Year: 2024
Type: article
Abstract: To the Editor: Meningiomas represent over a third of CNS tumors in the United States and demonstrate a variety of well-described histologic subtypes. Female sex hormones are associated with increased risk of meningioma, though the underlying pathophysiology is still unclear. Herein, we report a case of meningiomatosis with striking schwannoma-like histology, along with its corresponding cytogenetic and molecular alterations, in a patient on long-term progestin therapy. The patient was a 67-year-old woman with a history of endometrial adenocarcinoma status post adjuvant radiation therapy and brachytherapy in 2004 that metastasized to lung and abdominal soft tissue in 2007. She was started on megestrol acetate (40 mg PO BID) with subsequent resolution of the pulmonary and abdominal lesions. In 2013, the patient had a brain MRI for agitation, confusion, and amnesia that demonstrated multiple areas of nodular dural thickening and enhancement. During a follow-up visit in August 2017, the patient was found to have a new left ptosis and asymmetric gait, prompting an MRI of the orbits and brain. Imaging showed significant progression of multiple dural masses (>10 in total) along the left frontoparietal, inferior medial bilateral frontal, cribriform, left anterior temporal, and bilateral anterior paraclinoid regions, as well as the left lateral orbital wall (Fig. 1). The patient had no history of neurofibromatosis type 2 or cranial radiation. She underwent excisional biopsy of one of the right frontal lesions, with high clinical suspicion for metastatic disease. The 2017 brain MRI prior to excisional biopsy demonstrated multiple dural masses [(A), axial T2 FLAIR; (B) coronal gadolinium-enhanced T1 FS]. The biopsy revealed a neoplasm composed primarily of cells with striking nuclear palisading alternating with areas of relatively acellular myxoid/microcystic stroma, suggestive of Verocay bodies seen in schwannomas (Fig. 2). A minor component of the tumor (∼10%) demonstrated meningothelial architecture. Mitoses numbered <1 per 10 HPF. Hypercellularity, small cell change, macronucleoli, sheet-like growth, and spontaneous necrosis were absent. No brain tissue was present. The tumor cells were immunopositive for somatostatin receptor 2 and epithelial membrane antigen and immunonegative for PAX8 and S100. The MIB-1 proliferation index was 4.7%. The tumor strongly expressed progesterone receptor (PR) but was negative for estrogen receptor. The tumor was diagnosed as meningioma with elevated MIB-1 proliferation index, WHO grade 1. The tumor demonstrated striking nuclear palisading architecture strongly resembling Verocay bodies (hematoxylin and eosin) (A, B). It was immunopositive for epithelial membrane antigen (EMA) (C), somatostatin receptor 2 (SSTR2) (D), and progesterone receptor (PR) (E). The tumor was immunonegative for S100 (F) and estrogen receptor (ER) (G). The formally quantified MIB-1 proliferative index was 4.7% (H). Chromosomal microarray analysis showed loss of distal 1p and distal 2p (I). Magnifications: A, 100×; B-H, 400×. Given the usual histology of the meningioma, additional workup was performed, including chromosomal microarray analysis (Affymetrix Oncoscan assay) and next generation sequencing (Oncopanel). Chromosomal microarray analysis detected loss of distal 1p and 2p, and next generation sequencing showed a SMARCA4 p. G1162S missense mutation (variant allele frequency [VAF] 19%) and an AKT3 c.285-5T>C splice region mutation (VAF 26%) (Fig. 2). Following the patient’s diagnosis in 2017, megestrol acetate was discontinued, and she has undergone routine surveillance MRIs for her meningiomatosis. As of June 2022, most of the patient’s meningiomas have been stable or improved in size, though two of her orbital meningiomas have demonstrated slight interval enlargement. The clinical history of our case is not uncommon for patients on progestin therapy who develop meningiomas and is thus instructive for pathologists and clinicians. Progestin therapies (including megestrol acetate and cyproterone acetate, among others) increase the risk of meningioma, which frequently presents as meningiomatosis (1–8). In addition, the meningiomas in our case involved multiple anatomic locations, including the skull base. The skull base appears to be preferentially involved in progestin-associated meningiomas, particularly those arising in the setting of cyproterone acetate (1–4). Meningiomas generally do not progress following cessation of progestin therapy, but a small subset will continue to grow (4–6). The microscopic findings of this case broaden the histologic spectrum of meningiomas. Although fibroblastic meningiomas may sometimes show focal nuclear palisading, our described case is most unusual in that the tumor was predominantly composed of tumor cells arranged in schwannoma-like Verocay bodies with intervening acellular myxoid/microcystic stroma. Meningiomas with schwannoma-like architecture have been described in rare case reports, but these tumors presented as single masses without a documented history of progestin therapy (9, 10). Interestingly, microcystic or edematous stroma (present at least focally) may be a relatively common histologic feature of progestin or pregnancy-associated meningiomas (2, 11). In prior studies, progestin-associated meningiomas tended to be WHO grade 1, strongly PR positive, and of the transitional, meningothelial, or fibroblastic histologic subtype, though angiomatous, psammomatous, microcystic, metaplastic, chordoid, and atypical meningiomas were also described (1, 2, 4–8). Our case critically expands the molecular landscape of meningiomas associated with progestin therapy and, to our knowledge, is the first to describe the molecular features of meningiomas with schwannoma-like histology. Although the meningioma met histologic criteria for WHO grade 1 only, chromosomal copy number analysis detected loss of 1p, which is associated with more aggressive behavior (12). Our case also demonstrated a SMARCA4 missense mutation, which occurs at a mutational hotspot and is predicted to be pathogenic, and an AKT3 splice region mutation of unclear biological significance. In contrast, two previous investigations of progestin-associated meningiomas demonstrated mutations involving PIK3CA, TRAF7, and AKT1 (1, 2). SMARCA4 encodes part of the SWI/SNF chromatin remodeling complex and is mutated in a subset of meningiomas. In one study, investigators analyzed targeted next generation sequencing data from 255 meningiomas (not specifically progestin-associated) and identified SMARCA4 mutations in 3.5% of cases; these SMARCA4-mutant meningiomas ranged from WHO grade 1-2 and frequently harbored co-occurring mutations involving ARID1A and SMARCB1 (13). Akt3 is a component of the PI3K/Akt signaling pathway, a pathway implicated in the tumorigenesis of progestin-mediated meningiomas (1, 2). Additional studies are needed to more fully characterize the natural history and molecular alterations of both schwannoma-like meningiomas and progestin-associated meningiomas, including the clinical significance of chromosomal copy number changes such as 1p loss in these tumors. In summary, this usual and instructive case: (i) highlights a rarely reported, schwannoma-like histologic subtype of meningioma, (ii) illustrates several characteristic clinical features of progestin-associated meningiomas, such as presentation of multiple dural masses, and (iii) expands the known genomic landscape of meningiomas with schwannoma-like histology and meningiomas associated with progestin therapy. The authors have no sources of funding or conflicts of interest to declare. The authors have no duality or conflicts of interest to declare.
DOI: 10.1093/jnen/nlae008
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4391467925