mL have stratified prostate biopsy protocols?

Cancer Detection and Prevention 32 (2009) 314–318 www.elsevier.com/locate/cdp

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 UK Department of Urology, School of Cancer Studies, University of Liverpool, Duncan Building, Daulby Street, Liverpool, L69 3GA UK c Division of Pathology, School of Cancer Studies, University of Liverpool, Duncan Building, Daulby Street, Liverpool, L69 3GA UK

b

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

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: [email protected] (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 individual 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 haematospermia and with 4% requiring hospitalisation [6]. Documented urinary tract infection rates were less than 3%. Naughton

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

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.

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 prelabelled 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. 1. 12-core Prostate biopsy protocol. Key: (A) Right peripheral base; (B) Right peripheral mid-zone; (C) Right peripheral apex; (D) Left peripheral base; (E) Left peripheral mid-zone; (F) Left peripheral apex; (G) Right para-sagittal base; (H) Right para-sagittal mid-zone; (I) Right parasagittal apex; (J) Left para-sagittal base; (K) Left para-sagittal mid-zone; (L) Left para-sagittal apex.

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

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

315

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

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

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) Cancer detection rate = 46% 20.1–50 ng/mL (119) Cancer detection rate = 76% >50 ng/mL (73) Cancer detection rate = 93%

Malignant (112) Benign (132) Malignant (90) Benign (29) Malignant (68) Benign (5)

69.1 (43–83) 68.1 (47–89) 72.1 (53–87) 72.4 (60–85) 72.9 (49–90) 75 (61–90)

13.9 (10.1–19.9) 12.7 (10.1–19.9) 30.6 (20.1–49.1) 25.8 (20.3–47) 95.5 (51.2–6660) 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 >50

6 4

25 13

48 37

11 14

57 4

33 64

39 5

17 21

15 8

19 34

1 1

61 44

28 23

1 1

89 67

Table 3 Cancer detection rates for limited prostate biopsy templates. 10–20

20–50

>50

Peripheral and para-sagittal base and apex (8 cores) Periperhal base, apex and para-sagittal apex (6 cores) Peripheral base and apex (4 cores) Para-sagittal (6 cores) Para-sagittal base and apex (4 cores)

100% 99% 78% 54% 48%

100% 100% 98% 42% 38%

100% 100% 89% 62% 62%

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%. Surprisingly, a four-core protocol with cores from peripheral bases and apices had higher CDR (78–98%). Additional two cores

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

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

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

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 detection 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 proportion 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

317

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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