Diagnosis of benign prostatic hyperplasia (BPH) and prostate cancer (PCa) can be difficult to differentiate. Although prostate biopsy (PBx) is the gold standard for PCa diagnosis, it is associated with a risk of infection, rectal bleeding, acute urinary retention, and pain. Therefore, performing PBx should be minimized when clinically appropriate. Multiparametric magnetic resonance imaging (mpMRI) has emerged as an important adjunct in detection and evaluation of clinically significant PCa (CSPCa) and is currently recommended by guidelines for all men with a suspicion for PCa prior to PBx.¹ Prostate Imaging–Reporting and Data System^® (PI-RADS^®) is the standard for mpMRI acquisition and interpretation for PCa diagnosis. The current version v2.1 was revised in 2019, which included differentiation of BPH nodule and PCa suspicious nodule.² Although typical BPH nodules were assigned a T2 weighted (T2W) score of 2 on PI-RADS v2, they are now assigned a score of 1 on v2.1. That is because BPH nodules are highly unlikely to harbor CSPCa. Another important change was the role of diffusion weighted imaging (DWI) score to differentiate atypical transitional zone (TZ) nodules. TZ nodules are upgraded to PI-RADS score of 3 if they are evaluated as DWI score ≥4.

MRI for PCa Diagnosis and Lesion Localization

PI-RADS correlates with PCa aggressiveness; therefore, mpMRI can be used as an important biomarker for PCa diagnosis. A recent meta-analysis showed the PCa and CSPCa detection according to PI-RADSv2.1 score were 3% and 2% for PI-RADS 1, 9% and 4% for PI-RADS 2, 34% and 20% for PI-RADS 3, 70% and 52% for PI-RADS 4, and 97% and 85% for PI-RADS 5.³ MRI pathway detects more CSPCa than systematic PBx (SBx).⁴ Patients with a small lesion in large prostate, anterior cancer lesion, or prior negative biopsy history are the most challenging cases for transrectal ultrasound (TRUS) SBx.⁵ mpMRI guided targeted PBx can precisely detect and localize CSPCa in challenging cases (Fig. 1).

Figure 1. A 70-year-old male with a history of prior negative PBx and elevated PSA of 5.79 ng/ml presented with severe lower urinary tract symptoms with an International Prostate Symptom Score of 21 and was quite bothered by his symptoms. He was seeking a surgical option for BPH. Given his elevated PSA, a prostate mpMRI followed by an MRI-TRUS fusion guided PBx was performed to evaluate PCa. Axial view T2W imaging (A), apparent diffusion coefficient map (B), and dynamic contrast enhanced images (C) of the prostate. Prostate volume was 174 cc and PSA density was 0.03 ng/ml². A 7 mm PI-RADS 4 lesion (yellow circle) was detected at the 8–9:00 position of the prostate peripheral zone, which demonstrated restricted diffusion and washout kinetics. Sagittal view from the right (D), coronal view (E), and sagittal view from the left (F) of 3D MRI-TRUS fusion transrectal PBx. Targeted biopsies showed grade group 3 PCa.

PBx Can Be Safely Avoided in Differentiating BPH versus PCa in Selected Patients

Ahmed et al demonstrated mpMRI to triage men with elevated PSA without previous PBx history would decrease unnecessary PBx by 27%.⁶ Some investigators reported that MRI and clinical parameters including age, African American race, prior negative PBx history, abnormal digital rectal examination, PSA, PSA density, and PI-RADS score were predictors for CSPCa detection.^7,8

Combination of clinical and imaging features contributes to more accurate CSPCa detection than clinical or imaging features alone. Mehralivand et al found “clinical parameters only model” and “clinical + MRI-derived parameters model” could avoid 4% and 18% fewer unnecessary biopsies without missing CSPCa, compared to performing a biopsy to all patients with positive MRI results.⁸

Oishi et al evaluated men with negative mpMRI findings and found that a PSA density <0.15 ng/ml² with prior negative PBx history yielded a high negative predictive value in determining CSPCa on PBx.⁷ To safely avoid PBx for patients with persistent elevated PSA and large prostate, the combination of clinical features including PSA density less than 0.15 ng/ml² and previous negative PBx history and PI-RADS 1-2 as imaging features should be considered (Fig. 2). These parameters are important for differentiating BPH vs PCa in scenarios of persistent PSA elevation and prostate enlargement.

Figure 2. A 68-year-old health care worker with a history of prior negative PBx results, stable PSA of 8.4 ng/ml, and family history of PCa presented for evaluation of lower urinary tract symptoms. His followup mpMRI showed a prostate volume of 93 cc and no evidence of high grade PCa, unchanged from 1-year-prior mpMRI. Axial view of T2W imaging (A), dynamic contrast enhanced (B), apparent diffusion coefficient map (C), and DWI (D) images of the prostate. Total 14-core SBx showed benign prostatic tissue. Considering his low PSA density of 0.09 ng/ml², prior negative PBx history, and negative mpMRI findings, the elevated PSA value was likely due to BPH and CSPCa was unlikely to be found. However, after thorough discussion with the patient and using the shared decision-making model, a systematic 14-core PBx was performed. As expected, the PBx was benign.

Managing Patients with BPH and Persistent Suspicion for PCa

Approximately 15% of CSPCas are MRI invisible.⁷ Current diagnostic biomarkers including the prostate health index (PHI), 4Kscore^®, SelectMDx, ConfirmMDx, PCA3, MiPS, and ExoDX™ can help stratify the risk of PCa vs BPH.⁹ The diagnostic accuracy of these markers is higher than PSA. The combination of biomarkers and imaging diagnostics is a promising field. When PHI was combined with mpMRI, the area under the curve (AUC) for CSPCa detection was 0.75, compared to mpMRI and PSA alone (AUC=0.64 and 0.69). The combination model of 4K and PHI score could reduce 29% of PBx. Although these improvements have not been confirmed across all settings, these innovative biomarkers can aid in clinical decision making and contribute to safely avoiding unnecessary PBx. When a high clinical suspicion of PCa persists in the patient with elevated PSA, negative mpMRI, and previous negative biopsies, these biomarkers are useful in determining whether a saturation biopsy would be appropriate.

Multi-modal evaluation combining clinical features, imaging modalities, and novel biomarkers can safely reduce unnecessary PBx on patients with BPH.

Figure 3. A 78-year-old male with elevated PSA of 33 ng/ml. Axial view of T2W imaging (A), apparent diffusion coefficient map (B), DWI (C), and dynamic contrast enhanced (D) images of the prostate. Prostate volume was 74 cc and PSA density was 0.45 ng/ml². Enlarged diffusely heterogeneous prostate gland. A 2.9 cm PI-RADS 5 lesion was identified on the midline mid TZ (yellow arrowhead). A 2.3 cm PI-RADS 5 lesion was also detected on the right mid peripheral zone (green arrow). E, 3D MRI-TRUS fusion transperineal biopsy revealed grade group 4 PCa from the lesions. PSMA scan was performed for staging and confirmed anterior PCa focus and no metastasis. F, axial view of PSMA PET/computerized tomography images of the prostate. Abnormal PSMA uptake presented at the level of the mid anterior prostate gland (yellow arrowhead), but no abnormal uptake on BPH nodules.

Combination of MRI and Prostate-Specific Membrane Antigen (PSMA) Positron Emission Tomography (PET) for Evaluation of BPH versus PCa

MRI has several contraindications and limitations including pacemakers, metallic foreign body, claustrophobia, reactions to the contrast agent, lower inter-rater agreement, MRI invisible PCa, and others. Currently, significant advances to develop more sensitive imaging techniques for PCa detection include PET scanning.¹⁰

PSMA enzyme activity is known to be significantly elevated in PCa when compared to benign prostate tissue and BPH (Fig. 3). PSMA PET scan has been approved by the Food and Drug Administration for staging of patients at high risk of PCa metastasis, as well as for evaluation of biochemical failure. PSMA PET has shown an excellent safety profile with almost no adverse events.¹⁰ In addition, PSMA PET can be used as a biomarker to select patients for PSMA-targeted radioligand therapy.

The use of PSMA PET for patients prior to PBx has been less studied. In the case that MRI results are inconclusive or biopsy results are negative, further supportive evidence for the use of PSMA PET can potentially emerge. Furthermore, ¹⁸F-FDG (fluorodeoxyglucose) PET/computerized tomography may provide added value in identifying ¹⁸F-FDG-positive, PSMA negative disease.¹⁰ Of note, since PSMA expression is heterogeneous, it can result in false-negatives both in primary tumors and metastases. PRIMARY, the multicenter, prospective, cross-sectional clinical trial, will provide evidence on the additional value of PSMA PET to mpMRI for CSPCa detection in men undergoing initial PBx.