Biomarkers Provide Clues to Early Events in the Pathogenesis of Breast Implant-Associated Anaplastic Large Cell Lymphoma.

Almost 200 women worldwide have been diagnosed with breast implant-associated anaplastic large cell lymphoma (BIA-ALCL). The unique location and specific lymphoma type strongly suggest an etio-pathologic link between breast implants and BIA-ALCL. It is postulated that chronic inflammation via bacterial infection may be an etiological factor. BIA-ALCL resembles primary cutaneous ALCL (pcALCL) in morphology, activated T-cell phenotype, and indolent clinical course. Gene expression array analysis, flow cytometry, and immunohistochemistry were used to study pcALCL and BIA-ALCL cell lines. Clinical samples were also studied to characterize transcription factor and cytokine profiles of tumor cells and surrounding lymphocytes. BIA-ALCL and pcALCL were found to have common expression of transcription factors SOCS3, JunB, SATB1, and a cytokine profile suggestive of a Th1 phenotype. Similar patterns were observed in a CD30+ cutaneous lymphoproliferative disorder (LPD). The patterns of cytokine and transcription factor expression suggest that BIA-ALCL is likely to arise from chronic bacterial antigen stimulation of T-cells. Further analysis of cytokine and transcription factor profiles may allow early detection and treatment of BIA-ALCL leading to better prognosis and survival. LEVEL OF EVIDENCE 5: Risk.

Pioneers of Breast Implant-Associated Anaplastic Large Cell Lymphoma: History from Case Report to Global Recognition.

The first case of breast implant-associated anaplastic large cell lymphoma (breast implant ALCL) was described by John Keech and the late Brevator Creech in 1997. In the following 2 decades, much research has led to acceptance of breast implant ALCL as a specific clinicopathologic entity, a process that we bring up to life through the memories of 6 persons who were involved in this progress, although we acknowledge that many others also have contributed to the current state of the art of this disease. Dr. Keech recalls the events that led him and Creech to first report the disease. Ahmet Dogan and colleagues at the Mayo Clinic described a series of 4 patients with breast implant ALCL, and led to increased awareness of breast implant ALCL in the pathology community. Daphne de Jong and colleagues in the Netherlands were the first to provide epidemiologic evidence to support the association between breast implants and ALCL. Garry Brody was one of the first investigators to collect a large number of patients with the disease, present the spectrum of clinical findings, and alert the community of plastic surgeons. Roberto Miranda and L. Jeffrey Medeiros and colleagues studied the pathologic findings of a large number of cases of breast implant ALCL, and published the findings in 2 impactful studies in the medical oncology literature. The recognition and acceptance of this disease by surgeons, epidemiologists, and medical oncologists, working together, has led to subsequent studies on the pathogenesis and optimal therapy of this disease.

How to Diagnose and Treat Breast Implant-Associated Anaplastic Large Cell Lymphoma.

LEARNING OBJECTIVES: After reading this article, the participant should be able to: 1. Describe the diagnostic criteria for breast implant-associated (BIA) anaplastic large cell lymphoma (ALCL). 2. Appropriately evaluate a patient with suspected BIA-ALCL, including appropriate imaging, laboratory tests, and pathologic evaluation. 3. Understand the operative treatment of BIA-ALCL, and indications for systemic chemotherapy and/or radiation therapy in advanced disease. 4. Understand treatment outcomes and prognosis based on stage of disease. SUMMARY: The goal of this continuing medical education module is to present the assessment of a patient with suspected breast implant-associated anaplastic large cell lymphoma, the evaluation and diagnosis, the preoperative oncologic workup, the formation and execution of a surgical treatment plan, and the inclusion of adjunct treatments when indicated. In addition, staging and disease progression for treatment of breast implant-associated anaplastic large cell lymphoma are discussed.

Anaplastic large cell lymphoma occurring in women with breast implants: analysis of 173 cases.

BACKGROUND: The first silicone breast implant was inserted in 1962. In 1997, the first case of anaplastic large cell lymphoma (ALCL) in association with a silicone breast implant was reported. The authors reviewed 37 articles in the world literature reporting on 79 patients and collected another 94 unreported cases as of the date of submission. METHODS: The world literature was reviewed. Missing clinical and laboratory information was solicited from the authors and treating physicians. As several different specialties were involved, information was not in one place. Many (but not all) authors and treating physicians were responsive, resulting in incomplete data. RESULTS: ALCL lesions first presented as late peri-implant seromas, a mass attached to the capsule, tumor erosion through the skin, in a regional node, or discovered during revision surgery. The clinical course varied widely from a single positive cytology result followed by apparent spontaneous resolution, to disseminated treatment-resistant tumor and death. There was no preference for saline or silicone fill or for cosmetic or reconstructive indications. Where implant history was known, the patient had received at least one textured-surface device. Extracapsular dissemination occurred in 18 cases; nine of those were fatal. Histochemical markers were primarily CD-30 and Alk-1. Other markers occurred at a lower frequency. Risk estimates ranged from one in 500,000 to one in 3 million women with implants. CONCLUSION: Breast implant-associated ALCL is a novel manifestation of site- and material-specific lymphoma originating in a specific scar location, presenting a wide array of diverse characteristics and suggesting a multifactorial cause.

Anaplastic large cell lymphoma occurring in association with breast implants: review of pathologic and immunohistochemical features in 103 cases.

Primary lymphomas of the breast are uncommon, and mostly of B-cell type. In the late 1990s, reports began to appear,primarily in the Pathology literature, of an apparently new category of breast lymphoma of T-cell type, having a particular association with silicone breast implants. This condition came to be recognized as implant-associated anaplastic large cell lymphoma.Appearing initially as individual case reports, the pathologic features were somewhat variable and the diagnosis was difficult. This review describes the pathologic and immunohistochemical features of implant-associated anaplastic large cell lymphoma of the breast drawn from a series of 103 cases. Recommendations are given for the management of removed implants, for the approach to differential diagnosis and the choice of initial immunohistochemical panels.

Survival signals and targets for therapy in breast implant-associated ALK--anaplastic large cell lymphoma.

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, ALK-negative, T-cell, anaplastic, large-cell lymphoma: establishment and characterization of a model cell line (TLBR-1) for this newly emerging clinical entity.

BACKGROUND: Primary lymphomas of the breast are very rare (0.2-1.5% of breast malignancies) and the vast majority (95%) are of B-cell origin. Recently, 40 cases of clinically indolent anaplastic large-cell kinase (ALK)-negative, T-cell, anaplastic, non-Hodgkin lymphomas (T-ALCL) have been reported worldwide. METHODS: A tumor biopsy specimen from a patient in this series was obtained for characterization. By using a human stromal feeder layer and IL-2, a novel cell line, TLBR-1, was established from this biopsy and investigated by using cytogenetics and various biomolecular methods. RESULTS: Immunoperoxidase staining of the tumor biopsy showed a CD30/CD8/CD4 coexpressing T-cell population that was epithelial membrane antigen (EMA)(+) and perforin(+) . Multiplex polymerase chain reaction (PCR) of TCRγ genes showed monoclonality that suggested a T-cell origin, yet pan-T markers CD2/5/7, anaplastic large-cell kinase (ALK)-1, pancytokeratins, CD20, CD56, and Epstein-Barr virus (EBV) by in situ hybridization (ISH) were negative. TLBR-1 is IL-2 dependent, has a relatively long doubling time (55 hours), and displays different cellular shapes in culture. Cytogenetic analysis of tumor and TLBR-1 cells confirmed a highly anaplastic cell population with a modal number of 47 chromosomes lacking t(2;5). PCR screens for EBV and human T-lymphotropic virus types 1 and 2 (HTLV-1/2) were negative. Fluorescence-activated cell-sorting (FACS) analysis showed strong positivity for CD4/8, CD30, CD71, and CD26 expression, and antigen presentation (HLA-DR(+) CD80(+) CD86(+) ), IL-2 signaling (CD25(+) CD122(+) ), and NK (CD56(+) ) markers, and Western blots demonstrated strong Notch1 expression. Severe combined immunodeficiency (SCID) mouse TLBR-1 heterotransplants recapitulated the histology and marker characteristics of the original tumor. CONCLUSIONS: TLBR-1, a novel ALK-negative, T-cell, anaplastic, large-cell lymphoma, closely resembles the original biopsy and represents an important tool for studying this newly recognized disease entity.

Managing late periprosthetic fluid collections (seroma) in patients with breast implants: a consensus panel recommendation and review of the literature.

BACKGROUND: The goal of this consensus is to establish an algorithm for the management of patients who develop a late or delayed periprosthetic fluid collection. A work group of practicing plastic surgeons and device industry physicians met periodically by teleconference and discussed issues pertinent to the diagnosis and management of late periprosthetic fluid collections in patients with breast implants. Based on these meetings, treatment recommendations and a treatment algorithm were prepared in association with an editorial assistant. METHOD: The work group participants discussed optimal care approaches developed in their private practices and from evidence in the literature. RESULTS: The consensus algorithm and treatment and management recommendations represent the consensus of the group. CONCLUSIONS: The group concluded that late periprosthetic fluid collection (arbitrarily defined as occurring ≥ 1 year after implant) is an infrequently reported occurrence (0.1 percent) after breast implant surgery and that, at a minimum, management should include clinically indicated ultrasound-guided aspiration of fluid, with appropriate cultures and cytologic testing. Further evaluation and additional treatment is recommended for recurrence of periprosthetic fluid collection after aspiration, or clinical suspicion of infection or neoplasia.

Anatomic variation and asymmetry in female anterior thoracic contour: an analysis of 50 consecutive computed tomography scans.

This study examines the prevalence of anatomic variation and asymmetry in female thoracic contour and evaluates their effect on breast projection. A consecutive series of 50 female cross-sectional thoracic computed tomography (CT) scans was examined at the level of the fourth rib. Patients with thoracic wall trauma (including surgery) were excluded. Lateral width, anterior-posterior diameter, and 3 internal angles were compared bilaterally and were used to evaluate overall shape and thoracic contour. All patients demonstrated some degree of asymmetry between their right and left sides. A wide range of thoracic shapes was observed. Patients with sloped anterior chest walls have lateral projection of the nipple, while patients with flatter chest walls have anterior projection of the nipple. Evaluating anterior chest wall slope prior to augmentation can help physicians predict postoperative breast projection and thus prepare their patients for the future breast appearance and the potential for contact cleavage.