The role of PSA as a cancer screening tool has recently been evaluated by several large high profile studies with varying interpretations of the data.

Regardless of where one stands on the debate, among the clinical dilemmas of PSA-based screening is the negative biopsy conundrum where the reality remains that the best one can offer is,  “Good news Mr. Smith, I don’t think you have prostate cancer.”

Although a number of statistical models and nomograms exist to help objectify and predict the risk for finding cancer on re-biopsy based on demographics, prostate size, PSA, and number of biopsies, none truly captures the angst of both physician and patient or is able to adequately objectify a clinical endpoint (when have you looked “enough”).

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In this issue, J. Stephen Jones, MD, Cleveland Clinic, presents an outstanding comprehensive and practical review of the topic in which he notes that of the more than one million men in the United States who undergo a prostate biopsy every year, the dilemma of a PSA-prompted negative biopsy will befall more than half.

He points out that, indeed, men with a negative biopsy are a heterogeneous group and the first step in managing a patient such a patient is to determine whether the biopsy was truly “negative” (no high-grade prostatic intraepithelial neoplasia [HGPIN] or atypical small acinar proliferation [atypia]).  

Dr. Jones presents data to demonstrate that patients with atypia have an almost automatic indication to perform repeat biopsy, while patients with HGPIN merit delayed interval biopsy approximately every three years if healthy enough to justify treating a cancer if found. Otherwise, it is uncommon that patients without these pathological findings would benefit from more than two total biopsies in the absence of major change in PSA or DRE findings.

While other modalities intended to eliminate unnecessary biopsies, such as magnetic resonance imaging, PCA3 testing, and template biopsies are promising, none has been validated to date. Moreover Dr. Jones notes that medical management with antibiotics should be limited to the setting of infection, while the use of 5-alpha reductase inhibitors may improve cancer detection rates particularly if they fail to cause a 40%-50% decrease in PSA.

When a decision leads to repeat biopsy, Dr. Jones recommends using a 20-core transrectal saturation biopsy in the office setting under periprosatic block (based on higher cancer detection rates than a standard 12-core biopsy without incurring additional cost or demonstrable risk).

While clinicians can never fully manage uncertainty, they can estimate risk and provide appropriate objective counsel.  Such is the case for the negative prostate biopsy.  Clinicians “never say never,” but with objectification and risk stratification, they can often say “enough is enough.”

Robert G. Uzzo, MD, FACS, holds G. Willing “Wing” Pepper Chair in Cancer Research and is Professor and Chairman, Department of Surgery at Fox Chase Cancer Center, Temple University School of Medicine, Philadelphia