5.DIAGNOSTIC EVALUATION
5.1.Screening and early detection
5.1.1.Screening
Population or mass screening is defined as the ‘systematic
examination of asymptomatic men (at risk)’ and is usually initiated by health
authorities. The co-primary objectives are:
- reduction in mortality due to PCa;
- a maintained QoL as expressed by QoL-adjusted gain in life years (QALYs).
Prostate cancer mortality trends range
widely from country to country in the industrialised world [91].
Mortality due to PCa has decreased in most Western nations but the magnitude of the
reduction varies between countries. Currently, screening for PCa still remains one of
the most controversial topics in the urological literature [92].
Initial widespread aggressive screening in USA was
associated with a decrease in mortality [93]. In 2012 the US
Preventive Services Task Force (USPSTF) released a recommendation against PSA-based
screening [94], which was adopted in the 2013 AUA Guidelines [95] and resulted in a reduction in the use of PSA for early
detection [96]. This reduction in the use of PSA testing was
associated with higher rates of advanced disease at diagnosis (e.g., a 6% increase in the
number of patients with metastatic PCa [14,97-100]. While PCa mortality had decreased for two decades since
the introduction of PSA testing [101], the incidence of advanced
disease and, possibly, cancer-related mortality slowly increased from 2008 and accelerated
in 2012 [102]. Moreover, additional evidence suggests a long-term
benefit of PSA population screening in terms of reduction of cancer-specific mortality [103,104]. However, the temporal
relationship between PSA testing and decreased mortality, as well as a rising mortality
following immediately after the USPSTF and AUA Guidelines recommendation against PSA testing
questions the direct causative link between both points.
In 2017 the USPSTF issued an updated statement suggesting that men aged
55–69 should be informed about the benefits and harms of PSA-based screening as this
might be associated with a small survival benefit. The USPSTF has now upgraded this
recommendation to a grade C [105], from a previous grade
‘D’ [105-107]. They highlighted the fact that the
decision to be screened should be an individual one. The grade D recommendation remains in
place for men over 70 years old. This represents a major switch from discouraging PSA-based
screening (grade D) to offering early diagnosis to selected men depending on individual
circumstances.
A comparison of systematic and opportunistic screening
suggested over-diagnosis and mortality reduction in the systematic screening group compared
to a higher over-diagnosis with a marginal survival benefit, at best, in the opportunistic
screening regimen [108].
A Cochrane review published in 2013 [109], which
has since been updated [110], presents the main overview to date.
The findings of the updated publication (based on a literature search until April 3, 2013)
are almost identical to the 2009 review:
- Screening is associated with an increased diagnosis of PCa (RR: 1.3, 95% CI:
1.02–1.65).
- Screening is associated with detection of more localised disease (RR: 1.79, 95% CI:
1.19–2.70) and less advanced PCa (T3–4, N1, M1) (RR: 0.80, 95% CI:
0.73–0.87).
- From the results of 5 RCTs, randomising more than 341,000 men, no PCa-specific survival
benefit was observed (RR: 1.00, 95% CI: 0.86–1.17). This was the main endpoint in
all trials.
- From the results of four available RCTs, no overall survival (OS) benefit was observed
(RR: 1.00, 95% CI: 0.96–1.03).
The included studies applied a range of different screening measures and
testing intervals in patients who had ondergone prior PSA testing, to various degrees. None
included the use of risk calculators, MRI prior to biopsy (vs. a single PSA threshold) or AS
(as an alternative to RP) which no longer reflects current standard practice.
The diagnostic tool (i.e. biopsy procedure) was not associated with
increased mortality within 120 days after biopsy in screened men as compared to controls in
the two largest population-based screening populations (ERSPC and PLCO), in contrast to a
120-day mortality rate of 1.3% in screened vs. 0.3% in controls, respectively, in a Canadian
population-based screening study [111]. Increased diagnosis has
historically led to over-treatment with associated side effects. However, despite this, the
impact on the patient’s overall QoL is still unclear. Population level screening has
never been shown to be detrimental [112-114]. Nevertheless, all
these findings have led to strong advice against systematic population-based screening in
most countries, including those in Europe.
In case screening is considered, a single PSA test is not enough based on
the Cluster Randomized Trial of PSA Testing for Prostate Cancer (CAP) trial. The CAP trial
evaluated a single PSA screening vs. controls not undergoing PSA screening on PCa detection
in men aged 50 to 69 years old. The single PSA screening intervention detected more low-risk
PCa cases but had no significant effect on PCa mortality after a median follow-up of 10
years [115].
Since 2013, the European Randomized Study of Screening
for Prostate Cancer (ERSPC) data have been updated with 16 years of follow-up (see Table
5.1) [116]. The key message is that with extended follow-up, the
mortality reduction remains unchanged (21%, and 29% after non-compliance adjustment).
However the number needed to screen (NNS) and to treat is decreasing, and is now below the
NNS observed in breast cancer trials [116,117]. Long-term follow-up of the PLCO (Prostate, Lung, Colon,
Ovarian cancer screening trial) showed no survival benefit for screening at a median
follow-up of 16.7 years but a significant 17% increase in Gleason score 2–6 cancers
and 11% decrease in Gleason score 8–10 cancers [118].
Table 5.1: Follow-up data from the ERSPC study [116]
|
Years of follow-up
|
Number needed to screen
|
Number needed to treat
|
|
9
|
1,410
|
48
|
|
11
|
979
|
35
|
|
13
|
781
|
27
|
|
16
|
570
|
18
|
5.1.2.Early
detection
An individualised risk-adapted strategy for early detection may still be
associated with a substantial risk of over-diagnosis. It is essential to remember that
breaking the link between diagnosis and active treatment is the only way to decrease
over-treatment, while still maintaining the potential benefit of individual early diagnosis
for men requesting it [16,119].
Men at elevated risk of having PCa are those > 50 years [120] or at age > 45 years with a family history of PCa (either
paternal or maternal) [121] or of African descent [122,123]. Men of African descent are more
likely to be diagnosed with more advanced disease [124] and upgrade
was more frequent after prostatectomy as compared to Caucasian men (49% vs. 26%) [125].
Germline mutations are associated with an increased risk
of the development of aggressive PCa, i.e. BRCA2 [126,127]. Prostate-specific antigen
screening in male BRCA1 and 2 carriers detected more significant cancers at a younger
age compared to non-mutation carriers [32,33].
Men with a baseline PSA < 1 ng/mL at 40 years and < 2 ng/mL at 60
years are at decreased risk of PCa metastasis or death from PCa several decades later [128,129].
The use of DRE alone in the primary care setting had a sensitivity and
specificity below 60%, possibly due to inexperience, and can therefore not be recommended to
exclude PCa [130]. Informed men requesting an early diagnosis should
be given a PSA test and undergo a DRE [131]. Prostate-specific
antigen measurement and DRE need to be repeated [115], but the
optimal intervals for PSA testing and DRE follow-up are unknown as they varied between
several prospective trials. A risk-adapted strategy might be a consideration, based on the
initial PSA level. This could be every 2 years for those initially at risk, or postponed up
to 8 to 10 years in those not at risk with an initial PSA < 1 ng/mL at 40 years and a PSA
< 2 ng/mL at 60 years of age and a negative family history [132].
An analysis of ERSPC data supports a recommendation for an 8-year screening interval in
men with an initial PSA concentration < 1 μg/L; fewer
than 1% of men with an initial PSA concentration < 1 ng/mL were found to
have a concentration above the biopsy threshold of 3 μg/L at 4-year follow-up; the cancer
detection rate by 8 years was close to 1% [133]. The long-term
survival and QoL benefits of extended PSA re-testing (every 8 years) remain to be proven at
a population level. Data from the Goteborg arm of the ERSPC trial suggest that the age at
which early diagnosis should be stopped remains controversial, but an individual’s
life expectancy must definitely be taken into account. Men who have less than a 15-year life
expectancy are unlikely to benefit, based on data from the Prostate Cancer Intervention
Versus Observation Trial (PIVOT) and the ERSPC trials. Furthermore, although there is no
simple tool to evaluate individual life expectancy; co-morbidity is at least as important as
age. A detailed review can be found in Section 5.4 ‘Estimating life expectancy and
health status’ and in the SIOG Guidelines [134].
Multiple tools are now available to determine the need
for a biopsy to establish the diagnosis of a PCa, including imaging by MRI, if available
(see Section 5.2.4).
Urine and serum biomarkers as well as tissue-based biomarkers have been
proposed for improving detection and risk stratification of PCa patients, potentially
avoiding unnecessary biopsies. However, further studies are necessary to validate their
efficacy [135]. At present there is too limited data to implement
these markers into routine screening programmes (see Section 5.2.3).
Risk calculators may be useful in helping to determine (on an individual
basis) what the potential risk of cancer may be, thereby reducing the number of unnecessary
biopsies. Several tools developed from cohort studies are available including:
Since none of these risk calculators has clearly shown superiority, it
remains a personal decision as to which one to use [137]. A
comparative analysis showed risk calculators containing MRI to be most predictive, however,
regional modifications may be required before implementation [138].
5.1.3.Genetic
testing for inherited prostate cancer
Increasing evidence supports the implementation of genetic counselling and
germline testing in early detection and PCa management. Several commercial screening panels
are now available to assess main PCa risk genes [139]. However, it
remains unclear when germline testing should be considered and how this may impact localised
and metastatic disease management. Germline BRCA1 and
BRCA2 mutations occur in approximately 0.2% to 0.3% of
the general population [140]. It is important to understand the
difference between somatic testing, which is performed on the tumour, and germline testing,
which is performed on blood or saliva and identifies inherited mutations. Genetic
counselling is required prior to and after undergoing germline testing.
Germline mutations can drive the development of aggressive PCa. Therefore,
the following men with a personal or family history of PCa or other cancer types arising
from DNA repair gene mutations should be considered for germline testing:
- Men with metastatic PCa;
- Men with high-risk PCa and a family member diagnosed with PCa at age < 60 years;
- Men with multiple family members diagnosed with csPCa at age < 60 years or a family
member who died from PCa cancer;
- Men with a family history of high-risk germline mutations or a family history of
multiple cancers on the same side of the family.
Further research in this field (including not so well-known germline
mutations) is needed to develop screening, early detection and treatment paradigms for
mutation carriers and family members.
Table 5.2: Germline mutations in DNA repair genes associated with
increased risk of prostate cancer
|
Gene
|
Location
|
Prostate Cancer risk
|
Findings
|
|
BRCA2
|
13q12.3
|
- 2.5 to 4.6 [141,142]
- PCa at 55 years or under: RR: 8–23 [141,143]
|
up to 12 % of men with metastatic PCa harbour
germline mutations in 16 genes (including BRCA2 [5.3%]) [25]
2% of men with early-onset PCa harbour
germline mutations in the BRCA2 gene [141]
BRCA2
germline alteration is an independent predictor of metastases and worse
PCa-specific survival [29,144]
|
|
ATM
|
11q22.3
|
RR: 6.3 for metastatic prostate [25]
|
higher rates of lethal PCa among mutation
carriers [31]
up to 12% of men with metastatic PCa harbour
germline mutations in 16 genes (including ATM [1.6%]) [25]
|
|
CHEK2
|
22q12.1
|
OR 3.3 [145,146]
|
up to 12% of men with metastatic PCa harbour
germline mutations in 16 genes (including CHEK2 [1.9%]) [25]
|
|
BRCA1
|
17q21
|
RR: 1.8–3.8 at 65 years or under [147,148]
|
higher rates of lethal PCa among mutation
carriers [31]
up to 12% of men with metastatic PCa harbour
germline mutations in 16 genes (including BRCA1 [0.9%]) [25]
|
|
HOXB13
|
17q21.2
|
OR 3.4–7.9 [26,149]
|
significantly higher PSA at diagnosis, higher
Gleason score and higher incidence of positive surgical margins in the radical
prostatectomy specimen than non-carriers [150]
|
|
MMR genes MLH1
MSH2
MSH6
PMS2
|
3p21.3
2p21
2p16
7p22.2
|
RR: 3.7 [151]
|
Mutations in MMR genes are responsible for Lynch syndrome
[146]
MSH2
mutation carriers are more likely to develop PCa than other MMR gene mutation carriers [152]
|
BRCA2 = breast cancer gene 2; ATM = ataxia
telangiectasia mutated; CHEK2 = checkpoint kinase 2; BRCA1 = breast cancer gene 1; HOXB13 =
homeobox B13; MMR
= mismatch repair; MLH1 = mutL homolog 1; MSH2 = mutS homolog 2; MSH6 = mutS homolog 6;
PMS2 = post-meiotic segregation increased 2; PCa = prostate cancer; RR = relative risk;
OR = odds ratio.
5.1.4.Guidelines
for germline testing*
|
Recommendations
|
Strength rating
|
|
Consider germline testing in men with metastatic PCa.
|
weak
|
|
Consider germline
testing in men with high-risk PCa who have a family member diagnosed with
PCa at age < 60 years.
|
weak
|
|
Consider germline
testing in men with multiple family members diagnosed with PCa at age
< 60 years or a family member who died from PCa.
|
weak
|
|
Consider germline
testing in men with a family history of high-risk germline mutations or a
family history of multiple cancers on the same side of the family.
|
weak
|
*Genetic counseling is required prior to
germline testing.
5.1.5.Guidelines
for screening and early detection
|
Recommendations
|
Strength rating
|
|
Do not subject men to prostate-specific antigen (PSA)
testing without counselling them on the potential risks and benefits.
|
Strong
|
|
Offer an individualised risk-adapted strategy for
early detection to a well-informed man and a life-expectancy of at least 10 to
15 years.
|
Weak
|
|
Offer early PSA testing to well-informed men at
elevated risk of having PCa:
men from 50 years of age;
men from 45 years of age and a family history
of PCa;
men of African descent from 45 years of age;
men carrying
BRCA2 mutations from 40 years of age.
|
Strong
|
|
Offer a risk-adapted strategy (based on initial PSA
level), with follow-up intervals of 2 years for those initially at risk:
men with a PSA level of > 1 ng/mL
at 40 years of age;
men with a PSA level of > 2 ng/mL
at 60 years of age;
Postpone follow-up to 8 years in those not at risk.
|
Weak
|
|
Stop early diagnosis of PCa based on life expectancy
and performance status; men who have a life-expectancy of < 15
years are unlikely to benefit.
|
Strong
|
5.2.Clinical diagnosis
Prostate cancer is usually suspected on the basis of DRE and/or PSA levels.
Definitive diagnosis depends on histopathological verification of adenocarcinoma in prostate
biopsy cores.
5.2.1.Digital
rectal examination
Most PCas are located in the peripheral zone and may be detected by DRE
when the volume is > 0.2 mL. In ~18% of cases,
PCa is detected by suspect DRE alone, irrespective of PSA level [153]. A suspect DRE in patients with a PSA level < 2 ng/mL has a positive predictive value (PPV)
of 5–30% [154]. An abnormal DRE is associated with an
increased risk of a higher ISUP grade and is an indication for biopsy [155,156].
5.2.2.Prostate-specific antigen
The use of PSA as a serum marker has revolutionised PCa diagnosis [157]. Prostate-specific antigen is organ but not cancer specific;
therefore, it may be elevated in benign prostatic hypertrophy (BPH), prostatitis and other
non-malignant conditions. As an independent variable, PSA is a better predictor of cancer
than either DRE or transrectal ultrasound (TRUS) [158].
There are no agreed standards defined for measuring PSA [159]. It is a continuous parameter, with higher levels indicating
greater likelihood of PCa. Many men may harbour PCa despite having low serum PSA [160]. Table 5.3 demonstrates the occurrence of ISUP > grade 2 PCa at low PSA levels, precluding an
optimal PSA threshold for detecting non-palpable but csPCa. The use of nomograms may help in
predicting indolent PCa [161].
Table 5.3: Risk of PCa identified by systemic PCa biopsy in relation
to low PSA values [160]
|
PSA level (ng/mL)
|
Risk of PCa (%)
|
Risk of ISUP grade > 2 PCa (%)
|
|
0.0–0.5
|
6.6
|
0.8
|
|
0.6–1.0
|
10.1
|
1.0
|
|
1.1–2.0
|
17.0
|
2.0
|
|
2.1–3.0
|
23.9
|
4.6
|
|
3.1–4.0
|
26.9
|
6.7
|
5.2.2.1.PSA density
Prostate-specific antigen density is the
level of serum PSA divided by the prostate volume. The higher the PSA density, the more
likely it is that the PCa is clinically significant (see Section 6.2.1 - Treatment of
low-risk disease).
5.2.2.2.PSA velocity and doubling time
There are two methods of measuring PSA kinetics:
- PSA velocity (PSAV): absolute annual increase in serum PSA (ng/mL/year) [162];
- PSA doubling time (PSA-DT): which measures the exponential increase in serum PSA over
time [163].
Prostate-specific antigen velocity and PSA-DT may have a prognostic role in
treating PCa but have limited diagnostic use because of background noise (total prostate
volume, and BPH), different intervals between PSA determinations, and
acceleration/deceleration of PSAV and PSA-DT over time [164]. These
measurements do not provide additional information compared with PSA alone [165-168].
Prostate-specific antigen kinetics is mainly exponential, especially during
relapse. Two methods have been described to calculate PSA-DT: the 2 -points and the
log-slope method using more PSA measurements [169]. The latter is
considered more accurate as it eliminates inter- and intra-essay variations as well as any
physiological variations and potential imprecise measurements of low values [170,171]. To obtain a reliable evaluation,
at least 3 PSA measurements must be available, collected four weeks apart as a minimum from
the same clinical laboratory [164]. A minimum increase of between
0.2 and 0.4 ng/mL is required [172].
As PSA-DT values may fluctuate over time in some men, only values obtained
over the past 12 months should be considered to assess disease course [164]. The Memorial Sloan Kettering Cancer Center PSA Doubling Time
calculator is one of the most widely used tools: https://www.mskcc.org/nomograms/prostate/psa_doubling_time.
5.2.2.3.Free/total PSA ratio
Free/total (f/t) PSA must be used cautiously because it may be adversely
affected by several pre-analytical and clinical factors (e.g., instability of free PSA at
4°C and room temperature, variable assay characteristics, and concomitant BPH in large
prostates) [173]. Prostate cancer was detected in men with a PSA
4–10 ng/mL by biopsy in 56% of men with f/t PSA < 0.10, but in only 8% with f/t PSA
> 0.25 ng/mL [174]. A systematic review including 14 studies
found a pooled sensitivity of 70% in men with a PSA of 4–10 ng/mL [175]. Free/total PSA is of no clinical use if the total serum PSA
is > 10 ng/mL or during follow-up of known PCa. The clinical value of f/t PSA is limited
in light of the new diagnostic pathways incorporating MRI (see Section 5.2.4.2).
5.2.3.Biomarkers
in prostate cancer
5.2.3.1.Blood based biomarkers: PHI/4K
score/IsoPSA
Several assays measuring a panel of kallikreins in serum or plasma are now
commercially available, including the U.S. Food and Drug Administration (FDA) approved
Prostate Health Index (PHI) test (combining free and total PSA and the [-2]pro-PSA isoform
[p2PSA]), and the four kallikrein (4K) score test
(measuring free, intact and total PSA and kallikrein-like peptidase 2 [hK2] in addition to
age, DRE and prior biopsy status). Both tests are intended to reduce the number of
unnecessary prostate biopsies in PSA-tested men. A few prospective multi-centre studies
demonstrated that both the PHI and 4K score test out-performed f/t PSA PCa detection, with
an improved prediction of csPCa in men with a PSA between 2–10 ng/mL [176-179]. In a head-to-head comparison both tests performed
equally [180].
In contrast to the 4K score and PHI, which focus on the
concentration of PSA isoforms, IsoPSA utilises a novel technology which focuses on the
structure of PSA [181]. Using an aqueous two-phase solution, it
partitions the isoforms of PSA and assesses for structural changes in PSA. In a recent
multi-centre prospective validation in 271 men the assay AUC was 0.784 for high-grade vs.
low-grade cancer/benign histology, which was superior to the AUCs of total PSA and percent
free PSA [182].
5.2.3.2.Urine biomarkers: PCA3/SelectMDX/Mi
Prostate score (MiPS)/ExoDX
Prostate cancer gene 3 (PCA3) is a
prostate-specific, non-coding microRNA (mRNA) biomarker that is detectable in urine
sediments obtained after three strokes of prostatic massage during DRE. The commercially
available Progensa urine test for PCA3 is superior to
total and percent-free PSA for the detection of PCa in men with elevated PSA as it shows
significant increases in the area under the receiver-operator characteristic curve (AUC) for
positive biopsies [183-186]. PCA3 score increases with PCa volume, but there are
conflicting data about whether it independently predicts the ISUP grade [187]. Currently, the main indication for the Progensa test is to
determine whether repeat biopsy is needed after an initially negative biopsy, but its
clinical effectiveness for this purpose is uncertain [188]. Wei
et al. showed 42% sensitivity at a cut-off of 60 in the
primary biopsy setting with a high specificity (91%) and a PPV of 80% suggesting that the
assay may be used in the primary setting [189].
The SelectMDX test is similarly based on mRNA biomarker
isolation from urine. The presence of HOXC6 and DLX1 mRNA levels is assessed to provide an estimate of
the risk of both presence of PCa on biopsy as well as presence of high-risk cancer [190].
TMPRSS2-ERG fusion,
a fusion of the trans-membrane protease serine 2 (TMPRSS2) and the ERG
gene can be detected in 50% of PCas [191]. When detection of TMPRSS2-ERG in urine was added to PCA3 expression and serum PSA (Mi(chigan)Prostate Score
[MiPS]), cancer prediction improved [192]. Exosomes secreted by
cancer cells may contain mRNA diagnostic for high-grade PCa [193,194]. Use of the ExoDx Prostate IntelliScore urine exosome assay
resulted in avoiding 27% of unnecessary biopsies when compared to standard of care. However,
currently, both the MiPS-score and ExoDx assay are considered investigational.
In 6 head-to-head comparison studies of PCA3 and PHI, only Seisen et al. found a significant difference; PCA3 detected more cancers, but for the detection of
significant disease, defined as ISUP grade >
2, more than three positive cores, or > 50% cancer involvement in any core, PHI proved
superior [195]. Russo et al.
suggested in their systematic review that, based on moderate quality data, PHI and
the 4K panel had a high diagnostic accuracy and showed similar performance in predicting the
detection of significant disease with a AUC of 0.82 and 0.81, respectively [196]. However, in the screening population of the ERSPC study the
use of both PCA3 and 4K panel when added to the risk
calculator led to an improvement in AUC of less than 0.03 [197].
Based on the available evidence, some biomarkers could help in discriminating between
aggressive and non-aggressive tumours with an additional value compared to the prognostic
parameters currently used by clinicians [198]. However, upfront
multiparametric magnetic resonance imaging (mpMRI) is also likely to affect the utility of
above-mentioned biomarkers (see Section 5.2.4).
5.2.3.3.Tests to select men for a repeat
biopsy
In men with an elevated risk of PCa with a prior negative biopsy,
additional information may be gained by the Progensa-PCA3 and SelectMDX DRE urine tests, the serum 4Kscore and
PHI tests or a tissue-based epigenetic test (ConfirmMDx). The role of PHI, Progensa PCA3, and SelectMDX in deciding whether to take a repeat
biopsy in men who had a previous negative biopsy is uncertain and probably not
cost-effective [188]. The ConfirmMDx test is based on the concept
that benign prostatic tissue in the vicinity of a PCa focus shows distinct epigenetic
alterations. In case PCa is missed at biopsy, demonstration of epigenetic changes in the
benign tissue would indicate the presence of carcinoma. The ConfirmMDX test quantifies the
methylation level of promoter regions of three genes (Methylated APC, RASSF1 and
GSTP1) in benign prostatic tissue. A multi-centre study
found a NPV of 88% when methylation was absent in all three markers, implying that a repeat
biopsy could be avoided in these men [199]. Given the limited
available data and the fact that the role of mpMRI in tumour detection was not accounted
for, no recommendation can be made regarding the routine application of ConfirmMDX, in
particular in the light of current use of mpMRI before biopsy. Table 5.4 presents an
overview of the most commonly available commercial tests.
Table 5.4: Description of additional investigational tests after a
negative prostate biopsy*
|
Name of test
|
Test substrate
|
Molecular
|
FDA approved
|
|
Progensa
|
DRE urine
|
lncRNA PCA3
|
Yes
|
|
SelectMDX
|
DRE urine
|
mRNA HOXC6, DLX1
|
No
|
|
PHI
|
Serum
|
Total, free and p2PSA
|
Yes
|
|
4Kscore Test
|
Serum/plasma
|
Total, free, intact PSA, hK2
|
No
|
|
ConfirmMDX
|
Benign prostate biopsy
|
Methylated APC,
RASSF1 and GSTP1
|
No
|
*Isolated high-grade prostatic intraepithelial
neoplasia (PIN) in one or two biopsy sites is no longer an indication for repeat biopsy [200].
5.2.3.4.Guidelines for risk-assessment of
asymptomatic men
|
Recommendations
|
Strength rating
|
|
In asymptomatic men with a prostate-specific antigen
level between 2–10 ng/mL and a normal digital rectal examination, use one
oft the following tools for biopsy indication:
risk-calculator;
imaging;
|
Strong
|
|
an additional serum, urine or tissue-based
test.
|
Weak
|
5.2.4.The role
of imaging in clinical diagnosis
5.2.4.1.Transrectal ultrasound and
ultrasound-based techniques
Standard TRUS is not reliable at detecting PCa [201] and the diagnostic yield of additional biopsies performed on
hypoechoic lesions is negligible [202]. Prostate HistoScanningTM provided inconsistent results across studies [203]. New sonographic modalities such as micro-Doppler,
sonoelastography contrast-enhanced US or high-resolution micro-ultrasound provided promising
preliminary findings, either alone, or combined with so-called ‘multiparametric
US’. However, these techniques still have limited clinical appllicability due to lack
of standardisation, lack of large-scale evaluation of inter-reader variability and unclear
results in transition zones [204-206].
5.2.4.2.Multiparametric magnetic resonance
imaging
5.2.4.2.1.Multiparametric magnetic
resonance imaging performance in detecting PCa
Correlation with RP specimens shows that MRI has good sensitivity for the
detection and localisation of ISUP grade > 2
cancers, especially when their diameter is larger than 10 mm [207-209]. This good sensitivity was further confirmed in
patients who underwent template biopsies. In a recent Cochrane meta-analysis which compared
MRI to template biopsies (> 20 cores) in
biopsy-naïve and repeat-biopsy settings, MRI had a pooled sensitivity of 0.91 (95% CI:
0.83–0.95) and a pooled specificity of 0.37 (95% CI: 0.29–0.46) for ISUP grade
> 2 cancers [210].
For ISUP grade > 3 cancers, MRI pooled
sensitivity and specificity were 0.95 (95% CI: 0.87–0.99) and 0.35 (95% CI:
0.26–0.46), respectively.
MRI is less sensitive in identifying ISUP grade 1 PCa. It
identifies less than 30% of ISUP grade 1 cancers smaller than 0.5 cc identified on RP
specimens by histopathology analysis [207]. In series using template
biopsy findings as the reference standard, MRI has a pooled sensitivity of 0.70 (95% CI:
0.59–0.80) and a pooled specificity of 0.27 (95% CI: 0.19–0.37) for identifying
ISUP grade 1 cancers [210].
The probability of detecting malignancy by MRI-identified
lesions was standardised first by the use of a 5-grade Likert score [211], and then by the Prostate Imaging – Reporting and Data
System (PI-RADS) score which has been updated several times since its introduction [212,213]. In a meta-analysis of 13 studies
involving men with suspected or biopsy-proven PCa, the average PPVs for ISUP grade > 2 cancers of lesions with a PI-RADSv2 score of
3, 4 and 5 were 12%, 48% and 72% respectively, but with significant heterogeneity among
studies (Table 5.5) [214]. Another retrospective study of 3,449 men
with suspected or biopsy-proven untreated PCa imaged across 26 academic centres found
similar results with lesions of PI-RADS v2 scores of 3, 4 and 5 having a PPV for ISUP grade
> 2 cancers of 15% (95% CI: 11–19), 39%
(95% CI: 34–45) and 72% (95% CI: 61–82), respectively [215].
Table 5.5: Proportion of malignant MRI lesions by ISUP grade groups
and PI-RADS v2 scores [214]
|
PI-RADS v2
|
Total number of lesions
|
ISUP 1
|
ISUP 2
|
ISUP 3
|
ISUP > 4
|
|
3
|
707
|
14% (9.4–18.7)
|
9.3% (4.3–14.1)
|
1.5% (0.05–3)
|
0.7% (0–1.6)
|
|
4
|
886
|
21% (13.0–28.9
|
29.7% (13.9–45.5)
|
7.7% (3.4–12)
|
10.8% (5.7–15.9)
|
|
5
|
495
|
12% (5.3–18.7)
|
33.5% (8.0–59.0)
|
15.7% (6.4–25.1)
|
23% (8.2–37.9)
|
Intervals in parenthesis are 95% CIs.
5.2.4.2.2.Targeted biopsy improves the detection of ISUP
grade > 2 cancer as compared to systematic
biopsy.
In pooled data of 25 reports on agreement analysis (head-to-head
comparisons) between systematic biopsy (median number of cores, 8–15) and MRI-targeted
biopsies (MRI-TBx; median number of cores, 2–7), the detection ratio (i.e. the ratio
of the detection rates obtained by MRI-TBx alone and by systematic biopsy alone) was 1.12
(95% CI: 1.02–1.23) for ISUP grade > 2
cancers and 1.20 (95% CI: 1.06–1.36) for ISUP grade > 3 cancers, and therefore in favour of MRI-TBx.
However, the pooled detection ratios for ISUP grade > 2 cancers and ISUP grade > 3 cancers were 1.44 (95% CI: 1.19–1.75)
and 1.64 (95% CI: 1.27–2.11), respectively, in patients with prior negative systematic
biopsies, and only 1.05 (95% CI: 0.95–1.16) and 1.09 (95% CI: 0.94–1.26) in
biopsy-naïve patients [210]. Another meta-analysis of RCTs
limited to biopsy-naïve patients with a positive MRI found that MRI-TBx detected
significantly more ISUP grade > 2 cancers than
systematic biopsy (risk difference, -0.11 (95% CI: -0.2 to 0.0); p = 0.05), in prospective
cohort studies (risk difference, -0.18 (95% CI: -0.24 to -0.11); p < 0.00001), and in
retrospective cohort studies (risk difference, -0.07 (95% CI: -0.12 to -0.02); p = 0.004).
There was no significant increase in the detection rate when systematic biopsies were
combined to MRI-TBx [216].
Three prospective multi-centre trials evaluated MRI-TBx
in biopsy-naïve patients. In the PRostate Evaluation for Clinically Important Disease:
Sampling Using Image-guidance Or Not? (PRECISION) trial, 500 biopsy-naïve patients were
randomised to either MRI-TBx only or TRUS-guided systematic biopsy only. The detection rate
of ISUP grade > 2 cancers was significantly
higher in men assigned to MRI-TBx (38%) than in those assigned to SBx (26%, p = 0.005,
detection ratio 1.46) [217]. In the Assessment of Prostate MRI
Before Prostate Biopsies (MRI-FIRST) trial, 251 biopsy-naïve patients underwent
TRUS-guided systematic biopsy by an operator who was blinded to MRI findings, and MRI-TBx by
another operator. Magnetic resonance Imaging-TBx detected ISUP grade > 2 cancers in a higher percentage of patients
but the difference was not significant (32.3% vs. 29.9%, p = 0.38; detection ratio: 1.08)
[202]. However, MRI-TBx detected significantly more ISUP grade > 3 cancers than systematic biopsy (19.9% vs.
15.1%, p = 0.0095; detection ratio: 1.32). A similar trend for improved detection of ISUP
grade > 3 cancers by MRI-TBx was observed in
the Cochrane analysis; however, it was not statistically significant (detection ratio 1.11
[0.88–1.40]) [210]. The Met Prostaat MRI Meer Mans (4M) study
included 626 biopsy-naïve patients; all patients underwent systematic biopsy, and those
with a positive MRI (PI-RADSv2 score of 3–5, 51%) underwent additional in-bore
MRI-TBx. The results were close to those of the MRI-FIRST trial with a detection ratio for
ISUP grade > 2 cancers of 1.09 (detection
rate: 25% for MRI-TBx vs. 23% for systematic biopsy) [218]. However,
in this study, MRI-TBx and systematic biopsy detected an equal number of ISUP grade > 3 cancers (11% vs. 12%; detection ratio:
0.92).
The Target Biopsy Techniques Based on Magnetic Resonance
Imaging in the Diagnosis of Prostate Cancer in Patients with Prior Negative Biopsies
(FUTURE) randomised trial compared three techniques of MRI-TBx in the repeat-biopsy setting
[219]. In the subgroup of 152 patients who underwent both MRI-TBx
and systematic biopsy, MRI-TBx detected significantly more ISUP grade > 2 cancers than systematic biopsy (34% vs. 16%;
p < 0.001, detection ratio of 2.1), which is a finding consistent with the Cochrane
agreement analysis (detection ratio: 1.44). An ISUP grade > 2 cancer would have been missed in only 1.3%
(2/152) of patients, had systematic biopsy been omitted [220]. These
findings support that MRI-TBx significantly out-performs systematic biopsy for the detection
of ISUP grade > 2 in the repeat-biopsy
setting. In biopsy-naïve patients, the difference appears to be less marked but remains
in favour of MRI-TBx.
5.2.4.2.3.MRI-TBx without systematic
biopsy reduces the detection of ISUP grade 1 PCa as compared to systematic biopsy.
In pooled data of 25 head-to-head comparisons between systematic biopsy and
MRI-TBx, the detection ratio for ISUP grade 1 cancers was 0.62 (95% CI: 0.44–0.88) in
patients with prior negative biopsy and 0.63 (95% CI:
0.54–0.74) in biopsy-naïve patients [210]. In the
PRECISION and 4M trials, the detection rate of ISUP grade 1 patients was
significantly lower in the MRI-TBx group as compared to systematic biopsy (9% vs. 22%, p
< 0.001, detection ratio of 0.41 for PRECISION; 14% vs. 25%, p < 0.001, detection
ratio of 0.56 for 4M) [217,218]. In the
MRI-FIRST trial, MRI-TBx detected significantly fewer patients with clinically insignificant
PCa (defined as ISUP grade 1 and maximum cancer core length < 6 mm) than systematic
biopsy (5.6% vs. 19.5%, p < 0.0001, detection ratio of 0.29) [202]. Consequently, MRI-TBx without systematic biopsy significantly
reduces over-diagnosis of low-risk disease, as compared to systematic biopsy.
5.2.4.2.4.The added value of systematic
and targeted biopsy
Magnetic resonance imaging-targeted biopsies can be used in two different
diagnostic pathways: 1) the ‘combined pathway’, in which patients with a
positive MRI undergo combined systematic and targeted biopsy, and patients with a negative
MRI undergo systematic biopsy; 2) the ‘MRI pathway’, in which patients with a
positive MRI undergo only MRI-TBx, and patients with a negative MRI who are not biopsied at
all.
Choosing between these pathways depends not only on the
detection rates obtained by the two biopsy techniques, but also on whether or not they
detect the same patients. Many studies evaluated combined systematic and targeted biopsy in
the same patients and could therefore assess the absolute added value of each technique
(i.e. the percentage of patients diagnosed by only one biopsy technique). Data from the
Cochrane meta-analysis of these studies and from the MRI-FIRST and 4M trials suggest that
the absolute added value of MRI-TBx for detecting ISUP grade > 2 cancers is higher than that of systematic
biopsy (see Table 5.6).
Table 5.6: Absolute added values of targeted and systematic biopsies
for ISUP grade > 2 and > 3 cancer detection
|
|
ISUP > 2
|
ISUP > 3
|
|
ISUP grade
|
Cochrane meta-analysis* [210]
|
MRI-FIRST trial* [202]
|
4M trial [218]
|
Cochrane meta-analysis* [210]
|
MRI-FIRST trial* [202]
|
4M trial [218]
|
|
Biopsy-naïve
|
Added value of MRI-TBx
|
6.3%
(4.8-8.2)
|
7.6%
(4.6-11.6)
|
7.0% (ND)
|
4.7%
(3.5-6.3)
|
6.0%
(3.4-9.7)
|
3.2% (ND)
|
|
Added value of systematic biopsy
|
4.3%
(2.6-6.9)
|
5.2%
(2.8-8.7)
|
5.0% (ND)
|
2.8%
(1.7-4.8)
|
1.2%
(0.2-3.5)
|
4.1% (ND)
|
|
Overall prevalence
|
27.7% (23.7-32.6)
|
37.5% (31.4-43.8)
|
30% (ND)
|
15.5% (12.6-19.5)
|
21.1% (16.2-26.7)
|
15% (ND)
|
|
Prior negative biopsy
|
Added value of MRI-TBx
|
9.6%
(7.7-11.8)
|
-
|
-
|
6.3%
(5.2-7.7)
|
-
|
-
|
|
Added value of systematic biopsy
|
2.3%
(1.2-4.5)
|
-
|
-
|
1.1%
(0.5-2.6)
|
-
|
-
|
|
Overall prevalence
|
22.8% (20.0-26.2)
|
-
|
-
|
12.6% (10.5-15.6)
|
-
|
-
|
*Intervals in parenthesis are 95% CI.
The absolute added value of a given biopsy technique is
defined by the percentage of patients of the entire cohort diagnosed only by this biopsy
technique.
ISUP = International Society for Urological
Pathology (grade); MRI-TBx = magnetic resonance imaging-targeted biopsies;
ND = not defined.
In Table 5.6, the absolute added values refer to the percentage of patients
in the entire cohort; if the cancer prevalence is taken into account, the
‘relative’ percentage of additional detected PCa can be computed. Adding MRI-TBx
to systematic biopsy in biopsy-naïve patients increases the number of ISUP grade > 2 and grade > 3 PCa by approximately 20% and 30%,
respectively. In the repeat-biopsy setting, adding MRI-TBx increases detection of ISUP grade
> 2 and grade > 3 PCa by approximately 40% and 50%,
respectively. Omitting systematic biopsy in biopsy-naïve patients would miss
approximately 16% of ISUP grade > 2 PCa and
18% of ISUP grade > 3 PCa. In the
repeat-biopsy setting, it would miss approximately 10% of ISUP grade > 2 PCa and 9% of ISUP grade > 3 PCa.
5.2.4.2.5.Number of biopsy procedures
potentially avoided in the ‘MR pathway’
The diagnostic yield and number of biopsy procedures potentially avoided by
the ‘MR pathway’ depends on the Likert/PI-RADS threshold used to define positive
MRI. In pooled studies on biopsy-naïve patients and patients with prior negative
biopsies, a Likert/PI-RADS threshold of > 3
would have avoided 30% (95% CI: 23–38) of all biopsy procedures while missing 11% (95%
CI: 6–18) of all detected ISUP grade > 2
cancers (relative percentage) [210]. Increasing the threshold to
> 4 would have avoided 59% (95% CI:
43–78) of all biopsy procedures while missing 28% (95% CI: 14–48) of all
detected ISUP grade > 2 cancers [210]. Of note, the percentages of negative MRI (Likert/PI-RADS
score < 2) in the MRI-FIRST, PRECISION and 4M
trials were 21.1%, 28.9% and 49%, respectively [202,217,218].
5.2.4.2.6.Other considerations
5.2.4.2.6.1.Multiparametric magnetic
resonance imaging reproducibility
Despite the use of the PI-RADSv2 scoring system [212], MRI inter-reader reproducibility remains moderate at best
which currently limits its broad use by non-dedicated radiologists [221]. However, significant improvement in the accuracy of MRI and
MRI-TBx can be observed over time, both in academic and community hospitals, especially
after implementation of PI-RADSv2 scoring and multidisciplinary meetings using pathological
correlation and feedback [222-225]. An updated version of the
PI-RADS score (PI-RADSv2.1) has been recently published to improve reader reproducibility
but it has not yet been fully evaluated [213]. It is still too early
to predict whether quantitative approaches and computer-aided diagnostic systems will
improve the characterisation of lesions seen at MRI [226-228].
5.2.4.2.6.2.Targeted biopsy accuracy and
reproducibility
Clinically significant PCa not detected by the ‘MRI pathway’
can be missed because of MRI failure (invisible cancer or reader’s misinterpretation)
or because of targeting failure (target missed or undersampled by MRI-TBx). In two
retrospective studies of 211 and 116 patients with a unilateral MRI lesion, targeted biopsy
alone detected 73.5–85.5% of all csPCa (ISUP grade > 2); combining MRI-TBx with systematic biopsy
of the lobe with the MRI lesion detected 96–96.4% of all csPCas and combined targeted
and systematic biopsy of the contralateral lobe only identified 81.6–92.7% of csPCas
[229,230]. The difference may reflect
targeting errors leading to undersampling of the tumour. The accuracy of MRI-TBx is indeed
substantially impacted by the experience of the biopsy operator [221]. Increasing the number of cores taken per target may partially
compensate for guiding imprecision. In a retrospective study of 479 patients who underwent
MRI-TBx with 4 cores per target that were sequentially labelled, the first 3 cores detected
95.1% of the csPCas detected by the 4-core strategy [231]. In two
other retrospective studies of 330 and 744 patients who underwent MRI-TBx with up to 5 cores
per target, the one-core and 3-core sampling strategies detected respectively 63–75%
and 90–93% of the ISUP grade > 2 PCa
detected by the 5-core strategy [232,233].
These percentages are likely to be influenced by the lesion size and location, the prostate
volume or the operator’s experience, but no study has quantified the impact of these
factors yet.
5.2.4.2.6.3.Role of risk-stratification
Using risk-stratification to avoid biopsy procedures
Prostate-specific antigen density (PSAD) may help
refine the risk of csPCa in patients undergoing MRI as PSAD and the PI-RADS score are
significant independent predictors of csPCa at biopsy [234,235]. In a meta-analysis of 8 studies, pooled MRI NPV for ISUP
grade > 2 cancer was 84.4% (95% CI:
81.3–87.2) in the wole cohort, 82.7% (95% CI: 80.5–84.7) in biopsy-naïve
men and 88.2% (95% CI: 85–91.1) in men with prior negative biopsies. In the subgroup
of patients with PSAD < 0.15 ng/ml, NPV increased to respectively 90.4% (95% CI:
86.8–93.4), 88.7% (95% CI: 83.1–93.3) and 94.1% (95% CI: 90.9–96.6) [236]. In contrast, the risk of csPCa is as high as 27–40% in
patients with negative MRI and PSAD > 0.15–0.20 ng/mL/cc [218,235,237-240] (Table 5.7).
Combining MRI findings with the PCA3 score may also improve risk stratification [241]. Several groups have developed comprehensive risk calculators
which combine MRI findings with simple clinical data as a tool to predict subsequent biopsy
results [242]. At external validation, they tended to outperform
risk calculators not incorporating MRI findings (ERSPC and PBCG) with good discriminative
power (as measured by the AUC). However, they also tended to be miscalibrated with under- or
over-prediction of the risk of ISUP grade > 2
cancer [243,244]. In one study that
externally assessed four risk calculators combining MRI findings and clinical data, only two
demonstrated a distinct net benefit when a risk of false-negative prediction of 15% was
accepted. The others were harmful for this risk level, as compared to the ‘biopsy
all’ strategy [243]. This illustrates the
prevalence-dependence of risk models. Recalibrations taking into account the local
prevalence are possible, but this approach is difficult in routine clinical practice as the
local prevalence is difficult to estimate and may change over time.
Using risk-stratification to avoid MRI and biopsy procedures
A retrospective analysis including 200 men from a
prospective database of patients who underwent MRI and combined systematic and targeted
biopsy showed that upfront use of the Rotterdam Prostate Cancer Risk Calculator (RPCRC)
would have avoided MRI and biopsy in 73 men (37%). Of these 73 men, 10 had ISUP grade 1
cancer and 4 had ISUP grade > 2 cancer [245]. A prospective multi-centre study evaluated several diagnostic
pathways in 545 biopsy-naïve men who underwent MRI and systematic and targeted biopsy.
Using a PHI threshold of > 30 to perform MRI
and biopsy would have avoided MRI and biopsy in 25% of men at the cost of missing 8% of the
ISUP grade > 2 cancers [246]. Another prospective multi-centre trial including 532 men
(with or without history of prostate biopsy) showed that using a threshold of > 10% for the Stockholm3 test to perform MRI and
biopsy would have avoided MRI and biopsy in 38% of men at the cost of missing 8% of ISUP
grade > 2 cancers [247].
Table 5.7: Impact of the PSA density on csPCa detection rates in
patients with negative MRI findings
|
Study
|
Study design
|
Population
|
Biopsy protocol
|
csPCa definition
|
csPCa detection rate
|
|
Washino, et al.
2017 [235]
|
Retrosp.
Single-centre
|
n = 288
Biopsy naive
|
SBx (14 cores) + cognitive TBx
|
ISUP > 2 or MCCL > 4 mm
|
Whole cohort
(prevalence): 49%
PI-RADS 1-2:
0%
if PSAD < 0.15,
20% if PSAD = 0.15-0.29,
30% if
PSAD > 0.3
|
|
Distler,
et al. 2017 [234]
|
Retrosp. analysis of prospective database
Single-centre
|
n = 1,040
Biopsy naive + prior negative biopsy
|
TTP (24 cores) + fusion TBx
|
ISUP > 2
|
Whole cohort
(prevalence): 43%
PI-RADS 1-2 / Whole
cohort: 11% if PSAD < 0.15, 33% if
PSAD > 0.15
PI-RADS 1-2 / prior negative
biopsy:
7% if PSAD < 0.15,
27% if
PSAD > 0.15
|
|
Hansen,
et al. 2017 [237]
|
Retrosp.
Single-centre
|
n = 514
Prior negative biopsy or AS for ISUP 1 PCa
|
TTP (24 cores) + fusion TBx
|
ISUP > 2
|
Whole cohort
(prevalence): 31%
Likert 1-2:
9% if
PSAD < 0.10,
9% if PSAD
< 0.2,
29% if
PSAD > 0.2
|
|
Hansen,
et al. 2018 [238]
|
Retrosp.
Multi-centre
|
n = 807
Biopsy naive
|
TTP + cognitive or fusion TBx
|
ISUP > 2
|
Whole cohort
(prevalence): 49%
PI-RADS 1-2:
10%
if PSAD < 0.10,
21% if PSAD = 0.1-0.2,
33% if
PSAD > 0.2
|
|
Oishi,
et al. 2019 [239]
|
Retrosp. analysis of prospective database
Single-centre
|
n = 135
Biopsy
naive + prior negative biopsy + AS
+ Restaging
Only pts with negative
MRI (PI-RADS < 2)
|
SBx (12 cores)
|
ISUP > 2
|
Whole cohort
(prevalence): 18%
PSAD < 0.10: 6% (overall pop), 15%
(biopsy naïve), 0% (prior negative biopsy)
PSAD < 0.15: 10% (overall pop), 20%
(biopsy naïve), 0% (prior negative biopsy)
PSAD > 0.15:
40% (overall pop), 29% (biopsy naïve), 29% (prior negative biopsy)
|
|
Boesen,
et al. 2019 [240]
|
Retrosp. analysis of prospective database
Single-centre
|
n = 808
Biopsy-naive
|
SBx (10 cores) + fusion TBx
|
ISUP > 2
|
Whole cohort
(prevalence): 35%
PI-RADS 1-2:
3%
if PSAD < 0.10, 5% < 0.15,
5% if
PSAD < 0.2,
32% if PSAD > 0.2
|
|
Van der Leest, et
al. 2019 [218]
|
Prospective Multi-centre
|
n = 626
Biopsy naive
|
TTP Bx (median 24 cores) + fusion TBx
|
ISUP > 2
|
Whole cohort
(prevalence): 30%
PI-RADS 1-2:
1.3%
if PSAD < 0.10,
2% if PSAD < 0.15
|
csPCa = clinically significant prostate cancer;
Retrosp. = retrospective; n = number of patients;
SBx = systematic transrectal biopsy;
TBx = targeted biopsy; TTP = transperineal template biopsy; PSAD = PSA density; ISUP = international
Society of Urological Pathology; MCCL = maximum cancer core length.
5.2.4.2.6.4.Pre-biopsy MRI and MRI-TBx
may induce an ISUP prostate cancer grade shift, as a result of improved diagnosis
Magnetic resonance imaging findings are significant predictors of adverse
pathology features on prostatectomy specimens, and of survival-free BCR after RP or RT [82,248-250]. In addition, tumours
visible on MRI are enriched in molecular hallmarks of aggressivity, as compared to invisible
lesions [251]. Thus, MRI does identify aggressive tumours.
Nonetheless, improved targeting obtained by MRI-TBx can
artificially inflate the ISUP grade of the tumours by focusing at the areas of high-grade
cancer. As a result, ISUP grade > 2 cancers
detected by MRI-TBx are, on average, of better prognosis than those detected by the
classical diagnostic pathway. This is illustrated in a retrospective series of 1,345
patients treated by RP which showed that, in all risk groups, patients diagnosed by MRI-TBx
had better BCR-free survival than those diagnosed by systematic biopsy only [82]. To mitigate this grade shift, in case of targeted biopsies, the
2019 ISUP consensus conference recommended using an aggregated ISUP grade summarizing the
results of all biopsy cores from the same MR lesion, rather than using the result from the
core with the highest ISUP grade [85]. When long-term follow-up of
patients who underwent MRI-TBx is available, a revision of the risk-groups definition will
become necessary. In the meantime, results of MRI-TBx must be interpreted in the context of
this potential grade shift as an increasing proportion of patients diagnosed with ISUP grade
2 cancers by MRI-TBx might be eligible for AS [252].
5.2.4.2.7.Summary of evidence and
practical considerations on pre-biopsy MRI and MRI-TBx
Pre-biopsy MRI and MRI-TBx substantially improve the detection of ISUP
grade > 2 PCa. This improvement is most
notable in the repeat-biopsy setting, with marginal added value for systematic biopsies. It
is less marked in biopsy-naïve patients in whom systematic biopsy retains a higher
added value, at least for the detection of ISUP grade 2 cancers. MRI-TBx also detects
significantly less ISUP grade 1 cancers than systematic biopsies.
The ‘MRI pathway’ is appealing since it could
decrease the number of biopsy procedures, reduce the detection of low-grade PCa while
maintaining (or even improving) the detection of csPCa, as compared to systematic biopsy.
However, some cavaets need pointing out. First, MRI findings must be interpreted in the
light of the a priori risk of csPCa. Risk
stratification combining clinical data, MRI findings and (maybe) other biomarkers will help,
in the future, defining those patients that can safely avoid biopsy. Second, without
standardisation of MRI interpretation and of MRI-TBx technique the ‘MR pathway’
may lead to suboptimal care outside large-volume (expert) centres. Indeed, the inter-reader
reproducibility of MRI is moderate at best. Current biopsy-targeting methods remain
imprecise and their accuracy is substantially impacted by the operator’s experience.
As a result, 3 to 5 biopsy cores per target may be needed to reduce the risk of missing or
undersampling the lesion, even with US/MR fusion systems. Third, the use of pre-biopsy MRI
may induce grade shift, even with the use of an aggregated ISUP grade for each MR lesion
targeted at biopsy. Clinicians must interpret MRI-TBx results in the context of this
potential grade shift. A revision of the definitions of the risk groups will be needed in
the future to take into account wider use of MRI and MRI-TBx.
Finally, it must be emphasised that the ‘MR
pathway’ has only been evaluated in patients in whom the risk of csPCa was judged high
enough to deserve biopsy. Pre-biopsy MRI must not be used in patients who do not have an
indication for prostate biopsy based on their family history or clinical and biochemical
data. Because of its low specificity, MRI in very low-risk patients would result in an
inflation of false-positive findings and subsequent unnecessary biopsies.
5.2.4.3.Guidelines for imaging in PCa
detection
|
Introductory statement
|
LE
|
|
Systematic biopsy is an acceptable approach in case
magnetic resonance imaging (MRI) is unavailable.
|
3
|
|
Recommendations for all patients
|
Strength rating
|
|
Do not use
multiparametric magnetic resonance imaging (mpMRI) as an initial screening
tool.
|
Strong
|
|
Adhere to PI-RADS guidelines for mpMRI acquisition
and interpretation and evaluate mpMRI results in multidisciplinary meetings with
pathological feedback.
|
Strong
|
|
Recommendations in biopsy naïve patients
|
Strength rating
|
|
Perform mpMRI before prostate biopsy.
|
Strong
|
|
When mpMRI is positive (i.e. PI-RADS > 3), combine targeted and
systematic biopsy.
|
Strong
|
|
When mpMRI is negative (i.e., PI-RADS < 2), and clinical suspicion of PCa
is low, omit biopsy based on shared decision-making with the patient.
|
Weak
|
|
Recommendations in patients with prior negative
biopsy
|
Strength rating
|
|
Perform mpMRI before prostate biopsy.
|
Strong
|
|
When mpMRI is positive (i.e. PI-RADS > 3), perform targeted biopsy only.
|
Weak
|
|
When mpMRI is negative (i.e., PI-RADS < 2), and clinical suspicion of PCa
is high, perform systematic biopsy based on shared share decision-making with
the patient.
|
Strong
|
5.2.5.Baseline
biopsy
The need for prostate biopsy is based on PSA level, other biomarkers and/or
suspicious DRE and/or imaging (see Section 5.2.4). Age, potential co-morbidity and
therapeutic consequences should also be considered and discussed beforehand [253]. Risk stratification is a potential tool for reducing
unnecessary biopsies [253].
Limited PSA elevation alone should not prompt immediate
biopsy. Prostate-specific antigen level should be verified after a few weeks, in the same
laboratory using the same assay under standardised conditions (i.e. no ejaculation,
manipulations, and urinary tract infections [UTIs]) [254,255]. Empiric use of antibiotics in an asymptomatic patient in
order to lower the PSA should not be undertaken [256].
Ultrasound (US)-guided biopsy is now the standard of
care. Prostate biopsy is performed by either the transrectal or transperineal approach.
Cancer detection rates, when performed without prior imaging with MRI, are comparable
between the two approaches [257], however, some evidence suggests
reduced infection risk with the transperineal route (see Section 5.2.6.4) [258,259].
Transurethral resection
of the prostate (TURP) should not be used as a tool for cancer detection [260].
5.2.6.Repeat
biopsy
5.2.6.1.Repeat biopsy after previously
negative biopsy
The indications for repeat biopsy are:
- rising and/or persistently elevated PSA (see Table 5.3 for risk estimates);
- suspicious DRE, 5–30% PCa risk [153,154];
- intraductal carcinoma as a solitary finding, > 90% risk of associated high-grade PCa
[261];
- positive mpMRI findings (see Section 5.2.4.2).
The recommendation to perform a repeat biopsy after a diagnosis of atypical
small acinar proliferation and extensive high-grade PIN is based on earlier studies on
systematic biopsies using a 6–10 core biopsy protocol. In a contemporary series of
biopsies the likelihood of finding a csPCa after follow-up biopsy after a diagnosis of
atypical small acinar proliferation was only 6% [262].
The added value of other biomarkers remains unclear (see
Sections 5.2.3.1 and 5.2.3.2).
5.2.6.2.Saturation biopsy
The incidence of PCa detected by saturation repeat biopsy (> 20 cores)
is 30–43% and depends on the number of cores sampled during earlier biopsies [263]. Saturation biopsy may be performed with the transperineal
technique, which detects an additional 38% of PCa. The rate of urinary retention varies
substantially from 1.2% to 10% [264-267].
5.2.7.Prostate
biopsy procedure
5.2.7.1.Sampling sites and number of cores
On baseline biopsies, where no prior imaging with mpMRI has been performed,
or where mpMRI has not shown any suspicious lesion, the sample sites should be bilateral
from apex to base, as far posterior and lateral as possible in the peripheral gland.
Additional cores should be obtained from suspect areas identified by DRE; suspect areas on
TRUS might be consideration for additional biopsies. Sextant biopsy is no longer considered
adequate. At least 8 systematic biopsies are recommended in prostates with a size of about
30 cc [268]. Ten to 12 core biopsies are recommended in larger
prostates, with > 12 cores not being significantly more conclusive [269,270].
Eighteen to 24 template cores may be taken in
transperineal biopsy with acceptable morbidity, but it is unknown whether this number
improves detection of significant cancer [271-273]. As per
transrectal biopsy, for maximal detection of significant cancer, cores should be directed
towards the peripheral zone posteriorly and laterally, but in transperineal biopsy can also
more easily be directed to the anterior horns of the peripheral zone as well. In the setting
of a positive MRI with targeted biopsy cores being taken, the addition of template cores may
increase the detection of significant cancer slightly, but also increases the detection of
insignificant cancer [274,275]. The optimal
number of template cores in this setting is unknown.
Where mpMRI has shown a suspicious lesion MR-TBx can be obtained through
cognitive guidance, US/MR fusion software or direct in-bore guidance. Current literature,
including systematic reviews and meta-analyses, does not show a clear superiority of one
image-guided technique over another [219,276-279]. However, regarding approach, the only systematic
review and meta-analysis comparing MRI-targeted transrectal biopsy to MRI-targeted
transperineal biopsy, analysing 8 studies, showed a higher sensitivity for detection of
csPCa when the transperineal approach was used (86% vs. 73%) [280].
This benefit was especially pronounced for anterior tumours. Multiple (3–5) cores
should be taken from each lesion (see Section 5.2.4.2.7.2).
5.2.7.2.Antibiotics prior to biopsy
5.2.7.2.1.Transperineal prostate biopsy
A total of seven randomised studies including 1,330 patients compared the
impact of biopsy route on infectious complications. Infectious complications were
significantly higher following transrectal biopsy (37 events among 657 men) compared to
transperineal biopsy (22 events among 673 men) (RR: 1.81 [range 1.09–3.00], 95% CI)
[281-288]. In addition, a systematic review including 165
studies with 162,577 patients described sepsis rates of 0.1% and 0.9% for transperineal and
transrectal biopsies, respectively [289]. Finally, a
population-based study from the UK (n = 73,630) showed lower re-admission rates for sepsis
in patients who had transperineal vs. transrectal biopsies (1.0% vs. 1.4%, respectively) [290]. The available evidence demonstrates that the transrectal
approach should be abandoned in favour of the transperineal approach despite any possible
logistical challenges.
To date, no RCT has been published investigating different antibiotic
prophylaxis regimens for transperineal prostate biopsy. However, as it is a clean procedure
that avoids rectal flora, quinolones or other antibiotics to cover rectal flora may not be
necessary. A single dose of cephalosporin only to cover skin commensals has been shown to be
sufficient in multiple single cohort series [267,291]. Prior negative mid-stream urine (MSU) test and routine
surgical disinfecting preparation of the perineal skin are mandatory. In one of the largest
studies to date, 1,287 patients underwent transperineal biopsy under local anaesthesia only
[292]. Antibiotic prophylaxis consisted of a single oral dose of
either cefuroxime or cephalexin. Patients with cardiac valve replacements received
amoxycillin and gentamicin, and those with severe penicillin allergy received
sulphamethoxazole. No quinolones were used. Only one patient developed a UTI with positive
urine culture and there was no urosepsis requiring hospitalisation.
In another study of 577 consecutive patients undergoing
transperineal biopsy using single dose IV cephazolin prophylaxis, one patient (0.2%)
suffered prostatitis not requiring hospitalisation [267]. There were
no incidences of sepsis. In a further study of 485 patients using only cephazolin, 4
patients (0.8%) suffered infectious complications [293].
5.2.7.2.2.Transrectal prostate biopsy
Meta-analysis of eight RCTs including 1,786 men showed that use of a rectal
povidone-iodine preparation before biopsy, in addition to antimicrobial prophylaxis,
resulted in a significantly lower rate of infectious complications (RR [95% CIs] 0.55
[0.41–0.72]) [288,294-299]. Single
RCTs showed no evidence of benefit for perineal skin disinfection [300], but reported an advantage for rectal povidone-iodine
preparation before biopsy compared to after biopsy [301].
A meta-analysis of four RCTs including 671 men evaluated
the use of rectal preparation by enema before transrectal biopsy. No significant advantage
was found regarding infectious complications (RR [95% CIs] 0.96 [0.64–1.54]) [288,302-304].
A meta-analysis of 26 RCTs with 3,857 patients found no
evidence that use of peri-prostatic injection of local anaesthesia resulted in more
infectious complications than no injection (RR [95% CIs] 1.07 [0.77-1.48]) [288]. A meta-analysis of 9 RCTs including 2,230 patients found that
extended biopsy templates showed comparable infectious complications to standard templates
(RR [95% CIs] 0.80 [0.53-1.22]) [288]. Additional meta-analyses
found no difference in infections complications regarding needle guide type (disposable vs.
reusable), needle type (coaxial vs. non-coaxial), needle size (large vs. small), and number
of injections for peri-prostatic nerve block (standard vs. extended) [288].
A meta-analysis of eleven studies with 1,753 patients showed significantly
reduced infections after transrectal prostate biopsy when using antimicrobial prophylaxis as
compared to placebo/control (RR [95% CI] 0.56 [0.40–0.77]) [305].
Fluoroquinolones have been traditionally used for
antibiotic prophylaxis in this setting; however, overuse and misuse of fluoroquinolones has
resulted in an increase in fluoroquinolone resistance. In addition, the European Commission
has implemented stringent regulatory conditions regarding the use of fluoroquinolones
resulting in the suspension of the indication for peri-operative antibiotic prophylaxis
including prostate biopsy [306].
A systematic review and meta-analysis on antibiotic
prophylaxis for the prevention of infectious complications following prostate biopsy
concluded that in countries where fluoroquinolones are allowed as antibiotic prophylaxis, a
minimum of a full one-day administration, as well as targeted therapy in case of
fluoroquinolone resistance, or augmented prophylaxis (combination of two or more different
classes of antibiotics) is recommended [305]. In countries where use
of fluoroquinolones are suspended, cephalosporins or aminoglycosides can be used as
individual agents with comparable infectious complications based on a meta-analysis of two
RCTs [305]. A meta-analysis of three RCTs reported that fosfomycin
trometamol was superior to fluoroquinolones (RR [95% CI] 0.49 [0.27–0.87]) [305], but routine general use should be critically assessed due to
the relevant infectious complications reported in non-randomised studies [307]. Another possibility is the use of augmented prophylaxis
without fluoroquinolones, although no standard combination has been established to date.
Finally, targeted prophylaxis based on rectal swap/stool culture is plausible, but no RCTs
are available on non-fluoroquinolones. See figure 5.1 for prostate biopsy workflow to reduce
infections complications.
Based on a meta-analysis, suggested antimicrobial prophylaxis before
transrectal biopsy may consist of:
1.Targeted
prophylaxis - based on rectal swab or stool culture.
2.Augmented
prophylaxis - two or more different classes of antibiotics (of note: this option is against
antibiotic stewardship programmes).
3.Alternative
antibiotics:
fosfomycin trometamol (e.g., 3 g before and 3 g
24–48 hrs. after biopsy);
cephalosporin (e.g.,
ceftriaxone 1 g i.m; cefixime 400 mg p.o for 3 days starting 24 hrs. before biopsy)
aminoglycoside (e.g., gentamicin 3 mg/kg i.v.; amikacin 15 mg/kg i.m).
5.2.7.3.Summary of evidence and
recommendations for performing prostate biopsy (in line with the Urological Infections
Guidelines Panel)
|
Summary of evidence
|
LE
|
|
A meta-analysis of seven studies including 1,330
patients showed significantly reduced infectious complications in patients
undergoing transperineal biopsy as compared to transrectal biopsy.
|
1a
|
|
Meta-analysis of eight RCTs including 1,786 men
showed that use of a rectal povidone-iodine preparation before transrectal
biopsy, in addition to antimicrobial prophylaxis, resulted in a
significantly lower rate of infectious complications.
|
1a
|
|
A meta-analysis on eleven studies with 1,753
patients showed significantly reduced infections after transrectal biopsy
when using antimicrobial prophylaxis as compared to placebo/control.
|
1a
|
|
Recommendations
|
Strength rating*
|
|
Perform prostate
biopsy using the transperineal approach due to the lower risk of
infectious complications.
|
Strong
|
|
Use routine surgical disinfection of the perineal
skin for transperineal biopsy.
|
Strong
|
|
Use rectal cleansing with povidone-iodine in men
prior to transrectal prostate biopsy.
|
Strong
|
|
Do not use fluoroquinolones for prostate biopsy
in line with the European Commission final decision on EMEA/H/A-31/1452.
|
Strong
|
|
Use either target
prophylaxis based on rectal swab or stool culture; augmented prophylaxis
(two or more different classes of antibiotics); or alternative
antibiotics (e.g., fosfomycin trometamol, cephalosporin, aminoglycoside)
for antibiotic prophylaxis for transrectal biopsy.
|
Weak
|
|
Use a single oral dose of either cefuroxime or
cephalexin or cephazolin as antibiotic prophylaxis for transperineal biopsy.
Patients with severe penicillin allergy may be given sulphamethoxazole.
|
Weak
|
|
Ensure that prostate core biopsies from different
sites are submitted separately for processing and pathology reporting.
|
Strong
|
*Note on strength ratings:
The above strength ratings are explained here due to the major
clinical implications of these new recommendations. Although data showing the lower risk
of infection via the transperineal approach is low in certainty, its statistical and
clinical significance warrants its Strong rating. Strong ratings are also given for
routine surgical disinfection of skin in transperineal biopsy and povidone-iodine rectal
cleansing in transrectal biopsy as, although quality of data is low, the clinical
benefit is high and practical application simple. A ‘Strong’ rating is given
for avoiding fluoroquinolones in prostate biopsy due to its legal implications in
Europe.
Figure 5.1: Prostate biopsy workflow to reduce infectious
complications*
GRADE Working Group grades of evidence.
• High certainty: (⊕⊕⊕⊕) very confident that the true
effect lies close to that of the estimate of the effect.
• Moderate certainty: (⊕⊕⊕⊖) moderately confident in the effect
estimate:
the true effect is likely to be close to the estimate of the effect, but there is a
possibility that it is substantially different.
• Low certainty: (⊕⊕⊖⊖) confidence in the effect estimate
is
limited: the true effect may be substantially different from the estimate of the effect.
• Very low certainty: (⊕⊖⊖⊖) very little confidence in the
effect estimate: the true effect is likely to be substantially different from the
estimate of effect.
*Figure adapted from Pilatz et al., [308] with permission
from Elsevier.
5.2.7.4.Local anaesthesia prior to
biopsy
Ultrasound-guided peri-prostatic block is recommended [309]. It is not important whether the depot is apical or basal.
Intra-rectal instillation of local anaesthesia is inferior to peri-prostatic
infiltration [310]. Local anaesthesia can also be used
effectively for mpMRI-targeted and systemic transperineal biopsy [311]. Patients are placed in the lithotomy position.
Bupivacaine is injected into the perineal skin and subcutaneous tissues, followed two
minutes later by a peri-prostatic block. A systematic review evaluating pain in 3
studies comparing transperineal vs. transrectal biopsies found that the transperineal
approach significantly increased patient pain (RR: 1.83 [1.27–2.65]) [312]. In a randomised comparison a combination of
peri-prostatic and pudendal block anaesthesia reduced pain during transperineal biopsies
compared to peri-prostatic anaesthesia only [313]. Targeted
biopsies can then be taken via a brachytherapy grid or a freehand needle-guiding device
under local infiltration anaesthesia [311,314,315].
5.2.7.5.Complications
Complications of TRUS biopsy are listed in Table 5.8 [316]. Mortality after prostate biopsy is extremely rare and
most are consequences of sepsis [111]. Low-dose aspirin is no
longer an absolute contraindication [317]. A systematic review
found favourable infection rates for transperineal compared to TRUS biopsies with
similar rates of haematuria, haematospermia and urinary retention [318]. A meta-analysis of 4,280 men randomised between
transperineal vs. TRUS biopsies in 13 studies found no significant differences in
complication rates, however, data on sepsis compared only 497 men undergoing TRUS biopsy
to 474 having transperineal biopsy. The transperineal approach required more (local)
anaesthesia [257].
Table 5.8: Percentage of complications per TRUS biopsy session,
irrespective of the number of cores
|
Complications
|
Percentage of patients affected
|
|
Haematospermia
|
37.4
|
|
Haematuria > 1 day
|
14.5
|
|
Rectal bleeding < 2 days
|
2.2
|
|
Prostatitis
|
1.0
|
|
Fever > 38.5°C
|
0.8
|
|
Epididymitis
|
0.7
|
|
Rectal bleeding > 2 days +/−
surgical intervention
|
0.7
|
|
Urinary retention
|
0.2
|
|
Other complications requiring hospitalisation
|
0.3
|
5.2.7.6.Seminal vesicle biopsy
Indications for seminal vesicle (SV) (staging) biopsies are poorly
defined. At a PSA of > 15 ng/mL, the odds of tumour involvement are 20–25% [319]. A SV staging biopsy is only useful if it has a decisive
impact on treatment, such as ruling out radical tumour resection or for potential
subsequent RT. Its added value compared with mpMRI is questionable.
5.2.7.7.Transition zone biopsy
Transition zone sampling during baseline biopsies has a low detection
rate and should be limited to MRI-detected lesions or repeat biopsies [320].
5.2.8.Pathology
of prostate needle biopsies
5.2.8.1.Processing
Prostate core biopsies from different sites are processed separately.
Before processing, the number and length of the cores are recorded. The length of biopsy
tissue significantly correlates with the PCa detection rate [321].
To achieve optimal flattening and alignment, a maximum of
three cores should be embedded per tissue cassette, and sponges or paper used to keep
the cores stretched and flat [322,323].
To optimise detection of small lesions, paraffin blocks should be cut at three levels
and intervening unstained sections may be kept for immunohistochemistry (IHC) [320].
5.2.8.2.Microscopy and reporting
Diagnosis of PCa is based on histology. The diagnostic criteria include
features pathognomonic of cancer, major and minor features favouring cancer and features
against cancer. Ancillary staining and additional (deeper) sections should be considered
if a suspect lesion is identified [324-326]. Diagnostic
uncertainty is resolved by intradepartmental or external consultation [324]. Section 5.2.8.3 lists the recommended terminology for
reporting prostate biopsies [322]. Type and subtype of PCa
should be reported such as for instance acinar adenocarcinoma (> 95% of PCa), ductal
adenocarcinoma (< 5%) and poorly differentiated small or large cell neuroendocrine
carcinoma (< 1%), even if representing a small proportion of the PCa. The distinct
aggressive nature of ductal adenocarcinoma and small/large cell neuroendocrine carcinoma
should be commented upon in the pathology report [322].
5.2.8.2.1.Recommended terminology for
reporting prostate biopsies [255]
|
Recommendations
|
Strength rating
|
|
Benign/negative for malignancy; if appropriate,
include a description.
|
Strong
|
|
Active inflammation.
|
|
Granulomatous inflammation.
|
|
High-grade prostatic intraepithelial neoplasia
(PIN).
|
|
High-grade PIN with atypical glands, suspicious
for adenocarcinoma (PINATYP).
|
|
Focus of atypical glands/lesion suspicious for
adenocarcinoma/atypical small acinar proliferation, suspicious for cancer.
|
|
Adenocarcinoma, provide type and subtype.
|
|
Intraductal carcinoma.
|
Each biopsy site should be reported individually, including its
location (in accordance with the sampling site) and histopathological findings, which
include the histological type and the ISUP 2014 grade [84]. For
mpMRI targeted biopsies consisting of multiple cores per target the aggregated ISUP
grade and percentage of high-grade carcinoma should be reported per targeted lesion [85]. If the targeted biopsies are negative, presence of specific
benign pathology should be mentioned, such as dense inflammation, fibromuscular
hyperplasia or granulomatous inflammation [327]. A global ISUP
grade comprising all systematic (non-targeted) biopsies is also reported (see Section
4.2). The global ISUP grade takes into account all systemic biopsies positive for
carcinoma, by estimating the total extent of each Gleason grade present. For instance,
if three biopsy sites are entirely composed of Gleason grade 3 and one biopsy site of
Gleason grade 4 only, the global ISUP grade would be 2 (i.e. GS 7[3+4]) or 3 (i.e. GS
7[4+3]), dependent on whether the extent of Gleason grade 3 exceeds that of Gleason
grade 4, whereas the worse grade would be ISUP grade 4 (i.e. GS 8[4+4]). Recent
publications demonstrated that global ISUP grade is somewhat superior in predicting
prostatectomy ISUP grade [328] and BCR [329].
Lymphovascular invasion (LVI) and extraprostatic
extension (EPE) must each be reported, if identified. More recently, expansile
cribriform pattern of PCa as well as intraductal carcinoma in biopsies were identified
as independent prognosticators of metastatic disease [330] and
PCa-specific survival [331] and presence of both adverse
pathologies should be reported [85].
The proportion of systematic (non-targeted)
carcinoma-positive cores as well as the extent of tumour involvement per biopsy core
correlate with the ISUP grade, tumour volume, surgical margins and pathologic stage in
RP specimens and predict BCR, post-prostatectomy progression and RT failure. These
parameters are included in nomograms created to predict pathologic stage and SV invasion
after RP and RT failure [332-334]. A pathology report should
therefore provide both the proportion of carcinoma-positive cores and the extent of
cancer involvement for each core. The length in mm and percentage of carcinoma in the
biopsy have equal prognostic impact [335]. An extent of > 50%
of adenocarcinoma in a single core is used in some AS protocols as a cut off [336] triggering immediate treatment vs. AS in patients with
ISUP grade 1.
A prostate biopsy that does not contain glandular tissue should be
reported as diagnostically inadequate. Mandatory elements to be reported for a
carcinoma-positive prostate biopsy are:
- type of carcinoma;
- primary and secondary/worst Gleason grade (per biopsy site and global);
- percentage high-grade carcinoma (global);
- extent of carcinoma (in mm or percentage) (per biopsy site);
- if present: EPE, SV invasion, LVI, intraductal
carcinoma/cribriform pattern, peri-neural invasion;
- ISUP grade (global);
- In targeted biopsies aggregate ISUP grade and percentage high-grade carcinoma per
targeted site;
- In carcinoma-negative targeted biopsy report specific benign pathology, e.g.,
fibromuscular hyperplasia or granulomatous inflammation, if present [85];
5.2.8.3.Tissue-based prognostic
biomarker testing
After a comprehensive literature review and several panel discussions
an ASCO-EAU-AUA multidisciplinary expert panel made recommendations regarding the use of
tissue-based PCa biomarkers. The recommendations were limited to 5 commercially
available tests (Oncotype Dx®, Prolaris®, Decipher®,
Decipher PORTOS and ProMark®) with extensive
validation in large retrospective studies and evidence that their test results might
actually impact clinical decision-taking [337].
The selected commercially available tests significantly improved the
prognostic accuracy of clinical multivariable models for identifying men who would
benefit of AS and those with csPCa requiring curative treatment, as well as for guidance
of patient management after RP. In addition, a few studies showed that tissue biomarker
tests and MRI findings independently improved the detection of clinically significant
cancer in an AS setting, but it remains unclear which men would benefit of both tests.
Since the long-term impact of the use of these commercially available tests on
oncological outcome remains unproven and prospective trials are largely lacking, the
Panel concluded that these tests should not be offered routinely but only in subsets of
patients where the test result provides clinically actionable information, such as for
instance in men with favourable intermediate-risk PCa who might opt for AS or men with
unfavourable intermediate-risk PCa scheduled for RT to decide on treatment
intensification with hormonal therapy (HT).
5.2.8.4.Histopathology of radical
prostatectomy specimens
5.2.8.4.1.Processing of radical
prostatectomy specimens
Histopathological examination of RP specimens describes the
pathological stage, histopathological type, grade and surgical margins of PCa. It is
recommended that RP specimens are totally embedded to enable assessment of cancer
location, multifocality and heterogeneity. For cost-effectiveness, partial embedding may
also be considered, particularly for prostates > 60 g. The most widely accepted
method includes complete embedding of the posterior prostate and a single mid-anterior
left and right section. Compared with total embedding, partial embedding detected 98% of
PCa with an ISUP grade > 2 with accurate
staging in 96% of cases [338].
The entire RP specimen should be inked upon receipt in the laboratory
to demonstrate the surgical margins. Specimens are fixed by immersion in buffered
formalin for at least 24 hours, preferably before slicing. Fixation can be enhanced by
injecting formalin which provides more homogeneous fixation and sectioning after 24
hours [339]. After fixation, the apex and the base (bladder
neck) are removed and cut into (para)sagittal or radial sections; the shave method is
not recommended [83]. The remainder of the specimen is cut in
transverse, 3–4 mm sections, perpendicular to the long axis of the urethra. The
resultant tissue slices can be embedded and processed as whole-mounts or after quadrant
sectioning. Whole-mounts provide better topographic visualisation, faster
histopathological examination and better correlation with pre-operative imaging,
although they are more time-consuming and require specialist handling. For routine
sectioning, the advantages of whole mounts do not outweigh their disadvantages.
5.2.8.4.1.1.Guidelines for
processing prostatectomy specimens
|
Recommendations
|
Strength rating
|
|
Ensure total embedding, by conventional
(quadrant) or whole-mount sectioning.
|
Strong
|
|
Ink the entire surface before cutting, to
evaluate the surgical margin.
|
Strong
|
|
Examine the apex and base separately, using the
cone method with sagittal or radial sectioning.
|
Strong
|
5.2.8.4.2.Radical prostatectomy
specimen report
The pathology report provides essential information on the prognostic
characteristics relevant for clinical decision-making (Table 5.9). As a result of the
complex information to be provided for each RP specimen, the use of synoptic(-like) or
checklist reporting is recommended (Table 5.10). Synoptic reporting results in more
transparent and complete pathology reporting [340].
Table 5.9: Mandatory elements provided by the pathology report
|
Histopathological type: > 95% of PCa
represents conventional (acinar) adenocarcinoma.
|
|
Grading according to ISUP grade (or not
applicable if therapy-related changes).
|
|
Presence of intraductal and/or cribriform
carcinoma.
|
|
Tumour (sub)staging and surgical margin status:
location and extent of EPE, presence of bladder neck invasion, laterality of
EPE or SV invasion, location and extent of positive surgical margins.
|
|
Additional information may be provided on
multifocality, and diameter/volume and zonal location of the dominant
tumour.
|
Table 5.10: Example checklist: reporting of prostatectomy
specimens
|
Histopathological type
|
|
Type of carcinoma, e.g. conventional acinar, or
ductal
|
|
Histological grade
|
|
Primary (predominant) Gleason grade
Secondary Gleason grade
Tertiary Gleason grade (if applicable)
Global ISUP grade
Approximate percentage of Gleason grade 4 or 5
|
|
Tumour quantitation (optional)
|
|
Percentage of prostate involved
Size/volume of dominant tumour nodule
|
|
Pathological staging (pTNM)
|
|
If extraprostatic extension is present:
indicate whether it is focal or
extensive*;
specify sites;
indicate whether there is seminal vesicle
invasion.
If applicable, regional lymph nodes:
location;
number of nodes retrieved;
number of nodes involved.
|
|
Surgical margins
|
|
If carcinoma is present at the margin:
specify sites.
|
|
Other
|
|
Presence of lymphovascular/angio-invasion
Location of dominant tumour
Presence of intraductal carcinoma/cribriform
architecture
|
*Focal is defined as carcinoma glands
extending less than 1 high-power field (HPF) in the extraprostatic fat in 1 or 2 sections
and extensive is extension beyond or
in more sections.
5.2.8.4.3.ISUP grade in prostatectomy
specimens
Grading of conventional prostatic adenocarcinoma using the (ISUP 2014
modified) Gleason system is the strongest prognostic factor for clinical behaviour and
treatment response [84]. The ISUP grade is incorporated in
nomograms that predict disease-specific survival (DSS) after prostatectomy [341].
The ISUP grade is based on the sum of the most and second-most dominant
(in terms of volume) Gleason grade. ISUP grade 1 is GS 6. ISUP grades 2 and 3 represent
carcinomas constituted of Gleason grade 3 and 4 components, with ISUP grade 2 when 50%
of the carcinoma, or more, is Gleason grade 3 and ISUP grade 3 when the grade 4
component represents more than 50% of the carcinoma. In a carcinoma almost entirely
composed of Gleason grade 3 the presence of a minor (< 5%) Gleason pattern 4
component is not included in the Gleason score (ISUP grade 1), but its presence is
commented upon.
ISUP grade 4 is largely composed of Gleason grade 4
and ISUP grade 5 of a combination of Gleason grade 4 and 5 or only Gleason grade 5. A
global ISUP grade is given for multiple tumours, but a separate tumour focus with a
higher ISUP grade should also be mentioned. Tertiary Gleason grade 5, if > 5% of the
PCa volume, is an unfavourable prognostic indicator for BCR and should be incorporated
in the ISUP grade. If less than 5% its presence should be mentioned in the report [85,342].
5.2.8.4.4.Definition of extraprostatic
extension
Extraprostatic extension is defined as carcinoma mixed with
peri-prostatic adipose tissue, or tissue that extends beyond the prostate gland
boundaries (e.g., neurovascular bundle, anterior prostate). Microscopic bladder neck
invasion is considered EPE. It is useful to report the location and extent of EPE
because the latter is related to recurrence risk [343].
There are no internationally accepted definitions of
focal or microscopic, vs. non-focal or extensive EPE. Some describe focal as a few
glands [344] or < 1 HPF in one or at most two sections [345] whereas others measure the depth of extent in millimetres
[346].
At the apex of the prostate, tumour mixed with
skeletal muscle does not constitute EPE. In the bladder neck, microscopic invasion of
smooth muscle fibres is not equated to bladder wall invasion, i.e. not as pT4, because
it does not carry independent prognostic significance for PCa recurrence and should be
recorded as EPE (pT3a) [347,348]. Stage
pT4 is only assigned when the tumour invades the bladder muscle wall as determined
macroscopically [349].
5.2.8.4.5.PCa volume
The independent prognostic value of PCa volume in RP specimens has not
been established [345,350-353].
Nevertheless, a cut-off of 0.5 mL is traditionally used to distinguish insignificant
from clinically relevant cancer [350]. Improvement in prostatic
radio-imaging allows more accurate pre-operative measurement of cancer volume. It is
recommended that at least the diameter/volume of the dominant tumour nodule should be
assessed, or a rough estimate of the percentage of cancer tissue provided [354].
5.2.8.4.6.Surgical margin status
Surgical margin is an independent risk factor for BCR. Margin status is
positive if tumour cells are in contact with the ink on the specimen surface. Margin
status is negative if tumour cells are close to the inked surface [351] or at the surface of the tissue lacking ink. In tissues
that have severe crush artefacts, it may not be possible to determine margin status [355].
Surgical margin is separate from pathological stage,
and a positive margin is not evidence of EPE [356]. There is
insufficient evidence to prove a relationship between margin extent and recurrence risk
[345]. However, some indication must be given of the
multifocality and extent of margin positivity, such as the linear extent in mm of
involvement: focal, < 1 mm vs. extensive,
> 1 mm [357], or number of blocks with positive margin
involvement. Gleason score at the positive margin was found to correlate with outcome,
and should be reported [313].
5.3.Diagnosis - Clinical Staging
5.3.1.T-staging
The cT category used in the risk table only refers to the DRE finding.
The imaging parameters and biopsy results for local staging are, so far, not part of the
risk category stratification [358].
5.3.1.1.TRUS
Transrectal ultrasound is no more accurate at predicting organ-confined
disease than DRE [359]. Some single-centre studies reported good
results in local staging using 3D TRUS or colour Doppler but these good results were not
confirmed by large-scale studies [360,361].
5.3.1.2.MRI
T2-weighted imaging remains the most useful method for local staging on
MRI. At 1.5 Tesla, MRI has good specificity but low sensitivity for detecting T3 stages.
Pooled data from a meta-analysis showed a sensitivity and specificity of 0.57 (95% CI:
0.49–0.64) and 0.91 (95% CI: 0.88–0.93), 0.58 (95% CI: 0.47–0.68) and
0.96 (95% CI: 0.95–0.97), and 0.61 (95% CI: 0.54–0.67) and 0.88 (95% CI:
0.85–0.91), for EPE, SVI, and overall stage T3 assessement, respectively [362]. Magnetic resonance imaging cannot detect microscopic EPE.
Its sensitivity increases with the radius of extension within peri-prostatic fat. In one
study, the EPE detection rate increased from 14 to 100% when the radius of extension
increased from < 1 mm to > 3 mm [363]. In another study,
MRI sensitivity, specificity and accuracy for detecting pT3 stage were 40%, 95% and 76%,
respectively, for focal (i.e. microscopic) EPE, and 62%, 95% and 88% for extensive EPE
[364].
The use of high field strength (3 Tesla) or
functional imaging in addition to T2-weighted imaging improves sensitivity for EPE or
SVI detection [362] but the experience of the reader remains of
paramount importance [365] and the inter-reader agreement
remains moderate with kappa values ranging from 0.41 to 0.68 [366].
Several series suggested that MRI findings could
improve the prediction of the pathological stage when combined with clinical and biopsy
data [248]. However, all these studies were based on cohorts of
men diagnosed with systematic biopsy and their generalisability in the targeted biopsy
setting is questionable. For risk calculators predicting EPE and SVI based on MRI
findings, clinical data and combined systematic and targeted biopsy results have been
recently reported [367], but they have not undergone external
validation yet.
Given its low sensitivity for focal (microscopic)
EPE, MRI is not recommended for local staging in low-risk patients [368-370]. However, MRI can still be useful for treatment
planning.
5.3.2.N-staging
5.3.2.1.Computed tomography and magnetic
resonance imaging
Abdominal CT and T1-T2-weighted MRI indirectly assess nodal invasion by
using LN diameter and morphology. However, the size of non-metastatic LNs varies widely
and may overlap the size of LN metastases. Usually, LNs with a short axis > 8 mm in
the pelvis and > 10 mm outside the pelvis are considered malignant. Decreasing these
thresholds improves sensitivity but decreases specificity. As a result, the ideal size
threshold remains unclear [371,372].
Computed tomography (CT) and MRI sensitivity is less than 40% [373,374]. Among 4,264 patients, 654
(15.3%) of whom had positive LNs at LND, CT was positive in only 105 patients (2.5%) [371]. In a multi-centre database of 1,091 patients who
underwent pelvic LN dissection, CT sensitivity and specificity were 8.8% and 98%,
respectively [375]. Detection of microscopic LN invasion by CT
is < 1% in patients with ISUP grade < 4 cancer, PSA < 20 ng/mL, or localised
disease [376-378].
Diffusion-weighted MRI (DW-MRI) may detect metastases
in normal-sized nodes, but a negative DW-MRI cannot rule out the presence of LN
metastases [372,379].
5.3.2.2.Risk calculators incorporating
MRI findings
Because CT and MRI lack sensitivity for direct detection of positive
LNs, nomograms combining clinical and biopsy findings (such as the nomograms developed
by the Memorial Sloan Cancer Center (MSKCC) [380], by Briganti
et al. or by Gandaglia et
al. [381,382] have been used to
identify patients at higher risk of LN
invasion who should be considered for LN dissection. Although these nomograms are
associated with good performance, they have been developed using systematic biopsy
findings and may therefore not be sensitive to patients diagnosed with combined MRI-TBx
and systematic biopsy.
Two models incorporating MRI-TBx biopsy findings and
MRI-derived findings recently underwent external validation [367,383]. One model tested on an
external cohort of 187 patients treated by RP and extended LN dissection showed a
prevalence of LN invasion of 13.9% (vs. 16.9% in the development cohort). The C-index
was 0.73 (vs. 0.81 in the development cohort); at calibration analysis, the model tended
to overpredict the actual risk [383]. Another model was
validated in an external multi-centre cohort of 487 patients with a prevalence of 8% of
LN invasion (vs. 12.5% in the development cohort).The AUC was 0.79 (vs. 0.81 in the
development cohort). Using a risk cut-off of 7% would have avoided LN dissection in 56%
of patients, while missing LN invasion in 13 (34%) of the 38 patients with LN invasion
[367].
5.3.2.3.Choline PET/CT
In a meta-analysis of 609 patients, pooled sensitivity and specificity
of choline PET/CT for pelvic LN metastases were 62% (95% CI: 51–66%) and 92% (95%
CI: 89–94%), respectively [384]. In a prospective trial of
75 patients at intermediate risk of nodal involvement (10–35%), the sensitivity
was only 8.2% at region-based analysis and 18.9% at patient-based analysis, which is too
low to be of clinical value [385]. The sensitivity of choline
PET/CT increases to 50% in patients at high risk and to 71% in patients at very high
risk, in both cases out-performing contrast-enhanced CT [386].
However, comparisons between choline PET/CT and DW-MRI yielded contradictory results,
with PET/CT sensitivity found to be superior [387], similar [388,389] or inferior [385] than that of DW-MRI.
Due of its low sensitivity, choline PET/CT does not
reach clinically acceptable diagnostic accuracy for detection of LN metastases, or to
rule out a nodal dissection based on risk factors or nomograms (see Section 6.3.4.1.2).
5.3.2.4.Prostate-specific membrane
antigen-based PET/CT
Prostate-specific membrane antigen (PSMA) positron-emission tomography
(PET)/CT uses several different radiopharmaceuticals; the majority of published studies
used 68Ga-labelling for PSMA PET imaging, but some used
18F-labelling. At present there are no conclusive data
about comparison of such tracers, with additional new radiotracers being developed.
68Ga-labelled or 18F-labelled radiotracers for PSMA PET/CT imaging provide
good contrast-to-noise ratio, thereby improving the detectability of lesions.
Prostate-specific membrane antigen is also an attractive target because of its
specificity for prostate tissue, even if PSMA expression in other non-prostatic
malignancies or benign conditions may cause incidental false-positive findings [390-394].
A prospective, multi-centre study addressed the use of 68Ga-PSMA PET/CT in patients with newly diagnosed PCa and
negative bone scan findings. In 103 eligible patients at increased risk for metastatic
LNs prior to surgery, 97 extended pelvic lymph-node dissections (ePLND) were performed,
resulting in the identification of 85 LN metastases in 41 patients (42.3%).
Positron-emission tomography was positive in 17 patients, resulting in a
per-patient-based sensitivity and specificity of 41.5% (95% CI: 26.7–57.8) and
90.9% (95% CI: 79.3–96.6), respectively. A treatment change occurred in 12.6% of
patients [395]. Another prospective multi-centre trial
investigated the diagnostic accuracy of 18F-DCFPyL
([2-(3-(1-carboxy-5-[(6-18F-fluoropyridine-3-carbonyl)-amino]-pentyl)-ureido)-pentanedioic
acid] PET/CT for LN staging in 117 patients with primary PCa, prior to robot-assisted
radical prostatectomy (RARP) with ePLND. 18F-DCFPyL
PET/CT showed a high specificity (94.0%; CI: 86.9–97.5%), and a limited
sensitivity (41.2%,CI: 19.4–66.5%) for the detection of pelvic LN metastases [396]. This suggests that current PSMA-based PET/CT imaging
cannot yet replace diagnostic ePLND.
Prostate-specific antigen may be a predictor of a
positive PSMA PET/CT. In the primary staging cohort from a meta-analysis [397], however, only 4 studies reported PSMA PET-positivity
based on the PSA value, offering no robust estimates of positivity. The tracer uptake is
also influenced by the ISUP grade and the PSA level. In a series of 90 patients with
primary PCa, tumours with an ISUP grade between 1 and 3 showed significantly lower
tracer uptake than tumours with an ISUP grade > 4. Similarly, patients with PSA levels
> 10 ng/mL showed significantly higher
uptake than those with PSA levels < 10 ng/mL [398].
Comparison between PSMA PET/CT and MRI was recently performed in a
systematic review and meta-analysis including 13 studies (n = 1,597) [399]. 68Ga-PSMA was found to
have a higher sensitivity and a comparable specificity for staging pre-operative LN
metastases in intermediate- and high-risk PCa. The pooled sensitivity and specificity of
68Ga-PSMA PET were 0.65 (95% CI: 0.49–0.79) and
0.94 (95% CI: 0.88–0.97), respectively, while the corresponding values of MRI
were 0.41 (95% CI: 0.26–0.57) and 0.92 (95% CI: 0.86–0.95). 68Ga-PSMA PET was potentially a more effective and
appropriate imaging modality to predict LN metastasis prior to surgery as indicated by
the area under the symmetric receiver-operating characteristic (SROC) curve. Another
prospective trial reported superior sensitivity of PSMA PET/CT as compared to MRI for
nodal staging of 36 high-risk PCa patients [400].
PSMA PET/CT has a good sensitivity and specificity for LN involvement,
possibly impacting clinical decision-making. In a recent review and meta-analysis
including 37 articles, a subgroup analysis was perfomed in patients undergoing PSMA
PET/CT for primary staging. On a per-patient-based analysis, the sensitivity and
specificity of 68Ga-PSMA PET were 77% and 97%,
respectively, after eLND at the time of RP. On a per-lesion-based analysis, sensitivity
and specificity were 75% and 99%, respectively [397].
In summary, PSMA PET/CT is more appropriate in N-staging as compared to
MRI, abdominal contrast-enhanced CT or choline PET/CT; however, small LN metastases,
under the spatial resolution of PET (~5 mm), may still be missed.
5.3.3.M-staging
5.3.3.1.Bone scan
99mTc-Bone scan has been the most
widely used method for evaluating bone metastases of PCa. A meta-analysis showed
combined sensitivity and specificity of 79% (95% CI: 73–83%) and 82% (95% CI:
78–85%) at patient level and 59% (95% CI: 55–63%) and 75% (95% CI:
71–79%) at lesion level [401]. Bone scan diagnostic yield
is significantly influenced by the PSA level, the clinical stage and the tumour ISUP
grade and these three factors were the only independent
predictors of bone scan positivity in a study of 853 patients [402]. The mean bone scan positivity rate in 23 different
series was 2.3% in patients with PSA levels < 10 ng/ mL, 5.3% in
patients with PSA levels between 10.1 and 19.9 ng/mL and 16.2% in patients with PSA
levels of 20.0–49.9 ng/mL. It was 6.4% in men with organ-confined cancer and
49.5% in men with locally advanced cancers. Detection rates were 5.6% and 29.9% for ISUP
grade 2 and > 3, respectively [371]. In two studies, a major
Gleason pattern of 4 was found to be a significant predictor of positive bone scan [403,404]. Bone scanning should be
performed in symptomatic patients, independent of PSA level, ISUP grade or clinical
stage [371].
5.3.3.2.Fluoride PET and PET/CT, choline
PET/CT and MRI
18F-sodium fluoride (18F-NaF) PET or PET/CT was reported to have similar
specificity and superior sensitivity to bone scintigraphy for detecting bone metastases
in patients with newly diagnosed high-risk PCa [405,406]. However, in a prospective study 18F-NaF PET showed no added value over bone scintigraphy
in patients with newly diagnosed intermediate- or high-risk PCa and negative bone
scintigraphy results [407]. Recently, the interobserver
agreement for the detection of bone metastases and the accuracy of 18F-NaF PET/CT in the diagnosis of bone metastases were
investigated. Bone metastases were identified in 211 out of 219 patients with an
excellent interobserver agreement, demonstrating that 18F-NaF PET/CT is a robust tool for the detection of
osteoblastic lesions in patients with PCa [408].
It remains unclear whether choline PET/CT is more
sensitive than bone scan but it has higher specificity with fewer indeterminate bone
lesions [384,409,410].
Diffusion-weighted whole-body and axial MRI are more
sensitive than bone scan and targeted conventional radiography in detecting bone
metastases in high-risk PCa [411,412].
Whole-body MRI is also more sensitive and specific than combined bone scan, targeted
radiography and abdominopelvic CT [413]. A meta-analysis found
that MRI is more sensitive than choline PET/CT and bone scan for detecting bone
metastases on a per-patient basis, although choline PET/CT had the highest specificity
[401].
It is of note that choline PET/CT and DW-MRI can also
detect visceral and nodal metastases. Bone scan and 18F-NaF
PET/CT only assess the presence of bone
metastases.
5.3.3.3.Prostate-specific membrane
antigen-based PET/CT
A systematic review including 12 studies (n = 322) reported high
variation in 68Ga-PSMA PET/CT sensitivity for initial
staging (range 33–99% median sensitivity on per-lesion analysis 33–92%, and
on per-patient analysis 66–91%), with good specificity (per-lesion 82–100%,
and per-patient 67–99%), with most studies demonstrating increased detection rates
with respect to conventional imaging modalities (bone scan and CT) [414]. Table 5.11 reports the data of the 5 studies including
histopathologic correlation.
Table 5.11: PSMA PET/CT results in primary staging alone [414]
|
Study
|
Sensitivity
(per lesion)
|
Specificity
(per lesion)
|
PPV
(per lesion)
|
NPV
(per lesion)
|
|
Budaus
|
33%
|
100%
|
100%
|
69%
|
|
Herlemann
|
84%
|
82%
|
84%
|
82%
|
|
Van Leeuwen
|
58%
|
100%
|
94%
|
98%
|
|
Maurer
|
74%
|
99%
|
95%
|
94%
|
|
Rahbar
|
92%
|
92%
|
96%
|
85%
|
NPV = negative predictive value; PPV =
positive predictive value.
One prospective multi-centre study evaluated changes in planned
management before and after PSMA PET/CT in 108 intermediate- and high-risk patients
referred for primary staging. As compared to conventional staging, additional LNs and
bone/visceral metastases were detected in 25% and 6% of patients, respectively [415]; management changes occurred in 21% of patients. A recent
retrospective review investigated the risk of metastases identified by 68Ga-PSMA at initial staging in 1,253 patients (high-risk
disease in 49.7%) [416]. Metastatic disease was identified by
PSMA PET/CT in 12.1% of men, including 8.2% with a PSA level of < 10 ng/mL and
43% with a PSA level of > 20 ng/mL. Lymph node metastases were suspected in 107 men,
with 47.7% outside the boundaries of an ePLND. Bone metastases were identified in 4.7%.
In men with intermediate-risk PCa metastases were identified in 5.2%, compared to 19.9%
with high-risk disease.
In the PSMA PET/CT prospective multi-centre study in
patients with high-risk PCa before curative-intent surgery or RT (proPSMA), 302 patients
were randomly assigned to conventional imaging with CT and bone scintigraphy or 68Ga-PSMA-11 PET/CT. The primary outcome focused on the
accuracy of first-line imaging for the identification of pelvic LN or distant
metastases, using a predefined reference standard consisting of histopathology, imaging,
and biochemistry at 6-month follow-up. Accuracy of 68Ga-PSMA PET/CT was 27% (95% CI: 23–31) higher
than that of CT and bone scintigraphy (92% [88–95] vs. 65% [60–69]; p
< 0.0001). Conventional imaging had a lower sensitivity (38% [24–52] vs. 85%
[74–96]) and specificity (91% [85–97] vs. 98% [95–100]) than PSMA
PET/CT. Furthermore, 68Ga-PSMA PET/CT scan prompted
management change more frequently as compared to
conventional imaging (41 [28%] men [21–36] vs. 23 [15%] men
[10–22], p = 0.08), with less equivocal fin
