Prostate Cancer

Prostate cancer is one of the most common cancers affecting men. In the United States, the lifetime risk of being diagnosed with prostate cancer is approximately 11%, and the lifetime risk of death is 2.5%. Prostate cancer is a slow-growing cancer that takes years, or even decades, to develop into advanced disease. Several men with prostate cancer are asymptomatic. Late-stage cancer can present with bone pain, urinary symptoms, and/or weight loss. Most cases of prostate cancer are identified based on diagnostic tests to determine prostate-specific antigen (PSA) levels and are confirmed based on image-guided transrectal biopsy. Management of prostate cancer depends on age, life expectancy, comorbidities, risk stratification, and preferences of the patient. Management options include active surveillance, androgen deprivation therapy, radiotherapy, chemotherapy, and radical prostatectomy.

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Overview

Epidemiology

  • Worldwide:
    • 2nd most common cancer in men
    • > 1.3 million cases diagnosed annually
  • In the United States:
    • 3rd leading cause of cancer in men
    • Approximately 192,000 cases diagnosed annually
    • The lifetime risk of being diagnosed with prostate cancer is 11%.
    • The lifetime risk of dying from prostate cancer is 2.5%.
  • 5-year survival after diagnosis:
    • Localized disease or regional spread: nearly 100%
    • Distant metastatic disease: 31%

Risk factors

Inherent factors (major):

  • Age
    • Rare in men < 40 years of age
    • Peaks in men between 65 and 74 years of age
  • More common, and earlier onset in African Americans
  • Family history of prostate cancer, particularly in 1st-degree relatives diagnosed at < 65 years of age
  • Family history of other heritable cancers
    • Breast cancer, BRCA1 and BRCA2 gene mutations
    • Melanoma
    • Colorectal cancer, Lynch syndrome
    • Ovarian cancer
    • Pancreatic cancer

Medical factors:

  • Obesity
  • 5-alpha-reductase inhibitors (e.g., finasteride)
    • ↓ PSA levels
    • ↑ High-grade risk of prostate cancer
  • Trichomonas vaginalis infection

Social and environmental factors:

  • High-fat, low-vegetable diet
  • Smoking
  • Exposure to Agent Orange
    • Herbicide and defoliant chemical used during the Vietnam War between 1965 and 1972
    • Associated with more aggressive cancer
  • Exposure to chlordecone 
    • Insecticide used between 1973 and 2003 in the Caribbean
    • Binds to estrogen receptors and contributes to malignancy

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Pathophysiology

Prostate gland and zonal anatomy

Prostate gland:

  • An organ under the bladder
  • Primarily composed of glandular tissue that secretes fluid into the ejaculate (which makes up semen, together with sperm and seminal fluid)

Zonal anatomy:

  • Peripheral zone: 
    • Comprises > 70% of the prostate gland
    • Approximately 70% of prostate cancers are in the peripheral zone.
    • Closest to the rectum 
  • Central zone: 
    • 15%‒20% of prostate cancers are in the central zone. 
    • Surrounds the ejaculatory ducts
  • Transitional zone: 
    • 10%‒15% of prostate cancers are in the transitional zone. 
    • Surrounds the proximal urethra
    • Key area of concern for benign prostatic hyperplasia (BPH)
  • Fibromuscular stroma:
    • Cancer in the fibromuscular stroma is rare.
    • Does not contain glandular tissue
    • Surrounds the apex of the prostate

Prostate gland and main prostate zones: peripheral, transitional, and central zones in relation to other structures of the male genitourinary system

Image: “Zones of the prostate” by Mikael Häggström. License: CC0

Tumorigenesis

Under the influence of the factors listed below, prostate epithelium → prostate intraepithelial neoplasia (precursor lesion) → localized adenocarcinoma → metastasis and androgen-resistant cancer

  • Adenocarcinoma accounts for > 90% of cases: develops primarily from a mutation in the glandular tissue
  • Development of prostate cancer is affected by:
    • Environmental factors
      • Diet
      • Smoking
    • Androgens
      • Prostate cancer cells rely on testosterone for growth and survival.
      • Testosterone dependence is seen with antiandrogen therapy.
      • Mechanisms develop to overcome androgen blockade and eventually lead to androgen resistance.
    • Inherited genetic factors 
      • 2-fold ↑ risk in men with 1st-degree relatives with the disease
      • Germline MYC (oncogene in prostate cancer) variants
      • Other rare variants include BRCA2 and DNA mismatch repair genes (part of Lynch syndrome).
    • Acquired genetic factors
      • TMPRSS-ETS fusion gene is the most common gene alteration in prostate cancer (noted in 50% of cases).
      • Silencing of the gene encoding p27 (a protein controlling cell growth and division)
      • Amplification of MYC and deletion of PTEN: ↑ cell growth and ↑ androgen resistance

Pathogenesis of prostate cancer:
Normal prostate gland comprises basal and luminal cells. Majority of prostate cancers arise from the peripheral zone. Under the influence of diet, androgens, and inflammation caused by genetic variants, precursor lesions (prostatic intraepithelial neoplasia) develop. As further genetic or epigenetic alterations occur, the lesions progress to adenocarcinoma. Tumors initially regress with antiandrogen therapy, but eventual androgen resistance occurs.

Image by Lecturio.

Clinical Presentation

  • The majority of diagnosed patients are identified by screening for prostate cancer.
  • Usually asymptomatic in early stages
  • Manifestations in later stages:
    • Bone pain (most common site of disseminated prostate cancer)
    • Weakness from spinal-cord compression
    • Weight loss
    • Fatigue
    • Urinary retention
    • Hematuria
    • Erectile dysfunction
    • Hydronephrosis 

Diagnosis

Prostate-specific antigen

Prostate-specific antigen levels are determined to detect early cancer.

Background:

  • Protein produced by prostate cells (but not specific to malignancy)
  • A small amount enters the bloodstream in healthy individuals.
  • ↑ Serum PSA level in prostate cancer is due to:
    • ↑ Number of cells producing PSA, despite malignant cells synthesizing less PSA
    • Disruption in the normal architecture and basement membrane, allowing ↑ levels of PSA to enter the bloodstream

Interpretation:

  • PSA ≥ 4 ng/mL is considered positive and the most widely accepted standard, which balances the trade-offs between sensitivity and specificity.
  • Long-term use of 5-alpha-reductase inhibitors:
    • Associated with ↓ PSA levels with long-term medication use
    • Correction factor should be applied for accurate interpretation.
    • If there is an ↑ in PSA level, the patient should be referred to urology.
  • Other urological conditions that can elevate PSA levels:
    • BPH
    • Prostatitis
    • Urinary retention
    • Urological procedures (e.g., catheter placement, cystoscopy) 
  • Repeat testing is recommended in the case of ↑ PSA (after addressing factors possibly influencing the elevation)

Clinical variables to interpret PSA levels:

  • General age-adjusted PSA (ng/dL) thresholds are as follows: 
    • 40‒49 years of age: 2.5
    • 50‒59 years of age: 3.5
    • 60‒69 years of age: 4.5
    • 70‒79 years of age: 6.5
  • PSA density:
    • Ratio of PSA to prostate volume (measured using imaging studies)
    • Value ≥ 0.15 ng/mL/g is an indication for prostate biopsy
  • PSA velocity: 
    • Cancer grows faster and the increase in PSA levels is more rapid.
    • At least 3 measurements should be obtained over a 2-year period.
  • Free and complexed PSA: 
    • 2 forms of PSA: free, and complexed to protease inhibitors
    • In cancer: ↑ in PSA complexed to protease inhibitors

Digital rectal examination (DRE)

  • No longer recommended for asymptomatic patients
  • Low sensitivity and specificity
  • However, if an abnormality (e.g., nodule, asymmetry) is detected on rectal exam, evaluation should be conducted.

Prostate biopsy

  • Confirmatory test required for diagnosis
  • Biopsy is performed using an image-guided (transrectal ultrasound or MRI) transrectal approach.
  • Considerations before pursuing biopsy:
    • Age and ethnicity of the patient
    • Life expectancy of the patient
    • Comorbidities
    • Immediate and long-term risks of biopsy, and possible treatment options

Imaging studies

  • Evaluation of the extent of prostate cancer and volume determination:
    • MRI
    • Prostate Imaging Reporting and Data System (PI-RADS) 
      • Used to report the likelihood of cancer in a suspicious area
      • 5-point scale, with 1 representing high unlikeliness and 5 indicating high likeliness of cancer
  • To determine extra-prostatic extension and distant metastasis:
    • CT or MRI of the abdomen and pelvis
    • PET: Images may be superimposed with CT and MRI.
    • Bone scan

Imaging of a patient with metastatic prostate cancer:
(A) Magnetic resonance imaging (MRI) demonstrates the seminal vesicles (SV), the prostate lesion (tumor), and extracapsular extension (ECE).
(B) Bone scan shows solitary L5 vertebral body metastasis.

Image: “Rationale for stereotactic body radiation therapy in treating patients with oligometastatic hormone-naïve prostate cancer” by O. Bhattasali et al. License: CC BY 3.0

Staging

Parameters

The following elements are crucial determinants of outcome and are used for risk stratification in selecting a treatment approach:

  • Extent of tumor (T)
  • Spread to lymph nodes (N)
  • Metastasis (M) 
  • Pretreatment PSA levels
  • Histological grade group (based on the Gleason score)

Tumor-nodes-metastases staging

The TNM staging is based on the 8th-edition staging guidelines by the American Joint Committee on Cancer. There are 2 categories of staging:

  1. Clinical staging: based on physical exam, imaging, and biopsy
  2. Pathological staging: based on findings after prostatectomy
Table: Tumor staging
Tumor clinical stage (cT)Description
cTXPrimary tumor cannot be assessed.
cT0No evidence of primary tumor
cT1No palpable disease on DRE
  • T1a: cancer incidentally found in ≤ 5% of tissue obtained in a surgery for benign disease
  • T1b: cancer incidentally found in > 5% of tissue obtained in a surgery for benign disease
  • T1c: cancer found during biopsy for elevated PSA
cT2Palpable disease on DRE, but confined within the prostate
  • T2a: ≤ 50% on 1 side of the prostate
  • T2b: > 50% on 1 side of the prostate
  • T2c: both sides affected
cT3Palpable outside the prostate laterally, or involving the seminal vesicles
  • T3a: extra-prostatic extension (through the capsule)
  • T3b: extension to the seminal vesicles
cT4Tumor is fixed, or it can invade the adjacent structures (external sphincter, rectum, bladder, levator ani, or pelvic wall).
DRE: digital rectal examination
PSA: prostate-specific antigen
Table: Tumor staging
Tumor pathological stage (pT)*Description
pT2Organ confined
pT3Extra-prostatic extension
  • pTsa: unilateral or bilateral extension or microscopic bladder neck invasion
  • pT3b: invades seminal vesicles
pT4Tumor is fixed or invades other adjacent structures (external sphincter, rectum, bladder, levator ani, or pelvic wall).
*There is no pathological T1 classification.
Table: Lymph node (N) staging
Clinical node stage (cN)Description
cNXRegional lymph nodes not assessed
cN0No regional lymph-node involvement
cN1Metastasis in regional lymph node(s)
Table: Metastasis (M) staging
Metastasis stageDescription
M0No distant metastasis
M1Distant metastasis to:
  • M1a: non-regional lymph node(s)
  • M1b: bone(s)
  • M1c: other sites (with or without bone disease)

Histological grading

Grade group is based on the Gleason score.

  • Standard measure of differentiation of prostate cancer
  • 5 patterns graded from 1–5: 
    • 1 being closest to the normal tissue
    • 5 being the most abnormal
  • Biopsy specimen is examined under low magnification to identify the most common (1st number) and 2nd most common (2nd number) patterns. 
  • The 2 numbers are added to obtain the Gleason score.
  • Gleason score is used to predict clinical behavior and outcome.
    • Lower score and grade group: Cancer is likely to grow and spread slowly.
    • High score and grade group: Cancer is likely to grow and spread rapidly.
    • Order is as important as the total score in predicting prognosis (e.g., 3 + 5 = 8 has a more favorable prognosis than 5 + 3 = 8).
Grade groupGleason scorePattern
1 Gleason ≤ 6 Well-differentiated tumors
2 Gleason 3 + 4 = 7 Predominantly well-formed glands with few poorly formed glands
3 Gleason 4 + 3 = 7 Predominantly poorly formed glands with less well-formed glands
4 Gleason 8 Only poorly formed glands or predominantly well-formed glands; a lesser component with a lack of glands 
5 Gleason 9‒10 Advanced; lacks gland formation or exhibits necrosis 

Prognostic stage

The TNM stage, PSA, and histological grade group can be used to determine the prognostic stage group.

Table: Criteria for prognostic stage group
StageTumor (T)Node (N)Metastasis (M)PSA (ng/mL)Grade group
I cT1a‒c, cT2a, pT2 N0 M0 < 10 1
II IIA cT1a‒c, cT2a, pT2 N0 M0 ≥ 10, < 20 1
cT2b–c < 20
IIB T1‒T2 N0 M0 < 20 2
IIC T1‒T2 N0 M0 < 20 3‒4
III IIIA T1‒T2 N0 M0 ≥ 20  1‒4
IIIB T3‒T4 N0 M0 Any 1‒4
IIIC Any N0 M0 Any 5
IV IVA Any N1 M0 Any Any
IVB Any Any M1 Any Any
PSA: prostate-specific antigen

Risk stratification

Information regarding tumor stage, grade group, Gleason score, and PSA level is used to determine clinical-risk categories.

  • Risk may be assessed as:
    • Very low
    • Low
    • Intermediate
    • High
    • Very high 
  • Use of risk-evaluation guides:
    • Appropriateness in ordering imaging studies (e.g., do not obtain CT or bone scans in very low-/low-risk patients)
    • Treatment options

Management

Principles of treatment

  • Prostate cancer is associated with slow growth and may not be clinically significant during the lifetime of a patient.
  • Definitive treatments are associated with substantial side effects that impact the quality of life.
  • Multiple factors are considered in treatment:
    • Age and life expectancy
    • Overall health and comorbidities
    • Characteristics of the cancer and risk stratification
    • Patient preferences

Management options

Active surveillance:

  • Deferred treatment with monitoring:
    • Serial PSA and DREs over regular intervals
    • Repeat biopsies
    • MRI
  • Intention to treat for disease progression or change in patient preference
  • Preferred in patients with very low- or low-risk cancer

Radiation therapy (RT):

  • External beam RT (EBRT): can cause erectile dysfunction and radiation proctitis
  • Brachytherapy:
    • Radioactive seed implants 
    • Can cause bladder irritation

Surgery (radical prostatectomy):

  • Options:
    • Open surgery 
    • Laparoscopy with or without robotic assistance
  • Removal of the prostate gland, seminal vesicles, and pelvic lymph nodes, followed by reconstruction (reconnecting the bladder neck and the urethra)
  • Can cause erectile dysfunction and stress urinary incontinence 

Androgen deprivation therapy (ADT):

  • Luteinizing hormone-releasing hormone (LHRH) agonists:
    • Leuprolide acetate, goserelin, triptorelin, and histrelin
    • Initial release/surge of LH, then ↓ pituitary LH → ↓ testosterone
  • LHRH antagonists:
    • Degarelix, relugolix
    • ↓ Pituitary drive without an initial surge in LH → ↓ testosterone
  • Antiandrogens:
    • Androgen receptor antagonists: flutamide, bicalutamide, apalutamide, and enzalutamide
    • Androgen synthesis inhibitors: abiraterone, ketoconazole, and aminoglutethimide
  • Surgical castration with simple orchiectomy (removal of the testicles): ↓ testosterone levels
  • General side effects:
    • Reduced sexual desire
    • Impotence
    • Hot flashes
    • Gynecomastia and breast tenderness
    • Depression

Chemotherapy:

  • Docetaxel
  • Cabazitaxel

Immunotherapy:

  • Sipuleucel-T (Provenge) 
    • Vaccine
    • Made from autologous mononuclear cells
    • Induces immunity against prostate cancer 
    • For metastatic ADT-resistant prostate cancer
  • Pembrolizumab:
    • Programmed cell death receptor-1 ligand (PD-L1) inhibitor
    • For patients lacking the mismatch-repair (dMMR) mechanism, and for individuals with high levels of microsatellite instability (MSI-H)

Other therapies:

  • Targeted therapy 
    • Poly-ADP-ribose polymerase (PARP) inhibitors
    • For patients with germline or somatic DNA repair mutation (BRCA)
  • Radium-223
    • Emits alpha radiation
    • Prevents complications due to bone metastasis

Management

The following management options are based on prognostic stage, and should be guided by the age, health, and preferences of the patient:

  • Stage I:
    • Active surveillance (preferred)
    • RT or surgery: considered in patients with a high probability of progression
  • Stage II:
    • Active surveillance
      • If no symptoms
      • In the elderly
      • If serious health issues
    • RT with or without ADT
    • Surgery with or without EBRT
  • Stage III:
    • Recurrence after treatment is more likely.
    • EBRT plus ADT: Brachytherapy may be added.
    • Surgery followed by RT and/or ADT
  • Stage IV:
    •  Lymph-node involvement:
      • RT plus ADT
      • In young individuals with minimal regional lymph-node spread, surgery followed by ADT with or without RT can be considered.
    • Metastatic disease: ADT plus chemotherapy
    • Other options: 
      • ADT-resistant cancer: immunotherapy or PARP inhibitors
      • Symptomatic bone metastasis without visceral disease: radium-223

Differential Diagnosis

  • BPH: a condition caused by an increase in the number of stromal and epithelial cells within the prostate gland. Patients are usually > 50 years of age and present with symptoms of bladder obstruction and/or bladder-storage problems. Benign prostatic hyperplasia can lead to an increase in PSA levels. Diagnosis is based on history and invasive testing (cystoscopy, urodynamics, transrectal ultrasound imaging). Management is with medications and/or surgery.
  • Prostatitis: a group of inflammatory conditions of the prostate gland. Patients may be asymptomatic or present with urinary symptoms, such as perineal pain, increased urinary frequency and urgency, urinary obstruction, and fever. The diagnosis is generally clinical and supported by urinalysis and culture data. Management depends on the etiology, but can include antibiotics in cases of infection. Prostate-specific antigen levels may be elevated. To differentiate prostatitis from prostate cancer, PSA levels are remeasured after the treatment of prostatitis.
  • Erectile dysfunction (ED): the consistent inability to acquire or maintain an erection. Erectile dysfunction is associated with diabetes mellitus, heart disease, and certain drugs (e.g., antidepressants). Treatments for prostate cancer (RT, prostatectomy) can also result in ED. Management is with phosphodiesterase-5 inhibitors and vacuum-assisted erection devices.
  • Urinary incontinence (UI): the involuntary leakage of urine. There are many types of incontinence, including stress, urge, and mixed type. Radical prostatectomy can result in stress UI, which presents as urine leakage with exertion or as gravitational incontinence. Lifestyle intervention (Kegel exercises), medical therapy, and surgical procedures are options in managing post-surgical UI.

References

  1. American Urological Association. (2017). Clinically Localized Prostate Cancer: AUA/ASTRO/SUO Guideline. https://www.auanet.org/guidelines/prostate-cancer-clinically-localized-guideline#x6911
  2. American Urological Association. (2020). Medical student curriculum: Prostate cancer screening and management. https://www.auanet.org/education/auauniversity/for-medical-students/medical-students-curriculum/medical-student-curriculum/prostate-cancer/psa
  3. Kantoff, P., Taplin, M., Smith, J. (2020). Clinical presentation and diagnosis of prostate cancer. UpToDate. Retrieved Jan 21, 2021, from https://www.uptodate.com/contents/clinical-presentation-and-diagnosis-of-prostate-cancer
  4. Kantoff, P., Taplin, M., Smith, J. (2020). Initial staging and evaluation of men with newly diagnosed prostate cancer. UpToDate. Retrieved Jan 23, 2021, from https://www.uptodate.com/contents/initial-staging-and-evaluation-of-men-with-newly-diagnosed-prostate-cancer
  5. Klein, E. (2021). Prostate cancer: Risk stratification and choice of initial treatment. UpToDate. Retrieved Jan 23, 2021, from https://www.uptodate.com/contents/prostate-cancer-risk-stratification-and-choice-of-initial-treatment
  6. Netto, G., Amin, M. (2020). The Lower Urinary Tract and Male Genital System. Kumar, V., Abbas, A., Aster, J., Robbins, S. Robbins and Cotran (Eds.) Pathologic Basis of Disease (10th ed., pp 977–983). Elsevier, Inc. 
  7. Posielski, M., Richards, K. (2020). Prostate cancer staging. Medscape. https://emedicine.medscape.com/article/2007051-overview
  8. Mark, J.R. (2019). Prostate cancer. [Online] MSD Manual Professional Version. https://www.msdmanuals.com/professional/genitourinary-disorders/genitourinary-cancer/prostate-cancer
  9. American Cancer Society (2019). Prostate cancer stages and other ways to assess risk. https://www.cancer.org/cancer/prostate-cancer/detection-diagnosis-staging/staging.html
  10. American Cancer Society (2019). Initial treatment of prostate cancer, by stage. https://www.cancer.org/cancer/prostate-cancer/treating/by-stage.html
  11. Madan, R.A., Antonarakis, E.S., et al. (2020). Putting the pieces together: Completing the mechanism of action jigsaw for Sipuleucel-T. Journal of the National Cancer Institute, 112(6), 562–573. https://pubmed.ncbi.nlm.nih.gov/32145020/
  12. Antonarakis, E.S., Piulats, J.M., et al. (2020). Pembrolizumab for treatment-refractory metastatic castration-resistant prostate cancer: Multicohort, open-label phase II KEYNOTE-199 study. Journal of Clinical Oncology, 38(5), 395–405. https://pubmed.ncbi.nlm.nih.gov/31774688/
  13. Sandhu, S.K., Omlin, A., et al. (2013). Poly (ADP-ribose) polymerase (PARP) inhibitors for the treatment of advanced germline BRCA2 mutant prostate cancer. Annals of Oncology, 24(5), 1416–1418. https://pubmed.ncbi.nlm.nih.gov/23524863/

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