Meningiomas are the most frequently diagnosed primary tumors of the central nervous system, originating from the meninges—the protective layers of tissue that cover the brain and spinal cord. The majority of these tumors are slow-growing and not cancerous. A comprehensive classification system is used to categorize these tumors, which helps predict their potential behavior and informs medical management strategies.
The WHO Grading System
The World Health Organization (WHO) establishes the international standard for classifying tumors of the central nervous system, including meningiomas. This system is foundational for diagnosis and helps guide treatment decisions globally. The classification is a three-tiered grading scale that categorizes tumors based on their microscopic appearance and, more recently, their molecular features, which helps predict how a tumor is likely to behave.
Each grade corresponds to a different level of aggression. Grade I tumors are considered benign and are the most common, representing about 80% of all meningiomas. Grade II tumors, known as atypical meningiomas, show features that suggest a higher likelihood of returning after treatment. Grade III meningiomas, termed anaplastic or malignant, are the most aggressive, grow rapidly, and are considered cancerous.
Grade I Meningiomas
Constituting the vast majority of cases, Grade I meningiomas are characterized by their slow rate of growth and well-defined borders. These benign tumors are the least likely to recur, particularly after complete surgical removal. Their slow progression means that for some patients, especially those who are older or have no symptoms, a period of observation with regular imaging may be the recommended course of action.
Within this grade, pathologists recognize several distinct subtypes based on the tumor’s appearance under a microscope, known as its histology. The most common subtypes are meningothelial, fibrous, and transitional meningiomas. Despite these variations in cellular architecture, all are considered benign and share a favorable prognosis, and the specific subtype does not alter the overall management approach.
The location of the tumor can correlate with specific genetic changes. For example, meningiomas located at the base of the skull are more likely to have mutations in genes such as AKT1, SMO, or TRAF7. In contrast, those occurring over the surface of the brain (the convexity) more frequently show changes related to the NF2 gene. These findings are adding a new dimension to understanding even the most benign forms of these tumors.
Grade II and Grade III Meningiomas
Grade II meningiomas are designated as “atypical” and represent about 15-20% of cases. These tumors are defined by features that indicate more active growth, such as a higher rate of cell division. A pathologist might observe between 4 and 19 cell divisions (mitoses) within a specific sample area. Another defining characteristic of some Grade II tumors is evidence of brain invasion, where tumor cells grow into the adjacent brain tissue.
These atypical features mean that Grade II tumors have a greater tendency to recur after surgical removal compared to their Grade I counterparts. Because of this increased risk, the standard treatment approach involves surgery to remove the tumor, often followed by a course of radiation therapy. This combination is intended to address any remaining tumor cells and reduce the probability of the tumor returning.
Grade III meningiomas, also called anaplastic or malignant meningiomas, are the rarest and most aggressive form, accounting for only 1-3% of all cases. These are cancerous tumors characterized by very rapid growth, showing 20 or more mitoses in a given sample area. These tumors are highly invasive and have a strong propensity for recurrence, necessitating aggressive treatment protocols that include surgery followed by radiation.
How Classification is Determined
The process of classifying a meningioma begins after a sample of the tumor is obtained, either through a biopsy or during surgical resection. This tissue is then sent to a pathologist, a physician who specializes in diagnosing diseases by examining tissues and cells. The pathologist performs a detailed microscopic evaluation, known as histological analysis, to determine the tumor’s grade.
During this analysis, the pathologist looks for specific microscopic features. A primary feature is the mitotic count, which is the measure of how many cells are actively dividing. The pathologist also assesses the overall appearance of the cells, their density, and the structure of the tissue, looking for patterns that align with the established criteria for each grade. The presence of necrosis, or areas of dead tissue within the tumor, is another indicator of more aggressive behavior.
An important factor in grading is the assessment of brain invasion. If the pathologist sees tumor cells that have breached the boundary between the tumor and the brain, this finding alone can be sufficient to classify an otherwise benign-appearing meningioma as a Grade II tumor. This visual inspection of the tumor’s architecture and cellular activity is the traditional method for determining its classification.
The Role of Molecular Markers
In recent years, the classification of meningiomas has evolved beyond microscopic appearance to include the analysis of the tumor’s genetic makeup. This molecular profiling provides a deeper layer of information that can refine a diagnosis and help predict a tumor’s behavior with greater accuracy. Scientists can identify specific genetic mutations within the tumor cells that are associated with a higher risk of recurrence or more aggressive growth.
The 2021 update to the WHO classification system incorporated specific molecular markers as criteria for assigning a grade. For instance, the presence of a mutation in the TERT promoter or the homozygous deletion of the CDKN2A/B genes are now considered standalone markers for Grade III meningioma. This means a tumor can be classified as the highest grade based on these genetic findings, regardless of its appearance under the microscope.
This integration of molecular data allows for a more personalized risk assessment. A tumor that appears to be a lower grade histologically might be reclassified to a higher grade if it harbors high-risk genetic alterations. This modern approach helps to identify patients who may benefit from more aggressive treatment upfront, even when their tumor looks less threatening on initial microscopic review.