CNS & pituitary tumors

Contributed by Shayan Anwar, M.B.B.S.

Contributed by Mohammad Khurram Minhas, M.B.B.S.

Contributed by Aisha Memon, M.B.B.S.

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• MAPK pathway gene alterations
  • Virtually all PXAs harbor alterations in a gene of the MAPK pathway, causing aberrant activation of this pathway
  • The most frequent is the missense mutation of BRAF p.V600E occurring in 60 - 80% of PXAs (Acta Neuropathol 2011;121:397, PLoS One 2011;6:e17948, Brain Pathol 2019;29:85, Brain Pathol 2021;31:20)
  • In BRAF p.V600E negative tumors, other MAPK pathway gene alterations are found, mostly involving other BRAF alterations (non-p.V600e mutations, non-KIAA1549::BRAF fusions), NTRK1, NTRK2, NTRK3, RAF1 or NF1 (Brain Pathol 2018;28:172)
• CDKN2A or CDKN2B homozygous deletion
  • ~94% of PXAs harbor homozygous deletions of CDKN2A / B (Brain Pathol 2019;29:85, Brain Pathol 2021;31:20)
  • Combination of BRAF p.V600E mutation and CDKN2A or CDKN2B homozygous deletion is highly suggestive of PXA, although rare cases of ganglioglioma, epithelioid glioblastoma and high grade astrocytoma with piloid features may also have this molecular profile (Acta Neuropathol Commun 2018;6:47, Brain Pathol 2018;28:656, Brain Pathol 2018;28:663, Acta Neuropathol 2018;136:273)
• TERT alterations
  • TERT promoter mutations and less commonly, TERT amplification have been found in PXA, more commonly in anaplastic tumors (Acta Neuropathol 2013;126:907)
  • Presence of canonical pTERT mutation has been shown to be a robust indicator for poor prognosis in methylation class PXA (Acta Neuropathol Commun 2022;10:5)
• Some PXAs can also harbor gain of chromosome 7 and loss of chromosome 10 (+7 / -10), similar to glioblastomas; however, unlike glioblastomas, PXAs virtually never demonstrate tyrosine kinase receptor gene amplifications (such as EGFR amplification) (Acta Neuropathol 2018;136:793)

A 25 year old man presented with history of recurrent headaches and seizures. Magnetic resonance imaging (MRI) scan revealed a solid circumscribed lesion in the temporal cortex with abnormal intensity. Biopsy revealed pleomorphic tumor cells with admixed xanthomatous cells and multinucleated giant cells. Eosinophilic granular bodies were noted along with reticulin rich network. There was no visible mitosis, microvascular proliferation or necrosis. On molecular testing, there was a BRAF p.V600E mutation. What is the most likely diagnosis?

1. Epithelioid glioblastoma
2. Ganglioglioma
3. Giant cell glioblastoma
4. Pleomorphic xanthoastrocytoma
5. Subependymal giant cell astrocytoma

D. Pleomorphic xanthoastrocytoma. The clinical scenario describes characteristic radiological, histological and genetic profile of pleomorphic xanthoastrocytoma. Answers A and C are incorrect because BRAF p.V600E mutation is reported in as many as 50% of glioblastoma with epithelioid morphology and rarely in giant cell glioblastoma; however, these show mitoses (including atypical mitoses) or microvascular proliferation and necrosis on histology. Answer B is incorrect because ganglioglioma also harbors BRAF p.V600E mutation but has distinctive morphology. Answer E is incorrect because subependymal giant cell astrocytoma (SEGA) may rarely show BRAF p.V600E mutation but has characteristic radiological and morphological features.

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Reference: Pleomorphic xanthoastrocytoma

A 20 year old woman presented with history of epileptic seizures. Magnetic resonance imaging (MRI) scan revealed a solid circumscribed lesion in the temporal cortex with abnormal intensity. Biopsy revealed characteristic histological features of pleomorphic xanthoastrocytoma including pleomorphic tumor cells with admixed xanthomatous cells, multinucleated giant cells and eosinophilic granular bodies. What is the most frequently mutated gene?

1. BRAF V600E
2. EGFR
3. Histone H3
4. IDH1
5. TERT promoter

A. BRAF V600E. The most frequently found mutated gene in PXAs is BRAF, which encodes an intracellular component of the MAPK pathway. Answers B and E are incorrect because EGFR and TERT promoter mutations are rare in low grade gliomas. These are characteristically seen in high grade astrocytomas. Answer D is incorrect because IDH1 is characteristically mutated in adult type diffuse gliomas. Answer C is incorrect because H3 K27M is altered in diffuse midline gliomas.

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Reference: Pleomorphic xanthoastrocytoma