1. BPH

2. Benign Prostatic Hyperplasia

3. PROSTATE GLAND a walnut-sized gland found in the true pelvis of males just behind the symphysis pubis. composed of several regions or lobes that are enclosed by an outer layer of tissue (capsule) Three distinct zones: – peripheral zone (PZ) – central zone (CZ) – transitional zone (TZ)

4. PROSTATE GLAND Benign prostatic hyperplasia uniformly arise in the transitional zone 60-70% of carcinomas originate in the peripheral zone – 10-20% in the TZ – 5-10% in the CZ

5. Benign Prostatic Hyperplasia Characterized by hyperplasia of prostatic stromal and epithelial cells, resulting in the formation of large, fairly discrete nodules in the periurethral region of prostate With sufficient growth the nodules can compress the urethral canal causing partial, or sometimes complete obstruction of urethra inhibiting urine flow Not considered as a premalignant tumor [ PSA]

7. Incidence & Epidemiology Most common benign tumor in men Incidence is age-related 20% - men aged 41-50 50% - men aged 51-60 90% - men older than 80

8. ETIOLOGY Risk factors are poorly understood [multifactorial] BPH involves both the stromal and epithelial elements of the prostate undergoing hyperplastic changes Seems strongly tied to endocrine control [levels of free testosterone and estrogen] As men age the androgen receptors of the prostate becomes increasingly sensitive/hormonally dependent on testosterone and dihydrotestosterone (DHT) production

9. Dihydrotestosterone (DHT) In both cell types (stroma/epithelial), DHT binds to nuclear androgen receptors and signals the transcription of growth factors that are mitogenic Though testosterone can also bind to androgen receptors and cause growth stimulation, DHT is 10x more potent because it dissociates from androgen receptors more slowly

10. PATHOLOGY BPH originates from the transition zone Hyperplastic process resulting from increase number of cells

11. PATHOLOGY Nodular growth pattern composed of stroma and epithelium BPH nodules in the transition zone enlarge and compress the outer zones of the prostate  formation of surgical capsule

12. PATHOPHYSIOLOGY Symptoms are either obstructive or secondary response of the bladder to the outlet resistance As enlargement ensues, mechanical obstruction may result from intrusion into the uretheral lumen or bladder neck  high bladder outlet resistance

13. PATHOPHYSIOLOGY Stroma composed of smooth mm and collagen is rich in adrenergic nerve supply  autonomic stimulation sets a tone to the prostatic urethra Irritative voiding complaints are secondary response of the bladder to increased outlet resistance

14. Clinical Findings of BPH

15. Symptoms Obstructive Hesitancy  Force and caliber of stream Sensation of incomplete bladder emptying Double voiding Straining to urinate Post-void dribbling Irritative Urgency Frequency Nocturia

16. Symptoms AUA (American Urological Association) Symptom Score questionnaire – Single most important tool to evaluate patients with BPH – Recommended for all patients before initiating therapy – Self-administered – Identifies the need to treat – Monitors therapeutic response – Scoring: 0-35

17. Source: Smith’s General Urology, 17 th ed.

18. Signs Physical examination DRE Focused neurologic examination

19. Signs Size and consistency Smooth, firm, elastic enlargement of the prostate=BPH Induration=CA? – Further evaluation: PSA, transrectal US, biopsy

20. Laboratory Findings Assessment of renal function – Urinalysis – Serum creatinine Renal insufficiency: – 10% of patients with prostatism  upper-tract imaging –  Risk of postoperative complications from surgical intervention for BPH Serum PSA: Optional

21. Imaging Upper-tract imaging (intravenous pyelogram or renal US) – Recommended only in the presence of concomitant urinary tract disease or complications from BPH

22. Cystoscopy Not recommended to determine need for treatment Assist choosing surgical approach for invasive therapy

23. Additional Tests Cystometrograms and urodynamic profiles – Tests for bladder capacity & pressure, and lower urinary tract symptoms (bladder, urethra) respectively – Suspected neurologic disease – Failed prostate surgery Flow rate measurement, post-void residual urine, pressure-flow studies – Optional

24. Differential Diagnosis: Urethral Stricture Bladder Neck Obstruction – hx of previous urethral instrumentation, urethritis or trauma Bladder Stones- Hematuria and pain UTI- Mimics the irritative symptoms of BPH – Urinalysis and culture Neurogenic Bladder- hx of neurologic problems, stroke, dm, or back injury. – PE: diminished perineal or lower extremity sensation or alteration in bulbocavernous reflex

25. Treatment: Mild symptoms (score 0-7)- watchful waiting Surgical indications – refractory urinary retention – recurrent UTI – recurrent gross hematuria – bladder stones – renal insufficiency – large bladder diverticula

26. Medical Therapy: Alpha blockers – alpha-1-adrenoreceptors located in the prostate and bladder – Contractile response of prostate to agonists – Selective blockade of α1a receptors = fewer A.E. 5α-reductase inhibitors (Finasteride) – blocks conversion of testosterone to dihydrotestosterone – ↓ size of prostate – Improvement of symptoms (>40cm)

27. Medical Therapy: Combination therapy – Alpha blockers + 5α-reductase inhibitors Phytotherapy – use of plants or plant extracts for medicinal purposes – MOA, efficacy and safety unknown

28. Conventional Surgical Therapy: Transurethral resection of the prostate (TURP) – Done endoscopically – Symptom score and flow rate improvement – Longer hospital stay – TUR syndrome Transurethral incision of the prostate – More rapid less morbid Open Simple Prostatectomy – Done when the prostate is too large to be removed endoscopically

29. Conventional Surgical Therapy: Open Simple Prostatectomy – Glands >100g – With concomitant bladder diverticulum or bladder stone or dorsal lithotomy position is not possible

30. Conventional Surgical Therapy: – Simple Suprapubic Prostatectomy Procedure of choice in dealing with concomitant bladder pathology – Simple Retropubic Prostatectomy The bladder is not entered

31. Minimally Invasive Therapy: Laser Therapy Transurethral Electrovaporization of the Prostate Hyperthermia Transurethral Needle Ablation of the Prostate High Intensity Focused Ultrasound Intraurethral Stents Transurethral Balloon Dilation of the Prostate

32. Prostate Cancer

33. Molecular genetics, Pathophysio

34. Prostate Cancer  most common cancer diagnosed & is the 2 nd leading cause of cancer death in American men  Incidence continues to  with advancing age (no peak)  Lifetime risk of a 50-yr old man for latent CaP: 40%; clinically apparent: 9.5%; death from CaP: 2.9%

35. Risk factors: Increasing age Race Family history High dietary fat intake Exposure to chemicals (e.g. cadmium)

36. Molecular genetics Chromosome 1 – Gene responsible for familial prostatic cancer Tumor suppressor genes (8p, 10q, 13q, 16q, 17p, 18q) Found in the regions human genome

37. Pathology Nature : More than 95% are adenocarcinomas 5% are transitional cell carcinomas – 90% are neuroendocrine (“small cell”) carcinomas or sarcomas

38. Histologic characteristics - hyperchromatic, enlarged nuclei, w/ prominenent nucleoli - cytoplasm abundant & slightly blue- tinged or basophilic - absent basal cell layer - HMW keratin immunohistochemical staining

39. Origin of Prostatic cancer Peripheral zone- 70% Transitional zone- 10 to 20% Central zone- 5 to 10%

40. Prostatic Intraepithelial Neoplasia (PIN) - Precursor to invasive prostatic cancer - Basal cell layer of the glandular architecture is present Classifications: High grade PIN - associated with invasive Prostatic cancer in 50-80% of cases Low grade PIN - ~20% of the cases

41. Prostatic Intraepithelial Neoplasia (PIN) classic histologic features: - intermediate-to-large size preexisting glands displaying nuclear and nucleolar enlargement and fragmented basal cell layer

42. Grading and Staging Gleason score or Gleason sum primary grade + secondary grade Gleason grades: 1- 5 Gleason scores: 2 - 10 Tumor GradeScore Well-differentiated2 - 4 Moderately-differentiated5 - 6 Poorly-differentiated8-10

43. Gleason grades 1 & 2 - small, uniformly shaped glands, closely packed, w/ little infiltrating stroma

44. Gleason 1 The most important difference between Gleason pattern 1 and 2 is the presence or absence of circumscription

45. Gleason 2 The glands are round to oval and uniformly placed. There are no sharply- angulated or distorted glands.

46. Gleason 3 - Variable-sized glands that percolate between normal stroma Cribriform pattern - a small mass of cells is perforated by several gland lumens w/ no intervening stroma  cookie-cutter-like appearance of cell nests - smooth border

47. This example of Gleason grade 3 cancer shows abundant amphophilic cytoplasm, enlarged nuclei with prominent nucleoli. Higher magnification view of the previous slide. Most glands have occluded lumens. The nuclei are hyperchromatic.

48. Gleason 4 - Incomplete gland formation Several histological appearances: - sometimes glands appear fused, sharing a common cell border - sheets of cell nests or long cords of cells - cribriform glands (large masses, ragged borders w/ infiltrating fingerlike projections

49. The glands are fused and there is no intervening stroma. Glandular fusion is a hallmark of Gleason grade 4. Higher magnification view of the previous slide. Most glands have occluded lumens. The nuclei are hyperchromatic.

50. Gleason 5 - single infiltrating cells, no gland formation or lumen appearance comedocarcinoma  cribriform glands w/ central areas of necrosis

51. - Tumor cells are arranged in solid sheets with no attempts at gland formation.

52. TNM staging system - Primary tumor categorization (T stage) uses the results of the digital rectal examination (DRE) & transrectal ultrasound (TRUS) but not the results of biopsy

53. TNM staging *T2a & b – confined to prostate

55. Patterns of Progression - The likelihood of local extension outside the prostate (extracapsular extension) or seminal vesicle invasion & distant metastasis increases w/ tumor volume & more poorly differentiated cancers. - Penetration of the prostatic capsule by cancer is common & occurs along the perineural spaces

56. - Seminal vesical invasion – associated with a high likelihood of regional or bladder disease - Socally advanced prostatic cancer may invade the bladder trigone  ureteral obstruction

57. Lymphatic metastases: - Obturator lypmh node chain (most common) - Common iliac - Presacral - Periaortic lymph nodes Axial skeleton most usual site of distal metastases (lumbar spine is the most common)

58. - Vertebral body involvement w/ significant tumor masses extending into the epidural space  cord compression - Visceral metastases: lung, liver, adrenal gland - CNS involvement usually a result of direct extension from skull metastasis

59. Grading & Staging

60. Gleason Grading System Most commonly employed grading system in the US Low-power appearance of the glandular architecture under the microscope Primary grade = most common observed pattern Secondary grade = second most common Grade range from 1 to 5 Only one pattern present = 1° and 2° grade reported as same grade

61. Gleason Score or Gleason Sum Obtained by adding the primary and secondary grade together Range from 2 to 10 Gleason sum 2-4 = well-differentiated tumor Gleason sum 5-6 = moderately differentiated Gleason sum 7 = moderate - poor Gleason sum 8-10 = poorly differentiated

62. Gleason Grade Gleason grade 1 and 2 – Small, uniformly shaped glands, closely packed with little intervening stroma Gleason grade 3 – Variable-sized glands that percolate between stroma – Cribriform pattern = variant of Gleason grade 3; cookie-cutter-like appearance of cell nests

63. Gleason grade 4 – Incomplete gland formation – Glands appear fused; common cell border Gleason grade 5 – Single infiltrating cells – No gland formation or lumen appearance – Comedocarcinoma = unusual variant; appearance of cribriform glands with central areas of necrosis

64. TNM Staging System for CaP

65. CaP Chemoprevention Ideal tx intervention = arrest disease progression during latent period and decrease incidence of clinical disease Ideal agent = nontoxic and low cost Ideal patient = one at high risk of the disease Agents currently being studied in clinical trials: finasteride, dutasteride, vit E, selenium, COX-2 inhibitors, and SERMs

66. Patterns of Progression Grades 1 and 2 – Confined to the prostrate Grades 4 and 5 (plus large-volume) – Locally extensive – Metastatic to regional lymph nodes or bones

67. Clinical findings

68. Symptoms Early – Asymptomatic Locally advanced/Metastatic – symptomatic

69. Signs DRE --> induration --> further evaluation Locally advanced disease with bulky lymphadenopathy – Lymphedema of the LE Cord compression – Weakness/spasticity of LE – Hyperreflexic bulbocavernous reflex

70. Laboratory Findings Azotemia Anemia ALP ACP

71. Tumor Markers - PSA Not specific PSA velocity - 0.75 ng/mL/yr PSA density - 0.12 ng/ml/g Age adjusted PSA reference ranges PSA forms

72. Prostate Biopsy Systemic sextant prostate biopsy – Apex – Midsection – Base

73. Imaging TRUS – Biopsy and local staging – Measures prostatic volume

74. Prostatic carcinoma

75. Extracapsular extension

76. Seminal vesicle invasion

77. Endorectal MRI – Low signal intensity area – Right seminal vesicle invasion

78. Axial Imaging

79. Bone scan

80. Molecular Staging Circulating prostate cells in the peripheral blood Not always indicative of metastatic disease or treatment failure

81. Differential Diagnosis Carcinoma of the Prostate

82. Elevated PSA BPH Urethral Instrumentation Infection Prostatic Infarction Vigorous Prostate Massage

83. Induration of the Prostate Chronic Granulomatous prostatitis Previous TURP or needle biopsy Prostatic Calculi

84. Paget’s disease Sclerotic lesions on plain x-ray films and elevated levels of alkaline phosphatase PSA levels are usually normal and x-ray findings demonstrate subperiostealcortical thickening

85. Screening for CaP Carcinoma of the Prostate

86. CaP Screening PSA improves detection of clinically important tumors without signifi cantly increasing the detection of unimportant tumors most PSA-detected tumors are curable prostate cancer mortality is declining in regions where screening occurs curative treatments are available

87. CaP Screening the use of both DRE and serum PSA is preferable to either one used alone earlier screening starting at age 40 men with very low serum PSA level (1 ng/ml) may be able to be screened at less frequent intervals (every 2 to 3 years)

88. CaP Screening Normal PSA = 4 ng/ml or less Normal values for all men of ages and prostate volume Recent findings show a fall in prostate cancer mortality due to early detection efforts

89. CaP Screening Screening should be undertaken in men who are healthy enough to benefit from it Screening may be highly encouraged in certain populations with a higher disease prevalence and/or mortality such as African American men and those with a strong family history of the disease

90. Treatment : Localized Disease Carcinoma of the Prostate

91. General Considerations treatment decisions are based on: – the grade and stage of the tumor – the life expectancy of the patient – the ability of each therapy to ensure disease-free survival – its associated morbidity – patient and physician preferences

92. Watchful Waiting and Active Surveillance Low mortality with watchful waiting in early stage prostate cancer A more modern concept of watchful waiting is better termed active surveillance where men with very well-characterized, early stage, and low to intermediate grade cancer are followed very carefully and treated at the first sign of subclinical progression based on serial and regular physical examinations, serum PSA measurements, and repeat prostatic biopsy

93. Radical Prostatectomy An operation to remove the prostate gland and some of the tissue around it May be done by open surgery or by laparoscopic surgery through small incisions A few doctors now do it by guiding robotic arms that hold the surgery tools - robot- assisted prostatectomy

94. Radiation Therapy External Beam Therapy Uses a linear accelerator, a high-energy x-ray machine, to direct radiation to the prostate tumor Radiation works more effectively on small and moderately sized prostate glands Men with very large prostate glands often undergo a 3- to 6-month course of hormone therapy to shrink the prostate gland prior to radiation therapy.

95. Radiation Therapy External Beam Therapy Radiation is an outpatient procedure that does not carry the standard risks or complications that accompany major surgery, such as surgical bleeding, post-operative pain, or risk of stroke, heart attack or blood clot. The procedure itself causes no pain The risk of incontinence is minimal with radiation therapy

96. Radiation therapy Brachytherapy Also called seed implantation or interstitial radiation therapy Uses small radioactive pellets, or "seeds," each about the size of a grain of rice and are placed directly into your prostate Generally used only in men with early stage prostate cancer that is relatively slow growing May not be as effective in men with large prostate glands because many more seeds may be needed

97. Cryosurgery A procedure in which the prostate gland is frozen under controlled conditions in order to kill cancer cells Works best on prostates 40 grams or less in size as measured by ultrasound Special metal probes are inserted through the perineum and directly into preselected locations in the prostate gland Liquid nitrogen is then circulated through the probes to freeze the entire gland. The goal is to create an "ice ball" large enough and cold enough to kill the cancer

98. High Intensity Focused Ultrasound Utilizes transrectal ultrasound that is highly focused into a small area, creating intense heat of 80-100° C, which is lethal to prostate cancer tissue Can also be used to treat prostate cancer that has begun to spread beyond the capsule allows the surgeon to precisely ablate the prostate gland with pinpoint accuracy and thereby preserve the adjacent structures.

99. Treatment of Prostate CA

100. Recurrent Disease Relapse – Rising serum PSA after treatment – 3 consecutive rises in serum PSA above nadir (ASTRO) – Modification: rise of at least 2ng/ mL greater than the nadir level – “PSA Bounce”- not indicative or recurrence Increase risk for metastasis – Interval to PSA failure <3-6 years and a posttreatment PSA doubling time <3 months

101. Following Radical Prostatectomy Related to cancer grade, pathologic stage, and extent of extracapsular extension Likelihood for recurrence more likely in patients with: – Positive surgical margins – Established extracapsular extension – Seminal vesicle invasion – High grade disease – Persistenly detectable serum PSA levels immediately after surgery – Increased PSA doubling time Recurrent localized disease based on a long time from surgery to biochemical failure will benefit from salvage radiation

102. Following Radiation Therapy PSA levels continues to rise after radiation therapy Perform biopsy and CT Androgen deprivation or androgen ablation therapy Local recurrence: brachytherapy, cryosurgery, or salvage prostatectomy – high morbidity

103. Metastatic Disease Therapy Initial endocrine therapy – Most prostatic carcinomas are hormone dependent – LHRH agonists: goserelin acetate, triptorelin pamoate, histrelin acetate and leuprolide acetate by injection monthly Avoid the flare phenomenon – Orchiectomy less commonly performed today – Estrogen by feedback inhibition – Ketoconazole for advanced prostate cancer with SCC or DIC

104. Metastatic Disease Therapy Complete Androgen Blockade – Suppressing both testicular and adrenal androgens – Combining anti- androgen with LHRH agonists or orchiectomy Intermitent androgen deprivation – Delay in the appearance of hormone- refractory state – Improved quality of life High dose anti- androgen monotherapy – Alternative to castration Androgen deprivation side effects – Hot flashes, anemia, loss of libido and sexual function, loss of bone mineral density, increased weight, cognitive changes, increased total cholesterol –

105. Manipulations for Hormone Refractomy Prostate Cancer Patients who have a rise in serum PSA levels Complete androgen blockade therapy- secondary rise in PSA levels Emergence of hormone- refractory state due to mutations in the androgen receptor – Some anti-androgens may stimulate a mutated androgen receptor to produce more testosterone Discontinue the anti-androgen

106. Metastatic Disease Therapy Hormone refractory disease – Patients with metastatic disease where hormonal therapy failed – Incurable – Combination of agents are suggested: Mitoxantrone with prednisone Extramustine with taxane

107. Metastatic Disease Therapy Patients receiving monotherapy (LHRH agonist or orchiectomy) may respond to addition of an anti- androgen – Additional use of ketoconazole, aminoglutethimide, corticosteroids, and estrogenic compounds should be considered Chemotherapy