Meningioangiomatosis Combined with Calcifying Pseudoneoplasms of Neuraxis

Meningioangiomatosis (MA) is a rare hamartomatous or meningovascular lesion involving the central nervous system, and is sometimes associated with intracranial meningiomas. Calcifying pseudoneoplasms of the neuraxis (CAPNON) are rare, slow-growing benign tumor-like lesions that can occur anywhere along the neuraxis. Here, we report a rare case of MA combined with CAPNON. A 31-year-old woman was admitted to our hospital because of a high-density mass in the left frontal lobe, detected by computed tomography (CT) during a physical examination. She had a 3-year history of obsessive–compulsive disorder. We describe the imaging, histopathological, and molecular characteristics of the patient. To our knowledge, this is the first report describing MA combined with CAPNON. We reviewed the literature on MA and CAPNON over the last decade and summarized the points for differential diagnosis and treatment. It is difficult to preoperatively distinguish between MA and CAPNON. However, this coexisting condition should be considered when intra-axial calcification lesions are observed on radiological imaging. Accurate diagnosis and appropriate treatment are likely to benefit this patient group.


Introduction
Meningioangiomatosis (MA) is a rare hamartomatous or meningovascular lesion involving the central nervous system. It occurs sporadically, or may be associated with neurofibromatosis type 2 (NF-2). The sporadic symptoms are headaches, seizures, and a variety of other neurological symptoms. MA associated with NF2 is usually asymptomatic and found incidentally [1]. MA was first described by Bassoe and Nuzum in the autopsy of a patient with NF2 in 1915 [2]. Later, the brain lesion was named "meningioangiomatosis" by Worster-Drought et al. in 1937 [3]. Calcifying pseudoneoplasms of the neuraxis (CAPNON) are rare, slow-growing, benign tumor-like lesions that can occur anywhere along the neuraxis, including the brain and spine [4,5]. Originally described by Rhodes and Davis in 1978, CAPNON is also called fibro-osseous lesions [6]. In this article, we describe a rare co-existence of MA and CAPNON that has never been previously reported.
The authors report a case involving a 30-year-old woman with a high-density mass in the left frontal lobe, suspected to be a meningioma on computed tomography (CT). However, after surgical resection (Operative video see Supplementary Material: Video S1), the histopathological diagnosis of the lesion was MA combined with CAPNON. This study aims to provide a detailed analysis of this rare entity, including its clinical presentation and histopathological and imaging features, by collecting reports from other authors and our practical experience with a patient who underwent surgical resection at our institution. It is crucial to distinguish benign lesions from the more common vascular malformations and calcified vascular, neoplastic, or non-neoplastic differential diagnoses, because complete resection is curative [7]. In addition, we aim to analyze the possible mechanisms of its occurrence and development to provide references for treatment decisions.

Materials and Methods
We present a case of a patient with a histopathologically confirmed diagnosis of MA combined with CAPNON. Additionally, we conducted a comprehensive review of the literature on MA and CAPNON published in PubMed over the past 10 years. The search keywords included: meningioangiomatosis, calcifying pseudoneoplasm, and calcifying pseudotumor. The following parameters were collected from the qualifying articles: study type, number of patients, anatomical area, clinical presentation, radiological presentation, therapy, complications, and outcomes. In this review, we analyzed MA and CAPNON separately and discussed the mechanisms underlying their occurrence and development. This study was approved by the Ethics Committee of the Zhongnan Hospital of Wuhan University (no. 2019048).

Case Presentation
A 31-year-old woman was admitted for physical examination due to a high-density mass found by computed tomography (CT) in the left frontal lobe. The patient had a 3-year history of obsessive-compulsive disorder and experienced progressive improvement after taking sertraline tablets for 6 months. The CT scans ( Figure 1A-C) revealed an irregular hyperdense mass in the left frontal lobe, measuring approximately 19 × 15 × 14 mm. Subsequent magnetic resonance imaging (MRI) revealed a hypo-intense mass with an unclear boundary on the T1-weighted image ( Figure 1D) and an irregular mixed hypointense mass on the T2-weighted image ( Figure 1E) and T2 FLAIR ( Figure 1F). Irregular linear enhancement was observed on gadolinium-enhanced T1-weighted MRI ( Figure 1G-I). Based on these initial images, meningioma was suggested.
The patient underwent a left frontotemporal craniotomy and complete resection. The gray-white and gray-brown lesions were relatively compact, and the boundary between the lesions and the surrounding brain tissue was unclear ( Figure 2A). Immediate postoperative MRI confirmed the complete removal of the tumor. ( Figure 1J-L). The patient recovered well, and no recurrence was observed on the MRI ( Figure 1M-O) 3 months after surgery. However, the symptoms of the obsessive-compulsive disorder did not show considerable improvement.

Histopathology
Microscopic observation using hematoxylin and eosin (H&E) staining revealed that the lesion was primarily located between the pia mater and the cerebral cortex. A clear border was observed between the MA and CAPNON ( Figure 2B,E). In the superficial cortical areas of the brain parenchyma, proliferating vessels surrounded by spindle cells were observed. Psammoma bodies, partially surrounded by small proliferating blood vessels, were visible, which are a classic pathological feature of MA ( Figure 2B-D). Large calcifications were observed in the pia mater, and the calcified components were irregular or nested with proliferating spindle cells around them, which are typical signs of CAPNON ( Figure 2E-G).
Immunohistochemically, the meningothelial cells positively expressed CD34 ( Figure  2H), the somatostatin receptor (SSTR-2), the epithelial membrane antigen (EMA), vimentin ( Figure 2I), and the progesterone receptor (PR) to varying extents. The stained meningothelial cells were mainly located on the surface of the pia mater and around the blood vessels of the cerebral cortex. Neurons invading the lesion were immunopositive for neuronal nuclei (NeuN), whereas the glial cells were immunopositive for glial fibrillary acid protein (GFAP) and oligodendrocyte line transcription factor 2 (Olig-2). The Ki-67 proliferation index was low (1%).

Histopathology
Microscopic observation using hematoxylin and eosin (H&E) staining revealed that the lesion was primarily located between the pia mater and the cerebral cortex. A clear border was observed between the MA and CAPNON ( Figure 2B,E). In the superficial cortical areas of the brain parenchyma, proliferating vessels surrounded by spindle cells were observed. Psammoma bodies, partially surrounded by small proliferating blood vessels, were visible, which are a classic pathological feature of MA ( Figure 2B-D). Large calcifications were observed in the pia mater, and the calcified components were irregular or nested with proliferating spindle cells around them, which are typical signs of CAPNON ( Figure 2E-G).
Immunohistochemically, the meningothelial cells positively expressed CD34 ( Figure 2H), the somatostatin receptor (SSTR-2), the epithelial membrane antigen (EMA), vimentin ( Figure 2I), and the progesterone receptor (PR) to varying extents. The stained meningothelial cells were mainly located on the surface of the pia mater and around the blood vessels of the cerebral cortex. Neurons invading the lesion were immunopositive for neuronal nuclei (NeuN), whereas the glial cells were immunopositive for glial fibrillary acid protein (GFAP) and oligodendrocyte line transcription factor 2 (Olig-2). The Ki-67 proliferation index was low (1%).

Results
Based on the results of H&E and immunohistochemical staining for specific biomarkers, the histopathological diagnosis of this lesion was MA combined with CAPNON, accompanied by the proliferation of meningothelial cells.

Discussion
MA and CAPNON are two rare lesions of the nervous system. We conducted a comprehensive review of the literature on MA and CAPNON published on PubMed in the last 10 years. Our review included 62 cases of MA (Table 1) and 50 cases of CAPNON (Table 2).
Among the 50 patients with CAPNON, 23 were male and 27 were female, with a mean age of 47.63 years and ranging from 8 to 73 years old. Although CAPNON can occur anywhere along the neuraxis, the intracranial location was the most common (39/50, 78%), with the remaining cases occurring in the spine (9 cases) and the craniocervical junction (2 cases). Furthermore, among the 39 intracranial CAPNON cases, 26 (66.67%) were supratentorial and 13 (33.33%) were infratentorial. Ho et al. reported that nearly one-third of CAPNONs were "collision" lesions, where the CAPNON tissue coexisted with a separate, distinct entity [16]. In seven cases, coexistent primary tumors were described, including meningioma [17], lipoma [18][19][20], and low-grade glioma [21]. The most common symptoms of intracranial CAPNON were headaches (17/39, 43.59%) and/or seizures (13/39, 33.33%), with a few patients presenting with cranial nerve defects, such as hoarseness, decreased hearing, or gait disturbance. In a 2013 study by Stienen et al. [7]., the authors reviewed all reported cases of CAPNON between 1977 and December 2011. Of the 22 patients with intracranial CAPNON, who had a mean age of 45 years, 19 had supratentorial CAPNON. The modes of presentation included epileptic seizures in eight patients, headache in five, cranial nerve affection in four, and dizziness and limb paresis in three. This finding is consistent with that of our literature review.   Diagnosing MA and CAPNON can be challenging due to the lack of characteristic signs to differentiate between them on preoperative imaging. MA often presents with a certain extent of calcification and contrast enhancement on CT and MRI [22]. One study reported that calcification was prevalent in 89.6% of the patients with MA. The lesion is generally confined to the cortex [23,24], with mostly low signals on MRI-T1WI and dark, wavy "cyclotron" signals on T2WI. In contrast, CAPNON shows little or no contrast enhancement with severe or peripheral calcification on CT and MRI. Due to the lack of specific clinical presentations and typical imaging features [25], postoperative pathological diagnosis is crucial for both MA and CAPNON. MA is generally characterized by proliferative meningothelial and fibroblast-like cells that infiltrate the leptomeninges with hypercellular areas and sclerosis [10], which majorly involves the outer layers of the cortex. In the adjacent cortex, large ganglion cells are isolated by thickened blood vessels, and the neuronal fibers in the trapped ganglion cells show tangling changes. The histological features of MA include meningovascular and leptomeningeal hyperplasia and calcification. Immunohistochemical staining is not very effective in diagnosing MA due to the lack of consistent markers [13]. The common histological features of CAPNON include chondromyxoid regions, palisading spindle cells, fibrous stroma, calcifications, and psammoma bodies [26]. However, the presence of these components is highly variable among the reported cases. The major immunohistochemical findings were the presence of epithelial membrane antigen (EMA) and vimentin, as well as the absence of glial fibrillary acid protein (GFAP) and S-100 protein [7]. As shown in Table 2, EMA was positive in 17 cases (70.83%; 17/24), and vimentin was detected in all 10 cases (100%; 10/10). However, the S-100 and GFAP were negative in 14 (82.35%; 14/17) and 11 cases (61.11%; 11/18), respectively.
The differential diagnoses of MA mainly include meningioma, vascular malformation, and cavernous hemangioma. Meningiomas are usually associated with dural diseases, whereas MAs often involve the cerebral cortical surface. Vascular malformations and cavernous hemangiomas generally lack perivascular meningothelial cell proliferation or psammoma bodies. In contrast, the most prominent feature of CAPNON is its highly dense calcification; therefore, oligodendrocytoma, astrocytoma, meningioma, osteosarcoma, chondrosarcoma, and neoplastic calcinosis are all important differential diagnoses.
Surgical resection is the most effective treatment for MA and CAPNON. In this study, 58 MA cases (93.55%;58/62) and 46 CAPNON cases (92%;46/50) were selected for surgery, particularly in high-risk areas. For instance, Lucila Domecq Laplace et al. [27] reported three cases of CAPNON located in the posterior fossa with perilesional edema, and the vast majority were cured after total resection. However patients may experience recurrence because of incomplete evacuation [28], neoplastic malignancy [12], or coexisting with other malignant tumors [20,21]. In addition to surgery, medical treatment and followup observations have been reported [1,[29][30][31]. Shlomit et al. [29] reported a 67-year-old man with diffuse meningioma involving the occipital and right temporal lobes. After being diagnosed with MA by biopsy, the patient benefited from antiangiogenic therapy with bevacizumab, which led to clinical stability and marked radiological improvement. Similarly, indomethacin, an anti-inflammatory drug, was administered as a treatment option in a 44-year-old woman with chest CAPNON. After completing the treatment, the patient's symptoms were completely relieved, and the lesion disappeared on the CT and MR imaging [31]. These successful non-surgical treatments shed light on the mechanisms underlying the development and progression of MA and CAPNON.

Conclusions
Herein, we report a rare case of MA coexisting with CAPNON, which was treated with tumor resection and had a good prognosis. Histological H&E staining revealed proliferating vessels and psammoma bodies encased by blood vessels, suggesting that the pathogenesis of MA is associated with cortical vascular malformations and the secondary proliferation of meningothelial cells. The formation of psammoma bodies may be stimulated by vascular proliferation. Most current studies suggest that CAPNON may represent a series of reactive processes that can arise in association with diverse underlying pathologies, including inflammatory, degenerative, vascular, and neoplastic lesions. In the present case, meningeal vascular proliferation and fine leptomeningeal epithelial proliferation may have led to the benign reactive lesions of CAPNON. Although nonsurgical treatment has been successful in some cases, complete resection is still attempted, when feasible, to relieve the patient's symptoms and perform histopathological analysis. Definitive diagnosis is based on histopathological analyses to prevent the patient from having to undergo aggressive adjuvant therapy.