A clinicopathologic study of diencephalic pediatric low-grade gliomas with BRAF V600 mutation.
Among brain tumors, the BRAF (V600E) mutation is frequently associated with pleomorphic xanthoastrocytomas (PXAs) and gangliogliomas (GGs). This oncogenic mutation is also detected in ~5 % of other pediatric low-grade gliomas (LGGs) including pilocytic astrocytomas (PAs) and diffuse astrocytomas. In the current multi-institutional study of 56 non-PXA/non-GG diencephalic pediatric LGGs, the BRAF (V600) mutation rate is 36 %. V600-mutant tumors demonstrate a predilection for infants and young children (<age 3) and have a higher tendency for multicentricity. On neuroimaging, BRAF (V600)-mutant tumors appear as nodular, yet infiltrative contrast-enhancing masses. Morphologic examination reveals a monophasic, predominantly compact and partially infiltrative architecture. Due to the lack of classic morphologic features associated with PAs, pilomyxoid astrocytomas (PMAs), or diffuse astrocytomas, 75 % of the BRAF (V600)-mutant tumors could not be definitively classified on initial histopathologic evaluation. At a median follow-up of 55 months, the 5-year progression-free survival (PFS) rate for BRAF (V600)-mutant diencephalic low-grade astrocytomas (LGAs) was 22 ± 12 %, shorter than BRAF (V600)-WT PAs (52 ± 13 %) but higher than PMAs (10 ± 6 %). Of note, long-term PFS was observed in several adolescent patients with BRAF (V600)-mutant tumors. In children aged 0-12 years, 5-year PFS rate and median PFS in BRAF (V600)-mutant LGAs are 9 ± 9 % and 19 months (95 % CI 3-37 months), respectively. The PFS is comparable to that in BRAF (V600)-WT PMAs (5-year PFS rate: 10 ± 9 %; median PFS: 15 months, 95 % CI 3-32 months; p = 0.96) and significantly shorter than BRAF (V600)-WT PAs (5-year PFS rate: 46 ± 13 %; median PFS: 51 months, 95 % CI 20-∞ months; p < 0.05). In summary, diencephalic BRAF (V600)-mutant pediatric LGAs are associated with unique clinicopathologic features and have a more aggressive clinical course, especially in children under age 13. The low rate of CDKN2A deletion also suggests that these tumors are molecularly distinct from secondary pediatric high-grade gliomas.
Division of Pathology, Children's National Medical Center, 111 Michigan Ave, NW, Washington DC, 20010, USA. cho@childrensnational.org.|Research Center for Genetic Medicine, Children's National Medical Center, Washington DC, USA. cho@childrensnational.org.|Brain Tumor Institute, Children's National Medical Center, Washington DC, USA. cho@childrensnational.org.
Cheng-Ying
CY
Ho
Department of Pathology, Vanderbilt University Medical Center, Nashville, TN, USA.
Bret C
BC
Mobley
Research Center for Genetic Medicine, Children's National Medical Center, Washington DC, USA.|Department of Integrative Systems Biology, George Washington University, Washington DC, USA.
Heather
H
Gordish-Dressman
Department of Pathology, The Johns Hopkins Hospital, Baltimore, MD, USA.
Christopher J
CJ
VandenBussche
Department of Neurology, Children's National Medical Center, Washington DC, USA.|Brain Tumor Institute, Children's National Medical Center, Washington DC, USA.|Division of Pediatric Neuro-Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Gary E
GE
Mason
Department of Neurology, Children's National Medical Center, Washington DC, USA.|Brain Tumor Institute, Children's National Medical Center, Washington DC, USA.
Miriam
M
Bornhorst
Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA.
Adam J
AJ
Esbenshade
Department of Pathology, Inova Fairfaix Hospital, Fairfax, VA, USA.
Mahtab
M
Tehrani
Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.
Brent A
BA
Orr
Department of Pathology, University of South Carolina School of Medicine, Columbia, SC, USA.
Delecia R
DR
LaFrance
Department of Laboratory Medicine, Children's National Medical Center, Washington DC, USA.
Joseph M
JM
Devaney
Department of Laboratory Medicine, Children's National Medical Center, Washington DC, USA.
Beatrix W
BW
Meltzer
Department of Laboratory Medicine, Children's National Medical Center, Washington DC, USA.
Sean E
SE
Hofherr
Department of Pathology, The Johns Hopkins Hospital, Baltimore, MD, USA.
Peter C
PC
Burger
Department of Neurology, Children's National Medical Center, Washington DC, USA.|Brain Tumor Institute, Children's National Medical Center, Washington DC, USA.
Roger J
RJ
Packer
Department of Pathology, The Johns Hopkins Hospital, Baltimore, MD, USA.
Fausto J
FJ
Rodriguez
D000293:Adolescent; D000367:Age Factors; D001932:Brain Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology* / Q000628:therapy; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D004027:Diencephalon / Q000473:pathology*; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D005910:Glioma / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology* / Q000628:therapy; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation; D060787:Neoplasm Grading; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016896:Treatment Outcome
D019941:Cyclin-Dependent Kinase Inhibitor p16; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
BRAF; Diencephalic; Hypothalamic; Low-grade glioma; Pilocytic astrocytoma; Pilomyxoid astrocytoma; V600E