CNS Malignancies for internists

CNS Malignancy Primary brain tumors 2% of all cancers Mortality 4.6/100,000 person years Incidence increasing Brain mets can occur in up to 40% of all solid tumors PCNSL incidence increasing

Clinical presentation Headache Seizure Focal neurologic deficit Confusion Memory loss Personality change Nausea/vomiting

Differential Diagnosis Primary brain tumor Malignant Glioma Lymphoma Benign meningioma, adenoma, schwannoma Metastatic brain tumor Vascular Cerebellar hemorrhage: vascular anomaly, hypertensive, intratumoral Cerebellar infarct: embolic, thrombotic Infection: Abcess, virus, progressive multifocal leukoencephalopathy Inflammatory: Multiple sclerosis Post-infectious encephalomyelitis

T1 Contrast

Imaging Diagnosis Treatment planning Monitoring response CT MRI SPECT Functional MRI Monitoring response Diffussion-weighted, diffusion tensor, dynamic-contrast-enhanced, perfusion

Additional work-up History and physical for evidence of an extracranial primary or other disease Appropriate imaging to look for that primary Avoid corticosteroids if lymphoma or infection is suspected

Neurosurgery Who should get a biopsy? Alternate diagnosis? Diagnosis in question Results will influence management Do not need immediate relief of symptoms Non resectable; critical location Suspect low-grade glioma or PCNSL Alternate diagnosis? 11% of 56 enrolled on surgery trial had alternate diagnosis on central pathology review Patchell RA, et al., A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 322:494-500, 1990.

Primary brain tumors

Primary Brain Tumors Malignant gliomas Others 70% of primary brain malignancy 14,000 cases/year in US Incidence increasing, esp. in elderly 40% more common in men Twice as common in whites Median age 64 (GBM) or 45 (AA) Others

Primary Brain Tumors Etiology Family history Ionizing radiation risk factor No association with head injury, food, occupation, electromagnetic fields, cell phones Reduced risk with atopy, high IgE levels Family history 5% are familial, most without known cause NF type 1 or 2, Li-Fraumeni syndrome, Turcot syndrome

Initial medical management Corticosteroids: oral dex 4-16 mg/day Anti-epileptics: leviteracitam VTE treatment/prophy Stimulants: modafenil, methylphenidate, donepezil, memantine Anti depressants

ANTI NEOPLASTIC THERAPY CORTICOSTEROIDS ANTI EPILEPTICS VTE TREATMENT/PROPHY ANTI NEOPLASTIC THERAPY STIMULANTS ANTI DEPRESSANTS

Anti-neoplastic therapy Surgery: maximal resection Radiotherapy: WBRT Chemotherapy: TMZ Stupp R, et al., Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005; 352:987-96.

MGMT promotor methylation (GMB) Molecular genetics MGMT promotor methylation (GMB) Decreased DNA repair activity Increased susceptibility to TMZ 1p 19q deletion (anaplastic oligodendrogliomas and anaplastic oligoastrocytomas) Increased sensitivity to PCV Reason unknown

Brain metastases

Brain metastases Common tumors Sites Rates Represent >50% of all intracranial tumors 40% of cancers will develop brain mets Common tumors Lung Breast melanoma Sites 90-95% solid parenchymal, 5-10% meningeal 37-50% solitary, 50-63% multiple

Brain Metastases Prognosis 1-6 month survival Improved by (RTOG prognostic index): Age <65 KPS >70 Controlled primary w/out extracranial mets Other favorable factors: Solitary met Response to corticosteroids Longer disease-free interval Breast cancer diagnosis

Differential diagnosis Brain metastases Differential diagnosis Primary brain tumor Infection Inflammation Demyelinating disorders Infarction Radiation necrosis

Brain Metastases Surgery + WBRT === SRS +/- WBRT But you must know: Surgery + WBRT >>> Surgery Reduced brain recurrance and neuro death Surgery + WBRT === SRS +/- WBRT But you must know: radiosensitivity of the tumor # of tumors Accessibility for resection

Leptomeningeal metastases

Leptomeningeal Metastases Diagnosis: MRI 76% sen, 77% spec (false pos with intracranial hypotension, infection, connective tissue disease, deymelinating disease) CSF 90% sen, 100% spec Prognosis: <3 months Treatment: Radiotherapy for bulky disease or CSF flow obstruction IT chemotherapy through Ommaya: MTX Lipsomal cytarabine Thiotepa

PCNSL

PCNSL Rare: 2.7% of all primary brain tumors Incidence increased 3-fold from 1978-84 Immunocompetent: male>female age >60 Immunodeficiency is only risk factor HIV 3,600-fold increased risk CD4+ cell count <50 cells/uL highest risk

PCNSL Site Histology 65% solitary 38% in hemispheres 20% occular involvement Histology DLBCL (90%) Low-grade lymphoma Burkitt’s lymphoma T-cell lymphoma

PCNSL Imaging: MRI preferred CSF: cytology, flow, IgH PCR Eye exam Rule out systemic disease Rule out testicular and bone marrow involvement Biopsy is essential

-- high WBC >7 cells/uL -- high protein -- low glucose Non con T2 CSF -- high WBC >7 cells/uL -- high protein -- low glucose Initial positive in only 15% Con T1

PCNSL International Extranodal Lymphoma Study Group Age >60 ECOG PS >1 Elevated LDH High CSF protein Deep location

PCNSL Chemotherapy: High dose MTX + IT MTX Radiotherapy: WBRT for those <60

Memory failure, gait ataxia, incontinence

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