Brain Metastases: Classification, Etiology, Symptoms, Diagnosis, Treatment and Prognosis

Metastases are the most common intracranial tumors in adults, occurring more frequently than primary brain tumors. In most cases, metastatic lesions of the brain are diagnosed following an already established systemic malignant process, but in some patients it may be the first manifestation of the tumor.

Etiology

5 primary tumors are responsible for ~80% of all brain metastases:

• Lung cancer (30–60% of all brain metastases).
• Breast cancer (10–30% of all metastases).
• Melanoma (5–20% of all metastases). At the same time, melanoma has the highest individual rate of metastasis to the brain — 25–60% of patients with disseminated melanoma are found to have a brain lesion.
• Kidney cancer (5–10% of all metastases).
• Colorectal cancer (1–3% of all metastases).

Metastases in the brain are predominantly formed hematogenously; the cells penetrate the blood-brain barrier and linger at the gray-white matter interface due to the vascular features of this area.

Epidemiology

At the time of initial diagnosis, brain metastases are found in approximately 2% of all patients with all tumor types and 12–15% of patients with already advanced (metastatic) disease.

During the course of the disease, brain metastases develop in 10–30% of patients with solid malignancies. For some types of neoplasms, the incidence can be as high as 40–50% in high-risk groups (HER2+ and triple-negative breast tumors, melanoma, non-small cell lung cancer).

Autopsy studies show that brain metastases are found in about 25% of patients with cancer, even if they were not detected during life.

Leptomeningeal metastases (along meninges) are more common in breast cancer, melanoma, lymphoma, and non-small cell lung cancer.

Anatomy

The majority (80%) of CNS metastases are located supratentorially, i.e. affect the hemispheres of the brain.

Up to 20% are located infratentorially (cerebellum, brainstem). Meninges are involved in up to 8% of cases.

The most common localization of metastases is the gray-white matter interface.

Classification of brain metastases

By number of metastatic foci

• Solitary — 1 foci;
• Oligometastases — 2–4;
• Multiple — ≥5 foci (≥10 in some classifications).

This assessment is used when choosing between radiosurgery (SRS), whole brain radiation therapy (WBRT), and surgery.

By size

• Small — <10 mm;
• Medium — 10–30 mm;
• Large — larger than 30 mm.

Small foci are available for stereotactic radiosurgery (SRS). Medium-sized foci (10–30 mm) usually imply dose constraints for single stereotactic radiosurgery (or require fractionation), and foci >30 mm are often considered for surgical removal or fractionated radiosurgery (large total dose is broken down and delivered in multiple steps), as single-fraction SRS in such cases carries a high risk of radionecrosis and edema.

By structure of metastasis

• Solid metastasis is the typical form, parenchymatous foci (characteristic of lung, breast, kidney, and melanoma cancers).
• Cystic metastasis presents as an almost entirely fluid (anechogenic or hypointense on T1 MRI) component with a thin wall and minimal solid area, usually indicating slow growth. This type of metastasis is most characteristic of papillary thyroid cancer and mucinous carcinomas of the gastrointestinal tract.
• Cystic-solid metastasis is a mixed structure, contains both a distinct fluid component and a prominent solid area, often with uneven contrast accumulation (HER2+ breast cancer, colorectal cancer, EGFR+ non-small cell lung cancer, renal cancer).
• Hemorrhagic metastasis: at high risk of hemorrhage (melanoma, kidney cancer, choriocarcinoma).
• Leptomeningeal metastases: dissemination through the liquor (HER2+ and triple-negative breast cancer, non-small cell lung cancer, melanoma, medulloblastoma).

Clinical significance of the structure of metastasis

• Cystic and hemorrhagic metastases are more likely to cause cramping and edema, with an increased risk of brain herniation.
• Large cystic metastases do not respond well to SRS and more often require surgery.
• Hemorrhagic (melanoma, kidney cancer) may recur more often after SRS, have high risk of hemorrhage.

Clinical manifestations

Symptoms depend on the size, localization, growth rate and number of foci, as well as the involvement of liquor spaces and brain edema. The debut is usually acute or subacute.

Symptoms of metastatic brain lesions

• Headache 35–70% (due to intracranial hypertension);
• Focal neurologic symptoms 30–60% (motor deficit, aphasia, etc.);
• Seizures 15–35% (more common in cortical lesions, especially temporoparietal and frontal lobes; frequency is higher in melanoma and kidney metastases);
• Cognitive impairment and behavioral changes 20–40% (associated with frontal foci, edema, elevated ICP);
• Nausea and vomiting 15–30% (especially in the morning);
• Coordination and gait disorders (ataxia) 10–25% (cerebellar and brain stem metastases);
• Visual disturbances (hemianopsia, diplopia) 10–20% (occipital lobe, brain stem or cranial nerves affected).

Influence of focal localization on clinical manifestations

• Frontal lobe: behavioral changes, abulia, motor and speech disorders;
• Parietal lobe: motor and sensory disturbances, seizures;
• Temporal lobe: speech disorders (aphasia), seizures, auditory hallucinations;
• Occipital lobe: visual disturbances;
• Cerebellum: ataxia, dizziness, vomiting;
• Brain stem: dysarthria, diplopia, facial nerve paresis.

Up to 20–30% of metastases are asymptomatic and are detected by imaging to clarify the diagnosis.

Acute and threatening symptoms

Acute impairment of consciousness / seizure status / severe vomiting + headache may indicate the following:

• Dislocations (herniation) of the brain;
• Decompensation with increasing cerebral edema;
• Hemorrhage (typical in melanoma, kidney cancer, choriocarcinoma);
• Obstructive hydrocephalus (with infratentorial tumors of the posterior cranial fossa).

These conditions require emergency measures (seizure control, anti-edema therapy, emergency imaging [CT/MRI with contrast] and probably emergency neurosurgical intervention).

Diagnosis of brain metastases

Main methods

• MRI with contrast is the gold standard. The method is the most sensitive and allows detecting even small (5 mm) and asymptomatic metastases.
• CT with contrast is an alternative when MRI is contraindicated. The method is less sensitive, but well detects large foci, hemorrhages, pronounced mass effect.

Additional methods

• PET-CT, biopsy (in case of diagnostic doubts).
• Assessment of the patient’s systemic status as a standard for staging and cancer screening (chest, abdominal and pelvic CT, PET-CT).
• The molecular profile of the metastasis (EGFR, ALK, HER2, BRAF, etc.) is determined after obtaining histologic material and has a direct impact on the choice of systemic therapy and prognosis.

Differential diagnosis

Differential diagnosis is performed with other focal lesions of the brain. The key features suggestive of metastases are the presence of a known primary cancer history, multiple foci, their typical localization at the gray-white matter interface (corticosubcortical), severe perifocal edema, and clear annular enhancement on MRI with contrast.

The main conditions the metastases should be differentiated with:

Primary brain tumor

Gradual onset, focal neurologic symptoms, seizures, headache. On MRI, there is usually an infiltrative or solid mass (often solitary, as opposed to metastasis), edema, mass effect, and heterogeneous contrast accumulation.

Brain abscess

Often fever, leukocytosis, and a focus of infection (otitis media, sinusitis, bacteremia). Mimics the tumor on MRI (also has annular enhancement) but has clear diffusion restriction (DWI+) in the center. MR spectroscopy reveals specific amino acids/metabolites.

CNS lymphoma

On MRI, homogeneous enhancement and location in deep brain structures, especially in immunosuppressed patients. High diffusion restriction (DWI+), possible rapid regression after steroids, so it’s important to avoid them before biopsy.

Radiation necrosis

It occurs months to years after radiation therapy, may mimic a recurrence or new metastasis. Distinguished by MR perfusion and PET (necrosis means hypoperfusion, hypometabolism), may decrease on steroids.

Multiple sclerosis

(especially the tumor-like form). Young age, multifocal lesions in the white matter, FLAIR-hyperintense without mass effect or contrast; clinical course is recurrent, with remissions, often in the young.

Stroke

(especially in the subacute phase when there may be ring-shaped enhancement). Sudden onset, focal neurologic deficit, ischemic area visible on DWI/ADC MRI (diffusion restriction), more often localized across vascular basins.

Aneurysm

Sudden headache, on CT/MRI with contrast — vascular mass, on angiography — dilated artery, subarachnoid hemorrhage.

Encephalitis

Subacute onset, fever, confusion, and seizures — no focal mass. On MRI, changes are usually diffuse, often in the temporal lobes (e.g., in herpetic encephalitis), with no mass effect.

Cavernous sinus thrombosis

Acute onset with headache (often unilateral), eyelid swelling, ophthalmoplegia, and decreased vision. MRI/MR venography reveals thrombus in the venous sinuses. There is often infection of the facial, nasal, and sinus areas.

Cluster headache

Sharp pain around the eye, lacrimation, rhinorrhea, lasting minutes, recurring in series, not accompanied by neurologic deficit. No structural changes on the MRI.

Idiopathic hydrocephalus

Often in the elderly, a triad of symptoms (gait disturbance, dementia, urinary incontinence), there may be headache and nausea, on MRI ventricular dilation without focal masses.

Metabolic disorders

Causes diffuse rather than focal symptoms (confusion, seizures, tremors), with no focal mass on MRI. General tests (glucose, sodium, liver enzymes, creatinine, urea, etc.) help identify the cause.

Treatment of metastatic brain lesions

The main methods of treatment

• Surgical removal or biopsy to clarify the diagnosis;
• Stereotactic radiosurgery (SRS);
• Whole Brain Radiation Therapy (WBRT);
• Systemic (more often targeted) therapy for specific tumor types (e.g., EGFR+, ALK+, BRAF+, etc.).

General principles

• Personalization of the strategy depending on the number of foci, patient functional status, systemic disease control, and molecular subtype of the tumor.
• Symptomatic treatment: glucocorticoids, anticonvulsants, anticoagulants, etc.

Treatment for solitary metastases

• Surgery: for large, symptomatic, superficial (i.e., available for removal), life-threatening foci. Increases life expectancy in patients with good performance status.
• SRS (stereotactic radiosurgery) is an alternative for hard-to-reach or small foci (<3 cm), effective both after surgery and as a stand-alone method. Sometimes used before surgical removal to reduce the likelihood of recurrence.
• WBRT (whole brain radiation therapy): as adjuvant (after surgery) and/or when SRS and surgical treatment are not possible.

Treatment for multiple metastases

• Up to 4 foci (<3 cm each) — preferably SRS;
• 5–10 foci — SRS is acceptable in selected patients;
• >10 foci or >3 cm — WBRT remains the standard.

WBRT (whole brain radiation therapy): effectiveness and side effects

The effect of whole brain radiation therapy (WBRT) is to control (stabilize) intracranial foci and reduce the incidence of intracranial recurrences.

It is used in multiple (>10) metastases and when SRS is not possible, and in leptomeningeal lesions.

Side effects:

• Cognitive decline;
• Leukoencephalopathy (diffuse lesion of the white matter of the brain);
• Radiation necrosis (its likelihood increases with repeated radiation therapy).

Modern approaches: use of memantine (NDMA antagonist) and Intensity-Modulated Radiation Therapy (IMRT) with hippocampal exclusion reduce the risk of cognitive impairment.

The role of drug therapy

Challenges of drug treatment of brain metastases:

1. Hematoencephalicbarrier (BBB):

• A physiologic filter that prevents most chemotherapy agents from penetrating brain tissue. Most classical cytotoxic agents (cisplatin, paclitaxel, docetaxel) have low permeability through the BBB.
• It’s partially altered in the area of metastasis, but not always sufficient for effective drug concentration.

2. Heterogeneity of the tumor.

• The molecular profile of metastases may differ from the primary tumor.

3. The immunoprivileged environment of the brain.

• Less activity of T cells and antigen-presenting cells limits the efficacy of immunotherapy.

Targeted therapy shows encouraging results (intracranial control can reach more than 50–80%). It is used for tumors with potential sensitivity to therapy (e.g., lung cancer with EGFR/ALK, melanoma with BRAF, HER2+ breast cancer). The use of targeted therapies or immunotherapy may delay or replace radiation therapy.

Immunotherapy (PD-1/PD-L1 inhibitors) may be effective in metastatic non-small cell lung cancer, melanoma and HER2+ breast cancer.

CAR-T therapy targets tumors expressing certain antigens different from normal brain tissue and has shown encouraging results in clinical trials, but is not yet routinely used (the method is undergoing clinical trials and is currently experimental in CNS oncology; studies are limited due to the risk of systemic toxicity and unpredictable effects in the CNS).

Prognosis in brain metastases

The Disease-Specific Graded Prognostic Assessment (ds-GPA) scale is the most accurate prognostic tool for metastatic brain lesions. It considers biological and molecular characteristics of primary tumors (in addition to age, KPS functional status, number of brain metastases, and extracerebral metastases that are standard for GPA).

The scale is used for metastatic brain lesions in lung cancer, melanoma, breast cancer, kidney cancer, and colorectal cancer.

In practice, rigid and universal prognostic schemes should be avoided in metastatic brain lesions, preferring an individualized approach based on the type of primary tumor, molecular profile, functional status of the patient, and available treatments.

Modern treatment of metastatic brain lesions requires a multidisciplinary approach based on the type of primary tumor and molecular characteristics of the metastasis, the number and localization of foci, and the general condition of the patient. SRS and targeted therapies are becoming the treatment of choice in most patients with limited metastases and sensitive tumors.