The histomolecular criteria established for adult anaplastic pilocytic astrocytoma are not applicable to the pediatric population

Abstract

Pilocytic astrocytoma (PA) is the most common pediatric glioma, arising from a single driver MAPK pathway alteration. Classified as a grade I tumor according to the 2016 WHO classification, prognosis is excellent with a 10-year survival rate > 95% after surgery. However, rare cases present with anaplastic features, including an unexpected high mitotic/proliferative index, thus posing a diagnostic and therapeutic challenge. Based on small histomolecular series and case reports, such tumors arising at the time of diagnosis or recurrence have been designated by many names including pilocytic astrocytoma with anaplastic features (PAAF). Recent DNA methylation-profiling studies performed mainly on adult cases have revealed that PAAF exhibit a specific methylation signature, thus constituting a distinct methylation class from typical PA [methylation class anaplastic astrocytoma with piloid features-(MC-AAP)]. However, the diagnostic and prognostic significance of MC-AAP remains to be determined in children. We performed an integrative work on the largest pediatric cohort of PAAF, defined according to strict criteria: morphology compatible with the diagnosis of PA, with or without necrosis, ≥ 4 mitoses for 2.3 mm 2 , and MAPK pathway alteration. We subjected 31 tumors to clinical, imaging, morphological and molecular analyses, including DNA methylation profiling. We identified only one tumor belonging to the MC-AAP (3%), the others exhibiting a methylation profile typical for PA (77%), IDH-wild-type glioblastoma (7%), and diffuse leptomeningeal glioneuronal tumor (3%), while three cases (10%) did not match to a known DNA methylation class. No significant outcome differences were observed between PAAF with necrosis versus no necrosis (p = 0.07), or with 4-6 mitoses versus 7 or more mitoses (p = 0.857). Our findings argue that the diagnostic histomolecular criteria established for anaplasia in adult PA are not of diagnostic or prognostic value in a pediatric setting. Further extensive and comprehensive integrative studies are necessary to accurately define this exceptional entity in children.

Invited Review: DNA methylation‐based classification of paediatric brain tumours

“…As a consequence of their low frequency, paediatric brain tumours are often categorized according to their histological similarities to the more frequent adult counterparts, irrespective of possible biological differences. This is particularly problematic for malignancy assessment of paediatric glial tumours and can result in an over estimation of malignancy for some patients as exemplified by a subset of paediatric glioblastoma and anaplastic pilocytic astrocytoma . On top of this, the consequences of a misdiagnosis are particularly grave in the paediatric context, for example the application of an unnecessary brain irradiation due to an overestimation of the malignancy of a glioma may lead to lifelong cognitive, endocrine and cerebral vascular dysfunction as well as the risk of radiation induced secondary brain tumours .…”

“…Several studies have demonstrated that tumours with a more benign clinical course and molecular profiles of more indolent entities such as pilocytic astrocytomas or pleomorphic xanthoastrocytomas may frequently be identified among series of histological glioblastomas . A recent study further demonstrated that paediatric cases diagnosed as anaplastic pilocytic astrocytoma are an extremely heterogeneous group . The majority of samples represent molecular pilocytic astrocytomas and only rarely molecular glioblastomas or anaplastic astrocytomas with piloid features .…”

“…A recent study further demonstrated that paediatric cases diagnosed as anaplastic pilocytic astrocytoma are an extremely heterogeneous group . The majority of samples represent molecular pilocytic astrocytomas and only rarely molecular glioblastomas or anaplastic astrocytomas with piloid features . Thus, the most central role of DNA methylation‐based classification for paediatric gliomas with malignant histological features is the exclusion of a less malignant neoplasm with misleading histological features.…”

“…This rare tumour generally affects mid‐aged adults with only very few documented paediatric examples to date . The tumours show some reminiscence of classical pilocytic astrocytoma (frequent MAPK pathway activation, predominantly located in the cerebellum, some tumours have histological resemblance to pilocytic astrocytoma) but also clear differences (MAPK pathway alteration is much less frequently BRAF fusion, rather NF1 and FGFR1 alteration; additionally frequent alterations of CDKN2A and ATRX , frequent MGMT promoter hypermethylation, often signs of histologic malignancy).…”

Diffuse leptomeningeal glioneuronal tumor: a double misnomer? A report of two cases

“…Diagnosis was "unusual glioneuronal tumor with histological features of anaplasia". Central review was performed under the framework of the national RENOCLIP-LOC network and DNA-methylation profiling was performed using an EPIC array (Integragen, Evry, France) as previously described [10]. The raw IDAT files were uploaded to https://www.molecularneuropathology.org for supervised analysis using the Random Forest methylation class prediction algorithm, and copy number profiles were obtained as previously described [11].…”