Pilocytic astrocytoma: pathology, molecular mechanisms and markers

Abstract

Pilocytic astrocytomas (PAs) were recognized as a discrete clinical entity over 70 years ago. They are relatively benign (WHO grade I) and have, as a group, a 10-year survival of over 90 %. Many require merely surgical removal and only very infrequently do they progress to more malignant gliomas. While most show classical morphology, they may present a spectrum of morphological patterns, and there are difficult cases that show similarities to other gliomas, some of which are malignant and require aggressive treatment. Until recently, almost nothing was known about the molecular mechanisms involved in their development. The use of high-throughput sequencing techniques interrogating the whole genome has shown that single abnormalities of the mitogen-activating protein kinase (MAPK) pathway are exclusively found in almost all cases, indicating that PA represents a one-pathway disease. The most common mechanism is a tandem duplication of a ≈2 Mb-fragment of #7q, giving rise to a fusion between two genes, resulting in a transforming fusion protein, consisting of the N-terminus of KIAA1549 and the kinase domain of BRAF. Additional infrequent fusion partners have been identified, along with other abnormalities of the MAP-K pathway, affecting tyrosine kinase growth factor receptors at the cell surface (e.g., FGFR1) as well as BRAF V600E, KRAS, and NF1 mutations among others. However, while the KIAA1549-BRAF fusion occurs in all areas, the incidence of the various other mutations identified differs in PAs that develop in different regions of the brain. Unfortunately, from a diagnostic standpoint, almost all mutations found have been reported in other brain tumor types, although some retain considerable utility. These molecular abnormalities will be reviewed, and the difficulties in their potential use in supporting a diagnosis of PA, when the histopathological findings are equivocal or in the choice of individualized therapy, will be discussed.

Diagnostic accuracy of diffusion weighted imaging for differentiation of supratentorial pilocytic astrocytoma and pleomorphic xanthoastrocytoma

“…This finding could be explained by different histopathological features of PA and PXA. Histologically, PA is a tumor of low-moderate cellularity within markedly loose myxoid background [35], whereas PXA is a hypercellular tumor composed of pleomorphic cells with mesenchymal-like morphology [36]. As previously reported [37], ADC values were inversely related to tumor cellular attenuation and tumor cell nucleus-to-cytoplasm ratio in terms of water molecules diffusivity within brain tumors.…”

Standards and Guidelines for the Interpretation and Reporting of Sequence Variants in Cancer

“…Examples include activating KIT mutations (typically D816V) that are present in virtually all adults (93%) with indolent and aggressive forms of systemic mastocytosis 82e84 ; a BRAF mutation (typically V600E) that is used as a diagnostic and prognostic marker for papillary thyroid carcinoma in thyroid fine-needle aspiration samples 85e87 ; KIAA1549-BRAF fusion, which is diagnostic for pilocytic astrocytoma and is associated with a better clinical outcome 88,89 ; and EWSR1 fusions, mostly EWSR1-FLI1, seen in nearly 100% of the Ewings family of tumors, which have greatly enhanced the ability to differentiate Ewings family of tumors from other small blue round cell tumors. 90,91 Germline Pathogenic Variants Associated with Cancer Predisposition We recommend reporting germline variants with known evidence of clinical impact.…”

Heterogeneity of histopathological presentation of pilocytic astrocytoma – diagnostic pitfalls. A review

“…Mitogenactivated protein kinase pathway abnormalities are found in the vast majority of PA cases; thus PA is considered as a one-pathway disease [24]. Recent studies have pointed towards the role of activation of the PI3K/AKT pathway in addition to MAPK/ERK signalling pathways in histologically anaplastic and biologically aggressive PA variants [81].…”