Clinical significance and predictors of oncologic outcome after radical prostatectomy for invisible prostate cancer on multiparametric MRI

Prostate cancer (PCa) is the most common type of newly diagnosed malignancy in males [1], and it accounts for nearly 30% of all diagnosed male cancers [2]. In 2012, around 1,111,700 new cases and 307,500 deaths were recorded worldwide [3]. As PCa screening by measuring prostate-specific antigen (PSA) levels has become more widespread, the proportion of PCa presenting with low-risk factors has also increased. [4] According to the European Association of Urology guidelines, an extended 12-core systematic transrectal ultrasound (TRUS)-guided biopsy should be performed for patients with an elevated prostate specific antigen (PSA) level, which is endorsed as the optimal biopsy method [5]. However, this diagnostic strategy has disadvantages based on random sampling and is largely operator dependent. [6]

Accordingly, several complementary measures are being developed. Since its first usage in 1983, magnetic resonance imaging (MRI) has increasingly been used for PCa diagnosis because of its growing availability, multiparametric imaging, and the combination of anatomic and functional data [7]. The accuracy of multiparametric magnetic resonance imaging (mpMRI) has not only been established for biopsy specimens, but also for histopathologic correlations using prostatectomy specimens. Recent publications have demonstrated detection rates of significant PCa between 80 and 96% for MRI compared to whole-mount sections [8‐10] Therefore, imaging techniques have played an increasingly important role in the management of localized PCa. Moreover, mpMRI-TRUS fusion-targeted biopsy represents a substantial step forward in the detection of PCa. [11] Therefore, the clinical significance of invisible PCa on mpMRI tends to be overlooked.

However, despite advances in imaging and target biopsy, mpMRI still produces some false negatives and false positives [12‐14], and not all PCa is detected by mpMRI. Therefore, the aim of our study was to evaluate the clinical significance of invisible prostate cancer (iPCa) on mpMRI. We examined clinical and pathological characteristics to evaluate oncology outcomes following radical prostatectomy (RP) in patients with iPCa.

The widespread use of PSA testing has dramatically increased the number of low-risk PCa cases identified. Consequently, the proportion of low-risk PCa cases has increased, and treatment options for PCa are known to differ by risk classification [4]. However, several published studies have reported that the efficacy of contemporary PCa screening and diagnosis practices have limited sensitivity and specificity. The main disadvantages are failure to detect clinically significant cancer, imprecise PCa risk stratification (undersampling), and detection of small, low-risk, clinically insignificant cancers (overdetection) [21, 22]. Thus, the development of mpMRI has played a role in complementing these deficiencies.

In the past, widespread acceptance of mpMRI suffered from a lack of standardized diagnostic criteria for reporting results, leading to a substantial variability in interpretation [23]. To standardize the evaluation and reporting of prostate MRI, the European Society of Urogenital Radiology published guidelines based on an expert consensus in 2012, termed the Prostate Imaging Reporting and Data System (PI-RADS). This system was then upgraded to PI-RADS version 2 in 2015. As such, the role of mpMRI in diagnosing PCa is growing [15, 16].

The standardization of prostate mpMRI and the subsequent development of platforms for MRI-targeted biopsy represent a potential tool to the overcome limitations of conventional TRUS-biopsy. In addition, this has had a significant impact on the treatment direction. Notably, iPCa on mpMRI has been observed in several published studies, which is considered to be one standard of active surveillance [24‐26].

In addition, some studies have identified mpMRI as an important prerequisite for prostate biopsy. Wysock et al. [27] reported that 75 patients had a pre-biopsy MRI showing no suggestion of cancer. In 74 of those patients, no cancer with GS ≥7 was found by biopsy, which translates into a remarkable 98.7% negative predictive value for potentially aggressive disease. Thus, they suggested that a negative MRI result obviates the need for a biopsy.

However, negative findings on MRI have already been reported in several studies, and MRI-iPCa is also not uncommon in the PI-RADS era. Filson et al. reported that in a consecutive series of 1042 men undergoing template biopsy, regardless of MRI findings, the incidence of clinically significant PCa in men with no MRI-suspicious lesions was 16%. [12].

Further, in a study by Le et al., when looking carefully at whole-mount prostatectomy specimens, the incidence of clinically significant PCa not seen on expert-read MRI was 28%. [8], which was the same as in our study. A significant PCa was observed in some of the pathologic specimens of 213 patients with iPCa, and then we investigated their long-term oncologic outcomes. Most cases of iPCa showed low risk for G6 (76.1%), but PCa of G8 or higher was observed in 20 cases (6.6%), and T3 pathology was observed in 24 cases (13.1%). BCR was observed in 29 cases (13.6%) during the follow-up period. This showed that there may be AP and oncologic outcomes among invisible cancers.

In addition, 55 patients with iPCa who had a low risk of G6 in biopsy showed an upgraded feature of G7 or above in the final pathology. The possibility of upgrading to G6 has already been reported in many articles [19, 28]. We agree that some GS 6 cases thought to be insignificant may have the biological potential for de-differentiation. This suggests that in patients with a low risk of G6, iPCa on mpMRI finding is not a prerequisite for AS. Our findings will be able to complement this. We found that PSA is closely related to oncologic outcome and AP. Through this, we determined the optimal PSA cut-off value to predict BCR during the follow-up period. PSA > 6.2 ng/ml could be considered as a basis for determining the active treatment of iPCa. PSA is still the most reliable marker of PCa in the era of mpMRI and PI-RADS.

However, our study had several limitations. First, this was a retrospective review of data from patients treated at a single institution; therefore, multi-center, prospective studies are still needed. Second, as we previously mentioned, mpMRI scans were obtained after prostate biopsy. There may be some limitations on image interpretation, such as hemorrhages, compared to pre-biopsy images [29]. However, Park et al. reported that no consensus has yet been reached regarding the optimal timing of MRI for acute staging [30], although pre-contrast T1W images were always included in MRI protocols to improve image quality. This was because areas of hemorrhage appeared characteristically hyper-intense on T1W, which reduced the impact of hemorrhage in the interpretation of these images. Additionally, only patients with MRI images where there was no image interpretation restriction, based on PI-RADS grade determined by the experienced uroradiologist, were selected. Patients with any limitations of interpretation owing to pre-biopsy images were excluded. Despite these limitations, our study remains informative for clinicians who treat patients with iPCa on mpMRI.

As for the strengths of our study, to the best of our knowledge, this is the first investigation of long-term oncologic outcomes and prognostic factors in patients with iPCa based on PI-RADS who underwent RP. Furthermore, we investigated the long-term follow up oncologic outcomes of iPCa with an established protocol. No patients were treated with adjuvant androgen deprivation therapy or radiotherapy until BCR. This allowed us to observe the natural history of BCR after RP. Based on this, our study provides criteria for predicting adverse oncologic outcomes of patients with iPCa without further preoperative examination. Clinical information, especially increased PSA, may help to determine the direction of treatment for patients with iPCa beyond the use of MRI data alone. This may be a criterion for clinicians to consider a systematic prostate biopsy for iPCa or to administer aggressive treatment in patients with PCa that has already been diagnosed.

Our study used mpMRI as a preoperative image modality. Recently, modalities, such as prostate-specific membrane antigen ligand positron emission tomography, have been used for the diagnosis and treatment of prostate cancer, recently. We believe that the development of these modalities may be a way to overcome mpMRI limitations observed in our study [31, 32].

Our results demonstrate that iPCa on mpMRI can have AP, and its oncologic prognosis is not always good. Therefore, invisible tumors on mpMRI do not appear to predict insignificant clinical implications. Among such tumors, there is a clinically significant cancer incidence. In addition, our results showed that PSA is the most clinically reliable predictor of pathologic outcome and prognosis of iPCa. Specifically, PSA above 6.2 ng/ml was significant in iPCa in relation to its oncologic prognosis. In the present results, we suggest that aggressive treatment such as RP should be performed in patients with invisible cancer on mpMRI if it is clinically necessary, such as in patients with elevated PSA > 6.2 ng/ml. Finally, when prostate biopsy is clinically needed, such as in cases with PSA elevation, a negative mpMRI finding should not be a prerequisite for excluding systematic biopsy.