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Background: Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) is a severe adverse event (mortality of 10%). Its pathophysiology involves herpesviruses, particularly HHV‐6, but the exact mechanisms are still poorly understood. Objective: To describe severe cases of DRESS and especially their association with herpesvirus reactivation. Methods: This study was a multicentre case series conducted between 2007 and 2021 at five University Hospital Centres in France. The study included patients who had severe DRESS, which was defined as death, transfer to the intensive care unit (ICU), or severe damage to internal organs. We excluded patients without blood PCR sample, without a drug formally attributed or with RegiSCAR score < 6. We collected data on severity, causative drug, associated visceral damage and results of viral blood PCRs. HHV‐6 reactivation was studied in skin biopsies by detection of small non‐coding transcripts (HHV‐6 miR‐aU14) and a late viral protein (GP82/105). Results: Fifty‐two patients were included (29 female, median age 62, interquartile range (IQR) [37;72]). Eight patients (15%) died, 13 (27%) were admitted to ICU. Most patients (n = 34; 65%) had multisystem involvement: most frequent was liver (n = 46; 88%), then renal failure (n = 24; 46%). Forty patients (77%) had at least one blood viral reactivation among HHV‐6, EBV or CMV, of which 21 (53%) had at least two. Median time of blood HHV‐6 reactivation was 24 days (IQR [20;35]). HHV‐6 reactivation was demonstrated in 15 out of 20 skin biopsies, with a median time of 11 days [9;17]. Conclusions: We confirmed the high rate of HHV‐6 reactivation in severe DRESS and demonstrated cutaneous HHV‐6 reactivation using small non‐coding transcripts (HHV‐6 miR‐aU14), which preceded viral PCR positivity in blood. These results suggest that HHV‐6 reactivation during DRESS may start in skin. Furthermore, search for miR‐aU14 in skin biopsy could become a useful diagnostic tool for early detection of HHV‐6 reactivation. [ABSTRACT FROM AUTHOR]

Summary: The classification of pityriasis lichenoides (PL) into pityriasis lichenoides et varioliformis acuta (PLEVA), PL chronica (PLC) and febrile ulceronecrotic Mucha–Habermann disease (FUMHD) is based on both clinical and chronological features. In this retrospective monocentric study, we aimed to investigate the relevance of the classification in routine practice. We enrolled 49 patients (25 female, 24 male; median age 41 years). The lesions were papular in 76% of patients, necrotic in 12% and mixed in 12%. We found three histological patterns: 'classic' (65%), 'lymphomatoid' (13%) and 'mild' (22%). The 'lymphomatoid' pattern was associated with necrotic presentation and the 'mild' pattern with papular lesions (P = 0.01). Among the 27 patients with follow‐up, 18% had relapses and 44% had chronic disease. One patient had mycosis fungoides. Neither clinical nor histological findings were correlated with disease progression, and are a reflection of the intensity of epidermal injury rather than of the disease course. The term 'pityriasis lichenoides' should be preferred to the classic PLEVA/PLC/FUMHD classification. [ABSTRACT FROM AUTHOR]

Summary: Background: Lymphomatoid papulosis (LyP) type D (LyP D) and type E (LyP E) have recently been described in small series of cases or isolated case reports. Aim: To further describe the clinical and histological features of LyP D and E based on a retrospective multicentre study. Methods: The clinical and histopathological features of 29 patients with an initial diagnosis of LyP D or LyP E were retrospectively assessed using standardized forms. Results: After exclusion of 5 cases, 24 patients (14 LyP D, 10 LyP E) were enrolled in the study. The median follow‐up was 2.5 years (range 1 month to 13 years). LyP D was characterized by multiple recurrent self‐regressing small papules that developed central erosion or necrosis, whereas LyP E presented as papulonodular lesions that rapidly evolved into necrotic eschar‐like lesions > 10 mm in size. Epidermal changes were more frequent in LyP D, whereas dermal infiltrates were deeper in LyP E. Anaplastic cytology was rare and the DUSP22 rearrangement was never observed. Two patients (8%) had an associated cutaneous lymphoma. Conclusion: LyP D and E have distinct clinical findings and may be associated with other cutaneous lymphomas. [ABSTRACT FROM AUTHOR]

Clinicopathologic features of IgG/IgA pemphigus in comparison with classic (IgG) and IgA pemphigus. Pemphigus with IgA deposits, called intercellular IgA dermatosis (IAD)1 or IgA pemphigus,2 is rare. Some cases are associated with anti-desmocollin antibodies.3 Intermediate IgG and IgA forms were reported, called intercellular IgG/IgA dermatosis (IGAD)4 or IgG/IgA pemphigus.5 We conducted a clinical pathological study to compare IAD and IGAD. [Extracted from the article]

(f) High magnification of panel (e) circled area, showing many spherical calcifications within the papillary dermis. gl To investigate the origin of these cutaneous calcifications, osteogenic markers, assessed by immunohistochemistry were performed in three patients. The patients in this study have given written informed consent to publication of their case details. Mucocutaneous healing usually lasts 2-3 weeks.1 Calcinosis cutis is reported in various skin diseases, with dystrophic calcification following tissue damage being its most common cause.2 We describe four patients who presented TEN and atypical healing retardation due to calcinosis cutis. [Extracted from the article]

In our series, histology revealed mucin in seven patients, five with previous LE or clinical signs of LE, and only one with a positive lupus band test. During follow-up, one patient with LE antibodies showed recurrent cutaneous LE lesions, and the case was retrospectively concluded as TEN-like LE. In patients without previous LE/SS and no clinical sign of LE, especially those with a trigger drug, the pathophysiology of the LE autoantibodies remains unknown (possibly epitope spreading). [Extracted from the article]

KILT: A RANDOMIZED NON-COMPARATIVE PHASE II LYSA STUDY OF LACUTAMAB WITH GEMOX VERSUS GEMOX IN RELAPSED/REFRACTORY PERIPHERAL T-CELL LYMPHOMA B Background: b Peripheral T-cell Lymphoma (PTCL) is a heterogeneous group of mature T-cell lymphomas (TCL) with adverse outcomes. KIR3DL2 is a killer immunoglobulin-like receptor that is expressed across different subtypes of TCL, including approximately 40% of PTCL. [Extracted from the article]

At diagnosis of ECTL, only one patient displayed an enlarged node > 1-5 cm (not biopsied), and the median number of Sézary cells was 1440 per mm SP 3 sp (range 396-4930). Dear Editor, The prognosis of erythrodermic cutaneous T-cell lymphomas (ECTL) depends on lymph node (N) and visceral (M) involvement, and blood stage (B). Pathological data at progression were reviewed for eight patients: skin biopsy (four patients), node biopsy (five patients) and cerebrospinal fluid (one patient). [Extracted from the article]

As in other organs, the diagnosis of endogenous cutaneous overload diseases is based on histopathological analysis of the lesions using special stainings, even if the clinical appearance is sometimes very suggestive. The lesions are sometimes very subtle and can be included in the group of "invisible" dermatoses, such as primary macular cutaneous amyloidosis or calciphylaxis. Superficial dermal melanosis or pigmentary incontinence generally reflects the post-inflammatory stage of a chronic or recurrent interface dermatitis. Section levels should be systematically performed to look for active lesions of diagnostic interest: Alcian blue staining to identify dermal mucinosis (connectivitis) and pan-T markers (fixed pigmented erythema, lichenoid mycosis fungoides, and vitiligo). Some pathologies have a prognostic impact, either because they reflect an underlying disease, monoclonal gammopathies, in particular myeloma, being one of the most common conditions in this context (AL amyloidosis, xanthoma and xanthogranuloma, scleromyxedema), or because they can be associated with visceral damage (AL amyloidosis, scleromyxedema). The clinical-pathological comparison is mandatory to rule out differential diagnoses, especially for life-threatening diseases: nodular amyloidosis and primary cutaneous amyloidosis versus systemic AL amyloidosis, papular mucinosis versus scleromyxedema and calcific panniculitis versus calciphylaxis., (Copyright © 2024 The Author. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Mycosis fungoides (MF) has usually an indolent course. However, some patients develop a more aggressive disease and few prognostic parameters have been identified. Isolated cases of pustular MF (pMF) suggest an unfavourable prognosis., Objectives: We aim to describe the clinico-pathological characteristics and prognostic value of pMF., Methods: We retrospectively collected data of all cases of MF with histological pustules diagnosed from 2009 to 2020. The outcomes and clinico-pathological characteristics of pMF at diagnosis (pMFD) were compared to those of a cohort of non-pustular MF (NpMF)., Results: 33 pMF (including 22 pMFD) and 86 NpMF cases were included. The median age at diagnosis of pMF was 61 years [IQR=50-75]. The median follow-up of pMFD was 32 months [IQR=14-49]. Clinically, 33% of pMF had pustules. Large-cell transformation (LCT) occurred in 17 cases. pMFD were at a significantly more advanced-stage and more showed LCT at diagnosis than NpMF (50% vs 7%, p<0.001 and 23% vs 0%, p<0.001, respectively). In multivariate Cox analysis, the presence of histological pustule at diagnostic was associated with shorter OS in all patients (HR=13.90, CI95%[2.43-79]; p=0.003), and in early-stage patients (HR=11.09, CI95%[1.56-78.82]; p=0.02). In multivariate Fine and Gray model analysis, pMFD was associated with a higher cumulative incidence of LCT (SHR=13.90, CI95% [2.43-79]; p=0.003) in all patients. Median OS after the occurrence of histological pustules during follow-up of all pMF patients was 37 months, with a five-year OS of 25% (CI95% [0.06-0.5])., Conclusion: pMF often follows an aggressive course, with a high risk of LCT and shorter survival, even for early-stage patients. Histological pustules at diagnostic of MF might represent an independent poor prognostic factor, to be confirmed by further studies. Because pustules are not always clinically identified, histological pustules should be mentioned in pathology reports of MF and prompt discussion of a closer follow-up., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Malignant peripheral nerve sheath tumors (MPNSTs) are the leading cause of death in patients with neurofibromatosis type 1. They can result from premalignant neurofibromas, including neurofibromas with atypia and atypical neurofibromatous neoplasms of uncertain biologic potential. Some phenotypic characteristics have been described as associated with their development. The aim of this study was to outline our use of whole-body positron emission tomography with 18 F-fluorodeoxyglucose/magnetic resonance imaging in adults with neurofibromatosis type 1, especially in the screening of asymptomatic individuals with a higher risk of developing an MPNST, and to study its impact on neurofibroma classification (malignant vs premalignant) and MPNST staging over time. Individuals with neurofibromatosis type 1 who underwent a positron emission tomography with 18 F-fluorodeoxyglucose/magnetic resonance imaging between 2017 and 2021 were included, analyzing separately the screened population. Maximum standard uptake value and diffusion-weighted imaging were assessed. Biopsy/surgery confirmed the diagnosis. In all, 345 positron emission tomography with 18 F-fluorodeoxyglucose/magnetic resonance imaging were performed in 241 patients, including 149 asymptomatic (62%) but at-risk patients. Eight MPNSTs in 8 screened individuals (5%), 6 neurofibromas with atypia in 4 individuals (3%), and 29 atypical neurofibromatous neoplasms of uncertain biologic potential in 23 individuals (15%) were diagnosed. Over time, the proportion of grade 3 MPNST and the malignant/premalignant ratio in screened individuals significantly decreased (P = .03 and P < .001, respectively). This study emphasizes the diagnostic and screening performances of whole-body positron emission tomography with 18 F-fluorodeoxyglucose/magnetic resonance imaging in adults with neurofibromatosis type 1., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The PDCD1-encoded immune checkpoint receptor PD-1 is a key tumor suppressor in T cells that is recurrently inactivated in T cell non-Hodgkin lymphomas (T-NHLs). The highest frequencies of PDCD1 deletions are detected in advanced disease, predicting inferior prognosis. However, the tumor-suppressive mechanisms of PD-1 signaling remain unknown. Here, using tractable mouse models for T-NHL and primary patient samples, we demonstrate that PD-1 signaling suppresses T cell malignancy by restricting glycolytic energy and acetyl coenzyme A (CoA) production. In addition, PD-1 inactivation enforces ATP citrate lyase (ACLY) activity, which generates extramitochondrial acetyl-CoA for histone acetylation to enable hyperactivity of activating protein 1 (AP-1) transcription factors. Conversely, pharmacological ACLY inhibition impedes aberrant AP-1 signaling in PD-1-deficient T-NHLs and is toxic to these cancers. Our data uncover genotype-specific vulnerabilities in PDCD1-mutated T-NHL and identify PD-1 as regulator of AP-1 activity., (© 2023. The Author(s).)

T-follicular helper (TFH) markers are expressed in the microenvironnement of marginal zone B-cell lymphoma (MZL), and in lymphomas arising from TFH-cells, sometimes making the differential diagnosis difficult. In the skin, the "TFH-spectrum" is poorly defined, going from primary cutaneous lymphoproliferative disorder with small/medium CD4+ T-cells (SMLPD) to cutaneous localizations of systemic angioimmunoblastic T-cell lymphoma (cAITL), and may pass through intermediate forms (primary cutaneous T-follicular helper derived lymphoma, not otherwise specified (PCTFHL,NOS)). We retrospectively analyzed 20 MZL, 13 SMLPD, 5 PCTFHL, and 11 cAITL clinically, histologically, and molecularly, to define tools to differentiate them. Characteristics that might favor the diagnosis of MZL over SMLPD are: multiple skin nodules (p < 0.001), nodular architecture (p < 0.01), residual germinal centers with follicular dendritic cell network (p < 0.001), monotypic plasma cells (p < 0.001), and few staining with PD1 (p = 0.016) or CXCL13 (p = 0.03). PCTFHL and cAITL presented as multiple (p < 0.01) lesions, in older patients (p < 0.01), with systemic symptoms and/or biological alterations (p < 0.01). Immunophenotypic loss of T-cell markers (p < 0.001), BCL6 (p = 0.023) and/or CD10 staining (p = 0.08), and a higher proliferative index (≥ 30%, p = 0.039) favoured these diagnoses over SMLPD. Pathogenic variants were observed by genomic sequencing in 47% of MZL (TNFAIP3 (32%), EP300 (21%), NOTCH2 (16%), KMT2D (16%), CARD11 (10.5%)), 8% of SMLPD (TET2), 40% of PCTFHL (SOCS1 (20%), ARID1A (20%)) and 64% of cAITL (TET2 (63.6%), RHOA (36.4%), NOTCH1 (9%)). This study characterizes the various clinical and histological features between cutaneous lymphomas expressing TFH markers and highlights the value of the interest of screening for genomic mutations in difficult cases., (© 2023. The Author(s).)

Competing Interests: None disclosed.

Background: Urticarial lesions are observed in both cutaneous and systemic disorders. Familial forms of urticarial syndromes are rare and can be encountered in systemic autoinflammatory diseases., Objective: We sought to investigate a large family with dominantly inherited chronic urticarial lesions associated with hypercytokinemia., Methods: We performed a genetic linkage analysis in 14 patients from a 5-generation family, as well as whole-exome sequencing, cytokine profiling, and transcriptomic analyses on samples from 2 patients. The identified candidate protein was studied after in vitro expression of the corresponding normal and mutated recombinant proteins. An unsupervised proteomic approach was used to unveil the associated protein network., Results: The disease phenotype of the most affected family members is characterized by chronic urticarial flares associated with extremely high plasma levels of proinflammatory (IL-1β, IL-6, and TNF-α) and anti-inflammatory (IL-10 and IL-1 receptor antagonist [IL-1RA]) cytokines, with no secondary organ dysfunction, no susceptibility to infections, no fever, and normal C-reactive protein levels. Monocyte transcriptomic analyses identified an immunotolerant profile in the most affected patient. The affected family members carried a loss-of-function mutation in RNF213 that encodes mysterin, a protein with a poorly known physiologic role. We identified the deubiquitinase CYLD, a major regulator of inflammation, as an RNF213 partner and showed that CYLD expression is inhibited by wild-type but not mutant RNF213., Conclusion: We identified a new entity characterized by chronic urticarial lesions associated with a clinically blunted hypercytokinemia. This disease, which is due to loss of function of RNF213, reveals mysterin's key role in the complex molecular network of innate immunity., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)