Mycosis Fungoides Patients Research Articles

Effects of Extracorporeal Photopheresis on Quality of Life and the Course of Diseases in Patients With Mycosis Fungoides and Graft-Versus-Host Disease: A Single-Center Analysis.

The aim of the study was to systematically analyze the influence of extracorporeal photopheresis (ECP) on the quality of life (LQ) and the course of the disease in patients with Mycosis Fungoides (MF), as well as with Graft-versus-Host Disease (GvHD). LQ was monitored retrospectively by using the dermatology life quality index (DLQI) and Skindex-29 test before ECP onset and after the last ECP. Disease parameters were assessed by objective criteria i.e. number of associated medical drugs taken, intervals between therapeutic cycles, gradual change of the disease, and eventual side-effects and complications of ECP therapy. Fifty-one patients were treated with ECP during 2008-19; 19 out of 51 died, and follow-up was not completed in 13 patients. Finally, treatment protocols of 671 ECP procedures were evaluated in 19 patients (10 MF; 9 GvHD).MF and GvHD subpopulations did not differ in the individual scores of LQ questions, either before the outsetor after the last ECP. DLQI and Skindex-29 scores were ameliorated by the ECP therapy (p= 0.001 and p< 0.001, respectively) due to improvement of individual scores of feelings, daily/social activities (p< 0.05), and functionality (p≤ 0.05). The median interval between ECP cycles was extended from two to eight weeks (p= 0.001). Needs of GvHD patients for drugs being received for the underlying disease were reduced (p= 0.035). Two of the 10 MF patients worsened from stage IIA to IIIA. Severe or minor side effects leading to a therapy interruption were not recorded. Patients with GvHD experienced a notable decrease in the administration of drugs for their underlying condition, and there were no instances of severe side effects that resulted in the discontinuation of treatment. ECP is safe and effective for the treatment of MF and GvHD.

Risk of skin cancers in mycosis fungoides patients receiving PUVA therapy: A real-life experience from a single tertiary center.

Mycosis fungoides (MF) is the most common cutaneous T-cell lymphoma. Skin-directed therapies, including phototherapy, are the first-line treatment modalities. Psoralen plus ultraviolet A light photochemotherapy (PUVA) is quite effective in controlling the disease; however, long-term adverse effects, particularly carcinogenesis, are the cons of this treatment. There are various studies on the negative impact of PUVA on skin cancer in patients with autoimmune skin diseases. The data on the long-term effects of phototherapy on MF patients are scarce. All MF cases that received PUVA alone or combined with other treatments at a single tertiary center were analyzed. This study compared the development of non-melanoma skin cancers, melanoma, and solid organ tumors in MF patients with at least 5-year follow-up data with age- and sex-matched controls. A total of 104 patients were included in the study. Ninety-two malignancies were detected in 16 (15.4%) patients, and six developed multiple malignancies. Skin cancers consisted of 56 basal cell carcinomas, 16 Bowen's disease, four squamous cell carcinomas, three melanomas, two basosquamous cell carcinomas, one Kaposi sarcoma, and one keratoacanthoma were found in nine (8.7%) patients. Eight patients developed three solid cancers and six lymphomas. The risk of developing skin cancer was associated with the total number of PUVA sessions (<250 vs ≥250 sessions; hazard ratio (HR) 4.44, 95% confidence interval (CI) 1.033-19.068; p = .045). 9 (13.2%) of 68 patients who had follow-ups for at least 5 years developed skin cancer. Compared to an age- and sex-matched cohort, the prevalence of new skin cancer was considerably greater (p = .009). Patients with MF are predisposed to develop secondary malignancies, and continual exposure to PUVA may potentiate this risk. Annual digital dermoscopic follow-up in MF patients treated with UVA is advised for early diagnosis and treatment of secondary cutaneous malignancies.

A Man with Worsening Scaling Plaques and a New Onset Large Draining Ulcerated Tumor

Mycosis Fungoides (MF) is the most common form of cutaneous T-cell lymphoma, a rare condition which typically presents with erythematous patches and plaques, skin nodules and/or tumors. Advanced disease may progress to a more aggressive form known as a large-cell transformation (LCT). MF may be easily confused for psoriasis, a deep fungal infection, and pyoderma gangrenosum. Psoriasis and MF share common features associated with the abnormal functioning of T cells, and in the absence of an infectious process, pyoderma gangrenosum (PG) may be considered. Definitive diagnosis relies upon histopathology revealing characteristic features of MF including cerebriform nuclei, intraepidermal Pautrier microabscesses, epidermotropism and haloed lymphocytes, ruling out the other etiologies. Here is a case of a 62-year-old male with an atypical case of MF with LCT who presented with worsening skin eruption and a large draining ulcerated abdominal plaque. MF is typically a slow and indolent disease with multiple treatment options. Brentuximab vedotin (BV) is a monoclonal antibody targeting the CD30 antigen on cancer cells and is increasingly used in the treatment of MF patients with LCT. The patient was referred to hematology/oncology where further workup revealed CD30 positive large T-cells. He was started on BV and has already shown signs of significant disease regression.

Tape stripped stratum corneum samples are suitable for diagnosis and comprehensive proteomic investigation in mycosis fungoides.

Mycosis Fungoides (MF) is a common cutaneous T-cell lymphoma. It can sometimes be challenging to diagnose MF using current clinico-histopathological criteria. Non-invasive molecular profiling analysis has the potential to aid the diagnosis and understanding of MF. Lesional and body site matched normal stratum corneum samples were obtained from the same MF patients (n=28) using adhesive discs, followed by proteomic analyses using data-independent acquisition mass spectrometry (DIA-MS). Differential abundance analyses and bioinformatic analyses were performed to identify differentially abundant proteins and altered biofunctions between the MF and normal stratum corneum samples. In total, 1303 proteins were identified, of which 290 proteins were significantly changed in the MF cohort compared to the normal stratum corneum. Ingenuity pathway analysis (IPA) predicted the significant inhibition of cell death of cancer cells and significant activation of immune-related activities and viral infection in the MF lesions. MF lesions were also associated with upstream regulators relating to immuno-oncologic dysfunctions. The top-250 variating proteins efficiently separated normal stratum corneum from matched MF samples. Non-invasive proteomic analysis could transform the diagnosis of MF by reducing the need for invasive biopsy. The identification of altered biological functions may serve as useful biomarkers to predict MF progression.

The Transcription Factor Twist1 Has a Significant Role in Mycosis Fungoides (MF) Cell Biology: An RNA Sequencing Study of 40 MF Cases.

The purpose of this RNA sequencing study was to investigate the biological mechanism underlying how the transcription factors (TFs) Twist1 and Zeb1 influence the prognosis of mycosis fungoides (MF). We used laser-captured microdissection to dissect malignant T-cells obtained from 40 skin biopsies from 40 MF patients with stage I-IV disease. Immunohistochemistry (IHC) was used to determinate the protein expression levels of Twist1 and Zeb1. Based on RNA sequencing, principal component analysis (PCA), differential expression (DE) analysis, ingenuity pathway analysis (IPA), and hub gene analysis were performed between the high and low Twist1 IHC expression cases. The DNA from 28 samples was used to analyze the TWIST1 promoter methylation level. In the PCA, Twist1 IHC expression seemed to classify cases into different groups. The DE analysis yielded 321 significant genes. In the IPA, 228 significant upstream regulators and 177 significant master regulators/causal networks were identified. In the hub gene analysis, 28 hub genes were found. The methylation level of TWIST1 promoter regions did not correlate with Twist1 protein expression. Zeb1 protein expression did not show any major correlation with global RNA expression in the PCA. Many of the observed genes and pathways associated with high Twist1 expression are known to be involved in immunoregulation, lymphocyte differentiation, and aggressive tumor biology. In conclusion, Twist1 might be an important regulator in the disease progression of MF.

Correction: Wind et al. Topical Bimiralisib Shows Meaningful Cutaneous Drug Levels in Healthy Volunteers and Mycosis Fungoides Patients but No Clinical Activity in a First-in-Human, Randomized Controlled Trial. Cancers 2022, 14, 1510

The authors wish to make the following corrections to this paper [...].

QuPath Analysis for CD30+ Cutaneous T-Cell Lymphoma.

Mycosis fungoides is the most common subtype of cutaneous T-cell lymphoma, in which the expression of cluster of differentiation 30 (CD30)+ subtype can now be treated with the CD30 antibody conjugate brentuximab vedotin. Diagnostic methods are based on immunohistochemical (IHC) staining followed by manual assessment by pathologists, which is always a subjective calculation. QuPath, an open-source software for digital pathology image analysis, satisfies the requirements of objective approaches. Ten samples from mycosis fungoides patients with CD30 expression at different stages were stained for CD3 and CD30 by IHC staining, scanned, and quantitative analysis was performed using QuPath (version 2.1). Each slide was independently assessed by 3 board-certified dermatopathologists. Individual estimates for CD30+/CD3+ cells varied among the individual histopathologists (mean coefficient of variation, 0.46; range, 0-0.78). QuPath analysis showed excellent separation between the positively stained cells for CD3 and CD30 IHC and other cells and tissue structures, although the results correlated strongly with the respective mean estimates of the 3 histopathologists (Pearson-R 0.93). The results show a high interobserver variability evaluation of IHC markers, although quantitative image analysis offer a significant advantage for comparison. This is not only relevant for clinical routine but also especially critical in therapeutic studies addressing targeted molecules.

Predictors of radiation-induced skin reactions in patients with T-cell skin lymphomas after total skin irradiation: retrospective cohort study

INTRODUCTION: Skin reactions negatively affect a patient’s quality of life and may require radiation therapy premature interruption, what impairs illness control. Numerous agents determine tissue radiosensitivity, but demographic and lifestyle factors remain poorly understood. Those kind of patients herapeutic algorithm demands studies.OBJECTIVE: Radiation-induced skin reactions (RISR) formation and severity prognostic factors determination for primary malignant skin lymphomas patients.MATERIALS AND METHODS: 45 patients malignant T-cell skin lymphoma study, aged 38 to 82 years (29 mycosis fungoides patients, 2 lymphomatoid papulosis, 14 patients with primary anaplastic large cell skin lymphoma) received fast electrons total skin irradiation on the basis of the Federal State Institution «Russian Radiology and Surgical Technologies Scientific Center named after Academician A.M.Granov» of the Ministry of Health of the Russian Federation from 2012 to June 2022. Radiation therapy performed in the usual fractionation mode on linear electron accelerators Elekta Precise with 4–6 MeV bremsstrahlung total doses from 14 to 30 Gy (22±2.4 Gy). In order to identify the role of possible prognostic factors of skin toxicity — gender, age, body mass index (BMI), smoking status, lymphoma body surface area (BSA), the presence of concomitant diseases (diabetes mellitus and arterial hypertension) and previous chemotherapy.Statistics: Statistical analysis was performed using the IBM SPSS Statistics v. 26 program (developed by IBM Corporation). The value of p&lt;0.05 was considered statistically significant. Verification of the sample belonging to the normal general population was carried out using the Shapiro–Wilk criterion. Spearman's rank correlation coefficient was used for correlation analysis. The regression parameters were estimated using the least squares method.RESULTS: The analysis revealed positive associations between the severity of RISR and predictor factors: BMI (r=0.799, p&lt;0.01), smoking status (r=0.655, p&lt;0.01), age (r=0.534, p&lt;0.05), presence of diabetes mellitus (r=0.456, p&lt;0.05), arterial hypertension (r=0.227, p&lt;0.05), previous chemotherapy (r=0.422, p&lt;0.01) and lymphoma body surface area (r=0.378, p&lt;0.01). Severity of RISR scale value increase by those parameters. Negative links found between the severity of RISR and the total focal dose (SOD) of the beginning of their formation (r=–0.109, p&lt;0.05).CONCLUSION: Formation and severity prognostic factors for the RCC upon fast electrons total skin exposure for patients with primary malignant T-cell skin lymphomas (mycosis fungoides, lymphomatoid papulosis, primary anaplastic large cell lymphoma of the skin) were identified.

Cutaneous lymphomas—fast facts about an orphan disease—a short review

SummaryCutaneous lymphomas are a rare group of primary skin lymphoproliferative disorders, divided into T and B cell lymphomas. They differ substantially in clinical course and therapy. The two main subtypes of primary cutaneous T‑cell lymphomas include mycosis fungoides, which is the most common, and Sézary syndrome, the rare leukemic variant. Skin lesions seen in mycosis fungoides patients are erythematous patches, plaques, or tumors. Most patients remain at patch/plaque (early) stage, while some progress to tumor (advanced) stage during their clinical course. Sézary syndrome is characterized by erythroderma and involvement of lymph nodes and the peripheral blood. Treatment is dependent on the disease stage. Therapeutic options include skin-directed and systemic therapies. In localized, early stage mycosis fungoides, prognosis is usually good which changes in advanced stages. Significant progress has been made in recent years in the clinical management of progressive or relapsed cutaneous T‑cell lymphomas by the approval of new targeted therapies. Although there are no curative treatment options apart from allogeneic transplantation, response rates are often encouraging, in particular when using combination therapies. Primary cutaneous B cell lymphomas are rare and three main subtypes are recognized: primary cutaneous marginal zone lymphoma, primary cutaneous follicle center lymphoma, and primary cutaneous diffuse large B‑cell lymphoma, leg type. An accurate diagnosis of the subtype is important for therapeutic management. The most common clinical presentations are red-to-violaceous cutaneous nodules and papules. Primary cutaneous marginal and follicle center lymphoma have excellent 5‑year survival rates of 95–99%.

Characteristics associated with quality of life in the early stages of Mycosis Fungoides.

Mycosis fungoides (MF) is a lymphoproliferative disorder characterized by skin-homing atypical lymphocytes. This study aimed to evaluate the quality of life (QoL) in MF patients in the early stages of the disease and the associated factors using the Dermatology Life Quality Index (DLQI). Thirty MF patients (21 females/9 males) with a mean age of 46.73±15.9 years and in the early stages of the disease (26 stage Ι and 4 stage ΙΙ) were enrolled and were asked to fill the DLQI questionnaire. The mean DLQI score was 9.93±5.89. The QoL was largely affected by the disease in near half of the patients (46.7% of patients had a DLQI score11-20). QoL was significantly correlated with educational level and was more impaired in patients with lower educational status (DLQI score spearman rho=-0.382, P=0.037). QoL was not associated with sex, age, disease stage and disease duration. The symptom and feeling dimension of DLQI was significantly more impaired in patients with both patch and plaque compared to patch only (spearman rho= 0.397, P= 0.03). This study demonstrates how largely patients' QoL is influenced in the early stages of MF, especially in patients with lower educational levels.

Dysregulation of Plasma miR-146a and miR-155 Expression Profile in Mycosis Fungoides Is Associated with rs2910164 and rs767649 Polymorphisms.

Diagnosis of Mycosis Fungoides (MF) may be challenging, due to its polymorphic nature. The use of miRNAs as biomarkers to assist in diagnosis has been investigated, mainly in skin lesion biopsies. The purpose of this study is to evaluate the plasma levels of miR-146a and miR-155 in MF patients and to investigate their association with SNPs of their genes. Plasma miRNAs were quantified by RT-qPCR. Genomic DNA was used for SNPs' genotyping by Sanger sequencing. Plasma levels of miR-146a and miR-155 were significantly higher in patients vs. controls, in early MF patients vs. controls, and in advanced vs. early MF patients. Both miRNAs' levels were significantly higher in stage IIB vs. early-stage patients. miR-155 plasma levels were significantly higher in patients with skin tumors or erythroderma. CC genotype (rs2910164 C&gt;G) was significantly more frequent in healthy controls and associated with lower MF risk and lower miR-146a levels. The AA genotype (rs767649 T&gt;A) was significantly more frequent in patients and correlated with increased MF risk and increased miR-155 levels. The combination of GG+AA was only detected in patients and was correlated with higher MF susceptibility. Increased mir-146a and mir-155 plasma levels in MF is an important finding to establish putative noninvasive biomarkers. The presence of SNPs is closely associated with miRs' expression, and possibly with disease susceptibility.

Single-cell analyses reveal novel molecular signatures and pathogenesis in cutaneous T cell lymphoma

Sézary syndrome (SS) is a rare and aggressive type of cutaneous T cell lymphoma (CTCL) with a poor prognosis. Intra-tumoral heterogeneity caused by different disease compartments (e.g., skin, blood) and poor understanding of the pathogenesis has created obstacles to the precise diagnosis and targeted treatment of the disease. Here we performed a comprehensive analysis by integrating single-cell transcriptomic data of 40,333 peripheral blood mononuclear cells (PBMCs) and 41,580 skin cells, as well as single-cell chromatin accessibility data of 11,058 PBMCs from an SS patient and matched healthy controls (HCs). Validation and functional investigation were carried out in an independent cohort consisting of SS patients, mycosis fungoides (MF) patients, psoriatic erythroderma patients, and HCs, as well as multiple cell lines. The analysis revealed that skin-derived Sézary cells (SCs) had a shifting trend to more advanced mature phenotypes compared to blood-derived SCs. A series of specific marker genes (TOX, DNM3, KLHL42, PGM2L1, and SESN3) shared in blood- and skin-derived SCs were identified, facilitating the diagnosis and prognosis of MF/SS. Moreover, luciferase reporter assays and gene knockdown assays were used to verify that KLHL42 was transcriptionally activated by GATA3 in SS. Functional assays indicated that KLHL42 silencing significantly inhibited aggressive CTCL cell proliferation and promoted its apoptosis. Therefore, targeting inhibition KLHL42 might serve as a promising therapeutic approach in CTCL.

Reduced Overall T-Cell Receptor Diversity As an Indicator of Aggressive Cutaneous T-Cell Lymphoma

Introduction: Mycosis fungoides (MF) is a T-cell lymphoma that originates in the skin and can progress in late stages to involve blood, lymph nodes, or viscera. Large cell transformed mycosis fungoides (LCT-MF) is an aggressive subtype of MF associated with a higher likelihood of malignancy progression and mortality. Given that T-cell receptor (TCR) diversity is an indicator of cancer prognosis and outcome in several malignancies, we sought to investigate changes in T-cell repertoire diversity in LCT-MF. We interrogated the repertoire in non-leukemic MF, including both early-stage (patch and plaque, IA-IIA) and skin limited late-stage MF (tumor and erythroderma, IIB-IIIA). Methods: After approval by Thomas Jefferson University Institutional Review Board Committee, a review of clinical data was performed on patients with MF at the Jefferson Cutaneous Lymphoma Clinic. Patients included in the study had a confirmed diagnosis of MF based on clinical, histological, and molecular data as well as adequate specimens for analysis. We evaluated staging and disease progression by 2022 NCCN guidelines. We included 61 lesional skin samples and 43 serum samples from 32 MF patients and 23 aged-matched healthy subjects. We used high-throughput sequencing (HTS) assays to interrogate the TCRb complementarity determining region 3 (CDR3) sequences in blood and skin of enrolled patients as well as blood of healthy subjects 13 (Adaptive Biotechnologies). ImmunoSEQ Analyzer provided T-cell diversity metrics, Simpson's clonality score and maximum frequency, as well as Vb usage. Results: We first compared blood T-cell repertoire diversity among age-matched healthy subjects and MF patients without blood involvement. The diversities of the T-cell repertoire in blood of both non-leukemic MF and non-leukemic LCT-MF patients were significantly lower, compared to their age-matched healthy subjects. However, the diversity scores did not differ between the MF and LCT-MF cohorts in blood (Figure 1). In contrast, LCT-MF skin specimens possessed significantly lower T-cell clonal diversity (Figure 2) and distinct Vb usage in comparison to MF. There was no difference in T-cell diversity between early-stage and late-stage MF cohorts. Conclusion: Overall, our data demonstrate that LCT-MF T-cells in the skin, not blood, exhibit a less diverse clonal repertoire when compared to MF. We find that the transformation of malignant cells in the skin does not accompany changes in blood repertoire. Instead, the transformation events in the skin mirror a reduction of overall T-cell diversity in the skin of patients with LCT-MF, compared to their non-transformed counterparts. While skin T-cell repertoire diversity distinguishes transformed and non-transformed MF, the skin diversity metrics do not differ between early- and late-stage disease. This finding implies that the shift in skin T-cell diversity seen in LCT-MF is not related to stage. Rather, we posit that shifts in T-cell diversity may be influenced by the early transformation event itself. Figure 1: Simpson's clonality scores of blood T-cell repertoire in healthy subjects, MF, and LCT-MF. Statistically significant differences between cohort groups are marked by asterisks (** = p<0.001, *** = p <0.0001). Figure 2: Simpson's clonality scores of skin T-cell repertoire in MF and LCT-MF. Statistically significant differences between cohort groups are marked by asterisks (*** = p <0.0001). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Allogeneic Hematopoietic Cell Transplantation in Advanced Phase Mycosis Fungoides and Sézary Syndrome: A Retrospective Analysis of 57 Consecutive Patients

Background: Advanced stage Mycosis Fungoides (MF) and Sézary Syndrome (SS) are cutaneous T-cell lymphomas (CTCL) associated to dismal prognosis, with 5-year survival rates ranging from 47% for stage IIB to 18% for stage IVA2-IVB and with a high tendency to relapse. Allogeneic hematopoietic stem cell transplantation (allo-HCT) is considered the only curative treatment option. Recently, allo-HCT from haploidentical donor (Haplo-HCT) has been increasingly used also in MF/SS patients. We hereby report an update on long-term outcome of MF/SS patients who underwent allo-HCT at our Center from 2001 to 2022, currently including a larger population with an increased proportion of Haplo-HCT. Methods: We retrospectively collected clinical data of all consecutive patients with MF/SS transplanted at our Center between September 2001 and May 2022. Conditioning was based on reduced intensity (RIC) regimens, including flaudarabine/cyclophosphamide/TBI200, pentostatin/TBI200, and fludarabine/melphalan in transplants from HLA-identical sibling and unrelated donor (UD), and the thiotepa/fludarabine/cyclophosphamide/TBI200 regimen in Haplo setting. GvHD prophylaxis consisted of CsA, MMF and ATG. Post-transplant cyclophosphamide was added in Haplo-HCT. Results: As of August 2022, 57 CTCL patients underwent allo-HCT at our Institution: 22 (38.5%) from a HLA-identical sibling, 13 (23%) from a 10/10 matched UD, 12 (21%) from a 9/10 or 8/10 matched UD, 1 (1.8%) from cord blood, and 9 (15.7%) from a Haplo donor. Median age at transplant was 55 years (range 20-67). Indication for allo-HCT was MF in 36 patients (63%) and SS in 21 patients (37%). Median number of previous treatment lines was 6 (range 2-11) with a median time from diagnosis to transplantation of 46 months (10-274). Disease status at transplant was complete remission (CR) in 14 cases (24.5%), partial remission (PR) in 35 (61.5%) and progressive disease (PD) in 8 (14%). Stem cell source was peripheral blood in 53 patients (92.9%), bone marrow in 3 (5.2%) and cord blood in 1 (1.8%). After a median follow up of 81 months, 30 patients (52%) were alive, of whom 23 (76%) in CR. Acute GvHD occurred in 29 patients (51%; grade III-IV in 13, 23%), while chronic GvHD in 19 (33%; moderate/severe in 10 patients, 17%). Cause of death was disease progression in 17 patients (62.5%), acute GvHD in 4 (15%), infection in 2 (7.5%) and other in 4 (15%). In the whole cohort, 5-yr overall survival (OS) and disease-free survival (DFS) were respectively 57.6% (95% CI 44-71) and 37.9% (95% CI 25-51). According to donor type, 5-yr OS was 69%, 39% and 89% and DFS 57%, 19% and 57% for HLA-identical sibling, UD and Haplo, respectively (Figure 1). 5-yr OS was significantly higher in SS versus MF patients (78% vs 47%, p=0.03) and in patients who were in CR at the time of transplant (100% vs 43.5%, p<0.001). In the Haplo setting,.disease status at transplant was CR in 1 pt and PR in 8. After a median follow-up of 26 months, 7 out of 9 patients (78%) were still alive and in CR. Acute GvHD occurred in 6 patients (66%), grade III-IV in 2 (22%), while chronic GvHD occurred in 3 patients (33%), moderate/severe in 1 (11%). Two patients relapsed at +5 and +2 months, of whom the latter died 157 days after HCT. Conclusions: After a median follow up of more than 9 years for alive patients, we confirm that RIC allo-HSCT is a powerful therapeutic strategy in selected patients with advanced CTCL, and particularly in SS. With the limitation of a shorter follow-up, transplant outcomes following allo-HCT from haploidentical donor appear to be associated with very low toxicity, excellent OS and DFS comparable to HLA-identical sibling transplants. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The Role of the Immune Phenotype in Tumor Progression and Prognosis of Patients with Mycosis Fungoides: A Quantitative Immunohistology Whole Slide Approach.

Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphomas, characterized by mature, skin-tropic CD4+ T-helper cells. In order to study the immune tumor microenvironment in MF patients, we performed immunohistochemical stains on MF biopsies, digitized whole-slide tissue sections, and performed quantitative analysis of the different immune cell subsets to correlate tissue parameters with the clinical data of patients, such as progression-free survival or overall survival. Overall, 35 patients who were treated between 2009 and 2019 and for whom one or more paraffin tissue blocks were available have been included in the present study (58 tissue specimens in total). Conventional immunohistochemistry stains for CD3, CD4, CD8, CD20 and CD30 were used for the analysis of the immune phenotype, and quantitative analysis was performed using QuPath as a quantitative digital pathology tool for bioimage analysis of whole slides. Analysis of tissue parameters for prognostic significance revealed that patients with a stronger infiltration by CD8+ lymphocytes within the tumor cell compartment had a higher risk of disease progression (p = 0.031) and showed a shorter progress-free survival (p = 0.038). Furthermore, a significant association of the percentage of CD30+ cells (median: 7.8%) with the risk of disease progression (p = 0.023) and progression-free survival (p = 0.023) was found. In relation to the clinical features of our patient cohort, a higher risk of disease progression (p = 0.015) and a shorter progression-free survival (p = 0.032) for older patients (&gt;61 years) were observed. Our results demonstrated the prognostic relevance of large-cell transformation in mycosis fungoides and its strong association with the presence of CD30+ lymphocytes. Unlike previous reports, our study suggests an adverse prognostic role for CD8+ T cells in patients with mycosis fungoides. Moreover, our data indicate that the immune phenotype within the tumor microenvironment shows strong temporal heterogeneity and is altered in the course of tumor progression.

Stratum corneum cytokine levels in mycosis fungoides.

Mycosis fungoides (MF) is characterised by malignant CD4+ T-cell infiltrates in the skin. The functional characteristics of the malignant T cells and their interaction with the tumor immune microenvironment is largely unknown. We performed tape stripping of the stratum corneum (SC), a non-invasive technique, to gain insight into the cytokine secretion patterns in MF skin lesions. In addition, we assessed whether the SC cytokine profile of MF lesions is distinct from that of atopic dermatitis (AD) lesions. We compared nine cytokine levels in 20 patients with MF, 10 patients with AD and 10 healthy controls. In patients with MF and AD, lesional SC levels of IL-8 and MMP9 were significantly higher than in non-lesional SC and in healthy controls. VEGFα was significantly higher in lesional MF and AD skin than in healthy controls. The SC levels of IL-1α were significantly lower in MF and AD lesions than in healthy controls. There was no specific cytokine profile or inflammation pattern that could reliably distinguish MF from AD. In conclusion, in lesional SC of MF patients, pro-inflammatory cytokines can be detected. As a diagnostic method, tape stripping of lesional SC cannot discriminate MF skin from AD skin.

Clinical Features, Histological Characteristics, and Disease Outcomes of Mycosis Fungoides in Children and Adolescents: A Nationwide Multicentre Cohort of 46 Patients

Background: Our objective was to describe the clinical, histological characteristics, and disease outcome of a cohort of mycosis fungoides (MF) diagnosed during childhood including disease status at adulthood. Methods: This is a retrospective multicentre survey of patients aged under 18 years at diagnosis with histologically confirmed MF. Patients’ clinical and histological characteristics, treatments, and disease outcome (for patients followed for more than 12 months) were analysed. Results: Forty-six patients were included (median age at diagnosis: 11 years; M:F sex ratio: 3:1) with 39 (85%) followed for at least 12 months. Thirty-nine patients (85%) had stage I MF. Hypopigmented patches were observed in 48% and folliculotropism in 43% patients. Immunophenotype of the skin infiltrate was predominantly CD8+ in 17% of patients. Initial management included a wait-and-see strategy in 6/39 (15%), skin-directed treatment in 27 (69%), and systemic treatment in 6 (15%) patients, respectively, with partial or complete clinical response (PR or CR) observed in 28 patients (72%). 14/39 patients (36%) relapsed after initial response. After a median follow-up period of 54 months, disease status at last news was PR or CR in 31/39 (79%), stable disease in 6 (15%), and progression in 2 (5%) patients. Histological transformation was observed in 3/39 (8%). Of the 15 patients followed until adulthood, 13 (87%) had persistent MF. Discussion: This survey confirms the high frequency of hypopigmented and folliculotropic lesions and of CD8+ immunophenotype compared to adult MF patients. The long-term course is usually indolent but transformation may occur sometimes long after disease onset and the disease may persist during adulthood.

Evaluating the Perception of Mycosis Fungoides Patients About Their Disease Before and After Educating Them.

Patient-held beliefs are important for disease management and few studies have evaluated illness perception of Mycosis Fungoides (MF) patients. Here, we aimed to determine the effect of educating MF patients on their perception of their disease. Patients with diagnosed MF were asked to fill the Illness Perception Questionnaire-Revised (IPQ-R) once before education and once 3 months later. Fifty-five patients, 41 men and 14 women, with a mean age of 45.5 ± 13.9 years were enrolled. Regarding the main etiologic factor, most patients cited anxiety (91%). After education, the most significant changed belief on disease etiology was immune system dysfunction and the change was twenty-six percent which was observed more in patients with higher educational levels, shorter disease duration, and lower MF stages. Regarding the most prevalent clinical manifestations, most patients mentioned erythema (86%). After education, the greatest change in symptom perception was related to lymphadenopathy (32%) which was significantly associated with less disease duration and those treated with phototherapy. Before education, the mean perception score about the disease chronicity was 23.67 ± 3.549 that increased to 27.71 ± 1.66 (P < 0.001). This change was more observed in men (P = 0.03), those with less disease duration, and those treated with phototherapy. Generally, MF patients hold favorable perspectives about their disease and educating them positively improves their illness perception. Patients with higher educational levels and lower stages of the disease showed more significant changes in various aspects of illness perception. Hence, early education is recommended in patients with lower educational levels.

TCL-456 Real-World Use of Mogamulizumab among Patients With Mycosis Fungoides and Sézary Syndrome Before and During COVID-19 in the United States.

Per label, mogamulizumab (Moga) is administered on days 1, 8, 15, and 22 of the first 28-day cycle (loading) and on days 1 and 15 of each subsequent cycle (maintenance) for adult patients with relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS) after ≥1 prior systemic therapy. During the COVID-19 pandemic, professional organizations suggested dosing intervals for systemic cancer therapies be extended to limit in-person visits. This study examined the real-world use of Moga before and during the COVID-19 pandemic in the United States. Using the Symphony Health Solutions database, adults with ≥1 diagnosis of MF or SS (ICD-10 CM: C84.0x or C84.1x) and ≥1 Moga claim during 10/1/2018-5/6/2021 were identified. Within the MF (no SS diagnosis) and SS (any SS diagnosis) cohorts, patients were divided into 2 subgroups based on their Moga initiation date: 10/1/2018-3/31/2020 (pre COVID-19) and 4/1/2020-5/6/2021 (COVID-19). Patient characteristics and dosing intervals between Moga doses 1-4 (loading) and between subsequent doses (maintenance) were examined. Overall, 154 MF and 204 SS patients initiated Moga during the study period (mean age: 66.8 and 69.2 years; male: 64% and 55%, respectively). In the MF cohort, 98 and 56 patients were in the pre COVID-19 and COVID-19 subgroups. The mean dosing interval was shorter among patients in the COVID-19 subgroup for both the loading (9.1 vs. 13.2 days) and maintenance doses (15.2 vs. 16.1 days). In the SS cohort, 121 and 83 patients were in the pre COVID-19 and COVID-19 subgroups. Mean loading (9.0 vs. 11.1 days) and maintenance (15.0 vs. 16.8 days) dosing intervals were shorter for patients included in the COVID-19 subgroup. For both MF and SS patients, the COVID-19 subgroup had a higher proportion of patients with ≤10 days between loading doses and ≤21 days between maintenance doses compared to the pre COVID-19 subgroup. Among MF and SS patients, dosing intervals for Moga in loading and maintenance were not extended during the 1st year of the COVID-19 pandemic compared to pre COVID-19. There was a trend towards closer concordance with the label during COVID-19.

In vivo Dosimetry for Dose Verification of Total Skin Electron Beam Therapy Using Gafchromic® EBT3 Film Dosimetry.

Total skin electron beam therapy (TSEBT) is an important skin-directed radiotherapeutic procedure done in the treatment of cutaneous T-cell lymphomas, namely, mycosis fungoides (MF). This procedure is usually done at larger source-to-surface distances with the patient standing on a rotatory platform. As the patient has to stand in different positions without any rigid immobilization devices, there are chances that the total skin may not get uniformly irradiated which could lead to nonuniform dose distributions. Therefore, all the necessary arrangements should be made to evaluate the dose for different regions of the skin using suitable in vivo dosimeters at the radiotherapy centers offering these treatments. This study aimed to evaluate the consistency between the delivered and planned doses in vivo during TSEBT using Gafchromic EBT3 film dosimetry. The surface dose for the six MF patients treated for TSEBT at our hospital from 2018 to 2022 was measured and evaluated. 2 cm × 2 cm Gafchromic® EBT3 films were used to measure skin dose at reference body positions of clinical interest. All the patients were treated with the modified Stanford technique. The irradiated film strips were analyzed for the dose using the IMRT OmniPro software. The doses at respective positions were expressed as mean dose ± standard deviation and the deviation was calculated as the percentage of the prescribed dose. One hundred and fifty-four Gafchromic® EBT3 film strips irradiated on six TSEBT patients showed a maximum dose variation of 2.00 ± 0.14 Gy, in the central body regions. The dose variation in the peripheral areas such as hands and ears was larger. A variation of 2 ± 0.32 Gy was observed on the hands and ears. The uniformity of the dose delivered to maximum body parts was within -7% and +16% for the peripheral areas like hands. The American Association of Physicists in Medicine recommends a dose uniformity of 8% and 4% in the vertical and horizontal patient plane for direct incident beam; however, for oblique incidences like in the modified Stanford technique, the dose variation is about 15%. In vivo dosimetry using Gafchromic EBT3 film dosimetry for TSEBT yields objective data to find the under or overdose regions. That can be useful to provide quality treatment, especially when treatments tend to be as complex as TSEBT.