High-grade Meningiomas
High-grade Meningiomas
Purpose of review For standard first-line treatment of high-grade meningiomas, surgical resection and radiotherapy are regarded as standard of care. In the recurrent setting after exhaustion of all local treatment options, no effective therapies are known and several drugs have failed to show efficacy, but novel compounds may offer hope for better disease control.
Recent findings Upregulation of proangiogenic molecules and dysregulation of some signaling pathways such as the platelet-derived growth factor and mammalian target of rapamycin are recurrently found in high-grade meningiomas. Furthermore, in-vitro studies and single patient experience indicate that trabectedin may be an effective therapy in this tumor type. Unfortunately, so far there is a lack of conclusive clinical trials to draw definite conclusions of efficacy of these approaches.
Summary There remains a significant unmet need for defining the role of medical therapy in recurrent high-grade meningioma, and more basic research and multicentric well designed trials are needed in this rare and devastating tumor type. Potentially promising novel therapeutics include antiangiogenic drugs, molecular inhibitors of signaling cascades, immunotherapeutics or trabectedin. However, more basic research is required to identify more promising drug targets.
Video abstract available See the Video Supplementary Digital Content 1 (http://links.lww.com/CONR/A22).
Meningiomas represent the most common intracranial tumor and account for 24–30% of primary intracranial tumors. The annual incidence rate is as high as 13 : 100 000. Many small meningiomas are asymptomatic and found incidentally on imaging performed for other purposes. At autopsy, meningiomas have been found in up to 1.4% of cases. Sporadic meningiomas may be multiple in up to 10% of cases. Atypical meningiomas represent between 4.7 and 7.2% of meningiomas, although they have been reported in up to 20%, according to newer definition criteria. Anaplastic meningiomas account for 1.0–2.8% of cases, depending upon studies. Meningiomas have been reported at any age, but the peak of occurrence is in the sixth and seventh decade. In middle aged patients, women are markedly overrepresented with a two-fold to three-fold increased incidence over men. Spinal meningiomas have a strong predominance in women, with a frequency of up to 90% in certain series. Most meningiomas develop in intracranial, orbital or intraspinal locations. Within the cranial cavity, the majority of meningiomas occur over the cerebral convexities, often in a parasagittal position. Optic nerve sheath, petrous or sphenoid ridges, olfactory grooves, para/suprasellar regions, tentorium and posterior fossa are other common sites. Atypical and anaplastic meningiomas most commonly affect the falx and the lateral convexities. Metastases of malignant meningiomas most often seed the lungs, pleura, bone and liver.
The cause of meningiomas remains unclear. To date, the only clearly identified risk factor is radiation therapy to the scalp or head, most commonly for the treatment of a brain tumor. These patients are at increased risk to develop meningiomas with a time interval to tumor appearance of 20–35 years, regardless of the radiation therapy dose. Radiation therapy-induced meningiomas are often atypical or aggressive, with a high proliferation rate, and may occur at multiple sites. They also generally occur in younger age groups than sporadic meningiomas. Recently, repeated exposure to dental X-rays has been associated with an increased risk for intracranial meningiomas.
Patients with neurofibromatosis type 2 (NF2) typically develop multiple meningiomas, which tend to occur at a younger age. NF2 is an autosomal dominant disorder with a predisposition to develop multiple neoplastic lesions. It is linked to mutations of the tumor suppressor gene NF2, localized on chromosome 22. This gene codes for the cytoskeletal membrane protein merlin. Many sporadic meniningiomas also harbor inactivation of or mutations in the protein merlin.
The role of sex hormones in the pathogenesis of meningiomas remains unclear. At initial resection most meningiomas show expression of progesterone, estrogen or androgen receptors. This expression cannot however explain the higher incidence of meningiomas in women. In female patients, increased BMI, breastfeeding and cigarette smoking are clearly associated with an increased risk of developing meningiomas. There is however no clear association with reproductive and menstrual factors. The relationship between the use of exogenous hormones and meningioma remains unclear, limited by the small numbers of patients currently on oral hormone medications and a lack of hormone receptor data for meningioma tumors.
Tumor grade, brain invasion and extent of tumor invasion have been identified as independent prognostic factors for recurrence of meningioma. The recurrence of grade I convexity meningiomas was 1.2% after a mean follow-up period of 7.2 years.
The 5-year overall survival is 92% for grade I, 78% for grade II and 47% for grade III meningiomas. However, it must be noted that the figures for high-grade tumors are derived from relatively small and few case series and may not be highly reliable. As progressive meningiomas are often complicated by severe neurological complications and decreased quality of life, it is urgent to identify new treatment modalities.
Abstract and Introduction
Abstract
Purpose of review For standard first-line treatment of high-grade meningiomas, surgical resection and radiotherapy are regarded as standard of care. In the recurrent setting after exhaustion of all local treatment options, no effective therapies are known and several drugs have failed to show efficacy, but novel compounds may offer hope for better disease control.
Recent findings Upregulation of proangiogenic molecules and dysregulation of some signaling pathways such as the platelet-derived growth factor and mammalian target of rapamycin are recurrently found in high-grade meningiomas. Furthermore, in-vitro studies and single patient experience indicate that trabectedin may be an effective therapy in this tumor type. Unfortunately, so far there is a lack of conclusive clinical trials to draw definite conclusions of efficacy of these approaches.
Summary There remains a significant unmet need for defining the role of medical therapy in recurrent high-grade meningioma, and more basic research and multicentric well designed trials are needed in this rare and devastating tumor type. Potentially promising novel therapeutics include antiangiogenic drugs, molecular inhibitors of signaling cascades, immunotherapeutics or trabectedin. However, more basic research is required to identify more promising drug targets.
Video abstract available See the Video Supplementary Digital Content 1 (http://links.lww.com/CONR/A22).
Introduction
Meningiomas represent the most common intracranial tumor and account for 24–30% of primary intracranial tumors. The annual incidence rate is as high as 13 : 100 000. Many small meningiomas are asymptomatic and found incidentally on imaging performed for other purposes. At autopsy, meningiomas have been found in up to 1.4% of cases. Sporadic meningiomas may be multiple in up to 10% of cases. Atypical meningiomas represent between 4.7 and 7.2% of meningiomas, although they have been reported in up to 20%, according to newer definition criteria. Anaplastic meningiomas account for 1.0–2.8% of cases, depending upon studies. Meningiomas have been reported at any age, but the peak of occurrence is in the sixth and seventh decade. In middle aged patients, women are markedly overrepresented with a two-fold to three-fold increased incidence over men. Spinal meningiomas have a strong predominance in women, with a frequency of up to 90% in certain series. Most meningiomas develop in intracranial, orbital or intraspinal locations. Within the cranial cavity, the majority of meningiomas occur over the cerebral convexities, often in a parasagittal position. Optic nerve sheath, petrous or sphenoid ridges, olfactory grooves, para/suprasellar regions, tentorium and posterior fossa are other common sites. Atypical and anaplastic meningiomas most commonly affect the falx and the lateral convexities. Metastases of malignant meningiomas most often seed the lungs, pleura, bone and liver.
The cause of meningiomas remains unclear. To date, the only clearly identified risk factor is radiation therapy to the scalp or head, most commonly for the treatment of a brain tumor. These patients are at increased risk to develop meningiomas with a time interval to tumor appearance of 20–35 years, regardless of the radiation therapy dose. Radiation therapy-induced meningiomas are often atypical or aggressive, with a high proliferation rate, and may occur at multiple sites. They also generally occur in younger age groups than sporadic meningiomas. Recently, repeated exposure to dental X-rays has been associated with an increased risk for intracranial meningiomas.
Patients with neurofibromatosis type 2 (NF2) typically develop multiple meningiomas, which tend to occur at a younger age. NF2 is an autosomal dominant disorder with a predisposition to develop multiple neoplastic lesions. It is linked to mutations of the tumor suppressor gene NF2, localized on chromosome 22. This gene codes for the cytoskeletal membrane protein merlin. Many sporadic meniningiomas also harbor inactivation of or mutations in the protein merlin.
The role of sex hormones in the pathogenesis of meningiomas remains unclear. At initial resection most meningiomas show expression of progesterone, estrogen or androgen receptors. This expression cannot however explain the higher incidence of meningiomas in women. In female patients, increased BMI, breastfeeding and cigarette smoking are clearly associated with an increased risk of developing meningiomas. There is however no clear association with reproductive and menstrual factors. The relationship between the use of exogenous hormones and meningioma remains unclear, limited by the small numbers of patients currently on oral hormone medications and a lack of hormone receptor data for meningioma tumors.
Tumor grade, brain invasion and extent of tumor invasion have been identified as independent prognostic factors for recurrence of meningioma. The recurrence of grade I convexity meningiomas was 1.2% after a mean follow-up period of 7.2 years.
The 5-year overall survival is 92% for grade I, 78% for grade II and 47% for grade III meningiomas. However, it must be noted that the figures for high-grade tumors are derived from relatively small and few case series and may not be highly reliable. As progressive meningiomas are often complicated by severe neurological complications and decreased quality of life, it is urgent to identify new treatment modalities.