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1.
Plast Reconstr Surg ; 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31577659

RESUMO

Breast implant associated anaplastic large cell lymphoma (BIA-ALCL) has been included as a provisional entity in the revised version of the WHO Classification of Tumors of Haematopoietic and Lymphoid Tissue. To increase opportunities to intervene with early diagnosis, treatment and possible prevention, it is important to consider that BIA-ALCL may evolve from a pre-existing lymphoproliferative disorder (LPD) characterized by (1) an indolent localized (in situ) disease in about 80% of reported cases; (2) a requirement for external cytokine stimulation for cell survival; (3) CD30+ cells in some clinically benign seromas/capsules; (4) undetected T-cell clonality in some cases; (5) JAK/STAT mutations in only a minority of cases (6) cure by capsulectomy and implant removal in most cases. BIA-ALCL resembles CD30+ cutaneous LPD: ALK-, CD30+ anaplastic cells with an aberrant T cell phenotype; overexpression of oncogenes (JUNB, SATB1, pSTAT3, SOCS3) in lymphomatoid papulosis (LyP); frequent apoptosis; complete spontaneous regression in LyP and partial spontaneous regression in cutaneous ALCL. Unlike CD30+ cutaneous LPD, BIA-ALCL cannot be readily observed over time to study the different steps in progression to ALCL. BIA-ALCL also shares features of lymphomas of mucosa associated lymphoid tissue (MALT lymphomas) which are clinically indolent, initially localized, antigen driven, and caused by gram negative bacteria. Further studies of cytokines, clonality, mutations and other biomarkers are needed to identify possible premalignant steps in the evolution of benign late seromas to BIA-ALCL.

2.
J Dermatol ; 2019 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-31587349

RESUMO

The prevalence of atopy was investigated in 20 patients with Sézary syndrome (SS), 20 patients with plaque phase mycosis fungoides (MF), 9 patients with primary cutaneous marginal zone lymphoma (pcMZL) and 8 patients with primary cutaneous follicle center lymphoma (pcFCL) with the Phadiatop multi-allergen test. The relationship among serologic atopy, IgE reactivity against Staphyloccocal enterotoxin superantigens, and serum total IgE (IgE-t) levels and their prognostic implications in SS was investigated. Phadiatop test was positive in 45%, 15%, 33% and 0% of samples of SS, MF, pcMZL and pcFCL, respectively. IgE-t levels were also increased in SS, pcMZL and marginally MF. No correlation was found with patients' history of atopic disorders. Staphylococcal superantigen-specific IgE ≥ 0.35 kUa/L, most often against toxic shock syndrome toxin-1, was detected in 40% of Sézary samples followed by MF (20%). In the absence of serologic atopy (negative Phadiatop test), IgE-t levels for patients with SS and MF were not significantly higher than controls whereas the levels for pcMZL remained high. Furthermore, even with a negative Phadiatop test, IgE-t values were higher in sera of patients with SSAg-IgE ≥ 0.35 kUa/L vis-à-vis < 0.35 kUa/L across all diagnostic categories including controls albeit the difference was statistically significant only for SS. The presence of specific IgE antibodies ≥ 0.35 kUa/L, IgE-t > 122 kU/L or eosinophils > 500/µL had no impact on survival of patients with SS. These results indicate that a pathogenic link may exist between an atopic diathesis and development of SS and possibly pcMZL.

3.
Aesthet Surg J ; 2019 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-31589747

RESUMO

BACKGROUND: More than 700 women have developed an anaplastic large T cell lymphoma (ALCL) surrounding textured surface breast implants, termed breast implant-associated ALCL (BIA-ALCL). Most patients with BIA-ALCL present with an accumulation of fluid (delayed seroma) around the implant. However, benign seromas without malignant cells complicating scar contracture, implant rupture, trauma, infection and other causes are more common. For proper patient management and to avoid unnecessary surgery, it would be desirable to have a simple diagnostic test to identify malignant seromas. OBJECTIVES: To devleop an ancillary test for the diagnosis of malignant seromas and gain insight into the nature of the malignant cells and their microenvironment. METHODS: For this purpose we employed an immunologic assay on only 50 µl of aspirated seroma fluid. The assay measures 13 cytokines simultaneously by flow cytometry. To establish a baseline for clinical studies we measured cytokines secreted by BIA-ALCL and cutaneous ALCL lines. RESULTS: Our study of cell line culture supernatants, and 8 malignant compared to 9 benign seromas indicates that levels of IL-9, IL-10, IL-13, IL-22, and/or IFNγ> 1000 pg/ml distinguish malignant seromas from benign seromas. IL-6, known to be a driver of malignant cells, is also elevated in benign seromas and does not distinguish them from malignant seromas. CONCLUSION: The cytokine assay introduced in this study can be used together with levels of soluble CD30 to identify malignant seromas. Validation of these findings in a larger prospective patient cohort is warranted. The unique pattern of cytokine expression in malignant effusions surrounding breast implants gives further insight into the pathogenesis and cells of origin of BIA-ALCL.

4.
Am J Pathol ; 2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31610171

RESUMO

Breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL) is a CD30-positive, anaplastic lymphoma kinase-negative T-cell lymphoma. Nearly all cases have been associated with textured implants. Most cases are of effusion-limited, indolent disease, with an excellent prognosis after implant and capsule removal. However, capsular invasion and tumor mass have a more aggressive course and a fatal outcome risk. This review summarizes the current knowledge on BIA-ALCL cell of origin and immunologic factors underlying its pathogenesis. Cytokine expression profiling of BIA-ALCL cell lines and clinical specimens reveals a predominantly type 17 helper T-cell (Th17)/Th1 signature, implicating this as its cell of origin. However, a Th2 allergic inflammatory response is suggested by the presence of IL-13, with infiltration of eosinophils and IgE-coated mast cells in clinical specimens of BIA-ALCL. The microenvironment-induced T-cell plasticity, a factor increasingly appreciated, may partially explain these divergent results. Mutations resulting in constitutive Janus kinase (JAK)-STAT activation have been detected and associated with BIA-ALCL pathogenesis in a small number of cases. One possible scenario is that an inflammatory microenvironment stimulates an immune response, followed by polyclonal expansion of Th17/Th1 cell subsets with release of inflammatory cytokines and chemokines and accumulation of seroma. JAK-STAT3 gain-of-function mutations within this pathway and others may subsequently lead to monoclonal T-cell proliferation and clinical BIA-ALCL. Current research suggests that therapies targeting JAK proteins warrant investigation in BIA-ALCL.

5.
J Cutan Pathol ; 46(12): 913-924, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31403211

RESUMO

BACKGROUND: Sézary syndrome (SS) and erythrodermic mycosis fungoides (E-MF) represent two expressions of erythrodermic cutaneous T-cell lymphoma (E-CTCL). METHODS: Histopathologic features were compared on skin specimens from 41 patients with SS and 70 patients with E-MF. Immunopathologic findings were compared on 42 SS and 79 E-MF specimens. RESULTS: Specimens of SS usually showed band-like dermal infiltrates with intermediate-sized lymphoid cells and few plasma cells; on the other hand E-MF more often had a perivascular infiltrative pattern, predominance of small/mixed lymphoid cells and eosinophils. SS also had lower numbers of CD8+ cells and higher numbers of CD62L+ cells compared to E-MF. For E-MF patients, the presence of large Pautrier collections, infiltrates with intermediate-sized cells, increased number of mitotic figures and ≥50% CD62L+ cells in the dermal infiltrate correlated with a relatively poor disease-specific survival. However, only the presence of mitotic figures retained prognostic significance with clinical stage as a covariate. CONCLUSIONS: Clinical stage provides the most important prognostic information for patients with E-CTCL. However, mitotic activity for E-MF and CD8+ cells <20% for SS have additional value. We hypothesize that observed differences in plasma cell and eosinophil numbers may reflect the influence of CD62L+ central memory T-cells in the microenvironment.

7.
Blood ; 134(2): 171-185, 2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31151983

RESUMO

The success of programmed cell death protein 1 (PD-1)/PD-L1-based immunotherapy highlights the critical role played by PD-L1 in cancer progression and reveals an urgent need to develop new approaches to attenuate PD-L1 function by gaining insight into how its expression is controlled. Anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphoma (ALK+ ALCL) expresses a high level of PD-L1 as a result of the constitutive activation of multiple oncogenic signaling pathways downstream of ALK activity, making it an excellent model in which to define the signaling processes responsible for PD-L1 upregulation in tumor cells. Here, using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 library screening, we sought a comprehensive understanding of the molecular effectors required for PD-L1 regulation in ALK+ ALCL. Indeed, we determined that PD-L1 induction is dependent on the nucleophosmin-ALK oncoprotein activation of STAT3, as well as a signalosome containing GRB2/SOS1, which activates the MEK-ERK and PI3K-AKT signaling pathways. These signaling networks, through STAT3 and the GRB2/SOS1, ultimately induce PD-L1 expression through the action of transcription factors IRF4 and BATF3 on the enhancer region of the PD-L1 gene. IRF4 and BATF3 are essential for PD-L1 upregulation, and IRF4 expression is correlated with PD-L1 levels in primary ALK+ ALCL tissues. Targeting this oncogenic signaling pathway in ALK+ ALCL largely inhibited the ability of PD-L1-mediated tumor immune escape when cocultured with PD-1-positive T cells and natural killer cells. Thus, our identification of this previously unrecognized regulatory hub not only accelerates our understanding of the molecular circuitry that drives tumor immune escape but also provides novel opportunities to improve immunotherapeutic intervention strategies.

8.
Blood ; 133(26): 2776-2789, 2019 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-31101622

RESUMO

Anaplastic large cell lymphomas (ALCLs) represent a relatively common group of T-cell non-Hodgkin lymphomas (T-NHLs) that are unified by similar pathologic features but demonstrate marked genetic heterogeneity. ALCLs are broadly classified as being anaplastic lymphoma kinase (ALK)+ or ALK-, based on the presence or absence of ALK rearrangements. Exome sequencing of 62 T-NHLs identified a previously unreported recurrent mutation in the musculin gene, MSC E116K, exclusively in ALK- ALCLs. Additional sequencing for a total of 238 T-NHLs confirmed the specificity of MSC E116K for ALK- ALCL and further demonstrated that 14 of 15 mutated cases (93%) had coexisting DUSP22 rearrangements. Musculin is a basic helix-loop-helix (bHLH) transcription factor that heterodimerizes with other bHLH proteins to regulate lymphocyte development. The E116K mutation localized to the DNA binding domain of musculin and permitted formation of musculin-bHLH heterodimers but prevented their binding to authentic target sequence. Functional analysis showed MSCE116K acted in a dominant-negative fashion, reversing wild-type musculin-induced repression of MYC and cell cycle inhibition. Chromatin immunoprecipitation-sequencing and transcriptome analysis identified the cell cycle regulatory gene E2F2 as a direct transcriptional target of musculin. MSCE116K reversed E2F2-induced cell cycle arrest and promoted expression of the CD30-IRF4-MYC axis, whereas its expression was reciprocally induced by binding of IRF4 to the MSC promoter. Finally, ALCL cells expressing MSC E116K were preferentially targeted by the BET inhibitor JQ1. These findings identify a novel recurrent MSC mutation as a key driver of the CD30-IRF4-MYC axis and cell cycle progression in a unique subset of ALCLs.

9.
Aesthet Surg J ; 39(Supplement_1): S28-S35, 2019 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-30715174

RESUMO

Cytokines, their receptors, and downstream signaling partners, especially JAK1/2 and STAT3, are key biomarkers in lymphoproliferative disorders including systemic anaplastic large cell lymphoma (ALCL). Here we review their role in breast implant-associated anaplastic large cell lymphoma (BIA-ALCL). Early results suggest that, in addition to CD30, IL-9, IL-10, and IL-13 can distinguish malignant from benign seromas. IL-6 is increased in both benign and malignant seromas. IFNγ may identify a subset of BIA-ALCL with a different clinical course. Immunohistochemical detection of nuclear transcription factors-which regulate cytokine signaling-and phosphorylated janus kinases/signal transducers and activators of transcription can inform the identification and malignant potential of CD30+ cells. The innate immune response is the first line of defense against microbes suspected to initiate BIA-ALCL. Innate lymphoid cells are grouped according to the cytokines they produce and could potentially be identified as precursors to BIA-ALCL. Cytokines modulate the tumor microenvironment and hence the pathology of BIA-ALCL such as the influx of eosinophils and capsular fibrosis mediated by IL-13. The plasticity of T cells and innate immune cells theoretically can enable therapeutic manipulations toward a less aggressive phenotype. Cytokine receptors targeted in clinical trials of inflammatory and autoimmune disorders could afford opportunities for immunotherapy of BIA-ALCL.

10.
Aesthet Surg J ; 2019 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-30789639

RESUMO

BACKGROUND: Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is an uncommon type of non-Hodgkin lymphoma occurring in the fluid or capsule adjacent to textured breast implants. Diagnosis of BIA-ALCL of symptomatic patients requires demonstration of large anaplastic cells with uniform expression of CD30 protein on immunohistochemistry. OBJECTIVE: The authors investigated a novel, rapid, office-based, and economic in-situ enzyme-linked immunosorbent assay (ELISA) for screening BIA-ALCL patients. METHODS: A commercially available in-situ ELISA was standardized and validated for patients with confirmed BIA-ALCL diagnosis with clinical isolates. A panel of 9 pathologically confirmed BIA-ALCL patients was screened by serum, plasma, and periprosthetic effusion specimens and compared against serum, plasma, and nonneoplastic delayed seromas in 7 control patients. Statistical analysis demonstrated assay consistency and reliability. RESULTS: All BIA-ALCL effusions demonstrated CD30 ELISA detection at full and all serial concentrations. BIA-ALCL serum specimens and all control specimens were negative at full concentration and serial dilutions (1:100, 1:250, 1:500, and 1:1000). BIA-ALCL plasma specimens were weakly positive at full concentration and revealed no activity with serial dilution. CONCLUSIONS: This is the first study to demonstrate a viable alternative to CD30 immunohistochemistry for the screening of BIA-ALCL. Our study demonstrates 100% sensitivity in seroma fluid with no detectable CD30 in benign seroma samples. A CD30 ELISA represents a novel, low-cost screening test, which may be used to screen suspicious aspirations of delayed periprosthetic fluid collections in an office-based setting.

11.
Hum Pathol ; 78: 54-62, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29689246

RESUMO

More than 500 women worldwide have developed a CD30+ T-cell lymphoma around breast implants, strongly suggesting a cause-and-effect relationship, and designated as breast implant-associated anaplastic large cell lymphoma (BIA-ALCL). The mechanism of lymphomagenesis is unknown. Recently, a bacterial biofilm containing gram-negative bacilli was discovered on the surface of breast implants associated with ALCL. We and others have described overexpression of the proto-oncogene JUNB and mutations of JAK1/2, TP53 and STAT3 in BIA-ALCL. Here we report that BIA-ALCL cell lines and anaplastic lymphoma cells in clinical specimens produce IL-13, the signature cytokine of allergic inflammation. Supporting the link of BIA-ALCL to allergic inflammation, lymphoma cells were often surrounded by eosinophils and mast cells, features typically absent in systemic ALCL. Because of the link of IL-13 to allergy, we looked for IgE and found it decorating the surface of mast cells and antigen-presenting follicular dendritic cells in capsules and lymph nodes infiltrated by anaplastic lymphoma cells, but not uninvolved capsules. Plasma cells within capsules and regional lymph nodes were identified as a possible source of IgE. Together, these findings suggest the hypothesis that an amplified immune response with features of a chronic allergic reaction in a susceptible patient underlies the pathogenesis of BIA-ALCL.

12.
J Invest Dermatol ; 138(8): 1795-1804, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29510190

RESUMO

Cutaneous CD30+ lymphoproliferative disorders (LPDs), including lymphomatoid papulosis (LyP) and primary cutaneous anaplastic large-cell lymphoma, comprise the second most common group of cutaneous T-cell lymphomas. Previously, we reported that special SATB1, a thymocyte-specific chromatin organizer, was overexpressed and promoted malignant T-cell proliferation in a portion of CD30+ LPDs. Here, we investigated the expression pattern of SATB1 in CD30+ LPDs with a large cohort of patient samples, and examined the potential of SATB1 as a molecular marker to classify CD30+ LPDs with differential clinicopathological behaviors. SATB1 expression was identified in the CD30+ anaplastic T cells in 11 of 12 (91.7%) lymphomatoid papulosis and 16 of 42 (38.1%) primary cutaneous anaplastic large-cell lymphoma cases. SATB1+ cases showed T-helper 17 polarization, together with more prominent epidermal hyperplasia and granulocytic infiltration. SATB1+ lesions responded better to combined treatment of methotrexate and interferon. SATB1 activated the expression of T-helper 17 cytokines while repressing T-helper 1-related genes. The heterogeneity in SATB1 expression across CD30+ LPDs was associated with the extent of promoter DNA methylation. Hence, SATB1 expression defines a subtype of CD30+ LPDs with characteristic pathobiology and prognosis. These data provide valuable insights into the heterogeneity of cutaneous T-cell malignancies, which may lead to individualized therapy in the future.

13.
J Invest Dermatol ; 138(5): 1126-1136, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29248547

RESUMO

Primary cutaneous anaplastic T-cell lymphoma, characterized by the CD30+ anaplastic large T cells, comprises the second most common group of cutaneous T-cell lymphoma. Little is known about the mechanisms of disease progression. Here we report that enhancer of zeste homolog 2 (EZH2), the catalytic subunit of polycomb repressive complex 2 that mediates histone H3 lysine 27 trimethylation, is overexpressed in CD30+ anaplastic cells in primary cutaneous anaplastic T-cell lymphoma and large-cell transformed cutaneous T-cell lymphoma. Silencing EZH2 or inhibiting its histone methyltransferase activity conferred increased apoptosis and G1 cell-cycle arrest in primary cutaneous anaplastic T-cell lymphoma cells in vitro and a xenograft model in vivo. This was mediated by the de-repression of thioredoxin-interacting protein, a major redox control molecule, and consequent formation of reactive oxygen species. Silencing thioredoxin-interacting protein abrogated reactive oxygen species accumulation in EZH2 suppressed cells and rescued cell growth disadvantage. Moreover, EZH2 suppression de-repressed C-X-C motif chemokine ligand 10 and facilitated the recruitment of effector CD4+ and CD8+ T cells into the tumor microenvironment via a C-X-C motif chemokine ligand 10/receptor 3 interaction. These results demonstrate a dual role for polycomb repressive complex 2-mediated epigenetic silencing in tumor progression and antitumor immunity in primary cutaneous anaplastic T-cell lymphoma, and provide a rationale for the pharmacologic inhibition of EZH2 activity in large-cell transformed cutaneous T-cell lymphoma.

15.
Am J Hematol ; 92(9): 892-901, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28543380

RESUMO

With the emerging success of treating CD19 expressing B cell malignancies with ex vivo modified, autologous T cells that express CD19-directed chimeric antigen receptors (CAR), there is intense interest in expanding this evolving technology to develop effective modalities to treat other malignancies including solid tumors. Exploiting this approach to develop a therapeutic modality for T cell malignancies for which the available regimens are neither curative, nor confer long term survival we generated a lentivirus-based CAR gene transfer system to target the chemokine receptor CCR4 that is over-expressed in a spectrum of T cell malignancies as well as in CD4+ CD25+ Foxp3+ T regulatory cells that accumulate in the tumor microenvironment constituting a barrier against anti-tumor immunity. Ex vivo modified, donor-derived T cells that expressed CCR4 directed CAR displayed antigen-dependent potent cytotoxicity against patient-derived cell lines representing ATL, CTCL, ALCL and a subset of HDL. Furthermore, these CAR T cells also eradicated leukemia in a mouse xenograft model of ATL illustrating the potential utility of this modality in the treatment of a wide spectrum of T cell malignancies.


Assuntos
Neoplasias Hematológicas , Receptores de Antígenos de Linfócitos T , Receptores CCR4/antagonistas & inibidores , Linfócitos T Reguladores/imunologia , Animais , Linhagem Celular Tumoral , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/patologia , Neoplasias Hematológicas/terapia , Humanos , Leucemia de Células T/genética , Leucemia de Células T/imunologia , Leucemia de Células T/patologia , Leucemia de Células T/terapia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Receptores CCR4/genética , Receptores CCR4/imunologia , Linfócitos T Reguladores/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Oncotarget ; 8(16): 26245-26255, 2017 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-28412739

RESUMO

Peripheral T-cell lymphomas (PTCLs) are aggressive non-Hodgkin lymphomas with generally poor outcomes following standard therapy. Few candidate therapeutic targets have been identified to date. Retinoic acid receptor alpha (RARA) is a transcription factor that modulates cell growth and differentiation in response to retinoids. While retinoids have been used to treat some cutaneous T-cell lymphomas (CTCLs), their mechanism of action and the role of RARA in CTCL and other mature T-cell lymphomas remain poorly understood. After identifying a PTCL with a RARAR394Q mutation, we sought to characterize the role of RARA in T-cell lymphoma cells. Overexpressing wild-type RARA or RARAR394Q significantly increased cell growth in RARAlow cell lines, while RARA knockdown induced G1 arrest and decreased expression of cyclin-dependent kinases CDK2/4/6 in RARAhigh cells. The retinoids, AM80 (tamibarotene) and all-trans retinoic acid, caused dose-dependent growth inhibition, G1 arrest, and CDK2/4/6 down-regulation. Genes down-regulated in transcriptome data were enriched for cell cycle and G1-S transition. Finally, RARA overexpression augmented chemosensitivity to retinoids. In conclusion, RARA drives cyclin-dependent kinase expression, G1-S transition, and cell growth in T-cell lymphoma. Synthetic retinoids inhibit these functions in a dose-dependent fashion and are most effective in cells with high RARA expression, indicating RARA may represent a therapeutic target in some PTCLs.


Assuntos
Ciclo Celular/genética , Resistencia a Medicamentos Antineoplásicos/genética , Linfoma de Células T/genética , Receptor alfa de Ácido Retinoico/genética , Retinoides/farmacologia , Linhagem Celular Tumoral , Quinases Ciclina-Dependentes/genética , Quinases Ciclina-Dependentes/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Linfoma de Células T/metabolismo , Mutação , Proteólise , Interferência de RNA , RNA Interferente Pequeno/genética , Receptor alfa de Ácido Retinoico/metabolismo
17.
Oncoimmunology ; 6(3): e1273310, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28405495

RESUMO

Indoleamine 2,3-deoxygenase 1 (IDO1) induces immune tolerance in the tumor microenvironment (TME) and is recognized as a potential therapeutic target. We studied the expression of both IDO1 and the related tryptophan 2,3-dioxygenase (TDO) in several different subtypes of cutaneous T-cell lymphoma (CTCL), and evaluated the kynurenine (KYN) pathway in the local TME and in patient sera. Specimens from the total of 90 CTCL patients, including mycosis fungoides (MF, n = 37), lymphomatoid papulosis (LyP, n = 36), primary cutaneous anaplastic large cell lymphoma (pcALCL, n = 4), subcutaneous panniculitis-like T-cell lymphoma (SPTCL n = 13), and 10 patients with inflammatory lichen ruber planus (LRP), were analyzed by immunohistochemistry (IHC), immunofluorescence (IF), quantitative PCR, and/or liquid chromatography-tandem mass spectrometry (LC-MS/MS). Three CTCL cell lines also were studied. Expression of both IDO1 and TDO was upregulated in CTCL. In MF specimens and in the MF cell line MyLa2000, IDO1 expression exceeded that of TDO, whereas the opposite was true for LyP, ALCL, and corresponding Mac1/2A cell lines. The spectrum of IDO1-expressing cell types differed among CTCL subtypes and was reflected in the clinical behavior. In MF, SPTCL, and LyP, IDO1 was expressed by malignant cells and by CD33+ myeloid-derived suppressor cells, whereas in SPTCL CD163+ tumor-associated macrophages also expressed IDO1. Significantly elevated serum KYN/Trp ratios were found in patients with advanced stages of MF. Epacadostat, an IDO1 inhibitor, induced a clear decrease in KYN concentration in cell culture. These results show the importance of IDO1/TDO-induced immunosuppression in CTCL and emphasize its role as a new therapeutic target.

18.
Aesthet Surg J ; 37(7): 771-775, 2017 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-28402493

RESUMO

The objective was to analyze and discuss the implications of a nonmalignant CD30+ late seroma. Methods included collection of seroma fluid and peripheral blood from a patient with a late seroma 22 years after initial breast reconstruction. A panel of 24 monoclonal antibodies was used to detect T-cell receptor Vß regions present on ~70% of normal human peripheral blood T lymphocytes. Flow cytometry gated on CD3+ and CD30+ activated T lymphocytes. Cytospins were used to inspect the morphology of the T lymphocytes. Results from the seroma fluid cytology revealed a spectrum of activated T lymphocytes as seen in the blood of patients with immune disorders such as infectious mononucleosis. Cells were judged to be nonmalignant by routine pathology. Flow cytometry revealed >23% of CD3+ T lymphocytes belonged to an expanded T-cell family expressing TCRVß13.2. Most Vß13.2 cells expressed T-cell activation antigen CD30 indicating that CD30 is not restricted to anaplastic large cell lymphoma (ALCL) in seroma fluids. A smaller expanded population of CD30+ T lymphocytes expressing TCRVß 13.2 was detected in the blood. In conclusion, in this index case, an expanded population of CD30+ activated T lymphocytes was detected in seroma fluid surrounding a textured breast implant as well as in peripheral blood, consistent with a local and systemic immune response. The demonstration of an expanded CD30+ T-cell population in a polyclonal background suggests a possible role for bacterial superantigens as a pathogenic factor. These data further suggest that breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) may be the end stage of a CD30+ T-cell lymphoproliferative disorder. LEVEL OF EVIDENCE: 5.


Assuntos
Implante Mamário/efeitos adversos , Implantes de Mama/efeitos adversos , Neoplasias da Mama/cirurgia , Antígeno Ki-1/metabolismo , Linfoma Anaplásico de Células Grandes/diagnóstico , Seroma/patologia , Linfócitos T/metabolismo , Idoso , Biofilmes , Implantes de Mama/microbiologia , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico , Feminino , Citometria de Fluxo , Humanos , Linfoma Anaplásico de Células Grandes/sangue , Linfoma Anaplásico de Células Grandes/etiologia , Seroma/sangue , Seroma/imunologia , Linfócitos T/imunologia , Fatores de Tempo
19.
J Cutan Pathol ; 2017 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-28337783

RESUMO

Chronic lymphedema predisposes to develop malignant cutaneous tumors, including angiosarcoma, Kaposi's sarcoma and B-cell lymphoma. T-cell malignancy has rarely been associated with chronic lymph stasis. Here, we report a case of primary cutaneous anaplastic large cell lymphoma (pcALCL) with lymphatic spread associated with chronic lymphedema. The patient is a 56-year-old man who received orchiectomy and right inguinal lymphadenectomy for malignant seminoma 10 years ago, which led to prominent lymphedema of the right leg. He developed extensive skin nodules on the lymphedematous area for 3 months. Histopathology findings confirmed a diagnosis of pcALCL, which is a subtype of cutaneous T-cell lymphoma characterized by the presence of CD30+ T cells. Intralymphatic infiltration of malignant cells is prominent. The pathogenesis of intralymphatic cutaneous anaplastic large cell lymphoma is largely unknown. Our case suggests that chronic lymphedema resulted in persistent CD4+ T-cell inflammation, which then may contribute to the development of pcALCL.

20.
Proc Natl Acad Sci U S A ; 114(15): 3975-3980, 2017 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-28356514

RESUMO

Activating Janus kinase (JAK) and signal transducer and activator of transcription (STAT) mutations have been discovered in many T-cell malignancies, including anaplastic lymphoma kinase (ALK)- anaplastic large cell lymphomas (ALCLs). However, such mutations occur in a minority of patients. To investigate the clinical application of targeting JAK for ALK- ALCL, we treated ALK- cell lines of various histological origins with JAK inhibitors. Interestingly, most exogenous cytokine-independent cell lines responded to JAK inhibition regardless of JAK mutation status. JAK inhibitor sensitivity correlated with the STAT3 phosphorylation status of tumor cells. Using retroviral shRNA knockdown, we have demonstrated that these JAK inhibitor-sensitive cells are dependent on both JAK1 and STAT3 for survival. JAK1 and STAT3 gain-of-function mutations were found in some, but not all, JAK inhibitor-sensitive cells. Moreover, the mutations alone cannot explain the JAK1/STAT3 dependency, given that wild-type JAK1 or STAT3 was sufficient to promote cell survival in the cells that had either JAK1or STAT3 mutations. To investigate whether other mechanisms were involved, we knocked down upstream receptors GP130 or IL-2Rγ. Knockdown of GP130 or IL-2Rγ induced cell death in selected JAK inhibitor-sensitive cells. High expression levels of cytokines, including IL-6, were demonstrated in cell lines as well as in primary ALK- ALCL tumors. Finally, ruxolitinib, a JAK1/2 inhibitor, was effective in vivo in a xenograft ALK- ALCL model. Our data suggest that cytokine receptor signaling is required for tumor cell survival in diverse forms of ALK- ALCL, even in the presence of JAK1/STAT3 mutations. Therefore, JAK inhibitor therapy might benefit patients with ALK- ALCL who are phosphorylated STAT3.


Assuntos
Janus Quinase 1/genética , Linfoma Anaplásico de Células Grandes/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Receptores de Citocinas/metabolismo , Fator de Transcrição STAT3/genética , Quinase do Linfoma Anaplásico , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular , Receptor gp130 de Citocina/genética , Receptor gp130 de Citocina/metabolismo , Citocinas/genética , Citocinas/metabolismo , Humanos , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 1/metabolismo , Linfoma Anaplásico de Células Grandes/tratamento farmacológico , Linfoma Anaplásico de Células Grandes/genética , Camundongos , Fosforilação , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Receptores Proteína Tirosina Quinases/genética , Receptores de Citocinas/genética , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
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