Mycosis Fungoides and Associated Malignancies in a Dutch Nationwide Retrospective Cohort Study.

The prognosis of patients with mycosis fungoides is variable. As the current literature is scarce and shows mixed results this study investigates the incidence of other primary malignancies in mycosis fungoides patients. A retrospective, nationwide, population- based cohort study was performed with patients with mycosis fungoides between 2000 and 2020 in The Netherlands. All histopathology reports were requested from the Nationwide Network and Registry of Histo- and Cytopathology and screened for other primary malignancies. Lifelong incidence rates were used to compare the incidence of malignancies in mycosis fungoides patients and the general population. In total 1,024 patients were included with a mean follow-up of 10 years (SD 6). A total of 294 cases of other primary malignancies were found with 29% of the mycosis fungoides patients developing at least 1 other primary malignancy. Only cutaneous (odds ratio [OR] 2.54; CI 2.0-3.2) and haematological malignancies (OR 2.62; CI 2.00-3.42) had a statistically significant higher incidence than the Dutch population overall. Mycosis fungoides patients have a significantly increased risk of developing melanomas (OR 2.76; CI 2.11-3.59) and cutaneous squamous cell carcinomas mycosis fungoides (OR 2.34; CI 1.58-3.45). This study shows no association between mycosis fungoides and other solid organ tumours; however, such patients are significantly at risk of developing other haematological and cutaneous malignancies. Clinicians should be aware of this increased risk.

Cutaneous Involvement by Refractory Celiac Disease Type 2 Histologically Mimicking Mycosis Fungoides.

ABSTRACT: Refractory celiac disease (RCD) is a rare condition characterized by persistent malabsorptive symptoms and villous atrophy despite a gluten-free diet. While RCD type 1 has a normal intraepithelial lymphocyte phenotype, RCD type 2 is defined by the presence of immunophenotypically aberrant and monoclonal intraepithelial T lymphocytes, with a high propensity to transform to enteropathy-associated T-cell lymphoma (EATL). Although dermatological manifestations of celiac disease are common, presentation with cutaneous involvement by abnormal lymphocytes of RCD type 2 or EATL is rare, with few histologic descriptions in the literature. We describe the case of a 66-year-old man with a history of celiac disease presenting with a generalized, erythematous papular rash over his torso, upper arms, and legs. Biopsy of his skin lesions showed prominent hyperkeratosis with underlying spongiosis and interface change. Increased intraepithelial (epidermotropic) lymphocytes were observed, out of proportion to the level of spongiosis, but not overly atypical in appearance. Immunohistochemistry revealed an aberrant T-cell immunophenotype (CD3/2/7 positive; CD5/4/8 negative), raising suspicion for a cutaneous T-cell lymphoproliferative disorder. A duodenal biopsy demonstrated total villous atrophy with a morphologically bland population of epitheliotropic T lymphocytes showing the same aberrant immunophenotype. Similar cells were also identified by flow cytometry in the peripheral blood. In conjunction with the history of celiac disease, a diagnosis of RCD type 2 or 'EATL in situ' with cutaneous involvement was made. Cutaneous RCD type 2 or EATL should be considered as differential diagnoses in patients with a history of celiac disease and histopathology reminiscent of epidermotropic forms of cutaneous T-cell lymphoma.

Cutaneous Lymphoma in a Tertiary Skin Hospital and Referral Centre in Nepal.

BACKGROUND: Primary cutaneous lymphomas are a distinct group of rare lymphoid neoplasms with absence of extracutaneous lymphomas at the time of presentation. They are rare in Nepal and no data on cutaneous lymphoma have been published from this country till date. METHODS: This retrospective study included 15 cases of cutaneous lymphomas retrieved from the records of department of Dermatopathology, DI Skin Hospital and Referral Centre, Bansbari, Kathmandu, Nepal. Patients were diagnosed according to the current WHO classification for cutaneous lymphoma. RESULTS: A total of 15 cases were studied with median age of 45 years (range: 22 to 81 years) and male to female ratio of 1.5:1. Primary cutaneous lymphomas constituted 13 cases out of 15 and the most common type of cutaneous lymphoma was mycosis fungoides and variants 5 (33%), followed by CD30 positive primary cutaneous anaplastic large cell lymphoma constituting 2 (13%). T-cell cutaneous lymphoma constituted 13 (87%) and B-cell cutaneous lymphoma 2 (13%). CONCLUSIONS: Cutaneous T-cell lymphomas were more frequent than cutaneous B-cell lymphomas in Nepalese patients. Mycosis fungoides and variants are commonest type of primary cutaneous lymphomas.

Mycosis Fungoides Palmaris et Plantaris Mimicking "Dyshidrotic Eczema": A Case Report.

Mycosis fungoides palmaris et plantaris (MFPP) is a rare variant of mycosis fungoides (MF), a type of cutaneous T-cell lymphoma. MFPP primarily affects the palms and soles of the feet and is often misdiagnosed as dyshidrotic eczema due to its similar clinical presentation. This case report presents a middle-aged woman with MFPP whose initial presentation was mistaken for dyshidrotic eczema. Despite treatment with topical corticosteroids, the patient's lesions persisted, prompting further investigations that led to the diagnosis of MFPP. The patient was initiated on betamethasone dipropionate ointment and hydroxyzine for pruritus management, with a pivotal referral to oncology for comprehensive evaluation. This case highlights the importance of considering MFPP in the differential diagnosis of persistent eczematous lesions on the palms and soles, especially when treatment with topical corticosteroids is ineffective. J Drugs Dermatol. 2024;23(7):569-570.     doi:10.36849/JDD.8474.

The efficacy of long-term psoralen plus ultraviolet A and low-dose interferon-a combination therapy in mycosis fungoides: A literature review.

BACKGROUND/PURPOSE: Interferon (IFN)-a is often used in combination with psoralen plus ultraviolet A (PUVA) in patients with mycosis fungoides (MF) refractory to skin-targeted therapies in early or advanced stages. The main objective is to evaluate the effectiveness of combined PUVA and low-dose IFN-α-2a therapy in patients with early- and advanced-stage MF. METHODS: Sixty-eight patients who received a combination of PUVA twice or thrice a week and INF-a 3 MU thrice a week for at least 3 months were reviewed retrospectively. The treatment response was evaluated as complete remission (CR), partial remission, stable disease, or progression. RESULTS: At the initiation, the majority of patients (66.2%) had early-stage disease. In 27.9% of cases, this was the initial treatment administered following the diagnosis of MF. The median duration of combination therapy was 11 months. Complete remission was achieved in 45.6% of the patients with an overall response rate of 60.3%. The mean duration of response was 5 months. Complete remission was statistically significantly higher in early-stage patients (p < .05). No statistically significant correlation was observed between CR and gender, histopathological features, or laboratory parameters. In patients with CR, 80% experienced relapse, significantly higher in early-stage patients (p < .05). However, there was no significant difference in disease-free survival between early and advanced stages (p > .05). CONCLUSIONS: The study results indicated that PUVA + low-dose INF-a combination therapy was more effective in the early stage than in the advanced stage. Additionally, there was a high relapse rate after the cessation of treatment in patients who achieved CR.

Leukomelanoderma Resembling Hyperpigmented Mycosis Fungoides.

Acquired circumscribed hyperpigmented patches and plaques have various differential diagnoses, including post-inflammatory hyperpigmentation and mycosis fungoides (MF). Leukomelanoderma is an uncommon cutaneous condition in which the pathogenesis is not fully elucidated. It has been reported that leukomelanoderma occurs after allergic contact dermatitis from hydroquinone or acute cutaneous graft-versus-host disease (1,2). Hyperpigmented MF is a cutaneous T-cell lymphoma with a frequent CD8+ phenotype (3). Herein, we report a case of leukomelanoderma clinically and histologically resembling hyperpigmented MF. A 55-year-old Japanese woman was referred to our department for evaluation of reticulate pigmentation with pruritic erythema on the face. She had used commercially available depigmenting cosmetic reagents for 20 years and ointment containing 10% hydroquinone for 3 months. Physical examination revealed diffuse hyperpigmentation and demarcated hypopigmented macules on the face and neck (Figure 1, a). Dermoscopy showed depigmented spots and reticulated plus dotted hyperpigmentation; it presented a pseudo-pigment network (Figure 1, b). Histological examination of a tissue specimen biopsied from the lesion showed superficial band-like lymphocytic infiltration in dermis accompanying single cells or small clusters in epidermis (Figure 1, c). Interface changes were observed together with melanophages in the dermis. Melan-A-positive melanocytes were absent. Immunohistochemical analysis demonstrated that the epidermotropic lymphocytes were CD3+CD7-, and they had predominance of CD8+ cells (Figure 1, d). These immunohistochemical results mimicked MF. However, PCR analysis of the T-cell receptor g-gene rearrangement was negative. Closed patch test result with hydroquinone (5% pet.) was graded D2 (+?) and D3 (+). Ten months after discontinuing cosmetic reagents and hydroquinone, the pigmentary changes showed improvement. The pathomechanism of leukomelanoderma is unclear. Although post-inflammatory pigmentation due to allergic or contact dermatitis together with direct depigmenting effects from hydroquinone use has been suggested (1), the immunophenotype of T-cells has not been examined. As observed in our patient, interface changes with melanophages, in addition to frequent CD8+ phenotype of the epidermotropism and dermal infiltrate of lymphocytes, were characteristic for hyperpigmented MF (3). Moreover, minimal CD7 expression was a specific finding for MF (4). T-cell receptor clonality was negative in our patient, but the clonality appears to be detected by PCR in up to 50% of the patients with early MF (3). In contrast, the closed patch test was positive for hydroquinone in our patient, and it is reported that CD8+ T-cells are recruited to the interphase between the epidermis and the dermis of the patients with allergic contact dermatitis (5). CD8+ T-cells might contribute to acute cutaneous graft-versus-host disease-like interface changes and destroy melanocytes in the leukomelanoderma lesion. Allergic contact dermatitis presenting as leukomelanoderma was thus suggested in our patient. However, further reports and studies are required to support this issue. Therefore, we considered it necessary to follow the patient, since MF was not absolutely eliminated.

A retrospective study of prognostic factors and treatment outcome in advanced-stage Mycosis Fungoides and Sezary Syndrome.

Background: Mycosis fungoides (MF) and Sezary Syndrome (SS) comprise over half of all Cutaneous T-cell lymphoma diagnoses. Current risk stratification is largely based on TNMB staging, few research investigated the prognostic value of clinical exams. Current systemic therapy for advanced disease includes immunomodulatory drugs, chemotherapy, and HADC inhibitors. Few clinical trials or retrospective research compared the efficacy of different drugs.Method: Here, we performed a retrospective analysis of prognostic factors and treatment outcomes of 92 patients diagnosed with MF/SS at the Peking Union Medical College Hospital from 2013-2023.Results: Cox regression analysis identified that age ≥ 50 years, WBC ≥ 8 × 109/L, serum LDH ≥ 250U/L, ß2-MG ≥ 4.50 mg/L, and stage IV were associated with reduced overall survival, age ≥ 50 years, serum LDH ≥ 250U/L and stage IV were associated with reduced progression free survival. Kaplan-Meier analysis established that immunomodulatory therapy was associated with longer progression free survival.Conclusion: These results suggested new factors in predicting prognosis and selecting appropriate treatments in patients with advanced MF/SS.

Cutavirus Infection in Large-Plaque Parapsoriasis, a Premalignant Condition of Mycosis Fungoides.

BACKGROUND: Cutavirus (CuV) is associated with mycosis fungoides; however, the CuV status in parapsoriasis en plaques (PP), a premalignant inflammatory condition of mycosis fungoides, has not been fully delineated. METHODS: Fifty-five Japanese patients with chronic inflammatory skin diseases, including 13 patients with PP, were studied. RESULTS: CuV DNA was detected significantly more frequently in biopsies of the lesional skin from patients with PP (38%; 4 of 13) than in those from patients with other inflammatory skin diseases (2%; 1 of 42; P = .009). All CuV-positive PP cases were of the large-plaque parapsoriasis (LPP) subtype. The viral loads ranged from 83 450 to 2 164 170 copies/103 cells. We recovered near-full-length CuV sequences from the CuV-positive LPP biopsies, all of which were of the Japanese/Asian genotype. The CuV genome appeared to be present within lymphoid cells infiltrating the epidermis and dermis. CuV NS1 and VP1 gene transcripts were also detected in the affected tissues. CONCLUSIONS: The detection of high levels of CuV DNA with the expression of viral mRNA suggests a potential role for CuV in the pathogenesis of LPP, making it necessary to study further the impact of CuV, especially regarding the viral genotype, on the outcomes of patients with CuV-positive LPP.

Cutaneous T-cell Lymphoma.

Cutaneous T-cell lymphoma is a group of non-Hodgkin T-cell lymphomas that develop in and affect the skin but can potentially spread to other organs. There are many subtypes, the most common of which are mycosis fungoides, Sezary syndrome, lymphomatoid papulosis, and primary cutaneous anaplastic large cell lymphoma. Cutaneous lymphoma is a common cause of recalcitrant chronic skin rash and notoriously mimics other dermatologic and hematologic conditions, often resulting in diagnostic delays of months to years. This review provides an introduction to cutaneous T-cell lymphoma, with a primary focus on the clinical presentation, diagnosis, immunopathogenesis, and management of the condition.

[Translated article] Survival Analysis and Prognostic Factors in a Case Series of 148 Cutaneous T-Cell Lymphomas.

BACKGROUND AND OBJECTIVE: Cutaneous T-cell lymphomas (CTCL) such as mycosis fungoides (MF) and Sézary syndrome (SS) are rare lymphomas with varying prognoses. The aim of the study was to describe the survival of a cohort of patients with MF/SS and evaluate the prognostic factors impacting disease survival. MATERIALS AND METHODS: All cases of MF/SS diagnosed from 2008 through 2022 were retrospectively analyzed. The demographic variables, histological parameters, and analytical data were analyzed too. Progression-free survival (PFS) and disease-specific survival (DSS) were calculated. RESULTS: A total of 148 cases were included. A total of 121 (82%) and 27 cases were diagnosed with MF, and SS, respectively. A total of 37 patients (25%) experienced progression at some point disease progression. The median PFS and median DSS were 127 and 135 months, respectively. Age >60 years, diagnosis of SS, the presence of large cell transformation (LCT) at diagnosis, folliculotropism in early stages, high Ki-67 expression, the presence of the clonal T-cell receptor (TCR) in blood, elevated LDH and B2M levels, and advanced stages (IIB, IVA, T3, T4, N3/Nx) were associated with worse prognosis across the entire cohort. CONCLUSIONS: Stage IVA and the presence of LCT at diagnosis stood out as independent factors of unfavorable prognosis. LCT was the variable that most significantly impacted the patients' survival and was closely associated with tumor skin involvement and stage IIB.

Phase I/II clinical trial of brentuximab vedotin for pretreated Japanese patients with CD30-positive cutaneous T-cell lymphoma.

Brentuximab vedotin (BV), a conjugate of anti-CD30 antibody and monomethyl auristatin E, has emerged as a promising treatment option for refractory CD30+ mycosis fungoides (MF) and primary cutaneous anaplastic large-cell lymphoma (pcALCL). BV has been shown to be safe and effective in treating Hodgkin's lymphoma and peripheral T-cell lymphoma. This multicenter, prospective, single-arm phase I/II study evaluated the efficacy of BV in Japanese patients with CD30+ cutaneous lymphomas, namely CD30+ cutaneous T-cell lymphoma. Participants were divided into two groups: those with CD30+ MF or pcALCL (cohort 1, n = 13) and those with CD30+ lymphoproliferative disorders other than those in cohort 1 (cohort 2, n = 3). The studied population included the full analysis set (FAS), modified FAS (mFAS), and safety analysis set (SAF). These sets were identified in cohorts 1 and 1 + 2 and labeled FAS1 and FAS2, mFAS1 and mFAS2, and SAF1 and SAF2, respectively. Each treatment cycle lasted 3 weeks, and BV was continued for up to 16 cycles after the third cycle based on treatment response. The primary endpoint was the 4-month objective response rate (ORR4) determined by the Independent Review Forum (IRF). ORR4 was 69.2% for FAS1 and 62.5% for FAS2 (P < 0.0001). Secondary endpoints of ORR, assessed using the global response score (53.8% in FAS1) and modified severity-weighted assessment tool (62.5% in FAS1), using the IRF, provided results comparable to the primary findings. The incidence of ≥grade 3 adverse events (≥15%) in SAF1 was peripheral neuropathy in three patients (23%) and fever and eosinophilia in two patients (15%). In conclusion, BV showed favorable efficacy, tolerability, and safety profile in Japanese patients with relapsed or refractory CD30+ primary cutaneous T-cell lymphoma. The trial was registered with University Hospital Medical Information Network Clinical Trials Registry, Japan (protocol ID: UMIN000034205).

Chart review study of real-world clinical outcomes in patients with cutaneous T-cell lymphoma treated with extracorporeal photopheresis in the US in 2017-2019.

BACKGROUND: Response rates of approved systemic therapies for cutaneous T-cell lymphoma (CTCL) hover near 30%, suggesting unmet need. This study describes real-world treatment patterns and response rates of extracorporeal photopheresis (ECP) in CTCL patients. METHODS: A chart review was conducted in the United States of adults with CTCL who initiated ECP between January 1, 2017, and February 28, 2019, and received at least three months of ECP treatment as monotherapy or concomitant therapy. Clinical outcomes were collected quarterly for up to 18 months. RESULTS: The 52 patients were predominantly Caucasian. Half were male; median age was 69 years. Most patients had Sézary syndrome (50%) or mycosis fungoides (36.5%). Nearly 40% of patients had stage IV disease; 33% had lymph node involvement. Nineteen patients (36.5%) achieved response (>50% reduction in BSA affected); median time to response was 6.5 months. The percentage of patients rated as at least minimally improved was 59.5% at 6 months (N = 22), 75.0% at 9 months (N = 24), and 60.0% at 12 months (N = 15) after ECP initiation. CONCLUSIONS: Despite the ECP treated population in this study being older and having more advanced-stage disease than recent trials, response rates were comparable. These real-world findings support ECP as an effective treatment option for CTCL patients.

Estimation of the tissue and serum levels of IL-35 in Mycosis fungoides: a case-control study.

Mycosis fungoides (MF) is the most common primary cutaneous T-cell lymphoma (CTCL) with its etiology not yet fully understood. Interleukin (IL)-35 is an inhibitory cytokine that belongs to the IL-12 family. Elevated IL-35 in the plasma and the tumor microenvironment increases tumorigenesis and indicates poor prognosis in different types of malignancies. The objective of this study is to estimate the expression levels of IL-35 in tissue and serum of MF patients versus healthy controls. This case-control study included 35 patients with patch, plaque, and tumor MF as well as 30 healthy controls. Patients were fully assessed, and serum samples and lesional skin biopsies were taken prior to starting treatment. The IL-35 levels were measured in both serum and tissue biopsies by ELISA technique. Both tissue and serum IL-35 levels were significantly higher in MF patients than in controls (P < 0.001) and tissue IL-35 was significantly higher than serum IL-35 in MF patients (P < 0.001). Tissue IL-35 was significantly higher in female patients and patients with recurrent MF compared to male patients and those without recurrent disease (P < 0.001). Since both tissue and serum IL-35 levels are increased in MF, IL-35 is suggested to have a possible role in MF pathogenesis. IL-35 can be a useful diagnostic marker for MF. Tissue IL-35 can also be an indicator of disease recurrence.

Predictors for the use of systemic therapy in stage IB Mycosis fungoides.

BACKGROUND: The PROspective Cutaneous Lymphoma International Prognostic Index (PROCLIPI) study is aprospective analysis of an international database. Here we examine front-line treatments and quality of life (QoL) inpatients with newly diagnosed mycosis fungoides (MF). OBJECTIVES: To identify (i) differences in first-line approaches according to tumour-nodes-metastasis-blood (TNMB)staging; (ii) parameters related to a first-line systemic approach and (iii) response rates and QoL measures. METHODS: In total, 395 newly diagnosed patients with early-stage MF (stage IA-IIA) were recruited from 41 centresin 17 countries between 1 January 2015 and 31 December 2018 following central clinicopathological review. RESULTS: The most common first-line therapy was skin-directed therapy (SDT) (322 cases, 81·5%), while a smallerpercentage (44 cases, 11·1%) received systemic therapy. Expectant observation was used in 7·3%. In univariateanalysis, the use of systemic therapy was significantly associated with higher clinical stage (IA, 6%; IB, 14%; IIA,20%; IA-IB vs. IIA, P < 0·001), presence of plaques (T1a/T2a, 5%; T1b/T2b, 17%; P < 0·001), higher modified Severity Weighted Assessment Tool (> 10, 15%; ≤ 10, 7%; P = 0·01) and folliculotropic MF (FMF) (24% vs. 12%, P = 0·001). Multivariate analysis demonstrated significant associations with the presence of plaques (T1b/T2b vs.T1a/T2a, odds ratio 3·07) and FMF (odds ratio 2·83). The overall response rate (ORR) to first-line SDT was 73%,while the ORR to first-line systemic treatments was lower (57%) (P = 0·027). Health-related QoL improvedsignificantly both in patients with responsive disease and in those with stable disease. CONCLUSIONS: Disease characteristics such as presence of plaques and FMF influence physician treatment choices,and SDT was superior to systemic therapy even in patients with such disease characteristics. Consequently, futuretreatment guidelines for early-stage MF need to address these issues.

Morphoea presenting histopathologically as mycosis fungoides: an illustrative series of four cases.

AIMS: There have been exceptional reports of morphoea presenting with epidermal changes overlapping histopathologically with cutaneous T cell lymphoma of the mycosis fungoides type (MF). This phenomenon gives rise to an ambiguous clinicopathological scenario in which distinguishing these conditions may be challenging. The aim of this study is to characterise the clinical, histopathological and molecular findings of this phenomenon through a case series. METHODS AND RESULTS: Four patients with classical clinical presentation of morphoea but unusual histopathology displaying typical findings of morphoea, together with intra-epidermal CD8 positive lymphocytes indistinguishable from MF, were identified. The clinical phenotypes of morphoea were varied, and they all presented early in the active phase of the disease. They all exhibited intra-epidermal lymphocytes with tagging and cytological atypia. Pautrier-like microabscesses were also seen. Using molecular analysis, two cases showed clonal TCR gene rearrangement. Follow-up of all cases has been consistent with classical morphoea. CONCLUSION: Early morphoea can seldom present with atypical clonal intra-epidermal lymphocytes indistinguishable from MF. The fact that these changes can occur in several different clinical subtypes of morphoea raises the possibility that this could be a pattern of inflammation in early disease more common than currently appreciated.

Mycosis fungoides refractory to treatment - importance of a multidisciplinary approach.

We report a case of difficult-to-control mycosis fungoides (MF), where the role of the dental surgeon was crucial for the control and prognosis of the disease. A 62-year-old female patient diagnosed with MF had a previous record of red patches and small raised bumps on the face, along with a cancerous growth in the cervical and vulvar region. The patient was initially treated with methotrexate and local radiotherapy without resolution. Chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone was then started (CHOP protocol). The dental team of a reference hospital was consulted to evaluate swelling in the anterior region of the palate, which had been developing for two months, reporting discomfort when eating. The role of the dentistry team was fundamental in the differential diagnosis of oral lesions with dental infections, second neoplasia, or even a new site of disease manifestation, in addition to controlling mucosal changes resulting from chemotherapy. After ruling out dental infection, the dentistry team performed a lesion biopsy to confirm the diagnosis. The histopathological and immunohistochemical analysis showed atypical lymphoid infiltration of T cells (CD3+/CD4+/CD7-/CD8-), coexpression of CD25, and presence of CD30 cells, corresponding to the finding for MF. Identifying CD30 + allowed for a new chemotherapy protocol with brentuximab vedotin (BV) combined with gemcitabine. This protocol effectively controlled MF, which previous protocols had failed to do. The diagnosis by the dental team was essential for therapeutic change and improvement of the patient's clinical condition without the need for invasive medical procedures.

Phenotypic heterogeneity of mycosis fungoides cells leads to the difficulties in determining tumour origin.

Mycosis fungoides (MF) is a low-grade malignant cutaneous T-cell lymphoma that originates from memory T cells. It typically follows a unique and relatively indolent disease course. MF is used to be characterized by a tissue-resident memory T cell (TRM) phenotype, although recent molecular research has revealed its complexity, casting doubt on the cell of origin and the TRM-MF paradigm. Recent clonal heterogeneity studies suggest that MF may originate from immature early precursor T cells. During development, the tumour microenvironment (TME) influences tumour cell phenotype. The exact origin and development trajectory of MF remains elusive. Clarifying the origin of MF cells is vital for accurate diagnosis and effective treatment.