Autologous Fat Grafting for Oncologic Patients: A Literature Review

Abstract

Autologous fat grafting (AFG) serves as an effective method to address volume defects, contour irregularities, and asymmetry in both aesthetic and reconstructive procedures. In recent years, there has been growing concern about the potential of cancer recurrence and interference with cancer surveillance in oncologic patients receiving AFG. The adipose tissue contains adipose-derived stem cells (ASCs), a specific type of mesenchymal stem cells, that facilitate secretion of numerous growth factors which in turn stimulate tissue regeneration and angiogenesis. As such, it has been theorized that ASCs may also have the potential to stimulate cancer cell proliferation and growth when used in oncologic patients. Multiple research studies have demonstrated the ability of ACSs to facilitate tumor proliferation in animal models. However, clinical research in oncologic patients has yielded contradictory findings. Although the literature pertaining to oncologic safety in head and neck, as well as sarcoma, cancer patients remains limited, studies demonstrate no increased risk of tumor recurrence in these patient populations receiving AFG. Similarly, both the efficacy and safety of AFG have been well established in breast cancer patients through numerous clinical studies. More recently, preclinical research in animal models has shown that AFG has the potential to facilitate tissue regeneration and improve joint contracture following irradiation. Ultimately, further research is needed to elucidate the safety of AFG in a variety of oncologic patients, as well as explore its use in tissue regeneration, particularly in the setting of radiotherapy.

Level of Evidence: 4

Autologous fat grafting (AFG) has gained popularity in recent years as an effective method to address volume defects, contour irregularities, and asymmetry in both aesthetic and reconstructive procedures.^1-3 In 2019, The Aesthetic Society reported that 24,892 AFG procedures were performed for breast reconstruction alone, demonstrating a steady upward trend from previous years.⁴ High satisfaction rates by both surgeons and patients and minimal donor site morbidity make fat grafting an ideal adjunct in the setting of oncologic reconstruction.^5-9

AFG was first introduced in the late 1800s by Neuber who detailed the use of lipoma specimens collected from the forearm for correcting facial atrophic scarring caused by tuberculosis infections.^10,11 Within the same year, Czerny described the first use of AFG in breast reconstruction.¹² However, the use of the procedure declined throughout the following century due to high resorption rates.^13-16 This was initially demonstrated by Peer in 1956 who reported a 50% loss in graft volume following a 12- to 14-month period after the AFG procedure.¹³ In more recent years, there has been growing concern about the potential of cancer recurrence and interference with cancer surveillance.^3,17-21 The American Society of Plastic Surgeons responded to these concerns in 2007 by creating a task force to further evaluate the indications, efficacy, and overall safety of AFG.²² In 2009, this task force ultimately concluded that it could not provide definitive recommendations on the use of AFG in clinical practice due to the lack of substantial evidence in the literature at the time.²² Since 2009, research concerning the efficacy and safety of AFG has drastically increased. Additionally, procedural techniques for AFG have continued to be altered and refined in recent years to optimize fat graft retention rates and attain desirable long-term results.^23,24 This paper serves as a review of the current literature regarding AFG as it relates to oncologic reconstruction.

ONCOLOGIC CONCERNS OF AFG

Adipose tissue contains adipose-derived stem cells (ASCs), a specific type of mesenchymal stem cell (MSC) or progenitor cell. ASCs perform an essential role in facilitating adipocyte survival, and thus graft survival, through the secretion of numerous growth factors and cytokines, among which are fibroblast growth factor, transforming growth factor β, and vascular endothelial growth factor.^25-28 These growth factors and cytokines further function to stimulate tissue regeneration and angiogenesis.^25-28 They also allow for ASCs to generate a microenvironment that is potentially suitable for enhanced tumorigenesis.²⁹ Therefore, ASCs may also have the potential to stimulate cancer cell proliferation and growth when used in oncologic patients.³⁰

Gehmert et al demonstrated the presence of direct interaction between tumor cells, specifically breast cancer cells, and ASCs.³¹ Their results suggest that the platelet-derived growth factor PDGF-BB, produced by both murine and human breast cancer cells, can influence this interaction by promoting increased migration of human ASCs towards cancer cells.³¹ Several further studies have reported that ASCs can enhance the invasion and progression of metastatic breast cancer.^30,32-35 This has also been supported by a series of in vitro and in vivo studies by Zimmerlin et al that showed ASCs enhanced the proliferation of breast cancer cells indirectly through the secretion of growth factors.³⁵ The researchers cocultured metastatic pleural effusion cells with ASCs and demonstrated that active CD90+ tumor cells underwent enhanced tumorigenesis when injected with ASCs, whereas no tumor cell proliferation occurred with CD90– metastatic pleural effusion cells injected with ASCs.³⁵ They proposed this was likely due to ASC-mediated secretion of transforming growth factor β, vascular endothelial growth factor, and interleukin 6, as well as secretion of adipsin and leptin.³⁵ Likewise, similar outcomes were found by Rowan et al who used a murine xenograft model to demonstrate that coculturing of ASCs with triple-negative breast cancer cells resulted in increased cancer cell migration, and more specifically, an increase in micrometastases found in first-pass metabolism organs.³⁶ All these research outcomes support that ASCs may have the potential not only to lead to cancer recurrence but may also fuel the metastatic spread of cancer. However, a major limitation of many of these preclinical studies is their use of breast cancer cell lines acquired from cell banks, thus allowing for more mutations and durability of cells as compared with the residual tumor cells found in patients.²⁹ Additionally, most of these cell lines grow quickly in vitro and will form sizable tumors in vivo.³⁷ As such, these results may not be as applicable to the clinical setting. Nevertheless, these findings still raise significant concern for patient safety with clinical use of AFG in oncologic reconstruction.

Conversely, several preclinical studies have shown no effect of ASCs on tumor growth and proliferation.^38-41 Kucerova et al used in vitro and in vivo studies to demonstrate that ASCs may have a suppressive effect on cancer proliferation in glioblastoma cell lines.⁴² Similarly, MSCs inoculated into melanomas in an in vivo model resulted in tumor cell apoptosis and suppression of tumor growth.⁴¹ Regarding breast cancer specifically, Sun et al demonstrated that transplantation of ASCs into a mouse model resulted in inhibition of breast cancer growth.⁴⁰ Findings by Dieudonne et al support that adiponectin is responsible for apoptosis and reduced proliferation of breast cancer cells.³⁹ These contradictory results emphasize the complexity of the interaction between ASCs and the tumor microenvironment, and how this interaction is influenced by an extremely wide variety of factors.

HEAD AND NECK

AFG has been used in head and neck oncologic patients to correct contour irregularities⁴³ and has been suggested to positively influence the healing process of damaged irradiated tissue.^44,45 Presently, there remain significant concerns that fat grafting may lead to tumor recurrence in the setting of oncologic reconstruction in head and neck cancer patients, as well as potentially obscure cancer surveillance. The current literature on AFG used for head and neck oncologic reconstruction remains limited.

Honeybrook et al retrospectively assessed 62 patients who received AFG for the reconstruction of head and neck cancer defects. Only 3 patients (5%) were found to have complications as a result of AFG, with the majority of patients being satisfied with their cosmetic outcome postoperative.⁴⁶ In a prospective analysis of 12 patients who received AFG after head and neck tumor resection and radiation, Gutiérrez Santamaría et al reported no complications over the course of 12 months.⁴⁵ AFG improved cosmetic and functional outcomes according to 83% and 92% of patients, respectively. Neither study evaluated the recurrence rate following AFG or its impact on cancer screening and surveillance.^45,46

Karmali et al have performed the largest studies to date on the use of AFG in 116 head and neck cancer patients over a mean follow-up of 35.8 months.⁴³ The authors found a low rate of oncologic recurrence in patients receiving AFG (3 local, 2.6%; 1 regional nodal, 0.9%; and 2 distant metastases, 1.7%).⁴³ When locoregional recurrence (LRR) occurred, it did not develop in regions where AFG was performed. The total complication rate after AFG was low (5.1%), consisting of fat necrosis, oil cysts, and infection.⁴³ Aesthetic outcomes of 17 patients were assessed blindly both preoperatively and postoperatively through a 5-point Likert scale by laypersons as well as plastic surgeons. Results showed that both the laypersons and plastic surgeons found the patients to appear closer to normal after the AFG procedure.⁴³ However, this aesthetic analysis was largely subjective. The authors did not assess possible interference of AFG on cancer surveillance or compare the recurrence in AFG patients with a control group of patients without AFG. Moreover, the impact of AFG on patients’ quality of life has not been evaluated.

Based on the results of existing literature, AFG seems to be safe and effective for head and neck oncologic patients; more studies are needed to confirm this finding and the lack of interference of AFG on cancer surveillance.⁴³

SARCOMA

Sarcomas are a rare and malignant form of neoplasm that encompass a wide variety of histologic subtypes.^47,48 AFG can be used in patients with sarcomas to correct tissue defects that occur as a result of tumor resection.⁴⁹ It has been demonstrated that sarcoma recurrence after resection is associated with a worse prognosis and decreased survival.^50-54 Thus, it is imperative to assess whether AFG results in an increased risk of tumor recurrence in this patient population.

In a case study by Perrot et al, a 17-year-old female with a metaphyso-epiphyseal osteosarcoma underwent chemotherapy and surgical resection in 1994 with complete remission followed by 3 lipofilling procedures in 2005 and 2006 to correct the soft tissue defect. In 2007, the patient was found to have recurrence of osteosarcoma at the site of surgical resection and AFG with no evidence of further metastases.⁵⁵ This prompted the question of whether AFG was responsible for the osteosarcoma recurrence in this patient, as well as raised concern about the safety of AFG in sarcoma patients.

Pennati et al assessed 60 patients who underwent a total of 143 AFG procedures after prior resection of both soft tissue and bone sarcomas. The LRR rate after the AFG procedure was 3% (2 patients), with 1 additional patient (2%) exhibiting distant metastasis.⁴⁹ These rates were lower than LRR prior to AFG (17%) in this patient cohort. These findings suggest that LRR in sarcoma patients may be due to unique factors, including location and aggressiveness of the tumor, rather than the AFG procedure itself.

Soft tissue and bone sarcomas are one area where the data are lacking due to rarity of the tumors. Although Pennati et al demonstrated no increased risk of local recurrence after fat grafting, more longitudinal studies with larger patient inclusion are required to draw any definitive conclusions on fat grafting in sarcoma reconstruction.

BREAST

The majority of data on the use of AFG in oncologic patients relates to its use in breast cancer reconstruction. AFG has gained popularity as an adjunct reconstructive modality following both breast-conserving therapy (BCT) and mastectomy. Despite the plethora of literature on the use of AFG for breast reconstruction, there still exist some concerns regarding its oncologic safety in this patient population.

Breast-Conserving Therapy

BCT with subsequent irradiation is the most common management plan for low-stage breast cancer.^7,56 Breast asymmetry or contour irregularities are not uncommon following either BCT or postsurgical radiation, making AFG an ideal procedure to address these soft tissue defects.^57-59 However, due to subtotal resection of breast tissue in BCT, there is concern that the remaining tissue may contain tumor cells with the potential to be stimulated by AFG.⁶⁰

Recent literature has continued to demonstrate the oncologic safety of AFG following BCT in breast cancer patients.^8,61-65 In a matched cohort study of 72 patients undergoing delayed AFG following BCT, Hanson et al found no significant difference in LRR rates between patients who received AFG following BCT and those who underwent BCT alone (5.6% vs 5.6%, P = 1.00) after a median follow-up of approximately 5 years (range, 12-136 months).⁶¹ Similarly, Stumpf et al analyzed the oncologic safety of 65 patients who underwent immediate AFG and BCT matched 1:4 with 255 patients who underwent BCT alone without AFG over a mean follow-up of 5 years (range, 28-110 months AFG group vs 22-166 months control group). The authors found no significant difference in the rate of LRR between patients who received AFG (0.86%) and those who did not (0.70%, P > 0.05).⁶² These results demonstrate that AFG was not associated with an increased risk of LRR in BCT patients regardless of the time period in which the fat grafting procedure is performed (immediate vs delayed). However, Silva-Vergara et al conversely demonstrated an increased risk of LRR if AFG occurred within 36 months of breast cancer resection (P = 0.014).⁶³ As pointed out by the authors, these results could be due to inclusion bias. Despite these findings, there were no significantly increased risks of LRR or distant metastases in patients who received AFG compared with the controls in the overall cohort.⁶³

Mastectomy

Mastectomy is generally indicated for patients at higher risk of local tumor recurrence.^66,67 Although mastectomy is commonly followed by implant-based and/or autologous reconstruction, AFG has been gaining popularity as an adjunct method to restore breast volume in these patients. Presently, research has continued to demonstrate no significant association between AFG and tumor recurrence in breast cancer patients following mastectomy.^6,68-71

Cohen et al assessed both local and distant tumor recurrence rates in breast cancer patients undergoing AFG after mastectomy.⁶ The authors analyzed the outcomes of 248 breasts that received AFG vs 581 controls. Mean follow-up from initial surgery was 46 months in the AFG group and 39 months in the controls. No increased risk of either local (2.5% vs 1.9%, P = 0.75) or distant (1.9% vs 3.1%, P = 0.58) tumor recurrence was found between patients who received mastectomy + AFG compared with those who received mastectomy alone.⁶ Similarly, in a matched cohort study, Krastev et al found no significant differences in cumulative incidence of LRR between patients receiving AFG and mastectomy/BCT vs those who receive mastectomy/BCT alone (P = 0.33) after a mean follow-up of 5 years after AFG (9.3 years after initial surgery in the AFG group and 8.6 years in the controls).⁶⁸

Although many studies have demonstrated no significant effect of AFG on LRR following breast cancer resection, other studies have shown conflicting results.^60,71 Sorrentino et al showed that Luminal A (positive hormone receptors, negative HER-2) patients who received AFG had a significantly decreased LRR-free survival compared with controls, after 80 months (P = 0.02).⁷¹ However, the remaining number of Luminal A patients at 80 months was greatly reduced, and as such, no definitive conclusion can be drawn regarding oncologic safety in this particular patient population. Early findings by Petit et al additionally showed a significantly increased rate of LRR in patients with intraepithelial neoplasia who received lipofilling, compared with a control group, following either BCT or mastectomy.⁷² Despite these initial findings, further research from the same group has found contradictory results demonstrating no detrimental effect of AFG on oncologic safety in breast cancer patients, regardless of whether BCT or mastectomy was performed.⁶⁴ This is supported by a plethora of clinical studies.^{6,7,62,64,65,68-71,73,74}

A recent meta-analysis of 59 studies encompassing a total of 4292 patients who received AFG after both BCT and mastectomy found no significantly increased LRR rates in those who received AFG compared with those who did not.⁷ Results from the 7 matched cohorts included in the review demonstrated similar findings (P = 0.42).⁷ Additionally, no significant differences in LRR between AFG patients and controls were found within subgroups of tumor histology subtype or procedure (BCT vs mastectomy).⁷ The results of this meta-analysis may be limited by small patient sample sizes, insufficient follow-up time periods, and potential selection bias. Nonetheless, these results support that AFG does not increase tumor recurrence in breast cancer patients, following either BCT or mastectomy.

SCREENING AND SURVEILLANCE IN BREAST CANCER

In addition to the concern that AFG may lead to tumor recurrence in breast cancer patients, there has also been concern that it may lead to possible radiologic interference in breast cancer screening^8,22 The use of AFG has the potential to result in fat necrosis, oil cysts, and microcalcifications which may be mistaken for possible malignancy on imaging and lead to an increased number of biopsies in breast cancer patients.^6,8,22,75-78

Studies suggest that these aberrant radiographic findings may occur regardless of whether AFG or other surgical techniques are utilized for breast reconstruction.⁷⁹ Danikas et al demonstrated a 19% incidence of oil cysts and a 26% incidence of calcification following breast reduction.⁸⁰ In regards to the use of AFG in breast reconstruction, a recent study by Hanson et al found no significant difference in rates of palpable masses, fat necrosis, abnormal radiologic imaging, or indication for a breast biopsy between patients who received AFG and those who did not.⁶¹ Similarly, Rubin et al found no significant differences in calcification or oil cyst findings warranting biopsy between patients receiving AFG vs reduction mammaplasty.⁷⁷ Groen et al additionally demonstrated that despite the potential presence of these mammographic findings after AFG, they remained distinguishable from malignant lesions.⁸ Benign lesions associated with AFG may be easily distinguished from malignancy based on their distribution, size, and morphology.^2,17 These findings ultimately support that AFG does not interfere with radiologic surveillance in breast cancer patients.

COMPLICATIONS

Multiple studies have demonstrated the low complication rates of AFG when used for breast reconstruction.^8,9,75,81,82 In a systematic review of 6260 patients who underwent AFG for oncologic breast reconstruction, Groen et al found an overall complication rate of 8%, cyst formation in 7%, hematoma in 6%, fat necrosis in 4%, and infection in 1% of cases.⁸ Likewise, in another systematic review by Largo et al, researchers found an overall complication rate of 15.6% in 1453 patients who received AFG to healthy breast tissue over the course of 16.3 months.⁹ The majority of these complications were considered minor, including the formation of palpable nodules (7%) and the development of infection (0.7%).⁹

Regarding facial reconstruction, a systematic review by Gornitsky et al demonstrated a low complication rate in patients who received AFG in the facial region.⁸³ The complication rate in 1453 patients was 2% with the majority of complications attributed to skin irregularities or asymmetry.⁸³ In patients who received AFG following resection of head and neck tumors, minor complications, including fat necrosis, oil cysts, and infection, occurred in 5.1% of the 116 patients after a mean follow-up of over 3 years.⁴³ These findings serve to highlight the safety of AFG and its low complication rate, regardless of the recipient tissue site.

FUTURE DIRECTIONS

Although several retrospective studies have demonstrated the oncologic safety of AFG in breast cancer patients, higher-level-evidence studies based on randomized prospective designs are needed to confirm the safety of AFG in oncologic patients. These studies, however, are limited by the low recurrence rate after AFG and the long follow-up required. Furthermore, research regarding the use of AFG and its long-term safety in areas other than breast reconstruction (eg, sarcoma, head and neck cancer) currently remains limited.

In addition to addressing contour defects, asymmetry, and irregularities, AFG has the potential to facilitate tissue regeneration and accelerate wound healing following irradiation.^84-86 Panettiere et al demonstrated that the use of fat grafting in irradiated reconstructed breast tissue resulted in enhanced functional and cosmetic outcomes, including reduced tissue fibrosis as well as scar improvement.⁸⁵ Likewise, other researchers have found similar enhanced functional and aesthetic outcomes following AFG to irradiated head and neck tissue.⁴⁴ These improved outcomes are linked to the progressive cellular regeneration seen in the ultrastructure of irradiated tissue following AFG.⁸⁴ Along with tissue regeneration, AFG has also been found to reduce chronic pain in patients after radiation.⁸⁷ Maione et al demonstrated that patients who received AFG reported significantly lower levels of pain than patients who did not receive AFG (P ≤ 0.005) following post-BCT radiotherapy of the breast.⁸⁷ These favorable outcomes of tissue regeneration, wound healing, and pain reduction are strongly associated with the presence of ASCs.⁸⁸ Through secretion of numerous growth factors and cytokines, ASCs lead to neovascularization, reduced inflammation, and enhanced cell proliferation of damaged, irradiated tissue.^84,87-89

The myriad of regenerative benefits associated with the use of AFG following radiotherapy continue to emerge as more research is conducted on this topic. In more recent studies, AFG has been shown to improve joint contracture after radiation therapy, as demonstrated through the use of animal studies.⁸⁸ Another recent study by Haran et al suggests that AFG may additionally be effective in the treatment of capsular contracture following radiotherapy.⁹⁰ Future research should further assess the use of AFG in improving irradiated tissue of oncologic patients in a clinical setting.

CONCLUSIONS

AFG is a minimally invasive procedure that can be utilized for reconstruction in oncologic patients. Both its efficacy and safety have been well established in breast cancer patients, but further research is needed to elucidate the safety of AFG in other oncologic patients as well as explore its use in tissue regeneration, particularly in the setting of radiotherapy.

Disclosures

The authors declared no potential conflicts of interest with respect to the research, authorship, and publication of this article.

Funding

This supplement is sponsored by Allergan Aesthetics, an Abbvie Company (Irvine, CA, USA) and Suneva Medical, Inc. (San Diego, CA, USA).

REFERENCES