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Acta Neuropathologica

, Volume 130, Issue 4, pp 575–585 | Cite as

A clinicopathologic study of diencephalic pediatric low-grade gliomas with BRAF V600 mutation

  • Cheng-Ying Ho
  • Bret C. Mobley
  • Heather Gordish-Dressman
  • Christopher J. VandenBussche
  • Gary E. Mason
  • Miriam Bornhorst
  • Adam J. Esbenshade
  • Mahtab Tehrani
  • Brent A. Orr
  • Delecia R. LaFrance
  • Joseph M. Devaney
  • Beatrix W. Meltzer
  • Sean E. Hofherr
  • Peter C. Burger
  • Roger J. Packer
  • Fausto J. Rodriguez
Original Paper

Abstract

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.

Keywords

BRAF V600E Diencephalic Hypothalamic Low-grade glioma Pilocytic astrocytoma Pilomyxoid astrocytoma 

Notes

Acknowledgments

We would like to thank Dr. Peter Phillips for providing critical clinical information and Ms. Ashley Tipton for excellent technical assistance. This work was supported in part by the Lauren’s First and Goal and the Pilocytic/Pilomyxoid fund (to FJR).

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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Cheng-Ying Ho
    • 1
    • 3
    • 4
  • Bret C. Mobley
    • 6
  • Heather Gordish-Dressman
    • 3
    • 8
  • Christopher J. VandenBussche
    • 9
  • Gary E. Mason
    • 2
    • 4
    • 13
  • Miriam Bornhorst
    • 2
    • 4
  • Adam J. Esbenshade
    • 7
  • Mahtab Tehrani
    • 10
  • Brent A. Orr
    • 11
  • Delecia R. LaFrance
    • 12
  • Joseph M. Devaney
    • 5
  • Beatrix W. Meltzer
    • 5
  • Sean E. Hofherr
    • 5
  • Peter C. Burger
    • 9
  • Roger J. Packer
    • 2
    • 4
  • Fausto J. Rodriguez
    • 9
  1. 1.Division of PathologyChildren’s National Medical CenterWashington DCUSA
  2. 2.Department of NeurologyChildren’s National Medical CenterWashington DCUSA
  3. 3.Research Center for Genetic Medicine, Children’s National Medical CenterWashington DCUSA
  4. 4.Brain Tumor Institute, Children’s National Medical CenterWashington DCUSA
  5. 5.Department of Laboratory MedicineChildren’s National Medical CenterWashington DCUSA
  6. 6.Department of PathologyVanderbilt University Medical CenterNashvilleUSA
  7. 7.Department of PediatricsVanderbilt University Medical CenterNashvilleUSA
  8. 8.Department of Integrative Systems BiologyGeorge Washington UniversityWashington DCUSA
  9. 9.Department of PathologyThe Johns Hopkins HospitalBaltimoreUSA
  10. 10.Department of PathologyInova Fairfaix HospitalFairfaxUSA
  11. 11.Department of PathologySt. Jude Children’s Research HospitalMemphisUSA
  12. 12.Department of PathologyUniversity of South Carolina School of MedicineColumbiaUSA
  13. 13.Division of Pediatric Neuro-OncologyUniversity of Pittsburgh School of MedicinePittsburghUSA

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