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Pathology of prostate

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Pathology of Prostate
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Pathology of prostate

  1. 1. Prostate Pathology Dr Guvera Vasireddy Osmania medical college
  2. 2. Prostate  The prostate gland is a male reproductive organ whose main function is to secrete prostate fluid, one of the components of semen.  The muscles of the prostate gland also help propel this seminal fluid into the urethra during ejaculation .  One component of prostate fluid an enzyme called Prostate Specific Antigen (PSA) also aids in the success of sperm by liquefying semen that has thickened after ejaculation.  This thinning action allows sperm to swim more freely, according to the medical reference book "Prostate Specific Antigen" (Informal Health Care, 2001).
  3. 3. Prostate and Bladder obstruction  Unfortunately, while the prostate is in a great location for delivering this important fluid and squeezing things along when the time is right, its position around the urethra can be a liability if the gland swells or grows.  A swollen prostate compresses the urethra and irritates the walls of the bladder, interfering with normal urination.  More than half of men in their 60s suffer from a growth of the prostate called Benign Prostatic Hyperplasia (BPH), according to the OSU Medical Center. By age 70 or 80, a man's chance of suffering BPH jumps to 90 percent. Symptoms include frequent urination, dribbling or leaking urine and a stuttered or weak stream.  A growing prostate can also signal cancer. It is estimated that more than 200,000 men will be diagnosed with prostate cancer in 2010, according to the National Cancer Institute.
  4. 4. Prostate: anatomy and histology Prostate weighs 20 grams in normal adult Retroperitoneal organ ,encircling the neck of bladder and urethra Devoid of a distinct capsule Four distinct zones Tubulvalveolar organ Glands lined two layers of cells, basal cells and columnar secretory cells
  5. 5. Adult prostate The normal prostate contains several distinct regions, including a central zone (CZ), a peripheral zone (PZ), a transitional zone (TZ), and a periurethral zone. Most carcinomas arise from the peripheral glands of the organ and may be palpable during digital examination of the rectum. Nodular hyperplasia, in contrast, arises from more centrally situated glands and is more likely to produce urinary obstruction early than is carcinoma.
  6. 6. Histologically the prostate is composed of glands lined by two layers of cells. A basal layer of low cuboidal epithelium covered by a layer of columnar secretory cells. In many areas there are small papillary infoldings of the epithelium. These glands are separated by abundant fibromuscular stroma. Testicular androgens control the growth and survival of prostatic cells. Castration leads to atrophy of the prostate caused by widespread apoptosis.
  7. 7. H&E of normal gland HMW keratin stains basal layer
  8. 8. Benign Prostatic Hyperplasia BPH Extremely common lesion in men over age 50 Hyperplasia of glands and stroma Fairly large ,well delined nodules 20% in men over age 40,up to 70% by age 60, and 90% by age 70 Related to the action of androgen
  9. 9. BPH and the role of DHT  DHT ,Dihydrotestesterone is the ultimate mediator for prostatic growth.  The main component of the “hyperplastic” process is impaired cell death resulting in the accumulation of senescent cells in the prostate.  Androgens not only increase cellular proliferation, but also inhibit cell death.  The main androgen in the prostate, constituting 90% of total prostatic androgens, is dihydrotestosterone (DHT).  It is formed in the prostate from the conversion of testosterone by the enzyme type 2 5α-reductase, located almost entirely in stromal cells;  Epithelial cells of the prostate do not contain type 2 5α reductase, with the exception of a few basal cells. Thus stromal cells are responsible for androgen-dependent prostatic growth.
  10. 10. Other sources of DHT Type 1 5α-reductase is not detected in the prostate, or is present at very low levels. However this enzyme may produce DHT from testosterone in liver and skin, and circulating DHT may act in the prostate by an endocrine mechanism. Nodular hyperplasia is not considered to be a premalignant lesion
  11. 11. Mechanism of DTH induced growth  DHT binds to the nuclear androgen receptor (AR) present in both stromal and epithelial prostate cells.  DHT is more potent than testosterone because it has a higher affinity for AR and forms a more stable complex with the receptor.  Binding of DHT to AR activates the transcription of androgen- dependent genes.  DHT is not a direct mitogen for prostate cells, instead DHT- mediated transcription of genes results in the increased production of several growth factors and their receptors.
  12. 12. Growth factors  Most important among these are members of the fibroblast growth factor (FGF) family, and particularly FGF-7 (keratinocyte growth factor;).  FGF-7, produced by stromal cells, is probably the most important factor mediating the paracrine regulation of androgen-stimulated prostatic growth.  Other growth factors produced in BPH are FGFs 1 and 2, and TGFβ, which promote fibroblast proliferation.  Although the ultimate cause of BPH is unknown, it is believed that DHT-induced growth factors act by increasing the proliferation of stromal cells and decreasing the death of epithelial cells.
  13. 13. Simplified scheme of the pathogenesis of prostatic hyperplasia. The central role of the stromal cells in generating dihydrotestosterone (DHT) should be noted. DHT may also be produced in skin and liver by both type 1 and 2 5α-reductase.
  14. 14. BPH , Morphology  The prostate weighs between 60 and 100 grams  Enlargement occurs almost exclusively in the inner aspect of the prostate gland  Nodules ,vary in color and consistency  Histologic hallmark of BPH is nodularity due to glandular proliferation or dilation and to fibrous or muscular proliferation  Aggregation of small to large and cystically dilated glands  Needle biopsy don’t sample the transitional zone BPH occur
  15. 15. Clinical features  The increased size of the gland, and the smooth muscle-mediated contraction of the prostate cause urethral obstruction.  The increased resistance to urinary outflow leads to bladder hypertrophy and distension, accompanied by urine retention.  The inability to empty the bladder completely creates a reservoir of residual urine that is a common source of infection.  Increased urinary frequency, nocturia, difficulty in starting and stopping the stream of urine, overflow dribbling, dysuria (painful micturition).  Increased risk of developing bacterial infections of the bladder and kidney.  In many cases, sudden, acute urinary retention appears for unknown reasons that requires emergency catheterization.
  16. 16. Management  Decreasing fluid intake, especially before bedtime; moderating the intake of alcohol and caffeine containing products; and following timed voiding schedules.  α-blockers, which decrease prostate smooth muscle tone via inhibition of α1-adrenergic receptors.  Inhibitors of 5-α-reductase.  Transurethral resection of the prostate (TURP).  High-intensity focused ultrasound, laser therapy, hyperthermia, transurethral electro vaporization, and transurethral needle ablation using radiofrequency.
  17. 17. Prostate cancer
  18. 18. Epidemiology  Cancer of the prostate is a disease of men over age 50 and adenocarcinoma is the most common form.  One in six lifetime probability of being diagnosed with prostate cancer.  Prostatic cancer is uncommon in Asians and occurs most frequently among blacks.  Increased consumption of fats has been implicated.  Dietary products suspected of preventing or delaying prostate cancer development include lycopenes (found in tomatoes), selenium, soy products, and vitamin D.
  19. 19. Prostate Cancer Risk Factors Established • Advancing age • Presence of androgens • Family history (1st degree relative) • African ancestry Potential • High dietary fat • Obesity • Inherited mutations (BRCA1 or BRCA2 genes) • Vitamin D or E deficiency • Selenium deficiency?
  20. 20. Screening Recommendations • Discuss with the patient and if he decides to be screened • Annual PSA and DRE • Age 50-70 yrs (with at least 10 yr life expectancy) • Begin screening at age 40 if risk factors • African ancestry • First degree relative(s) with prostate cancer • A shared decision-making approach to PSA screening seems most appropriate
  21. 21. Prostate Cancer: Screening with PSA  No clear cut-point between normal and abnormal PSA levels. Even PSA cut-off of 1.1 ng/ml misses up to 15% of prostate cancer (The Cancer Prevention Trial – 2003)  Positive predictive value for PSA > 4ng/ml = 30% (i.e. About 1 in 3 men with elevated PSA have prostate cancer detected at time of biopsy  PPV increases to 45-60% for PSA > 10ng/ml  Nearly 75% of cancers detected in the grey zone (PSA 4-10) are organ confined; potentially curable.  <50% of prostate cancers organ confined if PSA >10
  22. 22. What is PSA (Prostate Specific Antigen)? A Serine protease (enzyme) found in the prostate Secreted by prostate epithelial cells Found in ejaculate As diagnostic tool for: Screening Staging Prognostic indicator Surveillance
  23. 23. Other causes of an elevated PSA 1. Age 2. Prostate size (BPH) 3. Infection/inflammation 4. Recent instrumentation (biopsy, catheterization, etc.) 5. Physiological variation 6. Recent ejaculation
  24. 24. Free/Total PSA Ratio: A Way to Improve Specificity Prostate cancer maybe associated with more protein-bound PSA (less free PSA) than in BPH F/T ratio is lower in patients with prostate cancer Can improve test specificity Useful when total PSA in 4-10 ng/ml range BPH Prostate Ca
  25. 25. Prostate Cancer Screening: Pros and Cons
  26. 26. Charles Brenton HugginsCharles Brenton Huggins (1901–1998)(1901–1998) Only Canadian-born doctor ever to receive the Nobel Prize in Physiology or Medicine. Nobel Prize received in 1966. For his discoveries concerning hormonal treatment of prostatic cancer. Born in Halifax, Nova Scotia. B.A (Acadia) ©The Nobel Foundation©The Nobel Foundation
  27. 27. Prostate Cancer: Presentation Early stages usually asymptomatic Most cases detected by serum PSA screening Palpable nodule or firmness on DRE Advanced stages Urinary retention/renal failure Bone pain Anemia Weight loss, fatigue Spinal cord compression
  28. 28. Prostate Cancer: Diagnosis Indications for trans rectal ultrasound (TRUS) guided biopsy Palpable nodule on DRE Elevated serum PSA Biopsy involves 10-18 needle cores taken mostly from the peripheral zone of the prostate Transrectal ultrasound alone/CT scan/MRI not sensitive enough to make the Diagnosis
  29. 29. The 2016 and 2004 WHO classifications of prostatic carcinoma
  30. 30. Adenocarcinoma of Prostate The most common form is adenocarcinoma Three variants 1. Acinar adenocarcinoma 2. Intraductal carcinoma 3. Ductal adenocarcinoma
  31. 31. Variants of acinar adenocarcinoma (AC) of the prostate in the 2016 WHO classification
  32. 32. Adenocarcinoma: Gross Morphology 70% arises in the peripheral zone of the gland Palpable in rectal exam Gritty and firm Spread by direct local invasion and through blood stream and lymph Local extension most commonly involves the seminal vesicles and the base of the urinary bladder
  33. 33. Adenocarcinoma Well defined gland pattern Histologic diagnosis in some cases is one of the most chalenges for pathologists Peri-neural invasion is common and typical
  34. 34. Adenocarcinoma: microscopic pathology  Well-defined, readily demonstrable gland patterns, that are typically smaller than benign glands.  Lined by a single uniform layer of cuboidal or low columnar epithelium.  Cancer glands are more crowded, and characteristically lack branching and papillary infolding.  The outer basal cell layer typical of benign glands is absent.
  35. 35. Adenocarcinoma: microscopic pathology  The cytoplasm of the tumor cells ranges from pale-clear as seen in benign glands to a distinctive amphophilic appearance.  Nuclei are large and often contain one or more large nucleoli.  There is some variation in nuclear size and shape, but in general pleomorphism is not marked.  Mitotic figures are uncommon.  α-methylacyl-coenzyme A-racemase (AMACR) is up- regulated in prostate cancer and can be detected by immunohistochemistry
  36. 36. perineural invasion by malignant glands malignant glands with enlarged nuclei, prominent nucleoli, and dark cytoplasm
  37. 37. Pseudohyperplastic variant foamy gland (xanthomatous) variant mucinous (colloid) adenocarcinoma signet ring cell variant Other morphological variants
  38. 38. Adenocarcinoma Hematogenous extension occurs chiefly to the bones The bony metastasis are typically osteoblastic .
  39. 39. Adenocarcinoma ,Clinical Course Microscopic cancers are asymptomatic, discovered incidently Patients with clinically localized disease do not have urinary symptoms Most arise peripherally ,away from urethra, therefore ,urinary symptoms occur late. Prognosis depends mainly on the extent of the disease at the time of the diagnosis.
  40. 40. Prostate Cancer Prognostic factors Depends upon grade, stage and treatment Early stage/well-differentiated Ca treated by radical prostatectomy:  85% + 10 year survival Metastatic disease <10% 5 year survival
  41. 41. Adenocarcinoma: Gleason’s Grading Gleason grading system is the best known for grading Five grades on the basis of glandular pattern and degree of differentiation as seen under low magnification Grading is of particular important in prostate cancer, because it is the best marker ,along with the stage ,for predicting prognosis
  42. 42. Adenocarcinoma: Gleason’s Grading Gleason grade is from 1-5 based on glandular architecture Gleason score is the total primary grade (1-5) + secondary grade (1-5) = 2-10 4-6/10=well-differentiated 7/10=moderately differentiated >8/10=poorly differentiated
  43. 43. Grading and grouping  Grade Group 1 (Gleason score ≤6) – Only individual discrete well- formed glands  Grade Group 2 (Gleason score 3+4=7) – Predominantly well-formed glands with a lesser component of poorly-formed/fused/cribriform glands.  Grade Group 3 (Gleason score 4+3=7) – Predominantly poorly- formed/fused/cribriform glands with a lesser component of well- formed glands.  Grade Group 4 (Gleason score 8) - Only poorly- formed/fused/cribriform glands or - Predominantly well-formed glands with a lesser component lacking glands†† or - Predominantly lacking glands with a lesser component of well-formed glands.  Grade Group 5 (Gleason scores 9-10) – Lacks gland formation (or with necrosis) with or w/o poorly-formed/fused/cribriform glands.
  44. 44. Prostate Cancer: Staging Can spread to adjacent organs (seminal vesicles, bladder), lymph nodes, bone Most bone mets are osteoblastic Prior to initiating treatment consider Bone scan (PSA>10, Gleason Score >7) CT scan pelvis/abdomen (PSA >10, Gleason Score >7)) These tests are typically not required in asymptomatic men with low risk prostate cancer
  45. 45. Adenocarcinoma Grading and Staging Staging in prostate cancer depends on the TNM system . Clinical staging includes combined clinical and radiological findings and PSA levels. Pathological staging includes tumor extent on biopsy and Gleason's grade. AJCC staging combines the both.
  46. 46. Tumor extent
  47. 47. N and M Status of Regional Lymph Nodes (N) N0 NO REGIONAL NODAL METASTASES N1 METASTASIS IN REGIONAL LYMPH NODES Distant Metastases (M) M0 NO DISTANT METASTASES M1 DISTANT METASTASES PRESENT M1a Metastases to distant lymph nodes M1b Bone metastases M1c Other distant sites
  48. 48. Prostate Cancer – Treatment - Survival Considerations Patient’s age Co-morbid health conditions Tumor stage Tumor grade (Gleason score) Often a patient choice Surgery and
  49. 49. Adenocarcinoma Treatment Surgery ,radiotherapy ,and hormonal therapy 90% of treated patients expected to live for 15 years Currently the most acceptable treatment for clinically localized cancer is radical surgery Too locally advanced cancers can be treated by radiotherapy Hormonal therapy (Antiandrogen therapy) could induce remission .
  50. 50. Early Stage Prostate Cancer Treatment Early stage Cancer 1. Radical Prostatectomy 2. External Beam Radiotherapy 3. Radioactive Seeds (Brachytherapy) 4. Active Surveillance 5. Observation – Watchful Waiting
  51. 51. Prostate Cancer Treatment: 1. Radical Prostatectomy
  52. 52. Advanced Prostate Cancer: Treatment Androgen Deprivation (Hormonal Rx) Orchidectomy LHRH analogues Antiandrogens Supportive therapies Analgesics Steroids Bisphosphonates/Vitamin D/Calcium for bone health Chemotherapy  Taxotere, Docetaxel Last line of treatment
  53. 53. Osteoblastic Bone Metastases
  54. 54. Spinal Cord Compression Metastatic prostate cancer is a common cause of spinal cord compression Clinical recognition is critical Signs and symptoms Back pain Neurological symptoms in saddle distribution Lack of rectal tone, fecal and urinary incontinence Paraplegia below the level of compression MRI is diagnostic
  55. 55. Spinal Cord Compression Treatment Emergency decompression laminectomy by spinal surgeons Emergency radiation to affected level Dexamethasone/steroids Emergency bilateral orchidectomies if patient not already on androgen deprivation
  56. 56. Prostate Cancer Prevention Modifiable Factors Diet Saturated fats Red Meat BBQ meats Lifestyle Exercise Drug therapy 5 α reductase inhibitor Vitamin D
  57. 57. Prostate Cancer Prevention  Two major studies using 5 α reductase inhibitors vs placebo  Similar reduction in prostate cancer diagnosis in the treatment arms (23-24%)  Not currently approved by Health Canada for prostate cancer prevention  PCPT (Thompson et al NEJM 2003)  Finasteride  Reduce (Andriole et al NEJM 2010)  Dutasteride

Notas do Editor

  • 2x risk if one 1st degree family relative
    2x risk if 1st degree relative with prostate cancer; 9x risk if 2 or more relatives with prostate cancer
  • PSA is involved in liquefaction of the seminal fluid- essential for sperm function. Prostate-specific antigen (PSA), also known as gamma-seminoprotein or kallikrein-3 (KLK3), is a glycoprotein enzyme encoded in humans by the KLK3 gene. PSA is a member of the kallikrein-related peptidase family and is secreted by the epithelial cells of the prostate gland. PSA is produced for the ejaculate, where it liquefies semen in the seminal coagulum and allows sperm to swim freely.[5] It is also believed to be instrumental in dissolving cervical mucus, allowing the entry of sperm into the uterus.[6]
    PSA is present in small quantities in the serum of men with healthy prostates, but is often elevated in the presence of prostate cancer or other prostate disorders.[7] PSA is not a unique indicator of prostate cancer, but may also detect prostatitis or benign prostatic hyperplasia.
  • Prostate biopsy not a good gold standard
    Morbidity from a biopsy (pain, UTI, sepsis)
    Prostate biopsy not a good gold standard. Possible morbidity from a biopsy (pain, UTI, sepsis)

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