RESUMO
Mycosis fungoides (MF) represents the most common type of primary cutaneous T-cell lymphoma. Recognition of MF variants with divergent immunophenotypes is important for accurate diagnosis and appropriate management, as they can be confused with other lymphoma subtypes. We present a case of a 49-year-old male previously diagnosed with a cutaneous lymphoproliferative disorder with an unusual NK/T-cell phenotype. He presented with a 10-year history of pelvic girdle rash involving the right hip and upper thigh. The lesions were characterized as atrophic patches concentrated in sun-protected areas and involving 10% of the body surface area. Shave biopsies revealed an atypical epidermotropic infiltrate composed of hyperchromatic small to medium-sized lymphocytes with perinuclear halos and "tagging" along the dermal-epidermal junction. The immunophenotype was unusual in that the neoplastic lymphocytes showed complete loss of pan T-cell antigens along with expression of CD56, cytotoxic markers, and weak CD20. All other B-cell markers were negative. The combination of clinical findings, in addition to the histopathologic and immunophenotypic profile, were diagnostic of null T-cell phenotype MF with aberrant expression of CD56 and CD20. Null T-cell phenotype MF is very uncommon, can be diagnostically challenging, and can mislead the diagnosis of aggressive lymphoma subtypes.
Assuntos
Antígenos CD20 , Antígeno CD56 , Micose Fungoide , Neoplasias Cutâneas , Humanos , Micose Fungoide/patologia , Micose Fungoide/diagnóstico , Micose Fungoide/metabolismo , Masculino , Pessoa de Meia-Idade , Antígeno CD56/metabolismo , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/metabolismo , Antígenos CD20/metabolismo , Imunofenotipagem/métodos , Fenótipo , Linfócitos T/patologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Diagnóstico Diferencial , Biomarcadores Tumorais/metabolismoRESUMO
The oncogene PIM2 is upregulated in several malignancies but has never been investigated in mycosis fungoides (MF), the most common type of cutaneous T-cell lymphoma (CTCL). PIM2 is a well-known oncogene and is regulated by cell signaling pathways like the JAK/STAT- and NF-kB-pathway, key regulators in the pathogenesis of CTCL. The aim of this study was to examine the role of PIM2 in MF. PIM2 gene expression was measured in 81 formalin-fixed paraffin-embedded skin biopsies from patients with MF and 46 control biopsies from healthy skin (HS) and benign inflammatory skin disease (BID). Validation of PIM2 protein expression was performed on selected biopsies with immunohistochemical staining. We found a significant difference in gene expression levels between both early stage MF and HS (p < 0.0001), and BID (p < 0.0001). In addition, the PIM2 gene expression was higher in advanced-stage MF compared to early stage disease (p = 0.0001). No significant difference in gene expression levels was found between patients with and without disease progression. In conclusion, we found PIM2 expression is significantly increased in MF compared to controls, and in advanced-stage MF compared to early stage MF. These findings could potentially have diagnostic value in discriminating early stage MF from BID.
Assuntos
Micose Fungoide , Proteínas Serina-Treonina Quinases , Proteínas Proto-Oncogênicas , Humanos , Micose Fungoide/genética , Micose Fungoide/patologia , Micose Fungoide/metabolismo , Masculino , Feminino , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Pessoa de Meia-Idade , Adulto , Idoso , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Imuno-Histoquímica , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Idoso de 80 Anos ou mais , Biópsia , Pele/patologia , Pele/metabolismo , Adulto JovemRESUMO
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.
Assuntos
Anticorpos Monoclonais Humanizados , Interferon alfa-2 , Monócitos , Micose Fungoide , Síndrome de Sézary , Síndrome de Sézary/imunologia , Síndrome de Sézary/metabolismo , Síndrome de Sézary/patologia , Síndrome de Sézary/terapia , Micose Fungoide/imunologia , Micose Fungoide/metabolismo , Micose Fungoide/patologia , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Análise da Expressão Gênica de Célula Única , Macrófagos/imunologia , Interferon Tipo I/imunologia , Monócitos/imunologia , Inflamação/imunologia , Inflamação/patologia , Interferon alfa-2/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Terapia Combinada , Linfócitos T CD4-Positivos/imunologiaRESUMO
BACKGROUND: Mycosis fungoides (MF) is a chronic, highly recurrent cutaneous T-cell lymphoma, whose pathogenesis has not yet been fully elucidated. Interleukin-15 was previously highlighted as a viability factor for cutaneous T-cell lymphoma with previous studies shedding light on its role in pathogenesis of MF and its plausibility as a potential therapeutic target. OBJECTIVE: This study was conducted to evaluate serum and tissue expression of IL-15 and IL-15Rα in early cases of MF (IA, IB, IIA) at baseline and following phototherapy. MATERIALS AND METHODS: Fourteen early MF cases were recruited. Samples were withdrawn prior to starting phototherapy treatment and following near complete clearance of the biopsied lesion or after a maximum of 36 sessions of phototherapy. Samples were assessed for change in expression of IL-15 and IL-15 Rα levels following treatment, whose levels were compared to healthy controls. RESULTS: Serum and tissue levels of IL-15 and IL-15Rα in early MF cases were significantly higher at baseline than their levels following phototherapy treatment and higher than healthy controls. However, they dropped significantly following treatment with no statistical difference between treated cases and controls, apart from serum IL-15Rα that remained significantly elevated than controls. CONCLUSION: Interleukin-15 and its receptor alpha appear to contribute to the pathogenesis of MF, being significantly elevated than healthy controls, which were normalized following phototherapy treatment, apart from serum IL-15Rα, which remained elevated. Controlling IL-15/IL-15Rα expression is a newly proposed mechanism of action of phototherapy in MF.
Assuntos
Linfoma Cutâneo de Células T , Micose Fungoide , Neoplasias Cutâneas , Humanos , Interleucina-15 , Estudos de Coortes , Neoplasias Cutâneas/patologia , Subunidade alfa de Receptor de Interleucina-15 , Micose Fungoide/radioterapia , Micose Fungoide/metabolismo , Fototerapia , Linfoma Cutâneo de Células T/patologiaRESUMO
Background: Discriminating between cutaneous anaplastic large cell lymphoma (cALCL) and CD30-positive transformed mycosis fungoides (CD30+ TMF) is challenging, particularly when they arise in the context of pre-existing mycosis fungoides. The development of molecular diagnostic tools was hampered by the rarity of both diseases and the limited understanding of their pathogenesis. Methods: In this study, we established a cohort comprising 25 cALCL cases and 25 CD30+ TMF cases, with transcriptomic data obtained from 31 samples. We compared the clinicopathological information and investigated the gene expression profiling between these two entities. Furthermore, we developed an immunohistochemistry (IHC) algorithm to differentiate these two entities clinically. Results: Our investigation revealed distinct clinicopathological features and unique gene expression programs associated with cALCL and CD30+ TMF. cALCL and CD30+ TMF displayed marked differences in gene expression patterns. Notably, CD30+ TMF demonstrated enrichment of T cell receptor signaling pathways and an exhausted T cell phenotype, accompanied by infiltration of B cells, dendritic cells, and neurons. In contrast, cALCL cells expressed high levels of HLA class II genes, polarized towards a Th17 phenotype, and exhibited neutrophil infiltration. An IHC algorithm with BATF3 and TCF7 staining emerged as potential diagnostic markers for identifying these two entities. Conclusions: Our findings provide valuable insights into the differential molecular signatures associated with cALCL and CD30+ TMF, which contribute to their distinct clinicopathological behaviors. An appropriate IHC algorithm could be used as a potential diagnostic tool.
Assuntos
Linfoma Anaplásico de Células Grandes , Micose Fungoide , Neoplasias Cutâneas , Humanos , Linfoma Anaplásico de Células Grandes/diagnóstico , Linfoma Anaplásico de Células Grandes/genética , Linfoma Anaplásico de Células Grandes/metabolismo , Antígeno Ki-1/genética , Antígeno Ki-1/metabolismo , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Micose Fungoide/diagnóstico , Micose Fungoide/genética , Micose Fungoide/metabolismo , Perfilação da Expressão GênicaRESUMO
BACKGROUND: European studies suggest an association between cutavirus (CuV) and cutaneous T-cell lymphoma (CTCL); however, the worldwide prevalence of CuV in patients with CTCL and its prognostic impact remain unknown. METHODS: We investigated the prevalence and viral loads of CuV DNA using biopsy specimens from the lesional skins of 141 Japanese patients with cutaneous malignancies, including 55 patients with various types of CTCL. RESULTS: CuV DNA was detected significantly more frequently in biopsies from patients with mycosis fungoides (MF) (38% [13/34]; the most common subtype of CTCL) than in those from patients with other cutaneous malignancies (6% [6/107]; P<0.001). The viral-load range in patients with CuV DNA-positive MF was 23-3922 copies/103 cells and 8-65 copies/µg of DNA. A phylogenetic analysis using the partial sequences of the CuV viral capsid protein 1 (VP1)/VP2 genes revealed that the CuV sequences identified here were clustered in a Japanese-specific clade distinct from that comprising CuV sequences from European patients with MF. Kaplan-Meier curves and a log-rank test showed that CuV positivity was associated with a shorter disease-specific survival in patients with MF (P = 0.031), whereas no significant difference in overall survival was observed (P = 0.275). No significant correlation was observed between CuV DNA load and survival in patients with CuV-positive MF. CONCLUSIONS: Our results suggest that CuV is associated with MF in a subset of Japanese patients. Large-scale prospective studies are warranted to clarify the role of CuV status, especially regarding the viral genotype, on adverse outcomes in patients with CuV-positive MF.
Assuntos
Linfoma Cutâneo de Células T , Micose Fungoide , Neoplasias Cutâneas , Humanos , Filogenia , Linfoma Cutâneo de Células T/genética , Linfoma Cutâneo de Células T/patologia , Micose Fungoide/genética , Micose Fungoide/metabolismo , Micose Fungoide/patologia , PrognósticoRESUMO
BACKGROUND: Mycosis Fungoides (MF) is a common cutaneous T-cell lymphoma. It can sometimes be challenging to diagnose MF using current clinico-histopathological criteria. Non-invasive molecular profiling analysis has the potential to aid the diagnosis and understanding of MF. METHOD: Lesional and body site matched normal stratum corneum samples were obtained from the same MF patients (n = 28) using adhesive discs, followed by proteomic analyses using data-independent acquisition mass spectrometry (DIA-MS). Differential abundance analyses and bioinformatic analyses were performed to identify differentially abundant proteins and altered biofunctions between the MF and normal stratum corneum samples. RESULTS: In total, 1303 proteins were identified, of which 290 proteins were significantly changed in the MF cohort compared to the normal stratum corneum. Ingenuity pathway analysis (IPA) predicted the significant inhibition of cell death of cancer cells and significant activation of immune-related activities and viral infection in the MF lesions. MF lesions were also associated with upstream regulators relating to immuno-oncologic dysfunctions. The top-250 variating proteins efficiently separated normal stratum corneum from matched MF samples. CONCLUSION: Non-invasive proteomic analysis could transform the diagnosis of MF by reducing the need for invasive biopsy. The identification of altered biological functions may serve as useful biomarkers to predict MF progression.
Assuntos
Linfoma Cutâneo de Células T , Micose Fungoide , Neoplasias Cutâneas , Humanos , Proteômica , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Micose Fungoide/diagnóstico , Micose Fungoide/metabolismo , Micose Fungoide/patologia , Epiderme/metabolismo , Linfoma Cutâneo de Células T/diagnóstico , Linfoma Cutâneo de Células T/metabolismo , Linfoma Cutâneo de Células T/patologiaRESUMO
BACKGROUND: Mycosis fungoides (MF) is considered the commonest type of cutaneous T-cell lymphoma representing about 50% of all primary cutaneous lymphomas. Differentiation between MF and another inflammatory dermatitis (BIDs) is important to ensure proper management. AIM: We aimed to evaluate the immunohistochemical expression of T OX, ICOS, and GATA binding protein 3 (GATA-3) in early stages MF (stage IA and IB) to establish their diagnostic value and to guide the use of inhibitors in the treatment of cutaneous T-cell lymphomas. MATERIALS AND METHODS: A retrospective study of 75 skin paraffin blocks (punch biopsy) 40 cases of MF and 35 cases of eczematous dermatitis as a group representing other inflammatory dermatitis were retrieved from archives of the pathology department of our University, during the period from October 2017 to May 2021. RESULTS: About 98% and 90% of patients in the MF group had positive T OX and ICOS, while 70% of them had positive GATA-3. High expression of T OX, ICOS, and GATA-3 was associated with higher stages. CONCLUSIONS: T OX is considered a diagnostic marker for early MF. The importance of identifying novel markers in MF expressed by immunohistochemistry, such as ICOS, has been established. According to our results, GATA-3 could be used as an accessory marker in the diagnosis of MF when combined with T OX and ICOS in a panel.
Assuntos
Dermatite , Linfoma Cutâneo de Células T , Micose Fungoide , Neoplasias Cutâneas , Humanos , Estudos Retrospectivos , Neoplasias Cutâneas/patologia , Micose Fungoide/diagnóstico , Micose Fungoide/metabolismo , Micose Fungoide/patologia , Linfoma Cutâneo de Células T/diagnóstico , Linfoma Cutâneo de Células T/patologia , Proteína Coestimuladora de Linfócitos T InduzíveisRESUMO
OBJECTIVE: Mycosis fungoides (MF) is the most common type of cutaneous lymphoma. The early stage of MF is a difficult diagnostic case, as it is often confused with many benign inflammatory dermatoses (BID). The study aimed to evaluate the diagnostic utility of TOX, FOXP3, CDD4 and GATA3 in differentiating early stages of MF from histologically overlapping BID lesions. MATERIAL AND METHOD: A retrospective cross-sectional study was performed, in which immunohistochemistry (IHC) was used to evaluate the expression of TOX, FOXP3, CD4 and GATA3 in formalin-fixed paraffin-embedded (FFPE) sections of skin lesions from 30 cases with BID and 30 patients with early-stage MF. RESULTS: The association between TOX expression and early-stage MF was statistically significant (P < 0.001). TOX had the highest sensitivity of 96.77% and accuracy of 85.71% in diagnosis of MF; followed by CD4 with sensitivity of 85.71% and accuracy of 78.95%; and then, GATA3 with sensitivity of 76.7% and finally FOXP3 with sensitivity of 70.0%. CONCLUSION: TOX is suggested to be of higher diagnostic value in the early stages of MF than the conventionally used CD4 and other markers examined.
Assuntos
Micose Fungoide , Neoplasias Cutâneas , Humanos , Estudos Retrospectivos , Estudos Transversais , Micose Fungoide/diagnóstico , Micose Fungoide/metabolismo , Micose Fungoide/patologia , Neoplasias Cutâneas/patologia , Fatores de Transcrição Forkhead , Fator de Transcrição GATA3RESUMO
BACKGROUND: The mechanisms involved in mycosis fungoides, and Sezary Syndrome progression are largely unknown. Over the last decade the interest in immune system contrast of neoplasm has grown owing to the introduction of immunotherapy. PD-1 and its ligand (PD-L1) are the target of several immunotherapy treatment. In the literature reports on the expression of PD-1 and PD-L1 have provided contrasting results. METHODS: In our analysis we investigated PD-1 expression in neoplastic cells and in tumor infiltrating lymphocytes (TILs) as well as PD-L1 expression in tumor cells and in tumor associated macrophages (TAMs). PD-L1 and PD-1 positive cells were counted in 5 high-power fields (HPF) and scored as the average number of positive neoplastic cells/TILs/TAMs per HPF. RESULTS: From databases of two institutions (Bologna and Florence) thirty-five patients corresponding to 43 biopsies were retrieved. In seven instances sequential biopsies were present. No statistically significant expression was observed comparing early to advanced stages by analysing PD-1 by tumor cells and TILs and of PD-L1 by tumor cells and TAMs. CONCLUSIONS: Our results corroborate that PD-1 and PD-L1 expression is not stage-dependent in mycosis fungoides and Sezary syndrome. However, PD-1 and PD-L1 expression in affected patients provides a rationale to schedule anti PD-1/PD-L1 drugs.
Assuntos
Antígeno B7-H1 , Micose Fungoide , Receptor de Morte Celular Programada 1 , Síndrome de Sézary , Neoplasias Cutâneas , Antígeno B7-H1/genética , Humanos , Linfócitos do Interstício Tumoral , Micose Fungoide/metabolismo , Receptor de Morte Celular Programada 1/genética , Síndrome de Sézary/metabolismo , Neoplasias Cutâneas/metabolismoRESUMO
Mycosis fungoides (MF) is the most common subtype of cutaneous T-cell lymphoma. Early-stage disease is characterized by superficial infiltrates of small- to medium-sized atypical epidermotropic T lymphocytes that are clonal related. Nevertheless, the percentage of atypical T cells is low with many admixed reactive immune cells. Despite earlier studies, the composition and spatial characteristics of the cutaneous lymphocytic infiltrate has been incompletely characterized. Here, we applied mass cytometry to profile the immune system in skin biopsies of patients with early-stage MF and in normal skin from healthy individuals. Single-cell suspensions were prepared and labeled with a 43-antibody panel, and data were acquired on a Helios mass cytometer. Unbiased hierarchical clustering of the data identified the major immune lineages and heterogeneity therein. This revealed patient-unique cell clusters in both the CD4+ and myeloid cell compartments but also phenotypically distinct cell clusters that were shared by most patients. To characterize the immune compartment in the tissue context, we developed a 36-antibody panel and performed imaging mass cytometry on MF skin tissue. This visualized the structure of MF skin and the distribution of CD4+ T cells, regulatory T cells, CD8+ T cells, malignant T cells, and various myeloid cell subsets. We observed clusters of CD4+ T cells and multiple types of dendritic cells (DCs) identified through differential expression of CD11c, CD1a, and CD1c in the dermis. These results indicated substantial heterogeneity in the composition of the local immune infiltrate but suggest a prominent role for clustered CD4-DC interactions in disease pathogenesis. Probably, the local inhibition of such interactions may constitute an efficient treatment modality.
Assuntos
Linfoma Cutâneo de Células T , Micose Fungoide , Neoplasias Cutâneas , Linfócitos T CD8-Positivos/metabolismo , Humanos , Linfoma Cutâneo de Células T/patologia , Micose Fungoide/metabolismo , Pele/patologia , Neoplasias Cutâneas/patologiaAssuntos
Brentuximab Vedotin/uso terapêutico , Antígeno Ki-1/metabolismo , Micose Fungoide/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Antineoplásicos Imunológicos/uso terapêutico , Humanos , Imuno-Histoquímica , Antígeno Ki-1/genética , Micose Fungoide/metabolismo , Micose Fungoide/patologia , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologiaRESUMO
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.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Imunoterapia/métodos , Linfoma Cutâneo de Células T/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Cutâneas/terapia , Idoso , Antineoplásicos Imunológicos/uso terapêutico , Linfócitos T CD4-Positivos/imunologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Ativação Linfocitária/imunologia , Linfoma Cutâneo de Células T/imunologia , Linfoma Cutâneo de Células T/metabolismo , Masculino , Pessoa de Meia-Idade , Micose Fungoide/imunologia , Micose Fungoide/metabolismo , Micose Fungoide/terapia , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Síndrome de Sézary/imunologia , Síndrome de Sézary/metabolismo , Síndrome de Sézary/terapia , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/metabolismo , Resultado do TratamentoRESUMO
CD147, a transmembrane glycoprotein that belongs to the immunoglobulin superfamily, and cyclophilin A (CypA), one of the binding partners of CD147, are overexpressed in tumor cells and associated with the progression of several malignancies, including both solid and hematological malignancies. However, CD147 and CypA involvement in cutaneous T-cell lymphoma (CTCL) has not been reported. In this study, we examined CD147 and CypA expression and function using clinical samples of mycosis fungoides (MF) and Sézary syndrome (SS) and CTCL cell lines. CD147 and CypA were overexpressed by tumor cells of MF/SS, and CypA was also expressed by epidermal keratinocytes in MF/SS lesional skin. Serum CypA levels were increased and correlated with disease severity markers in MF/SS patients. Anti-CD147 antibody and/or anti-CypA antibody suppressed the proliferation of CTCL cell lines, both in vitro and in vivo, via downregulation of phosphorylated extracellular-regulated kinase 1/2 and Akt. These results suggest that CD147-CypA interactions can contribute to the proliferation of MF/SS tumor cells in both a autocrine and paracrine manner, and that the disruption of CD147-CypA interactions could be a new therapeutic strategy for the treatment of MF/SS.
Assuntos
Basigina/metabolismo , Proliferação de Células , Ciclofilina A/metabolismo , Linfoma Cutâneo de Células T/patologia , Micose Fungoide/patologia , Síndrome de Sézary/patologia , Neoplasias Cutâneas/patologia , Basigina/genética , Estudos de Casos e Controles , Ciclofilina A/genética , Feminino , Humanos , Linfoma Cutâneo de Células T/genética , Linfoma Cutâneo de Células T/metabolismo , Masculino , Pessoa de Meia-Idade , Micose Fungoide/genética , Micose Fungoide/metabolismo , Índice de Gravidade de Doença , Síndrome de Sézary/genética , Síndrome de Sézary/metabolismo , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismoRESUMO
Mycosis fungoides (MF) is the most prevalent type of skin lymphoma. In its early stages, it has a favorable prognosis. However, in its late stages, it is associated with an increased risk of mortality. This systematic review aimed to identify the transcriptomic changes involved in MF pathogenesis and progression. A literature search was conducted using the database PubMed, followed by the extraction of 2245 genes which were further filtered to 150 recurrent genes that appeared in two or more publications. Categorization of these genes identified activated pathways involved in pathways such as cell cycle and proliferation, chromosomal instability, and DNA repair. We identified 15 genes implicated in MF progression, which were involved in cell proliferation, immune checkpoints, resistance to apoptosis, and immune response. In highlighting the discrepancies in the way MF transcriptomic data is obtained, further research can focus on not only unifying their approach but also focus on the 150 pertinent genes identified in this review.
Assuntos
Apoptose/genética , Instabilidade Cromossômica/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Micose Fungoide/genética , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Instabilidade Cromossômica/efeitos dos fármacos , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Micose Fungoide/tratamento farmacológico , Micose Fungoide/metabolismo , Fatores de RiscoRESUMO
Mycosis fungoides (MF) is the most common primary cutaneous T-cell lymphoma. While initially restricted to the skin, malignant cells can appear in blood, bone marrow and secondary lymphoid organs in later disease stages. However, only little is known about phenotypic and functional properties of malignant T cells in relationship to tissue environments over the course of disease progression. We thus profiled the tumor micromilieu in skin, blood and lymph node in a patient with advanced MF using single-cell RNA sequencing combined with V-D-J T-cell receptor sequencing. In skin, we identified clonally expanded T-cells with characteristic features of tissue-resident memory T-cells (TRM, CD69+CD27-NR4A1+RGS1+AHR+ ). In blood and lymph node, the malignant clones displayed a transcriptional program reminiscent of a more central memory-like phenotype (KLF2+TCF7+S1PR1+SELL+CCR7+ ), while retaining tissue-homing receptors (CLA, CCR10). The skin tumor microenvironment contained potentially tumor-permissive myeloid cells producing regulatory (IDO1) and Th2-associated mediators (CCL13, CCL17, CCL22). Given their expression of PVR, TNFRSF14 and CD80/CD86, they might be under direct control by TIGIT+CTLA4+CSF2+TNFSF14+ tumor cells. In sum, this study highlights the adaptive phenotypic and functional plasticity of MF tumor cell clones. Thus, the TRM-like phenotype enables long-term skin residence of MF cells. Their switch to a TCM-like phenotype with persistent skin homing molecule expression in the circulation might explain the multi-focal nature of MF.
Assuntos
Micose Fungoide/patologia , Células-Tronco Neoplásicas/patologia , Neoplasias Cutâneas/patologia , Linfócitos T/patologia , Idoso , Antígenos CD/biossíntese , Antígenos CD/genética , Antígenos de Neoplasias/biossíntese , Antígenos de Neoplasias/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Memória Imunológica , Linfonodos/metabolismo , Micose Fungoide/genética , Micose Fungoide/metabolismo , Células-Tronco Neoplásicas/química , Análise de Sequência de RNA , Pele/citologia , Pele/imunologia , Linfócitos T/química , Microambiente TumoralAssuntos
Dermatite/patologia , Erupções Liquenoides/diagnóstico , Doenças Linfáticas/patologia , Transtornos da Pigmentação/patologia , Pseudolinfoma/diagnóstico , Púrpura/patologia , Adulto , Antígenos CD7/metabolismo , Biópsia/métodos , Dermoscopia/métodos , Diagnóstico Diferencial , Feminino , Hemossiderina/metabolismo , Humanos , Imuno-Histoquímica/métodos , Erupções Liquenoides/patologia , Micose Fungoide/diagnóstico , Micose Fungoide/metabolismo , Patologia Clínica , Linfócitos T/metabolismoRESUMO
BACKGROUND: Mycosis fungoides (MF) is a primary cutaneous T-cell lymphoma (CTCL) that transforms from mature, skin-homing T cells and progresses during the early stages in the skin. The role of the skin microenvironment in MF development is unclear, but recent findings in a variety of cancers have highlighted the role of stromal fibroblasts in promoting or inhibiting tumorigenesis. Stromal fibroblasts are an important part of the cutaneous tumor microenvironment (TME) in MF. Here we describe studies into the interaction of TME-fibroblasts and malignant T cells to gain insight into their role in CTCL. METHODS: Skin from normal (n = 3) and MF patients (n = 3) were analyzed for FAPα by immunohistochemistry. MyLa is a CTCL cell line that retains expression of biomarkers TWIST1 and TOX that are frequently detected in CTCL patients. MyLa cells were cultured in the presence or absence of normal or MF skin derived fibroblasts for 5 days, trypsinized to detached MyL a cells, and gene expression analyzed by RT-PCR for MF biomarkers (TWIST1 and TOX), Th1 markers (IFNG, TBX21), Th2 markers (GATA3, IL16), and proliferation marker (MKI67). Purified fibroblasts were assayed for VIM and ACTA2 gene expression. Cellular senescence assay was performed to assess senescence. RESULTS: MF skin fibroblast showed increased expression of FAP-α with increasing stage compared to normal. Normal fibroblasts co-cultured with MyLa cells suppressed expression of TWIST1 (p < 0.0006), and TOX (p < 0.03), GATA3 (p < 0.02) and IL16 (p < 0.03), and increased expression of IFNG (p < 0.03) and TBX21 (p < 0.03) in MyLa cells. In contrast, MyLa cells cultured with MF fibroblasts retained high expression of TWIST1, TOX and GATA3. MF fibroblasts co-culture with MyLa cells increased expression of IL16 (p < 0.01) and IL4 (p < 0.02), and suppressed IFNG and TBX21 in MyLa cells. Furthermore, expression of MKI67 in MyLa cells was suppressed by normal fibroblasts compared to MF fibroblasts. CONCLUSION: Skin fibroblasts represent important components of the TME in MF. In co-culture model, normal and MF fibroblasts have differential influence on T-cell phenotype in modulating expression of Th1 cytokine and CTCL biomarker genes to reveal distinct roles with implications in MF progression.
Assuntos
Fibroblastos Associados a Câncer/metabolismo , Proteínas de Grupo de Alta Mobilidade/metabolismo , Linfoma Cutâneo de Células T/metabolismo , Proteínas Nucleares/metabolismo , Neoplasias Cutâneas/metabolismo , Microambiente Tumoral , Proteína 1 Relacionada a Twist/metabolismo , Actinas/genética , Actinas/metabolismo , Idoso , Fibroblastos Associados a Câncer/patologia , Linhagem Celular Tumoral , Senescência Celular , Técnicas de Cocultura , Endopeptidases/genética , Endopeptidases/metabolismo , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Fator de Transcrição GATA3/genética , Fator de Transcrição GATA3/metabolismo , Expressão Gênica , Proteínas de Grupo de Alta Mobilidade/genética , Humanos , Interferon gama/genética , Interferon gama/metabolismo , Interleucina-16/genética , Interleucina-16/metabolismo , Antígeno Ki-67/genética , Antígeno Ki-67/metabolismo , Linfoma Cutâneo de Células T/genética , Linfoma Cutâneo de Células T/patologia , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Micose Fungoide/genética , Micose Fungoide/metabolismo , Micose Fungoide/patologia , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Pele/citologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo , Linfócitos T/metabolismo , Proteína 1 Relacionada a Twist/genética , Vimentina/genética , Vimentina/metabolismoRESUMO
Primary cutaneous T-cell lymphoma (CTCL) comprises a heterogeneous group of neoplasms with variable clinical behavior. Immunophenotypic switch (IS) is a phenomenon that occurs during lymphoma progression and is defined by an alteration in the immunophenotypic expression of a tumor with retention of its genotypic signature. This has been well-recognized in hematopoietic neoplasms; however, it has been rarely reported in CTCL and its clinical implications are not well understood. We present the clinical, histopathologic, immunophenotypic, and genetic findings of three cases of CTCL that demonstrated IS post treatment with variable outcomes. We add our cases to the small number previously reported to increase awareness of this phenomenon and its diagnostic challenge.
Assuntos
Transformação Celular Neoplásica/imunologia , Imunofenotipagem/métodos , Linfoma Cutâneo de Células T/diagnóstico , Micose Fungoide/patologia , Neoplasias Cutâneas/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Conscientização , Biópsia/métodos , Transformação Celular Neoplásica/patologia , Pré-Escolar , Diagnóstico Diferencial , Progressão da Doença , Evolução Fatal , Feminino , Rearranjo Gênico/genética , Genes Codificadores dos Receptores de Linfócitos T/genética , Genótipo , Humanos , Linfoma Cutâneo de Células T/genética , Linfoma Cutâneo de Células T/imunologia , Masculino , Pessoa de Meia-Idade , Micose Fungoide/tratamento farmacológico , Micose Fungoide/metabolismo , Micose Fungoide/radioterapia , Neoplasias Cutâneas/imunologia , Resultado do TratamentoRESUMO
INTRODUCTION: Mycosis fungoides (MF), the most common type of cutaneous T-cell lymphoma, can lead to disfiguring lesions, debilitating pruritus and frequent skin infections. This study assessed response to brentuximab vedotin in patients with MF in the phase III ALCANZA study. METHODS: Baseline CD30 levels and large-cell transformation (LCT) status were centrally reviewed in patients with previously-treated CD30-positive MF using ≥2 skin biopsies obtained at screening; eligible patients required ≥1 biopsy with ≥10% CD30 expression. Patients were categorised as CD30min < 10% (≥1 biopsy with <10% CD30 expression), or CD30min ≥ 10% (all biopsies with ≥10% CD30 expression) and baseline LCT present or absent. Efficacy analyses were the proportion of patients with objective response lasting ≥4 months (ORR4) and progression-free survival (PFS). RESULTS: Clinical activity with brentuximab vedotin was observed across all CD30 expression levels in patients with ≥1 biopsy showing ≥10% CD30 expression. Superior ORR4 was observed with brentuximab vedotin versus physician's choice in patients: with CD30min < 10% (40.9% versus 9.5%), with CD30min ≥ 10% (57.1% versus 10.3%), with LCT (64.7% versus 17.6%) and without LCT (38.7% versus 6.5%). Brentuximab vedotin improved median PFS versus physician's choice in patients: with CD30min < 10% (16.7 versus 2.3 months), with CD30min ≥ 10% (15.5 versus 3.9 months), with LCT (15.5 versus 2.8 months) and without LCT (16.1 versus 3.5 months). Safety profiles were generally comparable across subgroups. CONCLUSION: These exploratory analyses demonstrated that brentuximab vedotin improved rates of ORR4 and PFS versus physician's choice in patients with CD30-positive MF and ≥1 biopsy showing ≥10% CD30 expression, regardless of LCT status. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov, NCT01578499.