The diagnostic evaluation of prostate cancer (PCa) has evolved significantly in the last century. For perspective, consider this: In the early 1900s, the only modality used to screen for PCa was the digital rectal examination (DRE). Refinements in the diagnostic algorithm have vastly improved over time.

Prostate Biopsy

Transrectal ultrasound (TRUS) has permitted image-guided, systematic prostate biopsy and has been utilized in practice since the latter half of the 20th century. PSA, first implemented in clinical practice in the early 1990s, was investigated in a study at our institution in 1994, where men with PSA 4-10 ng/mL or abnormal DRE underwent TRUS-guided prostate biopsy. Volumetric analysis was obtained by ultrasound; PSA density was calculated and demonstrated to be significantly different among those with and without cancer.¹ Novel high-resolution micro-US has significantly optimized the diagnostic capabilities for PCa. The OPTIMUM trial is ongoing, which has randomized 3 cohorts into micro-US-only biopsy, MRI/micro-US “FusionVu” biopsy, and MRI/US biopsy with conventional fusion system.²

Transperineal prostate biopsy has gained traction over the last 5-10 years with advantages including lower rates of infection and, especially in larger glands, optimized anterior prostatic cancer detection.³ The Figure simplifies the overarching pathways in modern prostate biopsy.

Figure. Nuances in the contemporary prostate cancer diagnostic algorithm. MRI indicates magnetic resonance imaging; PSA, prostate-specific antigen; TRUS, transrectal ultrasound–guided.

Pros for performing TRUS-guided biopsy include broad familiarity among all urologists, optimized sampling of the peripheral zone, facility, efficiency, and commonality in performing under local anesthesia. The increased risk of sepsis relative to transperineal biopsy is well documented; however, this can be minimized through approaches including rectal swabs to identify antibiotic resistance, periprocedural antibiotics, and augmented antibiotic prophylaxis at the time of biopsy. Transperineal biopsy has gained significant momentum; however, limitations include lack of familiarity with all urologists, especially with regard to comfort performing the procedure under local anesthesia, increased cost, decreased efficiency, and perhaps an increased risk of urinary retention post-biopsy.⁴ We have found that there seems to be a steeper learning curve in transperineal biopsy relative to transrectal biopsy, particularly among urology trainees. Taking all the available data, both approaches are viable and the decision to proceed will depend on clinical factors, patient-related factors, and surgeon experience. A strong niche for transperineal biopsy in our practice includes persistently elevated PSA with prior negative transrectal biopsy, large prostate with inability to access the anterior prostate via transrectal biopsy, in those with anterior lesions on MRI to be targeted, and in confirmatory biopsy for patients who elect active surveillance for PCa 12-18 months from initial biopsy.

MRI

MRI has become an important adjunct to the workup of PCa. Studies including PROMIS and PRECISION have helped clarify the ideal utility of MRI in PCa diagnosis. In PROMIS, the concept of pre-biopsy screening MRI was evaluated and found to be of value; the authors suggested that approximately 27% of patients could defer biopsy in the setting of a negative MRI. While the sensitivity for detection of Grade Group 2 PCa was 88% (range 84%-91%), it is important to consider the negative predictive value was 76% (69%-82%).⁵ While a negative MRI can be reassuring to patients and urologists alike, a negative MRI should be interpreted with caution and biopsy should still be advised with shared decision-making. PRECISION demonstrated superior diagnosis of clinically significant prostate cancer (csPCa) in those who underwent MRI prior to biopsy with MRI-targeted biopsies obtained vs standard 12-core TRUS prostate biopsy. Lower rates of clinically insignificant PCa were detected via this modality and optimization of positive core identification was noted.⁶ The PRIME study (NCT04571840) has been proposed to clarify detection of csPCA with biparametric MRI (T2 weighted and diffusion weighted, no dynamic contrast enhanced [DCE]) vs standard multiparametric magnetic resonance imaging (mpMRI) to assess whether IV contrast is required for prostate MRI. Patients will undergo standard mpMRI; however, radiologists will be blinded to the DCE phase. Biopsies in both biparametric MRI and mpMRI will undergo MRI-targeted prostate biopsies and the primary outcome will be proportion of men with csPCa. Benefits of deferring DCE would include faster MRI and risk mitigation of allergic and other contrast-related reactions.⁷

Pre-biopsy MRI in our practice is utilized primarily in patients with elevated PSA (<10 ng/mL) with negative DRE and clinical suspicion for PCa prior to biopsy. In patients with a palpable nodule and clinical concern for PCa we find it logical to proceed with transrectal prostate biopsy directly in most cases to optimize efficiency in diagnosis. We routinely favor cognitive fusion transrectal and transperineal prostate biopsy for larger lesions, predominantly peripheral zone lesions, and palpable lesions to improve diagnostic efficiency and avoid a backlog for software-assisted MRI/US fusion. We typically reserve software-assisted grid-based transperineal fusion biopsy for patients with small anterior lesions in large prostates that would otherwise be quite challenging to localize with cognitive fusion alone. In our practice, TRUS-guided biopsy is generally performed under local anesthesia, whereas transperineal biopsy is performed under general anesthesia to optimize patient comfort.

Biomarkers

Adjunct tests including tissue, blood, and urine-based assays have been developed for clinical practice (see Table).⁸ Tissue-based tests utilize multigene footprints and can be used to risk stratify patients diagnosed with low- and intermediate-risk PCa, especially those considering additional information to decide on active surveillance or radical treatment. Head-to-head comparisons for tissue- and blood-based tests are lacking, however, and their utility is nuanced.

Artificial Intelligence

Artificial Intelligence (AI) is developing at a swift pace. AI applications have been applied to mpMRI to assist radiologists in assigning a PI-RADS (Prostate Imaging–Reporting and Data System) score and have shown promise previously for detection of suspicious lesions in the peripheral zone.⁹ In prostate histopathology, AI models with acceptable accuracy may have a role in minimizing inter-rater variability and improving diagnostics, reducing cost, and improving efficiency.¹⁰

We have come a long way from the early days of open incisional prostate biopsy based solely on DRE. We look forward to continued technological improvements as we continue to push for optimized diagnostic precision in men at risk for PCa.