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Archives of Pathology & Laboratory... May 2024Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm that predominantly affects young children.
CONTEXT.—
Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm that predominantly affects young children.
OBJECTIVE.—
To investigate genetic alterations and their correlation with clinical characteristics and prognosis in pediatric LCH.
DESIGN.—
We performed targeted sequencing to detect mutations in LCH lesions from pediatric patients.
RESULTS.—
A total of 30 genomic alterations in 5 genes of the MAPK pathway were identified in 187 of 223 patients (83.9%). BRAF V600E (B-Raf proto-oncogene, serine/threonine kinase) was the most common mutation (51.6%), followed by MAP2K1 (mitogen-activated protein kinase kinase 1) alterations (17.0%) and other BRAF mutations (13.0%). ARAF (A-Raf proto-oncogene, serine/threonine kinase) and KRAS (KRAS proto-oncogene, GTPase) mutations were relatively rare (2.2% and 0.9%, respectively). Additionally, FNBP1 (formin-binding protein 1)::BRAF fusion and MAP3K10 (mitogen-activated protein kinase kinase 10) mutations A17T and R823C were identified in 1 case each, with possible constitutive activation of ERK1/2 phosphorylation. BRAF V600E was more frequent in patients with risk organ involvement, while MAP2K1 mutation was more prevalent in patients with single-system LCH (P = .001). BRAF V600E was associated with craniofacial bone, skin, liver, spleen, and ear involvement (all P < .05). Patients with other BRAF mutations had a higher proportion of spinal column involvement (P = .006). Univariate analysis showed a significant difference in progression-free survival among the 4 molecular subgroups for patients treated with first-line therapy (P = .02). According to multivariate analysis, risk organ involvement was the strongest independent adverse prognostic factor (hazard ratio, 8.854; P < .001); BRAF or MAP2K1 mutation was not an independent prognostic factor.
CONCLUSIONS.—
Most pediatric patients with LCH carry somatic mutations involving the MAPK pathway, correlating with clinical characteristics and outcomes for first-line chemotherapy.
PubMed: 38749502
DOI: 10.5858/arpa.2023-0236-OA -
Molecular Biotechnology May 2024Langerhans cell histiocytosis (LCH) is a rare condition predominantly affecting young children. Activation of the MAPK pathway has offered key new insights into the...
Langerhans cell histiocytosis (LCH) is a rare condition predominantly affecting young children. Activation of the MAPK pathway has offered key new insights into the pathogenesis of LCH; however, the precise mechanisms underlying its occurrence and development are still far from being completely elucidated. There is still a relapse/reactivation rate in patients with multisystem LCH. Therefore, this study aimed to investigate other potential LCH pathophysiologies and prospective therapeutic targets. The gene expression omnibus (GEO) database was used to retrieve gene expression profiles of LCH (GSE16395). Three distinct types of analyses were performed after identifying the common differentially expressed genes (DEGs) in LCH: hub gene identification, functional annotation, module construction, drug repositioning, and expression analysis via immunohistochemistry (IHC). We identified 417 common DEGs and 50 central hub genes. This functional study highlighted the significance of keratinization, skin development, and inflammation. In addition, we predicted new drug candidates (RS2 drugs targeting matrix metalloprotease1, MMP1) that could be used for LCH treatment. Finally, gene-miRNA and gene-TF networks and immune cell infiltration were analyzed for MMP1-related genes. MMP1 expression levels in LCH tissues were validated by IHC. Our study identified the central communal genes and novel drug candidates. These shared pathways and hub genes offer new perspectives on future mechanisms of action and therapeutic targets.
PubMed: 38748071
DOI: 10.1007/s12033-024-01186-7 -
Brain Tumor Research and Treatment Apr 2024Eosinophilic granuloma (EG), a subtype of Langerhans cell histiocytosis (LCH), the monostotic form, is a rare condition characterized by a solitary bone lesion. It is...
Eosinophilic granuloma (EG), a subtype of Langerhans cell histiocytosis (LCH), the monostotic form, is a rare condition characterized by a solitary bone lesion. It is even more unusual for this condition to be accompanied by an epidural hematoma (EDH). This case is unique in that it is the first to involve delayed EDH following a seizure. We describe a remarkable example of EG accompanied by an EDH and consider the rarity of this comorbidity. A 32-month-old boy developed a rapidly growing skull mass following a minor head injury. During surgical preparation for a biopsy, the patient experienced a single convulsion. Imaging following the seizure revealed an EDH in the vicinity of the mass. The mass was excised and confirmed to be an EG, but with positive margins. The patient underwent chemotherapy after systemic skeletal evaluation, in accordance with the LCH III protocol established by the Histiocytosis Society. EG is a rare neoplasm that typically presents as a painless growth on the skull that gradually enlarges over time. The correlation between EG and EDH is exceedingly uncommon, with only a few documented cases. This case study underscores the significance of considering EG in the differential diagnosis of an expanding cranium mass, even when associated with EDH. Prompt diagnosis and treatment can prevent serious complications and improve patient outcomes.
PubMed: 38742265
DOI: 10.14791/btrt.2024.0018 -
Brain Tumor Research and Treatment Apr 2024Langerhans cell histiocytosis (LCH) is a rare condition in adults, especially when it is limited to a single area of the skull, known as solitary calvarial involvement....
Langerhans cell histiocytosis (LCH) is a rare condition in adults, especially when it is limited to a single area of the skull, known as solitary calvarial involvement. In this case report, we present a unique instance of LCH affecting the parietal bone with a pus-draining fistula. This is a rare and unusual presentation at this location, which has been scarcely reported in medical literature. A 30-year-old woman with no prior comorbidity presented with complaints of headache that persisted for a year. She also had swelling on her scalp and a yellowish discharge for 3 weeks, but no neurological problems were observed. Radiology revealed thinning of the calvaria, with ragged margins along the inner table, multiple focal erosions, and involvement of overlying soft tissue and bony sequestrum. The patient underwent biparietal craniotomy and excision of the lesion. The histopathology report showed LCH. After 8 months of follow-up, there was no recurrence. The management of solitary calvarial involvement by LCH with masquerading presentation as a scalp infection can be achieved through complete excision of the lesions, resulting in a favorable outcome.
PubMed: 38742259
DOI: 10.14791/btrt.2023.0043 -
Indian Journal of Pathology &... May 2024Langerhans cell histiocytosis (LCH) is a rare disorder affecting usually children and rarely adults. The most common site affected is bone. The involvement of the...
Langerhans cell histiocytosis (LCH) is a rare disorder affecting usually children and rarely adults. The most common site affected is bone. The involvement of the thyroid gland in LCH is extremely rare and it is usually observed in an adult as a multisystemic disease. Adult males presented with anterior neck swelling, and fine needle aspiration cytology (FNAC) diagnosed it as suspicious for malignancy. On frozen sectioning, differential diagnosis was given as non-Hodgkin lymphoma and poorly differentiated malignancy. On immunohistochemistry (IHC), tumor cells were positive for CD1a and S100p. Thus, the final diagnosis offered was LCH-thyroid. The pathogenesis is unclear and believed to be related to immune dysfunction, cytokine mediators, viral infection, smoking, and genetic factors. Due to its rarity, thyroid LCH is often misinterpreted as other common disorders of the thyroid and results in delayed diagnosis. This case highlights the importance of histomorphology and the use of ancillary techniques such as IHC to arrive at a diagnosis in time and hence the treatment.
PubMed: 38727417
DOI: 10.4103/ijpm.ijpm_723_23 -
Expert Review of Hematology Jun 2024Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm, encompassing a diverse clinical spectrum ranging from localized bone or skin lesions to a multisystemic... (Review)
Review
INTRODUCTION
Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm, encompassing a diverse clinical spectrum ranging from localized bone or skin lesions to a multisystemic life-threatening condition. Over the past decade, there has been an expansion in understanding the molecular biology of LCH, which translated into innovative targeted therapeutic approaches.
AREAS COVERED
In this article, we will review the molecular alterations observed in pediatric LCH and the relationship between these molecular changes and the clinical phenotype, as well as targeted therapies in LCH.
EXPERT OPINION
Mitogen-activated protein kinase (MAPK) pathway mutation is a hallmark of LCH and is identified in 80% of the cases. Notably, BRAFV600E mutation is seen in ~50-60% of the cases, ~30% has other MAPK pathway mutations, while 15-20% have no detected mutations. While the first line therapeutic approach is vinblastine and prednisone, targeted therapies - specifically BRAF/MEK inhibitors - emerged as a promising second-line salvage strategy, particularly when a mutation is identified. Most patients respond to BRAF/MEK inhibitors but at least 75% reactivate after stopping, however, most patients respond again when restarting inhibitors.
Topics: Humans; Molecular Targeted Therapy; Child; Histiocytosis, Langerhans-Cell; Mutation; Proto-Oncogene Proteins B-raf; Genetic Markers; Protein Kinase Inhibitors; MAP Kinase Signaling System
PubMed: 38721670
DOI: 10.1080/17474086.2024.2353772 -
European Thyroid Journal Jun 2024Langerhans cell histiocytosis (LCH) may present as unifocal disease of the suprasellar region, with symptoms and signs of hypopituitarism, arginine vasopressin...
Langerhans cell histiocytosis (LCH) may present as unifocal disease of the suprasellar region, with symptoms and signs of hypopituitarism, arginine vasopressin deficiency (AVP-D), and weight gain. Transcranial biopsy is necessary to define diagnosis and guide treatment decisions, but it is associated with significant morbidity. We describe a patient with Hashimoto thyroiditis and a single hypothalamic mass in whom LCH diagnosis was made by thyroid fine-needle aspiration cytology (FNAC) performed despite nonspecific findings in thyroid imaging, on the basis of a slightly elevated [18F]-fluorodeoxyglucose (FDG) avidity on PET/CT and volume increase during follow-up.
Topics: Humans; Histiocytosis, Langerhans-Cell; Biopsy, Fine-Needle; Thyroid Gland; Female; Positron Emission Tomography Computed Tomography; Hashimoto Disease; Fluorodeoxyglucose F18; Adult; Male; Cytology
PubMed: 38718824
DOI: 10.1530/ETJ-24-0011 -
BMC Pediatrics May 2024Langerhans cell histiocytosis (LCH) is the most common histiocytic disorder in children, and liver involvement in LCH is rare. This retrospective study reported the...
Langerhans cell histiocytosis (LCH) is the most common histiocytic disorder in children, and liver involvement in LCH is rare. This retrospective study reported the clinical features and prognosis of patients with hepatic LCH. Liver involvement was defined by histopathological findings, liver dysfunction or abnormalities, or ultrasound imaging. A total of 130 patients (14.5%) with hepatic LCH out of 899 in the LCH population were enrolled. Patients with liver involvement had greater frequencies of skin, lung, hearing system, and haematologic system involvement, and hemophagocytic lymphohistiocytosis (P<0.001, 0.001, 0.002, 0.009, and <0.001, respectively). Overall survival and progression-free survival were lower in LCH patients with liver involvement than in those without liver involvement (P<0.001 and <0.001). In patients with liver involvement, the overall survival (OS) and progression-free survival (PFS) rates were lower in patients with cholangitis than in those without cholangitis (P<0.020 and 0.030). For the treatment response, the response rate of hepatic LCH patients to initial first-line therapy (n=89) was 22.5%. However, there was no significant difference in the response rate or recurrence rate between patients who shifted from first-line treatment to second-line treatment (n=29) or to targeted therapy (n=13) (P=0.453 and 1.000). The response rate of hepatic LCH patients who received initial second-line therapy (n=13) was 38.5%. Two of these patients subsequently experienced bone recurrence. The response rate of hepatic LCH patients who received initial targeted therapy (n=16) was 75.0%. Three patients subsequently experienced recurrence, including 2 in the bone and 1 in the liver and skin. A total of 39.3% of patients who received second-line treatment had severe myelosuppression (grade III-IV), and 50.8% had varying degrees of gastrointestinal events, whereas there was no severe toxicity in patients who received first-line treatment and targeted therapy. Four patients underwent liver transplantation because of liver cirrhosis. The patients' liver disease improved within a follow-up period of 18-79 months. This study demonstrated that LCH with liver involvement, especially cholangitis, indicates a poor prognosis. Targeted therapy provides a good treatment response and less toxicity. However, it may relapse after withdrawal. Liver transplantation is still a reliable salvage option for patients with end-stage liver disease.
Topics: Humans; Histiocytosis, Langerhans-Cell; Male; Female; Retrospective Studies; Child, Preschool; Infant; Child; Liver Diseases; Treatment Outcome; Adolescent; Prognosis
PubMed: 38714959
DOI: 10.1186/s12887-024-04764-5 -
Orbit (Amsterdam, Netherlands) May 2024
PubMed: 38713858
DOI: 10.1080/01676830.2024.2348017 -
Blood Research May 2024Histiocytic and dendritic cell neoplasms comprise diverse tumors originating from the mononuclear phagocytic system, which includes monocytes, macrophages, and dendritic... (Review)
Review
Histiocytic and dendritic cell neoplasms comprise diverse tumors originating from the mononuclear phagocytic system, which includes monocytes, macrophages, and dendritic cells. The 5th edition of the World Health Organization (WHO) classification updating the categorization of these tumors, reflecting a deeper understanding of their pathogenesis.In this updated classification system, tumors are categorized as Langerhans cell and other dendritic cell neoplasms, histiocyte/macrophage neoplasms, and plasmacytoid dendritic cell neoplasms. Follicular dendritic cell neoplasms are classified as mesenchymal dendritic cell neoplasms within the stroma-derived neoplasms of lymphoid tissues.Each subtype of histiocytic and dendritic cell neoplasms exhibits distinct morphological characteristics. They also show a characteristic immunophenotypic profile marked by various markers such as CD1a, CD207/langerin, S100, CD68, CD163, CD4, CD123, CD21, CD23, CD35, and ALK, and hematolymphoid markers such as CD45 and CD43. In situ hybridization for EBV-encoded small RNA (EBER) identifies a particular subtype. Immunoprofiling plays a critical role in determining the cell of origin and identifying the specific subtype of tumors. There are frequent genomic alterations in these neoplasms, especially in the mitogen-activated protein kinase pathway, including BRAF (notably BRAF V600E), MAP2K1, KRAS, and NRAS mutations, and ALK gene translocation.This review aims to offer a comprehensive and updated overview of histiocytic and dendritic cell neoplasms, focusing on their ontogeny, morphological aspects, immunophenotypic profiles, and molecular genetics. This comprehensive approach is essential for accurately differentiating and classifying neoplasms according to the updated WHO classification.
PubMed: 38713245
DOI: 10.1007/s44313-024-00015-9