Daniela Di Carlo ^1,2* Giulia Fichera ³ Veronique Minard-Colin ⁴ Coppadoro Beatrice ¹ Daniel Orbach ⁵ Cameron Aiison ⁶ Ramos Albiac Monica ⁷ Myriam Ben Arush ⁸ Merks Johannes ⁹ Gianni Bisogno ^1,2

• ¹ Department of Women's and Children's Health, University of Padova, Padova, Italy
• ² Pediatric Hematology-Oncology Division, University Hospital of Padova, Padova, Italy
• ³ Pediatric Radiology Unit, University Hospital of Padova, Padua, Italy, Padova, Italy
• ⁴ Gustave Roussy Cancer Campus, Villejuif, Île-de-France, France
• ⁵ Institut Curie, Paris, Ile-de-France, France
• ⁶ University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
• ⁷ Vall d'Hebron University Hospital, Barcelona, Catalonia, Spain
• ⁸ Rambam Health Care Campus, Haifa, Haifa, Israel
• ⁹ Princess Maxima Center for Pediatric Oncology, Utrecht, Netherlands, Netherlands

Background Orbital rhabdomyosarcoma (RMS) is often limited to the orbital cavity and has a favorable prognosis. In some cases, the tumor can erode orbital bone and behave as a parameningeal (PM) RMS and thus it is treated more intensively. However, current protocols do not give any guidance on how to consider different grades of bone erosion (BE) that can vary widely, hampering uniform classification and subsequent treatment assignment. With the aim of clarifying the role of BE as a risk factor, we analyzed patients with orbital RMS included in the European pediatric Soft tissue sarcoma Study Group (EpSSG) protocol.We retrospectively analyzed the radiological reports of 199 patients with orbital RMS (PM or not) and defined three grades of BE: minimal (thinning of the bone), moderate (focal bone lysis) or extensive (complete cortical destruction).Results BE was present in 55/199 (27.6%) patients and was classified as minimal in 27, moderate in 7, and extensive in 21. Tumors with extensive BE were more frequently large (> 5 cm, p 0.0008), invasive (T2, p=0.001). With a median follow-up of 70.4 months (range 7.1-167.7), 183 patients are alive, with a 5-year EFS and OS were 76% (95%CI 69.2-81.3) and 92% (95%CI 86.7-94.8), respectively. Patients without any BE had a better OS (95% vs. 81%, p = 0.001) but not EFS. Patients with no/minimal/moderate BE had a better EFS and OS compared to patients with extensive BE [EFS of 78.1 (95%CI 71.1-83.5) vs 57.1 (95%CI 33.8-74.9), p = 0.0114 respectively and an OS of 94.0 (95%CI 89.2-96.8) vs 71.1 (95%CI 46.6-85.9), p <0.0001 respectively]. Events and metastatic relapses (in all cases CNS/meningeal) were more frequent in patients with extensive BE.Only patients with orbital RMS and extensive BE should be considered as PM, and treated accordingly.