prostate%20cancer
PROSTATE CANCER

Prostate cancer is the cancer that occurs in the male's prostate.

It is the most common cancer in men >50 years of age.

Signs and symptoms include weak urinary stream, polyuria, nocturia, hematuria, erectile dysfunction, pelvic pain, back pain, chest pain, lower extremity weakness or numbness and loss of bowel or bladder control.

Prostate%20cancer Diagnosis

Diagnosis

Key Examinations for the Diagnosis of Prostate Cancer

  • Prostate-specific antigen (PSA) level
  • Digital rectal examination (DRE)
  • Prostate biopsy

Staging

  • Determines the extent of cancer upon diagnosis
  • Important factor in the choice of treatment and provides information about the prognosis of the disease

Tumor, Nodes and Metastasis (TNM) System

  • Developed by the American Joint Committee on Cancer (AJCC) and Union Internationale Contre le Cancer (UICC)
     Clinical T (cT)
    T - Primary Tumor
    TX Primary tumor cannot be assessed
    T0 No evidence of primary tumor
    T1 Clinically inapparent tumor not palpable or visible by imaging
    T1a Tumor incidental histological finding in 5% or less of tissue resected
    T1b Tumor incidental histological finding in more than 5% of tissue resected
    T1c Tumor identified by needle biopsy (secondary to elevated PSA level)
    T2 Tumor confined within the prostate gland (by needle biopsy)
    T2a Tumor involves 1/2 of one lobe or less
    T2b Tumor involves >1/2 of one lobe but not both lobes
    T2c Tumor involves both lobes
    T3 Tumor extends through the prostatic capsule
    T3a Extracapsular extension (unilateral or bilateral)
    T3b Tumor invades the seminal vesicle(s)
    T4 Tumor fixed or invades adjacent structures other than the seminal vesicles (bladder, rectum, levator muscles, and/or pelvic wall)
     Pathological T (pT)
     T - Primary Tumor
     T2  Confined in the organ
     T3    Positive extension extraprostatically
     T3a  Unilateral or bilateral extraprostatic extension
     T3b  Tumor invades seminal vesicle(s)
     T4  Fixed tumor or invades adjacent structures other than the seminal vesicles (ie external sphincter, rectum, bladder, levator muscles, and/or pelvic wall)
    N - Regional Lymph Nodes
    NX Regional lymph nodes cannot be assessed
    N0 No regional lymph node metastasis
    N1 Regional lymph node metastasis present
    M - Distant metastasis1
    M0 No distant metastasis
    M1 Distant metastasis
    M1a Non-regional lymph node(s)
    M1b Bone(s)
    M1c Other site(s) with or without bone disease
    1The most advanced category (M1c) should be used when >1 metastasis site is present
    Adapted from: TNM Staging System for Prostate Cancer (8th ed., 2017) in National Comprehensive Cancer Network. NCCN guidelines: prostate cancer version 2.2020. NCCN. 2020; European Association of Urology. 2019.

Staging

  • Should be based on the PSA level, tumor grade, and positive prostate biopsies
    Stage Tumor Node Metastasis PSA Grade Group
    I cT1a-c N0 M0 PSA <10 1
    cT2a N0 MO PSA <10 1
    pT2 NO MO PSA <10 1
    IIA cT1a-c N0 M0 PSA  ≥10<20 1
    cT2a N0 MO PSA ≥10<20 1
    pT2 NO MO PSA ≥10<20 1
    cT2b NO MO PSA <20 1
    cT2c NO MO PSA <20 1
    IIB T1-2 N0 M0 PSA <20 2
     IIC T1-2 N0 MO PSA <20 3
    T1-2 NO MO PSA <20 4
    IIIA T1-2 NO MO PSA ≥20 1-4
    IIIB T3-T4 N0 M0 Any PSA 1-4
     IIIC Any T N0 MO Any PSA 5
     IVA Any T N1 M0 Any PSA Any
    IVB   Any T  Any N  M1  Any PSA  Any
    Adapted from: National Comprehensive Cancer Network. NCCN guidelines: prostate cancer. Version 2.2020. NCCN. 2020; American Cancer Society. Prostate cancer staging. Aug 2019.

Risk Stratification

  •  Based on the PSA level, biopsy, Gleason score, and TNM classification
  • Helps in decision making for the management of patients diagnosed with prostate cancer
    Risk Group Clinical Stage   PSA   Grade Group or Gleason Pattern   Others
    Clinically Localized
    Very Low T1c and <10 ng/mL and Grade group 1 and <3 prostate biopsy fragments/cores positive, with ≤50% cancer in each fragment/core and PSA density <0.15 ng/mL/g
    Low T1-T2a  and <10 ng/mL  and Grade group 1    
    Intermediate T2b-T2c  or 10-20 ng/mL  or Grade group 2-3    
       Intermediate - Favorable  T2b-T2c  or  10-20 ng/mL  or  Grade group 1 or 2  and 1 intermediate risk factor (IRF) and percentage of positive biopsy core <50% 
       Intermediate - Unfavorable  T2b-T2c  or  10-20 ng/mL or Grade group 3 and/or   2 or 3 IRF and/or percentage of positive biopsy cores ≥50%
    High T3a or  >20 ng/mL  or Grade group 4 or Grade group 5    
    Locally Advanced
    Very High T3b-T4  or Any  or Primary Gleason pattern 5 or Grade group 4 or 5 in >4 cores   2 or 3 high-risk features
     Regional  Any T, N1, M0             
    Metastatic Any T, any N, M1            
    Adapted from: National Comprehensive Cancer Network. NCCN guidelines: prostate cancer version 2.2020. NCCN. 2020; European Association of Urology. Guidelines on prostate cancer. 2019; European Society for Medical Oncology. Prostate cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Jun 2020.

Cancer of the Prostate Risk Assessment (CAPRA)

  • A straightforward scoring system (0-10) that predicts likelihood of metastasis, cancer-specific mortality, and overall survival
  • Based on the patient’s age, PSA levels, Gleason score, clinical stage, and percent of malignant biopsy cores
  • Also predicts disease recurrence after radical prostatectomy

Assessment

  • Key determinant of primary treatment for patients diagnosed with prostate cancer include life expectancy estimation, family history and risk for germline mutations

Life Expectancy Estimation

  • A key determinant of primary treatment for prostate cancer when considering observation or active surveillance
  • Done using life tables by either the Minnesota Metropolitan Life Insurance Tables, the Social Security Administration Life Insurance Tables, or the WHO’s Life Tables by Country, and computed based on patient’s health status

Genetic Testing
Germline Testing

  • Recommended for prostate cancer patients with any of the following: Family history of prostate cancer, high-risk, very high-risk, regional or metastatic prostate cancer, Ashkenazi Jewish ancestry or intraductal/cribriform histology
  • Should include MLH1, MSH2, MSH6, PMS2, BRCA2, BRCA1, ATM, PALB2 and CHEK2
    •  Cancer predisposition next-generation sequencing (NGS) panel testing which includes above genetic mutations except for PALB2 may be considered
  • Recommended for very low-, low- and intermediate-risk groups if patient has strong family history of prostate cancer or with intraductal/cribriform histology

Molecular Assays

  • Provide a more personalized or precise approach to treatment
  • Available tumor-based molecular assays include Decipher, Oncotype DX Prostate, Prolaris and ProMark
  • Recommended somatic tests for the following patients:
    • Regional or metastatic prostate cancer: Tumor testing for somatic homologous recombination gene mutations 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 ≥10 years: Decipher, Oncotype DX Prostate, Prolaris, and ProMark
    • Unfavorable intermediate- and high-risk prostate cancer with life expectancy ≥10 years: Decipher and Prolaris tumor-based molecular assays
    • PSA resistance/recurrence after radical prostatectomy: Decipher molecular assay to be used during counseling for risk stratification
  • For patients with history of Abiraterone/Enzalutamide therapy for metastatic CRPC, 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

Gleason Score

  • Useful in determining tumor grade, prognostic risk, and management strategies
    Gleason Score Definition
    Gleason X Gleason score cannot be assessed
    Gleason <6 Well differentiated (slight anaplasia)
    Gleason 7 Moderately differentiated (moderate anaplasia)
    Gleason 8-10 Poorly differentiated/undifferentiated (marked anaplasia)

Grade Group

  • New histologic grading system developed by the International Society of Urological Pathology (ISUP) that assigns grade groups based on the Gleason score and thereby provides better management strategies
    Grade Group  Gleason Score 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 (4+5, 5+4) or
    10 (5+5) 
     Very high Lack of gland formation with or without poorly formed/fused/cribriform glands

Family History

  • Criteria that signify strong family history of prostate cancer and should prompt genetic testing include:
    • Brother, father or >1 family member ≤60 years old diagnosed or who passed away due to prostate cancer
    • Ashkenazi Jewish ancestral lineage: Associated with germline mutations in BRCA2 or BRCA1
    • ≥3 cancers of the following carcinomas present on the same side of the family, especially if diagnosed ≤50 years of age: Breast, bile duct, colorectal, endometrial, gastric, renal, ovarian, melanoma, pancreatic, prostate, urothelial, small intestines

Physical Examination

Digital Rectal Examination (DRE)

  • Detects prostatic enlargement with volume of >0.2 mL
  • Abnormal DREs are associated with high Gleason scores and may be considered for prostate biopsy

Laboratory Tests

Prostate-Specific Antigen (PSA) Level

  • A kallikrein-like serine protease produced by prostatic epithelial cells
  • Risk for prostate cancer increases with increasing level of PSA and may warrant a prostate biopsy
  • 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

Prostate Biopsy

  • Most common method used in diagnosing prostatic carcinoma
  • Should only be offered if PSA levels and DRE highly suggest prostate cancer
  • Transrectal ultrasound (TRUS)-guided core-needle prostate biopsy is highly recommended for men with PSA levels of >4 ng/mL
  • Indications:
    • Increased risk for prostate cancer and with PSA levels of 2.5-4 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 4-10 ng/mL
    • PSA levels too high for age range
  • Obtaining a minimum of 10-12 cores are recommended
  • Should be done under antibiotic coverage
  • The perineal approach (transperineal 3D prostate mapping biopsy) is a useful option for special circumstances (eg rectal amputation)

Other 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 B-cell lymphoma 2 (Bcl-2), BCL2 Associated X Protein (Bax)], proliferation rate markers (eg Ki67), p53 mutation/expression, p27, E-cadherin, deoxyribonucleic acid (DNA) plody, p16
  • Other biomarker tests recommended by the National Comprehensive Cancer Network (NCCN) include percent free PSA (%f PSA), Prostate Health Index (PHI), 4Kscore®, EPI, prostate specific antigen 3 (PCA3), ConfirmMDx and ExoDx Prostate(IntelliScore)
  • 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

Imaging

  • Should be based on PSA results, Gleason score, and patient’s health status
  • Pelvic and/or abdominal imaging is recommended for intermediate- to very high-risk patients with >10% probability of pelvic LN involvement in nomogram

Plain Film Radiography

  • May be used to assess for presence of bone pathologies in symptomatic patients

Ultrasonography

  • Transrectal ultrasound (TRUS) may be used to assess the prostate gland if PSA levels and DRE results are inconclusive
  • Also used as a guide during transrectal prostate biopsies

Computed Tomography (CT) Scan

  • May be used to assess for presence of bone pathologies
  • May be used for lymph node staging in asymptomatic patients at intermediate-high risk [PSA level >10 ng/ mL, Gleason score >8, or clinical stage >T3]

Magnetic Resonance Imaging (MRI)

  • Multiparametric MRI (mpMRI) by diffusion-weighted imaging or hydrogen 1 (H1)-spectroscopy may be done to assess if repeat prostate biopsy is needed in patients with negative results in TRUS
    • Detects large and poorly differentiated tumors and extracapsular extension, used for staging of pelvic lymph nodes, and detects bone metastases
  • Sensitivity at >2 cc: 67-75% for Gleason <6; 97% for Gleason 7; 100% for Gleason >8
  • Positive results may suggest repeat prostate biopsy

Radionuclide Bone Scan

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

Gallium 68-Prostate Specific Membrane Antigen (68GA-PSMA) PET/CT Scan

  • A PET tracer which demonstrates high sensitivity with histopathological diagnosis
  • Has better sensitivity and specificity compared to CT or bone scan
  • Can be utilized in staging prostate cancer

Screening

Recommended for men:

  • 50 years of age at average risk for prostate cancer and with life expectancy of >10 years
  • 45 years of age at high risk for developing prostate cancer (eg African American descent, with 1st-degree relatives diagnosed with prostate cancer who are <65 years old)
  • 40 years of age with 1st-degree relatives diagnosed with prostate cancer who are <65 years old and with previous PSA level of >1 ng/mL
  • With previous PSA level of >2 ng/mL taken at 60 years old
  • With initial screening which includes PSA and DRE
  • With negative results but at risk for prostate cancer, repeat screening should be done depending on the PSA result:
    • PSA <2.5 ng/mL = every 2 years
    • PSA >2.5 ng/mL = yearly
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