Oncological outcomes of lipofilling breast reconstruction: 195 consecutive cases and literature review

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Journal of Plastic, Reconstructive & Aesthetic Surgery (2016) xx, 1e7

Oncological outcomes of lipofilling breast reconstruction: 195 consecutive cases and literature review Claudio Silva-Vergara a,b,*, Joan Fontdevila b, Jordi Descarrega b, Fernando Burdio a, Tai-Sik Yoon b, Luis Grande a a b

Universitat Auto`noma de Barcelona, Department of Surgery, Barcelona, Spain Plastic and Reconstructive Surgery Service, Hospital Clı´nic Barcelona, Spain

Received 18 August 2015; accepted 22 December 2015

KEYWORDS Lipofilling; Fat graft; Breast cancer; Breast reconstruction

Summary Introduction: Lipofilling has become a widely used procedure in breast reconstruction after mastectomy or breast-conserving treatment. The possibility that this technique may increase stimulation of cancer development between the potential tumor bed and the lipoaspirates grafts has been raised regarding its safety. The aim of this study was to identify the oncological risks associated with this procedure in our institution. Methods: Between years 2007 and 2014 we record 195 consecutive patients with fat grafting technique for reconstructive purpose after breast cancer treatment. The loco-regional recurrence (LRR) as first event of relapse was the primary end point of this study. Results: We performed 319 lipofilling procedures in 132 mastectomy and 63 breastconserving surgery patients. Invasive carcinoma represents 81.6% of the series. The median follow-up from primary cancer surgery and fat grafting was 74 and 31 months respectively. Median time between oncologic surgery and lipofilling was 36 months. The authors observed a complication rate of 8.2%, most of them liponecrosis and oil cysts (7.2%). Four local, 2 regional and 4 distant recurrences were observed as first event of relapse in 10 patients with invasive ductal carcinoma. The loco-regional recurrence rate was 3.1% (1.08% per year). Conclusions: Although larger prospective trials are needed, these results support the fact that lipofilling following breast cancer treatment leads to a very low rate of complications and similar to other authors, it does not seem to interfere in patient’s oncological prognosis when compared with prior publications.

DOI of original article: http://dx.doi.org/10.1016/j.bjps.2016.01.016. * Corresponding author. Calle Villarruel 170, Barcelona, 08036, Spain. Tel.: þ34 93 227 5711. E-mail address: [email protected] (C. Silva-Vergara). http://dx.doi.org/10.1016/j.bjps.2015.12.029 1748-6815/ª 2016 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.

Please cite this article in press as: Silva-Vergara C, et al., Oncological outcomes of lipofilling breast reconstruction: 195 consecutive cases and literature review, Journal of Plastic, Reconstructive & Aesthetic Surgery (2016), http://dx.doi.org/10.1016/j.bjps.2015.12.029

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C. Silva-Vergara et al. ª 2016 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.

Introduction The autologous fat graft or lipofilling technique is widely used in plastic surgery for breast remodeling. However, concerns have been raised regarding the potential oncologic risks of these procedures. Cells could express protumorigenic factors, stem cells transform within the graft or even this new tissue compromise our ability to detect breast disease.1 A number of new techniques of fat preparation have been described with the ultimate goal of improving adipocyte purification and stem cell selection.2e4 The intentional placement of regenerating tissue at the site of a previous tumor bed, inevitably, raises questions regarding the possibility of promoting a cancer recurrence. In experimental in-vitro and animal studies, adipocytes and white adipose tissue progenitors are able to produce different growth factors involved in tumorigenesis.5e7 They could act on cancer cell cycle through autocrine, paracrine, and exocrine/endocrine secretions promoting tumor progression and in some particular stages may even have inhibitory effect.8e12 In 2007, the French Society of Plastic Surgery sent a recommendation to postpone lipofilling in the breast with or without breast cancer history unless it is carried out under prospective controlled protocol.13 Also the American Society of Plastic Surgeons had set up a task force in 2009 to assess indications, safety and efficacy of autologous fat grafting. They could not give definitive recommendations concerning the cancer risk based on a the limited number of studies available.14 The Italian Society of Plastic Surgery in 2010 advised surgeons to perform lipofilling with caution and with a precise consent form but did not impose any restrictions regarding lipotransfer indications.15 A recent systematic review by Krastev et al.16 concluded that only 9 articles out of 269 mentioned an oncologic follow-up but only one had a match-controlled group, with no significant differences in loco-regional recurrence (LRR) incidence rates between both groups.17 However, lipofilling group resulted at higher risk of recurrence when the analysis was limited to intraepithelial neoplasia.18 Following this pathway, the aim of our study was to analyze the oncologic outcome of lipofilling procedures in terms of LRR in patients with breast cancer at our institution.

Patients and methods From January 2007 to December 2014, all patients who underwent autologous fat grafting for reconstructive purposes after surgical removal of breast cancer at Barcelona Clinic Hospital were included. Both carcinoma in situ and invasive carcinoma were included. Phylloid cancer and other sarcomas were excluded. Clinical history, tumor histopathology, staging (TNM classification), chemotherapy,

radiation, hormonal treatment, oncological surgery, type of reconstruction, volume of fat transfer, number of procedures and complications were registered. The oncologic screening was performed by clinical evaluation, mammogram every year after primary surgery associated with breast ultrasound or magnetic resonance imaging when needed. Recurrences were classified into local, regional and distant. Recurrence in breast tissue and breast skin was categorized as local recurrence (LR). Axillary, infraclavicular, and internal mammary nodal recurrences were categorized as regional recurrence (RR). Loco-regional recurrence (LRR) refers to the cumulative number of them. The analyses of data were considering the last date of oncologic surgery performed (mastectomy or breast conservative treatment) to achieve disease-free margins before reconstruction.

Lipofilling technique The procedure was performed under local or general anesthesia, depending on quantities of fat required and patient’s clinical conditions. Donor sites (abdomen, flanks, inner knee, and external side of the thigh) were examined to identify the fat deposits and marked. Tumescence included 1 L of 0.9% normal saline with adrenaline (1:1,000,000). Harvesting was performed by conventional lipoaspiration with 3 mm cannulas. Fat was aspirated at 40 kPa to minimize adipocyte damage with a vacuum pump through an intermediary 400 ml modified drainage bottle as fat storage.19 Then fat was washed with saline solution and centrifuged at 2000 rpm (400 G) for 2 min to obtain purified fat. The cellular component with no additional cell enhancement was transferred to 10 ml syringes and injected with 1.9 mm blunt cannulas through several punctures around the breast area where filling was required.

Statistical analysis The primary outcome was the LRR of breast cancer. The location of the first relapse was used for analysis purposes (any distant recurrence detected simultaneously with a LRR was counted as a LRR). The KaplaneMeier and LogeRank test was used for estimated progression-free survival curves. Differences were considered statistically significant if the p value was <0.05. All analyses were carried out with SPSS 20 (IBM SPSS Statistics for Mac, Version 20.0. Armonk, NY: IBM Corp.). In case of no events, the observation was censored at the last follow-up visit.

Results We reviewed 319 lipofilling procedures from 195 patients. The median age and BMI at the time of the first lipofilling

Please cite this article in press as: Silva-Vergara C, et al., Oncological outcomes of lipofilling breast reconstruction: 195 consecutive cases and literature review, Journal of Plastic, Reconstructive & Aesthetic Surgery (2016), http://dx.doi.org/10.1016/j.bjps.2015.12.029

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Oncological outcomes of lipofilling breast reconstruction were 52 years (range, 29e77) and 24 kg/m2 (range, 18e38) respectively. Clinical and demographic patients’ characteristics are presented in Table 1. Patients underwent a mean of 1.6 lipofilling sessions (range, 1e6) and the majority of them (63.6%) required just one lipofilling procedure. Ninety-six patients (49.2%) had their first lipofilling performed within 3 years of their cancer surgery. None lipofilling was performed as immediate breast reconstruction. Lipofilling was performed under outpatient surgery in majority of the cases, otherwise, inpatients surgery were usually associated with other procedures. The main characteristics of lipofilling are depicted in Table 2. We observed 26 complications from 319 procedures (8.2%). The most common complication was liponecrosis and oil cyst, detected by routine clinical examination or during ultrasound performed by plastic surgeon at least

Table 1 series.

Clinical and demographic characteristics of the n

Location Left breast cancer Right breast cancer Bilateral breast cancer Treatment Immediate reconstruction Mastectomy surgery treatment (MST) Breast conservative treatment (BCT) Histopathologya Ductal intraepithelial neoplasia Lobular intraepithelial neoplasia Invasive ductal carcinoma Invasive lobular carcinoma Histologic gradea I II III pTa 1 2 3 4 pNa Positive lymph nodes Negative lymph nodes Receptorsa Estrogen Progesterone Her-2 Triple negative Adjuvant therapya Lymphadenectomy Radiotherapy Chemotherapy Hormonal therapy

%

88 87 19

45.4 44.8 9.8

46 132 63

23 67.7 32.3

30 1 129 8

17.9 0.6 76.8 4.8

26 72 62

16.0 44.4 38.3

82 58 3 5

49.4 34.9 1.8 3.0

68 101

40.2 59.8

122 100 35 16

73.5 60.2 21.3 9.8

113 96 131 117

61.1 49.2 67.2 60.0

Her-2, human epidermal growth factor receptor 2. a Incomplete oncological data in some patients.

3 Table 2 data.

Oncologic follow-up and Lipofilling operative

Median volume per procedure (ml) Median volume per patients (ml) Median follow-up from oncologic surgery (months) Median follow-up from the first lipofilling (months) Median time from oncologic surgery to lipofilling (months) Inpatient lipofilling procedure Ambulatory lipofilling procedure

n

[range]

160 190 74

[20e480] [20e1720] [18e350]

31

[3e89]

36

[4e324]

122 197

38% 62%

once in each patient between 6 and 12 months post lipofilling. Most of them easily drained at outpatient clinics. Major complications were one prosthetic rupture detected with ultrasound 2 month after a lipofilling procedure, one case of breast hematoma after lipofilling and surgical removed of contracture prosthesis and one case of breast infection that was resolved with antibiotic treatment (Table 3). The disease free survival from cancer surgery and lipofilling reconstruction was a median of 73 and 30 months respectively. During these 7 years since we start using lipofilling technique for breast reconstruction purpose, 4 local, 2 regional and 4 distant recurrences were observed as first oncological event of relapse. The primary breast cancer of all these 10 patients was invasive ductal carcinoma, the same type when recurrence showed up. Three patients died during the study period, only one of them due breast cancer progression with distant hepatic metastasis. In Table 4, oncological and lipofilling procedures features are depicted. The overall oncologic event rate was 5.1% (1.78% per year). The LR annual recurrence and distant metastasis rates, as a first episode of relapse was 1.08 and 0.71 respectively. The cumulative LR progression-free survival at the median follow-up time was 98.3% (Figure 1).

Discussion Autologous fat graft is a valuable and effective tool to help surgeons to correct defects after total or partial breast reconstruction, even after radiotherapy. It is a low cost

Table 3

Lipofilling complications.

Liponecrosis/Oil cyct Prosthesis rupture Hematoma Infection Donor site complication Total

n

%

23 1 1 1 0 26

7.2 0.3 0.3 0.3 0.0 8.2

Please cite this article in press as: Silva-Vergara C, et al., Oncological outcomes of lipofilling breast reconstruction: 195 consecutive cases and literature review, Journal of Plastic, Reconstructive & Aesthetic Surgery (2016), http://dx.doi.org/10.1016/j.bjps.2015.12.029

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BCT: Breast conservative treatment, MST: Mastectomy, LF: Lipofilling, HG: histologic grade, ER: Estrogenic receptors, PR: Progesterone receptors, Her-2: human epidermal growth factor receptor-2, CMT: chemotherapy, RT: Radiotherapy, HT: Hormone therapy.

Alive Alive Alive Alive Alive Alive Alive Dead Alive Alive 99 73 136 62 64 252 99 55 70 67 80 52 85 30 45 14 61 29 59 33 19 21 51 32 19 238 38 26 11 34 72 12 39 5 37 6 31 2 7 18 Local Local Local Local Regional Regional Distant Distant Distant Distant 930 80 470 230 230 200 170 320 930 220 5 1 1 1 1 1 3 1 4 2 Yes No No No Yes Yes Yes Yes Yes Yes No Yes No Yes No Yes No No Yes No Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes 80 0 e 0 0 e 0 0 þ 0 0 þ 80 0 e 40 90 e 90 60 e 80 60 þ 0 0 e 10 5 þ 2 3 3 2 1 2 3 2 3 2 3 0 11 8 0 0 5 3 4 1 21 26 22 12 14 35 40 24 22 44 MST BCT MST MST MST BCT MST MST MST MST 58 63 53 57 63 61 38 55 36 48 1 2 3 4 5 6 7 8 9 10

Table 4

Case Age Oncologic Tumor Positives HG ER PR Her- 2 CMT RT HT LF sessions Total LF Location of Time to Time to LF from Follow-up Follow-up from Overall (n) (y) surgery size lymph (%) (%) (þ/) (n) volume Recurrence recurrence cancer surgery from 1st cancer surgery survival (mm) nodes (n) (ml) (first event) from 1stLF (m) (m) LF (m) (m)

C. Silva-Vergara et al.

Oncological data of the original breast cancer and lipofilling reconstruction follow-up of all patients with recurrence.

4

procedure that can be performed under local anesthesia and in most cases under outpatient surgery. Despite being a non-free complications technique, most of them are liponecrosis and oil cyst detected on routine ultrasound finding of no clinical significance, easily recognized as benign lesions by trained radiologists.20,21 This makes autologous fat graft to be a popular choice for surgeons and patients.15,22,23 Although the use of autologous fat graft is rising in clinical practice, the real oncological impact on patients who have had breast cancer is still unknown.22,24e27 Few studies have focused on the follow-up evaluation of breast cancer patients after lipofilling. Basic research shows unlike results about interaction between stem cells with breast tissues and cancer cells. There is data that suggest adipose tissue progenitors can promote breast cancer in “in vitro” and in animal models,7,28e30 but in contrast, some studies show inhibiting tumor growth and metastasis.10,31 Our study shows a LRR rate of 1.08% per year, comparable with oncological outcomes publish by other authors with lipofilling reconstruction with rates between 0.42 and 2.79% (Table 5).15,17,23,32e36 Furthermore, LRR of breast cancer occurs in general patients without lipofilling reconstruction in rates of 1e2% per year,37 similar results to those with lipofilling. In addition, we did not find lipofilling fat-graft volume injected in the breast or the number of sessions performed associated with breast recurrence rate, as neither any evidence in literature linking these aspects. Petiti et al.15 published in 2011 a multicenter MilanLyon-Paris study with 513 breast cancer patients who underwent lipofilling from 2000 to 2010. They reported a LRR incidence rate of 1.50% per year for all patients and 1.38 vs. 2.07% when analyzing the mastectomy surgery treatment (MST) and BCT patients separately. In our series we had a 1.08% LRR per year and no difference between recurrences in MST and BCT group, 1.05 and 1.10% respectively. The same group of researchers also suggested that the risk of relapse is higher in patients who have a shorter period of time between oncologic surgery and lipofilling.18 They found no recurrence when lipofilling was carried out after 3 years from oncologic surgery. In our series, 3 out of 6 patients with LRR had their recurrence after this period. Our results show no difference in LRR between these two groups (p Z 0.26). The main limitation of our results is the design of the study. The retrospective setting and the lack of control group limits the validity of our data. Petit et al.17 and Gale et al.33 who’s case-control studies represents the highest level of evidence currently available, they found no significant differences between groups in terms of relapse. However, in a small subgroup of 37 patients with intraepithelial neoplasia, Petit17 found a significantly higher rate of local events (4 vs 0 patients) in patients who underwent lipofilling reconstruction. This was confirmed later with a case-control study for this specific subgroup with 59 intraepithelial neoplasia patients, with 6 recurrences vs. 3 in the control group. On the other hand, Gale et al.33 with 27 (12.8%) and in our series with 31 patients (18.5%) with intraepithelial carcinoma, we found no recurrence at all.

Please cite this article in press as: Silva-Vergara C, et al., Oncological outcomes of lipofilling breast reconstruction: 195 consecutive cases and literature review, Journal of Plastic, Reconstructive & Aesthetic Surgery (2016), http://dx.doi.org/10.1016/j.bjps.2015.12.029

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Oncological outcomes of lipofilling breast reconstruction

Figure 1

5

Loco-regional progression-free survival from fat grafting procedure (KaplaneMeier).

Conclusions Lipofilling following breast cancer treatment appears to be a safe technique and leads to a very low rate of complications. Long-term follow-up data are not available as yet, although

Table 5

similar to all other papers looking at loco-regional recurrence rates for lipofilling, short-term results does not appear to increase recurrence in breast cancer patients. The better understanding of stem cells interaction and its role in breast cancer should encourage for future longer follow-up

Summary of oncologic clinical studies with breast lipofilling.

Series

Delay et al.32 2002e2007 Rigotti et al.36 2000e2005 Ritjens et al.34 2005e2008 Petit et al.17 1997e2008 Petit et al.15 2000e2010 Riggio et al.35 2000e2007 Brenelli et al.23 2005e2008 Gale et al.33 2000e2014 Current Study 2007e2014

Carcinoma RT before Positive LRR Patients Mean Follow-up Follow-up Invasive (n) age (y) before after Carcinoma In-Situ (%) LF (%) lymph % (n) LF (m) LF (m) (%) nodes (%) 42

51

92

20

92.9

137

47

23

60

77.2

155

48

35.2

18.3

321

45

30

513

52

60

7.14

LRR rate per year (%)

85.7

NA

4.7 (2)

2.79

22.8

16.1

38.7

3.6 (5)

0.72

79.2

20.7

61.3

NA

0.6 (1)

0.42

26

84.4

11.5

NA

58.9

4.0 (13) 1.87

39.7

19.2

78.5

21.1

77.0

NA

2.5 (13) 1.58

50

56.5

92.2

91.7

8.3

18.3

45

3.3 (2)

0.43

59

50

76.6

34.4

64.5

11.8

94.9

NA

5.1 (3)

1.78

211

48

88

32

87.2

12.8

52.7

43

1.9 (4)

0.71

195

52

36.0

34.6

81.5

18.5

49.2

40.2

3.1 (6)

1.08

LF, Lipofilling; RT, Radiotherapy; LRR, Loco-Regional Recurrence; NA, not available.

Please cite this article in press as: Silva-Vergara C, et al., Oncological outcomes of lipofilling breast reconstruction: 195 consecutive cases and literature review, Journal of Plastic, Reconstructive & Aesthetic Surgery (2016), http://dx.doi.org/10.1016/j.bjps.2015.12.029

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6 prospective studies that allows us to understand what happens with these patients after 10 years.

Conflict of interest None.

Funding None.

Ethical approval N/A.

Author contributions Wrote the first draft of the manuscript: CSV. Contributed to the writing of the manuscript: JF JD FB TSY LG. ICMJE criteria for authorship read and met: CSV JF JD FB TSY LG. Agree with manuscript results and conclusions: CS JF JD FB TSY LG.

Disclosure The authors declare that the contents of the article are original and have not been previously published in any other publication, in whole or in parts thereof. No competing financial interests exist. All authors declare that they have read and approved the manuscript and that the requirements for authorship have been met.

Acknowledgments The authors thank oncologist Dr. Montserrat Mun ˜oz from “Hospital Clı´nic Barcelona”, reconstructive clinical fellow, Dr. Omar Weshahy and researcher Diana Al-Dali from Barcelona University for their contribution and thoughtful discussion of these issues.

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