Neuro-Oncology
Anti-LGI1 encephalitis
Oct. 03, 2024
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Support: service@medlink.com
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Central neurocytomas are typically low-grade intracranial lesions, which comprise approximately 0.5% of all brain tumors (29; 30; 50). These tumors are classified by the World Health Organization as grade 2, with a high rate of recurrence (42; 50; 30). Although central neurocytomas commonly manifest within the cerebral ventricular system (23; 24; 45; 12), they have also been reported in the cerebral hemispheres, limbic system, spinal cord, and other areas of the central nervous system (37; 41; 09; 52; 59; 30; 45; 58).
Central neurocytomas are similar in radiological and histological presentation to other brain tumors, such as glioblastoma IDHwt, oligodendroglioma, IDH-mutant astrocytoma, pleomorphic xanthoastrocytoma, and ependymoma; therefore, the diagnosis requires a careful evaluation (30; 58; 11). Diagnosis is generally achieved by a combination of MRI or CT imaging, with immunohistochemical confirmation of specific molecular markers (30). More advanced techniques, such as next-generation sequencing and DNA methylation profiling, can play an additional role in confirming the diagnosis. Prognosis is generally favorable, and primary treatments may include surgical resection or stereotactic radiosurgery (07; 35; 42; 30).
• Central neurocytomas are rare brain tumors located within the ventricular system. | |
• Obstruction of the ventricles by central neurocytomas can lead to hydrocephalus, intracranial hypertension, and mass effect. | |
• The presence of the immunohistochemical marker synaptophysin can aid in the differential diagnosis of central neurocytoma. | |
• Maximal safe resection with adjuvant radiotherapy is most frequently utilized for treating central neurocytomas and has a favorable prognosis. | |
• Stereotactic radiosurgery is an alternative primary treatment with a promising prognosis. | |
• These tumors have high rates of recurrence, which may occur after a long latency period. |
Central neurocytomas are thought to be derived from neuronal cells, neuronal progenitor cells, neuronal stem cells, or multipotent precursor cells that arise from the fornix, wall of the lateral ventricle, or the septum pellucidum (61; 21; 29; 30; 55; 07; 60; 23; 35; 50). Despite multiple sources of support for these hypotheses, the known incidence of occurrences throughout the rest of the central nervous system has yet to be elucidated (37; 41; 09; 52; 59; 30; 45; 58).
“Central” neurocytoma is used to reference those lesions that reside within the cerebral ventricular system, whereas “extraventricular,” and occasionally “atypical,” neurocytomas reside elsewhere in the central nervous system.
Growth of central neurocytoma may 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 untreated central neurocytoma, as the condition is rare and was first described in 1982 (17). Large single-institution studies have been published (30); however, the literature lacks multi-institutional or cohesive database studies on this topic.
Despite surgical advancements, the risk of central neurocytoma recurrence is high, with many articles reporting 2-year progression-free survival near 75% (20; 42). MIB-1 labeling index (LI) is the common marker, which may be used to predict survival and disease recurrence. MIB1-LI utilizes 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 a threshold of 2%, which may indicate the need for 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).
Histology. The diagnosis of central neurocytoma is complicated by shared histopathological characteristics with other brain tumors (63; 50). Central neurocytoma cells have perinuclear halos with a “fried egg” appearance, features seen in oligodendroglioma, as well as perivascular rosettes, which characterize 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 neurocytoma, with an MIB1-LI of greater than 2% is subclassified as atypical central neurocytoma and typically demonstrates 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 neuron-specific enolase, a glycolytic enzyme (25; 69; 18; 62; 22). However, neuron-specific enolase expression lacks neuronal specificity and has been reported in several nonneuronal neoplasms (33; 40; 35).
Conversely, several markers of oligodendroglioma and ependymoma are absent in central neurocytoma and further aid in histological diagnosis. For example, the transcription factor Olig2 is a key marker for oligodendroglioma and is not typically expressed in central neurocytoma (70; 14; 35; 50). Epithelial membrane antigen and glial fibrillary acidic protein may be used to eliminate other brain tumors, such as ependymoma, glioblastoma, and astrocytoma (16; 31; 08; 35). 1p19q co-deletion and IDH mutation are now defining features of oligodendroglioma, which is helpful in differentiating those tumors from central neurocytoma. Neurofilament is also largely absent in central neurocytoma but is present in pineal parenchymal tumors (33; 63; 35).
Genetic alterations and modulations in gene expression. Genetic studies of central neurocytoma have yet to reach a compelling verdict. Conflicting findings on the 1p19q codeletion in central neurocytoma 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 levels that inversely correlate with N-Myc levels, 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 neurocytoma. These factors may contribute to tumor proliferation as their involvement has been observed in other neoplasms, including glioblastoma and breast carcinoma (34; 55; 57; 48; 35).
Central neurocytomas share histopathological and immunohistochemical characteristics with other brain tumors that may originate 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; 70; 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.
Due to its origin in the cerebral ventricular system, central neurocytoma may cause obstructive hydrocephalus and intracranial hypertension (56; 65; 42), with associated symptoms of visual disturbance, headache, nausea or vomiting, and seizures (35; 65; 42; 30).
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 neurocytoma may be appreciated on MRI. Additional findings on MRI include intratumoral cysts and vascular flow (66; 65). However, because central neurocytoma mimics other brain tumors on imaging (eg, oligodendroglioma), further evidence, such as histopathological analysis, is needed for accurate diagnosis.
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; 67). 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; 67). 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 (68). Adjuvant stereotactic radiotherapy has previously been reported to have higher tumor control rates, lower recurrence rates, and lower mortality rates relative 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 is gaining support as a primary treatment for central neurocytoma (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 warrants future study of radiosurgery as the primary treatment for central neurocytoma. 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 neurocytoma 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). It is also used for patients with recurrent disease. Further research is required to establish recommendations regarding the continued use of chemotherapy as a salvage treatment for these tumors.
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 elevated proliferative index (as seen in atypical central neurocytoma) and increases with subtotal resection (29; 42; 50). Atypical central neurocytomas are associated with a 10-year survival rate of 63% and a 10-year local control rate of 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). Due to the potential for delayed recurrence, routine follow-up is highly recommended.
Patients with gross total resection have lower recurrence rates relative to those with subtotal resection (65; 15; 39; 67). Surgical treatment of central neurocytoma may have high complication rates due to tumor proximity to critical neurovascular structures. Gross total resection is reported in 30% to 50% of such cases (25; 01; 06; 15). Adjuvant radiation therapy has been shown to reduce disease recurrence and is almost always warranted after subtotal resection (35; 68; 42; 15; 39; 67).
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.
Surgical treatment of central neurocytoma during pregnancy requires careful monitoring. The primary 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 mortality, congenital malformations, and mental retardation (43). It is, therefore, important to consider the appropriate dosage and radiation modality when treating central neurocytoma in pregnant women.
Anesthesia for the surgical treatment of central neurocytoma adhere to similar guidelines as the standard craniotomy. 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.
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Isaac Yang MD
Dr. Yang of David Geffen School of Medicine at UCLA received a consulting fee from Baxter and research grants from BrainLab and Stryker as an independent contractor.
See ProfileGabrielle Hovis MD
Dr. Hovis of the University of California, Los Angeles, has no relevant financial relationships to disclose.
See ProfileRimas V Lukas MD
Dr. Lukas of Northwestern University Feinberg School of Medicine received honorariums from Novartis and Novocure for speaking engagements, honorariums from Cardinal Health, Novocure, and Merck for advisory board membership, and research support from BMS as principal investigator.
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Toll Free (U.S. + Canada): 800-452-2400
US Number: +1-619-640-4660
Support: service@medlink.com
Editor: editor@medlink.com
ISSN: 2831-9125
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