Posterior fossa tumors showing neuronal and glial differentiation, with or without a ganglion component, have been described in recent years [¹]. Rosette-forming glioneuronal tumor (RGNT) of the fourth ventricle (WHO grade I), a rare slow growing tumor affecting mainly the young, characterized by distinct neurocytic rosettes or perivascular pseudorosettes and an astrocytic component, is one of the rare benign mixed neuronal-glial neoplasms added in the most recent edition of WHO Classification of Central Nervous System (CNS) Tumors (2007) [²]. It was first described as a dysembryoplastic neuroepithelial tumor (DNET) of the cerebellum in 1995 [³] and was recognized as a new entity in 2002, largely based on the reports of Komori et al. who extensively described 11 cases [⁴–⁶]. RGNT was initially described as occurring solely in the fourth ventricle and with possible extension into the surrounding structures, including the cerebellar vermis, cerebello-pontine angle, midbrain and aqueduct of Sylvius [⁴, ⁷, ⁸]. However, reports of origin from other sites in the CNS, including the pineal region, have been documented [⁴, ⁹]. Scheithauer et al. [¹⁰] described RGNT in the optic chiasm in a 23-year-old Caucasian male with neurofibromatosis Type 1 (NF1). It was also reported in the cervical spinal cord of a 44-year-old woman [¹¹]. Recently, an unusual widespread intraventricular dissemination of RGNT was described in a 16-year-old Chinese girl with stable outcome 7 months post-radiotherapy [¹²].

Consistently, reports show a high frequency of somatic isocitrate dehydrogenase 1 (IDH1) and isoform IDH2 mutation among oligodendrogliomas, astrocytomas and secondary glioblastomas [¹³–²¹]. This mutation is exceedingly rare in primary glioblastomas and pilocytic astrocytomas, and virtually absent in meningiomas and ependymomas, suggesting a different pathobiological mechanism or stem cell glial precursor. In a limited study, IDH1 mutation in gangliogliomas was reported to be associated with poorer outcome, though IDH1-positive gangliogliomas showed “atypical” features pathologically [²⁰]. Whether these IDH1 mutant cases are diffuse gliomas with overrun neurons remains to be resolved. As RGNT shares some morphologic features with low grade gliomas and gangliogliomas, we carried out deoxyribonucleic acid (DNA) sequencing of IDH1 [residue (R)132] and IDH2 (R172) mutation hotspots to assess whether they also occur in this tumor.

Excluding this case, we identified 19 published papers with 43 diagnosed RGNT cases to date. The prevalence of some clinico-radiologic and histologic findings has not been quantified; hence, it is also the objective of this report to review the frequency of specific radiographic and histologic findings, as well as analyze treatment and outcome from previously-described cases to better elucidate the nature of this rare neoplasm.

A previously healthy 16-year old female presented for chronic episodes of right-sided headaches and vomiting, relieved with rest alone. On physical examination, her pupils were noted to be sluggishly reactive to light and bilateral papilledema was noted. Noncontrast computed tomographic study of the head revealed a mass centered in the pineal gland region with punctate calcification, extending into the posterior aspect of the third ventricle. There was marked associated obstructive hydrocephalus due to mass effect and compression of the cerebral aqueduct. A subsequent cranial magnetic resonance imaging (MRI) with gadolinium further defined a heterogeneous, non- enhancing 3.8 cm × 3.6 cm × 3 cm mass in the pineal region, encroaching into the posterior third ventricle (Fig. 1). MRI of the spine showed no metastatic disease. A biopsy of the tumor was performed via endoscopic third ventriculostomy. Tumor markers, including beta-human chorionic gonadotropin, and alpha-fetoprotein were not significantly elevated in both the blood and cerebrospinal fluid (CSF). The pathologic diagnosis was RGNT. The patient was referred for tumor debulking 8 weeks post-biopsy as follow-up MRI revealed increasing hydrocephalus. A suprasellar, infratentorial approach was undertaken and subtotal resection was achieved. Post-operatively, the patient showed significant improvement with no reported complications. Follow-up imaging 2 months post-resection revealed a residual mass in the pineal gland region with stable hydrocephalus. Of note, the patient has stable neurologic status and continues to see a pediatric endocrinologist for primary amenorrhea, which may be related to the chronic hydrocephalus.

The review of RGNT cases was carried out through searches in the literature using PubMed queries (up to and including January 2010) for original articles (including reviews) using a combination of the terms rosette forming glioneuronal tumor and RGNT. The cited references of the sources were also searched. The search yielded 30 papers reporting a total of 43 RGNT cases. The pertinent clinical, radiographic and histological data are presented in tables and further elucidated in the discussion.

Epidemiology of this neoplasm is limited since there are relatively few published cases. In our review (Fig. 3), this tumor was found to more commonly afflict young adults (mean: 30 ± 12.8 years ), with nearly a two-fold female predominance (1.9:1 female to male ratio), which is similar to earlier findings [⁴, ²⁴, ²⁹].

The clinico-radiologic characteristics in our patient are similar to those previously described. However, this tumor largely involves the pineal region, abuts the posterior third ventricle and impinges on the cerebral aqueduct causing hydrocephalus, which is a less common observation. Table 1 summarizes the clinical findings from previously published data. Our patient presented with headache and vomiting which are still the most commonly reported symptoms in the review (Table 2). Ataxia (39.5%), vertigo (16.3%), cranial nerve palsies (13.2%) and visual complaints (11.6%), are also commonly observed. Signs and symptoms appear to be related to the common location of this tumor (see Table 1) which is the fourth ventricle (31.8%) and contiguous structures (25%), and are related to posterior fossa involvement and early development of obstructive hydrocephalus from CSF flow interruption in the fourth ventricle. Li et al. [²⁵] reported intratumoral hemorrhage in one patient leading to incidental diagnosis, along with five other cases that did not have apparent symptoms (14%).

Paramount concern among studies of “new” tumor entities is in regard to their natural history. This tumor appears to have a variable growth pattern. Available data in 32 cases (Table 1) show an extremely large gap in the reported duration of symptoms, ranging from a few hours to 15 years from the first report of neurologic disturbance (mean duration: 27.2 ± 44.6 months). One patient [⁷] presented acutely in the emergency room secondary to intratumoral bleeding, which led to sudden obstructive hydrocephalus. A plausible explanation is that this tumor might have an extremely indolent growth that patients do not recognize or report symptoms, except in cases of inherent tumoral complications (e.g. infarction, hemorrhage). The brain MRIs show most consistently solid-cystic changes (54.5%) that are iso/hypointense on T1-weighted images and hyperintense on T2-weighted images and with high probability of enhancement (whether ring-enhancement or heterogenous pattern, 65.9%; Table 1). Average size was 30.3 ± 16.8 mm in the 29 cases with available information. Eleven patients (25%) showed calcifications while satellite lesions were noted in seven patients. Multiple lesions were extremely rare occurrences.

RGNT is a newly recognized CNS tumor having biphasic histologic characteristics [¹, ³⁰, ³¹]. The key features [²], described in virtually all the reports, include: (i) a neurocytic component composed of neurocytes forming rosettes (resembling Homer-Wright rosettes) around a synaptophysin-positive eosinophilic core and/or perivascular pseudorosettes that are arranged in arrays towards a vessel and (ii) an astrocytic component that is frequently described as closely resembling that of a pilocytic astrocytoma. A microcystic, myxoid matrix may be found in these neurocytic structures, while oligodendroglia-like cells (OLCs) may be seen in areas of the glial component. It has been reported that these OLCs have strong synaptophysin and Olig2 reactivity; however, they do not show 1p/19q co-deletion [¹²]. Olig2, a transcription factor that controls development and differentiation of oligodendrocytes, is known to have variable expression in oligodendrocytes, oligodendrogliomas, neuroepithelial tumors and other glioneuronal tumors [³²–³⁴]. In our review, Rosenthal fibers and EGBs are each present in over 60% of cases. Nearly 1/2 of cases have hyalinized blood vessels and myxoid stroma. In 1/3 of cases microcalcifications are noted (Table 3). “Dysmorphic” ganglion cells are reported in five cases [⁴, ⁵]. “Floating” Purkinje cells are specified in three cases [³, ²⁹]. Whether the reported “dysmorphic” ganglion cells are also “floating” Purkinje cells remain to be clarified. Mitoses and necrosis are generally absent. No ganglion cells were identified in our illustrative case. Neither the neurocytic nor the astrocytic cellular component shows atypia.

The immunohistochemical profile in our case is compatible with the previously published cases. Consistently described is immunoreactivity for synaptophysin in the neurocytic rosettes and perivascular pseudorosettes. Microtubule associated protein 2 (MAP2) and neuron specific enolase have also been reported to be expressed in the neurocytic cell processes. GFAP and S-100 immunoreactivity are variably present in the glial component, but are absent in the neurocytic component. Ki-67 labelling index is generally low, similar to the observation in our case (<1%). Review of cases with available information shows a mean Ki-67 index of 1.8 ± 0.75 (SD) (range: 0–3.8%).

RGNTs have been suggested to arise from cells of the subependymal plate (periventricular germinal matrix) [⁴] which have also been suggested as the site of origin of DNETs of the cerebellum [¹]. Whether this finding reflects normal or aberrant developmental placement of precursor or stem cells is uncertain. Increasing numbers of RGNTs have been recognized in locations other than the fourth ventricle. The alternate possibility of histologically similar tumors with underlying genetic differences is not excluded.

RGNT of the fourth ventricle is a distinct tumor entity that also arises in other locations of the CNS. Whether the tumor should be renamed will likely be a source of debate. The presence of Rosenthal fibers and EGBs in a piloid neoplasm involving the fourth ventricle or pineal region should prompt consideration of RGNT and a search for the typical neurocytic areas. We identify wildtype IDH1 and IDH2 genes but additional cases would be helpful to confirm this not unexpected genotype in RGNT. It should certainly be considered in the radiological differential diagnosis of solid-cystic tumors of the posterior fossa showing variable enhancement, with or without calcification. While the course is nearly always benign, the rare case of recurrence suggests that long-term follow up may be desirable.

H.V.V & O.E.S. supported in part by the Daljit S. & Elaine Sarkaria Chair in Diagnostic Medicine. W.H.Y. & T.F.C. supported in part by the Art of the Brain and the Henry Singleton Brain Tumor Fund.We thank Weidong Chen of the UCLA Department of Neurology and the personnel at the Brain Tumor Translational Resource for their invaluable assistance to the project.

Conflict of interest None.

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