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Optic nerve giant cell astrocytoma in tuberous sclerosis complex

Published:December 12, 2017DOI:https://doi.org/10.1016/j.jcjo.2017.10.038
      The retinal astrocytic hamartoma is a hallmark ophthalmic feature of tuberous sclerosis complex (TSC).
      • Shields J.A.
      • Shields C.L.
      Glial tumors of the retina and optic disc.
      The typical course of such tumours is a relatively slow-growing nonaggressive lesion in the retina that can be managed expectantly.
      • Shields J.A.
      • Eagle R.C.
      • Shields C.L.
      Aggressive retinal astrocytomas in four patients with tuberous sclerosis complex.
      Nonetheless, there have been several reports in the literature of aggressive astrocytic hamartomas that do not demonstrate this benign course.
      • Gunduz K.
      • Eagle Jr, R.C.
      • Shields C.L.
      • et al.
      Invasive giant cell astrocytoma of the retina in a patient with tuberous sclerosis.
      We present here a rare case of an aggressive tumour in a patient with TSC that has cell types more typical of the subependymal giant cell astrocytoma (SEGA) that is seen in the brains of such patients.
      J.M. was a patient with known TSC who was first seen in our pediatric ophthalmology clinic at the age of 5 years, at which point he was diagnosed with a small right optic nerve head hamartoma not affecting vision. Over the years, he was subsequently followed at multiple centres, and records indicate that he developed a chronic right retinal detachment. An examination under anaesthesia (EUA) at the age of 13 years revealed a disorganized retina and a large astrocytic tumour emanating from the right optic nerve head with underlying exudative retinal detachment, all of which appeared chronic in nature and was confirmed on B-scan ultrasound. The left retinal examination was unremarkable.
      At the age of 14 years, the patient was reassessed in our clinic for new-onset redness and photophobia and discomfort of the right eye. EUA revealed an intraocular pressure of 48 mm Hg in the right eye. Anterior segment examination revealed frank neovascularization of the iris, a shallow anterior chamber, and a secluded pupil, consistent with neovascular glaucoma. Transscleral diode cyclophotocoagulation was performed, and intravitreal bevacizumab (Avastin (R), Genentech, California, 0.1 mL of 25 mg/mL).
      Two weeks later, the patient’s pain had somewhat subsided, and the iris vessels had partially regressed. One month later, however, the right eye was still causing discomfort despite maximal intraocular pressure–lowering drops and difluprednate eye drops. Given that this was a blind and painful eye, the family decided to proceed with enucleation.
      Pathologic evaluation of the enucleated eye revealed the following findings:
      • 1.
        Optic nerve head giant cell astrocytoma: The tumour emanated directly from the optic nerve head and demonstrated osseous metaplasia, calcification, large-sized astrocytes, and significant hemorrhage and was associated with a subtotal retinal detachment (Fig. 1, top). The tumour can be seen extending into the substance of the optic nerve at the level of the lamina cribrosa (Fig. 2, top). A central area of dystrophic calcification can be seen in the centre of the optic nerve substance, distal to the globe (Fig. 2, middle).
        Fig. 1
        Fig. 1Left: Low-power scanning view of tumour arising from optic nerve head and subtotal retinal detachment. Right: The tumour is composed of large-sized astrocytes with focal accumulation of hemosiderin (brown pigment) (hematoxylin, phloxine and saffron (HPS)).
        Fig. 2
        Fig. 2Top: Tumour shown extending into optic nerve at level of lamina cribrosa (HPS). Middle: Von Kossa stain for calcium shows calcification of optic nerve distal to globe. Bottom: Neurofilament immunostain indicates axonal diminution in the optic nerve distal to globe. HPS = hematoxylin, phloxine and saffron.
      • 2.
        Optic nerve atrophy: There was significant atrophy of the optic nerve itself with loss of myelin and axons. A neurofilament immunostain highlights the atrophy of axons (Fig. 2, bottom).
      • 3.
        Retinal astrocytic hamartoma: In comparison to the optic nerve head astrocytoma, this tumour showed a proliferation of smaller glial cells and less vasculature.
      • 4.
        Combined retinal pigment epithelial and vascular hamartoma: This lesion consisted of large blood vessels, a disorganized retinal pigment epithelial proliferation, and a component of glial tissue.
      A case series by Shields et al. in 2004 reported 4 cases of atypically aggressive astrocytic hamartomas in patients with TSC.
      • Shields J.A.
      • Eagle R.C.
      • Shields C.L.
      Aggressive retinal astrocytomas in four patients with tuberous sclerosis complex.
      The tumour growth was extensive in all 4 patients, and all cases resulted in enucleation as a result of total retinal detachment and neovascular glaucoma. Histopathologically, the tumours consisted of cell types that are usually seen in the SEGA tumour of tuberous sclerosis rather than the typical cell types more commonly seen in the classic retinal astrocytic hamartoma of TSC.
      The optic nerve head giant cell astrocytoma observed in this case also has strikingly similar pathology to the SEGA seen in the brains of patients with tuberous sclerosis. The astrocytes are larger, show glassy eosinophilic cytoplasm, and have a bland spindle-shaped and gemistocytic appearance. The substantial blood supply; dystrophic calcification; positive histochemistry stains for iron; and positive immunohistochemistry stains for NSE, GFAP, and S100 provide further evidence for a SEGA as opposed to a retinal astrocytic hamartoma.
      These findings are consistent with tumours outlined in several other reports regarding astrocytic hamartomas,
      • Gunduz K.
      • Eagle Jr, R.C.
      • Shields C.L.
      • et al.
      Invasive giant cell astrocytoma of the retina in a patient with tuberous sclerosis.
      • Margo C.E.
      • Barletta J.P.
      • Staman J.A.
      Giant cell astrocytoma of the retina in tuberous sclerosis.
      • Pusateri A.
      • Margo A.
      Intraocular astrocytoma and its differential diagnosis.
      which described abundant necrosis and large cells with abundant eosinophilic cytoplasm, nuclear pleomorphism, and mitotic activity.
      The present case adds to the emerging evidence that an aggressive form of an astrocytic hamartoma, more accurately defined as a giant cell retinal astrocytoma, is a rare but possible feature in TSC. In contrast to prior reports that cite peripapillary giant cell astrocytomas that have subsequently invaded the optic nerve, the tumour in this case actually originated from the optic nerve head itself and resulted in complete optic nerve atrophy. It remains to be determined whether there is a correlation between the presence of SEGAs and concomitant giant cell retinal astrocytomas and whether the histopathologic features of these giant cell retinal astrocytomas represent a distinct and more aggressive subtype on the TSC disease spectrum. The pathologic characteristics of giant cell astrocytomas may be significant in terms of treatment implications, as new therapies emerge to treat certain tumour subtypes.
      • Nallasamy N.
      • Seider M.I.
      • Gururangan S.
      • Mruthyunjaya P.
      Everolimus to treat aggressive retinal astrocytic hamartoma in tuberous sclerosis complex.

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