Search Results (161)

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

Introduction: Cutaneous T cell lymphoma (CTCL), most commonly known as mycosis fungoides (MF), is characterized by an increasingly immunosuppressive tumor microenvironment (TME) as the disease progresses. Cancer-associated fibroblasts (CAFs) are key stromal components that support a permissive niche, in part through the secretion of small extracellular vesicles (sEVs), predominantly exosomes, that mediate intercellular communication. We investigated the immunomodulatory role of exosome-enriched sEVs derived from MF fibroblasts (MF-Fs) compared to normal fibroblasts (N-Fs). Materials and Methods: Primary MF-Fs from early-stage MF biopsies and N-Fs from healthy skin were cultured in vitro. sEVs enriched with exosomes were isolated by ultracentrifugation and characterized by flow cytometry (CD81), electron microscopy, Nanosight analysis, and protein quantification, and their uptake by normal peripheral blood mononuclear cells (nPBMCs) was confirmed using PKH26-labeled sEVs. nPBMCs, monocytes, CD4⁺ and CD8⁺ T cells from healthy donors were exposed to MF-F or N-F sEVs. Cell viability was assessed using MTT and trypan blue exclusion assays. Mass cytometry (CyTOF) profiled immune subsets and regulatory proteins for preliminary observation. Monocyte polarization was evaluated by flow cytometry for M1 (CD80, CD86) and M2 (CD163, CD206) markers and PD-L1 expression; M1/M2-associated cytokines and sEV-microRNAs were quantified by qRT-PCR. Results: Both MF-F and N-F sEVs were internalized by nPBMCs and reduced their viability, with a more pronounced effect observed for MF-F sEVs. In nPBMCs, MF-F sEVs also increased the frequency of M2-like macrophages, decreased M1 polarization, and enhanced PD-L1 expression. In primary monocytes, MF-F- compared with N-F-derived sEVs upregulated M2-associated cytokines (IL-10, TGF-β), increased PD-L1 expression, and generated M2-like cells that suppressed CD4⁺ and CD8⁺ T cell viability. Conclusions: MF-F sEVs promote an immunosuppressive TME and represent potential therapeutic or biomarker targets in MF. Full article

Cutaneous hematologic neoplasms in children are relatively rare and encompass a wide range of lymphoproliferative and myeloproliferative disorders. This review explores and updates the classification, clinical presentation, diagnostic challenges, histopathology, and management of pediatric lymphomas, lymphoproliferations, and leukemias that may be seen in the skin. The most frequent of them are lymphomatoid papulosis (LyP) and mycosis fungoides (MF), and are discussed first, with a particular focus on differential diagnosis and overlaps with benign lesions—mainly pityriasis lichenoides—which raises questions regarding the delineation of these entities and their potential interconnection. It is important to underline that most cutaneous lymphoproliferations are indolent in children: primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder, subcutaneous panniculitis-like T-cell lymphoproliferation (non-associated with HAVCR2 mutations), primary cutaneous marginal zone lymphoproliferative disorder, and EBV-related lymphoproliferative disorders. However, aggressive hematologic malignancies, although rarer, must not be missed; these are mostly leukemias (but not all forms) and blastic plasmacytoid dendritic cell neoplasm. We emphasize the importance of clinical–pathological correlation, with clonality studies playing a crucial role in some cases. Management strategies are briefly reviewed, ranging from skin-directed therapies like phototherapy and corticosteroids to systemic treatments for more aggressive forms of leukemia cutis and lymphomas. Full article

Cutaneous pseudolymphomas are benign reactive lymphoid proliferations that often mimic cutaneous lymphomas both clinically and histologically. A diverse array of inflammatory, infectious, and drug-induced dermatoses can closely resemble cutaneous T-cell lymphomas (CTCLs), particularly mycosis fungoides (MFs), posing significant diagnostic challenges. These mimickers may show histopathological features such as epidermotropism, dense lymphocytic infiltrates, or even clonality, making accurate differentiation crucial to avoid overtreatment. This review endeavors to comprehensively discuss the clinicopathologic features of the various inflammatory and infectious dermatoses that may simulate CTCL, drawing on illustrative examples across disease categories. By highlighting important comparative features and emphasizing the importance of clinicopathologic correlation, this review outlines practical strategies for distinguishing true lymphoma from its inflammatory mimics. 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

Background/Objectives: A “misnomer” is a term that is erroneous or inaccurate. Dermatology is replete with well-established misnomers such as “Mycosis fungoides”, “keratoacanthoma”, “actinomycosis”, “granuloma pyogenicum”, or “Kaposi sarcoma”. Misnomers have originated from misconceptions or mistranslations that were passed down historically, and reflect the comparative–descriptive origin of terminology. We aimed to collect and categorize (non-)dermatological misnomers and to assess strategies for abandoning them. Methods: A questionnaire-based survey with 411 senior academic physicians of five university hospitals in Switzerland was conducted to evaluate the frequency of misnomers across dermatology and other specialties. In addition, a systematic review was conducted, complemented by manual searches to collect medical misnomers. Results: The survey and systematic review yielded 536 non-dermatological and 168 dermatological misnomers, pointing to a particular abundance of misnomers in dermatology, which could be categorized into seven categories. A wrong pathological concept was the most common origin of misnomers. Amongst dermatologists, 60.0% regarded misnomers as a relevant problem in their specialty compared to only 35.5% of non-dermatologists. Preferred strategies for abandoning misnomers were avoidance, consensus definitions, and information in teaching. Conclusions: Our results show that misnomers are particularly abundant in dermatology, indicating the need to modernize terminology. 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 and Objectives: Mycosis fungoides (MF) is the predominant subtype of cutaneous T-cell lymphoma, whereas large plaque parapsoriasis (LPP) closely resembles early-stage MF, making differential diagnosis challenging. Immune markers, such as CD47, CD163, and B7-H3, play crucial roles in tumor immune evasion and macrophage polarization. However, their expression profiles and potential diagnostic or prognostic implications in early-stage MF and LPP remain poorly defined. Therefore, this study aimed to evaluate the expression of CD47, CD163, and B7-H3 in early-stage MF and LPP and analyze their associations with clinicopathological characteristics and patient outcomes. Materials and Methods: This retrospective study evaluated the immunohistochemical expression of CD47, CD163, and B7-H3 in 46 patients with early-stage mycosis fungoides (MF) and 46 patients with large plaque parapsoriasis (LPP). Expression levels were assessed using an immunoreactivity scoring system and analyzed for their associations with clinical parameters and disease-free survival (DFS). The study included patients diagnosed and followed at Sivas Cumhuriyet University between 1 March 2015 and 31 March 2025. Results: High CD47 expression was detected in 72.7% of MF patients, high B7-H3 expression in 45.7%, and high CD163 expression in 46.7% compared with LPP patients (p < 0.001). These markers showed positive correlations, and elevated expression, especially of B7-H3 and CD163, was associated with shorter disease-free survival in univariate analysis. Conclusions: The higher expression of CD47, CD163, and B7-H3 in early-stage MF compared with LPP suggests that these markers may contribute to the differential diagnosis and could represent potential therapeutic targets; however, their independent prognostic value requires confirmation in larger studies. Full article

Mycosis fungoides (MF) is a rare primary cutaneous T-cell lymphoma (pCTCL) that generally has an indolent course with a favorable prognosis. However, numerous clinical variants have been described that differ substantially from classic Alibert–Bazin MF, resulting in altered prognosis, treatment response, and patient outcomes. This narrative review considers rare MF variants—bullous, ichthyosiform, hypopigmented, folliculotropic, poikilodermatous, granulomatous, granulomatous slack skin, pagetoid reticulosis and syringotropic MF—with emphasis on practical diagnostic approaches for clinicians. Given that MF can mimic more than 50 different dermatoses and is frequently associated with prolonged diagnostic delay, we provided detailed clinical and dermoscopic features that should raise diagnostic suspicion and guide biopsy decisions. We discussed extensive differential diagnoses for each variant and highlighted MF’s status as dermatology’s “great imitator.” Additionally, we addressed the risk of second primary malignancy in patients with MF, as well as the genetic and microenvironmental factors proposed to contribute to its clinical heterogeneity. Furthermore, we evaluated existing classification systems and suggested future directions that integrate molecular data and tumor biology to improve prognostic assessment and guide therapeutic decision-making. 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

Background/Objectives: Hypopigmented mycosis fungoides (hMF) is a rare variant of mycosis fungoides (MF) often seen in younger patients and individuals with darker skin phototypes. The lesions develop as hypopigmented patches or plaques, and they are usually asymptomatic and respond well to topical treatment or phototherapy. Methods: We provide a systematic review on hMF with onset at or beyond 30 years of age, based on SCOPUS, PubMed, and Embase databases. A total of 13 original articles, totaling 34 patients, were included in this review. Evidence was limited to case reports and small series; PROSPERO registration is CRD420251181894. Results: The majority of cases did not progress beyond stage IB and commonly used treatment methods, including topical corticosteroids and phototherapy. In three patients, a progression of the disease occurred, and in two of them it was fetal. Among patients receiving phototherapy, PUVA therapy achieved complete remission more often than UVB (13 out of 17 cases vs. 8 out of 16 cases). Although recurrences occurred with both treatments, they were less frequent, and relapses took longer to develop in the PUVA group. Conclusions: In this cohort, PUVA appeared to be associated with higher complete response rates and longer remission duration than UVB. However, this advantage of PUVA is derived from low-level evidence and should be confirmed in prospective comparative studies. 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