Case 4 -

Rosette-Forming Glioneuronal Tumor of the Fourth Ventricle Anthony T. Yachnis University of Florida College of Medicine Gainesville, FL

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Clinical History This 53 year old woman came to clinical attention after a two month history of progressively worsening headaches. Two weeks before admission, the patient experienced intermittent speech problems (dysarthria) and a gait disturbance. An acute syncopal episode precipitated an emergency room visit and subsequent admission. Physical examination confirmed signs of cerebellar dysfunction (ataxia, dysdiadokinesia of the left arm and past pointing of the left finger). Imaging studies revealed a 5 x 3 cm. midline posterior fossa mass, which occupied most of the fourth ventricle and appeared to arise from the roof of this structure. The mass was relatively well-circumscribed, showed heterogeneous contrast enhancement on the T1-weighted MRI, and was associated with significant hydrocephalus. The patient subsequently underwent a left ventriculostomy and a midline suboccipital craniotomy with gross total excision of the neoplasm. Case 4 - Figure 1 - T1-weighted MRI showing heterogeneously contrast enhancing fourth ventricular tumor. Case 4 - Figure 2 - Rosette-forming glioneuronal tumor. Neurocyte-like area with perivascular pseudorosettes and myxoid stroma. Original magnification: 500X. Case 4 - Figure 3 - Rosette-forming glioneuronal tumor. Low grade astrocytic component with eosinophilic granular bodies. Case 4 - Figure 4 - Rosette-forming glioneuronal tumor immunostained for synaptophysin showing positive staining of the "core" of a rosette. Original magnification: 1000X. Diagnosis: Rosette-Forming Glioneuronal Tumor of the Fourth Ventricle Discussion: The World Health Organization [1] category of "neuronal and neuronal-glial mixed tumors" contains neoplasms with varying morphologic and phenotypic manifestations of neuronal and glial lineage. This category includes some well-defined clinicopathologic entities such as the ganglioglioma, the dysembryoplastic neuroepithelial tumor (DNET), and the central neurocytoma. More recently, the spectrum of neuronal-glial neoplasms has expanded to include several important emerging entities and variants of central nervous system tumors [2, 3] . While relatively uncommon, awareness of these entities is important because of their distinct clinicopathologic characteristics and important therapeutic implications. The rosette-forming glioneuronal tumor (RGNT) of the fourth ventricle was recently defined in the clinicopathologic series of Komori, Scheithauer and Hirose [4]. Two prior case reports by Kuchelmeister et al. [5] and Yamane et al. [6] had emphasized the overlap of some histologic features of this tumor with the dysembryoplastic neuroepithelial tumor (DNT). However, the series of eleven well-described cases reported by Komori and colleagues and the latest report by Preusser et al. [7] make a strong case for establishing the fourth ventricular RGNT as a distinct entity. Clinically, the tumor affects adults between the ages 18 and 59 years and a mean age at diagnosis in the early thirties. One patient reported by Komori and associates was 12 years of age. Headache is the most common presenting symptom and about half of affected individuals have cerebellar ataxia. Other signs of brainstem dysfunction are not typical. Imaging studies reveal a midline, fourth ventricular neoplasm that is generally well demarcated from adjacent structures and shows minimal peritumoral edema. While some tumors in the Komori series were solid, most were heterogenous with cystic areas and showed only focal contrast enhancement. Obstruction of the aqueduct of Sylvius is associated with hydrocephalus in some cases. The tumor may occasionally be multicentric [4, 7] . Intraoperatively, the RGNT is soft and gelatinous and typically extends to involve the adjacent cerebellar tissue. Histologically, the tumor is composed of two components [4]. The first is a uniform population of neurocyte-like cells that form perivascular pseudorosettes and neurocytic rosettes. Tumor cells have scant cytoplasm and round to slightly oval nuclei with finely granular chromatin and inconspicuous nucleoli. Perinuclear haloes are prominent in some areas and a mucin-like or myxoid change is characteristic. Separation of the tissue in mucoid areas may produce pseudopapillary arrangements. Rare ganglion cells are found in the myxoid material. The second histology consists of paucicellular, bland-appearing astrocytes with background fibrillarity and scattered eosinophilic granular bodies and Rosenthal fibers. Some areas appear gliotic and contain hemosiderin consistent with remote hemorrhage. Squash preparations and frozen sections will suggest a low grade astrocytic tumor because of this second element. There is focal vascular hyalinization and even focal vascular endothelial proliferation. Mitoses are not identified in either neoplastic element and the Ki67 labeling index is low (around 2%). The neurocytic element is at least focally immunoreactive for synaptophysin, especially in regions of perivascular pseudorosettes and within rosette cores. The tumor is strongly and diffusely positive for S-100 and shows moderate diffuse staining for class III beta tubulin. Neurofilament identifies scattered axon-like processes in the background while the perinuclear tumor cell cytoplasm is negative. GFAP identifies delicate tumor cell processes in the background of neurocyte-like areas and is strongly reactive in astrocytic areas. Chromogranin is negative in the tumor cells. Immunohistochemical studies help support the diagnosis but familiarity with this entity and its characteristic clinical and pathologic features will be most useful in arriving at the correct diagnosis. A histologic resemblance of the RGNT to the DNT has already been mentioned. However, as originally described, the DNT occurs most commonly in children with clinical histories of complex partial seizures due to superficial, intracortical temporal lobe tumors [8]. In addition to location, DNTs differ from RGNTs by their cytoarchitectural complexity, multinodularity, and association with adjacent areas of cortical dysplasia. A ventricular location for such tumors is exceptional but was observed in three of four DNTs that arose in the caudate nucleus [9]. With regards to the two cases reported as cerebellar DNTs, the neoplasm described by Kuchelmeister et al. [5] arose in the inferior cerebellar vermis and grew upwards into the deep white matter rather than into the fourth ventricle. The example of Yamane et al. [6] was primarily within the fourth ventricle but did not have an astrocytic component. The differential diagnosis also includes the central neurocytoma [1]. Although such tumors most typically present as midline, ventricular masses of the cerebrum arising in the region of the septum pellucidum, extraventricular examples are well described and their occurrence in the posterior fossa has been reported. In contrast to the RGNT, central neurocytomas are composed of a cytologically uniform neurocytic element, which bears a striking resemblance to the oligodendroglioma. Reactive-appearing astrocytes are scattered in the background of central neurocytomas rather than forming a distinct "second" element. Neurocytic tumors with increased mitotic and Ki67 labeling indices have been referred to as "atypical neurocytomas" and posterior fossa examples of such tumors have been described [10, 11, 12] . A distinctive rosetted glioneuronal tumor of the cerebrum (also called: "glioneuronal tumor with neuropil-like islands - GNTI") was initially described by Rosenblum and colleagues [13] and subsequently by others [14, 15] . Despite the similarity in name with the fourth ventricular tumor featured here, the GNTI presents as a supratentorial, cerebral hemispheric mass is composed primarily of an infiltrating astrocytomatous element that is focally interrupted by synaptophysin-immunoreactive neuropil-like islands containing neuronal cells showing variable degrees of differentiation. The GNTI may show proliferative activity and has a potential for local recurrence and an unfavorable clinical course. One spinal cord example disseminated in the meninges [16]. A "papillary glioneuronal tumor" is mentioned for the sake of completeness but all reported cases have been supratentorial in origin [17]. Finally, it should be remembered that otherwise typical pilocytic astrocytomas may contain oligodendrocyte-like areas. However, such areas are distinct from neurocytic elements of the RGNT. Clinical Follow-Up: The patient described here was treated with surgery alone and suffered only minimal residual neurologic deficits. There was no evidence of tumor recurrence a year after gross total resection. This is consistent with the findings of Komori et al. [4] in which four patients recovered fully after surgery alone, six had permanent neurologic deficits but no tumor progression, and one patient who had undergone radiation therapy died four years after diagnosis. References Kleihues P, Cavenee W. eds. Pathology and Genetics: Tumors of the Nervous System. Lyon, France: IARC Press, 2000 Cenacchi G, Giangaspero F. Emerging tumor entities and variants of CNS neoplasms. J Neuropathol Exp Neurol 2004; 63:185-192 McLendon RE, Provenzale J. Glioneuronal tumors of the central nervous system. Brain Tumor Pathol. 2002;19(2):51-8 Komori T, Scheithauer BW, Hirose T. A rosette-forming glioneuronal tumor of the fourth ventricle. 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Neurocytoma/rhabdomyoma (myoneurocytoma) of the cerebellum. Acta Neuropathol 1998;95:318-23 Warmuth Metz M, Klein R, Sorensen N, et al. Central neurocytoma of the fourth ventricle: case report. J Neurosurg 1999;91:506-09 Yasargil MG, von Ammon K, von Deimling A, et al. Central neurocytoma: histopathological variants and therapeutic approaches. J Neurosurg 1992;76:32-37 Teo JGC, Gultekin SH, Bilsky M, Gutin P, Rosenblum MK. A distinctive glioneuronal tumor of adult cerebrum with neuropil-like (including "rosetted") islands. Report of 4 cases. Am J Pathol 1999; 23:502-10 Prayson RA, Abramovich CM. Glioneuronal tumor with neuropil-like islands. Hum Pathol 2000; 31:1435-38 Keyvani K, Rickert CH, von Wild K, Paulus W. Rosetted glioneuronal tumor: A case with proliferating neuronal nodules. Acta Neuropathol 2001; 101:525-28 Harris BT, Horoupian DS. Spinal cord glioneuronal tumor with "rosetted" neuropil islands and meningeal dissemination: A case report. Acta Neuropathol 2000; 100:575-79 Komori T, Scheitahuer BW, Anthony DC, et al. Papillary glioneuronal tumor: A new variant of mixed neuronal-glial neoplasm. Am J Surg Pathol 1998; 22:1171-83