Breast Implant-associated Anaplastic Large Cell Lymphoma Cases Research Articles

Current Knowledge on Breast Implant-Associated Anaplastic Large Cell Lymphoma: Evidence from Italian Ministry of Health Registry Data.

Accurate estimation of Breast Implant-Associated Anaplastic Large Cell Lymphoma (BIA-ALCL) incidence is crucial for assessing breast-implant-associated risk. However, the size of the implanted population worldwide is unknown, making it challenging to appropriately estimate this figure. This study aims to provide a new reliable and reproducible method to estimate the breast-implanted-population (BIP), reporting a reliable annual BIA-ALCL incidence estimate. Moreover, we discuss all activities performed over the past decade in collecting complete histories, managing, and monitoring outcomes of each Italian case. Data from the National Breast Implant Registry and from manufacturers have been used to define a new formula to estimate the BIP at risk of developing a breast-implant-related event. From the BIA-ALCL registry, complete information on Italian cases has been collected and analysed. Overall survival is estimated by the Kaplan-Meier curve. From 2010 to June 2024, 111 BIA-ALCL cases were recorded in Italy. The estimated incidence rate showed an upward trend, ranging from 2.68 to 6.35 cases per 100,000 patient-years. Thanks to newly promoted disease awareness, most patients had a complete response to treatment, resulting in a three-year overall survival rate estimate of 98.2%. The BIP formula showed to be an innovative, effective and reproducible tool to make a reliable estimation of the implanted population, confirming that BIA-ALCL is a rare disease with an incidence rate estimate varying from 2.7 to 6.3 cases/100.000 patient-years in the last five years. Eleven-year experience in this field also confirmed that this disease has a favorable prognosis if properly treated. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Incidental Bystander or Essential Culprit: A Systematic Review of Bacterial Significance in the Pathogenesis of Breast Implant-Associated Anaplastic Large Cell Lymphoma.

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a distinct subtype of T-cell non-Hodgkin lymphoma that arises in the context of prolonged exposure to textured breast implants. The intent of this manuscript is to explore whether the bacterial presence in biofilms on these implants is a mere incidental finding or plays a pivotal role in the pathogenesis of BIA-ALCL. Our goal is to delineate the extent of bacterial involvement, offering insights into potential underlying mechanisms, and establishing future research priorities aimed at resolving the remaining uncertainties surrounding this complex association. A comprehensive systematic review of several databases was performed. The search strategy was designed and conducted by an experienced librarian using controlled vocabulary with keywords. The electronic search identified 442 publications. After evaluation, six studies from 2015 to 2021 were included, encompassing 201 female patients aged 23 to 75. The diagnosis span post-implantation ranged from 53 to 135.6 months. Studies consistently found bacteria near breast implants in both BIA-ALCL cases and controls, with varied microbial findings. Both BIA-ALCL cases and controls exhibited the presence of specific bacteria, including Pseudomonas aeruginosa, Klebsiella oxytoca, Staphylococcus aureus, and Ralstonia spp., without any statistically significant differences between groups. The use of antiseptic and antimicrobial agents during implant insertion did not demonstrate any impact on reducing or altering the risk of developing BIA-ALCL. Our systematic review reveals that the current evidence is inadequate to link bacterial etiology as a central factor in the development of BIA-ALCL. The limitations in the existing data prevent a complete dismissal of the role of biofilms in its pathogenesis. The observed gap in knowledge underscores the need for more focused and comprehensive research, which should be structured in a multi-faceted approach. Initially, this involves the utilization of sophisticated genomic and proteomic methods. Following this, it is crucial to delve into the study of immunological reactions specifically induced by biofilms. Finally, this research should incorporate extended observational studies, meticulously tracking the evolution of biofilm development and its correlation with the emergence of BIA-ALCL. In light of the inconclusive nature of current findings, further investigation is not only justified but urgently needed to clarify these unresolved issues.

BIA-ALCL Epidemiology in an Aesthetic Breast Surgery Cohort of 1,501 Patients.

Epidemiologic studies on Breast Implant-Associated Anaplastic Large Cell Lymphoma (BIA-ALCL) currently estimate the risk between 1:300 and 1:30,000, assessed mainly in large breast reconstruction populations. Aims of the study was to assess BIA-ALCL epidemiology in a cohort of patients who have received textured implants for cosmetic indications. In a prospective cohort observational study, 1,501 patients who received a cosmetic breast augmentation, between 2006 and 2016, were monitored recording any implant-related complication, including BIA-ALCL. Cross-checking clinical, pathology and external records data was used to identify cases. Prevalence, Implant-Specific Prevalence (I-SP), Incidence Rate (IR), Event Free Time (EFT) and Kaplan Meier survival estimate were calculated. All but 2 patients received macrotextured or microtextured devices bilaterally. Mean follow-up was 3.2 years (1 months to 16.4 years). Five BIA-ALCL cases were investigated, prevalence was 1:300 patients, I-SP was 6.9 cases/1000 individuals/BIOCELL and 1.3 cases/1000 individuals/Siltex devices, IR was 1.07 cases/1,000 women/year. Mean (SD) EFT was of 9.2 years. When using a denominator based on a cohort of cosmetic patients, BIA-ALCL occurrence is higher than previously reported, particularly with macrotextured devices. Given the similar IR between reconstructive and cosmetic cohorts, their even distribution can be consequent to underreporting due to poorer follow up and lower awareness in the latter group. The genetic predisposition in oncologic cohort reasonably affects the early onset more than the IR. Importance of accurate follow-up is confirmed. Stratification risks analysis can guide surgeons during patient's counseling in the decision for prophylactic explantation.

BRCA1/2 MUTATIONS IMPACT ON THE DEVELOPMENT OF BREAST IMPLANT‐ASSOCIATED LYMPHOMA (BIA‐ALCL) IN WOMEN WITH BREAST CANCER RECONSTRUCTED WITH TEXTURED BREAST IMPLANTS

Introduction: Breast Implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a subtype of T-cell lymphoma arising as a seroma and/or mass in relation to the capsule of textured breast implants. Previous research in a Dutch population suggests a higher-than-expected prevalence of BRCA1/2 carriers in women with BIA-ALCL. Here we analyze the risk of BIA-ALCL occurrence related to BRCA in a large population of women with implants followed long term after breast cancer (BC) mastectomy. Methods: We compared the prevalence of BRCA1/2 pathogenic variants (pv) between women from a large cohort of BC patients treated at Memorial Sloan Kettering Cancer Center (MSKCC) who did and did not develop BIA-ALCL after reconstruction with textured implants. Hazard ratios (HRs) of developing BIA-ALCL were estimated using Cox regression. To best control for age at BC diagnosis and length of follow up, we conducted a nested case-control within the cohort, matching 1:3, analyzed with conditional logistic regression. Results: Among 3312 women with BC assessed for pv in the context of MSK-IMPACT tumor and normal study at MSKCC the prevalence of BRCA mutations was 5.3%. Among 526 patients with textured implants post BC mastectomy, followed long term at MSKCC (median FU 82 mo, range 12, 316) and clinically assessed for BRCA1/2, the prevalence of pv of BRCA1/2 was 7.8%. Of 31 BIA-ALCL post-BC cases seen at MSKCC, 16 received capsulectomy at MSKCC and 5/13 (38.4%) were BRCA1–2 positive. Within the cohort of 526 patients with BC tested for BRCA, reconstructed with textured implants and followed long-term, the age-adjusted rate of developing BIA-ALCL for women with BRCA mutations was 11.0 times the rate of BIA-ALCL among women without BRCA (HR 95% CI 3.6, 33.9, p < .0001). Carrying bilateral versus unilateral implants (HR 6.9, 95% CI 0.9, 53.2), prior chemotherapy exposure (HR 0.7, 95% CI 0.2, 2.05), prior radiation therapy exposure (HR 0.5, 95% CI 0.1, 2.5) were not significantly associated with the rate of BIA-ALCL. Within this cohort, 13 BIA-ALCL cases were matched 1:3 with 39 controls. Median ages at BC mastectomy were 47.2 (37, 66) and 46.8 (35, 65) in cases and controls, respectively. The median time between reconstruction for BC and BIA-ALCL was 130 (80, 190) months. The odds ratio of BIA-ALCL associated with carriership of a BRCA1/2 pathogenic variant was 12.4 (Wald 95% CI 1.4, 109.5 p = 0.0074). Conclusions: In this study, we define the role of BRCA1/2 mutations as a significant risk factor in the development of BIA-ALCL in patients with BC reconstructed with textured implants. These results will help decision making for women with BRCA1/2 mutations undergoing breast reconstruction, or with textured implants in place. Analysis of pathogenic variants in other DNA repair genes in this cohort potentially affecting lymphomagenesis is ongoing. The research was funded by: NIH R03 grant number R03CA267435 Keywords: aggressive T-cell non-Hodgkin lymphoma, prevention and cancer interception No conflicts of interests pertinent to the abstract.

QS24. BIA-ALCL and Systemic ALCL Proliferate Differently in Response to Silicone Implant Shells Within a Three-dimensional Organotypic Model of the Breast Microenvironment

Purpose: Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a T-cell-derived lymphoma associated with device-based breast reconstruction, with a reported incidence anywhere between 1/1,000 and 1/30,000. As of October 2021, 1158 BIA-ALCL cases were reported with 35 deaths worldwide and in nearly every case, patients had a textured device at some point in time. Despite the increasing awareness and the high correlation with textured implants, the etiopathogenesis of BIA-ALCL remains largely unknown. We have developed a tissue-engineered biomimetic platform composed of patient-derived breast tissue derivatives that mimics the breast microenvironment to interrogate the role of the silicone shell in altering the behavior of normal and malignant T cell lines. Methods: AbbVie Biocell textured and smooth breast implant shells were shaped to line 96-well plates. Patient-derived breast tissue from mammaplasty procedures was digested into cellular components of adipocytes, stromal vascular fraction, and epithelial duct organoids. The breast tissue components were embedded in 0.3% type I collagen along with BIA-ALCL cell line IL89 and systemic ALCL cell line SUPM2 (200,000 cells/mL) and placed into 96-well plates with and without implant shell lining. Other experimental groups included IL89 and SUPM2 cultured within either a type I collagen ECM alone or low serum feeding media alone with or without implant shell lining. Low serum feeding media (0.5% BSA) was applied in all the groups to limit the additional effect of growth factors on cell proliferation. Imaging was performed every two days for ten days using confocal microscopy. Cell proliferation was quantified and analyzed using ImageJ and MetaMorph software. Results: IL89 cultured in low serum feeding media proliferated moderately over 10 days with no significant difference between groups. However, IL89 embedded in 3D-collagen appeared to have limited proliferation and even decreased over 10 days regardless of well lining. Notably, IL89 cultured within the biomimetic platform survived and even proliferated, of which cells exposed to this platform and a textured implant shell increased significantly (21.5%) when compared to those exposed to no implant shell (3.7%) (p<0.05). SUPM2 exposed to low serum media and no implant appeared to have an increased rate of proliferation (p>0.05). In collagen only, SUPM2 with all different implant shell linings stabilized or moderately proliferated with significant increases in textured and smooth groups when compared to no implant. In the biomimetic platform, SUPM2 had a higher rate of proliferation when compared to collagen only, which was not significant between groups. Conclusion: When cultured in a 3D breast biomimetic platform, BIA-ALCL cells proliferate within a simulated breast microenvironment even without the addition of growth factors, while limited or decreased proliferation is seen when cultured in the same conditions without such cellular components. We have shown a difference in the cell proliferation trends that occur when different ALCL lines are cultured in 2-dimensions (media only) versus 3-dimensions (collagen embedded), emphasizing the physiologic relevance of our 3-dimensional model. These data demonstrate the importance of recapitulating the cellular microenvironment ex vivo to elicit pathologic in vivo cell behaviors that do not occur under standard culture conditions.

New Data on the Epidemiology of Breast Implant-Associated Anaplastic Large Cell Lymphoma.

This study aimed to illustrate the epidemiological situation of breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) by focusing on the changes published after 2019 and particularly the new approaches of cosmetic and reconstructive breast surgery. Article search was performed from January 2019 to date using the PubMed database. Fourteen articles were included in the qualitative evaluation of international data. Moreover, the latest reports regarding the total number of BIA-ALCL cases and number of deaths were identified. Estimates of the risk and incidence have increased significantly recently, affecting 1 in every 2,969 women with breast implants and 1 in 355 patients with textured implants after breast reconstruction. The average exposure time to diagnosis was 8 (range: 0-34) years. Approximately 80% of BIA-ALCL cases were diagnosed at IA-IIA stages, for which the treatment was breast implant removal, full capsulectomy, and excision of all suspected lymph nodes. Globally, at least 949 cases were reported to date. At present, BIA-ALCL is an emerging pathology of interest. Data collection initiated since 2016 through different case registration databases is essential to ensure surveillance and to continue to increase the number of studies on this recently discovered pathology.

Considerations on the Demography of BIA-ALCL in European Countries Based on an E(A)SAPS Survey

BackgroundA growing body of evidence indicates that breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is associated with the use of certain breast implants. Regional variations have been reported, and a genetic susceptibility has also been suggested. However, large variations in the ability to correctly diagnose BIA-ALCL and to further report and register cases exist between countries and may in part explain variations in the demography.Material and MethodsA survey was conducted by The European Association of Societies of Aesthetic Plastic Surgery E(A)SAPS and sent to 48 European countries. The primary aim was to identify the total number of confirmed cases of and deaths from BIA-ALCL in each country during four consecutive measurements over a two-year period.ResultsAn increase in BIA-ALCL cases during four repeated measurements from a total of 305 in April 2019 to 434 in November 2020 was reported by 23 of the 33 responding countries. A nearly 100-fold variation in the number of cases per million inhabitants was noted, where Netherlands had the highest rate (4.12) followed by Finland (1.99). Countries with the lowest reported rates were Austria (0.078), Romania (0.052) and Turkey (0.048).ConclusionThe current study displays a notable variation ßin the number of confirmed BIA-ALCL cases across Europe, even for countries with established breast implant registers. Variations in diagnosis and reporting systems may explain the differences, but the influence of genetic variations and the prevalence of high-risk implants cannot be excluded. Incomplete sales data along with medical tourism preclude an absolute risk assessment.Level of Evidence IVThis journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Is Breast Implant Associated-Anaplastic Large Cell Lymphoma linked to textured implants?

Breast Implant Associated-Anaplastic Large Cell Lymphoma (BIA-ALCL) is a distinctive type of T-cell lymphoma arising around breast implants. We performed a review of the existing literature with the aim of providing an evidence-based overview of the available data on BIA-ALCL with a standardized evaluation of the quality of the studies and investigating the potential association between textured breast implants and BIA-ALCL.We analyzed the literature reporting estimates of relative or absolute risks of BIA-ALCL in case-control, cohort studies and case series studies. The total number of BIA-ALCL cases reported in literature is very low. Furthermore, most of the reported cases have been reported in case-control studies or case series. This means that our knowledge is based on a low level of evidence. Moreover, low-medium quality scores were observed in the included case series studies. In relation to the rarity of the event, better information could only derived by international cooperation to pool together data deriving from all over the world, with the clear need of better reporting patients and implant characteristics in case series and when adding data to public registries. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Next generation sequencing of breast implant-associated anaplastic large cell lymphomas reveals a novel STAT3-JAK2 fusion among other activating genetic alterations within the JAK-STAT pathway.

Breast implant associated anaplastic large cell lymphoma (BIA-ALCL) is a distinct type of ALCL, and a new provisional entity by the 2016 revision of the World Health Organization (WHO) classification of tumors of hematopoietic and lymphoid tissues. In contrast to systemic and primary cutaneous ALCLs, BIA-ALCLs have been genetically characterized by the absence of fusions and frequent activation of the JAK-STAT3 pathway through mutations in JAK1 and STAT3. In this study, we report the results of the genetic profiling of 9 BIA-ALCL cases supporting the role of the JAK-STAT pathway activation in this entity, including the identification of an activating STAT3-JAK2 fusion similar to those recently reported in T-cell lymphoproliferative disorders of the gastrointestinal tract. To our knowledge, this is the first fusion reported in BIA-ALCL, providing further insight into the overall genetic landscape of this rare entity as well as uncovering potential options for targeted therapy in cases with advanced disease.

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) in Poland: analysis of patient series and practical guidelines for breast surgeons.

Although breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is infrequent, with less than 1000 noted cases worldwide, patients consenting for breast implant surgery should be aware of its risk. We describe the first Polish multicenter case-series data on BIA-ALCL patients and present diagnostic and treatment recommendation for breast surgeons. In cooperation with the Polish Society of Surgical Oncology and Polish Lymphoma Research Group, we collected BIA-ALCL cases in Poland. We retrospectively reviewed clinical data of seven BIA-ALCL patients, diagnosed between July 2013 and November 2019. The median time from implant placement to the first BIA-ALCL symptoms was 65 months (range: 33-96 months). All the patients were exposed to textured implants at presentation. Capsulectomy with implant removal was performed in all the patients with immediate reimplantation in 2 cases. In a median follow-up of 19 months (range 5-81 months), there was no recurrence and all the patients stayed alive. Between 2013 and 2019, the incidence of BIA-ALCL in Polish female population age 30 and above ranged from 0 to 0.021/100 000/year. BIA-ALCL is scarce in the Polish population. In a short-term follow-up, patients' prognosis remains excellent. Due to the withdrawal of roughly textured implants from the market and the exclusion of likely the most potent etiologic factor, it might be expected that the incidence of BIA-ALCL will become even rarer.

The Crucial Role of Surgical Treatment in BIA-ALCL Prognosis in Early- and Advanced-Stage Patients.

Studies on breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) are trying to optimize medical and surgical treatments for early and advanced stages of this disease. The aim of this article is to share the experience gathered on the authors' prospectively collected 46 well-documented cases. Italian physicians are obliged to report BIA-ALCL cases to the Italian Ministry of Health. Because of this cooperation with health care professionals, the competent authority has coordinated and centralized the collection of information for each patient in 46 cases of BIA-ALCL. Statistical analyses with cumulative incidence and corresponding 95 percent confidence interval are provided for each year, dividing the number of new cases that occurred in a defined year and the population at risk of experiencing BIA-ALCL during the same year. The mean time to the onset of symptoms is reduced to 6.4 ± 3.77 years (range, 1 to 22 years). Increased knowledge has also shortened the average time to diagnosis, at 7.2 ± 3.71 years (range, 2 to 22 years). A late seroma appears in 91 percent of cases. The patient who died underwent limited surgery. The Italian incidence has been estimated as 2.8 per 100,000 patients receiving implants (95 percent CI, 0.88 to 4.84) in 2015; 2.1 (95 percent CI, 0.43 to 3.86) in 2016; 3.2 (95 percent CI, 1.11 to 5.31) in 2017; and 3.5 (95 percent CI, 1.36 to 5.78) in 2018. Although the number of cases has risen slightly, BIA-ALCL is still a rare disease with a stable incidence, easily recognized and with a favorable prognosis also in advanced stages if complete surgical excision is performed.

European Attitudes and Outcomes Regarding Breast Implant-Associated Anaplastic Large Cell Lymphoma: A Multinational Survey

Breast implants have been related to breast implant-associated anaplastic large cell lymphoma (BIA-ALCL). While some research has been conducted to study BIA-ALCL incidence, little is known regarding surgeon concern about the disease. This study aims to determine surgeon concern about BIA-ALCL within the European plastic surgeon community as related to their practice of breast plastic surgery. A 27-question online survey was sent to 2353 members of the European Plastic Surgery Society and EURAPS. 240 surgeons responded (10.2%) from 18 different societies. Questions were related to demographics, exposure to BIA-ALCL cases, clinical practices, awareness, and concern. Univariate and multivariable analyses were used. Of surveyed surgeons, 8% had encountered a case of BIA-ALCL, while 73% were concerned about the disease. The rate of concern seemed to be influenced by seven of the variables studied. However, multivariate analysis demonstrated that none of the combined variables analyzed predicted concern or disclosure of the risks of BIA-ALCL to patients. Textured silicone-filled implants were implicated in the disease (56.5% of cases, P = 0.005). Mentor® and Polytech® were the two brands involved in most of the reported cases (20% each). Consistent with epidemiological reports worldwide, this study confirms that BIA-ALCL is more prevalent in patients undergoing placement of textured silicone implants, the use of which was greater among surgeons not concerned about the risks of BIA-ALCL. Surgeons appear to approach their patients with similar risk disclosures regardless of practice pattern and type of breast implant used, but not regardless of their concern about the disease. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Breast Implant-Associated Anaplastic Large-Cell Lymphoma: Current Understanding and Recommendations for Management.

Worldwide, millions of women live with breast implants. Therefore, it is important that physicians be aware of an uncommon but possibly serious complication arising from breast implants: breast implant-associated anaplastic large cell lymphoma (BIA-ALCL). Breast implant-associated anaplastic large-cell lymphoma most commonly presents as a delayed fluid collection around a textured breast implant or as a mass in the capsule surrounding the implant. The exact pathogenesis of the disease remains unclear. The neoplastic cells of BIA-ALCL show strong uniform staining for CD30 and are consistently negative for activin receptor-like kinase 1. Patients with confirmed cases should be referred to a lymphoma specialist or breast medical oncologist for a complete oncologic evaluation before any surgical intervention. For disease confined to the fluid accumulation or capsule, or both, surgical removal of the implant and complete capsulectomy is the preferred treatment. Postoperative chemotherapy or radiation, or both, are not considered necessary for patients with limited-stage disease and are reserved for advanced disease stages. Generally, BIA-ALCL is a local disease that follows an indolent course and has an excellent prognosis. Although complete remission of disease has occurred in patients with BIA-ALCL, median overall survival is reduced. As of March 2018, approximately 529 unique, confirmed BIA-ALCL cases had been reported in 23 countries. To date, 16 patients have died from BIA-ALCL, and all had extracapsular involvement. The aim of this article is to summarize the diagnosis, evaluation, and management of BIA-ALCL, based on established guidelines, for all practitioners who may care for patients with breast implants.

Recurrent PDL1 expression and PDL1 (CD274) copy number alterations in breast implant–associated anaplastic large cell lymphomas

Breast implant-associated anaplastic large cell lymphoma (BI-ALCL) is a variant of anaplastic large cell lymphoma arising within seroma effusion associated with breast implants. BI-ALCL is a rare disease, recently recognized as a new provisional entity by the 2017 revised World Health Organization classification. All BI-ALCLs tested so far showed a "triple-negative" genetic profile-negative for ALK, DUSP22, and TP63 rearrangements-and were characterized by mutational and gene expression profiles consistent with aberrant activation of the JAK/STAT pathway. The active form of STAT3 (pSTAT3) is constantly expressed in BI-ALCLs and may favor tumor immune escape by triggering the transcription of PDL1 (CD274), a gene encoding the immune-checkpoint molecule programmed cell death ligand 1 (PDL1); immunohistochemical positivity for PDL1 has been recently described in 3 BI-ALCL cases, and one of them also harbored PDL1 gene amplification. We evaluated PDL1 and pSTAT expression by immunohistochemistry and PDL1 copy number alterations (CNAs) at chromosome 9p24.1 by fluorescent in situ hybridization in a cohort of 9 BI-ALCL cases; we also investigated the presence of tumor-infiltrating programmed cell death 1 (PD1)+ T cells (tumor-infiltrating lymphocytes, or TILs) and PDL1+ tumor-associated macrophages (TAMs) in BI-ALCL microenvironment. Tumor cells expressed PDL1 in 5 (56%) of 9 cases and harbored PDL1 CNAs in 3 (33%) of 9 cases; immunohistochemistry for pSTAT3 was positive in all 6 cases tested (100%), indicative of active JAK/STAT signaling. We observed PDL1 CNAs only among PDL1-positive cases, whereas PD1+ TILs and PDL1+ TAMs were present at variable levels in both PDL1-positive and PDL1-negative BI-ALCLs. We report frequent PDL1 expression and recurrent PDL1 CNAs in BI-ALCLs: our data suggest that 9p24.1 alterations represent a common mechanism of PDL1 overexpression in this disease, likely acting in synergy with constitutive pSTAT3 signaling. In PDL1-positive cases without chromosomal aberration, PDL1 expression may be induced by JAK/STAT signaling alone and/or others alternative pathways. BI-ALCL microenvironment hosts variable amounts of PD1+ TILs and PDL1+ TAMs, suggesting the presence of an active PD1/PDL1 axis. These findings may be of therapeutic value in advanced-stage patients who may benefit from a PD1/PDL1 blocking treatment.

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

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). The first report of the registry findings is presented here. 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. 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.

Cytological diagnostic features of late breast implant seromas: From reactive to anaplastic large cell lymphoma.

Late breast implant seroma may be the presentation of a breast implant-associated anaplastic large cell lymphoma (BI-ALCL), which claims for a prompt recognition. However, BI-ALCL diagnosis on fine-needle aspiration (FNA) might be challenging for pathologists lacking experience with peri-implant breast effusions. Sixty-seven late breast implant seromas collected by FNA from 50 patients were evaluated by Papanicolaou smear stain and immunocytochemistry on cell blocks. A diagnostic algorithm based on the cellular composition, cell morphology and percentage of CD30+ cells was developed. Histological evaluation of the corresponding peri-prosthetic capsules was also performed. Most of the effusions (91% of the samples) were classified as reactive and 9% as BI-ALCL. In the BI-ALCL cases, medium-to-large atypical cells expressing CD30 represented more than 70% of the cellularity, whereas in in the reactive effusions CD30+ elements were extremely rare (<5%) and consisted of non-atypical elements. The reactive effusions were categorized into three patterns: i) acute infiltrate with prominent neutrophilic component (33% of the samples); ii) mixed infiltrate characterized by a variable number of neutrophils, lymphocytes and macrophages (30% of the samples); iii) chronic infiltrate composed predominantly of T lymphocytes or macrophages with only sporadic granulocytes (37% of the samples). The inflammatory cytological patterns were consistent with the histology of the corresponding capsules. Our results indicate that cytological analysis of late breast implant effusions, supported by the knowledge of the heterogeneous cytomorphological spectrum of late seromas, is a valuable approach for the early recognition of BI-ALCL.

Abstract P5-03-02: Breast implant associated anaplastic large cell lymphoma (BIA-ALCL)– The UK experience and first reported case of neoadjuvant brentuximab

Abstract Introduction The incidence of BIA-ALCL is on the rise. It is a recognised rare risk of breast implants. It commonly presents with a sudden, dramatic seroma around an implant, or occasionally a breast mass. Diagnosis is based on cellular morphology and staining positive for CD30 and negative for anaplastic lymphoma kinase (ALK). The aetiology and management of BIA-ALCL remains unclear. Clemens et al. suggest the conventional Ann-Arbor staging system and aggressive local and systemic treatments may not be appropriate. In the majority of cases, BIA-ALCL is confined to the seroma or the inner aspect of the capsule, so total capsulectomy alone may be sufficient. Systemic therapy may only be required in the minority where disease extends beyond the capsule. We present the UK BIA-ALCL data using the new specific staging system. Results We report 11 cases of BIA-ALCL from seven regional centres. Treatment was multidisciplinary between breast/plastic surgery and haemato-oncology and based on best available evidence and expert opinion. Mean lead-time from implant to diagnosis was 10 years. Using the new classification, eight Stage I cases that presented with recurrent seroma were treated successfully with implant removal and total capsulectomy. Four patients had bilateral breast augmentation (BBA); two had bilateral risk-reducing mastectomies (RRM) with implant reconstruction; two had a unilateral mastectomy and implant reconstruction for breast cancer, one of which had previously received adjuvant chemo- radio- and endocrine therapy. All but one patient with bilateral implants had surgery to remove both implants and ipsilateral total capsulectomy. Of these, three also had contralateral capsulectomy and the pathology was benign. One patient had unilateral capsulectomy and bilateral exchange of implants. Three patients presented with Stage IIA disease. One had previous RRM and implant reconstruction and presented with a mass. Treatment was CHOP+ (Echelon2 trial), radiotherapy and implant removal, she remains well at two years. One patient with previous BBA following a routine implant exchange developed a BIA-ALCL mass at the drain site. She was treated with local excision, adjuvant CHOP and radiotherapy. She is well at four years. The third patient had BBA and presented with a mass adjacent to the implant and progressed rapidly through neoadjuvant CHOP to develop life threatening chest wall/thoracic cavity involvement. She achieved complete pathological response with six cycles of Brentuximab followed by bilateral total capsulectomy and implant removal. This is the first reported case of neo-adjuvant antibody therapy in BIA-ALCL. Discussion Our data support the published literature demonstrating the majority of BIA-ALCL is stage I/II and can be safely managed with surgery alone. Chemotherapy was targeted at patients with more advanced local disease. Brentuximab, a monoclonal antibody is not licenced for BIA-ALCL but is used in refractory in ALCL. BIA-ALCL related death, although rare, is due to uncontrolled local disease progression. Conclusion BIA-ALCL cases must be staged according to the new system to avoid overtreatment. Brentuximab should be considered first line therapy for locally advanced BIA-ALCL. Citation Format: Johnson L, O'Donoghue J, Stark H, Collis N, Lennard A, Butterworth M, McLean N, Youssef M, Gui G, Lyburn I, Bristol J, Hurren J, Smith S, Jacklin R, Cunningham D, MacNeill F. Breast implant associated anaplastic large cell lymphoma (BIA-ALCL)– The UK experience and first reported case of neoadjuvant brentuximab [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-03-02.