Meningiomas are the most common primary intracranial tumors, arising from the meninges — the membranous layers that surround the brain and spinal cord. They account for approximately 30% of all primary brain tumors. While most meningiomas are benign, some can be atypical or malignant. Understanding their types, grades, and molecular characteristics is crucial for diagnosis, treatment, and prognosis.

In 2021, the World Health Organization (WHO) updated its classification of meningiomas, incorporating molecular findings alongside traditional histopathologic criteria. This blog post will cover the types and grades of meningiomas and provide a detailed overview of their histologic, immunohistochemical (IHC), and molecular characteristics.

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Types and Grades of Meningioma

Meningiomas are categorized based on their histological characteristics and are graded by the WHO to reflect their biological behavior and potential for recurrence. The WHO grades meningiomas into three categories: According to WHO 2021 Central nervous system tumors.

Histologic Findings

WHO Grade	Type	Histologic Features
Grade I	Meningothelial	Uniform cells with oval nuclei, whorls, and psammoma bodies.
	Fibrous (Fibroblastic)	Elongated cells with abundant collagen deposition, arranged in fascicles.
	Transitional (Mixed)	Features of both meningothelial and fibrous types.
	Psammomatous	Numerous psammoma bodies.
	Angiomatous	Prominent vascular channels, often thin-walled.
	Microcystic	Loose, spongy appearance with microcystic spaces.
	Secretory	Eosinophilic pseudopsammoma bodies, prominent secretory granules.
	Lymphoplasmacyte-rich	Dense lymphoplasmacytic infiltrate.
	Metaplastic	Metaplastic changes, such as osseous or cartilaginous differentiation.
Grade II	Atypical Choroid Clear cell	Increased mitotic activity (4–19 per 10 high-power fields), sheeting architecture, necrosis, hypercellularity, prominent nucleoli, and brain invasion.
Grade III	Anaplastic Papillary Rhabdoid	High mitotic rate (≥20 per 10 high-power fields), frank anaplasia, papillary or rhabdoid morphology, and evidence of brain invasion.

Immunohistochemical (IHC) Findings

IHC staining is used to identify the expression of specific proteins that help differentiate meningioma types and predict their behavior.

Marker	Expression	Associated Meningioma Type
EMA (Epithelial Membrane Antigen)	Positive in most meningiomas	All meningioma types
Vimentin	Positive in nearly all cases	All meningioma types
SSTR2A (Somatostatin Receptor 2A)	Strongly positive in most Grade I meningiomas	Grade I meningiomas
Ki-67 (MIB-1)	Low in Grade I, increased in Grade II and III	Grading and prognosis
Progesterone Receptor (PR)	Positive in many Grade I meningiomas, less in higher grades	Grade I, decreasing in Grade II and III
GFAP (Glial Fibrillary Acidic Protein)	Negative or weakly positive	Helps exclude non-meningothelial tumors
p53	Overexpression associated with higher grade	Higher grades (Grade II and III)

Mitotic count takes precedence over morphologic subtype

Molecular Findings (WHO 2021 Updates)

The WHO 2021 update incorporates molecular features into the classification of meningiomas, emphasizing the significance of genetic and molecular alterations in diagnosis and prognosis. Key molecular findings include:

Genetic Alteration	Description	Associated Meningioma Type
NF2 Mutations	Loss of function mutations in the NF2 gene (chromosome 22q)	Most common in Grade I meningiomas, especially in transitional and fibroblastic types.
TRAF7 Mutations	Mutations in TRAF7, often with KLF4 or AKT1 mutations	Found in secretory meningiomas and other Grade I types.
AKT1 Mutations	AKT1 mutations (E17K)	Found in Grade I meningiomas, particularly meningothelial types.
TERT Promoter Mutations	Associated with poor prognosis	Predominantly seen in Grade III meningiomas and some recurrent Grade II meningiomas.
SMO Mutations	Mutations in the SMO gene	Found in a subset of Grade I meningiomas, especially meningothelial types.
POLR2A Mutations	Deletions/mutations in the POLR2A gene	Often seen with NF2 mutations, linked to radiation-induced meningiomas.

NOTE THAT TRAF 7 AND NF2 are mutually exclusive

WHO 2021 Classification Updates

The WHO 2021 classification emphasizes a more integrated approach that combines histological, IHC, and molecular data to provide a more comprehensive diagnosis and better predict patient outcomes. Key updates include:

• Molecular Profiling: Molecular features, such as specific gene mutations (e.g., NF2, TRAF7, AKT1, SMO, TERT), are now integral to the classification.
• Brain Invasion Criteria: Brain invasion is now considered a standalone criterion for upgrading a meningioma to Grade II, regardless of mitotic count.
• Proliferative Indices: The Ki-67 labeling index and other proliferative markers are increasingly used to support grading decisions, especially for distinguishing between Grade I and Grade II tumors.

Conclusion

Meningiomas are complex tumors with diverse histological and molecular characteristics. The WHO 2021 updates provide a more nuanced classification that integrates histopathological features with molecular markers, improving diagnostic accuracy and patient management. For clinicians and researchers, understanding these changes is vital for developing personalized treatment strategies and advancing meningioma research.

By keeping up-to-date with these classifications and findings, pathologists can provide more accurate reports and tailored treatment options, ultimately enhancing patient outcomes.

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References

1. International Agency for Research on Cancer. (2021). WHO Classification of Tumors of the Central Nervous System(5th ed.). Lyon, France: IARC Press.
2. Louis, D. N., Perry, A., Reifenberger, G., von Deimling, A., Figarella-Branger, D., Cavenee, W. K., Ohgaki, H., Wiestler, O. D., Kleihues, P., & Ellison, D. W. (2021). The 2021 WHO Classification of Tumors of the Central Nervous System: A summary. Acta Neuropathologica, 142(4), 553–571. https://doi.org/10.1007/s00401-021-02340-4
3. Abedalthagafi, M. (2020). Meningiomas: An update on clinicopathological and molecular perspectives. Acta Neuropathologica Communications, 8(2). https://doi.org/10.1186/s40478-020-00921-2
4. Sahm, F., Schrimpf, D., Stichel, D., Jones, D. T. W., Hielscher, T., Huang, K., … & von Deimling, A. (2017). DNA methylation-based classification and grading system for meningioma: A multicentre, retrospective analysis. The Lancet Oncology, 18(5), 682-694. https://doi.org/10.1016/S1470-2045(17)30155-9
5. Clark, V. E., Erson-Omay, E. Z., Serin, A., Yin, J., Cotney, J., Özduman, K., … & Kurekci, N. (2013). Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO. Science, 339(6123), 1077-1080. https://doi.org/10.1126/science.1233009
6. Patel, A. J., Wan, Y. W., Al-Ouran, R., Revelli, J. P., Myers, J. N., & Fuller, G. N. (2019). Molecular profiling predicts meningioma recurrence and reveals loss of immunogenicity. Nature Communications, 10, 5298. https://doi.org/10.1038/s41467-019-13253-2