Contributed by Wen Zhong, MD and Tom Pearce, MD, PhD
CLINICAL HISTORY
A man in his 30's presented to the emergency department following a tonic-clonic seizure with generalization. He had no history of prior seizures and denied any trauma, vision changes, imbalance, memory issues, weakness or paresthesia. Brain MRI discovered two separate areas of expansile T2 FLAIR hyperintensity, with discrete lesions seen in the left frontal lobe and right medial parietooccipital region. Neither lesion showed enhancement following administration of contrast. A CT scan of the chest, abdomen and pelvis revealed no evidence of primary malignancy. Given the radiological characteristics, multifocal glioma was suspected, with a differential diagnosis of acute disseminated encephalomyelitis and nonenhancing tumefactive multiple sclerosis. The patient subsequently underwent craniotomies for resection of both lesions with a 6-week interval.
IMAGING FINDINGS
Axial MRI T2 FLAIR: an expansile mass-like T2/FLAIR hyperintensity is seen in the centrum semiovale underneath the left superior frontal middle gyri (4x3 cm) and a second lesion is located in the medial aspect of the right occipital lobe at the region of the splenium (4x2 cm). There was abnormal parenchymal diffusion restriction, midline shift, or post-contrast enhancement (not shown). The intervening tissue between the lesions showed no MRI signal abnormalities.
MICROSCOPIC EXAMINATION
H&E stained sections of the left frontal lesion revealed a diffusely infiltrating glial neoplasm involving cortex and white matter. Many tumor cells had bland cytomorphology, but in some areas, increased nuclear pleomorphism and frequent gemistocytic appearance were appreciated. Mitotic figures were identified but necrosis and endothelial proliferation were absent. Sections from the right parietooccipital lesion also consisted with an infiltrating glial neoplasm composed of cells exhibiting round to ovoid nuclei with mild nuclear atypia. There were very sparse mitotic figures with no evidence of endothelial proliferation or tumor necrosis.
Immunohistochemically, many tumor cells in the frontal lesion showed starburst-like staining pattern by GFAP, which was different from the parietooccipital lesion, where a diffuse GFAP positivity was observed. Both neoplasms demonstrated diffuse expression of IDH1 R132H, but a positive clonal staining pattern of p53 protein was only seen in the frontal lesion, with nuclear positivity in greater than 70% of tumor cells, compared to faint nuclear staining in a subset of tumor cells in the parietooccipital lesion. ATRX in the frontal lesion demonstrated a biphasic pattern with decreased but not complete loss of nuclear staining in tumor cells with preserved strong nuclear reactivity in background non-neoplastic cells, whereas the nuclear positivity of ATRX was strongly retained in both tumor and normal in the parietooccipital lesion. The Ki67 proliferation index was considerably higher in the frontal lesion (up to 10%) than in the parietooccipital lesion (1% overall).
Molecular analysis was performed on both neoplasms. In addition to IDH1 R132H mutation predicted by immunohistochemical staining, the frontal lesion additionally harbored a TP53 mutation. Despite the abnormal ATRX immunostaining pattern, no ATRX mutation was identified. In contrast to the frontal lesion, the parietooccipital lesion contained a TERT promoter mutation, 1p/19q copy number loss and MGMT promoter methylation. Aside from IDH1 R132H, the two tumors did not share any additional pathologic mutations, insertions/deletions, or copy number alterations.
