Targets missed: predictors of MRI-targeted biopsy failing to accurately localize prostate cancer found on systematic biopsy

In modern clinical practice, MP-MRI and subsequent MRI/US fusion-guided prostate biopsy are methods used for the optimized detection, staging, and active surveillance of PCa [11‐13]. MRI/US fusion technology affords improved visualization of areas suspicious for cancer and aids in detecting PCa foci occult on systematic biopsy [11, 14]. Furthermore, multiple investigations have demonstrated that performing MRI-targeted biopsy superiorly detects clinically significant PCa, and less often samples insignificant cancers compared to a systematic extended-sextant biopsy. Thus, MRI-targeted biopsy would theoretically spare both clinicians and patients from detection of indolent, clinically insignificant cancers and the associated downstream psychological effects and public health costs [9, 11, 15, 16]. With this improved diagnostic accuracy, evidence suggests that selected men on active surveillance meeting certain clinical criteria may safely forgo repeat biopsy for at least 2-year intervals when incorporating MP-MRI in the surveillance algorithm [12, 17]. This would thereby decrease the incidence of iatrogenic complications from repeat biopsies, lower cost of PCa care, and reduce the psychological burden on a patient who would otherwise be undergoing more frequent biopsy procedures.

However, using MRI-targeted biopsy alone for the detection of new clinically significant PCas remains controversial. For men on active surveillance (AS) who are undergoing MRI-targeted biopsy, several studies have reported an optimized detection rate of clinically significant cancer detection using MRI-targeted biopsy [12, 15]. However, Marliere et al. [18] observed improved cancer detection when a concurrent standard template biopsy is additionally performed. A recent multi-institutional, international randomized trial supported MRI-targeted biopsy without systematic sampling performed better than a systematic 10- to 12-core TRUS-guided biopsy schema in detecting clinically significant PCa [19].

In the present study, we observed the majority (77.7%) of the “target miss” biopsies identified were histologically determined to be grade group 1 PCa. Only seven patients had “target miss” biopsies with a higher grade group 2 or grade group 3 PCa. These cases of clinically significant, intermediate-risk PCa are essential to detect early in the disease course to allow for a discussion regarding definitive treatment with curative intent given the recognized heightened risk for stage progression. The goal of PCa screening has appropriately shifted toward early detection of clinically significant cancers with limiting the detection and potential overtreatment in cases of more indolent disease. Hence, optimizing the detection of higher grades of PCa is critical for which MRI has augmented screening efficacy [20].

The PI-RADS suspicion score is generated using a 5-point scale, with a score of 5 being the most concerning for a malignant tumor, and has become an increasingly utilized tool to describe suspicious lesions detected on MRI of the prostate [21, 22]. We observed the PI-RADS score demonstrated statistical significance for the comparative determination of fusion-guided biopsy that resulted in PCa detection vs. cases of “target miss” disease where systematic biopsies detected cancer (p < 0.001). Furthermore, total lesion volume (p = 0.022) and lesion density (p < 0.001) met criteria for statistical significance in our study. Due to limited statistical power, multivariable analyses were not performed, but we acknowledge that lesion volume, and in turn, lesion density may have some overlap with the PI-RADS score as greatest axial dimension of targetable lesions is incorporated into the PI-RADSv2 scoring system. It is acknowledged that not all MRI lesions with PI-RADS suspicion scores assigned would represent PCa foci. Hence, we enriched our population for those with PCa proven to be present on systematic or targeted biopsy core sampling for internal comparison for each patient included in the analysis.

Muthigi et al. [23] described a retrospective review of MRI/US fusion-guided biopsy in relation to the upgrading of high-risk prostatic disease uncovered by standard biopsy to lower-risk disease discovered through targeted biopsy. Their multivariable analysis found upgrading of disease to be significant relative to PSA (p < 0.001), prostate gland volume (p < 0.001), and a lower number of target cores (p = 0.001). Based on these findings, predictors of missing targets may be used in the future to guide those cases best served by added systematic biopsy sampling to optimize detection of all clinically significant cases of cancer while obviating the need for always conducting the full systematic extended-sextant schema of needle sampling [24].

To determine the distance of a “target miss” lesion from a positive cancer sextant sampled with the systematic biopsy approach, a sextant mapping guide was used for spatial comparison (Fig. 2). The majority of the “target miss” biopsies fell either in the same sextant or within one sextant of the malignant lesion: 77.2%. This suggests that the targeted and systematic template cores may have sampled the same relative area but yielded different pathological results. The underlying reason for this finding is not fully elucidated in the present study and is most likely multifactorial. Tumor heterogeneity, with varying grades of cancer in a single lesion and even detection of atypical small acinar proliferation, which is a benign finding often found adjacent to cancer foci, is a well-substantiated finding in PCa. In addition, MRI/US fusion-guided biopsy is subject to potential error in the multiple steps required to achieve a precise biopsy of an MRI target, including MRI segmentation, TRUS segmentation, fusion misregistration, and patient anatomic differences (bladder filling, rectal contents, and prostate gland deformation with TRUS). Furthermore, it is well recognized that deployment of the TRUS-guided needle biopsy is not always achieving biopsy in the sextant pursued in the systematic biopsy approach. This may further complicate the baseline comparison, though the MRI-US software fusion devices allow for three-dimensional mapping of systematic biopsy core samples for retrospective evaluation of spatial deployment within the three-dimensional prostate gland volume. Additionally, patient mobility during targeted sampling was not specifically collected as a parameter in our dataset, but has been reported as a known risk of altering lesion location and configuration during fusion alignment between real-time TRUS and the previously acquired diagnostic MP-MRI [23, 25]. Based on the findings from the current study, perhaps systematic sampling may be of higher yield sampling within the sextant MRI-targeted lesions are found or in immediately adjacent sextants within the prostate rather than a full extended-sextant sampling throughout the gland.

Strengths of this study include a well-corroborated and standardized procedure for the diagnostic MP-MR imaging, MRI/US fusion-guidance for targeted biopsy, and extended-sextant mapping for the special localization of PCa foci. The most current MRI suspicion scoring system, PI-RADSv2, and the newly adopted PCa grading system using prognostic grade groups were utilized to characterize malignant lesions in this study. Despite these advances in the established workflow used, 35 out of 127 patients (27.6%) who underwent targeted biopsy were determined to have negative targeted lesions with cancer found via the systematic approach. MRI/US fusion-guided biopsy shows promise to continue to be an effective method for the localization of suspicious prostatic tissue lesions, but has room for improvement. As the majority of “target miss” cases had PCas found in the same sextant or immediately adjacent sextant to the targeted lesion(s), potential elimination of systematic sampling in other, more distant sextants may be considered in an effort to decrease the burden of biopsy sampling.

This study is limited in being a single-institution patient cohort with overall patient numbers limiting statistical power. While all biopsies were performed by two experienced, fellowship-trained urologic oncologists at a tertiary care center, this may not reflect urologic practice in academic centers newly adopting these techniques or the community practice setting at-large. Furthermore, this study made the assumption that each biopsy collected an accurate representation of the prostatic tissue histology while it is recognized that systematic biopsy does not always represent the highest-grade disease when radical prostatectomy specimens have been evaluated. Though this is a limitation, evaluation of targeted biopsy and systematic biopsy on the subset of patients who have gone on to radical prostatectomy would significantly limit the number of patients evaluated and would also incorporate a selection bias that all patients would have PCa that prompted early definitive treatment. Future directions of validation via a larger, multi-institution patient cohort may build upon these findings and better define the systematic biopsy schema needed to supplement targeted biopsy sampling in order to optimize detection of clinically significant cancers without oversampling.