Prostate cancer diagnosis: should patients with prostate specific

antigen >10 ng/mL have stratified prostate biopsy protocols?

Joe Philip MRCSIa,*, Ramaswamy Manikandan FRCS (Urol.)b,Pradip Javle FRCS (Urol.)a, Christopher S. Foster FRCPath., PhDc

a Department of Urology, Leighton Hospital, Crewe, Cheshire, CW1 4QJ UKb Department of Urology, School of Cancer Studies, University of Liverpool, Duncan Building, Daulby Street, Liverpool, L69 3GA UKc Division of Pathology, School of Cancer Studies, University of Liverpool, Duncan Building, Daulby Street, Liverpool, L69 3GA UK

Accepted 20 December 2008

Abstract

Background: Trans-rectal ultrasound (TRUS) guided systematic prostate biopsy is a standard tool in prostate cancer (CaP) diagnosis.

Extended biopsy techniques using 10–12 cores are the norm. Controversy exists on extended TRUS biopsy in men with PSA >10 ng/mL. We

evaluated cancer detection rates on an individual core basis, to stratify prostate biopsy protocols based on PSA levels. Patients and methods:

Over a five-year period, 1036 patients underwent TRUS guided prostate biopsy for raised serum PSA (>2.5 ng/mL). 436 patients had

PSA >10 ng/mL. Patients with PSA <50 ng/mL underwent a 12-core TRUS guided prostate biopsy including six peripheral biopsies. The six

peripheral biopsies were directed laterally towards the base, mid-zone and apices. Remainder were standard para-sagittal sextant biopsies.

Patients were stratified into three groups (PSA 10–20 ng/mL, 20–50 ng/mL and >50 ng/mL). Results: Mean age of 436 patients with

PSA >10 ng/mL was 70.3years. 270 (62%) men had cancer. Cancer detection rates for different PSA levels were 46% (10–20 ng/mL), 76%

(20–50 ng/mL) and 93% (>50 ng/mL). Higher PSA levels and advanced clinical stage were associated with increased cancer detection rates.

All patients with clinical T3 and T4 disease had biopsy diagnosed CaP. Conclusion: TRUS guided prostate biopsy in patients with

PSA >10 ng/mL did not require 12 cores to diagnose CaP. CaP diagnosis required 8 cores in men with PSA 10–20 ng/mL. These cores were

right and left peripheral basal and apical, and right and left para-sagittal basal and apical biopsy. Only 6 cores were necessary to diagnose CaP

in men with PSA >20 ng/mL which were right and left peripheral basal and apical, and para-sagittal apical biopsies. We suggest limited

TRUS prostate biopsy protocols for men with PSA >10 ng/mL.

# 2008 Elsevier Ltd. All rights reserved.

Keywords: Prostate cancer; PSA; Prostate biopsy; Limited biopsy protocols

www.elsevier.com/locate/cdp

Cancer Detection and Prevention 32 (2009) 314–318

1. Introduction

The advent of prostate specific antigen (PSA) testing has

lead to an increase in the number of men attending prostate

assessment clinics. A substantial increase in incidence of

prostate cancer (CaP) has been reported in U.K. [1]. CaP is

now the commonest cancer in men, accounting for nearly

35,000 new cancer cases in the UK in 2004 and over 10,000

deaths in 2006 [2]. Diagnosis of early CaP comprises PSA

* Corresponding author. Tel.: +44 7816081684.

E-mail address: indianajoe@gmail.com (J. Philip).

0361-090X/$ – see front matter # 2008 Elsevier Ltd. All rights reserved.

doi:10.1016/j.cdp.2008.12.004

assay, digital rectal examination (DRE) and trans-rectal

ultrasound (TRUS) guided biopsies.

Traditionally, an elevated PSA level (>2.5 ng/mL) and/or

an abnormal DRE necessitate a TRUS guided systematic

biopsy for tissue diagnosis before initiating treatment. The use

of PSA as a focal point in providing evidence that an indi-

vidual man requires a prostatic biopsy for cancer detection is

generally accepted [3]. Studies have shown complications in

up to 60% of these patients [4,5]. Studies in our department

have confirmed similar findings with over 80% of patients

reporting transient haematuria, rectal bleeding or haematos-

permia and with 4% requiring hospitalisation [6]. Documen-

ted urinary tract infection rates were less than 3%. Naughton

J. Philip et al. / Cancer Detection and Prevention 32 (2009) 314–318 315

Fig. 1. 12-core Prostate biopsy protocol. Key: (A) Right peripheral base;

et al. reported significantly greater rectal bleeding and

haematospermia after increasing the number of cores taken

[7]. Ghani et al. analysed the literature on prostate biopsy

complications; reporting an increase in median haematuria

rate from 39% to 71% when comparing six cores to more than

eight cores [8].

Older men who attend for a biopsy show a haemophilic

tendency with most of these men taking anticoagulants or

antiplatelet drugs. In these men with high co-morbidity,

complications trivial in younger men could become

potentially life threatening. Limiting the number of prostate

biopsies would be clinically advantageous in reducing

potential and serious complications. We hypothesized that

patients with markedly raised PSA values did not need

extended prostate biopsy protocols. Cancer positive cores in

men with PSA >10 ng/mL undergoing 12-core biopsy

protocols were mapped in order to identify optimal limited

biopsy protocols in these men.

(B) Right peripheral mid-zone; (C) Right peripheral apex; (D) Left per-

ipheral base; (E) Left peripheral mid-zone; (F) Left peripheral apex; (G)

Right para-sagittal base; (H) Right para-sagittal mid-zone; (I) Right para-

sagittal apex; (J) Left para-sagittal base; (K) Left para-sagittal mid-zone; (L)

Left para-sagittal apex.

2. Patients and methods

Over a five-year period from 1999 to 2004, 1036 men

attended the Urology Department’s prostate assessment

clinic with a raised PSA level (>2.5 ng/mL) and underwent

a TRUS guided prostate biopsy. 436 patients had PSA

levels >10 ng/mL and were included in this study. Biopsies

were performed in a standardized manner using a BK

Medical1 ultrasound machine with a 7.5 MHz trans-rectal

ultrasound probe and an 18 gauge core biopsy needle with an

Achieve1 spring loaded biopsy gun. A standard 12-core

biopsy was employed throughout. Patients received 10 mL

of 1% lignocaine peri-prostatic nerve block for local

anaesthesia and antibiotic prophylaxis.

The 12-core biopsy technique incorporates 6 laterally

targeted biopsies in addition to the conventional para-sagittal

sextant biopsies [9]. The peripheral biopsies were obtained by

directing the needle towards the lateral aspect of the prostate

for cores A–F, from the base, mid-zone and apices (Fig. 1). All

patients underwent prostate biopsy according to protocol. All

12-core biopsy specimens were collected separately in pre-

labelled containers of 10% neutral buffered formalin.

Histopathological analysis was performed on an individual

core basis according to current histological practice [10,11].

Men with PSA values >50 ng/mL had limited systematic

biopsies. These patients had a minimum of six cores from the

peripheral zones as described in the protocol and further cores

(if taken) from the para-sagittal zones. The distribution of

cancer detection patterns was assessed with the objective of

stratifying biopsy protocols.

Fig. 2. Clinical stage (DRE) and cancer detection rate.

3. Results

Mean age of the 436 men with PSA >10 ng/mL was 70.3

years (range: 43–90 years, SD 7.8). In total, 270 patients

were diagnosed with cancer (62%) of whom 253 (58%) were

diagnosed after the initial biopsy. Table 1 explains the

patient demographics and cancer detection rates for the

different PSA levels.

Clinical staging (DRE) and cancer detection rates are

summarised in Fig. 2. Higher PSA levels and advanced

clinical stage were associated with increased cancer

detection rates. All clinical T3 and T4 patients had cancer

diagnosed on biopsy. 58 of the 137 (42%) patients with

normal DRE were diagnosed with CaP. Accuracy increased

with PSA levels with positive predictive value increasing

from 56% in patients with PSA 10–20 ng/mL, 85% for levels

20–50 ng/mL and 93% in patients with PSA >50 ng/mL.

158 (82.3%) patients with PSA >20 ng/mL were

diagnosed with CaP on biopsy (Table 2). Of these, all but

two had Gleason scores of >5 with 32% having poorly

J. Philip et al. / Cancer Detection and Prevention 32 (2009) 314–318316

Table 3

Cancer detection rates for limited prostate biopsy templates.

10–20 20–50 >50

Peripheral and para-sagittal base and apex (8 cores) 100% 100% 100%

Periperhal base, apex and para-sagittal apex (6 cores) 99% 100% 100%

Peripheral base and apex (4 cores) 78% 98% 89%

Para-sagittal (6 cores) 54% 42% 62%

Para-sagittal base and apex (4 cores) 48% 38% 62%

Table 1

Patient demographics and cancer detection rates.

PSA range (n) Biopsy diagnosis (n) Mean age (range) (years) Median PSA (range) (ng/mL)

10.1–20 ng/mL(244) Malignant (112) 69.1 (43–83) 13.9 (10.1–19.9)

Cancer detection rate = 46% Benign (132) 68.1 (47–89) 12.7 (10.1–19.9)

20.1–50 ng/mL (119) Malignant (90) 72.1 (53–87) 30.6 (20.1–49.1)

Cancer detection rate = 76% Benign (29) 72.4 (60–85) 25.8 (20.3–47)

>50 ng/mL (73) Malignant (68) 72.9 (49–90) 95.5 (51.2–6660)

Cancer detection rate = 93% Benign (5) 75 (61–90) 103 (52.2–492)

Table 2

Biopsy characteristics of 158 prostate cancer patients with a PSA >20 ng/mL.

PSA (ng/mL) Age in years Extent of disease % of cores involved Gleason score Previous

biopsy

<60 60–69 70–79 >80 One lobe Bi-lobar <25 26–50 51–75 >75 <5 5–7 8–10 Yes No

20–50 6 25 48 11 57 33 39 17 15 19 1 61 28 1 89

>50 4 13 37 14 4 64 5 21 8 34 1 44 23 1 67

differentiated CaP. 48% of men had more than six cores

involved. 61% had bi-lobar disease.

The percentage cancer detection rates for different biopsy

protocols are in Table 3. Standard six-core biopsy protocol

resulted in cancer detection rates of only 42–62%. Surpris-

ingly, a four-core protocol with cores from peripheral bases

and apices had higher CDR (78–98%). Additional two cores

Fig. 3. Suggested 8-core biopsy protocol (PSA 10–20 ng/mL).

from the para-sagittal apex gave a 100% CDR in men with

PSA >20 ng/mL.

All 112 cancers in men with PSA 10–20 ng/mL would

have been detected with an eight-core biopsy protocol

(Fig. 3) and the 158 men (PSA >20 ng/mL) with cancer

would have had their diagnosis confirmed with a six-core

biopsy protocol (Fig. 4).

Fig. 4. Suggested 6-core biopsy protocol (PSA >20 ng/mL).

J. Philip et al. / Cancer Detection and Prevention 32 (2009) 314–318 317

4. Discussion

The data reported in this paper supports the hypothesis

that it is unnecessary to perform 12-core needle biopsy

sampling of the prostate in men with a PSA level >10 ng/

mL in order to diagnose CaP. Programmes for the detection

of CaP depend on PSA determination as a key criterion

for biopsy; the specificity and sensitivity of this parameter is

questionable [12]. A TRUS guided systematic prostate

biopsy is required to obtain tissue for confirmatory

histopathological diagnosis is therefore a necessity. Despite

increased awareness of CaP, our study had 19% of the men

attending the clinic with PSA levels more than 20 ng/mL.

Most urology departments are offering men attending the

prostate clinic extended and multiple biopsy protocols

even in men with higher PSA levels. Prostate biopsy is

accompanied by potentially significant morbidity as well as

being an uncomfortable procedure [13]. Most studies report

significant complications such as haematuria and rectal

bleeding. Eichler et al. in their review had reported 80–82%

haematuria and haemospermia rates with 12-core biopsies

with a marked reduction in complication rates with reduced

number of cores [14]. Ghani et al. also reported reduced

rectal bleeding with reduction in cores [8]. We have mapped

limited biopsy protocols to detect CaP in men with markedly

raised (>10 ng/mL) PSA levels maintaining a 100% cancer

detection rates.

The overall cancer detection rate in this current patient

cohort was 43% in keeping with published data [15,16].

There was a proportional increased cancer detection rate

with older men and higher PSA levels as well as in men with

advanced clinical stage. The necessity of 10–12-core biopsy

protocols to diagnose CaP in men with PSA levels below

10 ng/mL has been well elucidated [9,17–20]. Peripheral

biopsies have been reported to increase cancer detection

rates. [9,20,21]. However, the necessity for extended

protocols in men with PSA levels of more than 20 ng/mL

is debatable. Previous reports have only analysed cancer

detection rates comparing sextant biopsy versus extended

protocols [21]. Gerstenbluth et al. used a sextant plus

additional lesion directed biopsies reporting cancer detec-

tion rates of 87% at cut off PSA of 20 ng/mL [22]. We report

a cancer detection rate of 82% in this group which is lower

but only 4% required a repeat biopsy. Our assessment clinic

has most patients attending from the primary care with a

single raised reading. We feel that adequate clinical

assessment and at least one repeat PSA assay would reduce

biopsy rates, even in men with PSA levels >20 ng/mL.

Patients with high PSA values (>20 ng/mL) had

undifferentiated tumours identified by an increased propor-

tion of men with high Gleason scores (Table 3). They also

had an elevated tumour volume with more men having

bilobar disease and a greater number of positive cores. PPV

for CaP was also very high in this group (82%+). Our

attempt to map optimum biopsy protocols have been

hampered by the variable number of cores undertaken in

men with PSA >20 ng/mL. However, all these men had an

initial set of peripheral biopsies and the variability was in the

number of para-sagittal biopsies. Also, the variable sites of

positive cores precluded standard limited biopsy protocols

such as the sextant biopsy protocols. We have therefore

mapped hybrid limited protocols maintaining 100% CDR

(Figs. 3 and 4)

Patients with PSA levels between 10–20 ng/mL needed

only 8 cores to diagnose CaP with the biopsy protocol to

include the peripheral and para-sagittal basal and apical

biopsies. In patients with PSA level of >20 ng/mL; a

protocol of six cores to include the right and left peripheral

basal and apical, and para-sagittal apical biopsies would give

a 100% CaP detection rate.

5. Conclusion

Patients with PSA values > 20 ng/mL had a CDR of 82%.

These men tend to have poorly differentiated tumours with a

higher tumour volume. However, variable positive core sites

require a limited but hybrid protocols to obtain maximum

cancer yield. TRUS guided prostate biopsy in patients with

PSA 10–20 ng/mL required only 8 cores to diagnose CaP.

Patients with PSA >20 ng/mL would have had cancer

diagnosed with a six-core biopsy concentrated on the apical

region. We suggest limited biopsy protocols for men with PSA

values >10 ng/mL.

Conflict of interest

None.

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