Metastatic Rhabdoid Meningioma with BRAF V600E

Pediatric Hematology and Oncology, Early Online:1–5, 2014 C Informa Healthcare USA, Inc. Copyright ISSN: 0888-0018 print / 1521-0669 online DOI: 10.3109/08880018.2014.936058

ORIGINAL ARTICLE

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Metastatic Rhabdoid Meningioma with BRAF V600E Mutation and Good Response to Personalized Therapy: Case Report and Review of the Literature Oz Mordechai,1 Sergey Postovsky,1,2 Eugene Vlodavsky,2,3 Ayelet Eran,4 Shlomi Constantini,5 Eynat Dotan,6 Emmanuela Cagnano,7 and Myriam Weyl-Ben-Arush1,2 1

Department of Pediatric Hematology Oncology, Rambam Health Care Campus, Haifa, Israel; 2 Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel; 3 Institute of Pathology, Rambam Health Care Campus, Haifa, Israel; 4 Department of Radiology, Rambam Health Care Campus, Haifa, Israel; 5 Pediatric Neurosurgery Unit, Sourasky Medical Center, Tel Aviv, Israel; 6 Department of Oncology, Sourasky Medical Center, Tel Aviv, Israel; 7 Department of Pathology, Sourasky Medical Center, Tel Aviv, Israel

Rhabdoid meningioma is an aggressive phenotype of meningioma, associated with a poor prognosis. We present a very rare case of high-grade meningioma with rhabdoid features that eventually expressed in a coma state. Comprehensive genomic proﬁling using a Next Generation Sequencing (NGS) assay revealed three genomic alterations: activating BRAF mutation (V600E), loss of CDKN2A/2B, and APC I1307K. After treatment with BRAF inhibitor (dabrafenib), the child’s clinical condition improved progressively. After seven months, an MEK inhibitor was added (trametinib). Keywords BRAF mutation, MEK inhibitor, meningioma, targeted therapy

INTRODUCTION The vast majority of meningiomas are slowly growing, benign, grade I tumors. Some subtypes are associated with less favorable prognosis and categorized into WHO grade III, as in the rhabdoid variant of meningioma. The term “rhabdoid” represents a phenotype of a number of unrelated, poorly differentiated, aggressive tumors [1] and is characterized histologically by loosely cohesive sheets of cells with abundant eosinophilic cytoplasm, eccentric nuclei with prominent nucleous, and an excess of intermediate filaments [2]. The association between the aggressive behavior and the rhabdoid phenotype in meningioma has been shown in some articles, such as Perry et al., which reported a poor prognosis in a series of 15 meningiomas with rhabdoid features—13 (87%) patients had had at least one recurrence, two (13%) had documented extracranial metastases, and eight (53%) had Received 20 May 2014; accepted 15 June 2014. Address correspondence to Prof. Myriam Weyl Ben-Arush, Department of Pediatric Hematology Oncology, Meyer Children’s Hospital, Rambam Health Care Campus, POB 9602, Haifa 31096, Israel. E-mail: m [email protected]

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FIGURE 1 On MRI, nodular, thick, dural enhancement is noted along brain convexity, along the falx, and over the right orbital roof (arrows), compatible with pachymeningeal tumor spread (A, B). Following treatment, these findings completely resolved (C, D). Incidentally, linear dural effusion and a small left-sided subdural hematoma are noted on the post-treatment images, compatible with shunt complications.

died [2]. Kepes et al. showed a similar association between aggressive behavior and meningioma showing rhabdoid and papillary appearance [3]. Case Report A 6-year old Ashkenazi Jewish female presented with a history of headache, behavioral change, phonophobia, and photophobia of 1-month duration. Neurological examination revealed irritability without cranial nerves or motor deficit. Brain MRI demonstrated a large (∼5 cm) right-sided temporal extra-axial tumor (Figures 1A–D). Frontotemporal craniotomy was performed with tumor macroscopic excision. Histopathological examination demonstrated the diagnosis of meningioma that was first considered to be papillary, then revised to WHO grade III rhabdoid meningioma (Figure 2). Spine MRI and CSF cytology excluded metastasis and the patient received external involved-field radiation therapy (5400 cGy). Pediatric Hematology and Oncology


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FIGURE 2 Histology from biopsy (right temporal mass) demonstrated a high-grade, nonlymphoid neoplasm that displays epithelioid and some rhabdoid features. INI1 is retained (so rhabdoid excluded). S-100 protein was positive (cytoplasmatic and nuclear) and, on the other hand, the complete absence of SOX 10 (nuclear expression) makes malignant melanoma very unlikely. A fully malignant variant of PXA (pleomorphic xanthoastrocytoma) remained in consideration (molecular V600E mutation, partial positive for GFAP), as did anaplastic meningioma (WHO grade III) with rhabdoid tumor. CD1a and CD34 were negative.

After three months, the child developed recurrent headache with photophobia. Brain imaging revealed massive right hemisphere dural and parenchymal recurrence, and hydrocephalus with leptomeningeal spread. Despite immediate insertion of a ventriculo-peritoneal shunt and urgent administration of craniospinal radiation at a total dose of 36 cGy, her neurological status deteriorated rapidly with left hemiplegia, anisocoria and lethargy. A specimen from the tumor was sent for comprehensive genomic profiling using a Next Generation Sequencing (NGS) assay in a CLIA laboratory (Foundation One). The assay interrogates 236 genes as well as 47 introns of 19 genes involved in rearrangements and revealed three genomic alterations: activating BRAF mutation (V600E), loss of CDKN2A/2B, and APC I1307K. According to these genetic alterations, we decided to start with BRAF inhibitors. In this case, because of the need for an oral solution (given by gastrostomy), approval of the Helsinki committee was sought and provided. We decided to start therapy with compassionate treatment with a BRAF inhibitor (dabrafenib) at a dose of 30 mg twice daily for 1 month and then at 35 mg twice daily. The child’s clinical condition improved progressively with objective neurological improvement confirmed by her starting to walk unaided. Two months after the start of therapy, brain MRI demonstrated partial resolution (Figure 1, images C and D) which then remained stable. Therefore, seven months later, an MEK inhibitor, trametinib, was added to increase the efficacy of dabrafenib, at a dose of 0.45 mg daily and then 0.9 mg according to the PK values. One year from the start of targeted therapy, our patient went to school by herself, with complete recuperation of the right hemiplegia and normal neurological functions. However, 14 months from the beginning of therapy, there was rapid deterioration. The child complained of severe headache, and there was irritability and severe progression as demonstrated on an MRI. At that point, Temodal was added and her disease is now stable. C Informa Healthcare USA, Inc. Copyright

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DISCUSSION BRAF encodes the signaling protein BRAF which is downstream of Ras and activates the MAPK pathway. A transitional mutation in nucleotide 1799 (T-A), also known as BRAF-V600E, dramatically increases BRAF activity and accounts for approximately 80% of BRAF mutations [4]. Constitutive activation of the MAPK pathway in cancers has been frequently observed in various malignancies and mutations in BRAF that have been reported in up to 60% of melanoma cases, between 40–70% of thyroid carcinomas, and up to 18% of colorectal cancers [5]. The MAPK pathway plays an important role in the pathogenesis of adult malignant astrocytoma (MA) and increasing evidence supports the importance of this pathway in the development of pediatric MAs as well [6]. BRAF V600E mutation is present in 10–15% of grade II–IV diffusely infiltrative pediatric astrocytomas [7] and has been reported to be common in pleomorphic xanthoastrocytoma (66%) [8]. Gliomas, with BRAF V600E mutation had a strong trend toward an increased risk for progression (hazard ratio = 2.48, P = 0.07) [10]. Loss of CDKN2A/B contributes to inactivation of the p-16-CDK4/Cyclin/Rb pathway and loss of cell cycle control [10]. Loss of CDKN2A/B is frequent in WHO grade III meningioma, but not in grade I/II. Loss of p16 (located on the CDKN2A locus on 9p21) is correlated with increased WHO glioma grade II–III and has been seen in BRAFdriven pediatric low-grade gliomas that behaved more aggressively [6]. Another study suggests that p16 deletion is an adverse marker independent of BRAF status [9]. The APC (Adenomatous Polyposis Coli) gene encodes a tumor suppressor with critical roles in regulating cell division and adhesion [11]. I1307K is a substitution that may result in upregulation of Wnt signaling. APC I307K has been described as a germline variant that is present in 5.7% of the Ashkenazi Jewish population and is associated with an increased risk of breast and colon cancer [12]. Activating BRAF mutations, such as V600E, may confer sensitivity to BRAF inhibitors and some specific inhibitors of BRAF have been developed and are now used in advanced melanoma with any V600E mutation. Verumafenib showed advantage on dacarbazine in a phase 3 randomized control trial with an overall survival of 84% at six months (compared to 64% in the dacarbazine group) [13]. Dabrafenib also has prolonged progression-free survival and overall survival when compared to dacarbazine in patients with BRAF V600E mutated melanoma [14–16] and there is clinical evidence that dabrafenib crosses the blood brain barrier. In this case, trametinib was added, as studies demonstrated that most mutant melanomas acquire drug resistance after 6–7months, and roughly 10% have tumor progression at earlier stages [17]. To overcome resistance upon treatment with a BRAF inhibitor, targeting novel downstream kinases of the pathway or a combination of therapies might be helpful. Combined inhibition of BRAF (dabrafenib) and MEK1/2 (trametinib) was performed in metastatic melanoma patients with BRAF V600E mutation in an open-label randomized phase II study and showed significant improvement both in median progression-free survival (9.4 vs. 5.8months) and complete/partial response (76 vs. 54%), superior to dabrafenib or immunotherapy [18]. In summary, we present a very rare brain tumor with characteristics of rhabdoid meningioma and aggressive behavior. With the aid of personalized medicine and biological treatment, the child gained a year of functionality and good quality of life.

Declaration of Interest The authors declare no conflict of interest. The authors alone are responsible for the content and writing of the paper. Pediatric Hematology and Oncology

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