Abstract
Pilocytic astrocytoma (PA) is the most common pediatric glioma, arising from a single driver MAPK pathway alteration. Classified as a grade I tumor according to the 2016 WHO classification, prognosis is excellent with a 10-year survival rate > 95% after surgery. However, rare cases present with anaplastic features, including an unexpected high mitotic/proliferative index, thus posing a diagnostic and therapeutic challenge. Based on small histomolecular series and case reports, such tumors arising at the time of diagnosis or recurrence have been designated by many names including pilocytic astrocytoma with anaplastic features (PAAF). Recent DNA methylation-profiling studies performed mainly on adult cases have revealed that PAAF exhibit a specific methylation signature, thus constituting a distinct methylation class from typical PA [methylation class anaplastic astrocytoma with piloid features—(MC-AAP)]. However, the diagnostic and prognostic significance of MC-AAP remains to be determined in children. We performed an integrative work on the largest pediatric cohort of PAAF, defined according to strict criteria: morphology compatible with the diagnosis of PA, with or without necrosis, ≥ 4 mitoses for 2.3 mm2, and MAPK pathway alteration. We subjected 31 tumors to clinical, imaging, morphological and molecular analyses, including DNA methylation profiling. We identified only one tumor belonging to the MC-AAP (3%), the others exhibiting a methylation profile typical for PA (77%), IDH-wild-type glioblastoma (7%), and diffuse leptomeningeal glioneuronal tumor (3%), while three cases (10%) did not match to a known DNA methylation class. No significant outcome differences were observed between PAAF with necrosis versus no necrosis (p = 0.07), or with 4–6 mitoses versus 7 or more mitoses (p = 0.857). Our findings argue that the diagnostic histomolecular criteria established for anaplasia in adult PA are not of diagnostic or prognostic value in a pediatric setting. Further extensive and comprehensive integrative studies are necessary to accurately define this exceptional entity in children.
Highlights
Pilocytic astrocytoma (PA) is the most common pediatric brain tumor (17.6% of childhood primary brain tumors), with peak incidence between 5 and 15 years [19]
We described the largest series of pediatric pilocytic astrocytoma with anaplastic features (PAAF) cases selected on the basis of the 2016 update of the World Health Organization (WHO) classification
Anaplasia in PA is defined by detailed criteria: ≥ 4 mitoses for 10 HPFs, with or without necrosis [3, 19, 26]
Summary
Pilocytic astrocytoma (PA) is the most common pediatric brain tumor (17.6% of childhood primary brain tumors), with peak incidence between 5 and 15 years [19]. Other alterations of MAPK have been observed, such as mutations of BRAF, FGFR1, KRAS, PTPN11, and NF1 genes, and fusions of NTRK2 and FGFR1 [11,19].
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