—  SHORT COURSE #13  —

Interpretation of Prostate Needle Biopsies

Case 1 - Sampling Considerations in Prostate Needle Biopsies

Rajal Shah and Ming Zhou


Case 1:
A 51-year-old African American men had a serum PSA 4.5 ng/ml in June 2004. The patient underwent a sextant biopsy, which revealed multifocal HGPIN. After 6 months, he underwent a repeat biopsy with an "extended biopsy template" of 12 cores with a diagnosis of prostate adenocarcinoma, Gleason score 3+4=7.

Contemporary Needle Biopsy Sampling Considerations in the Diagnosis of Prostate Cancer

Recent changes in the pathological parameters of prostate cancer in PSA screening era
The profile of newly detected prostate cancer has significantly changed due to wide spread utilization of PSA testing after its introduction in the late 1980s [1]. The "stage shift" has been the most remarkable change, with a steady trend of detecting and treating earlier stage, smaller volume disease in younger and healthier men [1]. The diagnosis of prostate cancer now is mostly triggered by an abnormal/rising PSA. This is reflected in the incidence of non-palpable cancers (stage T1C), which has increased in proportion by seven-fold between 1988 and 1996, from 10% to 73% of all cancers detected [2].

The traditional sextant biopsy
The evolution of prostate biopsies has rapidly changed over the past several years. In 1989, the sextant prostate biopsy was introduced and rapidly became the standard over directed biopsies of hypoechoic lesions and palpable nodules [3]. This technique has dominated the earlier phase of PSA era as the primary sampling approach for the prostate cancer detection. This technique primarily utilizes paramedian (parasagittal) plane sampling approach directed towards base, mid and apex portion of the prostate bilaterally (Fig 1 and 2A). Little was done regarding the refinement of this technique until, recently Stamey suggested moving the biopsies more laterally to better sample the anterior horns of peripheral zone [4]. This recommendation was supported by the zonal anatomy of the prostate as well as origin of the tumor [5]. It became clear that the majority of prostate cancers (approximately 80%) originated in the peripheral zone and thus some investigators began exploring alternative systemic biopsy schemes to more extensively sample the peripheral zone and thus improve the cancer detection rate. As with any situation that involves sampling, the possibility of sampling error exists. This notion was supported in prostate biopsy series by a study demonstrating an inverse relationship between prostate gland size and cancer detection rates as determined by sextant biopsies [6].

Fig 1: Sextant Biopsy Approach:



Fig 2A and B: Cross section of prostate with A= Paramedian sextant approach and B=laterally directed biopsy approach for extended scheme, TZ= Transition Zone, PZ=Peripheral Zone

In recent years, it has become increasingly evident that the sextant biopsies could miss up to 30% of cancers [7, 8]. Daneshgari et al in a computer simulation model suggested that sextant biopsies, although an improvement, would still miss many cancers as only 20% of prostates had a tumor distribution which would be detected with the paramedian template, which is utilized by the sextant approach [9]. Furthermore, other investigators have demonstrated that sextant protocol in particular tends to under-sample certain areas of the prostate such as "anterior horns" and the lateral aspects of the peripheral zone, where majority of prostate cancer are distributed [10, 11, 12]. Furthermore, small tumors seem to concentrate more along the sub capsular distribution along the dorsolateral part of prostate [13, 14].

Contemporary sampling approaches:

1) Extended Biopsy template
Based upon these observations, others have advocated the use of an extended pattern technique at initial prostate biopsy in order to further increase the likelihood of detecting cancer. Extended biopsy pattern is typically defined as essentially a sextant template, with at least four additional cores from the lateral peripheral zone (Fig 2B), and also biopsies directed to lesions found on palpation or imaging [15]. Eskew et al first advocated an extended pattern, finding a statistically significant advantage (35% greater detection) with the additional cores of a 5 region biopsy [16, 17]. Of note, their template also included three biopsies from the midline at the apex, mid-gland and base besides four laterally directed biopsies, however only few cancers were detected by 3 centrally placed biopsies. With their 11 site pattern technique, Babaian et al detected 31% more cancers at initial biopsy compared to the sextant biopsy approach [18]. Their template included additional cores from the midline, transitional zones, and two cores from the anterior horns.

More recently, Gore et al evaluated a 12-core biopsy scheme in 396 patients, of which 67% were first time biopsy patients [19]. A standard sextant scheme was combined with a laterally directed sextant scheme at the apex, mid and base bilaterally. The cancer detection in this group was 42%. Standard sextant biopsy would have detected only 71% of the cancers and importantly, the lateral sextant biopsy scheme along with the apical and base biopsies from the standard sextant scheme detected all of the cancers in this subgroup.

We have utilized extended biopsy technique as the initial prostate biopsy approach to demonstrate its significance for detection of overall and clinically significant cancers [15]. When potential confounding factors were adjusted, the final multivariable regression models demonstrated a significant independent effect of an extended pattern biopsy at initial setting with an overall odds ratio of cancer detection of 1.55 (C.I. 1.09-2.19). To put this finding in clinical context, the Number Needed to Treat (NNTT) based on the final models were derived. For every 10 extended pattern prostate biopsies performed, one additional cancer was detected.

Comparison of various biopsy approaches
Presti et al retrospectively simulated various extended biopsy schemes and then compared to the "gold-standard" 12-biopsy scheme (assuming it detects 100% of the cancers in the population). Following rates were observed for various approaches as shown in figure 3 [20]. They concluded that the optimal biopsy scheme for initial biopsy patients is at least 10-core scheme as shown in last scheme of figure 3.

Figure 3


Significance of prostate cancer detected in extended template
The goal of the prostate biopsy is to detect clinically significant cancers. Critics of the extended prostate biopsy approach have used the theoretical argument that more clinically insignificant cancers must, by definition, be detected using extended biopsy approach. However, no studies have substantiated this argument. Eskew et al found that increased sampling of the prostate through extended biopsy techniques does not increase the detection of potentially insignificant tumors; however it appears to detect earlier stage cancer [17]. Similarly, in our recent study, we have demonstrated that use of extended biopsy was not found to be associated with increased detection of clinically "insignificant" cancers [15, 21]

Significance of HGPIN and Atypical small acinar proliferation (ASAP) in extended biopsy practice
Moore et al addressed the prognostic significance of HGPIN and ASAP in the contemporary needle biopsy setting. Based on their results, the significance of HGPIN as a predictive marker for prostate cancer in repeat biopsy in the contemporary setting appears to be significantly less but the significance of ASAP continues to be associated with a high risk of cancer. They concluded that patients diagnosed with HGPIN in the initial extended biopsy setting may not warrant a repeat biopsy [22]. This issue is further addressed in detail in the later sections of PIN and ASAP.

Effect of extended biopsy approach on the Gleason grading of the prostate cancer
Recent studies have suggested that utilization of an extended biopsy sampling approach improves the correlation between the biopsy and radical prostatectomy Gleason grading [30]. It has also been demonstrated to improve the reliability of biopsy Gleason grade in the setting of patients receiving radiation therapy [31].

2) Saturation biopsy technique for repeat biopsy approach
Saturation biopsy is an uncommon extensive sampling approach, which is utilized in subsets of patients with high index of clinical suspicion in which previous attempts are not diagnostic. Under anesthesia a mean of 23 (range 14 to 45) saturation cores are obtained. Using an inward radial step approach, prostates are biopsied starting at far lateral peripheral zone (anterior horn) and continuing until the mid gland is reached. The process is repeated contra lateral side.

Stewart et al used this approach to evaluate 224 patients who previously had negative sextant biopsy results and persistent indications for repeat biopsy. Interestingly, 34% of patients were found to have cancer with this technique [23]. They did not specify in which locations cancer was ultimately detected within the prostate gland. This result compares to 38.4% of patients who had previously undergone sextant biopsy who were found to have prostate cancer on repeat biopsy using the 5-region technique [24]. Therefore, this approach appears to have only limited advantages in situations were initial approach is sextant biopsy.

Saturation biopsies are also now increasingly utilized for patients with an initial biopsy diagnosis of microfocal adenocarcinoma of ≤6, who are considering active surveillance treatment option. This management option remains viable if there is no high grade component. Interestingly, in a study performed by Boccon et al, 68% of patients with microfocal Gleason 6 prostate cancer at initial extended biopsy were upgraded to a clinically significant cancer at repeat saturation biopsy suggesting that even contemporary extended biopsy practice may not be sufficient to detect all cancers, specifically located anteriorly [32].

3) The role of transition zone biopsies
Although approximately 20% of prostate cancers originate in transition zone (anterior prostate), isolated transition zone tumors detected on prostate biopsy are uncommon. The addition of transition zone biopsies to the initial biopsy strategy increases detection rates by only 1.8% to 4.3%, and there are few data to support the recommendation for routine transition zone sampling [25, 26, 27]. However, in men undergoing repeat biopsy the yield of malignancy from the transition zone is higher, ranging from 10% to 13% [28, 29]. Thus, the transition zone biopsies may be indicated in patients in whom initial biopsies fail to reveal cancer but PSA continues to increase.

Summary
In conclusion, there is clearly a trend toward extended biopsy approach to improve the detection of cancer. Ten to 12-core schemes is optimal in majority of initial and repeat biopsy patients. This biopsy schemes are heavily weighted towards the lateral aspect and the apex of the prostate to maximize peripheral zone sampling. The use of "saturation" biopsy appears to be limited in subset of patients with high index of clinical suspicion in which previous attempts, particularly sextant approach are not diagnostic. Most of the studies conclude that cancers detected by such approach are clinically significant, though there is trend for detecting them at low volume and at earlier stage.

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