Investigations
1st investigations to order
serum prostate-specific antigen (PSA)
Test
Serum PSA levels may be increased in patients with prostate cancer; however, other non-malignant conditions (e.g., prostatitis and benign prostatic hyperplasia) may increase PSA levels. PSA levels may also vary according to race.[51]
Routine PSA screening is controversial. In the US, shared decision-making prior to PSA screening is recommended for selected patients.[52][55][56] Guidelines differ on when to start screening discussions. The American Cancer Society recommends a screening discussion at age 50 years in men who are at average risk of prostate cancer and have a life expectancy of at least 10 years.[55] The US Preventive Services Task Force recommends considering screening for prostate cancer from ages 55 to 69 years.[56] The American Urological Association and Society of Urologic Oncology recommend offering a baseline screening test at ages 45 to 50 years in men at average risk of developing prostate cancer.[52]
Early PSA screening at ages 40 to 45 years may be considered for men at higher risk (e.g., black ancestry, germline mutations, strong family history of prostate cancer).[52][55]
Decisions about screening and re-screening intervals should be individualised following discussion of the risks and benefits. For men with a newly elevated PSA, a repeat test may be considered after a few weeks, and before further evaluation, because PSA levels may fluctuate and often normalise on retesting.[52][53]
PSA testing may be combined with digital rectal examination (DRE) as part of screening because approximately 25% of men diagnosed with prostate cancer have a normal PSA.[54] DRE is recommended in all patients with an abnormal PSA to aid decisions regarding biopsy.[26] However, DRE as a stand-alone screening test is not recommended.[26]
Total PSA is the initial test of choice (i.e., the sum of both the free and bound forms). Risk of prostate cancer typically increases with increasing PSA level. However, elevated PSA levels should be correlated with patient age as PSA typically increases with age, regardless of presence of prostate cancer.[57]
Men with PSA levels above the median for their age group are at higher risk for aggressive prostate cancer. Conversely, men 60 years or older with PSA <1 microgram/L (<1 nanogram/mL), or men 75 years or older with a PSA <3 micrograms/L (<3 nanograms/mL), are at very low risk for aggressive prostate cancer.[26]
Age-specific PSA thresholds have not been universally adopted because there is a lack of strong evidence to differentiate between using an age-specific threshold or a fixed PSA threshold.[58][59] In the UK, PSA levels above the age-specific threshold can be used to inform the decision to refer patients with possible symptoms of prostate cancer for further evaluation.[59]
An increase in PSA of 0.75 micrograms/L/year (0.75 nanograms/mL/year) may be a sign of prostate cancer, even if this increase occurs within the standard age-specific reference range.[60]
In certain circumstances it may be helpful to measure the percentage of free PSA: for example, in men with previously negative prostate biopsies and whose PSA level is between 4 and 10 micrograms/L (4 and 10 nanograms/mL).[61] A free PSA of <10% suggests the presence of aggressive prostate cancer.
PSA density (the ratio of serum PSA level to prostate volume) can be calculated to inform risk stratification and guide treatment planning. Risk of clinically significant prostate cancer is increased with increasing PSA density.[62][63] A PSA density <0.15 micrograms/L/g (<0.15 nanograms/mL/g) is one of the criteria for very low-risk disease.[3][64] See Classification.
PSA doubling time (PSADT) and PSA velocity (PSAV) may be used in the pre-treatment setting for risk stratification and to predict response to treatment, and during follow-up to monitor disease progression. Currently, PSAV is more often used in the pre-treatment setting, while PSADT is usually reserved for monitoring PSA during follow-up.[65] There is disagreement as to the value of PSAV and PSADT as an adjunct to routine PSA evaluation; decisions about further evaluation should not be based solely on PSAV results.[52][66][67][69]
Result
elevated PSA (value should be correlated with patient age); elevated PSA density; decreased PSADT; elevated PSAV
prebiopsy multiparametric MRI
Test
Prebiopsy multiparametric MRI (if available) is recommended to help identify candidates for biopsy.[3][71][72] Results may inform MRI-targeted biopsy. Multiparametric MRI can accurately differentiate clinically significant tumours from clinically insignificant tumours (particularly if carried out in accordance with the Prostate Imaging Reporting and Data System [PI-RADS] protocol), which can help minimise unnecessary biopsies.[73][74][75][76] See Criteria.
Results of prebiopsy assessment should be discussed with patients as part of shared decision-making before proceeding to biopsy.
It is important to carefully select patients for biopsy to minimise overdiagnosis and unnecessary biopsies, and to ensure those with clinically significant tumours are identified and managed appropriately.
Selecting patients for biopsy should be individualised based on patient-specific risk factors (e.g., age, PSA level, abnormal digital rectal examination [DRE] findings, comorbidities, family history) and prebiopsy assessment.[3][26] Risk calculators are available that can help assess risk (e.g., Prostate Biopsy Collaborative Group calculator).[70]
National Comprehensive Cancer Network (NCCN) guidelines recommend biopsy for average-risk patients aged 45-75 years and high-risk patients aged 40-75 years, if they have a PSA >3 micrograms/L (>3 nanograms/mL) and/or a very suspicious DRE.[3] Biopsy may be considered for selected patients aged >75 years who have a PSA ≥4 micrograms/L (≥4 nanograms/mL) or a very suspicious DRE.[3]
Result
may identify clinically significant lesions on the prostate
prostate biopsy
Test
A prostate biopsy is required to confirm diagnosis (i.e., presence of prostatic intraepithelial neoplasia or carcinoma), tumour grade (based on the Gleason score), and the presence of perineural invasion. It is the first step in the diagnostic work-up if PSA is elevated and/or if there are suspicious findings on digital rectal examination (DRE).
It is important to carefully select patients for biopsy to minimise overdiagnosis and unnecessary biopsies, and to ensure those with clinically significant tumours are identified and managed appropriately.
Selecting patients for biopsy should be individualised based on patient-specific risk factors (e.g., age, PSA level, abnormal DRE findings, comorbidities, family history) and prebiopsy assessment.[3][26] Risk calculators are available that can help assess risk (e.g., Prostate Biopsy Collaborative Group calculator).[70]
National Comprehensive Cancer Network (NCCN) guidelines recommend biopsy for average-risk patients aged 45-75 years and high-risk patients aged 40-75 years, if they have a PSA >3 micrograms/L (>3 nanograms/mL) and/or a very suspicious DRE.[3] Biopsy may be considered for selected patients aged >75 years who have a PSA ≥4 micrograms/L (≥4 nanograms/mL) or a very suspicious DRE.[3]
Prostate biopsy samples are obtained by systematic core needle biopsy. The biopsy needle can be inserted into the prostate via the rectum (transrectal approach) or perineum (transperineal approach). The transperineal approach is often preferred due to lower risk of infection. Transrectal ultrasound (TRUS) is used to guide the needle, regardless of the biopsy approach used. The biopsy procedure typically involves obtaining 10-12 biopsy cores (5 or 6 cores on each side of the prostate), although the NCCN guidelines recommend an extended-pattern biopsy, with at least 12 biopsy cores.[26]
The addition of MRI-targeted biopsy to systematic biopsy is recommended when a suspicious lesion has been identified by prebiopsy multiparametric MRI.[26][93] Combined MRI-targeted and systematic biopsy improves detection of clinically significant prostate cancer and reduces regrading of tumours on final histopathological analysis.[94][95][96][97] The optimal technique for MRI-targeted biopsy has not been determined; options include cognitive (visual) fusion biopsy, software-assisted TRUS-MRI fusion biopsy, and direct (in-bore) MRI-guided biopsy.[98][99]
A negative prostate biopsy does not exclude a diagnosis of prostate cancer, particularly if clinical suspicion is high and/or PSA is persistently elevated or rising.
In the presence of a negative biopsy and elevated PSA, close follow-up with DRE and PSA should be performed within 6-12 months of the negative biopsy, with consideration of repeat biopsy with MRI targeting depending on the results.
If PSA is persistently elevated and/or DRE is abnormal following a negative biopsy, multiparametric MRI and biomarker testing should be considered to inform repeat biopsy with MRI targeting.[26][100][101][102]
Result
may detect malignant cells in one or more biopsy specimens (assigned to Grade Group 1-5)
Investigations to consider
prebiopsy biomarker testing
Test
Biomarker testing may be considered to further refine patient selection for biopsy, especially in patients with mildly elevated PSA levels.[3][26][72]
Percentage of free PSA: measures plasma levels of free/unbound PSA.[61]
Prostate Health Index: measures plasma levels of free PSA, total PSA, and a precursor form of PSA ([-2] proPSA).[77]
4Kscore: measures plasma levels of total PSA, free PSA, intact PSA, and human kallikrein 2 (findings are combined with age, digital rectal examination findings, and prior biopsy status).[78][79][80][81]
SelectMDx: measures urine levels of HOXC6 and DLX1 mRNA.[82]
Prostate cancer gene 3 (PCA3): overexpressed in prostate cancer, and can be detected in the urine.[77][83][84][85]
ExoDx Prostate IntelliScore (EPI): measures exosomal RNA expression of PCA3, ERG (V-ets erythroblastosis virus E26 oncogene homologs), and SPDEF (SAM pointed domain-containing Ets transcription factor) in the urine.[86][87]
MyProstateScore: measures total serum PSA, postDRE urine expression of PCA3, and the TMPRSS2:ERG fusion gene.[83][88][89][90]
IsoPSA: detects PSA isoforms in blood.[91][92]
All of these tests can be used in biopsy-naive patients and those with a prior negative biopsy (i.e., before repeat biopsy), although PCA3 is mainly used in the latter.
The optimal use of biomarker tests (e.g., in combination with prebiopsy MRI and/or with each other) in selecting patients for biopsy is unclear.
Results of prebiopsy assessment should be discussed with patients as part of shared decision-making before proceeding to biopsy.
Result
may be positive for serum or urine biomarkers (test results are presented as a risk score)
testosterone
Test
Routine test for patients in whom treatment (e.g., androgen deprivation therapy) is considered once a diagnosis has been confirmed.[115]
Result
normal
LFTs
Test
Routine test for patients in whom treatment (e.g., androgen deprivation therapy) is considered once a diagnosis has been confirmed.
Result
normal
FBC
Test
Routine test for patients in whom treatment (e.g., androgen deprivation therapy [ADT]) is considered once a diagnosis has been confirmed.
Anaemia may occur due to advanced disease, ADT, nutritional decline, bone marrow infiltration, the chronic inflammatory state, and rarely gross haematuria.
Symptomatic anaemia may warrant blood transfusion.
Result
normal, except for advanced disease
renal function
Test
Routine test for patients in whom treatment (e.g., androgen deprivation therapy) is considered once a diagnosis has been confirmed.
Abnormal renal function tests may indicate more locally advanced disease with tumour causing obstruction of ureters, resulting in renal failure.
Result
normal, except for locally advanced disease causing obstruction
bone scan (technetium-99)
Test
Imaging of the bone is required for staging and detecting metastases in patients with unfavourable intermediate-risk, high-risk, or very high-risk prostate cancer who have symptomatic disease and/or life expectancy greater than 5 years.[3] See Classification.
High-risk and very high-risk patients with life expectancy less than 5 years should undergo bone imaging and soft-tissue imaging of the pelvis and/or abdomen (depending on nomogram prediction of lymph node involvement).[3]
Asymptomatic patients diagnosed with very low-risk, low-risk, or intermediate-risk prostate cancer who have a life expectancy of 5 years or less do not require further work-up or treatment until symptoms appear.[3]
A technetium-99 bone scan is the standard technique for initial bone imaging. However, other imaging studies (e.g., CT, MRI, PET/CT, or PET/MRI) can be used if findings on bone scan are equivocal.
Result
may identify bone lesions
CT scan
Test
Imaging of the bone is required for staging and detecting metastases in patients with unfavourable intermediate-risk, high-risk, or very high-risk prostate cancer who have symptomatic disease and/or life expectancy greater than 5 years.[3] See Classification.
High-risk and very high-risk patients with life expectancy less than 5 years should undergo bone imaging and soft-tissue imaging of the pelvis and/or abdomen (depending on nomogram prediction of lymph node involvement).[3]
Asymptomatic patients diagnosed with very low-risk, low-risk, or intermediate-risk prostate cancer who have a life expectancy of 5 years or less do not require further work-up or treatment until symptoms appear.[3]
A technetium-99 bone scan is the standard technique for initial bone imaging. However, other imaging studies (e.g., CT, MRI, PET/CT, or PET/MRI) can be used if findings on bone scan are equivocal.
CT is a standard technique for initial soft-tissue imaging of the pelvis, abdomen, and chest.
The primary role of CT scan in prostate cancer is to evaluate the prostate size and to assess for the presence of enlarged pelvic lymph nodes.
Intra-prostatic disease, extra-capsular extension, or seminal vesicle involvement cannot be evaluated accurately by CT because it lacks the soft-tissue resolution.
Result
may identify enlarged prostate and/or metastatic disease (e.g., enlarged pelvic lymph nodes, and metastatic lesions in bone and soft tissue)
MRI
Test
Imaging of the bone is required for staging and detecting metastases in patients with unfavourable intermediate-risk, high-risk, or very high-risk prostate cancer who have symptomatic disease and/or life expectancy greater than 5 years.[3] See Classification.
High-risk and very high-risk patients with life expectancy less than 5 years should undergo bone imaging and soft-tissue imaging of the pelvis and/or abdomen (depending on nomogram prediction of lymph node involvement).[3]
Asymptomatic patients diagnosed with very low-risk, low-risk, or intermediate-risk prostate cancer who have a life expectancy of 5 years or less do not require further work-up or treatment until symptoms appear.[3]
A technetium-99 bone scan is the standard technique for initial bone imaging. However, other imaging studies (e.g., CT, MRI, PET/CT, or PET/MRI) can be used if findings on bone scan are equivocal.
MRI is a standard technique for initial soft-tissue imaging of the pelvis, abdomen, and chest.
On axial T1-weighted images, the prostate appears homogeneous and zonal anatomy is not easily differentiated. However, nodal and bony disease is identifiable.
On axial T2-weighted images, the zonal anatomy of the prostate is clearly visualised. The peripheral zone is, typically, of high signal intensity. This is contrary to the tumour, which appears as low signal intensity.
Result
may identify suspicious intra-prostatic lesions and/or metastatic disease (e.g., enlarged pelvic lymph nodes, and metastatic lesions in bone and soft tissue)
prostate-specific membrane antigen (PSMA)-PET/CT
Test
Imaging of the bone is required for staging and detecting metastases in patients with unfavourable intermediate-risk, high-risk, or very high-risk prostate cancer who have symptomatic disease and/or life expectancy greater than 5 years.[3] See Classification.
High-risk and very high-risk patients with life expectancy less than 5 years should undergo bone imaging and soft-tissue imaging of the pelvis and/or abdomen (depending on nomogram prediction of lymph node involvement).[3]
Asymptomatic patients diagnosed with very low-risk, low-risk, or intermediate-risk prostate cancer who have a life expectancy of 5 years or less do not require further work-up or treatment until symptoms appear.[3]
A technetium-99 bone scan is the standard technique for initial bone imaging. However, other imaging studies (e.g., CT, MRI, PET/CT, or PET/MRI) can be used if findings on bone scan are equivocal.
CT and MRI are standard techniques for initial soft-tissue imaging of the pelvis, abdomen, and chest.
Prostate-specific membrane antigen (PSMA) targeted imaging with PET/CT or PET/MRI is superior to conventional imaging (bone scan, CT, MRI) for staging and detecting metastases in patients with prostate cancer.[103][104][105][106][107][108] Based on these findings, PSMA-PET/CT (with gallium [Ga-68] PSMA-11, piflufolastat F-18, or flotufolastat F-18) may be considered as alternatives to conventional imaging for initial staging.[3]
Result
may identify suspicious intraprostatic lesions and/or metastatic disease (e.g., enlarged pelvic lymph nodes, and metastatic lesions in bone and soft tissue)
PSMA-PET/MRI
Test
Imaging of the bone is required for staging and detecting metastases in patients with unfavourable intermediate-risk, high-risk, or very high-risk prostate cancer who have symptomatic disease and/or life expectancy greater than 5 years.[3] See Classification.
High-risk and very high-risk patients with life expectancy less than 5 years should undergo bone imaging and soft-tissue imaging of the pelvis and/or abdomen (depending on nomogram prediction of lymph node involvement).[3]
Asymptomatic patients diagnosed with very low-risk, low-risk, or intermediate-risk prostate cancer who have a life expectancy of 5 years or less do not require further work-up or treatment until symptoms appear.[3]
A technetium-99 bone scan is the standard technique for initial bone imaging. However, other imaging studies (e.g., CT, MRI, PET/CT, or PET/MRI) can be used if findings on bone scan are equivocal.
CT and MRI are standard techniques for initial soft-tissue imaging of the pelvis, abdomen, and chest.
Prostate-specific membrane antigen (PSMA) targeted imaging with PET/CT or PET/MRI is superior to conventional imaging (bone scan, CT, MRI) for staging and detecting metastases in patients with prostate cancer.[103][104][105][106][107][108] Based on these findings, PSMA-PET/MRI (with gallium [Ga-68] PSMA-11, piflufolastat F-18, or flotufolastat F-18) may be considered as alternatives to conventional imaging for initial staging.[3]
Result
may identify suspicious intraprostatic lesions and/or metastatic disease (e.g., enlarged pelvic lymph nodes, and metastatic lesions in bone and soft tissue)
genetic and molecular testing
Test
Genetic testing for germline and/or somatic mutations affecting homologous recombination repair genes (e.g., BRCA1, BRCA2, ATM, PALB2, and CHEK2), DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2), HOXB13, and tumour mutational burden should be considered, particularly in the metastatic disease setting. Results of germline testing can inform management decisions and prognosis, and may highlight potential risk for other cancers and risk among family members.
Molecular testing may be used to provide additional prognostic information, refine risk stratification, and help in decision-making. Several tissue-based molecular assays have been validated and are commercially available, including Prolaris, Decipher, and the 17-gene Genomic Prostate Score (Oncotype Dx Prostate).[109][110][111] Guidelines recommend their use in situations where assay results are likely to change management.[3][112]
Results of genetic and molecular testing should be discussed with patients as part of shared decision-making to inform decisions regarding management and treatment.
Result
may identify genetic mutations or molecular biomarkers with prognostic significance
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