ASSESSMENT OF CORRELATIONS BETWEEN THE CELLULAR AND MOLECULAR FEATURES OF METASTATIC BONE MARROW NEUROBLASTOMA DISEASE, THE MORPHOLOGICAL PATTERN OF BONE MARROW INVASION AT DIAGNOSIS AND THE CLINICAL DISEASE CHARACTERISTICS

Background: Neuroblastoma (NB) is the most common extracranial solid tumor in children and is responsible for 15% of all childhood cancer-related deaths. High-risk (HR) NB patients frequently present with bone marrow (BM) metastases, which is associated with poor overall survival (OS) and event-free survival (EFS). The BM microenvironment plays a crucial role in tumor progression, and BM infiltration at diagnosis is a key factor in staging and prognosis. Despite aggressive multimodal therapies, treatment resistance in BM- infiltrating tumor cells remains a major obstacle to improved outcomes. Materials and Methods: We retrospectively analyzed 52 BM specimens from patients treated for NB stage M at the Pediatric Hematology-Oncology Unit, Department of Women’s and Children’s Health of Padua University, from January 2004 to April 2021. Patients were categorized based on BM infiltration patterns: clump (A pattern) and diffuse (B pattern) infiltration, determined by morphological evaluation. Clinical data, including OS, EFS, and systemic symptoms (fever and pain), were assessed. Thirty BM trephine biopsies were assessed histologically, based on the two morphological patterns. Fibrosis within the BM biopsies was assessed, and correlations between infiltration patterns, fibrosis, and prognosis were evaluated. The SIOPEN score, based on MIBG scintigraphy, was used to evaluate disease extent. Results: BM infiltration was present in 85% of patients. Of these, 57% exhibited A pattern and 43% B pattern infiltration. Five-year OS was 47% for A pattern, 36% for B pattern, and 100% for patients without BM involvement. Five-year EFS was 44% for A pattern, 16% for B pattern, and 100% for BM-negative patients. Patients with B pattern had significantly higher rates of progression or relapse (85%). Based on histological evaluation, the existence of two different infiltration BM patterns was confirmed. The presence of fibrosis was noted in A pattern patients and was associated with systemic symptoms and better outcomes. Patients with B pattern had higher median SIOPEN scores (41 vs. 21 for A pattern and 9 for BM-negative patients), correlating with a worse prognosis despite initial good treatment responses. Conclusion: BM infiltration patterns, assessed morphologically and histologically, in HR NB have distinct prognostic implications. Diffuse (B pattern) infiltration is associated with poorer OS and EFS, while clump (A pattern) infiltration, particularly in the presence of fibrosis, correlates with better outcomes, potentially due to a stronger inflammatory response. The SIOPEN score further highlights the unfavorable prognosis of patients with B pattern despite a good initial response. Understanding these patterns can guide more personalized therapeutic strategies for HR NB patients.