CNS & pituitary tumors

Gliomas, glioneuronal tumors, and neuronal tumors

Pediatric type diffuse low grade gliomas

Diffuse low grade glioma, MAPK pathway altered



Last author update: 5 May 2022
Last staff update: 5 May 2022

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PubMed Search: Diffuse low grade glioma, MAPK pathway altered OR pediatric low grade glioma[title]

Mariana Voudouri, M.D.
George Zanazzi, M.D., Ph.D.
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Cite this page: Voudouri M, Zanazzi G. Diffuse low grade glioma, MAPK pathway altered. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/cnstumordiffuselowgradegliomaMAPK.html. Accessed November 29th, 2023.
Definition / general
  • Low grade, infiltrative, pediatric glioma with an alteration in a MAP kinase pathway gene such as FGFR1 or BRAF
  • Tumor is IDH wild type, histone H3 wild type and does not have a homozygous deletion of CDKN2A
Essential features
  • Predominantly in children
  • Arises anywhere in the central nervous system, often in the cerebral hemispheres or posterior fossa
  • Histopathologically heterogeneous, often resembling low grade astrocytoma or oligodendroglioma
  • MAP kinase pathway alteration without alterations in IDH1 / IDH2, histone H3 or homozygous deletion of CDKN2A
Terminology
  • Pediatric low grade glioma
  • Formerly, pediatric oligodendroglioma or diffuse astrocytoma
ICD coding
  • ICD-10:
    • D33.0 - benign neoplasm of brain, supratentorial
    • D33.1 - benign neoplasm of brain, infratentorial
    • D43.0 - neoplasm of uncertain behavior of brain, supratentorial
    • D43.1 - neoplasm of uncertain behavior of brain, infratentorial
Epidemiology
  • Predominantly in children
  • Precise incidence data not yet available
Sites
  • Cerebral hemispheres, diencephalon, brainstem, cerebellum and spinal cord, with possible site predilections depending on histology and genetic alterations (Cancer Cell 2020;37:569)
Pathophysiology
  • Missense mutation, intragenic duplication or fusion may constitutively activate a receptor tyrosine kinase, such as FGFR or NTRK, leading to aberrant recruitment of the G protein RAS, which activates the RAF / MEK / ERK cascade (Acta Neuropathol Commun 2020;8:30)
  • Missense mutations in RAS or RAF (especially BRAF V600E) can cause gliomagenesis in the absence of an upstream alteration (Acta Neuropathol Commun 2020;8:30)
Etiology
  • Precise etiology is unclear
Clinical features
  • Symptoms related to increased intracranial pressure, such as headache, nausea and vomiting
  • May have site dependent neurological deficits
  • Longstanding epilepsy is common
Diagnosis
Radiology description
  • Diffuse lesion, highlighted by T2 FLAIR on MRI, with possible cystic elements
  • May be heterogeneously enhancing on MRI
Radiology images

Contributed by Mariana Voudouri, M.D. and George Zanazzi, M.D., Ph.D.

MRI coronal T2 brainstem tumor

MRI axial T2 / FLAIR right cerebellar tumor

MRI axial T1 post contrast right cerebellar flocculus tumor

Prognostic factors
  • Currently unclear but rarely undergo malignant transformation
Case reports
  • 9 year old boy with brainstem mass growing slowly over 8 years and low grade astrocytoma containing FGFR2-VPS35 fusion (Cold Spring Harb Mol Case Stud 2020;6:a005660)
  • 15 year old with seizure and temporal lobe mass containing oligodendroglioma-like cells and BRAF V600E mutation (Brain Pathol 2020;30:515)
  • 16 year old boy with developmental delay, germline 7q11.22 deletion and a low grade astrocytoma with BRAF V600E mutation in right temporal lobe (Clin Case Rep 2017;6:274)
Treatment
Gross description
Microscopic (histologic) description
  • General features: infiltrative, glial tumor cells without a neuronal component
  • BRAF V600 altered tumors tend to have densely fibrillary areas and microcalcifications (Acta Neuropathol 2015;130:575)
  • FGFR1 altered tumors tend to have oligodendrocyte-like cells, rare or no mitoses, no necrosis and no microvascular proliferation (Acta Neuropathol 2016;131:833)
  • In a large study excluding NF1 patients, 5.9% of pediatric low grade gliomas exhibited astrocytic differentiation and 3.0% exhibited oligodendroglial differentiation (Cancer Cell 2020;37:569)
Microscopic (histologic) images

Contributed by Mariana Voudouri, M.D. and George Zanazzi, M.D., Ph.D.

Astrocytic morphology

Pleomorphism

Oligodendroglial morphology

GFAP

ATRX

Ki67

Negative stains
Molecular / cytogenetics description
Sample pathology report
  • Brain tumor, right frontal lobe, resection:
    • Integrated diagnosis: diffuse low grade glioma, MAPK pathway altered
    • Histological diagnosis: diffuse astrocytoma, low grade
    • Molecular information:
      • IDH1 R132H: negative (immunohistochemistry; consistent with wild type)
      • H3 G34R / V: negative (immunohistochemistry; consistent with wild type)
      • CDKN2A: intact (fluorescence in situ hybridization)
      • BRAF V600E: positive (immunohistochemistry; consistent with mutation)
    • Comment: Sections demonstrate a diffusely infiltrating glioma with moderate cellularity. The tumor is composed of fibrillary astrocytic cells. No mitotic activity, microvascular proliferation or necrosis noted. No Rosenthal fibers or eosinophilic granular bodies are present. A CNS WHO grade has yet to be assigned.
Differential diagnosis
Board review style question #1

A nonenhancing tumor was discovered in the right frontal lobe of a 5 year old boy. Resection revealed fibrillary astrocytic tumor cells without mitotic activity, microvascular proliferation or necrosis. Tumor cells showed immunopositivity for Olig2 and GFAP. What molecular alteration would you expect?

  1. BRAF V600E
  2. Histone H3 G34R
  3. Histone H3 K27M
  4. IDH1 (R132H)
Board review style answer #1
Board review style question #2
An 8 year old girl with lower cranial nerve deficits was found to have a large, infiltrative, minimally enhancing lesion in the left cerebellum, cerebellopontine angle and extending to the thalamus. She underwent a biopsy. Targeted next generation sequencing of the tumor reveals a missense KRAS mutation. What signaling pathway is most likely to be activated in this tumor?

  1. EGFR
  2. MAP kinase
  3. TGF beta
  4. Wnt
Board review style question #2
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