False positives in PIRADS (V2) 3, 4, and 5 lesions: relationship with reader experience and zonal location

To our knowledge, this study is the first to investigate the FP findings of PIRADS (V2) 3-5 lesions in a pure clinical setting with emphasis on reader experience and zonal location, in a patient population undergoing TRUS MRI fusion-guided targeted prostate biopsy. Our results show that inexperience is independently and significantly associated with a FP reading while zonal location is not. Furthermore, the evaluation of the TZ is mainly what makes the difference between the inexperienced and experienced radiologist. In general, the TZ is an anatomic area that is considered difficult when interpreting MP-MRI of the prostate. The challenging aspect of detecting PCa in the TZ is probably because of the heterogeneous appearance of the TZ which is mainly due to the BPH it contains. Our study shows that the evaluation of the TZ is even more difficult for the inexperienced radiologist. We also found that, to a lesser degree, other potential sources of a FP reading for the inexperienced reader are anatomic variants of the CZ and low-grade prostatitis. One of the main advantages of MP-MRI is its potential to reduce unnecessary biopsies [17, 18]. Nonetheless, in case of an inexperienced radiologist and a suspected TZ lesion, this could lead to more unnecessary biopsies. The PIRADS 3 classification had a high number of FPs, for both the inexperienced and the experienced radiologists. Even though this is likely to be expected as PIRADS is a Likert scale, efforts for reducing the number of unnecessary biopsies in this specific group should be made. A possible solution could be the addition of PSA density [19]. Consequently, all lesions with a PIRADS score of 3 and a cut off value of for example below 0.15 could be refrained from biopsy. However, before implementation this needs to be investigated further with special attention to the number of missed significant cancers with this approach. Also noteworthy, FP rates do not only depend on factors accountable to the reader, but also on inaccuracies related to the biopsy technique itself, most likely in case of smaller lesions [20‐22]. Nonetheless, when analyzing the FPs in the patient cohort of this study that were read by the inexperienced radiologists the majority appeared to be classical examples of misclassification for the TZ as well as for the PZ. In our study, we found that only in 9% of the FP cases for the inexperienced radiologists and in 50% of the FP cases for the experienced radiologist technical issues could have been the reason for a FP lesion. A study by Sheriden et al. [23] reported that 28% of the FP PIRADS 5 lesions could have been missed at biopsy. The difference with our study is that they only investigated PIRADS 5 lesions that are usually large and therefore technique-wise less likely to be missed at biopsy. The findings of this study have two potential clinical implications. First, the relative underperformance of inexperienced readers underlines that reading MP-MRI of the prostate should be reserved to experienced radiologists. The importance of subspecialty training is a well-acknowledged issue in breast and cardiac imaging. This should not be different for MRI of the prostate. After internal evaluation of the results of this study, we decided to reduce the number of radiologists reporting MP-MRI of the prostate and educate internally. Since then, only two of six specialized abdominal radiologists have been reporting MP-MRI of the prostate at our institution. The second potential implication of our findings is that training sessions for inexperienced radiologists should, along with a sufficient caseload with histopathological correlation, pay special attention to the TZ [24, 25], CZ, and low-grade prostatitis.

The overall detection (or true positive) rate of the experienced reader in this study (68% overall detection rate in PIRADS 3-5 lesions) was slightly higher than other expert centers performing MRI targeted prostate biopsy (59%–62%) [26, 27]; however, both studies were performed using PIRADS V1 which could also have accounted for the slight differences. In 2013, Bratan et al. [13] were the first to investigate the FPs. However, this publication was from the pre-PIRADS era, and they did not assess different levels of experience. In another study published in 2017, the issue of experience was addressed [5]. They reported that reader experience may help to reduce overcalling and avoid over targeting of lesions, which is in concordance with our results. Nevertheless, none of these studies specifically looked at the combination of reader experience and zonal location in FP lesions.

Our study had several limitations. First, because of its retrospective design, MRI protocols were heterogeneous (i.e., different magnetic field strengths and slightly varying MRI sequence settings), and possibly of suboptimal quality (e.g., majority of scans were obtained with a 1.5T scanner; and no endorectal coil or the inability to control imaging parameters due to referrals from outside hospitals). However, this is completely in line with routine clinical practice, and this issue is also frequently encountered in multicenter studies [5, 18], which in fact increases the generalizability of our results. Second, we were not able to analyze false negatives and their relation to reader experience, which could have been done if the reference standard would have been prostatectomy specimens or if long-term follow-up data would have been available. Third, this study did not investigate other factors potentially associated with a FP reading, such as clinical variables and apex-base location [23]. Fourth, this study consisted of patients who had received prior biopsy (either negative or with cancer but on active surveillance) possibly reducing the future generalizability of the results. It is expected that as we move forward, more biopsy-naïve patients will undergo MP-MRI and targeted biopsy. Fifth, we did not include Gleason 3 + 3 lesions in our FP definition. In the era of the increasing number of active surveillance candidates, we are well aware of the importance of being able to discriminate between clinically significant (currently regarded as Gleason ≥ 3 + 4) and insignificant PCa (currently regarded as Gleason ≤ 3 + 3). However, including 3 + 3 in the FP definition on MP-MRI would, unfairly, imply that there are proven MRI features that are prospectively able to discriminate Gleason 3 + 3 from 3 + 4. There are retrospective and validation studies that have investigated the relationship between ADC values and Gleason grades, and they have shown promising results [28]. Yet substantial overlaps between the different grades and ADC values exist [28], making it not very useful in a clinical setting. Due to the lack of robust discriminatory imaging features, publications addressing pitfalls on prostate MRI usually only contain examples of benign disease or FPs related to more technical issues [10, 11]. Likewise, the clinically important decision between Gleason 3 + 3 and 3 + 4 can also be challenging on histopathology slides in biopsy specimens. There is substantial interobserver variability together with shortcomings of the Gleason grading scoring system itself [29]. This is probably also the reason why some supposedly Gleason 3 + 3 tumors, even though not very common, can metastasize or show aggressive behavior (such as extraprostatic extension or even seminal vesical invasion) [30, 31]. Furthermore, targeted biopsies obtained from the cancer-suspicious lesions detected on MP-MRI might not accurately represent the true aggressiveness found in a prostatectomy specimen [32‐34], with some studies even mentioning percentages of upgrading from 3 + 3 to 3 + 4 in 67.4% of the cases [32]. So even though there is an absolute clinical need for discriminating significant from insignificant PCa, it is radiologically not meaningful when assessing FPs. Future studies should focus on this unsolved issue.

In conclusion, inexperience of the radiologist is significantly and independently associated with a FP reading, while zonal location is not. Inexperienced radiologists have a significantly higher FP rate in the TZ.