Prevalence, tropism, and activity of cutavirus in circulating blood lymphocytes, stool, and skin biopsy specimens of patients with cutaneous T-cell lymphoma and parapsoriasis en plaques.

A significant association has been established between a newly emerging human parvovirus, cutavirus (CuV), and cutaneous T-cell lymphoma/mycosis fungoides (CTCL/MF) and its precursor parapsoriasis en plaques (PP). CTCL is a heterogeneous group of skin malignancies of T cells, the cause of which remains unknown. This study aimed to determine the activity, spread, and cell tropism of the skin-persistent CuV. CuV DNA was detected in both skin biopsies (6/20, 30%) and peripheral blood mononuclear cells (PBMCs) (4/29, 13.8%) from 49 CTCL/MF or PP patients, while none from 33 patients with any other type of skin disease or healthy subjects harbored CuV DNA. CuV DNA persisted in the skin or PBMCs for up to 15 years, despite circulating CuV-specific IgG. Spliced CuV mRNA was expressed in skin, indicating viral activity. Also, both of two available stool samples contained encapsidated CuV genomes, suggesting that the patients excrete infectious virus into the environment. Finally, CuV was observed to target circulating and skin-resident CD4 + T cells and some skin keratinocytes and macrophages. This is especially intriguing as malignant T cells in CTCL develop from CD4 + T cells. Hence, CuV should be further investigated for the overall role it plays in the complex tumor microenvironment of CTCL/MF.

Critical Review-A Tribute to Louis Brocq Lymphomatoid Papulosis, the Key in Exploring the Relationship of Parapsoriasis and Mycosis Fungoides.

ABSTRACT: Both parapsoriasis and LyP appear clinically as inflammatory dermatoses with a paradoxical link to cMF. A key element in addressing the relationship of parapsoriasis and MF were the results of the French and Dutch long-term registries tracking the emergence of lymphomas in the setting of LyP. Both cMF and cALCL emerged almost equally in these long-term studies. This ultimately supports that the stem cells in both cMF and cALCL are probably derived from a common stem cell shared by CD4+/CD8+ memory stem cells defining cMF and CD30+ stem cells defining cALCL. The discovery of inducible Skin Associated Lymphoid Tissue (iSALT) mesenchymal hubs incorporating Tregs, with their pleiotropic functions represents a paradigm shift and formed a translational tool in this analysis of the paradox. LyP can be recast as activated inhibitory lymphomatoid T-cell hubs derived from inducible iTregs in iSALT and the source of the common stem cell LyP line. iSALT Treg integrated mesenchymal hubs provided an emerging translational tool in redefining integrated lymphomatoid pathways. Brocq's complex scheme defining parapsoriasis as hybrid inflammatory dermatoses with a paradoxical link to cMF became a template to preserve parapsoriasis as a clinical diagnosis. Two major iSALT Treg generated inhibitory integrated lymphomatoid hubs emerged. The major CD30+TNF lymphomatoid hub has been linked to cALCL. Clinically defined chronic regressing and relapsing parapsoriasis with the histopathology of patch stage MF can be redefined as lymphomatoid parapsoriasis. This twin inhibited oncogenic memory based hub is defined by Treg modulated, CD4+/CD8+memory linked PD-1/DL-1 cytoxic complex and lichenoid histopathology.

Significant Association of Cutavirus With Parapsoriasis en Plaques: High Prevalence Both in Skin Swab and Biopsy Samples.

Cutavirus (CuV) is associated with cutaneous T-cell lymphoma (CTCL), of which parapsoriasis is a precursor. Our study reveals a significantly higher CuV-DNA prevalence in skin swabs of parapsoriasis patients (6/13; 46.2%) versus those of healthy adults (1/51; 1.96%). Eight patients (8/12; 66.7%) had CuV DNA in biopsied skin, and 4 developed CTCL.

Cell adhesion molecule 1 expression in mycosis fungoides versus parapsoriasis versus inflammatory dermatosis: an immunohistochemical comparative study.

Cell adhesion molecule 1 (CADM1) is one of the immunoglobulin super family adhesion molecules, that is proposed to contribute in the pathogenesis of various types of cutaneous T-cell lymphoma, including mycosis fungoides (MF). In this work, we decided to examine the immunohistochemical expression of CADM1 in MF specimens compared to premycotic parapsoriasis, benign inflammatory dermatosis and normal control skin specimens. 125 participants were enrolled (50 MF, 25 parapsoriasis, 25 inflammatory dermatosis, and 25 healthy controls). Patients were selected from the Outpatient Clinic of Dermatology and Venereology Department, Tanta University Hospitals. From all, 4 mm punch skin biopsies were taken and examined for CADM1 immunohistochemical expression. The current study revealed statistically significant upregulation of CADM1 expression in MF specimens in comparison to parapsoriasis, inflammatory dermatosis, and normal control specimens. Additionally, there was statistically significant positive correlation between CADM1 expression and progression of TNMB staging of MF disease. Therefore, it is possible to recommend CADM1 as a beneficial diagnostic immunohistochemical marker for differentiation between early stages of MF and both the premycotic parapsoriasis and benign inflammatory dermatosis. Moreover, it may be of value in early detection of neoplastic transformation of parapsoriasis as well as in assessment of MF progression.

Dupilumab-associated cutaneous adverse events among adult patients with atopic dermatitis: A retrospective study.

Dupilumab, a monoclonal antibody inhibiting interleukin (IL) 4 and IL-13, is approved for the treatment of moderate to severe atopic dermatitis (AD) in children aged ≥6 years, adolescents, and adults. Both clinical trials and real-life data demonstrate its efficacy and safety. However, some cutaneous adverse events (cAEs) have been observed during real-world experiences. The authors' aim was to analyze the spectrum of cAEs in patients receiving dupilumab for the treatment of AD in a real-world setting. A retrospective review of electronic medical records was conducted for 916 patients (475 males and 541 females; mean age, 50.23 ± 19.66 years [range, 18-91 years]) who had received dupilumab for a minimum of 1 month for the treatment of AD from December 2018 to November 2022 at the Department of Dermatology of University Federico II of Naples (Italy). The mean duration of dupilumab treatment was 27.31 ± 21.26 months. A total of 148 of 916 (16.15%) (90 males; mean age, 50.91 ± 15.34 years) patients reported other cAEs apart of AD flare; namely, facial redness (82 of 916; 8.95%), psoriasis (39 of 916; 4.25%), alopecia areata (11 of 916; 1.2%), skin peeling (11 of 916; 1.2%), parapsoriasis (three of 916; 0.32%), and vitiligo (two of 916; 0.21%). Thirty-one of 916 (3.38%) patients discontinued dupilumab because of cAEs (18 of 916; 1.96%) for facial redness, 10 of 916 (1.09%) for psoriasis, and three of 916 (0.32%) for parapsoriasis. In our population, most of the cAEs were mild and did not require discontinuation of dupilumab. These findings would enable dermatologists understand the cutaneous side effects of dupilumab better, resulting in improved treatment plan decisions in clinical practice.

From Benign Inflammatory Dermatosis to Cutaneous Lymphoma. DNA Copy Number Imbalances in Mycosis Fungoides versus Large Plaque Parapsoriasis.

Background and Objectives: Mycosis fungoides (MF) and large plaque parapsoriasis (LPP) evolution provide intriguing data and are the cause of numerous debates. The diagnosis of MF and LPP is associated with confusion and imprecise definition. Copy number alterations (CNAs) may play an essential role in the genesis of cancer out of genes expression dysregulation. Objectives: Due to the heterogeneity of MF and LPP and the scarcity of the cases, there are an exceedingly small number of studies that have identified molecular changes in these pathologies. We aim to identify and compare DNA copy number alterations and gene expression changes between MF and LPP to highlight the similarities and the differences between these pathologies. Materials and Methods: The patients were prospectively selected from University Clinic of Dermatology and Venereology Timișoara, Romania. From fresh frozen skin biopsies, we extracted DNA using single nucleotide polymorphism (SNP) data. The use of SNP array for copy number profiling is a promising approach for genome-wide analysis. Results: After reviewing each group, we observed that the histograms generated for chromosome 1-22 were remarkably similar and had a lot of CNAs in common, but also significant differences were seen. Conclusions: This study took a step forward in finding out the differences and similarities between MF and LPP, for a more specific and implicitly correct approach of the case. The similarity between these two pathologies in terms of CNAs is striking, emphasizing once again the difficulty of approaching and differentiating them.

Interleukin (IL)-13/IL-22/IL-31 skewing within the skin-homing T-cell population in papuloerythroderma.

Papuloerythroderma (PEO) is a representative form of senile erythroderma with an unclear pathogenesis. This study aimed to characterize the T-cell phenotypes responsible for the pathogenesis of PEO. Cytokine profiles and cutaneous lymphocyte antigen (CLA) expression on circulating T lymphocytes in patients with PEO were simultaneously analyzed using flow cytometry. The patients with PEO showed significantly higher circulating interleukin (IL)-4-, IL-13-, IL-22-, and IL-31-producing CD4+ and CD8+ T-cell levels than healthy subjects. However, their levels significantly decreased after remission of PEO. No difference was observed in the proportions of circulating interferon (IFN)-γ- and IL-17-producing CD4+ and CD8+ T cells between the patients with PEO and healthy subjects. In particular, the proportion of circulating IL-4-, IL-13-, IL-22-, and IL-31-producing CD4+ and CD8+ T cells was much higher in the CLA+ subset than in the CLA- subset. There was a positive correlation between IL-13-, IL-22-, and IL-31-producing CD4+ T cells and the disease severity score of PEO. Moreover, a positive correlation was also observed between the proportion of IL-22- or IL-31-producing cells and circulating IL-13-producing cells in both CD4+ and CD8+ T cells, and approximately 50% of both IL-22- and IL-31-producing CD4+ and CD8+ T cells coproduced IL-13. IL-13/IL-22/IL-31 skewing within the skin-homing T-cell population may be involved in the pathogenesis of PEO.

From SARS-CoV-2 hematogenous spreading to endothelial dysfunction: clinical-histopathological study of cutaneous signs of COVID-19.

BACKGROUND: To date, very few studies on clinical-histopathological correlations of cutaneous disorders associated with COVID-19 have been conducted. CASE PRESENTATION: The Case 1 was a 90-year-old man, who tested positive for SARS-CoV-2 from a nasopharyngeal swab. Two days later, he was hospitalized and after eleven days transferred to Intensive Care Unit. A chest CT showed bilateral ground-glass opacities. Just that day, an erythematous maculo-papular rash appeared on trunk, shoulders and neck, becoming purpuric after few days. Histological evaluations revealed a chronic superficial dermatitis with purpuric aspects. The superficial and papillary dermis appeared edematous, with a perivascular lympho-granulocytic infiltrate and erythrocytic extravasation. At intraepithelial level, spongiosis and a granulocyte infiltrate were detected. Arterioles, capillaries and post-capillary venules showed endothelial swelling and appeared ectatic. The patient was treated with hydroxychloroquine, azithromycin, lopinavir-ritonavir and tocilizumab. Regrettably, due to severe lung impairment, he died. The Case 2 was a 85-year-old man, admitted to Intensive Care Unit, where he was intubated. He had tested positive for SARS-CoV-2 from a nasopharyngeal swab two days before. A chest RX showed bilateral atypical pneumonia. After seven days, a cutaneous reddening involving trunk, upper limbs, neck and face developed, configuring a sub-erythroderma. Histological evaluations displayed edema in the papillary and superficial reticular dermis, and a perivascular lymphocytic infiltrate in the superficial dermis. The patient was treated with hydroxychloroquine, azithromycin, lopinavir-ritonavir and tocilizumab. Sub-erythroderma as well as respiratory symptoms gradually improved until healing. CONCLUSIONS: The endothelial swelling detected in the Case 1 could be a morphological expression of SARS-CoV-2-induced endothelial dysfunction. We hypothesize that cutaneous damage could be initiated by endothelial dysfunction, caused by SARS-CoV-2 infection of endothelial cells or induced by immune system activation. The disruption of endothelial integrity could enhance microvascular permeability, extravasation of inflammatory cells and cytokines, with cutaneous injury. The Case 2 developed a sub-erythroderma associated with COVID-19, and a non-specific chronic dermatitis was detected at histological level. We speculate that a purpuric rash could represent the cutaneous sign of a more severe coagulopathy, as highlighted histologically by vascular abnormalities, while a sub-erythroderma could be expression of viral hematogenous spreading, inducing a non-specific chronic dermatitis.

Shall we exclude parapsoriasis from the medical vocabulary?

Since the first description of parapsoriasis more than 100 years ago, parapsoriasis has been a questionable condition and occasionally considered a precursor of cutaneous lymphoma. The name "parapsoriasis" is related to a heterogenous group of diseases that show a distinct clinical presentation; however, the histopathological criteria are not strongly specific. Pathologists do not consider parapsoriasis as a possible histopathological diagnosis, but dermatologists use the term as clinical hypothesis. We aim to provide an historical review of parapsoriasis focusing on histopathological criteria, considering its possible relation with cutaneous skin lymphoma, based on articles from PubMed and standard dermatopathological books. Parapsoriasis does not have well-defined histopathological criteria, so its use should be avoided. Being aware of parapsoriasis complexity, a consensus meeting can help to create a guideline regarding this topic.

Poikilodermatous Mycosis Fungoides: Comparative Study of Clinical, Histopathological and Immunohistochemical Features.

BACKGROUND: Poikilodermatous mycosis fungoides (pMF) is characterized by poikiloderma areas, typically involving the major flexural areas and trunk. Its presentation can be generalized or admixed with other forms of MF. Previous studies fail to correlate the clinical presentation with prognosis and laboratory findings. Some reports show pityriasis lichenoides chronica (PLC) preceding the poikiloderma. OBJECTIVES: Correlate prognostic, histopathological and molecular aspects of pMF with its clinical presentation. METHODS: Retrospective analysis of 14 cases of generalized pMF (GpMF), 22 of localized pMF (LpMF) and 17 of pMF admixed with other forms of MF (mix-pMF). RESULTS: Female predominance and lower age at diagnosis was found in all groups compared to classic MF, a high prevalence of PLC-like lesions in the GpMF group and a high rate of hypopigmented lesions in the mix-pMF group. There were 2 deaths within the GpMF group. Histology was similar to previously reported findings, as was the prevalence of CD4 T-cell infiltrate, compared to CD8. The T-cell clonality positivity was lower in the GpMF group, compared to other groups (27% GpMF, 80% LpMF and 100% mix-pMF). DISCUSSION: This is the first article to categorize the different forms of pMF and correlate them with clinical and laboratory findings. The dermatological presentation differs among the groups. There was a high frequency of PLC-like lesions within the GpMF group and of hypopigmented lesions in mix-pMF. The histological and immunohistochemical findings were similar to those previously reported. Aggressive treatments are not recommended due to the good prognosis of all pMF forms. The low positivity of T-cell clonality in the GpMF group should be investigated.