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Patient Registry and Outcomes for Breast Implants and Anaplastic Large Cell Lymphoma Etiology and Epidemiology (PROFILE): Initial Report of Findings, 2012–2018

McCarthy, Colleen M., MD, MS; Loyo-Berríos, Nilsa, PhD, MSc; Qureshi, Ali A., MD; Mullen, Erin; Gordillo, Gayle, MD; Pusic, Andrea L., MD, MPH; Ashar, Binita S., MD, MBA; Sommers, Katie, MPH; Clemens, Mark W., MD

Plastic and Reconstructive Surgery: March 2019 - Volume 143 - Issue 3S - p 65S-73S
doi: 10.1097/PRS.0000000000005571
Original Articles
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Background: In January of 2011, the US Food and Drug Administration released a safety communication regarding the potential association between breast implants and anaplastic large cell lymphoma (ALCL). In August of 2012, the American Society of Plastic Surgeons, The Plastic Surgery Foundation, and the Food and Drug Administration signed a cooperative research and development agreement to develop a patient registry entitled the “Patient Registry and Outcomes for Breast Implants and Anaplastic Large Cell Lymphoma Etiology and Epidemiology” (PROFILE).

Methods: The first report of the registry findings is presented here.

Results: From August of 2012 to March of 2018, a total of 186 distinct cases of breast implant–associated ALCL (BIA-ALCL) in the United States were reported to PROFILE. At the time of this present analysis, complete detailed case report forms have been received for 89 (48%) cases. Median time from implantation of any device to BIA-ALCL diagnosis was 11.0 years (range = 2–44 years; n = 89). At the time of presentation, 96% of cases had local symptoms and 9% had concurrent systemic symptoms. The most common local symptom was a periprosthetic fluid collection seen in 86% of patients. All patients had a history of a textured device; there were no patients who had a smooth-only device history. At the time of initial case report submission, 3 deaths were reported.

Conclusions: The PROFILE Registry has shown to be an essential tool in unifying the collection of data pertaining to BIA-ALCL. These data have broadened our understanding of the disease and emphasize the critical importance of detailed tracking of BIA-ALCL cases.

New York, N.Y.; Silver Spring, Md.; Marina Del Rey, Calif.; Arlington Heights, Ill.; Indianapolis, Ind.; Boston, Mass.; and Houston, Texas

From the Plastic and Reconstructive Service and Department of Surgery, Memorial Sloan-Kettering Cancer Center; Center for Devices and Radiological Health, U.S. Food and Drug Administration; Marina Plastic Surgery; American Society of Plastic Surgeons; Department of Surgery, Indiana University; Division of Plastic Surgery, Brigham and Women’s Hospital; and Department of Plastic Surgery, University of Texas MD Anderson Cancer Center.

Received for publication September 21, 2018; accepted December 17, 2018.

Disclosure:Dr. Clemens was an investigator for the ATHENA Trial (Mentor Corporation), is an investigator for the Motiva FDA Approval Trial (Establishment Labs), and was a former Allergan Consultant (2012–2015). None of the other authors has any financial relationships or affiliations to disclose. This study and the Patient Registry and Outcomes for Breast Implants and Anaplastic Large Cell Lymphoma Etiology and Epidemiology” (PROFILE) is a project coordinated and supported by The Plastic Surgery Foundation.

Colleen M. McCarthy, MD, MS, Plastic and Reconstructive Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, MRI 1007 New York, N.Y. 10065, mccarthc@mskcc.org

Breast implant–associated anaplastic large cell lymphoma (BIA-ALCL) is a T-cell lymphoma that can develop around breast implants.1–3 The World Health Organization now provisionally classifies BIA-ALCL as an anaplastic, kinase–negative, T-cell lymphoma that most commonly presents as an indolent periprosthetic effusion, but can form invasive masses and metastasis in rare cases.4

In January of 2011, the US Food and Drug Administration (FDA) released a safety communication regarding the potential association between breast implants and ALCL.5 At the time of the safety communication, 34 case reports were known worldwide, patient tracking was performed at only a few academic centers, and no established patient registries existed for reporting of cases in the United States. Medical device adverse event reports are submitted to the FDA's safety information and adverse event reporting program, MedWatch,6 and are publicly available through the Manufacturer and User Facility Device Experience, which includes both domestic and international adverse event reports. This is a passive surveillance system by patients, providers, facilities, and manufacturers. However, it is limited by potential incomplete, inaccurate, and/or unverified data.7 Although the Manufacturer and User Facility Device Experience database can give early warnings on adverse events, this system is not designed to capture detailed granular data on patient demographics, therapeutic regimens, and oncologic outcomes.

In August of 2012, the American Society of Plastic Surgeons (ASPS), The Plastic Surgery Foundation (PSF), and the FDA signed a cooperative research and development agreement to develop an infrastructure where all past and future cases of BIA-ALCL could be centralized. This collaboration resulted in a patient registry entitled the “Patient Registry and Outcomes For breast Implants and anaplastic large cell Lymphoma etiology and Epidemiology” (PROFILE) Registry.

The specific aims of the PROFILE Registry are to describe the demographic and clinical characteristics of patients diagnosed with BIA-ALCL, the pathologic findings of the disease, and to determine both the recurrence-free and overall survival.

The proposal for establishment of PROFILE and proposed analyses of the data was reviewed/approved through the FDA Institutional Review Board, from 2012 to July 2018. As of June 15, 2018, PROFILE is under approval of the Western Institutional Review Board. Reporting physicians are not required to obtain additional institutional review board approval, unless mandated by their home institution.

The first published report of the registry findings from August 2012 through to March 2018 is presented here.

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METHODS

Registry Design and Identification of Patient Population

The PROFILE Registry is designed to allow for the centralized collection of all past and future pathologically confirmed cases of BIA-ALCL. Since its inception, the PROFILE registry has been open to all physician reporters practicing in the United States, who have obtained patient informed consent (if applicable at their institution) to report their patient data to the PROFILE registry. Although international cases have not been considered eligible for inclusion, there is interest in expanding PROFILE or collaborating with outside of US entities to better understand BIA-ALCL globally.

PROFILE is also designed to obtain follow-up data on the reported cases, to collect the data necessary to describe the patient’s vital status at the time of the follow-up, further treatment received since the initial case report, and all late effects, if applicable. This process is to be repeated at regular intervals up to 10 years following initial case submission. The follow-up data collection is ongoing. All reporting physicians have been contacted and asked to complete the PROFILE “follow-up case report form (CRF).” Follow-up data are not included in the present analysis.

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Data Collection Model

Data are collected both retrospectively and prospectively on pathologically confirmed cases of BIA-ALCL in the United States. All physicians who contact the registry are asked to first complete both a “Business Associate Agreement” and a PROFILE “Release and Consent Form” to (1) submit their case details, including protected health information (PHI) to PROFILE, and (2) allow the submitted data to be shared with the FDA. The PROFILE database is then screened by Registry Staff to rule out duplicate entries. Data received is then screened for data quality.

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Data Collection and Entry Process

The PROFILE CRF captures data necessary to describe a patient’s demographic characteristics, type and duration of breast implant exposure, use of acellular dermal matrix (ADM), clinical presentation, pathologic findings, treatment, and treatment outcomes of patients with BIA-ALCL.

Data collection started on August 2012, and it is ongoing. The analysis presented in this report includes data that were captured through March 2018. From August 2012 to September 2017, case submission was completed using a pencil and paper format. The data were transferred from the paper CRF directly into the PROFILE database by the PROFILE Data Coordinator. Beginning October 2017, an outside database vendor was employed to use their web-based infrastructure to allow the direct capture of data from the physician reporter into the PROFILE database. Using the “smart capabilities” of the online data entry system, questions were streamlined based on initial responses entered, which minimized the perceived burden on the reporter. Additionally, the database vendor, standing as a separate entity from PROFILE, was able to house PHI and thus was able to independently screen for duplicate cases.

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Data Quality

The PROFILE Data Coordinator and members of the PROFILE Steering Committee routinely reviewed the completed case reports to ensure data quality. All cases submitted and included in the present analysis were reviewed, before analysis to ensure quality of reported information, by at least 2 members of the PROFILE Steering Committee. Missing or conflicting data entries were clarified with the reporting physicians to ensure fidelity of reported data. This included review of operative reports, clinic notes, and pathology reports submitted in compliance with institutional review board and PHI regulations.

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Statistical Analyses

Data were analyzed descriptively to characterize the population of patients with BIA-ALCL. Descriptors include the demographic and other characteristics of patients with breast implants who have BIA-ALCL in terms of age, race, ethnicity and other personal attributes (medical history, presence of immunological markers, etc.), breast implant history, breast implant characteristics, use and if so type of ADM, as well as the clinical presentation, pathologic findings, clinical course, treatment, and treatment outcomes of BIA-ALCL in patients with breast implants.

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RESULTS

From August 2012 to March 2018, a total of 186 distinct cases of BIA-ALCL in the United States were reported to PROFILE. At the time of this present analysis, complete initial detailed CRFs have been received for 89 (48%) cases. Efforts to collect data on the remaining 97 (52%) reported cases are ongoing. Figure 1 illustrates these 186 distinct cases, by year of diagnosis. Figure 2 illustrates when these distinct cases were submitted to PROFILE. The patient numbers and percentages provided in the descriptive analyses of this article are based on the 89 cases with complete CRFs.

Fig. 1.

Fig. 1.

Fig. 2.

Fig. 2.

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Patient and Implant Characteristics

Table 1 summarizes the patients’ demographic and clinical characteristics for the BIA-ALCL cases for whom the physician reporter completed a CRF. Median patient age at the time of diagnosis was 52.5 years (range = 31–84 years). Race was reported as White for 82 patients (92%), Black/African American for 1 patient (1%), and was not reported in 6 cases (7%). Fourteen patients (16%) had a history of a nonbreast malignancy, including 1 patient with a history of non-Hodgkin’s lymphoma.

Table 1.

Table 1.

Forty-two patients (47%) had a history of cosmetic breast augmentation alone; 47 (53%) had a history of postmastectomy implant reconstruction. Four patients who underwent postmastectomy reconstruction had a history of prior cosmetic augmentation. All 47 patients in the reconstructive cohort had a diagnosis of breast carcinoma. No patient had a history of bilateral prophylactic mastectomies. Most of the 47 reconstructive patients underwent a postmastectomy reconstruction. There were 30 patients with 2-stage tissue expander/implant reconstruction and 16 patients with single-stage reconstruction. Fifteen women completed chemotherapy; 5 women received chest wall irradiation (see Table 2).

Table 2.

Table 2.

In the 89 patients with complete data, median time from implantation of their current implant to diagnosis of disease was 9.0 years (range = 0.08–27 years). Notably, there was 1 patient who was diagnosed with BIA-ALCL only at 0.08 years. The earliest time to development of BIA-ALCL in an implant-naive patient was 2.2 years. Median time from implantation of any device to diagnosis was 11.0 years (range = 2–44 years). All 89 patients had a breast implant (not tissue expander) at the time of diagnosis.

In total, 38 women (43%) had a history of multiple device exposure. Of this subset, 7 patients had prior permanent implants, whereas the remaining 31 patients had a history of prior temporary tissue expanders (see Table 3).

Table 3.

Table 3.

Implant details are presented in Table 4. Implant filler was reported as saline in 39 women (44%) and silicone in 46 (52%). One patient had a combined saline/silicone implant. In 3 patients, fill type was not reported. At the time of diagnosis, 70 patients (79%) had an implant with a textured shell; in 4 cases (5%) the implant type was smooth. In 15 (16%) cases the texture of the device was not reported.

Table 4.

Table 4.

In the 4 cases in which the diagnosis of BIA-ALCL was made in a patient with a smooth shelled device(s), all 4 patients had a history of prior implantation. In all 4 of these cases, patients had a history of a prior textured permanent implant. In 1 case, a patient had a history of a prior textured tissue expander.

The use of ADM was reported in 7 patients (8% of cases) ultimately diagnosed with BIA-ALCL. Twenty patients (22%) had a documented complication before a diagnosis (see Table 5). The most common complication was implant rupture, which occurred in 12 patients (13.5%). Infection was documented in 2 patients; no patient had a documented history of a hematoma.

Table 5.

Table 5.

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Presentation

Table 6 summarizes the clinical findings of BIA-ALCL. At the time of presentation, 85 (96%) patients had local symptoms and 8 (9%) had concurrent systemic symptoms. The most common local symptom was a periprosthetic fluid collection or seroma in 85.9% of patients (n = 73). When capsular contracture was present, it was most commonly grade III or IV. Palpable breast masses were only found in 15.7% (n = 13) cases. Pain, breast skin lesions, and redness were all uncommon but present in a subset of patients. When systemic symptoms were present, they included fevers, night sweats, weight loss, and nonbreast skin lesions.

Table 6.

Table 6.

In 2 cases (2%), patients were asymptomatic at the time of diagnosis. In the first of these cases, the patient had a history or prior cosmetic breast augmentation. She was subsequently diagnosed with unilateral breast carcinoma and elected to undergo explantation of bilateral breast implants concurrent with her bilateral mastectomies. Pathological examination of her periprosthetic capsules bilaterally revealed unilateral BIA-ALCL. In the second case, the patient had a history of cosmetic breast augmentation and was similarly diagnosed with a unilateral breast carcinoma. She proceeded with a unilateral lumpectomy alone. Routine screening of her silicone implant with magnetic resonance imaging subsequently revealed a ruptured device. She returned to the operating room for removal and replacement at which time periprosthetic fluid was encountered. Based on cytological evaluation of the fluid, BIA-ALCL was diagnosed.

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Diagnosis

Table 7 provides details regarding BIA-ALCL diagnosis. The majority of patients, 87 (98%), was diagnosed with unilateral BIA-ALCL. By contrast, 2 patients (2%) were diagnosed with bilateral BIA-ALCL. Notably, one of these patients had a history of B-cell non-Hodgkin lymphoma. Both patients had a history of bilateral breast augmentation, developed a unilateral seroma, and proceeded to surgery for bilateral explantation and capsulectomies. Pathologic examination of excised capsules revealed bilateral BIA-ALCL in both cases.

Table 7.

Table 7.

All known cases were anaplastic lymphoma kinase negative and CD30 positive. Most commonly (39.3%, n = 35), patients were diagnosed with stage IE disease (Lugano Modification Ann Arbor Staging). Tumor-node-metastasis solid tumor staging was not available at time of publication.

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Treatment and Outcomes

Eighty-one patients (91%) with BIA-ALCL were reported to have undergone surgical resection (see Table 8). In only 66 of these 81 cases, details surrounding the nature of their surgical procedure were submitted. In all these 66 cases, patients reportedly underwent explantation and capsulectomy. In 9 of these 66 cases, patients underwent explantation with the concurrent replacement of a breast implant(s). Whether the replacement implants had smooth or textured shells was not specified. Details regarding the type of capsulectomy performed were only available in 5 of the 66 cases. In only 1 of these 5 cases, a total capsulectomy was performed; in the remaining 4 cases, a partial capsulectomy was documented.

Table 8.

Table 8.

Two patients (2%) with BIA-ALCL were not treated surgically for their disease. In one of these cases, it is documented that the patient refused surgical treatment. In the other case, it is only noted that the patient received chemotherapy. In 5 cases (6%), treatment was not reported.

Adjuvant chemotherapy (28.1%, n = 25) and external beam radiation therapy to the chest wall (13.5%, n = 12) supplemented BIA-ALCL treatment in a minority of cases.

At the time of initial case report submission, 3 deaths were reported. One patient (1%) died of disseminated BIA-ALCL, 9 years after cosmetic breast augmentation. Eight years after augmentation, she developed a palpable mass adjacent to her device and was diagnosed with BIA-ALCL confined to the breast. She reportedly refused any surgical therapy, although she did undergo both chemotherapy and radiation. Ultimately, she developed widely metastatic disease and succumbed to the disease within 1 year. The second patient died of metastatic breast carcinoma, and a third patient reportedly died of natural causes.

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DISCUSSION

PROFILE, a collaboration between the ASPS, the PSF, and the FDA, has been shown to be an essential tool in unifying the collection of data and building a comprehensive knowledge base pertaining to BIA-ALCL. Because of the recent nature of this disease, granular details of cases are critical to understanding characteristics of the patients, implants used, diagnosis, treatment, and outcomes. This article represents the initial report of the first BIA-ALCL patient registry that was established worldwide.

These registry data add several first reports to the literature on BIA-ALCL. In the 89 patients with complete data, there was a clinical history of ADM use in 7 cases (7.9%). Extent of ADM use such as a small patch, inferolateral sling, or full wrap was not reported, and the role of ADM as a potential biological block in each of these situations would require further investigation. A history of fat grafting in 7 patients (7.9%) has also not been previously reported. This is the first US report of a confirmed case in a woman of African American race. This is also the first report of BIA-ALCL detected incidentally during the resection of a second primary of breast cancer. Without denominator data and with just a single tissue expander case, it is not possible to calculate a risk estimate for textured tissue expanders and this type of case remains exceedingly rare. This is the first report of BIA-ALCL detected incidentally during the resection of a second primary of breast cancer. Bilateral BIA-ALCL case reports have been previously reported,6 though this represents the first series of cases from a registry. Bilateral cases require pathology evaluation to determine if these cases represent metastasis or the occurrence of 2 separate primary clones in the same individual. Bilateral cases support the National Comprehensive Cancer Network treatment recommendations for bilateral capsulectomy in confirmed cases.7,8

Although presentation with periprosthetic effusions and/or mass has been widely reported,9–11 the disease characteristics in the current analysis further elucidate disease presentation. Ninety-four percent (83 patients) of registry patients presented with a seroma and/or a mass. Thirty-three percent (29 patients) were found to have a capsular contracture at time of presentation. In all but 1 case, capsular contracture accompanied another symptom. Registry patients had rates of associated skin lesions (n = 7, 8.2%), overlying skin redness (n = 12, 14.1%), and systemic symptoms (n = 8, 9%), all of which were accompanied by at least 1 additional symptom. These symptoms, when present, may further raise suspicion of BIA-ALCL and may warrant investigation.

Since 2011, the FDA has regularly updated the information available on its public website regarding known BIA-ALCL cases, including deaths and known risks.12 The strengths of the PROFILE Registry include the systematic collection of a comprehensive set of critical data elements specifically relating to BIA-ALCL. The registry’s ability to rule out duplicate entries minimizes the risk of overreporting of cases. And finally, PROFILE accepts submissions from physician reporters only, theoretically optimizing the accuracy of the reporting pertaining to specific clinical variables. This knowledge base will ultimately be used to support discussions surrounding the safety, effectiveness, and the benefit/risk profile of breast implants and will be instrumental in determining which factors have a role in the etiology of BIA-ALCL. The more we can learn about this disease, the better positioned we will be to ensure patients are more fully informed of the benefits and risks of breasts implants.

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Limitations

There are several limitations that need to be considered. PROFILE depends on voluntary reports from participating physicians. Some institutions, though not all, require the physician to obtain informed consent from their patients for their data to be entered into the registry. As such, we note that over half of the confirmed cases provided had incomplete information, and therefore, the registry data may not be representative of all BIA-ALCL cases in the United States. Despite 186 unique confirmed cases of BIA-ALCL being reported to PROFILE, physician reporters only provided detail data reporting on 89 (48%) of those cases. The PROFILE Steering Committee has worked to improve the completion of data by contacting reporting physicians. However, the discrepancy between case notification and full reporting persists, despite numerous telephone calls and email follow-up to participating physicians. All cases in this analysis were reviewed, and secondary attempts to complete data for each case were made before this analysis. Barriers for completion of data sets include in some cases incomplete medical records. The large number of data fields in the registry and required time commitment were cited as barriers for completion. Individual physicians may be unable to secure institutional review board approval to submit patient protected information or have institutional barriers preventing their participation in the registry.

And finally, although PROFILE can report the absolute number of unique and distinct cases of BIA-ALCL, without a denominator (the total number of breast implants placed in the United States), the incidence rate remains difficult to determine.

The present study is an initial report of the PROFILE registry. Data to date have broadened our understanding of patient characteristics and disease presentations not previously described. The FDA recommends all confirmed BIA-ALCL cases be reported to the PROFILE registry as this information provides important details that may not be obtained from data received though FDA MedWatch reporting system.12 This study emphasizes the critical importance of disease awareness, physician reporting, and the detailed tracking of BIA-ALCL cases.

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CONCLUSIONS

This registry is the first of its kind in the United States. PROFILE offers a systematic way to collect complete and consistent data on patients diagnosed with the BIA-ALCL. At a time when the safety of breast implants remains under scrutiny, the ongoing collection of data from this registry will continue to be critical in the evaluation of ALCL and breast implants. The FDA will continue to use the input it receives from all stakeholders, including patient groups, to inform its collaboration with the ASPS/PSF in the management of the PROFILE Registry and in the proposed enhanced surveillance activities and research to characterize BIA-ALCL in patients with breast implants.

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ACKNOWLEDGMENTS

The authors would like to thank all reporters of cases to the Patient Registry and Outcomes for Breast Implants and Anaplastic Large Cell Lymphoma Etiology and Epidemiology (PROFILE) without whose cooperation and participation the findings of this study would not be possible. They would also like to acknowledge Keith Hume, MA, Hongying (Helen) Jiang, PhD, RAC, Dongyi (Tony) Du, MD, PhD, Sung Yoon, MD, and Benjamin Eloff, PhD, for their contributions.

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REFERENCES

1. de Jong D, Vasmel WL, de Boer JP, et al.Anaplastic large-cell lymphoma in women with breast implants. JAMA. 2008;300:2030–2035.
2. Brody GS, Deapen D, Taylor CR, et al.Anaplastic large cell lymphoma occurring in women with breast implants: analysis of 173 cases. Plast Reconstr Surg. 2015;135:695–705.
3. Srinivasa DR, Miranda RN, Kaura A, et al.Global Adverse Event Reports of Breast Implant-Associated ALCL: an international review of 40 Government Authority Databases. Plast Reconstr Surg. 2017;139:1029–1039.
4. Feldman AL, Harris NL, Stein H, et al.Swerdlow SH, Campo E, Harris NL, et al.Breast implant-associated anaplastic large cell lymphoma. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 2017:Revised 4th ed. Lyon, France: International Agency for Research on Cancer; 421–422.
5. FDA/CDRH. FDA update on the safety of silicone gel-filled breast implants. June 2011. Available at: https://www.fda.gov/downloads/medicaldevices/productsandmedicalprocedures/implantsandprosthetics/breastimplants/ucm260090.pdf. Accessed September 1, 2018.
6. Bautista-Quach MA, Nademanee A, Weisenburger DD, et al.Implant-associated primary anaplastic large-cell lymphoma with simultaneous involvement of bilateral breast capsules. Clin Breast Cancer. 2013;13:492–495.
7. Clemens MW, Horwitz SMNCCN consensus guidelines for the diagnosis and management of breast implant-associated anaplastic large cell lymphoma. Aesthet Surg J. 2017;37:285–289.
8. Horwitz SM, Zelenetz AD, Gordon LI, et al.NCCN guidelines insights: Non-Hodgkin’s lymphomas, Version 2.2018. J Natl Compr Canc Netw. 2016;14:1067–1079.
9. Aladily TN, Medeiros LJ, Amin MB, et al.Anaplastic large cell lymphoma associated with breast implants: a report of 13 cases. Am J Surg Pathol. 2012;36:1000–1008.
10. Laurent C, Delas A, Gaulard P, et al.Breast implant-associated anaplastic large cell lymphoma: two distinct clinicopathological variants with different outcomes. Ann Oncol. 2016;27:306–314.
11. Miranda RN, Aladily TN, Prince HM, et al.Breast implant-associated anaplastic large-cell lymphoma: long-term follow-up of 60 patients. J Clin Oncol. 2014;32:114–120.
12. FDA/CDRH. Breast Implant-Associated Anaplastic Large Cell Lymphoma (BIA-ALCL). March 2018. Available at: https://www.fda.gov/medicaldevices/productsandmedicalprocedures/implantsandprosthetics/breastimplants/ucm239995.htm. Accessed September 1, 2018.
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