causing a shift of PCa graded as biopsy GS ≤6 towards GS 3+4=7 (14, 19). After revision of biopsy specimens, upgrading to ISUP 2005 mGS 3+4=7 occurs in 19–45% of men originally diagnosed with cGS ≤6 (6-9). The upgrading rate of 30% in our study is in line with these previous findings. To our knowledge, we are the first to report on a higher GS upgrad- ing rate in men who died of PCa. Although statistically not significant, the GS upgrading rate also tended to be higher in the present study in men who developed BCR and PCa metastasis. Previous studies reported on the superior prognostic prediction of the biopsy ISUP 2005 mGS as compared with the cGS, both for BCR after RP (9-11) and for PCa-specific survival in men on WW (12). Recent evidence suggests further improvement of prognostic prediction with the biopsy ISUP 2014 mGS (16). The findings of our study support that the ISUP 2014 mGS is a more accurate tool for prognostic assessment based on prostate biopsy than the cGS. As the main goal of the present study was to explain (part of) the PCa deaths in the ERSPC Rotterdam with GS ≤6 at prevalence screening by undergrading with the cGS, our study was not designed for a comparison between grading with the ISUP 2005 mGS and the ISUP 2014 mGS.
Although enabling a more accurate prognostic prediction, upfront grading with the ISUP 2014 mGS probably would not have affected the PCa death rate in our cohort from the pre-active surveillance era as 90 out of 98 (92%) men received active treatment with curative intent. Nowadays, active surveillance is increasingly implemented in biopsy GS ≤6 PCa. As the oncological safety of Active Surveillance in men with (limited) Gleason pattern 4 is not yet proven it is essential to select only those men with low-grade disease (20). The mGS, that was implemented ever since the rise of active surveillance as a treatment modality, probably allows a superior patient selection for active surveillance as compared with the cGS. In the near future, patients with (limited) Gleason pattern 4 could be selected for active surveillance based on the grade 4 growth pattern. Cribriform growth and IDC in prostate biopsy have been shown to be equally associated with a poor cancer-specific survival as compared with men without cribriform/IDC growth (18). The present study confirmed cribriform/IDC growth as a risk factor for PCa death, with a higher rate of cribriform/IDC growth in GS reclassified men with fatal PCa. Cribriform growth and IDC were combined for analysis as both entities often coexist and can be hard to distinguish. Combining cribriform growth and IDC does not alter the prognostic value and morpho- logical distinction between the separate entities by additional immunohistochemistry is no longer needed.
Besides biopsy undergrading, undersampling by sextant biopsy is probably the most important cause of “missed” high-grade tumor components in the fatal PCa with GS ≤6 at prevalence screening. Extended systematic biopsy core schemes increase the PCa detec- tion rate by a factor of 1.3 (21). Systematic biopsy insufficiently samples anterior tumors (22, 23), not only leading to underdetection but also undergrading of tumors. Upgrading
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of biopsy GS ≤6 on RP occurs in approximately 40% of cases (24, 25). In our cohort a total of 7 men with cT1/2 cGS ≤ 6 and PCa death were not reclassified with the mGS. Three of these men were treated by RP. As shown in supplementary table 1, all 3 had a high-grade tumor component in the RP specimen (cGS 5+4, 3+5 and 4+3), indicating insufficient tumor sampling by random sextant biopsy. The development of a high-grade tumor component after the initial diagnosis during WW could not be responsible for the PCa death in the 15 men with cT1/2 cGS ≤6, since all but one of these men received active treatment (5 RP and 9 RT).
Besides grading with the ISUP 2014 mGS, GS upgrading could be caused by a general shift upwards of the perception of patterns (Gleason inflation) after the introduction of the mGS. Furthermore, pathological (double reading) revision of the biopsy specimens with correction of initial diagnostic errors could also yield GS upgrading. Highly variable levels of intraobserver (43 – 78%) and interobserver (36 – 81%) agreement of the GS have been reported (26-28). The 86% interobserver agreement in our study is in line with the approximately 80% interobserver agreement found in most studies using the mGS [10]. In the present study, consensus review was only carried out for the mGS. However, we would not expect a variation of interobserver cGS variability between subgroups after stratification for PCa death, nor would we expect a variation in Gleason inflation. Thus, the difference in the rate of upgrading to mGS 3+4=7 between men who did and did not die of PCa in our cohort is most likely primarily based on undergrading with the cGS.
The strength of this study lies in the double reading of the biopsy specimens and the ac- curate long-term follow-up. However, as we only had follow-up until the end of 2012, more PCa deaths might have occurred in our cohort afterwards. The present study is also limited by the fact that our small cohort included only a fraction of all cGS 3+3 and 3+4 PCa in the prevalence screening round of the ERSPC Rotterdam. Finally, the sextant prostate biopsy performed in our cohort detects less (significant) PCa as compared with extended biopsy core schemes used in current clinical practice.
Conflicts of Interest
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