Inside the Pathology
Keywords: skull base, meningiomas, recurrence
Meningiomas represent a group of neoplasms deriving from the arachnoidal cap cells and showing a wide range of morphologic aspects. According to the 2016 WHO classification, three grades of malignancies are recognized: grade I, with a low recurrence rate (7–25%), grade II with a significant increased risk of recurrence (29–52%) and decrease in survival, and grade III, truly malignant lesions, with an increased risk not only of recurrence (50–94%), but also of distant metastasis and death from disease.
The present chapter deals with meningiomas of the skull base that is a complex anatomical region that forms the floor of the cranial cavity and whose proximity to cranial nerves and important vasculature make surgical treatment more challenging. As gross total resection is not always achieved, it is wise to identify the factors that are able to precisely predict the recurrence in meningiomas of this site. Moreover, grades II and III meningiomas are very infrequent in the skull base region. Therefore, grading and extent of resection may not be considered enough strong predictors of recurrence in this site.
In one of the largest modern series of patients surgically treated for meningiomas, with a long follow-up time, a diverging pattern of recurrence was observed in skull base compared with non–skull base tumors, suggesting that they may be genetically different.
Herein molecular features and biological factors that have been explored in both types of meningiomas are thoroughly described.
3.1 Skull Base: Elements of Anatomy and Embryology
The skull base is a complex anatomical region that forms the floor of the cranial cavity. The knowledge of this structure is essential to understand the difficulties of surgical procedures in this site. 1 Because of its embryology, it represents a key player in the development of adjacent structures as the brain, the neck, and craniofacial skeleton. 2, 3
It develops mainly in the midline, where it is composed of basioccipital, sphenoid, ethmoid, and frontal bones, and it extends laterally, with paired temporal bones. The intracranial portion of the skull base is generally divided into three regions: the anterior, the middle, and the posterior cranial fossa (ACF, MCF, and PCF, respectively).
Anteriorly, the ACF is limited by the posterior wall of the frontal sinus; the posterior limit is marked by the anterior clinoid processes and the planum sphenoidale, while the frontal bones form the lateral walls. The floor of the ACF is made of the orbital portion of the frontal bone and, in the center, by the ethmoid bone, with its cribriform plate that is passed by the olfactory tracts. Therefore, the ACF region takes contact with delicate structures as the olfactory bulb, the optic nerves, the supracavernous internal carotid artery, the superior and inferior orbital fissures that convey cranial nerves and veins.
The anterior limit of the MCF is formed by the greater wings of the sphenoid which extend laterally and upward to meet the temporal bones and part of the parietal bones. The body of the sphenoid bone forms the center of the MCF and is composed of the sella turcica, a prominent concave structure that guests the hypophysis and that is delimited at both sides by the cavernous sinuses. The latter are crossed by the internal carotids and the abducens nerves bilaterally; maxillary, ophthalmic, trochlear, and oculomotor nerves run within their lateral walls. The petrous portion of the temporal bone limits the MCF posteriorly; it houses the trigeminal ganglion in the Meckel cave, a duplication of the dura that lies in its anteromedial tip.
The anterior portion of the PCF is formed by the basal portion of the occipital bone and the basisphenoid, while the posterior surfaces of the petrous temporal bones and the lateral aspect of the occipital bones form the lateral wall.
The skull base is an intriguing structure also because of its distinct embryologic origins. While the anterior region origins from the neural crest, just like other facial bones, the posterior region derives from the paraxial mesoderm and the division of these two areas is marked by the middle of the basisphenoid. Endochondral ossification is the mechanism by which the skull base takes origin from a cartilage plate (chondrocranium) that later is replaced by bones, unlike other craniofacial bones that derive from intramembranous ossification. SOX9 transcription factor is essential in the neural crest chondrogenesis of the skull base, 4 in SOX9-knockout mice, the sphenoid bone is missing.
3.2 Surgical Resectability
Several different neoplastic processes can manifest in the skull base, with different distribution in the anterior, middle, and posterior regions, respectively (▶ Table 3.1). Meningiomas can occur in the whole skull base and all their aspects will be thoroughly treated in this chapter. Even though they mostly are benign lesions, in this site, complex anatomy and proximity to cranial nerves and important vasculature make surgical treatment of skull base meningiomas more challenging. However, modern imaging techniques CT, MRI, positron emission tomography [PET]) provide precise anatomical detail 5 that may be of help in planning surgery. Furthermore, neuromonitoring and microsurgical instruments have greatly improved surgical resectability of skull base meningiomas. 6 In the surgery of ACF and MCF lesions, the preservation of visual functions is crucial, much to affect the selection of the best therapeutic approach. In case of lesions of the cavernous sinus, stereotactic radiotherapy in addition to subtotal resection has been regarded an acceptable treatment that preserves cranial nerves functions. 7 PCF meningiomas represent the most challenging tumor, especially the petroclival, due to the proximity to neurovascular structures. In the past, most of them were considered unresectable.
Endolymphatic sac tumor
Sinonasal undifferentiated carcinoma
Meningioma of the jugular foramen
Juvenile nasal angiofibroma
Skull base metastases
Arachnoid granulation (dural sinus)
Hemangiopericytoma/fibrous solitary tumor
Glomus jugulare paraganglioma
Nerve sheath tumor
Skull base metastases
Hemangiopericytoma/fibrous solitary tumor
Giant cell tumor
3.3.1 Definition and Epidemiology
Meningiomas represent a group of neoplasms deriving from the arachnoidal cap cells and showing a wide range of morphologic aspects. They account for 36% of all brain tumors and only for 2.8% in pediatric population. 8 Most of them are sporadic, but a history of prior radiation is the only predisposing environmental risk factor that has been recognized. Chemical, dietary factors, occupation, head trauma, and the use of mobile phone have all been investigated as possible risk factors, but no conclusive evidences have been provided in this regard. 9
Intracranial meningiomas occur preferentially on the parasagittal structures of the cerebral convexities such as the falx and the venous sinus, but they frequently involve also skull base structures such as olfactory grooves, sphenoid ridges, para-/suprasellar regions, optic nerve sheaths, petrous ridges, tentorium, and posterior fossa.
The 2016 WHO classification 10 recognized three grades of malignancy based on morphologic parameters. Grade I meningiomas, which represent the majority, are benign tumors with a low recurrence rate (7–25%); grade II represents an intermediate category with a significant increased risk of recurrence (29–52%) and decrease in survival; grade III, truly malignant lesions, has an increased risk not only of recurrence (50–94%), but also of distant metastasis and death from disease.
Among grade I meningiomas, nine histological variants are included:
Meningothelial: A frequent variant, characterized by lobules of medium-sized epithelioid tumor cells, delimited by collagenous septa. Indistinct cell borders explain the term “syncytial meningioma” that was used in the past. Occasional atypical cells may be observed, but they have no prognostic relevance.
Fibrous: Intersecting fascicles, also showing a storiform pattern, of fibroblast-like spindle cells are characteristic of this variant. There is often a prominent collagen deposition (▶ Fig. 3.1).
Transitional: The most common variant, composed of a mixture of meningothelial and fibrous types. Whorls are well represented, often in association with psammoma bodies (▶ Fig. 3.2).
Psammomatous: Common variant in the spinal cord of older women; psammoma bodies represent over half of the tumor and over time their confluence evolves into calcifications that may obscure meningothelial cells (▶ Fig. 3.3).
Angiomatous: Meningiomatous cells are intermingled with numerous (exceeding 50% of the total tumor volume) small- to middle-sized blood vessels, that are thin- or thick walled, and variably hyalinized; tumor cells with degenerative nuclear atypia may be observed but almost all cases are benign. Angioblastic meningioma is another entity and is the term that was referred in the past to solitary fibrous tumor/hemangiopericytoma (SFT/HPC), a tumor that may exhibit aggressive behavior (see below) (▶ Fig. 3.4).
Microcystic: Neoplastic cells have thin elongated processes that are arranged in a cobweb-like background due to the collection of intercellular clear fluid and often display nuclear degenerative atypia. Hypervascularity may be observed (▶ Fig. 3.5).
Secretory: Pseudopsammoma bodies are pathognomonic morphologic features, consisting of intracellular lumina containing periodic acid–Schiff-positive (PAS-positive) eosinophilic secretions (▶ Fig. 3.6), which are also positive to carcinoembryonic antigen (CEA). It may be explained as an advanced form of epithelial differentiation; cells surrounding them usually react to cytokeratin. Very rare is the pure form; this morphologic aspect usually develops inside a meningothelial or transitional meningioma. Secretory meningiomas may have a particular clinical relevance because they can cause severe cerebral edema more frequently than other variants.
Lymphoplasmacyte-rich: In this variant, a dense infiltrate of lymphocytes and plasma cells exceeds the neoplastic proliferation so that to obscure it. It may also be referred with the definition of “inflammation-rich meningioma.”
Metaplastic: This variant, while retaining immunohistochemical and ultrastructural features of meningothelial cells, may include areas of cartilaginous, osseous (▶ Fig. 3.7), lipomatous, myxoid, and xanthomatous tissue, either singly or in combination.
Fig. 3.1 Fibrous meningioma. The neoplasm is composed of spindled cells forming parallel, storing, and interlacing bundles in a collagen-rich matrix. (Hematoxylin and Eosin stain, 20x magnification.)
Fig. 3.2 Transitional meningioma. Histological variant containing meningothelial and fibrous patterns, as well as transitional features. Focal xanthomatous degeneration may be observed on the left side. (Hematoxylin and Eosin stain, 20x magnification.)
Fig. 3.3 Psammomatous meningioma. In this variant, psammoma bodies are predominant over tumor cells. (Hematoxylin and Eosin stain, 10x magnification.)
Fig. 3.4 Angiomatous meningioma. Numerous blood vessels characterize this histological variant and are intermixed with meningothelial meningioma cells. (Hematoxylin and Eosin stain, 10x magnification.)
Fig. 3.5 Microcystic meningioma. A cobweb-like background is provided by cells with thin, elongated processes. (Hematoxylin and eosin stain, 20x magnification.)
Fig. 3.6 Secretory meningioma. Focal epithelial differentiation consists of intracellular lumina containing periodic acid–Schiff-positive pseudopsammoma bodies. (Periodic acid–Schiff histochemical stain, 20x magnification.)
Fig. 3.7 Metaplastic meningioma. Osseous metaplastic tissue makes part of the neoplasm. (Hematoxylin and Eosin stain, 10x magnification.)
Three subtypes of meningiomas are of grade II:
Atypical: Despite the name, cellular atypia is not a diagnostic feature. The diagnosis is made when one of the three major criteria is satisfied:
High mitotic index (≥4 mitoses/10 HPF) (▶ Fig. 3.8).
Brain invasion (presence of irregular, tongue-like protrusions of tumor cells that infiltrate the parenchyma, without the interposition of leptomeninges) (▶ Fig. 3.9) in meningiomas that otherwise appear benign.
At last three of five morphologic parameters (sheeting architecture, presence of small cells with high nuclear/cytoplasmic ratio, hypercellularity, prominent nucleoli, and spontaneous necrosis) (▶ Fig. 3.10).
Chordoid: Its name derives from the striking resemblance to chordoma, a bone tumor composed by ribbons or cords of epithelioid to spindle cells arranged in a basophilic mucoid matrix; foamy or vacuolated “physaliphorous-like” cells are also present (▶ Fig. 3.11). Pure forms are rare; they are usually intermingled with more typical meningioma tissue. The presence of a well-developed chordoid pattern has been associated with an aggressive behavior.
Clear cell: Usually of the spinal cord or of the PCF, they are composed by sheets of polygonal clear cells, whose aspect is due to cytoplasmic glycogen accumulation, that is positive to PAS diastase (▶ Fig. 3.12). Psammoma bodies and whorls formation are rare. Interstitial and perivascular collagen deposition is a distinctive feature; in cases of coalescence, large acellular zones of hyalinization or amianthoid-like collagen may be observed.
Fig. 3.8 Atypical meningioma. High mitotic rate (arrows) was detected throughout this atypical meningothelial meningioma. (Hematoxylin and Eosin stain, 40x magnification.)