Asunto(s)
Micosis Fungoide , Parapsoriasis , Receptores de Antígenos de Linfocitos T , Neoplasias Cutáneas , Humanos , Micosis Fungoide/genética , Micosis Fungoide/patología , Micosis Fungoide/inmunología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/inmunología , Parapsoriasis/genética , Parapsoriasis/patología , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/inmunología , Masculino , Femenino , Persona de Mediana Edad , Factores de TiempoRESUMEN
Brentuximab vedotin (BV), a conjugate of anti-CD30 antibody and monomethyl auristatin E, has emerged as a promising treatment option for refractory CD30+ mycosis fungoides (MF) and primary cutaneous anaplastic large-cell lymphoma (pcALCL). BV has been shown to be safe and effective in treating Hodgkin's lymphoma and peripheral T-cell lymphoma. This multicenter, prospective, single-arm phase I/II study evaluated the efficacy of BV in Japanese patients with CD30+ cutaneous lymphomas, namely CD30+ cutaneous T-cell lymphoma. Participants were divided into two groups: those with CD30+ MF or pcALCL (cohort 1, n = 13) and those with CD30+ lymphoproliferative disorders other than those in cohort 1 (cohort 2, n = 3). The studied population included the full analysis set (FAS), modified FAS (mFAS), and safety analysis set (SAF). These sets were identified in cohorts 1 and 1 + 2 and labeled FAS1 and FAS2, mFAS1 and mFAS2, and SAF1 and SAF2, respectively. Each treatment cycle lasted 3 weeks, and BV was continued for up to 16 cycles after the third cycle based on treatment response. The primary endpoint was the 4-month objective response rate (ORR4) determined by the Independent Review Forum (IRF). ORR4 was 69.2% for FAS1 and 62.5% for FAS2 (P < 0.0001). Secondary endpoints of ORR, assessed using the global response score (53.8% in FAS1) and modified severity-weighted assessment tool (62.5% in FAS1), using the IRF, provided results comparable to the primary findings. The incidence of ≥grade 3 adverse events (≥15%) in SAF1 was peripheral neuropathy in three patients (23%) and fever and eosinophilia in two patients (15%). In conclusion, BV showed favorable efficacy, tolerability, and safety profile in Japanese patients with relapsed or refractory CD30+ primary cutaneous T-cell lymphoma. The trial was registered with University Hospital Medical Information Network Clinical Trials Registry, Japan (protocol ID: UMIN000034205).
Asunto(s)
Brentuximab Vedotina , Antígeno Ki-1 , Neoplasias Cutáneas , Humanos , Brentuximab Vedotina/administración & dosificación , Brentuximab Vedotina/uso terapéutico , Masculino , Persona de Mediana Edad , Antígeno Ki-1/inmunología , Antígeno Ki-1/análisis , Femenino , Anciano , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/inmunología , Estudios Prospectivos , Japón , Adulto , Anciano de 80 o más Años , Micosis Fungoide/tratamiento farmacológico , Micosis Fungoide/patología , Micosis Fungoide/inmunología , Linfoma Cutáneo de Células T/tratamiento farmacológico , Linfoma Cutáneo de Células T/patología , Antineoplásicos Inmunológicos/uso terapéutico , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/efectos adversos , Inmunoconjugados/administración & dosificación , Inmunoconjugados/uso terapéutico , Inmunoconjugados/efectos adversos , Resultado del Tratamiento , Pueblos del Este de AsiaAsunto(s)
Progresión de la Enfermedad , Micosis Fungoide , Neoplasias Cutáneas , Humanos , Micosis Fungoide/genética , Micosis Fungoide/patología , Micosis Fungoide/inmunología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/inmunología , Regulación Neoplásica de la Expresión Génica , Masculino , Femenino , Piel/patología , Piel/inmunología , Persona de Mediana Edad , Linfocitos T/inmunologíaRESUMEN
Cutaneous T-cell lymphomas (CTCL) are a diverse group of malignant blood disorders characterized by initial skin infiltration, and sometimes, tumor spreading to lymph nodes, blood, and viscera. Mycosis fungoides is the most common form. Sézary syndrome is a distinctive form of CTCL marked by a significant presence of circulating tumor cells in peripheral blood. These diseases are characterized by the plasticity and heterogeneity of the tumor cells in the different tissue compartments, and a difficulty in identifying these tumor cells for diagnostic purposes and therapeutic monitoring. Progress has been made in the understanding of the pathophysiology of these diseases in recent years, and we provide here a review of these advancements.
Asunto(s)
Linfoma Cutáneo de Células T , Neoplasias Cutáneas , Humanos , Linfoma Cutáneo de Células T/diagnóstico , Linfoma Cutáneo de Células T/patología , Linfoma Cutáneo de Células T/inmunología , Linfoma Cutáneo de Células T/metabolismo , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/diagnóstico , Francia , Síndrome de Sézary/patología , Síndrome de Sézary/diagnóstico , Síndrome de Sézary/inmunología , Micosis Fungoide/diagnóstico , Micosis Fungoide/patología , Micosis Fungoide/inmunología , Derivación y ConsultaAsunto(s)
Eosinofilia , Eosinófilos , Micosis Fungoide , Neoplasias Cutáneas , Humanos , Micosis Fungoide/patología , Micosis Fungoide/diagnóstico , Micosis Fungoide/inmunología , Estudios Retrospectivos , Eosinofilia/inmunología , Eosinofilia/patología , Eosinofilia/diagnóstico , Eosinófilos/inmunología , Eosinófilos/patología , Masculino , Femenino , Persona de Mediana Edad , Pronóstico , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/diagnóstico , Anciano , Adulto , Piel/patología , Piel/inmunología , Anciano de 80 o más AñosRESUMEN
INTRODUCTION: Primary cutaneous T cell lymphomas (CTCL) are a heterogenous group of non-Hodgkin lymphomas derived from skin-homing T cells. These include mycosis fungoides and its leukemic variant Sezary syndrome, as well as the CD30+ lymphoproliferative disorders. AREAS COVERED: In this review, we provide a summary of the current literature on CTCL, with a focus on the immunopathogenesis and treatment of mycosis fungoides and Sezary syndrome. EXPERT OPINION: Recent advances in immunology have provided new insights into the biology of malignant T cells. This in turn has led to the development of new therapies that modulate the immune system to facilitate tumor clearance or target specific aspects of tumor biology.
Asunto(s)
Linfoma Cutáneo de Células T , Síndrome de Sézary , Neoplasias Cutáneas , Humanos , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/terapia , Linfoma Cutáneo de Células T/terapia , Linfoma Cutáneo de Células T/inmunología , Síndrome de Sézary/terapia , Síndrome de Sézary/inmunología , Micosis Fungoide/terapia , Micosis Fungoide/inmunología , Animales , Linfocitos T/inmunología , Inmunoterapia/métodosRESUMEN
ABSTRACT: Sézary syndrome (SS) is an aggressive leukemic expansion of skin-derived malignant CD4+ T cells. Drug monotherapy often results in disease relapse because of the heterogenous nature of malignant CD4+ T cells, but how therapies can be optimally combined remains unclear because of limitations in understanding the disease pathogenesis. We identified immunologic transitions that interlink mycosis fungoides with SS using single-cell transcriptome analysis in parallel with high-throughput T-cell receptor sequencing. Nascent peripheral CD4+ T cells acquired a distinct profile of transcription factors and trafficking receptors that gave rise to antigenically mature Sézary cells. The emergence of malignant CD4+ T cells coincided with the accumulation of dysfunctional monocytes with impaired fragment crystallizable γ-dependent phagocytosis, decreased responsiveness to cytokine stimulation, and limited repertoire of intercellular interactions with Sézary cells. Type I interferon supplementation when combined with a monoclonal antibody targeting the chemokine receptor type 4 (CCR4), unleashed monocyte induced phagocytosis and eradication of Sézary cells in vitro. In turn, coadministration of interferon-α with the US Food and Drug Administration-approved anti-CCR4 antibody, mogamulizumab, in patients with SS induced marked depletion of peripheral malignant CD4+ T cells. Importantly, residual CD4+ T cells after Sézary cell ablation lacked any immunologic shifts. These findings collectively unveil an auxiliary role for augmenting monocytic activity during mogamulizumab therapy in the treatment of SS and underscore the importance of targeted combination therapy in this disease.
Asunto(s)
Anticuerpos Monoclonales Humanizados , Interferón alfa-2 , Monocitos , Micosis Fungoide , Síndrome de Sézary , Síndrome de Sézary/inmunología , Síndrome de Sézary/metabolismo , Síndrome de Sézary/patología , Síndrome de Sézary/terapia , Micosis Fungoide/inmunología , Micosis Fungoide/metabolismo , Micosis Fungoide/patología , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Análisis de Expresión Génica de una Sola Célula , Macrófagos/inmunología , Interferón Tipo I/inmunología , Monocitos/inmunología , Inflamación/inmunología , Inflamación/patología , Interferón alfa-2/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Terapia Combinada , Linfocitos T CD4-Positivos/inmunologíaRESUMEN
ABSTRACT: PCR-based fragment analysis of the T-cell receptor (TCR) gene is used extensively in diagnostic labs to assess clonality in T-cell populations in multiple tissue sites. Of the numerous TCR assays that have been reported, studies assessing use on biopsies suspicious for mycosis fungoides specifically are lacking. We compared clonality findings from a previously run 2-tube/2-fluorochrome dye assay to a redesigned 1-tube/1-fluorochrome dye assay on formalin-fixed skin biopsies. Overall, the accuracy of the 2-tube assay was marginally better (75.7% vs. 71.4%), when using clinical history combined with histologic diagnosis as the gold standard. The 2-tube assay had better sensitivity (73.7% vs. 65.8%), while the 1-tube assay had superior specificity (93.8% vs. 87.5%). Clonality results were easier to interpret with the 1-tube assay. In nearly 19% of cases, a change of assays on the same biopsy resulted in a change of clonality interpretation. For laboratories that change TCR-γ clonality assays, follow-up biopsies for mycosis fungoides assessment may result in a change of diagnosis.
Asunto(s)
Micosis Fungoide , Neoplasias Cutáneas , Micosis Fungoide/genética , Micosis Fungoide/patología , Micosis Fungoide/diagnóstico , Micosis Fungoide/inmunología , Humanos , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/inmunología , Biopsia , Reacción en Cadena de la Polimerasa , Femenino , Masculino , Persona de Mediana Edad , Anciano , Células ClonalesRESUMEN
Flow cytometric identification of circulating neoplastic cells (Sezary cells) in patients with mycosis fungoides and Sezary syndrome is essential for diagnosis, staging, and prognosis. Although recent advances have improved the performance of this laboratory assay, the complex immunophenotype of Sezary cells and overlap with reactive T cells demand a high level of analytic expertise. We utilized machine learning to simplify this analysis using only 2 predefined Sezary cell-gating plots. We studied 114 samples from 59 patients with Sezary syndrome/mycosis fungoides and 66 samples from unique patients with inflammatory dermatoses. A single dimensionality reduction plot highlighted all TCR constant ß chain-restricted (clonal) CD3+/CD4+ T cells detected by expert analysis. On receiver operator curve analysis, an aberrancy scale feature computed by comparison with controls (area under the curve = 0.98) outperformed loss of CD2 (0.76), CD3 (0.83), CD7 (0.77), and CD26 (0.82) in discriminating Sezary cells from reactive CD4+ T cells. Our results closely mirrored those obtained by exhaustive expert analysis for event classification (positive percentage agreement = 100%, negative percentage agreement = 99%) and Sezary cell quantitation (regression slope = 1.003, R squared = 0.9996). We demonstrate the potential of machine learning to simplify the accurate identification of Sezary cells.
Asunto(s)
Citometría de Flujo , Micosis Fungoide , Síndrome de Sézary , Neoplasias Cutáneas , Humanos , Síndrome de Sézary/patología , Síndrome de Sézary/diagnóstico , Síndrome de Sézary/inmunología , Citometría de Flujo/métodos , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/inmunología , Masculino , Micosis Fungoide/patología , Micosis Fungoide/diagnóstico , Micosis Fungoide/inmunología , Femenino , Persona de Mediana Edad , Inmunofenotipificación/métodos , Anciano , Linfocitos T CD4-Positivos/inmunología , Aprendizaje Automático , AdultoRESUMEN
Lichen sclerosus et atrophicus (LSA) is a chronic inflammatory dermatosis of unknown etiology involving the genital and/or extragenital area, showing histopathologically a characteristic homogeneization and sclerosis of the superficial collagen with variably dense lymphoid infiltrates. Intraepidermal lymphocytes may be observed, and in some cases may pose differential diagnostic problems with mycosis fungoides (MF). We studied the histopathologic features of 121 cases of LSA with dense lymphoid infiltrates (genital: 94; male:female: 93:1; age range: 2 to 87 y; median age: 11 y; extragenital: 27; male:female: 0.1:1; age range: 11 to 79 y; median age: 59 y), to better characterize the intraepidermal lymphoid infiltrate and to compare genital with extragenital cases. Epidermotropic lymphocytes mimicking the histopathologic features of MF were present in 93.6% of the genital specimens but none of the extragenital cases. Interestingly, typical features of LSA were mssing in 39.4% of genital LSA, and in a further 25.5% were present only focally. Immunohistochemical analyses showed a predominance of CD8+ T-lymphocytes within the epidermis. Molecular studies of the T-cell receptor genes revealed a monoclonal population of T-lymphocytes in nearly half of the cases. Our study shows that MF-like histopathologic features are extremely common in genital LSA but are never encountered in extragenital cases. A diagnosis of MF in the genital area should be made only upon compelling features, keeping in mind the frequent pseudolymphomatous aspects of LSA.
Asunto(s)
Neoplasias de los Genitales Femeninos/patología , Neoplasias de los Genitales Masculinos/patología , Liquen Escleroso y Atrófico/patología , Micosis Fungoide/patología , Neoplasias Cutáneas/patología , Piel/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biopsia , Niño , Preescolar , Diagnóstico Diferencial , Europa (Continente) , Femenino , Genes Codificadores de los Receptores de Linfocitos T , Neoplasias de los Genitales Femeninos/genética , Neoplasias de los Genitales Femeninos/inmunología , Neoplasias de los Genitales Masculinos/genética , Neoplasias de los Genitales Masculinos/inmunología , Humanos , Liquen Escleroso y Atrófico/genética , Liquen Escleroso y Atrófico/inmunología , Masculino , Persona de Mediana Edad , Micosis Fungoide/genética , Micosis Fungoide/inmunología , Valor Predictivo de las Pruebas , Piel/inmunología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/inmunología , Linfocitos T/inmunología , Adulto JovenRESUMEN
Cutaneous T cell lymphomas (CTCL) are rare but aggressive cancers without effective treatments. While a subset of patients derive benefit from PD-1 blockade, there is a critically unmet need for predictive biomarkers of response. Herein, we perform CODEX multiplexed tissue imaging and RNA sequencing on 70 tumor regions from 14 advanced CTCL patients enrolled in a pembrolizumab clinical trial (NCT02243579). We find no differences in the frequencies of immune or tumor cells between responders and non-responders. Instead, we identify topographical differences between effector PD-1+ CD4+ T cells, tumor cells, and immunosuppressive Tregs, from which we derive a spatial biomarker, termed the SpatialScore, that correlates strongly with pembrolizumab response in CTCL. The SpatialScore coincides with differences in the functional immune state of the tumor microenvironment, T cell function, and tumor cell-specific chemokine recruitment and is validated using a simplified, clinically accessible tissue imaging platform. Collectively, these results provide a paradigm for investigating the spatial balance of effector and suppressive T cell activity and broadly leveraging this biomarker approach to inform the clinical use of immunotherapies.
Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Inmunoterapia/métodos , Linfoma Cutáneo de Células T/terapia , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Neoplasias Cutáneas/terapia , Anciano , Antineoplásicos Inmunológicos/uso terapéutico , Linfocitos T CD4-Positivos/inmunología , Femenino , Humanos , Estimación de Kaplan-Meier , Activación de Linfocitos/inmunología , Linfoma Cutáneo de Células T/inmunología , Linfoma Cutáneo de Células T/metabolismo , Masculino , Persona de Mediana Edad , Micosis Fungoide/inmunología , Micosis Fungoide/metabolismo , Micosis Fungoide/terapia , Receptor de Muerte Celular Programada 1/inmunología , Receptor de Muerte Celular Programada 1/metabolismo , Síndrome de Sézary/inmunología , Síndrome de Sézary/metabolismo , Síndrome de Sézary/terapia , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/metabolismo , Resultado del TratamientoRESUMEN
ABSTRACT: Mycosis fungoides (MF) expresses T-cell markers and the alpha-beta T-cell receptor (TCR) complex. Here, we describe a case of MF with dual expression of TCR delta and TCR beta and a case of MF expressing the B-cell marker CD20. Both anomalies were detected after we instituted a broad-spectrum immunostaining panel for cutaneous T-cell lymphomas. These findings suggest anomalous immunophenotypes may be more common in MF than previously appreciated. Histopathologists should be aware of unexpected malleability in the immunophenotype of MF to avoid confusion with other subtypes of cutaneous lymphoma. Further research into the prevalence and significance of CD20 and TCR-delta expression in MF is encouraged.
Asunto(s)
Biomarcadores de Tumor/inmunología , Linfocitos Intraepiteliales/inmunología , Micosis Fungoide/inmunología , Neoplasias Cutáneas/inmunología , Adulto , Anciano , Antígenos CD20/inmunología , Femenino , Humanos , Inmunofenotipificación , MasculinoRESUMEN
Mycosis fungoides (MF) and Sézary syndrome (SS), the most common types of cutaneous T-cell lymphoma (CTCL), are characterized by proliferation of mature CD4+ T-helper cells. Patients with advanced-stage MF and SS have poor prognosis, with 5-year survival rates of 52%. Although a variety of systemic therapies are currently available, there are no curative options for such patients except for stem cell transplantation, and thus the treatment of advanced MF and SS still remains challenging. Therefore, elucidation of the pathophysiology of MF/SS and development of medical treatments are desired. In this study, we focused on a molecule called OX40. We examined OX40 and OX40L expression and function using clinical samples of MF and SS and CTCL cell lines. OX40 and OX40L were co-expressed on tumor cells of MF and SS. OX40 and OX40L expression was increased and correlated with disease severity markers in MF/SS patients. Anti-OX40 antibody and anti-OX40L antibody suppressed the proliferation of CTCL cell lines both in vitro and in vivo. These results suggest that OX40-OX40L interactions could contribute to the proliferation of MF/SS tumor cells and that the disruption of OX40-OX40L interactions could become a new therapeutic strategy for the treatment of MF/SS.
Asunto(s)
Antígenos de Diferenciación/genética , Linfoma Cutáneo de Células T/tratamiento farmacológico , Micosis Fungoide/tratamiento farmacológico , Ligando OX40/genética , Síndrome de Sézary/tratamiento farmacológico , Anticuerpos Antiidiotipos/inmunología , Anticuerpos Antiidiotipos/farmacología , Antígenos de Diferenciación/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Linfoma Cutáneo de Células T/genética , Linfoma Cutáneo de Células T/inmunología , Linfoma Cutáneo de Células T/patología , Micosis Fungoide/genética , Micosis Fungoide/inmunología , Micosis Fungoide/patología , Ligando OX40/antagonistas & inhibidores , Síndrome de Sézary/genética , Síndrome de Sézary/inmunología , Síndrome de Sézary/patologíaRESUMEN
BACKGROUND: Intravenous TTI-621 (SIRPα-IgG1 Fc) was previously shown to have activity in relapsed or refractory haematological malignancies. This phase 1 study evaluated the safety and activity of TTI-621 in patients with percutaneously accessible relapsed or refractory mycosis fungoides, Sézary syndrome, or solid tumours. Here we report the clinical and translational results among patients with mycosis fungoides or Sézary syndrome. METHODS: This multicentre, open-label, phase 1 study was conducted at five academic health-care and research centres in the USA. Eligible patients were aged 18 years or older; had injectable, histologically or cytologically confirmed relapsed or refractory cutaneous T-cell lymphoma (CTCL) or solid tumours; Eastern Cooperative Oncology Group performance status of 2 or less; and adequate haematological, renal, hepatic, and cardiac function. TTI-621 was injected intralesionally in a sequential dose escalation (cohorts 1-5; single 1 mg, 3 mg, or 10 mg injection or three 10 mg injections weekly for 1 or 2 weeks) and in expansion cohorts (cohorts 6-9; 2 week induction at the maximum tolerated dose; weekly continuation was allowed). In cohort 6, patients were injected with TTI-621 in a single lesion and in cohort 7, they were injected in multiple lesions. In cohort 8, TTI-621 was combined with pembrolizumab 200 mg injections per product labels. In cohort 9, TTI-621 was combined with the standard labelled dose of subcutaneous pegylated interferon alpha-2a 90 µg. The primary endpoint was the incidence and severity of adverse events. The study is registered with ClinicalTrials.gov, NCT02890368, and was closed by the sponsor to focus on intravenous studies with TTI-621. FINDINGS: Between Jan 30, 2017, and March 31, 2020, 66 patients with mycosis fungoides, Sézary syndrome, other CTCL, or solid tumours were screened, 35 of whom with mycosis fungoides or Sézary syndrome were enrolled and received intralesional TTI-621 (escalation, n=13; expansion, n=22). No dose-limiting toxicities occurred; the maximum tolerated dose was not established. In the dose expansion cohorts, the maximally assessed regimen (10 mg thrice weekly for 2 weeks) was used. 25 (71%) patients had treatment-related adverse events; the most common (occurring in ≥10% of patients) were chills (in ten [29%] patients), injection site pain (nine [26%]), and fatigue (eight [23%]). No treatment-related adverse events were grade 3 or more or serious. There were no treatment-related deaths. Rapid responses (median 45 days, IQR 17-66) occurred independently of disease stage or injection frequency. 26 (90%) of 29 evaluable patients had decreased Composite Assessment of Index Lesion Severity (CAILS) scores; ten (34%) had a decrease in CAILS score of 50% or more (CAILS response). CAILS score reductions occurred in adjacent non-injected lesions in eight (80%) of ten patients with paired assessments and in distal non-injected lesions in one additional patient. INTERPRETATION: Intralesional TTI-621 was well tolerated and had activity in adjacent or distal non-injected lesions in patients with relapsed or refractory mycosis fungoides or Sézary syndrome, suggesting it has systemic and locoregional abscopal effects and potential as an immunotherapy for these conditions. FUNDING: Trillium Therapeutics.
Asunto(s)
Antígeno CD47/antagonistas & inhibidores , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inmunoglobulina G/uso terapéutico , Micosis Fungoide/tratamiento farmacológico , Síndrome de Sézary/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Anciano , Antígeno CD47/inmunología , Femenino , Humanos , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inmunoglobulina G/administración & dosificación , Inmunoglobulina G/efectos adversos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Micosis Fungoide/inmunología , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/inmunología , Síndrome de Sézary/inmunología , Neoplasias Cutáneas/inmunologíaRESUMEN
The International Society for Cutaneous Lymphoma (ISCL) proposes a diagnostic algorithm for early mycosis fungoides (MF) that includes clinical, histological, immunophenotypical, and molecular criteria. Here, we analyzed the immunologic markers and features of T-cell clonality in 38 early MF cases and 22 non-MF cases to validate the ISCL algorithm. We found that CD5 and CD7 expression differed significantly between early MF and non-MF cases, with epidermal discordance of CD7 expression more frequently identified in early MF. Notably, increasing the cut-off value for CD7 expression from 10% to 22.5% improved its sensitivity. Furthermore, TCR-γ and ß chain rearrangements were more frequently detected in early MF than in non-MF cases. Based on these findings, we propose CD5 and CD7 deficiency as mandatory immunopathologic criteria and PCR-based testing for TCR-γ and ß chains as required molecular/biologic criteria to improve the efficiency of early MF diagnosis using the ISCL algorithm.
Asunto(s)
Algoritmos , Internacionalidad , Linfoma/patología , Micosis Fungoide/diagnóstico , Sociedades Médicas , Adulto , Antígenos CD/metabolismo , Biomarcadores/metabolismo , Femenino , Reordenamiento Génico de Linfocito T , Humanos , Masculino , Persona de Mediana Edad , Micosis Fungoide/genética , Micosis Fungoide/inmunología , Micosis Fungoide/patología , Curva ROC , Receptores de Antígenos de Linfocitos T/genéticaRESUMEN
Cutaneous T-cell lymphomas (CTCL) represent the majority of primary cutaneous lymphomas (CL). Mycosis fungoides (MF) and cutaneous CD30+ lymphoproliferative disorders account for 80% of all CTCL. CTCL show overlapping histological features. Thus clinical-pathological correlation is of importance to achieve final diagnosis. MF shows a characteristic evolution with patches, plaques, and in a subset of patients (10%-20%) with tumors. Therapy is stage-adapted with skin-directed therapies such as UV-light therapies and corticosteroids in early disease stage (i.e., patch and limited plaque stage) and systemic therapies (retinoids, interferon, mono chemotherapy, targeted therapy) and/or radiation therapy (local or total skin beam electron) in advanced stages. Novel therapies include targeted therapy such as mogamulizumab (anti-CCR4) or brentuximab vedotin (anti-CD30) and histone deacetylase inhibitors. Considering the impact of targeted therapies, biomarkers such as CD30 are not only crucial for the diagnosis and correct classification of an individual lymphoma case, but also for therapy as they may represent therapeutic targets. In the recently revised WHO classification 2017 and the updated WHO-EORTC classification for CL 2018, primary cutaneous CD8+ acral T-cell lymphoma has been introduced as a new still provisional entity. It displays characteristic clinical, histological, and phenotypic features and exhibits an excellent prognosis. Rare, but aggressive CTCL include cutaneous primary cutaneous aggressive epidermotropic CD8-positive T-cell lymphoma and cutaneous gamma/delta T-cell lymphoma, which present with rapid onset of necrotic or ulcerated plaques and tumors. As they have a poor prognosis, treatment includes multiagent chemotherapy and hematopoietic stem cell transplantation.
Asunto(s)
Micosis Fungoide , Neoplasias Cutáneas , Humanos , Micosis Fungoide/diagnóstico , Micosis Fungoide/inmunología , Micosis Fungoide/patología , Micosis Fungoide/terapia , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/terapiaRESUMEN
Mycosis fungoides with large cell transformation (MFLCT) can be difficult to distinguish from primary cutaneous CD30+ T cell lymphoproliferative disorders (PC CD30+ LPD), especially primary cutaneous anaplastic large cell lymphoma (PC-ALCL). This diagnostic distinction is critical for appropriate patient management. GATA3 has been proposed to be useful in the discrimination between these two entities. We identified 25 cases of MFLCT and 24 cases of PC CD30+ LPDs (including lymphomatoid papulosis (n=14), PC-ALCL (n=6), and CD30+ LPD, not otherwise specified (n=4)) diagnosed at our institution from 2002 to 2019. Sections from archived specimens were stained to evaluate for GATA3 expression by immunohistochemistry and compared among cutaneous CD30+ T cell LPDs. The majority of the MFLCT cohort had strong, diffuse expression of GATA3 ranging from 0 to 100% of dermal T cells (mean 53.20%) with 15/25 cases (60%) showing GATA3 expression greater than 50%, while the PC CD30+ LPD group showed variable, moderate GATA3 labeling ranging from 0 to 60% of dermal T cells (mean 23.26%), with 5/6 cases (83%) showing GATA3 expression less than 40% (p =0.003). The calculated sensitivity and specificity were 56% and 74%, while positive and negative predictive values were 70% and 61%, respectively. Based on the percent staining of positive cells, using 50% as a cutoff value for expression, GATA3 might be a useful immunohistochemical marker to discriminate MFLCT from PC CD30+ LPDs, including PC-ALCL.
Asunto(s)
Biomarcadores de Tumor/análisis , Factor de Transcripción GATA3/análisis , Inmunohistoquímica , Antígeno Ki-1/análisis , Linfoma Anaplásico de Células Grandes/química , Papulosis Linfomatoide/metabolismo , Micosis Fungoide/química , Neoplasias Cutáneas/química , Adulto , Anciano , Anciano de 80 o más Años , Diagnóstico Diferencial , Femenino , Humanos , Linfoma Anaplásico de Células Grandes/inmunología , Linfoma Anaplásico de Células Grandes/patología , Papulosis Linfomatoide/inmunología , Papulosis Linfomatoide/patología , Masculino , Persona de Mediana Edad , Micosis Fungoide/inmunología , Micosis Fungoide/patología , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/patología , Adulto JovenRESUMEN
An 88-year-old Inuit man from Northern Canada presented with an extensive skin rash associated with numerous violaceous skin nodules on his palms and lower extremities. Biopsy of a skin nodule revealed Kaposi's sarcoma (KS), a human herpesvirus 8 (HHV8)-associated malignancy, whereas biopsy of the erythematous skin showed an atypical infiltrate of CD4-positive T-cells that, together with TCR gene rearrangement and presence of clonal T-cells in peripheral blood by flow cytometry, was consistent with a T-cell lymphoma, mycosis fungoides (MF) subtype. Serology was negative for HIV and HTLV-I/II and no immunodeficiency syndrome was identified. The patient was successfully treated with an oral retinoid for KS, and with topical hydrocortisone and ultraviolet B (UVB) phototherapy for MF. This case highlights the existence of HHV8-related lesions in native persons of Northern Canada, and also that MF-induced immunosuppression combined with immunosenescence may play a role in the development of non-HIV-related KS.
Asunto(s)
Inuk , Micosis Fungoide/patología , Neoplasias Primarias Múltiples/patología , Sarcoma de Kaposi/patología , Neoplasias Cutáneas/patología , Acitretina/uso terapéutico , Administración Cutánea , Anciano de 80 o más Años , Antiinflamatorios/uso terapéutico , Herpesvirus Humano 8 , Humanos , Hidrocortisona/uso terapéutico , Huésped Inmunocomprometido , Inmunosenescencia , Masculino , Micosis Fungoide/inmunología , Micosis Fungoide/terapia , Neoplasias Primarias Múltiples/inmunología , Neoplasias Primarias Múltiples/terapia , Sarcoma de Kaposi/tratamiento farmacológico , Sarcoma de Kaposi/etnología , Sarcoma de Kaposi/inmunología , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/terapia , Terapia Ultravioleta/métodosRESUMEN
Cancer cells are known to reprogram normal fibroblasts into cancer-associated fibroblasts (CAFs) to act as tumor supporters. The presence and role of CAFs in mycosis fungoides (MF), the most common type of cutaneous T-cell lymphoma, are unknown. This study sought to characterize CAFs in MF and their cross talk with the lymphoma cells using primary fibroblast cultures from punch biopsies of patients with early-stage MF and healthy subjects. MF cultures yielded significantly increased levels of FAPα, a CAF marker, and CAF-associated genes and proteins: CXCL12 (ligand of CXCR4 expressed on MF cells), collagen XI, and matrix metalloproteinase 2. Cultured MF fibroblasts showed greater proliferation than normal fibroblasts in ex vivo experiments. A coculture with MyLa cells (MF cell line) increased normal fibroblast growth, reduced the sensitivity of MyLa cells to doxorubicin, and enhanced their migration. Inhibiting the CXCL12/CXCR4 axis increased doxorubicin-induced apoptosis of MyLa cells and reduced MyLa cell motility. Our data suggest that the fibroblasts in MF lesions are more proliferative than fibroblasts in normal skin and that CAFs protect MF cells from doxorubicin-induced cell death and increase their migration through the secretion of CXCL12. Reversing the CAF-mediated tumor microenvironment in MF may improve the efficiency of anticancer therapy.
Asunto(s)
Fibroblastos Asociados al Cáncer/inmunología , Quimiocina CXCL12/metabolismo , Micosis Fungoide/inmunología , Receptores CXCR4/metabolismo , Neoplasias Cutáneas/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Apoproteínas/efectos de los fármacos , Apoproteínas/inmunología , Biopsia , Fibroblastos Asociados al Cáncer/metabolismo , Estudios de Casos y Controles , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Movimiento Celular/inmunología , Transformación Celular Neoplásica/inmunología , Células Cultivadas , Quimiocina CXCL12/antagonistas & inhibidores , Técnicas de Cocultivo , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Resistencia a Antineoplásicos/inmunología , Femenino , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Micosis Fungoide/tratamiento farmacológico , Micosis Fungoide/patología , Cultivo Primario de Células , Receptores CXCR4/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Piel/citología , Piel/patología , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología , Adulto JovenRESUMEN
SATB1 is an important T-cell specific chromatin organizer in cutaneous T-cell lymphoma, whereas its expression and function in mycosis fungoides (MF) remain ambiguous. Our study aimed to investigate the clinicopathological significance of SATB1 in a cohort of 170 patients with MF. SATB1 expression was heterogeneous among the patients with MF in each clinical stage. High SATB1 expression was associated with epidermal hyperplasia, eosinophil infiltration, less large-cell transformation, and favorable prognosis in MF cases. SATB1 and CD30 coexpression distinguished cutaneous CD30+ lymphoproliferative disorders from MF large-cell transformation. SATB1 silencing in MF lines showed that SATB1 upregulated the genes involved in eosinophil recruitment, including signal transducer and activator of transcription 3 and IL13, and downregulated the genes in cell-cycle progression, which may explain the inferior prognosis for low SATB1-expressing cases. Moreover, SATB1 was inversely correlated with PD-1 expression, indicating an exhausted status of SATB1-negative malignant T cells. SATB1 was positively correlated with toll-like receptors expression, suggesting innate immune activation in high SATB1-expressing MF cases. Therefore, variable SATB1 expression promotes heterogeneity in pathology and clinical outcome of patients with MF.