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Most men who undergo prostate biopsy will not be found to have cancer. Nevertheless, a significant number of those men may harbor cancer that was simply not identified during biopsy because the biopsy needle missed its location.

It is widely assumed that rising PSA following a negative prostate biopsy is more likely to indicate cancer, so this is the most common indication for repeat biopsy. By contrast, most men with stable PSA levels are more often observed without further investigation.

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However, no data support that approach, and multiple studies indicate that approximately one fourth of all patients undergoing a second biopsy will be found to have prostate cancer (PCa). There is no consensus on how to manage this heterogeneous growing population, so this article addresses the issues that must be understood to navigate the scenario posed by patients that have had a prior negative biopsy.

Although missing small low-grade cancers might actually allow the patient to avoid unnecessary treatment, many of these cancers are early high-grade tumors. Identification of these tumors may offer the ideal scenario for curative therapy. 1

Patients most likely to have unrecognized cancer are those who underwent inadequate biopsy strategies or had pathologies associated with underlying cancer, such as high-grade prostatic intraepithelial neoplasia (HGPIN) or atypia, begging the question of what one means by the term “negative biopsy.” For the purposes of this report, any initial biopsy that failed to identify malignancy will be regarded as negative, recognizing that HGPIN and atypia fall into that definition, and although negative for malignancy, cannot be equated to benignity.

The likelihood of prostate cancer unrecognized during initial biopsy

Aggregate data on the number of prostate biopsies performed in the United States are incomplete, but it is often stated that more than one million are performed annually.

Considering that most studies of modern extended biopsies identify cancer in 40%-50% of initial biopsies, there are reasonably more than one half million new cases each year of men with negative prostate biopsies. In addition, repeat biopsies identify cancer in approximately 25% of these men, so one might reason that once a negative biopsy is confirmed, the same percentage of these men harbor unrecognized cancer, whereas the remainder have no malignancy but are at risk of unnecessary biopsy and its attendant low but real hazards. 

Systematic prostate biopsy emerged in 1989 when Hodge and Stamey reported on the efficacy of transrectal ultrasound (TRUS)-guided biopsies compared with those performed in a directed fashion based on digital rectal examination findings. 2,3

Their original “sextant” (six cores) biopsies were directed at the parasagittal location midway between the lateral border and the midline of the prostate, which Stamey observed would detect most cancers of the significant size that they were identifying in radical prostatectomy specimens.

Importantly, this occurred early in the PSA era, when most known tumors were significantly larger than those encountered most commonly in recent experience. Subsequent studies have shown that sextant biopsy in the current era misses up to half of all small tumors and up to one third of tumors eventually detected even using repeat sextant biopsy. 4,5

As a result, extended biopsy techniques that obtain 8-14 cores have become the standard of care, and it is difficult to justify use of sextant biopsy at this time. Nevertheless, even these extended biopsy schemes can miss up to half of small tumors, most of which probably have limited potential clinical impact. 6 Thus, large numbers of men harbor PCa despite a negative biopsy. If it is low grade, the risk of progression is probably negligible, but small high-grade tumors carry significant risk, and identifying tumors that can be fatal if advanced—but curable if treated early—may be the ideal target of PCa screening.

Significant bias exists among urologists that PSA dynamics after a negative biopsy should drive the decision for repeat biopsy. However, there is little if any justification of this principle in the literature.

The Prostate Cancer Prevention Trial risk calculator has shown that there is a substantial risk of positive biopsy following one prior negative biopsy regardless of PSA dynamics, 7 although our group has reported that this risk calculator does not maintain its predictive accuracy as well in current clinical practice later in the PSA era, when biopsy is performed with extended, instead of sextant, biopsy. 8

It is important to recognize that men with persistently high PSA following prostate biopsy may harbor unrecognized and potentially harmful PCa, so having a low threshold to perform at least one repeat biopsy is in order. This report considers approaches to optimize detection of high-grade tumors while trying to minimize the use of unnecessary biopsy.

It is possible to identify characteristics suggestive of unrecognized PCa. The most obvious is if the patient underwent initial sextant biopsy. Presti showed that these patients have an approximately 40% risk of a positive second biopsy, which is notably almost as high as modern series of patients that undergo initial biopsy. 9

Extended prostate biopsy schemes

Eskew and McCullough were the first to report superior cancer detection with an extended prostate biopsy scheme. 10 In 2000, Presti et al prospectively determined that sextant biopsies alone were inadequate because 20% of cancers were missed. 11

They recommended an eight-core biopsy protocol using a combination of parasagittal and lateral biopsies along with lesion-directed biopsies and anterior biopsies. Gore et al evaluated the optimal combinations of biopsies using a 12-core biopsy protocol. 12 For patients undergoing initial biopsy, a sextant protocol picked up only 71% of the cancers that were detected with their 12-core biopsy regimen consisting of a sextant plus lateral mid, base, and apex biopsies. Of note, the 12-core biopsy regimen outperformed the best combination of eight-core biopsies.

In a large, multi-institution study of community urologists involving 2,299 patients undergoing 12-core biopsy, the overall cancer detection rate was 44%, which is similar to the results of most single-institution academic centers when extended biopsy is applied. 13 As a result of these studies, most authorities recommend a minimum of 12 cores be obtained during initial biopsy.

Counterintuitively, extended biopsy protocols do not result in increased complications. Berger and colleagues compared complication rates between 6-, 10-, and 15-core biopsy protocols. 14 Their study resulted in no difference in major complications (fever, prostatitis, epididymitis, or urinary retention), although there was an increased number of patients with hematospermia after 10- and 15-core biopsies. We, too, have found that patients undergoing saturation biopsy do not have increased complications compared with routine biopsy (data in press).