Chordomas are
tumors thought to originate from notochordal remnants that occur in midline structures from the cloves of the skull base to the sacrum. In adults, the most common location is the sacrum, followed by the clivus and then mobile spine, while in children a clival origin is most common. Most
chordomas are slow growing. Clinical presentation of
chordomas tend to occur late, with local invasion and large size often complicating surgical intervention.
Radiation therapy with
protons has been proven to be an effective adjuvant
therapy. Unfortunately, few adjuvant systemic treatments have demonstrated significant effectiveness, and
chordomas tend to recur despite intensive multimodal care. However, insight into the molecular underpinnings of
chordomas may guide novel therapeutic approaches including selection for immune and molecular
therapies, individualized prognostication of outcomes, and real-time noninvasive assessment of disease burden and evolution. At the genomic level, elevated levels of
brachyury stemming from duplications and mutations resulting in altered transcriptional regulation may introduce druggable targets for new surgical adjuncts. Transcriptome and epigenome profiling have revealed promoter- and enhancer-dependent mechanisms of
protein regulation, which may influence therapeutic response and long-term disease history. Continued scientific and clinical advancements may offer further opportunities for treatment of
chordomas. Single-cell transcriptome profiling has further provided insight into the heterogeneous molecular pathways contributing to
chordoma propagation. New technologies such as spatial transcriptomics and emerging biochemical analytes such as
cell-free DNA have further augmented the surgeon-clinician's armamentarium by facilitating detailed characterization of intra- and intertumoral biology while also demonstrating promise for point-of-care
tumor quantitation and assessment. Recent and ongoing clinical trials highlight accelerating interest to translate laboratory breakthroughs in
chordoma biology and immunology into clinical care. In this review, the authors dissect the landmark studies exploring the molecular pathogenesis of
chordoma. Incorporating this into an outline of ongoing clinical trials and discussion of emerging technologies, the authors aimed to summarize recent advancements in understanding
chordoma pathogenesis and how neurosurgical care of
chordomas may be augmented by improvements in adjunctive treatments.