Clinical Lessons from Three Long-Term Survivors of Central Nervous System-Relapsed Pediatric Neuroblastoma: Diagnostic Challenges and Durable Disease Control Following Individualized Multimodal Therapy

Background Central nervous system (CNS) relapse represents an uncommon but increasingly recognized pattern of neuroblastoma recurrence. Despite advances in multimodal therapy, CNS involvement remains associated with considerable diagnostic challenges and historically poor survival. Evidence guiding the management of CNS-relapsed neuroblastoma remains limited because most published studies include small heterogeneous cohorts with variable treatment strategies. Methods We retrospectively analyzed three pediatric patients with neuroblastoma who developed CNS relapse and were treated at a tertiary pediatric oncology center. Clinical characteristics, neuroimaging findings, cerebrospinal fluid (CSF) studies, pathological features, treatment approaches, treatment-related toxicities, and long-term outcomes were reviewed. Results All three patients developed intracranial parenchymal relapse accompanied by leptomeningeal dissemination, while one patient additionally exhibited diffuse spinal leptomeningeal involvement throughout the neuraxis. Although MRI consistently demonstrated CNS disease in all patients, CSF cytology and flow cytometry were positive in only one patient, highlighting the limited diagnostic sensitivity of CSF evaluation. All patients received individualized multimodal therapy consisting of systemic chemotherapy combined with intrathecal methotrexate, cytarabine, and dexamethasone. Additional local treatment included focal radiotherapy in one patient and surgical resection in another. At the latest follow-up, all three patients remained alive with durable disease control. Two patients achieved complete radiological remission, while one maintained long-term partial remission with sustained clinical stability for 48 months following CNS relapse. Conclusions This case series emphasizes two clinically important observations. First, negative CSF studies should not exclude CNS relapse when radiological findings strongly suggest disease recurrence. Second, individualized multimodal treatment incorporating systemic chemotherapy, intrathecal chemotherapy, and selected local therapies may achieve prolonged disease control in carefully selected patients. Although larger multicenter studies are required to establish optimal treatment strategies, these cases demonstrate that long-term survival following CNS-relapsed neuroblastoma is achievable.