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.

Systemic treatments with monoclonal antibodies in mycosis fungoides and Sézary syndrome.

Mycosis fungoides (MF) and Sézary syndrome (SS) are the most prevalent non-Hodgkin lymphomas that comprise cutaneous T-cell lymphomas (CTCL), accounting for more than 70% of cases. Following the Tumor Lymph nodes Metastasis Blood system, disease staging is carried out, and within ten years, about thirty percent of patients in the early stages will have advanced disease. Plaques, folliculotropism, and age over 60 are risk factors for progression. A 5-year survival rate of less than 20% is associated with LCT in MF. Treatment requires an interdisciplinary approach; skin-directed therapies are available for early stages of the disease, but there are no curative options for advanced stages of the disease other than allogeneic stem cell transplantation. Because of their severe symptoms and poor treatment efficacy, patients in advanced stages have a lower quality of life and a lower chance of survival. In patients with CD30-expressing CTCL, Brentuximab Vedotin has demonstrated better response rates and progression-free survival (PFS); in advanced SS, mogamulizumab has significantly increased PFS. These findings emphasize the need to standardize prognostic factors and improve CTCL treatment.

Skin-directed therapy and biologic response modifiers in mycosis fungoides.

The most common and widespread type of cutaneous T-cell lymphoma is mycosis fungoides (MF), and it has a multiphasic clinical and biological course, with early stages being indolent for many years and later stages being faster and more aggressive. The clinical stage has a significant impact on the management and course of treatment: in the early stages, skin-directed therapies (SDT) plus/or biologic response modifiers (BRM); in the later stages, radiotherapy and/or systemic therapies. Even though national and international societies and groups periodically update their clinical recommendations, there is still no universally accepted approach. This paper reviews and discusses the various SDT and BRM options, either separately or in combination.

Non-invasive techniques in the clinical diagnosis of cutaneous lymphomas.

In clinical practice, cutaneous lymphomas can be challenging to diagnose or even suspect because they mimic a variety of other inflammatory and neoplastic dermatological conditions. Support for non-invasive skin analysis methods like reflectance confocal microscopy and dermoscopy is still anecdotic. Practically speaking, a deeper and more comprehensive study with a larger number of cases focusing on the effective usefulness of non-invasive techniques should be taken into consideration because they have demonstrated the ability to identify macro and micro features supporting the clinical suspicion of lymphomas, as well as being useful for differential diagnosis and supporting the selection of the biopsy site. The author provides a brief and narrative synopsis of the reflectance confocal microscopy and dermoscopy characteristics of cutaneous lymphomas in this manuscript.

Radiation therapy in mycosis fungoides.

Radiation therapy (RT) is administered with varying intentions, sometimes even several times in the same or in different body areas, to over 50% of patients with neoplastic conditions. Numerous techniques are available to patients in the clinical evolution of mycosis fungoides (MF), and there are several indications for radiation therapy (RT). RT as a skin-directed therapy is very widely used in these patients, either alone or in conjunction with other therapies. The application of RT, a tried-and-true therapy that improves MF patients' quality of life and treatment, can be encouraged by a multidisciplinary approach and an understanding of current methods and action mechanisms.

When mycosis fungoides seems not to be within the spectrum of clinical and histopathological differential diagnoses.

The most prevalent primary cutaneous T-cell lymphoma, mycosis fungoides (MF), is characterized by the development of plaques and nodules after an erythematous patchy phase that is non-specific. An infiltrate of atypical small- to medium-sized cerebriform lymphocytes in the superficial dermis, with variable epidermotropism, is the histopathological hallmark of the disease. In more advanced stages of the illness, large-cell transformation may be seen. Early diagnosis of MF can be very challenging based only on histopathologic or clinical findings, so it is critical to have a clinical-pathological correlation. Many atypical variants of MF that deviate from the classic Alibert-Bazin presentation of the disease have been described over the past 30 years, sometimes with different prognostic and therapeutic implications. Clinically or histopathologically, they can mimic a wide range of benign inflammatory skin disorders. To make a conclusive diagnosis in these cases, it is recommended to take multiple biopsies from various lesions and to carefully correlate the clinical and pathological findings. We have outlined the various facets of the illness in this review, positioning MF as a "great imitator", with an emphasis on the more recently identified variations, differential diagnosis, and its benign mimics.

Beyond the pale: Insights into hypopigmented mycosis fungoides - A case report.

Hypopigmented mycosis fungoides (MF) is a rare variant of cutaneous T-cell lymphoma, a type of extranodal non-Hodgkin lymphoma. This report presents the case of a 9-year-old boy with a 2-year history of asymptomatic, hypopigmented skin lesions that were resistant to topical treatment. He was initially treated for a fungal skin infection and had received multiple courses of topical antifungals and steroids but showed no improvement, which led to further evaluation and a referral to a dermatologist. A skin biopsy was performed, and the diagnosis of hypopigmented MF was confirmed through skin histopathology and immunohistochemistry study. His lesions responded well to cycles of narrowband ultraviolet B phototherapy, showing almost complete clearance after 4 months without any side effects.

Physical and clinical results of a radiation bra in patients treated with total skin electron beam therapy.

Total skin electron beam therapy (TSEBT) in female patients with large or pendulous breasts is usually associated with shaded inframammary folds. In this analysis, 18 patients with cutaneous malignancy and pendulous breasts were irradiated with a radiation bra and five patients received TSEBT without bra. All patients had moderate or severe sagging of the breasts. The median inframammary dose in the radiation bra group was 89% of the prescription dose versus 4% in the group without bra. The usage of the radiation bra enables an adequate radiation dose for the inframammary folds during TSEBT with no additional local irradiation.

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.

Single cell sequencing delineates T-cell clonality and pathogenesis of the parapsoriasis disease group.

BACKGROUND: Mycosis fungoides (MF), the most common cutaneous T-cell lymphoma, is often underdiagnosed in early stages due to similarities with benign dermatoses such as atopic dermatitis (AD). Furthermore, the delineation from so-called "parapsoriasis en plaque," a disease that can appear either in a small- or large-plaque form, is still controversial. OBJECTIVE: To characterize the parapsoriasis disease spectrum. METHODS: We performed single-cell RNA sequencing of skin biopsies from patients within the parapsoriasis-to-early-stage MF spectrum, stratified for small and large plaques, and compared them to AD, psoriasis and healthy control skin. RESULTS: 6 out of 8 large-plaque lesions harbored either an expanded alpha/beta or gamma/delta T-cell clone with downregulation of CD7 expression, consistent with a diagnosis of early-stage MF. By contrast, 6 out of 7 small-plaque lesions were polyclonal in nature thereby lacking a lymphomatous phenotype, and also revealed a less inflammatory microenvironment than early-stage MF or AD. Of note, polyclonal small- and large-plaque lesions characteristically harbored a population of NPY+ innate lymphoid cells and displayed a stromal signature of complement upregulation and antimicrobial hyperresponsiveness in fibroblasts and sweat gland cells, respectively. These conditions were clearly distinct from AD or psoriasis, which uniquely harbored CD3+CRTH2+ IL13-expressing "Th2A" cells or strong type 17 inflammation, respectively. CONCLUSION: These data position polyclonal small- and large-plaque dermatitis lesions as a separate disease entity, that characteristically harbors a so far undescribed ILC population. We thus propose the new term "polyclonal parapsoriasis en plaque" to this kind of lesions, as they can be clearly differentiated from early and advanced-stage MF, psoriasis and AD on several cellular and molecular levels.

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.

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.

Assessing Health-Related Quality of Life in Mycosis Fungoides and Sézary Syndrome: Unmet Needs.

Mycosis fungoides (MF) and Sézary syndrome (SS) can impair multiple dimensions of health-related quality of life (HRQoL). Currently, there is no standardized assessment tool for measuring HRQoL in patients with MF/SS. Here, we describe the existing literature on multiple dimensions of HRQoL in MF/SS with a special focus on the gaps in the current knowledge and identify future directions necessary to assess the HRQoL of patients with this disease.

A case report of refractory advanced-stage mycosis fungoides: successful treatment and improved patient quality of life with mogamulizumab.

Mycosis fungoides (MF), the most common form of cutaneous T-cell lymphoma, is characterized by patches, plaques, and, in advanced stages, tumors and erythroderma. Early-stage MF may progress to advanced-stage disease in up to one-third of patients, conferring a worse prognosis and typically requiring systemic treatment for extracutaneous involvement. The most frequently reported signs and symptoms are pain, pruritus, scaling, and skin redness, with pruritus, the most bothersome symptom, exerting a profound impact on patients' health-related quality of life (HRQoL). These dermatologic signs and symptoms can overlap with those of other benign inflammatory dermatoses, such as eczema and psoriasis, and therefore, diagnostic delay is common in patients with MF. Moreover, identifying patients with features adversely affecting prognosis (e.g. large-cell transformation or folliculotropic variant) is a significant challenge. We report the case of a 75-year-old female patient who was misdiagnosed with eczema and then pityriasis rubra pilaris and consequently did not receive treatment for MF for 4 years. The patient was eventually correctly diagnosed with MF [stage IIIB (T4 N1 M0 B1)] in September 2018. The patient received several systemic treatments; however, she did not respond to or tolerate the treatments. Due to lack of treatment response, in July 2021, she was initiated on mogamulizumab, an anti-CC chemokine receptor 4 antibody with demonstrated effectiveness and licensed approval for adults with MF/Sézary syndrome who have received one or more prior systemic therapies. Treatment rapidly led to a complete response in blood after 1 week and in skin after 4 months. Mogamulizumab was well tolerated by the patient, who also reported a significant improvement in her HRQoL. After 1 year in complete response, mogamulizumab was discontinued. This case highlights the need for accurate and early diagnosis of MF to initiate disease-specific treatment and the importance of considering patient HRQoL when treating this condition.