There are few data reported in the literature on the incidence of isolated CNS relapses in patients with high-risk NBL. The previously reported rate of incidence of CNS relapses was from 2.3%18 to 16%19 and up to 25% in small institution studies20, with a mean of 3.8%12. However, most of studies did not report only isolated CNS relapses. It is estimated that they account for about 50% of all CNS relapses12,18. In the German Childhood Cancer Registry, 85 patients with CNS involvement were identified, including 57 with isolated CNS relapse21.
Among 127 patients with stage 4 NBL over one year of age diagnosed in Memorial-Sloan-Kettering, eight patients (6%) developed CNS relapses. In this cohort, there was a tendency towards the higher number of CNS relapse among patients treated with immunotherapy without HDC than in patients that received HDC without immunotherapy (7/67 vs 1/60, respectively)22. The retrospective analysis performed by the Children’s Oncology Group showed the CNS relapses at first recurrence in 8/434 patients (2%)18, and in the French cohort, CNS relapses were diagnosed in 8/127 patients (6%)12. In the German study, the incidence of CNS relapses was reported in 49/451 patients (11%), treated with HDC23. In the Chinese series, brain metastases occurred in 11/106 patients (10.4%), accounting for 20% of all relapses24. The frequency of CNS relapses seems not to change in time (1985-200012, 1990-201021). However, the influence of immunotherapy is still unclear. There are data supporting the thesis that by reducing the incidence of systemic relapses, the number of isolated CNS relapses increases25, but in the SIOPEN analysis the increased risk of CNS relapse after immunotherapy was not confirmed26. In our study although the incidence of isolated CNS relapses was higher in intensively treated patients and after immunotherapy, the difference was not statistically significant
Studies referred to above, except for Matthay et al12, reported on data of studies including children over one year of age at the time of diagnosis. As the relatively high number of infants were observed in our cohort, and in this group isolated CNS relapses were 50% of all relapses, the number of CNS relapses may be underestimated in the whole high-risk group, also including patients under one year of age with MYCN amplification. Additionally, in some studies, only patients who received HDC were assessed23, which excluded early relapses, that seem to be more common in young intensively treated patients.
In the current study, we presented 13 patients with isolated CNS neuroblastoma relapse. The pattern of relapses seems to change with treatment intensification, resulting in early relapses, taking the form of intracranial bleeding, especially in infants.
There are no clear risk factors for isolated CNS relapse. The data in the literature are inconsistent18,22. Identification of statistically significant risk factors for CNS relapse was presented in two previously published studies. The risk factors for CNS recurrence reported by the previous research were lumbar puncture at diagnosis and LDH in one cohort22 or age, lumbar puncture and MYCN amplification in another cohort12. In our group, disseminated disease in infants with MYCN amplification was the risk factor for the early CNS relapse (isolated CNS relapse was found in 25% of all MYCN amplified infants). HDC alone, probably, does not prevent the CNS relapse27. In the presented data, occurrence of isolated CNS relapses is slightly higher in intensively treated patients, with employment of HDC, but the difference is not statistically significant.
Treatment of this kind of relapse is not established. Chemotherapy has been previously reported to be effective in single cases of patients with CNS NBL relapses, especially when there was the possibility of removing tumor24. With the employment of new treatment modalities, such as protocol employing intrathecal radiolabelled antibodies28, this kind of relapse is potentially curable.
In all reported patients, the parenchymal or leptomeningeal involvement were isolated settings. It supports the theory that CNS metastases are mainly blood-borne22,29 and they may be related to the genetic alterations of NBL cells on intensive therapy12. Specific genomic lesions, like 18q22.1 gain may predispose to CNS metastases30. These lesions are recurrently acquired during metastatic progression. TERT gene (5p), associated with telomere maintenance and poor prognosis in NBL31, is one of the candidate genes associated with CNS involvement30. Patients with CNS relapse have also different specific pattern of microRNA expression, with downregulation of miR-29a as a potential biomarker, with its potential role in CNS progression32. NBL cells penetrating to CNS on hematogenous way may keep their proliferative potential and may be a source of metastases19,29,33. In some studies, increased incidence of CNS metastases was observed after chemotherapy intensification22,98. Our results also suggest that natural history of disease may be changed by intensive treatment. The reason for it may be disruption of blood – brain barrier especially in very young children.
The symptoms of relapse are like described in previous reports. However, it’s important to underline that symptoms are not always present, especially in young children. In our setting, we found patients who either had no clinical symptoms and relapse was found on routine imaging (two patients) or had severe neurological symptoms of bleeding and invaginations was the first clinical presentation (four patients). The intraparenchymal hematoma occurring prior to radiologically detectable CNS metastases are rarely described in the literature34.
The disease control in other tissues may be improved in case of carrying out HDC followed by ASCR and immunotherapy. It may decrease the incidence of disseminated relapses and increase the number of isolated relapses, including CNS relapses25. The diagnosis and treatment of isolated CNS relapse may be a more difficult challenge than disseminated relapses involving CNS.
Routine CNS examination must be taken into consideration at the scheduled time of disease assessment, even without having reported clear symptoms of CNS involvement. Also, whenever the neurological symptoms occur during therapy, the relapse should be excluded The MIBG examinations performed on routine time points may not reveal metastases. Evaluation of CNS relapses in MIBG scintigraphy may be difficult – the CNS lesions may be interpreted as skull lesions and leptomeningeal infiltration may be not seen. Moreover, it was described in the literature that the MIBG scintigraphy may be negative in confirmed relapses, even in nodular lesions12. Although NBL cells are found in histopathology at the time of intracranial bleeding, no radiological symptoms of tumors may be present on radiological examinations, especially if CT/MRI are carried out without contrast.