Evidence distribution across osteosarcoma tumour types: An evidence gap map to inform the WHO classification of tumours

Introduction
Osteosarcomas comprise a heterogeneous group of malignant osteogenic tumours with histopathological, biological and clinical variability. The scientific evidence underpinning different osteosarcoma types varies considerably. The WHO Classification of Tumours (WCT) provides an international standard for tumour classification based on evidence, although published evidence varies in both quantity and quality. Given the implications of osteosarcoma tumour classification for diagnosis, grading and treatment, a systematic overview of the distribution of the evidence is required. This study aimed to map the available evidence for osteosarcoma tumour types to inform the WCT.

Methods
An evidence gap map (EGM) was developed following methodologies adapted from the Campbell Collaboration and 3ie. Comprehensive searches of PubMed and Embase were conducted for studies published from 2018 to 2024 inclusive, focused on osteosarcoma tumour types classified according to the WCT (5th edition). Eligible studies addressed defined tumour characteristics, including pathogenesis, histopathology, diagnostic imaging, diagnostic molecular pathology, prognosis or prediction. Studies were screened by title and abstract and coded, and levels of evidence- level one (highest) to level five (lowest) - were assigned using an adapted Hierarchy of Evidence for Tumour Pathology.

Results
Of the 14,938 records identified, 2,571 studies were included. Available evidence differed substantially by tumour type. Osteosarcoma accounted for more than 90% of the included studies, predominantly assigned at levels three and four. Parosteal, periosteal, high-grade surface and low-grade central osteosarcomas had sparse reports and predominantly low-level evidence, with absolute gaps regarding several tumour characteristics, particularly for molecular pathology and prediction. No level one evidence was identified for histopathology across all osteosarcoma types.

Conclusions
This EGM demonstrates a marked imbalance in the evidence base of osteosarcoma tumour types, with robust evidence largely confined to osteosarcoma. These findings highlight priority areas for targeted evidence generation, particularly for rare osteosarcoma types, to better inform tumour classification.