Factors affecting the diagnosis of prostate cancer through 12 quadrant guided prostate biopsy

Abstract

Purpose

Investigate the factors affecting the efficacy of the widely used 12-quadrant prostate biopsy for the diagnosis of prostate cancer.

Methods

The data of 1846 male patients between 45 and 75 years of age was evaluated. The patients were subdivided into groups according to age, blood prostate-specific antigen (PSA) levels prostate volume (PV), digital rectal examination (DRE) findings, and pathology results. The tumour detection rates in the 12-quadrant biopsies were compared with PV, PSA levels, and DRE results of the grouped patients.

Results

The tumour detection rate decreased with increasing PV in patients 45–75 years of age and with a PSA level ≤ 14.5. No decrease was detected in patients 45–60 years of age or those aged 61–75 years with a PSA ≤ 6.99 and suspicious DRE findings. A decrease in the tumour detection rate with increasing PV was observed in the other three subgroups of patients in this age group, who had a PSA ≤ 6.99, and normal DRE findings but a PV ≤ 40, PV 41–80, or PV ≥ 81.

Conclusions

Even though there is no statistically significant relationship between PV and the prostate cancer detection rate in patients 45–60 years of age, the cancer detection rate decreased with increasing PV in three of the four subgroups of patients between the ages of 61 and 75 years. Our study results have demonstrated that an individualised approach can play an important role in the diagnosis and treatment of prostate cancer.

Keywords:

• Diagnosis
• prostate cancer
• prostate volume
• transrectal ultrasound
• needle biopsy
• DRE

Introduction

Prostate cancer is one of the most common neoplasm in men [1]. Considering the increase in the elderly population in both developed and developing countries, increases in the rate of prostate cancer and its related pathologies can also be expected. Thus, both in the US and Europe, attempts to reduce the high rates of morbidity and mortality associated with prostate cancer have included screening programmes aimed at early diagnosis of this disease [2]. The first biopsy of the prostate was performed by Astraldi [3]. Today, the accepted method for the histopathological diagnosis of prostate cancer is transrectal ultrasound (TRUS)-guided prostate biopsy [4], which is used in conjunction with the sextant prostate biopsy, as described by Hodge et al. [5]. Positive results of 20–30%, after repeat biopsies carried out following sextant biopsy, have led to interest in new protocols for the histological diagnosis of prostate cancer [6]. However, despite the increase in the rate of cancer detection with an increasing number of biopsies, especially of the peripheral lateral zone, a consensus regarding the optimal number of biopsy cores and sites has yet to be reached [7]. An additional concern is that 65–90% of patients report discomfort during a prostate biopsy [8], such that one-third of the patients for whom a second biopsy is recommended reject the examination [9].

TRUS-guided prostate biopsy has undesirable minor and major complications, including pain, rectal bleeding, urethrorrhagia, haematuria, haemospermia, and infection ranging from a simple urinary tract infection to sepsis [10,11]. Moreover, most patients are aware that the process is painful and their anxiety is likely to increase once they are informed about the minor and major risks of the procedure. To avoid these and other, similar problems during TRUS-guided prostate biopsy, it is important to determine the optimal number of biopsy sites for each patient, taking into account age, prostate-specific antigen (PSA) level, digital rectal examination (DRE) findings, and prostate volume (PV).

The aim of this retrospective study was to determine the optimal number of TRUS-guided prostate biopsy sites by analysing the age, PSA values, DRE findings, PV, and pathological data of patients who underwent a first-time standard 12-quadrant biopsy.

Methods

This was a retrospective study of 1846 patients who underwent 12-quadrant TRUS-guided prostate biopsy at the Ministry of Health Istanbul Training and Research Hospital between December 2006 and March 2012, and at the Kanuni Sultan Süleyman Training and Research Hospital or Silivri State Hospital between December 2013 and August 2018. All patients had a PSA < 15 ng/ml and were between 45 and 75 years of age. Other patients were excluded due to insufficient sampling.

The standard prostate biopsy protocol consisted of a 12-quadrant biopsy involving the base, lateral zone, and far remote lateral zone with respect to the midline, and the medial and lateral zones of the apex. TRUS and TRUS-guided biopsies were performed using a Toshiba SSA-250 ultrasound device and a biplanar (6-MHz end fire sector and 7-MHz linear) transrectal probe. Biopsies were taken using 21-cm and 18-G automatic biopsy needles. PV was calculated using the formula: height × width × length × 0.52, as measured using TRUS.

The patients were prescribed prophylactic antibiotic therapy (quinolones) to be taken 2 d before and for 3 d after the biopsy. Also, 1 h before the biopsy, colon cleansing was performed using sodium phosphate (BT) enema.

Patients were divided into two age groups: 45–60 and 61–75 years of age. They were also subdivided based on the PSA level (PSA ≤ 6.99 ng/ml and 7–14 ng/ml), DRE findings (normal and suspicious), PV (≤40, 41–80, and 81–120 ml) and tumour pathology results (positive and negative). The tumour capture rates as a function of the PV were compared. The distribution of the patients’ characteristics among groups and subgroups is summarised in Table 1.

Table 1. The distribution of patients’ characteristics among groups ABD subgroups.

Age (years)	PSA (ng/ml)	DRE		PV (cc)	Age (mean ± SD)	PSA (mean ± SD)	PV (mean ± SD)
			1a	≤40 cc	55.2 ± 3.6	4.5 ± 1.1	28.2 ± 7.7
Group 1 (45–60)	≤6.99	normal	1b	41–80	56.0 ± 3.1	5.0 ± 1.0	52.7 ± 8.9
			1c	≥81	57.6 ± 2.7	5.4 ± 1.9	94.6 ± 15.0
			2a	≤40 cc	55.2 ± 3.8	3.5 ± 1.6	26.7 ± 8.5
Group 2 (45–60)	≤6.99	suspected	2b	41–80	56.2 ± 2.9	3.9 ± 1.4	52.5 ± 11.2
			2c	≥81	n = 0
			3a	≤40 cc	55.6 ± 3.3	9.5 ± 1.8	29.5 ± 8.3
Group 3 (45–60)	7–14.5	normal	3b	41–80	57.1 ± 2.5	9.4 ± 1.9	55.3 ± 10.4
			3c	≥81	57.2 ± 2.8	10.0 ± 1.2	97.1 ± 15.5
			4a	≤40 cc	56.2 ± 2.8	9.0 ± 2.1	23.7 ± 5.7
Group 4 (45–60)	7–14.5	suspected	4b	41–80	59.5 ± 0.7	9.0 ± 0.4	61.0 ± 9.8
			4c	≥81	n = 0
			5a	≤40 cc	65.9 ± 3.7	4.9 ± 1.1	30.0 ± 7.6
Group 5 (61–75)	≤6.99	normal	5b	41–80	56.8 ± 3.8	5.2 ± 0.9	54.0 ± 9.9
			5c	≥81	68.7 ± 3.5	5.6 ± 0.9	93.1 ± 12.0
			6a	≤40 cc	67.2 ± 4.4	3.5 ± 1.9	26.1 ± 7.9
Group 6 (61–75)	≤6.99	suspected	6b	41–80	67.8 ± 4.0	4.7 ± 1.4	48.9 ± 8.5
			6c	≥81	65.5 ± 2.8	4.3 ± 2.4	92.2 ± 12.0
			7a	≤40 cc	67.1 ± 4.0	9.7 ± 2.0	35.5 ± 7.4
Group 7 (61–75)	7–14.5	normal	7b	41–80	68.2 ± 4.2	9.6 ± 2.0	55.7 ± 10.4
			7c	≥81	67.5 ± 4.3	9.9 ± 2.0	95.6 ± 12.6
			8a	≤40 cc	68.7 ± 4.5	9.9 ± 2.1	28.8 ± 7.4
Group 8 (61–75)	7–14.5	suspected	8b	41–80	67.6 ± 3.6	10.0 ± 2.1	54.3 ± 10.8
			8c	≥81	67.6 ± 4.6	9.7 ± 0.9	90.0 ± 8.1

PSA: Prostate Specific Antigen; DRE: digital rectal examination; PV: prostate volume.

Statistics were calculated using SPSS for Windows software version 16.0 (SPSS Inc., Chicago, IL). The χ² test and Fisher’s exact test were used for comparisons of ratios, and a t test was used to compare averages. A p value <.05 was considered to indicate statistical significance.

Results

The 1846 patients had an average age of 63.3 ± 6.6 years (range: 45–75 years). A tumour was not detected in the pathological examinations of the biopsies of 1495 (81.0%) patients (average age = 62.9 ± 6.6 years) but was detected in those of 351 (19.0%) patients (average age = 65.2 ± 6.1 years). Patients with a tumour detected during the pathological examination were significantly older (p=.000). A comparison of PV and tumour pathology independent of age, PSA level, and DRE findings showed that the average PV of the 351 patients (35.9 ± 16.8 ml) with a prostate tumour was significantly lower (p = .000) than the average PV of the 1495 patients (44.7 ± 20.0 ml) without tumour.

When the patients were divided into three groups according to PV, a tumour was present in 248 of the 991 (25%) patients with a PV ≤ 40 ml, in 92 of the 749 (12.3%) patients with a PV of 41–80 ml, and in 11 of the 106 (10.4%) patients with a PV ≥ 81 ml. As the PV increased, the tumour detection rate decreased (p=.000).

The correlation between the PV and PSA level of all patients included in the study was linear and positive (r = 0.23; p=.000), as was the relationship between patient age and PSA level (r = 0.23; p=.000) and between patient age and PV (r = 0.20; p=.000).

A comparison of the following subgroups failed to demonstrate statistically significant relationships: 1a vs. 1b (p=.538), 1a vs. 1c (p=.424), 1b vs. 1c (p=.359), 2a vs. 2b (p=.171), 2a vs. 2c (p = 1.000), 2b vs. 2c (p = 1.000), 3a vs. 3b (p=.097), 3a vs. 3c (p=.592), 3b vs. 3c (p = 1.0), 4a vs. 4b (p=.110), 4a vs. 4c(p = 1.00), 4b vs. 4c(p = 1.00), 5a vs. 5c (p=.072), 5b vs. 5c (p = 1.00), 6a vs. 6b (p=.100), 6a vs. 6c (p=.298), 6b vs. 6c (p = 1.000), 7b vs. 7c (p=.699) and 8b vs. 8c (p=.536). However, statistically significant relationships were determined for 5a vs. 5b (p=.000), 7a vs. 7b (p=.003), 7a vs. 7c (p=.022), 8a vs. 8b (p=.003) and 8a vs. 8c (p=.033) (Table 2).

Table 2. The comparisons of prostate volume with the presence of tumour regarding patients’ age, serum PSA level and the findings of DRE among groups.

					Pathology
Age (years)	PSA (ng/ml)	DRE		PV (c.c.)	Normal	Tumour	Total	p
			1a	≤40 cc	n = 229 89.8%	n = 26 10.2%	n = 255
Group 1 (45–60)	≤6.99	normal	1b	41–80	n = 127 92%	n = 11 8%	n = 138	.562
			1c	≥81	n = 4 80%	n = 1 20%	n = 5
			2a	≤40 cc	n = 26 76.5%	n = 8 23.5%	n = 34
Group 2 (45–60)	≤6.99	suspected	2b	41–80	n = 9 100%	n = 0 0%	n = 9	.171
			2c	≥81	n = 0	n = 0	n = 0
			3a	≤40 cc	n = 66 82.5%	n = 14 17.5%	n = 80
Group 3 (45–60)	7–14.5	normal	3b	41–80	n = 65 92.9%	n = 5 7.1%	n = 70	.092
			3c	≥81	n = 7 100%	n = 0 0%	n = 7
			4a	≤40 cc	n = 4 26.7%	n = 11 73.3%	n = 15
Group 4 (45–60)	7–14.5	suspected	4b	41–80	n = 2 100%	n = 0 0%	n = 2	.110
			4c	≥81	n = 0	n = 0	n = 0
			5a	≤40 cc	n = 236 74.4%	n = 81 25.6%	n = 317
Group 5 (61–75)	≤6.99	normal	5b	41–80	n = 222 89.5%	n = 26 10.5%	n = 248	.000
			5c	≥81	n = 26 89.7%	n = 3 10.3%	n = 29
			6a	≤40 cc	n = 43 66.2%	n = 22 33.8%	n = 65
Group 6 (61–75)	≤6.99	suspected	6b	41–80	n = 27 84.4%	n = 5 15.6%	n = 32	.076
			6c	≥81	n = 4 100%	n = 0 0%	n = 4
			7a	≤40 cc	n = 123 71.9%	n = 48 28.1%	n = 171
Group 7 (61–75)	7–14.5	normal	7b	41–80	n = 184 84.8%	n = 33 15.2%	n = 217	.002
			7c	≥81	n = 51 87.9%	n = 7 12.1%	n = 58
			8a	≤40 cc	n = 16 29.6%	n = 38 70.4%	n = 54
Group 8 (61–75)	7–14.5	suspected	8b	41–80	n = 21 63.6%	n = 12 36.4%	n = 33	.001
			8c	≥81	n = 3 100%	n = 0 0%	n = 3

PSA: Prostate Specific Antigen; DRE: digital rectal examination; PV: prostate volume.

Discussion

Prostate cancer is one of the most common solid tumours among men in the world [1]. Radical prostatectomy is the gold standard treatment for patients with life expectancy of more than 10 years [12]. The main complication of this surgery is urinary incontinence which affect the quality of the life [12]. Androgen-deprivation therapy is now first-line treatment for advanced prostate cancer [13].

In the study of Chen et al., tumour foci were detected in the peripheral zone of 74%, and in the transition zone of 2%, of 180 biopsy samples [14]. These authors concluded that transitional sampling should not be performed during first biopsies. Similarly, none of the patients evaluated in this study underwent transition zone sampling as part of the 12-quadrant biopsy protocol, whereas the peripheral zone was consistently sampled. In two other studies, sampling in the far lateral zone during a 6-quadrant biopsy resulted in a significant increase in the tumour capture rate [14–16]. The 12-quadrant biopsy carried out in our patients included the lateral sampling protocol described in the literature.

Previous studies have shown that biopsies based on the hypoechoic, isoechoic, and hyperechoic ultrasound appearance of suspected lesions do not improve the detection of prostate cancer [17,18]. Thus, these lesions were not biopsied in the 12-quadrant laterally focussed protocol followed in this study. However, it is well-established that the rate of tumour detection on prostate biopsy decreases dramatically with increasing PV. This was confirmed in our study, in an analysis of the overall study population, which showed that the rate of tumour detection in patients aged 45–75 years and with a PSA level ≤ 14.5 decreased significantly as the PV increased.

These findings were confirmed in a subgroup analysis of patients 45–60 years of age; in the group who were 61–75 years of age and who had a PSA level ≤ 6.99; and in the subgroups with suspicious DRE. Consistent with the literature, the prostate cancer detection rate decreased in patients 61–75 years of age with a PSA level ≤ 6.99, normal DRE findings, and a PV ≤ 40, 41–80, or ≥81 ml. Thus, in these patients a 12-quadrant TRUS-guided prostate biopsy focussed on the peripheral zone is not sufficient; instead, in patients with an above-normal PV, the number of biopsy sites targeted should be increased. By contrast, in patients 45–60 years of age, with a PSA level ≤ 14.5 and normal or suspected DRE findings, the absence of a reduction in the tumour detection rate with increasing PV indicated the sufficiency of our peripheral-zone-oriented 12-quadrant TRUS-guided prostate biopsy.

Ultrasound-guided prostate biopsy is widely used in the US and Europe, but there is no standardised patient preparation protocol or technique [19,20]. Our patients received prophylactic antibiotic therapy 2 d before the biopsy and underwent colon cleansing with a BT enema 1 h prior to the biopsy. A lidocaine gel was used for local anaesthesia during the procedure.

To precisely evaluate the success of tumour capture by TRUS-guided prostate biopsy, autopsies carried out in studies using similar patient criteria should be assessed. In the autopsy studies investigated by Haas et al., who evaluated patients geographically and according to age group, among white American males who underwent TRUS-guided prostate biopsy the tumour detection rates were 8% in patients aged 21–30 years; 31% in patients aged 31–40 years; 37% in patients aged 41–50 years; 44% in patients aged 51–60 years; 65% in patients aged 61–70 years; and 85% in patients aged 71–80 years. In the same study and age groups, the cancer detection rates in Greek men were 0, 0, 3, 5, 14, 31, and 40%, respectively [21]. These results demonstrate ethnic and geographic differences in prostate cancer detection and occurrence.

Due to the high mortality rate associated with prostate cancer worldwide [2], screening programmes have been implemented, with TRUS-guided prostate biopsy universally regarded as the gold standard for the histopathological diagnosis of prostate cancer and for treatment monitoring. A study carried out in 2002 determined that urologists in the US performed an average of 500,000 prostate biopsies each year [20]. However, rigorous methodological studies of this widely used but invasive procedure are still lacking. Our results contribute to filling this knowledge gap.

After adding 6- and 10-quadrant biopsies to the previous 4-quadrant repeat biopsies, the cancer detection rates increased by 33 and 17%, respectively [22]. In another study, the prostate cancer detection rate was 33% in patients with a PSA level < 4 ng/ml, and 62% in those with a PSA level > 10 ng/ml [23]. In their 2011 study, Xu et al. evaluated 129 patients with suspected prostate cancer who underwent repeat biopsies; the tumour detection rate was 26.3%. In another study, a univariate analysis showed that DRE findings, total PSA level, the free/total PSA ratio, PV, PSA density and volume/biopsy ratio were all significant predictors of prostate cancer detection on repeat biopsies; however, in the multivariate analysis, only the DRE findings and total PSA were independent predictive factors [24]. A study of repeat biopsies in patients with an enlarged prostate showed that among the parameters examined, only PV was of predictive value [25]. Similar results were reported in another study, which suggested the need for additional biopsies in patients with an above-normal PV [26].

In the study of Djavan et al., of 1051 men with a PSA level of 4–10 ng/ml, 820 cases that had a negative initial classical sextant biopsy underwent repeat biopsy 6 weeks later. Prostate cancer was detected in 10% of the patients in this group. The total PV and transitional zone volume – but not the free/total PSA ratio was significantly higher in patients with a positive repeat biopsy than in patients with a positive initial biopsy [27]. Levine et al. detected prostate cancer in 43, 27 and 24% of their patients with a PV < 30, 30–50, and >50 ml, respectively. On repeat biopsy of patients with a large PV, the rate of positive results doubled [28].

The Vienna Nomogram proposed by Djavan et al. and Vashi et al. offers an easy-to-use tool with which to select the optimal number of prostate biopsy cores based on patient age and total PV in patients with a PSA between 2 and 10 ng/ml. The cancer detection rate is theoretically 90% [29,30]. Use of the nomogram was shown to significantly improve cancer detection (by 66.4% compared to the control group) [31].

Some dietary habits are known to affect the incidence of prostate cancer [32]. Studies on whether or not dietary habits affect the localisation of prostate cancer may influence the number and localisation of the foci biopsied. As in prostate cancer, comorbidities such as hypertension, diabetes, and dyslipidaemia usually increase with aging. In particular, there are studies that associate high-risk prostate cancer with diabetes mellitus, whereas there some are studies that are associated with high-risk prostate cancer of diabetes, whereas low levels of prostate cancer are detected in hypogonadal men receiving testosterone replacement therapy [33,34]. There is a need for studies that consider comorbidities in the determination of numbers of foci for prostate biopsy.

Conclusions

In contrast to studies reporting an increase in prostate cancer detection in patients 45–60 years of age with an increased PV and a PSA level ≤ 14 ng/ml, this was not seen in this study, in which a similar group of patients underwent 12-quadrant prostate biopsy. However, prostate cancer detection decreased in older patients (61–75 years of age) with these same PV and PSA findings. Therefore, in these patients, an increase in the number of biopsy foci may improve the detection rate of prostate cancer and thereby reduce the need for repeat biopsies.

Disclosure statement

No potential conflict of interest was reported by the authors.