Astrocytoma, IDH mutant Grade 4

Case contributed by Frank Gaillard
Diagnosis certain



Patient Data

Age: 30 years

Note: This case was submitted prior to the 5th Editon of the WHO classification of CNS tumors and therefore uses earlier terminology in the pathology and discussion. The concept of "secondary glioblastoma" no longer exists, rather representing astrocytoma IDH-mutant grade 4 tumors

A large area of FLAIR hyperintensity involving both cortex and white matter is seen within the left frontal lobe, extending into the insular cortex and anterior temporal lobe. Abnormal signal just extends into the medial temporal structures on the left. No definite signal abnormality in the right anterior temporal lobe, although minor abnormality is not excluded with the amount of artefact present. Ill-defined areas of mild relative hyperdensity on the CT (not shown) at the anterior aspect of the FLAIR abnormality corresponds to subtle T2 hypointensity, with mild diffusion restriction, relative elevated CBV and equivocal mild enhancement, although there is a tiny focus of faint enhancement just adjacent to the anterior horn of the left lateral ventricle. Spectroscopy demonstrates decreased NAA and small lipid/lactate peaks with no definite significant elevated choline allowing for poor baseline. The lesion exerts moderate mass effect, with 5 mm of subfalcine herniation at the level of the septum pellucidum. There is mild effacement of the left lateral ventricle.

Conclusion: Large left frontotemporal abnormality involving both white matter and cortex produces moderate mass-effect as described. This most likely to represents a diffuse glioma.

First biopsy



The paraffin sections show cores of a moderately hypercellular glial tumor. This consists predominantly of moderately pleomorphic fibrillary astrocytes with a quantitatively smaller population of gemistocytic astrocytic cells. Tumor cells show moderate nuclear pleomorphism. No mitotic figures are identified. There is no vascular endothelial cell hyperplasia and no necrosis is seen.


  • GFAP positive
  • IDH-1 positive (R132H mutated)
  • MGMT negative (likely methylated)
  • p53 positive p16 positive
  • Topoisomerase labeling index: approximately 8%. 

FINAL DIAGNOSIS: Diffuse astrocytoma (WHO Grade II) with a gemistocytic component. 

MRI brain (4 months later)


Extensive high FLAIR signal is again seen involving the cortex and deep white matter of the left frontal lobe extending into the insular cortex to involve temporal lobe - distribution of signal abnormality is similar when compared to the previous scan, but there is increase in bulk and extent. Within the left frontal lobe, along the anterior margin of the FLAIR signal abnormality, there is nodular enhancement with two larger rounded enhancing foci (one centered within the left caudate head). These are far more conspicuous when compared to the previous scan. No evidence of diffusion restriction. Spectroscopy demonstrates increased choline/creatinine ratio with corresponding decreased NAA on today's study. Significant elevation CBV, particularly around the enhancing components is also observed on the perfusion sequences. Localized mass effect is again observed with partial effacement of left lateral ventricle. Stable subfalcine herniation. No hydrocephalus. No new lesion identified.

Conclusion: The large left frontotemporal region of signal abnormality demonstrates new areas of contrast enhancement and spectroscopy changes suggestive of higher grade (at least WHO Gd III), although in the setting of gemistocytes the presence of enhancement is harder to interpret.

Note: biopsy location appears to be posteroinferior to the current and previous location of enhancement, and therefore may have under-graded the tumor.

Second biopsy


MICROSCOPIC DESCRIPTION: Paraffin sections show fragments of a densely hypercellular astrocytic glioma. Tumor cells show marked nuclear and cellular pleomorphism. Frequent mitotic figures are identified and there is prominent microvascular proliferation. Foci of palisaded necrosis are also noted. The features are of glioblastoma (WHO Grade IV). Neither oligodendroglioma or PNET components are identified.


  • GFAP: positive
  • Nestin: positive
  • IDH-1 R132H: positive (mutated)
  • MGMT: negative (likely methylated)
  • p53: positive
  • p16: positive T
  • topoisomerase labeling index: approximately 30% 

FINAL AGNOSIS: secondary glioblastoma (WHO Grade IV) 

The patient went on to be treated with combined chemoradiotherapy (Stupp protocol).

MRI brain (2.3 years later)


Repeat MRI two years after the prior (second) resection, and combined chemoradiotherapy, demonstrates a significant reduction of mass effect, and ex-vacuo dilatation of the frontal horn of the lateral ventricle. There has, however, been the development of significant and fairly diffuse heterogeneous enhancement throughout the frontal lobe, with associated increase in CBV. This is in keeping with tumor recurrence / progression. 

Third biopsy


MICROSCOPIC DESCRIPTION: Sections show fragments of a moderately hypercellular astrocytic glioma. Tumor cells show moderate nuclear and cellular pleomorphism. Scattered mitotic figures are identified. There is prominent microvascular proliferation with multi-layering of atypical cells around vessel lumina. Areas of palisaded tumor necrosis are also identified.

Immunohistochemistry results show tumor cells stain:

  • GFAP Positive
  • Nestin Positive (high)
  • NogoA Positive
  • IDH-1 R132H Positive (mutated)
  • ATRX Negative (mutated)
  • MGMT Negative (likely methylated)
  • p53 Positive
  • p16 CDKN2A Negative
  • Topoisomerase labeling index: Approximately 30%.

Today's features, combined with the history of previously diagnosed low-grade glioma with confirmed IDH1 mutation are now consistent with the diagnosis of secondary glioblastoma.

Case Discussion

Although representing a minority of all glioblastomas, secondary glioblastomas are recognized and represent the eventual development of grade IV features in a previously grade II tumor. This is certainly suggested by the fact that this tumor is IDH1 mutated. The histology from the first biopsy may, however, have under-graded the tumor, due to not obtaining the enhancing component. This is not to say that this is not a secondary GBM, merely that it may already have been a GBM on the first study, but the highest component may have been missed. 

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