Genetic and histopathological associations with outcome in pediatric pilocytic astrocytoma

Abstract

OBJECTIVE Pilocytic astrocytomas (PAs) have a generally favorable prognosis; however, progression or recurrence after resection is possible. The prognostic value of histopathological qualifiers (defined below) or BRAF alterations is not well understood. The aim of this study was to identify the prognostic value of genetic and histopathological features of pediatric PAs. METHODS Patients treated for a WHO grade I PA at a single institution were analyzed for histopathological and genetic features and outcomes. “Histopathological qualifier” refers to designations such as "WHO grade I PA with increased proliferative index." BRAF alterations include gene fusions and point mutations. Patients with neurofibromatosis type 1 were excluded. RESULTS A total of 222 patients were analyzed (51% female, mean age 9.6 years). Tumors were located in the cerebellum/fourth ventricle (51%), optic pathway/hypothalamus (15%), brainstem (12%), and cerebral cortex (11%). BRAF alterations were screened for in 77 patients and identified in 56 (73%). Histopathological qualifiers were present in 27 patients (14%). Resection was performed in 197 patients (89%), 41 (21%) of whom displayed tumor progression or recurrence after resection. Tumor progression or recurrence was not associated with histopathologic qualifiers (p = 0.36) or BRAF alterations (p = 0.77). Ki-67 proliferative indices were not predictive of progression or recurrence (p = 0.94). BRAF alterations, specifically KIAA1549 fusions, were associated with cerebellar/fourth ventricular tumor location (p < 0.0001) and younger patient age (p = 0.03). Patients in whom gross-total resection was achieved had lower rates of progression and recurrence (p < 0.0001). CONCLUSIONS Histopathological features/qualifiers and BRAF alterations were not associated with tumor recurrence/progression in pediatric PAs. The extent of resection was the only factor analyzed that predicted outcome.

Prognostic utility and characteristics of MIB-1 labeling index as a proliferative activity marker in childhood low-grade glioma: a retrospective observational study

“…In contrast, Horbinski et al ( 2010 ) published a case series including 118 patients, showing no correlation of MIB-1 LI and adverse treatment outcome including recurrence, progression, metastatic spread or death. Similar results were reported by Cherlow et al ( 2019 ) of 85 PLGG patients included in the ACNS0221 trial, as well as by Cler et al ( 2022 ), showing no correlation of KI-67 with PFS in a series of PAs. Comparable results could be shown by Bowers et al ( 2002 ) in a small series of pediatric low-grade oligodendrogliomas.…”

“…Nevertheless, with nonautomated measurement of MIB-1 LI representing the most prevalently used method to this day, application of manual MIB-1 LI assessment may contribute to the transferability and viability of the analyzed data in neuropathology practice. Potentially limited accuracy and interobserver variability, moreover, should be considered a possible explanation of the partially conflicting results of previous studies on the prognostic utility of MIB-1 LI in PLGG (Bowers et al 2002 , 2003 ; Fisher et al 2002 ; Dorward et al 2010 ; Margraf et al 2011 ; Tu et al 2018 ; Horbinski et al 2010 ; Cherlow et al 2019 ; Cler et al 2022 ).…”

“…While nowadays amending an integral part to histopathological routine diagnostics in CNS tumors, assessment of MIB-1 LI has previously shown to contribute to differentiation of the degree of malignancy in tumors of the central nervous system, while a significant correlation to WHO grade in human glioma has been reported (Matsumoto et al 1998 ; Pollack et al 2002 ; Skjulsvik et al 2014 ; Hsu et al 1997 ; Krishnan et al 2019 ). However, as compared to distinct solid CNS and non-CNS malignancies, previous analyses of smaller PLGG cohorts addressing the prognostic value of KI-67/MIB-1 LI in PLGG, many of them from the pre-molecular era, draw conflicting conclusions and necessitate further assessment (Bowers et al 2002 , 2003 ; Fisher et al 2002 ; Dorward et al 2010 ; Margraf et al 2011 ; Tu et al 2018 ; Horbinski et al 2010 ; Cherlow et al 2019 ; Cler et al 2022 ).…”

“…The prognostic significance of MIB-1 labeling index (LI) in PLGG, however, remains unclear, as previously published data of smaller case series partly show contradictory results and draw conflicting conclusions (Bowers et al 2002 , 2003 ; Fisher et al 2002 ; Dorward et al 2010 ; Margraf et al 2011 ; Tu et al 2018 ; Horbinski et al 2010 ; Cherlow et al 2019 ; Cler et al 2022 ). In 2003, Bowers et al reported of a study including 118 Pilocytic astrocytoma (PA) patients, showing a shortened PFS in patients with tumors bearing a MIB-1 LI > 2%.…”

Pilocytic astrocytoma: The paradigmatic entity in low‑grade gliomas (Review)

“…5 ) ( 22 ). The most common alteration is a rearrangement of the BRAF gene, resulting in the gene fusion KIAA1549-BRAF ( 22 , 23 ). Other alterations of the MAPK pathway include NF1 mutations, BRAFV600E mutations, other types of BRAF fusions, KRAS mutations, FGFR1 mutations of fusions, NTRK family receptor tyrosine kinase fusions and RAF1 gene fusions.…”