Breast Implant-Associated Anaplastic Large Cell lymphoma: Brief overview of current data and imaging findings.

In 2016, the World Health Organization added Breast Implant-Associated Anaplastic Large Cell lymphoma as a provisionally recognized lymphoma to the family of existing Anaplastic Large Cell lymphomas. Current estimates of the lifetime risk of the disease in women with textured breast implants range from 1:1,000 to 1:30,000. The mean interval from implant placement to diagnosis is 10.7 ± 4.6 years and the most common clinical symptom at presentation is breast swelling. A high level of clinical suspicion is recommended in patients presenting with breast symptoms and/or peri-implant fluid collection occurring more than 1 year after breast implant placement. Ultrasound is the imaging modality of choice, with a high sensitivity for peri-implant fluid and a high specificity for peri-implant mass. When ultrasound is inconclusive, breast MRI is indicated. As of today, all confirmed cases have tested positive for CD30 immunohistochemistry and the disease has shown to have an excellent prognosis when it is diagnosed earlier (localized disease), and when complete surgery, consisting of explantation, capsulectomy, and removal of any associated capsule mass, is performed. This overview summarizes the available epidemiological and clinical data of Breast Implant-Associated Anaplastic Large Cell lymphoma, with an emphasis on imaging features.

Biological and genetic landscape of breast implant-associated anaplastic large cell lymphoma (BIA-ALCL).

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is an uncommon form of non-Hodgkin lymphoma (cancer of the immune system) that can develop around breast implants. Breast implants are among the most commonly used medical devices for cosmetic or reconstructive purposes. In the past few years, the number of women with breast implants diagnosed with anaplastic large cell lymphoma (ALCL) has increased, and several studies have suggested a direct association between breast implants and an increased risk of this disease. Although it has been hypothesized that chronic stimulation of the immune system caused by implant materials and biofilms as well as a possible genetic predisposition play an important role in this disease, the cellular and molecular causes of BIA-ALCL are not fully understood. This review aims to describe the current understanding around the environmental and molecular drivers of BIA-ALCL as well as the genetic and chromosomal abnormalities identified in this disease to date.

The mechanism of cancer drug addiction in ALK-positive T-Cell lymphoma.

Rational new strategies are needed to treat tumors resistant to kinase inhibitors. Mechanistic studies of resistance provide fertile ground for development of new approaches. Cancer drug addiction is a paradoxical resistance phenomenon, well-described in MEK-ERK-driven solid tumors, in which drug-target overexpression promotes resistance but a toxic overdose of signaling if the inhibitor is withdrawn. This can permit prolonged control of tumors through intermittent dosing. We and others showed previously that cancer drug addiction arises also in the hematologic malignancy ALK-positive anaplastic large-cell lymphoma (ALCL) resistant to ALK-specific tyrosine kinase inhibitors (TKIs). This is driven by the overexpression of the fusion kinase NPM1-ALK, but the mechanism by which ALK overactivity drives toxicity upon TKI withdrawal remained obscure. Here we reveal the mechanism of ALK-TKI addiction in ALCL. We interrogated the well-described mechanism of MEK/ERK pathway inhibitor addiction in solid tumors and found it does not apply to ALCL. Instead, phosphoproteomics and confirmatory functional studies revealed that the STAT1 overactivation is the key mechanism of ALK-TKI addiction in ALCL. The withdrawal of TKI from addicted tumors in vitro and in vivo leads to overwhelming phospho-STAT1 activation, turning on its tumor-suppressive gene-expression program and turning off STAT3's oncogenic program. Moreover, a novel NPM1-ALK-positive ALCL PDX model showed a significant survival benefit from intermittent compared with continuous TKI dosing. In sum, we reveal for the first time the mechanism of cancer drug addiction in ALK-positive ALCL and the benefit of scheduled intermittent dosing in high-risk patient-derived tumors in vivo.

Linfoma anaplásico de grandes células relacionado ao implante mamário: revisão sistemática da literatura / Breast implant-associated anaplastic large-cell lymphoma: a systematic literature review

O linfoma anaplásico de grandes células associado ao implante de mama (Breast Implant Associated Anaplastic Large Cell Lymphoma - BIA-ALCL) é uma doença maligna recentemente descoberta, rara e possivelmente associada aos implantes mamários texturizados. Essa revisão da literatura teve como objetivo trazer novas atualizações acerca da epidemiologia, fisiopatologia e fatores de risco para desenvolvimento do BIAALCL. Foi realizado o levantamento de dados do período de dezembro de 2018 a fevereiro de 2019, através das bases de dados PUBMED, LILACS e Scielo sendo selecionados 10 artigos publicados entre 2016 e 2018. Foi encontrada uma incidência variando entre 2,8:100.000 a 1:3 milhões de pacientes com implantes mamários. Os dados coletados corroboram para a teoria de que não há uma relação direta de causa e efeito entre os implantes mamários, mormente os texturizados, e o desenvolvimento do BIA-ALCL, podendo esses ser considerados somente como fatores de risco e não agentes causadores. A teoria fisiopatológica mais aceita é a de que os implantes mamários com maior área de superfície levariam a formação de maior biofilme por maior adesão bacteriana gerando inflamação crônica mais proeminente, levando ao gatilho para a transformação maligna das células T. As informações explicitadas nessa revisão devem auxiliar na ampliação de estudos acerca da doença e criação de políticas públicas para a prevenção e diagnóstico precoce de tal enfermidade. Pelos dados encontrados há necessidade de que cirurgiões plásticos realizem acompanhamento mais próximo de seus pacientes, assim como orientem os pacientes antes das cirurgias sobre a existência da doença.

Breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL) is a newly discovered and rare cancer possibly associated with textured breast implants. This literature review investigates its epidemiology, pathophysiology, and risk factors. PubMed, LILACS, and SciELO databases were searched from December 2018 to February 2019, and 10 articles published between 2016 and 2018 were selected. The incidence of BIA-ALCL ranged from 2.8:100,000 to 1:3 million breast implants. The obtained data corroborate the hypothesis that there is no direct cause and effect relationship between breast implants, especially textured implants, and BIA-ALCL, and these implants can be considered risk factors but not causative factors. The most accepted hypothesis on disease pathophysiology is that breast implants with larger surface areas may promote bacterial adhesion and biofilm formation, leading to severe chronic inflammation, triggering the malignant transformation of T cells. This review provides knowledge on BIA-ALCL and helps develop and implement public policies for disease prevention and timely diagnosis. The data highlight that long-term follow up is necessary and that surgeons should advise patients of the potential risk of developing BIA-ALCL before performing the implant surgery.

Theories of Etiopathogenesis of Breast Implant-Associated Anaplastic Large Cell Lymphoma.

Breast implant-associated anaplastic large cell lymphoma is a malignancy of T lymphocytes that is associated with the use of textured breast implants in both esthetic and reconstructive surgeries. Patients typically present with a delayed seroma 8-10 years following implantation or-less commonly-with a capsular mass or systemic disease. Current theories on disease pathogenesis focus on the interplay among textured implants, Gram-negative bacteria, host genetics, and time. The possible roles of silicone leachables and particles have been less well substantiated. This review aims to synthesize the existing scientific evidence regarding breast implant-associated anaplastic large cell lymphoma etiopathogenesis.

Current Risk Estimate of Breast Implant-Associated Anaplastic Large Cell Lymphoma in Textured Breast Implants.

BACKGROUND: With breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) now accepted as a unique (iatrogenic) subtype of ALCL directly associated with textured breast implants, we are now at a point where a sound epidemiologic profile and risk estimate are required. The aim of this article is to provide a comprehensive and up-to-date global review of the available epidemiologic data and literature relating to the incidence, risk, and prevalence of BIA-ALCL. METHODS: All current literature relating to the epidemiology of BIA-ALCL was reviewed. Barriers relating to sound epidemiologic study were identified, and trends relating to geographical distribution, prevalence of breast implants, and implant characteristics were analyzed. RESULTS: Significant barriers exist to the accurate estimate of both the number of women with implants (denominator) and the number of cases of BIA-ALCL (numerator), including poor registries, underreporting, lack of awareness, cosmetic tourism, and fear of litigation. The incidence and risk of BIA-ALCL have increased dramatically from initial reports of 1 per million to current estimates of 1/2,832, and is largely dependant on the "population" (implant type and characteristics) examined and increased awareness of the disease. CONCLUSIONS: Although many barriers stand in the way of calculating accurate estimates of the incidence and risk of developing BIA-ALCL, steady progress, international registries, and collegiality between research teams are for the first time allowing early estimates. Most striking is the exponential rise in incidence over the last decade, which can largely be explained by the increasingly specific implant subtypes examined-driven by our understanding of the pathologic mechanism of the disease. High-textured high-surface area implants (grade 4 surface) carry the highest risk of BIA-ALCL (1/2,832).

Molecular Drivers of Breast Implant-Associated Anaplastic Large Cell Lymphoma.

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a rare T-cell lymphoproliferative disorder occurring in patients with breast implants. Genomic characterization performed in BIA-ALCL to date has demonstrated qualitatively similar molecular abnormalities to those seen in its more common counterpart [ALK-negative systemic anaplastic large cell lymphoma (sALCL)] including JAK/STAT activation and MYC/TP53 dysregulation. Despite these observed similarities at the molecular level, the outcomes of sALCL and BIA-ALCL are markedly different with sALCL typically associated with an aggressive course and inferior outcomes compared with BIA-ALCL. This review describes the findings of high-throughput sequencing and other genomic characterization to date in BIA-ALCL and the insights these studies have given into the molecular drivers of this rare lymphoma subtype.

Breast Implant Illness: A Way Forward.

The link between breast implants and systemic disease has been reported since the 1960s. Although many studies have looked at either supporting or refuting its existence, the issue still persists and has now been labeled "breast implant illness." The rise of patient advocacy and communication through social media has led to an increasing number of presentations to plastic surgeons. This article summarizes the history of breast implants and systemic disease, critically analyzes the literature (and any associated deficiencies), and suggests a way forward through systematic scientific study.

[Use of crizotinib for refractory ALK-positive lymphomas]. / Primenenie krizotiniba pri refrakternykh formakh ALK- pozitivnykh limfom.

AIM: To evaluate the safety and efficacy of crizotinib used in pediatric patients with relapsed or refractory ALK-positive anaplastic large-cell lymphoma (ALCL). SUBJECTS AND METHODS: The paper describes the experience with crizotinib used in 8 patients with refractory ALK-ALCL before and after allogeneic hematopoietic stem cell transplantation (HSCT). RESULTS: All the 8 (100%) patients treated with crizotinib were recorded to have complete responses, including complete metabolic ones (tumor disappearance as evidenced by positron emission tomography (PET)/computed tomography. CONCLUSION: Low and manageable toxicity of crizotinib and complete PET-negative responses in patients with resistant ALK lymphomas favor the need to test the drug as first-line therapy, by possibly decreasing the intensification of chemotherapy.

Lymphomatoid papulosis: Treatment response and associated lymphomas in a study of 180 patients.

BACKGROUND: Lymphomatoid papulosis (LyP) is a CD30(+) lymphoproliferative disorder, with a self-regressing clinical course and malignant histopathology. OBJECTIVE: The aim of this study was to evaluate characteristics, risk factors, associated malignancies, long-term outcome, and treatment of LyP in a large cohort representing the experience of the MD Anderson Cancer Center. METHODS: Patient charts and clinical and histopathologic data of 180 patients with LyP were retrospectively assessed. RESULTS: A total of 56.7% of patients was men. Histologic subtype A was found in 47.2%, type B in 17.2%, type C in 22.8%, type D in 7.8%, type E in 0.6%, and mixed subtype in 4.4% of the patients. One hundred fourteen lymphomas were observed in 93 patients, with mycosis fungoides (61.4%) and anaplastic large cell lymphoma (26.3%) being the most common forms. Risk factors for development of lymphoma included sex and histologic subtype. Number of lesions and symptom severity were not associated with lymphoma development. Patients with type D were less likely to have lymphomas. Treatment provided symptomatic relief but did not prevent progression to lymphoma. LIMITATIONS: The limitation of this study is the retrospective study design. CONCLUSION: Patients with LyP are at increased risk of associated lymphomas. Thorough patient counseling is needed and long follow-up periods are required to detect and treat secondary lymphomas.

Breast Implant-Associated Anaplastic Large Cell Lymphoma: Proposal for a Monitoring Protocol.

BACKGROUND: The authors report four cases of breast implant-associated anaplastic large cell lymphoma (ALCL) from a single institution and propose a multidisciplinary protocol. METHODS: From 2012 to 2014, four breast implant-associated ALCL cases were diagnosed. The authors performed the original operation, and no patients were referred to their practice. Cases 1, 2, and 4 were CD4/CD30/ALK ALCL with previous textured-implant reconstruction, whereas case 3 was CD8/CD30/ALK ALCL with previous polyurethane-implant augmentation. A retrospective study of all patients who underwent breast implant positioning was performed to identify any misdiagnosed cases. RESULTS: Of 483 patients, 226 underwent reconstruction with latissimus dorsi flap and prosthesis, 115 had skin-sparing/nipple-sparing mastectomy and prosthesis, 117 underwent an expander/implant procedure, and 25 underwent breast augmentation. Fifty-eight cases (12 percent) underwent implant replacement for capsular contracture, 15 (3.1 percent) experienced late-onset seroma, and four (0.83 percent) had both capsular contracture and seroma. Seventy-seven symptomatic patients (16 percent) underwent surgical revision (capsulectomy/capsulotomy) and/or seroma evacuation. The second look on histologic specimens did not identify misdiagnosed cases. A multidisciplinary protocol for suspected implant-associated ALCL was established. Ultrasound and cytologic examinations are performed in case of periprosthetic effusion. If implant-associated ALCL is diagnosed, implant removal with capsulectomy is performed. If disseminated disease is detected through positron emission tomography/computed tomography of the total body, the patient is referred to the oncology department. CONCLUSIONS: A multidisciplinary protocol is mandatory for both early diagnosis and patient management. Until definitive data emerge regarding the exact etiopathogenesis of breast implant-associated ALCL, the authors suggest offering only autologous reconstruction if patients desire it. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V.

Histone modifications predispose genome regions to breakage and translocation.

Chromosome translocations are well-established hallmarks of cancer cells and often occur at nonrandom sites in the genome. The molecular features that define recurrent chromosome breakpoints are largely unknown. Using a combination of bioinformatics, biochemical analysis, and cell-based assays, we identify here specific histone modifications as facilitators of chromosome breakage and translocations. We show enrichment of several histone modifications over clinically relevant translocation-prone genome regions. Experimental modulation of histone marks sensitizes genome regions to breakage by endonuclease challenge or irradiation and promotes formation of chromosome translocations of endogenous gene loci. Our results demonstrate that histone modifications predispose genome regions to chromosome breakage and translocations.

The epidemiology and targeted therapies for relapsed and refractory CD30+ lymphomas.

BACKGROUND: Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (sALCL) both have consistent expression of CD30, a cytokine receptor that is expressed by activated T and B cells but is largely absent from normal tissue. METHODS: A literature search was conducted via PubMed, Google Scholar, and UpToDate to identify relevant peer-reviewed original research or review articles on HL, sALCL, and CD30 targeted therapies. RESULTS: These lymphomas are both more common among males, young adults and the elderly. Although many patients with HL and sALCL can achieve long-term remission after standard first-line therapy, up to a third of these patients are refractory to or relapse after initial therapy. Among these relapsed/refractory patients, many experience disease progression and/or death despite subsequent treatment, and treatment-related adverse events and mortality are not uncommon. To address the need for safer and more effective therapies for these relapsed/refractory patients, researchers have developed therapies that specifically target CD30-expressing cells. Brentuximab vedotin, an antibody-drug conjugate that selectively delivers a toxic microtubule-disrupting agent to malignant cells with CD30 expression, is the first such therapy to be approved in the US and Europe. In clinical trials, brentuximab vedotin has demonstrated efficacy and safety in patients with HL after failure of autologous stem cell transplantation (ASCT), or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates, and in patients with sALCL after failure of at least one prior multi-agent chemotherapy regimen. CONCLUSION: HL and sALCL are both CD30+ lymphomas, and therapies like brentuximab vedotin that target cells expressing CD30 hold promise for the treatment of these diseases.

Galectin-1-mediated cell adhesion, invasion and cell death in human anaplastic large cell lymphoma: regulatory roles of cell surface glycans.

Galectin-1 is known to be one of the extracellular matrix proteins. To elucidate the biological roles of galectin-1 in cell adhesion and invasion of human anaplastic large cell lymphoma, we performed cell adhesion and invasion assays using the anaplastic large cell lymphoma cell line H-ALCL, which was previously established in our laboratory. From the cell surface lectin array, treatment with neuraminidase from Arthrobacter ureafaciens which cleaves all linkage types of cell surface sialic acid enhanced Arachis hypogaea (PNA), Helix pomatia (HPA) and Phaseolus vulgaris-L (L-PHA) lectin binding reactivity to cell surface of lymphoma cells suggesting that neuraminidase removes cell surface sialic acid. In cell adhesion and invasion assays treatment with neuraminidase markedly enhanced cell adhesion to galectin-1 and decreased cell invasive capacity through galectin-1. α2,6-linked sialic acid may be involved in masking the effect of the interaction between galectin-1 and cell surface glycans. H-ALCL cells expressed the ß-galactoside-α2,6-sialyltransferase ST6Gal1. On resialylation assay by recombinant ST6Gal1 with CMP-Neu5Ac, α2,6-resialylation of L-PHA reactive oligosaccharide by ST6Gal1 resulted in inhibition of H-ALCL cell adhesion to galectin-1 compared to the desialylated H-ALCL cells. On knockdown experiments, knockdown of ST6Gal1 dramatically enhanced cell adhesion to galectin-1. N-glycosylation inhibitor swainsonine treatment resulted in enhancement of cell adhesion to galectin-1. In glycomic analysis using the lectin blocking assay treatment with PNA, Artocarpus integrifolia (Jacalin), Glycine max (SBA), Helix pomatia (HPA), Vicia villosa (VVA), Ulex europaeus (UEA-1), Triticum vulgaris (WGA), Canavalia ensiformis (ConA), Phaseolus vulgaris-L (L-PHA), Phaseolus vulgaris-E4 (E-PHA), Datura stramonium (DSA) lectins resulted in modulation of lymphoma cell to galectin-1 suggesting that several types of glycans may regulate cell adhesion to galectin-1 by steric hindrance. The adhesive capacity of H-ALCL cells is regulated by phosphatidylinositol 3 phosphate kinase (PI3K) and actin cytoskeleton, and the invasive capacity of H-ALCL cells is regulated by PI3K, mitogen-activated protein kinase (MAPK), Rho and actin cytoskeleton. Furthermore, galectin-1-induced cell death in H-ALCL cells was accompanied by inhibition of CD45 protein tyrosine phosphatase (PTP) activity. In conclusion, cell adhesion and invasion to galectin-1 appeared to be regulated by cell surface sialylation and N-glycosylation, and galectin-1 regulates cell death through inhibition of CD45 PTP activity of H-ALCL.

Dual ALK and MYC rearrangements leading to an aggressive variant of anaplastic large cell lymphoma.

Anaplastic lymphoma kinase (ALK) and MYC are oncogenes often dysregulated in pediatric lymphomas. NPM-ALK/t(2;5)(p23;q35) is a genetic hallmark of ALK anaplastic large cell lymphoma (ALCL). MYC gene translocations are frequently detected in high-grade B-cell lymphomas. ALKALCL cases with concurrent MYC translocation are exceedingly rare and are more aggressive and chemoresistent compared with other ALKALCL. We report a patient who presented with ALKALCL possessing coexistent MYC rearrangement, massive tumor dissemination, and early widespread relapse. This case underscores the importance of recognition of close correlation between dual ALK and MYC rearrangements and the characteristic clinical features in this unusual ALCL variant.