The impact of a second MRI and re-biopsy in patients with initial negative mpMRI-targeted and systematic biopsy for PIRADS ≥ 3 lesions

Prostate cancer (PCa) diagnosis has undergone a significant transformation with the introduction of multiparametric MRI (mpMRI) in recent years. Using mpMRI before a prostate biopsy has revolutionized risk stratification in various clinical scenarios. By using MRI-targeted biopsy (MRI-TBx) for suspicious lesions, the incidental detection of clinically insignificant PCa has been reduced [1], and the diagnosis of the insignificant disease has been minimized [2, 3]. However, there is ongoing controversy regarding whether MRI-targeted biopsy can result in a grade shift through overgrading the index lesion, potentially leading to unnecessary overtreatment of PCa that could otherwise be appropriately managed through active surveillance [4]. Furthermore, a negative re-biopsy mpMRI has demonstrated an overall negative predictive value (NPV) of 82% for all cancers and 98% for ISUP ≥ 2 cancer [5]. Despite the growing consensus among urologists regarding the routine use of mpMRI before prostate biopsy, the specificity remains limited, reaching only 37% [6]. Interestingly, limited data are available for patients who have undergone negative MRI-TBx and systematic prostate biopsy (RBx) following an initial positive mpMRI. A recent mini-systematic review focused on the proportion of PCa detected in the setting of repeated biopsy [7]. The review reported an overall cancer detection rate ranging from 0% to 7.5% and a clinically significant Pca (csPCa) detection rate ranging from 0% to 2.5% for patients with a PI-RADS 3 lesion. Notably, patients with a Likert 5 lesion had an overall cancer detection rate of 87.5%. However, this systematic review had limitations, as it relied on a small number of studies with a limited patient population. In particular, little is known regarding the evolution of MRI lesions that were negative during the initial MRI-TBx and their status upon a second MRI.

In response to the European Association of Urology’s expressed need for its guideline update, we aim to address this knowledge gap and evaluate the proportions of detected Pca and csPCa, as well as identify clinical predictors of Pca, in patients with initial negative MRI-TBx and RBx who underwent a second mpMRI and a repeated biopsy.

Internal Review Board approval was obtained for the present study and retrospective data collection in accordance with the policies of each participating institution.

A total of 290 patients who met the following criteria were included from 10 tertiary referral centers: positive MRI (PI-RADS ≥ 3) with negative MRI-TBx and RBx (initial biopsy). Patients were included if they had a positive MRI (PI-RADS ≥ 3) along with negative results on both MRI-TBx and RBx (initial biopsy). All patients had a second prostate mpMRI and a subsequent biopsy (re-biopsy), including either MRI-TBx and/or RBx (Fig. 1).

In the second MRI, upgrading and downgrading of PI-RADS were defined as any increase or decrease in the PI-RADS value compared to the first MRI, respectively.

The exclusion criteria were patients who underwent a systematic biopsy before the initial MRI-TBx and RBx, and patients in follow-up with MRIs only after the initial biopsy.

Table 1 describes the characteristics at the moment of the initial and repeated biopsy for the 290 evaluated patients. The interval from the initial to repeated mpMRI and from the initial to repeated biopsy was 16 mo (IQR 12–20) and 18 mo (IQR 12–21), respectively.

Table 2 provides insights into the follow-up of prostate lesions described at the first MRI. Notably, 42% of the patients showed the presence of new lesions at the second MRI. Among the lesions described at the first MRI with a PI-RADS classification, 42% remained stable, while 39% exhibited upgrading and 19% showed downgrading. Among 131 men with PI-RADS 4 or 5 lesions at the initial MRI 20.1% of lesions were downgraded to PI-RADS ≤ 3 in the second MRI.

Supplementary Table 1 presents the clinical and radiological triggers for repeat biopsy.

On the whole, 108 patients (37.2%) were diagnosed with PCa and 74 (25.5%) with csPCa at re-biopsy. Most RBx were negative (69%), with a smaller proportion falling into csPCa. MRI-TBx were negative in 58.6%. Supplementary table 2 provides detailed information regarding the location of newly diagnosed cancer, indicating whether it was found in the original MRI area of concern, new suspicious MRI areas, or through a systematic approach.

The majority of patients in both groups had negative biopsy results. Approximately 10% of patients in each group showed positive findings in the Target biopsy and Positive Pca at Systematic biopsy. Notably, the combined Positive Systematic + Target biopsy approach yielded higher detection rates, with 16.1% and 17.2% positivity for patients with Lesions detected at the first MRI and New lesions detected at the second MRI, respectively.

Figure 2 illustrates in a Sankey diagram the evolution of MRI lesions from the first to the second MRI and the subsequent diagnosis through prostate biopsy.

The median follow-up from second negative biopsy was 20 months (5.7–34.7). Further MRI and subsequent biopsy were performed in 19 patients, of whom only 2 patients were diagnosed with PC.

The present study provides significant findings regarding PCa and csPCa detection in patients with positive mpMRI, negative MRI-TBx plus systematic biopsy, treated with a re-biopsy after a second MRI. Several clinically and radiologically significant changes were observed between the first and second MRI scans and a significant shift in the distribution of PI-RADS scores was observed between the two biopsies. Among the lesions observed in the initial MRI, 42% remained stable, 39% showed upgrading, and 19% exhibited downgrading in the second MRI. Moreover, more than 40% of the patients showed the presence of new lesions at the second MRI. In accordance with our biopsy findings after second MRI, the persistence of the mpMRI positivity should be carefully considered as a trigger for presence of prostate cancer. Other studies have aimed at assessing the medium-term radiological and clinical follow-up of biopsy-negative lesions [11‐14]. Specifically, Kornienko et al. [13] found that among 84 men with PI-RADS 4 or 5 lesions who underwent a repeat MRI, more than half of the lesions were downgraded to PI-RADS 3 after a median follow-up of 28 months. However, it is worth noting that 41% of these men, who also underwent repeated biopsy, were diagnosed with clinically significant disease, all of whom had persistent MRI lesions. Stavrinides et al. [14] reported that in the 58 men who had follow-up MRIs, most scores were downgraded, primarily to Likert 3, and this downward trend continued in subsequent MRIs. A small number of patients maintained a Likert 4 phenotype in their serial imaging, and notably, the two men subsequently diagnosed with cancer on follow-up MRI-targeted biopsy consistently had high scores (Likert 4) in their sequential MRI scans. In accordance with a recent systematic review [7], our results support the idea that patients with persistent MRI lesions are at a higher risk of disease. However, drawing definitive conclusions in comparison with previous literature is challenging due to various factors that can influence the studied population, including different targeting, MRI acquisition and protocols [15], reporting protocols (PI-RADS v2 instead of Likert), overall number of included patients, time span between the first and second prostate biopsy, and per protocol defined time between the first and second MRI. Furthermore, it must be notice that in our study we identified low concordance between the subsequent MRIs, underscoring the importance of integrating in the assessment of PI-RADS score, the comparison with previous examinations. This is crucial due to the potential changes that can occur in the prostate over time. The relevance of this approach has already been established with the PRECISE score [16] for patients who are under active surveillance. We strongly believe that a similar approach can also be valuable for specific patient populations, like the one included in the present study.

Indeed, this specific population with high PI-RADS scores and negative target biopsies may reveal some degree of prostate inflammation, which can pose challenges in MRI interpretation. Pepe and Pennisi [17] estimated that approximately 37% of PI-RADS 5 lesions were associated with inflammation. For this reason, it is crucial to determine the histopathology of target biopsy-negative lesions. In our study, we found that the presence of ASAP on the initial biopsy strongly predicted the presence of PCa and csPCa. This supports the growing interest in exploring glandular-stromal alterations, as well as acute or chronic inflammation and vascular changes, which have been observed in a majority of false-positive MRI lesions. Interestingly, these changes are more prevalent and synchronous in MRI-TB tissue compared to systematic biopsy cores from the same patients [18, 19].

In 37.2% of patients, PCa was detected, while csPCa was detected in 25.5% of patients. This highlights the potential limitations of the first TBx and emphasizes the need for further confirmatory biopsies in cases with inconsistent results between MRI images and MRI-guided biopsy findings. Interestingly, the second biopsy involved an increased proportion of software fusion biopsies and targeted transperineal biopsies.

The transperineal approach has a well-established accuracy in cancer detection compared to the transrectal approach [15, 20]. Its role in the re-biopsy is also highlight in the PICTURE study [21]. Transperineal template prostate mapping identified csPCa in 6.5% (11/168; 95% CI 3.3–11%) (Gleason ≥ 3 + 4 of any length or MCCL ≥ 4 mm of any grade) and PCa in 9.3% (20/215; 95% CI 5.8–14%) after a non-MRI-guided transrectal ultrasonography-guided biopsy. Contrary to expectations, the advantages of using targeted transperineal biopsies in our specific patient group were not confirmed [20, 22].

Similarly, the use of MRI-TBx did not significantly enhance the detection abilities of PCa compared to cognitive biopsy. On the contrary, the number of RBx cores was independently associated with the presence of PCa and csPCa, again highlighting the need to combine TBx and RBx. This is also seen in the assessment of the concordance with the final pathology where the combination of systematic and target biopsies was higher. Again, systematic biopsies still play a role in the diagnostic process [23]. These findings are supported by studies where RBx demonstrate greater added value in lobes where an MRI-visible lesion is present compared to those without [24]. This indicates that the primary role of RBx is to detect cancers that are correctly identified on MRI but missed during targeted biopsies or to detect lesions, which were not completely identified by the mpMRI. Additionally, perilesional biopsies appear to enhance the detection rate of csPCa when combined with targeted biopsies alone [25]. Therefore, systematic biopsies can be considered a valuable safety net that compensates for potential quality issues throughout the diagnostic process. It is important to emphasize that the MRI pathway for detecting targeted MRI-visible tumors necessitates diagnosing and treating a significant number of men in order to prevent a single prostate cancer-related death [26]. The inclusion of additional MRIs and biopsies within this pathway may further increase the number of men diagnosed and treated per death prevented. Thus, the more we learn about follow-up procedures, the less stringent we need to be in the initial diagnostic approach.

Our study has several limitations that should be considered. The retrospective design of the study introduces inherent risks of selection bias and no fixed protocol for follow-up. The actual impact of the follow-up regimen, which includes an initial negative biopsy followed by a second MRI and subsequent biopsy, should be compared to other groups that may follow different protocols, such as biopsy without a second MRI or clinical follow-up alone. There were multiple biopsy options available for comparison, including different techniques, software for fusion biopsies, and the number of targeted biopsies. This variability in biopsy options may introduce confounding factors and limit the ability to draw definitive conclusions. Fourthly central readings of imaging were not performed, which could have provided more standardized and reliable results. Due to this limitation, it was not feasible to evaluate the correlation between the PRECISE score of the second MRI and the detection of csPCa. Additional information in the PRECISE score, such as changes in lesion appearance observed in DWI, has the potential to improve the MRI outcomes beyond the PI-RADS score.

Radiologists may exhibit enhanced performance at second MRI, thereby improving their capabilities.

Current evidence indicates that transperineal sampling exhibits improved cancer detection rates for lesions in the anterior/apical region [22]. However, the current study lacks available data to determine whether the access route served as a significant predictor in patients with anterior/apical lesions who initially underwent transrectal biopsy.

Lastly, this study was conducted at multiple centers, introducing the possibility of institutional or regional biases. The variation in practices and patient populations across different centers may influence the study outcomes.

However, these limitations could also be viewed as a strength of this study, as they reflect real-life clinical practice and underscore the significance of follow-up for suspicious MRI findings, even after initial MRI-guided negative biopsies. The implementation of a structured MRI follow-up algorithm, especially for patients with inconclusive results and high-grade PI-RADS scores, can improve diagnostic accuracy and optimize patient care.

This study highlights the significance of the follow-up needed in the lesion characterization of suspicious MRI findings, even after an initial negative MRI TBx and RBx. The identified of PCa, and above all, csPCa in this setting of patient offers valuable insights for risk assessment and inform decision-making regarding subsequent diagnostic procedures and treatment choices. Patients presenting with inconsistent findings between MRI and prostate biopsy, presence of high-grade PI-RADS, low number of systematic biopsies at first biopsy and presence of ASAP, should undergo thorough evaluation and be included in a structured algorithm for MRI follow-up and eventually repeated biopsy.

This approach is crucial to ensure accurate diagnosis and appropriate management for these individuals, although the long-term prognostic impact of this approach is clearly unknown. Further validation and prospective studies are warranted to confirm and extend these findings to larger patient populations with diverse follow-up regimens and available follow-up protocols. Knowledge on follow-up may relax the initial diagnostic algorithm.