BENIGN PROSTATIC HYPERPLASIA

Zonal Anatomy of the Prostate Peripheral zone 70% of volume of young adult prostate 60-70% of CaP Central zone 25%: young adult prostate 5-10% of CaP Transition zone 5%: young adult prostate 10-20% of CaP Benign Prostatic Hyperplasia

Incidence & Epidemiology most common benign tumor in men age related incidence prevalence 20% (41–50 y/o) 50% (51–60y/o) >90% (>80y/o). age related symptoms (prostatic obstruction) age 55 = 25% obstructive voiding symptoms age 75 = 50% ↓ force & caliber of urinary stream.

Risk factors: Etiology Genetics Race ~50% of men < 60 y/o (autosomal dominant) ↑ relative risk 4x in 1° ♂ relatives Race Etiology multifactorial and endocrine controlled stromal and epithelial elements  hyperplastic nodules positive correlation between levels of free testosterone and estrogen and the volume of BPH

Pathology hyperplastic process  ↑ in cell number  (cont.) Microscopic evaluation: nodular growth pattern that is composed of varying amounts of: Stroma Collagen (non-responsive to either form of medical therapy) smooth muscle (alpha-blocker therapy) epithelium (5-alpha-reductase inhibitors)  enlarged BPH nodules  compress outer prostate zones = surgical capsule separates TZ from PZ cleavage plane for open enucleation of the prostate during open simple prostatectomies performed for BPH.

Pathophysiology obstructive component of the prostate mechanical prostatic enlargement  intrusion into the urethral lumen or bladder neck  obstruction  high bladder outlet resistance dynamic obstruction variable symptomatology prostatic stroma is rich in adrenergic nerve supply level of autonomic stimulation thus sets a tone to the prostatic urethra alpha-blocker therapy  ↓ tone  ↓ outlet resistance. secondary response of the bladder to the outlet resistance irritative voiding complaints Bladder outlet obstruction  detrusor muscle hypertrophy and hyperplasia; collagen deposition  mucosal herniation bet. Detrusor muscle bundles  FALSE DIVERTICULA (mucosa and serosa only) Cystoscopic examination: trabeculation (thickened detrusor muscle bundles)

Clinical Findings Symptoms: Obstructive Irritative Hesistancy ↓ force and caliber of stream Sensation of incomplete bladder emptying Double voiding Straining to urinate Post-void dribbling Irritative Frequency Urgency Nocturia AUA Symptom Score questionnaire Single most important tool used in the evaluation of patients with BPH recommended for all patients before the initiation of therapy

0-7: mild 8-19: moderate 20-35: severe 7 items that ask patients to quantify the severity of their obstructive or irritative complaints on a scale of 0–5 0-7: mild 8-19: moderate 20-35: severe

Signs: Lab Findings: PE, DRE and neurologic exam Smooth, firm, elastic enlargement of the prostate Induration: possibility of cancer Lab Findings: Urinalysis Exclude infection/hematuria Serum creatinine Assess renal function Serum PSA (optional)

Imaging: Intravenous pyelogram or renal US only in the presence of concomitant urinary tract disease or complications from BPH(hematuria,UTI) Cystoscopy (not recommended) may assist in choosing the surgical approach in patients opting for invasive therapy Cystometrograms and urodynamic profiles patients with suspected neurologic disease or those who have failed prostate suregery

Differential Diagnosis urethral stricture, bladder neck contracture Hx of previous urethral instrumentation, urethritis, or trauma bladder stone Hematuria and pain CaP DRE abnormalities or an elevated PSA UTI Mimic irritative sx of BPH Urinalysis Can be a complication of BPH bladder carcinoma irritative voiding complaints urinalysis: hematuria Neurogenic bladder d/o hx of neurologic disease, stroke, DM, or back injury ↓ perineal or LE sensation or alterations in rectal sphincter tone or the bulbocavernosus reflex.

Treatment A. Watchful Waiting B. Medical Therapy With mild symptoms (0-7) Optional: moderate/severe symptoms B. Medical Therapy C. Conventional Surgical Therapy D. Minimally Invasive Therapy

Absolute surgical indications refractory urinary retention (failing at least one attempt at catheter removal) recurrent UTI from BPH recurrent gross hematuria from BPH bladder stones from BPH renal insufficiency from BPH large bladder diverticula

Medical Therapy Alpha-blockers 5-Alpha-reductase inhibitors contractile properties of the prostate and bladder neck mediated primarily by the subtype alpha-1areceptors 5-Alpha-reductase inhibitors Blocks testosterone dihydrotestosterone Epithelial component; ↓ size of gland and improvement of sx 6 months of tx

Medical Therapy Combination Therapy Phytotherapy Doxasozin + Finasteride Patients most likely to benefit : those with larger glands and higher PSA values Phytotherapy Use of plants or plant extracts for medicinal purposes saw palmetto berry, (Serenoa repens) , the bark of Pygeum africanum, the roots of Echinacea purpurea and Hypoxis rooperi, pollen extract, leaves of the trembling poplar. S. repens: most well-studied agent usually at 320 mg/day.

Conventional Surgical Therapy Transurethral resection of prostate (TURP) Risks : retrograde ejaculation (75%), impotence (5–10%), and incontinence (<1%) Complications: bleeding, urethral stricture or bladder neck contracture, perforation of the prostate capsule with extravasation TUR syndrome: hypervolemic, hyponatremic state due to absorption of the hypotonic irrigating solution Transurethral incision of the prostate moderate to severe symptoms and a small prostate often have posterior commissure hyperplasia (elevated bladder neck) More rapid and less morbid than TURP two incisions using the Collins knife at the 5- and 7-o’clock positions. The incisions are started just distal to the ureteral orifices and are extended outward to the verumontanum TUR syndrome nausea, vomiting, confusion, hypertension, bradycardia, and visual disturbances. risk of the TUR syndrome increases with resection times >90 minutes. Treatment includes diuresis and, in severe cases, hypertonic saline administration.

Conventional Surgical Therapy Open Simple Prostatectomy When prostate is too large to be removed endoscopically: open enucleation (glands >100 g) Open prostatectomy: concomitant bladder diverticulum or a bladder stone is present or if dorsal lithotomy positioning is notpossible Simple suprapubic prostatectomy Transvesically Operation of choice in dealing with concomitant bladder pathology Simple retropubic prostatectomy the bladder is not entered A transverse incision is made in the surgical capsule of the prostate, and the adenoma is enucleated

Minimally Invasive Therapy Laser Therapy Two main energy sources of lasers have been utilized—Nd:YAG and holmium:YAG. coagulation necrosis techniques: Transurethral laser-induced prostatectomy (TULIP) with TRUS guidance. Visual contact ablative techniques: more time-consuming procedures because the fiber is placed in direct contact with the prostate tissue, which is vaporized

Minimally Invasive Therapy Interstitial laser therapy places fibers directly into the prostate, usually under cystoscopic control; may result in fewer irritative voidingsymptoms, because the urethral mucosa is spared and prostate tissue is resorbed by the body rather than sloughed Advantages of laser surgery : minimal blood loss rare instances of TUR syndrome ability to treat patients receiving anticoagulation therapy ability to be done as an outpatient procedure. Disadvantages lack of availability of tissue for pathologic examination longer postoperative catheterization time more irritative voiding complaints High cost of laser fibers and generators.

Minimally Invasive Therapy Transurethral electrovaporization of the prostate uses the standard resectoscope but replaces a conventional loop with a variation of a grooved rollerball. High current densities cause heat vaporization of tissue, resulting in a cavity in the prostatic urethra. Hyperthermia Microwave hyperthermia is most commonly delivered with a transurethral catheter. Transurethral needle ablation of the prostate uses a specially designed urethral catheter that is passed into the urethra. Interstitial radio frequency needles are then deployed from the tip of the catheter, piercing the mucosa of the prostatic urethra High-intensity focused ultrasound Intraurethral stents keep the prostatic urethra patent.

Prostate Cancer

INCIDENCE & EPIDEMIOLOGY Most common cancer Second leading cause of cancer death Risk factors: age Under 40: 1:10,000 40-59: 1 in 103 60-79: 1 in 8 diet ↑ (fat, meat) ↓ (low fat, fish, plant based, lycopene, omega 3 FA, vit. E, selenium) Family history Recurrent prostatitis prostate cancer is lower in countries where people eat predominantly low-fat, plant based diet

PATHOLOGY 95% are Adenocarcinoma The other 5% 90%: Transitional Cell Carcinomas’ The remaining are small cell carcinomas or sarcomas Cytologic characteristics: hyperchromatic, enlarged nuclei with predominant nucleoli . Cytoplasm : abundant; N-C ratio not helful in dx

60 to 70% (peripheral) 10-20% (transition) 5-10% (central)

PRESENT- Normal glands, BPH, precursor lesions (PIN) BASAL LAYER ABSENT – prostate CA PRESENT- Normal glands, BPH, precursor lesions (PIN) If diagnosis of prostate cancer is in question, HMW keratin immunohistochemical staining is used Stains basal cells, prostate cancer is negative

Prostatic Intraepithelial Neoplasia and Atypical Small Acinar Proliferation (ASAP) are thought to be precursor lesions Men found to have these lesions may be at an increased risk for developing prostate cancer

GLEASON GRADING SYSTEM The Gleason score is obtained by adding the primary and secondary grades together Gleason Grades ranges from 1 to 5 Gleason scores range from 2 to 10 Gleason Score of: 2-4: Well differentiated 5-6: Moderately Differentiated 8-10: Poorly differentiated

GLEASON GRADING SYSTEM The most important difference between Gleason pattern 1 and 2 is the presence or absence of circumscription respectively. The focus of cancer is not circumscribed. The glands are round to oval and uniformly placed. There are no sharply-angulated or distorted glands.  Even at low magnification, one can easily appreciate the variation in size, shape, and spacing of glands. Many small glands have occluded or abortive lumens. There is no evidence of glandular fusion.

GLEASON GRADING SYSTEM The glands are fused and there is no intervening stroma. Glandular fusion is a hallmark of Gleason grade 4. Tumor cells are arranged in solid sheets with no attempts at gland formation.

TNM STAGING SYSTEM Clinical staging system: DRE and TRUS NOT biopsy

Clinical Findings Symptoms Most early stage CaP are asymptomatic Presence of symptoms suggests locally advanced or metastatic disease Obstructive or irritative voiding: local growth of tumor Bone pain: metastatic disease to the bones Paresthesias and weakness of the LE: cord compression

Symptoms Difficulty voiding or urinary retention Weak or interrupted flow of urine Frequent urination (especially at night) Pain or burning during urination. Increased urinary frequency Blood in urine Back pain Painful ejaculation

Clinical Findings B. Signs (Physical Exam) Digital Rectal Exam (induration) regional lymphadenopathy specific signs of cord compression

Clinical Findings C. Laboratory Findings Azotemia: bilateral ureteral obstruction (from direct extension into the trigone or from retroperitoneal adenopathy) Anemia: metastatic disease Alkaline phosphatase: elevated in bone metastases Acid phosphatase: disease outside the confines of prostate

Clinical Findings D. Tumor Markers- Prostate Specific Antigen PSA velocity PSA density Age-adjusted reference ranges for PSA Racial variations in CaP detection Molecular forms of PSA

Prostate Specific Antigen PSA Velocity Rate of change of serum PSA Annual PSA velocity 0.75 ng/mL - increase risk of cancer, failure of treatment, and development of metastases PSA velocity significant only when several PSA assays are carried out by the same lab over a period of at least 18 mos. B. PSA Density Ratio of PSA to gland volume Elevated approx. 0.12 ng/mL/g of BPH tissue

Prostate Specific Antigen C. Age-adjusted reference ranges for PSA Rise in PSA with increasing age results from prostate gland growth BPH, higher incidence of subclinical prostatitis, growing prevalence of insignificant prostate cancers Age (years) PSA normal ranges (ng/mL) 40-49 0-2.5 50-59 0-3.5 60-69 0-4.5 70-79 0-6.5

Prostate Specific Antigen D. Racial Variations in CaP detection African-American: higher baseline, worst outcomes E. Molecular Forms of PSA 2 forms: free and protein bound 90%- 1-antitrypsin, others - 2-macroglobulin

Clinical Findings E. Prostate Biopsy Systematic sextant prostate biopsy Most commonly employed technique used in detecting CaP Obtained under TRUS guidance (apex, midsection, & the base of each side of the prostate at the midsagittal line halfway between the lateral border & midline of the gland) To predict extracapsular extension & risk of relapse following radical prostatectomy

Systematic sextant prostate biopsy Indications: Men over age 40 with elevated PSA Abnormal digital rectal examination (DRE) Abnormal ultrasound of the prostate (TRUS) Urinary symptoms without an obstructive etiology of symptoms

Clinical Findings F. Combined Modality Risk Assessment Risk Group Criteria Recurrence after therapy Risk Lower Risk Higher Need for Routine Radiographic Imaging Low PSA <10, Gleason <6 and T1,T2a 6-20% Gleason 2-4, <50% +biopsies, PSA <6 >50% + biopsies None Intermediate PSA 10-20, Gleason 7 and/ T2b, T3a 26-60% <50% +biopsies, PSA <15, Gleason 3/4 >50% + biopsies, Gleason 3/4 Bone scan for PSA >15 High PSA >20, Gleason 8-10 and/ T3b 31-100% PSA 10, T1/T2 disease 7113 variables Bone scan, CT/MRI of pelvis

Imaging 1. TRUS Useful in performing prostatic biopsies Providing local staging information if cancer is detected Allows uniform spatial separation & sampling of the regions of the prostate & also makes lesion-directed biopsies possible CaP appears as a hypoechoic lesion in the peripheral zone Provides more accurate local staging than does DRE

TRUS

TRUS Sonographic criteria for extracapsular extension: Bulging of the prostate contour or Angulated appearance of the lateral margin Sonographic criteria for seminal vesicle invasion: Posterior bulge at the base of the seminal vesicle Asymmetry in echogenicity of the seminal vesicle associated w/ hypoechoic areas at the base of the prostate

TRUS Axial transrectal ultrasonographic (TRUS) scan shows extensive hypoechoic area (arrows) in the right peripheral zone.

TRUS Enables measurement of the prostate volume (calculation of PSA density) PSA density = (π/6) X (AP diameter) X (transverse diameter) X sagittal diameter Cryosurgery & brachytherapy

Imaging 2. Endorectal magnetic resonance imaging (MRI) staging accuracy: 51 – 92% high image quality operator-dependent expensive

Imaging 3. Axial Imaging (CT,MRI) Criteria: (-) bone scans Selectively performed to exclude lymph node metastases in high risk patients who are thought to be candidates for definitive local therapy Criteria: (-) bone scans T3 cancers or a PSA>20ng/mL Primary Gleason grade 4 or 5 cancers

Imaging 4. Bone Scan Can be omitted in patients w/ Newly diagnosed, Untreated prostate cancer who are asymptomatic Have T1 and T2 disease Serum PSA concentrations < 15 ng/mL

Imaging 5. Antibody Imaging ProstaScint: mAb to an intracellular component of PSMA SPECT images obtained 30mins to assess vasculature and at 72-120 hours Recognizes the intracellular domain of PSMA; only soft tissues are imaged and the test may suffer from both false + and -

Prostate CA Differential Diagnosis Factors That Increase PSA BPH Urethral instrumentation Infection Prostatic infarction Vigorous prostate massage Causes of Induration of the prostate: Chronic granulomatous prostatitis Previous TURP or needle biopsy Prostatic calculi

Prostate CA Differential Diagnosis Paget’s Disease Sclerotic Lesions on plain XRAY films Elevated Alkaline Phosphatase PSA levels usually normal XRAY - subperiosteal cortical thickening Paget's Disease (Osteitis Deformans)

Screening for CaP PSA improves the detection of clinically important tumors Most PSA detected tumors are curable Mortality of prostate cancer is declining in areas where screening occurs Screening consist of a combination of DRE and serum PSA

PSA

Treatment of Localized Disease

1. General Considerations Treatment decisions are based on the: Grade and stage of the tumor Life expectancy of the patient Ability of therapy to ensure disease-free survival Morbidity Patient and physician preferences

2. Watchful waiting Therapeutic benefit of radical treatment for early stage prostate cancer has not yet been proven Older prostate ca patients may have concomitant illnesses Small, well-differentiated prostate cancer have very slow growth rates

3. Radical prostatectomy Understanding the anatomy of the pelvis resulted in lower rate of complications Prognosis treated by radical prostatectomy correlates with the pathologic stage of the specimen Patients with adverse prognostic factors undergoing surgery is decreasing-> established normograms based on serum PSA, clinical DRE stage, and Gleason sum derived from biopsy

3. Radical protastectomy Patients with organ confined CA disease free survival rate 70%-85% and 75% for those with extensive extracapsular extension High grade tumors (Glial sum >7) have higher risk of progression Morbidity – related to the experience of the surgeon

3. Radical prostatectomy Immediate intraoperative complications: blood loss rectal injury ureteral injury Perioperative complications: deep venous thrombosis pulmonary embolism lymphocoele formation wound infection Late complications: urinary incontinence impotence -blood loss (more common in retropubic approach) -rectal injury (rare with retropubic approach, common in perineal approach, can be repaired) -ureteral injury (exceedingly rare.)

4. Radiation therapy-external beam therapy Standard XRT Delivery of 6500 – 7000 cGy to the prostate Depend upon bony landmarks to define treatment borders or a single CT slice to define target volume Often fails to provide adequate coverage of the target volume Improved with the use of 3D treatment planning software Acute toxicity reduced with use of conformal radiotherapy

4. Radiation therapy-external beam therapy 3 Dimensional conformal radiotherapy ability to calculate dose in 3 dimensions ability to generate 3 dimensional dose displays and dose volume histograms less normal tissue is irradiated because of the use of multiple complex field toxicity is reduced

5. Radiation therapy-brachytherapy Placing radioactive seeds under TRUS guidance With computer software- can preplan a precise dose of radiotherapy to be delivered by TRUS guidance

6. Cryosurgery Less invasive form for tx of localized CaP Use of subfreezing tissue to destroy tissue Freezing the prostate is carried out using a multiprobe cryosurgical device Multiple hollow-core probes are placed percutaneously under TRUS guidance In the short term, can result in negative post treatment prostatic biopsies and low or undetectable serum PSA levels

Treatment of Locally Advanced Disease RADIOTHERAPY Most patients with T3 CaP are treated with neoadjuvant hormonal therapy followed by XRT. Superior to XRT alone

Treatment of Recurrent Disease

1. Following Radical Prostatectomy Site of Reccurrence established with: Interval from surgery to the detectable PSA concetration PSA doubling time Selective Imaging studies Recurrence is related to: Cancer grade Pathologic stage Extent of extracapsular extension Recurrence more common in: Positive surgical margins Positive extracapsular extension Seminal vesicle invasion High grade disease.

1. Following Radical Prostatectomy Systemic relapse Persistently detectable PSA immediately after surgery PSA levels detectable in the early postoperative period PSA levels that double rapidly Local recurrence PSA levels undetectable initially then becoming detectable after a long time after radical protastectomy PSA doubling time is prolonged

2. Following Radiation Therapy Rising PSA levels Prostate Biopsy - identify local recurrence Imaging with bone scans and CT - identify distant recurrence Most patients are treated with Androgen Ablation Therapy Patients with Local Recurrence – salvage radical prostatectomy or cryotherapy

Treatment of Metastatic Disease

1. Initial endocrine therapy Most prostatic carcinomas are hormone dependent. Free testosterone -> enters prostate cell -> converted to DHT(major intracellular androgen) -> binds a cytoplasmic receptor protein -> complex moves to nucleus -> transcription Androgen deprivation at several levels along the Pituitary – Gonadal Axis

1. Initial endocrine therapy LHRH agonist and orchiectomy - most common forms of primary androgen blockade used Ketoconazole – rapid onset of action, used in advanced Prostate Ca presenting with spinal cord compression and DIC Complete Androgen Blockade - Antiandrogen plus LHRH agonist or orchiectomy: suppresses both testicular and adrenal androgen (allows better initial and longer response) Antiandrogen - competitively binding the receptor for DHT (responsible for prostatic growth and development)

2. Early manipulations for endocrine therapy failure Patients receiving complete androgen blockade therapy who demonstrate a rise in serum PSA levels must discontinue use of antiandrogen PSA receiving monotherapy (LHRH agonist or orchiectomy whose PSA starts rising may respond to the addition of an antiandrogen

3. Hormone Refractory Disease Failure of Hormonal Therapy Brisk and significant fall in PSA levels predictive of survival Standard Chemotherapy agent Estramustine/Taxane Combination Second Line Chemotherapy Mitoxantrone or Prednisone

BPH PROSTATIC CANCER PROSTATIC ZONE TRANSITIONAL PERIPHERAL AGE PREDILECTION INCREASES WITH AGING RISK FACTORS GENETICS,AGING GENETICS, RACE, AGING, DIET SYMPTOMS OBSTRUCTIVE, IRRITATIVE OBSTRUCTIVE, IRRITATIVE, BONE PAIN, CORD COMPRESSION SX SIGNS (DRE) SMOOTH, FIRM, ELASTIC, ENLARGED INDURATION OTHER SIGNS REGIONAL LYMPHADENOPATHY, CORD COMPRESSION SIGNS DIAGNOSIS DRE PROSTATE BIOPSY, (PSA- SCREENING ONLY) TREATMENT WATCHFUL WAITING, MEDICAL (ALPHA BLOCKER, 5- ALPHA REDUCTASE inhibitor ) SURGERY (TURP, OPEN, TUIP) MINIMALLY INVASIVE TX WATCHFUL WAITING/ACTIVE SURVEILLANCE RADICAL PROSTATECTOMY RADIOTHERAPY= EXT. / INT. CRYOSURGERY HIFU