Clinical Observations| Volume 53, ISSUE 3, P238-242.e1, September 2015

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Pathological Findings of a Subependymal Giant Cell Astrocytoma Following Treatment With Rapamycin

  • Sylvia Cheng
    Communications should be addressed to: Dr. Cheng; Division of Hematology/Oncology/BMT; Department of Pediatrics; British Columbia Children's Hospital; Vancouver, British Columbia V6H 3V4, Canada.
    Department of Pediatrics, The University of British Columbia, Vancouver, British Columbia, Canada

    Division of Hematology/Oncology/BMT, British Columbia Children's Hospital, Vancouver, British Columbia, Canada
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  • Cynthia Hawkins
    Department of Laboratory Medicine and Pathobiology, The Hospital for Sick Children, Toronto, Canada

    The Arthur and Sonia Labatt Brain Tumour Research Centre, Toronto, Canada
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  • Michael D. Taylor
    The Arthur and Sonia Labatt Brain Tumour Research Centre, Toronto, Canada

    Department of Surgery, The Hospital for Sick Children, Toronto, Ontario, Canada
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  • Ute Bartels
    Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada

    Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada
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      Tuberous sclerosis complex is a heritable multisystem disorder associated with genes involved in the formation of a tumor-suppressor complex acting through the Ras homologue enriched in brain protein to limit activation of the mammalian target of rapamycin complex I. Mutations in these genes result in enhanced mammalian target of rapamycin signaling and may cause neurological manifestations including brain tubers, subependymal nodules, and subependymal giant cell astrocytomas. These astrocytomas are tumors that arise near the foramen of Monro and may lead to obstructive hydrocephalus. Standard therapy has been surgical resection. More recently, mammalian target of rapamycin inhibitor, everolimus, has been approved for treatment after demonstration of efficacy in prospective clinical trials.


      We report a 15 year-old girl with tuberous sclerosis complex who proceeded to surgical resection of her subependymal giant cell astrocytoma after 3 months of treatment with mammalian target of rapamycin inhibition. We compared her subependymal giant cell astrocytoma tissue specimen with 12 untreated subependymal giant cell astrocytomas accessed from The Hospital for Sick Children in Toronto, Canada.


      This girl's histopathological findings were consistent with subependymal giant cell astrocytomas with no exposure to mammalian target of rapamycin inhibitors. There were no major differences identified on immunohistochemistry at targets downstream of mammalian target of rapamycin complex 1 or in neighboring signaling pathways. The majority of cells were reactive to glial fibrillary acidic protein, mitogen-activated protein kinase, phospho-S6, caspase 3 (95% positivity), and NP-1.


      In this one individual, rapamycin therapy did not change the histopathological characteristics of subependymal giant cell astrocytoma. Mammalian target of rapamycin inhibition involves complex signaling pathways inducing subependymal giant cell astrocytoma shrinkage. However, its effect is not easily characterized within tumor tissue.


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        • Krueger D.A.
        • Care M.M.
        • Holland K.
        • et al.
        Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis.
        N Engl J Med. 2010; 363: 1801-1811
        • Crino P.B.
        • Nathanson K.L.
        • Henske E.P.
        The tuberous sclerosis complex.
        N Engl J Med. 2006; 355: 1345-1356
        • Northrup H.
        • Krueger D.A.
        • International Tuberous Sclerosis Complex Consensus Group
        Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 international tuberous sclerosis complex consensus conference.
        Pediatr Neurol. 2013; 49: 243-254
        • Grajkowska W.
        • Kotulska K.
        • Jurkiewicz E.
        • Matyja E.
        Brain lesions in tuberous sclerosis complex. Review.
        Folia Neuropathol. 2010; 48: 139-149
        • Franz D.N.
        • Leonard J.
        • Tudor C.
        • et al.
        Rapamycin causes regression of astrocytomas in tuberous sclerosis complex.
        Ann Neurol. 2006; 59: 490-498
        • Franz D.N.
        • Belousova E.
        • Sparagana S.
        • et al.
        Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial.
        Lancet. 2013; 381: 125-132
        • Tyburczy M.E.
        • Kotulska K.
        • Pokarowski P.
        • et al.
        Novel proteins regulated by mTOR in subependymal giant cell astrocytomas of patients with tuberous sclerosis complex and new therapeutic implications.
        Am J Pathol. 2010; 176: 1878-1890
        • Abad M.A.
        • Enguita M.
        • DeGregorio-Rocasolano N.
        • Ferrer I.
        • Trullas R.
        Neuronal pentraxin 1 contributes to the neuronal damage evoked by amyloid-beta and is overexpressed in dystrophic neurites in Alzheimer's brain.
        J Neurosci. 2006; 26: 12735-12747
        • Louis D.N.
        • Ohgaki H.
        • Wiestler O.D.
        • et al.
        The 2007 WHO classification of tumours of the central nervous system.
        Acta Neuropathol. 2007; 114: 97-109
        • Lam C.
        • Bouffet E.
        • Tabori U.
        • Mabbott D.
        • Taylor M.
        • Bartels U.
        Rapamycin (sirolimus) in tuberous sclerosis associated pediatric central nervous system tumors.
        Pediatr Blood Cancer. 2010; 54: 476-479
        • Bissler J.J.
        • McCormack F.X.
        • Young L.R.
        • et al.
        Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis.
        N Engl J Med. 2008; 358: 140-151
        • Curatolo P.
        • Moavero R.
        mTOR Inhibitors in Tuberous Sclerosis Complex.
        Curr Neuropharmacol. 2012; 10: 404-415
        • Franz D.N.
        Everolimus in the treatment of subependymal giant cell astrocytomas, angiomyolipomas, and pulmonary and skin lesions associated with tuberous sclerosis complex.
        Biologics. 2013; 7: 211-221
        • Krueger D.A.
        • Wilfong A.A.
        • Holland-Bouley K.
        • et al.
        Everolimus treatment of refractory epilepsy in tuberous sclerosis complex.
        Ann Neurol. 2013; 74: 679-687
        • Krueger D.A.
        • Care M.M.
        • Agricola K.
        • Tudor C.
        • Mays M.
        • Franz D.N.
        Everolimus long-term safety and efficacy in subependymal giant cell astrocytoma.
        Neurology. 2013; 80: 574-580