Abstract
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. 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. 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. 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.
Highlights
Breast implant–associated (BIA) T-cell anaplastic large cell lymphoma (ALCL) is a recently recognized clinical entity, with 80 cases identified worldwide to date and four disease-specific fatalities [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15]
We identify increased STAT3 activation related to dysregulation of the SHP-1 phosphatase and autocrine production of interleukins as a driver of cell survival in breast implant–associated anaplastic large cell lymphomas
Initial report, we have established and characterized 2 new cell lines from patients with BIA-ALCL, including 1 of the 4 fatal cases, designated T-cell breast lymphoma (TLBR)-2 and -3. Using these models of BIA-ALCLs, we describe fully the phenotypic and functional features of this newly emerging clinical entity, including identification of aberrancies in cell signaling and apoptosis regulators that seem to be excellent molecular targets for therapy
Summary
Breast implant–associated (BIA) T-cell anaplastic large cell lymphoma (ALCL) is a recently recognized clinical entity, with 80 cases identified worldwide to date and four disease-specific fatalities [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15]. BIA-ALCL presents commonly as a late seroma and/or tumor mass attached to the scar capsule containing malignant cells an average of 5.8 years after implant placement Seroma-associated ALCL was proposed by Roden and colleagues [5] in 2008 to address BIA-ALCL, which shares morphologic features of both primary systemic ALKÀ ALCL and pc-ALCL but is distinct in its presentation with malignant seroma fluid and varied clinical progression (indolent to aggressive). T-ALCLs express a range of immune markers, including T-cell antigens, cytotoxic granules, and antigen presentation molecules, and, like other T-cell neoplasms, show clonal T-cell receptor (TCR) gene rearrangement [21,22,23]
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