Do Biopsies of the Transition Zone Impact Prostate Cancer Treatment Planning?

Contemporary prostate biopsy series have demonstrated the prevalence of dominate anterior-based malignant lesions including those of the transition zone (TZ) [1-4]. Prostate cancer involves the TZ in up to 60% of cases [5]. TZ cancers are difficult to detect by Digital Rectal Examination (DRE) and often poorly visualized on imaging studies [6]. Overall, trans rectal ultrasound guided needle biopsies directed at the transition zone increase the detection of prostate cancer by only 1.5 – 13% [7]. In addition, the reliability of TZ detected Trans rectal ultrasound guided needle biopsies has been called into question [6]. Hearer and colleagues reported that 40% of patients with trans rectal biopsy diagnosed TZ cancers did not have TZ cancer at the time of radical prostatectomy (RP) [6]. Individual variability in peripheral zone tissue volume, the presence and extent of benign prostatic hyperplasia (BPH) and relative resistance of the TZ to needle penetration may affect the ability to accurately sample the TZ. [6]. 

The diagnosis of anterior prostate cancer malignancies is often difficult due to the posterior approach of Trans Rectal Ultrasound (TRUS) guided needle biopsies. Transperineal Template-guided Mapping Biopsy (TTMB) techniques have emerged to address the potential shortcoming of TRUS biopsies [8-10]. Advantages of transperineal biopsy techniques include the ability to systematically map the gland and provide more accurate information regarding prostate cancer grade, volume and spatial distribution of cancer and decrease the infectious morbidity of TRUS biopsy. TTMB has been demonstrated to accurately identify high-grade cancers when compared to whole-mount Radical Prostatectomy (RP) pathology [11]. The majority of clinically significant prostate cancers missed at TRUS biopsy are located in the anterior prostate with Gleason score upgrading in approximately 39% of patients [1,2,8]. 

Although the presence of TZ malignancies are common, malignancies exclusively restricted to the TZ are noted in only 2-5% of cases [3,13]. In this study, we evaluate whether biopsy of the TZ provides information regarding Gleason score upgrading which may influence prostate cancer treatment decisions.

From January 2005 – June 2012, 1,230 consecutive patients underwent TTMB for an elevated PSA or following a negative TRUS biopsy for a persistently elevated PSA and/or the presence of Atypical Small Acinar Proliferation (ASAP) or High-Grade Prostatic Intraepithelial Neoplasia (HGPIN). TTMB was performed via an anatomic technique with sampling of 24 regional biopsy regions performed by a single operative (GSM) [8, 9]. 

Two days prior to TTMB, tamulosin (0.8mg) was initiated and continued for two weeks. TTMB was performed in the operating room in the dorsal lithotomy position under general anesthesia. All patients received peri operative antibiotics. The prostate gland was scanned from the proximal seminal vesicles/base of the prostate gland to the apex using the 5.0-7.5MHz transducer. A volumetric ultrasonographic evaluation was obtained to determine prostate size. In addition, the prostate gland and TZ volumes were estimated as an ellipsoid with the formula: length x width x height x π/6. Transperineal biopsies were obtained through template apertures corresponding to the 24 regional biopsy locations [8, 9]. For each of the 24 regions, as many as 4 biopsy cores were taken depending on prostate size. Eighteen gauge, 25cm long Max-Core biopsy needles (C.R. Bard Inc., Covington, GA, USA) were used. For each biopsy core, the template coordinate and the offset from the base were recorded. Biopsies were taken to sample the entire gland including the TZ (sites 7, 8, 17, 18), the posterior (sites 3, 4, 12, 13, 21, 22), posterior lateral (sites 2, 5, 11, 14, 20, 23), anterior lateral (sites 1, 6, 9, 10, 15, 16) and anterior apex (sites 19, 24). All pathologic assessment was performed by a pathologist with significant expertise in prostate pathology (EA). 

For each patient, the location of each positive biopsy core, the number of positive cores, the percentage involvement of each core and the presence/absence of perineural invasion was recorded. Evaluated predictors for TZ Gleason score upgrading included age, PSA, body mass index (BMI), number of TRUS biopsies and cores, prostate volume, transition zone volume, PSA density (PSAD=PSA/prostate volume), transition zone PSA density (TZPSAD=PSA/TZ volume), Transition Zone Index (TZI=transition zone volume/prostate volume), total number of TTMB cores, hypertension and TURP.  

Independent sample t-tests, one-way analysis of variance and 2-sided Pearson chi-square tests were applied to the clinical and biopsy parameters to determine the significance of any differences between the groups. Predictors for positive diagnosis of prostate cancer were determined by binary logistic regression, as were predictors of Gleason score upgrading by TZ biopsy alone. For all test, a p value ≤ 0.05 was considered statistically significant.  Statistical analysis was performed using STATA (version 15.0, STATA Corporation, LP, College station, TX).

Table 1 summarizes the clinical parameters of the 1,230 consecutive patients undergoing TTMB. The mean and median age of the entire cohort was 65.3 and 66.0 years, respectively. Seven hundred and fifty-nine patients (61.7%) were diagnosed with prostate cancer. Patients with prostate cancer were statistically older (66.1 vs. 64.0 years, p<0.001), underwent fewer prior TRUS biopsies and a lesser number of TRUS biopsy cores (p<0.001) and were less likely to present with diabetes mellitus (p=0.012). No statistical differences in pre-biopsy PSA, BMI or prior tobacco usage were noted.  

Table 1. Clinical Parameters of the study population. 

Table 2 summarizes the TTMB parameters of patients with and without prostate cancer. Patients with prostate cancer presented with statistically smaller glands (51.4cm3 vs 77.9cm3, p<0.001), fewer TTMB cores were obtained (55.6 vs 57.2, p=0.019), had a smaller transition zone volume (20.1cm3 vs 38.2cm3, p<0.001), a higher PSAD (0.195 vs 0.122, p<0.001) a higher TZPSAD (0.597 vs 0.271, p<0.001) and a smaller transition zone index (0.398 vs 0.507, p<0.001). Of the 759 patients with prostate cancer, 454 (58.8%) presented with clinically significant prostate cancer Table 3. The mean and median number of positive prostate cancer cores were 9.1 and 7.0, respectively with 86 patients (11.3%) having more than 20 positive cores. 358 patients (47.2%) had involvement of the transition zone with 40 patients (5.4%) having TZ involvement only. One hundred patients (13.2%) had Gleason score upgrading based on the TZ pathology when compared to a standard 12 core TRUS biopsy (sites 3, 4, 5, 6, 11, 12, 13, 14, 20, 21, 22, 23). Of those TZ upgraded patients, 50 (6.6%) were diagnosed with Gleason 3+4, 28 (3.7%) with Gleason 4+3, 15 (2.0%) with Gleason score 8 and 7 (0.9%) with Gleason score 9-10. In multivariate analysis Table 4, predictors of TZ upgrading were limited to the number of prior TRUS biopsy sessions. 

Table 2. TTMB parameters of the study population.

Table 3. Characteristics of prostate cancer patients 

Table 4. Predicting TZ upgrading (logistic regression)

Anterior prostate cancers (TZ and anterior apex) are often poorly visualized on imaging studies [6]. In our current study, 47.2% of all cancers involved the TZ but only 40 patients (5.4%) had cancers exclusively confined to the TZ. Consequently, 94.6% of all prostate cancers would have been diagnosed without a TZ biopsy. However, TZ biopsies did potentially influence treatment decisions in 13.2% of patients by upgrading Gleason scores compared to a standard 12-core TRUS biopsy. Of those 13.2%, 6.6% of patients had Gleason score 4+3 histology or higher.  In addition, the fact that approximately half of all prostate cancers involved the TZ has implications regarding patient eligibility for focal therapies and potentially active surveillance. 

TTMB techniques may be more effective in obtaining biopsies of the TZ due to the ability to easily access the anterior gland [2,8,9]. TRUS biopsy techniques may be hampered by the fact that TZ tissue can be relatively resistant to needle penetration [6]. McNeal and Noldus observed that TZ needle biopsies selectively sampled tissue between BPH nodules and spared hyperplastic nodules [14]. They postulated this phenomenon was secondary to the mobility of hyperplastic nodules and extended this argument to include TZ-localized prostate cancer nodules. In contrast, TTMB is less likely to be influenced by such because of the use of a fixed template with transperineal needle stabilization of the prostate gland prior to biopsy and visualization of the biopsy needles in the transverse and sagittal planes [2,8,9]. 

 Strengths of our study include its prospective nature. All patients underwent the same intensive TTMB procedure by one investigator. Weaknesses of our study include the necessity for general anesthesia and operating room time which have limited wide spread adoption of TTMB. In the future, refinements in MRI and/or genomic testing will play greater roles in determining patient selection for prostate biopsy to include TZ biopsy.

47.2% of patients had TZ involvement with 5.4% having prostate cancer isolated to the TZ. TZ biopsies resulted in Gleason score upgrading in 13.2% of patients with resultant possible implications concerning treatment approaches to include eligibility for focal therapies and active surveillance.