Prostate Cancer Diagnostics

Last updated: 04 July 2024

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Laboratory Tests and Ancillaries

Content on this page:

Laboratory Tests and Ancillaries

Laboratory Tests and Ancillaries

Prostate-Specific Antigen (PSA) Level

PSA is a kallikrein-like serine protease produced by prostatic epithelial cells. It is organ specific but is not specific to cancer and therefore may be elevated in benign conditions (eg benign prostatic hypertrophy, prostatitis). The risk for prostate cancer increases with increasing levels of PSA and may warrant a prostate biopsy.  

PSA also predicts extension outside the prostate gland, seminal vesicle invasion, and lymphadenopathies. Baseline results should be obtained prior to starting treatment as it is also a good measurement for therapeutic efficacy. Other parameters (PSA testing derivatives) include free PSA level, PSA velocity, and PSA density.  

Prostate Biopsy  

Prostate biopsy is the most common method used in diagnosing prostatic carcinoma. It should only be offered if the PSA levels and DRE highly suggest prostate cancer.  

The indications for prostate biopsy include patients who have an increased risk for prostate cancer and with PSA levels of 2.5 to 4 ng/mL, increased PSA levels of >0.35 ng/mL within 1 year from baseline of <4 ng/mL, increased PSA levels of >0.75 ng/mL within 1 year from baseline of 4 to 10 ng/mL, or PSA levels that are too high for the age range.  

Transrectal ultrasound (TRUS)-guided core-needle prostate biopsy is highly recommended for men with PSA levels of >4 ng/mL. Transperineal biopsies are favored compared to TRUS-guided biopsies due to reduced risk of infection.  

Obtaining a minimum of 10-12 cores is recommended during the procedure and it should be done under antibiotic coverage. The perineal approach (transperineal 3D prostate mapping biopsy) is useful for special circumstances (eg, rectal amputation).  

Confirmatory prostate biopsy, with or without multiparametric magnetic resonance imaging (mpMRI), may be considered if active surveillance is being considered for very low-risk patients and with or without molecular tumor analysis in low- to favorable intermediate-risk patients.  

The indications for repeat biopsy after previously negative results include persistently elevated and/or increasing PSA levels, suspicious DRE results, and positive mpMRI findings.  

Please see Digital Rectal Examination (DRE) under Physical Examination for further information.  

Other Biomarker Tests  

These biomarker tests have been associated with prostate cancer diagnosis but are not routinely performed. Biomarkers other than PSA that are used for prostate cancer include apoptosis markers (eg Bcl-2, Bax), proliferation rate markers (eg Ki67), p53 mutation or expression, p27, E-cadherin, DNA plody, and p16.    

Other biomarker tests recommended by the National Comprehensive Cancer Network (NCCN) include percent free PSA (%f PSA), Prostate Health Index (PHI), four kallikrein (4K) score®, prostate cancer antigen 3 (PCA3), ConfirmMDx, and ExoDx Prostate (IntelliScore) (EPI) test.  

Tests that are currently being studied include Mi-Prostate Score (MiPS) and SelectMDx. An increase in serum acid phosphatase levels may indicate poor prognosis in patients with localized and disseminated disease.  

Genetic Testing

Germline Testing

Germline testing is recommended for patients with a personal history of prostate cancer with any of the following:

  • Metastatic, regional (node-positive), very-high-risk localized, or high-risk localized prostate cancer diagnosed at any age
  • Family history or ancestry (excluding relatives with clinically localized Grade Group 1 disease):
    • ≥First-, second-, or third-degree relative with breast, colorectal or endometrial cancer at ≤50 years old, or male breast, ovarian, exocrine pancreatic, metastatic, regional, very-high-risk, high-risk prostate cancer at any age
    • ≥First-degree relative with prostate cancer at ≤60 years old
    • ≥2 first-, second-, or third-degree relatives with breast or prostate cancer at any age
    • ≥3 first- or second-degree relatives with Lynch syndrome-related cancers, especially if diagnosed <50 years of age
    • Family history of familial cancer risk mutation (BRCA1, BRCA2, ATM, PALB2, CHEK2, MLH1, MSH2, MSH6, PMS2, EPCAM)
    • Ashkenazi Jewish ancestry 
  • Personal history of breast cancer

Germline testing may also be considered in patients with a personal history of prostate cancer with either an intermediate-risk prostate cancer with intraductal or cribriform histology, or a prior personal history of any of the following cancers: Exocrine pancreatic, colorectal, gastric, melanoma, pancreatic, upper tract urothelial, glioblastoma, biliary tract, and small intestinal cancer. 

This testing should include MLH1, MSH2, MSH6, PMS2, BRCA2, BRCA1, ATM, PALB2, and CHEK2. Cancer predisposition next-generation sequencing (NGS) panel testing which includes the above genetic mutations except for PALB2 may be considered. Germline testing is also recommended for very low-, low-, and intermediate-risk groups if the patient has a strong family history of prostate cancer or with intraductal or cribriform histology. Genetic counseling is needed before germline testing. 

Molecular Assays  

Molecular assays provide a more personalized or precise approach to treatment. Available tumor-based molecular assays include Decipher®, Oncotype Dx® Prostate, Prolaris®, and ProMark®.   The following are the recommended somatic tests for the corresponding patients:

  • Regional or metastatic prostate cancer: Tumor testing for somatic homologous recombination gene mutations (HRRm) which includes MLH1, MSH2, MSH6, PMS2, BRCA2, BRCA1, ATM, CHEK2, and microsatellite instability-high (MSI-H) or mismatch repair deficiency (dMMR) (to check for Lynch syndrome)
  • Cancer predisposition NGS panel testing which includes BRCA2, BRCA1, ATM, CHEK2, PALB2, MLH1, MSH2, MSH6, PMS2 should be considered
  • Low- and favorable intermediate-risk prostate cancer with life expectancy of ≥10 years: Decipher®, Decipher PORTOS, Oncotype Dx®, Prolaris®, and ProMark® 
  • Unfavorable intermediate- and high-risk prostate cancer with life expectancy of ≥10 years: Decipher® and Prolaris® tumor-based molecular assays
  • PSA resistance or recurrence after radical prostatectomy: Decipher® molecular assay to be used during coun­seling for risk stratification 

For post-prostatectomy patients, Decipher® molecular assay is recommended if not previously done to test for adverse features. For patients with a history of Abiraterone/Enzalutamide therapy for metastatic castration-resistant prostate cancer (mCRPC), androgen receptor splice variant 7 (AR-V7) testing in circulating tumor cells may be considered to help with treatment decision-making. Tumor testing for MSI-H or dMMR is recommended for patients with mCRPC and can be considered in those with regional or castration-naive metastatic prostate cancer. 

Grade Group  

New histologic grading system developed by the International Society of Urological Pathology (ISUP) assigns grade groups based on the Gleason score and thereby provides better management strategies.

    Grade Group Gleason Score Gleason Pattern  Risk Group  Description
    1  ≤6  ≤3+3 Very low  Only individual, discrete, well-formed glands
    2  7 3+4  Intermediate  Predominantly well-formed glands with lesser component of poorly formed/fused/cribriform/glomeruloid glands
    3  7 4+3  Intermediate Predominantly poorly formed/fused/cribriform/glomeruloid glands with lesser component of well-formed glands
    4  8  4+4, 3+5, 5+3 High Only poorly formed/fused/cribriform/glomeruloid glands or
    Predominantly well-formed glands and lesser component lacking glands or
    Predominantly lacking glands with lesser component of well-formed glands
     5  9 or 10   4+5, 5+4 or 5+5 Very high Lack of gland formation with or without poorly formed/fused/cribriform glands
      Reference: NCCN. NCCN guidelines: prostate cancer. Version 4.2023. NCCN. Sep 2023.

Imaging

Imaging procedures should be based on age, risk, PSA results, Gleason score, and the patient’s health status. Pelvic and/or abdominal imaging is recommended for high-risk to very high-risk patients and for intermediate-risk patients with >10% probability of pelvic lymph node involvement in the nomogram. Imaging may be considered in symptomatic very low-, low- and intermediate-risk patients. Bone imaging should be performed for any patient with symptoms consistent with bone metastases.  

Plain Film Radiography  

Plain film radiography may be used to assess the presence of bone pathologies in symptomatic patients.  

Ultrasonography  

Transrectal ultrasound may be used to assess the prostate gland if PSA levels and DRE results are inconclusive. It is also used as a guide during transrectal prostate biopsies. It is also considered in patients with suspected recurrence after surgery.  

Computed Tomography (CT) Scan  

CT scan may be used to assess for the presence of bone pathologies, gross extracapsular disease, nodal metastatic disease, and/or visceral metastatic disease. It may be used for pelvic and/or abdominal examination as part of initial evaluation and for follow-up evaluation for recurrence or progression.  

It may be used for lymph node staging in asymptomatic patients at intermediate to high risk (PSA level of >10 ng/mL, Gleason score of >8, or clinical stage of >T3).  

MRI  

Multiparametric MRI by diffusion-weighted imaging or H1-spectroscopy may be done to assess if repeat prostate biopsy is needed in patients with negative results in TRUS. It detects large and poorly differentiated tumors and extracapsular extension, is used for staging of pelvic lymph nodes, and detects bone metastases with up to 98-100% sensitivity and specificity.  

It may be used for pelvic and/or abdominal examination as part of initial evaluation and for follow-up evaluation for recurrence or progression. mpMRI is preferred over CT for abdominal or pelvic staging. Positive results may suggest a repeat prostate biopsy.  

Sensitivity at >2 cc is as follows: 67-75% for Gleason <6; 97% for Gleason 7; and 100% for Gleason >8.  

Radionuclide Bone Scan  

A radionuclide bone scan is a conventional technetium-99m-methylene diphosphonate (99mTc-MDP) bone scan used to assess for possible bone involvement. It may be performed for symptomatic patients with PSA results of >10 ng/mL, Gleason score of >8, long life expectancy, higher T stage, and those with decreasing PSA doubling time (PSADT). It may be considered in patients with increasing PSA or positive DRE post-radiotherapy who may benefit from additional local or systemic therapy. It is recommended for patients at high- to very-high risk and in patients at intermediate risk with T2, Gleason score of 7, and a PSA level of 10-20 ng/mL and/or with life expectancy of >5 years.  

Positron Emission Tomography (PET) or CT Scan and PET/MRI  

F-18 sodium fluoride, C-11 choline, and F-18 fluciclovine PET/CT or PET/MRI with F-18 piflufolastat prostate-specific membrane antigen (PSMA), gallium-68 PSMA-11 (68Ga-PSMA-11), F-18 flotufolastat PSMA, F-18 sodium fluoride, C-11 choline, or F-18 fluciclovine may be considered after a bone scan for further evaluation of the bones with equivocal bone scan results, for detection of biochemically recurrent disease, and as workup for progression. Gallium-68 prostate-specific membrane antigen (68Ga-PSMA) PET/CT scan demonstrates high sensitivity with histopathological diagnosis and has better sensitivity and specificity compared to CT or bone scan for the detection of recurrences at lower PSA levels. Additionally, it can be utilized in staging prostate cancer. Consider C-11 choline or F-18 fluciclovine PET/CT or PET/MRI for soft tissue and bone evaluation if other workups did not show any evidence of metastasis.