(P 027) LEPTOMENINGEAL ENHANCEMENT WITH NEUROLOGIC CHANGES IN PEDIATRIC BONE SARCOMA PATIENTS: A DIAGNOSTICAL CHALLENGE

Objective: Bone sarcomas such as osteosarcoma (OS) and Ewing sarcoma (EWS) are a clinically and molecularly heterogenous group of solid tumors that constitute 3-5 % of all pediatric malignancies. Metastasis is the dominant cause of mortality for pediatric sarcomas with each subtype demonstrating tropism for specific organ compartments. Common metastatic sites include lung, bone, and bone marrow. While the clinical characteristics, management, and outcomes are well characterized for common metastatic sites, the natural history, radiographic features, and outcomes for uncommon metastatic sites are incompletely understood. Herein, we describe a unique case of a 10-year-old girl with paraspinal EWS who developed signs of increasing intracranial pressure one month off therapy. Magnetic resonance (MR) imaging demonstrated numerous leptomeningeal nodules concerning for metastatic relapse. However, cytology of cerebral spinal fluid (CSF) obtained from an external ventricular drain was negative for malignant cells. Further diagnostic workup uncovered molecular evidence of Cryptococcus within CSF. Fortunately, initiation of anti-fungal treatment resulted in resolution of leptomeningeal disease. This case illustrates several diagnostic and management-related difficulties given the rarity of relapsed leptomeningeal disease in pediatric sarcomas. The objective of this retrospective study is to define the differential diagnosis, clinical and imaging findings, and outcomes for pediatric bone sarcoma patients with leptomeningeal disease at relapse.

Methods: A single institution retrospective study was performed to obtain de-identified data from sarcoma patients treated at Nationwide Children’s Hospital from 2008 to 2022. Primary and metastatic clinical presentation, all prior treatment, pathology, and imaging results were obtained. Descriptive statistics were utilized to describe outcomes such as time to leptomeningeal disease, number of relapses prior to leptomeningeal metastasis, and survival after leptomeningeal relapse.

Results: We queried our sarcoma patient database (153 total patients) and identified 6 patients who developed leptomeningeal metastasis. Histological diagnoses include osteosarcoma, Ewing sarcoma, and rhabdomyosarcoma. Our current analysis focuses on EWS and OS. Leptomeningeal disease was diagnosed by imaging alone except for our index patient who underwent CSF analysis. For patients with recurrent tumor, median time to leptomeningeal relapse was 6.5 years (+/- 2.5 years), with a median of one relapse prior to developing leptomeningeal disease. Treatment modalities for leptomeningeal relapse included palliative craniospinal radiation and systemic chemotherapy. All patients with relapsed leptomeningeal metastasis succumbed to their disease with a median survival of 1.5 months (+/- 0.5 months). The index patient with cryptococcal meningitis clinically improved and remains alive on antifungal therapy.

Conclusion: Leptomeningeal relapse is a rare, fatal, and incompletely understood complication for patients with bone sarcomas. Diagnostic uncertainty given the rarity of leptomeningeal relapse is a critically unmet need. The differential diagnosis for leptomeningeal enhancement on post contrast MR imaging in pediatric patients is vast including a diverse array of infectious, vascular, inflammatory, and malignant etiologies. Radiographic findings are not specific to any particular diagnosis. For instance, our patient series highlights how diffuse leptomeningeal contrast enhancing lesions within the cerebellum can occur in both infectious and malignant diagnoses. While diagnostic for liquid malignancies, CSF cytology is unlikely to provide the diagnosis for sarcoma patients with concern for leptomeningeal relapse as evidenced by the low diagnostic yield of cytology in patients with primary brain tumors and leptomeningeal disease. Novel diagnostic tools such as cell-free DNA sequencing from CSF hold promise in confirming leptomeningeal relapse, especially in EWS where the molecular fusions are almost always identified at diagnosis. Lastly, advances in whole genome/exome sequencing, copy number variation, and RNA-sequencing may be essential in elucidating tumor evolution that occurs along the metastatic cascade and potentially uncover therapeutic targets.