# Brain Tumors: WHO Classification and Advanced Imaging

## Overview

### Approach to Brain Masses

The most fundamental distinction in brain tumor imaging is **intra-axial versus extra-axial**. Intra-axial masses arise within the brain parenchyma and include gliomas, metastases, and lymphoma. Extra-axial masses arise outside the brain parenchyma and include meningiomas, schwannomas, and epidermoid/dermoid cysts. Key MRI features for characterization include location, enhancement pattern, edema, mass effect, diffusion characteristics, perfusion, and spectroscopy.

### WHO Classification (2021 Update)

The 2021 WHO classification integrates molecular markers with histology for tumor classification. Key molecular markers include IDH mutation status, 1p/19q codeletion, MGMT methylation, and H3K27M mutation. Grading follows a WHO Grade 1-4 system based on histologic and molecular features.

## Intra-Axial Tumors

### Gliomas

#### Diffuse Astrocytoma (IDH-Mutant, WHO Grade 2-4)

IDH-mutant astrocytomas occur in younger patients (30-50 years) and carry a better prognosis than IDH-wildtype tumors. They appear as T2/FLAIR hyperintense lesions that may show minimal or no enhancement in Grade 2. Higher grades show progressive enhancement, necrosis, and edema. IDH-mutant Grade 4 astrocytoma is classified distinctly from glioblastoma (IDH-wildtype).

#### Oligodendroglioma (IDH-Mutant, 1p/19q-Codeleted)

Oligodendroglioma requires both IDH mutation and 1p/19q codeletion for diagnosis. It is classically cortically based with frontal lobe predominance. Calcification is common, present in approximately 70% of cases and best seen on CT. It appears as a T2/FLAIR hyperintense lesion with heterogeneous signal. Oligodendroglioma has a better prognosis and greater chemosensitivity compared to astrocytomas.

#### Glioblastoma (IDH-Wildtype, WHO Grade 4)

Glioblastoma is the most common and most aggressive primary brain tumor in adults. Its diagnosis requires IDH-wildtype status with specific molecular features (TERT promoter mutation, EGFR amplification, or +7/-10 chromosome changes). On imaging it presents as a large heterogeneous mass with thick irregular rim enhancement, central necrosis, and surrounding T2/FLAIR edema. The **butterfly glioma** pattern describes extension across the corpus callosum via white matter tracts. Restricted diffusion may be present in cellular areas. Importantly, the infiltrative non-enhancing component extends beyond the visible enhancing margin.

#### Diffuse Midline Glioma (H3K27M-Altered)

Diffuse midline glioma occurs in midline structures including the thalamus, brainstem, and spinal cord, predominantly in children and young adults. Previously called diffuse intrinsic pontine glioma (DIPG) when located in the pons, it appears as an expansile T2/FLAIR hyperintense lesion with variable enhancement. It is universally aggressive and classified as WHO Grade 4.

### Metastases

Metastases are the most common intracranial tumor overall in adults. Common primary tumors include lung, breast, melanoma, renal, and colon cancers. On MRI they are well-circumscribed, located at the gray-white junction (reflecting hematogenous spread), and show ring or solid enhancement with disproportionate vasogenic edema relative to lesion size. They are often multiple; a single metastasis must be differentiated from a high-grade glioma. Hemorrhagic metastases classically arise from melanoma, renal cell carcinoma, choriocarcinoma, and thyroid carcinoma (the "MR CT" mnemonic). Leptomeningeal carcinomatosis presents as enhancing leptomeningeal coating with communicating hydrocephalus.

### Primary CNS Lymphoma (PCNSL)

In immunocompetent patients, PCNSL presents as a solitary or few lesions in periventricular, deep gray matter, or corpus callosum locations. In immunocompromised patients (HIV/AIDS), it is often ring-enhancing and multifocal. In immunocompetent patients it shows homogeneous enhancement and restricted diffusion (reflecting hypercellularity). The key differentiator from glioblastoma is that lymphoma shows restricted diffusion and homogeneous enhancement, while GBM shows necrosis and rim enhancement. Steroids should not be given before biopsy because lymphoma may temporarily resolve, confounding the diagnosis (the "ghost tumor" phenomenon).

## Extra-Axial Tumors

### Meningioma

Meningioma is the most common extra-axial tumor and the most common primary intracranial tumor overall. It arises from arachnoid cap cells and is dural-based. Imaging features include a well-circumscribed mass with a broad-based dural attachment, homogeneous enhancement, the **dural tail sign** (thickened enhancing dura adjacent to the mass), a **CSF cleft** (trapped CSF between the tumor and brain surface), and common calcification. T2 signal is variable, with low signal indicating a fibrous tumor and high signal indicating a more cellular tumor. Common locations include the convexity, parasagittal region, sphenoid wing, olfactory groove, cerebellopontine angle, and tentorium. Atypical or malignant meningiomas show irregular margins, brain invasion, heterogeneous enhancement, and peritumoral edema.

### Schwannoma (Vestibular Schwannoma)

Schwannoma arises from Schwann cells of the vestibulocochlear nerve (CN VIII) and presents as a cerebellopontine angle mass extending into the internal auditory canal (the "ice cream on a cone" configuration). It shows homogeneous or heterogeneous enhancement. Bilateral vestibular schwannomas are pathognomonic for NF2. The key distinction from a meningioma is that a schwannoma is centered on the IAC, while a meningioma is dural-based.

### Epidermoid Cyst

An epidermoid cyst is a congenital inclusion cyst of ectodermal origin, with the cerebellopontine angle being the most common location. It is T1 hypointense and T2 hyperintense (similar to CSF) but restricts on DWI (unlike an arachnoid cyst). It does not enhance and insinuates around structures without displacing them.

## Advanced MRI Techniques

### MR Perfusion (DSC Perfusion)

| Lesion | rCBV | Key Application |
|--------|------|-----------------|
| High-grade glioma | Elevated (neoangiogenesis) | Grading gliomas |
| Low-grade glioma | Normal or mildly elevated | Distinguishing from high-grade |
| Lymphoma | Variable, often less than GBM | Differentiating from GBM |
| Metastases | Elevated in enhancing component | — |
| Radiation necrosis | Low | Distinguishing from recurrent tumor |
| Recurrent tumor | Elevated | Post-treatment surveillance |

MR perfusion measures relative cerebral blood volume (rCBV). **High-grade gliomas** show elevated rCBV due to neoangiogenesis. **Low-grade gliomas** show normal or mildly elevated rCBV. **Lymphoma** may have elevated rCBV but typically less than GBM. **Metastases** show elevated rCBV in the enhancing component. The most important clinical application is distinguishing **radiation necrosis** (low rCBV) from **recurrent tumor** (elevated rCBV).

### MR Spectroscopy (MRS)

MR spectroscopy measures metabolite concentrations. **Choline (Cho)** reflects cell membrane turnover and is elevated in tumors. **NAA (N-acetyl aspartate)** is a neuronal marker that decreases in tumors due to neuronal destruction. **Lactate** reflects anaerobic metabolism and is elevated in high-grade tumors and necrosis. **Lipid** reflects cell membrane breakdown and is elevated in necrosis and high-grade tumors. The **Cho/NAA ratio** is elevated in tumors and helps grade tumors and distinguish them from non-neoplastic processes. An **alanine peak** is characteristic of meningioma.

### Diffusion-Weighted Imaging (DWI)

Restricted diffusion (DWI bright, ADC dark) indicates high cellularity and is seen in lymphoma, epidermoid cysts, and abscesses. GBM typically does not show restricted diffusion except in cellular areas. DWI is particularly useful in distinguishing an abscess (central restricted diffusion) from a necrotic tumor (no central restriction).

### Diffusion Tensor Imaging (DTI) / Tractography

DTI maps white matter tracts for pre-surgical planning, showing whether a tumor displaces, infiltrates, or destroys tracts. It is critical for surgical planning near eloquent white matter such as the corticospinal tract and arcuate fasciculus.

<image>An MRI panel comparing the four most common adult brain tumors. (1) Glioblastoma: axial T1 post-contrast showing a large ring-enhancing mass with central necrosis in the right temporal lobe with surrounding edema and midline shift. (2) Metastasis: axial T1 post-contrast showing multiple ring-enhancing lesions at the gray-white junction with disproportionate surrounding edema. (3) Meningioma: axial T1 post-contrast showing a homogeneously enhancing extra-axial mass with a broad dural base and dural tail sign. (4) Primary CNS lymphoma: axial T1 post-contrast showing a homogeneously enhancing periventricular mass with restricted diffusion shown on DWI inset. Each tumor is labeled.</image>

<image>An MR spectroscopy comparison panel. Top: spectrum from a high-grade glioma showing elevated choline peak, decreased NAA peak, and presence of a lactate/lipid peak. Bottom: spectrum from normal brain tissue showing normal NAA (tallest peak), normal choline, and normal creatine for comparison. The choline/NAA ratio is annotated on each spectrum. Key metabolite peaks are labeled (Cho, Cr, NAA, Lac/Lipid) with their chemical shift positions (ppm).</image>

<image>An illustration showing the MRI features distinguishing extra-axial from intra-axial masses. Left: an extra-axial meningioma with labeled features including the CSF cleft between tumor and brain, broad dural base, dural tail enhancement, buckling of the gray-white junction, and displacement of cortical vessels between the tumor and brain surface. Right: an intra-axial glioblastoma arising within the brain parenchyma with expansion of the cortex, no CSF cleft, and cortical vessels displaced outward over the tumor surface. Key differentiating features are labeled.</image>

## Clinical Pearls

The single most important distinction in brain tumor imaging is intra-axial versus extra-axial; the CSF cleft, cortical vessel displacement, and gray-white junction buckling identify extra-axial lesions. GBM and metastasis can look identical as ring-enhancing lesions; multiple lesions favor metastases, while corpus callosum involvement and infiltrative non-enhancing T2/FLAIR signal favor GBM. Primary CNS lymphoma shows restricted diffusion and homogeneous enhancement, and pre-biopsy steroids should be avoided as they may cause the tumor to transiently disappear. In the 2021 WHO classification, the term "glioblastoma" is reserved for IDH-wildtype tumors; IDH-mutant Grade 4 astrocytomas are classified separately due to their better prognosis. MR perfusion (rCBV) is the most useful advanced technique for distinguishing recurrent tumor (high rCBV) from radiation necrosis (low rCBV) on post-treatment imaging. An epidermoid cyst restricts diffusion while an arachnoid cyst does not, and this is the key to distinguishing these two cerebellopontine angle lesions that appear similar on standard sequences.

## References

- Louis DN, et al. "The 2021 WHO Classification of Tumours of the Central Nervous System." *Neuro-Oncology*, 2021
- Young GS. "Advanced MRI of Adult Brain Tumors." *Neurologic Clinics*, 2007
- ACR Appropriateness Criteria: Headache -- Suspected Brain Tumor, 2019