Pleomorphic xanthoastrocytoma (PXA) is a rare astrocytoma predominantly affecting children and young adults. We performed comprehensive genomic characterization on a cohort of 67 patients with histologically defined PXA (n = 53, 79%) or anaplastic PXA (A-PXA, n = 14, 21%), including copy number analysis (ThermoFisher Oncoscan, n = 67), methylation profiling (Illumina EPIC array, n = 43) and targeted next generation sequencing (n = 32). The most frequent alterations wereCDKN2A/Bdeletion (n = 63; 94%) andBRAFp.V600E (n = 51, 76.1%). In 7BRAFp.V600 wild-type cases, alternative driver alterations were identified involvingBRAF,RAF1andNF1. Downstream phosphorylation of ERK kinase was uniformly present. Additional pathogenic alterations were rare, withTERT,ATRXandTP53mutations identified in a small number of tumors, predominantly A-PXA. Methylation-based classification of 46 cases utilizing a comprehensive reference tumor allowed assignment to the PXA methylation class in 40 cases. A minority grouped with the methylation classes of ganglioglioma or pilocytic astrocytoma (n = 2), anaplastic pilocytic astrocytoma (n = 2) or control tissues (n = 2). In 9 cases, tissue was available from matched primary and recurrent tumors, including 8 with anaplastic transformation. At recurrence, two tumors acquiredTERTpromoter mutations and the majority demonstrated additional non-recurrent copy number alterations. Methylation class was preserved at recurrence. For 62 patients (92.5%), clinical follow-up data were available (median follow-up, 5.4 years). Overall survival was significantly different between PXA and A-PXA (5-year OS 80.8% vs. 47.6%;P = 0.0009) but not progression-free survival (5-year PFS 59.9% vs. 39.8%;P = 0.05). WHO grade remained a strong predictor of overall survival when limited to 38 cases defined as PXA by methylation-based classification. Our data confirm the importance of WHO grading in histologically and epigenetically defined PXA. Methylation-based classification may be helpful in cases with ambiguous morphology, but is largely confirmatory in PXA with well-defined morphology.
Vaubel, R., Zschernack, V., Tran, Q.T., Jenkins, S., Caron, A., Milosevic, D., et al. (2021). Biology and grading of pleomorphic xanthoastrocytoma-what have we learned about it?. BRAIN PATHOLOGY, 31(1), 20-32 [10.1111/bpa.12874].
Biology and grading of pleomorphic xanthoastrocytoma-what have we learned about it?
Giannini, Caterina
2021
Abstract
Pleomorphic xanthoastrocytoma (PXA) is a rare astrocytoma predominantly affecting children and young adults. We performed comprehensive genomic characterization on a cohort of 67 patients with histologically defined PXA (n = 53, 79%) or anaplastic PXA (A-PXA, n = 14, 21%), including copy number analysis (ThermoFisher Oncoscan, n = 67), methylation profiling (Illumina EPIC array, n = 43) and targeted next generation sequencing (n = 32). The most frequent alterations wereCDKN2A/Bdeletion (n = 63; 94%) andBRAFp.V600E (n = 51, 76.1%). In 7BRAFp.V600 wild-type cases, alternative driver alterations were identified involvingBRAF,RAF1andNF1. Downstream phosphorylation of ERK kinase was uniformly present. Additional pathogenic alterations were rare, withTERT,ATRXandTP53mutations identified in a small number of tumors, predominantly A-PXA. Methylation-based classification of 46 cases utilizing a comprehensive reference tumor allowed assignment to the PXA methylation class in 40 cases. A minority grouped with the methylation classes of ganglioglioma or pilocytic astrocytoma (n = 2), anaplastic pilocytic astrocytoma (n = 2) or control tissues (n = 2). In 9 cases, tissue was available from matched primary and recurrent tumors, including 8 with anaplastic transformation. At recurrence, two tumors acquiredTERTpromoter mutations and the majority demonstrated additional non-recurrent copy number alterations. Methylation class was preserved at recurrence. For 62 patients (92.5%), clinical follow-up data were available (median follow-up, 5.4 years). Overall survival was significantly different between PXA and A-PXA (5-year OS 80.8% vs. 47.6%;P = 0.0009) but not progression-free survival (5-year PFS 59.9% vs. 39.8%;P = 0.05). WHO grade remained a strong predictor of overall survival when limited to 38 cases defined as PXA by methylation-based classification. Our data confirm the importance of WHO grading in histologically and epigenetically defined PXA. Methylation-based classification may be helpful in cases with ambiguous morphology, but is largely confirmatory in PXA with well-defined morphology.File | Dimensione | Formato | |
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