Osteosarcoma: A Comprehensive Morphological and Molecular Review with Prognostic Implications

Osteosarcoma (OS) is the most common primary malignant bone tumor, predominantly affecting adolescents and young adults. Despite advances in surgery and multi-agent chemotherapy, survival rates for metastatic or recurrent OS remain poor, highlighting the need for novel prognostic and therapeutic strategies. This review integrates histopathologic, molecular, and immune perspectives to provide a comprehensive understanding of OS biology in the context of precision medicine. We discuss classic morphologic and radiographic features alongside recent insights into the tumor microenvironment, including the role of tumor-infiltrating lymphocytes, tumor-associated macrophages, and immune checkpoint expression. Emerging molecular markers, such as gene expression-based immune risk signatures, circulating tumor DNA, and gasdermin D overexpression, are evaluated for their prognostic and therapeutic relevance. Key dysregulated pathways, including WNT/β-catenin and JAK/STAT, are examined in relation to metastasis, chemoresistance, and immune evasion, with emphasis on current targeted approaches under development. By bridging histopathology, immunogenomics, and translational research, this work outlines how integrated biomarker assessment can refine patient stratification and guide the implementation of individualized treatment strategies in OS.