104 A rare and aggressive brain tumour, known as high-grade astrocytoma with piloid features (HGAP), is challenging current approaches to diagnosis and treatment after new research highlighted its unique molecular profile and unpredictable behaviour. The findings were published in the journal Acta Neuropathologica Communications. HGAP has only recently been formally classified and remains difficult to identify through traditional pathology. It bears resemblance to both glioblastoma and pilocytic astrocytoma under the microscope, yet has a distinct DNA methylation pattern that is now essential for diagnosis. Researchers at a leading US cancer centre conducted a retrospective study of 18 patients diagnosed with HGAP, in what is one of the most comprehensive institutional reviews to date. The study revealed that HGAP most frequently occurs in the cerebellum and thalamus and is predominantly found in middle-aged adults. Imaging of these tumours showed a mix of appearances, including homogenous enhancement and rim-enhancing patterns with necrotic centres. Such features often mimic other high-grade gliomas, which can lead to misdiagnosis unless molecular testing is performed. All but one of the cases in the study had methylation profiling to confirm the HGAP classification, reinforcing the importance of this genetic testing for accurate identification. A defining hallmark of HGAP is the frequent loss of the tumour suppressor genes CDKN2A and CDKN2B, which are associated with poorer outcomes in other gliomas. Over 60% of patients in the study showed this mutation, while many also had mutations in ATRX and the MAPK signalling pathway, including BRAF and FGFR1 alterations. Treatment strategies varied widely, reflecting the lack of standardised protocols for this newly recognised tumour. The majority of patients received a combination of surgery, radiotherapy, and chemotherapy with temozolomide. A small number were treated with targeted therapies such as BRAF and MEK inhibitors, showing some promise in selected cases. One patient receiving such targeted treatment remained alive 20 months post-diagnosis, despite disease progression. The study reported a median progression-free survival of just over five months. While overall survival data were not fully reached, researchers believe this reflects both the tumour’s aggressive biology and the difficulty in achieving complete surgical removal, especially for tumours located in critical brain regions. Many patients were not eligible for gross total resection due to the anatomical challenges posed by the tumour’s common locations. Histologically, HGAP presents with a wide spectrum of features, making its identification even more complex. Some tumours in the study showed classic signs associated with low-grade gliomas, such as Rosenthal fibres and granular bodies, while others exhibited the more sinister signs of high mitotic activity and necrosis. This variation further complicates the grading and management of the disease. HGAP is currently designated as a WHO Grade 3 tumour, although its biological behaviour may warrant a higher grade in the future. The authors of the study called for more research into the optimal treatment pathway and highlighted the need for better inclusion criteria in clinical trials, as many patients with HGAP are currently excluded due to the tumour not being classified as glioblastoma.