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Clinics in Laboratory Medicine Sep 2017Cutaneous T-cell lymphomas comprise a heterogeneous group of diseases characterized by monoclonal proliferations of T lymphocytes primarily involving skin, modified skin... (Review)
Review
Cutaneous T-cell lymphomas comprise a heterogeneous group of diseases characterized by monoclonal proliferations of T lymphocytes primarily involving skin, modified skin appendages, and some mucosal sites. This article addresses the basic clinical, histologic, and immunohistochemical characteristics of this group of diseases, with additional attention to evolving literature on dermoscopy, reflectance confocal microscopy, flow cytometry, and molecular data that may increasingly be applied to diagnostic and therapeutic algorithms in these diseases. Select unusual phenotypes or diagnostic examples of classic phenotypes are demonstrated, and flags for consideration while making a pathologic diagnosis of cutaneous T-cell lymphoma are suggested.
Topics: Dermoscopy; Humans; Immunohistochemistry; Lymphoma, T-Cell, Cutaneous; Microscopy, Confocal; Phenotype; Skin Neoplasms
PubMed: 28802499
DOI: 10.1016/j.cll.2017.06.006 -
British Journal of Hospital Medicine... Apr 2022Cutaneous T-cell lymphoma is a rare type of extranodal non-Hodgkin's lymphoma that primarily affects the skin. The uncertain pathogenesis and variable clinical... (Review)
Review
Cutaneous T-cell lymphoma is a rare type of extranodal non-Hodgkin's lymphoma that primarily affects the skin. The uncertain pathogenesis and variable clinical presentation make the diagnosis and management of cutaneous T-cell lymphoma a challenge. Cutaneous T-cell lymphoma is a chronic, relapsing illness with treatment aimed at symptomatic relief and improving patient related quality of life. Early-stage cutaneous T-cell lymphoma typically follows an indolent course, often being mistaken for benign dermatological conditions which can lead to a diagnostic delay. Advanced stage cutaneous T-cell lymphoma has a poor prognosis with significant morbidity. Accurate diagnosis and early involvement of a specialist team is paramount to ensure correct management and improved patient outcomes. Promising advances are being made to develop novel agents which could improve prognosis and quality of life. This article provides an overview of the two main subtypes of cutaneous T-cell lymphoma: mycosis fungoides and Sézary syndrome. Clinical presentation, histopathological correlation and diagnostic challenges are reviewed alongside example case studies.
Topics: Delayed Diagnosis; Humans; Lymphoma, T-Cell, Cutaneous; Neoplasm Recurrence, Local; Quality of Life; Sezary Syndrome; Skin Neoplasms
PubMed: 35506718
DOI: 10.12968/hmed.2021.0149 -
The Lancet. Oncology Sep 2018Cutaneous T-cell lymphomas are rare non-Hodgkin lymphomas with substantial morbidity and mortality in advanced disease stages. We compared the efficacy of mogamulizumab,... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Cutaneous T-cell lymphomas are rare non-Hodgkin lymphomas with substantial morbidity and mortality in advanced disease stages. We compared the efficacy of mogamulizumab, a novel monoclonal antibody directed against C-C chemokine receptor 4, with vorinostat in patients with previously treated cutaneous T-cell lymphoma.
METHODS
In this open-label, international, phase 3, randomised controlled trial, we recruited patients with relapsed or refractory mycosis fungoides or Sézary syndrome at 61 medical centres in the USA, Denmark, France, Italy, Germany, the Netherlands, Spain, Switzerland, the UK, Japan, and Australia. Eligible patients were aged at least 18 years (in Japan, ≥20 years), had failed (for progression or toxicity as assessed by the principal investigator) at least one previous systemic therapy, and had an Eastern Cooperative Oncology Group performance score of 1 or less and adequate haematological, hepatic, and renal function. Patients were randomly assigned (1:1) using an interactive voice web response system to mogamulizumab (1·0 mg/kg intravenously on a weekly basis for the first 28-day cycle, then on days 1 and 15 of subsequent cycles) or vorinostat (400 mg daily). Stratification was by cutaneous T-cell lymphoma subtype (mycosis fungoides vs Sézary syndrome) and disease stage (IB-II vs III-IV). Since this study was open label, patients and investigators were not masked to treatment assignment. The primary endpoint was progression-free survival by investigator assessment in the intention-to-treat population. Patients who received one or more doses of study drug were included in the safety analyses. This study is ongoing, and enrolment is complete. This trial was registered with ClinicalTrials.gov, number NCT01728805.
FINDINGS
Between Dec 12, 2012, and Jan 29, 2016, 372 eligible patients were randomly assigned to receive mogamulizumab (n=186) or vorinostat (n=186), comprising the intention-to-treat population. Two patients randomly assigned to mogamulizumab withdrew consent before receiving study treatment; thus, 370 patients were included in the safety population. Mogamulizumab therapy resulted in superior investigator-assessed progression-free survival compared with vorinostat therapy (median 7·7 months [95% CI 5·7-10·3] in the mogamulizumab group vs 3·1 months [2·9-4·1] in the vorinostat group; hazard ratio 0·53, 95% CI 0·41-0·69; stratified log-rank p<0·0001). Grade 3-4 adverse events of any cause were reported in 75 (41%) of 184 patients in the mogamulizumab group and 76 (41%) of 186 patients in the vorinostat group. The most common serious adverse events of any cause were pyrexia in eight (4%) patients and cellulitis in five (3%) patients in the mogamulizumab group; and cellulitis in six (3%) patients, pulmonary embolism in six (3%) patients, and sepsis in five (3%) patients in the vorinostat group. Two (67%) of three on-treatment deaths with mogamulizumab (due to sepsis and polymyositis) and three (33%) of nine on-treatment deaths with vorinostat (two due to pulmonary embolism and one due to bronchopneumonia) were considered treatment-related.
INTERPRETATION
Mogamulizumab significantly prolonged progression-free survival compared with vorinostat, and could provide a new, effective treatment for patients with mycosis fungoides and, importantly, for Sézary syndrome, a subtype that represents a major therapeutic challenge in cutaneous T-cell lymphoma.
FUNDING
Kyowa Kirin.
Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Australia; Drug Administration Schedule; Drug Resistance, Neoplasm; Europe; Female; Histone Deacetylase Inhibitors; Humans; Japan; Lymphoma, T-Cell, Cutaneous; Male; Middle Aged; Mycosis Fungoides; Neoplasm Recurrence, Local; Neoplasm Staging; Progression-Free Survival; Sezary Syndrome; Time Factors; United States; Vorinostat
PubMed: 30100375
DOI: 10.1016/S1470-2045(18)30379-6 -
American Journal of Hematology Jan 2023Cutaneous T-cell lymphomas are a heterogenous group of T-cell neoplasms involving the skin, the majority of which may be classified as Mycosis Fungoides (MF) or Sézary...
DISEASE OVERVIEW
Cutaneous T-cell lymphomas are a heterogenous group of T-cell neoplasms involving the skin, the majority of which may be classified as Mycosis Fungoides (MF) or Sézary Syndrome (SS).
DIAGNOSIS
The diagnosis of MF or SS requires the integration of clinical and histopathologic data.
RISK-ADAPTED THERAPY
TNMB (tumor, node, metastasis, blood) staging remains the most important prognostic factor in MF/SS and forms the basis for a "risk-adapted," multidisciplinary approach to treatment. For patients with disease limited to the skin, expectant management or skin-directed therapies is preferred, as both disease-specific and overall survival for these patients is favorable. In contrast, patients with advanced-stage disease with significant nodal, visceral or the blood involvement are generally approached with systemic therapies, including biologic-response modifiers, histone deacetylase inhibitors, or antibody-based strategies, in an escalating fashion. In highly-selected patients, allogeneic stem-cell transplantation may be considered, as this may be curative in some patients.
Topics: Humans; Lymphoma, T-Cell, Cutaneous; Mycosis Fungoides; Neoplasm Staging; Sezary Syndrome; Skin Neoplasms
PubMed: 36226409
DOI: 10.1002/ajh.26760 -
Blood Apr 2019Primary cutaneous lymphomas are a heterogeneous group of T- and B-cell lymphomas that present in the skin with no evidence of extracutaneous disease at the time of... (Review)
Review
Primary cutaneous lymphomas are a heterogeneous group of T- and B-cell lymphomas that present in the skin with no evidence of extracutaneous disease at the time of diagnosis. The 2005 World Health Organization-European Organization for Research and Treatment of Cancer (WHO-EORTC) consensus classification has served as a golden standard for the diagnosis and classification of these conditions. In September 2018, an updated version of the WHO-EORTC was published in the fourth edition of the WHO Classification of Skin Tumours Blue Book. In this classification, primary cutaneous acral CD8 T-cell lymphoma and Epstein-Barr virus positive (EBV) mucocutaneous ulcer are included as new provisional entities, and a new section on cutaneous forms of chronic active EBV disease has been added. The term "primary cutaneous CD4 small/medium T-cell lymphoma" was modified to "primary cutaneous CD4 small/medium T-cell lymphoproliferative disorder" because of its indolent clinical behavior and uncertain malignant potential. Modifications have also been made in the sections on lymphomatoid papulosis, increasing the spectrum of histologic and genetic types, and primary cutaneous marginal zone lymphomas recognizing 2 different subtypes. Herein, the characteristic features of these new and modified entities as well as the results of recent molecular studies with diagnostic, prognostic, and/or therapeutic significance for the different types of primary cutaneous lymphomas are reviewed. An update of the frequency and survival of the different types of primary cutaneous lymphomas is provided.
Topics: Herpesvirus 4, Human; Humans; Lymphoma, B-Cell; Lymphoma, T-Cell, Cutaneous; Molecular Diagnostic Techniques; Prognosis; Skin Neoplasms; Therapeutics; World Health Organization
PubMed: 30635287
DOI: 10.1182/blood-2018-11-881268 -
Molecular Cancer Sep 2021In early-stage mycosis fungoides (MF), the most common primary cutaneous T-cell lymphoma, limited skin involvement with patches and plaques is associated with a...
BACKGROUND
In early-stage mycosis fungoides (MF), the most common primary cutaneous T-cell lymphoma, limited skin involvement with patches and plaques is associated with a favorable prognosis. Nevertheless, approximately 20-30% of cases progress to tumors or erythroderma, resulting in poor outcome. At present, factors contributing to this switch from indolent to aggressive disease are only insufficiently understood.
METHODS
In patients with advanced-stage MF, we compared patches with longstanding history to newly developed plaques and tumors by using single-cell RNA sequencing, and compared results with early-stage MF as well as nonlesional MF and healthy control skin.
RESULTS
Despite considerable inter-individual variability, lesion progression was uniformly associated with downregulation of the tissue residency markers CXCR4 and CD69, the heat shock protein HSPA1A, the tumor suppressors and immunoregulatory mediators ZFP36 and TXNIP, and the interleukin 7 receptor (IL7R) within the malignant clone, but not in benign T cells. This phenomenon was not only found in conventional TCR-αβ MF, but also in a case of TCR-γδ MF, suggesting a common mechanism across MF subtypes. Conversely, malignant cells in clinically unaffected skin from MF patients showed upregulation of these markers.
CONCLUSIONS
Our data reveal a specific panel of biomarkers that might be used for monitoring MF disease progression. Altered expression of these genes may underlie the switch in clinical phenotype observed in advanced-stage MF.
Topics: Adult; Aged; Biomarkers; Biopsy; Computational Biology; Disease Progression; Female; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Lymphoma, T-Cell, Cutaneous; Male; Middle Aged; Mycosis Fungoides; Phenotype; RNA-Seq; Sequence Analysis, RNA; Single-Cell Analysis
PubMed: 34583709
DOI: 10.1186/s12943-021-01419-2 -
Nature Communications Mar 2022Cutaneous T cell lymphoma (CTCL) represents a heterogeneous group of non-Hodgkin lymphoma distinguished by the presence of clonal malignant T cells. The heterogeneity of...
Cutaneous T cell lymphoma (CTCL) represents a heterogeneous group of non-Hodgkin lymphoma distinguished by the presence of clonal malignant T cells. The heterogeneity of malignant T cells and the complex tumor microenvironment remain poorly characterized. With single-cell RNA analysis and bulk whole-exome sequencing on 19 skin lesions from 15 CTCL patients, we decipher the intra-tumor and inter-lesion diversity of CTCL patients and propose a multi-step tumor evolution model. We further establish a subtyping scheme based on the molecular features of malignant T cells and their pro-tumorigenic microenvironments: the T group, demonstrating a cytotoxic effector memory T cell phenotype, shows more M2 macrophages infiltration, while the T group, featured by a central memory T cell phenotype and adverse patient outcome, is infiltrated by highly exhausted CD8 reactive T cells, B cells and Tregs with suppressive activities. Our results establish a solid basis for understanding the nature of CTCL and pave the way for future precision medicine for CTCL patients.
Topics: Humans; Lymphoma, T-Cell, Cutaneous; Single-Cell Analysis; Skin Neoplasms; Transcriptome; Tumor Microenvironment
PubMed: 35241665
DOI: 10.1038/s41467-022-28799-3 -
Cancer Discovery May 2022Cutaneous T-cell lymphoma (CTCL) is a rare cancer of skin-homing T cells. A subgroup of patients develops large cell transformation with rapid progression to an...
ABSTRACT
Cutaneous T-cell lymphoma (CTCL) is a rare cancer of skin-homing T cells. A subgroup of patients develops large cell transformation with rapid progression to an aggressive lymphoma. Here, we investigated the transformed CTCL (tCTCL) tumor ecosystem using integrative multiomics spanning whole-exome sequencing (WES), single-cell RNA sequencing, and immune profiling in a unique cohort of 56 patients. WES of 70 skin biopsies showed high tumor mutation burden, UV signatures that are prognostic for survival, exome-based driver events, and most recurrently mutated pathways in tCTCL. Single-cell profiling of 16 tCTCL skin biopsies identified a core oncogenic program with metabolic reprogramming toward oxidative phosphorylation (OXPHOS), cellular plasticity, upregulation of MYC and E2F activities, and downregulation of MHC I suggestive of immune escape. Pharmacologic perturbation using OXPHOS and MYC inhibitors demonstrated potent antitumor activities, whereas immune profiling provided in situ evidence of intercellular communications between malignant T cells expressing macrophage migration inhibitory factor and macrophages and B cells expressing CD74.
SIGNIFICANCE
Our study contributes a key resource to the community with the largest collection of tCTCL biopsies that are difficult to obtain. The multiomics data herein provide the first comprehensive compendium of genomic alterations in tCTCL and identify potential prognostic signatures and novel therapeutic targets for an incurable T-cell lymphoma. This article is highlighted in the In This Issue feature, p. 1171.
Topics: Cell Transformation, Neoplastic; Ecosystem; Genomics; Humans; Lymphoma, T-Cell, Cutaneous; Skin Neoplasms
PubMed: 35247891
DOI: 10.1158/2159-8290.CD-21-1207 -
Blood May 2005Primary cutaneous lymphomas are currently classified by the European Organization for Research and Treatment of Cancer (EORTC) classification or the World Health... (Review)
Review
Primary cutaneous lymphomas are currently classified by the European Organization for Research and Treatment of Cancer (EORTC) classification or the World Health Organization (WHO) classification, but both systems have shortcomings. In particular, differences in the classification of cutaneous T-cell lymphomas other than mycosis fungoides, Sezary syndrome, and the group of primary cutaneous CD30+ lymphoproliferative disorders and the classification and terminology of different types of cutaneous B-cell lymphomas have resulted in considerable debate and confusion. During recent consensus meetings representatives of both systems reached agreement on a new classification, which is now called the WHO-EORTC classification. In this paper we describe the characteristic features of the different primary cutaneous lymphomas and other hematologic neoplasms frequently presenting in the skin, and discuss differences with the previous classification schemes. In addition, the relative frequency and survival data of 1905 patients with primary cutaneous lymphomas derived from Dutch and Austrian registries for primary cutaneous lymphomas are presented to illustrate the clinical significance of this new classification.
Topics: Humans; Immunophenotyping; Lymphoma, T-Cell, Cutaneous; World Health Organization
PubMed: 15692063
DOI: 10.1182/blood-2004-09-3502 -
Cancer Letters Dec 2022Cutaneous T cell lymphoma (CTCL) is characterized by the accumulation of malignant T cells in the skin. However, advanced CTCL pathophysiology remains elusive and...
Single-cell RNA sequencing unveils the communications between malignant T and myeloid cells contributing to tumor growth and immunosuppression in cutaneous T-cell lymphoma.
Cutaneous T cell lymphoma (CTCL) is characterized by the accumulation of malignant T cells in the skin. However, advanced CTCL pathophysiology remains elusive and therapeutic options are limited due to the high intratumoral heterogeneity and complicated tumor microenvironment (TME). By comparing the single-cell RNA-seq (scRNA-seq) data from advanced CTCL patients and healthy controls (HCs), we showed that CTCL had a higher enrichment of T/NK and myeloid cells. Subpopulations of T cells (CXCR3, GNLY, CREM, and MKI67 T cells), with high proliferation, stemness, and copy number variation (CNV) levels, contribute to the malignancy of CTCL. Besides, CCL13 monocytes/macrophages and LAMP3 cDC cells were enriched and mediated the immunosuppression via inhibitory interactions with malignant T cells, such as CD47-SIRPA, MIF-CD74, and CCR1-CCL18. Notably, elevated expressions of S100A9 and its receptor TLR4, as well as the activation of downstream toll-like receptor and NF-κB pathway were observed in both malignant cells and myeloid cells in CTCL. Cell co-culture experiments further confirmed that the interaction between malignant CTCL cells and macrophages contributed to tumor growth via S100A9 upregulation and NF-kb activation. Our results showed that blocking the S100A9-TLR4 interaction using tasquinimod could inactivate the NF-κB pathway and inhibit the growth of CTCL tumor cells, and trigger cell apoptosis. Collectively, our study revealed a landscape of immunosuppressive TME mediated by interactions between malignant T cells and myeloid cells, and provided novel targets and potential treatment strategies for advanced CTCL patients.
Topics: Humans; NF-kappa B; DNA Copy Number Variations; Toll-Like Receptor 4; Skin Neoplasms; Lymphoma, T-Cell, Cutaneous; Myeloid Cells; Immunosuppression Therapy; Sequence Analysis, RNA; Tumor Microenvironment
PubMed: 36265653
DOI: 10.1016/j.canlet.2022.215972