The Role of Cytokines in Cutaneous T Cell Lymphoma: A Focus on the State of the Art and Possible Therapeutic Targets.

Cutaneous T cell lymphomas (CTCLs), encompassing mycosis fungoides (MF) and Sézary syndrome (SS), present a complex landscape influenced by cytokines and cellular responses. In this work, the intricate relationship between these inflammatory proteins and disease pathogenesis is examined, focusing on what is known at the clinical and therapeutic levels regarding the most well-known inflammatory mediators. An in-depth look is given to their possible alterations caused by novel immunomodulatory drugs and how they may alter disease progression. From this narrative review of the actual scientific landscape, Interferon-gamma (IFN-γ) emerges as a central player, demonstrating a dual role in both promoting and inhibiting cancer immunity, but the work navigates through all the major interleukins known in inflammatory environments. Immunotherapeutic perspectives are elucidated, highlighting the crucial role of the cutaneous microenvironment in shaping dysfunctional cell trafficking, antitumor immunity, and angiogenesis in MF, showcasing advancements in understanding and targeting the immune phenotype in CTCL. In summary, this manuscript aims to comprehensively explore the multifaceted aspects of CTCL, from the immunopathogenesis and cytokine dynamics centred around TNF-α and IFN-γ to evolving therapeutic modalities. Including all the major known and studied cytokines in this analysis broadens our understanding of the intricate interplay influencing CTCL, paving the way for improved management of this complex lymphoma.

Lymphomatoid Papulosis With T-cell Receptor-Gamma Delta Expression: A Clinicopathologic Case-series of 26 Patients of an Underrecognized Immunophenotypic Variant of Lymphomatoid Papulosis.

Lymphomatoid papulosis (LyP) has several histopathologic presentations. LyP featuring gamma-delta (γδ) T-cell receptor expression may masquerade as and may be misdiagnosed as aggressive cutaneous T-cell lymphoma, particularly primary cutaneous γδ T-cell lymphoma (PCGDTL) or γδ mycosis fungoides. We performed a clinicopathologic analysis of the largest series of LyP featuring γδ T-cell expression. We identified 26 patients with a diagnosis of LyP with γδ T cells from our institutions, as well as through a comprehensive review of the literature, and characterized these cases. Most cases were treated with topical steroids or not treated at all. The majority of cases showed a CD4 - CD8 + phenotype and featured at least one cytotoxic marker. Histopathologic features included an intraepidermal or dermal infiltrate with large cells and frequent angiotropism. One case was initially misdiagnosed as PCGDTL, requiring further therapy. Our case series, the largest international cohort of γδ T cell predominant LyP cases, confirms marked clinicopathologic heterogeneity that may contribute to misdiagnosis, reasserting the need to identify classic clinical features, CD30 + T-cell components, and markers of cytotoxicity when dealing with this differential diagnosis. A limitation of this study includes somewhat limited follow-up, histologic, and immunophenotypic information for some cases.

Genetic predisposition to early mycosis fungoides: investigating genetic polymorphisms in tissue-resident memory T-cell genes.

OBJECTIVES: Mycosis fungoides (MF) is the most common cutaneous T-cell lymphoma; it arises from tissue-resident memory T-cells (TRM). In the present study, we investigated potential functional genetic variations that may predispose MF development. METHODS: A case-control study was conducted using whole-exome sequencing, with a focus on genes that are essential to TRM function. RESULTS: We included 21 patients and 19 healthy subjects in the study. Single nucleotide polymorphisms in the following genes were significantly more common in patients than in healthy subjects: GZMB, HLA-DRB1, CD103, and NOTCH1. Moreover, the number of patients carrying single nucleotide polymorphisms in LAG3, NR4A2, and CD26L was significantly greater in the patient group than in the control group. CONCLUSIONS: The presence of genetic variations in one or more TRM functional gene may predispose patients to develop MF. Further studies involving a larger patient population and a comparative analysis of protein expression will be necessary to validate these findings.

Extracorporeal Photopheresis in Dermatological Diseases.

Extracorporeal photopheresis (ECP) is an apheresis procedure that is conventionally used as a first-line treatment for cutaneous and leukemic subtypes of T-cell lymphoma, such as Sezary's syndrome and mycosis fungoides. Over the past three decades, its immunotherapeutic properties have been tested on a variety of autoimmune conditions, including many dermatologic diseases. There is ample evidence of ECP's ability to modify leukocytes and alter cytokine production for certain dermatologic diseases that have been refractory to first-line treatments, such as atopic dermatitis. However, the evidence on the efficacy of ECP for the treatment of these dermatologic diseases is unclear and/or lacks sufficient evidence. The purpose of this paper is to review the literature on the utilization and clinical efficacy of ECP in the treatment of several [autoimmune] dermatologic diseases and discuss its applications, guidelines, recommendations, and future implementation for dermatologic diseases.

Differential Upregulation of Th1/Th17-Associated Proteins and PD-L1 in Granulomatous Mycosis Fungoides.

Granulomatous Mycosis Fungoides (GMF) is a rare form of mycosis fungoides (MF) characterized by a granulomatous infiltrate associated with the neoplastic lymphoid population and is considered to have a worse prognosis compared with regular MF. The upregulation of the T helper (Th) axis, especially Th17, plays an important role in the pathogenesis of several inflammatory/infectious granulomatous cutaneous diseases, but its role in GMF is still not elucidated to date. In this study, we evaluated the immunohistochemical expression of Th1 (Tbet), Th2 (GATA-3), Th17 (RORγT), T regulatory (Foxp3), and immune checkpoint (IC) (PD-1 and PD-L1) markers in a cohort of patients with GMF and MF with large cell transformation (MFLCT). Skin biopsies from 49 patients (28 GMF and 21 MFLCT) were studied. Patients with GMF were associated with early clinical stage (p = 0.036) and lower levels of lactate dehydrogenase (p = 0.042). An increased percentage of cells positive for Tbet (p = 0.017), RORγT (p = 0.001), and PD-L1 (p = 0.011) was also observed among the GMF specimens, while a stronger PD-1 intensity was detected in cases of MFLCT. In this cohort, LCT, RORγT < 10%, Foxp3 < 10%, age, and advanced stage were associated with worse overall survival (OS) in univariate analysis. GMF demonstrated Th1 (cellular response) and Th17 (autoimmunity) phenotype, seen in early MF and granulomatous processes, respectively, which may be related to the histopathological appearance and biological behavior of GMF. Further studies involving larger series of cases and more sensitive techniques are warranted.

Diagnostic Validation of Anti-TOX Antibody for Early-Stage Mycosis Fungoides Through Digital Analysis of Tissue Samples.

ABSTRACT: Mycosis fungoides (MF) has become one of the most difficult diagnostic challenges for both dermatologists and dermatopathologists because its clinical presentation and microscopic findings may mimic benign reactive processes, specifically those displaying histopathological features of interface dermatitis. The goal of our study was to prove with digital scanning and automated sample methodology through algorithmic analysis, combined with the utility of TOX marker a more precise, faster, and objective evaluation of each sample. Moreover, this would offer high levels of reproducibility with the possibility of establishing cut-off points, allowing us to distinguish between inflammatory dermatoses (ID) and MF. A retrospective longitudinal-descriptive and observational study was conducted to compare the diagnostic criteria (immunohistochemical studies of anti-TOX stain) in patients with clinical suspicion of MF by dividing them into 2 groups: samples with a positive biopsy for MF (MF group) and those with a negative biopsy, therefore diagnosed as an ID (control group). The algorithm assessed 5 selected areas with lymphocytic representative cellularity, and based on the intensity, nuclear staining was classified as 0 (negative), 1+ (weak/yellow), 2+ (moderate/orange), and 3+ (strong/scarlet red) nuclei. The results showed statistically significant differences ( P = 0.040) between the mean number of (2+) nuclei in the positive final diagnosis group (MF group) and the negative final diagnosis group (ID group).

Vitamin D in Cutaneous T-Cell Lymphoma.

Cutaneous T-cell lymphoma (CTCL) is characterized by the proliferation of malignant T cells in inflamed skin lesions. Mycosis fungoides (MF)-the most common variant of CTCL-often presents with skin lesions around the abdomen and buttocks ("bathing suit" distribution), i.e., in skin areas devoid of sun-induced vitamin D. For decades, sunlight and vitamin D have been connected to CTCL. Thus, vitamin D induces apoptosis and inhibits the expression of cytokines in malignant T cells. Furthermore, CTCL patients often display vitamin D deficiency, whereas phototherapy induces vitamin D and has beneficial effects in CTCL, suggesting that light and vitamin D have beneficial/protective effects in CTCL. Inversely, vitamin D promotes T helper 2 (Th2) cell specific cytokine production, regulatory T cells, tolerogenic dendritic cells, as well as the expression of immune checkpoint molecules, all of which may have disease-promoting effects by stimulating malignant T-cell proliferation and inhibiting anticancer immunity. Studies on vitamin D treatment in CTCL patients showed conflicting results. Some studies found positive effects, others negative effects, while the largest study showed no apparent clinical effect. Taken together, vitamin D may have both pro- and anticancer effects in CTCL. The balance between the opposing effects of vitamin D in CTCL is likely influenced by treatment and may change during the disease course. Therefore, it remains to be discovered whether and how the effect of vitamin D can be tilted toward an anticancer response in CTCL.

Tailoring Radiation Therapy for Patients With Limited Cutaneous T Cell Lymphoma: Preliminary Clinical Experience With Subtotal Skin Electron Therapy.

BACKGROUND/AIM: Total skin electron beam therapy (TSEBT) is an effective treatment for managing cutaneous T-cell lymphoma (CTCL), but may result in unnecessary toxicity. With the production of a custom rolling shield holding a configurable stack of plastic slats to block uninvolved skin, we implemented a program for subtotal skin electron beam therapy (STSEBT). We report our preliminary experience with STSEBT vs. TSEBT to manage CTCL. PATIENTS AND METHODS: A retrospective review of 32 CTCL patients who were treated at a single institution between February 28th, 2017, and May 25th, 2022, was completed. Of these cases, seven patients received STSEBT and 25 received TSEBT. RESULTS: Thirty-two patients underwent a course of STSEBT or TSEBT. The median follow-up was 465 days and the median age at diagnosis was 70.8 years. Stage distribution was as follows: one (3%) IA, 16 (50%) IB, 6 (19%) IIB, two (6%) IIIA, five (16%) IVA, and two (6%) IVB. The overall response rate was 96%. For patients receiving TSEBT (n=25), three (12%), 10 (40%), and 11 (44%) had a CR, NCR, and PR, respectively. For the patients receiving STSEBT, four (57.1%), three (42.9%), and zero (0%) had a CR, NCR, and PR, respectively. There was one patient (4%) with no response. Cumulative incidence of progressive skin disease requiring additional electron therapy at three months was 21.1% [IQR=8.6, 51.5%], 36.8% [IQR=20, 68%] at six months, and 57.9% [IQR=38.5, 87.1%] at one year. Low rates of toxicities were recorded. CONCLUSION: This analysis demonstrated that treatment of CTCL patients with low disease burden with STSEBT results in similar overall response and time to progression compared to treatment with TSEBT.

Clinical and Real-World Effectiveness of Mogamulizumab: A Narrative Review.

Mogamulizumab (MOG) is an antibody targeting the CCR4 receptor, authorized for relapsed or refractory peripheral T-cell (PTCL) and cutaneous T-cell lymphomas (CTCL). Its adoption in guidelines and endorsement by FDA and EMA established it as a systemic treatment, especially for advanced disease stages due to its comparatively lower toxicity. Clinical trials and real-world evidence have underscored its efficacy in advanced CTCLs, including mycosis fungoides and Sézary syndrome; PTCLs; and adult T-cell leukemia/lymphoma (ATLL), showcasing positive outcomes. Notably, the drug has demonstrated significant response rates, disease stability, and extended periods of progression-free survival, suggesting its applicability in cases with multiple treatment lines. Its safety profile is generally manageable, with adverse events (AEs) primarily related to the skin, infusion-related reactions, drug eruptions, autoimmune diseases, and skin disorders. The latter seem to appear as CCR4 can promote the skin-specific homing of lymphocytes, and MOG is directed against this receptor. While combination with immunostimulatory agents like interferon alpha and interleukin 12 has shown promising results, caution is urged when combining with PD1 inhibitors due to the heightened risk of immune-mediated AEs. The introduction of MOG as a systemic treatment implies a significant advancement in managing these diseases, supported by its favorable safety profile and complementary mechanisms.

Possible effects of plasminogen activator inhibitor-1 on promoting angiogenesis through matrix metalloproteinase 9 in advanced mycosis fungoides.

Mycosis fungoides (MF) progresses slowly before advancing to skin tumors followed by lymph node and visceral involvement. Among MF progression, stage IIB is an initial time point of tumor formation in MF. Since MF in tumor stage possess abundant blood vessels, it is important to evaluate the pro-angiogenic factors before and after MF in stage IIB. In this report, we investigated pro-angiogenic soluble factors in MF patients, as well as its pro-angiogenetic effects on tumor cells and stroma cells. We first evaluated the serum levels of pro-angiogenic factors in 9 MF patients without tumor formation and 8 MF patients with tumor formation. Among them, the serum MMP-9 and plasminogen activator inhibitors 1 (PAI-1) was significantly increased in MF with tumor formation compared in MF without tumor formation, leading to favorable formation of human dermal microvascular endothelial cells tube networks. Moreover, PAI-1 stimulation significantly increased the mRNA expression and protein production MMP-9 on monocytes derived M2 macrophages and HUT-78. Furthermore, since MMP-9 production from tumor cells as well as stromal cells is suppressed by bexarotene, we evaluate the baseline serum pro-angiogenic factors including MMP-9 in 16 patients with advanced cutaneous T cell lymphoma treated with bexarotene. The serum levels of MMP-2 and MMP-9 was significantly increased in bexarotene non-responded patients compared to responded patients. Our present study suggested the significance of MMP-9 and PAI-1 for the progression of MF stage toward to the tumor stage, and could be a therapeutic target in future.

Allogeneic transplantation and cellular therapies in cutaneous T-cell lymphoma.

INTRODUCTION: Mycosis fungoides (MF) and Sezary syndrome (SS) are the most common types of cutaneous T-cell lymphoma. Although many available treatments offer temporary disease control, allogeneic hematopoietic stem cell transplant (allo-HSCT) is the only curative treatment option for advanced stage MF and SS. CAR T-cell therapy is a promising new avenue for treatment. AREAS COVERED: In this review, we discuss the evidence supporting the use of allo-HSCT for the treatment of MF/SS, including disease status at the time of transplant, conditioning regimen, total body irradiation (TBI), and donor lymphocyte infusion (DLI). We also address the potential role for CAR T-cell therapy in CTCL. EXPERT OPINION: Allo-HSCT is an effective treatment for patients with advanced MF and SS. However, significant research is required to determine optimal treatment protocols. Data support the use of reduced-intensity conditioning regimens and suggests that the use of TBI for debulking of skin disease may result in more durable remissions. Donor lymphocyte infusions (DLI) appear to be particularly effective in inducing complete remission in MF/SS patients with relapsed or residual disease. Challenges with CAR-T therapies in T-cell lymphoma include T-cell fratricide due to shared antigens on malignant and nonmalignant T-cells, penetrance into the skin compartment, and CAR-T cell persistence.

[Translated article] Cost of Treating Cutaneous T-Cell Lymphoma in Spain: Analysis of MICADOS Study Data by Disease Stage.

BACKGROUND AND OBJECTIVE: The cost of treating cutaneous T-cell lymphoma (CTCL) in Spain is unknown. With the advent of new treatments, it is more important than ever to gain an accurate picture of the true costs involved. The MICADOS study had 2 primary objectives: 1)to evaluate the impact of CTCL on patient quality of life, and 2)to evaluate the costs associated with the disease. This article reports the results of the cost analysis. METHODS: We estimated the cost of treating CTCL over a period of 1year from the perspective of the Spanish National Health System. Twenty-three dermatologists and hematologists from 15 public hospitals analyzed data for adult patients with mycosis fungoides (MF) or Sézary syndrome (SS). RESULTS: A total of 141 patients (57.4% male) with a mean age of 63.6 years (95%CI: 61.4-65.7 years) were included. The mean direct annual cost of treating CTCL was €34,214 per patient. The corresponding costs by stage were €11,952.47 for stageI disease, €23,506.21 for stageII disease, €38,771.81 for stageIII disease, and €72,748.84 for stageIV disease. The total direct annual cost of treating MF/SS in public hospitals in Spain was estimated at €78,301,171; stageI disease accounted for 81% of all costs, stageII for 7%, and stagesIII andIV for 6% each. CONCLUSIONS: The MICADOS study offers an accurate picture of the direct cost of treating CTCL in patients with MF/SS in Spain and shows that costs vary significantly according to disease stage. Patient-borne and indirect costs should be analyzed in future studies.

Allogeneic stem cell transplant for treatment of mycosis fungoides and Sezary syndrome: a systematic review and meta-analysis.

Allogeneic hematopoietic stem cell transplant (allo-HSCT) has been noted to be a potential curative treatment in cases of advanced-stage mycosis fungoides (MF) or Sezary syndrome (SS). To assess outcomes of allo-HSCT for MF/SS we performed a systematic review and meta-analysis including 15 manuscripts and 557 patients, published from 2010-2023. Meta-analysis revealed 1-year and 3+year overall survival (OS) of 51% (95% CI 39-64%) and 40% (32-49%). Progression-free survival at 1 year and 3+years were 42% (31-53%) and 33% (25-42%). Non-relapse mortality was 18% (13-23%). Relapse occurred in of 47% (40-53%) with a median time to relapse of 7.9 months (range 1.6-24 months). Rates of acute and chronic graft-versus-host disease (GVHD) were 45% (35-55%) and 40% (33-48%). Reduced-intensity conditioning (RIC) was associated with superior OS compared to myeloablative conditioning (MAC) (58% vs. 30%, p < 0.001). Of patients with relapse after allo-HSCT, 46% treated with donor lymphocyte infusion (DLI) achieved complete remission. These data support use of allo-HSCT for treatment of advanced-stage MF/SS and suggest superiority of RIC over MAC. Rates of GVHD were comparable to allo-HSCT in general. The improved OS for RIC and high rate of CR with DLI underscore the importance of the graft-versus-lymphoma effect in allo-HSCT for MF/SS.

TOX, TWIST1, STAT4, and SATB1 protein expressions in early-stage mycosis fungoides.

BACKGROUND: Diagnosis of early mycosis fungoides (eMF) is challenging and often delayed as many of its clinical and histopathologic features may mimic various benign inflammatory dermatoses (BIDs). The products of the thymocyte selection-associated high mobility group box (TOX), twist family BHLH transcription factor 1 (TWIST1), signal transducer and activator of transcription 4 (STAT4), and special AT-rich sequence-binding protein 1 (SATB1) genes function as transcription factors and are involved in the pathogenesis of MF. OBJECTIVES: We aim to determine the diagnostic value of TOX, TWIST1, STAT4, and SATB1 protein expressions in eMF. METHODS: This non-randomized, controlled, prospective analytic study was conducted by performing immunohistochemistry staining with TOX, TWIST1, STAT4, and SATB1 polyclonal antibodies in lesional skin biopsies of eMF and BID patients. Nuclear staining of lymphocytes was compared between eMF and BIDs, and the capacity of these antibodies to predict eMF was determined. RESULTS: Immunostainings with anti-TWIST1 showed an increase in protein expression (p = 0.003) and showed a decrease with anti-SATB1 antibodies in eMF compared to BIDs (p = 0.005) while anti-TOX and anti-STAT4 antibodies did not exhibit significant differences (p = 0.384; p = 0.150). Receiver operating characteristic analysis showed that immunohistochemical evaluations of TWIST1 and SATB1 protein expressions can differentiate eMF (area under the curve [AUC]: 0.728, 95% confidence interval [CI]: 0.605-0.851, p = 0.002; AUC: 0.686, 95% CI: 0.565-0.807, p = 0.013). CONCLUSIONS: TWIST1 and SATB1 are potential diagnostic markers for the histologic diagnosis of eMF.

Cost of Treating Cutaneous T-Cell Lymphoma in Spain: Analysis of MICADOS Study Data by Disease Stage. / Evaluación de los costes asociados a la enfermedad de pacientes con linfoma cutáneo de células T en España: análisis en función del estadio clínico (estudio MICADOS).

BACKGROUND AND OBJECTIVE: The cost of treating cutaneous T-cell lymphoma (CTCL) in Spain is unknown. With the advent of new treatments, it is more important than ever to gain an accurate picture of the true costs involved. The MICADOS study had 2 primary objectives: 1)to evaluate the impact of CTCL on patient quality of life, and 2)to evaluate the costs associated with the disease. This article reports the results of the cost analysis. METHODS: We estimated the cost of treating CTCL over a period of 1year from the perspective of the Spanish National Health System. Twenty-three dermatologists and hematologists from 15 public hospitals analyzed data for adult patients with mycosis fungoides (MF) or Sézary syndrome (SS). RESULTS: A total of 141 patients (57.4% male) with a mean age of 63.6 years (95%CI: 61.4-65.7 years) were included. The mean direct annual cost of treating CTCL was €34,214 per patient. The corresponding costs by stage were €11,952.47 for stageI disease, €23,506.21 for stageII disease, €38,771.81 for stageIII disease, and €72,748.84 for stageIV disease. The total direct annual cost of treating MF/SS in public hospitals in Spain was estimated at €78,301,171; stageI disease accounted for 81% of all costs, stageII for 7%, and stagesIII andIV for 6% each. CONCLUSIONS: The MICADOS study offers an accurate picture of the direct cost of treating CTCL in patients with MF/SS in Spain and shows that costs vary significantly according to disease stage. Patient-borne and indirect costs should be analyzed in future studies.

Spatially Resolved Transcriptomes of CD30+-Transformed Mycosis Fungoides and Cutaneous Anaplastic Large-Cell Lymphoma.

Mycosis fungoides with large-cell transformation (MF-LCT) occurs in a minor proportion of aggressive lesions, which express CD30 similar to primary cutaneous anaplastic large-cell lymphoma (pcALCL). We investigated the differences in spatially resolved transcriptome profiles of MF-LCT and pcALCL using CD30 morphology markers and 28 and 24 regions of interest (ROIs) in MF-LCT and pcALCL, respectively. Differentially expressed genes, pathway analysis, and immune-cell deconvolution by selective analysis of CD30-positive tumor cells and CD30-negative extratumoral areas were undertaken. In CD30-positive ROIs of MF-LCT, 190 differentially expressed genes were upregulated (29 were directly or indirectly associated with extracellular matrix remodeling), whereas 255 differentially expressed genes were downregulated, compared with those of pcALCL. Except for cornified envelope formation and keratinization, all six pathways enriched in CD30-positive ROIs of MF-LCT were associated with extracellular matrix remodeling. In CD30-positive ROIs in MF-LCT compared with those in pcALCL, immune-cell deconvolution revealed significantly increased fibroblasts and M2 macrophages (P = 0.012 and P = 0.023, respectively) but decreased M1 macrophages (P = 0.031). In CD30-negative ROIs in MF-LCT compared with those in pcALCL, memory B (P = 0.021), plasma (P = 0.023), and CD8 memory T (P = 0.001) cells significantly decreased, whereas regulatory T cells (P = 0.024) increased. Predomination of extracellular matrix remodeling pathways and immunosuppressive microenvironment in MF-LCT indicates pathophysiological differences between MF-LCT and pcALCL.

Generalized early inflammatory morphea mimicking interstitial T-cell lymphoma: A diagnostic pitfall.

Early generalized morphea can clinically mimic mycosis fungoides. The microscopic features of early inflammatory morphea may show variable degrees of infiltration and do not have the characteristic dermal collagen sclerosis. We report the case of a 63-year-old female patient who presented with a 2-month history of an asymptomatic skin rash. Physical examination revealed multiple erythematous to dusky patches on the trunk and thighs, resembling the patch stage of mycosis fungoides. Two skin biopsies were performed, both of which showed prominent interstitial lymphoid infiltration in the reticular dermis without dermal sclerosis. Small lymphocyte exocytosis and lining along the dermal-epidermal junction were observed focally in the epidermis. Small clusters of plasma cells and eosinophils were observed in perivascular areas. Although no predominant clonality was found for CD4 and CD8 stains, 50% loss of CD5 antigen and 90% loss of CD7 antigen expression were apparent in immunohistochemical studies. Subsequent blood tests showed a normal blood cell count and positive human T-lymphotropic virus Type 1 antibodies. The overall findings suggested interstitial mycosis fungoides or early adult T-cell lymphoma-leukemia. The patient refused aggressive treatment, and 3 months later, she presented with indurated plaques from the previous rash. A repeat biopsy revealed the typical features of morphea. This report discussed the pitfalls in the clinical and histopathological diagnosis of early generalized inflammatory morphea that both clinicians and pathologists should consider.