Meningeal Lesions



Meningeal Lesions





Meningioma


General

Meningiomas arise from the arachnoid cap cells that inhabit the most superficial portion of the arachnoid membrane, just below the inner surface of the dura. These cells are most concentrated around the arachnoid villi where they form a cap over each villus, yet can be found wherever there are meninges, both as single cells and as small syncytial clusters that resemble minute meningiomas. Electron microscopy and immunohistochemistry support these histologic similarities, with intercellular tight junctions and epithelial membrane antigen (EMA) reactivity being seen in both. Rests of these cells created during development explain the appearance of meningiomas in extradural locations, such as the ventricles (Figure 9-1).

Although the great majority of meningiomas are benign and have a characteristic appearance, some can prove challenging both in appropriate grading and in identification. The 2016 World Health Organization (WHO) classification of central nervous system (CNS) tumors codifies a grading system for meningiomas that is among the most complicated of any tumor type, the application of which can be intimidating without experience or guidance. However, grading of meningiomas has become standard practice and has important prognostic implications and should never be omitted from the pathology report. In some cases, grading of meningiomas can be a secondary issue when a lesion presents with one of the more unusual patterns, and identification of the tumor as meningothelial takes precedence.


Clinical Context

Meningiomas constitute approximately 37% of all primary CNS-related neoplasms, making them the most common primary intracranial tumors (1). They are primarily a tumor of adults, and among those younger than 20 years, they are not even among the 10 most frequent tumor types (2). Meningiomas preferentially affect women at a ratio of approximately 3:2, although sex differences in meningioma incidence vary by location, with thoracic spinal meningiomas occurring at a 9:1 female to male ratio. Meningiomas present at a mean age of around 64 years, with no difference
in incidence among races. Groups who have lower incidences of meningiomas, specifically men and children, tend to have more aggressive tumors when they do occur. Most meningiomas present with symptoms and/or signs related to location and mass effect or to peritumoral edema, but lesions that invade the full thickness of the skull can present as fleshy scalp masses (3).






FIGURE 9-1 Meningothelial clusters such as these in the parasagittal dura (arachnoid villi) are physiologic, small, and nonproliferating.

The familial tumor syndrome most consistently associated with the development of meningiomas is neurofibromatosis type 2 (NF2), in which patients harbor a germline mutation in the NF2 gene at locus 22q12. Although meningiomas have been reported in patients with other tumor syndromes, the statistical relevance of such observations is unclear. In general, meningiomas in the context of NF2 occur earlier in life, are multiple, and are slightly more clinically aggressive than sporadic meningiomas (4,5). Dozens of meningiomas may pepper the dura of patients with NF2. NF2 also predisposes one to developing schwannomas and spinal ependymomas.

Germline mutations in the SMARCB1 gene, which is also the gene responsible for the familial rhabdoid tumor predisposition syndrome, have been implicated in familial cases of multiple meningiomas (6,7). SMARCE1 germline mutations are associated specifically with clear cell meningiomas (see below section Clear Cell Meningioma). Other germline mutations associated with meningiomas have included SUFU (8) and BAP1 (9).

Prior exposure to ionizing radiation has been solidly linked to the development of meningiomas in the setting of low-dose x-ray treatment for tinea capitis (10), and in the setting of high-dose therapeutic radiation for malignancy (11,12).


Meningiomas may occur anywhere in the neuraxis, with a strong preference for the meninges overlying the cerebral convexities and parasagittal areas (lateral to the superior sagittal sinus). Other common sites for meningiomas include the falx, wing of the sphenoid bone (“sphenoid ridge” that is the anterior limit of the temporal fossa), cribriform plate (olfactory groove), tentorium, and supra- or parasellar region. Intraventricular meningiomas typically form in the trigone of the posterior-lateral ventricle, where the bulk of the choroid plexus lies, and may rarely arise in other parts of the lateral ventricles or even the third and fourth ventricles.


Radiology






FIGURE 9-2 An enhancing dural lesion that tapers into a “dural tail” is the characteristic, though nonspecific, neuroimaging finding of meningioma.

Most meningiomas can be diagnosed clinically on the basis of their characteristic appearance on contrast-enhanced neuroimaging, where they cut a lens-shaped silhouette that tapers off into the surrounding dura. Meningiomas are best visualized radiologically with administration of contrast material because they are generally isointense to gray matter on computed tomography (CT) and T1-weighted magnetic resonance imaging (MRI), and can be difficult to distinguish from their surroundings. Fortunately, gadolinium contrast agent brilliantly illuminates meningiomas, such that lesions as small as a grain of rice can be detected. The “dural tail” sign, or the thin edge of surrounding contrast enhancement, provides the radiologist with a reasonably reliable means of identifying a meningioma (Figure 9-2). Although many other dura-based lesions also show a dural tail, the great majority of such cases will be meningiomas. T2-weighted MRI can often discriminate between meningiomas and their surroundings, although the intensity of the lesion’s signal may vary, depending on the histologic pattern
(13). Peritumoral edema is highly variable, being associated with more aggressive meningiomas and either secretory or angiomatous histologic pattern. Other features that signal meningioma on imaging are hyperostosis and calcification (on CT).

Meningiomas may also present with unusual radiologic findings. Occasionally, a cystic space will form along the edge or in the middle of the lesion, giving it an overall cyst with nodule configuration. En plaque growth of meningiomas usually occurs along the base of the brain in the middle fossa and can give the impression of other processes. Osteolytic growth, bone invasion, and primary intradiploic occurrence are all seen in meningiomas but are much less common.


Prognosis/Treatment

Surgical removal is the treatment of choice for meningiomas, except in cases where the risks of surgery may outweigh the benefits. In cases with subtotal resection, or with a grade II or grade III diagnosis, adjuvant radiotherapy may be employed to effectively reduce the risk of recurrence and mortality (14); however, clear class I evidence for its efficacy is lacking, as are uniform guidelines for its application (15).

Most patients with meningiomas are cured of their disease by surgical excision, if the entire lesion can be removed. This is an important point because incomplete resection is the single best predictor of recurrence; around 90% of patients with a completely resected grade I meningioma will be free of recurrence at 5 years, but that percentage falls to 60% to 70% with incomplete removal (16). Whether a meningioma can be totally resected is mostly a function of location, with those in the skull base or involving major vascular structures being among the most difficult to excise. Grade II meningiomas have an increased rate of recurrence, around 40%, even when the tumor is completely resected, and grade III lesions have a recurrence rate of 60% or more (17,18). Survival is not adversely affected in cases of grade I meningioma, but the mortality rates for grade II and grade III meningiomas are approximately 20% and 70% at 5 years, respectively (17). Neuroimaging findings may also be used with extent of resection to predict risk of recurrence (19).

Invasion into bone may also be a factor in tumor recurrence and has been shown to negatively impact recurrence and overall survival in cases of atypical meningioma (20), but currently it has no clear place in the WHO grading scheme. Whether bone resection or radiation affects outcomes in these cases deserves to be explored.

Although the incidence of metastasis is only approximately 1 per 1,000 primary meningiomas, it is a well-documented phenomenon, even in cases with grade I histology (21,22,23,24,25). The most common metastatic site is the lung, with reports of vertebra and scattered other sites making up the remainder. Some of the suggested risk factors for metastasis in meningiomas are invasion of venous sinuses, aggressive histologic features, and craniotomy for primary tumor resection (25).



Histopathology

Where applicable, although this section mainly addresses the histologic patterns of meningioma, specific genetic findings that are characteristic for a given pattern are discussed along with the defining microscopic findings. The genetics of meningiomas as a general group are discussed in the following section.


Who Grade I Meningiomas

Differentiating between the patterns of grade I meningiomas in the diagnostic line of the pathology report is generally not necessary, but an awareness of the many faces of meningioma will prevent diagnostic confusion when unusual patterns arise. All of these patterns below are generally WHO grade I but may be higher grade if they meet other histologic criteria or invade the brain.


Meningothelial

This pattern is composed of whorls and small sheets of syncytial, polygonal cells with smooth eosinophilic cytoplasm, regularly contoured oval nuclei, minute nucleoli, and pale, finely granular chromatin (Figures 9-3 and 9-4). Scattered nuclei contain pseudoinclusions, or cytoplasmic intrusions, similar to those seen in papillary thyroid carcinoma. Present in most patterns of meningioma, pseudoinclusions are sharply circumscribed, devoid of contents, and compress the surrounding chromatin against the nuclear envelope. The whorls in this pattern are often vague and lobular, their edges blending with the surrounding tumor cells (Figure 9-5). Collagen deposition is minor, but fibrous septa and perivascular collagen can be present.


Fibrous






FIGURE 9-3 Cytologic crush preparations show the individual cells of meningioma: monotonous, pale, oval, regular nuclei, and vaguely tissue-paper–like cytoplasm.

Fibrous meningiomas share few of the morphologic characteristics of their meningothelial siblings and can be mistaken for other
entities, specifically schwannoma (when in the cerebellopontine angle) and solitary fibrous tumor. The architecture ranges from fascicular to storiform (Figures 9-6 and 9-7), with few whorls or psammoma bodies and abundant collagen deposition. Collagen is deposited both in thick bands along blood vessels and as a dense, diffuse background matrix admixed with tumor cells. Dense bands of acellular collagen can replace the vast majority of the tumor, leaving only traces of the tumor’s cells. These cases
are sometimes called “sclerotic” meningiomas (Figure 9-8). The typical nuclear features of oval shape with regular outlines and pale chromatin are distorted into elongate nuclei with irregular outlines.






FIGURE 9-4 Most meningiomas are resistant to crushing. Tight cellular whorls and monotonous nuclei with pseudoinclusions are characteristic.






FIGURE 9-5 Meningothelial meningiomas are highly syncytial with subtle whorls and little background collagen.






FIGURE 9-6 Fibrous meningiomas often grow in fascicles with irregular nuclei and lack whorls and psammoma bodies.


Transitional






FIGURE 9-7 A storiform pattern manifests in some fibrous meningiomas.

This pattern, transitional between meningothelial and fibrous, comprises the largest fraction of meningiomas and is the archetype of meningioma (Figure 9-9). The centers of the cellular whorls often hyalinize over time, leaving bubble-gum–colored spheres of protein, which,
after more time, transform into psammoma bodies. Psammoma bodies are common in several patterns of meningioma and can provide a helpful diagnostic cue when other features are lacking.






FIGURE 9-8 Dense acellular bands of collagen crowd the few remaining tumor cells in sclerotic fibrous meningiomas.


Psammomatous






FIGURE 9-9 The transitional pattern of meningioma, with whorls and collagen deposition, spans the gap in appearance between meningothelial and fibrous patterns.

This striking pattern is an ordinary meningioma that has numerous whorls that have mineralized and formed lamellated spheres of calcium, or psammoma bodies (Figure 9-10). As might be inferred from the heavy calcification, these lesions are generally slow-growing (if at all),
lack atypical features, and have a low MIB1 index. In extreme cases, it may be difficult to identify the residual meningioma cells among the extensive calcifications. Most psammomatous meningiomas occur in the spinal canal in women older than 40 years. Even among intracranial examples, there remains a strong predilection for women (26).






FIGURE 9-10 Psammomatous meningiomas result from extensive calcification of meningothelial whorls, sometimes with little of the original tumor left.


Angiomatous

This pattern overlaps with microcystic meningioma, with vacuolated cells and cobweb cytoplasm in many cases, but requires 50% or greater area of blood vessels to tumor tissue for inclusion, as put forward in one large series examining these lesions pathologically (27). The authors of this series recognized two patterns of angiomatous meningioma, macrovascular and microvascular, the macrovascular comprising a little more than half of the total cases. The macrovascular pattern displayed mostly large blood vessels with prominent hyalinization and intervening areas of usual meningioma, with syncytial whorls and short fascicles. The microvascular pattern was composed of small blood vessels with delicate walls in a background of microcystic meningioma in almost all cases, at least focally (27) (Figure 9-11). The vast majority of angiomatous meningiomas are grade I. Like secretory meningiomas, angiomatous ones are also associated with exaggerated peritumoral edema (28).

Theoretically, in the rare instance of an angiomatous meningioma in the posterior fossa, one could mistake a microvascular angiomatous meningioma with microcystic change for a hemangioblastoma. A dural-based location on imaging would heavily favor the former, as would positive immunostaining for somatostatin receptor 2A (SSTR2A), EMA, or progesterone receptors, and no inhibin immunostaining.







FIGURE 9-11 Angiomatous meningioma with striking vascularity and intervening microcystic cells (microvascular pattern).


Microcystic






FIGURE 9-12 Microcystic meningiomas typically exhibit variably sized cells containing clear cytoplasm, “cobweb-like” vacuolization, and degenerative nuclear atypia.

Microcystic meningioma is most notable for not resembling the other members of the meningioma group. Although microcystic change is common focally in meningiomas of other patterns, some cases express it diffusely, creating diagnostic confusion for the pathologist expecting whorls and regular oval nuclei. In contrast to other subtypes, microcystic meningioma has large cells with clear cytoplasm formed from large vacuoles separated by cobweb-like strands (Figure 9-12). The cytoplasmic vacuoles in this lesion
vary greatly in size, lacking the regularity of those usually seen in renal clear cell carcinoma or hemangioblastoma, with single large vacuoles sometimes occupying the entire cytoplasm. Nuclei in microcystic meningioma are prone to degenerative atypia, becoming hyperchromatic, irregular, and variable in size, ranging from small to gigantic (Figure 9-13). Some of the meningioma characteristics that microcystic lesions retain are hyalinized blood vessels and thick collagen bands, either of which can be diagnostically helpful. Nuclear pseudoinclusions are also retained. Although the cytoplasm of microcystic meningioma is clear, or nearly so, this generally indolent grade I pattern should not be mistaken for the grade II clear cell meningioma. Microcystic meningioma can occur as a purely intraosseous lesion and can be mistaken clinically for metastasis (29).






FIGURE 9-13 Degenerative nuclear atypia is common in microcystic and angiomatous meningiomas and is prognostically unimportant.


Secretory

The defining feature of this meningioma pattern is the “pseudopsammoma body,” which is an intracellular, eosinophilic, spherical cytoplasmic inclusion that occurs in scattered cells within an otherwise usual meningioma (Figure 9-14). These structures are periodic acid-Schiff (PAS)-positive and immunoreactive for cytokeratins and carcinoembryonic antigen (CEA) (30). Secretory meningiomas usually also contain mast cell infiltrates. Although overwhelmingly benign, these lesions may have a higher rate of postoperative complication due to severe peritumoral edema. About 35% of patients with secretory meningiomas in one series had severe peritumoral edema that persisted after excision, and over a third of these patients required mechanical ventilation and intracranial pressure monitoring (31).

In a recent series, mutations in two genes, KLF4 and TRAF7, were both present in nearly all tested cases of secretory meningioma and were not found together in a large group of meningiomas of other patterns,
other brain tumors, metastatic tumors, or a small set of tumors from other organs, although isolated TRAF7 mutations were found in a few other meningiomas. KLF4 is more restricted to secretory meningiomas and has only shown one hotspot mutation in that context, K409Q. These mutations appear to be mutually exclusive with mutations in NF2, which are the most common genetic finding in meningiomas overall, suggesting that secretory meningiomas arise through a related but separate pathway from most others (32).






FIGURE 9-14 The distinctive secretory bodies of secretory meningioma are periodic acid-Schiff–positive and immunoreactive for cytokeratin and carcinoembryonic antigen, causing potential for confusion with carcinoma.


Lymphoplasmacyte Rich

This rare class of meningiomas has not been studied in great numbers, the largest series being 19 cases, and remains controversial as a distinct pathologic entity (33). A dense, sometimes overwhelming, lymphoplasmacytic infiltrate crowds, and sometimes conceals, the native tumor cells (Figure 9-15). Plasma cells in these lesions frequently contain Russell bodies. Some patients with this lesion have had a polyclonal hypergammaglobulinemia (33,34,35). No evidence suggests that the lymphoplasmacytic infiltrate is neoplastic. An examination of 16 cases showed that plasma cells make up a minor component of the inflammation and generally don’t express IgG4. That work also found that the predominant inflammatory cell type was macrophages and recommended the term “inflammation-rich meningioma” as a more accurate term (36). Immunostaining for SSTR2A might sometimes be useful to demonstrate the meningothelial component of this lesion. EMA immunostaining would label both tumor cells and plasma cells. Dural lesions that could possibly be confused with this entity include low-grade lymphoma, sarcoidosis, Rosai–Dorfman disease, Castleman disease, Langerhans histiocytosis, idiopathic pachymeningitis, and “plasma cell granuloma.”







FIGURE 9-15 The rare lymphoplasmacyte-rich meningioma can be obscured by inflammatory cells and raise a long differential diagnosis of inflammatory lesions and lymphomas.


Metaplastic






FIGURE 9-16 Lipidized tumor cells give the appearance of metaplastic adipose tissue in some meningiomas.

Mesenchymal tissue including bone and cartilage can develop within otherwise regular meningiomas. Although still generally considered a part of metaplastic meningiomas, evidence suggests that those with apparent adipose metaplasia (Figure 9-16) may result from lipidization of tumor cells (37,38). The term metaplastic has been applied to meningiomas with a prominent myxoid background into which tumor cells are singly dispersed, a description that overlaps significantly with that
of chordoid meningioma. Although the vast majority of metaplastic meningiomas are grade I, metaplasia has also been described rarely in malignant meningiomas (39).








TABLE 9-1 Summary of World Health Organization 2016 Meningioma Grading Scheme














Grade I Grade II Grade III
0–3 mitoses/10 hpf 4–19 mitoses/10 hpf ≥20 mitoses/10 hpf
Two or fewer atypical histologic features OR
Three or more of necrosis, macronucleoli, loss of architecture, small cell change, or hypercellularity
OR
Brain invasion
OR
Clear cell or chordoid pattern
OR
Papillary or rhabdoid pattern
OR
Otherwise overtly sarcoma- or carcinoma-like


WHO Grade II Meningiomas

WHO grade II meningiomas have an increased rate of recurrence and tumor-associated mortality compared with WHO grade I meningiomas. In addition to the chordoid and clear cell patterns that automatically earn grade II status, there are three other avenues by which this grade can be achieved: increased mitotic count, a total of three or more atypical histologic features, or brain invasion (17,18) (Table 9-1). Atypia of mitotic figures, pleomorphism, and nuclear atypia do not predict the behavior of meningiomas and are not components of their grading. About 15% to 20% of all meningiomas are grade II.


Atypical Meningioma

Atypical meningiomas, WHO grade II, may be diagnosed by two sets of histologic criteria: (1) mitotic rate; or (2) a combination of three or more histologic features of atypia. In meningiomas, an elevated mitotic count is defined as a rate of 4 or more mitoses in 10 contiguous 400× fields, in the area of greatest mitotic activity in the examined tissue. Twenty or more mitoses elevate the neoplasm to grade III. Although not part of the meningioma grading scheme itself, a MIB1 immunostain is helpful in finding the area of maximal proliferation. Examining contiguous fields within the area of greatest proliferation is not specifically suggested in the WHO manual but recapitulates the methodology used in the articles that established these criteria (17,18).

There are five histologic features that indicate increased aggressiveness of meningiomas, even when the mitotic rate is lower than that required for atypical status: necrosis, loss of architecture, hypercellularity, macronucleoli,
and high nucleus to cytoplasm ratio (small cell formation) (Figures 9-17 to 9-19). If three or more of these features are identified in a lesion, in any amount, the lesion meets criteria for “atypical meningioma, WHO grade II” according to the 2016 classification (40). Necrosis can be multifocal or geographic throughout a lesion and need not be in a particular pattern or amount. That is, any necrosis counts, as long as it is spontaneous. Widespread necrosis occasionally can be the result of presurgical embolization
of a meningioma, in which case it does not count as an atypical feature (Figure 9-20). Loss of architecture, or “sheetlike” growth pattern, means that the tumor cells lose their whorling or fascicular arrangement and grow in a homogeneous, patternless fashion. Hypercellularity has been quantified as 53 or more nuclei per high-power field (hpf) diameter (18) but can be evaluated subjectively in most cases. Small cell formation typically
occurs as multifocal aggregates of very small tumor cells with round nuclei and scant cytoplasm that resemble lymphocytes.

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Oct 22, 2018 | Posted by in NEUROLOGY | Comments Off on Meningeal Lesions

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