Patterns of care and survival outcomes in patients with an extraventricular neurocytoma: An individual patient data analysis of 201 cases
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.227262
Source of Support: None, Conflict of Interest: None
Keywords: Extraventricular, neurocytoma, pattern of care, radiotherapy, surgery
Neurocytoma is a rare neuronal tumor recognized by the World Health Organization (WHO) as a separate entity in 2007. Neurocytomas more commonly arise from the ventricles and are known as central neurocytomas, with an estimated incidence of 0.1–0.5% of all primary brain tumors., However, in the recent years, neurocytomas have been reported to arise from the brain parenchyma as well as from the spinal cord and are termed as extraventricular neurocytomas (EVNs). EVNs comprise only a handful of cases reported so far, and in different series, they comprise 10% of total neurocytomas. Spinal neurocytomas (SNC) are extremely rare tumors with only 35 cases reported so far. In general, a neurocytoma is considered as a low-grade tumor and surgical excision is considered adequate with the aim of achieving gross total resection (GTR). However, even after complete resection, many patients experience recurrence of the tumor. EVNs and SNCs pose a greater challenge in management because of the difficulty in achieving complete surgical resection. Treatment options for EVNs and SNCs are derived from case reports and small case series, making it difficult to decide the optimum treatment protocol. However, most centers recommend adjuvant radiation therapy to optimize tumor control and survival. Hence, we intended to perform an individual patient data analysis to find the patterns of care, failure patterns, and prognostic factors, as well as to derive a possible treatment algorithm for EVN.
We performed a comprehensive search of PubMed, SCOPUS, and Google Scholar with the following MeSH terms: “Neurocytoma, Extra ventricular neurocytoma, Spinal neurocytoma AND Treatment, Survival” to find all possible publications pertaining to EVN. We also conducted a detailed reference search of the available articles to retrieve missing articles and conducted a Google search to find any additional publications. After a thorough search, duplicates were removed and the remaining articles were examined in detail. Articles that furnished the basic demography, treatment details, and survival information were included in the present analysis. A total of 108 articles were found eligible for the analysis. Individual patient data were tabulated in an excel chart under the headings: age, gender, surgery, type of surgery, radiation and type of radiation, chemotherapy, recurrence, duration of progression free interval, and death. [Figure 1] depicts data synthesis from the eligible studies.
The data were analyzed; categorical variables were summarized as frequency and percentage and quantitative variables as median and range. Kaplan–Meier method was used for survival analysis. Univariate analysis was performed to find the impact of age, gender, type of surgery, use of radiation, and use of chemotherapy on survival outcomes. A P value of <0.05 was taken as significant. The Statistical Package for the Scoial Sciences, version 16 (IBM, USA) was used for all statistical analyses.
A total of 201 cases from 108 publications were found eligible for analysis. Age was reported in 187 cases. The median age for the entire cohort was 30 years (range: 0.6–78 years); 67 patients were in the pediatric (≤20 years) age group. There were two prominent peaks in the second and fifth decade, in which the incidence was relatively higher [Figure 2]. Gender was reported in 185 cases with a mild male preponderance (97 males and 88 females). Twenty-eight percent of the patients had a tumor in the frontal lobe. This was followed by a tumor in the temporal lobe (18%), thoracic spine (9%), parietal lobe (8%), cervical spine (7%), and cerebellum (7%). The site distribution is depicted in [Figure 3]. Seizure was the most common presenting symptom seen in 35% patients, followed by headache in 31% patients. For SNCs, a total of 35 cases were found eligible for the analysis. The median age for SNCs was 33 years (range: 6–67 years), and the male:female ratio was 1.2:1. A total of 48.57% of the patients with a SNC had the tumor in the thoracic spine. This was followed by a tumor in the cervical spine in 37.1% patients. Radiological features were reported in 26 cases. Tumors were heterogeneously enhancing in 18 cases (69.2%) whereas the rest were homogenously enhancing. In twenty-two (84.6%) patients, the tumors had a foci of calcification, of which 13 had tumor in the frontal lobe. Nine (13.4%) patients of the pediatric age group had calcification in their tumors. Details of the patient characteristics have been described in [Table 1].
Surgical details were available for 132 cases; 51.5% underwent a gross total resection (GTR), whereas 41.7% underwent a subtotal resection (STR). For SNC, 11 (31.4%) patients underwent a GTR whereas 19 (54.3%) patients underwent a STR. The MIB labeling index was reported in 88 cases with the median MIB labeling index being 5 (range: 1–60). Out of 85 patients in whom the grade was reported, 20 (23.5%) patients had a grade I tumor, whereas 63 (74.1%) had a grade II tumor. Interestingly, two cases were reported to be grade III tumors. Information regarding adjuvant radiation was available for 102 cases. Out of the 102 cases, 41 (40.2%) received radiation and the rest were treated with surgery alone. The dose of adjuvant radiation varied widely from 43.2–64 Gy, with the median dose being 54 Gy. Two patients received gamma knife radiosurgery at a dose of 20 Gy. One patient additionally received craniospinal radiation. Twelve out of the 41 patients experienced recurrence even after radiation. One patient experienced CSF dissemination after radiation and another had cerebellar metastasis.
Only 5 (2.5%) patients received chemotherapy as a part of the adjuvant treatment. Temozolomide was the most common agent used in 2 cases. Interestingly, even after chemotherapy, 2 patients experienced recurrence. One of the patients with a recurrent tumor had CSF dissemination as well.
The median follow-up was 16 months (1–276 months). The median progression free survival (PFS) was 77 months (53.3–100.7) for the entire cohort, whereas the median PFS for pediatric EVNs was 180 months (0–385.6) [Figure 4]. However, a univariate analysis could not find any impact of gender, type of surgery (GTR vs. STR), use of adjuvant radiation or chemotherapy, MIB labeling index, and grade, on the survival of the patients with an EVN.
Pattern of recurrence and salvage treatment
The status at last follow-up was recorded in 117 cases (58.2%). Recurrence was reported in 33 cases. Interestingly, 2 patients with a primary tumor in the brain had CSF dissemination, and two patients with a spinal primary tumor had cerebellar dissemination. Salvage treatment was recorded for 13 out of 33 recurrent cases. Four patients underwent salvage re-surgery alone; 2 patients received salvage radiation alone, 2 received salvage surgery with radiation, whereas 1 patient received salvage surgery with radiation, and another one underwent salvage surgery, radiation therapy and temozolomide administration.
The present study aimed to examine the patterns of care for EVNs across the globe and at the same time find the possible optimum treatment for these tumors. EVNs were reported to arise in a wide area of the central nervous system (CNS). However, the enthusiasm to report such cases leaves out important disease- and treatment-related information posing a significant challenge in interpreting data. Majority of the reported cases lacked survival information, which is a barrier for commenting on survival. Despite limitations, we searched for all possible publication of EVNs till June 2016. The present analysis found that EVNs comprise approximately 15% of all neurocytomas affecting all age groups. In an interesting revelation, we found EVNs to have two distinct peaks in the second and fifth decades, and this finding in the context of central neurocytomas has not been reported till date. Though these tumors arise across the entire CNS, a quarter of the cases are located in the frontal lobe and 18% are located in the temporal lobe. Interestingly, SNCs comprise only 17.4% of all EVNs. Due to their varied locations, these tumors present with a wide array of symptoms, with seizure being the most commonly found symptom in nearly one-third of the cases, followed by headache. Notably, tumors located in the neocortical temporal lobe or mesial temporal lobe present with seizures of a different character and pose a diagnostic challenge. This reflects the need to keep EVNs as an important entity in the differential diagnosis of lesions in young patients presenting with seizures. However, the majority of spinal tumors presented with sensory or motor deficit. Radiologically, most patients presented with a solid and cystic mass with heterogeneous contrast enhancement. Calcification within the tumor was noted in a higher frequencyof patients. These radiological features highlight the importance of keeping an EVN as a differential diagnosis, along with an oligodendroglioma, anaplastic ganglioglioma, and other epileptogenic tumors, among young patients.
Surgery has long been advocated as the standard of care for neurocytomas and the same has been reported for EVNs. A GTR is considered to be the cornerstone of treatment as in all other low-grade CNS tumors. However, because of its proximity to critical structures and an eloquent location, SNCs pose a challenge for neurosurgeons attempting to achieve GTR. Hence, many patients undergo STR or biopsy only. This was very clear in the present analysis as only half of the patients underwent GTR and 7% underwent biopsy only. This was further emphasized by the fact that GTR reduced to 31% for SNCs.
Being a low-grade tumor with a long tumor-doubling time, GTR is considered optimum for a neurocytoma. However, patients with atypical features and a subtotal resection have been reported to experience a high rate of recurrence, and adjuvant radiation is advocated by authors to improve disease control. Various series have reported an excellent recurrence-free survival after GTR. As EVNs are often surrounded by brain parenchyma, it is difficult to achieve GTR; this is equally true for SNCs. Recurrences are common and could be as high as 50–60% in patients with a subtotal resection. In the present analysis, 21 (10.4%) out of 64 cases where a STR had been achieved, experienced a recurrence, but only 10 (7.5%) out of 68 cases where a GTR had been achieved experienced a recurrence. This reflects the importance of GTR as well as the possible benefit of adding adjuvant therapy in further managing patients who have undergone a STR.
EVNs are associated with a poor outcome compared to the central neurocytoma and this fact further emphasizes the need for adjuvant therapy. However, it should be noted that EVNs are found in close proximity to critical areas of the brain rendering GTR often difficult. In addition, infiltrations in the brain parenchyma make it difficult to achieve GTR and recurrence is expected. These recurrences are difficult to salvage with surgery as the location precludes a re-surgery. Hence, adjuvant radiation appears to have an important role for these patients with STR. Rades et al., reported a significantly improved outcome in patients with a neurocytoma with STR treated with or without radiation. The authors had earlier reported a 100% local control in neurocytomas, whereas only a 75% local control was achievable in EVNs, when treated with adjuvant radiation after a STR. These small studies are prone to have a bias and cannot form level 1 evidence; however, they should be considered as hypothesis generating studies.
Though with the current evidence, it is difficult to recommend adjuvant radiation to all patients, it appears logical to add adjuvant radiation in patients who underwent subtotal excision, especially if the tumor had been located in eloquent locations, as a second look surgery on further progression would not be possible in these tumors. The patterns of care also support these findings, as adjuvant radiation has more frequently been advocated in patients with STR. Radiation therapy may play a definite role in salvaging patients who have had a recurrence after surgery in the post-resection setting.,,
There is no clear consensus on the radiation target volume. However, as these lesions are usually low-grade tumors, it is reasonably safe to extrapolate the data from that of low-grade gliomas. Fluid attenuated inversion recovery abnormality with or without a margin may be included in the clinical target volume. A conformal radiation delivery technique is preferred to avoid irradiation of the normal brain tissue outside the target volume. A wide dosage schedule has been used in the published literature, but a dose of 50.4 to 54 Gy at conventional fractionation is most commonly practiced., Patients should be explained the possible occurrence of long-term neurocognitive effects and the risk of second malignancies, as these patients are expected to survive long.
The role of chemotherapy has not been studied in this rare tumor, and in the present analysis also, less than 3% received chemotherapy.,,, As these tumors generally are diagnosed as grade I or II tumors, the role of adjuvant chemotherapy is doubtful. However, it may be used in a case-to-case basis in patients with recurrent tumors when other options of salvage therapy are exhausted. The optimal regimen and the number of cycles to be used are still disputed. However, a few case reports show a modest response with temozolomide. Chemotherapy, therefore cannot be recommended as an adjuvant treatment for the treatment of EVNs with the available evidence. [Table 2] summarizes all case series of EVNs, highlighting their demography, differences in patterns of care, and survival reporting.,,,,,,,,, A possible treatment algorithm for the management of EVNs is given in [Figure 5].
The present analysis has several limitations. First, most studies did not cite all relevant information pertaining to the cases. The majority of cases were reported as case reports so adjuvant treatment, follow-up, recurrence, pattern of salvage, and overall survival information are not available. This prevents us from analyzing the overall survival. In addition, across different centers, the standard of care is variable, and hence, the pattern of care will be biased by the local practice prevalent. However, owing to its rarity, it is unrealistic to expect a uniform treatment protocol to be immediately established for EVNs. In this regard, this analysis plays a pivotal role in reporting the patterns of care and the prognostic factors influencing this rare disease.
EVN is a rare tumor with an inferior outcome compared to a neurocytoma. Surgery forms the cornerstone of therapy and GTR appears to confer a survival advantage. Very few patients received radiation and we could not correlate the impact of radiation with survival. Hence, GTR should remain the standard of care, and adjuvant radiation may be employed for incompletely resected and atypical EVNs, particularly of spinal location.
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Conflicts of interest
There are no conflicts of interest.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2]