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In a pattern consistent with the worldwide trend toward choosing extended over non-extended prostate biopsy methods, transrectal 12-core prostate biopsy (TR12PBx) is currently one of the most preferred biopsy methods for detecting prostate cancers. A systematic review of prostate biopsy methods noted that TR12PBx strikes a satisfactory balance with sufficiently high rates of cancer detection and sufficiently low rates of biopsy-associated comorbidity, and that taking more than 12 cores adds no significant benefit . TR12PBx also meets the criteria for initial biopsy provided by the representative clinical guidelines [2,3]. Yet several studies have reported that repeat biopsy after negative initial extended transrectal biopsy detects prostate cancer in 17–21% of men [4–6], suggesting that these initial extended transrectal biopsies may miss a substantial number of cancers.
To clarify the incidence and clinical importance of cancers missed by TR12PBx, it is necessary to analyze the results obtained using biopsy protocols that include not only all of the TR12PBx sampling sites, but also additional sampling sites. To the best of our knowledge, there are currently three biopsy protocols that meet these requirements. The first is three-dimensional 26-core prostate biopsy (3D26PBx), a combination of transperineal 14-core prostate biopsy (TP14PBx) and TR12PBx (Fig. 1), introduced by our group [7–9]. In a previous analysis of 321 men examined through 3D26PBx, we reported that 3D26PBx increased cancer detection by 24% compared to TR12PBx . The second is transrectal 21-core biopsy . The transrectal 21-core biopsy can detect significantly more cancers (increased detection of 9.8%) than the TR12PBx. The third is transrectal 14-core biopsy (TR12PBx plus two extreme anterior apical biopsy sites) . The addition of only two extreme anterior apical sampling sites to TR12PBx increased the cancer detection rate by 7.5%. Although these studies mainly focused on cancer detectability, characteristics of cancers missed by TR12PBx have not been fully assessed to date.
Figure 1. Transverse, sagittal and coronal projections of three-dimensional 26-core prostate biopsy (3D26PBx), a combination of transperineal 14-core prostate biopsy (TP14PBx) and transrectal 12-core prostate biopsy (TR12PBx). The sampling sites are named: anterior 1 (A1), anterior 2 (A2), posterior 1 (P1), posterior 2 (P2), anterolateral (AL), posterolateral (PL) and transition zone (TZ) in TP14PBx; parasagittal apex (pa), parasagittal midprostate (pm), parasagittal base (pb), lateral apex (la), lateral midprostate (lm) and lateral base (lb) in TR12PBx.
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When a patient undergoes an initial TR12PBx and the result is negative for cancer, how much risk does he have for a clinically important cancer that is missed? What are characteristics of the cancers missed by TR12PBx? To address these questions, we evaluated the characteristics of cancers that were detected or missed by TR12PBx in a cohort of 715 men undergoing 3D26PBx.
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In the present study, we evaluated the characteristics of cancers missed by initial TR12PBx, more precisely, cancers missed by TR12PBx in patients who underwent 3D26PBx (TR12-negative cancers), and thus showed the diagnostic performance of TR12PBx. Initial TR12PBx missed 21% of cancers that were detectable through 3D26PBx; however, it should be noted that more than half of TR12-negative cancers had a biopsy GS ≤6, and most of them had a biopsy primary Gleason grade ≤3. Furthermore, the median number of positive cores in TR12-negative cancers was only two out of 26, suggesting that a substantial number of TR12-negative cancers can be expected to be low-grade and low-volume diseases.
Although our RP cohort is highly selective, most TR12-negative cancers treated with RP were significant cancers. Yet 87% were organ-confined disease and 75% were primary Gleason grade 3 cancers with favourable prognosis. Combined with the biopsy findings, this indicates that TR12-negative cancers have lower malignant potential than TR12-positive cancers, and that most of them can be expected to be organ confined, although a small number of TR12-negative cancers appear to be significant cancers that would exhibit biological aggressiveness.
The characteristics of the location of TR12-negative cancers are clearly shown in the present study. Our analysis of positive transperineal sites in TR12-negative cancers confirmed that TR12-negative cancers were located in the anterior portion of the gland rather than the posterior portion. The cancer location of TR12-negative cancers in RP specimens also supports this notion, suggesting that TR12PBx would be insufficient to detect anterior cancers. The results obtained in the present study are similar to those obtained by Moussa et al., who reported that the addition of only two extreme anterior apical cores to TR12PBx transrectal sampling improved cancer detection by 7.5% and that these two cores achieved the highest rate of unique cancer detection. They therefore introduced the 14-core biopsy scheme (TR12PBx biopsy plus two extreme apical cores) as an initial biopsy to detect more anterior apical cancers.
On the basis of these findings, simply adding more transrectal sampling sites from the bottom of the prostate gland to TR12PBx would not increase its cancer detection rate efficiently. Indeed, several studies have tested transrectal extended biopsy methods using more than 12 cores; however, most of these so-called ‘saturation’ transrectal biopsy protocols did not outperform TR12PBx [17–19]. The transrectal 21-core biopsy  can identify more cancers than TR12PBx can, although the 9.8% increase in cancer detection that results from the nine additional samplings appears to be inefficient. In the present study, the addition of two far-anterior transperineal sampling to the TR12PBx improved its cancer detection rate by 11%. From these results, we consider that a few additional samplings in the anterior apical portion are effective for detecting cancers missed by TR12PBx.
In recent analyses on men with a PSA level <20 ng/mL without locally advanced tumours on DRE findings, there were no significant differences among subgroups defined by age, PSA level, prostate volume or DRE in the incidence of TR12-negative cancers. Therefore, we could not identify any subgroup in which TR12PBx would be entirely insufficient for cancer detection and in which more sampling would therefore be needed. There is the potential concern that TR12PBx may probably miss anterior aggressive cancers in men with normal DRE, although our analysis of cancer characteristics according to DRE findings shows that a large proportion of TR12-negative cancers probably consist of low-grade and low-volume disease, regardless of DRE findings. We consider that these results are sufficient grounds to eliminate such concerns.
Recently, the value of MRI for detecting prostate cancers and determining their location has been extensively studied . Lawrentschuk et al. retrospectively analyzed patients with anteriorly predominant tumours on MRI who had undergone prostate biopsy and reported that MRI would be useful in the detection of anterior tumours that are difficult to detect using transrectal biopsy. It appears that MRI is a promising tool for detecting anterior cancers, although its cost is high.
Pathological evaluation in the present study is based on the 2005 International Society of Urologic Pathology Consensus [13,14]. Fused glands, ill-defined glands with poorly formed glandular lumina and most of the cribriforms are previously categorized into Gleason pattern 3 but, in the 2005 consensus, are categorized into Gleason pattern 4. Furthermore, two new modifications to the Gleason scoring system are recommended in the evaluation of biopsy specimens. One is that any high-grade pattern, no matter how small quantitatively, should be incorporated into the GS, although any secondary grade that occupies <5% of the specimen would not have been reported under the previous system. The other modification is that all higher tertiary grade components of the tumour, which were previously ignored, should be incorporated into the GS. Accordingly, the rates of high-grade patterns scored according to the 2005 consensus are higher than those scored under the previous system. This phenomenon has been confirmed in a study by Billis et al. showing that GS that had been scored under the previous system were upgraded by re-evaluation under the 2005 consensus in 26.7% of the biopsy specimens. Similarly, the GS of some of the patients in the present study would have been lower if they had been evaluated under the previous system. We consider that these findings strengthen our view that many TR12-negative cancers can be expected to be low-grade diseases.
The present study does not indicate that we should aim to actively detect TR12-negative cancers in all candidates for initial prostate biopsy because a substantial number of TR12-negative cancers are low-grade and low-volume diseases. Overdiagnosis and overtreatment are now issues of major concern in the management of prostate cancer. Draisma et al. have reported that the rate of overdiagnosis of prostate cancer has been estimated at 23–66% of screening-detected cancers. The main purpose of prostate biopsy is not only to detect more prostate cancers, but also to detect more life-threatening cancers. Even if we missed a case of prostate cancer at an initial biopsy, we would be able to determine the need for a repeat biopsy through the PSA test in most cases, and most cancers detected by repeat biopsy are manageable and not life-threatening . If the goal of screening were simply to detect life-threatening cancers, the addition of sampling sites to the TR12PBx protocol would not be essential in all candidates for initial biopsy.
Another important purpose of biopsy, however, is to accurately characterize any tumours to allow for a more informed treatment decision-making process. If a custom treatment is to be devised for each individual patient, more sampling is required to generate more information, although more sampling leads to a greater detection of indolent cancers. This clinical dilemma makes it difficult to determine the optimal biopsy scheme. We now consider that the addition of anterior sampling sites to the initial TR12PBx would be a reasonable option for younger men with a long life expectancy or for men with suspected anterior cancer as assessed by MRI. On the basis of the analysis in subgroups divided by DRE findings, the finding that a DRE was normal does not mean that additional sampling of the anterior prostate should be performed. At repeat biopsy after negative TR12PBx, however, anterior samplings are highly recommended.
The present study has several limitations that should be considered. Given that 3D26PBx does not identify all cancers, it is possible that TP12PBx may fail to detect an even greater percentage of cancers than reported in the present study. We recommend transperineal sampling for the detection of TR12-negative cancers, although we realize that the transperineal approach may be unfamiliar to many urologists. A recently reported technique for simple and effective local anaesthesia would render transperineal extended biopsy more feasible . Furthermore, because of the limited duration of the follow-up in the present study, we could not report the oncological outcome of TR12-negative cancers. Long-term observation will be required to acquire a better understanding of the diagnostic performance of TR12PBx.
In conclusion, TR12PBx missed 21% of cancers that were detected by 3D26PBx on initial biopsy. Although many of the undetected cancers were expected to be low-grade and low-volume diseases, it should be noted that the initial TR12PBx has a small but definite risk of missing anterior significant cancers.