Clinical Validation of the 2005 ISUP Gleason Grading System in a Cohort of Intermediate and High Risk Men Undergoing Radical Prostatectomy

Abstract

In 2005, the International Society of Urological Pathology (ISUP) introduced several modifications to the original Gleason system that were intended to enhance the prognostic power of Gleason score (GS). The objective of this study was to clinically validate the 2005 ISUP Gleason grading system for its ability to detect metastasis. We queried our institutional RP database for men with NCCN clinically localized intermediate to high-risk disease undergoing radical prostatectomy (RP) between 1992 and 2010 with no additional treatment until the time of metastatic progression. A case-cohort design was utilized. A total of 333 available RP samples were re-reviewed and GS was reassigned per the 2005 ISUP Gleason system. Cumulative incidence of metastasis was 0%, 8.4%, 24.5% and 44.4% among specimens that were downgraded, unchanged, had one point GS increase and two point GS increase, respectively. The hazard ratio for metastasis raised in GS 8 and 9 compared to GS 7 from 2.77 and 5.91 to 3.49 and 9.31, respectively. The survival c-index of GS increased from 0.70 to 0.80 when samples were re-graded at 5 years post RP. The c-index of the reassigned GS was higher than the original GS (0.77 vs 0.64) for predicting PCSM at 10 years post RP. The regraded GS improved the prediction of metastasis and PCSM. This validates the updated Gleason grading system using an unambiguous clinical endpoint and highlights the need for reassignment of Gleason grading according to 2005 ISUP system when considering comparisons of novel biomarkers to clinicopathological variables in archival cohorts.

Fig 1. Study diagram and patient selection criteria.

Fig 2. (A) Fused glands (400x). In the original Gleason grading this pattern was considered pattern 3. According to the 2005 ISUP Gleason system it would be graded as pattern 4; B) Adenocarcinoma with glomeruloid features currently assigned a Gleason pattern 4 (100x); C) Ill-defined glands (100x). This pattern would be graded as Gleason pattern 4 by the ISUP 2005 Gleason grading; and D) Individual cells (100x).

This pattern was originally accepted under Gleason pattern 3 and would be assigned a Gleason pattern 5 according to the 2005 ISUP Gleason system.

Fig 3. Cumulative incidence of metastasis at 5 years post radical prostatectomy.

A) Difference in re-graded 2005 ISUP modified and original Gleason score; B) Difference in primary re-graded 2005 ISUP modified and original Gleason score; and C) Difference in secondary re-graded 2005 ISUP modified and original Gleason score.

Fig 4. Cumulative incidence curves of A) metastasis by original Gleason score, B) metastasis by reviewed Gleason score.

The number at risk in each group is shown in the footnote lines. Patients in the sub-cohort who do not experience the event are weighted by the inverse of the sampling fraction in following the case-cohort design.

Fig 5. A) Survival concordance index. Reviewed Gleason score by the 2005 ISUP modified Gleason system has the highest c-index compared to original Gleason score. B) Decision curve analysis at 5 years post radical prostatectomy shows the net benefit of original and reviewed Gleason score across probability thresholds.

The reviewed Gleason score shows the highest net benefit.