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Journal of the American Academy of... May 2023
Topics: Humans; Sezary Syndrome; Mycosis Fungoides; Antibodies, Monoclonal, Humanized; Skin Neoplasms
PubMed: 36481378
DOI: 10.1016/j.jaad.2022.12.001 -
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 -
Journal Der Deutschen Dermatologischen... Sep 2021Mycosis fungoides (MF) and Sézary syndrome (SS) are primary cutaneous T-cell lymphomas (CTCL) with not yet fully understood etiology and pathogenesis. Conceptually, MF...
Mycosis fungoides (MF) and Sézary syndrome (SS) are primary cutaneous T-cell lymphomas (CTCL) with not yet fully understood etiology and pathogenesis. Conceptually, MF and SS are classified as distinct entities arising from different T helper cell subsets. MF is the most common CTCL entity, while SS is very rare. MF presents clinically with patch, plaque and/or tumor stages, but can also evolve as erythroderma, which in turn is pathognomonic for SS. SS is characterized by a detectable tumor-cell burden (Sézary cells) in the peripheral blood consistent with advanced-stage disease and a poor prognosis. In early-stage disease of MF, which is the predominant form, the prognosis is generally favorable. However, in up to 30 % of patients, there is progression of skin lesions, which can ultimately lead to visceral involvement. The histological manifestation of MF can be subtle in early-stage disease and therefore a careful clinicopathological correlation is paramount. The treatment of MF/SS is dependent on the disease stage. Therapeutic options include both skin-directed and systemic regimens. Apart from allogeneic stem cell transplantation (alloSCT), there is as yet no curative therapy for MF/SS. Accordingly, the treatment approach is symptom oriented and aims to reduce the tumor burden and improve health-related quality of life. However, the therapeutic landscape for CTCL is constantly being expanded by the discovery of novel therapeutic targets.
Topics: Humans; Lymphoma, T-Cell, Cutaneous; Mycosis Fungoides; Quality of Life; Sezary Syndrome; Skin Neoplasms
PubMed: 34541796
DOI: 10.1111/ddg.14610 -
Nature Communications Nov 2021Cutaneous 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...
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.
Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; CD4-Positive T-Lymphocytes; Female; Humans; Immunotherapy; Kaplan-Meier Estimate; Lymphocyte Activation; Lymphoma, T-Cell, Cutaneous; Male; Middle Aged; Mycosis Fungoides; Programmed Cell Death 1 Receptor; Sezary Syndrome; Skin Neoplasms; Treatment Outcome
PubMed: 34795254
DOI: 10.1038/s41467-021-26974-6 -
Journal Der Deutschen Dermatologischen... Apr 2023Mycosis fungoides and Sézary syndrome are the most important representatives of the heterogeneous group of cutaneous T-cell lymphomas. The diseases are rare and the... (Review)
Review
Mycosis fungoides and Sézary syndrome are the most important representatives of the heterogeneous group of cutaneous T-cell lymphomas. The diseases are rare and the diagnosis, which always requires a clinical-pathological correlation, is often delayed, especially in early forms of mycosis fungoides. The prognosis of mycosis fungoides depends on its stage and is usually favorable in the early stages. Clinically relevant prognostic parameters are missing and their development is the subject of current clinical research. Sézary syndrome, characterized by initial erythroderma and blood involvement, is a disease with a high mortality rate, in which good responses can now be achieved in many cases with new treatment options. The pathogenesis and immunology of the diseases is heterogeneous, with recent results pointing primarily to changes in specific signal transduction pathways that may be suitable as future treatment targets. Current therapy for mycosis fungoides and Sézary syndrome is primarily palliative with topical and systemic options either used alone or in combination. Only with allogeneic stem cell transplantation durable remissions can be achieved in selected patients. Similar to other areas of oncology, the development of new therapies for cutaneous lymphomas is currently changing from relatively untargeted empiricism to disease-specific, targeted pharmacotherapy based on knowledge from experimental research.
Topics: Humans; Sezary Syndrome; Mycosis Fungoides; Skin Neoplasms; Lymphoma, T-Cell, Cutaneous; Prognosis
PubMed: 36971307
DOI: 10.1111/ddg.15051 -
International Journal of Molecular... Mar 2022Epigenetic modifications rarely occur in isolation (as single "epigenetic modifications"). They usually appear together and form a network to control the epigenetic... (Review)
Review
Epigenetic modifications rarely occur in isolation (as single "epigenetic modifications"). They usually appear together and form a network to control the epigenetic system. Cutaneous malignancies are usually affected by epigenetic changes. However, there is limited knowledge regarding the epigenetic changes associated with cutaneous lymphomas. In this review, we focused on cutaneous T-cell lymphomas such as mycosis fungoides, Sézary syndrome, and anaplastic large cell lymphoma. With regard to epigenetic changes, we summarize the detailed chemical modifications categorized into DNA methylation and histone acetylation and methylation. We also summarize the epigenetic modifications and characteristics of the drug for cutaneous T-cell lymphoma (CTCL). Furthermore, we discuss current research on epigenetic-targeted therapy against cutaneous T-cell lymphomas. Although the current method of treatment with histone deacetylase inhibitors does not exhibit sufficient therapeutic benefits in all cases of CTCL, epigenetic-targeted combination therapy might overcome this limitation for patients with CTCL.
Topics: Epigenesis, Genetic; Humans; Lymphoma, T-Cell, Cutaneous; Mycosis Fungoides; Sezary Syndrome; Skin Neoplasms
PubMed: 35408897
DOI: 10.3390/ijms23073538 -
Hematology/oncology Clinics of North... Aug 2019Non-Hodgkin's lymphoma (NHL) encompasses a diverse collection of systemic and primary cutaneous lymphomas. Cutaneous T-cell lymphomas (CTCLs) represent about 13% of all... (Review)
Review
Non-Hodgkin's lymphoma (NHL) encompasses a diverse collection of systemic and primary cutaneous lymphomas. Cutaneous T-cell lymphomas (CTCLs) represent about 13% of all NHLs, which are further subdivided into a heterogeneous group with vastly different presentations and histologic features. Diagnosis requires integration of clinical, pathologic, and molecular features. Among CTCLs, mycosis fungoides and Sézary syndrome are the most prevalent. Treatment is aimed at limiting morbidity and halting disease progression. Hematopoietic stem cell transplantation is the only therapy with curative intent.
Topics: Antineoplastic Agents; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma, T-Cell, Cutaneous; Mycosis Fungoides; Progression-Free Survival; Sezary Syndrome; Skin Neoplasms
PubMed: 31229162
DOI: 10.1016/j.hoc.2019.04.004 -
Blood Advances Sep 2023The pathogenesis of cutaneous T-cell lymphoma (CTCL) remains unclear. Using single-cell RNA or T-cell receptor (TCR) sequencing of 32 619 CD3+CD4+ and CD26+/CD7+ and...
The pathogenesis of cutaneous T-cell lymphoma (CTCL) remains unclear. Using single-cell RNA or T-cell receptor (TCR) sequencing of 32 619 CD3+CD4+ and CD26+/CD7+ and 29 932 CD3+CD4+ and CD26-/CD7- lymphocytes from the peripheral blood of 7 patients with CTCL, coupled to single-cell ATAC-sequencing of 26,411 CD3+CD4+ and CD26+/CD7+ and 33 841 CD3+CD4+ and CD26-/CD7- lymphocytes, we show that tumor cells in Sézary syndrome and mycosis fungoides (MF) exhibit different phenotypes and trajectories of differentiation. When compared to MF, Sézary cells exhibit narrower repertoires of TCRs and exhibit clonal enrichment. Surprisingly, we identified ≥200 mutations in hematopoietic stem cells from multiple patients with Sézary syndrome. Mutations in key oncogenes were also present in peripheral Sézary cells, which also showed the hallmarks of recent thymic egression. Together our data suggest that CTCL arises from mutated lymphocyte progenitors that acquire TCRs in the thymus, which complete their malignant transformation in the periphery.
Topics: Humans; Sezary Syndrome; Dipeptidyl Peptidase 4; Skin Neoplasms; Mycosis Fungoides; Lymphoma, T-Cell, Cutaneous; Receptors, Antigen, T-Cell
PubMed: 37531660
DOI: 10.1182/bloodadvances.2022008562 -
Acta Dermato-venereologica Jan 2020Most patients with mycosis fungoides are diagnosed with early-stage disease. However, prevalence of early-stage disease is unknown, and evidence of its burden is scarce....
Most patients with mycosis fungoides are diagnosed with early-stage disease. However, prevalence of early-stage disease is unknown, and evidence of its burden is scarce. The aim of this study is to estimate the prevalence of early-stage mycosis fungoides, how long patients live with early-stage disease and to characterise these patients. Data were obtained from 4 key publications and from US cancer registries (Surveillance, Epidemiology and End Results Program; SEER). The derived incidence of early-stage mycosis fungoides was 0.26/100,000 (UK), 0.29/100,000 (US) and 0.38/100,000 (US-SEER) and the prevalence was 4.8/100,000 (UK), 5.2/100,000 (US) and 6.6/100,000 (US-SEER). Early-stage disease may last for 18 years. From SEER registries, 3,132 were diagnosed at early stage (mostly stage IA). Median age at diagnosis was 58 years. Compared with stage IA, the relative risk of death was 1.3 for stage IB and 3.5 for stage IIA. We confirm the rarity of early-stage mycosis fungoides, a differential prognosis and the potential for elevated burden of disease.
Topics: Disease Progression; Female; Humans; Male; Middle Aged; Mycosis Fungoides; Neoplasm Staging; Prognosis; Skin Neoplasms
PubMed: 31663598
DOI: 10.2340/00015555-3367 -
Hematological Oncology Jun 2023Cutaneous lymphomas are a heterogeneous group of several distinct entities of lymphoproliferative diseases. The diagnosis of a cutaneous lymphoma is a challenge, and it... (Review)
Review
Cutaneous lymphomas are a heterogeneous group of several distinct entities of lymphoproliferative diseases. The diagnosis of a cutaneous lymphoma is a challenge, and it is always the result of a careful analysis of several information's consisting of clinical history, clinical picture, histological and molecular analyses. For this reason, experts taking care of patients with a skin lymphoma need to know all the peculiar diagnostic elements very well, in order not to run into mistakes. In this article, we will focus the discussion on some issues as the skin biopsy (when and where). In addition, we will discuss the approach to the erythrodermic patient, whose differential diagnoses include mycosis fungoides, and Sézary syndrome, beside more frequent inflammatory conditions. Finally, we will address the issue of quality of life and the possible support of the suffering patient with a cutaneous lymphoma, well knowing that the current therapeutic possibilities are unfortunately limited.
Topics: Humans; Quality of Life; Lymphoma, T-Cell, Cutaneous; Mycosis Fungoides; Sezary Syndrome; Skin Neoplasms
PubMed: 37294972
DOI: 10.1002/hon.3147