1. Inflammation and Prostate
Diseases Progression
Alessandro Sciarra
Chairman Prostate Unit
Policlinico Umberto I
University La Sapienza
- Rome, Italy

2. BPH: long period before clinical evidence

3. Prostate Cancer: long period before clinical evidence
Normal LGPIN HGPIN Carcinoma
10-20 years 1-10 years

4. Question 1 ?
May inflammation significantly
condition the development and future
progression of prostate diseases ?

5. Question 2 ?
May inflammation be considered
a risk factor so to be integrated
in risk stratification analyses
for prostate diseases ?

6. Association infiammation – prostatic diseases
Evidences: • Epidemiologic
• Genetic
• Mechanism of action
• Histologic
• Clinical

8. 5 years Follow-up
 In the group with CI at 1° biopsy, 20% of pts developed PC and 6% HPIN
 In the group without CI at 1° biopsy , 6% of pts developed PC. P<0.05

9. Association between inflammation and BPH
Urology 71: 475-479, 2008. ©2008 Elsevier

10. Association infiammation – prostatic diseases
Evidences • Epidemiologic
:
• Genetic
• Mechanism of action
• Histologic
• Clinical

14. Association infiammation – prostatic diseases
Evidences • Epidemiologic
:
• Genetic
• Mechanism of action
• Histologic
• Clinical

15. Inflammation and BPH
Linfocita
Macrofago Citochine
Neutrofilo Radicali ossigeno

16. Cytokines and inflammation in the prostate
Kramer et al, Eur Urol, 2007; 51:1202-16

17. Inflammation: possible pathogenesis
 repeated tissue damage
 excessive production of
oxidative damages
 post-translational DNA
modifications
 increased cell proliferation
and angiogenesis

18. Inflammation:two possible actors
NOS and COX

21. Increased apoptosis (TUNEL) with rofecoxib

22. The role of inflammation in the human prostate
FGFs
IGFs
TGF-β
Modification epithelial Cyr61 Epithelial hyperplasia
function Citochine
↑ IL-8
↓ PDF
Tissue damage Infiammation Angiogenesis Diseases
Progression
↑ IL-8
Modification stromal FGFs
IGFs Stromal hyperplasia
function
TGF-β
Cyr61
Citochine
Inflammation can stimulate prostatic disease progression
Lucia et al, Curr Urol Rep, 2008; 9:272-78

26. Which inflammation induces prostatic progression?
Evidences: • Histological data – PSA
• Clinical data

27. Histopathological aspects of BPH
Inflammatory aspects
Histological aggressiveness
• 0 = no contact between inflammatory cells and
glandular epithelium
• 1 = contact between inflammation and epithelium
• 2 = interstitial infiltrate with glandular disruption
• 3 = glandular disruption on more than 25%
Irani; J Urol 1997

29. Infiammation: precancerous prostatic lesions
PIA PIN CARCINOMA
(proliferative (prostatic
inflammatory atrophy) intraepithelial neoplasia)
Prostata infiammata

30. Inflammation: potential precursor
lesions ?

31. Which inflammation induces prostatic progression?
Evidences • Histological data – PSA
:
• Clinical data:
- Frequency of the process
- Association with progression

32. • Prospective analysis on 167 prostate during autopsy.
• Pathologic analysis identified all carcinoma focus, BPH nodule and acute or chronic
inflammation area.
• The prevalence of the association between carcinoma, BPH and infiammation, has
been evaluated.
Delongchamps et al, J Urol 2008, 179:1736-40

33. Inflammation and BPH
67.6%
88
32.4%
16
6
Acuta Cronica Acuta + cronica
In BPH areas ,75% were associated with chronic inflammation (p= 0.01).
Delongchamps et al, J Urol 2008, 179:1736-40

34. Infiammation and BPH
Distribution of infiammation Inflammation association with age
CONCLUSIONs: Chronic inflammation was commonly found during autopsies.
Inflammation was directly associated with BPH
Delongchamps et al, J Urol 2008, 179:1736-40

35. A. Sciarra et al. Eur Urol 2000

36. Inflammation and prostate volume:
who influences the other ?
Chronic inflammation: F(1,2)=408.64; p=0.002
Acute inflammation: F(1,2)=2.292; p=0.269
50 chronic
chronic - trend
40
30
20
acute
10 acute - trend
0
30-39 40-49 50-59 60-69 70-79 80-89
cc
A. Sciarra et al. Eur Urol 2000

37. Inflammation and progression risk: MTOPS
544 patients from MTOPS study with acute (only 31) or chronic inflammation at basal
prostate biopsy , compared with cases without infiammation
Patients with inflammation were elderly (64 vs. 62.8 years, p=0.001), with higher volume
prostates (41.1 vs. 36.8 ml; p=0.0002) and higher PSA levels (3.3 vs. 2.5 ng/ml;
p<0.0001).
In these patients with inflammation a higher risk of acute urinary retention episodes
and a positive trend in favour of clinical progression was found (21.0 vs. 13.2%;
p=0.083).
Inflammation contributes to BPH progression
Roehrborn CG,. AUA meeting 2005, Abstract No. 1277

38. Impact of inflammation on BPH progression
No infiammation
Infiammation
C. Roehrborn, 2005. Studio MTOPS

39. Inflammation:
risk factor for BPH progression or PC development
Roehrborn C. 2006

40. Inflammation as precursor of Prostate Cancer:
Rationale for Preventive Strategies ?

44. How to select patients with BPH and inflammation ?
Evidences: • Symtoms
• Imaging
• Markers

45. How to select patients ?
Histology, no very often available
Different stages for prostatic inflammation
No inflammation Low
Moderate Severe

46. How to select patients ? LUTS and IPSS
Relationship between inflammation and symptoms in BPH

47. Multiparametric magnetic resonance with spectroscopic analysis: a
modern approach in prostatic imaging
Prostate 1H-MRSI (cancer)
Ch:
Choline = cellular turnover
Ci:
Citrate = terminal metabolites of Krebs
cycle
Cr:
Creatine = it increases in hypermetabolism

48. 1
2
3
4
G PC
H
LGPC
PIN
tio
n HG
mma
in fla
l
r ma
No

49. Systemic Markers for infiammation
Case-control nested study (4971 cases)
on the association between
inflammatory markers and symptomatic
BPH based on the placebo arm of PCPT
study
Shenk et al, Am J Epidemiol, 2010; 171:571-82

50. IL-8 as marker of inflammation in BPH
IL-8 levels in prostatic secretion
Sensibility and specificity of IL-8 to identify BPH associated ot inflammation versus BPH alone
were85.7% and 91.3% respectively, using a cut-off of 3992 pg/mL
Liangren et al, Urology, 2009; 74:340-4

51. Urinary markers for inflammation
• 90 tissue prostatic samples obtained from BPH patients waiting for surgery
• Urinary samples obtained after digital rectal examination
• Inflammatory score was classified on the basis of inflammatory cells extension:
– 0: no inflammation
– 1: mild inflammation
– 2: moderate inflammation
– 3: severe infiammation
Robert et al, Prostate, 2011, in press

52. Mean level of genes expression in 90 samples from BPH
cases on the basis of inflammation score
Robert G et al Nijmegen med Centre

53. Possible results from a long term block of prostatic
inflammation
• Improvement of LUTS correlated to prostatic
inflammation
• Prevention of LUTS progression correlated to prostatic
inflammation
• Reduction of the risk of BPH-related complications
(AUR)
• Synergic effect with other drugs used to block BPH
progression

54. Which drug for prostatic inflammation - BPH
Evidences: • Experimental
– Studies on primary cultures
– Inhibition on inflammatory factors
– Effect on proliferation/apoptosis
• Clinical
– Long term therapy
– Combination with alpha1 blockers
– Combination with 5 ARI

55. Serenoa Repens exane: specific for prostate tissue
o 2
o t ip
tic
ta
os
pr
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ite
Ep
1
% APOPTOSIS
t ipo
ico 2
stat ipo
ro it
op t ic
eli sta
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ob
la i tip
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Fi b ta o1 2
os t ip ipo
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sti 1 2 ell ell
bla ipo ipo am
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ro
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Fi b ta ta
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cu cu de de ale ale ipo ipo o1
ti sti ti sti en n t t t ip t ipo
la s la s or re mo mo lo lo
ob bla ob bla ut to idi idi ico co
Fib
r ro
Fib
r ro ss ssu id id st sti
Fi b Fi b Te Te Ep Ep Te Te
CELL TYPE

56. Serenoa Repens exane: Hypothesis for a mechanism of action
Stromal and epithelial human prostate cells
Modification lipid-fatty acid asset (1-5) (Ev Lev 2b)
Cellular membrane damage-increased permeab. (nuclear, mitochondrial)
(1-5) (Ev Lev 2b)
antiinflammatory
Reduction Effect Chromatin Mitochondrial inhibition 5 lipoxigenase
5AR I-II AR-ER condensation Block/distruction (5)(Ev Lev 2b)
(2,3)(Ev. Lev 4) (2,4)(Ev Lev 2b)
Reducion ecosanoid prod.
= leucotren (5)(Ev Lev 2b)
Increased ratio
Apoptosis/proliferation
(2,6,7)(Ev Lev 2b)
1-Buck J Urol 2004
2-Bayne Prostate 1999,J urol 2000
3-Habib Eur Urol 2009
4-Petrangeli JCP 2009
5-Paubert-Braquet Prostglandin 199897
6-Vacherot Prostate 2009
7-Vela Navarrete J Urol 2005

57. RESULTS
CELL COUNT INFLAMMATORY PATTERNS
IL-6, CCL-5, COX-2
Apoptosis-prolifetion NF-KB ANALYSIS

58. Which drug for prostatic inflammation - BPH
Evidences • Experimental
:
– Studies on primary cultures
– Inhibition on inflammatory factors
– Effect on proliferation/apoptosis
• Clinical
– Long term therapy
– Combination with alpha1 blockers
– Combination with 5 ARI

59. Increased apoptosis (TUNEL) using the combination of rofecoxib - finasteride

60. How to treat BPH- inflammation
Patient
IPSS≤7 IPSS>7
LUTS moderate-
LUTS mild severe
Symptoms or parameters correlated
to prostatic inflammation
Low volume High volume Low volume High volume
Low PSA Elevated PSA Low PSA Elevated PSA
No treatments 5 ARI preventive α-blocker Combination 5 ARI –
treatment alpha blocker
Anti-inflammatory Anti-inflammatory on
on the prostate the prostate
Modificato da Roehrborn C.G., BJU 2004