Majd Al Assaad1,2, Gunes Gundem3, Benjamin Liechty1, Andrea Sboner1,2, Juan Medina3, Elli Papaemmanuil3, Cora N. Sternberg2,4, Asher Marks5, Mark M. Souweidane6, Jeffrey P. Greenfield6, Ivy Tran7, Matija Snuderl7, Olivier Elemento2,8, Marcin Imielinski1,2, David J. Pisapia1,2 and Juan Miguel Mosquera1,2 1Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York 10065, USA; 2Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, New York 10065, USA; 3Isabl, Inc., New York, New York 10065, USA; 4Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medicine, New York, New York 10065, USA; 5Pediatric Hematology/Oncology, Yale Medicine, New Haven, Connecticut 06520, USA; 6Pediatric Neurological Surgery, Weill Cornell Medicine, New York, New York 10065, USA; 7Department of Pathology, NYU Langone Health and School of Medicine, New York, New York 10016, USA; 8Department of Physiology and Biophysics, Weill Cornell Medicine, New York, New York 10065, USA Corresponding authors: djp2002med.cornell.edu; jmm9018med.cornell.edu

Pilocytic astrocytomas are the most common pediatric brain tumors, typically presenting as low-grade neoplasms. We report two cases of pilocytic astrocytoma with atypical tumor progression. Case 1 involves a 12-yr-old boy with an unresectable suprasellar tumor, negative for BRAF rearrangement but harboring a BRAF p.V600E mutation. He experienced tumor size reduction and stable disease following dabrafenib treatment. Case 2 describes a 6-yr-old boy with a thalamic tumor that underwent multiple resections, with no actionable driver detected using targeted next-generation sequencing. Whole-genome and RNA-seq analysis identified an internal tandem duplication in FGFR1 and RAS pathway activation. Future management options include FGFR1 inhibitors. These cases demonstrate the importance of escalating molecular diagnostics for pediatric brain cancer, advocating for early reflexing to integrative whole-genome sequencing and transcriptomic profiling when targeted panels are uninformative. Identifying molecular drivers can significantly impact treatment decisions and improve patient outcomes.

Received February 1, 2023. Accepted July 31, 2023.