Approach

Patients are often asymptomatic at presentation, and initial suspicion is raised following screening with prostate-specific antigen (PSA), and digital rectal exam (DRE) if performed.[26]​ Rarely, patients may present with symptoms and signs of urinary obstruction or other genitourinary symptoms.

An image-guided prostate biopsy (using transrectal ultrasound [TRUS] guided needle biopsy with or without magnetic resonance imaging [MRI] targeting) confirms diagnosis and aids grading. Staging is determined using imaging studies and biopsies when indicated.

History and clinical evaluation

Initial workup should include a family history of prostate and other cancers (including known germline mutations). Genetic risk assessment, including counseling and genetic testing, should be considered for men with a strong personal or family history of cancer (e.g., prostate, breast, ovarian, endometrial, colorectal cancer) or an inherited syndrome (e.g., Lynch syndrome), or a known or suspected pathogenic variant in a cancer susceptibility gene.

Clinical evaluation should focus on symptoms of urinary obstruction (e.g., frequency, nocturia, hesitancy) and other genitourinary symptoms (e.g., hematuria, dysuria). These symptoms may indicate more advanced disease or (more commonly) benign prostatic hyperplasia. Rarely, patients may present with systemic symptoms of malignancy including weight loss/anorexia, bone pain, lethargy, and palpable lymph nodes.

If DRE is performed at screening or during initial workup, prostate consistency and symmetry, and the presence of any palpable indurations or nodules, should be noted. An asymmetric and/or indurated or nodular prostate suggests cancer and should prompt further evaluation. The overall size of the prostate may be noted. However, estimating the size of the prostate on exam is inaccurate and unreliable.

Prostate-specific antigen (PSA)

Serum PSA levels may be increased in patients with prostate cancer; however, other nonmalignant conditions (e.g., prostatitis and benign prostatic hyperplasia) may increase PSA levels. PSA levels may also vary according to race.[51]

Decisions about screening and rescreening intervals should be individualized 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 normalize on retesting.[52][53]

PSA testing may be combined with 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] 

Screening men at average risk

Routine PSA screening is controversial. In the US, shared decision-making prior to PSA screening is recommended for selected patients.[52][55]​​[56][57]​​​​ 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]

Screening men at higher risk

  • Early PSA screening starting at ages 40 to 45 years is recommended for men at higher risk (e.g., black ancestry, germline mutations, strong family history of prostate cancer).​​[52][55]​​​

Total PSA

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.[58]

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 nanogram/mL, or men 75 years or older with a PSA <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.[59][60]​​​ 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.[60]

An increase in PSA of 0.75 nanograms/mL/year may be a sign of prostate cancer, even if this increase occurs within the standard age-specific reference range.[61]

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 nanograms/mL.[62] A free PSA of <10% suggests the presence of aggressive prostate cancer.

PSA density

PSA density (the ratio of serum PSA level to prostate volume) can be calculated to inform risk stratification and guide treatment planning. Prostate tumor volume and density calculator Opens in new window Risk of clinically significant prostate cancer is increased with increasing PSA density.[63][64]

A PSA density <0.15 nanograms/mL/g is one of the criteria for very low-risk disease.[3][65]​​​ See Classification.

PSA doubling time and PSA velocity

PSA doubling time (PSADT) and PSA velocity (PSAV) may be used in the pretreatment 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 pretreatment setting, while PSADT is usually reserved for monitoring PSA during follow-up.[66] 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][67][68][69]​​​​[70]​​

Pathologic and laboratory evaluation

A prostate biopsy is required to confirm diagnosis (i.e., presence of prostatic intraepithelial neoplasia or carcinoma), tumor grade (based on the Gleason score), and the presence of perineural invasion. It is often the first step in the diagnostic workup if PSA is elevated and/or if there are suspicious findings on DRE. However, it is important to carefully select patients for biopsy to minimize overdiagnosis and unnecessary biopsies, and to ensure those with clinically significant tumors are identified and managed appropriately.

Prebiopsy assessment

Selecting patients for biopsy should be individualized 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).[71] National Comprehensive Cancer Network (NCCN) guidelines recommend biopsy for average-risk patients ages 45-75 years and high-risk patients ages 40-75 years, if they have a PSA >3 nanograms/mL and/or a very suspicious DRE.[3] Biopsy may be considered for selected patients ages >75 years who have a PSA ≥4 nanograms/mL or a very suspicious DRE.[3] 

Prebiopsy multiparametric MRI (if available) is recommended to help identify candidates for biopsy.[3][72][73]​​​ Results may also inform MRI-targeted biopsy. Multiparametric MRI can accurately differentiate clinically significant tumors from clinically insignificant tumors (particularly if carried out in accordance with the Prostate Imaging Reporting and Data System [PI-RADS] protocol), which can help to minimize unnecessary biopsies.[74][75][76][77]​​​ See Criteria.

Biomarker testing may be considered to further refine patient selection for biopsy, especially in patients with mildly elevated PSA levels.[3][26][73]​​​​​

  • Percentage of free PSA: measures plasma levels of free/unbound PSA.[62]

  • Prostate Health Index (PHI): measures plasma levels of free PSA, total PSA, and a precursor form of PSA ([-2] proPSA).[78]

  • 4Kscore: measures plasma levels of total PSA, free PSA, intact PSA, and human kallikrein 2 (findings are combined with age, DRE findings, and prior biopsy status).[79][80][81][82]

  • SelectMDx: measures urine levels of HOXC6 and DLX1 mRNA.[83] 

  • Prostate cancer gene 3 (PCA3): overexpressed in prostate cancer, and can be detected in the urine.[78][84][85][86]

  • 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.[87][88]

  • MyProstateScore: measures total serum PSA, postDRE urine expression of PCA3, and the TMPRSS2:ERG fusion gene.[84][89][90]​​[91]

  • IsoPSA: detects PSA isoforms in blood.[92][93]​​ 

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.

Biopsy procedure

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). 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][94]​​ Combined MRI-targeted and systematic biopsy improves detection of clinically significant prostate cancer and reduces regrading of tumors on final histopathologic analysis.[95][96][97][98] 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.[99][100]

Negative biopsy and elevated PSA

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][101][102]​​[103]

Imaging and staging

For asymptomatic patients with very low-risk, low-risk, or intermediate-risk prostate cancer who have a life expectancy of 5 years or less, no further workup or treatment is necessary until symptoms appear.[3][104]​ See Classification.

Imaging of the bone and soft tissue (pelvis, abdomen, chest) is required for staging and detecting metastases in patients with unfavorable intermediate-risk, high-risk, or very high-risk prostate cancer who have one or more of the following:[3]

  • Symptomatic disease

  • Life expectancy greater than 5 years.

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 [see below]).[3]

Bone imaging

A technetium-99 bone scan is the standard technique for initial bone imaging. However, other imaging studies (e.g., computed tomography [CT], MRI, positron emission tomography [PET]/CT, or PET/MRI) can be used if findings on bone scan are equivocal.[3]

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.[105][106][107][108][109][110]​​​​ Based on these findings, PSMA-PET/CT or 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] 

Soft-tissue imaging

CT and MRI are standard techniques for initial soft-tissue imaging of the pelvis, abdomen, and chest.

PSMA-targeted PET/CT or PET/MRI (with Ga-68 PSMA-11, piflufolastat F-18, or flotufolastat F-18) may be considered as alternatives to conventional CT or MRI for soft-tissue imaging at initial staging.[3]

Investigations that inform treatment and prognosis

Following diagnosis, routine laboratory tests (including complete blood count, liver function tests, renal function, and testosterone levels) are required if treatment is planned.

Genetic and molecular testing

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 tumor mutational burden should be considered, particularly in the metastatic disease setting.

Results of germline testing can inform management decisions and prognosis, and may also 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).[111][112][113]​ Guidelines recommend their use in situations where assay results are likely to change management.[3][114]​ 

Results of genetic and molecular testing should be discussed with patients as part of shared decision-making to inform decisions regarding management and treatment.

Nomograms

Nomograms (e.g., the Partin nomogram and the Memorial-Sloan-Kettering Cancer Center nomogram) can be used to provide individualized disease-related risk estimations that facilitate management-related decisions.[3][115] Brady Urological Institute: the Partin tables Opens in new window Memorial-Sloan-Kettering Cancer Center: prostate cancer nomograms Opens in new window These nomograms use characteristics such as serum PSA level, clinical stage, and tumor grade (Gleason score) to calculate the risk of tumor spread outside of the prostate (e.g., to lymph nodes).[3][115]

Compared with other prediction tools, nomograms have the highest accuracy and the best discriminating characteristics for predicting outcomes in patients with prostate cancer.[116]

Results of nomograms should be discussed with patients as part of shared decision-making to inform decisions regarding management and treatment.

Orthopedic surgery evaluation

In more advanced disease, especially in the presence of metastatic disease in a weight-bearing bone, an orthopedic surgery evaluation is warranted to determine whether surgical stabilization is necessary.

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