Clinical manifestations

Presentation and course

Central neurocytoma growth in the ventricles can obstruct the interventricular foramina, resulting in hydrocephalus, intracranial hypertension, and mass effect (56; 65; 42). Common presenting symptoms include headache, nausea and vomiting, visual disturbances, memory loss, muscle weakness, altered mental status, and seizures (35; 65; 42; 30). Relatively little is known about the long-term natural course of patients with central neurocytoma without treatment as the condition is very rare and was only first described in 1982 (17). Large single-institution studies have been published (30); however, this area is still in want of multi-institutional or cohesive database studies.

Prognosis and complications

Despite surgical advancements, the risk of recurrence is high, with many articles reporting 2-year progression-free survival near 75% (20; 42). MIB1-LI is the common guideline, which may be used to predict survival and disease recurrence. This guideline follows the fraction of Ki-67 labeled cells, a hallmark of cellular proliferation in cancerous cells (03; 19; 30). Most articles classify more aggressive or surgically complicated central neurocytomas as having an MIB1-LI greater than the 2% threshold and may be suggestive of more assertive treatment (38; 53; 08). However, other groups have found more lenient cutoffs, with a 10-year progression-free survival of 48% in central neurocytomas with an MIB1-LI of greater than 4% compared to 90% in central neurocytomas with an MIB1-LI less than or equal to 4% (20; 35).

Biological basis

Histology. There can be difficulty when diagnosing central neurocytomas as they share many histopathological characteristics with other brain tumors (63; 50). Central neurocytoma cells have perinuclear halos with a “fried egg” appearance, features also characteristic of oligodendroglioma and perivascular rosettes similar to ependymomas (63; 66; 50). Similarly, central neurocytoma cells also imitate oligodendroglioma cells in that both cell types are round, small, and exhibit a “honeycomb pattern” with diffuse construction (63; 35). Central neurocytoma cells have round nuclei with granular “salt and pepper” chromatin and low mitotic activity (07; 63; 66). These histologic similarities can lead to potential misdiagnosis of this rare tumor. A subset of central neurocytomas, with an MIB1-LI of greater than 2%, are subclassified as atypical central neurocytomas that demonstrate a higher recurrence rate.

Molecular markers. Tissue diagnosis with immunohistochemistry remains the gold standard for eliminating differential diagnoses. Central neurocytomas stain positive for synaptophysin, a transmembrane glycoprotein marker of neuronal cells that is absent in both oligodendrogliomas and ependymomas (53; 35; 50; 30). Most studies also report a positive staining for the neuronal glycolytic enzyme, neuron-specific enolase (25; 68; 18; 62; 22). However, neuron-specific enolase expression in central neurocytomas lacks neuronal specificity, and neuron-specific enolase has also been reported to be expressed in several nonneuronal neoplasms (33; 40; 35).

Conversely, several markers positive in oligodendrogliomas and ependymomas are absent in central neurocytomas and further aid in histological diagnosis. Olig2 is a key marker for oligodendrogliomas, and its absence may suggest a central neurocytoma (69; 14; 35; 50). Epithelial membrane antigen and glial fibrillary acidic protein may be used to eliminate other brain tumors, such as ependymomas, glioblastomas, and astrocytomas (16; 31; 08; 35). 1p19q co-deletion and IDH mutation are now defining features of oligodendrogliomas, which is helpful in differentiating those tumors from central neurocytomas. Neurofilament is also largely absent in central neurocytomas but is present in pineal parenchymal tumors (33; 63; 35).

Genetic alterations and modulations in gene expression. Genetic studies of central neurocytomas have yet to reach a compelling verdict. Conflicting findings on the 1p19q codeletion in central neurocytomas have reported codeletion of chromosome 1p/19q, but other studies report no 1p/19q codeletion (53). N-Myc is overexpressed in central neurocytomas (29; 32; 23). On the other hand, BIN-1, which has expression inversely related to N-Myc, is under-expressed in central neurocytoma. Thus, it is speculated that mutation in a factor involved in the pathway regulating N-Myc/BIN-1 expression may be a precursor to central neurocytoma formation (32; 23; 35). Additionally, insulin-like growth factor 2, platelet-derived growth factor D, and neuregulin 2 have been found to be overexpressed in central neurocytomas and may contribute to tumor proliferation as their involvement has been observed in other neoplasms, including glioblastoma and breast carcinoma (34; 55; 57; 48; 35).

Differential diagnosis

Confusing conditions

Central neurocytomas have many histopathological and immunohistochemical similarities to other brain tumors that potentially manifest in the ventricular system, particularly oligodendrogliomas and ependymomas. Therefore, careful differential diagnosis is required.

The presence and absence of certain immunohistochemical markers is the major tool for the differential diagnosis of central neurocytomas from other brain tumors. Synaptophysin will stain positively in central neurocytomas, whereas Olig2, an epithelial membrane antigen, and glial fibrillary acidic protein will not (16; 31; 69; 53; 08; 14; 35). It is possible that advanced molecular studies, including genetic evaluation via next-generation sequencing and epigenetic evaluation via DNA methylation profiling, can be of assistance in solidifying the diagnosis. These studies should be considered to help aid in the classification of these rare tumors.

Diagnostic workup

On CT imaging, central neurocytomas appear as isodense to slightly hyperdense intraventricular masses that are frequently contrast-enhancing (66). Calcifications are commonly seen, and cystic regions and hemorrhage can also be present but are less frequently observed (66; 65). On T1-weighted MRI, central neurocytomas appear as hypointense to isointense lesions, whereas on T2-weighted MRI, central neurocytomas are typically isointense to hyperintense (35; 66; 65). The characteristic “soap bubble” appearance of central neurocytomas may be appreciated on MRI. Additional findings observable on MRI studies include intratumoral cysts and vascular flow (66; 65). However, because central neurocytomas mimic many other brain tumors on imaging (eg, oligodendrogliomas), further evidence, such as histopathological analysis, is needed for accurate diagnosis.

Management

Surgery. Surgical excision via craniotomy followed by a transcortical or interhemispheric transcallosal approach for maximal safe resection is the standard of care for patients with central neurocytoma (14; 65; 42). Previous studies have reported a 5-year survival rate of 99% with gross total resection, compared to 86% for patients receiving subtotal resection (25; 51; 46; 02; 42; 30). Gross total resection may exhibit lower recurrence rates; however, data have shown conflicting results (63; 30). Although safe maximal resection is the goal of surgical intervention, the physical proximity of central neurocytomas to critical brain structures yields a 30% to 50% gross total resection rate (25; 01; 06; 42; 39; 30). In cases of subtotal resection, adjuvant radiation therapy is recommended (25; 01; 06; 42; 30). Surgical resection is currently considered the primary initial treatment modality by most clinicians in the neuro-oncologic community.

Adjuvant radiotherapy. Multiple studies have reported better prognosis for patients receiving adjuvant radiotherapy after subtotal resection compared to subtotal resection alone (65; 30; 54). Wang and colleagues reported that patients who received adjuvant radiotherapy after subtotal resection (8.3%) had recurrence rates comparable to patients receiving gross total resection (8.8%), which were both markedly lower than patients receiving subtotal resection alone (34.5%) (65). Furthermore, in a series of 68 patients, She and colleagues noted an improvement in progression-free survival when receiving adjuvant radiotherapy following subtotal resection (54). Studies have reported improved 5-year survival, 10-year survival, and tumor control rates in subtotal resection patients receiving adjuvant radiotherapy compared to subtotal resection patients with no adjuvant radiotherapy (51; 47; 44; 20; 30). Single-session, high-dose stereotactic radiosurgery is considered a safe and effective adjuvant radiotherapy modality for central neurocytomas and may be preferable over fractionated stereotactic radiotherapy. Yamanaka and colleagues treated 36 central neurocytoma patients with adjuvant stereotactic radiotherapy and observed a 5-year and 10-year progression-free survival of 94% and 86%, respectively (67). Adjuvant stereotactic radiotherapy has previously been reported to have higher tumor control rates, lower recurrence rates, and lower mortality rates compared to adjuvant fractionated stereotactic radiotherapy (51; 44; 13). In one study, Han and colleagues described a population of 55 patients, nearly half of whom received radiotherapy (15). Their conclusions stated that adjuvant radiation is necessary in cases in which gross total resection was not achieved.

Stereotactic radiosurgery. Stereotactic radiotherapy as a primary treatment for central neurocytomas is gaining support (26; 27; 35). Kim and colleagues reported that patients treated with primary stereotactic radiotherapy had favorable local control rates compared to patients receiving surgery with adjuvant stereotactic radiotherapy (26; 27). Lee and colleagues reported a 73% depression in tumor volume at 48 months’ follow-up in a cohort of 28 central neurocytomas (35). This study also concluded that there was no significant difference between the adjuvant and primary radiosurgery cohorts in tumor volume reduction, which may be indicative of further studies using radiosurgery as the primary treatment for central neurocytomas. Although stereotactic radiotherapy harbors the risk of associated complications, such as radiation necrosis and neurotoxicity, these risks are relatively low (07; 26; 27; 13; 35; 42). Bui and colleagues reviewed 150 patients treated with stereotactic radiotherapy and found that only 2% experienced radiation-associated adverse events (06). Although larger cohort studies are needed, stereotactic radiotherapy appears to be a viable primary treatment modality for central neurocytoma. However, due to the rarity of the tumor and the broad radiologic differential diagnosis, it is not routine practice to perform stereotactic radiosurgery without histological confirmation of diagnosis via biopsy.

Chemotherapy. Much of the chemotherapeutic landscape for central neurocytomas has not changed over the last decade. Although uncommon, chemotherapy has occasionally been used as an alternative to radiotherapy as an adjuvant treatment of central neurocytomas (10; 04; 64; 05). It is most often used in cases in which radiation therapy is not an option for the patient or the tumor is resistant to radiation treatments; however, heterogenic responsiveness is common (64; 05). Continued use of chemotherapy as a salvage treatment for these tumors warrants more research at this time.

Outcomes

Central neurocytomas often have a good prognosis with maximal safe resection and adjuvant radiotherapy (07; 35; 42; 30). However, the risk of recurrence increases with subtotal resection as well as a higher proliferative index, as noted in atypical central neurocytomas (29; 42; 50). Atypical central neurocytomas are associated with 10-year survival in 63% and 10-year local control rates in 46% (36). Approximately one third of all central neurocytomas (atypical as well as non) recur or progress within the first 10 years (42; 50; 30; 28). In turn, due to the potential for delayed recurrence, routine follow-up is highly recommended.

Patients with gross total resection have lower recurrence rates compared to those with subtotal resection (65; 15; 39). Surgical treatment of central neurocytomas may have high complication rates due to its proximity to important cerebral structures. As a result, gross total resection is only achieved in 30% to 50% of cases (25; 01; 06; 15). Adjuvant radiation therapy has been shown to further decrease disease recurrence and is almost always warranted after subtotal resections (35; 67; 42; 15; 39).

Small cohorts of patients treated with primary stereotactic radiosurgery have also experienced similar outcomes (35; 42). Although these tumors are classified as benign, the suboptimal progression-free survival is concerning and warrants continued long-term surveillance in these patients. Primary stereotactic radiosurgery is becoming a viable treatment option, but radiation also carries various risks, such as radiation necrosis, neurotoxicity, increased intracranial pressure, and short-term memory loss.

Special considerations

Pregnancy

Surgical treatment of central neurocytomas during pregnancy, as with other brain tumors, requires careful monitoring. The main consideration when performing craniotomies during pregnancy is to maintain adequate perfusion to mother and fetus. During pregnancy, cerebral arteries experience forced dilation, decreased cerebrovascular resistance, and decreased perfusion (49). Therefore, maintaining hemodynamic stability through appropriate fluid administration and monitoring is critical.

Radiotherapy to central neurocytomas during pregnancy also poses risks to the fetus, including lethality, congenital malformations, and mental retardation (43). It is, therefore, important to consider the appropriate dosage and radiation modality when treating central neurocytomas in women who are pregnant.

Anesthesia

Anesthesia for surgical treatment of central neurocytomas follows similar guidelines as craniotomies in general. General anesthesia, intravenously or via mask, is used with careful monitoring of cardiovascular and respiratory stability. Patient-oriented preoperative studies should be conducted by an anesthesiologist in order to determine the correct dosage, modality, and type of anesthesia to be administered.