Primary extradural meningiomas (PEMs) represent about 2% of all meningiomas.1 Familiar to neurosurgeons, meningiomas represent one of the most common intracranial tumors encountered. When they occur extracranially, they are typically treated by surgeons unfamiliar with this tumor type. The clinical and radiographic presentation of benign, atypical, and malignant PEMs may be similar; therefore, all types demand careful operative planning and postoperative treatment. This manuscript describes the key features of these challenging tumors to aid in diagnosis, presents the largest published review of all reported PEMs, and provides much needed treatment guidelines to surgeons unfamiliar with these challenging tumors.
Primary extradural meningiomas (PEMs) represent about 2% of all meningiomas and are often encountered by non-neurosurgeons. These lesions typically present as enlarging, painless, benign masses that can be surgically cured. Imaging is critical for defining involvement of adjacent structures; however, diagnosis depends on classic histologic patterns. Treatment for benign PEMs (WHO I) consists of resection with wide margins, whereas adjuvant therapy after resection of atypical (WHO II) or malignant (WHO III) PEMs should be considered. By using the collective experience from our comprehensive cancer center, including neuro-oncologists, neuroradiologists, and neurosurgeons, in addition to a complete literature review, the authors have established treatment guidelines not previously reported. This manuscript describes key features of these challenging tumors to aid in diagnosis, presents the largest published review of all reported PEMs (n = 163), and provides salient treatment guidelines to surgeons unfamiliar with these challenging tumors. Cancer 2011. © 2010 American Cancer Society.
MATERIALS AND METHODS
A literature review of PEMs was compiled through MEDLINE/OVID using the keywords intraosseous meningioma, extradural meningioma, ectopic meningioma, extracranial meningioma, cutaneous meningioma, calvarial meningioma, and extraneuraxial meningioma, covering the years from 1902 to 2009. This search yielded 65 articles. We examined these articles and their references to identify articles with sufficient informative data for developing treatment guidelines. From this list, we compiled 162 different cases, which we present in Table 1.
|Age, y||Sex||Tumor Location||Sx||Sx Duration, y||Hx of Trauma||Tumor Histology||Tumor Type||Treatment||Time Until Recurrence, y||Survival, y||Year Published Ref|
|29||Males||Spine, C1-C4||Neck pain||0.5||Yes||B||I||STR||N/A||N/A||197770|
|65||Females||Frontal||H, seizures, dizziness||2a||No||B||I||GTR||N/A||4||197971|
|26||Females||Sphenoid||H, double vision||0.67||No||B||I||GTR||N/A||N/A||197971|
|65||Males||Nasal/Ethmoid||NO, orbital swelling||0.1||No||B||I||GTR||N/A||0.67||198041|
|60||Females||Temporal||H, VII nerve paralysis||40||No||B||IIIC||STR||N/A||0.01b||198337|
|62||Males||Temporal||H, personality change||5||No||B||IIIC||None||N/A||N/Ac||198337|
|96||Females||Temporal||HL, M, dementia||1||No||B||IIC||None||N/A||2||198337|
|73||Females||Ethmoid||NO, E, M||N/A||No||B||IIC||GTR||N/A||3||198337|
|23||Males||Paranasal||NO, cheek swelling||0.33||No||B||I||GTR||N/A||1.25||198374|
|17||Males||Nasopharynx||HL||3||No||B||I||GTR, radiation (unknown dose)||N/A||N/A||198375|
|7||Males||Jugular foramen||H, otalgia, facial palsy||3||No||B||IIB||GTR||N/A||1||198375|
|50||Females||Ethmoid/Sphenoid||HL, H, chronic sinusitis||2||No||MA||IIC||GTR||2||N/A||198476|
|67||Females||Intranasal||H, loss of vision||7||No||B||IIC||5000 rad; 3000 at recur.||1||N/A||198476|
|51||Females||Cheek, temporal, & intranasal||NO, HL, loss of vision||2||No||B||IIC||GTR||3||N/A||198476|
|64||Males||Zygomatic||NO, E, H||1||No||B||IIC||GTR; radiation||N/A||N/A||198476|
|22||Females||Nostril||M, eye pain||0.06||No||B||I||GTR||23||28||198476|
|49||Females||Temporal||M, chewing pain||2||No||B||IIC||GTR||N/A||N/A||198476|
|76||Males||Maxillary||NO, E, H||16||No||B||I||GTR||1||N/A||198529|
|60||Females||Supraorbital||NO, E, M, vision loss||0.5||No||B||I||GTR||N/A||0.5||198632|
|69||Females||Intratemporal fossa||H, cheek swelling||0.06||No||B||IIC||GTR||N/A||0.75||198778|
|84||Females||Infratemporal fossa||Temporal muscle pain||N/A||No||B||IIC||GTR||N/A||1.5||198778|
|18||Males||Ethmoid||NO, decreased vision||5||No||B||I||GTR||N/A||1.5||198781|
|63||Females||Maxillary||Maxillary swelling, swallowing||2||No||B||I||None||N/A||N/A||198782|
|38||Males||Adrenal||Hypertension, nephrotic syndrome||2||No||B||I||GTR||N/A||N/A||198883|
|78||Females||Adrenal||Chest pain, hypertension||1||No||B||I||GTR||N/A||N/A||198883|
|61||Males||Frontoparietal||M||0.17||No||B||IIC||GTR, 5000 rad||2||3||198884|
|19||Males||Temporal fossa||Eye pain, temporal swelling||11||No||B||IIC||GTR||N/A||N/A||199139|
|61||Males||Frontoparietal||M||0.17||No||B||IIC||GTR, 5000 rad||2||3||198884|
|19||Males||Temporal fossa||Eye pain, temporal swelling||11||No||B||IIC||GTR||N/A||N/A||199139|
|42||Males||Temporal||HL, facial swelling, nerve paralysis||0.67||No||MA||IIC||STR||N/A||1||199335|
|11||Males||Nasal/Ethmoid||E, vision problems||3||No||B||I||GTR||N/A||3||199394|
|25||Females||Retroperitoneum||Upper quad pain||0.17||No||MA||I||GTR||0.5||2c||199642|
|37||Males||Zygomatic arch; temporal bone||HL||0.5||No||B||IIC||GTR||N/A||N/A||1997102|
|71||Males||Orbit||Loss of vision||0.5||No||B||I||GTR||N/A||N/A||1999106|
|60||Females||Parieto-occipital||Tinnitus||N/A||No||B||IIIB||Etidronate disodium for 6mo||N/A||N/A||20045|
|50||Males||Spine, C1-C4||Hand numbness||N/A||No||B||I||GTR||N/A||3||2006123|
|22||Females||Spine, C1-C5||Hand weakness, gait disturbance||4||No||B||I||STR||N/A||1||2007131|
|13||Females||Ethmoid||H, NO, proptosis||0.83||No||A||I||GTR||N/A||2||2008132|
|44.6M: F, 1:1.4||H or Focal pain (22.7%); M (52.1%); Nerve palsy (18.4%)||3.36||Yes, 3.7||B, 143 A, 9MA, 11||I, 80 IIB, 6 IIC, 70 IIIB, 1 IIIC, 6||GTR 85.9%||Median, 3||Mean, 2.7|
The PEM cases reviewed for demographics, symptoms, medical history, treatment, and follow-up data are presented in Table 1. Including our illustration, 163 cases of PEM appear in the literature. The male-to-female ratio was 1:1.4, and patients were an average of 44.6 years old at diagnosis. Although the majority of tumors were located in skull convexities (52.5%), we found other tumors located in various regions such as the neck, chest, shoulder, spine, and peritoneum (Fig. 3). Patients with skull PEMs most commonly present with a nonpainful mass in the region of the tumor (52.1%), focal pain in the area of the tumor (22.7%), or (rarely) with cranial nerve deficits (18.4%). Other rare symptoms of skull PEMs include seizures, dizziness, behavioral disturbances, loss of vision, and eye proptosis. Patients with nonskull PEMs most commonly present with enlarging, nonpainful masses. Symptom duration before treatment averaged 3.36 years. We also found 87.7% of tumors were benign (WHO I), 5.5% atypical (WHO II), and 6.8% malignant (WHO III). A history of trauma at the site of the tumor was seldom seen and present in only 3.7% of cases. Most cases were treated by gross total resection (GTR) (85.9%) with no adjuvant therapies. Of the 163 cases we identified, only 19 had reported recurrences. Thirty-seven percent (7 of 19) of recurrences had malignant histology, whereas 63% were of benign histology. Eight and four-tenths percent (12 of 143) of benign tumors recurred and 63.6% (7 of 11) of malignant tumors recurred. Overall median time to recurrence was about 3 years. There was no significant difference between median time to recurrence by histology or tumor location (Fig. 4). Virtually all patients in this collected series were alive at last follow-up. Of 163 cases, only 4 were noted to die of the disease. The mean follow-up time for patients free of disease was 2.7 years (0.01 to 28 years). On the basis of the PEM classification system of Lang et al,2 we found that 49.6% of tumors were Type I, 3.5% Type IIB, 42.8% Type IIC, 0.6% Type IIIB, and 3.5% Type IIIC (Table 2).
|No. of Cases (%)|
A 61-year-old human with hypertension, type 2 diabetes mellitus, and tobacco use presented with a 1-month history of increasing right parietal headache that was worse at night and relieved with aspirin. He denied any recent history of head trauma, head surgery, or cancer. He had a large, firm, nontender, nonerythematous scalp mass centered over his right parietal boss. A brain magnetic resonance image (MRI) revealed a 5 × 5 cm, round, well-demarcated intraosseous, partially enhancing mass in the right parietal skull (Fig. 1A). A computed tomography (CT) scan of his head confirmed surrounding hyperostotic bone (Fig. 1B). The patient underwent a wide right parietal en bloc excision of the skull mass, removal of underlying dura, and cranioplasty without difficulty. Histopathological findings revealed soft meningiomatous tumor with numerous psammoma bodies (Fig. 2). Some tumor cells appeared sarcomatoid and septated by dilated vascular spaces. Tumor cells were negative for epithelial membrane antigen (EMA), cytokeratin, CD31, and CD34 immunostaining. Decalcification of intraosseous lesions typically results in lack of EMA immunoreactivity. The tumor did not demonstrate significant mitotic activity, necrosis, brain invasion, or a sheeting growth pattern. Despite a negative EMA status, the histologic pattern was diagnostic for meningioma. Four-year follow-up brain MRI imaging revealed no recurrence.
Primary Extradural Meningiomas
The clinical presentation depends on the size and location of the tumor. Skull convexity PEMs present as scalp masses that grow slowly, over months to years, possibly related to cranial sutures, and are more commonly seen in periorbital or frontoparietal regions.3 They typically present as firm, painless masses that do not cause any overlying scalp changes.4 PEMs may be incidentally found; however, numerous symptoms have been attributed to their size and location. These symptoms include focal neurological deficits, seizures, vomiting, dizziness, tinnitus, headache, and vague cranial paresthesias.5–7 Skull base PEMs are also typically slow growing and painless, but more likely to present with ophthalmoplegia, visual field deficits, proptosis, deformity, nasal obstruction, or epistaxis.2, 6 PEMs may also appear in more remote portions of the body, including neck and shoulder subcutaneous tissues, in paraspinal regions, and in organs of the thoracic and peritoneal cavities (Fig. 3). These extracranial lesions typically present as enlarging, painless masses.
Demographics, classification, epidemiology
PEMs are also slightly more common in females.4 PEMs typically occur as solitary lesions in older adults, with a median age at diagnosis in the fifth decade; however, PEMs also show a second peak in incidence in patients in the second decade.2
PEMs were recently classified by Lang and colleagues according to their location: Type I PEMs are purely extracalvarial tumors with no bone attachment, Type II are purely calvarial tumors, and Type III are calvarial tumors with extracalvarial extension.2 Types II and III are further subdivided into convexity (C) or skull base (B). Similar to the Simpson grading system for intradural meningiomas,6 the Lang classification scheme helps predict chance of recurrence. Type IIC or IIIC PEMs very rarely recur after complete resection, whereas Type IIB or IIIB recur in 26% of cases over a lifetime.2
The origin of PEMs is unclear. PEMs have been theorized to arise from undifferentiated mesenchymal stem cells that get trapped or misplaced in intraosseous locations.8 Conceivably, PEMs could arise from undifferentiated arachnoid cap cells associated with blood vessels or cranial nerves traversing the skull.5 Some authors have noticed an association with cranial sutures and suggest that arachnoid cap cells get trapped here during embryogenesis or molding of the cranium at birth.3, 9, 10 Local trauma has been proposed as a causative factor for some PEMs and intradural meningiomas, suggesting that tiny meningoceles with arachnoid cap cells get trapped in fractures. Our literature review revealed a history of trauma in only 3.7% of cases (Table 1). Others have proposed that cellular dedifferentiation of mature mesenchymal arachnoidal cells could also explain PEMs.11
The majority of PEMs are osteoblastic and produce hyperostosis in surrounding bone. Noncontrasted CT shows a focally thickened, hyperdense lesion expanding the calvaria that usually enhances densely after contrast administration.12 The expansion of bone and a “ground glass” appearance are often confused with fibrous dysplasia.13 In less than 20% of cases, PEMs present as osteolytic lesions.14-19 Skull x-rays and CT show a hypodense lesion causing thinning, expansion, and interruption of the inner and outer cortical layers.14 T1-weighted MRI images reveal hypointense lesions, whereas T2-weighted images are hyperintense. Vivid homogenous enhancement after gadolinium administration is the rule. Dural tails are not present in skull PEMs, unless they have extensively eroded through the inner cortical table and have begun to spread along the dura; however, the underlying dura may enhance because of irritation or invasion.20 Angiography typically reveals enlarged, tortuous arterial feeders, a dense tumor blush, and early venous drainage.7, 12, 17 Radionuclide bone scans are usually normal in PEMs; however, when scans show uptake of agent, scans can be used to monitor tumor progression over time or after treatment.5, 21 Osteoblastic PEMs can resemble meningioma en plaque, osteoma, osteosarcoma, Paget disease, or fibrous dysplasia.13, 22 Osteolytic PEMs can resemble hemangioma, chondroma, chondrosarcoma, dermoid, epidermoid, brown tumor, multiple myeloma, plasmacytoma, giant cell tumor, aneurysm bone cyst, eosinophilic granuloma, or metastatic cancer.3, 4, 12, 15 MRI is the best imaging tool to help guide diagnosis.
Microscopically, PEMs demonstrate the pathognomonic traits of intradural meningiomas, including psammoma bodies, eosinophilic tumor cell clusters, and whorls with indistinct borders.5, 16 Nuclei are oval, regular, and may have pseudoinclusions. Bone may be normal or replaced with fat, fibrosis, or tumor cells. Our illustration presented with classical whorls surrounded by bony trabeculae and meningothelial cells that exhibited prominent nucleoli, features indicative of cytologic atypia (Fig. 2). The most common histopathology subtype is meningotheliomatous meningioma, occurring in about 60% of cases; however, all other histopathology subtypes have been reported in PEMs.7, 9, 15, 17, 19, 23, 24 In the 163 cases that we reviewed, 87.7% of tumors were benign, 5.5% were atypical, and 6.8% were malignant (Table 2).25 These rates of atypical or malignant PEMs in our study are higher than reported elsewhere (around 2%).7, 22 Other reports support our finding that malignant features such as tumor invasion into dura or soft tissues, increased mitosis, hypercellularity, cellular and nuclear atypical papillary features, giant cells, necrosis, and metastases may be more frequent in PEMs than in intradural meningiomas.26-28 Lang et al reported that 26% of their PEM cases had atypical or histological features.2 Osteolytic PEMs may have higher incidence of atypical or malignant features. Some authors have reported a radiographic picture of osteolytic skull lesion, scalp swelling, and extracranial soft tissue mass that turned out to be a malignant PEM.26-28 Similar to intradural meningiomas, PEMs typically have positive immunostaining for vimentin and epithelial membrane antigen, and they are occasionally positive for S-100. PEMS are negative for desmin, cytokeratin, and glial fibrillary acidic protein.18, 19 Cytogenetic analysis such as chromosome 22 abnormalities and MIB-1 staining has not been well studied in PEMs.
The clinical and radiographic presentation of benign, atypical, and malignant PEMs may be similar, necessitating careful operative planning and postoperative treatment because prognosis differs. Benign PEMs have a good prognosis with a tumor-related death rate of less than 5%, differing significantly from the rate of 30% associated with atypical or malignant PEMs.2 The treatment of choice for benign PEMs is GTR of any infiltrated structures. Skull PEMs require immediate cranioplasty during the same procedure. Preoperative planning for cranioplasty with the aid of 3-dimensional CT may help construction of custom-made synthetic cranioplasty plates. Skull base lesions may not be completely resectable, but decompression of most vital neurovascular structures should be feasible. Preoperative embolization has not been routinely described in the treatment of these lesions, but should be considered for large, complex PEMs where incomplete resection is anticipated. This should be judiciously considered with tumors near cranial nerves, where embolization could compromise blood supply to these vital structures. If dura is resected because of possible infiltration, then duraplasty with synthetic materials or pericranium should be performed to prevent postoperative cerebrospinal fluid leak. PEMs involving skull base, especially anterior skull base, may be best treated by a multidisciplinary team of surgeons that include a trained skull base neurosurgeon, ophthalmologic surgeon, ENT surgeon, and craniofacial plastic surgeon. For most of these benign tumors, GTR appears curative. Surgical treatment of atypical or malignant PEMs is not consistently described in the literature. When possible, we recommend wide en bloc resection including a 1-cm negative margin.
WHO I PEMs should be considered for radiotherapy after incomplete resection, recurrence, or in the case of medically inoperable disease, especially if the patient is symptomatic. Stereotactic radiosurgery (SRS), stereotactic radiotherapy (SRT), 3-D conformal, and other types of modern radiation approaches have proved effective in such instances of benign meningiomas.29-37 Radiation doses are in the range of 13 to 20 Gy for SRS and 45 to 60 Gy for SRT. Completely resected WHO I PEMs should not receive radiotherapy because surgery may be curative.
The use of radiotherapy as an adjuvant after complete resection of WHO II or III intradural meningioma and after Simpson Grade III-V resections (subtotal resections) is frequently recommended. It is not clear that there would be similar benefit in the case of PEMs after Simpson Grade I (GTR included all involved structures) or II (GTR excluded involved bone and/or dura) resections, especially in extracranial sites where resection margins might be more generous than in the case of cranial PEMs. Incompletely resected or recurrent WHO II and III tumors, however, should be considered for postoperative radiotherapy, using doses and techniques similar to those mentioned above.38-42
Data showing modest antitumor benefit have emerged for several systemically administered therapeutics. Several traditional cytotoxic chemotherapeutics have demonstrated some efficacy including hydroxyurea (an oral ribonucleotide reductase inhibitor),43 irinotecan (a topoisomerase inhibitor),44 and temozolomide (a DNA methylating agent).45 In addition, interferon alpha has been shown to have some antitumor activity.46
On the basis of epidemiologic data and case reports suggesting a link between exogenous estrogens and progestins with meningioma growth, hormonal inhibitors targeting estrogen47 and progesterone48, 49 have been evaluated in meningioma patients, but have shown no significant antitumor benefit. A growing understanding of aberrant oncogenic cell signaling pathways in meningioma50, 51 have led to the evaluation of therapeutics that may inhibit key mediators of these pathways. Meningiomas express both platelet-derived growth factor (PDGF) and the PDGF receptor (PDGFR), suggesting the possibility of an autocrine signaling loop.52-55 Imatinib, an oral inhibitor of PDGFR as well as Bcr-Abl and c-Kit tyrosine kinases, has exhibited modest antitumor benefit in a phase 2 study.56 A subsequent study of imatinib plus hydroxyurea has recently completed accrual, and preliminary assessment of outcome has shown encouraging data.57 The epidermal growth factor receptor (EGFR) is expressed in approximately 50% of meningiomas.58, 59 A trial of the EGFR tyrosine kinase inhibitors erlotinib and gefitinib has shown some evidence of antitumor benefit.60
Recently, meningiomas have been shown to express vascular endothelial growth factor (VEGF) and its receptor, VEGFR; expression levels increase with increasing tumor grade.61 Preliminary results of clinical trials targeting VEGF and VEGFR have shown encouraging benefit. Specifically, over half the patients with recurrent atypical or malignant meningiomas treated with either sunitinib or PTK787 (multikinase inhibitors of both VEGFR and PDGFR) have remained progression-free for at least 6 months.62, 63 Nearly 90% of meningiomas express somatostatin receptors, especially the sst2A subtype, and in vitro studies confirm that somatostatin can inhibit meningioma cell growth.64 A recent pilot study demonstrated that Sandostatin, a sustained-release somatostatin preparation, resulted in a partial response or stable disease in 62% of recurrent meningioma patients.65 On the basis of this encouraging data, a formal clinical trial of pasireotide, a somatostatin analogue with broader somatostatin receptor affinity than Sandostatin,66 has recently been initiated for recurrent or progressive meningioma patients.
A single chemotherapeutic agent cannot be recommended for PEMs. WHO I PEMs that undergo GTR should not receive adjuvant chemotherapy, as surgery is likely curative. Chemotherapy should be reserved for unresectable, growing WHO I and all WHO II and III PEMs. We recommend using one of the above mentioned therapies that have demonstrated some response in clinical trials.
Follow-up and treatment algorithm
We recommend that postoperative imaging with MRI be done within 48 hours to establish extent of resection. Tumor recurrence or progression can be monitored with yearly MRI for 5 years, then every 2 years for benign PEMs. Long-term monitoring is recommended because some tumors have been reported to recur up to 10 years after surgery.2 Patients with incompletely resected or completely resected tumors with an atypical or malignant histology should be followed much closer, with serial imaging every 3 months. At recurrence, surgery should be reconsidered for all tumor grades. Recurrent WHO I PEMs that are completely resected should be observed. We recommend radiation therapy for incompletely resected tumors that are symptomatic, as well as those that show radiographic recurrence using the above mentioned doses. Chemotherapy at recurrence is even more under-reported. One dramatic response was seen with 200 mg/day of etidronate disodium for 6 months in a patient with an unresectable benign tumor involving the sagittal sinus.5 We recommend the same guidelines described above for up-front chemotherapy. Because of the lack of clear treatment guidelines in the literature, we have provided a treatment algorithm for these challenging tumors (Fig. 5).
CONFLICT OF INTEREST DISCLOSURES
The authors made no disclosures.