Brain Tumors (Primary and Metastatic)

Risk factors

• Prior ionizing radiation to the head (strongest established environmental risk)
• Hereditary syndromes: neurofibromatosis 1 and 2, tuberous sclerosis, Li-Fraumeni, Lynch, Turcot, von Hippel-Lindau
• Immunosuppression (primary CNS lymphoma, especially in HIV)
• Female sex and hormonal exposure (meningioma express progesterone receptors)
• Known systemic malignancy with brain-tropic biology (lung, breast, melanoma)

Pathophysiology

Primary tumors arise from glial cells (astrocytes, oligodendrocytes, ependyma), arachnoid cap cells (meningioma), neurons, or embryonal precursors. Glioblastoma is characterized by IDH-wildtype status, TERT promoter mutations, EGFR amplification, and chromosome 7 gain / 10 loss. Metastatic disease seeds via hematogenous spread, typically lodging at gray-white junctions of watershed arterial territories. Mass effect, vasogenic edema, and disruption of the blood-brain barrier produce the clinical syndrome.

Clinical presentation

Differential diagnosis

• Brain abscess — Fever, ring-enhancing lesion with restricted diffusion on DWI, recent dental work, endocarditis, or sinus/otologic source
• Primary CNS lymphoma — Periventricular, deep gray, or corpus callosum involvement; homogeneous enhancement; restricted diffusion; HIV or immunosuppression; AVOID empiric steroids before biopsy
• Demyelinating disease (MS, tumefactive) — Open-ring enhancement, less edema than tumor, oligoclonal bands in CSF, age <50, prior episodes
• Ischemic stroke or subacute hemorrhage — Vascular territory, acute onset, evolution on serial imaging, no progressive growth
• Neurocysticercosis — Endemic exposure, multiple cystic lesions with scolex, calcifications, eosinophilia
• Subdural empyema or hematoma — Crescentic extra-axial collection, trauma or sinusitis history

Diagnostic workup

Diagnostic algorithm

flowchart TD
  A[New focal deficit,<br/>seizure, or<br/>progressive headache] --> B[MRI brain<br/>with contrast]
  B --> C{Single or<br/>multiple lesions?}
  C -->|Multiple, gray-white<br/>junction| D[Metastatic<br/>workup CT C/A/P]
  C -->|Single intra-axial<br/>infiltrative| E[Likely primary<br/>glioma]
  C -->|Extra-axial<br/>dural-based| F[Likely<br/>meningioma]
  D --> G[Find primary;<br/>SRS vs resection<br/>+ systemic Rx]
  E --> H[Resection +<br/>histology +<br/>molecular markers]
  F --> I[Observe vs<br/>resect vs SRS<br/>by size and grade]
  H --> J[Stupp protocol<br/>if GBM]

Treatment

Complications

• Cerebral herniation (uncal, central, tonsillar) — neurosurgical emergency
• Status epilepticus
• Hydrocephalus from CSF outflow obstruction
• Radiation necrosis (months to years post-RT, may mimic recurrence on imaging)
• Chemotherapy toxicity (cytopenias, hepatotoxicity, PCP pneumonia with prolonged steroids)
• Cognitive decline from disease and treatment

PANCE pearls

• Ring-enhancing lesion in an adult: MAGIC DR mnemonic — Metastasis, Abscess, Glioma, Infarct (subacute), CNS lymphoma (in immunocompromised), Demyelination, Radiation necrosis.
• Multiple ring-enhancing lesions at gray-white junction in a smoker = metastatic disease until proven otherwise.
• Steroids dramatically shrink lymphoma — withhold until tissue is obtained or diagnosis becomes obscured.
• MGMT promoter methylation predicts temozolomide response in GBM.
• Meningiomas calcify, often have a dural tail on MRI, and are typically extra-axial.

References

• WHO 2021 — Louis DN et al. The 2021 WHO Classification of Tumors of the Central Nervous System. Neuro-Oncology 2021;23:1231-1251.
• NCCN — NCCN Clinical Practice Guidelines in Oncology: Central Nervous System Cancers (current version).
• Stupp Trial — Stupp R et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. NEJM 2005;352:987-996.
• ASCO/SNO/ASTRO 2022 — Vogelbaum MA et al. Treatment for Brain Metastases: ASCO-SNO-ASTRO Guideline. J Clin Oncol 2022;40:492-516.