A 56-year-old woman is brought to the emergency department after a generalized tonic-clonic seizure witnessed by her husband. The patient has no history of seizures or other medical conditions but has been having recurrent headaches for the past several months. Physical examination shows mild weakness with increased deep tendon reflexes in the left upper extremity. MR imaging of the brain reveals a large mass in the right frontal lobe. Stereotactic biopsy of the mass yields hypercellular white matter with extensive astrocytic aberration, microvascular proliferation, and areas of necrosis lined by tumor cells. Molecular studies of the abnormal cells are most likely to demonstrate which of the following findings?
This patient's seizure, headache, motor weakness, and brain mass composed of abnormal astrocytes with necrosis and microvascular proliferation raises strong suspicion for glioblastoma (GBM), a highly aggressive tumor that stems from glial or pluripotent neural stem cells. A number of characteristic oncogenic mutations are usually present in GBM, but >95% of cases are associated with the overexpression of epidermal growth factor receptor (EGFR) on the surface of neoplastic cells.
EGFR is a tyrosine-kinase signal transduction system that conducts external growth signals into the nucleus, thereby promoting cellular survival and proliferation. Mutations that enhance this pathway (eg, overexpression of EGFR or EGFR-ligand) are associated with uncontrolled cellular proliferation and are seen in GBM and other cancer types (eg, non–small cell lung cancer, breast cancer, prostate cancer). Therefore, drugs that inhibit the EGFR/EGFR-ligand interaction (eg, erlotinib) are often used as part of treatment.
(Choice A) Tuberous sclerosis is an autosomal dominant disorder associated with abnormal tuberin and hamartin. It generally causes benign tumors in the skin (eg, ash-leaf lesions, angiofibromas), central nervous system (eg, subependymal giant cell astrocytomas [SEGA]), and other tissues. SEGA commonly presents as an intraventricular mass composed of large cells with abundant eosinophilic cytoplasm; necrosis and microvascular proliferation would be atypical.
(Choice B) Multiple endocrine neoplasia type 2 is an autosomal dominant disorder associated with constitutive activation to the RET proto-oncogene, leading to increased risk for medullary thyroid cancer, pheochromocytoma, and hyperparathyroidism. GBM is not classically linked to RET protein alterations.
(Choice C) Neurofibromatosis type 2 is due to mutations that inactivate the merlin tumor suppressor protein. It is associated with vestibular schwannomas and meningiomas; patients may also have eye and skin lesions. A frontal lobe mass would be unusual.
(Choice E) In immunosuppressed patients, primary CNS lymphoma often expresses Epstein-Barr virus (EBV) genes and is thought to be linked to EBV reactivation in B lymphocytes (the site of latent infection). However, biopsy would reveal atypical lymphoid cells, not astrocyte aberration.
Educational objective:
Glioblastoma is an aggressive primary brain neoplasm that generally presents with slowly worsening headache, seizure, and/or focal neurologic issues. Most cases are associated with oncogenic mutations that increase epidermal growth factor receptor expression on the tumor cells, leading to increased transduction of growth signals that promote cellular survival and proliferation.