A Fatal Case of Severe Leg Edema and Necrotic Ulcers in a 14-Year-Old Boy.

A 14-year-old boy presented with edema, ulcers, tenderness, and progressive functional limitation of both legs, first diagnosed as Henoch-Schonlein vasculitis. Then, he underwent one inguinal lymph node excision and two skin biopsies which reported an angiocentric lymphoproliferative process, EBER (Epstein-Barr virus-encoded small RNA) positive, consistent with hydroa vacciniforme-like lymphoproliferative disorder (HVLPD); after eight weeks, his face presented with edema and ulcers, characteristic of the original patients described with HVLPD. The patient's parents refused treatment and took him back home, and he died a few months later. Our case study highlights an atypical localization of the disease, as it initially presented in the lower extremities rather than the face, posing a diagnostic challenge that was ultimately resolved through biopsy.

Real-world Use of Mogamulizumab Among Patients With Mycosis Fungoides and Sézary Syndrome Before and During COVID-19 in the United States.

PURPOSE: During the coronavirus disease 2019 (COVID-19) pandemic, professional organizations suggested extending dosing intervals for systemic cancer therapies to limit in-person visits. Mogamulizumab, indicated for adults with relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS) after ≥1 prior systemic therapy, should be administered every 7 days of the first 28-day cycle (loading) and every 14 days of each subsequent cycle (maintenance) according to the approved prescribing information in the United States (US). This study examined the real-world use of mogamulizumab before and during the COVID-19 pandemic in the US. METHODS: Using Symphony Health's Integrated Dataverse (IDV) database, adults with ≥1 diagnosis of MF or SS and ≥1 mogamulizumab claim between October 1, 2018 and December 22-, 2022 were identified. Patients in MF and SS cohorts were divided into 3 subgroups based on the date they initiated mogamulizumab treatment: pre-COVID-19 (October 1, 2018-March 31, 2020), COVID-19 Phase 1 (April 1, 2020-July 31, 2021), and COVID- 19 Phase 2 (August 1, 2021-December 22, 2022). FINDINGS: During the study, 270 patients with MF and 337 patients with SS initiated mogamulizumab. The pre-COVID-19, COVID-19 Phase 1, and COVID-19 Phase 2 subgroups included 95, 81, and 94 patients with MF and 124, 119, and 94 patients with SS, respectively. In the MF cohort, mean loading dosing intervals were 13, 12, and 9 days for the pre-COVID-19, COVID-19 Phase 1, and COVID-19 Phase 2 subgroups, respectively, and mean maintenance dosing intervals were 16, 16, and 16 days, respectively. In the SS cohort, mean loading dosing intervals were 16, 11, and 11 days, and mean maintenance dosing intervals were 19, 18, and 16 days, respectively. For both cohorts, more patients in the COVID-19 Phase 1 and Phase 2 subgroups than in the pre-COVID-19 subgroup had gaps of ≤10 days between loading doses and ≤21 days between maintenance doses. IMPLICATIONS: In patients with MF and SS, loading dosing intervals in the pre-COVID-19 period were longer than the loading schedule per the approved prescribing information, but there was a trend towards closer concordance in the COVID-19 periods. Maintenance dosing intervals in patients with MF were consistently similar to the approved schedule across treatment periods, and in patients with SS became more closely aligned over time. Thus, dosing intervals for mogamulizumab in both loading and maintenance cycles do not appear to have been extended during the COVID-19 Phase 1 and Phase 2 periods compared with the pre-COVID-19 period, despite recommendations to extend dosing intervals for systemic cancer therapies during COVID-19.

A Retrospective Cohort Study to Determine Real-World Treatment Patterns in Patients with Sézary Syndrome in the United States.

INTRODUCTION: Sézary syndrome (SS) is a rare leukemic cutaneous T cell lymphoma. This study was conducted to examine the real-world treatment patterns among patients with SS in the USA from 2018 to 2020. METHODS:  This was a retrospective cohort study using the Symphony Health Solutions claims database. Adult patients with ≥ 1 diagnosis code for SS were classified into three non-mutually exclusive cohorts: 2018, 2019, and 2020. Patient characteristics and treatment patterns were examined across the 3 years of study and reported descriptively for each year. Annual treatment patterns were also described for the five states with the highest proportions of SS patients in 2020. RESULTS: Overall, 869, 882, and 853 SS patients were identified in 2018, 2019, and 2020, respectively (median age: 70 years for each year; male: 54.4%, 54.8%, and 55.6%, respectively). The use of any systemic and parenteral systemic treatments increased over time. While utilization rates for many specific systemic therapies decreased over the study period, mogamulizumab use increased, making it the most commonly used systemic treatment in 2020 (29.2%) among patients with any systemic treatment. The five states with the highest proportions of SS patients in 2020 were Florida, New York, California, Texas, and Pennsylvania. Systemic treatment patterns varied considerably by state. CONCLUSION: Some systemic therapies showed decreased usage over time while a few showed increased utilization, with mogamulizumab showing the largest increase. Treatment patterns for SS varied by region. Further research is needed to examine the factors that drive treatment selection for patients with SS.

Clinical and Histologic Variants of CD8+ Cutaneous T-Cell Lymphomas.

Although the vast majority of CTCL subtypes are of the CD4+ T-helper cell differentiation phenotype, there is a spectrum of CD8+ variants that manifest wide-ranging clinical, histologic, and phenotypic features that inform the classification of the disease. CD8, like CD4, and cytotoxic molecules (including TIA and granzyme) are readily detectable via IHC staining of tissue and, when expressed on the phenotypically abnormal T-cell population, can help distinguish specific CTCL subtypes. Nonetheless, given that the histopathologic differential for CD8+ lymphoproliferative disorders and lymphomas may range from very indolent lymphomatoid papulosis (LyP) to aggressive entities like CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma (AECTCL), CD8 and/or cytotoxic molecule expression alone is insufficient for diagnosis and is not in itself an indicator of prognosis. We present a review of CTCL subtypes that can demonstrate CD8 positivity: CD8+ mycosis fungoides (MF), LyP type D, subcutaneous panniculitis-like T-cell lymphoma (SPTCL), primary cutaneous gamma/delta T-cell lymphoma (PCGDTL), CD8+ AECTCL, and acral CD8+ T-cell lymphoproliferative disorder (acral CD8+ TCLPD). These diseases may have different clinical manifestations and distinctive treatment algorithms. Due to the rare nature of these diseases, it is imperative to integrate clinical, histologic, and immunohistochemical findings to determine an accurate diagnosis and an appropriate treatment plan.

Development of Subcutaneous Panniculitis-Like T-cell Lymphoma After Immune Checkpoint Inhibitor Treatment.

Program death 1 (PD-1) inhibitors such as nivolumab are immune checkpoint inhibitors that have revolutionized the treatment of metastatic melanoma. Despite its success in treating melanoma, immune activation can lead to immune-related adverse effects, which are experienced by half of melanoma patients treated with PD-1 inhibitors. Despite the common frequency of immune-mediated adverse events, the development of a secondary lymphoma is exceedingly rare. We present the case of a 53-year-old woman diagnosed with stage IV metastatic melanoma, treated with nivolumab, who subsequently developed fatal subcutaneous panniculitis-like T-cell lymphoma (SPTCL).

Pathogenic variants of mycosis fungoides identified using next-generation sequencing.

Mycosis fungoides (MF), the predominant form of cutaneous T-cell lymphoma (CTCL), poses diagnostic challenges due to its clinical and histological resemblance to benign skin disorders. Delayed diagnosis contributes to therapeutic delays, prompting exploration of advanced diagnostics tools. Next-generation sequencing (NGS) may enhance disease detection by identifying pathogenic variants common to CTCL but absent in benign inflammatory disorders. We aim to discuss novel and common pathogenic variants in CTCL to enhance the utility of NGS as a diagnostic adjunct. This pilot study employed (NGS) to identify pathogenic variants in 10 MF cases. Cases were selected based on PCR-confirmed T-cell receptor clonality, with adequate DNA for NGS. GatorSeq NGS Panel, Illumina NextSeq500, and QIAGEN Clinical Insight QCI software facilitated sequencing, analysis, and variant interpretation. NGS revealed eight novel mutations in genes including HLA-DRB1, AK2, ITPKB, HLA-B, TYRO3, and CHD2. Additionally, previously reported MF-associated mutations such as DNMT3A, STAT5B, and SOCS1 (mouse study only) were detected as well. Detected variants were involved in apoptotic, NF-kB, JAK-STAT, and TCR signaling pathways, providing insights into MF pathogenesis. Mutations in genes like APC, AK2, TYRO3, and ITPKB that regulate tumor proliferation and apoptosis were noted. MF cases were associated with HLA gene mutations. NGS may enhance MF diagnosis, as the detection of pathogenic variants, particularly those known to occur in MF, favors a neoplastic diagnosis over an inflammatory diagnosis. Continuing this work may lead to the discovery of therapeutic targets.

Phototherapy and mycosis fungoides: what's new?

The most common cutaneous T-cell lymphoma, mycosis fungoides (MF), is clinically characterized by erythematous-violaceous nodules and erythematous-scaly patches. In the early stages of MF, phototherapy is currently the first line of treatment and plays a significant role. This study aims to review and analyze the various phototherapy options for cutaneous lymphoma.

Mogamulizumab and Concomitant Hypofractionated Low-Dose Total Skin Electron Beam Therapy (2 × 4 Gy) in Cutaneous T-Cell Lymphoma: Proof of Principle, Report of Two Cases.

Patients with advanced-stage mycosis fungoides (MF IIB-IVB) and Sézary syndrome (SS) have poor prognoses, with survival ranging from 4.7 to 1.4 years depending on the disease stage. There is a need for therapeutic approaches that lead to long-lasting responses and improved quality of life and survival. Mogamulizumab, a humanized antibody against the CCR4 molecule, and low-dose total skin electron beam therapy (TSEBT) are two known established treatments for MF and SS as a monotherapy. However, little is known about the potential additive effect on the combination of both treatments. We report here for the first time the concurrent use of low-dose hypofractionated TSEBT (2 × 4 Gy) with mogamulizumab. Based on two relapsed/refractory and advanced-stage CTCL patients, we show that this combination may be well tolerated in advanced-stage MF or SS and may potentially lead to an additive treatment effect on response times, particularly in the skin and blood within two weeks. We propose that this combination may be a treatment option for patients with SS. Further research is needed to understand the efficacy and tolerability profile of this therapeutic combination and to determine if there is an additive effect of the combination on the response rates when compared with the monotherapy.

Evaluation of Sézary cell marker expression and cell death behaviour upon in vitro treatment by flow cytometry in Sézary syndrome patients.

The diagnosis of Sézary syndrome (SS) relies on the identification of blood Sézary cells (SC) by different markers via flow cytometry. Treatment of SS is challenging since its pathogenesis is characterized by cell death resistance rather than hyperproliferation. In this study, we establish an integrated approach that considers both the expression of SC markers and sensitivity to cell death both spontaneously and upon in vitro treatment. Peripheral blood mononuclear cells were isolated from 20 SS patients and analysed for the SC markers CD7 and CD26 loss as well as CD158k and PD1 gain. The cells were then treated with different established and experimental therapies in vitro and cell death was measured. Spontaneous and therapeutically induced cell death were measured and correlated to cellular marker profiles. In the marker-positive cells, spontaneous cell death sensitivity was reduced. Different treatments in vitro managed to specifically induce cell death in the putative CTCL cell populations. Interestingly, a repeated analysis after 3 months of treatment revealed the CTCL cell death sensitivity to be restored by therapy. We propose this novel integrated approach comprising the evaluation of SC marker expression and analysis of cell death sensitivity upon treatment that can also enable a better therapy stratification.

Atypical Cutaneous Manifestation of Mycosis Fungoides: A Case Report.

Mycosis fungoides (MF) is a cutaneous T-cell lymphoma (CTCL) that is characterized by atypical CD4+ T-cell aggregates in the epidermis. It is typically divided into three clinical phases, which consist of the patches, plaques, and tumor stages. There have been atypical manifestations of MF described in the literature, and it is hypothesized that the skin microbiota plays a role in the skin phenotype of MF patients. Here, we describe an MF patient with multiple, large, ulcerated, and purulent lesions that developed after she swam in the ocean. Our patient was found to have a unique set of bacteria isolated from the wound.

Exploring the educational needs of patients with cutaneous lymphoma using an educational needs assessment tool.

Background: Cutaneous T-cell lymphomas (CTCL) are a group of rare non-Hodgkin lymphomas characterized by initial localization of malignant T-lymphocytes in the skin. Support and information from nurses and patient support groups have proven useful for patients with CTCL, but little is known about the educational needs of these patients. Objectives: To investigate the self-reported educational needs among CTCL patients using an educational needs assessment tool and to explore differences related to sex, age, disease duration, clinical stage, and education. Methods: This observational single center study analyzed 70 patients with CTCL in routine dermatological outpatient care. The patients were asked to complete a questionnaire to capture their educational needs in regard to CTCL. The questionnaire was inspired by the educational needs assessment tool, designed and validated for patients with rheumatoid disease. The questionnaire included a general question, "In general, how much information do you want to receive about your lymphoma disease?", and five domains covering information relating to disease process (6 items), treatment (4 items), feelings (2 items), self-management of itch, sleep, and rest (2 items), and support systems (3 items). The domain scores ranged from 0 to 18 and the total score from 0 to 51, with a higher score indicating a greater need for education. Results: When asked "In general, how much information do you need?", females wanted to know more compared with males (2.6 vs. 2.1, p=0.006), and patients with higher education wanted to know more than patients with lower education (2.5 vs. 2.0, p=0.025). The domains concerning treatment (80%) and disease process (75%) revealed the greatest needs for education. Patients with a disease duration <2 years reported a greater educational need for the domain support system, compared with patients with longer disease duration. Patients with lower education reported a greater educational need about feelings compared with patients with higher education. Conclusions: We found that 65% of the CTCL patients in the cohort, particularly females, expressed a need for education, especially regarding disease process and treatment. A deeper understanding of the educational needs would enable healthcare providers to give personalized information.

Single nucleotide polymorphism profiles of canine T-cell and null-cell lymphomas.

Background: The histopathological classification of T-cell lymphoma (TCL) in humans has distinctive mutational genotyping that suggests different lymphomagenesis. A similar concept is assumed to be observed in dogs with different TCL phenotypes. Objective: This study aimed to identify the previously reported single-nucleotide polymorphisms (SNPs) in both human beings and dogs in canine TCLs and null-cell lymphomas (NCLs) and to design compatible oligonucleotides from each variant based on the multiplex polymerase chain reaction. Methods: Genomic DNA was extracted from 68 tumor specimens (62 TCLs and 6 NCLs) and 5 buffy coat samples from dogs with TCL. Four TCL subtypes and NCL were analyzed in 44 SNPs from 21 genes using the MassARRAY. Results: The greatest incidences of SNPs observed in all TCL subtypes and NCL ware SATB1 c.1259A > C, KIT c.1275A > G, SEL1L c.2040 + 200C > G, and TP53 c.1024C > T, respectively. Some SNP locations were statistically significant associated with NCL, including MYC p.S75F (p = 0.0003), TP53 p.I149N (p = 0.030), PDCD1 p.F37LX (p = 0.012), and POT1 p.R583* (p = 0.012). Conclusion: Each TCL histological subtype and NCL are likely to contain distinctive mutational genetic profiles, which might play a role in lymphoma gene-risk factors and might be useful for selecting therapeutic target drugs for each canine patient.