Recurrent CLTC::SYK Fusions and CSF1R Mutations in Juvenile Xanthogranuloma of Soft Tissue

Pediatrics Oncology Medicine Life Sciences Genetics Hematology Immunology
Juvenile Xanthogranuloma Soft Tissue Tumors CLTC::SYK Fusion CSF1R Mutation Targeted Therapy Molecular Pathology Histologic Features

Research on Juvenile Xanthogranuloma Reveals Novel Genetic Mutations

Juvenile xanthogranuloma (JXG), a rare histiocytic neoplasm, typically manifests in the skin but occasionally presents extracutaneously in locations such as soft tissue or the central nervous system (CNS). The genetic drivers underlying these extracutaneous variants remain poorly understood. Recently, a team of researchers from several international medical institutions published an original research paper unveiling novel genetic mutations and potential therapeutic targets for these rare histiocytic tumors. The study, combining clinicopathological and molecular data, offers new scientific insights to inform treatment strategies and molecular diagnostics.

Background and Research Motivation

JXG, as a form of histiocytic disease, generally presents as self-limiting skin lesions that often regress spontaneously in children early in life. However, for the rare cases that occur in extracutaneous locations such as soft tissue or the CNS, challenges in diagnosis and management arise due to their rarity and variability. Recent studies have identified specific somatic mutations in other histiocytic diseases, such as Erdheim-Chester Disease (ECD), but the genetic drivers of extracutaneous JXG remain largely unknown. Therefore, this study aimed to comprehensively explore genetic mutations driving extracutaneous JXG using molecular and clinical investigation to guide pathological diagnosis and treatment.

Study Sources and Team Introduction

The paper was authored by Paul G. Kemps and an international team spanning institutions such as Leiden University Medical Center in the Netherlands, Amsterdam University Medical Centers, and Heidelberg University Hospital in Germany. Published in the December 2024 issue of Blood, the study incorporates histopathological examinations and innovative sequencing techniques to reveal key genetic mechanisms linked to JXG lesions.

Research Design and Methodology

The study involved 16 pediatric patients with extracutaneous JXG (younger than 18 years of age) and 5 adult patients with soft-tissue or CNS xanthogranulomas. Cases were identified from the Dutch nationwide pathology database (PALGA), spanning a 51-year period (1971–2022). The study followed a multi-step approach, detailed as follows:

1. Case Collection

The research team used PALGA’s database to screen pathology reports using specific keywords (e.g., “extracutaneous localization”). Case selection was based on histopathological features and immunohistochemistry (IHC) results, testing for specific markers such as CD68 and CD163. Cases meeting the WHO classification standards were included for further analysis.

2. DNA and RNA Analysis

  • DNA/RNA Sequencing: The study employed Targeted Locus Capture (TLC), a next-generation sequencing (NGS) technique. This methodology excels at detecting genomic rearrangements in formalin-fixed paraffin-embedded (FFPE) samples, including archival material decades old.
  • Capture Panel: A set of 126 target genes commonly mutated in hematologic and histiocytic neoplasms was included, with bioinformatics tools (e.g., Proximity Ligation-Based Identification of Rearrangements) used to analyze structural variants and gene fusions.

3. Histopathology and Immunohistochemistry

The team applied immunofluorescence and IHC to analyze tumor cell-targeted protein markers. These included SYK kinase expression (e.g., phosphorylated SYK), activation of the mTOR pathway (P-S6, Cyclin D1), and MAPK-related molecules (P-ERK, P-AKT).

4. DNA Methylation Profiling

Genome-wide methylation arrays were employed to assess epigenetic differences across various xanthogranuloma-related lesions, exploring methylation patterns as potential diagnostic or biological features.

Study Results

Key Genetic Alterations Identified

The study identified three major groups of mutations associated with extracutaneous JXG in the 16 pediatric patients:

  1. CLTC::SYK Gene Fusion:

    • Found in 6 patients, this fusion combines the clathrin heavy chain (CLTC) gene with the spleen tyrosine kinase (SYK) gene, leading to continuous activation of SYK kinase and mTOR signaling.
    • The tumors generally lacked Touton giant cells but shared other histopathological features of JXG.

  2. CSF1R (Colony-Stimulating Factor 1 Receptor) Mutations:

    • Detected in 7 patients, CSF1R mutations (e.g., exon 12 insertions/deletions) drive activation of the PI3K-AKT and MAPK pathways. Some lesions demonstrated spontaneous regression.

  3. Activating MAP2K1 and NTRK1 Mutations:

    • Found in 2 cases of systemic JXG, both mutations are associated with spontaneous disease remission over time.

Pathological and Molecular Features

  • Histological and Epigenetic Similarity: Despite molecular heterogeneity, tumors harboring CLTC::SYK fusion and CSF1R mutations exhibited similar histological features, immune phenotypes, and methylation profiles.
  • CNS Findings with BRAF Mutations: Two CNS-xanthogranuloma patients harbored BRAF V600E mutations, responding robustly to the targeted therapy dabrafenib.

Research Implications and Value

Scientific Contributions

This study presents the first comprehensive description of the CLTC::SYK fusion and CSF1R mutations in JXG, integrating molecular pathology with clinical observations. By refining diagnostic tools and expanding the understanding of molecular pathology, the research deepens the evolutionary framework of histiocytic tumors.

Clinical Applications

Targetable mutations uncovered in this study, such as SYK and CSF1R activation, provide actionable avenues for JXG management. Potential treatments include SYK inhibitors (e.g., fostamatinib) and mTOR inhibitors (e.g., rapamycin).

Clinical Observations

The study highlights variability in clinical outcomes, with some lesions regressing spontaneously and others requiring intervention. Genetic testing and tailored therapies may reduce the burden of invasive procedures in young patients.

Conclusion

By integrating clinicopathological data and advanced sequencing technologies, this study provides valuable insights into the understanding and management of juvenile xanthogranuloma. The discovery of novel genetic mutations and their molecular mechanisms paves the way for improved molecular diagnostics and precision therapies. This research not only exemplifies the study of rare diseases but also advances the molecular understanding of histiocytic neoplasms.