Central neurocytoma: management recommendations based on a 35-year experience.

Leenstra JL, Department of Radiation Oncology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.

Treatment for central neurocytoma: a meta-analysis based on the data of 358 patients

Rades D, Strahlenther Onkol. 2003 Apr;179(4):213-8.

Abteilung für Strahlentherapie und Radioonkologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Deutschland. Rades.Dirk@gmx.net

J Neurosurg 2001 Nov;95(5):879-82

The purpose of this report was to review the results of stereotactic radiosurgery in the management of patients with residual neurocytomas after initial resection or biopsy procedures.

Four patients underwent stereotactic radiosurgery for histologically proven neurocytoma. Clinical and imaging studies were performed to evaluate the response to treatment. Radiosurgery was performed to deliver doses to the tumor margin of 14, 15, 16, and 20 Gy, depending on tumor volume and proximity to critical adjacent structures. More than 3 years later, imaging studies revealed significant reductions in tumor size. No new neurological deficits were identified at 53, 50, 42, and 38 months of follow up.

The authors' initial experience shows that stereotactic radiosurgery appears to be an effective treatment for neurocytoma.

J Neurol Neurosurg Psychiatry 2001 Apr;70(4):489-93

OBJECTIVES: A series of three recurrent central neurocytomas treated by gamma knife radiosurgery (GKRS), which were initially totally resected, are described. Up to now, no reports exist on this treatment modality for this rare tumour entity.

METHODS: Three male patients, aged between 20 and 25 years, presented with large intraventricular tumours. Total tumour removal was achieved by a single surgical procedure (one patient) or two operations (two patients). Neuropathological investigation showed a central neurocytoma, immunohistochemically all three tumours expressed a neuronal antigenic profile typical for neurocytomas, and the MIB-1 proliferation index ranged from 2.4% to 8.7%. Each patient experienced a tumour recurrence after 5 to 6 years. The recurrence was multifocal in two and a singular tumour mass in one patient. Gamma knife radiosurgery was performed. The tumours were enclosed within the 30% to 60% isodoseline, and delivered a tumour marginal dose of 9.6 to 16 Gy. During the follow up period, the patients were tested clinically and the volume of the tumours was measured on MRI.

Central neurocytoma

Histopathology 2000 Aug;37(2):160-5

AIMS: Central neurocytoma is a rare central nervous system tumour typically found in the lateral ventricles and at the septum pellucidum. Histologically, it resembles oligodendrogliomas and yet ultrastructurally, it shows neuronal differentiation. Its molecular oncogenesis is not known. The aim of this study was to examine whether major genetic events found in oligodendrogliomas and neuronal tumours, namely allelic deletions of chromosomes 1p and 19q and N-myc amplification, can be found in central neurocytomas. As there was one report describing gain of chromosome 7 in central neurocytomas, we also examined epidermal growth factor receptor (EGFR) amplification, as the EGFR gene is located at chromosome 7p.

METHODS AND RESULTS: Nine central neurocytomas and matched blood samples were examined for loss of heterozygosity (LOH) of 1p and 19q13.2-13.4 with 23 finely mapped microsatellite markers. N-myc amplification was studied by fluorescence in-situ hybridization using paraffin-embedded sections. EGFR amplification was tested for by differential PCR. Six of nine (67%) tumours showed LOH at one or more loci at 1p and 5/9 (56%) of cases showed LOH at 19q. However, common regions of deletion cannot be identified. The majority of informative markers are retained at 1p (84%) and 19q (86%). Only one tumour showed amplification of N-myc and none of the cases showed amplification of EGFR. C

ONCLUSION: Central neurocytomas are genetically distinct from oligodendrogliomas, and chromosomes 1p and 19q probably do not play an important role in their pathogenesis. N-myc and EGFR amplification are rare.

J Neurosurg 2000 Jul;93(1):77-81

OBJECT: Central neurocytomas are rare neuronal tumors commonly found in the intraventricular regions. Little is known about the tumorigenesis of these neoplasms. The aim of this study was to provide an overview of genetic imbalances in central neurocytomas.

METHODS: In this study, comparative genomic hybridization was used to identify DNA sequence copy number changes (losses and gains) in a series of 10 central neurocytomas. Tumor DNA and normal reference DNA were differentially labeled and allowed to cohybridize to normal metaphase chromosomes. After hybridization and fluorescent staining of the bound DNA, regions of gain or of loss of DNA sequences were detected as changes in the tumor/normal fluorescence intensity ratio along the target metaphase chromosomes. A gain of DNA sequence was detected in chromosomes 2p, 10q, and 18q. A protooncogene, Bcl2, which maps to 18q21, was evaluated by immunohistochemical analysis to determine its role in the formation of central neurocytomas.

CONCLUSIONS: In this study the authors identified recurrent genetic changes on chromosomes 2p, 10q, and 18q in central neurocytomas and highlighted chromosomal regions for additional mapping and cloning of candidate genes that are important in the development of central neurocytomas.

Am J Surg Pathol 2001;25:1252-1260 Abstract quote

Neurocytic neoplasms usually arise within the lateral ventricles, generally as circumscribed, slowly growing masses curable by total resection. Both subtotal resection and histologic atypia are associated with an increased risk of recurrence. In contrast, neurocytic neoplasms situated within brain parenchyma, so-called “extraventricular neurocytomas” (EVNs), are not as well characterized. The relationships between histologic features and extent of resection versus clinical behavior have not been defined. We evaluated pathologic features, clinical data, and neuroimaging of 35 examples. The tumors occurred in 18 males and 17 females, age 5–76 years (median 34 years). All tumors involved the cerebrum. On imaging, EVNs were solitary, variably contrast-enhancing, and often (57%) cystic. Tumor cells were arranged in sheets, clusters, ribbons, or rosettes, in association with fine neuropil dispersed in broad zones that separated cell aggregates. Ganglion cell differentiation was seen in 66%. All tumors showed strong synaptophysin immunoreactivity. Despite the lack of apparent astrocytes in hematoxylin and eosin-stained sections, focal glial fibrillary acidic protein reactivity was seen in 46%. Eleven EVNs were designated “atypical” based on the presence of necrosis, vascular proliferation, or elevated mitotic activity (3 mitoses/10 high power fields). Nineteen tumors were subtotally resected or biopsied, whereas 14 were totally resected grossly. Seventeen patients underwent radiotherapy (mean 55 Gy). In 30 cases with follow-up, 10 tumors recurred, 3 causing death at 6, 14, and 43 months. All 10 recurrences followed subtotal resection. No totally resected tumors recurred. Thus, the majority of EVNs are well differentiated and appear unlikely to recur after gross total resection. Subtotal resection, atypical histologic features, and high cell proliferation rates correlate with recurrence.

BACKGROUND: Central neurocytoma was described as a well differentiated tumor of neuronal origin, distinct from ganglion cell tumors and neuroblastoma. An initially perceived benign biologic behavior has been questioned by subsequent reports of anaplastic and recurrent tumors. We report six cases of central neurocytoma, with variable clinical and pathologic features that stimulate discussion on the management of these tumors.

METHODS: Of the 95 oligodendrogliomas treated in our institution in the last 40 years, three tumors were reclassified as central neurocytomas on histologic reappraisal. Three additional cases prospectively diagnosed as central neurocytomas are reported. The clinical, pathologic, and radiologic features are reviewed.

RESULTS: Early recurrence, not related to malignant histologic features, was noted in two patients who had not received postoperative radiotherapy. Anaplastic histologic changes were not accompanied by malignant biologic behavior in another patient. Neither patient with recurrent tumor was controlled by radiotherapy alone. Chemotherapy with carboplatin reduced tumor size temporarily in one of these patients.

CONCLUSION: An entirely benign nature for this tumor is questioned and it appears that there may be malignant variants. Surgery should aim for maximum possible excision, as the location of the tumor allows. The role of postoperative radiotherapy remains controversial and may be considered in cases of subtotal excision of tumors with anaplastic histologic features. Chemotherapy may be of benefit in cases recurring despite surgery and radiotherapy.

Ann Pathol 2000 Dec;20(6):558-63 Abstract quote

Central neurocytoma is a rare neuronal tumor affecting young adults and usually located in the lateral ventricles. Post-operative prognosis is generally good.

Histologically, central neurocytoma is composed of isomorphous small round or ovoid cells alternating with irregularly shaped patches of fibrillary matrix similar to the neuropile.

In a series of 10 cases, two central neurocytomas were histologically "atypical" at first examination. One was intra-ventricular, and the second had an intra-parenchymatous juxta-ventricular location. Both were highly cellular with mitotic activity, and tumor necrosis was seen in one. Neuronal differentiation was assessed by synaptophysin immunoreactivity in all 10 cases and by ultrastructural examination in four, including the two "atypical" forms. Neuronal differentiation was less marked in these "atypical" forms, one also presenting focal GFAP immunoreactivity. The proliferative potential was determined by MIB-1 labeling index and compared with clinical outcome. The eight classical central neurocytomas had a MIB-1 labeling index < 2.3%, whereas the two "atypical" forms had a MIB-1 labeling index > 5.2% and both recurred.

We think that there is a spectrum of small-cell neuronal tumors. The two extremes could be the central neurocytoma and the primary cerebral neuroblastoma, while the intermediate forms might be qualified as "atypical neurocytoma". In our series, the histological and immunohistochemical criteria of biological aggressiveness appeared to be high mitotic activity, tumor necrosis, loss of neuronal differentiation and high MIB-1 labelling index.

J Neurooncol 2000 Jun;48(2):161-72 Abstract quote

Central neurocytoma (CN) is described as a rare intra-ventricular benign neuronal tumor of the brain.

Two primary tumors first diagnosed as malignant and extra-ventricular neurocytomas are reported here.

Histologically, the tumor of the first patient, a forty-one-year-old man, consisted of monotonous cells with round nuclei, but no fibrillar background. The second tumor, in a nineteen-year-old girl, showed areas of moderately pleomorphic round cells, with numerous rosettes and ganglion cell differentiation, in an abundant fibrillary network. Both presented calcifications. Mitoses were more frequent in recurrences and spinal locations than in the primaries. All tumors stained strongly for synaptophysin, and GFAP was partly positive in the first case only.

Patients received post-surgical radiotherapy and were still alive eight and six years, respectively, after initial surgery. The interpretation of atypical cases, such as ours is not easy: the diagnoses finally retained were oligodendroglioma in the first case and ganglioneuroblastoma in the second case. Furthermore, neurocytomas atypical either by their unusual topographical or histological presentation or by their poor prognosis, have been frequently entitled in this way on synaptophysin positivity. So, we were prompted to reassess the entity of CN, seventeen years after the first description, to re-appreciate the reality of anatomo-clinical variants and to discuss the value of synaptophysin positivity in these tumors.

In conclusion, it seems preferable to individualize true classical CN, which has a favorable outcome, from so-called extra-ventricular, atypical and anaplastic, clinically malignant neurocytomas for which complementary treatment is required.

Cancer 2001 Jan 1;91(1):136-43 Abstract quote

BACKGROUND: Central neurocytomas are composed of mature neuronal elements, frequently arranged in rosettes similar to those present in pineocytomas. This suggests the possibility of similar patterns of differentiation, including photoreceptor differentiation. The authors analyzed the immunoreactivity of central neurocytomas for retinal S-antigen, neuronal, glial, and neuroendocrine markers.

METHODS: Thirty-three central neurocytomas were analyzed with reference to their clinicopathologic characteristics, immunoreactivity, and the possibility that anaplastic histologic features correlated with aggressive clinical behavior.

RESULTS: There were 18 male and 15 female patients. The median age at diagnosis was 30 years (range, 3-69 years). All of the tumors with specified location were related to the ventricles. Thirty-two tumors were diagnosed at surgery and 1 at autopsy. Histologic features included mineralization (20 of 33), foci of necrosis (4 of 33), chronic inflammation (4 of 33), ganglion cell differentiation (1 of 33), and lipomatous differentiation (1 of 33). None of the lesions had significant nuclear pleomorphism, mitotic activity, or vascular endothelial proliferation. Immunohistochemistry included expression of synaptophysin (33 of 33), neuron specific enolase (31 of 33), S-100 protein (25 of 33), retinal S-antigen (14 of 24), somatostatin (8 of 27), glial fibrillary acidic protein (4 of 33), neurofilament protein (3 of 22), and leucine enkephalin (1 of 27). At follow-up, 15 of 23 patients were alive an average of 8.1 years (range, 0.91-35.9 years) after surgery.

CONCLUSIONS: Central neurocytomas behave as slowly growing neoplasms that remain confined within one or several supratentorial ventricles and are associated with long survival after surgical excision. Malignant forms with aggressive clinical behavior were not found. The neoplastic cells can express photoreceptor differentiation possibly relating central neurocytomas to pineocytomas. Adipocyte differentiation may be present, and the possibility of a relation between the central neurocytoma and cerebellar liponeurocytoma should be entertained.

Surg Neurol 1996 Jan;45(1):49-56 Abstract quote

BACKGROUND: Central neurocytomas are rare brain tumors recognized by their typical radiologic and histologic features. In general, a good prognosis is achieved by total removal. The histogenesis is still under debate, but a neuronal origin is widely assumed.

METHODS: This study presents the clinical and immunohistologic findings of five patients and the results of cell culture experiments of two patients with central neurocytoma treated surgically between 1983 and 1993.

RESULTS: The patient age at diagnosis ranged from 21 to 30 years (mean, 25 years). The male-to-female ration was 1:4. Raised intracranial pressure due to hydrocephalus was the main cause of the clinical manifestations. Total resection was achieved in two cases. Four patients received radiotherapy. One patient suffered a recurrence 1 year after surgery, requiring a second resection and radiotherapy. Follow-up studies took place between 1 and 10.5 years (mean, 7.1 years). To date, all patients are free of their tumors. Two patients suffered from permanent memory disturbances after surgery. Immunohistochemistry confirmed the neuronal nature of the tumors. Cell-culture studies, which have been carried out for the first time, demonstrated concomitant expression of neuronal (synaptophysin) and glial (GFAP) markers.

CONCLUSION: Total removal is the therapy of choice. In tumor recurrence or limited surgery (e.g. due to severe affliction of the fornical structures), radiotherapy has shown to be efficacious. The cell-culture experiments give new insight on the histogenesis of central neurocytoma, indicating that the tumor arises from an undifferentiated precursor cell with the capacity of bipotential neuroglial differentiation.

Cancer 1999 Apr 1;85(7):1606-10 Abstract quote

BACKGROUND: Although central neurocytomas are considered benign, recent reports suggest that some patients with histologic atypia and/or elevated proliferation potential may have a poor outcome.

METHODS: A retrospective review identified 15 cases of central neurocytoma. Clinical follow-up was available for 14 patients. Each tumor was evaluated for the presence of atypical histologic features, including cellular pleomorphism, endothelial proliferation, and necrosis. The proliferation potential was assessed by MIB-1 immunohistochemistry. The correlation among histology, MIB-1 labeling index (MIB-1 LI), and clinical outcome was evaluated.

RESULTS: Histologic atypia was identified in 3 tumors (20%). The MIB-1 LI ranged from 0.1% to 6.0%, and 5 cases (33%) had an MIB-1 LI >2%. The correlation between histologic atypia and MIB-1 LI was poor, with only 1 tumor having both atypia and MIB-1 LI >2%. Clinical follow-up ranged from 13 to 255 months postoperatively (mean, 68 months). Although most patients were alive and well at last follow-up, three developed symptomatic recurrence and one died as a result of increased tumor growth. The tumors from all 4 patients with a poor outcome had MIB-1 LI >2%, but only 1 had histologic atypia.

CONCLUSIONS: The proliferation potential of central neurocytoma is a useful predictor of clinical outcome, whereas histologic atypia alone is not prognostically significant. It would be appropriate to recognize a subgroup of central neurocytomas with elevated proliferation potential as WHO Grade 2 lesions. The terms "atypical" and "anaplastic" are not appropriate to describe these lesions, as they imply a certain histologic appearance. The most accurate designation would be "proliferating neurocytoma."

J Clin Neurosci 1999 Jul;6(4):319-323 Abstract quote

The clinicopathological features of 20 cases of central neurocytomas are described.

They accounted for 0.28% of all intracranial tumours diagnosed during a 16 year period (1980-1995). Lower mean age of the patients at diagnosis (23.1 years), male preponderance (M:F=1.8:1) and higher incidence of involvement of the right lateral ventricle (10/20 cases) were noted in this series, in contrast to reports from Western literature. Total removal of the tumour was done in 14 cases while the remaining six underwent partial resection.

Morphogically, the tumours had a striking resemblance to oligodendrogliomas (11/20 had been earlier diagnosed as oligodendrogliomas) and an interesting finding was the presence of dilated vascular channels in 12/20 tumours. The diagnosis was confirmed in all cases by immunohistochemistry and/or electron microscopy. While 18 cases were histologically benign, two had features of atypical neurocytoma.

Five patients died due to postoperative complications. The remaining patients received postoperative radiation and their follow-up revealed that all of them were doing well at 12 to 72 months after surgery.

These neoplasms should be suspected in any young patient with radiological evidence of an intraventricular lesion; for their differentiation from gliomas, immunohistochemistry and electron microscopy should be done. This is important because, unlike gliomas, these tumours have a relatively favourable prognosis and their current treatment of choice is complete surgical removal without adjuvant chemo- or radiotherapy.

RESULTS: Within follow up periods of 1 to 5 years, control MRI showed a significant decrease of the tumour mass in all cases. None of the patients developed new neurological symptoms after GKRS. Two patients returned to work in their previous employment, whereas one patient remained permanently disabled due to a pre-existing visual impairment and abducens palsy.

CONCLUSION: GKRS proved to be a useful tool in the treatment of recurrent central neurocytomas. Tumour control and even tumour shrinkage can be achieved with a single procedure and a low risk of morbidity.