High-Grade Astrocytoma With Piloid Features: An Aggressive Clinicogenomic Entity Distinct From Pilocytic Astrocytoma.

High-grade astrocytoma with piloid features (HGAP) has recently emerged as an aggressive glioma entity with distinct molecular alterations, yet its clinicogenomic distinction from pilocytic astrocytoma (PA) remains to be fully elucidated. This study aims to clarify the clinical, pathological, and genomic differences between pediatric PA, adult PA, and HGAP, and to provide evidence supporting the recognition of HGAP as a new, aggressive entity. We retrospectively analyzed 100 genetically and histopathologically confirmed PA cases (87 pediatric, 13 adult) and 25 HGAP cases (all > 19 years old) diagnosed at Seoul National University Hospital between 2015 and 2024. Next-generation sequencing using a brain tumor-specific gene panel and immunohistochemistry evaluation. Pediatric PAs (median age 7 years) were predominantly cerebellar (61%) and showed classic biphasic histology (72%) with frequent KIAA1549-BRAF fusion (72%) and BRAF V600E mutations (13%) and rarely KRAS mutation (2.3%). Adult PAs (median age 35 years), when HGAP was excluded, were less often cerebellar (53.8%) and rarely KRAS mutation (2.3%), more frequently supratentorial (23%) or spinal (15%) than pediatric PAs, and showed a higher incidence of KRAS mutations (23.1%), and more patternless or diffuse oligoastrocytic histology (31%), but did not differ in recurrence rate or prognosis compared to pediatric PA. In contrast, HGAPs predominantly affected adults (median age 53 years, ranges: 19-87 years), frequently involved cerebellum (40%), and exhibited high-grade histopathological features. Molecular profiling revealed HGAPs harbored frequent CDKN2A/B deletions (76%) and mutations of NF1 (64%), ATRX (52%), PTPN11 (28%), FGFR1/FGFR4 (20%), TERTp (16%), and TP53 (16%). Patients with HGAP had significantly shorter progression-free and overall survival compared to both pediatric and adult PA. HGAP represents a clinically aggressive and molecularly distinct high-grade glioma, clearly separable from pediatric and adult PA. Its poor prognosis and unique genetic drivers justify its recognition as a new entity. Accurate molecular profiling is essential for diagnosis and management of these tumors, and the poor survival outcomes observed in HGAP highlight the need for further larger cohort studies to identify optimal therapeutic strategies.