Clinical and histological features of histiocytoid Sweet syndrome associated with VEXAS syndrome.

BACKGROUND: "Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic" (VEXAS) syndrome is caused by acquired somatic mutations in the ubiquitin-activating enzyme 1 (UBA1) gene. Sweet-syndrome-like skin disorders (and especially histiocytoid Sweet syndrome (HSS)) may be associated with VEXAS syndrome. OBJECTIVE: To characterize the clinical and histopathological features of HSS in patients with VEXAS syndrome. METHODS: The skin biopsies with a histological diagnosis of HSS had been collected at Rennes University Medical Center (Rennes, France) between October 2011 and January 2022. Sanger sequencing and digital PCR were used to screen skin, blood, and bone marrow samples for UBA1 variants, and thus classify patients as having VEXAS syndrome or not. We evaluated the clinical, histological, and molecular (UBA1) characteristics of patients with or without VEXAS syndrome. RESULTS: We compared 15 skin biopsies from seven patients found to have VEXAS syndrome and 19 skin biopsies from 15 patients without VEXAS syndrome. Persistent inflammatory syndrome, macrocytosis, anemia, and hematological malignancies were more prevalent in patients with VEXAS syndrome (86%, 86%, 100%, and 86%, respectively) than in patients without (36%, 40%, 53%, and 53%, respectively). These features sometimes appeared after the first skin manifestations, and a UBA1 mutation was found in the skin of five patients with VEXAS syndrome. Dermal infiltration by myeloperoxidase-positive, CD163-positive, reniform histiocytoid cells and a periadnexal distribution were more frequently observed in VEXAS syndrome biopsies (100% and 20% respectively, vs. 58% and 0% in non-VEXAS syndrome biopsies, respectively). CONCLUSION: Our findings might help the pathologist to consider a diagnosis of VEXAS syndrome and to initiate early genetic testing.

Anti-fibrotic effects of nintedanib on lung fibroblasts derived from patients with Progressive Fibrosing Interstitial Lung Diseases (PF-ILDs).

The tyrosine kinase inhibitor nintedanib has been recently approved for the treatment of Interstitial Lung Diseases (ILDs) that manifest a progressive fibrosis phenotype other than Idiopathic pulmonary Fibrosis (IPF). Nintedanib reduces the development of lung fibrosis in various animal models resembling features of PF-ILD and in vitro, it inhibits the fibrosing phenotype of human lung fibroblasts (HLFs) isolated from patients with IPF. To get insight on the cellular and molecular mechanisms that drive the clinical efficiency of nintedanib in patients with non-IPF PF-ILD, we investigated its effects on the fibrosing functions of HLFs derived from patients with PF-hypersensitivity pneumonitis (PF-HP, n = 7), PF-sarcoidosis (n = 5) and pleuroparenchymal fibroelastosis (PPFE, n = 4). HLFs were treated with nintedanib (10 nM-1 µM) and then stimulated with PDGF-BB (25-50 ng/ml) or TGF-ß1 (1 ng/ml) for 24-72 h to assess proliferation and migration or differentiation. At nanomolar concentrations, nintedanib reduced the levels of PDGF receptor and ERK1/2 phosphorylation, the proliferation and the migration of PF-HP, PF-sarcoidosis and PPFE HLFs stimulated with PDGF-BB. Moreover, nintedanib also attenuates the myofibroblastic differentiation driven by TGF-ß1 but only when it is used at 1 µM. The drug reduced the phosphorylation of SMAD2/3 and decreased the induction of collagen, fibronectin and α-smooth muscle actin expression induced by TGF-ß1. In conclusion, our results demonstrate that nintedanib counteracts fundamental fibrosing functions of lung fibroblasts derived from patients with PF-HP, PF-sarcoidosis and PPFE, at concentrations previously reported to inhibit control and IPF HLFs. Such effects may contribute to its clinical benefit in patients suffering from these irreversible ILDs.

FACILITATE: A real-world, multicenter, prospective study investigating the utility of a rapid, fully automated real-time PCR assay versus local reference methods for detecting epidermal growth factor receptor variants in NSCLC.

Accurate testing for epidermal growth factor receptor (EGFR) variants is essential for informing treatment decisions in non-small cell lung cancer (NSCLC). Automated diagnostic workflows may allow more streamlined initiation of targeted treatments, where appropriate, while comprehensive variant analysis is ongoing. FACILITATE, a real-world, prospective, multicenter, European study, evaluated performance and analytical turnaround time of the Idylla™ EGFR Mutation Test compared with local reference methods. Sixteen sites obtained formalin-fixed paraffin-embedded biopsy samples with ≥ 10% neoplastic cells from patients with NSCLC. Consecutive 5 µm sections from patient samples were tested for clinically relevant NSCLC-associated EGFR variants using the Idylla™ EGFR Mutation Test and local reference methods; performance (concordance) and analytical turnaround time were compared. Between January 2019 and November 2020, 1,474 parallel analyses were conducted. Overall percentage agreement was 97.7% [n = 1,418; 95% confidence interval (CI): 96.8-98.3], positive agreement, 87.4% (n = 182; 95% CI: 81.8-91.4) and negative agreement, 99.2% (n = 1,236; 95% CI: 98.5-99.6). There were 38 (2.6%) discordant cases. Ninety percent of results were returned with an analytical turnaround time of within 1 week using the Idylla™ EGFR Mutation Test versus ∼22 days using reference methods. The Idylla™ EGFR Mutation Test performed well versus local methods and had shorter analytical turnaround time. The Idylla™ EGFR Mutation Test can thus support application of personalized medicine in NSCLC.

Arsenic trioxide inhibits the functions of lung fibroblasts derived from patients with idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic and fatal interstitial lung disease. Currently, no treatment can block or reverse the development of lung fibrosis in patients suffering from IPF. Recent studies indicate that arsenic trioxide (ATO), a safe, effective anti-cancer pro-oxidant drug, prevents the differentiation of normal human lung fibroblasts (NHLFs) in vitro and reduces experimental pulmonary fibrosis in vivo. In this context, we investigated the anti-fibrotic effects of ATO on the main fibrosis functions of human lung fibroblasts (HLFs) isolated from patients with IPF. IPF and non-IPF (control) HLFs were incubated with 0.01-1 µM ATO and stimulated with pro-fibrotic factors (PDGF-BB or TGF-ß1). We measured their rates of proliferation, migration and differentiation and the cell stress response triggered by ATO. ATO did not affect cell viability but strongly inhibited the proliferation and migration of PDGF-BB-stimulated IPF and control HLFs. ATO also prevented myofibroblastic differentiation, as assessed by the expression of α-smooth muscle actin (α-SMA) and collagen-1, and the phosphorylation of SMAD2/3 in TGF-ß1-stimulated HLFs. These antifibrotic effects were associated with increased expression of the transcription factor NRF2 and its target genes NQO1 and HMOX1. Genetic silencing of NRF2 inhibited the ATO-induced cell stress response but did not prevent the ATO-dependent inhibition of α-SMA expression in TGF-ß1-stimulated HLFs. The results demonstrate that ATO, at concentrations similar to exposure in blood plasma of ATO-treated cancer patients, counteracted pro-fibrotic activities of HLFs from IPF patients. We propose to consider ATO for clinical exploration to define the therapeutic potential in patients with IPF.

Beneficial effects of citrulline enteral administration on sepsis-induced T cell mitochondrial dysfunction.

Severe sepsis induces a sustained immune dysfunction associated with poor clinical behavior. In particular, lymphopenia along with increased lymphocyte apoptosis and decreased lymphocyte proliferation, enhanced circulating regulatory T cells (Treg), and the emergence of myeloid-derived suppressor cells (MDSCs) have all been associated with persistent organ dysfunction, secondary infections, and late mortality. The mechanisms involved in MDSC-mediated T cell dysfunction during sepsis share some features with those described in malignancies such as arginine deprivation. We hypothesized that increasing arginine availability would restore T cell function and decrease sepsis-induced immunosuppression. Using a mouse model of sepsis based on cecal ligation and puncture and secondary pneumonia triggered by methicillin-resistant Staphylococcus aureus inoculation, we demonstrated that citrulline administration was more efficient than arginine in increasing arginine plasma levels and restoring T cell mitochondrial function and proliferation while reducing sepsis-induced Treg and MDSC expansion. Because there is no specific therapeutic strategy to restore immune function after sepsis, we believe that our study provides evidence for developing citrulline-based clinical studies in sepsis.

Micronodular thymic carcinoma with lymphoid hyperplasia: relevance of immunohistochemistry with a small panel of antibodies for diagnosis-a RYTHMIC study.

Micronodular thymic carcinoma with lymphoid hyperplasia (MNTCLH) is a rare form of thymic carcinoma. We present the experience of RYTHMIC, the French national network devoted to the treatment of thymic epithelial tumors through multidisciplinary tumor boards with a review of all tumors by pathologists for classification and staging. Six cases of MNTCLH were diagnosed during a review of 1007 thymic epithelial tumors. Histologically, epithelial cells with atypia and mitoses formed micronodules that were surrounded by an abundant lymphoid background with follicles. There was neither obvious fibro-inflammatory stroma nor necrosis. Spindle cells areas were common. Initial diagnosis was micronodular thymoma in two cases, cellular atypia being overlooked, eclipsed by the micronodular pattern. Immunohistochemistry with a panel of five antibodies showed that cytokeratins (AE1-AE3) and p63-positive epithelial cells also expressed CD5 and that there was no TdT-positive cells within the tumors. CD20 highlighted the lymphoid hyperplasia. Additionally epithelial cells also expressed CD117 and diffusely Glut 1. Twenty-seven micronodular thymomas with lymphoid stroma diagnosed during the same period did not show the CD5 and CD117 positivities seen in MNTCLH and contained TdT-positive lymphocytes. Three of the 6 patients with MNTCLH had adjuvant radiotherapy. Three patients with follow-up information were alive without recurrence at 38, 51, and 95 months. Our study shows that immunohistochemistry, such as that used in the RYTHMIC network with a small panel of antibodies, may easily help to confirm the correct diagnosis of MNTCLH, a rare and low-aggressive form of thymic carcinoma, and avoid the misdiagnosis of micronodular thymoma.

[Thymoma and squamous thymic carcinoma diagnosis; experience from the RYTHMIC network]. / Diagnostic des thymomes et carcinomes thymiques malpighiens ; expérience du réseau RYTHMIC.

The RYTHMIC network, supported by the French National Cancer Institute is dedicated to the management of patients with thymic epithelial tumors through regional and national multidisciplinary tumor boards. Tumor board decisions are based on the initial pathology diagnoses. However, following clinical inclusion in the network, a central pathology review is organized, implicating a panel of pathologists, for histotype and stage classification, which is different from a classical second opinion from pathologist to pathologist for a difficult case. Thanks to the participation of all French pathologists, more than 1000 cases have been reviewed by the panel. The aim of this review is to share with the French pathology community, the experience of the group. It underlines the importance of macroscopy and surgeon-pathologist involvement to allow a good central review, the main histopathological and immunophenotypical patterns of the most frequent thymomas and thymic carcinoma types, the differential diagnoses, as well as the difficulties for the panel to reproducibly assess on slides, stage, for some cases.

Impact of expert pathologic review of thymic epithelial tumours on diagnosis and management in a real-life setting: A RYTHMIC study.

BACKGROUND: Classification of thymic epithelial tumours (TETs) is known to be challenging; however, the level of discordances at a nationwide level between initial and expert diagnosis and their clinical consequences are currently unknown. RYTHMIC is a national network dedicated to the management of TET based on initial histological diagnosis, followed by an additional expert review of all cases. Our aim was to evaluate the discordances between initial and expert diagnoses and whether they would have led to different clinical management. PATIENTS AND METHODS: We conducted a retrospective analysis of the cohort of patients discussed at RYTHMIC tumour board from January 2012 to December 2016. Assessment of disagreement was made for histological typing and for staging. The discordances were classified as major or minor based on whether they would have changed or not the proposed therapeutic strategy, respectively. Follow-up of the patients with major discordances was conducted until December 2018. RESULTS: Four hundred sixty-seven patients were reviewed, and 183 (39%) discordances were identified either related to histological subtype (132) and/or stage (72). Major discordances were identified in 27 patients (6%). They included 16 patients with TET for whom treatment recommendation based on the central review would have been post-operative radiotherapy, whereas it had not been the case. However, follow-up did not show any progression among the 15 patients with high-grade histology and/or stage resected thymomas. On the other hand, among the remaining 11 patients including 7 with a diagnosis other than TET, the overall management or follow-up would have been completely different with the expert diagnosis. CONCLUSION: Our real-life cohort reveals a high level of discordances considering TET diagnosis and supports expert review for optimal clinical management.

[Lysozyme-induced nephropathy: A rare cause of renal failure in chronic myelomonocytic leukemia]. / La néphropathie induite par le lysozyme : une cause rare d'insuffisance rénale dans la leucémie myélomonocytaire chronique.

INTRODUCTION: Lysozyme-induced nephropathy is a rare and unknown complication of chronic myelomonocytic leukemia with overproduction of lysozyme by tumoral cells leading to proximal tubular cells injuries. The present case reports a lysozyme nephropathy secondary to chronic myelomonocytic leukemia. OBSERVATION: We reported a case of a 82-years-old woman who presented an acute renal failure in a context of diarrhea and vomiting. Her background was characterized by untreated chronic myelomonocytic leukemia and high blood pressure. Despite rehydration, renal function deteriorated. Renal biopsy revealed a tubulo-interstitial lysozyme-induced nephropathy with a vacuolization of the tubular epithelium by eosinophilic droplets stained by anti-lysozyme antibody, without tumoral infiltration of the renal parenchyma. CONCLUSION: Lysozyme-induced nephropathy is a rare disease which can be suspected biologically and needs histologic confirmation. Other causes of renal failure secondary to chronic myelomonocytic leukemia have to be eliminated first in these patients. The treatment is symptomatic and is associated with treatments of the underlying hematologic pathology.

Impact of Expert Pathologic Review of Lymphoma Diagnosis: Study of Patients From the French Lymphopath Network.

Purpose To prospectively assess the clinical impact of expert review of lymphoma diagnosis in France. Materials and Methods From January 2010 to December 2013, 42,145 samples from patients with newly diagnosed or suspected lymphomas were reviewed, according to the 2008 WHO classification, in real time by experts through the Lymphopath Network. Changes in diagnosis between referral and expert review were classified as major or minor according to their potential impact on patient care. Results The 42,145 reviewed samples comprised 36,920 newly diagnosed mature lymphomas, 321 precursor lymphoid neoplasms, 314 myeloid disorders, and 200 nonhematopoietic neoplasms, with 4,390 benign lesions. There were 4,352 cutaneous and 32,568 noncutaneous lymphomas. The most common mature noncutaneous lymphomas were diffuse large B-cell lymphomas (32.4%), follicular lymphomas (15.3%), classic Hodgkin lymphomas (13%), peripheral T-cell lymphomas (6.3%) of which angioimmunoblastic T-cell lymphomas (2.3%) were the most frequent, and mucosa-associated lymphoid tissue lymphomas (5.8%). A diagnostic change between referral and expert review occurred in 19.7% of patients, with an estimated impact on patient care for 17.4% of patients. This rate was significantly higher for patients sent with a provisional diagnosis seeking expert second opinion (37.8%) than for patients sent with a formal diagnosis (3.7%). The most frequent discrepancies were misclassifications in lymphoma subtype (41.3%), with 12.3% being misclassifications among small B-cell lymphoma entities. Fewer than 2% of changes were between benign and malignant lymphoid conditions. Minor changes (2.3%) mostly consisted of follicular lymphoma misgrading and diffuse large B-cell lymphoma subtype misclassification. Conclusion To our knowledge, this study provides the largest ever description of the distribution of lymphoma entities in a western country and highlights how expert review significantly contributes to a precise lymphoma diagnosis and optimal clinical management in a proportion of patients.

[Bile salt nephropathy/cholemic nephrosis]. / Néphropathie à cristaux biliaires/néphropathie cholémique.

Bile cast nephropathy is a tubulo-interstitial nephropathy. Its diagnosis may be under-estimated. It develops in patients who have cholestatic jaundice, with high bilirubinemia. Bile salts are freely filtered through glomerulus. Under certain circumstances, it forms casts into the tubule and cause an acute tubular necrosis. The diagnosis evidence is histologic, but fulfilment of renal biopsy is often made difficult, because of the hemostatic abnormalities that patients with hepatocellular injury develop. The treatment is supportive and etiological. We report here the case of a patient who presented a drug-induced hepatic jaundice, complicated with acute kidney failure secondary to bile cast nephropathy. We present the histological diagnosis evidence.

18F-FDG PET/CT in Hepatosplenic Gamma-Delta T-Cell Lymphoma.

Hepatosplenic T-cell lymphoma (HSTCL) is a rare and often difficult-to-diagnose subtype of lymphoma that can occur in the chronically immunosuppressed patient. We present the typical FDG PET/CT findings of HSTCL in a renal transplant recipient. The whole-body metabolic and morphologic information provided by FDG PET/CT can be of great additional value in establishing this diagnosis, thus allowing for a timely start of treatment.

A fatal case with disseminated Myceliophthora thermophila infection in a lymphoma patient.

We report a lethal Myceliophthora thermophila infection in an immunocompromised patient. Based upon the clinical and mycological presentation, an initial diagnosis of invasive aspergillosis was made, possibly delaying optimal management in the patient. Melanized fungi are emerging pathogens that require early identification to improve their unfavorable prognosis.