Survival Signals and Targets for Therapy in Breast Implant–Associated ALK⁻Anaplastic Large Cell Lymphoma

Abstract

Purpose: Anaplastic lymphoma kinase (ALK)-negative, T-cell, anaplastic, non-Hodgkin lymphoma (T-ALCL) in patients with textured saline and silicone breast implants is a recently recognized clinical entity for which the etiology and optimal treatment remain unknown.Experimental Design: Using three newly established model cell lines from patient biopsy specimens, designated T-cell breast lymphoma (TLBR)-1 to -3, we characterized the phenotype and function of these tumors to identify mechanisms of cell survival and potential therapeutic targets.Results: Cytogenetics revealed chromosomal atypia with partial or complete trisomy and absence of the NPM-ALK (2;5) translocation. Phenotypic characterization showed strong positivity for CD30, CD71, T-cell CD2/5/7, and antigen presentation (HLA-DR, CD80, CD86) markers, and interleukin (IL)-2 (CD25, CD122) and IL-6 receptors. Studies of these model cell lines showed strong activation of STAT3 signaling, likely related to autocrine production of IL-6 and decreased SHP-1. STAT3 inhibition, directly or by recovery of SHP-1, and cyclophosphamide-Adriamycin-vincristine-prednisone (CHOP) chemotherapy reagents, effectively kill cells of all three TLBR models in vitro and may be pursued as therapies for patients with breast implant-associated T-ALCLs.Conclusions: The TLBR cell lines closely resemble the primary breast implant-associated lymphomas from which they were derived and as such provide valuable preclinical models to study their unique biology.

Breast Implant–Associated Anaplastic Large Cell Lymphoma

“…[11][12][13][14][15][16][17] Moreover, all breast implant-associated ALCLs are ALK − compared with systemic ALCL, where the cases can present as ALK+ or as ALK − . Finally, prognosis differs drastically between systemic ALK − ALCL and breast implant-associated ALCL, with the former being an aggressive disease and the latter having a more indolent course.…”

“…[18][19][20] Various studies have proposed different etiopathogenesis hypotheses attempting to associate the increased incidence of breast implant-associated ALCL with the recent introduction of textured surface implants, leading to an excessive inflammatory reaction. 14,21 In fact, some authors have argued that this disease represented only an inflammatory response and not a real malignancy, but recent studies by Lechner et al dismissed this suggestion. 14,15 The four new cases described in the current study add relatively new information to the growing literature.…”

“…14,21 In fact, some authors have argued that this disease represented only an inflammatory response and not a real malignancy, but recent studies by Lechner et al dismissed this suggestion. 14,15 The four new cases described in the current study add relatively new information to the growing literature. Those were presented to the National Ministry of Health and also to the U.S. Food and Drug Administration.…”

Breast Implant-Associated Anaplastic Large-Cell Lymphoma Can Be a Diagnostic Challenge for Pathologists

“…In some patients, under the influence of additional mutations, this reactive process in contact with the breast implant would turn into a true aggressive lymphoma [2]. The first results from the new cell lines TLRB-1, TLRB-2 and TLRB-3 tend to confirm this hypothesis and allow a better understanding of the molecular mechanisms involved across this disease spectrum [17]. …”

Chemotherapy-resistant breast implant-associated anaplastic large cell lymphoma

“…Both saline-filled and silicone implants have been associated with ALCL. There are suggestions that texturing (a process to make the outer surface of the implant rough to reduce implant contracture) might play a role in the development of ALCL secondary to chronic inflammation and increased antigenic stimulation 4. A mini-meta analysis of 49 patients with BIA-ALCL found the median age at diagnosis was 54 years, and the median time for development of ALCL was 9 years from implant surgery 3…”