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Nature Reviews. Disease Primers Oct 2021The historic term 'histiocytosis' meaning 'tissue cell' is used as a unifying concept for diseases characterized by pathogenic myeloid cells that share histological... (Review)
Review
The historic term 'histiocytosis' meaning 'tissue cell' is used as a unifying concept for diseases characterized by pathogenic myeloid cells that share histological features with macrophages or dendritic cells. These cells may arise from the embryonic yolk sac, fetal liver or postnatal bone marrow. Prior classification schemes align disease designation with terminal phenotype: for example, Langerhans cell histiocytosis (LCH) shares CD207 antigen with physiological epidermal Langerhans cells. LCH, Erdheim-Chester disease (ECD), juvenile xanthogranuloma (JXG) and Rosai-Dorfman disease (RDD) are all characterized by pathological ERK activation driven by activating somatic mutations in MAPK pathway genes. The title of this Primer (Histiocytic disorders) was chosen to differentiate the above diseases from Langerhans cell sarcoma and malignant histiocytosis, which are hyperproliferative lesions typical of cancer. By comparison LCH, ECD, RDD and JXG share some features of malignant cells including activating MAPK pathway mutations, but are not hyperproliferative. 'Inflammatory myeloproliferative neoplasm' may be a more precise nomenclature. By contrast, haemophagocytic lymphohistiocytosis is associated with macrophage activation and extreme inflammation, and represents a syndrome of immune dysregulation. These diseases affect children and adults in varying proportions depending on which of the entities is involved.
Topics: Erdheim-Chester Disease; Histiocytosis, Langerhans-Cell; Histiocytosis, Sinus; Humans; Inflammation; Xanthogranuloma, Juvenile
PubMed: 34620874
DOI: 10.1038/s41572-021-00307-9 -
Histopathology Jan 2022Cutaneous histiocytoses constitute a heterogeneous group of diseases characterised by the cutaneous accumulation of cells with the cytological and phenotypic features of... (Review)
Review
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.
Topics: Child; Disease Progression; Histiocytosis; Histiocytosis, Langerhans-Cell; Humans; Skin; Xanthogranuloma, Juvenile
PubMed: 34958507
DOI: 10.1111/his.14569 -
Hematological Oncology Jun 2021Children with Langerhnans cell histiocytosis (LCH) develop granulomatous lesions with characteristic clonal CD207+ dendritic cells that can arise as single lesions or... (Review)
Review
Children with Langerhnans cell histiocytosis (LCH) develop granulomatous lesions with characteristic clonal CD207+ dendritic cells that can arise as single lesions or life-threatening disseminated disease. Despite the wide range of clinical presentations, LCH lesions are histologically indistinguishable based on severity of disease, and uncertain classification as an immune versus neoplastic disorder has historically challenged the development of optimal clinical strategies for patients with LCH. Recently, activating somatic mutations in MAPK pathway genes, most notably BRAFV600E, have been discovered in almost all cases of LCH. Further, the stage of myeloid differentiation in which the mutation arises defines the extent of disease and risk of developing LCH-associated neurodegeneration. MAPK activation in LCH precursor cells drives myeloid differentiation, inhibits migration, and inhibits apoptosis, resulting in accumulation of resilient pathologic dendritic cells that recruit and activate T cells. Recurrent somatic mutations in MAPK pathway genes have also been identified in related histiocytic disorders: juvenile xanthogranuloma, Erdheim-Chester disease, and Rosai-Dorfman disease. New insights into pathogenesis support reclassification of these conditions as a myeloid neoplastic disorders. Continued research will uncover opportunities to identify novel targets and inform personalized therapeutic strategies based on cell of origin, somatic mutation, inherited risk factors, and residual disease.
Topics: Amino Acid Substitution; Cell Differentiation; Cell Movement; Dendritic Cells; Histiocytosis, Langerhans-Cell; Humans; MAP Kinase Signaling System; Mutation, Missense; Precision Medicine; Proto-Oncogene Proteins B-raf; T-Lymphocytes
PubMed: 34105821
DOI: 10.1002/hon.2857 -
La Clinica Terapeutica 2020To better understand the real prevalence of cutaneous manifestations, in Neurofibromatosis type 1. (Review)
Review
OBJECTIVE
To better understand the real prevalence of cutaneous manifestations, in Neurofibromatosis type 1.
MATERIALS AND METHODS
We reviewed all clinical charts of 1102 NF1 patients followed by February 1983 to February 2020 at the "Sapienza" University of Rome, Italy. NF1 patients are seen usually every year by a dermatologist.
RESULT
Café-au-lait macules were shown in 1063 patients (96.5%), axillary and inguinal freckling in 991 (90%) and neurofibromas in 861 (78.1%). Other skin manifestations included: lipoma (6.2%), nevus anemicus (3.9%), psoriasis (3.4%), spilus nevus (3.2%), juvenile xanthogranuloma (3.2%), vitiligo (2.3%), Becker's nevus (1.9%), melanoma (0.7%) and poliosis (0.5%).
CONCLUSION
Neurofibromatosis type 1 is a multisystem disorder primarily involving the skin and nervous system. The clinical manifestations are extremely variable even within a family. This study was performed to delineate the prevalence of cutaneous manifestations in NF1.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Child; Child, Preschool; Female; Humans; Italy; Male; Middle Aged; Neurofibromatosis 1; Prevalence; Skin Diseases; Young Adult
PubMed: 32901776
DOI: 10.7417/CT.2020.2242 -
Actas Dermo-sifiliograficas Nov 2020Juvenile xanthogranulomas (JXGs) are rare, benign lesions that belong to the large group of non-Langerhans cell histiocytoses. JXG presents with 1 or more erythematous... (Review)
Review
Juvenile xanthogranulomas (JXGs) are rare, benign lesions that belong to the large group of non-Langerhans cell histiocytoses. JXG presents with 1 or more erythematous or yellowish nodules that are usually located on the head or neck. Most JXG lesions are congenital or appear during the first year of life. Extracutaneous involvement is rare, but the literature traditionally suggests investigating the possibility of ocular compromise. JXG is mainly a clinical diagnosis, but a skin biopsy may sometimes be needed for confirmation. JXGs on the skin are self-limiting and usually do not require treatment. This review describes the clinical and therapeutic aspects of JXG, emphasizing available evidence and the diagnosis of extracutaneous involvement.
Topics: Biopsy; Histiocytosis, Non-Langerhans-Cell; Humans; Skin; Xanthogranuloma, Juvenile
PubMed: 32721389
DOI: 10.1016/j.ad.2020.07.004 -
Dermatology Online Journal Mar 2024Juvenile xanthogranuloma is the most frequent form of non-Langerhans cell histiocytosis in children. Clinically, it presents as well defined, yellowish papules that are...
Juvenile xanthogranuloma is the most frequent form of non-Langerhans cell histiocytosis in children. Clinically, it presents as well defined, yellowish papules that are typically located on the head, neck, upper trunk, and proximal region of the extremities. Although solitary lesions are the most common presentation, few cases of multiple juvenile xanthogranuloma have been described, more frequently associated with extracutaneous involvement. We report a 2-month-old girl with 22 cutaneous papules, clinically and histologically compatible with juvenile xanthogranulomas. Screening of visceral involvement was performed with no evidence of systemic disease. Identifying high-risk factors of systemic disease in patients with multiple juvenile xanthogranuloma is essential to perform an appropriate management of this entity.
Topics: Humans; Xanthogranuloma, Juvenile; Female; Infant
PubMed: 38762861
DOI: 10.5070/D330163291 -
Pediatric Blood & Cancer May 2023To perform a systematic review to investigate the available literature regarding systemic juvenile xanthogranuloma (SJXG) and report the population characteristics,... (Review)
Review
OBJECTIVE
To perform a systematic review to investigate the available literature regarding systemic juvenile xanthogranuloma (SJXG) and report the population characteristics, clinical manifestation, therapy, and outcome.
REVIEW METHODS
A search of PubMed, Embase, and Cochrane Library for all articles published between 1981 and 2022 was performed with variations and combinations of the following search terms: extracutaneous, visceral, systemic, and juvenile xanthogranuloma (JXG). Data extracted included demographics, organ involvement, treatment, outcome, and permanent sequelae.
RESULTS
A total of 103 articles encompassing 159 patients met the inclusion criteria. The median onset age was 9 months, with a male predominance (61%). The distribution of major involved organs varied by age, and younger onset age was associated with more organ involvement. The most commonly involved site was the central nervous system (CNS) (40.9%), followed by the liver (31.4%), the lung (18.9%), and the eye (18.2%). At the termination of follow-up, 93 patients (58.5%) were alive with no disease, 56 (35.2%) were alive with disease, and 10 (6.3%) were dead of disease. There was a significant difference in outcome between patients with and without spleen involvement (p = .0003), and patients with spleen involvement suffered a higher risk of death. Permanent sequelae mainly comprised CNS symptoms and ocular manifestations.
CONCLUSIONS
SJXG can involve varying numbers and combinations of extracutaneous sites. There is no standard therapy for SJXG and clinicians should choose individualized therapy modalities.
Topics: Humans; Male; Infant; Female; Xanthogranuloma, Juvenile; Eye; Central Nervous System; Disease Progression; Liver
PubMed: 36779547
DOI: 10.1002/pbc.30232 -
Pediatrics in Review Oct 2022Histiocytic disorders of childhood represent a wide spectrum of conditions that share the common histologic feature of activated or transformed "histiocytes." Langerhans...
Histiocytic disorders of childhood represent a wide spectrum of conditions that share the common histologic feature of activated or transformed "histiocytes." Langerhans cell histiocytosis (LCH) is the most common, with an incidence of approximately 5 per million children. LCH may be difficult to distinguish from more ubiquitous causes of skin rashes, bone pain, or fever. Current chemotherapy fails to cure more than 50% of children with multifocal disease, and treatment failure is associated with increased risks of long-term sequelae. Somatic activating mitogen-activated protein kinase (MAPK) pathway-activating mutations (most often BRAFV600E) have been identified in hematopoietic precursors in patients with LCH. Opportunities to improve outcomes with targeted therapies are under investigation. Juvenile xanthogranuloma (JXG) and Rosai-Dorfman disease (RDD) are less common than LCH and are distinguished by specific histologic and clinical features. Recurrent MAPK pathway gene mutations are also identified in JXG and RDD. In many cases, these conditions spontaneously resolve, but disseminated disease can be fatal. Although there has been historic debate regarding the nature of these conditions as inflammatory versus neoplastic, LCH, JXG, and RDD are now considered myeloid neoplastic disorders. In contrast, hemophagocytic lymphohistiocytosis (HLH) is clearly a disorder of immune dysregulation. HLH is characterized by extreme immune activation driven by hyperactivated T cells. HLH arises in approximately 1 child per million and is nearly universally fatal without prompt recognition and immune suppression. Outcomes of treated children are poor, with approximately 60% survival. Emapalumab, which targets interferon-γ signaling, was recently approved for patients with recurrent or refractory HLH, and additional cytokine-directed therapies are under investigation.
Topics: Child; Histiocytes; Histiocytosis, Langerhans-Cell; Histiocytosis, Sinus; Humans; Interferon-gamma; Mitogen-Activated Protein Kinases; Xanthogranuloma, Juvenile
PubMed: 36180546
DOI: 10.1542/pir.2021-005367 -
Dermatology (Basel, Switzerland) 2021Dermoscopy is useful for the evaluation of juvenile xanthogranuloma (JXG). The classical "setting sun" pattern is characteristic of JXG, but its sensibility appears to...
BACKGROUND
Dermoscopy is useful for the evaluation of juvenile xanthogranuloma (JXG). The classical "setting sun" pattern is characteristic of JXG, but its sensibility appears to be limited. An extensive description of other dermoscopic findings is not available in the literature.
OBJECTIVES
The aim of this study was to valuate and describe the clinical and dermoscopic characteristics of a series of JXG cases.
METHODS
This is a retrospective descriptive study, including cases with histopathologic diagnosis of JXG, and the availability of clinical and dermoscopic images, assessed for the presence of dermoscopic features based on the available literature.
RESULTS
A total of 17 lesions were analyzed. 70.6% showed global symmetry, 35.3% presented the typical "setting sun" pattern. All lesions showed yellow-orange and/or pink-red structureless color. Other dermoscopic features were yellow globules (35.3%), shiny white streaks (23.5%), brown globules (17.6%), pale-brown network (11.8%), negative network (11.8%), erosion/ulceration (11.8%), rosettes (5.9%), and hemorrhage (5.9%). Scales were seen in 64.7% of patients. Vascular structures were observed in all the lesions, mostly in an irregular distribution (76.5%). The observed vessel types were dotted (52.9%), linear (52.9%), branching-arboriform (29.4%), comma-like (23.5%), hairpin-like (17.6%), globular (17.6%), coiled (11.8%), and milky-red globules (5.9%).
CONCLUSIONS
Symmetry, yellow/orange-pink/red color, yellow globules, shiny white streaks, and irregularly distributed different types of vascular structures are the main dermoscopic features of JXG. This is the largest dermoscopic registry of JXG published to date.
Topics: Adolescent; Adult; Age Factors; Child; Dermoscopy; Female; Humans; Male; Middle Aged; Retrospective Studies; Xanthogranuloma, Juvenile; Young Adult
PubMed: 33075787
DOI: 10.1159/000510265