Adverse Event Reports and Safety Measures for Breast Implant–associated Anaplastic Large Cell Lymphoma in Japan

Abstract

Background:

A causal association between breast implant–associated anaplastic large cell lymphoma (BIA-ALCL) and macrotextured breast implants has been established. In response, global surveillance of implant-based breast reconstruction safety has intensified. We investigated the frequency of BIA-ALCL in patients receiving gel-filled breast implants and tissue expanders approved in Japan.

Methods:

We reviewed adverse event reports submitted to the Pharmaceuticals and Medical Devices Agency between April 1, 2013, and March 31, 2024, and examined safety measures implemented by marketing authorization holders and the Ministry of Health, Labour and Welfare.

Results:

A total of 736 adverse events were reported in patients with gel-filled breast implants, whereas 296 were reported in those with tissue expanders. Following the global recall of Allergan’s Biocell products, adverse event reports rose markedly between FY2019 and FY2022. In Japan, 2 confirmed cases of BIA-ALCL were reported in FY2021 and FY2023, and 8 suspected cases were reported between FY2020 and FY2023. Allergan voluntarily recalled its Biocell products due to their risk of BIA-ALCL and issued a field safety notice with risk information and recommendations. The Ministry of Health, Labour and Welfare issued public notices referencing academic society guidelines and updated the package insert precautions for gel-filled breast implants.

Conclusions:

Fewer BIA-ALCL cases have been reported in Japan than in the United States and Europe, likely due to early, coordinated safety measures.

Takeaways

Question: What is the incidence of breast implant–associated anaplastic large cell lymphoma (BIA-ALCL) in Japan, and how have safety measures impacted adverse event reporting?

Findings: We reviewed 1032 adverse event reports submitted to the Pharmaceuticals and Medical Devices Agency (2013–2023), identifying 1 confirmed and 7 suspected BIA-ALCL cases. Reports peaked in FY2019–2022 following the Allergan Biocell recall, then declined in FY2023. Japan’s low BIA-ALCL incidence may reflect effective regulatory measures and public awareness.

Meaning: Japan’s experience highlights how early regulatory actions, restricted product use, and education may contribute to a lower BIA-ALCL incidence compared with Western countries.

INTRODUCTION

Breast tissue can be reconstructed using breast implants in cases where a breast has been removed due to a tumor or trauma, or in cases of chest underdevelopment.¹ There are 2 types of breast reconstruction: primary reconstruction, which is done simultaneously with mastectomy, and secondary reconstruction, which is performed later after mastectomy, typically involving the use of a skin expander to stretch the breast skin beforehand. The advantages of primary reconstruction include fewer required procedures and easier breast shaping due to preservation of the native contour. However, it also poses risks such as breast skin necrosis and radiation-induced capsular contracture. Secondary reconstruction has the advantage of allowing more time to choose a reconstruction method and avoiding reconstruction during cancer treatment. Conversely, secondary reconstruction requires additional surgery, and the placement of implants after radiation therapy may lead to skin stiffening.²

Since 2013, more than 15 million breast implants have been placed worldwide.³ In Japan, an estimated 100,000 expanders and implants were used for breast reconstruction between 2013 and 2022.³ Although the number of procedures peaked in 2018 and has since declined, it is estimated that approximately 4000 implants continue to be placed annually.⁴ These trends underscore the need for robust data collection and timely implementation of safety measures to support the safe use of these devices.

Breast implants are categorized into 2 types based on their surface properties: smooth and textured.⁵ An analysis conducted by the US Food and Drug Administration (FDA) revealed that Allergan’s Biocell products, which have macrotexture characterized by deep indentations and a large surface area, are linked to approximately 6 times the risk of developing breast implant–associated anaplastic large cell lymphoma (BIA-ALCL). BIA-ALCL is a type of T cell non-Hodgkin lymphoma. On July 24, 2019, the FDA requested that Allergan, now known as AbbVie, voluntarily recall Biocell textured breast implants and expanders from the market.⁶ On the same day, the FDA issued a safety communication addressed to patients with breast implants, individuals considering implant surgery, and healthcare providers, highlighting known risks of BIA-ALCL and recommending monitoring practices for symptoms, such as breast swelling or pain.⁶ This has led to voluntary recalls and market withdrawals of the product not only in the United States but also internationally, including in France, Canada, Australia, and Japan.^7–10 In this context, the regulatory authorities in the United States, Canada, and Australia have established websites to provide safety information about breast implants.^11–13 Ongoing research is being conducted, and the safety of these products is gaining attention worldwide.^14–16 Between 2012 and 2018, 92.1% of patients with BIA-ALCL were White.¹⁷ Among major lymphoma subtypes, anaplastic lymphoma kinase-negative anaplastic large cell lymphoma accounted for 7.8% of cases in North America and 2.6% in Asia.¹⁸ Ohishi et al¹⁹ indicated that specific ethnic and genetic backgrounds may be linked to the frequency of BIA-ALCL. Nevertheless, 1 study confirmed multiple cases in this population, indicating that its incidence in Japan warrants close monitoring.²⁰ Moreover, limited data are available on the incidence of BIA-ALCL following breast implant placement and the effectiveness of current safety measures in Japan. We aimed to investigate the frequency of BIA-ALCL reports in Japan and evaluate the adequacy of current safety practices.

MATERIALS AND METHODS

Ethical Considerations

This study did not require institutional review board approval or patient informed consent because it was based on publicly available information and involved no patient records.

Identification of Products Targeted for Investigation

The breast implants included in this study are approved in Japan for breast reconstruction, referred to in the nomenclature name as “gel-filled mammary prosthesis” or “dermal dilator”. (See table, Supplemental Digital Content 1, which displays the definitions of breast implant–related products [“gel-filled mammary prosthesis” and “dermal dilator”], https://links.lww.com/PRSGO/E706.) Specifically, 4 gel-filled mammary prosthesis products and 2 dermal dilator products were identified as survey subjects from the package insert search system of the Pharmaceuticals and Medical Devices Agency (PMDA).²¹ (See table, Supplemental Digital Content 2, which displays the approved gel-filled mammary prosthesis and dermal dilator in Japan, https://links.lww.com/PRSGO/E707.) “Gel-filled mammary prosthesis” or “dermal dilator” are synonyms for “gel-filled breast implant” and “tissue expander,” respectively.

Data Source

We identified adverse events associated with breast implants by examining domestic adverse event reports²² available on the Ministry of Health, Labour and Welfare (MHLW) website (https://www.mhlw.go.jp/stf/shingi/shingi-yakuji_127871.html) between April 1, 2013, and March 31, 2024.²³ Our analysis covered various aspects of adverse event reports, including the reporting period, medical device nomenclature, brand name, marketing authorization holder (MAH), device problem, adverse event problem, location of occurrence (domestic or overseas), number of reports, and the type of corrective action taken in Japan. Additionally, we searched PMDA’s Japanese Adverse Medical Device Event Report (JAMDER) database for medical devices (https://www.pmda.go.jp/safety/info-services/devices/0090.html) to find relevant cases for our study. We extracted data on multiple parameters from JAMDER, including the fiscal year of reporting, patient age, patient outcomes, medical device nomenclature, device problems, and adverse event problems.²⁴

Data Analysis

Frequency of BIA-ALCL Reports Due to Breast Implants

Due to the uncertainty regarding the equivalence of BIA-ALCL and lymphoma, the term “lymphoma” was excluded, and data were extracted that included the term “ALCL” as an adverse event. Patient outcomes—categorized as death, unknown, not recovered, remission, recovered, other, and no health damage—were confirmed using JAMDER for medical devices by comparing information extracted from adverse event reports on the MHLW website. Because JAMDER does not disclose information that identifies specific products, outcome data were linked only when the fiscal year of reporting, device problem, and adverse event problems exactly matched entries on the MHLW website. Table 1 provides a brief summary of the differences between the items published by PMDA and MHLW. In addition to comparing the number of BIA-ALCL cases reported in Japan, we conducted a literature review of the frequency of BIA-ALCL reports in other countries.

Table 1.

Data Source Characteristics

	MHLW	PMDA
Webpage of data source	https://www.mhlw.go.jp/stf/shingi-yakuji_39212.html	https://www.pmda.go.jp/safety/info-services/devices/0090.html
Frequency of page update	Never	Periodically
Publication item	• Reporting period • Medical device nomenclature • Brand name • MAH • Device problem • Adverse event problem • Location of occurrence (domestic or overseas) • Number of reports • Type of corrective action taken in Japan	• Fiscal year of reporting • Medical device nomenclature • Device problem • Adverse events problem • Patient age • Patient outcome

Status of Implementation of Safety Measures for Breast Implant Products

We conducted a survey based on publicly available information posted on the websites of the MHLW and MAHs to investigate safety corrective measures related to breast implants between 2012, when breast implants were approved in Japan, and 2023.

Statistical Analysis

We used descriptive statistics for this study. All analyses were conducted using the analytic tools of Microsoft 365.

RESULTS

Frequency of BIA-ALCL Reports Due to Breast Implants in Japan

Based on data from the MHLW website, Figure 1 presents trends in adverse event reports for each breast implant product submitted by MAHs to the PMDA from April 1, 2013, to March 31, 2024. No adverse event reports were submitted during the survey period for the Motiva Breast Implant or Motiva Flora Tissue Expander from Vorpal Technologies K.K. As of 2020, only 10 reports had been filed for the Sientra Breast Implant, which was approved in 2020. In contrast, 70.3% (726 of 1032) of all reports involved Allergan’s (now AbbVie) Natrelle Breast Implant and Natrelle 410 Breast Implant. Cases in which “ALCL” was listed among the adverse problems are shown in Supplemental Digital Content 3; all involved gel-filled breast implants. (See table, Supplemental Digital Content 3, which displays the BIA-ALCL–related adverse event reports submitted to PMDA, https://links.lww.com/PRSGO/E708.)

Fig. 1.

Annual number of adverse events reported in Japan for the products listed in Supplemental Digital Content 2.

Two cases of BIA-ALCL were confirmed. One confirmed case of BIA-ALCL was reported for the Natrelle 410 Breast Implant in FY2021, 6 years after implantation. The case presented as a stage IIA tumor, was treated with surgery and hematologic therapy (details unknown), and entered remission. The second case for the Natrelle 410 Breast Implant was initially reported as suspected BIA-ALCL but was later confirmed; this patient had a stage IA mass 5 years after implantation, underwent surgery, and remained under follow-up. Eight suspected cases of BIA-ALCL were reported for the Natrelle 410 Breast Implant: 1 case in FY2020 and FY2021, and 2 cases in FY2022 and FY2023. In addition, 1 case was reported for the Natrelle Breast Implant in FY2022 and 2023. Cases related to BIA-ALCL accounted for only 0.78% (8 of 1032) of the total adverse event reports. Reported patient outcomes were linked using JAMDER for medical devices, which is updated regularly with the latest information from MAHs, whereas the MHLW website locks data every 6 months and only reflects information as of the last day of the reporting period. As a result, not all data could be cross-referenced between the 2 sources. All cases diagnosed as BIA-ALCL were reported as recovered, with no instances of serious outcomes such as death or nonrecovery.

Safety Measures Implemented Regarding the Risk of BIA-ALCL in Breast Implants

The timing and content of safety measures implemented by MAHs or MHLW to mitigate BIA-ALCL risk are summarized in Supplemental Digital Content 4. (See table, Supplemental Digital Content 4, which displays the timeline of safety measures on BIA-ALCL by MAHs and MHLW, https://links.lww.com/PRSGO/E709.) On July 25, 2019, despite the absence of reported BIA-ALCL cases in Japan, Allergan initiated a voluntary recall of Biocell products to mitigate the risk in new patients, following the US FDA’s updated analysis of adverse events associated with breast implants.¹⁰ At that time, the relevant academic societies (Japan Oncoplastic Breast Surgery Society, Japan Society of Plastic and Reconstructive Surgery, Japanese Breast Cancer Society, and Japan Society of Aesthetic Plastic Surgery) obtained information on alternative products from the MAH and issued a safety notification for patients. The notification provided guidance on appropriate responses, such as the use of alternative products and changes in surgical procedures, for individuals who had received, were planning to receive, or were awaiting breast implantation. In response to this, the MHLW issued a statement informing users and patients about the guidance provided by relevant academic societies. Additionally, the MHLW issued a notification on June 7, 2019, instructing MAHs to revise the package inserts for gel-filled breast implants to continually inform users of the safety risks associated with BIA-ALCL.

On July 30, 2021, the MHLW reported the first domestic case of BIA-ALCL involving a breast implant approved in Japan. Notifications were issued for each subsequent case through the fourth. However, as of March 16, 2022, the MHLW announced that routine case reports would no longer trigger new measures. Future notifications will be issued only if new, significant information arises, such as changes in the recommended follow-up schedule by relevant academic societies.²⁵

DISCUSSION

A significant increase in adverse event reports related to breast implants was observed from FY2019 to FY2022, likely due to increased detection of device problems and adverse events following Allergan’s 2019 recall of Biocell products. Report numbers declined in FY2023, which may be attributed to the plateau in breast reconstruction procedures following their 2018 peak, as well as the continued emphasis on self-examinations and routine medical follow-ups since 2019. (See table, Supplemental Digital Content 5, which displays the number of breast implant reconstruction cases in Japan by fiscal year, https://links.lww.com/PRSGO/E710.)

A review of 1032 adverse event reports for breast implants submitted between April 1, 2013, and March 31, 2024, confirmed 2 cases of BIA-ALCL and 8 cases of suspected BIA-ALCL. To objectively evaluate the frequency in Japan, we investigated the frequency of BIA-ALCL reports in other countries and found that a total of 588 cases (17 of which were fatal) had been reported in the United States by 2023,²⁶ and a total of 592 cases (20 of which were fatal) had been reported in Europe by 2020.²⁷ Three primary factors may account for the remarkably low frequency of BIA-ALCL reports in Japan. First, when the products were approved, authorities imposed strict conditions to ensure appropriate use. These included the establishment of institutional and physician standards in collaboration with academic societies, and immediate reporting of any ALCL cases during the usage evaluation period. Second, as mentioned in the Frequency of BIA-ALCL Reports Due to Breast Implants in Japan section, MAHs, government agencies, and academic societies have been proactive in providing information about the risks of BIA-ALCL, which has led to widespread awareness and early detection. Furthermore, the approval dates of breast implants differ substantially among regions. Gel-filled implants were introduced in the United States in 1962 and in Europe in 1997, whereas they were not approved in Japan until 2012. This difference in approval timelines may also influence the reported incidence of BIA-ALCL, as previous data have suggested a median time to diagnosis of approximately 10 years after implantation.²⁸ Although the reported frequency of BIA-ALCL reports is low (0.78%), ongoing evaluation of the broader health risks associated with gel-filled breast implants and tissue expanders is essential. Figures 2 and 3 present annual trends in reported adverse events across various health effect categories. These events were analyzed using standardized International Medical Device Regulators Forum (IMDRF) terminology, release number: 2024, which classifies clinical signs, symptoms, and health impacts in a globally harmonized framework developed by international regulatory authorities.²⁹ The specific method for mapping the reported adverse event terms to IMDRF terminology is summarized in Supplemental Digital Content 6. (See table, Supplemental Digital Content 6, which displays a list of reported adverse event terms mapped to the IMDRF terminology, https://links.lww.com/PRSGO/E711.) Mapping was conducted using level 1—the broadest tier—of the IMDRF’s 3-level hierarchy of health effect terms. For gel-filled breast implants, the number of reports increased across all health effect categories beginning in 2019 and declined again in 2023. The most frequently reported health effect category was surgical intervention (287 cases), followed by generalized disorders (251 cases) and other (109 cases). Surgical intervention (eg, implant removal, exchange, or extraction) was the most frequently reported category because such procedures often prompt reporting to MAHs. The next most frequently reported issue was related to generalized disorders, including capsular contracture, pain, and necrosis. This trend may be linked to the increased use of smooth-surfaced implants, which are more likely than macrotextured types to cause capsular contracture and necrosis, following the recall of Biocell products in 2019.³⁰ The “other” category mainly includes cases with no reported health effects or insufficient detail for classification.

Fig. 2.

Number of adverse events reported in Japan in each fiscal year following the approval of all gel-filled breast implants.

Fig. 3.

Number of adverse events reported in Japan in each fiscal year following the approval of tissue expanders (Natrelle 133 Tissue Expander only).

Unlike gel-filled mammary prostheses, no significant trends were observed in various health effect categories for tissue expanders. The most frequently reported health effect category was surgical intervention (111 cases), followed by other (109 cases) and infection (55 cases). The high frequency of reports in the “other” category may be explained by the relatively short duration that tissue expanders remain in the body compared with gel-filled breast implants, resulting in fewer observable health effects. The “infection” category, which came in third place, may be influenced by the poor blood flow and weak immune response of the thin skin in the early stages of reconstruction.³¹

This study has some limitations. First, evaluating and comparing the safety of medical devices based solely on the number of adverse event reports is challenging, as device characteristics may differ and discrepancies often exist between the year of occurrence and the year of reporting. Furthermore, because there is no accurate information on the number of incidents, it is not realistic to calculate the incidence rate.

Second, the IMDRF terminology was first published in 2019 and is intended for use in adverse event reporting to the PMDA. However, before this, MAHs were free to write freely without using IMDRF terminology. In this study, we conducted retrospective mapping based on Supplemental Digital Content 6, though variations may exist due to differences in analyst interpretation (Supplemental Digital Content 6, https://links.lww.com/PRSGO/E711).

CONCLUSIONS

This study analyzed adverse event reports related to breast implants in Japan over 10 years. A notable increase in reports was observed from FY2019 to FY2022, likely driven by heightened awareness following the 2019 recall of Biocell products. Report numbers declined in FY2023, coinciding with the stabilization of breast reconstruction procedures and the promotion of self-examinations and routine follow-ups.

Among 1032 reports, only 2 confirmed cases and 8 suspected cases of BIA-ALCL were identified. Compared with the United States and Europe, where more than 580 cases have been reported, the frequency in Japan remains remarkably low. This may reflect both genetic factors and effective regulatory measures, including stringent approval conditions and active risk communication by regulatory authorities, MAHs, and academic societies.

Although BIA-ALCL frequency is low, continued monitoring of broader health risks associated with breast implants is essential. The use of IMDRF terminology enhances consistency in adverse event analysis and supports global surveillance efforts.

DISCLOSURE

The authors have no financial interest to declare in relation to the content of this article.

ACKNOWLEDGMENTS

The authors thank Editage (https://www.editage.com/) for English language editing. Although Koko Akaishi belongs to PMDA, Tokyo, Japan, the views expressed in this article do not necessarily represent the views of PMDA.