Editorial Comment to Prostate cancer detection after a negative prostate biopsy: Lessons learnt in the Cleveland Clinic experience


Prediction of prostate cancer (PCa) after a negative initial prostate biopsy (PBx) is imperative in counseling with patients to pursue further PBx. Although patient anxiety about the possibility of PCa is common, it is still difficult to make the recommendation for repeat PBx. Digital rectal exam findings, repeated prostate-specific antigen (PSA) measurements (such as free PSA percentage, complex PSA, PSA density, PSA velocity) and suspicious histological findings, such as atypical small acinar proliferation (ASAP) and high-grade prostatic intraepithelial neoplasia (HGPIN), have historically been considered good risk indicators1 for PCa.

In this study, Zaytoun et al.2 recommended the following three additional measures to assist in the decision-making process for PBx patients, based on experience from the Cleveland Clinic and supported by a Medline literature search.

  • 1The 14-core PBx protocol including the critical area of the apex is recommended for use at the first PBx to maximally optimize the yield.
  • 2There is no defined cut-off value of PSA to indicate repeat PBx and no single PSA-derived index is adequate; however, a free PSA percentage cut-off of 11% and a PSA velocity of more than 0.75 are valuable clinical indicators.
  • 3Multifocal HGPIN, but not focal HGPIN, is associated with a significantly higher risk of PCa, but only the presence of ASAP is strongly recommended for repeat PBx within 3–6 months.

As the authors address in this well-organized review article, we should consider these recommendations as one of the guidelines. Although the authors recommend a 14-core protocol using the standard 12-core biopsy scheme plus two additional cores taken from the extreme anterior apex, the optimal number of cores is still controversial.3 Ravery et al.4 and Guichard et al.5 showed the superiority of a transrectal 20- or 21-core PBx over the conventional transrectal 12-core PBx in 1491 and 1000 patients, respectively. Conversely, Pepe et al.6 and Jones et al.7 noted that a transrectal protocol above 24-core offered no advantage over a 12-core PBx. Similarly, the limits of free PSA percentage or PSA velocity as indicators are still controversial, which the authors have addressed in the text. However, attention should be paid to ASAP. Zhou et al.8 showed that 122 out of 239 (51.0%) ASAP patients diagnosed at initial PBx were found to have PCa after repeat PBx. A total of 53 out of the 122 PCa patients were analyzed and 37 (69.8%) were found to have pathologically significant cancer. Just 14 were potentially pathologically insignificant (Gleason score below 6, tumor volume < 0.5 mL, organ confined).

It is also very important to decide whether a third or fourth PBx should be carried out in patients in whom the second PBx samples were negative for PCa. In a prospective European study,9 1051 men underwent PBx every 6–8 weeks. Cancer detection rates on third and fourth biopsies were just 5% (36/737) and 4% (4/94), respectively; therefore, third and fourth biopsies should only be carried out in high-risk men. Although the authors presented a directive for prescribing repeat PBx, further analysis will still be needed for determining when further biopsies should be considered.