PEG10 amplification at 7q21.3 potentiates large-cell transformation in cutaneous T-cell lymphoma.

Mycosis fungoides (MF), the most common form of cutaneous T-cell lymphoma, undergo large-cell transformation (LCT) in the late stage, manifesting aggressive behavior, resistance to treatments, and poor prognosis, but the mechanisms involved remain unclear. To identify the molecular driver of LCT, we collected tumor samples from 133 MF patients and performed whole-transcriptome sequencing on 49 advanced-stage MF patients, followed by integrated copy number inference and genomic hybridization. Tumors with LCT showed unique transcriptional programs and enriched expressions of genes at chr7q. Paternally expressed gene 10 (PEG10), an imprinted gene at 7q21.3, was ectopically expressed in malignant T cells from LCT, driven by 7q21.3 amplification. Mechanistically, aberrant PEG10 expression increased cell size, promoted cell proliferation, and conferred treatment resistance by a PEG10/KLF2/NF-κB axis in in vitro and in vivo models. Pharmacologically targeting PEG10 reversed the phenotypes of proliferation and treatment resistance in LCT. Our findings reveal new molecular mechanisms underlying LCT and suggest that PEG10 inhibition may serve as a promising therapeutic approach in late-stage aggressive T-cell lymphoma.

Comparing the quality of ChatGPT- and physician-generated responses to patients' dermatology questions in the electronic medical record.

BACKGROUND: ChatGPT is a free artificial intelligence (AI)-based natural language processing tool that generates complex responses to inputs from users. OBJECTIVES: To determine whether ChatGPT is able to generate high-quality responses to patient-submitted questions in the patient portal. METHODS: Patient-submitted questions and the corresponding responses from their dermatology physician were extracted from the electronic medical record for analysis. The questions were input into ChatGPT (version 3.5) and the outputs extracted for analysis, with manual removal of verbiage pertaining to ChatGPT's inability to provide medical advice. Ten blinded reviewers (seven physicians and three nonphysicians) rated and selected their preference in terms of 'overall quality', 'readability', 'accuracy', 'thoroughness' and 'level of empathy' of the physician- and ChatGPT-generated responses. RESULTS: Thirty-one messages and responses were analysed. Physician-generated responses were vastly preferred over the ChatGPT -responses by the physician and nonphysician reviewers and received significantly higher ratings for 'readability' and 'level of empathy'. CONCLUSIONS: The results of this study suggest that physician-generated responses to patients' portal messages are still preferred over ChatGPT, but generative AI tools may be helpful in generating the first drafts of responses and providing information on education resources for patients.

Direct to Patient Synchronous Teledermatology During COVID-19 Pandemic.

Background: During the COVID-19 pandemic, teledermatology became a popular mode of health care delivery. Thus, deciphering which diagnoses are best suited for synchronous video visits is important to guide providers on appropriate patient care. Methods: We conducted a retrospective study of 1,647 submitted synchronous video visits from September 1, 2020 to March 31, 2021 at a single, large academic institution. Results: Video visits' follow-up rate was significantly associated with diagnosis subtype (p < 0.001). Compared with patients with skin lesions and nonskin dermatologic conditions, patients with a rash had higher odds of being recommended to have their follow-up visit as a video visit (odds ratio [OR] = 0.222, p < 0.001; OR = 0.296, p < 0.001). Patients with a rash had lower odds of being recommended to have their follow-up visit as an in-person office visit when compared with skin lesions (OR = 9.679, p < 0.001), nonskin dermatologic conditions (OR = 4.055, p < 0.001), and other skin dermatologic conditions (OR = 2.23, p < 0.01). Demographically, employed, middle-aged patients with private insurance made up the majority of video visit usage. African American patients were less likely to utilize a video visit compared with Asian patients (OR = 2.06, p < 0.038). Conclusions: Certain dermatologic diagnoses, most notably rashes, are more conducive to video visit management. Rashes made up 86% of new patient video visits, were more likely to have video visit follow-up if needed and were more likely to not require further follow-up indicating that the management of rashes from initial diagnosis to completion in care is suitable for video visit management.

Retrospective pharmacogenetic study of psoriasis highlights the role of KLK7 in tumour necrosis factor signalling.

BACKGROUND: Multiple treatment options are available for the management of psoriasis, but clinical response varies among individual patients and no biomarkers are available to facilitate treatment selection for improved patient outcomes. OBJECTIVES: To utilize retrospective data to conduct a pharmacogenetic study to explore the potential genetic pathways associated with drug response in the treatment of psoriasis. METHODS: We conducted a retrospective pharmacogenetic study using self-evaluated treatment response from 1942 genotyped patients with psoriasis. We examined 6 502 658 genetic markers to model their associations with response to six treatment options using linear regression, adjusting for cohort variables and demographic features. We further utilized an integrative approach incorporating epigenomics, transcriptomics and a longitudinal clinical cohort to provide biological implications for the topmost signals associated with drug response. RESULTS: Two novel markers were revealed to be associated with treatment response: rs1991820 (P = 1.30 × 10-6) for anti-tumour necrosis factor (TNF) biologics; and rs62264137 (P = 2.94 × 10-6) for methotrexate, which was also associated with cutaneous mRNA expression levels of two known psoriasis-related genes KLK7 (P = 1.0 × 10-12) and CD200 (P = 5.4 × 10-6). We demonstrated that KLK7 expression was increased in the psoriatic epidermis, as shown by immunohistochemistry, as well as single-cell RNA sequencing, and its responsiveness to anti-TNF treatment was highlighted. By inhibiting the expression of KLK7, we further illustrated that keratinocytes have decreased proinflammatory responses to TNF. CONCLUSIONS: Our study implicates the genetic regulation of cytokine responses in predicting clinical drug response and supports the association between pharmacogenetic loci and anti-TNF response, as shown here for KLK7.

Cutaneous T-cell lymphomas: 2023 update on diagnosis, risk-stratification, and management.

DISEASE OVERVIEW: Cutaneous T-cell lymphomas are a heterogenous group of T-cell neoplasms involving the skin, the majority of which may be classified as Mycosis Fungoides (MF) or Sézary Syndrome (SS). DIAGNOSIS: The diagnosis of MF or SS requires the integration of clinical and histopathologic data. RISK-ADAPTED THERAPY: TNMB (tumor, node, metastasis, blood) staging remains the most important prognostic factor in MF/SS and forms the basis for a "risk-adapted," multidisciplinary approach to treatment. For patients with disease limited to the skin, expectant management or skin-directed therapies is preferred, as both disease-specific and overall survival for these patients is favorable. In contrast, patients with advanced-stage disease with significant nodal, visceral or the blood involvement are generally approached with systemic therapies, including biologic-response modifiers, histone deacetylase inhibitors, or antibody-based strategies, in an escalating fashion. In highly-selected patients, allogeneic stem-cell transplantation may be considered, as this may be curative in some patients.

Cutaneous B-cell lymphomas: 2023 update on diagnosis, risk-stratification, and management.

DISEASE OVERVIEW: Approximately one-fourth of primary cutaneous lymphomas are B-cell derived and are generally classified into three distinct subgroups: primary cutaneous follicle center lymphoma (PCFCL), primary cutaneous marginal zone lymphoma (PCMZL), and primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL, LT). DIAGNOSIS: Diagnosis and disease classification is based on histopathologic review and immunohistochemical staining of an appropriate skin biopsy. Pathologic review and an appropriate staging evaluation are necessary to distinguish primary cutaneous B-cell lymphomas from systemic B-cell lymphomas with secondary skin involvement. RISK-STRATIFICATION: Disease histopathology remains the most important prognostic determinant in primary cutaneous B-cell lymphomas. Both PCFCL and PCMZL are indolent lymphomas that infrequently disseminate to extracutaneous sites and are associated with 5-year survival rates that exceed 95%. In contrast, PCDLBCL, LT is an aggressive lymphoma with an inferior prognosis. RISK-ADAPTED THERAPY: PCFCL and PCMZL patients with solitary or relatively few skin lesions may be effectively managed with local radiation therapy. While single-agent rituximab may be employed for patients with more widespread skin involvement, multiagent chemotherapy is rarely appropriate. In contrast, management of patients with PCDLBCL, LT is comparable to the management of patients with systemic DLBCL.

Two cases of challenging cutaneous lymphoid infiltrates presenting in the context of COVID-19 vaccination: A reactive lymphomatoid papulosis-like eruption and a bona fide lymphoma.

COVID-19 infection and vaccination may be associated with a wide variety of cutaneous and immune manifestations. Here, we describe two patients who presented with monoclonal cutaneous T-cell infiltrates that showed cytologic and immunophenotypic features concerning for lymphoma shortly following COVID-19 vaccination. In one case, the eruption completely resolved. The second patient showed initial resolution, but her disease recurred and progressed following a breakthrough SARS-CoV-2 infection. These cases suggest that immune stimulation following exposure to SARS-Cov-2 protein(s) in vaccine or infection may facilitate the development of a lymphoma or lymphoproliferative disorder in susceptible individuals. Moreover, they show that separating these cases from pseudolymphomatous reactive conditions is often challenging and requires close clinical correlation.

CD30 expression in cutaneous B-cell lymphomas.

INTRODUCTION: CD30 expression has been infrequently described in cutaneous B-cell lymphomas (CBCLs). We examined CD30 expression in reactive lymphoid hyperplasia (RLH) and CBCL and correlated expression with clinicopathologic features. METHODS: CD30 was examined in 82 CBCL patients and 10 RLH patients that had been evaluated in our cutaneous lymphoma clinics. The CBCL patients included: primary cutaneous follicle center lymphoma (PCFCL), Grade 1/2 systemic/nodal follicular lymphoma (SFL); primary cutaneous marginal zone lymphoma/lymphoproliferative disorder (PCMZL/LPD); systemic marginal zone lymphoma (SMZL); primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT); and extracutaneous/systemic diffuse large B-cell lymphoma (eDLBCL). We scored CD30 expression for intensity and extent and related CD30 expression to age at first diagnosis, sex, site of biopsy, clinical appearance, extracutaneous involvement, multiple cutaneous lesions, B-symptoms, lymphadenopathy, positive positron emission tomography/computed tomography (PET/CT), elevated lactate dehydrogenase (LDH), and positive bone marrow biopsy. RESULTS: CD30 expression was identified in 35% of CBCL, ranging from few, weak, scattered cells to strong and diffuse expression. It was most common in PCFCL and was not expressed in PCDLBCL-LT. Rare PCFCL expressed strong, diffuse CD30. Some cases of PCMZL/LPD, SMZL, FL, and RLH showed scattered, strongly positive cells. CD30 expression in CBCL was associated with favorable clinical features: younger age, negative PET/CT, and an LDH within normal limits. CONCLUSIONS: CD30 may be expressed in CBCL, possibly causing diagnostic confusion. CD30 expression was most commonly identified in PCFCL and is associated with favorable clinical features. In cases with strong and diffuse expression, CD30 could be a therapeutic target.

Patch/plaque mycosis-fungoides-like presentations of DUSP22-translocated T-cell lymphomas.

The DUSP22-IRF4 gene rearrangement results in downregulation of DUSP22, a presumed tumor suppressor in T-cell lymphomagenesis. It has been described in some cases of primary cutaneous and systemic anaplastic large-cell lymphoma, lymphomatoid papulosis, and transformed mycosis fungoides. Here we describe two patients with clinical lesions resembling patch/plaque mycosis fungoides that did not meet WHO criteria for large-cell transformation on histopathology yet showed a DUSP22 translocation. One patient who had a history of systemic anaplastic large-cell lymphoma with DUSP22 translocation presented with cutaneous involvement by his systemic lymphoma along with lymphomatoid papulosis and mycosis-fungoides-like lesions, all showing an identical immunophenotype and T-cell clone. These cases expand the spectrum of DUSP22-rearranged lymphomas to include mycosis-fungoides-like presentations without large-cell transformation.

Evaluation of Teledermatology Practice Guidelines and Recommendations for Improvement.

Background: The current coronavirus disease 2019 (COVID-19) pandemic has forced dermatology practices to rapidly adopt or expand teledermatology services. To date, teledermatology clinical practice guidelines (CPGs) have not been evaluated for quality. This may hinder the implementation and sustainability of high-quality teledermatology services. The objective of this study is to evaluate teledermatology CPGs by using a comprehensive, validated appraisal tool and provide actionable recommendations for improvement for future guideline developers. Materials and Methods: A systematic literature search was performed to identify all CPGs published in teledermatology. Identified guidelines meeting inclusion criteria were scored for guideline quality by three researchers using the Appraisal of Guidelines and Research and Evaluation tool (AGREE II). Results: Three guidelines met inclusion criteria, including guidelines published by the American Telemedicine Association, the British Association of Dermatologists, and the Australian College of Dermatologists and the University of Queensland. Each of these guidelines exhibited unique strengths and areas for improvement. Areas of strength include clear objective statements, stakeholder involvement, and clarity of presentation. Areas for improvement include rigor of guideline development, applicability, and editorial independence. Conclusions: All guidelines were determined to be of sufficient quality for adoption based on AGREE scoring. Adoption of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) evidence appraisal framework would improve the rigor of development of each guideline. Administering and publishing questionnaires to assess financial competing interests and external review processes would shed more light on the presence and/or extent of author bias. One inherent limitation of CPG selection criteria is that large providers of teledermatology services, such as the United States Veterans Affairs, were not examined in this review. However, the results of this study provide actionable targets to improve the quality of the teledermatology CPGs examined in this study.

Cutaneous T-cell lymphomas: 2021 update on diagnosis, risk-stratification, and management.

DISEASE OVERVIEW: Cutaneous T-cell lymphomas are a heterogenous group of T-cell neoplasms involving the skin, the majority of which may be classified as Mycosis Fungoides (MF) or Sézary Syndrome (SS). DIAGNOSIS: The diagnosis of MF or SS requires the integration of clinical and histopathologic data. RISK-ADAPTED THERAPY: TNMB (tumor, node, metastasis, blood) staging remains the most important prognostic factor in MF/SS and forms the basis for a "risk-adapted," multi-disciplinary approach to treatment. For patients with disease limited to the skin, expectant management or skin-directed therapies is preferred, as both disease-specific and overall survival for these patients is favorable. In contrast, patients with advanced-stage disease with significant nodal, visceral or blood involvement are generally approached with systemic therapies, including biologic-response modifiers, histone deacetylase inhibitors, or antibody-based strategies, in an escalating fashion. In highly-selected patients, allogeneic stem-cell transplantation may be considered, as this may be curative in some patients.

Immunophenotypic switch in cutaneous T-cell lymphoma: A series of three cases and review of the literature.

Primary cutaneous T-cell lymphoma (CTCL) comprises a heterogeneous group of neoplasms with variable clinical behavior. Immunophenotypic switch (IS) is a phenomenon that occurs during lymphoma progression and is defined by an alteration in the immunophenotypic expression of a tumor with retention of its genotypic signature. This has been well-recognized in hematopoietic neoplasms; however, it has been rarely reported in CTCL and its clinical implications are not well understood. We present the clinical, histopathologic, immunophenotypic, and genetic findings of three cases of CTCL that demonstrated IS post treatment with variable outcomes. We add our cases to the small number previously reported to increase awareness of this phenomenon and its diagnostic challenge.

Cutaneous follicle center lymphomas with plasmacytic differentiation.

Follicle center lymphomas, including primary cutaneous follicle center lymphoma (PCFCL), may rarely show plasmacytic differentiation. Such cases can pose a diagnostic challenge and can be mistaken for other lymphomas that more commonly include plasma cells. Here, we report four cases of PCFCL and one case of systemic follicular lymphoma involving the skin with associated monotypic plasma cells, including the clinical, morphologic and immunophenotypic features.

Cutaneous B-cell lymphomas: 2021 update on diagnosis, risk-stratification, and management.

DISEASE OVERVIEW: Approximately one-fourth of primary cutaneous lymphomas are B-cell derived and are generally classified into three distinct subgroups: primary cutaneous follicle center lymphoma (PCFCL), primary cutaneous marginal zone lymphoma (PCMZL), and primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL, LT). DIAGNOSIS: Diagnosis and disease classification is based on histopathologic review and immunohistochemical staining of an appropriate skin biopsy. Pathologic review and an appropriate staging evaluation are necessary to distinguish primary cutaneous B-cell lymphomas from systemic B-cell lymphomas with secondary skin involvement. RISK-STRATIFICATION: Disease histopathology remains the most important prognostic determinant in primary cutaneous B-cell lymphomas. Both PCFCL and PCMZL are indolent lymphomas that infrequently disseminate to extracutaneous sites and are associated with 5-year survival rates that exceed 95%. In contrast, PCDLBCL, LT is an aggressive lymphoma with an inferior prognosis. RISK-ADAPTED THERAPY: Both PCFCL and PCMZL patients with solitary or relatively few skin lesions may be effectively managed with local radiation therapy. While single-agent rituximab may be employed for patients with more widespread skin involvement, multi-agent chemotherapy is rarely appropriate. In contrast, management of patients with PCDLBCL, LT is comparable to the management of patients with systemic DLBCL.

Exome-wide association study reveals novel psoriasis susceptibility locus at TNFSF15 and rare protective alleles in genes contributing to type I IFN signalling.

Psoriasis is a common inflammatory skin disorder for which multiple genetic susceptibility loci have been identified, but few resolved to specific functional variants. In this study, we sought to identify common and rare psoriasis-associated gene-centric variation. Using exome arrays we genotyped four independent cohorts, totalling 11 861 psoriasis cases and 28 610 controls, aggregating the dataset through statistical meta-analysis. Single variant analysis detected a previously unreported risk locus at TNFSF15 (rs6478108; P = 1.50 × 10-8, OR = 1.10), and association of common protein-altering variants at 11 loci previously implicated in psoriasis susceptibility. We validate previous reports of protective low-frequency protein-altering variants within IFIH1 (encoding an innate antiviral receptor) and TYK2 (encoding a Janus kinase), in each case establishing a further series of protective rare variants (minor allele frequency < 0.01) via gene-wide aggregation testing (IFIH1: pburden = 2.53 × 10-7, OR = 0.707; TYK2: pburden = 6.17 × 10-4, OR = 0.744). Both genes play significant roles in type I interferon (IFN) production and signalling. Several of the protective rare and low-frequency variants in IFIH1 and TYK2 disrupt conserved protein domains, highlighting potential mechanisms through which their effect may be exerted.

Mycosis fungoides and Sézary syndrome: 2019 update on diagnosis, risk-stratification, and management.

DISEASE OVERVIEW: Cutaneous T-cell lymphomas (CTCL) are a heterogenous group of T-cell neoplasms involving the skin, the majority of which may be classified as Mycosis fungoides (MF) or Sézary syndrome (SS). DIAGNOSIS: The diagnosis of MF or SS requires the integration of clinical and histopathologic data. RISK-ADAPTED THERAPY: TNMB (tumor, node, metastasis, blood) staging remains the most important prognostic factor in MF/SS and forms the basis for a "risk-adapted," multi-disciplinary approach to treatment. For patients with disease limited to the skin, skin-directed therapies are preferred, as both disease-specific and overall survival for these patients is favorable. In contrast, patients with advanced-stage disease with significant nodal, visceral or blood involvement are generally approached with systemic therapies. These include biologic-response modifiers, histone deacetylase (HDAC) inhibitors, or antibody-based strategies, in an escalating fashion. In highly-selected patients, allogeneic stem-cell transplantation may be considered, as this may be curative in some patients.

Merkel cell carcinoma arising in association with cutaneous T-cell lymphoma: A potential diagnostic pitfall.

Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous neuroendocrine carcinoma with increased prevalence in patients with immunosuppression or B-cell neoplasms. To the best of our knowledge, an association with cutaneous T-cell lymphoma (CTCL) has not been previously described. In this report, we present two cases of MCC arising in the setting of CTCL. The first case was a female during her 70s with previously diagnosed stage IVA1 Sezary syndrome. Biopsy of a scaly patch showed two distinct abnormal cell populations. The first population consisted of hyperchromatic dermal and epidermotropic lymphocytes, expressing CD3 and CD4 with diminished CD7. The second population consisted of intraepidermal clusters of larger atypical cells that expressed synaptophysin, neurofilament, CK20, and Merkel cell polyomavirus transcript. The combination of findings was consistent with intraepidermal MCC in a background of CTCL. Excision showed residual intraepidermal MCC without dermal involvement. The second case was a male during his 50s with a longstanding history of mycosis fungoides, who presented with a new lesion on his right thigh. Biopsy and excision showed dermal MCC without secondary involvement by CTCL. Our cases show that MCC may rarely occur in the setting of T-cell lymphoma, and that intraepidermal MCC may mimic epidermotropic T-cells.

Genome-wide Association Analysis of Psoriatic Arthritis and Cutaneous Psoriasis Reveals Differences in Their Genetic Architecture.

Psoriasis vulgaris (PsV) is a common inflammatory and hyperproliferative skin disease. Up to 30% of people with PsV eventually develop psoriatic arthritis (PsA), an inflammatory musculoskeletal condition. To discern differences in genetic risk factors for PsA and cutaneous-only psoriasis (PsC), we carried out a genome-wide association study (GWAS) of 1,430 PsA case subjects and 1,417 unaffected control subjects. Meta-analysis of this study with three other GWASs and two targeted genotyping studies, encompassing a total of 9,293 PsV case subjects, 3,061 PsA case subjects, 3,110 PsC case subjects, and 13,670 unaffected control subjects of European descent, detected 10 regions associated with PsA and 11 with PsC at genome-wide (GW) significance. Several of these association signals (IFNLR1, IFIH1, NFKBIA for PsA; TNFRSF9, LCE3C/B, TRAF3IP2, IL23A, NFKBIA for PsC) have not previously achieved GW significance. After replication, we also identified a PsV-associated SNP near CDKAL1 (rs4712528, odds ratio [OR] = 1.16, p = 8.4 × 10(-11)). Among identified psoriasis risk variants, three were more strongly associated with PsC than PsA (rs12189871 near HLA-C, p = 5.0 × 10(-19); rs4908742 near TNFRSF9, p = 0.00020; rs10888503 near LCE3A, p = 0.0014), and two were more strongly associated with PsA than PsC (rs12044149 near IL23R, p = 0.00018; rs9321623 near TNFAIP3, p = 0.00022). The PsA-specific variants were independent of previously identified psoriasis variants near IL23R and TNFAIP3. We also found multiple independent susceptibility variants in the IL12B, NOS2, and IFIH1 regions. These results provide insights into the pathogenetic similarities and differences between PsC and PsA.

Fine mapping major histocompatibility complex associations in psoriasis and its clinical subtypes.

Psoriasis vulgaris (PsV) risk is strongly associated with variation within the major histocompatibility complex (MHC) region, but its genetic architecture has yet to be fully elucidated. Here, we conducted a large-scale fine-mapping study of PsV risk in the MHC region in 9,247 PsV-affected individuals and 13,589 controls of European descent by imputing class I and II human leukocyte antigen (HLA) genes from SNP genotype data. In addition, we imputed sequence variants for MICA, an MHC HLA-like gene that has been associated with PsV, to evaluate association at that locus as well. We observed that HLA-C(∗)06:02 demonstrated the lowest p value for overall PsV risk (p = 1.7 × 10(-364)). Stepwise analysis revealed multiple HLA-C(∗)06:02-independent risk variants in both class I and class II HLA genes for PsV susceptibility (HLA-C(∗)12:03, HLA-B amino acid positions 67 and 9, HLA-A amino acid position 95, and HLA-DQα1 amino acid position 53; p < 5.0 × 10(-8)), but no apparent risk conferred by MICA. We further evaluated risk of two major clinical subtypes of PsV, psoriatic arthritis (PsA; n = 3,038) and cutaneous psoriasis (PsC; n = 3,098). We found that risk heterogeneity between PsA and PsC might be driven by HLA-B amino acid position 45 (Pomnibus = 2.2 × 10(-11)), indicating that different genetic factors underlie the overall risk of PsV and the risk of specific PsV subphenotypes. Our study illustrates the value of high-resolution HLA and MICA imputation for fine mapping causal variants in the MHC.