In children, neurocytomas are extremely rare tumors in the central nervous system. Since this entity was introduced in 1982, approximately 60 cases have been reported among patients age ≤ =18 years of age. The current analysis was performed to define the best available neurocytoma therapy in children.
All reported neurocytoma cases were reviewed for age, extent of resection, radiotherapy, radiotherapy dose, local control, and survival. Data were obtained from the literature and the authors. Statistical analysis was performed with the Kaplan–Meier method and log-rank test.
Fifty-nine children were categorized by therapy: complete tumor resection (CTR; n = 20), complete tumor resection plus radiotherapy (CTR-RT; n = 11), incomplete tumor resection (ITR; n = 14), and incomplete tumor resection plus radiotherapy (ITR-RT; n = 14). Local control rates were better after CTR, CTR-RT, and ITR-RT than after ITR, at 5 years (86%, 100%, and 100% vs. 60%; P < 0.001) and at 10 years (86%, 100%, and 100% vs. 45%; P < 0.001). The 5-year and 10-year survival rates were 100% after CTR, 100% after CTR-RT, 100% after ITR-RT, and 93% after ITR (P = 0.4). In the ITR-RT group, no difference was observed between doses ≤ 50 gray (Gy) and ≥ 54 Gy when compared for local control (P = 1.0) and survival rates (P = 1.0). Radiotherapy-related psychomotor retardation or secondary brain tumors were not reported.
Neurocytomas are described as rare benign lesions of the central nervous system. However, atypical lesions can be defined as showing an MIB-1 labeling index > 2–3% or atypical histologic features such as focal necrosis and increased mitotic activity.1–3 Atypical neurocytomas may behave more aggressively, sometimes like malignant tumors resulting in craniospinal dissemination.4–9 The entity “neurocytoma” was established in 1982 to distinguish these lesions occurring mainly in adults from neuroblastomas, which mainly affect children.10 However, neurocytomas may also occur in children, which has to be considered a rarity with only approximately 60 cases reported in children ≤ 18 years. The optimal treatment for children needs to be clarified. A potential benefit of radiotherapy after incomplete resection is still debated.
The current analysis compares four therapies—complete tumor resection alone (CTR), complete tumor resection followed by radiotherapy (CTR-RT), incomplete tumor resection alone (ITR), and incomplete tumor resection followed by radiotherapy (ITR-RT)—for local control and survival to define the optimal treatment of neurocytomas in children.
MATERIALS AND METHODS
All neurocytoma cases reported since 1982 were reviewed for age, gender, extent of resection, radiotherapy, local control, and survival. If the data available in the literature were incomplete, the authors were contacted for additional data, which were available for approximately 70% of the series. The minimal follow-up for inclusion was 12 months. The Kaplan–Meier method11 was used to calculate local control and survival rates, and these rates were correlated among the four different therapies. The comparison of the outcome of the four groups was performed with the log-rank test.
Data were complete for 59 children (n = 55 from the literature and n = in 4 from our institutions). Of these children, 23 (39%) were female and 36 (61%) were male. The median age of the children in the whole series was 16 years (range, 1–18 years). Four children (7%) were ≤ 5 years old, 9 children (15%) were 6–10 years old, 13 children (22%) were 11–15 years old, and 33 children 56%) were 15–18 years old. In 30 of 59 children (51%), the main portion of the tumor was located in 1 or 2 of the lateral ventricles. In 8 children (14%), the tumor was located in the third or fourth ventricle. In 10 children (17%), the tumor was located mainly in the left or right frontal lobe. In 5 children (8%), the tumor was located in other lobes (parietal, temporal, occipital). Other tumor locations were the foramen of Monro (n =2), pons (n = 1), septum pellucidum (n = 1), and spinal cord (n = 2). Presenting symptoms were mostly related to increased cranial pressure. The most common symptoms were headache (n = 30 [51%]) and nausea/emesis (n = 24 [41%]). Other relevant symptoms at first presentation included the following: loss of memory/concentration (n = 10 [17%]), vision problems (n = 8 [14%]), ataxia (n = 7 [12%]), seizures (n = 6 [10%]), motor deficits (n = 6 [10%]), sensory deficits (n = 5 [8%]), and loss of consciousness (n = 3 [5%]). In one child, neurocytoma was an incidental finding after minor trauma. Histology revealed an atypical neurocytoma in 10 children (17%) with atypical histologic features being observed in 4 tumors and an MIB-1 labeling index (> 2%) being found in 6 tumors.
The 59 children were categorized by therapy: CTR (n = 20), CTR-RT (n = 11), ITR (n = 14), and ITR-RT (n = 14). Patient characteristics related to treatment regimen are summarized in Table 1. The median follow-up period in the whole series was 36 months (range, 12–456 months). The follow-up was ≥ 36 months for 37 children (63%), ≥ 60 months in 18 children 31%), and ≥ 120 months in 7 children (12%).
Table 1. Comparison of the Four Groups for Age, Gender, and Atypical Lesions
CTR: complete tumor resection; CTR-RT: complete tumor resection followed by radiotherapy, ITR: incomplete tumor resection; ITR-RT: incomplete tumor resection followed by radiotherapy.
Median age, (yrs) (range)
For the entire cohort, the 5-year and 10-year local control rates were 86% and 76%, respectively (Fig. 1). The 5-year and 10-year-survival rates were 98% and 98%, respectively (Fig. 2). The median time to local disease recurrence in 11 children was 29 months (range, 9–216 months), and 33 months (range, 9–216 months) for 9 children with typical neurocytoma versus 18 and 29 months, respectively, for 2 children with atypical neurocytoma. Treatment for the recurrent lesion was surgery in six children, radiotherapy in four children, and unknown in one child.
The local control rates at 5 years and 10 years were 86% and 86% after CTR, 100% and 100% after CTR-RT, 100% and 100% after ITR-RT, and 60% and 45% after ITR, respectively (P = 0.0009; Fig. 3).
A tumor-related death occurred in 1 child 10 months after ITR. None of the treatment regimens evaluated proved to be significantly superior to the others with regard to survival (P = 0.4). Survival rates were 100% after CTR, 100% after CTR-RT, 100% after ITR-RT, and 93% after ITR-RT both at 5 years and at 10 years (Fig. 4).
To evaluate a possible dose-effect relation for radiotherapy after ITR, the ITR-RT group was divided into 2 subgroups according to the total radiotherapy dose, i.e., ≤ 50 gray (Gy; n = 6) and ≥ 54 Gy (n = 6). The radiotherapy dose was unknown in two children. Local control rates were 100% in both dose groups after 5 years and 10 years (P = 1.0), as were the survival rates (P = 1.0).
Until now, no radiotherapy-related secondary brain tumors have been reported by the authors of the articles included in the current analysis. The majority of the authors described the status of the children during follow-up as well, symptom free, without neurologic deficits, or without psychomotor retardation. However, in one child treated with ITR-RT, mild psychmotor retardation was observed, most likely due to radiotherapy. In another child, persisting vision problems have been described, most likely due to brain surgery, although a certain relation to postoperative radiotherapy cannot be excluded completely. A third child showed residual left hemiparesis after surgery and radiotherapy, but was already suffering from major neurologic deficits before the treatment.
The current analysis was performed to contribute to the definition of the optimal treatment of neurocytomas in children. Four therapies were compared for local control and survival. Data were not obtained from the literature alone, but also from the authors of the articles. This approach provided more detailed information with a longer follow-up than the data from the literature alone.
Our study is retrospective and includes children treated at different institutions. This should be taken into account when interpreting the results. As there was no striking imbalance of age and gender among the four groups, these parameters did not impact the results in a relevant manner.
The findings suggested that CTR, CTR-RT, and ITR-RT provide better local control than ITR. As in adult patients,12 no significant improvement of local control or survival was observed in children receiving CTR-RT. The current analysis demonstrated that ITR-RT in children significantly improved local control, but not survival. This result is comparable to the neurocytoma treatment of adult patients.12 The lack of a survival benefit for ITR-RT can be explained by the usually benign character of neurocytomas.
The finding that postoperative radiotherapy did not improve survival in children leads to the question, should radiotherapy be reserved for the treatment of a local recurrence? We believe that both survival and local control are important end points. Recurrent neurocytomas may be associated with malignant behavior such as craniospinal dissemination, or may lead to intraventricular hemorrhage.4–9 Furthermore, although radiotherapy is not without risks, neither is a second surgical procedure on the brain. Thus, ITR-RT can be recommended during initial treatment, at least for adult patients.12, 13
For children, we are more reserved about recommending radiotherapy. Radiotherapy may lead to psychomotor retardation, which was observed in one child in the presented series. The authors of the other articles included in our analysis did not mention such radiotherapy-related late toxicity. However, there may be more children with psychomotor retardation who have not yet been detected because no complete neuropsychologic testing has been performed. Furthermore, according to the literature, the development of a radiotherapy-induced malignancy is a more important issue in children.14, 15
Regarding the extraordinarily good prognosis for children with a 10-year survival rate of almost 100% (Fig. 2), we would recommend radiotherapy during the initial treatment in children only in limited situations. It may be considered for atypical neurocytomas, which are known to be more aggressive and to have a worse prognosis than typical lesions.16 In the current series, the 8 children with atypical neurocytomas, who received postoperative irradiation (5 after ITR, 3 after CTR), were still free from local disease recurrence after a median follow-up of 30 months (range, 18–48 months), whereas the 2 children (1 ITR, 1 CTR) with atypical neurocytomas, who did not receive irradiation, developed disease recurrence after 18 and 29 months, respectively (P = 0.05, chi-square test). Children with atypical lesions treated with radiotherapy were even doing better than children with atypical lesions who received ITR without radiotherapy (0 of 8 vs. 8 of 13 disease recurrences; P = 0.04). Thus, our findings suggested that radiotherapy was beneficial after ITR of atypical neurocytomas. If postoperative radiotherapy is considered, a dose of 50 Gy appears appropriate to achieve a high rate of long-term freedom from disease recurrence in children, whereas higher doses are required in adult patients.13
The authors thank the contacted authors, who provided us with additional data, for their kind cooperation and support.