Prostate

Benign and malignant diseases of the prostate, along with brief overview of the normal anatomy, physiology and histology.

1. Prostate: Benign and malignant Zaid Azhar 2017-097

2. Overview Introduction Location and size Structure - gross and microscopic Neurovascular supply Function Slide 4-5 Slides 6-12 Slides 13-15 Slide 16

3. Prostate Intro Largest accessory gland of the male reproductive system.

4. Location The prostate surrounds the urethra just below the urinary bladder.

5. Size Dimensions : 3cm long 4cm wide and 2cm in AP depth. Walnut sized in normal males. Mean weight : 11 grams.

6. Gross structure

7. Gross structure 2/3 rd is glandular. 1/3 rd is fibromuscular. Lies in the prostatic sheath formed by visceral layer of pelvic fascia which fixes the prostate via puboprostatic ligament anteriorly and rectovesical septum posteriorly.

8. Zonal classification

9. Lobular classification

10. Microscopic structure

11. Microscopic structure Dense fibromuscular stroma

12. Microscopic structure Tuboalveolar glands Corpus amylacium

13. Neurovascular supply Arterial supply Inferior vesical arteries Middle rectal artery Internal pudendal Artery

14. Neurovascular supply Venous drainage Prostatic venous plexus outside capsule drains into internal iliac veins Lymphatic drainage Internal iliac lymph nodes

15. Neurovascular supply Nervous supply Inferior hypogastric plexuses Sympathetic

16. Functions Prostate releases prostatic fluid with the following functions: Forms around 20% volume of semen. Important for proper functioning of sperm cells therefore male fertility. Prostate Specific antigen ( PSA ) enzyme makes the semen thinner. Spermine insures sperm cell motility. The muscles of the prostate ensure forceful expulsion of semen into the urethra and outwards during ejaculation. Closing of the urethra up to the bladder during ejaculation. Conversion of testosterone is to a biologically active form, DHT ( dihydrotestosterone ).

17. Case 1 A 60-year-old man presents to his primary care physician with a 3-month history of increasing urinary frequency and nocturia 3 times every night. He has limited his fluid consumption and caffeine intake in the evening without much benefit. There is no personal or family history of prostate cancer. Examination demonstrates no suprapubic mass or tenderness. A rectal examination demonstrates normal rectal tone and a moderately enlarged prostate without nodules or tenderness.

18. Benign Prostatic Hyperplasia

19. Benign Prostatic Hyperplasia - Content Introduction Epidemiology Pathogenesis Symptoms - LUTS Examination – DRE, other Labs – Imaging, Urine tests Treatment – Medical, Surgical, Minimally invasive Slides 20-22 Slide 23 Slides 24-25 Slides 26-27 Slides 28-30 Slides 31-33 Slides 34-41

20. Benign Prostatic Hyperplasia Aka nodular hyperplasia of prostate. Enlargement of the prostate. Results in partial or complete obstruction of the urethra. Originates in the transitional zone.

21. Location of transitional zone

22. Microscopic comparison Normal BPH

23. BPH epidimeology Globally, BPH affects about 210 million males ( 6% of the population ). Histological evidence of BPH can be seen as follows: Age 40 : 20% Age 60 : 70% Age 80 : 90% Approximately around 30% of males over 50 show symptoms

24. BPH Pathophysiology BPH involves hyperplasia of prostatic stromal and epithelial cells. BPH involves hyperplasia (an increase in the number of cells) rather than hypertrophy (a growth in the size of individual cells ). Formation of large , fairly discrete nodules in the transition zone of the prostate. The nodules impinge on the urethra and cause obstruction to passage of urine. Resistance to urine flow requires the bladder to work harder and lead to progressive hypertrophy, instability, or weakness (atony) of the bladder muscle

25. BPH Pathogenesis Stems from action of DHT on Androgen receptors. Increased growth factor production and growth factor receptor activation.

26. Obstructive symptoms of BPH Decrease in force & caliber of the stream due to urethral compression. Hesitancy occurs because the detrusor takes a longer time to generate the initial increased pressure to overcome the urethral resistance. Intermittency occurs because the detrusor is unable to sustain the increased pressure until the end of voiding. Terminal dribbling of urine & incomplete sense of bladder emptying.

27. Irritative symptoms of BPH Frequency Incomplete emptying during each void results in shorter intervals between voids. The presence of enlarged prostate provokes the bladder to trigger a voiding response more frequently than in normal individuals, especially if the prostate is growing intravesically . Nocturia as normal cortical inhibitors are lessened and the normal urethral and sphincteric tone is reduced during sleep Urgency & dysuria.

28. Examination

29. Digital Rectal Examination Patient lies on side with legs pressed against abdomen. A lubricated, gloved finger of one hand is inserted gently into the rectum. A full bladder allows the prostate to be palpable: BPH: enlarged, smooth Tumor: stony hard, nodular

30. Examination - Other A distended bladder may be noted on palpation or percussion Abdominal exam may reveal palpable kidney or flank pain if there is hydronephrosis or pyelonephritis. If disease is advanced and has resulted in renal failure signs of renal failure may also be seen.

31. BPH Labs - Imaging Ultrasonography useful for measuring bladder & prostate volume as well as residual urine. Estimation of prostatic size as most urologists prefer to perform TURP for glands under 100gProject Methodology

32. BPH Labs – Urine tests Uroflowmetry : at a volume of 125-150ml, normal individuals have average flow rates of 12ml/sec & peak flow close to 20ml/sec Mild 11-15 ml/sec Moderate between 7 and 10 ml/sec Severe < 7ml/sec

33. BPH Labs – Urine tests Urinalysis and microscopy i nfection presence of hematuria . Residual urine estimated by U/S or catheterizations. Volumes >150 ml are considered significant since they constitute approximately one-third of normal bladder volume. Serum urea & creatinine: to assess kidney function

34. Treatment of BPH Because BPH is not invariably progressive, the timing of intervention for each patient is variable. Absolute indications for treatment include severe obstructive symptoms & renal insufficiency. Relative indications include moderate symptoms of prostatism , recurrent UTI and hematuria. Until recently, surgery was the mainstay of therapy for BPH. In the last decade or so , there has been a tremendous resurgence of interest in non surgical therapies.

35. BPH Treatment - Medicine Alpha – 1 adrenergic antagonists Ideally suited for treatment of obstruction because they can reduce resistance along bladder outlet without impairing detrusor contractility. E.g. Tamsulosin , Prazosin . Indication is that the prostate size should be less than 40gm and it may cause retrograde ejaculation 5 alpha – reductase inhibitor Finestride is an anti androgen that inhibits 5 alpha – reductase which converts testosterone to dihydrotestosterone . Indication is that the prostate size should be less than 40gm

36. BPH Treatment - Surgery Transurethrally (TURP ) Retropubically (RPP ) Through the bladder ( transvesical ; TVP ) From the perineum

37. BPH Treatment - Surgery Transurethral Resection of Prostate (TURP) The obstructing portion of the prostate is removed via urethra.

38. BPH Treatment - Surgery Retropubical Resection of Prostate (RPP) Recti sheet are split and bladder exposed. Anterior capsule of prostate exposed. Obstructing portion of prostate removed.

39. BPH Treatment - Surgery Transvesical Resection of Prostate (TVP) The bladder is opened, and the prostate enucleated by putting a finger into the urethra. Perineal Resection of Prostate This has now been abandoned for the treatment of BPH.

40. BPH Treatment – Minimally invasive Transurethral needle ablation High frequency radio waves to cause thermal injury to the prostate High-intensity focused Ultrasound

41. BPH Treatment – Minimally invasive Prostate stents In recent years, metallic spirals & stents have been used as permanent indwelling prostheses. These stents may be placed endoscopically & under radiologic guidance .

42. Case 2 A 60-year-old black male presents to his primary care physician with complaints of difficulty in passing urine. He describes a weak stream and a sense of incomplete voiding. He describes nocturia (5 episodes per night) and has been taking an alpha-blocker for this with minimal improvement. He says he can last about 60 to 90 minutes without urinating. He denies any suprapubic tenderness, dysuria, or hematuria. He further denies any back pain or gastrointestinal complaints. Rectal exam reveals his prostate to be approximately 60 g, asymmetrical with a large 2-cm nodule at the right base. PSA was 50ng/mL

43. Prostatic Cancer

44. Prostatic cancer- Content Introduction Epidemiology Etiology and Mutations Grading, Staging and progression Signs and symptoms Labs – Serum, biopsy and Imaging Treatment – Prostectomy and Radiation therapy Slide 45 Slide 46 Slides 47-48 Slides 49-52 Slides 53-54 Slides 55-57 Slides 58-61

45. PCA - Introduction Prostate cancer is the 2nd most common cause of cancer deaths in USA . Most prostate cancers are adenocarcinomas arising from prostatic acinar cells. Prostate normally atrophies between the 5th & 7th decades of life with some atypical and hyperplastic changes. Among dysplastic changes, prostatic intraepithelial neoplasia (PIN) considered premalignant lesion found in 30% of patients with prostate cancers. 70% of prostate cancers arise in the peripheral zone of the prostate; 15-20% arise in the central zone; 10-15% arise in the transition zone. Most prostate cancers are multicentric .

46. PCA - Epidemiology Prostate cancer is the second most frequently diagnosed cancer. The sixth leading cause of cancer death. in males worldwide

47. Etiology Genetic predispositon Age Race Family history Hormone levels - androgens Environmental factors Diet – increased ingestion of fats, soy products

48. PCA – Genetic mutations X- Linked Androgen Receptor gene Polymorphic sequence of CAG Shorter the chain, more sensitivity to androgens, greater risk of cancer Project Methodology ETS/TMPRSS2 ETS family of transcription factor is placed under TMPRSS2 promoter due to a mutation Overexpression of ETS leads to production of invasive epithelial cells MYC oncogene – amplification at 8q24 GSTP1 gene – epigenetic hypermethylation TP53 gene – loss by deletion BRCA2 gene – loss in tumor suppression HOXb13 – controls prostatic development

49. Microscopic comparison Normal Prostate carcinoma

50. PCA - Grading Gleason grading system is the most widely used. It’s based on glandular differentiation 2-4 - well differentiated 5-7 - moderately differentiated 8-10  poorly differentiated

51. PCA - Staging

52. PCA - Staging

53. PCA progression Cancers arising in close proximity are prone to spread early to the urethra, periprostatic tissues, bladder and seminal vesicles Seminal vesicle invasion is associated with high likelihood of distant metastases Rectal invasion is rare due to the tough Denonvilliers ’ fascia in between Osseous metastasis is most common form of hematogenous metastasis Common sites are lumbar spines, proximal femur, thoracic spines, ribs, sternum and skull Local Metastases Distal Metastases

54. PCA - Symptoms Most prostate cancers are discovered because of elevated PSA or with incidental finding on rectal examination. Prostate cancers rarely cause symptoms but may present with bladder outlet obstruction, acute urinary retention, hematuria or incontinence

55. PCA - Signs Digital Rectal Examination Irregular firm or hard prostatic nodule during rectal examination . Median sulcus is absent

56. PCA Labs - Serum Prostate Specific Antigen (PSA) Glycoprotein secreted in the cytoplasm of the prostatic cells. normal value in young adult 0-4 ng/ dL . PSA elevation is proportional to the size of the transitional zone. 1g of prostate cancer will raise PSA by 0.3 ng/ dL . PSA production by the malignant cell depends on the degree of differentiation, well differientiated gland will secrete more PSA. Prostate cancer with poor differentiation have normal PSA.

57. PCA Labs - Biopsy Diagnosis of prostate cancers is confirmed by needle and core biopsy. Ultrasound guided systematic sampling of the prostate provides the most accurate information for staging and grading the cancer.

58. PCA Labs - Imaging Trans-rectal Ultrasound (TRUS) Can identify 60 % of cancers even if non-palpable. More accurate than DRE at detecting extra-capsular extension. Allow biopsy of seminal vesicles which improve staging accuracy. Disadvantage of TRUS include the inability to look at the pelvic lymph nodes.

59. PCA - Treatment The current therapy of patients with low stage disease (stage T1 and T2) is radical prostatectomy & radiotherapy to the prostate. Treatment mortality is under 1%. For patients  75 years of age, treatment is “watchful waiting”

60. PCA – Treatment Prostatectomy Retropubic approach allows simultaneous access to the prostate and the pelvic LN, but it is often associated with a greater amount of blood loss from the dorsal vein complex. Perineal approach requires separate incision for pelvic LN, associated with minimal blood loss and it is preferred for obese individuals. 5 yrs disease free survival for Stage T1 is 92% and for stage T2 is 86%

61. PCA – Treatment Radiation Therapy All modern techniques use CT scans for accurate localization of the prostate. Generally, prostate is subjected to 6800-7000 rads and the pelvic LNs are subjected to 4500-5000 rads . Total treatment duration is 6-7 weeks. 5 yrs disease free survival rate for Stage T1 is 83% and for Stage T2 is 72%. PSA level is useful for assessing the response to RT Rising PSA or PSA level persistently more than 30 ng/ dL indicate poor response to RT.

62. PCA - Treatment T3 and T4 disease: Androgen ablation coupled with radiotherapy is standard treatment for younger men with T3 and T4 disease. Metastatic disease Androgen ablation will provide relief for symptomatic patients. Systemic chemotherapy with docetaxel should be considered in youger fitter men.

63. Comparison between BPH and PCA No weight loss Marked obstructive symptoms On DRE gland consistency is firm and median sulcus palpable Elevated PSA PSA values between 4-10 Weight loss No obstructive symptoms Hard consistency of gland and median sulcus not palpable Elevated PSA and ALP PSA values greater than 10 BPH PCA

64. Resources SIU school of Medicine database Wholifeprostate.com Ucdavis.com Academicamc.edu Pubmed health Prostate cancer by Nancy Dawson Urologic Pathology: The Prostate by Myron Tannenbaum Stats by The Lancet Systemic analysis of Global Burden of Disease 2163-2196 Images courtesy of Netter’s atlas, Gray’s Anatomy for Students