Mogamulizumab demonstrated improved outcomes vs. vorinostat across a range of disease and patient characteristics in patients with mycosis fungoides or Sézary syndrome in the MAVORIC trial.

This post-hoc analysis further examined MAVORIC data to assess factors associated with long-term response (ORR >12 months), time to next treatment (TTNT), and impact of concomitant steroid use, lymphopenia, and mogamulizumab-associated rash (MAR) on patient response.

A higher proportion of patients achieved ORR lasting ≥4, 6, 8, or 12 months in the mogamulizumab vs. vorinostat arm. Long-term response was also observed in mogamulizumab-treated patients with more advanced disease (stage IVA1 [17/20], B2 blood involvement [18/20], and SS [14/20]). PFS was significantly longer (9.4 vs. 3.1 months; p < 0.0001) in mogamulizumab vs. vorinostat-treated patients taking concomitant steroids. Mogamulizumab-treated patients experienced longer TTNT vs. vorinostat. Lymphopenia and MAR were associated with response to mogamulizumab.

MAVORIC demonstrated greater efficacy with mogamulizumab vs. vorinostat in relapsed/refractory patients with CTCL, including those with more advanced disease. Concomitant steroid use improved ORR and PFS but did not impact vorinostat outcomes. Overall responses occurred more frequently in mogamulizumab-treated patients that developed lymphopenia than those that did not. A higher percentage of patients with MAR had an overall response than those without MAR.

We report the results of a pilot study investigating the combination of brentuximab vedotin (BV) and lenalidomide in patients with relapsed/ refractory T-cell lymphoma.

A dose escalation study design was utilized. Primary and secondary endpoints included maximum tolerated dose (MTD), adverse events, and response rates.

Six patients were treated with BV and two dose levels of lenalidomide, in 21-day cycles. The protocol-determined MTD was BV 1.8 mg/kg and lenalidomide 25 mg, however, all patients required subsequent dose reductions with ongoing treatment. The most common adverse event was peripheral neuropathy in four of six patients. Two patients achieved complete responses and three achieved partial responses.

The combination is deliverable with dose attenuation. Further study is needed to define clinical benefit.

This trial was registered on ClinicalTrials.gov (NCT number 03302728).

Mycosis fungoides, the most prevalent subtype of cutaneous T-cell lymphoma, primarily targets areas of the skin that of not exposed to sunlight. Nevertheless, it can involve extracutaneous tissues at any disease stage, especially during its advanced phases. Research suggests that all extracutaneous organs might be susceptible, though such cases are more commonly reported in autopsy studies and less so in clinical setting. The most recent comprehensive review of such extracutaneous manifestations in mycosis fungoides occurred almost a decade ago. With the aim of enhancing clinicians' understanding of these extracutaneous manifestations to improve diagnostic accuracy and patient outcomes, this updated review provides a current synthesis of the rare instances of extracutaneous involvement in mycosis fungoides.

A recently proposed staging system for folliculotropic mycosis fungoides (FMF) used clinical and histopathologic data to define 2 prognostic classes (ie early, advanced) for plaque-stage disease.

In this external retrospective single-center cohort, we assessed the prognostic ability of the proposed re-classification system and high-risk histopathologic features overall.

Patients with FMF were staged clinically. Skin biopsy specimens were reviewed for high-risk features. Patients with plaque-stage FMF were subcategorized as having early or advanced disease.

Of 81 patients with FMF (early-stage, n = 43; advanced-stage, n = 38), 40 had plaque-stage FMF (early plaque-stage, n = 24; advanced plaque-stage, n = 16). There was no difference in overall survival between early and advanced plaque-stage FMF. Of all cases, univariate analysis revealed associations between angioinvasion/angiodestruction and overall survival (hazard ratio, 6.04; 95% CI, 1.88-19.42; P = .003) and disease-specific survival (hazard ratio, 7.17; 95% CI, 1.76-29.33; P = .006), and between large cell transformation and disease-specific survival (hazard ratio, 4.91; 95% CI, 1.47-16.35; P = .010).

Few disease-specific deaths in the plaque-stage subgroup precluded analysis of disease-specific survival.

In this cohort, addition of histopathologic data to subdivide plaque-stage FMF into early and advanced groups added no prognostic value. However, certain histopathologic features including angioinvasion/angiodestruction and large-cell transformation did offer prognostic power overall.

The International Consensus Classification (ICC) of myeloid and lymphoid neoplasms follows the precedent set in the Revised European-American lymphoma classification for modern lymphoma classifications by defining specific diseases on the basis of all the available morphologic, immunophenotypic, genetic, and clinical findings. Primary cutaneous lymphomas exhibit a broad range of clinical behavior ranging from lesions which spontaneously regress to those which run an aggressive, often fatal course. Accurate separation of entities is therefore essential for prognostication and to ensure appropriate treatment is administered. However, despite marked differences in clinical course, many subtypes of primary cutaneous lymphoma exhibit remarkably similar, often overlapping, and sometimes indistinguishable pathologic features. While molecular analysis has furthered our understanding of some of these disease entities, it does not yet facilitate robust distinction. Thus, clinical correlation retains a central role in both the diagnosis and classification of primary cutaneous lymphoma. This review aims to draw attention to problem areas in differential diagnosis and hopefully offer some practical suggestions for resolving difficult cases. It will also highlight recent advances in the field and discuss how they reinforce the current classification system and how they might impact of future classifications and treatment strategies.

Background: Dermoscopy, a non-invasive diagnostic technique, is being increasingly used to evaluate cutaneous T-cell lymphomas such as mycosis fungoides (MF) and Sézary syndrome (SS). However, its diagnostic accuracy and role in staging remain underexplored. Objective: This study aimed to assess the dermoscopic patterns in MF and SS, correlating the findings with the disease stage and lesion type to evaluate dermoscopy's diagnostic utility. Methods: A retrospective, monocentric analysis was conducted on patients with histologically confirmed MF or SS. Dermoscopic images were evaluated for vascular patterns, pigmentation, scaling, and keratin plugs. The statistical analysis assessed the correlations between these dermoscopic features and the TNMB staging and lesion type. A literature review was also performed to contextualize the findings, focusing on studies describing dermoscopic features in MF based on retrospective, prospective, and cross-sectional data. Results: The study included 30 patients with histologically confirmed MF or SS (19 males and 11 females; mean age: 64.5 years). The dermoscopic evaluation revealed that all the lesions were pigment-free, with vascular structures as the predominant feature. Linear vessels (40%) and serpentine vessels (13.3%) were the most frequently observed, along with dotted vessels (36.7%) and clods (10%). The vessel distribution was diffuse (40%) or perifollicular (36.7%), with a predominant red (56.7%) or orange (40%) background. Scaling was present in 76.7% of cases, either diffuse (40%) or perifollicular (36.7%), and keratin plugs were detected in 40% of the lesions. No statistically significant correlations were found between dermoscopic features and the TNMB stage or lesion type (p > 0.05). A cluster analysis identified two patient groups with differing vascular and scaling features but no clear association with disease stage. The literature review identified studies that commonly reported features in MF dermoscopy, including fine, short linear vessels and an orange-yellow background, particularly in early-stage MF. Spermatozoa-like structures have been marked as highly specific for diagnosing MF. Some studies also suggested a transition in vascular morphology from linear vessels in early disease to branched vessels and ulceration in advanced stages. Conclusions: Our results showed some vascular patterns have some potential but lack sensitivity for staging MF and SS. The terminology used and the reproducibility of our results compared to those reported in the literature showed little consistency, with none of our cases showing spermatozoa-like structures. Moreover, the same issues with the use of non-reproducible terminology were noted across the studies because it is not standardized and due to different incongruent dermoscopic patterns. More significant prospective studies with standardized descriptors and larger groups are needed to refine its diagnostic and staging utility.

Mycosis fungoides (MF) and Sézary syndrome (SS) are the most common subtypes of cutaneous T-cell lymphoma. While MF generally follows an indolent course, a subset of patients will experience progressive and/or treatment-refractory disease. SS is an aggressive cutaneous T-cell lymphoma associated with high morbidity and mortality secondary to immune compromise and opportunistic infection. Although allogeneic hematopoietic cell transplant (allo-HCT) is currently the only available potentially curative treatment modality for MF/SS and is included in the National Comprehensive Cancer Network and the American Society for Transplantation and Cellular Therapy treatment guidelines, there is no published guidance regarding referral criteria, timing and allo-HCT approach to help guide clinicians caring for these patients.

Delphi survey of 32 specialists in dermatology (n = 9), transplant hematology/oncology (n = 10), nontransplant hematology/oncology (n = 8), and radiation oncology (n = 5) from across the United States. Consensus required agreement of ≥75% of participants.

Sixteen consensus statements were generated on 4 topics: 1) criteria for referral for consideration for allo-HCT, 2) allo-HCT preparative regimens and procedures, 3) disease status at the time of allo-HCT, and 4) multidisciplinary management in the pre- and post-transplant settings.

These clinical practice guidelines provide a framework for decision-making regarding allo-HCT for MF/SS and highlight areas for future prospective investigation.

Lichen planus (LP) is a chronic inflammatory disorder that affects the skin, mucous membranes, nails, and hair. Cutaneous LP (CLP) is characterized by violaceous, polygonal, flat-topped papules and plaques that are intensely pruritic. Although it can develop on any part of the body, it most commonly affects the flexor surfaces of the wrists, lower back, and ankles. This report presents an atypical case of LP in a 33-year-old woman who initially exhibited poikilodermatous changes with bluish-gray patches, persisting for a decade. Due to the overlapping clinical and histopathological features, an extensive diagnostic workup including pan-computed tomography, lymph node biopsy, and immunohistochemistry was performed to exclude poikilodermatous mycosis fungoides. One year later, skin examination and histopathological evaluation revealed the classical features of LP, leading to a definitive diagnosis. This case highlights an unusual presentation in which poikiloderma preceded the classic clinical picture of LP. Our findings contribute to the existing knowledge of LP by emphasizing the importance of recognizing atypical presentations for accurate diagnosis and management.

Denileukin diftitox (DD)-cxdl is a fusion protein comprising diphtheria toxin fragments A and B and human interleukin-2. This phase III, multicenter, open-label, single-arm registrational trial evaluated the efficacy and safety of DD-cxdl in patients with relapsed/refractory (R/R) cutaneous T-cell lymphoma (CTCL).

In the main study, which followed a dose-finding lead-in, DD-cxdl was administered intravenously daily (5 days; 9 µg/kg/d once daily) every 21 days for up to eight cycles. Patients in the primary efficacy analysis set (PEAS) were required to have stage IA-IIIB CTCL (mycosis fungoides and/or Sézary syndrome) and at least ≥one previous systemic therapy. The primary efficacy end point was objective response rate (ORR) using the Global Response Score. Secondary end points were duration of response (DOR), time to response (TTR), skin tumor burden, and safety and tolerability.

The PEAS included 69 patients (median age, 64.0 years). The ORR was 36.2% (95% CI, 25.0 to 48.7), including 8.7% with complete response. The median DOR was 8.9 months (95% CI, 5.0 to not estimable), and the median (Q1-Q3) TTR was 1.4 (0.7-2.1) months. A total of 84.4% of patients showed decreased skin tumor burden, with 48.4% showing a ≥50% decrease. Treatment-emergent adverse events (TEAEs) of special interest, most of which were grade 1 or 2, included infusion reaction (73.9%), hypersensitivity (68.1%), hepatotoxicity (36.2%), and capillary leak syndrome (20.3% [grade ≥3, 5.8%]). Other common TEAEs were nausea (43.5%) and fatigue (31.9%).

Efficacy and safety results show that DD-cxdl would potentially fulfill a serious, unmet medical need for patients with R/R CTCL.

The diagnostic challenges in early mycosis fungoides (MF) and other cutaneous T-cell lymphomas (CTCLs) persist despite advancements in molecular methods.

To provide a preliminary assessment of next-generation sequencing (NGS) in analysing TRG (T-cell receptor gamma locus) sequences for distinguishing CTCLs from benign inflammatory skin disorders.

NGS was used to assess TRG sequences in skin samples from clinicopathologically proven CTCLs and benign inflammatory skin disorders.

Our study analysed skin samples from a total of 36 participants, comprising 22 cases of CTCL, including 14 MF and 8 other CTCLs, alongside 14 cases of benign inflammatory skin disorders. According to LymphoTrack® criteria, monoclonality was detected in 16 (73%) of the 22 patients with CTCL. Specifically, in cases of MF, 10 of 14 (71%) were identified as monoclonal, with all 4 non-monoclonal cases being in the patch stage. For the other cases of CTCL, six of eight displayed monoclonality. Among the 22 patients with CTCL, 10 (45%) had multiple biopsies, with 8 (36%) displaying the same dominant clone across different sites. Among the 14 benign cases, only the case of erythrodermic psoriasis exhibited monoclonality. Our decision tree analysis suggests that a high frequency of the most abundant clone, its ratio to the third most abundant clone and TRG VγI segment usage are effective markers that can help in the diagnosis of CTCL.

A combination of the clone frequencies and TRG V segment usage may enhance diagnosis of MF and other CTCLs, helping to differentiate them from benign conditions. However, molecular diagnosis for patch-stage MF remains challenging.

Cutaneous T-cell lymphomas are a heterogeneous group of non-Hodgkin lymphomas. Early stages are often controlled with skin-directed therapy, such as topical corticosteroids, topical chlormethine gel, or UV therapy, whereas advanced stages often warrant a more aggressive approach with systemic antibody targeted therapy including mogamulizumab, brentuximab vedotin, or alemtuzumab. A retrospective cohort case series of 27 patients from Aarhus University Hospital, Denmark is presented, evaluating real-world outcomes of patients with cutaneous T-cell lymphomas treated with intravenous systemic targeted therapies from 2013 to 2023. The median age was 72 and the majority had Sézary syndrome or mycosis fungoides. All patients had relapsed/refractory advanced stage cutaneous T-cell lymphoma. Six patients received mogamulizumab, 12 patients received brentuximab vedotin, and 15 patients received alemtuzumab. Six patients received more than 1 of the systemic targeted treatments. Overall response rates were 78% for mogamulizumab, 65% for brentuximab vedotin, and 61% for alemtuzumab. Median time to progression was 2.5, 4, and 11 months, respectively. In conclusion, this paper offers a unique perspective on the complexities of clinical practice when managing advanced-stage cutaneous T-cell lymphomas and demonstrates the effectiveness of the therapies described, with particular emphasis on the promising results observed with alemtuzumab administered in a low-dose protocol.

Low-dose total skin electron beam therapy (TSEBT) is an effective treatment option for mycosis fungoides (MF) with proven palliative effects and reduced toxicity. Presented is an institutional analysis of survival/response rate and quality of life for MF patients with subgroup analysis of those possessing pathologic large cell transformation (LCT). This is a single institutional retrospective review of patients with mycosis fungicides treated from 2014 to 2023 with low-dose TSEBT. All patients received 12 Gy in 6 fractions every other day with the modified Stanford technique, with boosts to shadowed sites between treatments, completed in 2 weeks. Outcomes evaluated included clinical response, duration of and time to response, patient-reported quality of life, and physician-scored disease burden. Forty-six patients were included in the study, 28 male and 18 female, with a median age 66.5 (range 32.7-90.6). Stage IB was most common at the time of TSEBT (41.3%). Median follow up was 44.5 months. The overall response rate was 91.3% (52.2% partial response, 19.6% complete and near complete response). The median duration of response was 8.2 months (range, 6.1-28.7), and the median time to best response was 3.5 months (range, 2.7-5.6). Quality of life (QOL) and disease burden continued to show significant benefit after TSEBT (p<0.001). In a subgroup analysis, 18 patients (39.1%) were found to have large cell transformation (LCT) at diagnosis. LCT was associated with higher presenting stage prior to TSEBT (p=0.016) and a better response to treatment (p=0.040). However, median duration of response was only 7.4 months in the patients with LCT vs. 39.4 months in the patients without (p=0.003). Condensed Low-dose TSEBT is a convenient treatment with favorable clinical outcomes and low toxicities in patients with mycosis fungoides. Patients with LCT may have shorter duration of treatment response. Further studies are warranted to validate this finding.

Early mycosis fungoides (MF) and inflammatory dermatoses including psoriasis and chronic spongiotic dermatitis are often difficult to differentiate. We explored diagnostic markers differentiating MF from psoriasis and chronic spongiotic dermatitis via spatially resolved single-cell transcriptome analysis. Single-cell transcriptomics of intraepidermal T cells of MF patches, psoriasis, and chronic spongiotic dermatitis were analyzed using CosMx spatial molecular imager utilizing surface markers, including CD3 and CD4. An immunohistochemical study with potential markers was performed to verify clinical utility. Compared with psoriasis and chronic spongiotic dermatitis, 41 upregulated differentially expressed genes (DEGs) in MF were associated with the T-cell receptor (TCR) signaling pathway and apoptosis regulation. Protein-protein interaction network analysis of these DEGs revealed a main cluster associated with TCR signaling. Pathway enrichment analysis showed that apoptosis, Th17 cell differentiation, and TCR signaling pathways were enriched in MF. GNLY and FYB1, DEGs with the highest fold-change values, were selected as potential diagnostic biomarkers for MF. For immunohistochemistry, biopsy specimens from 150 patients diagnosed with patch MF with CD4+ immunophenotype (n = 56), psoriasis (n = 48), and chronic eczema (n = 46) were included. The sensitivity and specificity of granulysin (GNLY) for distinguishing MF and psoriasis/chronic spongiotic dermatitis were 67.9% and 93.6%, respectively. For FYN-binding protein 1 (FYB1), those values were 73.2% and 69.2%, respectively. The area under the receiver operating characteristic curve values of GNLY and FYB1 were 0.86 and 0.79, respectively. In conclusion, granulysin and FYB1 can be promising diagnostic biomarkers for differentiating early-stage MF from psoriasis and chronic spongiotic dermatitis.

Cutaneous T-cell lymphoma is a heterogeneous group of T-cell neoplasms, of which mycosis fungoides and Sezary syndrome are the most common. The prognosis depends on the stage of the disease. The early stage follows a protracted course with a five-year disease-specific survival of greater than 95% and is treated with skin-directed topical therapies, phototherapy, and oral drugs like methotrexate. Advanced disease has a five-year overall survival of less than 25% and requires management by systemic chemotherapeutic agents. This review article is the second part out of the two covering the staging, prognosis, and treatment from a dermatologist's perspective.

There are few studies in the literature comparing the effectiveness of topical treatments in early-stage mycosis fungoides (MF).

It was aimed to evaluate the clinical efficacy, side effects and topical treatment compliance with bexarotene or clobetasol propionate in early-stage MF.

A total of 40 patients with stage IA-IB MF were enrolled in the study. Twenty patients were treated with 1% bexarotene gel and 20 patients were treated with 0.05% clobetasol propionate ointment.

In the bexarotene group, 11 patients (55%) had complete clinical response (CCR) and 5 patients (25%) had partial response (PR) while in the clobetasol propionate group, 10 patients (50%) had CCR and 9 patients (45%) had PR. The median duration of remission was 10.5 months in the bexarotene group and 4 months in the clobetasol propionate group. The remission period was statistically significantly longer in the bexarotene group (p = 0.032). Irritation symptoms were statistically significantly more common in the bexarotene group (p = 0.001).

The limitation of the study was its retrospective design.

Both topical bexarotene and topical clobetasol propionate were found to be effective in MF. Irritation symptoms were more common with topical bexarotene. Moreover, the remission period with topical bexarotene was significantly longer.

Mycosis fungoides (MF) and Sézary syndrome (SS) are the most common subtypes of the heterogeneous group of cutaneous T-cell lymphomas (CTCL). With the expansion of the biologic treatment landscape, new treatment options have become available in recent years, most notably the C-C chemokine receptor 4 (CCR4)-directed monoclonal antibody mogamulizumab. Based on the phase III pivotal trial, mogamulizumab is recommended by the German S2k guidelines for the second-line treatment of stage IB and above SS and MF, after at least one prior systemic therapy. Since then, new insights on safety and efficacy of mogamulizumab were generated by post hoc analyses and real-world evidence. A panel of CTCL-experts discussed available literature and own experiences and developed relevant recommendations on the use of mogamulizumab in clinical practice in Germany. The recommendations cover patient criteria, prior therapies, use of mogamulizumab as monotherapy or combination therapy, management of side effects, duration of therapy, and monitoring schedules. The aim of these clinical recommendations is to support healthcare professionals in their decision-making and use of mogamulizumab in daily practice.

Mycosis fungoides (MF), Sézary syndrome (SS) and other cutaneous T-cell lymphomas (CTCLs) can have a severe impact on quality of life (QoL) and itch, but early MF is insufficiently investigated despite representing most patients. This single center study investigated associations between QoL/itch/depressive symptoms and clinical phenotypes in patients with CTCL with particular focus on early MF-stages.

Patients were included during routine dermatological care. The primary outcomes included Dermatology Life Quality Index (DLQI), EuroQoL 5D (EQ-5D) index, Montgomery-Åsberg Depression Rating Scale - Self report (MADRS-S), and itch measured with a visual analogue scale (VAS-itch).

In the total CTCL cohort (n=76), median EQ-5D index was impaired in female vs male patients (0.73 vs 0.85, p = 0.040). Among early MF patients (n=58), increased disease activity correlated with impaired DLQI (r = 0.413, p = 0.0014) and EQ-5D index (r = -0.317, p = 0.0161). Early MF patients with plaques vs only patches reported impaired EQ-5D index (median 0.725 vs 0.848, p = 0.0032) and increased itch (median VAS 3.27 vs 0.43, p = 0.0006). MF patients with stage IB vs IA reported impaired DLQI (median 5.00 vs 1.00, p = 0.0006), impaired EQ-5D index (median 0.725 vs 0.848, p = 0.0040) and increased itch (median VAS 3.37 vs 0.54, p = 0.0487).

Although early MF patients reported generally a mild impact on QoL, this study highlights the need for disease management optimization for subgroups of early MF patients, including those with plaques, stage IB and higher disease activity.

Mycosis fungoides (MF) is a rare malignancy that is characterized by the presence of circulating tumour cells (CTCs) in a subgroup of patients. Reliably distinguishing MF from inflammatory skin conditions is challenging.

To evaluate the potential benefits of next-generation sequencing (NGS)-based T-cell receptor rearrangement repertoire analysis in detecting clonal rearrangements in MF and inflammatory skin conditions.

Skin biopsies and blood samples from 33 patients with MF and 10 patients with inflammatory skin conditions were analysed using TRB and TRG NGS. Twenty-seven patients had early-stage IA (n = 19) and IB (n = 8) MF, and six had advanced-stage disease (IIB, n = 5; IIIA, n = 1).

Analysis applying standard abundance thresholds identified at least one clonal rearrangement in the skin DNA of 97% (n = 32/33) of patients with MF and in 90% (n = 9/10) of those with inflammatory skin conditions. To enhance specificity, an abundance and distribution-based approach was applied, which considered only rearrangements that significantly stood out from the physiological background as clonal (MF, n = 29/33; inflammatory skin conditions, n = 1/10), allowing for highly sensitive (88%) and specific (90%) discrimination between MF and other inflammatory skin conditions. CTCs were detected in 46% (n = 11/24) of patients with early-stage MF and in 60% (n = 3/5) of those with late-stage MF.

NGS-based T-cell receptor repertoire analysis is a highly sensitive and specific method for the differential diagnosis of early-stage MF vs. inflammatory skin conditions, and for the sensitive molecular detection of CTCs.

Human T-lymphotropic virus type-1 (HTLV-1) is endemic in some countries, including Brazil. HTLV-1 is the etiological agent of adult T-cell leukemia-lymphoma (ATLL), a rare and aggressive CD4+ T-lymphocyte malignancy. ATLL affects 1-5% of virus carriers. Dermatological involvement occurs in 40-70%. Diagnosis is based on clinicopathologic correlation and HTLV-1 serology. There are few therapeutic options so far.

This is an observational retrospective cohort study with ATLL patients followed in a tertiary hospital in São Paulo, Brazil. Data were collected at diagnosis. Survival curves using the Kaplan-Meier method were analyzed with log-rank test, univariate and multivariate analyses were performed with the Cox proportional hazards model.

Forty-four patients were studied, 24 females (54.5%), and 20 males (45.5%). The median age at diagnosis was 59.4 years. Classification at diagnosis was: 16 (36.4%) chronic (93.7% unfavorable, 6.2% favorable), 14 (31.8%) acute, 10 (22.7%) smoldering, four (9.1%) lymphoma, and none with primary cutaneous tumoral. Regarding skin lesions, 18 (40.9%) had plaques; 15 (34.1%) nodules/tumors; 11 (25.0%) papules; 10 (22.7%) erythroderma; seven (15.9%) patches; two (4.5%) ichthyosis; one (2.3%) purpuric lesions. Epidermotropism/exocytosis of lymphocytes was observed in 25 patients (62.5%), and Pautrier microabscesses in three (7.3%). Four patients (10.0%) had subcutaneous involvement, two (5.0%) folliculotropism, two (5.0%) angiocentrism, and one (2.5%) perineural involvement. Ten patients (25.0%) presented a lichenoid pattern. Thirty-four patients (79.1%) had increased lactate dehydrogenase; 20 (45.5%) lymphocytosis; six (13.6%) flower cells in peripheral blood; six (14.6%) hypercalcemia; five (12.2%) hypoalbuminemia. Beta-2 microglobulin was increased in all 24 cases investigated. Monoclonal T-lymphocytes were observed in the blood of 23 patients (76.7%) and the skin of 19 (76.0%). Thirty patients (68.2%) died. Median overall survival was 32.3 months. Acute and chronic unfavorable forms had worse prognoses, with median overall survival of 23.3 and 34.1 months, respectively (p = 0.0011). After multivariate analysis, Shimoyama classification (acute) and urea levels were associated with poorer prognoses.

We described a large Brazilian cohort of ATLL with cutaneous involvement. Description of clinical, pathology, laboratory, and follow-up data, and factors associated with poorer survival is essential to provide better care and to improve the quality of life of these patients.

This report describes the cases of two patients with mycosis fungoides and Sézary syndrome (MF/SS) who achieved clinical benefit with mogamulizumab combination therapies. Case 1 is a 56-year-old male with stage IIIB (T4NxM0B1) MF, which later progressed into SS, with ongoing skin symptoms (erythema, lichenified skin, and pruritis) and axillary and inguinal lymphadenomegaly. Skin-directed and systemic therapies failed to achieve a long-lasting response in this patient. Mogamulizumab (1 mg/kg once weekly for 4 weeks; once every 2 weeks thereafter) yielded temporary improvement in skin symptoms, but progression in the skin was confirmed after ~2 months. Subsequently, the combination of mogamulizumab with psoralen plus ultraviolet light A (PUVA) yielded a partial response; however, PUVA was discontinued due to phototoxicity and mogamulizumab was continued as monotherapy. At the latest evaluation, clinical improvement in the skin and reduced lymphadenomegaly were evident with ongoing mogamulizumab monotherapy; the patient is awaiting allogeneic hematopoietic stem cell transplantation. Case 2 is an 80-year-old male with stage IIIB (T4NxM0B1) granulomatous variant MF who presented with diffuse erythema with desquamation, ectropion, and inguinal lymphadenopathy. Treatment with oral prednisone and bexarotene failed to achieve adequate, long-lasting responses. Mogamulizumab (1 mg/kg once weekly for 4 weeks; once every 2 weeks thereafter) monotherapy yielded an initial improvement, characterized by less intense erythema, but the improvement was not sustained. Mogamulizumab was supplemented with oral prednisone and then PUVA; this combination resulted in improvement in the skin. PUVA was stopped due to unavailability, and methotrexate (10 mg once weekly) was initiated alongside continued mogamulizumab; this led to improvement in erythema. The patient continued mogamulizumab plus methotrexate with improving clinical status, prior to their death, which was deemed to be unlikely to be related to treatment. Our experience suggests that, in principle, mogamulizumab can be used in combination with other therapies; however, further research is needed.

Mycosis fungoides (MF) and Sezary syndrome (SS) are common entities among primary cutaneous lymphomas. Large cell transformation is challenging for diagnosis and therapy. Molecular mechanisms by which these lymphomas undergo this transformation are poorly defined. We studied the immunohistochemical status of p53 in these entities and assessed whether p53 expression could be a useful tool for diagnosis and assessment of transformation. We extracted patients with transformed and untransformed SS or MF from the French Study Group on Cutaneous Lymphoma database between 2014 and 2021, followed in the Rennes University Hospital. An immunohistochemical study of p53 expression was performed on the biopsies sampled as part of routine care. We compared p53 overexpression in the different groups. We included 25 patients with MF, 7 patients with transformed MF (T-MF), 11 patients with SS, and 5 patients with transformed SS (T-SS). Using a cut-off set at 30% expression of neoplastic cells, we noted an overexpression of p53 in T-MF and T-SS compared with nontransformed forms (47% vs. 12%, respectively, P < 0.01) and in MF compared with SS (23% vs. 7%, respectively, P < 0.01). Overexpression of p53 with a cut-off at 30% therefore seems to be a discriminating tool in the differential diagnosis of MF/SS versus their transformed forms as well as the differential diagnosis between MF and SS.

To highlight the importance of early recognition of hypopigmented mycosis fungoides (HMF) in cases of cutaneous hypochromia in children, with a view to an effective diagnostic and therapeutic approach.

Two cases of HMF in children are reported. The first case involves an eight-year-old boy with hypochromic macules on the trunk and root of the upper and lower limbs, while the second case is a six-year-old boy with widespread hypochromic patches. Both patients presented with prolonged evolution of hypopigmentation, leading to the suspicion of HMF after excluding other differential diagnoses. Histopathological and immunohistochemical tests were fundamental in confirming the diagnosis of HMF.

HMF is a less prevalent and less publicized form of mycosis fungoides and is more common in children and people with a high phototype. Its diagnosis is challenging and often requires multiple biopsies for confirmation. Treatment includes phototherapy and immunosuppressive therapy, depending on the patient's age and extent of lesions. Early recognition of HMF is crucial for proper management and to avoid complications associated with malignant evolution.

Background/objectives: Mycosis fungoides (MF) is a rare malignancy, with an indolent course in the early stages of the disease. However, due to major molecular and clinical heterogeneity, patients at an advanced stage of the disease have variable responses to treatment and considerably reduced life expectancy. Today, there is a lack of specific markers for the progression from early to advanced stages of the disease. To address these challenges, the non-interventional BIO-MUSE trial was initiated. Here, we report on a case study involving one patient, where combined omics analysis of tissue and blood was used to reveal the unique molecular features associated with the progression of the disease. Methods: We applied 10× genomics-based single-cell RNA sequencing to CD3+ peripheral T-cells, combined with T-cell receptor sequencing, to samples collected at multiple timepoints during the progression of the disease. In addition, GeoMx-based digital spatial profiling of T-helper (CD3+/CD8-), T-cytotoxic (CD3+/CD8+), and CD163+ cells was performed on skin biopsies. Results. The results pinpoint targets, such as transforming growth factor β1, as some of the mechanisms underlying disease progression, which may have the potential to improve patient prognostication and the development of precision medicine efforts. Conclusions: We propose that in patients with MF, the evolution of the malignant clone and the associated immune response need to be studied jointly to define relevant strategies for intervention.

Cutaneous T-cell lymphoma (CTCL) is a rare T-cell malignancy characterized by inflamed and painful rash-like skin lesions that may affect large portions of the body's surface. Patients experience recurrent infections due to a compromised skin barrier and generalized immunodeficiency resulting from a dominant Th2 immune phenotype of CTCL cells. Given the role of the unfolded protein response (UPR) in normal and malignant T-cell development, we investigated the impact of UPR-inducing drugs on the viability, transcriptional networks, and Th2 phenotype of CTCL. We found that CTCL cells were >5-fold more sensitive to the proteasome inhibitor bortezomib (Btz) and exhibited a distinct signaling and transcriptional response compared to normal CD4+ cells. The CTCL response was dominated by the induction of the HSP70 family member HSPA6 (HSP70B') and, to a lesser extent, HSPA5 (BiP/GRP78). To understand the significance of these two factors, we used a novel isoform selective small-molecule inhibitor of HSPA5/6 (JG-023). JG-023 induced pro-apoptotic UPR signaling and enhanced the cytotoxic effects of proteasome inhibitors and other UPR-inducing drugs in CTCL but not normal T cells. Interestingly, JG-023 also selectively suppressed the production of Th2 cytokines in CTCL and normal CD4+ T cells. Conditioned media (CM) from CTCL were immunosuppressive to normal T cells through an IL-10-dependent mechanism. This immunosuppression could be reversed by JG-023, other HSP70 inhibitors, Btz, and combinations of these UPR-targeted drugs. Our study points to the importance of the UPR in the pathology of CTCL and demonstrates the potential of proteasome and targeted HSPA5/6 inhibitors for therapy.

Cutaneous T-cell lymphomas (CTCL) are a heterogeneous group of extranodal non-Hodgkin's lymphomas characterised by a cutaneous infiltration of malignant monoclonal T lymphocytes. While this broad spectrum of disease with its varied etiopathogenesis, clinical features and management options are well characterised, an approach from a dermatologist's perspective is lacking in the literature. We strive to elucidate the approach from a clinician's point of view, especially in respect of clinical examination, investigations, staging and management options that are available in the realm of the dermatologists. This review article is the first part out of the two, covering the etiopathogenesis, clinical features and evaluation.

Cutaneous T-cell lymphomas (CTCL) are a rare collection of diseases, frequently associated with diagnostic challenges and complex management dilemmas. The multidisciplinary team is vital for accurate clinico-pathological diagnoses and for collaborative therapeutic decisions throughout the management journey, which frequently involves multiple lines of therapy. Radiotherapy (RT) is a highly effective skin-directed therapy for CTCL, commonly delivered as localised fields or as total skin electron beam therapy (TSEBT). Mycosis fungoides (MF) is the most common of the CTCL, and patients typically experience high rates of morbidity and long natural histories of relapse and progression. Patients with MF typically present with incurable disease; in these patients, RT has an established role in symptom- and disease-control, achieving excellent response rates and proven therapeutic benefits. The role of RT continues to evolve, with modern practices favouring lower doses to reduce toxicity risks and allow for re-irradiation. Less commonly, there are situations where RT has an integral role in the potential cure of patients with MF: firstly, in the setting of unilesional MF where localised RT alone may be curative, and secondly, in the setting of preconditioning prior to curative-intent allogeneic hematopoietic stem cell transplant for patients with advanced MF/Sezary syndrome, where conventional-dose TSEBT is indicated as the most effective single agent for maximal debulking of skin disease. Radiotherapy also has an important role in the management of the less common CTCL, including the curative treatment of localised primary cutaneous anaplastic large cell lymphoma. Despite proven efficacy and quality of life benefits, disparity exists in access to RT and TSEBT. World-wide, stronger multidisciplinary collaborations and greater patient advocacy are required to increase access to RT and improve equity of care for our patients with CTCL.

Background/Objectives: Cutaneous T-cell lymphoma (CTCL), including Mycosis fungoides (MF) and Sézary syndrome (SS), is a challenging-to-diagnose lymphoproliferative malignancy characterized by T-cell dysfunction and progressive cutaneous and extra cutaneous involvement. Disease severity assessment in CTCL is crucial for guiding treatment. This study aims to evaluate the interrater agreement and interrater reliability of mSWAT among dermatology residents and identify lesion types most prone to scoring variability. Methods: Sixteen dermatology residents with varied experience levels assessed 14 patients with confirmed MF/SS diagnoses. Using mSWAT, residents independently scored lesions severity on a standardized set of patient's photos. The results were compared with reference mSWAT scores provided by an experienced clinician. Descriptive statistics and the Shapiro-Wilk test were applied to evaluate data distributions, while Student's t-test assessed score deviations from reference values. Furthemore, we conducted a pilot the high frequency ultrasound (HFUS) study on a single patient, whose mSWAT score and photographs are also presented in the manuscript. Results: Significant discrepancies were observed in 64.29% of cases (9/14), with tumors and infiltrative lesions in erythrodermic SS patients posing particular scoring challenges. Misclassification of tumors as patches or plaques was a frequent issue, leading to underestimations in mSWAT scores. Residents' assessments of infiltrative lesions were also notably inconsistent. Conclusions: This study highlights significant interobserver variability in mSWAT scoring among less experienced dermatology residents, particularly with tumor and erythrodermic lesions. Findings underscore the need for enhanced training and standardized scoring protocols to improve mSWAT reliability. Similar to other comparable indices, such as PASI, the mSWAT should be employed consistently by the same physician during each assessment to systematically monitor and evaluate the skin condition of a patient under observation. However, broader application requires the acquisition of sufficient experience. The study suggests the use of the HFUS as an objective method of assessment of the skin lesion infiltration in MF/SS patients.

Peripheral blood involvement by MF/SS has significant implications for prognosis and treatment. Flow cytometry is commonly used to assess MF/SS by analyzing the ratio of CD26- and/or CD7-CD4 + T cells and assessment of immunophenotypic abnormalities. However, distinguishing normal from abnormal cells is not always easy. In this study, we aimed to establish quantitative thresholds to better distinguish normal CD4 + T cells from neoplastic CD4 + T cells. A retrospective analysis of flow cytometry data was performed on 30 MF/SS patients with a detectable abnormal T cell population (positive), 63 patients with suspected or confirmed cutaneous involvement without a detectable abnormal T cell population (negative), and 60 healthy controls (control). CD3 and CD4 median fluorescence intensity (MFI) was normalized to internal control subsets. Among the positive cases, 50% had CD3 expression outside ± 2 SD from the mean of the negative and control group in the CD4 + CD26- subset. The corresponding specificity of this threshold was 94%. The ± 2 SD threshold showed a sensitivity of 57% and a specificity of 94% for the CD3 intensity among the CD7-negative subset. For CD4 intensity, the ± 2 SD threshold had a sensitivity of 33.3% and specificity of 95% for the CD26-negative subset and a sensitivity of 37% and specificity of 95% for the CD7-negative subset. In our study, although changes in CD3 and CD4 intensity greater than ± 2 SD were specific for MF/SS, more subtle differences in the intensity of CD3 and CD4 should not be used as the sole abnormality to make a diagnosis of circulating MF/SS.

Background: Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma.

Objectives: This study was conducted to evaluate efficacy and safety of interferon (IFN) α-2a combined with phototherapy for early-stage MF.

Methods: Thirteen patients with early-stage MF received subcutaneous injections of IFN α-2a at 3 million IU combined with phototherapy three times per week for 6 months. Treatment efficacy was measured by changes in body surface area (BSA) score and modified severity-weighted assessment tool (mSWAT) score at 1, 3, and 6 months after treatment. Histopathologic examinations of skin lesions were performed before and after treatment.

Results: After 3 months of treatment, all 13 patients achieved a partial response, and BSA and mSWAT scores were significantly lower than those at baseline (p < 0.001). After 6 months, BSA and mSWAT scores were significantly lower than those at baseline (p < 0.001) and after 3 months (p < 0.05). Eleven patients achieved complete remission and two patients achieved a partial response (overall response rate, 100%). Histopathologic examination showed a significant decrease in the number of atypical lymphocytes in both epidermis and dermis. No severe adverse effects occurred.

Conclusion: IFN α-2a in combination with phototherapy may be an effective and safe alternative modality for early-stage MF.

Cutaneous T cell lymphoma (CTCL) is a potentially fatal clonal malignancy of T cells primarily affecting the skin. The most common form of CTCL, mycosis fungoides, can be difficult to diagnose, resulting in treatment delay. We performed single-cell and spatial transcriptomics analysis of skin from patients with mycosis fungoides-type CTCL and an integrated comparative analysis with human skin cell atlas datasets from healthy and inflamed skin. We revealed the co-optation of T helper 2 (TH2) cell-immune gene programs by malignant CTCL cells and modeling of the tumor microenvironment to support their survival. We identified MHC-II+ fibroblasts and dendritic cells that can maintain TH2 cell-like tumor cells. CTCL tumor cells are spatially associated with B cells, forming tertiary lymphoid structure-like aggregates. Finally, we validated the enrichment of B cells in CTCL and its association with disease progression across three independent patient cohorts. Our findings provide diagnostic aids, potential biomarkers for disease staging and therapeutic strategies for CTCL.

Pediatric Mycosis fungoides (MF) management extrapolates from adult guidelines, despite differing clinical aspects. Recommendations are essential to address unique challenges in this distinct patient group.

This project aims to derive consensus recommendations for pediatric MF management.

Experts from pediatric dermatology, general dermatology, dermatopathology, and pediatric hematology-oncology (N = 83) were invited to contribute to consensus recommendations. The process involved 3 electronic Delphi rounds, concluding with a final consensus meeting using a modified Nominal Group Technique for unresolved items.

Consensus included more clinical severity measures than tumor-node-metastasis-blood staging: pruritus, functional or esthetic impairment (eg, palms, soles, genitalia), quality of life impact, and psychological aspects (eg, embarrassment, anxiety, depression), plus parental anxiety. Ten recommendations were made for managing early and advanced pediatric MF. Disagreement emerged in choosing therapies beyond stage I of the disease.

This multinational initiative aimed to standardize optimal pediatric MF management and successfully generated consensus recommendations. Additional work is needed for structured, prospective protocols in advanced-stage pediatric MF.

Lack of pediatric hematologists-oncologists and patients' representatives.

Documentation of extended clinical severity and outcome measures is recommended. Addressing the need for structured protocols in advanced-stage pediatric MF and implementing systematic, prospective data collection is crucial.