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Prostate cancer

Cancer of prostate gland in men.

Introduction

Cancer of prostate gland in men.

  • M/C cancer in men
  • #2 M/C cause of cancer mortality in men worldwide (after lung cancer)
Map showing estimated age-standardized incidence rates for prostate cancer worldwide in 2018, in males including all ages. | Ferlay J EM, Lam F, Colombet M, Mery L, Pineros M, Znaor A, Soerjomataram I. et al. Global cancer observatory: cancer today. Lyon, France: International Agency for Research on Cancer. Available from: https://gco.iarc.fr/today, Accessed 02 February 2019. [Internet]

Aetiology

Risk factors:

  • Age: Prostate cancer incidence relates strongly to age, with age-specific incidence rates rising sharply from the age of 50 years and being highest in men aged 90 and above
  • Positive family history
  • Increased height
  • Obesity
  • Hypertension
  • Lack of exercise
  • Persistently elevated testosterone levels
  • Agent Orange exposure
  • Western diet

Pathophysiology

Zonal anatomy:

The commonly used concept of zonal anatomy of the prostate was first proposed in 1968 by McNeal. He proposed that the prostate has four distinct regions: the non-glandular anterior fibromuscular zone (or stroma) and the glandular peripheral, central and transitional zones.
Human prostate anatomy and epithelial cell constitution. A. The prostate is located beneath the bladder and is composed of 3 distinct zones; the central zone (CZ) that contains the ductal tube from the seminal vesicle to where it meets the descending urethra, the peripheral zone (PZ) which is situated at the posterior of the gland and is the region from where the vast majority of PIN and cancer arises, and the transitional zone (TZ) that is directly below the bladder and surrounds the transitional urethra. BPH occurs in this region of the prostate. B. Diagrammatic representation of a normal prostatic acinus; the epithelial bilayer of basal and luminal cells, surrounded by fibromuscular stroma. The relative content of different epithelial cells in the normal prostate are summarised graphically; luminal (60%), basal (40%) with the stem cells constituting ~ 1% of total epithelia. C. Cellular composition of a cancerous acinus. Cancer is characterised by luminal hyperproliferation, loss of the basal layer, breakdown of basement membrane, immune cell infiltration and stromal reactivity. Cancer skews the epithelial cell percentages; the luminal cells make up > 99% of tumours, basal CSCs are estimated to constitute < 0.1% of tumour epithelial cells. | Packer, J. R., & Maitland, N. J. (2016). The molecular and cellular origin of human prostate cancer. Biochimica et Biophysica Acta (BBA) – Molecular Cell Research, 1863(6, Part A), 1238–1260. https://doi.org/https://doi.org/10.1016/j.bbamcr.2016.02.016
  • Non-glandular zones:
    • Anterior fibromuscular zone (or stroma)
  • Glandular zones:
    • Peripheral zone: Most cancers originate
    • Central zone: Middle lobe develops
    • Transition zone: BPH ‘lateral lobes’ form

Pre-malignant lesions:

Phenotypic, micro-environmental and molecular changes incurred through the pre-malignant states of prostate cancer. The prostate is an organ in which pre-neoplastic disorders, including proliferative inflammatory atrophy (PIA) and PIN are relatively common. Tumours develop almost exclusively in the peripheral zone of the organ mimicking the zonal selectivity of hypothesised pre-malignancies; PIA and PIN | Packer, J. R., & Maitland, N. J. (2016). The molecular and cellular origin of human prostate cancer. Biochimica et Biophysica Acta (BBA) – Molecular Cell Research, 1863(6, Part A), 1238–1260. https://doi.org/https://doi.org/10.1016/j.bbamcr.2016.02.016

Clinical features

Lower urinary tract symptoms (LUTS):

LUTS are very common as men get older, with studies estimating a prevalence of greater than 50% in men aged 50 years and above, increasing further with increasing age.
  • Storage symptoms: Frequency, nocturia, urgency, urge incontinence
  • Voiding symptoms: Poor stream, intermittent stream, hesitancy, straining to void, terminal dribbling
  • Post-micturition symptoms: Incomplete emptying, post-micturition dribble

Other genito-urinary symptoms:

  • Visible haematuria: High-risk symptom for possible urological cancer, including prostate cancer
  • Erectile dysfunction: Also associated with prostate cancer

Diagnosis

Prostate cancer should be suspected in men over 50 years old presenting with lower urinary tract symptoms (LUTS), visible haematuria or erectile dysfunction.

Digital rectal examination (DRE):

Assess the prostate in terms of its shape, symmetry, nodularity, and firmness, as some prostate cancer is diagnosed on the basis of DRE-detected subtle abnormalities in terms of symmetry or nodularity.

Prostate specific tests:

  • Prostate specific antigen (PSA) (> 4 ng/ml): At least 2 abnormal PSA levels or the presence of a palpable nodule on DRE to justify a biopsy and further investigation
  • Prostate cancer antigen 3 (PCA3): RNA based genetic test performed from a urine sample obtained immediately after a prostatic massage
  • Prostate health index (PHI): Blood test that includes free PSA, total PSA, and proPSA isoform of free PSA
  • Mi-prostate score: Predictive algorithm that includes PSA, PCA3 and urine TMPRSS2:ERG (genetic fusion found in about 50% of all prostate cancers)
  • “4K” test: Measures serum total PSA, free PSA, intact PSA and human kallikrein antigen 2

Prostate MRI:

standard imaging modality for the diagnosis of prostate cancer. It can identify and grade suspicious prostate nodules to help with staging and localization, check for extracapsular extension, evaluate the seminal vesicles for possible tumor involvement and determine enlargement of regional lymph nodes that might indicate early metastatic disease.
  • Prostate imaging, reporting and data system (PIRADS) score (now v3): Assigned to each individual lesion using T2 weighting, diffusion-weighted imaging (DWI), and dynamic contrast enhancement to assign scores based on a Likert (5-point) scale based on the probability of clinically significant malignancy
PIRADS Classification for Peripheral (right) and Transition (left) Zone Lesions | Roberts MJ, Teloken P, Chambers SK, et al. Prostate Cancer Detection. [Updated 2018 Jun 11]. In: Feingold KR, Anawalt B, Boyce A, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK279042/

Prostate specific membane antigen (PSMA) based positron emmision tomography (PET) correlated with computed tomography (CT):

gold standard imaging modality for staging of intermediate and advanced prostate cancer.
CT of pelvis showing prostatic tumor extending into the (thick-walled) bladder and spread to involve pelvic lymph nodes: the patient had multiple lower urinary tract symptoms | Roberts MJ, Teloken P, Chambers SK, et al. Prostate Cancer Detection. [Updated 2018 Jun 11]. In: Feingold KR, Anawalt B, Boyce A, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK279042/

Transrectal ultrasound (TRUS) guided prostate biopsies:

12 core sextant biopsy: M/C used pattern is to take two specimens from each of three areas (base, mid-gland, and apex) on both sides

Gleason scoring system:

Based on microscopic arrangement, architecture or pattern of the glands in the prostate rather than on the individual cellular characteristics that define most other cancers. The pattern is given a grade from 1 to 5 with 1 representing an almost normal microscopic glandular pattern and appearance, to 5 where no glandular architecture remains, and there are only sheets of abnormal cancer cells.
Gleason grading and progression hypotheses: A) Gleason patterns adapted from the 2010 ISUP consensus on pathology. Cumulative Gleason grades are given for the 2 dominant patterns in cancerous tissue, meaning a score of 2–10 can be awarded. B) Clonal model of Gleason progression. Here Gleason 3 and 4 tissues have distinct progenitors that stem respective indolent and aggressive cancers. C) Transitional model of Gleason progression. A Gleason 3 cell accumulates further epigenetic/mutational changes required for the cell to progress and form a more advanced Gleason pattern. | Packer, J. R., & Maitland, N. J. (2016). The molecular and cellular origin of human prostate cancer. Biochimica et Biophysica Acta (BBA) – Molecular Cell Research, 1863(6, Part A), 1238–1260. https://doi.org/https://doi.org/10.1016/j.bbamcr.2016.02.016
Gleason grade — Lower grades are associated with small, closely packed glands. Cells spread out and lose glandular architecture as grade increases. Gleason score is calculated from grade as described in the text. | Public Domain, https://commons.wikimedia.org/w/index.php?curid=440437

Management

The first decision in managing prostate cancer is determining whether any treatment at all is needed. Prostate cancer, especially low-grade tumors, often grow so slowly that frequently no treatment is required; particularly in elderly patients and those with comorbidities that would reasonably limit life expectancy to 10 additional years or less.

Active surveillance:

Regular, periodic PSA testing and at least one additional biopsy 12-18 months after the original diagnosis. Active surveillance is appropriate for men with low-grade prostate cancer (Gleason 3+3=6 or less with a PSA less than 20) and limited sized cancers.

Radical prostatectomy + pelvic lymphadenectomy (PLDN)

Involves removal of prostate, iliac & obturator lymph nodes and seminal vescicles. Surgery is mainly suggested for high-risk locally advanced prostate carcinoma with > 70 years age, with > 10 years life span or G3, G4 stage tumours

Radiotherapy:

After RP, radiotherapies are considered as the second major therapeutic modalities for localized high-risk prostate cancers.
  • External-beam radiotherapy (EBRT):
    • Proton beam therapy (PBT): More precise form of EBRT which use ionizing radiation
  • Brachytherapy (radioactive seed implants) + androgen deprivation therapy (ADT):
    • Low-dose rate brachytherapy (LDRB)
    • High-dose rate brachytherapy (HDRB)

Androgen deprivation therapy (ADT):

  • Surgical: Bilateral orchiectomy
  • Medical:
    • LHRH agonists (goserelin, buserelin)
    • Antiandrogens (flutamide, enzalutamide, xtandi)
  • For hormone resistant cases (usually after a few years of ADT):
    • Chemotherapy: Cabazitaxel, paclitaxel
    • Radiotherapy
    • Immunotherapy: Sipuleucel T (T cell vaccine)
    • Radiopharmaceutical therapy: Ra223 (via α-rays), I131 (via β-rays)

Focal ablative therapy:

Ablative energies utilized to precisely treat a localized malignant prostatic lesion. Ablative therapies typically have lower costs and substantially fewer side effects than traditional definitive whole-gland therapy. Optimal patients would be those with a single, isolated Gleason 7 (3 + 4 or 4 + 3) lesion and no evidence of extraprostatic or more widespread disease on MRI or prostatic biopsies.
  • High-intensity focused ultrasound: Uses focused ultrasound to heat and ablate prostatic tissue including isolated malignant lesions.
  • Focal laser ablation: Uses laser fibers to heat and destroys prostatic cancer nodules based on MRI imaging using MRI-Fusion guided targeting.
  • Targeted cryoablation of prostate cancer (TCAP)

Hormone therapy:

In 1941, Urologist Charles Huggins MD from the University of Chicago discovered that androgen deprivation (castration) would cause prostate glands to atrophy and prostate cancer to regress. He was awarded the Nobel Prize for Medicine in 1966 for this discovery which is the basis for all hormonal (testosterone deprivation based) treatment used in prostate cancer. This was the first effective systemic therapy for prostate cancer, and it still is extremely useful in putting cancer into remission. This beneficial hormonal effect typically lasts an average of about two years, but virtually all prostate cancers will eventually escape and regrow.
  • Luteinizing hormone-releasing hormone (LHRH) agonists: Leuprolide, goserelin
  • Preceded by prophylactic anti-androgen therapy (bicalutamide) to prevent any clinical response to the temporary testosterone surge that typically accompanies initiation of hormonal therapy with these agents.
  • Calcium + Vitamin D supplementation, along with bisphosphonate/RANK-L inhibitor: Recommended in long-term hormonal treatment (≥ 1 year) to prevent bone loss

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