We thank Mr Nigel Mercer for his reflections and overall positive support of our recent paper and understand these comments represent his personal viewpoints and not the opinions of the Plastic, Reconstructive and Aesthetic Surgery Expert Advisory Group, Medicines and Healthcare products Regulatory Agency, or Sure Insurance ltd (Santa Monica, CA). It is important for us to clarify several points that Mr Mercer has raised in his letter. Mr Mercer comments that we “make reference to 1300 plus cases of breast implant associated anaplastic large cell lymphoma (BIA-ALCL) being mostly related to highly textured, salt loss implants. Without relating incidence to sales data, the relative risks between implants remains unclear to both the profession and the public.” We want to bring to Mr Mercer's attention that the United States FDA reports that when manufacture history was known, approximately 91% of world cases involved prior exposure to an Allergan Biocell macrotextured device (Allergan, Irvine, CA).1 In addition, the incidence of BIA-ALCL increases with higher texture grade.2 Utilizing sales data, Silimed (Silimed Corporation, Rio De Janeiro, Brazil) polyurethane implants and Allergan Biocell implants confer the highest risk of developing BIA-ALCL (odds ratio of 23.4 and 16.52, respectively, compared with Siltex).3 In the only prospective level 2 evidence on BIA-ALCL risk, the Allergan Biocell Continuing Access and Reconstruction (CARE) trial demonstrated 8 cases of BIA-ALCL out of 17,656 patients, a risk of 1 in 2207 (95% confidence interval, 1120-5112).4 In a more recent study, Cordeiro shows an even higher risk of BIA-ALCL with Allergan Biocell breast implants, with 1:355 women.5 In summary, there is an extensive body of evidence conclusively showing an increased risk of BIA-ALCL associated with specific manufacturers and a significant difference across numerous studies of the occurrence of BIA-ALCL being manufacturer and texture specific. It is critical to note that neither Nagor (Cumbernauld, UK) nor Polytech (Dieburg, Germany) have released annualized sales data to an independent reviewer for an accurate risk calculation. Surely Mr Mercer joins us in calling for manufacturers to release these critical data for independent review. Simply dividing a few ALCL cases by all-time world aggregated sales data is wholly inaccurate and misleading, particularly when the national markets of some of these implants have no established BIA-ALCL registries to capture cases. Consider that prior to Allergan releasing sales data to several academic institutions for review, best calculations of Biocell risk up to that point was 1:500,000 patients. Accurate disease risk calculations directly led to the US FDA device recall of Biocell, which quickly precipitated a worldwide ban. Considering this precedence, manufacturers such as Polytech may understandably be hesitant to supply this level of transparency, but it is in the best interest of patient safety and critical to the integrity of our profession. If manufacturers do not supply these data, we are unable to calculate their implant specific risk and cannot infer or compare risks across devices.
In Mr Mercer's letter, the terms incidence/risk and prevalence seem to be employed interchangeably. In particular, a BIA-ALCL risk of 1:16,500 implants is reported, but this estimate seems to be calculated simply by dividing the number of BIA-ALCL cases by the number of breast implants and tissue expanders sold in the UK. Because there is no specific time frame, this cannot be considered an incidence but more likely a “prevalence.” Therefore this is neither an incidence nor a risk and is completely dependent on the accurate reporting of disease within that population.
Accurate numbers of BIA-ALCL cases (the numerator) optimally come from either mandatory/opt-out national breast implant registries or long-term post-market approval studies. Consider, Medicines and Healthcare products Regulatory Agency and Health Canada report BIA-ALCL prevalence based on calculations per implant sold within that country, which is potentially biased by several facts, such as
in the UK, not all brands of implant are sold;
not all implants sold in the UK have been implanted into patients;
an unknown number of implants sold have been explanted;
an unknown number of implants sold have been replaced;
not all implants sold in the UK have been implanted into British patients,
and conversely some patients have been implanted abroad;
not considering contralateral symmetrization, 25% of the population at risk (post-oncologic) may undergo a single implant positioning with a prevalence in UK of 1:16,550, while the remaining 75% (aesthetic) usually receive 2 implants, with a twofold prevalence (not a risk) of 1:8250. Moreover, we know that in 97% of cases, BIA-ALCL occurs on only in 1 of the 2 implanted devices.
For an appropriate case tracking, the health care system of the country where diagnoses are issued should consider all patients, independent of where the surgery was performed. Due to possible underestimation, we recommend calculating occurrence per active population at risk, as calculated by de Boer et al, Doren et al, and Santanelli di Pompeo et al, because the per-sold-implant calculation does not appropriately reflect the magnitude of the BIA-ALCL impact on patients and consequently on health care systems.6–8
Finally, Mr Mercer comments that “We, therefore, cannot assume that any implant is safe, perhaps including smooth implants, where the reported incidence of Breast Implant Illness (BII) is greater with smooth implants.” Although BII is beyond the scope from our paper, there exists no formalized risk calculation of BII in the literature, and therefore any attempt to stratify risk across implant type, fill, surface characteristic, or manufacturer is not based on data or outcomes. Therefore, we urge caution and patience before making speculative or sweeping generalizations in particular to BII, which is only recently recognized as an entity by government authorities and patient advocacy groups. To be clear, no BIA-ALCL cases have been reported in case reports, case series, or registries worldwide with a clinical history of only smooth-surface devices.9,10 Mr Mercer raises an industry-promoted misconception about BIA-ALCL cases that “clustering” represents surgeons with poor technique, which gives patients lymphoma. We acknowledge clustering of cases in the United States, Australia and New Zealand, United Kingdom, Netherlands, France, Italy, and Poland with widespread geographic variation in global risk estimates. Importantly, these differences in clustering and subsequent risk profiles are the result of increased awareness, improved surveillance, access to care, and long-term follow-up rather than epidemiologic, technique, or pathologic phenomena.11 Attempts to link surgeon technique to ALCL has no credible data support, and more importantly surgeon-shaming threatens to undermine the reporting of future ALCL cases required to build robust outcomes databases for scientific investigation. In summary, we appreciate Dr Mercer's close reading of our manuscript while fostering healthy academic discourse. Let us all agree to improve open and transparent BIA-ALCL research.
Contributor Information
Fabio Santanelli di Pompeo, Full professor of plastic surgery, Faculty of Medicine and Psychology, Sapienza University of Rome, Department NESMOS, Sant’Andrea Hospital, Rome, Italy.
Mark W Clemens, Associate professor of plastic surgery, Department of Plastic Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA, and a breast surgery section editor for Aesthetic Surgery Journal.
Michael Atlan, Associate professor of plastic surgery, Aesthetic Plastic Reconstructive Unit/CHU TENON PARIS - APHP, Université Pierre et Marie Curie, Paris, France. Université Pierre et Marie Curie, UPMC PARIS VI, Paris, France.
Giovanni Botti, Plastic surgeon in private practice in Salò, Italy.
Peter G Cordeiro, Professor of surgery, Plastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Daphne De Jong, Full professor of pathology, Amsterdam UMC-Vrije Universiteit Amsterdam, Department of Pathology and Cancer Center Amsterdam, Amsterdam, the Netherlands.
Arianna Di Napoli, Associate professor of pathology, Pathology Unit, Department of Clinical and Molecular Medicine, Sapienza University, Sant’Andrea Hospital, Rome, Italy.
Dennis Hammond, Plastic surgeon in private practice in Grand Rapids, MI, USA.
Cara L Haymaker, Assistant professor of immunology, Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Steven M Horwitz, Professor of medicine, Lymphoma Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Kelly Hunt, Professor of surgery, Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Peter Lennox, Division head, Department of Surgery, Division of Plastic and Reconstructive Surgery, University of British Columbia, Vancouver, British Columbia, Canada, and a clinical editor for Aesthetic Surgery Journal.
Patrick Mallucci, Plastic surgeon in private practice in London, UK.
Roberto N Miranda, Associate professor of hematopathology, Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Alexandre M Munhoz, Professor of plastic surgery, Plastic Surgery Department, Hospital Moriah, Hospital Sírio-Libanês, Higienópolis, São Paulo, Brazil.
Demosthenes Panagiotakos, Professor in biostatistics, research methods, and epidemiology, School of Health Sciences and Education, Harokopio University in Athens, Athens, Greece.
Eric C Swanson, Plastic surgeon in private practice in Leawood, KS, USA.
Suzanne D Turner, Professor of cellular and molecular tumour biology, Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
Guido Firmani, Plastic surgery resident, Faculty of Medicine and Psychology, Sapienza University of Rome, Department NESMOS, Sant’Andrea Hospital, Rome, Italy.
Michail Sorotos, Assistant professor of plastic surgery, Faculty of Medicine and Psychology, Sapienza University of Rome, Department NESMOS, Sant’Andrea Hospital, Rome, Italy.
Disclosures
Dr Santanelli di Pompeo would like to disclose that the NESMOS Department with which they are affiliated has received research funds from Motiva, Establishment Labs (Alajuela, Costa Rica) in 2017, and from GC Aesthetics (Dublin, Ireland) in 2018 and 2020. The NESMOS Department has also received mini-implants from Establishment Labs, GC Aesthetics and Sebbin (Boissy l'Aillerie, France) for research purposes. FSDP is a paid consultant for BellaSeno GmbH, has received reimbursements for travel/lodgment expenses from ICEAG in 2015 and SCHEER-WG in 2019, 2020 and 2021, and is a member of Notified Body 0373, part of the Superior Institute of Health, which carries out CE Mark certification activities for the Italian Ministry of Health for the year 2021. They have no ownerships or investments to disclose. Dr Hammond has a consulting agreement with the Mentor Corporation (Irvine, CA) and Establishment Labs. Dr Turner receives research funding from Allergan Inc (Irvine, CA). The remaining authors declared no potential conflicts of interest with respect to the research, authorship, and publication of this article.
Funding
The authors received no financial support for the research, authorship, and publication of this article.
REFERENCES
- 1. US Food and Drug Administration . Medical device reports of breast implant-associated anaplastic large cell lymphoma. US Food and Drug Administration. 2020. Accessed October 1, 2020. https://www.fda.gov/medical-devices/breast-implants/medical-device-reports-breast-implant-associated-anaplastic-large-cell-lymphoma
- 2. Munhoz AM, Clemens MW, Nahabedian MY. Breast implant surfaces and their impact on current practices: where we are now and where are we going? Plast Reconstr Surg Glob Open. 2019;7(10):e2466. doi: 10.1097/GOX.0000000000002466 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Magnusson M, Beath K, Cooter R, et al. The epidemiology of breast implant-associated anaplastic large cell lymphoma in Australia and New Zealand confirms the highest risk for grade 4 surface breast implants. Plast Reconstr Surg. 2019;143(5):1285–1292. doi: 10.1097/PRS.0000000000005500 [DOI] [PubMed] [Google Scholar]
- 4. Clemens MW, McGuire PA. Discussion: a prospective approach to inform and treat 1340 patients at risk for BIAALCL. Plast Reconstr Surg. 2019;144(1):57–59. doi: 10.1097/PRS.0000000000005756 [DOI] [PubMed] [Google Scholar]
- 5. Cordeiro PG, Ghione P, Ni A, et al. Risk of breast implant associated anaplastic large cell lymphoma (BIA-ALCL) in a cohort of 3546 women prospectively followed long term after reconstruction with textured breast implants. J Plast Reconstr Aesthet Surg. 2020;73(5):841–846. doi: 10.1016/j.bjps.2019.11.064 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. de Boer M, van Leeuwen FE, Hauptmann M, et al. Breast implants and the risk of anaplastic large-cell lymphoma in the breast. JAMA Oncol. 2018;4(3):335–341. doi: 10.1001/jamaoncol.2017.4510 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Doren EL, Miranda RN, Clemens MW. U.S. epidemiology of breast implant-associated anaplastic large cell lymphoma. Plast Reconstr Surg. 2017;139(5):1042–1050. doi: 10.1097/PRS.0000000000003282 [DOI] [PubMed] [Google Scholar]
- 8. Santanelli di Pompeo F, Sorotos M, Clemens MW, Firmani G, European Association of Plastic Surgeons (EURAPS) Committee on Device Safety and Development . Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL): review of epidemiology and prevalence assessment in Europe. Aesthet Surg J. 2021;41(9):1014–1025. doi: 10.1093/asj/sjaa285 [DOI] [PubMed] [Google Scholar]
- 9. Ashar B. FDA Perspective: BIA-ALCL and breast implant safety. Article presented at: 2nd World Consensus Conference on BIA-ALCL at MD Anderson Cancer Center; November 6-7, 2020, Houston, TX.
- 10. Clemens MW, Medeiros LJ, Butler CE, et al. Complete surgical excision is essential for the management of patients with breast implant-associated anaplastic large-cell lymphoma. J Clin Oncol. 2016;34(2):160–168. doi: 10.1200/JCO.2015.63.3412 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Lynch EB, DeCoster RC, Clemens MW, Rinker BD, Yang M, Vasconez HC, Clemens MW. Current risk of breast implant-associated anaplastic large cell lymphoma: a systematic review of epidemiological studies. Ann Breast Surg. 2021;5:30. doi: 10.21037/abs-20-96 [DOI] [PMC free article] [PubMed] [Google Scholar]