Chordoma-Current Understanding and Modern Treatment Paradigms

Abstract

Chordoma is a low-grade notochordal tumor of the skull base, mobile spine and sacrum which behaves malignantly and confers a poor prognosis despite indolent growth patterns. These tumors often present late in the disease course, tend to encapsulate adjacent neurovascular anatomy, seed resection cavities, recur locally and respond poorly to radiotherapy and conventional chemotherapy, all of which make chordomas challenging to treat. Extent of surgical resection and adequacy of surgical margins are the most important prognostic factors and thus patients with chordoma should be cared for by a highly experienced, multi-disciplinary surgical team in a quaternary center. Ongoing research into the molecular pathophysiology of chordoma has led to the discovery of several pathways that may serve as potential targets for molecular therapy, including a multitude of receptor tyrosine kinases (e.g., platelet-derived growth factor receptor [PDGFR], epidermal growth factor receptor [EGFR]), downstream cascades (e.g., phosphoinositide 3-kinase [PI3K]/protein kinase B [Akt]/mechanistic target of rapamycin [mTOR]), brachyury-a transcription factor expressed ubiquitously in chordoma but not in other tissues-and the fibroblast growth factor [FGF]/mitogen-activated protein kinase kinase [MEK]/extracellular signal-regulated kinase [ERK] pathway. In this review article, the pathophysiology, diagnosis and modern treatment paradigms of chordoma will be discussed with an emphasis on the ongoing research and advances in the field that may lead to improved outcomes for patients with this challenging disease.

Keywords: chordoma; spinal oncology; spinal tumor.

Figure 1

Diagram illustrating some of the molecular pathways involved in chordoma pathophysiology. PDGFR, platelet-derived growth factor receptor; EGFR, epidermal growth factor receptor; c-MET, hepatocyte growth factor receptor; FGFR, fibroblast growth factor receptor; PLCγ, phospholipase C gamma; PIP2, phosphatidylinositol 4,5 bisphosphate; PIP3, phosphatidylinositol 3,4,5 triphosphate; Akt, active human serine/threonine protein kinase; mTOR, mammalian target of rapamycin; PI3K, phosphoinositide 3 kinases; GRB2, growth factor receptor bound protein 2; GAB1, GRB-associated binding protein 1; GAB2, GRB-associated binding protein 2; SOS, son of sevenless protein (guanine nucleotide exchange factor); RAS, rat sarcoma protein; RAF, rapidly accelerated fibrosarcoma protein; MEK, mitogen activated protein kinase kinase; ERK/MAPK, extracellular signal-related kinases/mitogen activated protein kinases; EMT, epithelial-mesenchymal transition.

Figure 2

Radiographic appearance of a sacral chordoma. Sagittal T2-weighted MRI (A) demonstrating predominant hyperintensity with hypointense septations, scattered calcification and microhemorrhage. Sagittal T1 pre-contrast MRI (B) demonstrating diffuse hypointense signal. Sagittal T1-weighted post-contrast MRI (C) demonstrating marked, heterogenous contrast enhancement. Axial CT (D) demonstrating an expansile soft tissue mass with lytic bony destruction.

Figure 3

Histological findings in chordoma. (Left, ×40) Chords of tumor cells in a myxoid background with occasional microhemorrhage/calcification (arrow). (Right, ×400) Physaliferous cells with multiple intracytoplasmic vacuoles.

Figure 4

Diagram illustrating the role of cyclin D-dependent kinases (CDK4, CDK6) in progression from G1 phase to S phase. Palbociclib inhibits the action of CDK4/6, halting cell cycle progression. P16INK4a is often deficient in chordomas due to loss of the CDKN2A gene. RB, retinoblastoma protein; pRB, phosphorylated retinoblastoma protein; PI3K, phosphoinositide 3 kinases; Akt, active human serine/threonine protein kinase; mTOR, mammalian target of rapamycin; SOS, son of sevenless protein (guanine nucleotide exchange factor); MEK, mitogen activated protein kinase kinase; ERK/MAPK, extracellular signal-related kinases/mitogen activated protein kinases; JAK, janus kinase; STAT, signal transducer and activator of transcription.