The histiocytoses are rare disorders characterized by the accumulation of macrophage, dendritic cell, or monocyte-derived cells in various tissues and organs of children and adults. More than 100 ...different subtypes have been described, with a wide range of clinical manifestations, presentations, and histologies. Since the first classification in 1987, a number of new findings regarding the cellular origins, molecular pathology, and clinical features of histiocytic disorders have been identified. We propose herein a revision of the classification of histiocytoses based on histology, phenotype, molecular alterations, and clinical and imaging characteristics. This revised classification system consists of 5 groups of diseases: (1) Langerhans-related, (2) cutaneous and mucocutaneous, and (3) malignant histiocytoses as well as (4) Rosai-Dorfman disease and (5) hemophagocytic lymphohistiocytosis and macrophage activation syndrome. Herein, we provide guidelines and recommendations for diagnoses of these disorders.
The modulation of canonical macroautophagy/autophagy for therapeutic benefit is an emerging strategy of medical and pharmaceutical interest. Many drugs act to inhibit autophagic flux by targeting ...lysosome function, while others were developed to activate the pathway. Here, we report the surprising finding that many therapeutically relevant autophagy modulators with lysosomotropic and ionophore properties, classified as inhibitors of canonical autophagy, are also capable of activating a parallel noncanonical autophagy pathway that drives MAP1LC3/LC3 lipidation on endolysosomal membranes. Further, we provide the first evidence supporting drug-induced noncanonical autophagy in vivo using the local anesthetic lidocaine and human skin biopsies. In addition, we find that several published inducers of autophagy and mitophagy are also potent activators of noncanonical autophagy. Together, our data raise important issues regarding the interpretation of LC3 lipidation data and the use of autophagy modulators, and highlight the need for a greater understanding of the functional consequences of noncanonical autophagy.
Malignant superficial mesenchymal tumors are a very diverse group of neoplasms with few clinical and radiological discriminatory factors. Hence, some of these cancers are rarely suspected based on ...clinical and radiological grounds, others may be easily misdiagnosed, and the histological analysis of a biopsy or resection is central in the diagnostic process. In children, the age at presentation is a major element of the differential diagnosis. Some tumors have a very distinct epidemiology, while others may be seen at any age. More recently, the advances in molecular biology have greatly improved the diagnosis of mesenchymal tumors and new entities are still being described. In the present review, we provide an overview of the diversity of malignant superficial mesenchymal tumors in children, including new and/or rare entities. We discuss the important diagnostic features, be they clinical, histological, or molecular. Special attention was given to the genetic features of these tumors, particularly when they were helpful for the diagnosis or treatment.
Cutaneous histiocytoses in children Fraitag, Sylvie; Emile, Jean‐Francois
Histopathology,
January 2022, 2022-Jan, 2022-01-00, 20220101, 2022, Letnik:
80, Številka:
1
Journal Article
Recenzirano
Cutaneous histiocytoses constitute a heterogeneous group of diseases characterised by the cutaneous accumulation of cells with the cytological and phenotypic features of macrophages or dendritic ...cells. The clinical spectrum ranges from self‐resolving, skin‐limited conditions to severe, multiorgan disease with a high morbidity rate. Until recently, cutaneous histiocytoses were classified according to the immunophenotype of the pathological cells, with differentiation between Langerhans cell histiocytosis (LCH) CD1a+, CD207 (langerin)+ and non‐Langerhans cell histiocytosis (CD68+, CD163+, CD1a−, CD207−). Over the last 12 years, a number of new pathophysiological findings (in particular, molecular pathology results) regarding histiocytoses have contributed to a new classification based on molecular alterations, as well as on clinical and imaging characteristics and the phenotype. The most frequent entities in children are juvenile xanthogranuloma and LCH.
A study of families from southern Tunisia affected by general pustular psoriasis uncovered the genetic cause of their disease: a mutation affecting the function of the interleukin-36–receptor ...antagonist.
Psoriasis is a chronic inflammatory skin disease affecting 2 to 3% of persons of European descent.
1
Psoriasis vulgaris, the most common form of the disease, accounts for 80% of cases and has a strong, albeit complex, genetic component.
2
Numerous chromosomal loci have been implicated in genomewide association studies, but analyses of these loci have yielded only a few candidate genes, which mediate inflammatory cytokine signaling and adaptive immune responses.
3
–
5
The disease follows mendelian transmission in a small minority of families.
Generalized pustular psoriasis is a life-threatening, multisystemic inflammatory disease involving repeated flare-ups of sudden onset, which are characterized by . . .
Dermatophyte infections are unusual but can cause serious invasive disease. In this report, autosomal recessive CARD9 deficiency indicated a potential genetic susceptibility to deep dermatophytosis, ...a severe invasive fungal infection.
Deep dermatophytosis is a rare, invasive, sometimes life-threatening, fungal infection caused by dermatophytes.
1
These filamentous fungi are ubiquitous and usually cause benign infections that are limited to keratinized tissues and lead to onychomycosis, tinea corporis, tinea cruris, tinea pedis, or tinea capitis.
2
In deep dermatophytosis, dermatophytes invade the dermis and hypodermis and disseminate to the skin, hair, nails, lymph nodes, and brain.
3
Deep dermatophytosis has been reported in patients with the human immunodeficiency virus and patients who are receiving immunosuppressive therapy.
3
It was first described in 1959 in otherwise apparently healthy persons as “dermatophytic disease.”
1
Forty-five cases have been reported . . .
The diagnosis of cutaneous and subcutaneous spindle cell neoplasms in children is often challenging and has potential therapeutic and prognostic implications. Although correctly diagnosing ...dermatofibrosarcoma protuberans and infantile fibrosarcoma is paramount, pathologists should not ignore a number of diagnostic pitfalls linked to mostly rare tumors with completely different clinical outcomes. In the last decade, a spectrum of novel entities has been described; information from molecular biology has helped to shape this new landscape for spindle cell tumors. Here, we review the most noteworthy neoplasms in this spectrum, with a focus on their histological similarities: fibroblastic connective tissue nevus, medallion-like dermal dendrocyte hamartoma, or plaque-like CD34-positive dermal fibroma, which share features with fibrous hamartoma of infancy; lipofibromatosis and lipofibromatosis-like neural tumor; and plexiform myofibroblastoma, a recently described neoplasm that should be distinguished from plexiform fibrohistiocytic tumor. These tumors also have genetic similarities, particularly gene rearrangements involving
3 or
1. These genetic features are not only essential for the differential diagnosis of infantile fibrosarcoma but are also of diagnostic value for lipofibromatosis-like neural tumors. The more recently described
1, and
gene fusions are also discussed.
Multiple papulonodular skin lesions at birth can indicate the presence of various benign and malignant disorders. Although the lesions’ clinical aspect (color and consistency, in particular) may ...steer the clinician towards one disorder or another (infantile myofibromatosis, xanthogranuloma, or metastatic neuroblastoma), the diagnosis can only be confirmed by the histopathologic assessment of a biopsy. In neonates, a rapid but accurate diagnosis is critical because skin lesions may be the first manifestation of a malignant disorder like leukemia cutis or metastatic neuroblastoma. Here, we review the various disorders that may manifest themselves as multiple skin lesions at birth.
Summary Background Indolent systemic mastocytosis, including the subvariant of smouldering systemic mastocytosis, is a lifelong condition associated with reduced quality of life. Masitinib inhibits ...KIT and LYN kinases that are involved in indolent systemic mastocytosis pathogenesis. We aimed to assess safety and efficacy of masitinib versus placebo in severely symptomatic patients who were unresponsive to optimal symptomatic treatments. Methods In this randomised, double-blind, placebo-controlled, phase 3 study, we enrolled adults (aged 18–75 years) with indolent or smouldering systemic mastocytosis, according to WHO classification or documented mastocytosis based on histological criteria, at 50 centres in 15 countries. We excluded patients with cutaneous or non-severe systemic mastocytosis after a protocol amendment. Patients were centrally randomised (1:1) to receive either oral masitinib (6 mg/kg per day over 24 weeks with possible extension) or matched placebo with minimisation according to severe symptoms. The primary endpoint was cumulative response (≥75% improvement from baseline within weeks 8–24) in at least one severe baseline symptom from the following: pruritus score of 9 or more, eight or more flushes per week, Hamilton Rating Scale for Depression of 19 or more, or Fatigue Impact Scale of 75 or more. We assessed treatment effect using repeated measures methodology for rare diseases via the generalised estimating equation model in a modified intention-to-treat population, including all participants assigned to treatment minus those who withdrew due to a non-treatment-related cause. We assessed safety in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov , number NCT00814073. Findings Between Feb 19, 2009, and July 15, 2015, 135 patients were randomly assigned to masitinib (n=71) or placebo (n=64). By 24 weeks, masitinib was associated with a cumulative response of 18·7% in the primary endpoint (122·6 responses of 656·5 possible responses weighted generalised estimating equation) compared with 7·4% for placebo (48·9 of 656·5; difference 11·3%; odds ratio 3·6; 95% CI 1·2–10·8; p=0·0076). Frequent severe adverse events (>4% difference from placebo) were diarrhoea (eight 11% of 70 in the masitinib group vs one 2% of 63 in the placebo group), rash (four 6% vs none), and asthenia (four 6% vs one 2%). The most frequent serious adverse events were diarrhoea (three patients 4% vs one 2%) and urticaria (two 3% vs none), and no life-threatening toxicities occurred. One patient in the placebo group died (unrelated to study treatment). Interpretation These study findings indicate that masitinib is an effective and well tolerated agent for the treatment of severely symptomatic indolent or smouldering systemic mastocytosis. Funding AB Science (Paris, France).
PDF
