The aim of this study was to identify predictors of upgrading at prostatectomy in men with GG 1 and pretreatment biparametric MRI. PSA density was the only significant predictor for upgrading, but according to exploratory analyses its clinically importance merely applies to patients with a bpMRI and PI-RADS 1–3. For patients with PI-RADS 4–5, the probability of upgrading was high also if their PSA density was low.
Our results regarding the overall impact of PSA density are in line with previously published studies. In a population-based study, approximately half of the men with GG 1 cancer who underwent prostatectomy had adverse pathology (defined as upgrading from GG 1 or upstaging to T3a or T3b) in the prostatectomy specimen (10). Age, PSA, PSA density above 0.15 ng/ml/cm3, clinical stage T3 and more than 4 mm cancer length on biopsy predicted adverse pathology. Another study that compared PSA and PSA density as predictors for upgrading after prostatectomy in men with GG 1 concluded that PSA density is a significantly better predictor than PSA (15).
In our study, upgrading was also present in about half of the men, consistent with previous publications (11, 12). In a recent study, upgrading from GG 1 to GG 2–5 was found in 40% of men with very-low-risk disease and 59% with low-risk disease (12). The authors recommend, as stated in guidelines, confirmatory testing for patients eligible for active surveillance (repeat biopsy, prostate MRI or genomic markers), as this can identify patients at risk for adverse pathology after surgery.
Our finding that PSA density is of clinical importance mainly for patients with PI-RADS 1–3 on bpMRI, not for patients with PI-RADS 4–5, has, to the best of our knowledge, not been previously reported. It is, however, supported by previous studies showing that the pre-diagnostic probability of significant prostate cancer in patients with PI-RADS 1–3 lesions is associated with PSA density: the risk of harbouring a significant cancer is high if PSA density is above 0.15 ng/ml/cm3 (4, 14).
Our results are clinically important when considering active surveillance. They clearly suggest that men with GG 1 and PI-RADS 4–5 on bpMRI are at great risk of having GG 2–5, regardless of the PSA density. Patients should be informed about this and recommended either repeated targeted biopsies or radical treatment. On the other side, PSA density should strongly influence the treatment decision for men with GG 1 and PI-RADS score 1–3. Men with PI-RADS score 1–3 and low PSA density should be advised to start on active surveillance and men with high PSA density to have either a systematic biopsy or treatment. A previous randomised study showed that GG 2–5 cancers are commonly located in the ventral part of the prostate in men with GG 1 on systematic transrectal biopsy and a high PSA density, mandating specific ventral biopsy sampling in this patient group (16)
In our main regression analyses, we found that neither the PI-RADS score nor the MRI tumour stage was associated with upgrading. This is in contrast to two other studies, that reported an association between PI-RADS score and upgrading after prostatectomy in men with GG 1 (17) (18). One of them did, however, include patients with GG 1–5 on biopsy, of which only 58 had GG 1 (18). The other study included only patients with GG 1 and they found that PI-RADS score 4–5 was associated with upgrading (17). Nevertheless, in our study the confidence intervals were wide, so we cannot exclude that the reason why no significant association was detected could be related to our relatively small sample size.
A strength of our study is that data were prospectively collected. Limitations include the small sample size and the unknown selection process leading to surgery. The latter means that our results are not representative for all patients diagnosed with GG 1, as the patients in our study might have been recommended surgery because of MRI findings, a high PSA density or rising PSA values. Moreover, inter-rater discrepancy for MRI reading and tumour grading may affect the external validity of our results (19). Prostate MRI is routinely performed before biopsy, and there were several radiologists involved in the PI-RADS scoring of the MRI scans. Staging, however, was accomplished by a dedicated MRI uroradiologist with several years of experience. In addition, biparametric MRI is increasingly used, and it is important that studies with bpMRI are done, but it is a limitation that the results are not valid for multiparametric MRI. Another limitation is how the biopsies were taken. This register-based study has recruited patients over several years and the routine for how biopsies are performed has changed over time. Hence, some patients had systematic biopsies, while others are diagnosed after guided biopsies. Furthermore, the histological specimens were not reviewed. This may, however, just as easily be seen as a strength as a limitation. In routine clinical practice, specimens are not reviewed, thus our study and its findings reflects the reality for many patients and clinicians.