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.

Evaluation of mortality, prognostic parameters, and treatment efficacy in mycosis fungoides.

BACKGROUND AND OBJECTIVES: Mycosis fungoides (MF), the most common primary cutaneous T-cell lymphoma, is characterized by a variable clinical course, presenting either as indolent disease or showing fatal progression due to extracutaneous involvement. Importantly, the lack of prognostic models and predominantly palliative therapy settings hamper patient care. Here, we aimed to define survival rates, disease prediction accuracy, and treatment impact in MF. PATIENTS AND METHODS: Hundred-forty MF patients were assessed retrospectively. Prognosis and disease progression/survival were analyzed using univariate Cox proportional hazards regression model and Kaplan-Meier estimates. RESULTS: Skin tumors were linked to shorter progression-free, overall survival and a 3.48 increased risk for disease progression when compared to erythroderma. The Cutaneous Lymphoma International Prognostic Index identified patients at risk in early-stage disease only. Moreover, expression of Ki-67 >20%, CD30 >10%, CD20+, and CD7- were associated with a significantly worse outcome independent of disease stage. Only single-agent interferon-α and phototherapy combined with interferon-α or retinoids/bexarotene achieved long-term disease control in MF. CONCLUSIONS: Our data support predictive validity of prognostic factors and models in MF and identified further potential parameters associated with poor survival. Prospective studies on prognostic indices across disease stages and treatment modalities are needed to predict and improve survival.

Additional Findings of 18 F-AIF-FAPI-42 PET/CT in a Patient With Mycosis Fungoides-Type Cutaneous T-Cell Lymphoma : Comparisons With 18 F-FDG PET/CT.

ABSTRACT: A 44-year-old woman presented with extensive skin patches and pruritus persisting for 3 years. Histopathological examination of the skin from the right abdomen confirmed mycosis fungoides-type cutaneous T-cell lymphoma. Staging PET with 18 F-FDG PET/CT) showed increased uptake in the skin on the right abdomen and left hip. Subsequently 18 F-FAPI-42 PET/CT revealed additional foci of abnormal uptake on the skin of the chest and back.

Experience With Bexarotene to Treat Cutaneous T-Cell Lymphomas: A Study of the Spanish Working Group of Cutaneous Lymphomas.

BACKGROUND AND OBJECTIVES: Bexarotene has been approved to treat advanced stage cutaneous T-cell lymphomas (CTCL) since 1999. However, very few data have been published on its long-term safety and efficacy profile. The aim of this study is to determine the tolerability to bexarotene and outcomes by collecting the 2nd largest case series to date on its long-term use vs CTCL. MATERIAL AND METHOD: This was a multicenter retrospective review of 216 patients with mycosis fungoides (174), or Sézary syndrome (42) on a 10-year course of bexarotene alone or in combination with other therapies at 19 tertiary referral teaching hospitals. RESULTS: A total of 133 men (62%) and 83 women (38%) were included, with a mean age of 63.5 year (27-95). A total of 45% were on bexarotene monotherapy for the entire study period, 22% started on bexarotene but eventually received an additional therapy, 13% were on another treatment but eventually received bexarotene while the remaining 20% received a combination therapy since the beginning. The median course of treatment was 20.78 months (1-114); and the overall response rate, 70.3%. Complete and partial response rates were achieved in 26% and 45% of the patients, respectively. Treatment was well tolerated, being the most common toxicities hypertriglyceridemia (79%), hypercholesterolemia (71%), and hypothyroidism (52%). No treatment-related grade 5 adverse events were reported. CONCLUSIONS: Our study confirms bexarotene is a safe and effective therapy for the long-term treatment of CTCL.

GZ17-6.02 interacts with bexarotene to kill mycosis fungoides cells.

GZ17-6.02, composed of curcumin, harmine and isovanillin, has undergone phase I evaluation in patients with solid tumors (NCT03775525) with an RP2D of 375 mg PO BID. The biology of GZ17-6.02 in malignant T cells and in particular those derived from mycosis fungoides (MF) patients, has not been studied. GZ17-6.02 alone and in combination with standard-of-care agents was effective in killing MF cells. All three components are necessary for optimal killing of MF cells. GZ17-6.02 activated ATM, the AMPK, NFκB and PERK and inactivated ERK1/2, AKT, ULK1, mTORC1, eIF2α, and reduced the expression of BCL-XL and MCL1. GZ17-6.02 increased ATG13 S318 phosphorylation and the expression of Beclin1, ATG5, BAK and BIM. GZ17-6.02 in a dose-dependent fashion enhanced autophagosome formation and autophagic flux, and tumor cell killing. Signaling by ATM and AMPK were both required for efficient killing but not for the dose-response effect whereas ER stress (eIF2α) and macroautophagy (Beclin1, ATG5) were required for both efficient killing and the dose-response. Knock down of the death receptor CD95 reduced killing by ~20% and interacted with autophagy inhibition to further reduce killing, collectively, by ~70%. Inhibition of autophagy and knock down of death-mediators downstream of the mitochondrion, AIF and caspase 3, almost abolished tumor cell killing. Hence in MF cells, GZ17-6.02 is a multi-factorial killer, utilizing ER stress, macroautophagy, death receptor signaling and directly causing mitochondrial dysfunction.

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) / Cost of Treating Cutaneous T-Cell Lymphoma in Spain: Analysis of MICADOS Study Data by Disease Stage

Antecedentes y objetivo No se dispone de datos españoles sobre el coste asociado al linfoma cutáneo de célulasT (LCCT). Además, la incorporación de nuevos tratamientos hace necesario analizar el coste real de la enfermedad. El estudio MICADOS analizó dos objetivos principales: Por un lado, evaluó el impacto en la calidad de vida en los pacientes con LCCT, y por otro lado, estudió los costes de la enfermedad. En esta publicación se recoge el segundo de los objetivos del estudio. Métodos El coste de la enfermedad se estudió bajo la perspectiva del Sistema Nacional de Salud (SNS) con un horizonte temporal de un año. Participaron 23 dermatólogos y hematólogos de 15 hospitales públicos españoles. Se incluyeron pacientes adultos con LCCT del tipo micosis fungoide (MF) y síndrome de Sézary (SS). Resultados Se incluyeron 141 pacientes, el 57,4% masculinos, con una edad media de 63,6 años (IC95%: 61,4-65,7). Los costes directos anuales medios por pacientes del estudio fueron de 34.214€, siendo de 11.952,47€ en estadioI, 23.506,21€ en estadioII, 38.771,81€ en estadioIII y 72.748,84€ en estadioIV. El coste anual directo total estimado de todos los pacientes en España con MF/SS resultó en 78.301.171€, donde el 81% de los costes fueron atribuibles a pacientes en estadioI, el 7% al estadioII, el 6% al estadioIII y el 6% al estadioIV. Conclusiones Este estudio ofrece una evaluación precisa del coste directo del LCCT en pacientes con MF/SS en España, mostrando costes que varían sustancialmente en función del estadio. Los costes soportados por el paciente y los costes indirectos deberán considerarse en futuras investigaciones (AU)

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 (AU)

[Translated article] 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 (AU)

Antecedentes y objetivo No se dispone de datos españoles sobre el coste asociado al linfoma cutáneo de célulasT (LCCT). Además, la incorporación de nuevos tratamientos hace necesario analizar el coste real de la enfermedad. El estudio MICADOS analizó dos objetivos principales: Por un lado, evaluó el impacto en la calidad de vida en los pacientes con LCCT, y por otro lado, estudió los costes de la enfermedad. En esta publicación se recoge el segundo de los objetivos del estudio. Métodos El coste de la enfermedad se estudió bajo la perspectiva del Sistema Nacional de Salud (SNS) con un horizonte temporal de un año. Participaron 23 dermatólogos y hematólogos de 15 hospitales públicos españoles. Se incluyeron pacientes adultos con LCCT del tipo micosis fungoide (MF) y síndrome de Sézary (SS). Resultados Se incluyeron 141 pacientes, el 57,4% masculinos, con una edad media de 63,6 años (IC95%: 61,4-65,7). Los costes directos anuales medios por pacientes del estudio fueron de 34.214€, siendo de 11.952,47€ en estadioI, 23.506,21€ en estadioII, 38.771,81€ en estadioIII y 72.748,84€ en estadioIV. El coste anual directo total estimado de todos los pacientes en España con MF/SS resultó en 78.301.171€, donde el 81% de los costes fueron atribuibles a pacientes en estadioI, el 7% al estadioII, el 6% al estadioIII y el 6% al estadioIV. Conclusiones Este estudio ofrece una evaluación precisa del coste directo del LCCT en pacientes con MF/SS en España, mostrando costes que varían sustancialmente en función del estadio. Los costes soportados por el paciente y los costes indirectos deberán considerarse en futuras investigaciones (AU)