Understanding the Cell Cycle in the Pathophysiology of Chordomas: A Molecular Look

Abstract

Chordomas are rare, slow-growing infiltrative tumors that are typically located in the skull base or sacral spine, although they can be found anywhere within the axial skeleton. Classically, these tumors show characteristic physaliferous cells filled with vacuolated cytoplasm of mucoid matrix. The 3 histologic types of chordomas are the conventional, chondroid, and dedifferentiated types, with the last 2 having the worst prognosis given an increase risk of sarcomatous degeneration. They are classically immunoreactive to S-100 and a number of cytokeratins (6, 15, 17, 19, 20). Although most chordomas are sporadic, there are cases of familial chordomas (6, 12, 13). Current treatment has changed over the last few decades, but remains focused on surgical excision followed by conventional or proton-beam radiotherapy. Recurrences are common and are seen in up to 68% of cases, and are managed with repeat surgery or radiotherapy. The 5- and 10-year survival rates for patients with chordomas are in the range of 68% and 40%, respectively (10, 14). Recent clinical research has demonstrated the effectiveness and increased overall survival in patients with chordomas via en bloc or wide margin vertebrectomies without violation of the tumor capsule, followed by radiotherapy (8, 9). Despite the groundbreaking innovation in clinical treatment and management of patients with chordomas, the molecular understanding remains far behind. Chordomas are cytogenetically quite diverse tumors. Molecular cytogenetic studies have demonstrated that a variety of chromosomal markers exist in primary and recurrent chordomas, as well as frequent quantitative changes in the tumor cell genome. For example, case studies have reported that the most common abnormality is a monosomy of chromosome 1 and gain of chromosome 7 (2, 11, 22, 23). Also, other studies have shown chromosome 1p and 3p anomalies to be associated early on in chordoma genesis. Likewise, 1q anomalies have been correlated with recurrence in