard protocol in
2015.
Gadoteric acid (Dotarem®, Guerbet GmbH, Sulzbach/Taunus,
Germany) was used as intravenous contrast agent in a weight-adapted
dose of 0.2 ml/kg body weight in all examinations. The T2-weighted
sequences were used in axial orientation to determine RGT and skin
flap thickness. The dynamic, contrast-enhanced 3D T1-weighted scan
was acquired at six time points up until 2015 and thereafter only at
points 0, 30 s, 120 s and 210 s after injection of contrast agent bolus.
• to describe frequency, localization and volume of RGT after bilateral
PME, unilateral PME and curative mastectomy using breast MRI,
• to define risk constellations, in which RGT must be expected more
frequently and
• to analyze the occurrence of primary breast cancer after PME during
2.4. Image analysis
The retrospective evaluation of the breast MRI-image data was
performed at a dedicated RIS-PACS workstation (ImpaxEE®, AGFA
Healthcare). As a first step, two radiologists (OG, BK) evaluated the
electronic image data regarding the presence of RGT and other postoperative changes independently from each other using an electronic
questionnaire. In the case of RGT localization, MRI tissue characteristics
such as ACR-grade and parenchymal background enhancement were
recorded. Postoperative changes such as scars, liponecrosis and seromas
were also noted. The thickness of the subcutaneous tissue was measured
bilaterally at two opposing sites (3 o'clock and 9 o'clock, respectively).
As a second step conflicting classifications were discussed between
the two readers and a consensus was found.
As a third step the maximum sagittal (a), transverse (b) and coronal
(c) diameters of RGT in a Cartesian system were independently assessed
by three radiologists (BK, OG, FS). The RGT volume (V) then was extrapolated using the geometric formula of an ellipsoid (V = 4/3πabc).
As a fourth step, the RGT volume was calculated semi-automatically
using special software (Intellispace®, Philips Healthcare) by three evaluators (KA, BK, OG). The results of the two volumetric techniques were
collected using a structured electronic questionnaire (Excel®, Microsoft
Corp., Redmond, WA, USA).
clinical follow-up.
2. Materials und methods
2.1. Inclusion and exclusion criteria
The study protocol was approved by the Local Ethics Committee. All
participants of the university's Center for Hereditary Breast and Ovarian
Cancer Cologne (CHBOC) who underwent unilateral or bilateral PME
and received at least one postoperative breast MRI for proof or exclusion of RGT at the Radiology Department of the University Hospital of
Cologne, Germany, from January 1st, 2006 to December 31st, 2016
were included in the study. We excluded all participants
• who had breast MRI's at other centers of the German Consortium for
Hereditary Breast and Ovarian Cancer (GC-HBOC),
• without a postoperative breast MRI,
• whose postoperative breast MRI was performed at another clinical
site
• without pathogenic BRCA1/2 germline mutation.
2.2. Patient and examination characteristics
2.5. Statistical analysis
The patient data, as well as the genomic and clinical data, were
obtained from the electronic register of the CHBOC, the HospitalInformation-System (HIS) (ORBIS® OpenMed, AGFA HealthCare, NV,
Mortsel, Belgium) and the Radiology-Information-System (RIS-Nice®,
AGFA HealthCare, NV, Mortsel, Belgium) of the University Hospital.
Two radiologists (OG, BK) checked the registries and HIS-/RIS-recordings in reference to the patient's clinical status (bilateral vs. unilateral
PME). In the case of a unilateral PME, the status of the contralateral
breast was recorded (curative mastectomy vs. breast conserving
therapy). Concurrently, it was noted whether and, if so, at what time
before and/or after the mastectomy a breast MRI was performed in the
University Hospital. The last breast MRI performed before the
The evaluators' assessments were documented in a customized
spreadsheet (Excel®, Microsoft Corp., Redmond, WA, USA).
Quantitative variables were summarized by median and interquartile
range (IQR, 25th to 75th percentile), qualitative variables by absolute
and relative frequency (%). Bland-Altman or scatter plots were used for
data illustration. Relationships were described by linear regression and
Pearson's correlation coefficient. Volumes between patient subgroups
were compared using the non-parametric Mann-Whitney U test, proportions using Fisher's exact test. In the essential exploratory analysis pvalues < 0.05 were considered statistically significant. Calculations
were carried out using SPSS Statistics software (IBM Corp., Armonk,
NY, USA).
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Table 1
Aggregated results classified according to the number of mastectomies carried out per surgical institution..
Number of ME per institution
Criteruin; Median (IQR) or n (%)
Prophylactic Healthy ME
Prophylactic Diseased ME
Curative ME
0–20
Breast volume prior to ME, ml
Breast volume after ME, ml
Width of subcutaneous tissue, mm
Sagittal diameter of RGT, mm
Residual retroareolar breast tissue
Sagittal diameter of (all) RGT: 0 mm
Sagittal diameter of (all) RGT: < 5 mm
Sagittal diameter of (all) RGT: ≥5 mm
ACR II: glandular/fatty tissue 25% - < 50%
ACR III: glandular/fatty tissue 50% - < 75%
Breast volume prior to ME, ml
Breast volume after ME, ml
Width of subcutaneous tissue, mm
Sagittal diameter of RGT, mm
Residual retroareolar breast tissue
Sagittal diameter of (all) RGT: 0 mm
Sagittal diameter of (all) RGT: < 5 mm
Sagittal diameter of (all) RGT: ≥5 mm
ACR II: glandular/fatty tissue 25% - < 50%
ACR III: glandular/fatty tissue 50% - < 75%
Breast volume prior to ME, ml
Breast volume after ME, ml
Width of subcutaneous tissue, mm
Sagittal diameter of RGT, mm
Residual retroareolar breast tissue
Sagittal diameter of (all) RGT: 0 mm
Sagittal diameter of (all) RGT: < 5 mm
Sagittal diameter of (all) RGT: ≥5 mm
ACR I: glandular/fatty tissue < 25%
ACR II: glandular/fatty tissue 25% - < 50%
ACR III: glandular/fatty tissue 50% - < 75%
Breast volume prior to ME, ml
Breast volume after ME, ml
Width of subcutaneous tissue, mm
Sagittal diameter of RGT, mm
Residual retroareolar breast tissue
Sagittal diameter of (all) RGT: 0 mm
Sagittal diameter of (all) RGT: < 5 mm
Sagittal diameter of (all) RGT: ≥5 mm
ACR I: glandular/fatty tissue < 25%
ACR II: glandular/fatty tissue 25% - < 50%
ACR III: glandular/fatty tissue 50% - < 75%
133 (70–182)
4 (3–7)
9 (7–13)
3 (0–7)
35/68 (51.5%)
30/68 (44.1%)
9/68 (13.2%)
29/68 (42.6%)
16/38 (42.1%)
22/38 (57.9%)
104 (63–140)
4 (3–5)
7 (5–11)
0 (0–5)
8/26 (30.8%)
18/26 (69.2%)
2/26 (7.7%)
6/26 (23.1%)
6/8 (75%)
2/8 (25%)
54 (40–111)
3 (2–4)
10 (8–17)
3 (0–7)
24/44 (54.5%)
20/44 (45.5%)
7/44 (15.9%)
17/44 (38.6%)
0/24 (0%)
16/24 (66.7%)
8/24 (33.3%)
92 (55–172)
3 (3–6)
9 (7–13)
2 (0–7)
67/138 (48.6%)
68/138 (49.3%)
18/138 (13%)
52/138 (37.7%)
0/70 (0%)
38/70 (54.3%)
32/70 (45.7%)
108 (93–151)
2 (2–3)
9 (7–14)
0 (0–5)
14/39 (35.9%)
25/39 (64.1%)
5/39 (12.8%)
9/39 (23.1%)
6/14 (42.9%)
8/14 (57.1%)
71 (66–93)
2 (2–2)
9 (5–15)
0 (0–7)
5/12 (41.7%)
7/12 (58.3%)
0/12 (0%)
5/12 (41.7%)
3/5 (60%)
2/5 (40%)
109 (53–228)
2 (1–4)
11 (7–14)
0 (0–4)
15/48 (31.3%)
31/49 (63.3%)
6/49 (12.2%)
12/49 (24.5%)
2/18 (11.1%)
6/18 (33.3%)
10/18 (55.6%)
93 (65–151)
2 (2–3)
10 (7–14)
0 (0–5)
34/99 (34.3%)
63/100 (63%)
11/100 (11%)
26/100 (26%)
1/37 (2.7%)
15/37 (40.5%)
20/37 (54.1%)
106 (106–106)
3 (2–4)
8 (6–13)
0 (0–0)
7/38 (18.4%)
31/38 (81.6%)
2/38 (5.3%)
5/38 (13.2%)
4/7 (57.1%)
3/7 (42.9%)
29 (29–29)
1 (1–1)
4 (3–13)
0 (0–0)
1/12 (8.3%)
11/12 (91.7%)
0/12 (0%)
1/12 (8.3%)
1/1 (100%)
0/1 (0%)
126 (61–209)
4 (1–5)
10 (6–13)
0 (0–5)
13/49 (26.5%)
35/50 (70%)
3/50 (6%)
12/50 (24%)
0/15 (0%)
3/15 (20%)
12/15 (80%)
124 (61–155)
3 (1–5)
9 (5–13)
0 (0–0)
21/99 (21.2%)
77/100 (77%)
5/100 (5%)
18/100 (18%)
0/23 (0%)
8/23 (34.8%)
15/23 (65.2%)
40–60
> 60
total
Abbreviations:ME ‘mastectomy’ RGT ‘residual glandular tissue’ IQR ‘interquartile range (25th to 75th percentile)’.
3. Results
3.2. Surgical units
3.1. Study group
The 262 mastectomies were performed in 41 hospitals. Concerning
76 mastectomies the surgical center was not apparent from the available registers. The units were divided into three groups: 0–20 mastectomies per unit, 40–60 mastectomies per unit, > 60 mastectomies per
unit. The subgroup analyses showed a significantly higher RGT volume
following mastectomies in the surgical units with 0–20 mastectomies
compared to those with ≥40 mastectomies (p < 0.033). The proportion of RGT present following bilateral PME (subgroup A) and curative
mastectomy (subgroup C) was also higher in less frequented units (0–20
mastectomies/unit versus 40–60 mastectomies/unit): subgroup A
51.5% versus 30.8%, subgroup B 35.9% versus 41.7%, subgroup C
18.4% versus 8.3% (Table 1).
169 women met the inclusion criteria and did not fall under any of
the exclusion criteria (Table 1, supplementary data). Thus, the evaluations were based on 338 MR-tomographically examined breasts in
169 women with BRCA1/2 mutations. The median age of the 69 patients included with bilateral PME was 38.3 years ± 8.9 years standard
deviation (minimum 21.2 years, maximum 58.6 years) and 42.3
years ± 8.4 years standard deviation (minimum 21.5 years, maximum
62.4 years) for the 100 patients with unilateral PME. All 100 patients
with unilateral PME (100%) had either an immediate or a delayed
curative mastectomy. The mastectomized breasts were analyzed separately and subdivided into the following subgroups:
3.3. Surgical techniques
1. Subgroup A: bilateral PME in healthy mutation carriers (138 breasts
in 69 patients)
2. Subgroup B: unilateral PME of the healthy breast in mutation carriers with contralateral breast cancer (100 breasts in 100 patients)
3. Subgroup C: curative mastectomy of the diseased breasts (100
breasts in 100 patients).
According to the data of the CHBOC register, of the 338 breasts
operated on (169 women), 283 breasts (83.8%) underwent skin or
nipple-sparing mastectomy and 41 breasts (12.1%) underwent modified
standard mastectomy, namely removal of the breast and nipple, 31 of
which had secondary breast reconstruction and 10 did not. In 14 breasts
(4.1%), it was unclear whether the surgical method was skin/nipple
sparing or standard mastectomy with no reconstruction due to the
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Fig. 1. Graphical representation of the depth of RGT in the sagittal “areola to
thoracic wall” plane depending on the surgical technique used in bilateral PME
(subgroup A), unilateral PME in contralaterally diseased women (subgroup B)
and curative mastectomies in women with contralateral PME (subgroup C).
Circle = statistical outlier, asterisk = numeric extreme value.
Fig. 2. Bland-Altmann plot comparing the volumetric (software-based) and
Cartesian (diameter-based) determinations of RGT in 128 breasts. The abscissa
represents the mean of both determinations per breast and the ordinate represents the difference between the two determinations. It shows limits of
agreement of −3.8 to 5.7 (ml) with bias of 0.95 (95% CI 0.53 to 1.38,
p < 0.001) towards larger volumes for the software-based method compared
to the volumetric method.
retrospective methodological approach and the inclusion of 41 breast
units which implemented different documentation standards.
In subgroup A (bilateral PME) nipple sparing mastectomies were
performed in 108 (78.3%) and skin sparing mastectomies were carried
out in 18 (13.0%) of 136 cases. Concerning eight breasts the surgical
technique was specified as either nipple sparing or skin-sparing (Fig. 1,
supplementary data). Two breasts underwent standard mastectomy
without reconstruction (1.4%). In two cases, no information was given
on the surgical technique. In subgroup B (unilateral PME) 16 out of 100
breasts (16.0%) and in subgroup C (unilateral curative mastectomy) 23
out of 100 breasts (23.0%) had a standard mastectomy without reconstruction. 53 of the 100 unilateral PMEs (53.0%) and 46 of the 100
curative mastectomies (46.0%) were performed using nipple sparing
technique. There were 22 skin sparing mastectomies (22.0%) and three
mastectomies (3.0%) without further specification in subgroup B and
subgroup C, respectively. In six cases the CHBOC register did not provide any information on the surgical technique used.
3.4. vol calculation techniques
Fig. 2 shows the results of the manually performed volume calculations by Cartesian determinations of the maximum diameter (step 3)
compared with the results of the semi-automatic software-based calculations (step 4) in the form of a Bland-Altmann-Plot. For the softwarebased method an above-average standard deviation towards larger
volumes was found compared to the volumetric method. In the following, the software-based volumetric results were used.
Fig. 3. Statistical outlier: 38 year-old patient who had undergone bilateral PME
for a pathogen BRCA1/2 germline mutation and bilateral reconstruction with
silicone prostheses in 2013. Breast volume measured 83 ml (right side) and
105 ml (left side) preoperatively and 78 ml (right side) and 57 ml (left side) post
PME.
3.5. Frequency of RGT
Overall, RGT was detected in 128 of the 338 breasts following
mastectomy (37.9%). 68 of the 128 breasts (53.1%) were related to
bilateral PME (subgroup A), 37 breasts (28.9%) to unilateral PME
(subgroup B) and 23 (18%) to curative mastectomy (subgroup C). RGT
appeared significantly more often after bilateral PME than unilateral
PME (p < 0.0001). The comparison of subgroup A and subgroup C did
not show a statistically significant difference (p < 0.102), neither did
the comparison of subgroup B and subgroup C (p < 0.199), which may
have been due to the low number of cases (Table 1).
3.5.1. RGT volume before and after mastectomy
The postoperative volumes in subgroup A averaged 3 ml (minimum
3 ml, maximum 6 ml), in subgroup B 2 ml (2 ml, 3 ml), in subgroup C
3 ml (1 ml, 5 ml) (Fig. 3). In 79 of the 128 breasts with RGT preoperative MRI scans were available. The results of a patient with
average preoperative volumes (right breast 83 ml, left breast 105 ml)
and postoperative RGT volumes of 78 ml on the right side and 57 ml on
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Fig. 4. Graphical representation of the volume of preoperative breast tissue on the abscissa and the RGT after mastectomy on the ordinate per breast (red dots) in
patients with both preoperative and postoperative breast MRI. A positive correlation is shown between preoperative breast volume and RGT volume when considering all 76 breasts (Fig. 4A), the subgroup of bilateral PME ( Fig. 4B), the subgroup with unilateral PME ( Fig. 4C) and the subgroup with curative mastectomy (
Fig 4D) (p < 0.001). Three outliers with RGT of 78 ml, 57 ml and 29 ml after bilateral PME (blue dots) were excluded from statistical analysis.
A All 76 breasts with RGT and preoperative breast MRI
B 52 breasts with bilateral PME
C 15 breasts with unilateral PME
D Nine breasts with curative mastectomy.
Fig. 5. Graphical representation of the width of the
postoperative soft tissue on the ordinate and the preoperative gland volume on the abscissa divided into two
groups: retroareolar RGT < 5 mm in the sagittal diameter (left) and ≥5 mm (right) demonstrating a significant reduction of soft tissue in bigger preoperative
volumes in the second group (right).
3.5.2. Localization of RGT
In 122 of the 128 breasts affected, the RGT was localized in the
retroareolar breast region (94.6%). In subgroup A the RGT was detected
in the retroareolar breast region in 67 out of 70 cases (95.7%), in
subgroup B in 34 out of 36 cases (94.4%) and in subgroup C in 21 out of
23 cases (91.3%). Independent of subgroup allocation, retroareolar
left side were excluded from the statistical calculations as statistical
outliers. The regression analysis confirmed a linear relationship between the RGT volume before and after mastectomy across all subgroups as well as in the independently analyzed subgroups, indicating
that larger preoperative baseline volumes contain more RGT post
mastectomy (Fig. 4A–D).
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localized mainly in the retroareolar breast region (122 of 128 breasts)
with multifocal RGT being an exception and concerning only 10% of
the bilaterally mastectomized breasts (seven breasts). While 97.1% of
the bilateral PMEs were carried out using skin or nipple-sparing technique, 16% of the unilateral PMEs and 23% of the curative mastectomies were carried out using standard mastectomy technique with and
without reconstruction. Therefore, RGT is a common postoperative
finding that appears to be related to the selected surgical technique. In
accordance with the present results Woitek et al. evaluated postoperative MRI scans of 58 patients after prophylactic skin-sparing
mastectomy (SSM) and nipple-sparing mastectomy (NSM) and found
RGT in 20% of all breasts and significantly more frequently after NSM
than SSM [24]. Van Verschuer et al. histologically analyzed 105 NippleAreola-Complexes (NACs) and adjacent skin islands in 90 women after
prophylactic skin-sparing (31 cases) and curative mastectomies (71
cases). They found evidence of RGT in 61% of the NAC samples and
24% of the skin samples but did not differentiate between the two
surgical indications [23].
In the present study, a significantly higher RGT volume was found in
breasts mastectomized in the less frequented surgical units with > 20
mastectomies compared to those with ≥40 mastectomies (p < 0.033),
which indicates that the individual surgeon's expertise or the cumulative team experience has a marked impact on the clinical outcome.
For the two-point measurements (horizontal direction, 3 o'clock and
9 o'clock), the thickness of the subcutaneous tissue averaged 10.5 mm
with maximum values of 52.3 mm. In accordance with our approach
Zippel et al. used postoperative MRI to evaluate residual breast tissue in
88 breasts after prophylactic (n = 43) and curative mastectomies
(n = 45) and reconstruction using silicone prostheses at four points
with similarly high mean and maximum values (mean 11.2 mm, maximum 53.4 mm) [25]. Additionally, there was an association between
the thickness of the subcutaneous tissue and RGT volume, especially at
locations other than the retroareolar breast region. These findings are
concordant with the histological results of Torresan et al. who showed a
significant association (p < 0.005) between the presence of RGT and
skin flap thickness of more than 5 mm [22].
The sagittal diameter of retroareolar RGT was ≥5 mm in 96 of the
130 mastectomzied breasts (74%) and thus exceeded the recommended
5 mm limit for the maintenance of subdermal vascularization [26,27].
The mean and maximum diameters were larger after bilateral PME
when compared with unilateral PME and curative mastectomy. These
results support the hypothesis that different surgical indications and
chosen techniques influence the clincial outcome significantly. Baltzer
et al. used breast MRI to measure the retroareolar fibroglandular tissue
relative to the entire glandular body at 5 mm and 10 mm retroareolar
diameters on a total of 105 BRCA1/2 mutation carriers [28]. The proportion of retroareolar glandular tissue assuming a sagittal diameter of
5 mm averaged only 1.3% of the total glandular tissue. However, increasing the diameter to 1 cm showed a highly significant increase of
the proportion to 3% (p < 0.001). Even a proportion of 1.3% appears
clinically relevant taking into account the fact that both carcinomas we
detected during the follow_up appeared as microscopically undetectable RGT.
The median time to follow-up was 4.3 years (minimum 6 months
and maximum 19 years). Two out of 169 women developed breast
cancer following PME after two and five years, respectively. Despite the
use of nipple-sparing technique (78.3% in subgroup A), no carcinoma
was observed in the retroareolar breast region. This is in accordance
with the results of the multi-center study by Orzalesi et al. who found
following 1006 nipple-sparing mastectomies (12.3% PME), recurrence
of cancer in the NAC in 0.7% over a mean follow-up period of 1101
days [29]. Yao et al. analyzed 397 nipple-sparing mastectomies in
BRCA1/2 mutation carriers (74.6% PME) with a total of four breast
cancers (one carcinoma after PME) on average in the follow-up period
of 32.6 months, with no NAC involvement [30]. Manning et al. did not
record any oncological events after a total of 177 nipple-sparing
RGT was most often found following nipple sparing mastectomy
(Fig. 1). Multifocal RGT was an exception and concerned only seven
breasts in subgroup A (10%). In subgroup B and subgroup C, there was
no case of multifocal RGT.
3.5.3. Sagittal diameter of RGT
The retroareolar extension of RGT, defined as the sagittal RGT
diameter measured between the areola and the thoracic wall, averaged
2 mm (minimum 0 mm, maximum 7 mm) in subgroup A, 0 mm (0 mm,
5 mm) in subgroup B and 0 mm (0 mm, 0 mm) in subgroup C. In subgroup A 52 of the 138 breasts showed RGT with a sagittal diameter of
≥5 mm (37.7%), in subgroup B 26 of the 100 breasts showed such a
diameter (26%) and in subgroup C 18 of the 100 breasts (18%) were
found to have RGT with ≥5 mm sagittal diameter (Table 1). A sagittal
RGT diameter ≥5 mm showed a significant correlation between the
thickness of the subcutaneous tissue and the preoperative initial volume
with increasingly narrow flap at larger initial volumes (Fig. 5).
3.5.4. Thickness of the subcutaneous tissue
The mean thickness of the subcutaneous tissue was 9 mm (minimum
7 mm, maximum 13 mm) in subgroup A, 10 mm (7 mm, 14 mm) in
subgroup B and 9 mm (5 mm, 13 mm) in subgroup C (Table 1). The
regression analysis of RGT and the postoperative subcutaneous soft
tissue showed a positive trend towards larger RGT volumes in thicker
soft tissue flaps (Fig. 6). RGT in the retroareolar breast region showed a
negative trend towards narrower soft-tissue flaps in breasts with larger
initial volumes (Fig. 7).
3.6. Clinical follow-up
The median time to follow-up under the CHBOC program was 4.3
years (minimum six months, maximum 19 years). Breast cancers were
recorded in two patients five years after bilateral PME and two years
after unilateral PME respectively in locations without RGT as visualized
by the index breast MRI. In the first case of retroareolar RGT, in the
index-MRI, the carcinoma was located in the periphery of the left upper
outer quadrant according to the clinical documentation. In the second
case there was no RGT visualized in the index-MRI.
4. Discussion
In the present study, RGT was detected in 128 of 338 mastectomized
breasts (37.9%). In more than 50% (68 of 128 breasts), RGT was related
to bilateral PME and was present significantly more often after bilateral
PME than after unilateral PME and curative mastectomy. RGT was
Fig. 6. Correlation of the width of the postoperative soft tissue (plotted on the
ordinate) and the postoperative RGT (plotted on the abscissa), including all
three subgroups demonstrating a positive trend.
131
Surgical Oncology 29 (2019) 126–133
O. Grinstein, et al.
Fig. 7. Comparison of the thickness of the postoperative soft tissue (ordinate) and the preoperative gland volume (abscissa) divided into two groups: RGT localization
other than in retroareolar breast region (left) and RGT in the retroareolar breast region (right) demonstrating a negative trend in the second group.
outcome. In view of these findings, radiologists should report on RGT
more consistently and the continuation of structured image-based surveillance of BRCA1/2 mutation carriers has to be discussed even following PME if RGT persists. However, large-scale, prospective, longterm studies are needed in order to assess the oncological risk associated with RGT and to define the role of breast MRI in the management
of patients following PME.
mastectomies in BRCA 1/2 mutation carriers during an average followup period of 2.15 years [31]. However, the short follow-up period is
indeed a mentionable limitation of these studies. Hartmann et al. followed-up 639 women at increased hereditary risk for breast cancer,
who underwent PME, for a median of 14 years [32]. Seven of these
women developed breast cancer 2–25 years after mastectomy, only one
of them in the NAC. Skytte et al. surveyed 307 healthy BRCA1/2 mutation carriers; 96 of them having undergone bilateral PME [33]. Three
of them developed breast cancer at intervals of two, five and seven
years after PME. Two of the carcinomas were located on the thoracic
wall and one in the axilla. Based on those results, the working group
calculated a cumulative ten-year incidence for the cohort of mastectomized mutation carriers of about 10%. Since no image correlation took
place in these studies, it prompts the question about underlying RGT.
The present study has the following methodological limitations:
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://
doi.org/10.1016/j.suronc.2019.04.009.
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The Breast 39 (2018) 8e13
Contents lists available at ScienceDirect
The Breast
journal homepage: www.elsevier.com/brst
Original article
Nipple-sparing bilateral prophylactic mastectomy and immediate
reconstruction with TiLoop® Bra mesh in BRCA1/2 mutation carriers:
A prospective study of long-term and patient reported outcomes using
the BREAST-Q
D. Casella a, G. Di Taranto b, *, M. Marcasciano a, b, S. Sordi c, A. Kothari d, T. Kovacs d,
F. Lo Torto b, E. Cigna e, D. Ribuffo b, C. Calabrese c, d
a
Department of Oncologic and Reconstructive Breast Surgery, “Breast Unit Integrata di Livorno, Cecina, Piombino, Elba, Azienda USL Toscana Nord Ovest”,
Italy
b
Plastic Surgery Unit, Department of Surgery “P. Valdoni”, Sapienza University, Rome, Italy
c
Oncologic and Reconstructive Surgery Breast Unit, Oncology Department, Careggi University Hospital, Florence, Italy
d
Breast Surgery Unit, Guy's Hospital, Guy's and St. Thomas' NHS Foundation Trust, London, UK
e
Plastic and Reconstructive Surgery Unit, Hospital of Pisa, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 August 2017
Received in revised form
19 December 2017
Accepted 6 February 2018
Available online 18 February 2018
Background: Although demand for prophylactic mastectomy is increasing over time among women at a
high risk for breast cancer, there is a paucity of studies on long term patient-reported outcomes after this
procedure.
Methods: Between January 2011 and January 2015, 46 patients documented BRCA1/2 mutation carriers,
eligible for prophylactic nipple-sparing mastectomy (NSM) and immediate breast prosthetic reconstruction were registered at our Institution. Patients underwent NSM and subcutaneous reconstruction
with implant covered by a titanium-coated polypropylene mesh (TiLoop®). The BREAST-Q questionnaire
was given to patients prior to surgery and at 1 and 2 years follow-up points. Capsular contracture was
evaluated by Baker scale. Surgical outcomes along with the changes in BREAST-Q score were analyzed
over time.
Results: Complications were reported in only one case and after two years the capsular contracture rates
were acceptable (grade I: 65,2%; grade II: 32,6%; grade III 2,2%). At one year and two year follow-ups
patients reported high rates in the measures of overall satisfaction with breasts (72,5 and 73,7 respectively), psychosocial well-being (78,4 and 78,6), sexual well-being (58,8 and 59,4), physical well-being
(77,6 and 80,6) and overall satisfaction with outcome (75,7 and 79,7). A statistically significant increase in all BREAST-domains from the preoperative to the postoperative period was reported at one and
two years follow-ups (p < 0,05).
Conclusion: Following bilateral prophylactic NSM and immediate subcutaneous reconstruction with
TiLoop®, patients demonstrated high levels of satisfaction and quality of life as measured by BREAST-Q.
2-years outcomes confirmed high patient comfort with increased scores from the preoperative baseline
level.
© 2018 Elsevier Ltd. All rights reserved.
Keywords:
Nipple-sparing mastectomy (NSM)
Prophylactic mastectomy
TiLoop
BRCA mutation
Subcutaneous breast reconstruction
1. Introduction
Considerable efforts have been made over the past decades
* Corresponding author. Via dei Campani, 26, 00185 Rome, Italy.
E-mail address: giuseppe.ditaranto@uniroma1.it (G. Di Taranto).
https://doi.org/10.1016/j.breast.2018.02.001
0960-9776/© 2018 Elsevier Ltd. All rights reserved.
toward the development of surgical management of breast cancer
[1,2]. Surgical targets have rapidly evolved, aiming to optimize
cosmetic outcomes and reduce patient morbidity, while still
providing an oncologically-safe surgical procedure [3e6]. Surgeons
moved from the radical mastectomy to the acceptance of breast
conservation and aesthetic outcomes improvement as the achievable goals of surgical procedures. Skin sparing mastectomy (SSM)
D. Casella et al. / The Breast 39 (2018) 8e13
and Nipple sparing mastectomy (NSM) have low local recurrence
rates, comparable with total mastectomy and allows for immediate
breast reconstruction [2]. Several studies revealed similar survival
outcomes for NSM patients compared to SSM patients in the cancer
setting and NSM has also shown favorable outcomes for risk
reduction (RR) surgery [3].
Though NSM has been validated as an oncologically safe option,
there are still some concerns regarding the risk of tumor recurrence
in patients at the highest risk of breast cancer, such as BRCA1/2
mutation carriers [3]. It is reported that the risk of developing
breast cancer in women with a BRCA1/2 mutation is of between 60
and 80% and that prophylactic mastectomy reduce the risk of breast
cancer by up to 95% [7e9]. Due to the lack of long-term outcomes
data in literature, the adoption of NSM in this patient population
remains a subject of controversy. A recent study on 201 BRCA1/2
mutation carriers reported that NSM is associated with a low rate of
complications and risk of breast cancer, comparable with SSM [3].
Although there is a growing body of evidence on oncologic and
surgical safety of NSM, in this group of women, there is a paucity of
studies on patient-reported outcomes. Few studies have examined
the impact of nipple preservation, following nipple sparing prophylactic mastectomy (NSPM) and immediate breast reconstruction on health-related quality of life (HRQOL) [4e6,8e10]. Previous
evaluations of patient outcomes after NSM have shown high levels
of satisfaction, but these studies have all been somewhat limited by
their retrospective design and heterogeneous or small sample size
populations. The increased demand for NSM highlight the need for
objective evaluation of HRQOL outcomes [11,12].
The aim of this study was to determine whether NSM, with
immediate breast reconstruction using silicone implants and
TiLoop® Bra mesh, could be established as a safe procedure and
examine how HRQOL is influenced by nipple-areola complex
preservation in a BRCA1/2 mutation carrier population. We prospectively evaluated the HRQOL using the BREAST-Q, a validated
patient-reported outcome instrument developed specifically for
patients undergoing breast reconstruction.
2. Materials and methods
2.1. Patients
Between January 2011 and January 2015, patients with proven
BRCA1 or BRCA2 gene mutation, undergoing prophylactic bilateral
mastectomy at our institution, Azienda Ospedaliero-Universitaria
Careggi, were enrolled for this study. These women, wanted and
were suitable for nipple-sparing mastectomy and immediate breast
prosthetic reconstruction; patients with “variants of uncertain
significance” BRCA1/2 gene mutations were excluded. Inclusion
criteria were documented BRCA1/2 mutation, body mass index
(BMI) between 25 and 35 kg/m2, no previous breast surgery, no
evidence of cancer on clinical examination or imaging (magnetic
resonance imaging (MRI), mammogram and ultrasound) and suitability for immediate reconstruction with subcutaneous implants.
Prior to surgery, all patients were evaluated for both autologous or
alloplastic breast reconstruction, taking into account patient preference, body habitus, co-morbidities and prior abdominal surgery.
We enrolled in this study only patients willing to undergo prosthetic breast reconstruction, who refused autologous reconstruction or presenting any contraindication to these procedures. This
study was approved by our institutional Ethics Committee and all
patients provided written informed consent.
2.2. Operative technique
We have previously published our surgical technique for NSM
9
and immediate reconstruction with implant and TiLoop® Bra mesh
[13e15]. Briefly, the mastectomy was performed through an
inframammary or lateral incision and skin flaps were raised in the
subdermal plane. Once the breast tissue had been resected, the
nipple tissue was cored out, while preserving the NAC skin. The
excised tissue along with a specimen of the tissue underlying the
NAC was sent to the pathologist for definitive histological evaluation. Patients underwent immediate reconstruction through
definitive implant placement using a titanium-coated polypropylene mesh (TCPM), specifically TiLoop® Bra (TiLOOP® Bra, pfm
medical, Cologne, Germany). The skin flaps were assessed and
when considered adequate, after confirming definitive implant
with a sizer, a TiLoop® Bra mesh bag was adjusted around the
implant. Using absorbable sutures, a TiLoop® sheet was folded onto
itself to create a bag which eventually functioned as a pocket for the
breast implant. In the case of larger implants, two TCPM sheets
were used and stitched together. The TCPM bag, with the implant
inside, was then placed in a totally subcutaneous pre-pectoral position. Medial and lateral borders were secured to the muscular
fascia with interrupted absorbable sutures. One vacuum drain was
inserted in the inframammary fold and patients received oral antibiotics until surgical drains were removed. Patients were evaluated every two weeks for the first 2 months and follow-up visits
were performed every 2 months thereafter. All the procedures were
performed by the same surgeons.
2.3. Outcomes and measures
A secure digital database was prospectively created in order to
collect data on patient demographics, BRCA mutation, medical
history, family history, surgical complications and capsular
contracture. Surgical complications were named as implant
removal, skin-nipple necrosis, seroma, wound dehiscence, surgical
site infection and hematoma. HRQOL and cosmetic outcome evaluation were conducted using the preoperative and the postoperative BREAST-Q modules for reconstructive surgery [16e24].
Enrolled patients received the preoperative questionnaire from the
BREAST-Q reconstructive module after consultation with both the
surgical oncologist and the plastic surgeon one month before the
mastectomy. Patients were required to answer The BREAST-Q
postoperative module at 1 and 2 years after mastectomy. At these
time points, surveys were given directly to patients during their
scheduled clinic visit. All aspects of the BREAST-Q reconstructive
module (Satisfaction with Breasts, Satisfaction with Outcome,
Psychosocial Well-being, Physical Well-being and Sexual Wellbeing) were included with exception of questions regarding
abdominal donor site.
In keeping with the developers' guidance, patients who failed to
answer more than half the items within each domain were
excluded from the analysis for that particular domain [16,23,24].
Baker Scale was used for scoring capsular contracture during
postoperative follow-ups, at one and two years after mastectomy.
The completed questionnaires were reviewed by the senior authors
(RD, CE) and our co-authors from the Breast Unit of Guy's Hospital,
London.
2.4. Statistical analysis
Descriptive statistic accounted for patient sociodemographic,
clinical characteristics, complications and capsular contracture
grade. Using the QScore Scoring Software, BREAST-Q scores were
converted from survey raw scores (1 through 4 or 5) to a continuous
range from 0 to 100, with a higher score representing greater
satisfaction or better HRQOL. The scores for each BREAST-Q matrix
indexes were determined at each time point and then entered into
10
D. Casella et al. / The Breast 39 (2018) 8e13
the database, along with the other data collected from patients and
medical records. Both absolute BREAST-Q scores and changes in
scores before and after treatment were analyzed. The Shapiro-Wilk
test was used to verify for normal distribution of continuous variables. Consequently, Breast-Q scores were analyzed using Student
t-distribution. P values less than 0.05 were considered statistically
significant.
3. Results
3.1. Patient characteristics
A total of 46 women BRCA1/2 mutation carriers were enrolled in
to this study. Table 1 describes the demographic characteristics of
participants. The 91,3% of the patients was Caucasian and the mean
age at the time of NSPM was 43,2 years (range 23e65 years). The
mean BMI was 28,4 kg/m2 (range 25e35 kg/m2). The mean time
interval from patients' mutation diagnosis to surgery was 7.3
months (range 4e14 months). The drain was removed between the
fourth and ninth postoperative day (mean value: 6,5 days). Complications were recorded in 1 patient, who developed necrosis of
the breast skin flaps that required explantation. She underwent
revision reconstruction using sub-pectoral expanders, followed by
second stage replacement of the expander by definitive breast
implant and lipofilling after 6 month. There were no cases of NAC
necrosis and one patient had positive histological evaluation at the
definitive analysis. Incidental stage 0, non invasive breast cancer
was found in 1 patient. We did not detect any cases of severe
capsular contracture (grade IV) at both follow-up points and, after
two years, 30 patients were evaluated as grade I (65,2%), 15 patients
as grade II (32,6%) and 1 patients grade III (2,2%). After one year in 7
cases an additional intervention in the form of lipofilling was
required for either, visible implant creasing or implant edge
palpability [25,26]. The mean volume of injected fat was 20,3 ml
per breast. A one year follow-up clinic visit was scheduled in all
cases before a second operation (Figs. 1 and 2).
3.2. Measure of HRQOL
All patients adequately answered for the five domains of the
questionnaire. Tables 2 and 3 show the self-reported measures of
Table 1
Demographic characteristics.
Patient characteristic
All patient (46)
Age [years, mean (range)]
BMI [kg/m2, mean (range)]
Ethnicity (n, %)
Caucasian
Hispanic
Asian
Marital status (n, %)
Married
Divorced
Separated
Single
Comorbidities (n, %)
Diabetes
Connective tissue diseases
Smoking (n, %)
Never smoker
Past smoker
Active smoker
BRCA Mutation (n, %)
BRCA1
RCA2
43,2 (23e65)
28,4 (25e35)
42 (91,3)
2 (4,3)
2 (4,3)
27 (58,7)
4 (8,7)
2 (4,3)
13 (28,3)
3 (6,5)
1 (2,1)
28 (60,9)
10 (21,7)
8 (17,4)
30 (6,52)
16 (34,8)
HRQOL, evaluated with BREAST-Q questionnaire, at the preoperative setting compared to 1 year and 2 years respectively, after
reconstruction. Significant increases from the base line were reported in the domains for overall satisfaction with breasts
(p < 0,05), psychosocial well-being (p < 0,05) and sexual well-being
(p < 0,05) at both follow-ups. The scores tended to improve overtime at the second follow-up. The measure for physical impact of
the surgery declined from the preoperative to postoperative evaluations, but this was not observed to be statically significant.
Overall satisfaction with outcome index, measured postoperatively, was higher and improved over time throughout the
post-operative period, but this was not significant (p ¼ 0,091).
4. Discussion
Consequent to extensive coverage by the media there is an
enhanced awareness amongst women about hereditary breast
cancer. Newer testing guidelines and patient choice has led to an
increase in BRCA mutation testing and genetic counseling, allowing
patients to consciously consider prevention and therapy-related
complications, while making decisions about surgical management of breast cancer [27e31]. The number of women seeking gene
testing continues to rise and in Italy some medical societies are
claiming implementation of specific health pathways, targeting
toward early diagnosis and reduction of BRCA-related cancer risk
rate [32]. Italian press named “right of gene” the request of introducing BRCA mutations screening among the basic healthcare
services the national health system provides by law.
For women at highest risk for breast cancer, risk-reducing surgery has been associated with the greatest potential benefit in
terms of decreasing the chance of developing breast cancer and
demand for prophylactic mastectomy is increasing over time
amongst this cohort of women [3]. In this regard, the value of a
spared NAC for women psychological and sexual functions has been
described before. However, little is known about the impact of
these risk-reducing strategies on quality of life, and more research
is needed in order to achieve robust and sound scientific evidence
[3e8].
Our prospective study looks at the immediate and long term
surgical and BREAST-Q outcomes for a series of 46 patients who
underwent NSM and immediate reconstruction with TiLoop® Bra
mesh. Our data demonstrates the safety and reliability of this
technique, reporting satisfactory long term results with low
complication rates and high patient satisfaction. 2-year outcomes
for quality of life confirm high patient satisfaction following prophylactic mastectomy and suggest that NSM and TiLoop® immediate pre-pectoral breast reconstruction has the potential for
providing a valid and safe aesthetic alternative. Furthermore, 2
years following surgery, patients reported significantly high scores
in the self-reported measures of overall satisfaction with breasts
(73,7), psychosocial well-being (78,6) and sexual well-being (59,4).
The patients demonstrated a significant increase in self-reported
measures from the preoperative to the postoperative period at
one and two years follow-ups. All the postoperative data were
evaluated both in absolute terms and in relation to preoperative
results, as changes in scores were considered a more reliable and
comparable measurement. Indeed, recently Howard et al. prompted to define the precise “minimally important differences” for
BREAST-Q scores and proposed new baseline scores for BREAST-Q
results in NSM surgery [5]. This study prospectively analyzed a
heterogeneous population of 39 patients undergoing NSM for
cancer treatment (n ¼ 17) or (Risk Reducing) RR (n ¼ 22) and immediate 1- and 2-stage implant or autologous immediate breast
reconstruction and demonstrated high levels of satisfaction and
quality of life as measured by BREAST-Q [5]. Another prospective
D. Casella et al. / The Breast 39 (2018) 8e13
11
Fig. 1. A 42-year-old woman who underwent bilateral prophylactic NSM (inframammary fold incision) and direct-to-implant reconstruction: preoperative (left) and 2 year's
postoperative (right).
Fig. 2. A 38-year-old woman who underwent bilateral prophylactic NSM (lateral incision) and direct-to-implant reconstruction: preoperative (left) and 3 months' postoperative
(right).
study designed by Peled at al, reported preoperative and one year
follow-up outcomes of 28 NSM patients undergoing RR or cancer
treating mastectomy and expander-implant reconstruction, evaluated with the BREAST-Q [4]. Other studies adopted BREAST-Q
questionnaire for evaluating patients following NSM, but this was
collected retrospectively and almost all the authors applied only
the postoperative modules [6,10,21,22,33]. Furthermore as populations of these studies encompass woman with different characteristics, undergoing mastectomy for either therapeutic or
prophylactic reasons and reconstruction with several techniques, it
would be incongruous comparing our results with the measures
provided by other authors. As postulated by Howard, preoperative
measurements of breast health, psychosocial well-being, and
sexuality establish a baseline measurement with which to determine if surgery decreases or increases these quality of life outcomes
[5]. We agree that without a baseline measurement it is impossible
to know if a score, even if high or at a long term follow-up after
surgery, is actually a change from the baseline score. Nevertheless,
our scores correlated well with the data from Howard's study,
regarding only the small cohort of patients (n ¼ 22) undergoing RR
mastectomy [5].
Interestingly, as previously reported by other studies, we found
in our clinical practice that RR and cancer patients who apply
BREAST-Q questionnaire routinely at our institution scored relatively similar preoperative values (data not shown) [4,5]. It is
possible that a new diagnosis of BRCA1 or 2- gene mutation would
have a similar negative psychological impact as a cancer diagnosis
in our patients series. Following this hypothesis, patients at high
risk for breast cancer behave as they feel carriers of a disease rather
than a simple gene mutation, affecting their psychological status
and social life. However, RR patients scored high BREAST-Q results
at 1-year and 2-years follow-up and expressed great overall satisfaction with outcome. We mainly ascribe these results to the relief
experimented by patients after breast removal due to the decreased
Table 2
BREAST-Q scores recorded preoperatively and one year postoperatively, expressed as mean ± standard deviation. Changes in scores are expressed as delta (postoperative score
minus preoperative score). *P < 0,05.
Domain
Preoperative mean (±SD)
Postoperative mean (±SD)
Delta mean
p-value
Satisfaction-breasts
Psychosocial wellness
Sexual well-being
Physical impact (chest)
Overall satisfaction with outcome
59,3
66,4
52,7
80,9
e
72,5
78,4
58,8
77,6
75,7
13,2
12
6,1
3.3
e
0.0033*
0.0132*
0.0253*
0.0984
e
(±12,2)
(±13,7)
(±14,4)
(±10,4)
(±10,1)
(±13,3)
(±12,6)
(±14,2)
(±12,3)
12
D. Casella et al. / The Breast 39 (2018) 8e13
Table 3
BREAST-Q scores recorded preoperatively and two year postoperatively, expressed as mean ± standard deviation. Changes in scores are expressed as delta (postoperative score
minus preoperative score). *P < 0,05.
Domain
Preoperative mean (±SD)
Postoperative mean (±SD)
Delta mean
p-value
Satisfaction-breasts
Psychosocial wellness
Sexual well-being
Physical impact (chest)
Overall satisfaction with outcome
59,3
66,4
52,7
80,9
e
73,7
78,6
59,4
80,6
79,7
14,4
12,2
6,7
0,3
e
0.0145*
0.0193*
0.0179*
0.0846
e
(±12,2)
(±13,7)
(±14,4)
(±10,4)
likelihood of developing a breast cancer rather than to the simple
breast aesthetic outcome. Indeed, in our study only three patients
required a breast augmentation, while the others were satisfied
with their breast shape and volume and did not ask for an
augmentation. We believe that the reported increased scores could
result as a merge of both the reduced risk of breast cancer concerning the patients and the acceptable aesthetic result provided by
the subcutaneous reconstruction.
NSM and immediate breast reconstruction offers a safe option,
providing a fast recovery and an appealing alternative from both an
aesthetic and psychological point of view, improving cosmesis
following mastectomy. In our opinion, among different reconstructive techniques, immediate one-stage reconstruction is a valid
choice for preserving women's quality of life after mastectomy. In
particular subcutaneous prosthetic reconstruction with TiLoop®
Bra mesh guarantees higher levels of patient-reported outcomes
[13e15]. The main advantages of this technique are the preservation of the pectoralis major muscle with reduced or absent
muscular pain and a comparable rate of other minor complications,
less invasiveness, reduction of surgical times (one-stage technique),
early discharge and rapid recovery [13e15].
Furthermore in our study, we reported low complication rates.
Comparing to cancer treating surgery, this good rate could be
ascribed to several factors. First, our patients are mutation carriers
undergoing prophylactic bilateral mastectomy for risk reducing
purpose. Therefore, they did not undergo any chemotherapy or
radiotherapy, which have been associated to an increased rate of
postoperative complication, such as delayed healing, wound
dehiscence, skin flaps and nipple necrosis and severe capsular
contracture [27,28,34,35]. Another possible explanation of the low
complications rate could rely on our subcutaneous reconstructive
technique [34]. Indeed, it requires short intraoperative time. Tiloop does not require any rehydration or long treatment before
use with an estimated setting time as low as 3e5 min, reducing the
intraoperative time of exposure of the implant and the mesh, along
with the possibility of intraoperative contamination and infections.
Nevertheless, we consider that our follow-up is short for
drawing conclusion in the setting of capsular contracture and other
implant-related complications; we believe that our complications
rate could increase over time and we strictly follow up patients for
contracture evaluation.
To our knowledge, this is the first study prospectively evaluating
long-term outcomes after bilateral NSM and immediate breast
reconstruction in a population of BRCA1/2 mutation carriers,
applying BREAST-Q questionnaire to preoperative and postoperative points and analyzing scores and their changes over time.
Indeed patients showed high levels of overall satisfaction with
outcome and wellness. We believe that our data could help clinicians in counseling women at high risk for breast cancer and provide patients with reliable outcomes after prophylactic
mastectomy.
Acknowledgments and conflict of interest
The authors have no commercial, proprietary, or financial
(±9,8)
(±13,7)
(±13,5)
(±13,6)
(±11,8)
interest in the products or companies described in this article. Our
study was performed with respect to the ethical standards of the
Declaration of Helsinki, as revised in Tokyo 2004. The study complies with the policy of the journal on ethical consent.
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Research Article
Breast Care 2019;14:217–223
DOI: 10.1159/000496398
Published online: February 15, 2019
Patient-Reported Satisfaction after
Prophylactic Operations of the Breast
Katja Keller a, b, c Cornelia Meisel a, b, c Nannette Grübling a, b, c
Andrea Petzold a, b, c Pauline Wimberger a, b, c Karin Kast a, b, c
a
Department of Gynecology and Obstetrics, Medical Faculty and University Hospital Carl Gustav Carus, Technische
Universität Dresden, Dresden, b National Center for Tumor Diseases (NCT), Partner Site Dresden, Dresden, and
c
German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany
Keywords
Prophylactic mastectomy · Satisfaction · BRCA1/BRCA2
mutations · Long-term follow-up · Breast cancer
Abstract
Background: Prophylactic mastectomies in carriers of mutations in BRCA1 or BRCA2 are becoming increasingly more accepted. We investigated the outcome after prophylactic
mastectomy, especially regarding satisfaction with the procedure, in a monocenter study. Methods: BRCA1/2 mutation
carriers and non-carriers with elevated pedigree-based cancer risk were followed prospectively in a structured surveillance program between 2000 and 2017. A retrospective telephone survey was conducted among all patients with documented prophylactic mastectomy. Complications and
satisfaction with the decision for prophylactic mastectomy
were recorded. Results: 39 patients who opted for a prophylactic mastectomy (38 BRCA1/2 mutation carriers and 1 noncarrier) were interviewed. Mostly nipple-sparing mastectomy with reconstruction was performed (87%). Half of the patients (22/39; 56.4%) had a history of unilateral breast cancer.
The median time since prophylactic mastectomy was 5.6
years. While 61.5% did not report any complications, flap loss
was seen in 15% (3/20) and moderate limitations in everyday
life were present in 20% (7/35). An improvement in quality
of life was noticed by 82% after prophylactic mastectomy
and no patient expressed regret with regard to the decision.
Conclusions: Prophylactic mastectomy is a procedure with
© 2019 S. Karger AG, Basel
E-Mail karger@karger.com
www.karger.com/brc
risk for long-term complications in some cases. Our results
confirm high satisfaction with the decision and improved
quality of life.
© 2019 S. Karger AG, Basel
Introduction
BRCA1/2 mutation carriers face a high lifelong risk for
breast and ovarian cancer. For both genes, the breast cancer risk until the age of 80 years is 70%, and for ovarian
cancer it is 40% and 17% for BRCA1 and BRCA2, respectively [1]. Intensified screening programs with breast
magnetic resonance imaging (MRI) aim to improve the
prognosis of breast cancers through early detection, and
there is evidence for a survival benefit by surveillance [2].
But mutation carriers increasingly opt for risk-reducing
operations of the breast. For healthy carriers, not only a
reduction of 90–95% in the risk of subsequent breast cancer was shown by bilateral prophylactic mastectomy, but
also improved overall survival was described [3]. In patients with unilateral breast cancer, the benefit of contralateral prophylactic mastectomy is less clear [4, 5]. Prior
to the risk-reducing surgery, comprehensive counseling
at different time points is necessary. Counseling should
take place in specialized centers and should contain different reconstruction methods, such as the use of implants and autologous tissue. The decision is guided by a
woman’s activity and plans, body shape, and personal
preferences.
Karin Kast, MD
Carl Gustav Carus University Dresden, Technische Universität,
University Hospital Dresden, Fetscherstraße 74
DE–01307 Dresden (Germany)
E-Mail karin.kast @ universitätsklinikum-dresden.de
Table 1. Questionnaire for the telephone interview
Questions
Spectrum of answers
Type of mastectomy
Type of reconstruction
Number of operations
Complications after surgery
Satisfaction with cosmetic result
Pain
Improvement of quality of life
Limitations in everyday life
Limitations in leisure time and activities
Same decision for prophylactic surgery again?
Negative impact on family/partnership?
Salpingo-oophorectomy
MRM
none
total
none
not at all
none
none
none
none
yes
yes
yes
SM
implant
moderate
rather unsatisfied
little
little
little
little
no
no
no
autologous tissue
severe
indifferent
moderate
moderate
moderate
moderate
different
indifferent
satisfied
strong
severe
severe
severe
very satisfied
severe
MRM, modified radical mastectomy; SM, subcutaneous mastectomy.
Satisfaction of patients depends on the esthetic outcome, freedom from lasting symptoms with limitations
in daily life, and reduction of anxiety after surgery. According to 1 meta-analysis, most patients would decide to
have the same procedure performed again [5]. But after
unilateral sporadic breast cancer, reduced satisfaction of
patients with contralateral prophylactic mastectomy with
one or more unplanned following surgeries was described
[6]. In addition, more body image problems and less sexual pleasure, but less anxiety and improved social activities were reported in a study of women with familial risk
for breast cancer at 1 year after prophylactic bilateral
breast cancer [7].
With this study, we aimed to investigate the complication rate and satisfaction of carriers at the Dresden center
of the German Consortium Hereditary Breast and Ovarian Cancer (GC-HBOC) after prophylactic operations of
the breast with and without prior breast cancer diagnosis.
Methods
Between 2000 and 08/2017, all patients who fulfilled certain
criteria of familial cancer risk were counseled interdisciplinarily,
and molecular genetic analysis was carried out as described previously at the Dresden center of the GC-HBOC [8]. Prophylactic
risk-reducing operations were offered to all women with a pathologic mutation in BRCA1 or BRCA2. After consenting to participate in the study, each family was documented in the mutual database of the GC-HBOC. Follow-up was performed for all women
who took part in our center’s intensified surveillance program or
by personal contact with carriers and individuals with very high
pedigree-based risk who sought additional counseling for prophylactic operations. All women after risk-reducing bilateral mastectomy are offered to undergo one last MRI to rule out remaining
breast tissue in order to objectify the surgical outcome under research conditions 1 year after the procedure.
Between 04/2017 and 08/2017, a telephone survey was conducted among all patients with a documented history of prophy-
218
Breast Care 2019;14:217–223
DOI: 10.1159/000496398
lactic surgery of the breast in our database. Altogether, 44 women
were eligible, of whom 39 were interviewed by a breast surgeon and
5 were lost to follow-up. The interview consisted of 18 questions
on type of surgery, status of reconstruction, early and late complications, and number of operations (table 1). Moreover, satisfaction, limitations in daily life, and extent of anxiety reduction were
enquired about (table 1).
The data cut of the database was 08/2017. Statistical analyses
were performed with SPSS.
Results
Altogether, 1,319 families were counseled at the Dresden center, with 330 families carrying a pathogenic mutation in BRCA1 or BRCA2, of which roughly 11% of the
women at risk opted for a prophylactic mastectomy. Of
the 39 patients with documented prophylactic mastectomy and a telephone interview, 38 were carriers of a pathogenic mutation. 1 patient with prophylactic mastectomy
without BRCA1/2 mutation was from a family with very
high pedigree-based risks. The median age at the time of
the interview was 47 years. The median time since breast
cancer in affected individuals was 7.8 years and the median time since prophylactic mastectomy was 5.6 years.
The characteristics of the participants of the telephone
interview are displayed in table 2.
In 43.6% (17/39) of the women, an exclusively prophylactic operation was performed (bilateral mastectomy in
a healthy individual). About half of the patients (22/39;
56.4%) were affected with unilateral breast cancer (table 3), some of whom had a primary mastectomy, e.g. after neoadjuvant chemotherapy, while others opted for a
secondary bilateral mastectomy after initial breast-conserving surgery (table 2). Of the 39 patients under investigation, 25 (64.1%) reported having undertaken a bilateral prophylactic salpingo-oophorectomy (table 2).
Keller/Meisel/Grübling/Petzold/
Wimberger/Kast
Table 2. Characteristics of the participants
in the telephone interview
Characteristics
n
Value
Participants, all
Healthy mutation carrier
Healthy without BRCA1/2 mutation
Patients with unilateral breast cancer
Age at time of interview, years, median (range)
Time since breast cancer, years, median (range)
Time since prophylactic mastectomy, years, median (range)
Prophylactic salpingo-oophorectomy, yes/no
Prior chemotherapy, yes/no
Prior radiation therapy, yes/no
39
17
1
21
39
21
39
39
21
21
47 (26‒75)
7.8 (3‒33)
5.6 (1‒32)
24/15
17/4
5/16
Most of the patients with bilateral mastectomy were
treated with nipple-sparing subcutaneous mastectomy
(34/39; 85%) and alloplastic or autologous reconstruction, while some wished to receive a modified bilateral
mastectomy (10%) without reconstruction (fig. 1a). All of
the latter were unilaterally affected carriers of mutations
in BRCA1 or BRCA2.
Of the 35 patients with reconstruction, 43% (15/35)
opted for breast implants, while 57% (20/35) were reconstructed with autologous tissue (fig. 1b). Reconstruction
with implants was mostly performed during a single surgery (12/15; 80%). 2 patients needed 2 different surgeries
and 1 patient had her implants successfully placed only
after 4 surgeries, due to wound healing problems. For autologous reconstruction, a median of 3 surgeries were
necessary. Only 4 out of 20 patients (20%) with autologous reconstruction had their surgery completed within
a single operation.
Reconstruction was performed without any complications in 61.5% (24/39) of the patients and moderate complication such as infection or rebleeding occurred in 11
patients (11/39; 28.2%). 3 women (7.7%) faced severe
complications: 2 with loss of the transplanted tissue flap
and 1 with loss of the breast implant (fig. 1d). No lifethreatening complications were observed.
Most patients were satisfied or very satisfied with the
cosmetic outcome of their prophylactic mastectomy at
the time of the interview (33/39; 85%). Only 4 reported
discontent (4/39; 10%) with the cosmetic outcome and 2
(2/39; 5.1%) would elect a different type of operation. For
example, one of these patients would prefer a subcutaneous rather than a subpectoral location for her implant.
Patients with autologous reconstruction displayed higher
satisfaction with the result (19/20; 95%) compared to
those operated with implant reconstruction (11/15;
73.3%). Moreover, patients after unilateral breast cancer
were more often satisfied with the result (16/18; 88.9%)
than healthy carriers (14/17; 82.4%).
In terms of long-term surgery-associated morbidity,
59% (23/39) of the patients had no pain. Severe pain was
not reported by any of the patients. About half of the pa-
Table 3. Tumor characteristics
Satisfaction after Prophylactic Operation
Breast Care 2019;14:217–223
DOI: 10.1159/000496398
n
Size of tumor
Tis
T1
T2
T3/T4
Unknown
1
13
6
0
2
Total
22
Nodal status
N0
N1
Unknown
13
6
2
Total
21
Metastases
M0
M1
Unknown
22
0
0
Total
22
Tumor biology
HR+, HER2–
HR–, HER2–
HR–, HER2+
HR+, HER2+
Unknown
6
12
1
1
2
Total
22
HR, hormone receptor; HER2, human epidermal growth factor
receptor 2.
tients experienced no limitations in everyday life (20/39;
51.3%) or in the selection of their recreational activities
or hobbies (25/39; 64.1%). Severe limitations were not reported by any patient, moderate limitations in everyday
life were reported by 7 patients (7/39; 18%), and moderate
limitations in leisure time activities by 4 (4/39; 10.3%)
(fig. 1e). A moderate restriction in everyday life was, for
example, that it was no longer possible to lift or carry
219
a
b
Type of mastectomy
Type of reconstrucƟon
10%
10%
subcutaneous
mastectomy
90%
d
38%
moderate complicaƟons
63%
severe compliĐĂƟons
no
e
f
Decision for prophylacƟc surgery
LimitaƟŽŶƐ
30
25
20
20
0
without complicaƟŽŶƐ
24%
yes - fewer
10
ComplicaƟons
13%
yes - moderate
24%
reconstrucƟon with breast
implants
reconstrucƟon with
autologous ƟƐƐue
yes - very
16%
22%
39%
modiĮed bilateral
mastectomy
Improvement of quality of life
c
51%
without reconstrucƟon
7
10
0
0
limŝƚĂƟon everyday life
very
yes again
5%
12
moderate
no diīerent
4
no not at all
limŝƚĂƟon leisure and hobbies
fewer
95%
no
Fig. 1. Results of the telephone interview. a Type of mastectomy, b type of reconstruction, c improvement of
quality of life, d Complications, e Limitation in everyday life/leisure time activities, f decision for prophylactic
surgery.
heavy weight, and in leisure time activities that a prone
position was no longer possible.
Improvement in quality of life was seen in 78% of patients, with reduction of anxiety being the most important reason (fig. 1c). While 95% of the patients would opt
for the same procedure again, 5.1% would choose another type of surgery. None of the 39 individuals under investigation reported regrets in terms of their decision for
prophylactic mastectomy (fig. 1f). One of the patients had
a local recurrence, but none developed metastatic disease.
Discussion
We searched our database for women with documented prophylactic mastectomy after interdisciplinary counseling and molecular genetic analysis of the breast cancer
genes in our GC-HBOC center in Dresden. With about
11%, the percentage of carriers who decided to undergo
prophylactic mastectomy was low. About half of them
had a history of breast cancer, although overall survival
benefit has primarily been shown in healthy carriers. In
the past, differences in uptake of prophylactic mastectomy were reported among different cultures. Compared
to more conservative countries such as France and Poland, uptake in countries such as the USA, Sweden or The
220
Breast Care 2019;14:217–223
DOI: 10.1159/000496398
Netherlands was higher [9–12]. With the outing of Angelina Jolie in 2013, the procedure lost its taboo, and we
noticed an increase in requests for the surgery at our center. Only recently did another center of the GC-HBOC
report a higher rate of prophylactic mastectomy, namely
27% and 44% among affected and healthy BRCA1/2 mutation carriers, respectively [13]. This difference might be
mainly explained by the different approach they adopted
in their study. Schott et al. [13] sent questionnaires to all
patients who were counseled at the center in Heidelberg,
whereas we recorded operations that were actively communicated. However, cultural reasons cannot be completely excluded in comparing centers in the former
western part of Germany with those in the former eastern
part.
Unplanned additional operations, wound healing
problems, and flap loss were described as negative side
effects in the meta-analysis of Lostumbo et al. [5]. In a
recent one-center study, the overall complication rate
was reported to lie at 15.9%, with significantly less complications after autologous reconstruction compared to
alloplastic reconstruction [14]. Generally, wound infections and seromas are more common in alloplastic breast
implants [14, 15]. Autologous reconstruction was reported to be associated with longer hospital stays, but
also with fewer operations, less reconstruction failures
Keller/Meisel/Grübling/Petzold/
Wimberger/Kast
(7.3 vs. 1.3%) and a shorter time to full achievement of
reconstruction [16–18]. Complication rates are higher
after neoadjuvant chemotherapy or after radiation therapy in smoking or obese patients [19]. After alloplastic
breast reconstruction, Mousa et al. [20] reported postoperative complications in 45% of patients, of which 29%
occurred after prior neoadjuvant chemotherapy and 25%
after prior radiotherapy. In 30% of patients, revisional
surgery (closure of wound, debridement, exchange or removal of implant) was needed. In our cohort, the overall
complication rate was 38%, which might be due to the
high percentage of women participating in the study after treatment for prior breast cancer. With the exception
of 2 women, all patients would elect the same procedure
again. The number of severe complications such as flap
loss after autologous reconstruction is rather high. The
operations took place in different hospitals all over Germany. In order to guarantee high oncologic safety and
the best possible aesthetic outcome with low complication rates, these complex operations should only be performed in centers with interdisciplinary teams of oncologic and plastic surgeons [21, 22]. But the patient’s wish
is not regulated further, for instance by limited insurance
coverage.
In spite of complications, most women after prophylactic mastectomy reported high satisfaction with their
decision in the meta-analysis of Lostumbo et al. [5].
This is in accordance with our findings. Even in cases
of dissatisfaction with the cosmetic outcome, all our patients would opt to undergo the risk-reducing operation again.
Satisfaction with cosmetic outcome was higher after
autologous reconstruction, which is in accordance with
the literature [17, 23–27]. But due to the small numbers
in our analysis and differences in preconditions for the
individual woman, this implies no general advice to prefer one method over the other. In our study, patients
after unilateral breast cancer reported higher satisfaction compared to healthy patients. Although this was
expected, one other group found partly different results.
Kazzazi et al. [24] describe higher satisfaction among
healthy individuals or after bilateral breast cancer with
mastectomy and reconstruction compared to those with
unilateral breast cancer with bilateral mastectomy and
reconstruction. As an explanation, lack of time for making the decision for contralateral mastectomy is suggested.
Most study participants reported improvement in
quality of life primarily due to reduction of anxiety. Those
with unchanged quality of life reported having taken a
rational decision without feeling stressed by anxiety before the operation. With a mean follow-up time of 14.5
years, a retrospective study by Frost et al. [28] found satisfaction with the procedure in 70% of all patients. More-
Satisfaction after Prophylactic Operation
over, increase in emotional stability and decrease in stress
was perceived in about 25% of patients. A number of
smaller studies with a short follow-up of 1–2 years provide similar data [7, 28–31], but long-term prospective
studies are still needed for the comprehensive counseling
of patients at high risk for breast cancer.
The strength of our analysis lies in the qualified telephone interview conducted by a breast surgeon. Especially for patients with prior unilateral breast cancer, it is
sometimes challenging to answer questions on intention,
number of surgeries, or type of complication. A limitation of our study is the restricted follow-up of the 1,319
families at our center. Not all families are represented
with at least 1 participant in our intensified surveillance
program. Therefore, underestimation of the rate of uptake of prophylactic mastectomies is possible. Moreover,
our sample is too small to compare the impact of type of
mastectomy and reconstruction on complications and
quality of life. It should also be mentioned that no validated questionnaire was used to enquire about patient
satisfaction.
Prophylactic mastectomy is the most effective procedure to improve survival rates in healthy carriers of a mutation in BRCA1/2 and possibly also in unilaterally affected carriers. As we can confirm, psychosocial benefits
outweigh possible early and late side effects of the surgery.
Knowledge on genetic and non-genetic risk modifiers
might help to define individual risk and the timing of the
procedure in the future.
Acknowledgements
We thank Rita Schmutzler, Christoph Engel, and all investigators of the GC-HBOC for establishing the background on the basis
of which this work was possible. At the center in Dresden, we especially thank Dominique Weise, Sylke Schmidtke, Kristin Eichhorn, and Nannette Kranz for their continuous commitment in
patient management, documentation, and analysis. We thank Evelin Schröck, Andreas Rump, Karl Hackmann, Arne Jahn, and Johannes Wagner for genetic counseling and analysis. We thank all
the patients for their individual contribution to this research. Finally, we thank the German Cancer Aid for their support of the
GC-HBOC with grant no. 110837.
Statement of Ethics
The study protocol has been approved by the research institute’s committee on human research.
Funding Sources
German Cancer Aid grant no. 110837 for GC-HBOC.
Breast Care 2019;14:217–223
DOI: 10.1159/000496398
221
Author Contributions
Disclosure Statement
K.Ke.: Conception of the work, analysis and interpretation of
data, writing of the manuscript, final approval of the version to be
published; C.M.: conception of the work, acquisition, interpretation of the data, final approval of the version to be published; K.
Ka.: conception of the work, acquisition, interpretation of data,
critical revision of the manuscript for important intellectual content, final approval of the version to be published; all other authors:
acquisition of data, critical revision of the manuscript for important intellectual content, final approval of publication.
The authors have no conflicts of interest to declare.
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