1. Prostate Pathophysiology Charles L. Hitchcock, MD PhD Associate Professor - Clinical Department of Pathology

2. Learning Objectives Primary Objective: Discuss benign and cancerous growth of the prostate gland. Secondary Objectives: Discuss screening and diagnosis of prostatic tumors. Describe clinical and histological features of benign prostatic hyperplasia (BPH) and prostate cancers, their identification and treatments. Identify issues related to prostate cancer screening and modifiable behaviors that impact its development

3. Objective 1 Discuss screening and diagnosis of prostatic tumors.

4. Prostatic Zones B: bladder U: prostatic urethra SV: seminal vesicle 1: Peripheral zone 65% glands 2: Central zone 30% glands 3: Transitional zone 5% of glands 4: Anterior fibromuscular zone

5. Nonglandular Tissue Capsule Sphincters Fibromuscular tissue

6. Digital Rectal Exam DRE For Detecting Prostate Cancer

7. Benign Nodular Hyperplasia

8. Transrectal US + Biopsy

9. Screening For Prostate Cancer

10. Prostate Specific Antigen PSA PSA is a 33 kDa serine protease Normally produced by prostatic glandular epithelium. Functions in liquefaction of the seminal coagulum

11. What does a PSA Value Mean A PSA value between 4 ng/ml and 10 ng/ml do not distinguish between a benign and a neoplastic process, but does indicate a 20- 25% risk for prostate cancer. The most common benign processes include: glandular hyperplasia, prostatitis, trauma, and DRE. The risk of prostate cancer >50% for PSA values > 10 ng/mL, and then increases as the PSA level rises.

12. Key Points Transition zone around the urethra – most common site of BPH. Peripheral zone = most common site of cancers DRE - poor screen for cancer Cystoscopy good for BPH diagnosis

13. Key Points Elevated PSA is not diagnostic of cancer. PSA and DRE should be used together for screening. Cannot distinguish between a clinically indolent and aggressive carcinoma. Leads to increased biopsies and risk of infection and bleeding. PSA should not be performed without a patient’s informed consent.

14. Objective 2 Describe clinical and histological features of benign prostatic hyperplasia (BPH) and prostate cancers, their identification and treatments.

15. Clinical Presentations of Prostate Tumors – Early Onset Frequency Urgency Hesitancy Incomplete emptying Straining Decrease force Dribbling Nocturia Hematuria Benign Prostatic HyperplasiaProstate Cancer Yes NoYes

16. Clinical Features of Prostatic Tumors Late onset BPH Bladder diverticula Hydronephrosis Pyelonephritis Late onset prostatic cancer Metastatic disease Bone pain – low back Weight loss

17. Key Points Clinical presentation of BPH and prostatic cancer may be identical when early. Normal glandular tissue has two cell layers Fibromuscular stroma propel secretions out of the gland.

18. Glandular Tissue Ducts and acini have a similar caliber and appearance. Columnar secretory epithelial cells Underlying basal cells Basement membrane Neuroendocrine Cell

19. Normal Prostate Fibromuscular Stroma Gland Fibromuscular Stroma

20. Normal Prostate Fibromuscular Stroma Secretory Cells Basal Cells

21. Benign Prostatic Hyperplasia Normal Prostate Hyperplasia Nodules Urethra

22. Benign Prostatic Hyperplasia

23. Fibromuscular Hyperplasia Glandular Hyperplasia

24. Dihydrotestosterone and BPH

25. Treatment of BPH

26. Laser PVP TURP

27. Prostate Carcinoma

28. Capsular Invasion Perineural Invasion Lymphatic Invasion

29. Adenocarcinoma

30. Score 1-2 – 10xScore 5 – 10x Gleason Grading

31. Prostatic Carcinoma TNM Staging

32. Prostatic Carcinoma Treatment Watchful waiting or active surveillance Surgery: Lymphadenectomy Radical prostatectomy, cryosurgery TURP Complications: impotence, shortening of the penis, incontinence of urine and/or stool, inguinal hernia Radiation - external & internal Complications: impotence, incontinence, and increased risk for bladder and rectal cancers

33. Prostatic Carcinoma Treatment Hormonal Orchiectomy Estrogen GnRH analogs (leuprolide) - suppresses LH-RH synthesis Antiandrogens (flutamide) - inhibits androgen uptake & nuclear binding Adrenal androgen synthesis blockade (ketoconazole) Complication: hot flashes, impaired sexual function, osteoporosis, diarrhea, pruritus Chemotherapy Immunotherapy

34. Prostatic Carcinoma Treatment Radiation - external & internal Complications: impotence, incontinence, and increased risk for bladder and rectal cancers Hormonal Orchiectomy Estrogen GnRH analogs (leuprolide) - suppresses LH-RH synthesis Antiandrogens (flutamide) - inhibits androgen uptake & nuclear binding Adrenal androgen synthesis blockade (ketoconazole) Complication: hot flashes, impaired sexual function, osteoporosis, diarrhea, pruritus Chemotherapy Immunotherapy

35. Key Points Clinical presentation of BPH and prostatic cancer may be identical with early onset. Normal glandular tissue has two cell layers. Fibromuscular stroma propels secretions out of the gland. The incidence of BPH increases with age. Glandular and stromal hyperplasia commonly occurs in the transitional zone. TX: Watchful waiting, hormonal blockade, surgery

36. Key Points – 2 Prostate Cancer Often multifocal – separate tumors Adenocarcinomas Gleason grading system TNM Staging – incidental (I) to metastatic (IV) Six methods of treatment

37. Objective 3 Identify issues related to prostate cancer screening and modifiable behaviors that impact its development.

38. Risk Factors – Nodular Prostatic Hyperplasia Age – incidence increases with age, with 70% of men over 60 having it. Family history – does increase the risk Obesity High BP Low HDL Diabetes Peripheral vascular disease Poor diet and lack of exercise Heart Disease Risk Factors

39. Risk Factors – Prostate Cancer Gender Most common malignancy in U.S. men >217,000 new cases in 2013 (25% of new cancers in men) 2 nd leading cause of death among men >32,000 deaths in 2013. ~1/6 lifetime death risk mortality African-American men is 2x > Caucasian men Incidence increased in 1988-92 but has declined in 1992-95, and has leveled off since 1995

40. Risk Factors – Prostate Cancer Age Incidence of latent carcinoma is: 20% in men 50-59 ~70% in 70-80 64% of all prostate cancers are diagnosed in men > 65 years Ethnicity and Race incidence in AA 1.5 - 2x > Caucasian men U.S. >> Asia and South America High fat diet - ?

41. Risk Factors – Prostate Cancer Hereditary form in ~ 10% of all cases and up to 40 percent of early onset disease. Family history of prostate carcinoma Hereditary prostate cancer gene 1, or HPC1, linked in prostate cancer families to the RNASEL gene.

42. Prostate Screening

43. PSA – Key Points “The PSA test measures the blood level of PSA, a protein that is produced by the prostate gland. The higher a man’s PSA level, the more likely it is that he has prostate cancer. However, there are additional reasons for having an elevated PSA level, and some men who have prostate cancer do not have elevated PSA. The PSA test has been widely used to screen men for prostate cancer. It is also used to monitor men who have been diagnosed with prostate cancer to see if their cancer has recurred (come back) after initial treatment or is responding to therapy. Some advisory groups now recommend against the use of the PSA test to screen for prostate cancer because the benefits, if any, are small and the harms can be substantial. None recommend its use without a detailed discussion of the pros and cons of using the test.” http://www.cancer.gov/cancertopics/factsheet/detection/PSA

44. Key Points – Prostate Cancer Prostate cancer is primarily a disease of older men. African-American men have up to twice the incidence and mortality of Caucasian men. The RNASEL gene is associated with hereditary forms of prostate cancer. Early onset may be asymptomatic, or associated with hematuria or dysuria; whereas bone pain is a common symptom of late onset. DRE detection of prostatic cancer is derived from the fact that 70% arise in the peripheral zone.

46. Thank you

47. Survey We would appreciate your feedback on this module. Click on the button below to complete a brief survey. Your responses and comments will be shared with the module’s author, the LSI EdTech team, and LSI curriculum leaders. We will use your feedback to improve future versions of the module. The survey is both optional and anonymous and should take less than 5 minutes to complete. Survey