Evidence That Some Breast Implant Associated Anaplastic Large Cell Lymphomas Arise in the Context of Allergic Inflammation

Breast Implant Associated Large Cell Lymphoma (BIA-ALCL) is a recently recognized lymphoma found surrounding breast implants of more than 380 women worldwide. The etiology of BIA-ALCL is unknown although a bacterial biofilm overlying BIA-ALCL associated implants has been demonstrated. Here we provide evidence that BIA-ALCL may be mediated by chronic allergic inflammation in a group of BIA-ALCL patients. We studied 3 BIA-ALCL lines (TLBR-1/2/3), seroma fluids and/or resected capsular tissues of 14 patients with BIA-ALCL. Resected capsules revealed chronic inflammation including fibrosis, plasma cells, lymphocytes, primary and secondary lymphoid follicles, mast cells and eosinophils. IL-13, the signature cytokine of allergic inflammation, was secreted by BIA-ALCL lines and localized to small lymphocytes and anaplastic cells in most clinical samples. Th2 transcription factor GATA3 co-localized to anaplastic cells producing IL-13. IL-13 is known to induce Ig class switch of B cells to produce IgE. Accordingly, IgE was detected bound to follicular dendritic antigen presenting cells in lymphoid follicles in 3 cases and mast cells in 5 cases. As a likely source of IgE, plasma cells staining for IgE were found in capsular tissues and regional lymph nodes. Activated mast cells produce prostaglandin D₂ (PGD₂). The receptor for PGD₂, CRTH2, was expressed by each of 3 BIA-ALCL lines and anaplastic cells in 5 of 6 clinical samples analyzed. Ligands that activate CRTH2 stimulate chemotaxis (i.e. directed migration) of leukocytes active in mediating allergic responses, viz., eosinophils, basophils, and Th2 cells. Not unexpectedly, eosinophils were found surrounding anaplastic cells in 4 of 5 cases with IgE observed on mast cells. In contrast, only few scattered tissue and intravascular eosinophils were present in 1 of 15 benign capsules. Together, these findings suggest that some BIA-ALCL are associated with a chronic allergic immune response to as yet undefined antigen(s).