Prognostic relevance of MIB-1 labeling index in VHL-associated and sporadic spinal hemangioblastomas: a subgroup analysis from a multicentric study

Abstract

Spinal hemangioblastomas (sHB) are rare vascular tumors, with distinct clinical courses between von Hippel-Lindau (VHL)-associated and sporadic cases. The MIB-1 labeling index has been proposed as a surrogate marker for tumor proliferation, but its prognostic value remains unclear in this context. In this subgroup analysis from a multicenter retrospective study, we analyzed 116 primary sHB patients with available MIB-1 indices. Patients were stratified by VHL status. Statistical comparisons included ROC analyses for local progression-free survival (PFS) prediction and Kaplan-Meier survival curves for local PFS, stratified by a MIB-1 index cut-off derived from Youden's index. The MIB-1 index was significantly lower in VHL-associated tumors compared to sporadic ones (mean 2.17% vs. 3.02%, p = 0.008). In VHL-associated sHB, a higher MIB-1 index (≥ 2%) correlated with an increased risk of local tumor progression (AUC 0.74, 95% CI 0.49-0.98), whereas this was not observed in sporadic cases (AUC 0.56, 95% CI 0.23-0.88). Kaplan-Meier analysis showed that VHL patients with MIB-1 ≥ 2% had significantly shorter PFS (p = 0.05), while no significant association was found in sporadic tumors (p = 0.87). Our findings suggest that while VHL-associated sHB exhibit lower proliferative indices overall, elevated MIB-1 labeling indices might serve as a prognostic marker of shorter local PFS in this subgroup. In contrast, MIB-1 index appears to have limited prognostic relevance in sporadic sHB. These results highlight the importance of further molecular stratification and proliferation assessment in sHB to better inform clinical decision-making.

Keywords: Local tumor progression; MIB-1 index; Progression-free survival; Spinal hemangioblastoma; Von Hippel-Lindau disease.

Fig. 1

Flowchart of patient selection

Fig. 2

A Comparison of MIB-1 labeling index between sporadic and VHL-associated sHB. The MIB-1 index was significantly lower in VHL-associated tumors (p = 0.008). B Forest plot illustrating predictors of elevated MIB-1 index based on a cut-off value of ≥ 3% in the logistic regression model. Sporadic tumors had a higher OR for increased MIB-1 index compared to VHL-associated tumors (OR 2.35, 95% CI 1.05–5.27, p = 0.037), while the EoR did not confound this observation. C ROC curve illustrating the predictive value of MIB-1 labeling index for local tumor progression in VHL-associated sHB (AUC 0.74, 95% CI 0.49–0.98). D ROC curve for sporadic sHB, where MIB-1 index showed limited prognostic value (AUC 0.56, 95% CI 0.23–0.88)

Fig. 3

Representative microphotographs of tissue sections from spinal hemangioblastoma (sHB). Hematoxilin-Eosin staining (upper row) and Ki-67 (MIB-1) immunohistochemistry A VHL-associated sHB with low proliferative activity (1%) B sporadic sHB with high proliferative activity (5%)

Fig. 4

A Comparison of MIB-1 labeling index between patients with and without local tumor progression (Total: n = 97). Patients with local progression showed a significantly higher MIB-1 index (p = 0.036). B Bubble plot showing the relationship between MIB-1 index and time to local progression or last follow-up, with bubble colour indicating extent of resection (complete vs. incomplete) and line + size representing local progression status (Total: n = 97). Circles label those with a sporadic tumor, and squares those with a VHL-associated sHB. The black crosses indicate those cases who had a local recurrence. The red dashed line marks the MIB-1 index cut-off value of 2%

Fig. 5

PFS according to MIB-1 labeling index stratified by subgroup. A In the entire cohort, higher MIB-1 index (≥ 2%) showed a trend toward shorter PFS without reaching statistical significance (p = 0.12). B In sporadic sHB, no significant difference in PFS was observed between high and low MIB-1 index groups (p = 0.87). The mean PFS was 59.6 months (95% CI: 40.3–78.8) for MIB-1 index < 2%, and 66.9 months (95% CI: 58.4–75.3) for MIB-1 ≥ 2%. C In VHL-associated sHB, a higher MIB-1 index (≥ 2%) was associated with significantly shorter PFS (p = 0.05). The mean PFS was 135.4 months (95% CI: 121.2–149.6) for MIB-1 < 2%, and 126.0 months (95% CI: 84.9–167.2) for MIB-1 index ≥ 2%