1. Pathology of Prostatic Enlargement

2. Introduction Anatomy – 5 lobes.
Simplified: 3 lobes ; right, left, middle
3 zones : base, middle, apex
Median/Posterior – (BPH/Cancer)
Function ?
Hormone response – Estrogen like
Enlargement – Inflammation / growth
Neoplastic / Non neoplastic growth.
BPH / Cancer.

3. Male Urogenital System

4. Male Urogenital System

5. Enlargement of Prostate:
BPH – Benign Prostatic Hyperplasia
Inflammations – infections
Neoplasms – Carcinoma.

6. Introduction Common non-neoplastic lesion.
Involves peri urethral zone.
BPH is common as men age.
75% among men aged 70-80years
Over 90% in people aged over 90y
Rare before the age of 40y.
? Physiological …

7. BPH-Pathophysiology:
Excess hormones – estrogen like.
Nodular hyperplasia of glands & stroma.
From normal 20 to 30 50 to 100 gm.
Press upon the prostatic urethra.
Obstruction - difficulty on urination
Dysuria, retention, dribbling, nocturia
Infections, hydronephrosis, renal failure.
Not a premalignant condition*

8. BPH - Mechanism Hormonal imbalance with ageing.
Estrogen sensitive peri-urethral glands.
Accumulation of dihydrotestosterone in the prostate and its growth-promoting androgenic effect
Some Drugs (Finasteride) inhibit dihydrotestosterone and diminishes prostatic enlargement.

9. BPH-Morphology
Microscopically, nodular prostatic hyperplasia consists of nodules of glands and intervening stroma. (Mostly glands)
The glands variably sized, with larger glands have more prominent papillary infoldings.
Nodular hyperplasia is NOT a precursor to carcinoma.

10. BPH-mechanism of obstruction:
Median lobe (3rd lobe)
Ball valve mechanism

11. BPH-Complications: Urethral compression Ball valve mechanism
Bladder hypertrophy
Trabeculation
Diverticula formation
Hydroureter – bilateral
Hydronephrosis

12. BPH-Bladder Gross – Identify Cues?
Trabeculations
Hypertrophy of wall
Stone - urolithiasis
Inflammation
Median lobe- ball valve.
Enlarged prostate.

13. BPH-Bladder morphology:
Hypertrophy
Trabeculation
Median lobe protrusion.

14. Benign Prostatic Hyperplasia:

15. Normal Prostate:

16. Nodular BPH:

17. BPH - Morphology

18. Adenocarcinoma Prostate:
Adenocarcinoma of the prostate is common in elderly men.
It is rare before the age of 50, but seen in over half of men 80 years old.
Many of these carcinomas are small and clinically insignificant.
Is second only to lung carcinoma as a cause for tumor-related deaths among males.

19. Adenocarcinoma of Prostate
The most common form of cancer in men
the 2nd leading cause of death
Incidence of clinical cancer in US:
50-70 / 100,000
Less common in Asians
More common in blacks
Higher incidence of “latent” cancer
From 20% in fifties to 70% in seventies
Etiologic factors:
Familial (genetic) predisposition
Environmental factors
Androgen receptor sensitivity
etc.

20. Cancer Statistics – 2002 USA

21. Cancer Statistics – 2002 USA

22. Adeno-Ca Prostate ? ? ?

23. Adeno-Carcinoma + BPH

24. BPH with Adenocarcinoma:

25. Adenocarcinoma Prostate: (HP)

26. Diagnosis: Digital examination – hard, gritty, fixed.
Ultrasonography (trans-rectal)
Tumor Marker – PSA
Biopsy - TURP
None of these methods can reliably detect small cancers.
Occult cancer is more common than clinical ca.

27. Prognosis of Adenocarcinoma:
Grade & Stage  Prognosis.
Urinary obstruction, metastasize to lymph nodes and bones.
Bladder, kidney damage.
Hematuria.
Spread to Lungs or liver – rare.

28. TURP-Bits (Diagnosis + Treat )

29. Main Diagnostic Tools Digital Rectal Examination (DRE) Serum PSA
Trans-Rectal Ultra-sonography (TRUS)

30. Serum PSA: changing views
Former PSA Thresholds:
0 – 3.99 ng/mL Normal
4 – 9.99 ng/mL Suspicious
> 10 ng/mL Probable tumor >>> Biopsy
 PSA Cut-off point for Biopsy:
From 4 to 2.5 ng/mL
Gilbert SM, Cavallo CB, Kahane H, Lowe FC. Evidence for prompting prostate biopsy: review of 36,316 biopsies. Urology, 2005; 65:

31. Modifications in PSA Suspicious cases: PSA Density: > 0.15
PSA Velocity: Annual rate of PSA rise >0.75 ng/ml/year is Highly suggestive of Cancer
Percent Free PSA:
Calculated as %fPSA (fPSA X 100 / PSA)
LOW %fPSA (<6-10%) favors cancer
HIGH %fPSA (>23%) favors BPH

32. Prostate Biopsy Evolution
1 - 2 cores (Finger-guided)
Sextant biopsy (TRUS-guided)
Extended 5-region biopsy (10-18 cores)

33. TRUS guided Biopsy

34. Sextant Biopsy
BASE
MIDDLE
APEX

35. Extended 5-Region Biopsy (> 10 cores)

36. Agenda: Overview of prostatic adenocarcinoma
Diagnostic tools: changing attitudes
Cancer diagnosis: minimal pathologic criteria
Difficult diagnoses: IHC and other solutions
Gleason grading: 2005 ISUP consensus
Staging: AJCC/UICC TNM
Cancer Reporting checklist (CAP approved)
Future outlook

37. Minimal Pathologic Criteria for Ca.
1- Infiltrating acini
2- Enlarged hyperchromatic nuclei
3- Prominent ( > 2-3 m) nucleoli
4- CLOSE BACK TO BACK ACINI
5- LOSS OF BASAL LAYER
6- MONOLAYERING

38. Normal
Cancer Cytology

39. Agenda: Overview of prostatic adenocarcinoma
Diagnostic tools: changing attitudes
Cancer diagnosis: minimal pathologic criteria
Difficult diagnoses: IHC and other solutions
Gleason grading: 2005 ISUP consensus
Staging: AJCC/UICC TNM
Cancer Reporting checklist (CAP approved)
Future outlook

40. Adenocarcinoma (Gleason pattern 1-2)
Difficult Diagnoses
Adenocarcinoma (Gleason pattern 1-2)
Adenosis (benign)

41. Main Differential Diagnoses
1- Structural mimic of cancer:
Atypical Small Acinar Proliferation (ASAP)
2- Cytologic mimic of cancer:
High-Grade Intraepithelial Neoplasm (HGPIN)

42. 1- ASAP

43. ASAP
Qualitative limitation
Quantitative limitation

44. Atypical Small Acinar Proliferation (ASAP)
1977
NOT a distinct entity
Indicates suspicion BUT NOT PROOF of Ca.
Next step:
Aditional sections (resolving 10%)
IHC staining (34E12)
Rebiopsy 3-9 months later (from the entire gland)
PPV: 37%

45. 2- HGPIN

46. High Grade Prostatic Intraepithelial Neoplasm (HGPIN)
1986
A medium-sized acinus with stratified (flat, tufting, micropapillary or cribriform) atypical nuclei & prominent nucleoli
Patchy basal cell immunostaining
Rebiopsy (3-6 months interval for 2 years):
PPV 23%
May be isolated (Not accompanied by cancer):
No rise of PSA
Combined HGPIN / ASAP:
PPV 44%

47. IHC in prostate Cancer Indications:
1- Distinction of Benign from Malignant
High molecular weight cytokeratin (34E12, CK5/6)
Negative cytoplasmic marker (in basal cells)
P63
Negative nuclear stain (in basal cells)
AMACR (P504S)
Positive cytoplasmic marker (in tumor cells)
Also positive in HGPIN, 31% of Bladder Ca. & 70% of Colorectal Ca.

48. HMW-CK (34E12)
Normal Glands
Negative in Carcinoma

49. AMACR (P504S) stain in Carcinoma

50. Incresing IHC resolution:
P63 / AMACR cocktail

51. 34E12 / P63 / AMACR 2-chromogen cocktail
Incresing IHC resolution:
34E12 / P63 / AMACR 2-chromogen cocktail

52. IHC in prostate Cancer (Cont.)
Indications:
2- Differential Dx from urothelial carcinoma:
PSA PSAP 34E12 Leu7
Prostate Ca –
Urothelial Ca – – –

53. IHC in prostate Cancer (Cont.)
Indications:
3- Differential Dx in metastatic carcinoma:
Bone Tumor:
PSA stain

54. Agenda: Overview of prostatic adenocarcinoma
Diagnostic tools: changing attitudes
Cancer diagnosis: minimal pathologic criteria
Difficult diagnoses: IHC and other solutions
Gleason grading: 2005 ISUP consensus
Staging: AJCC/UICC TNM
Cancer Reporting checklist (CAP approved)
Future outlook

55. Gleason Grading (Donald F Gleason 1966)
Glandular architecture (NOT cytology)
Low magnification(40 ;100)
Five grades (1-5)
Combined Score:
1grade (pattern) + 2 grade (pattern)
Scores 2-4: Low grade (Well-diff,)
Scores 5-7: Intermed grade (Mod.-diff.)
Scores >7: High grade (Poorly-diff.)

56. 2005 ISUP Consensus Grading 50 uropathologists Agreement > 2/3

57. CONSENSUS: In needle Biopsy:
Combined score 2+1 or 2+2 are exceptional
Add the most common grade + the highest grade (even if limited)
e.g., report small focus of 5 as:
Disregard grade 2 if two higher grades are present
Assign individual scores to separate cores only if submitted separately

58. CONSENSUS: In radical prostatectomy:
Report limited higher grade as tertiary pattern
e.g., score: 4 + 3
and tertiary pattern: 5
Assign separate scores to discrete nodules
e.g., a peripheral nodule and a central nodule

59. Cribriform Pattern: grade 3

60. Cribriform Pattern: grade 4

61. Cribriform Pattern: grade 5

62. Ductal Adenocarcinoma: 4+4

63. Colloid (Mucinous) Ca: 4+4

64. Small Cell Ca. (No grading)

65. Pseudohyperplastic Ca. : 3+3

66. Glomeruloid Pattern: 3 or 4

67. Agenda: Overview of prostatic adenocarcinoma
Diagnostic tools: changing attitudes
Cancer diagnosis: minimal pathologic criteria
Difficult diagnoses: IHC and other solutions
Gleason grading: 2005 ISUP consensus
Staging: AJCC/UICC TNM
Cancer Reporting checklist (CAP approved)
Future outlook

68. Old Staging System (A-D)

69. Current Staging of Prostatic Ca
TNM classification (AJCC / UICC):
Clinical TNM (cTNM)
Pathological TNM (pTNM)

70. Primary Tumor (T) - Clinical

71. Primary Tumor (pT) - Pathological

72. Lymph Nodes (N) & Metastasis (M)

73. TNM Stage Grouping

74. TNM Descriptors

75. Residual Tumor Descriptor

76. Vascular Invasion Descriptor

77. Isolated Tumor cells in Nodes (ITC)

78. Agenda: Overview of prostatic adenocarcinoma
Diagnostic tools: changing attitudes
Cancer diagnosis: minimal pathologic criteria
Difficult diagnoses: IHC and other solutions
Gleason grading: 2005 ISUP consensus
Staging: AJCC/UICC TNM
Cancer Reporting checklist (CAP approved)
Future outlook

79. Specimen type & macro description: 1- Needle biopsy 2- TUR
Reporting checklist for prostatic Ca. (based on AJCC/UICC TNM, 6th edition CAP approved)
Specimen type & macro description:
1- Needle biopsy
Size & No. of cores
Notify if < 5mm in aggregate
2- TUR
size & weight of specimen
Describe suspicious areas
3- Enucleation
As above
4- Radical prostatectomy
Structures included (seminal vesicles LN etc.)
Optional

80. Histologic type of tumor Histologic Grade (Gleason score)
Reporting checklist for prostatic Ca. (based on AJCC/UICC TNM, 6th edition CAP approved)
Histologic type of tumor
Histologic Grade (Gleason score)
Primary & secondary patterns
Tertiary pattern only for radical prostatectomy
Isolated scoring for isolated tumor nodules
Tumor quantitation
Needle biopsy:
% of tissue involved by tumor
Total linear mm. Of Ca. / Total length of cores
No. of positive cores / total No. of cores
TUR:
No. of positive chips / total No. of chips

81. Tumor quantitation (Cont.)
Reporting checklist for prostatic Ca. (based on AJCC/UICC TNM, 6th edition CAP approved)
Tumor quantitation (Cont.)
Enucleation & Radical prostatectomy
% of tissue involved by tumor
Tumor size (dominant nodule / nodules)
Pathologic staging (pTNM) only for radical
Surgical margins only for radical
Perineural invasion
Periprostatic fat & seminal vesicle invasion
Lymphatic (small vessel) invasion
Venous (large vessel) invasion
Additional pathologic findings (e.g., HGPIN - BPH - therapy related changes)

82. Agenda: Overview of prostatic adenocarcinoma
Diagnostic tools: changing attitudes
Cancer diagnosis: minimal pathologic criteria
Difficult diagnoses: IHC and other solutions
Gleason grading: 2005 ISUP consensus
Staging: AJCC/UICC TNM
Cancer Reporting checklist (CAP approved)
Future outlook

83. Future Outlook: Molecular pathology
1- Carcinogenesis:
Overexpression of some genes (DNA microarray)
Hepsin: a trans-membrane serine protease
-Methyl Acyl coA racemase (AMACR-p504s)
Underexpression (turn-off) of some genes
Cancer suppressor genes (e.g., PTEN, KAI-1)
Glutathione S-transferase gene promoter (GSTP1)
2- Early tumor detection and Prognosis:
P53 mutation in more advanced cases
DNA ploidy correlating tumor grade & stage
smad-4 protein (TGF- related) overexpression in advanced Cancer
EZH2: transcription factor overexpressed in aggressive & metastatic disease

84.             
slide 2 of 9
                   

85.             
slide 3 of 9
                   

86. Seminal vesicle
            
slide 4 of 9
                   

87. Seminal vesicle Older man
            
slide 5 of 9
                   

88. Seminal vesicle
Young man

89. Presenting sympton
A 74 year old man presented with a three month history of weakness and tiredness
For the past month he was also seen to have haematuria.
He was admitted to a district hospital and after two weeks was found to be in urinary retention
He was treated with a catheter, but transferred when his urinary output fell and he became increasingly breathless.

90. Past history.
2 prostate operations in the past ? For what reason

91. On examination
Blocked catheter noted – irrigated and developed haematuria.
Patient unable to move legs (on further questioning he has been paraplegic for 1 month)
Pallor noted
Rectal exam – hard lumpy prostate.

92. Clinical diagnosis 1. Prostate Ca.
2. Spinal cord compression secondary to bony metastases
3. Anemia secondary to ? Renal failure and haematuria
4. CCF secondary to fluid overload and anemia.

93. Investigations
Creatiine 4.7
Hb 5.7
X-rays to follow

94. X-rays of pelvis and spine
Multiple lytic lesions

95. Destruction of disc and ? vertebral collapse

96. Treatment
He was booked for trans-urethral resection of the prostate and bilateral orchidectomy.
Samples of prostatic tissue and testicular tissue were sent for pathology

97. TURP-Prostate Biopsy
Normal Prostatic glands
Stroma
Tumor tissue

98. TURP-Prostate Biopsy
Normal Prostatic glands
Stroma
Tumor tissue

99. TURP-Prostate Biopsy
Normal Prostatic glands
Stroma
Tumor tissue

100. TURP-Prostatic Carcinoma
High power view showing
Tumor tissue
Forming glands

101. TURP-Prostatic Carcinoma
Tumor embolism in a dilated lymphatic vessel.

102. Orchidectomy - Testes biopsy
Atrophic semineferous tubules
Inflammatory tissue