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2018 NPB-16

This case was originally published in 2018. 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 63-year-old man presented with headache and new-onset seizure. MRI revealed a lobulated, enhancing mass in the right frontal lobe with focal cystic areas, surrounding edema, and mass effect on the frontal horn of the right lateral ventricle. He underwent right frontal craniotomy for tumor resection.

Tissue Site
Right frontal lobe

Whole Slide Image

The whole slide image provided is an H&E stained slide of the right frontal lobe from a craniotomy and resection.

Questions

  1. What is the BEST diagnosis?

    1. Anaplastic meningioma

    2. Fibrosarcoma

    3. Gliosarcoma

    4. Pleomorphic xanthoastrocytoma

    5. Solitary fibrous tumor/hemangiopericytoma

  2. What genetic abnormalities are typically seen in this entity?

    1. BRAF V600E mutations

    2. H3F3A K27M mutations

    3. IDH1 mutations and 1p/19q codeletion

    4. NAB2-STAT6 gene fusions

    5. TP53 mutations, PTEN mutations, and CDKN2A deletions

  3. Which histochemical marker is MOST helpful in diagnosing this case?

    1. Alcian blue

    2. Mucicarmine

    3. Oil red O

    4. PAS

    5. Reticulin

View Answer Key

Discussion and Diagnosis

Subsequent testing proved the tumor to be IDH-wildtype, establishing the diagnosis of gliosarcoma, IDH-wildtype, WHO grade IV, a variant of glioblastoma that is most commonly found in adults aged 40 to 60 years and is comprised of amalgamated gliomatous and sarcomatous components. Approximately 2% to 8% of glioblastomas are gliosarcoma. Gliosarcoma may arise de novo or develop following radiation treatment of glioblastoma. Neuroimaging of gliosarcoma shows features similar to glioblastoma.

Gliosarcoma has a characteristic biphasic histologic appearance with alternating or intermingled areas of glial and mesenchymal differentiation (Image A, Image B, Image C, and Image D). IHC for GFAP highlights the glial component (Image E and Image F) while the sarcomatous component is negative for GFAP. Conversely, pericellular reticulin staining is evident in the sarcomatous component (Image G) and not in the glial component. Mitotic activity is conspicuous in both components (Image H), and proliferative index, as illustrated by Ki67 IHC, is elevated (Image I). DNA sequencing typically shows no IDH1/IDH2 mutations.

Image A: H&E stain.

Image A: H&E stain.

Image B: H&E stain.

Image B: H&E stain.

Image C: H&E stain.

Image C: H&E stain.

Image D: H&E stain.

Image D: H&E stain.

Image E: GFAP, IHC stain.

Image E: GFAP, IHC stain.

Image F: GFAP, IHC stain.

Image F: GFAP, IHC stain.

Image G: Histochemistry, reticulin stain.

Image G: Histochemistry, reticulin stain.

Image H: H&E stain.

Image H: H&E stain.

Image I: Ki67, IHC stain.

Image I: Ki67, IHC stain.

Molecular studies have shown the morphologically distinct areas in gliosarcoma most likely arise from a monoclonal glial origin and do not result from so-called “collision” of two distinct but coexisting tumors. Documented molecular abnormalities include TP53 mutations, PTEN mutations, and CDKN2A deletions, and both mesenchymal and glial areas show similar molecular profiles. Most cases also show gains of chromosome 7, but EGFR amplification is infrequent. Prognosis is poor, like that of IDH-wildtype glioblastoma, with only a small percentage of patients surviving past five years. Treatment plans typically involve surgical excision followed by radiotherapy and chemotherapy. Gliosarcoma can be multifocal at presentation, invade the skull, and rarely demonstrate hematogenous metastasis outside the CNS.

Small biopsy specimens may not adequately demonstrate both neoplastic components, potentially bringing malignant meningioma, solitary fibrous tumor/hemangiopericytoma (SFT/HPC), sarcomas of various types, pleomorphic xanthoastrocytoma (PXA), and anaplastic astrocytoma into the differential diagnosis. The glial areas of gliosarcoma show characteristic features of glioblastoma, including hypercellularity, conspicuous mitotic activity, microvascular proliferation, and palisaded necrosis (Image J). SFT/HPC is a cellular, spindle-cell mesenchymal tumor that may arise in the CNS from meninges and may mimic a predominantly sarcomatous gliosarcoma. Tumor cells in SFT/HPC are nonreactive for GFAP IHC but are diffusely immunoreactive for STAT6 (nuclear). The vast majority of SFT/HPCs show NAB2-STAT6 gene fusion.

Image J: H&E stain.

Image J: H&E stain.

PXA (WHO grade II) and anaplastic PXA (WHO grade III) are meningocerebral astrocytic neoplasms most commonly seen in the temporal lobe in association with seizure disorders. More common in children and young adults than in older patients, PXA and anaplastic PXA exhibit variable histopathologic features, often including large xanthomatous glial cells with intracellular lipid inclusions. Eosinophilic granular bodies are frequently present, as are scattered aggregates of perivascular lymphocytes. Despite the pleomorphic appearance of PXA, mitotic activity is usually inconspicuous, and prognosis is generally favorable with five-year survival rates approaching 80%. Similar to gliosarcoma, reticulin histochemistry highlights pericellular basement membranes around individual tumor cells. In PXA, tumor cells show variable cytoplasmic GFAP immunoreactivity. The most common molecular alterations include BRAF V600E mutations and loss of chromosome 9.

Gliosarcoma, IDH-wildtype, WHO grade IV

Take Home Points

  • Gliosarcoma, IDH-wildtype, WHO grade IV, is a variant of glioblastoma.
  • Gliosarcoma has a characteristic biphasic histologic appearance with alternating or intermingled areas of glial and mesenchymal differentiation that are thought to arise from monoclonal glial cells.
  • Documented molecular abnormalities include TP53 mutations, PTEN mutations, and CDKN2A deletions, and both mesenchymal and glial areas show similar molecular profiles. Most cases also show gains of chromosome 7, but EGFR amplification is infrequent.

References

  1. Actor B, Cobbers JM, Buschges R, et al. Comprehensive analysis of genomic alterations in gliosarcoma and its two tissue components. Genes Chromosomes Cancer. 2002;34:416-27.
  2. Burger PC, Giangaspero F, Ohgaki H, Biernat W. Gliosarcoma. In: Louis DN, Ohgaki H, Wiestler OD, et al, eds. WHO Classification of Tumours of the Central Nervous System. Revised 4th edition. Lyon, France: IARC; 2016:48-9.
  3. Fritchie KJ, Jin L, Rubin BP, et al. NAB2-STAT6 gene fusion in meningeal hemangiopericytoma and solitary fibrous tumor. J Neuropathol Exp Neurol. 2016;75:263-71.
  4. Gokden M. If it is not a glioblastoma, then what is it? A differential diagnostic review. Adv Anat Pathol. 2017;24:379-91.
  5. Ida CM, Rodriguez FJ, Burger PC, et al. Pleomorphic xanthoastrocytoma: Natural history and long-term follow-up. Brain Pathol. 2015;25:575-86.
  6. Jain A, Correia J, Schweder P, et al. Analysis of outcomes of multidisciplinary management of gliosarcoma: A single-center study, 2000-2013. World Neurosurg. 2017;106:30-6.
  7. Reis RM, Konu-Lebleblicioglu D, Lopes JM, Kleihues P, Ohgaki H. Genetic profile of gliosarcomas. Am J Pathol. 2000;156:425-32.

Answer Key

  1. What is the BEST diagnosis?
    A. Anaplastic meningioma
    B. Fibrosarcoma
    C. Gliosarcoma
    D. Pleomorphic xanthoastrocytoma
    E. Solitary fibrous tumor/hemangiopericytoma
  2. What genetic abnormalities are typically seen in this entity?
    A. BRAF V600E mutations
    B. H3F3A K27M mutations
    C. IDH1 mutations and 1p/19q codeletion
    D. NAB2-STAT6 gene fusions
    E. TP53 mutations, PTEN mutations, and CDKN2A deletions
  3. Which histochemical marker is MOST helpful in diagnosing this case?
    A. Alcian blue
    B. Mucicarmine
    C. Oil red O
    D. PAS
    E. Reticulin
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