FINAL DIAGNOSIS: SUBEPENDYMAL GIANT CELL ASTROCYTOMA
The patient was admitted with a mass in the third ventricle and underwent a left frontal craniotomy. Greater than 99% of the tumor was resected. The lesion arose from the left hypothalamus and extended into the third ventricle. Her post-operative course was uneventful and she was discharged home. Follow up MRI showed a very small area of residual tumor involving the left thalamus. No other stigmata of tuberous sclerosis have been identified at this time (see below).
The subependymal giant cell astrocytoma most commonly occur in the wall of the lateral ventricle near the foramen of Monro. It often presents as a well demarcated intraventricular tumor that does not invade into the periventricular parenchyma. Concomitant subependymal nodules or cortical ganglioneuronal hamartomas (tubers) may be seen in the setting of TS. SEGA are enhancing on MRI.
Microscopically, SEGA are characterized by heterogeneous cell populations predominantly composed of variably sized astrocytic appearing cells, which often have abundant eosinophilic cytoplasm and are morphologically similar to gemistocytic astrocytes. These cells are pleomorphic and can become quite large, but usually do not attain the size of cells in a pleomorphic xanthoastrocytoma or glioblastoma multiforme. The nuclei are pleomorphic, having finely granular chromatin with prominent nucleoli, and some have cytoplasmic intranuclear pseudo-inclusions. Other areas may demonstrate more spindled cells arranged in fascicles, and still other areas may demonstrate neuronal differentiation, characterized by large cells with glassy eosinophilic cytoplasm, eccentric nuclei and prominent nucleoli. There are often perivascular acellular zones with circularly oriented fibrillar material which is GFAP negative, in contrast to the perivascular pseudorosettes of an ependymoma which will have radially "spoke-like" oriented fibrillar material radiating from the central vessel and are GFAP positive. Mast cells and calcifications are common features in SEGA, as was the case here. Although these tumors may be vascular, endothelial hyperplasia is rare. Mitosis may be seen in over half of the cases, but they are usually not prominent, as they were in this case. The proliferation index is usually not high. Foci of micronecrosis may be seen. The presence of necrosis and mitoses do not portend a bad prognosis.
The histogenesis of SEGA is not understood. Ultrastructurally and immunophenotypically, there is evidence for both neuronal and astrocytic differentiation. Reactivity for glial fibrillary astrocytic protein (GFAP) may be diffuse or focal, while S100 protein expression is usually stronger and more widespread. Focally, other cells may show reactivity for neuronal markers such as neuron specific enolase (NSE) or neuron associated cytoskeletal proteins such as beta tubulin. Synaptophysin may show some focal positivity. HMB 45 is negative. However, many of the cells stain with neither neuronal nor glial markers. Electron microscopic studies have confirmed both the astrocytic and neuronal nature of these neoplasms, demonstrating intermediate filaments, electron dense core vesicles and even synaptic structures in individual cells of some tumors; sometimes both neuronal and astrocytic elements are seen within different cells of the same tumor. The mixed ultrastructural and immunophenotypic character of SEGAs suggest that the tumor is composed of one or more cell lines capable of divergent differentiation. DNA studies reveal diploid DNA content with a low proliferation rate.
SEGA have been reported in 6% of patients with tuberous sclerosis, an autosomal dominant disease, but the incidence may be as high as 14%. SEGA usually presents in the second decade of life as a mass in the third ventricle which often obstructs the foramen of Monro causing hydrocephalus. They are slow growing tumors with a favorable long term prognosis. Treatment is usually limited to surgical excision, and even in the cases of incomplete excision, long term survival is excellent, due to the slow growth of residual tissue. However, long term recurrences and death may occur in some cases, death is often related to the complications of treatment and not the tumor itself.
SEGAs are characteristically associated with TS, largely a hamartomatous disease, but there are a few cases in the literature reporting SEGA arising in the apparent absence of TS. Finding SEGA in the absence of TS could be the initial presentation of TS or a "forme fruste" of TS, perhaps due to a new mutation. A review by Shepard et al found SEGA only in patients with TS in a review of 345 TS patients. Many of these older cases reported were before the advent of MRI, and it is possible that some cortical tubers remained undetected. If the diagnosis of SEGA is made, a careful search for other manifestations of TS should be performed, and careful follow up is indicated. Mutations in two apparent tumor suppressor genes, TSC1 on 9q and TSC2 on 16p, have recently been implicated as an etiology for TS.