Case 78

A 20 year old male with a right brain mass

1. If the tumor cells are IDH negative, SOX10 positive, overexpression of P53, and ATRX loss, what's the most likely diagnosis?

   A: IDH wild type glioblastoma

   B: Lymphoma

   C: Repeat IDH2, favor IDH mutated glioma

   D: Diffuse hemispheric glioma, H3G34 mutant

   E: Diffuse midline glioma, H3 K27–altered

   F: MPNST

   
   

Answer

The correct answer is D. Sections of the entirely submitted specimens show a highly to densely cellular infiltrating neoplasm. Tumor cells are arranged in sheets with focal vague perivascular clearing and exhibit prominent secondary structuring in regions of infiltrated neocortex with perineuronal satellitosis and perivascular spread. Naked tumor nuclei are fairly uniformly round to ovoid but enlarged, hyperchromatic, and densely packed so as to focally resemble a ‘round blue cell’ tumor or embryonal morphology. Scattered microcalcifications are noted. Mitoses are numerous with 5 identified in a single randomly selected HPF. There is multifocal microvascular proliferation, as well as pseudopalisading necrosis and geographic necrosis with dead blood vessels. Immunohistochemistry is performed showed that tumor cells diffusely express SOX10 and many have scant rims of cytoplasmic GFAP positivity, confirming glial origin. The tumor is negative for Olig2. Synaptophysin highlights overrun neuropil but is largely negative within the tumor. IDH1 R132H is negative. P53 is diffusely overexpressed and there is loss of nuclear ATRX. A Ki67 highlights up to 60% of nuclei in select HPFs.

H3 G34-mutant diffuse hemispheric glioma 

Histopathology:

• Morphology: The tumor can present in two main patterns:

  1. Glioblastoma-like pattern: Highly cellular, infiltrative, with brisk mitotic activity. Microvascular proliferation and necrosis are common but not mandatory for diagnosis. Multinucleated and pleomorphic cells might also be seen.

  2. Embryonal-like pattern: Small, monomorphic cells with hyperchromatic nuclei and scant cytoplasm. Rarely, Homer Wright rosettes can be observed. This pattern generally shows less microvascular proliferation and necrosis.

• Ganglion cell differentiation: This is rare but has been reported in some cases.

Immunophenotype:

• Positive markers:

  • MAP2 and FOXG1 are typically positive, which can help differentiate this tumor from other gliomas.

• Negative markers:

  • ATRX expression is lost.

  • OLIG2 is negative, which is a distinguishing feature from other gliomas, where OLIG2 is usually expressed.

• p53: There is nuclear accumulation in the majority of tumor cells, which is a hallmark of p53 mutation.

• GFAP: This shows variable expression. In cases with a more primitive embryonal-like morphology, GFAP can be negative.

• Ki-67: The proliferation index is typically high, reflecting the tumor’s aggressive nature.

Mutation-specific testing:

• H3 G34 mutations (p.G35R and p.G35V) are critical to diagnosis. Mutation-specific antibodies are available, but false negatives have been reported.