Prostate cancer

Prostate cancer is the second most common cancer in men after skin cancer and the second leading cause of cancer death in men after lung cancer. The risk of developing prostate cancer increases with age. It is more common in African Americans. In early stages, prostate cancer generally causes no symptoms and is typically detected by screening. The preferred diagnostic procedures are digital rectal examination (DRE), PSA testing, and ultrasound-guided transrectal prostate biopsy. Bone metastases are common in advanced prostate cancer and can be diagnosed using a bone scan. Because most patients with prostate cancer are of advanced age, life expectancy and the histological evaluation of a tumor biopsy should be taken into account when planning treatment. Radical prostatectomy and radiotherapy are indicated in young patients. In older patients, “watchful waiting” (i.e., purely symptomatic treatment) and “active surveillance” (i.e., continuous restaging and initiation of curative measures if tumor progresses) are also a treatment option since localized prostate cancer typically has a slower growth rate and a better prognosis compared to other malignancies.

• Second most common cancer in men following skin cancer
  • Mostly affects elderly men
• Second leading cause of cancer deaths in American men (after lung cancer)

References:^[1][2][3][4]

Epidemiological data refers to the US, unless otherwise specified.

Risk factors

• Advanced age (> 50 years)
• Family history
• African-American race
• Genetic disposition (BRCA-2, Lynch syndrome)
• Obesity and diet high in animal fat

Advanced age is the main risk factor for developing prostate cancer! Sexual activity and benign prostatic hypertrophy (BPH) are not associated with developing prostate cancer !; ; ;
References:^[1][5][2][3]

Early-stage prostate cancer

• Typically asymptomatic
  • Early prostate cancers are found during screening tests.
  • Incidental prostate cancer: Some prostate cancers are found incidentally during a transurethral resection of the prostate

Advanced-stage prostate cancer

• Fatigue
• Loss of appetite → weight loss
• Urinary symptoms
  • Urinary retention
  • Hematuria: especially blood at the end of the urine stream (terminal hematuria) indicates damage to the vessels of the bladder or prostate by the tumor.
  • Incontinence
  • Hydronephrosis
• Erectile dysfunction
• Metastatic disease
  • Bone pain (bone metastasis, especially lumbosacral spine)
  • Neurological deficits due to spinal cord compression
  • Lymphedema : usually causes swelling, pain, and redness in the legs; may also involve genitals

References:^[2][6]

Approach

• Physical examination and a digital rectal examination (DRE) are performed to screen for prostate cancer.
• Measurement of prostate-specific antigen levels for screening is controversial because of the risk of overdiagnosis and overtreatment.
• An irregular and nodular prostate in DRE is suspicious for malignancy.
• Since DRE or PSA irregularities are not specific to prostate cancer, multiple ultrasound-guided biopsies are collected to confirm the diagnosis.
• In cases of confirmed prostate cancer, staging is used to assess the extent of disease and plan adequate treatment.

Screening and basic diagnostics

• Digital rectal examination (DRE)
  • Indication
    • If prostate cancer is suspected
    • As a screening test
  • Findings upon palpation
    • Physiological findings: smooth, non-firm, symmetric, roughly heart-shaped, painless prostate with a palpable sulcus between right and left lobes
    • Early stage: localized indurated nodules, otherwise smooth, non-firm, painless prostate
    • Advanced stage: asymmetric areas or frank nodules, painless prostate
• Blood
  • Measure prostate-specific antigen levels : indications
    • If prostate cancer is suspected
    • Marker to monitor metastasis or cancer recurrence following treatment of PSA-positive prostate cancer
    • For potential screening
      • Benefit is controversial
      • Usefulness should be evaluated on a case-by-case basis by the physician and patient.
        • Current guidelines of the American Urological Association:
        • Greatest benefit in men aged 55–69 years with an interval of two years after shared decision-making based on a man's preferences
        • PSA test considered on a case-by-case basis in men above age 40 years with risk factors (e.g., family history, African-American race, gene changes (BRCA-1/ 2, Lynch syndrome)
        • PSA test not recommended in men < 40 years of age or men between 40–54 years who are at average risk
        • The US Preventive Services Task Force (USPSTF) recommends against any routine PSA-based screening for prostate cancer.
    • Interpretation: a total PSA > 4 ng/mL suggests malignancy
      • PSA levels may be elevated for a variety of reasons including cancer, benign prostate hyperplasia, urinary tract infection, prostatitis, trauma, and following manipulation of the prostate gland.
      • Following factors suggest malignancy
        • Total PSA > 4 ng/mL (or > 2,5 ng/mL)
        • Increase in PSA levels > 0.35–0.75 ng/mL per year
        • A free total PSA ratio < 0.2 is associated with a higher risk of developing cancer (free PSA = PSA that is not complexed with alpha-1 anti-chymotrypsin; total PSA = free PSA + PSA bound to protease inhibitors)
      • Future handling depends upon baseline PSA levels:
        • PSA < 1 ng/mL: repeat PSA testing at 4-year intervals
        • PSA 1–2 ng/mL: repeat PSA testing at 2-year intervals
        • PSA > 2 ng/mL: repeat PSA testing on a yearly basis
  • ↑ Alkaline phosphatase in bone metastases
  • ↑ Prostatic acid phosphatase (PAP)
• Urine: urinalysis and urine culture to rule out hematuria or urinary tract infection

Normal PSA values do not exclude the presence of prostate cancer!

Inflammation, manipulation of the prostate, and other malignant or benign prostate disease causing elevated enzyme levels may lead to false-positive PSA results.

Confirmatory test

• Prostate biopsy
  • Indication: histological confirmation of suspicious findings on DRE, suspicious PSA levels or velocities, or clinically suspected prostate cancer
  • Technique: ∼ 12 prostate samples are biopsied; from different areas of the prostate guided by transrectal ultrasonography (TRUS) under local anesthesia and prophylactic antibiotics.
  • TRUS findings suggestive of malignancy
    • Hypoechoic regions (sometimes hyperechoic) and not well-demarcated areas
    • Increased vascularity
    • Changes in the outer peripheral zone
    • Invasion of the prostatic capsule by the tumor
  • Interpretation: When prostate cancer is present in the biopsy, the tumor is graded using the Gleason score.
    • Gleason score: based on microscopic appearance of prostate cancer; a higher score indicates a worse prognosis (see also “Pathology” section)
      • ≤ 6: low-risk or well-differentiated prostate cancer
      • 7: intermediate risk or moderately differentiated prostate cancer
      • 8–10: high-risk or poorly differentiated prostate cancer
  • Complications: UTI, prostatitis, hematuria, hematospermia, acute urinary retention , adverse psychological effects
• Experimental methods
  • Adapted MRI pulse sequence (assessment of density differences and using comparison algorithms)
  • PCA 3 (prostate cancer antigen 3) testing: detecting prostate cancer by collecting post-prostatic massage urine samples

Staging

• Indication: in confirmed prostate cancer to assess the extent of the disease
  • Should be performed, if advanced cancer is suspected by either PSA levels > 10 ng/mL or a Gleason score ≥ 7.-
• Imaging
  • Abdominal ultrasound and CT/MRI of the abdomen/pelvis: e.g., assess for extraprostatic extension, liver metastasis, and urinary obstruction
  • Spinal x-ray and bone scintigraphy with technetium-99m: to detect bone metastases; (hyperdense osteoblastic lesions in vertebral bodies on spinal x-ray)
• Laparoscopic pelvic lymphadenectomy is performed prior to performing elective prostatectomy in T3 stage cancers if lymph node metastasis is suspected.
  • Technique: usually, at least 10 pelvic lymph nodes are removed
• Pelvis MRI scan: to assess the operability in cT3/4 stage cancers, or, if invasion of the prostate capsule cannot be excluded by other diagnostic procedures An MRI scan is of great utility in the planning of surgery especially for identifying and preserving cavernous nerves intraoperatively. In addition, an MRI scan can help determining the volume of radiation to be delivered .

References:^{[5][2][7][8][9][10][11]}

• Most common type: adenocarcinoma expressing PSA
• Most common localization: peripheral zone (posterior lobe) of prostate

Types of prostate cancer

• Adenocarcinoma is characterized by a microglandular growth pattern with a highly prismatic epithelium. It is the most common type of prostate cancer.
  • Expression of cytokeratin and PSA
• Rare prostate cancers
  • Small cell prostate cancer
  • Mucinous adenocarcinoma
  • Ductal carcinoma
  • Transitional cell (or urothelial) cancer
  • Squamous cell carcinoma
  • Rhabdomyosarcoma
  • Leiomyosarcoma

Localization of the tumor

• Prostate cancer most commonly occurs in; the peripheral zone → approx. 85% of all cancers.
• Prostate cancer in the transition zone is less common → approx. 15% of all cancers.
• Prostate cancer in the inner gland is very rare.

References:^[12][2]

Approach

The treatment plan is based upon the patient's age, life expectancy, medical condition, and preferences. Results of imaging studies, PSA levels, and the Gleason score are taken into consideration when evaluating the different treatment options.

Management of localized disease

• Active surveillance: regular follow-ups with cancer restaging instead of treating
  • Preferred option for most early-stage cancers )
  • Treatment is only started if the tumor progresses.
• Watchful waiting: less intensive type of follow-up than active surveillance
  • Best approach in elderly patients with slow-growing tumors, a life-limiting comorbidity, or a life expectancy < 10 years who are more likely to die from other causes.
  • Systemic or local treatment to relieve symptoms is initiated if symptomatic progression of the tumor occurs.
• Definitive treatment: radiation therapy and/or prostatectomy
  • Radiation therapy
    • Indication: localized disease
    • Technique
      • External beam radiation
      • Brachytherapy
      • Androgen deprivation therapy (ADT) may be combined with radiotherapy if the chance of cancer recurrence based on PSA level and/or Gleason score is high.
  • Radical prostatectomy
    • Indication:
      • Localized disease
      • Salvage prostatectomy: performing radical prostatectomy after unsuccessful primary radiation therapy
    • Technique
      • Approach: open retropubic, open perineal, robot-assisted or laparoscopic
      • Removal of the entire prostate gland, including the prostatic capsule, the seminal vesicles, and the vas deferens
      • In addition, lymphadenectomy of pelvic lymph nodes, and adjuvant radiotherapy may be performed.
    • Postoperative monitoring of PSA levels: PSA level should drop to undetectable levels.
  • Antiandrogen therapy
    • Indication: androgen sensitive localized high-grade or metastatic prostate cancer
    • Medical castration
      • Gonadotropin-releasing hormone (GnRH) agonists (e.g., leuprolide) or antagonist (e.g., degarelix)
        • Continuous administration of GnRH receptor agonists causes a transient increase in androgen levels during the first few weeks of therapy, followed by a sustained decrease.
      • May be combined with an antiandrogen (e.g., flutamide, bicalutamide) for complete androgen blockade.
    • Surgical castration: bilateral orchiectomy

Radical prostatectomy involves removal of the vas deferens, resulting in infertility!

Management of disseminated disease

• Antiandrogen therapy
  • Androgen deprivation monotherapy is only suggested in patients with severe comorbidities that cannot undergo definitive therapy.
• Chemotherapy with docetaxel
• Osteoclast inhibitors (e.g., bisphosphonates, denosumab) in bone metastases

Management of castration-resistant prostate cancer (CRPC)

CRPC is characterized by disease progression (elevated serum PSA levels, progression of pre-existing metastasis, or new metastases) despite ADT (surgical or medical castration).

• General approach
  • Continue ADT
  • Additional systemic therapy: e.g., chemotherapy with docetaxel, immunotherapy with sipuleucel-T
• CRPC + asymptomatic bone metastases: IV zoledronic acid; every 3–4 weeks or denosumab
• CRPC + symptomatic bone metastases
  • Single or few focal symptomatic metastases: palliative external beam radiotherapy
  • Multifocal symptomatic metastases: IV radiopharmaceuticals (radium-223)

References:^{[2][11][13][14][15][16][17][18][19][20][21][22][23]}

• Metastasis
  • Regional metastasis → pelvic lymph nodes
  • Distant metastasis → bone metastases (most common location)
    • Prostate cancer spreads to the bones early.
    • Symptoms/clinical findings: see section on “Clinical features”
    • Pathology: metastases from prostate cancer are predominantly osteoblastic. Also, osteolytic metastases can be found, causing pathologic fractures.
  • Variants: Occult prostate cancer = prostate cancer that is not detected by symptoms caused by the primary cancer but by cancer metastasis (e.g., back pain caused by bone metastases)
• Complications following surgery or radiotherapy
  • Erectile dysfunction
  • Urinary incontinence
  • Infertility
  • Surgery-specific risks
    • Anastomosis strictures or insufficiency
    • Bleeding and infection
  • Radiotherapy-specific risks
    • Radiation proctitis
    • Enteritis (e.g., diarrhea)
    • Cystitis and Urethritis
    • Anal bleeding, ulcers, perforation (rare)
    • Secondary malignancies (rare)
• Complications following Androgen deprivation therapy
  • Decreased libido and erectile dysfunction
  • Hot flashes
  • Gynecomastia
  • Osteoporosis

References:^{[24][25][2][26][27][20]}

We list the most important complications. The selection is not exhaustive.