Introduction
Meningiomas are the most common primary intracranial tumors in adults accounting for 37.6% of all primary brain and central nervous system (CNS) tumors.1 These tumors arise from the meningothelial (arachnoid) cells of the arachnoid mater and are typically found along the meningeal surfaces of the calvarium, spinal canal, and orbit. Many of these slow-growing tumors are discovered incidentally. Some cases may manifest with neurological deficits that vary according to tumor location and compression of adjacent structures. Patients commonly present with headaches, weakness, and seizures while higher-grade tumors behave more aggressively, often with extracranial metastasis. 2
The meningiomas were traditionally graded according to the histological criteria which was believed to predict these tumors' biological course. However, the 2021 WHO Classification of Tumors of the Central Nervous System (WHO CNS5), has incorporated some major changes in the diagnostic criteria based on the growing understanding of the various biological pathways underlying meningiomas from diverse bioinformatic studies. 3
Discussion
The fifth edition of the WHO Classification of Tumors of the Central Nervous System (WHO CNS5), published in 2021, is the sixth version of the international standard for diagnosing CNS tumors. Based on the updates of the consortium to inform molecular and practical approaches to CNS tumor taxonomy (cIMPACT‑NOW) which was created in 2016 under the sponsorship of the International Society of Neuropathology (ISN), the WHO CNS5 had continued the trend of incorporating the molecular characteristics of tumors into the histological and immunohistochemical findings. Meningiomas, which constitute about one-third of the primary brain tumors, are no exception. The WHO has laid down the essential and desirable criteria for diagnosis which include molecular alterations along with the histologic criteria. (Table 1)
Imaging
These tumors can be picked up on Magnetic Resonance Imaging (MRI) as characteristic isodense, uniformly contrast-enhancing dural masses while calcification is best visualized on Computed tomography (CT).2 Certain histologic subtypes show peritumoral edema and some may show cyst formation within or at the periphery. 2 Gadolinium-enhanced MRI with the help of qualitative and quantitative radiographic features can even provide clues to the histological grade of meningiomas, local failure, and patient outcomes. 2, 4, 5 However, histopathological examination has been the gold standard of diagnosis, grading, and prognostication.
General changes in CNS5 classification
One of the general changes made in the taxonomy of tumors in CNS5 is that “type” has now replaced “entity” and “subtype” has replaced the “variant” in line with the changes made in the classification of tumors of other organ systems. Again, only the types are listed in the main WHO classification, while subtypes are mentioned under the individual type of tumors e.g. the type meningioma is mentioned in the main classification while the subtypes of meningioma i.e. Meningothelial meningioma, Fibrous meningioma, Transitional meningioma, atypical meningioma, anaplastic (malignant) meningioma, etc. are mentioned in the chapter on meningioma.
As far as the grading goes, the Roman numerals have now been replaced with Arabic numerals i.e. Grade II meningiomas (atypical meningiomas) are now referred to as Grade 2 meningiomas (atypical meningiomas).
The etiopathogenesis of meningiomas
Exposure to ionizing radiation (particularly in childhood) and endogenous or exogenous hormones, etc. have been linked to an increased risk for the development of meningiomas. 2
Among the germline mutations and familial syndromes predisposing to the development of meningiomas, Type 2 neurofibromatosis (NF2) is most common. Patients suffering from NF2 have a greater tendency to develop grade 2 and 3 or multiple meningiomas. 6 Other familial syndromes associated with meningiomas include Gorlin syndrome (Nevoid basal cell carcinoma syndrome), BAP1 tumor predisposition syndrome (BAP1-TPDS), Familial schwannomatosis, multiple endocrine neoplasia 1 (MEN1), Cowden syndrome, Werner syndrome, Rubinstein-Taybi syndrome, Familial multiple meningiomas etc. 7
In meningiomas, monosomy of chromosome 22 is the most frequently reported genetic abnormality, with 60-70% of tumors showing allelic losses in 22q12.2, the region encoding the NF2 gene. 2, 7 The frequency of this abnormality increases with tumor grade, occurring in 50% of benign and 75-85% of atypical (Grade 2) or anaplastic (Grade 3) meningiomas. 7 Other causes of NF2 gene deficiency include promoter methylation, epigenetic inactivation, and somatic mutations. 8
Higher-grade meningiomas (Grade 2 and 3) are associated with complex genetic changes, such as: 2
Losses on 1p, 6p/q, 10q, 14q, and 18p/q.
Less frequent losses on 2p/q, 3p, 4p/q, 7p, and 8p/q.
Heterozygous or homozygous deletions of tumor suppressor genes CDKN2A, p14ARF, and/or CDKN2B located on chromosome 9p.
Genomic sequencing has identified two subsets of meningiomas: 2
NF2-mutant meningiomas: Defined by NF2 mutations and/or loss of chromosome 22.
NF2-wildtype meningiomas: Harbor mutations in genes such as AKT Serine/Threonine Kinase 1/Protein Kinase B (AKT1), tumor necrosis factor receptor-associated factor 7 (TRAF7), Smoothened Frizzled Class Receptor (SMO), and/or Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha (PIK3CA).
The first subset i.e. with NF2 mutation and/or loss of chromosome 22q, may go on to accumulate additional copy-number losses, genomic instability, mutations in the promoter region of the telomerase reverse transcriptase (TERTp) gene, etc. while the NF2-wild subset with AKT1, KLF4, SMO, PIK3CA, and/or TRAF7 mutations show balanced copy-number profiles. 2
Interestingly, the localization of meningiomas often indicates the underlying mutations.9
For example
Histopathological subtypes and molecular associations
The WHO classification system presently describes 15 different meningioma subtypes which are as follows:
Meningothelial meningioma
Fibrous meningioma
Transitional meningioma
Psammomatous meningioma
Angiomatous meningioma
Microcystic meningioma
Secretory meningioma
Lymphoplasmacyte-rich meningioma
Metaplastic meningioma
Chordoid meningioma
Clear cell meningioma
Rhabdoid meningioma
Papillary meningioma
Atypical meningioma
Anaplastic (malignant) meningioma
The chapter on meningioma in the CNS5 describes in detail the morphologic features of each subtype. The WHO CNS grading criteria have been laid down for all meningiomas (Table 2) and are to be applied across all these histologic subtypes.
It must be noted that similar to the previous edition, clear cell and chordoid meningiomas are assigned CNS Grade 2 based on morphological diagnosis alone. For a diagnosis of atypical meningioma, CNS Grade 2 criteria must be met.
Papillary and rhabdoid meningiomas were previously considered Grade 3 meningiomas. However, as per the new CNS tumor classification, they are now assigned CNS Grade 3 only if they meet the criteria of CNS Grade 3 meningiomas. 2 (Table 2)
Invasion of dura, bone, or soft tissue or the presence of pleomorphic/atypical nuclei do not affect the CNS grading. However, bone invasion has been associated with a worse prognosis in atypical meningiomas. 2, 10
In the new version of the classification, molecular markers are introduced as diagnostic criteria for selected subtypes and the application of WHO CNS grading. For example:
The secretory subtype of meningioma is diagnosed by characteristic morphologic features and/or combined KLF4 and TRAF7 mutations. 2, 11
Any meningioma with a TERTp mutation and/or CDKN2A/B homozygous deletion is now assigned WHO CNS Grade 3, irrespective of histological diagnosis or criteria of anaplasia.2
Additionally, several characteristic mutations and copy number variations (CNVs) have been identified in various subtypes of meningiomas. However, these findings require more extensive studies to fully characterize their independent prognostic value and to establish their potential as targets for therapeutic interventions. 11 (Table 3)
AKT1 p.E17K mutations combined frequently with TRAF7 mutations or SMO and PIK3CA mutations are exclusively seen in meningothelial meningiomas. In contrast, 22q deletion and mutation of the retained NF2 allele are noted in fibrous, transitional, and psammomatous meningiomas.2 Psammomatous meningiomas which usually occur in the region of the thoracic spine in middle-aged or elderly women, may additionally show epigenetic changes.2 Metaplastic, microcystic, and angiomatous meningiomas all show a high frequency of chromosome 5 gain. 12 Deletion of Chromosome 2p has been reported in chordoid meningiomas while the vast majority of clear cell meningiomas harbor SMARCE1 mutations, which can be either germline or somatic.2, 11
The majority of atypical meningiomas exhibit loss of NF2 combined with either genome instability (large-scale chromosomal alterations) or loss of SMARCB1.13 Recurrent losses of chromosome 1p, 6q, 14q,18q and gain of 1q are indicators of poor prognosis.14 TERTp mutation and homozygous deletion of CDKN2A and/or CDKN2B are associated with CNS WHO Grade 3 meningiomas, which have a high risk of recurrence and a short interval to progression. 2
Papillary meningiomas are often associated with PBRM1 mutation/deletion, while rhabdoid meningiomas are linked to mutations in BRCA1-associated protein-1 (BAP1). Loss of H3 p.K28me3 (K27me3), seen in about 10–20% of anaplastic meningiomas, is associated with aggressive behavior, recurrence, and shorter overall survival. 2 In pediatric meningiomas, YAP1 fusions have been identified as a potential NF2-independent oncogenic driver. 15
Table 1
Diagnostic criteria formeningiomas as per CNS 5 2
Table 2
CNS WHO Grading ofmeningiomas and recurrence rates: 2
Table 3
Integrated diagnosis and layered reporting- the way forward
In addition to the light microscopic features, immunohistochemical stains for Somatostatin receptor 2a (SSTR2a), Epithelial membrane antigen (EMA), progesterone receptor (PR), and Ki 67 are used for the diagnosis of meningiomas.
Molecular methods like in-situ hybridization, RNA sequencing, and high-throughput DNA sequencing are increasingly being used to detect various molecular alterations. Some surrogate IHC stains are also used as an alternative to DNA-based molecular methods e.g. loss of SMARCE1 and BAP1 can be detected by IHC in clear cell meningiomas and rhabdoid meningiomas respectively. Loss of H3 p.K28me3 (K27me3), which is indicative of aggressive behavior of meningiomas, can also be detected by IHC. 2
Methylome profiling can determine the DNA methylation patterns, and separate subgroups of meningiomas, including those with a higher risk of recurrence. 2
The integrated diagnosis of meningiomas incorporates all these information by combining the histological diagnosis with the findings of molecular studies. The layered reporting of meningiomas uses the integrated diagnosis (combined histological and molecular diagnosis), followed by histopathological classification, CNS WHO Grade, and molecular information. This not only provides a structured and informative diagnosis to the treating clinicians but also sets a trend of mentioning the molecular markers that may be therapeutically targeted for precision oncology.
Conclusion
The recent World Health Organization (WHO) classification has incorporated molecular information to guide the integrated diagnosis and management of meningiomas. The inclusion of CDKN 2A/B and TERTp mutations into the new classification, and the increasing use of molecular diagnostics have paved the way for the emergence of potential therapeutically targetable biomarkers which may lead to effective targeted therapy, based on the results of precision medicine trials.
