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.
Highlights
In the most recent revised classification of histiocytic disorders, [21], cutaneous juvenile xanthogranuloma (JXG) lesions and those JXG lesions with a systemic component, but not associated with a molecular alteration, are categorized separately into the cutaneous or “C”-group histiocytosis
Pediatric extracutaneous JXG with mitogen activated pathway kinase (MAPK) molecular alterations as an L-group histiocytosis, has been less studied in relation to its possible shared origins with Langerhans cell histiocytosis (LCH) and pediatric Erdheim Chester Disease (ECD) [10, 16, 38, 40, 46, 51] while the BRAF V600E mutation constitutes the majority of molecular alterations in ECD and LCH [3, 5, 30, 53], only three reported JXG neoplasms, all in male pediatric patients with localized central nervous system (CNS) involvement, are known to harbor the BRAF mutation; none showed evidence of systemic disease or a prior history of LCH [56]
Fourteen CNS-JXG cases (64%) had informative molecular status for the BRAF V600E point mutation, which included 10 pediatric CNS-JXG neoplasms that were included in the primary analysis
Summary
In the most recent revised classification of histiocytic disorders, [21], cutaneous juvenile xanthogranuloma (JXG) lesions and those JXG lesions with a systemic component, but not associated with a molecular alteration, are categorized separately into the cutaneous or “C”-group histiocytosis. Extracutaneous JXG lesions with mitogen activated pathway kinase (MAPK) / extracellular-signal-regulated kinase (ERK) pathway activating mutations are categorized into the Langerhans “L-group” histiocytosis, including three rare BRAF V600E JXG “L-group” neoplasm [56] In this revised classification, Langerhans cell histiocytosis (LCH) and Erdheim Chester Disease (ECD), are categorized in the “L group” of histiocytic neoplasms. They are often a challenge to diagnose and have a generally poor prognosis; in adults these neoplasms often have an excellent response to inhibitor therapy [15, 24, 48]. Both systemic JXG with CNS involvement and CNS-limited JXG appear to have poorer outcomes, as compared to pediatric JXG without CNS disease; none of these prior pediatric JXG studies have investigated the BRAF mutational status [13, 58]
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