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Current Hematologic Malignancy Reports Jun 2017Diagnosis and management of mycosis fungoides and Sézary syndrome (MF/SS) require accurate clinicopathological correlation and a multidisciplinary approach. We reviewed... (Review)
Review
PURPOSE OF REVIEW
Diagnosis and management of mycosis fungoides and Sézary syndrome (MF/SS) require accurate clinicopathological correlation and a multidisciplinary approach. We reviewed major advances in the field regarding diagnostic and prognostic tools as well as skin-directed therapies (SDTs) and systemic agents for MF/SS published in the past 2 years.
RECENT FINDINGS
Improved technology (T-cell receptor high-throughput sequencing) and increased multicenter collaboration (Cutaneous Lymphoma International Consortium) have led to diagnostic/prognostic advances. Concurrently, numerous genomic studies have enhanced understanding of disease pathogenesis. Advances in SDTs include topical resiquimod, a novel potent Toll-like receptor (TLR) agonist; consensus CTCL phototherapy guidelines; and use of low-dose radiation therapy. Novel systemic therapies for advanced disease of note include targeted antibody drug conjugates (brentuximab vedotin), immune checkpoint inhibitors, and allogeneic hematopoietic stem cell transplantation (HSCT). Our "toolbox" to diagnose and treat the spectrum of MF/SS continues to expand. Further characterization of genomic data going forward will enable a rational approach to selecting and combining therapies to improve patient care.
Topics: Biomarkers, Tumor; Combined Modality Therapy; Disease Management; Genomics; Humans; Mycosis Fungoides; Prognosis; Sezary Syndrome; Skin Neoplasms; Treatment Outcome
PubMed: 28540671
DOI: 10.1007/s11899-017-0387-9 -
Experimental Dermatology Aug 2017The practice of pre-emptive individualized medicine is predicated on the discovery, development and application of biomarkers in specific clinical settings. Mycosis... (Review)
Review
The practice of pre-emptive individualized medicine is predicated on the discovery, development and application of biomarkers in specific clinical settings. Mycosis fungoides and Sézary syndrome are the two most common type of cutaneous T-cell lymphoma, yet diagnosis, prognosis and disease monitoring remain a challenge. In this review, we discuss the current state of biomarker discovery in mycosis fungoides and Sézary syndrome, highlighting the most promising molecules in different compartments. Further, we emphasize the need for continued multicentre efforts to validate available and new biomarkers and to develop prospective combinatorial panels of already discovered molecules.
Topics: Biomarkers; Gene Expression; Humans; Mycosis Fungoides; Sezary Syndrome
PubMed: 27897325
DOI: 10.1111/exd.13261 -
International Journal of Molecular... Feb 2023Sézary syndrome (SS) is a rare and aggressive type of cutaneous T-cell lymphoma, with an abnormal inflammatory response in affected skin. The cytokines IL-1B and IL-18,...
Sézary syndrome (SS) is a rare and aggressive type of cutaneous T-cell lymphoma, with an abnormal inflammatory response in affected skin. The cytokines IL-1B and IL-18, as key signaling molecules in the immune system, are produced in an inactive form and cleave to the active form by inflammasomes. In this study, we assessed the skin, serum, peripheral mononuclear blood cell (PBMC) and lymph-node samples of SS patients and control groups (healthy donors (HDs) and idiopathic erythroderma (IE) nodes) to investigate the inflammatory markers IL-1B and IL-18 at the protein and transcript expression levels, as potential markers of inflammasome activation. Our findings showed increased IL-1B and decreased IL-18 protein expression in the epidermis of SS patients; however, in the dermis layer, we detected increased IL-18 protein expression. In the lymph nodes of SS patients at advanced stages of the disease (N2/N3), we also detected an enhancement of IL-18 and a downregulation of IL-1B at the protein level. Moreover, the transcriptomic analysis of the SS and IE nodes confirmed the decreased expression of and , whereas the pathway analysis indicated a further downregulation of -associated genes. Overall, the present findings showed compartmentalized expressions of IL-1B and IL-18 and provided the first evidence of their imbalance in patients with Sézary syndrome.
Topics: Humans; Dermatitis, Exfoliative; Inflammasomes; Interleukin-18; Leukocytes, Mononuclear; Sezary Syndrome; Skin; Skin Neoplasms
PubMed: 36902104
DOI: 10.3390/ijms24054674 -
Anais Brasileiros de Dermatologia 2021Cutaneous T-cell lymphomas are a heterogeneous group of lymphoproliferative disorders, characterized by infiltration of the skin by mature malignant T cells. Mycosis... (Review)
Review
Cutaneous T-cell lymphomas are a heterogeneous group of lymphoproliferative disorders, characterized by infiltration of the skin by mature malignant T cells. Mycosis fungoides is the most common form of cutaneous T-cell lymphoma, accounting for more than 60% of cases. Mycosis fungoides in the early-stage is generally an indolent disease, progressing slowly from some patches or plaques to more widespread skin involvement. However, 20% to 25% of patients progress to advanced stages, with the development of skin tumors, extracutaneous spread and poor prognosis. Treatment modalities can be divided into two groups: skin-directed therapies and systemic therapies. Therapies targeting the skin include topical agents, phototherapy and radiotherapy. Systemic therapies include biological response modifiers, immunotherapies and chemotherapeutic agents. For early-stage mycosis fungoides, skin-directed therapies are preferred, to control the disease, improve symptoms and quality of life. When refractory or in advanced-stage disease, systemic treatment is necessary. In this article, the authors present a compilation of current treatment options for mycosis fungoides and Sézary syndrome.
Topics: Humans; Lymphoma, T-Cell, Cutaneous; Mycosis Fungoides; Quality of Life; Sezary Syndrome; Skin Neoplasms
PubMed: 34053802
DOI: 10.1016/j.abd.2020.12.007 -
Current Hematologic Malignancy Reports Jun 2023Cutaneous T cell lymphomas (CTCLs) exhibit a wide variety of clinical features, histologic characteristics, and genetic drivers. We review novel molecular findings that... (Review)
Review
PURPOSE OF REVIEW
Cutaneous T cell lymphomas (CTCLs) exhibit a wide variety of clinical features, histologic characteristics, and genetic drivers. We review novel molecular findings that inform our understanding of the pathogenesis of CTCL, with a focus on the tumor microenvironment (TME).
RECENT FINDINGS
There is increasing evidence challenging the model of T:mycosis fungoides (MF) and T:Sézary syndrome (SS) phenotype. Phylogenetic analysis performed using whole-exome sequencing (WES) raises the possibility that MF can arise without a common ancestral T cell clone. The detection of ultraviolet (UV) marker signature 7 mutations in the blood of patients with SS raises questions about the role of UV exposure in CTCL pathogenesis. There is also increasing interest on the role of the TME in CTCL. Existing therapies such as the RXR retinoid bexarotene and the anti-CCR4 monoclonal antibody mogamulizumab may act through the CTCL TME by impacting the CCL22:CCR4 axis, while cancer-associated fibroblasts (CAFs) in the CTCL TME contribute to drug resistance, as well as a Th2 milieu and tumor growth via secretion of pro-tumorigenic cytokines. Staphylococcus aureus (SA) is a frequent cause of morbidity among CTCL patients. SA may positively select for malignant T cells through adaptive downregulation of alpha-toxin surface receptors and promotion of tumor growth via upregulation of the JAK/STAT pathway. Recent molecular advancements have contributed to our understanding of the pathogenesis of CTCL and shed light into the potential mechanisms of existing therapies. Further understanding of the CTCL TME may fuel the discovery of novel therapies for CTCL.
Topics: Humans; Janus Kinases; Phylogeny; Skin Neoplasms; STAT Transcription Factors; Signal Transduction; Lymphoma, T-Cell, Cutaneous; Mycosis Fungoides; Sezary Syndrome; Biomarkers; Tumor Microenvironment
PubMed: 37017872
DOI: 10.1007/s11899-023-00692-w -
Italian Journal of Dermatology and... Aug 2022The mechanisms involved in mycosis fungoides, and Sezary Syndrome progression are largely unknown. Over the last decade the interest in immune system contrast of...
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.
Topics: B7-H1 Antigen; Humans; Lymphocytes, Tumor-Infiltrating; Mycosis Fungoides; Programmed Cell Death 1 Receptor; Sezary Syndrome; Skin Neoplasms
PubMed: 35373781
DOI: 10.23736/S2784-8671.22.07275-9 -
Journal Der Deutschen Dermatologischen... Mar 2016Sézary syndrome, the leukemic variant of cutaneous T-cell lymphoma, is still an enigmatic disease with a fatal prognosis. Recent research, however, has identified a... (Review)
Review
Sézary syndrome, the leukemic variant of cutaneous T-cell lymphoma, is still an enigmatic disease with a fatal prognosis. Recent research, however, has identified a multitude of dysregulated molecular pathways that contribute to malignant transformation and therapy resistance of Sézary cells (SC). With respect to T-cell development, SC either represent naive T cells, T effector memory or T central memory cells. Functionally, SC may differentiate into Th2, Treg, or even Th17 cells. Despite their plasticity, SC express characteristic diagnostic marker proteins including CD158k, CD164, FcRL3, and PD-1 as well as skin-homing receptors such as CLA and CCR4. Already tested in (pre)clinical trials, CD158k, PD-1, CTLA-4, and CCR4 also represent promising therapeutic targets. Molecular alterations in SC include transcription factors such as STAT3, 4, and 5, as well as TWIST1 and TOX. TWIST1 induces expression of DNM3os containing the miR-199a2/214 cluster, a key hub controlling multiple cancer networks. In addition, activation of NFκB and the MAPK pathway as well as altered TCR signaling cause apoptosis resistance. Recently, whole genome and exome sequencing has revealed somatic copy number variations as predominant mutations in SC, primarily affecting apoptosis, NFκB signaling, DNA integrity, and T-cell activation. In order to facilitate development of novel therapies, improved in vivo models, which better reflect the pathogenesis and clinical course of Sézary syndrome, are currently being generated.
Topics: Genetic Predisposition to Disease; Humans; Immunogenetic Phenomena; Metabolic Networks and Pathways; Models, Genetic; Models, Immunological; Molecular Targeted Therapy; Neoplasm Proteins; Polymorphism, Single Nucleotide; Sezary Syndrome; Skin Neoplasms; T-Lymphocytes
PubMed: 26972187
DOI: 10.1111/ddg.12900 -
BioMed Research International 2016Sézary syndrome (SS), an aggressive form of erythrodermic pruritic cutaneous T cell lymphoma (CTCL), from an immunological perspective characterized by increased Th2... (Review)
Review
Sézary syndrome (SS), an aggressive form of erythrodermic pruritic cutaneous T cell lymphoma (CTCL), from an immunological perspective characterized by increased Th2 cytokine levels, elevated serum IgE and impaired cellular immunity. Not only the clinical appearance but also the hallmark immunological characteristics of SS often share striking similarities with acute flares of atopic dermatitis (AD), a common benign chronic inflammatory skin disease. Given the overlap of several immunological features, the application of similar or even identical therapeutic approaches in certain stages of both diseases may come into consideration. The aim of this review is to compare currently accepted immunological aspects and possible therapeutic targets in AD and SS.
Topics: Cytokines; Dermatitis, Atopic; Humans; Immunoglobulin E; Lymphoma, T-Cell, Cutaneous; Sezary Syndrome; Th2 Cells
PubMed: 27294147
DOI: 10.1155/2016/9717530 -
Journal of the American Academy of... Nov 2021Primary cutaneous T-cell lymphomas (CTCLs) other than mycosis fungoides (MF) and Sézary syndrome (SS) encompass a heterogenous group of non-Hodgkin lymphomas with... (Review)
Review
Primary cutaneous T-cell lymphomas (CTCLs) other than mycosis fungoides (MF) and Sézary syndrome (SS) encompass a heterogenous group of non-Hodgkin lymphomas with variable clinical courses, prognoses, and management approaches. Given the morphologic and histologic overlap among the CTCL subtypes and other T-cell lymphomas with cutaneous manifestations, thorough evaluation with clinicopathologic correlation and exclusion of systemic involvement are essential prior to initiating therapy. Staging and treatment recommendations vary, depending on the subtype, clinical behavior, and treatment response. Generally, for subtypes in which staging is recommended, Ann Arbor or tumor, node, metastasis staging specific to CTCL other than MF or SS are used. For many subtypes, there is no standard treatment to date. Available recommended treatments range widely, from no active or minimal intervention with skin-directed therapy to aggressive systemic therapies that include multi-agent chemotherapy with consideration for hematopoietic stem cell transplant. Emerging targeted therapies, such as brentuximab, a chimeric antibody targeting CD30, show promise in altering the disease course of non-MF/SS CTCLs.
Topics: Humans; Lymphoma, T-Cell, Cutaneous; Mycosis Fungoides; Prognosis; Sezary Syndrome; Skin Neoplasms
PubMed: 33945836
DOI: 10.1016/j.jaad.2021.04.081 -
American Journal of Clinical Dermatology Jun 2020The majority of patients with Sézary syndrome (SS) present with classic symptoms of erythroderma, lymphadenopathy, and pruritus. However, there have been numerous... (Review)
Review
The majority of patients with Sézary syndrome (SS) present with classic symptoms of erythroderma, lymphadenopathy, and pruritus. However, there have been numerous reports of patients with SS who have non-classic signs. In this review, we report the less common clinical presentations of SS and discuss their relevant treatments. Our search included all literature on SS since 2008, the year the World Health Organization (WHO) incorporated the diagnostic criteria for SS into the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. We reviewed 896 articles and identified 505 patients with non-classic presentations of SS. Of these 505 patients, the most common non-classic signs of SS were keratoderma, onychodystrophy, alopecia, leonine facies, and ectropion. Given the aggressive and highly symptomatic nature of SS, it is imperative that clinicians recognize the less common signs of the disease to prevent delays in diagnosis and treatment. To our knowledge, this is the first review of the clinical variations of SS with a focus on non-classic signs and symptoms.
Topics: Alopecia; Biopsy; Ectropion; Humans; Nail Diseases; Nails; Sezary Syndrome; Skin; Skin Neoplasms
PubMed: 31953789
DOI: 10.1007/s40257-020-00501-7