This case was originally published in 2017. The information provided in this case was accurate and correct at the time of initial program release. Any changes in terminology since the time of initial publication may not be reflected in this case.
A previously well 15-year-old boy presented to his primary care physician complaining of daily headaches of increasing intensity. The pain was variable throughout the day, somewhat responsive to NSAIDs, and not associated with any nausea or vomiting. The patient was diagnosed with otitis media and prescribed antibiotics. Several weeks later, a routine eye examination revealed asymmetrical papilledema, and the patient was referred for imaging. CT identified a large left frontotemporal brain mass. Follow-up MRI revealed the mass to be poorly circumscribed, T2-bright, and heterogeneously contrast enhancing (Image A). Physical examination revealed a cranial nerve defect and impaired coordination. The patient underwent biopsy of the mass.
Brain, left temporal lobe
Whole Slide Image
The whole slide image provided is an H&E stained slide of left frontotemporal brain mass from a biopsy.
Which of the following is the BEST histologic diagnosis for this process?
Choroid plexus carcinoma
CNS embryonal tumor, NOS
Which of the following genetic findings would be MOST consistent with the given pattern of IHC staining?
H3F3A G34R mutation
1DH1 R132H mutation
Which of the following diagnostic categories would be indicated by a genetic finding of fusion of the RELA and C11orf95 genes?
Choroid plexus carcinoma
Discussion and Diagnosis
The best diagnosis in this case is glioblastoma, IDH-wildtype. Additional molecular genetic workup indicated the presence of point mutations in H3F3A (G34R), TP53, and ATRX. No IDH1 or IDH2 mutations were detected by sequencing. The MRI shows an infiltrative mass involving the left frontal and temporal lobes (Image A). H&E stained sections show infiltration of surrounding cortex and formation of secondary structures along blood vessels and around neurons (Image B) with necrosis and endothelial proliferation (Image C). Two patterns are visible among tumor cells (Image D); one is densely cellular and embryonal like, and the other is more glial and epithelioid in appearance. Immunohistochemically, the glial element expresses more GFAP (Image E) and the embryonal-like element expresses more synaptophysin (Image F). Both components show loss of ATRX reactivity (Image G) and express strong and diffuse p53 (Image H). Immunostaining for IDH1 R132H is negative (Image I).
The 2016 revision to the WHO Classification of Tumours of the CNS, 4th edition, generally categorizes adult diffuse gliomas, grades II to IV, along genetic lines into IDH-mutant or wildtype and 1p/19q codeleted or not. The loss of chromosome arms 1p and 19q is essentially definitional for oligodendrogliomas in the setting of an IDH mutation. The presence of IDH mutations in diffuse astrocytomas segregates them into two biologically distinct groups, with the mutant cases being lower grade, MGMT promoter methylated, and more responsive to treatment. These less aggressive IDH-mutant astrocytomas also generally have loss-of-function mutations in ATRX and TP53. Conversely, IDH-wildtype diffuse astrocytomas are clinically aggressive and generally do not have mutations in ATRX or TP53.
Pediatric infiltrating gliomas are substantially less common and represent a group of tumors that are genetically distinct from those of adults. IDH mutations are uncommon in pediatric gliomas and occur almost exclusively in adolescents, thus the vast majority of high-grade gliomas (HGG) in children are IDH-wildtype. Of those wildtype cases, a large subset is represented by the new WHO diagnostic entity diffuse midline glioma with H3 K27M mutation. These tumors are WHO grade IV regardless of histology, mostly found in the brainstem and thalamus, resistant to treatment, and usually fatal within nine months. By definition, these midline cases contain point mutations in codon 27 of genes H3F3A (encodes histone H3.3 protein), HIST1H3B, or HIST1H3C (both encode histone H3.1 protein) that all result in a lysine to methionine substitution (K27M).
The case in this exercise belongs to a subgroup of IDH-wildtype pediatric HGGs that occur in the cerebral hemispheres and consistently show mutations in the H3F3A gene. However, unlike the K27M-mutant midline cases, the hemispheric tumors have mutations in codon 34 that result in substitution of glycine with either arginine or valine (G34R/V). These tumors overwhelmingly harbor inactivating mutations in TP53 and ATRX. Adult lower grade diffuse astrocytomas also have TP53 and ATRX mutations, but nearly always in the context of IDH mutations and improved survival, similar to IDH-mutant glioblastomas. Although a small subset, H3F3A G34-mutant pediatric HGGs are important to recognize because they can present a difficult diagnostic challenge in that they frequently have an embryonal-like component that may be overrepresented in the biopsied material. A recent series showed a portion of CNS-embryonal tumors (originally diagnosed as CNS-PNET) by morphology and IHC were genetically H3F3A G34-mutant HGGs. Another series showed that tumors diagnosed as “CNS-PNET” and harboring G34 mutations had methylation profiles matching those of G34-mutant glioblastomas. The distinction between glioblastoma and embryonal tumor is critical because the latter are treated with multiagent chemotherapy and craniospinal radiation, whereas glioblastomas generally receive local radiation and temozolomide. Another subset of tumors diagnosed as “CNS-PNET” was shown to have RELA gene fusions, indicating that they are better classified as ependymoma with RELA fusion, a new diagnosis from the 2016 WHO CNS update.
The remaining, IDH-wildtype, histone 3-wildtype pediatric HGGs are genetically diverse and predominantly arise in the cerebral hemispheres. Based on DNA methylation profiling, most fall into either the “receptor tyrosine kinase type 1” (RTK I) or the “mesenchymal” patterns of glioblastoma. These groups are more similar to adult IDH-wildtype glioblastomas, frequently exhibiting monosomy of 10, gains of chromosome 7, and homozygous deletions of CDKN2A/B (p16). Amplifications of receptor tyrosine kinases, such as PDGFRA or EGFR, are present in some of these cases, though not as frequently as in adult glioblastomas. DNA methylation profiling has also identified “pleomorphic xanthoastrocytoma (PXA)-like” and “low-grade glioma (LGG)-like” patterns among cases histopathologically diagnosed as glioblastomas. In that series, both groups had three year survival rates comparable to anaplastic PXA and pilocytic astrocytoma.
Though rare, IDH-mutant glioblastomas in children are similar to those in adults and have median survival around two years. After removing PXA-like, LGG-like, and IDH-mutant cases, pediatric HGGs have similar outcomes as those in adults (median survival around 12 months) and receive similar treatment. Those occurring in the brainstem have the shortest survival, median around six to nine months. MGMT promoter methylation is thought to correlate with better prognosis and response to temozolomide, but the evidence is not as well established in children as in adults where the promoter methylation is more common. Most H3F3A G34-mutant HGGs exhibit methylation of the MGMT promoter, in spite of being globally hypomethylated.
Take Home Points
- Most pediatric diffuse HGGs are genetically distinct from their adult counterparts.
- A portion of pediatric hemispheric HGGs harbor H3F3A G34 mutations, TP53, and ATRX mutations.
- H3F3A G34-mutant HGGs frequently display an embryonal-like histomorphology.
- Most H3F3A G34-mutant HGGs are MGMT promoter methylated.
- IDH mutations are relatively rare in pediatric HGGs and associated with better outcomes.
- Gajjar A, Bowers DC, Karajannis MA, et al. Pediatric brain tumors: innovative genomic information is transforming the diagnostic and clinical landscape. J Clin Oncol. 2015;33:2986-98.
- Jones C, Karajannis MA, Jones DT, et al. Pediatric high-grade glioma: biologically and clinically in need of new thinking [Epub ahead of print]. Neuro Oncol. 2016 Jun 9.
- Korshunov A, Capper D, Reuss D, et al. Histologically distinct neuroepithelial tumors with histone 3 G34 mutation are molecularly similar and comprise a single nosologic entity. Acta Neuropathol.
- Neumann JE, Dorostkar MM, Korshunov A, et al. Distinct histomorphology in molecular subgroups of glioblastomas in young patients. J Neuropathol Exp Neurol. 2016;75:408-14.
- Sturm D, Orr BA, Toprak UH, et al. New brain tumor entities emerge from molecular classification of CNS-PNETs. Cell. 2016;164:1060-72.
- Sturm D, Witt H, Hovestadt V, et al. Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell.
- Which of the following is the BEST histologic diagnosis for this process?
- A. Anaplastic ependymoma
- B. Anaplastic ganglioglioma
- C. Choroid plexus carcinoma
- D. CNS embryonal tumor, NOS
- E. Glioblastoma
- Which of the following genetic findings would be MOST consistent with the given pattern of IHC staining?
- A. EGFR amplification
- B. H3F3A G34R mutation
- C. 1DH1 R132H mutation
- D. MYCN amplification
- E. PDGFR amplification
- Which of the following diagnostic categories would be indicated by a genetic finding of fusion of the RELA
and C11orf95 genes?
- A. Choroid plexus carcinoma
- B. Ependymoma
- C. Glioblastoma
- D. Medulloblastoma
- E. Pleomorphic xanthoastrocytoma