BRAF V600E mutation in Juvenile Xanthogranuloma family neoplasms of the central nervous system (CNS-JXG): a revised diagnostic algorithm to include pediatric Erdheim-Chester disease

Abstract

The family of juvenile xanthogranuloma family neoplasms (JXG) with ERK-pathway mutations are now classified within the “L” (Langerhans) group, which includes Langerhans cell histiocytosis (LCH) and Erdheim Chester disease (ECD). Although the BRAF V600E mutation constitutes the majority of molecular alterations in ECD and LCH, only three reported JXG neoplasms, all in male pediatric patients with localized central nervous system (CNS) involvement, are known to harbor the BRAF mutation. This retrospective case series seeks to redefine the clinicopathologic spectrum of pediatric CNS-JXG family neoplasms in the post-BRAF era, with a revised diagnostic algorithm to include pediatric ECD. Twenty-two CNS-JXG family lesions were retrieved from consult files with 64% (n = 14) having informative BRAF V600E mutational testing (molecular and/or VE1 immunohistochemistry). Of these, 71% (n = 10) were pediatric cases (≤18 years) and half (n = 5) harbored the BRAF V600E mutation. As compared to the BRAF wild-type cohort (WT), the BRAF V600E cohort had a similar mean age at diagnosis [BRAF V600E: 7 years (3–12 y), vs. WT: 7.6 years (1–18 y)] but demonstrated a stronger male/female ratio (BRAF V600E: 4 vs WT: 0.67), and had both more multifocal CNS disease ( BRAFV600E: 80% vs WT: 20%) and systemic disease (BRAF V600E: 40% vs WT: none). Radiographic features of CNS-JXG varied but typically included enhancing CNS mass lesion(s) with associated white matter changes in a subset of BRAF V600E neoplasms. After clinical-radiographic correlation, pediatric ECD was diagnosed in the BRAF V600E cohort. Treatment options varied, including surgical resection, chemotherapy, and targeted therapy with BRAF-inhibitor dabrafenib in one mutated case. BRAF V600E CNS-JXG neoplasms appear associated with male gender and aggressive disease presentation including pediatric ECD. We propose a revised diagnostic algorithm for CNS-JXG that includes an initial morphologic diagnosis with a final integrated diagnosis after clinical-radiographic and molecular correlation, in order to identify cases of pediatric ECD. Future studies with long-term follow-up are required to determine if pediatric BRAF V600E positive CNS-JXG neoplasms are a distinct entity in the L-group histiocytosis category or represent an expanded pediatric spectrum of ECD.

ALK-positive histiocytosis: a new clinicopathologic spectrum highlighting neurologic involvement and responses to ALK inhibition

“…Furthermore, significant associations between specific kinase alterations and clinicopathologic phenotypes have recently been observed 6 . These findings pave the way for molecular (sub)classification of histiocytic neoplasms 1,6,8,28 , and highlight the potential for targeted therapy beyond BRAF or MEK inhibition in histiocytosis patients.…”

Dasatinib induces a dramatic response in a child with refractory juvenile xanthogranuloma with a novel MRC1-PDGFRB fusion

“…Additional reports have identified NF1, MAPK1, PI3KD and other mutations. 6,20,22 To our knowledge, this case represents the first description of a patient with a JXG tumor harboring an MRC1-PDGFRB fusion. This fusion juxtaposes the intact tyrosine kinase domain of PDGFRB next to the extracellular domain of the c-type mannose receptor 1 (macrophage mannose receptor, MRC1, CD206) and is predicted to activate PDGFR signaling.…”

“…For example, although the BRAF V600E mutation is identified in approximately one-half of all cases of LCH and Erdheim-Chester disease, 7,17 it is rare in Rosai-Dorfman disease (RDD) 18,19 and even rarer in JXG. 20,21 An increasing number of studies in the literature describe the somatic mutations other than BRAF V600E found in JXG tumors. In a recent study including 55 patients with JXG, WES, transcriptome, targeted DNA, and/or targeted RNA sequencing identified kinase driver mutations in MAP2K1, NRAS, KRAS, CSF1R, and KIT, among others.…”

Clinical Analysis of Pediatric Systemic Juvenile Xanthogranulomas: A Retrospective Single-Center Study

“…However, there do exist some conflicts in the diagnostic criteria. To solve these problems, Picarsic et al ( 17 ) proposed a revised diagnostic algorithm to distinguish between CNS-JXG and pediatric ECD, which included an initial morphologic diagnosis with a final integrated diagnosis after clinical-radiographic and molecular correlation. They advised long-term follow-up to determine if pediatric BRAF V600E positive CNS-JXG is a distinct entity in the L-group histiocytosis category or represents an expanded pediatric spectrum of ECD.…”