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A neuro-oncologic challenge: the case of a large, aggressive, malignant meningioma of the skull base with paranasal sinus involvement

Abstract

Background

Malignant meningiomas, rare tumors that account for approximately 1%-3% of all meningioma, have high recurrence, morbidity, and mortality rate and a particularly poor outcome. Surgical excision followed by adjuvant radiotherapy is the current approach for the treatment of these tumors.

Methods

In the case reported, the disease, characterized by a high proliferative index (Ki67 60%-70%), was treated with endoscopic surgery limited to the extracranial portion; then the patient underwent radiotherapy, on the residual tumor volume, to a total dose of 66 Gy delivered in 33 fractions (2 Gy/fraction) by helical intensity-modulated radiation therapy with image-guided radiotherapy daily checks (tomotherapy).

Results

Two and a half years after the treatment, the patient is alive and a partial response is maintained. The patient is healthy overall with grade I fatigue and grade II hearing loss as late toxicity (Common Terminology Criteria for Adverse Events 4.1).

Conclusions

Within a multidisciplinary approach, new radiotherapy techniques confirm their effectiveness and reliability for the treatment of malignant meningioma.

Tumori 2016; 102(Suppl. 2): e5 - e8

Article Type: CASE REPORT

DOI:10.5301/tj.5000442

Authors

Paolo Ghirardelli, Luca Triggiani, Sara Pedretti, Fausta Bonetti, Roberto Liserre, Stefano Gipponi, Pierpaolo Panciani, Luciano Buttolo, Salvatore Grisanti, Mauro Urpis, Luigi Spiazzi, Stefano Maria Magrini, Michela Buglione

Article History

Disclosures

Financial support: None.
Conflict of interest: None.

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Introduction

Meningioma is the most frequently reported intracranial tumor (1). Pathologically confirmed meningioma prevalence is estimated to be slightly less than 100/100,000, but many meningioma cases are not managed surgically, and these estimates might therefore be low. Moreover, subclinical meningioma is increasingly diagnosed with imaging procedures done for other causes (1). Data from the Central Brain Tumor Registry of the United States have documented an age-adjusted meningioma incidence rate of about 8 and 4 per 100,000 person-years for female and male patients, respectively (1).

Benign meningiomas account for >90% of the total. Approximately 10% of these tumors may show aggressive behavior (2) and different pathologic peculiarities such as higher mitotic index, hypercellularity, or anaplasia. These meningioma variants are called atypical meningioma (5%-7%) and malignant meningioma (1%-3% of the total), respectively (3). Malignant meningioma has a poor prognosis with a median recurrence time of 35 months after surgery and adjuvant radiotherapy (3). A small minority of these tumors (1%-2%) show extracranial spread with paranasal sinus involvement.

Surgical resection, often followed by adjuvant radiotherapy, is considered the gold standard for the treatment of these tumors. Chemotherapy is not considered standard care. Despite that, in particular cases such as skull base meningioma, where total removal is unfeasible, the development of new radiotherapy technologies has made definitive radiotherapy a safe and effective alternative.

Case report

A 70-year-old man was referred to our institution in October 2012 with hyposmia and frequent epistaxis. Cranial and facial computed tomography (CT) demonstrated a solid lesion of the sphenoid sinus involving the ethmoidal cells and internal carotid arteries bilaterally. Magnetic resonance imaging (MRI) before surgery showed an enhancing bulky mass impinging the brainstem, extending from the C2 level, as the caudal limit, to the sellar region cranially, and involving the inner ear canals bilaterally and the cavernous sinus, reaching the tentorium cerebelli and making contact with optic chiasm and pons (Fig. 1A and B).

Presurgical magnetic resonance imaging: sagittal (left) and axial (right) views. The extracranial portion of the disease was removed and the intracranial portion (red arrows) persisted after surgery.

The surgical team removed the extracranial portion of the neoplasm, but the intracranial portion remained close to the brainstem.

The definitive pathologic diagnosis was malignant meningioma (WHO 2007) with a high proliferative index (60%-70%). Histology showed vimentin positivity, epithelial membrane antigen immunoreactivity, and diffuse necrosis.

In order to verify a possible treatment option with somatostatin analogs, an octreoscan (111In-pentetreotide) was done; the examination demonstrated high activity of somatostatin receptors.

Postsurgical treatment was considered by our multidisciplinary neuro-oncology group. A wait and see policy was not considered due to the aggressive nature of the disease. The following therapeutic options were discussed and rejected: (1) additional surgery, precluded by the disease extent; (2) chemotherapy, excluded because of the scarce evidence available in the literature; (3) the use of somatostatin analogs, excluded due to the possible toxicity related to the presence of gallstones, since the patient refused cholecystectomy, and owing to the paucity of clinical experiences with this drug for meningioma. Thus, radiotherapy was considered the most viable option, also taking into account the high proliferative index of the disease.

Radiotherapy treatment

The proposed radiotherapy dose was 66 Gy in 33 fractions.

The main issue in planning definitive radiotherapy was the close proximity to the clinical target volume (CTV) of healthy tissues (organs at risk [OAR]) highly sensible to high radiation doses. In fact, the dose constraints for brainstem, optical chiasma, and optical nerves are lower (max 54 Gy) than the dose needed to treat malignant meningioma. A highly conformal treatment was therefore proposed. The patient was informed about and accepted the risks related to the treatment.

Radiotherapy on the tumor volume up to a total dose of 66 Gy delivered in 33 fractions (2 Gy/fraction) using helical intensity-modulated radiation therapy with daily image-guided radiotherapy control of setup (tomotherapy) was proposed.

A thermoplastic mask was performed in order to immobilize the patient and a simulation CT was performed to identify treatment volumes.

The gross tumor volume (GTV) was defined using the coregistration of the diagnostic contrast-enhanced T1-weighted MRI and the simulation CT.

The CTV coincided with GTV in order to limit the dose to healthy organs such as the optic chiasm, brainstem, and cochlea. Two planning target volumes (PTV) were then defined and treated: one with a 3 mm margin between CTV and PTV, with a prescribed dose of 54 Gy, and another without margin between CTV and PTV, where the prescription dose was 66 Gy.

The high-dose PTV volume was equal to 94.26 cm3; the 54 Gy PTV volume was equal to 208.08 cm3. Nevertheless, in order to better respect the dose constraints to the OARs, the plan was accepted even if the D95 (dose received almost by the 95% of the volume) of the PTV66 was 56.5 Gy. The D95 of PTV 54 instead was 56.5 Gy.

The dose distribution to the targets and OARs is shown in Figure 2. The plan was within most of the OAR constraints, even though the high-dose volume was close to the healthy organs; a tradeoff was accepted between PTV coverage and dose to optic chiasma (Dmax: 57.37 Gy) and both cochlea (Dmax: 62.42 Gy and 57.97 Gy to right and left cochlea, respectively).

Isodose distribution (in red, the 95% isodose of planning target volume [PTV] 66 Gy; in yellow, the 95% isodose of PTV 54 Gy) and organs at risk dose-volume histogram. cad = right eye lens; cas = left eye lens; chiasma = optic chiasm; coclea dx = right cochlea; coclea sin = left cochlea; encefalo = brain; mandibola = mandible; midollo = spinal cord; nod = right optic nerve; nos = left optic nerve; parotide ds = right parotid; parotide sin = left parotid; PRV midollo = spinal cord planning respect volume; PRV tronco = brainstem planning respect volume; tronco = brainstem.

Clinical outcome

The treatment was well tolerated: the patient had 6 visits during the treatment and no acute toxicities were observed. After the end of the treatment, he had a clinical evaluation every 4 months.

After 2.5 years from the end of radiotherapy, at the last follow-up visit, the patients is in good general and neurological performance status (Karnofsky Performance Status 80 and Order I); the only reported symptoms are grade I fatigue and grade I hearing loss, demonstrated with audiometric examination.

The clinical examination and imaging procedures did not show any local or systemic progression of disease. Pituitary hormones levels remain within the normal range. MRI-documented disease extension appears to be slightly reduced at the last scan (5/2015) (Fig. 3); an octreoscan performed in December 2014 confirms stable hyperactivity of somatostatin receptors.

Last-follow-up magnetic resonance imaging: (left) in the sagittal scan, lack of the extracranial portion of disease, removed by the surgeons, is evident; (right) in the axial view, slight reduction of disease is evident.

Discussion

Radiotherapy after partial resection of large, partially resected, and high-grade meningioma is considered a feasible treatment option (National Comprehensive Cancer Network 1.2015; http://www.nccn.org/professionals/physician_gls/pdf/cns.pdf).

In fact, meningioma, in particular high-grade meningioma, often presents a difficult challenge for neurosurgeons. No randomized controlled data or ongoing prospective studies to compare surgery alone or followed by radiotherapy to radiotherapy alone are available, and retrospective data pertaining to large cohorts of patients, homogeneous for selection criteria, dose, and radiotherapy technique, are also scarce.

The largest of these studies, published in 2013, reports on 507 patients with skull base meningioma treated with fractionated stereotactic radiotherapy (376/507) and intensity-modulated radiotherapy (131/507) at the University Hospital of Heidelberg. Among those patients, 238/507 had no histology available and only 35/507 (20 atypical and 15 malignant) were classified as high-risk meningioma. The reported local control rates are 95% and 88%, respectively, at 5 at 10 years for the whole cohort, and 81% and 53% for high-risk meningioma; few patients had symptomatic worsening or side effects and 37.5% of patients showed clinical improvement (4).

A recently published French article reports a series of 136 patients who underwent postoperative or primary fractionated stereotactic radiotherapy for skull base meningioma. The population treated with adjuvant radiotherapy showed significantly worse progression-free survival than patients treated with definitive radiotherapy (p = 0.043); in this population, high-risk lesions were not histologically proven, and the overall progression-free survival was 96.9%, 93.8%, and 91.5% after 3, 5, and 10 years (5).

A neurosurgical study including 28 patients with atypical skull base meningioma who underwent microsurgical resection, followed by adjuvant radiotherapy in 12, reports worse outcome data, possibly related to more aggressive histology: after a median follow-up of 2.4 years, 13/28 patients had radiologic signs of tumor recurrence or enlargements. Three patients developed postoperative complications such as hemiparesis (1/3) and facial palsy (2/3). Multivariate analysis identified gross total resection and MIB-1 index less than 8% as favorable prognostic factors (6). An elevated proliferation level has been associated with higher tumor recurrence in patients treated with surgery alone for malignant meningioma. The relapse-free survival in patients with MIB-1 index <4% is statistically significantly better than for patients with ≥4% (maximum 39%). The choice to treat our patient was guided by the high (70%) MIB-1 index and by the macroscopic extent of the disease after surgery (7).

The presented case was treated considering that the proliferative index of the disease, the malignant histology, and the postsurgical persistence of a large residual mass all constitute strong indications for radiotherapy. This also has been the policy of our neuro-oncology multidisciplinary team in the past (2). Present-day radiotherapy techniques additionally allow a safer delivery of high doses to large-volume disease. Even if the time elapsed from the end of the treatment of the patient we reported is relatively short, about half of the patients treated by Wang and colleagues (6) relapsed within 2.5 years from the end of the treatment; in our case, at this time point, the objective of stopping the progression of the disease has been maintained. In addition, the follow-up period is probably sufficient to affirm that the functional outcome of the treatment is good. The persisting positivity at octreoscan of the residual mass represents a possible index of residual disease activity. However, since the experiences of meningioma treatment with somatostatin analogues or radiolabeled analogues are scarce and the results debatable (8-9-10), the use of these drugs might be reserved, as documented in the literature, for further progression of the disease.

Conclusion

The optimal treatment for skull base meningioma remains controversial; the reported case confirms that the improvement in radiotherapy techniques allows us to use this therapeutic approach as a safe and effective alternative when surgical management is not feasible.

Disclosures

Financial support: None.
Conflict of interest: None.
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Authors

Affiliations

  • Radiation Oncology Department, University and Spedali Civili Hospital, Brescia - Italy
  • Pathology Department, University and Spedali Civili Hospital, Brescia - Italy
  • Neuro-radiology Department, University and Spedali Civili Hospital, Brescia - Italy
  • Neurology Department, University and Spedali Civili Hospital, Brescia - Italy
  • Neurosurgery Department, University and Spedali Civili Hospital, Brescia - Italy
  • Medical Oncology Department, University and Spedali Civili Hospital, Brescia - Italy
  • Medical Physics, Spedali Civili Hospital, Brescia - Italy

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