# BRAF-mutant high-grade glioma with pleomorphic and pseudopapillary features (HPAP): A PLNTY mimic demonstrating tumor progression during longitudinal follow-up

## TL;DR

A rare case of a brain tumor with specific genetic mutations shows how tumors can evolve and progress over time.

## Contribution

A rare BRAF p.V600E-mutant HPAP case with PLNTY-like features and subclonal pTERT mutation is described, revealing tumor progression dynamics.

## Key findings

- The tumor showed prolonged indolent growth followed by rapid expansion linked to subclonal pTERT mutation.
- DNA methylation profiling confirmed the diagnosis as HPAP with high confidence.
- Intratumoral genetic heterogeneity suggests distinct evolutionary phases in HPAP.

## Abstract

High-grade glioma with pleomorphic and pseudopapillary features (HPAP) is a recently recognized glioma subtype defined by DNA methylation profiling. While it exhibits overlapping histological features with various CNS tumors, such as polymorphous low-grade neuroepithelial tumor of the young (PLNTY) and pleomorphic xanthoastrocytoma, its molecular pathogenesis and clinical behavior remain incompletely understood.

We report a rare case of HPAP with BRAF p.V600E mutation and PLNTY-like histological features that showed rapid tumor progression during long-term follow-up. A 47-year-old woman harbored a lesion that remained asymptomatic and slow-growing for over 20 years, but later exhibited contrast enhancement and rapid expansion. Partial tumor resection was performed with hippocampal preservation based on intraoperative genetic testing and functional considerations. No regrowth of the residual hippocampal lesion was observed at 12 months postoperatively. Histologically, the tumor showed oligodendroglioma-like morphology, strong CD34 immunopositivity, consistent with PLNTY-like features, but indicated a high proliferative index. Molecular analysis revealed co-occurring BRAF p.V600E and TERT promoter (pTERT, c.-124C>T) mutations, with a lower variant allele frequency for the pTERT mutation. This disparity, confirmed by droplet digital PCR, suggests that the BRAF p.V600E mutation was an early, clonal event, whereas the pTERT mutation likely arose later in a subclonal population. DNA methylation profiling classified the tumor as HPAP with high confidence (NCI-Bethesda score: 0.969), and uniform manifold approximation and projection showed clustering within HPAP reference cases.

This case represents a rare example of BRAF p.V600E-mutant HPAP with PLNTY-like features in which a subclonal pTERT mutation likely emerged during tumor evolution, contributing to rapid tumor progression. The combination of a prolonged indolent phase followed by rapid growth, along with the intratumoral genetic heterogeneity observed, provides novel insights into the biological diversity and evolutionary dynamics of HPAP.