• Information
  1. Introduction
  2. Benign Prostatic Hyperplasia
  3. Risk Factors for Carcinoma
  4. Diagnosis
  5. Prostate Specific Antigen
  6. Histology
  7. A-D Staging
  8. TNM Clinical Staging
  9. Composite Prognostic Score and Management Overview
  10. Treatment Modalities
  11. Androgen Independent PrCa
  12. Followup Evaluations

A. Introduction

1. Prevalence of PrCa ~7% of men overall
2. Incidence increases with age
3. Expect ~234,000 new cases in 2006 in USA; <5% with distant metastases
4. ~32,000 deaths per year from PrCa in USA
5. Lifetime risk of diagnosis 16%; risk of death 3% [4]
6. A substantial portion of new cases are detected by serum PSA (prostate specific antigen) levels
7. Unclear what percentage of the new cases are "clinically insignificant" [30]
   1. Autopsy studies show that many men die with localized PrCa
   2. Currently, major goal is to distinguish aggressive tumors from slower ones
   3. Thus, treatment (which has morbidity) would be directed only at aggressive tumors
   4. Frequent PSA and followup ± androgen blockade reasonable for early, non-aggressive tumors
8. Likely that PrCa are associated with benign prostatic hyperplasia (BPH)
9. About 9% of PrCa are familial and linked to loss of tumor suppressor gene

B. Benign Prostatic Hyperplasia (BPH)

1. Characteristics
   1. Occurs in >50% men >50 years old; >80% men over 70 years old
   2. Hyperplasia of normal tissue
   3. Frequently contains foci of frankly neoplastic tissue (discovered only at autopsy)
   4. Accompanied by small increase in PSA levels (>95% have levels <10ng/mL)
   5. May be responsible for ~20% of PSA elevations in setting of small (<1.0mL) cancers
2. Symptoms
   1. Obstruction causing slow urinary flow
   2. Prostatic volume increase
   3. Risk of prostate infection increased
3. Treatment
   1. Surgery - usually transurethral prostatectomy (TURP) or radical prostatectomy
   2. Peripheral alpha-adrenergic blocking agents (terazosin, doxazosin) improve symptoms
   3. Anti-androgen therapy - finasteride (Proscar®) 5mg po qd may have long term efficacy
   4. Finasteride for 7 years also reduced overall but not high grade PrCa [5]

C. Risk Factors for Carcinoma

1. Increasing Age
   1. >50 years at autopsy: 10%+ for CA
   2. >80 years at autopsy: 70%+ for CA
2. High Testosterone Levels
   1. Incidence increased in Blacks
   2. Incidence decreased in Asians
3. Genetics [2]
   1. Nearly 10% of PrCa are familial
   2. Overall, ~40% of risk for PrCa is hereditable [6]
   3. Hereditary contribution by mutant androgen receptor, SRD5A2, CYP17 implicated
   4. Abnormal expression of GSTP1, NKX3.1, and PTEN have been demonstrated in PrCa
4. Genetic Variant of 5-alpha Reductase (5AR) SRD5A2 Gene [7]
   1. 5AR catalyzes conversion of testosterone to dihydrotestosterone (DHT)
   2. DHT is the major androgenic growth factor for prostate cells and cancers
   3. SRD5A2 codon 49 alanine to threonine variant is associated with increased DHT levels
   4. Mutant enzyme has ~5.5 fold higher Vmax than normal enzyme
   5. This mutation increased risk of clinically significant disease by 3.5-7.5 fold in African and Hispanic American men
   6. Population attributable risk of this mutation may be as high as 8%
   7. Finasteride, a 5AR, reduces overall but not high grade PrCa [5]
5. Diet [1,2]
   1. Slightly increased risk high intake of red animal meats
   2. Charcoal cooked red meats especially implicated
   3. High intake of lycopene (tomatoes) associated with reduced risk for PrCa
   4. Vitamin E, selenium, and cruciferous vegetables also associated with reduced risk
   5. alpha-Tocopherol associated with 12% reduced risk [8]
6. Familial PrCa
   1. HPC1 locus on chromosome (chr) 1q24-25 may play a role
   2. HPC1=hereditary PrCa 1 gene has not been clearly defined
   3. HPC1 may be the RNASEL - latent endoribonuclease
   4. MSR1 on chr 8p22 also implicated
   5. Persons with familial disease present at earlier age, more aggressive tumors
   6. This locus may be most important in African Americans with early onset PrCa
7. High insulin growth factor concentrations (IGF-1)
8. Vasectomy carries no increased risk for PrCa after >25 years followup [10]
9. Chronic prostatits may increase PrCa risk

D. Diagnosis

1. Various general screening and staging methods are available
   1. Rectal Examination
   2. Serum PSA
   3. Ultrasonography
2. Screening for PrCa [11,12,13]
   1. The American College of Physicians generally recommends screening after counseling
   2. Whether or not to screen really depends on patients' preferences based on outcomes
   3. At present, definitive data showing that early detection from screening improves outcomes is not available
   4. In general, most other cancers are more effectively treated when found early
   5. PrCa is somewhat unusual in its properties and variable prognosis
   6. PrCa may be detected in ~25% of "positive" digital exams and PSA's by chance
   7. Autoantibodies against prostate cancer tissue may be useful in screening [27]
3. Serum PSA (see also below)
   1. Goal is to detect organ-confined prostate neoplasms which can be removed and cured
   2. PSA appears to increase the detection of these neoplasms (>10 year lead time to diagnosis) [1]
   3. PSA is considerably more sensitive and specific than Digital Rectal Examination (DRE)
   4. PSA is also elevated in prostatitis, BPH, prostate stones, and other benign diseases
   5. Definitive data that early detection improves outcome are currently lacking
   6. PSA is generally recommended for men ages 40-70 after physician counselling
   7. The American College of Physicians recommends general screening after counseling
   8. Biannual PSA determinations beginning age 40-45 have been recommended [14]
   9. PSA is a very accurate measure of disease relapse after therapy
4. Yearly rectal examination all men >40 years
   1. Sensitivity ~50%
   2. Specificity ~94%
5. Transrectal Ultrasonography
   1. Should be used to evaluate all high PSA readings or abnormal digital rectal exams
   2. Generally used to guide biopsy of gland
   3. Does not detect isoechoic lesions (~10% of CA's)
   4. Detects hypoechoic lesions >4mm
   5. ~20% of hypoechoic areas in prostate are cancerous
   6. No role in general population screening
6. Biopsy
   1. Generally ultrasound guided
   2. No anesthesia required now with new 18 gauge needle / transrectal gun
   3. Multiple samples are taken - usually sextant (6) biopsies
   4. Additional samples can be taken if cancer found in <3 initial samples
   5. Elevated alphamethyl-coenzyme A racemase on biopsy can distinguish between PrCa and BPH/normal tissue [15]
7. Prognostic Markers [21,30]
   1. The following are good predictors of clinically significant PrCa:
   2. Serum PSA level, PSA density, rate of change of PSA (PSA velocity) [17]
   3. Gleason Score (GS)
   4. Clinical Staging (TNM System)
   5. Composite prognostic score best for management decisions (see below) [21]
8. Identifying Disease Extent [30]
   1. Clinical staging usually underestimates extent of disease
   2. Methods to identify persons at risk for aggressive disease are being developed
   3. Adjunctive treatments are considered for use after surigcal "cures"
   4. PSA level increase >2.0ng/mL during year prior to diagnosis of PSA is poor prognostic [17]
   5. Magnetic nanoparticles with high resolution MRI detects small LN metastases [29]
   6. Analysis of surgical prostatectomy specimens gives improved prognostic accuracy [30]
   7. Radionucleotide bone scanning is best method for assessment of bony metastases

E. Prostate Specific Antigen (PSA) [1,12,18]

1. Screening with PSA Increasing [12,13]
   1. American Cancer Society recommends screening for age >50 and >10 year life expectancy
   2. American College of Physicians recommends discussion with patient prior to screening
   3. Emerging consensus for PSA screening in men with >10-15 year life expectancy [9]
   4. For persons with PSA <4.0ng/mL and normal prostate exam, screen q1-2 years
   5. Screening every 2 years for "average" risk persons beginning age 40-45 is probably more effective than annual screening beginning age 50 [14]
   6. Initial PSA level is a prognostic marker for PrCa recurrence [19,20]
   7. Isolated PSA increase should be confirmed >2 weeks later before biopsy due to variations in PSA
   8. No consistent cutpoint of PSA with simultaneous high sensitivity and specificity [16]
2. PSA >10ng/mL has a sensitivity ~65%, specificity ~97% for PrCa
   1. Age and race (black/white) specific reference ranges increase sensitivity, specificity
   2. Correction for volume (calculating PSA density) increases sensitivity and specificity
   3. Good correlation between pathological level of disease and PSA level
   4. PSA >40ng/mL nearly always indicates metastases
3. Intermediate Levels (3-10ng/mL)
   1. Age specific reference ranges for blacks and whites should be used
   2. In white patients >50 yrs, level >3.5ng/mL is 95% likely to be PrCa
   3. For PSA 2.6-4.0 ng/mL and normal prostate exam, 22% of biopsies show PrCa
   4. Of these 22%, ~20% had spread out of the prostate gland (extracapsular) [22]
   5. 15% of men with PSA <4.0ng/mL had biopsy proven PrCa; 15% of these had Gleason score 7 or higher [22]
   6. Levels >2.5ng/mL have been recommended for biopsy but this is controversial [23,24]
   7. In general, extracapsular disease is clinically very significant
4. Free Serum PSA Levels
   1. PrCa patients tend to have lower free serum PSA levels than BPH patients
   2. In patients with an enlarged gland, a free PSA of <23.5% detected 90% of PrCa
   3. Free PSAs in patients with elevated total PSA eliminated 20-30% of biopsies
   4. For free PSA <26% of total, sensitivity of test for PrCa was ~95% and eliminated 20% biopsies
   5. The lower the value for free PSA correspond to higher likelihood of aggressive PrCa
5. Differential Diagnosis of Elevated PSA
   1. Benign Prostatic Hypertrophy
   2. Prostatitis / Abscess
   3. Prostate Infarction
   4. PrCa
6. PSA to Monitor Therapy
   1. PSA is used to monitor surgical, radiation, and medical therapies
   2. PSA should drop to nearly 0 after successfull total therapeutic ablation
   3. PSA is increasingly used as a marker for treatment failure
   4. After radical prostatectomy, persistent PSA >0.4ng/mL has 100% relapse likelihood

F. Histology

1. Gleason Scoring (GS) system is currently standard
2. Pathologist grades two areas of specimen for highest / lowest differentiation
   1. Scores each area 1 (greatest) to 5 (least) differentiation
   2. Most prevalent Gleason grade first, then least differentiated area
   3. Gleason score for prostate biopsy is sum of most prevalent patter + highest grade pattern
   4. Gleason score for radical prostatectomy is sum of two most prevalent patterns
   5. "Tertiary" Gleason score in prostatectomy is next most prevalent pattern
   6. Men with Gleason score 7 and tertiary Gleason score of 5 have higher PSA relapse rates than those without tertiary scores of 5 []
3. Gleason Scores Total 2 through 10
   1. More differentiated tumors (lower score) do better
   2. High Grade (undifferentiated; high GS) tumors have very poor prognosis
   3. GS significantly predicts extracapsular disease
4. In general, GS <6 are considered "good prognosis"
5. Prognosis in Clinically Localized Disease
   1. GS <5: normal life expectancy
   2. GS 2-4 have 4-7% chance of recurrence within 15 years
   3. GS 5 has 6-11% chance of recurrence within 15 years
   4. GS 5-7: ~4.5 years reduction in life expectancy
   5. GS 6 has 0-30% and 7 has 30-70% chance of relapse within 15 years [30]
   6. GS 8-10: ~7 years reduction in life expectancy
   7. GS 8-10 have 60-87% chance of relapse within 15 years
6. Composite prognostic score most appropriate for management decisions (see below) [21]

G. A-D Staging

1. Stage A1 - microscopic CA in situ, no clinical symptoms (discovered accidently)
2. Stage A2 - multiple (diffuse) areas within gland, GS >4
3. Stage B1 - palpable, macroscopic tumor <1.5cm
4. Stage B2 - palpable, macroscopic tumor >1.5cm
5. Stage C1 - tumor with extracapsular extension, not fixed to pelvic wall
6. Stage C2 - tumor with extracapsular extension, fixed to pelvic wall
7. Stage D1 - metastatic disease, <4 pelvic lymph nodes (LN)
8. Stage D2 - metastatic disease, >3 pelvic nodes or extrapelvic spread

H. TNM Clinical Staging [11]

1. T1a - nonpalpable tumor with <5.1% tissue with cancer, low grade
2. T1b - nonpalpable tumor with >5% tissue with cancer and/or high grade
3. T1c - nonpalpable tumor but prostate specific antigen (PSA) elevated
4. T2a - palpable, half of one lobe or less
5. T2b - palpable, involves more than half of one lobe, not both lobes
6. T2c - palpable, involves both lobes
7. T3a - palpable, unilateral capsular penetration
8. T3b - bilateral capsular extension
9. T3c - tumor invades seminal vesicles
10. T4a - tumor invades bladder neck, external sphincter, and/or rectum
11. T4b - tumor invades levator muscles and/or fixed to pelvic wall
12. TNM Stage (A-D Stage) and Description
    1. Stage IA (Stage A1): T0NxM0, not palpable, focal disease
    2. Stage IB (Stage A2): T0NxM0, not palpable, diffuse disease
    3. Stage II (Stage B): T1 or T2 NxM0, confined to prostate
    4. Stage III (Stage C): T3NxM0, local extension
    5. Stage IV-A (Stage D1): Tany, Nx, M0, elevated prostatic acid phosphatase
    6. Stage IV-B (Stage D1): Tany, N1-4, M0, positive LN after surgery
    7. Stage IV-C (Stage D2): Tany, Nany, M1 (bone metastases most commonly)
13. Stage I and II tumors may have indolent course for 15 years, then progress [28]

I. Composite Prognostic Score and Management Overview [20,21]

1. Risk Stratification
   1. Low Risk: T1c, T2a, and PSA level <10ng/mL, and GS <7
   2. Intermediate Risk: T2b or T2c or GS 7 or PSA 10-20ng/mL
   3. High Risk: Stage T3a or or GS 8-10 or PSA >20ng/mL
   4. Very High Risk: Stage T3b or T4
   5. Variants on this composite system have been developed [19,20]
2. Very Favorable Prognosis
   1. GS 3 or 4
   2. PSA levels <5.1ng/mL
   3. These patients may do well with "watchful waiting"
   4. However, treatment for low risk men associated with mortality benefit [26]
3. Management Options for Low Risk [30]
   1. Life Expectancy <10 years: "watchful waiting", 3D conformal radiotherapy, brachytherapy
   2. Life Expectancy >10 years: "watchful waiting", 3D conformal radiotherapy, brachytherapy, or radical prostatectomy ± dissection of pelvic LN
   3. Treatment of organ-confined, Gleason <8 prostate ca associated with reduced mortality versus watchful waiting [26]
4. Management Options for Intermediate Risk
   1. Life Expectancy <10 years: "watchful waiting", 3D conformal radiotherapy ± brachytherapy OR radical prostatectomy ± dissection of pelvic LN
   2. Life Expectancy >10 years: 3D conformal radiotherapy ± brachytherapy, OR radical prostatectomy ± dissection of LN
5. Management Options for High Risk
   1. 3D conformal radiotherapy with androgen-suppression therapy OR
   2. Radical prostatectomy with dissection of pelvic LN
6. Management Options for Very High Risk
   1. 3D conformal radiotherapy with androgen-suppression therapy OR
   2. Androgen suppression therapy
7. Pathological-stage groupings do not predict outcome for any given form of treatment [1]

J. Treatment Modalities [12]

1. Radical Prostatectomy
2. External Beam Radiation
3. Radioactive Implants
4. Androgen Suppression Therapy (ASTx, Hormone Ablation Therapy) [31]
   1. Mainstay of therapy are LHRH agonists leading to suppression of FSH and LH
   2. Androgen Receptor Blockers - nonsteroidal and steroidal types
   3. Used alone or in combination
5. Treatment of Pain
6. Treatment modality often depends on type of specialist consulted [32]
7. Therapeutic Efficacy
   1. For localized disease, monitoring for recurrence done by serial PSA ± PAP levels
   2. For disseminated disease, PSA and clinical symptoms are used
8. Chemoprevention [5,30,38]
   1. Finasteride (Proscar®) is a 5AR inhibitor, reduces prostate volume 20-30%
   2. Reduces obstructive BPH symptoms, also decreases libedo
   3. Finasteride 5mg qd x 7 years in 4368 men reduced PrCa from 24.4% to 18.4%
   4. High Grade (GS >6) tumors increased 5.1% in finasteride treated group versus placbo but with further evaluation this increase was found to be an artifact [38]
   5. Therefore, overall, finasteride 5mg qd does reduce overall PrCa rates significantly

K. Androgen Independent PrCa (AIPC) [33,34]

1. Most PrCa are initially highly androgen dependent
   1. Androgen withdrawal leads to apoptosis of most PrCa cells
   2. Eventually, many tumors become androgen-independent, usually in 12-18 months
2. Most metastatic AIPC express high levels of androgen receptor
3. About 50% of the androgen-independent PrCa androgen receptors have mutations
4. Androgen Receptor Pathway Mutations
   1. Receptor is active independent of ligand
   2. Receptor binds anti-androgen (such as flutamide) and is activated
   3. Post-receptor signalling pathway is activated (as in her-2/neu positive PrCa)
   4. Mutations independent of androgen receptor maintain neoplastic growth
   5. ay render receptor active even in absence of ligand
5. Unlike breast cancer, a second hormonal therapy is not associated with a response

L. Followup Evaluations

1. PSA and Prosatic Acid Phosphatase (PAP)
   1. Used to follow disease response and recurrence
   2. ~5% with localized PrCa have rise in PSA 3-5yrs post radical prostatectomy
   3. PSA doubling time after treatment is likely most important prognostic indicator [35]
   4. Rapid (<9 month) PSA doubling time, Gleason 8-10, and time to biochemical (PSA) recurrence <3 years after RP are independent predictors of PrCa specific mortality [36]
   5. Pretreatment PSA doubling time >2.0ng/mL per year has a 12X risk from PrCa after external beam radiation therapy (EBRT) [37]
   6. Patients with rapid PSA doubling time prior to EBRT may benefit from androgen suppression therapy after EBRT [37]
2. Digital rectal is sometimes repeated but is insensitive
3. Bone scans done q3-12 months depending on staging
4. Regional lymph node assessment (Stages C and D): 1 and 3 years or as clinically indicated
5. Prostate volume measurement
6. Biopsy - Stages A/B and C: 18-24 months after radiation or as clinically indicated
7. Upper Urinary Tract Evaluation as clinically indicated, especially with hydronephrosis

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