Breast cancer and reconstruction

Breast cancer is the most common cancer in the UK and is by far the most common cancer among women, where it accounts for 31% of all new cancer cases with a life-time incidence of 1 in 8.1 Approximately 50 000 women are diagnosed with breast cancer each year, 16 000 of whom undergo mastectomy and there are approximately 12 000 deaths from the disease.2 In the USA, the National Cancer Institute predicts 232 340 new cases and 39 620 deaths from breast cancer in 2013 with over 96 000 undergoing breast reconstruction following surgery.3 Surgical treatment options include mastectomy or breast conserving surgery (BCS), which is either quadrantectomy or lumpectomy plus axillary node dissection if nodal disease exists, often combined with radiotherapy (RT). Veronesi et al4 showed through a seminal randomised controlled trial beginning in 1973, comparing mastectomy with BCS, that long-term survival (after 20-year follow-up) was no different for those with tumours <2 cm in diameter. Hence, BCS has become the treatment of choice for this group.5 ,6

The mix of patients undergoing mastectomy or various forms of BCS leaves the reconstructive surgeon facing a variety of defects in the group of patients wanting reconstruction. There is a need for not just restoring volume but creating an aesthetically pleasing shape and also dealing with the aftermath of RT including pain, retraction, fibrosis, oedema, telangiectasia, atrophy as captured in the Late Effects Normal Tissue/Subjective Objective Management Analytic (LENT/SOMA) system for grading RT side effects.7 Reconstruction of the breast can occur either immediately postmastectomy or in a delayed setting several months or years later. Reconstructive options include implants or with autologous tissue as either a pedicled or free flap containing skin, fat and a variable amount of muscle harvested as a composite block of tissue. Existing reconstructive options are not without morbidity. Mioton et al8 reviewed over 13 000 breast reconstructions in the USA from 2006 to 2010 using the prospective and multicentre American College of Surgeons-National Surgical Quality Improvement Program (ACS-NSQIP) database. Autologous reconstructions (using mostly tissue from the abdomen or back) were performed in 25% of patients and implants were the reconstructive modality in 75%. Autologous reconstruction patients had higher rates of overall complications (12.5% vs 5.4%), wound infection (5.5% vs 3.5%), flap/prosthesis failure (3.1% vs 0.9%) and reoperation (9.6% vs 6.8%). There are of course general complications of major surgery and prolonged length of stay (3–5 days typically) such as deep vein thrombosis, pulmonary embolism, pneumonia and the need for blood transfusions.9

Implant-based reconstructions include complications, such as implant exposure/extrusion, rupture, deformation/distortion, rippling, migration and discontent among patients with implant animation and edge visibility. The placement of the implant itself can lead to reduced or absent sensation at the nipple in one in seven women.10 Furthermore, the body's natural reaction to a foreign body is to form a fibrous capsule around it as part of the healing process. This fibrous capsule shrinks over time (capsular contracture), which can lead to implant prominence, distortion of aesthetics (especially symmetry), increased palpability and pain.10 In its core study presentation to the Federal Drug Administration (FDA), Allergan's 10-year cumulative risk study found that 24.6% of patients who underwent implant-based reconstruction developed capsular contracture necessitating implant removal and/or replacement.11 Implanting foreign bodies to fill space and provide volume and shape is felt to be unnatural by some patients and underscores their refusal to proceed with implant-based reconstruction.12 Such reservations were reinforced during the silicone implant scandal in the 1990s and has not been helped by the more recent poly implant prothese (PIP) implant scandal13 and to a lesser extent the metal on metal hip replacement controversy.14

Another technique that has received much recent focus, is autologous fat grafting (AFG), where the patient's own fat is harvested using a liposuction technique, typically from the abdomen or thighs and then transplanted into the cavity left by removal of the gland postmastectomy or BCS. It holds the potential of reconstruction using nature's choice of filler—body fat, which is easily harvestable, often in good supply, where the donor site defect could be appreciated by patients with minimal scarring, no foreign body reaction and the potential for boosting skin trophicity and rejuvenation by combating the signs and symptoms of RT damage and aging, all performed as a day-case procedure.15 ,16

The history of fat grafting

In 1893, Neuber described the first reported case of autologous fat transfer for the purposes of reconstruction, implanting upper arm fat tissue to correct a depression in the face.17 In 1895, Czerny performed the first breast reconstruction when he transplanted a large lipoma from the dorsal flank to the breast.18 In the 1950s technical problems with harvesting and viability were brought into sharp focus when a study showed minimal graft survival 1 year post-transplantation.19 The corollary was that fat grafting fell out of favour at a time when synthetic implants were on the rise. The technique lay essentially dormant for a while but was revived in the early days of liposuction following Illouz's20 seminal paper describing the ability to remove fat cells from small port incisions using a cannula. Liposuction offered surgeons not just a method of body contouring but access to nature's own choice of filler—body fat through a low morbidity and safe approach that resulted in minimal scarring.

In 1987, Bircoll21 described the first reported case of harvesting fat using a liposuction technique with subsequent placement into the breasts using small syringes. This was performed in 1984 on a 20-year-old Caucasian woman who suffered a dog bite in the right thigh but who also had bilateral breast hypoplasia—with the harvested fat being used to treat both areas.21 Despite significant advances, obtaining consistently good aesthetic and reconstructive results for fat grafting to the breast remained challenging with complications such as cyst formation, fat necrosis and calcification relatively frequent compared with other body areas and volume maintenance being major hurdles.22 ,23 This has been put down to the technique not being well understood at the time with the many technical factors influencing graft take and maintenance not being appreciated.25

Controversy and prohibition of fat grafting

In 1987, following concerns that potential scarring and calcifications could mask the detection of breast cancer and that adipocytes might directly stimulate the formation of cancer, the American Society of Plastic and Reconstructive Surgeons (ASPRS) Ad Hoc Committee on New Procedures prohibited the use of AFG to the female breast through a position statement which stated The committee is unanimous in deploring the use of autologous fat injection in breast augmentation.25

The advent of structural fat grafting

In the period that followed, Coleman26 developed the concept of structural fat grafting. The principle being that fat must be transplanted in small aliquots using multiple tunnels, in a multilayered and multidirectional way, formed by thin cannulas and syringes. This maximises the number of adipocytes in contact with the host tissue, optimising their chances of receiving sufficient nutrition and immobilisation to survive and become incorporated into the recipient site.27 Any fat that necroses, can cause an inflammatory reaction, with the sequelae of fibrosis and/or cystic formation plus or minus calcification and potential local infection.28 These principles are particularly important in the breast, where unlike the other anatomical areas, fat is being implanted into a loose and poorly vascularised space postmastectomy or BCS.26

A number of studies subsequently showed structural fat grafting to the breast to be efficacious.29––31 In 2009, the American Society of Plastic Surgeons (ASPS) Fat Grafting Task Force announced that fat grafting to the breast is not a strongly recommended procedure, as there is limited scientific data on safety and efficacy.23 They also stated that: “there appears to be no interference with breast cancer detection.”23

Growing knowledge on fat grafting

There has been much focus on how to boost fat graft survival including the development of centrifugation techniques for distilling the fat fraction from the harvested fluid (which will also contain blood residues in the precipitate and an oily supernatant composed of lysed cells and free triglycerides) and the understanding that adipose tissue is an endocrine organ with distinct circadian mechanisms and is rich in mesenchymal stem cells (MSCs).16 ,32 Such adipose-derived stem cells (ADSCs) can differentiate into a range of cells types (eg, chondrocytes, myocytes and osteoblasts) and secrete angiogenic factors such as vascular endothelial growth factor.32 ,33

ADSCs have now become the most studied adult stem cell and are thought to play a key role in the restorative, reconstructive and sustainable qualities of transferred fat.16 ,34––38

Current controversy and concerns

Pearl et al39 have cited concerns with respect to fat grafting into an area of previous malignant change. They highlighted basic science and animal studies which found that engrafted MSCs were less able to regulate growth patterns and how this could potentially lead to breast cancer recurrence.37 ,40 Wang et al41 have emphasised the role that adipose tissue may play in breast cancer progression and metastasis. Recent studies have shown that adipokine signalling may foster cancer initiation and progression with adipose tissue progenitors cooperating in breast cancer angiogenesis, growth and metastatic progression.42 There are also concerns about how AFG may lead to mammographic confusion with 16.7% of patients in one sample showing the subsequent development of clustered microcalcifications.43 The greatest concern thus comes in the use of AFG—which stimulates angiogenesis—to reconstruct what was a tumour bed that is, postmastectomy or BCS.

What have we learnt from prior systematic reviews?

The table below summarises previous systematic reviews assessing AFG to the breast.

The quality of the previous systematic reviews is assessed in table 1 below using the validated assessment tool ‘Assessment of Multiple Systematic Reviews (AMSTAR)’.44–46

From table 2, it can be noted that two reviews do not state the years searched or only searched a narrow range of databases.23 ,49 All the reviews were restricted to the English language, which creates substantial language bias. All of these reviews suffer from significant heterogeneity across the included studies with cosmetic as well as reconstructive indications among populations with congenital and acquired defects or use of cointerventions such as simultaneous implant or flap-based procedures along with AFG.

Many of the included studies did not report on patient satisfaction and those that did, did not use a standardised and validated instrument for such measurement. The follow-up periods were also highly variable, so the time point at which outcomes are measured is highly variable.

Why is it important to do this systematic review?

AFG is an active research front. A basic search using the database SCOPUS for ‘fat grafting’ reveals how research and interest in this area has increased in recent years (figure 1).

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Figure 1

Number of articles published per year and indexed by SCOPUS under the search term “fat grafting”.

Since the most recent systematic review looking at the use of AFG in breast reconstruction by Claro et al48 concluded its search in June 2011, there have been approximately 235 more articles published in this area. A new systematic review is needed to update our understanding of this rapidly evolving reconstructive technique and potentially answer the questions previous studies have.

Primary objectives

In the context of using AFG for breast reconstruction in women postmastectomy or post-BCS, we aim to determine its

1. Oncological outcomes

2. Clinical outcomes

3. Aesthetic and functional outcomes

4. Patient-reported outcomes

5. Process outcomes

6. Radiological outcomes

Secondary objectives

1. To determine optimal methods of fat harvesting, preparation and injection.

2. To determine the indications for the procedure.

3. To help refine patient selection for the procedure.