Search Results (88)

Cutaneous T-cell lymphoma (CTCL), including mycosis fungoides (MF) and Sézary syndrome (SS), is defined by malignant CD4+ T-cell clones that evolve within and remodel the skin and systemic immune compartments. For disease biology and immune remodeling, we prioritize evidence from human primary samples; for therapeutic implications, we integrate clinical-trial and translational biomarker studies. We organize evidence by compartment (skin vs. blood) and, within skin, by stage (patch/plaque vs. tumor). Early patch/plaque MF often shows features consistent with constrained inflammation: skin-resident memory T-cell (TRM)-like malignant clones are in a Th1-leaning microenvironment with relatively preserved cytotoxic surveillance. Progression to tumor-stage MF (and/or large-cell transformation) is frequently associated with clonal dominance, Th2 cytokine polarization, upregulation of checkpoint pathways, and remodeling of myeloid/fibroblast populations. SS is typically associated with leukemic clonal dominance, systemic Th2 skewing, and broad impairment of cytotoxic immune control. These trajectories support an interpretive framework that aligns immune-directed therapies with compartment- and stage-associated biology; these include strategies that (i) deplete malignant clones (e.g., CCR4, CD30, KIR3DL2 targeting), (ii) re-engage exhausted effectors (PD-1/PD-L1 axis), (iii) reprogram cytokine balance (IFN-γ, IL-12, extracorporeal photopheresis), or (iv) suppress malignant signaling programs with secondary immune effects (JAK/STAT inhibition). We highlight potential candidate predictive biomarkers at varying levels of maturity, most of which require prospective validation, including antigen density, compartmental tumor burden, tumor cell fraction, effector-cell substrate, and interferon/cytokine signatures. Full article

Background/Objectives: Cutaneous T-cell lymphomas (CTCL), most commonly mycosis fungoides and Sézary syndrome, are rare non-Hodgkin lymphomas. Advanced disease responds poorly to current treatments, highlighting the need for new molecularly targeted therapies. WEE1 is a central regulator of the G2/M checkpoint and S-phase progression and has emerged as a therapeutic target in several malignancies, yet it has not been systematically explored in CTCL. Methods: We screened a library of more than 2200 kinase inhibitors in CTCL cell lines and selected adavosertib for further study. Its effects were tested in four CTCL lines; primary keratinocytes and fibroblasts; patient-derived malignant CD4⁺ T cells and healthy donor CD4⁺ T cells; and a MyLa xenograft model, using viability, apoptosis, cell-cycle, Western blot, and phospho-protein array assays. Results: Adavosertib reduced viability at submicromolar IC₅₀ values (0.26–0.56 µM) across all four CTCL lines while largely sparing primary skin cells and was more active in malignant than in healthy donor CD4⁺ T cells. It induced apoptosis and cell-line-specific S-phase and/or G2/M accumulation, lowered WEE1 and phospho-CDK1 (Tyr15), and increased phospho-H2A.X. A phospho-protein array showed activation of checkpoint and stress signalling. In a preliminary xenograft experiment, adavosertib slowed MyLa tumour growth. Conclusions: These preclinical data identify WEE1 as a therapeutic target in CTCL and support further preclinical and early-phase clinical evaluation of adavosertib in this disease. Full article

Background: Mycosis fungoides (MF) and Sézary syndrome (SS) are the predominant cutaneous T-cell lymphomas. Although malignant T cells in MF/SS overexpress CCR4 and respond to the anti-CCR4 antibody mogamulizumab, skin response rates vary. We hypothesized that immune components within the tumor microenvironment contribute to differential outcomes. Methods: Imaging mass cytometry with a 37-antibody panel was used to characterize immune and structural elements in FFPE tissues from sixteen MF/SS patients (6 MF, 10 SS) treated with Mogamulizumab, including seven skin responders and nine non-responders. Single-cell phenotyping and spatial analyses were performed using the Visiopharm^® Phenoplex™ platform, with supervision. Results: We identified 68,974 cells pre-treatment and 58,852 cells post-treatment. Malignant CD4⁺ T cells showed reduced baseline CD27, CD103, CD25, and ICOS expression compared with non-malignant CD4⁺ cells. Baseline MF lesions were enriched for IL-13⁺ and CD103⁺ malignant T cells, whereas SS lesions contained higher proportions of CD27⁺ and LAG3⁺ cells. IL 13⁺ malignant cells decreased after treatment, most prominently in MF. Myeloid profiles differed by disease and response: MF lesions exhibited baseline enrichment of M1-like macrophages (CD86⁺, HLA-DR⁺), while SS lesions were predominantly M2-polarized macrophages (CD163⁺, CD206⁺). Responders showed increased M1-like macrophages, whereas non-responders displayed reduced M1-features. An increase in DC3-like cells was observed in non-responders following treatment. Conclusions: This single-cell spatial atlas reveals shared and subtype-specific immune features in MF/SS. Th2-skewed malignant T-cell status and myeloid polarization correlate with clinical response, supporting their potential as spatial biomarkers for patient stratification in mogamulizumab therapy. Full article

Background: Novel Sézary syndrome (SS) biomarker genes identified previously through transcription profiling were examined for changes in expression after mogamulizumab treatment. Incorporating new biomarkers for measuring response to disease would improve clinical care. Objective: To assess novel SS biomarker and cytokine genes in patients treated with mogamulizumab with clinical response, blood response, and immunologic parameters. Methods: We performed a real-world case–control and case–case study analyzing the expression of SS biomarker genes in peripheral blood mononuclear cells (PBMCs) from six SS patients treated with mogamulizumab using qRT-PCR. Results: We demonstrated a reduced expression of SS biomarker genes in PBMCs of SS patients following mogamulizumab therapy. In our cohort, five of the SS biomarker genes (PLS3, TWIST1, KCNK1, DNM3 and TOX) showed statistically consistent high expression compared to normal PBMCs at baseline. After treatment with mogamalizumab, these five SS biomarkers showed significant correlations with skin response (p < 0.05) and three (TOX, TCRL3 and DNM3) with blood response (p < 0.05). A decrease in GATA3 expression correlated to an improvement in skin severity, and STAT4 inversely correlated to Sézary cell decrease (p < 0.05). Two cytokine genes, IL4 and IFNG, reflective of an immune response that is abnormal in SS, showed a trend to normalized expression with IL-4 decreasing and IFNG increasing after treatment. Limitations: This was a real-world study of patients who failed prior treatments, with a small sample size and variable timing between patient sample collection. Conclusions: Unique SS biomarker, cytokine and T cell transcription factor genes are valuable in assessing molecular and immune responses following treatment. Full article

Primary cutaneous anaplastic large cell lymphoma (pcALCL) is a type of cutaneous T-cell lymphoma (CTCL) classified as a CD30+ lymphoproliferative disorder along with lymphomatoid papulosis. Although it is the second most common subtype of CTCL after mycosis fungoides/Sézary syndrome, it remains rare, with an incidence of fewer than 0.5 cases per million person-years. Despite its histologic similarity to systemic anaplastic large cell lymphoma, pcALCL follows a largely indolent course with excellent outcomes, with disease-specific survival rates of 86–95% in contemporary series. This narrative review summarizes the clinical presentation, diagnostic evaluation, and management of pcALCL based on a semi-structured literature search, with emphasis on prospective studies and clinically relevant retrospective data. Diagnosis remains challenging due to overlap with other CD30-positive lymphoproliferative disorders and reactive conditions, requiring careful clinicopathologic correlation and exclusion of systemic disease. While regional lymph node involvement may be present, available evidence suggests it does not significantly impact prognosis, highlighting the importance of avoiding overtreatment. Management strategies are guided by disease extent, with strong evidence supporting skin-directed therapies, particularly radiation, for localized disease. For multifocal or relapsed disease, brentuximab vedotin demonstrates the most robust prospective data and has reshaped the treatment landscape; however, alternative systemic therapies, including methotrexate and retinoids, remain relevant in selected patients. Overall, current management is supported largely by non-randomized data, and key gaps remain in risk stratification, optimal sequencing of therapies, and management of uncommon aggressive variants. Full article

Cutaneous T-cell lymphoma (CTCL), primarily mycosis fungoides (MF) and Sézary syndrome (SS), has long been characterized as a neoplasm of mature memory T cells, based on monoclonal T-cell receptor (TCR) rearrangements and tissue-resident memory (TRM)/central memory (TCM) T-cell phenotypes. This review synthesizes converging population-genetic, multi-omic, and single-cell evidence to argue that this characterization is incomplete and that a progenitor-based model better accounts for the full spectrum of disease biology. We present evidence that initiating mutations arise in hematopoietic stem or early lymphoid progenitor survive thymic selection, and diversify after TCR assembly, resulting in branched evolution across both blood and skin. In SS, paired analyses reveal > 200 shared variants between CD34⁺ progenitors and Sézary cells, as well as signal-joint T-cell receptor excision circle (sjTREC) positivity, providing direct progenitor-level evidence. In MF, convergent signals, multiple malignant clonotypes per lesion, greater blood–skin than skin–skin clonotype overlap, and compartment-specific CNV subclones, implicate hematogenous seeding and reseeding. Population-scale lymphoid clonal hematopoiesis and lymphoid-pattern mosaic chromosomal alterations define a compatible antecedent state. Spatial single-cell atlases and trajectory analyses map site-conditioned programs in skin, including Th2-skewed cytokines, microbial responses, and UV signatures, that select and expand subclones and explain inter- and intra-patient heterogeneity. This framework reconciles mature immunophenotypes with upstream initiation and clarifies why compartment-focused therapies often reshape rather than eradicate disease. It yields testable predictions and actionable implications: trials should pair multicompartment cytoreduction with strategies that attenuate progenitor-derived reservoirs, restore immune balance, and repair skin barrier dysfunction. A progenitor-initiated, niche-adapted model provides a coherent scaffold for more durable control in CTCL. Full article

Background: Sézary syndrome (SS) is an aggressive leukemic variant of cutaneous T-cell lymphoma (CTCL) with distinct clinical and biological features compared to rarer entities such as primary cutaneous CD8⁺ aggressive epidermotropic cytotoxic T-cell lymphoma (PCAECTCL). Although recurrent genomic alterations in CTCL have been described, comparative analyses at the pathway level across biologically divergent subtypes remain limited. Here, we leveraged a conversational artificial intelligence (AI) platform for precision oncology to enable rapid, integrative, and hypothesis-driven interrogation of publicly available genomic datasets. Methods: We conducted a secondary analysis of somatic mutation and clinical data from the Columbia University CTCL cohort accessed via cBioPortal. Cases were stratified into SS (n = 26) and PCAECTCL (n = 13). High-confidence coding variants were curated and mapped to biologically relevant signaling pathways and functional gene categories implicated in CTCL pathogenesis. Pathway-level mutation frequencies were compared using Fisher’s exact tests, with effect sizes quantified as odds ratios. Tumor mutational burden (TMB) was compared using the Wilcoxon rank-sum test. Subtype-specific co-mutation patterns were evaluated using pairwise association analyses and visualized through oncoplots and network heatmaps. A conversational AI agent, AI-HOPE, was used to iteratively refine cohort definitions, prioritize pathway-level signals, and contextualize findings. Results: TMB was comparable between SS and PCAECTCL (p = 0.96), indicating no significant difference in global mutational load. In contrast, pathway-centric analyses revealed marked qualitative differences. SS demonstrated enrichment of alterations in epigenetic regulators, tumor suppressor and cell-cycle control pathways, NFAT signaling, and DNA damage response mechanisms, consistent with transcriptional dysregulation and immune modulation. PCAECTCL exhibited relatively higher frequencies of alterations involving epigenetic regulators and MAPK pathway signaling, suggesting distinct oncogenic dependencies. Co-mutation analysis revealed a more constrained and focused interaction landscape in SS, whereas PCAECTCL displayed broader and more heterogeneous co-mutation networks, indicative of divergent evolutionary trajectories. Notably, ERBB2 mutations were significantly enriched between subtypes (p = 0.031), highlighting a potential subtype-specific therapeutic vulnerability. Conclusions: This study demonstrates that SS is distinguished from PCAECTCL not by increased mutational burden but by distinct pathway-level architectures, particularly involving epigenetic regulation, immune signaling, and transcriptional control. These findings generate biologically grounded, testable hypotheses for subtype-specific therapeutic targeting and underscore the value of conversational AI as a scalable framework for accelerating discovery in translational cancer genomics. Full article

T-cell non-Hodgkin lymphomas, which arise from post-thymic mature T cells, constitute approximately 10–15% of all non-Hodgkin lymphomas. Their leukemic presentations, referred to here as mature T-cell leukemias, are relatively uncommon and present significant diagnostic and therapeutic challenges requiring an informed approach to diagnosis and management. The initial presentation is often persistent T-cell lymphocytosis that must be distinguished from reactive (non-malignant) causes. Unlike B-cell lymphocytosis, where clonality usually indicates malignancy, T-cell clonality can be detected in benign conditions such as autoimmune disorders and viral infections. Thus, establishing clonality is helpful but not sufficient, and a systematic diagnostic approach integrating clinical features, morphology, immunophenotype, and molecular findings is critical. This review outlines our approach to the diagnosis and treatment of four major subtypes of mature T-cell leukemias: T-cell prolymphocytic leukemia (T-PLL), adult T-cell leukemia/lymphoma (ATLL), T-large granular lymphocytic leukemia (T-LGL), and Sézary syndrome (SS). Each section includes a discussion of clinical features, workup, and treatment options. Full article

Background/Objectives: Mycosis fungoides (MF) and Sézary syndrome (SS) are chronic cutaneous T-cell lymphomas frequently associated with pruritus, psychological distress, and impaired quality of life (QoL). While the impact of MF/SS on patients’ quality of life is well recognized, data on the burden experienced by cohabitants remain limited. The aim of this study was to assess dermatology-specific quality of life in patients with MF/SS and their cohabitants and to explore its associations with pruritus severity, depressive symptoms, and disease stage. Methods: This cross-sectional study included 25 patient–cohabitant pairs (25 patients with MF/SS and their cohabitants living in the same household) recruited at a tertiary dermatology center. Patients completed the Dermatology Life Quality Index (DLQI), Beck Depression Inventory I (BDI-I), and pruritus intensity scales (Numeric Rating Scale and Visual Analogue Scale), whereas cohabitants completed the Family Dermatology Life Quality Index (FDLQI) to assess the family burden of the disease. Associations between quality-of-life measures, clinical characteristics, pruritus, and depressive symptoms were analyzed. Results: Patients reported moderate impairment in dermatology-specific quality of life (mean DLQI score of 9.3 ± 6.1), which was significantly greater in patients with advanced-stage disease (p = 0.022). Cohabitants also experienced moderate impairment in quality of life (mean FDLQI score of 8.0 ± 4.8), independent of disease stage. DLQI scores showed significant positive correlations with pruritus severity, depressive symptoms, and cohabitants’ FDLQI scores. Pruritus severity was a key determinant of impaired quality of life but did not differ significantly between disease stages. Conclusions: MF/SS are associated with a substantial multidimensional burden affecting both patients and their cohabitants. Quality-of-life impairment in family members correlates closely with patient-reported symptoms and well-being, supporting the concept of MF/SS as conditions affecting the patient–family unit. Incorporating caregiver perspectives and systematic symptom assessment may improve holistic management of MF/SS. Full article

Primary cutaneous lymphomas (PCLs) are a heterogeneous group of extranodal T- and B-cell neoplasms confined to the skin at diagnosis, characterised by distinct biological drivers, clinical behaviour, and therapeutic challenges compared with systemic lymphomas. Over the past decade, advances in genomic profiling, single-cell and spatial transcriptomics, and tumour microenvironment analysis have substantially refined the understanding of PCL pathogenesis, highlighting immune evasion, clonal heterogeneity, and compartment-specific disease dynamics as key determinants of outcome and treatment response. These insights have coincided with a rapidly evolving therapeutic landscape that includes immunomodulatory agents, targeted therapies, and ADCs, while also exposing persistent limitations related to diagnostic delay, response heterogeneity, resistance, and lack of validated predictive biomarkers. In this review, we provide a dermatology-focused synthesis of primary cutaneous lymphomas, integrating contemporary classification and clinicopathologic features with molecular pathogenesis and tumour microenvironmental insights of direct clinical relevance. We discuss current diagnostic and staging approaches, critically appraise established and emerging therapeutic strategies in cutaneous T- and B-cell lymphomas, and highlight unresolved clinical challenges and unmet needs, including biomarker integration, longitudinal disease monitoring, and translation of molecular advances into routine practice. Full article

Inducible costimulator (ICOS) is a costimulatory immune checkpoint receptor expressed on activated T-cells, while the ICOS ligand (ICOSL) is expressed on antigen-presenting cells. The ICOS–ICOSL axis promotes the survival of memory and effector T-cells and induces several immune responses. In addition, the ICOS–ICOSL interaction induces cell proliferation, cell survival, and cytokine production. The roles of ICOS and ICOSL in cutaneous T-cell lymphoma (CTCL) are unclear. In this study, we examined the roles of ICOS and ICOSL in CTCL. The tumor cells co-expressed ICOS and ICOSL, and the upregulated expression of ICOS and ICOSL reflected disease severity. Anti-ICOS and anti-ICOSL neutralizing antibodies inhibited both the in vitro and in vivo proliferation of CTCL cell lines. The anti-ICOSL neutralizing antibodies induced apoptosis and suppressed CCR4 expression on tumor cells, inhibiting CCR4–CCL17-mediated migration. These results suggest that the ICOS–ICOSL axis plays an essential role in CTCL pathogenesis, and targeting the ICOS–ICOSL axis could be a viable strategy for treating CTCL. Full article

Background/Objectives: Mycosis fungoides (MF) and Sézary syndrome (SS) are cutaneous T-cell lymphomas (CTCLs) with variable clinical outcomes. Peripheral blood (PB) involvement in MF/SS is an independent predictor of prognosis. Accurate laboratory determination of PB involvement by MF/SS cells, however, is an ongoing challenge. Both flow cytometry (FC) and morphology-based quantification are limited by the overlap of CTCL cells and reactive T-cells. This study looks at the optimization over time of CTCL blood burden evaluation. Methods: This retrospective study reviews CTCL blood assessment at Northwestern Memorial Hospital from 2012 to 2021. Test ordering and reporting practices for morphology-based Sézary cell counts and FC were evaluated. For each assay, quantitative and qualitative results were analyzed and compared including percentages and absolute counts of abnormal T-cell populations and pathologist interpretations. Results: A total of 514 patients were evaluated, with increasing numbers of both tests ordered over time. FC quantitative metrics showed a moderate to high correlation with morphology metrics, especially for absolute CD4+/CD7− counts (correlation coefficient = 0.901, p-value < 0.001). Qualitative pathologist interpretations had moderate agreement between methods (kappa = 0.58). The recent addition of TRBC1 clonality assessment to our FC assay further optimizes the evaluation for CTCL blood burden. Conclusions: Flow cytometry offers a reliable approach for blood staging in MF/SS, and morphologic assessment may be redundant. This study provides a foundation for designing a new FC approach with TRBC1. This comprehensive review of the evolution of our laboratory practices may serve as a guide for other institutions with similar clinical needs. Full article

Beyond their traditional role as short-lived antimicrobial cells, neutrophils are increasingly recognized as key regulators of adaptive immunity and tumor progression. This AI-assisted integrative review investigated the neutrophil–T-cell axis, particularly the role of Galectin-9 (Gal-9), across adult T-cell leukemia/lymphoma (ATL), Sézary syndrome (SS), coronavirus disease 2019 (COVID-19), and psoriasis. Leveraging AI tools (GPT-5 and Adobe Acrobat AI Assistant) for literature synthesis (2000–2025) and expert validation, we aimed to identify common immunological mechanisms. Across all conditions, neutrophils displayed persistent activation, elevated Gal-9 expression, and modulated T-cell interactions. In ATL and SS, neutrophilia correlated with poor survival and TCR signaling dysregulation, suggesting Gal-9-mediated immune modulation. In COVID-19 and psoriasis, neutrophil-derived Gal-9-linked innate hyperactivation to T-cell exhaustion and IL-17-driven inflammation. These findings define a recurring neutrophil–Gal-9 regulatory module connecting innate and adaptive immune responses. This study underscores the feasibility of combining AI-driven literature synthesis with expert review to identify unifying immunological mechanisms and therapeutic targets across malignancy and inflammation. Full article

Background/Objectives: Advanced-stage mycosis fungoides (MF) and Sézary syndrome (SS) are aggressive forms of cutaneous T-cell lymphoma (CTCL) for which treatment options are limited and prognosis is poor. Brentuximab vedotin (BV), an anti-CD30 antibody–drug conjugate, has demonstrated high response rates in patients with CD30 expression ≥ 10%. However, data on its efficacy in cases with low CD30 expression (<10%) remain scarce. Methods: This retrospective analysis evaluated the real-world efficacy of BV in patients with advanced-stage MF/SS and low CD30 expression. A retrospective analysis was conducted on 32 patients across 11 German CTCL expert centers. All patients had advanced-stage MF or SS with CD30 expression < 10% and received BV at the standard dose. Treatment response was assessed using EORTC-ISCL criteria. Results: All patients had received prior systemic therapies (median: 3) with 36% having undergone prior mono- or polychemotherapy. The study population included 30 MF (stage IIB) and two SS cases. The overall response rate (ORR) in this population was 53.1% (17/32). A complete response (CR) was achieved in 12.5% (4/32), a partial response (PR) was achieved in 40.6% (13/32), stable disease (SD) was seen in 18.8% (6/32), and progressive disease (PD) was seen in 28.1% (9/32). The median progression-free survival (PFS) was 4.0 months (arithmetic mean: 6.38; range: 0.5–15.5), and the median time to next treatment (TTNT) was 7.25 months (arithmetic mean: 7.30; range: 2.00–15.5). Conclusions: BV demonstrated encouraging activity in heavily pretreated advanced MF/SS with low CD30 expression, achieving an ORR comparable to that observed in patients with higher CD30 levels. While response rates were similar, PFS was shorter. These findings suggest that BV remains a potential therapeutic option in this patient population and merits further prospective investigation. Full article

Background/Objectives: High-frequency ultrasonography (HFUS) has gained increasing attention in dermatology as a non-invasive imaging technique capable of visualizing cutaneous structures with high resolution. In cutaneous T-cell lymphomas (CTCL), including mycosis fungoides (MF)/Sézary syndrome (SS), HFUS may provide an objective method for assessing disease activity and monitoring treatment response. This study aimed to evaluate the clinical utility of HFUS in detecting therapy-induced changes in subepidermal low-echogenic band (SLEB) thickness. Methods: We conducted a prospective, single-center study between May 2021 and May 2025. Thirty-three patients with histologically confirmed MF (n = 31) or SS (n = 2) underwent HFUS at baseline and after 4–8 weeks of treatment. SLEB thickness was measured before (E1) and after early treatment (E2). Patients received systemic agents, phototherapy, or topical regimens. Statistical analysis included mixed-model ANOVA with repeated measures to assess SLEB changes, and post hoc tests were applied to explore the influence of therapy type, age, and gender. Results: Among 31 evaluable patients with MF, HFUS revealed a significant reduction in SLEB thickness after treatment (0.90 ± 1.10 mm vs. 0.69 ± 0.89 mm; F(1,29) = 8.88, p = 0.006, η² = 0.23). The type of early therapy (systemic vs. topical) did not significantly affect outcomes (p = 0.452). Age emerged as a relevant factor: patients ≥ 66 years exhibited higher baseline SLEB values and a significant reduction post-treatment (p < 0.001), whereas no comparable effect was observed in younger patients. Gender did not significantly influence SLEB changes. Conclusions: HFUS is a sensitive and clinically applicable imaging tool for monitoring treatment response in MF/SS. Reductions in SLEB thickness were observed across therapeutic modalities and aligned with early clinical improvement. HFUS may serve as a valuable adjunct to standard clinical and histopathological evaluation in the routine management of MF/SS. Full article