Specific Genetic Alterations Characterize Seroma‐ and Tumor‐type Breast‐implant Associated Anaplastic Large Cell Lymphoma (Bia‐alcl) as a Distinct Disease Entity

This is the authors' abstract. We don't add key points for this paper.

Background: Breast Implant-Associated Anaplastic Large Cell lymphoma (BIA-ALCL) is a distinctive clinical subtype in the family of ALCL. In most patients, BIA-ALCL remains confined to the periprosthetic seroma space (seroma-BIA-ALCL), while a mass in the capsule or breast tissue is seen in approximately 20% (tumor-BIA-ALCL). Seroma-BIA-ALCL can be adequately treated with explantation and capsulectomy resulting in 5 year survival of ≥ 90%. In tumor-BIA-ALCL systemic chemotherapy is required, and in rare cases, women may die of disseminated disease. As we previously showed in a population-based study, women with breast implants have a more than 400 times increased risk to develop breastALCL than women without breast implants with a life-time risk of 1:7000. Data on molecular tumor characteristics for BIA-ALCL is limited and largely refer to activation of the JAK-STAT signaling pathway by mutations and other mechanisms, presumably epigenetic and regulatory factors. The common ALCL-related translocations have alos been convincingly demonstrated to be absent. No specific molecular characteristics that distinguish BIA-ALCL from other subtypes of ALCL have been identified. Methods: From the Dutch BIA-ALCL cohort of all BIA-ALCL cases diagnosed in the Netherlands between 1990 to 2017 (n = 50), we selected BIA-ALCL tumor (n = 16) and seroma (n = 19) FFPE samples of 29 patients. We performed shallow whole genome sequencing (sNGS) in these samples and in 7 cases with not-implant-associated ALCL in the breast to identify copy number aberrations (CNAs). Whole Exome Sequencing (WES) was performed for 4 tumor-BIA-ALCL and 3 seroma-BIA-ALCL cases with normal germline tissue available. Results: Copy number losses of chromosomes 20, 2p and 15q were found at significantly higher frequency in BIA-ALCL compared to nodal- and cutaneous-type ALCL. The most frequent aberration for both seroma-BIA-ALCL and tumor-BIA-ALCL, loss of a 3Mb chromosomal region 20q13.12-q.13.13 was found in 19/29 (65.5%) patients with a minimal common lost region spanning 20q13.12-q12.2. A considerably higher genome instability level was observed for seroma-BIA-ALCL compared to tumor-BIA-ALCL with features of complex subclonality. A significant higher frequency of loss at chromosomes 4, 8p and 15q in seroma-BIA-ALCL was seen. We observed an overall high mutational load in tumor-BIA-ALCL, while mutational load in seroma-BIA-ALCL was low. The majority of recurrent mutations were identified in the IL6-JAK1-STAT3 pathway as previously reported. Conclusions: Chromosome 20 loss distinguishes BIA-ALCL from other ALCL subtypes, providing a distinctive differential diagnostic parameter. Progression from seroma-BIA-ALCL to tumor-BIA-ALCL may be mediated by a pool of subclones driven by retention of chromosome 4q, 8p and 15q, while upon progression to tumor-BIA-ALCL the process becomes dominantly mutation-driven.