An Integrated Management Paradigm for Skull Base Chordoma Based on Clinical and Molecular Characteristics

Background: Mounting evidence supports that skull base chordoma (SBC) is a heterogenous disease spanning a wide spectrum of biologic behavior. However, it remains unclear how the tumors' genotype can be used to guide management.

Objective: Previous work categorized SBCs in three groups based on the percentage of cells within the tumor having 9p21 and 1p36 deletions by FISH: The low risk Group A (9p21 del 0–3% AND 1p36 del 0–15%), the high-risk Group C (9p21 del ≥ 25% AND 1p36 del >15%), and an intermediate risk Group B (all other combinations). By integrating this genetic information with data relevant to the extent of resection (EOR) and use of adjuvant radiation (AdjXRT), we sought to refine an evidence-based management algorithm for SBC.

Methods: Of 263 SBC cases, 152 had complete FISH information. Kaplan–Meier survival estimation and Cox proportional hazard modeling were employed to determine the contributions of the genotype, the EOR and AdjXRT to progression-free survival (PFS) after surgery.

Results: Consistent with prior data, groups A, B and C had dramatically different outcomes ([Fig. 1A]). Reinforcing the significance of the tumors' genotype on outcomes, these differences remained dramatic even when only considering cases with gross total resections (GTRs) ([Fig. 1B]). In group C, both the EOR and AdjXRT altered outcomes ([Fig. 2]). In group B, while EOR was very significant, AdjXRT only improved outcomes in patients without GTRs ([Fig. 3]). In group A, all but one patient had GTRs, and AdjXRT did not significantly alter the course of disease ([Fig. 4]). The one patient had bulky residual disease within the brainstem, and it eventually progressed after 4 years. Notably, the high GTR rates are likely explained by the significantly smaller tumor size (p = 0.011) in this group (mean = 0.98 cc) compared to the other two groups (group B and C, mean = 4.28 cc) and general lack of invasiveness (less likely to have coronal extension, or span more than two segments of the clivus, p < 0.001). Also of note is that group A tumors were more likely to occur in young people (p = 0.005), and more likely to be asymptomatic at presentation p < 0.001). Recurrent tumors were more common in group C, followed by group B and then group A. Patients developing metastatic disease had higher percentages of 1p36 deletions (p = 0.007), as well as Ki67 proliferation indices (p = 0.007).

Conclusions: Although the genotype appears to be the strongest prognostic factor, GTRs have a significant impact in intermediate and high risk groups. Adjuvant radiation improves outcomes in group C regardless of the EOR. However, in group B, radiation is beneficial only in cases where GTR cannot be achieved. The genotype can also be predictive of certain tumor phenotypes, as well as of the clinical presentation.

Publication History

Article published online:
12 February 2021