Prognostic Differences in ISUP Grade Group 4: a Systematic Review and Meta-Analysis

The ISUP (Internal Society of Urologic Pathology) recently adopted a five-tiered prognostication system. There is evidence to suggest that the ISUP grade group 4 is a heterogeneous entity regarding prognosis. Our aim was to systematically examine the existing evidence to determine if outcome differences exist within the ISUP grade group 4. A systematic search of the literature for all studies examining the heterogeneity of the ISUP grade group 4 was conducted. Available studies were combined with meta-analysis to evaluate prognostic differences within the ISUP grade group 4 measured by all-cause mortality (ACM) and the prostate cancer-specific mortality (PCSM). Eight studies were identified and utilised a variety of outcome measures to answer the question of heterogeneity within the ISUP grade group 4. Four of these studies examined prognosis using both ACM and PCSM. These were combined into a meta-analysis. The combined group of 5 + 3/3 + 5 had statistically significant higher ACM (hazard ratio [HR] 1.23, 95% confidence internal [Cl] 1.08-1.41) when compared to the 4 + 4 group. There was no difference in the PCSM between the two groups (HR 1.34, 95% CI 0.89-2.01). However, heterogeneity was high for this analysis secondary to a range of methodological differences. Our meta-analysis showed that Gleason grade 3 + 5/5 + 3 had higher ACM than Gleason grade group 4 + 4. Measures of PCSM were statistically insignificant, although heterogeneity was high. Evidence suggests that heterogeneity is likely, although inconclusive. Further studies with consistent methodologies are required to answer this question.