Non-germinomatous germ cell tumors of the CNS: Classification, diagnosis, and treatment.

Abstract

Non-germinomatous germ cell tumors (NGGCTs) are rare, histologically diverse malignancies that primarily affect children and adolescents. Unlike germinomas, NGGCTs are less responsive to chemotherapy and radiation, resulting in a less favorable prognosis and necessitating intensified multimodal therapy. This chapter provides a comprehensive overview of NGGCTs, including histological subtypes, clinical presentation, diagnostic strategies, and established as well as emerging treatment paradigms. We discuss current classification systems, the roles of tumor markers and neuroimaging, and challenges in histopathologic diagnosis. Treatment approaches vary globally but typically include intensive chemotherapy combined with craniospinal or whole-ventricular irradiation. Long-term outcomes remain suboptimal for high-risk subtypes, especially those with yolk sac tumor, choriocarcinoma or embryonal carcinoma components. Recent genomic and epigenomic studies have revealed recurrent alterations in the RTK/MAPK and PI3K/mTOR pathways, along with distinctive methylation signatures and copy number aberrations, offering insights into tumorigenesis and potential therapeutic targets. Ongoing trials continue to focus on refining risk stratification and minimizing treatment-related toxicities. These efforts, along with advances in molecular characterization, may ultimately improve survival and long-term quality of life in patients with CNS NGGCTs.