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2019 NPB-09

This case was originally published in 2019. 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.

Clinical History

A previously healthy 14-year-old boy presents to the emergency department with new-onset emesis and headache. MRI reveals a 3-cm enhancing lesion within the lateral aspect of the right frontal hemisphere. A surgical biopsy is performed.

Tissue Site
Right frontal lobe

Whole Slide Image

The whole slide image provided is an H&E-stained slide of the right frontal lobe of the brain from a brain biopsy.

Questions

  1. What is the MOST likely diagnosis?

    1. Atypical teratoid rhabdoid tumor

    2. Glioblastoma

    3. Medulloblastoma

    4. Metastatic carcinoma

    5. Primary central nervous system (CNS) anaplastic lymphoma

  2. Which of the following is MOST accurate about pediatric midline gliomas with H3 K27M histone mutations?

    1. They are classified as grade IV gliomas regardless of histologic appearance.

    2. They have a better prognosis than pediatric gliomas without the mutation.

    3. They often show IDH1 mutations.

    4. They only occur in the brainstem.

    5. They usually resemble pilocytic astrocytomas.

  3. H3 G34R/V mutations are found in which of the following?

    1. Ependymoma

    2. High-grade gliomas

    3. Low-grade gliomas

    4. Medulloblastoma

    5. Primary CNS anaplastic lymphoma

View Answer Key

Discussion and Diagnosis

High-grade gliomas are the most common primary CNS neoplasm in the adult population and can also be seen, less commonly, in the pediatric population. In the last decade, an abundance of information has emerged in the medical literature describing some of the genetic alterations encountered in pediatric high-grade gliomas and other primary CNS neoplasms. This information is essential to providing clues about the pathogeneses of these deadly diseases, how they will progress, and how they might be treated.

The most recent World Health Organization (WHO) classification of tumors of the CNS describes pediatric diffuse astrocytomas by an integrated approach that uses tumor location, histopathological features, and molecular/genetic alterations to establish a pathological diagnosis. As such, several new glioma entities have been introduced, including diffuse midline glioma, H3 K27M mutant. This tumor occurs (as the name implies) in the midline (eg, brainstem, thalamus, and spinal cord). Also, by definition, it has a mutation in one of the histone H3 genes conferring a K27M substitution in either H3F3A or HIST1H3B/C gene products. Diffuse midline gliomas show an infiltrative growth pattern and may or may not have mitoses, endothelial proliferation, and necrosis. Regardless of the histologic features, they are designated as WHO grade IV and portend a poor prognosis with two-year survival rates of less than 10%.

Another hotspot mutation in the H3F3A gene found within some pediatric high-grade gliomas confers either a G34R or G34V substitution in the gene product. Gliomas with this genetic alteration tend to occur in the cerebral hemispheres rather than in midline locations. They usually occur in older children or young adults in contrast to the K27M cases (median age is 13 to 14 years for G34R/V subtypes and 6 to 7 years for K27M cases). Prognosis for G34R/V gliomas is still poor but somewhat better than the K27M gliomas (median survival of 24 months for G34R/V and 12 months for K27M). Because a separate distinct entity of “diffuse gliomas with G34R/V mutations” is not recognized in the 2016 version of the WHO Classification of Tumours of the Central Nervous System, the appropriate way to indicate a diagnosis for this entity is to use the histopathological features to establish the subtype of astrocytoma, followed by the molecular classification. These should not be lumped with other IDH-wildtype gliomas as they carry a disease-defining genetic alteration that portends aggressive behavior regardless of the histologic appearance. In the example presented in the current case, there is a dense infiltrate of astrocytic tumor cells with moderate pleomorphism and endothelial proliferation (Image A, right side of panel). Tumor cells are immunoreactive for GFAP (Image B). This tumor shows increased p53 expression (Image C) and loss of ATRX immunostaining (Image D), typical findings for this entity. An immunostain for G34R/V is also immunoreactive, indicating either a G34R or G34V alteration (Image E). Therefore, an appropriate diagnosis would be “glioblastoma, H3 G34R or G34V (by IHC) mutant, WHO grade IV.” Sequencing analysis could be performed to further distinguish these genetic alterations and the diagnosis updated accordingly.

Image A: H&E stain.

Image A: H&E stain.

Image B: IHC stain, GFAP.

Image B: IHC stain, GFAP.

Image C: IHC stain, p53.

Image C: IHC stain, p53.

Image D: IHC stain, ATRX.

Image D: IHC stain, ATRX.

Image E: IHC stain, G34RV (cocktail antibodies recognizing both G34R and G34V mutated gene products).

Image E: IHC stain, G34RV (cocktail antibodies recognizing both G34R and G34V mutated gene products).

Glioblastoma, H3 G34R or G34V (by IHC) mutant, WHO grade IV

Take Home Points

  • Molecular alterations within pediatric diffuse gliomas are variable and often define pathobiological behavior of the tumors.
  • Molecular testing is essential in pediatric diffuse gliomas, as pathological behavior does not always correlate with histological appearance alone.
  • In a diffuse midline glioma, regardless of the histologic features, tumors with H3 K27M alterations are designated as WHO grade IV and portend a poor prognosis.

References

  1. Brat, DJ, Aldape K, Colman H, et al. cIMPACT‐NOW update 3: recommended diagnostic criteria for “Diffuse astrocytic glioma, IDH‐wildtype, with molecular features of glioblastoma, WHO grade IV”. Acta Neuropathologica. 2018:136:805-10.
  2. Jones, C, Baker, SJ. Unique genetic and epigenetic mechanisms driving paediatric diffuse high-grade glioma. Nat Rev Cancer. 2014;14:651-61.
  3. Louis D, Ohgaki H, Wiestler OD, et al. WHO Classification Of Tumours Of The Central Nervous System. Lyon, France: International Agency For Research On Cancer; 2016.

Answer Key

  1. What is the MOST likely diagnosis?
    A. Atypical teratoid rhabdoid tumor
    B. Glioblastoma
    C. Medulloblastoma
    D. Metastatic carcinoma
    E. Primary central nervous system (CNS) anaplastic lymphoma
  2. Which of the following is MOST accurate about pediatric midline gliomas with H3 K27M histone mutations?
    A. They are classified as grade IV gliomas regardless of histologic appearance.
    B. They have a better prognosis than pediatric gliomas without the mutation.
    C. They often show IDH1 mutations.
    D. They only occur in the brainstem.
    E. They usually resemble pilocytic astrocytomas.
  3. H3 G34R/V mutations are found in which of the following?
    A. Ependymoma
    B. High-grade gliomas
    C. Low-grade gliomas
    D. Medulloblastoma
    E. Primary CNS anaplastic lymphoma
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