Download atrophy and inflammatory lesions: the other side of prostate

Policlinico S. Orsola-Malpighi
EZIOPATOGENESI DELLE
NEOPLASIE PROSTATICHE:
Ruolo dell’infiammazione
Michelangelo Fiorentino, MD, PhD
1° Workshop SIUrO Giovani
Bologna 27 Aprile 2012
• Prostate atrophy and prostate inflammatory lesions
have been deemed for a long time of little
pathological interest
• Atrophy was considered a physiologic feature of
prostate tissue aging
• Inflammation was reported when particularly intense
or acute or granulomatous.
• Most of these lesions were therefore included in the
broad categories of “BPH” or “prostatitis”
• Currently most pathologists do not mention the
presence of atrophic lesions in their pathology
reports
The interest for inflammatory/atrophic lesions in prostate
cancer grew in the 90’s based on prior observations in
other organs such as stomach, liver and large bowel
A genetic susceptibility to
develop viral/bacterial
infections or the inability to
counter physical/chemical
injuries may :
• produce an irreversible cell
damage
• cause loss of tolerance to
normal prostate antigens
and induce an autoimmune
self-perpetuating reaction
• create a “field effect” for the
development of CaP
From Nelson WG et al. NEJM 2003;349:366-381
Causes of prostate atrophy and
inflammation
From De Marzo et al. Nature Rev Cancer April 2007
Propionebacterium Acnes
is the most represented bacterial strain in the prostate
Mean levels of serum IL-6 by selected genotypes. *P-values from linear regression models
adjusted for age at randomization, case status and baseline BMI. 0 = homozygous dominant;
1 = heterozygous and 2 = homozygous recessive.
Meyer M S et al. Carcinogenesis 2010;31:1597-1603
Mean levels of serum CRP by selected genotypes. *P-values from linear regression models
adjusted for age at randomization, case status and baseline BMI. 0 = homozygous dominant;
1 = heterozygous and 2 = homozygous recessive.
Meyer M S et al. Carcinogenesis 2010;31:1597-1603
Steps to prostate cancer through
inflammation/atrophy
• Injury of the luminal cell layer (any kind)
• Reactive (defensive) hyperplasia of basal and secretory cells
(PIA/PAH) with initiation of genetic instability
• Cytokines released by the inflammatory cells slowly induce
epithelial proliferation and angiogenesis
• Continued proliferation of genetically unstable cells leads to
accumulation of genomic changes and to neoplastic
transformation through PIN
From De Marzo et al. Nature Rev Cancer April 2007
Atrophy/PAH/PIN
Inflammation and atrophy as risk
factors for CaP
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PROs
Epidemiological studies on
enviromental exposures;
viral/bacterial infections ;
chemoprevention trials with
NSAIDs
Morphologic transition between
PAH and PIN
PAH and CaP share the downregulation of known tumor
suppressor genes (NKX3.1,
CDKN1B, PTEN), care-taker
genes genes (GSTP1), genes
with anti-viral (RNASEL) or antibacterial functions (MSR1)
No highly penetrant hereditary
prostate cancer genes have
been discovered so far
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CONs
No strong evidence of the
prostate inflammatory “field
effect “ in animal models
PAH lesions are not clonal
The causes of prostate
inflammation are extremely
variable
The target cell type of the
inflammatory damage is not
defined
Inflammatory lesions of the
prostate are more common than
CaP
The “inflammatory” hypothesis
for CaP has not been widely
accepted among scientists
• No systematic classification of atrophic and inflammatory
lesions of the prostate was done before 2006
Simple Atrophy
• Most lesions show relative lack
of cytoplasm both apically and
laterally compared with normal
epithelium.
• There are no vascularized
papillary infoldings and may be
irregularly shaped and
angulated
• The acini are generally spaced
apart and the number of acini
per unit area is not increased
and similar to the normal
epithelium
• Most of the lesions contain at
least some chronic (rarely
acute) inflammatory cells in
stroma, epithelium, or lumen.
Simple Atrophy with Cyst
Formation
• The epithelium is the same of
SA
• The acini are not simply
dilated, but must seem cystlike
• Many of the acini are arranged
in a back-to-back shape with
little intervening stroma
• The amount of cytoplasm is
sometimes almost invisible
• There is usually no or very little
inflammation
Partial Atrophy
• This is the most debated lesion
• The diagnosis is not highly
reproducible since it does not
depend solely on the
architectural arrangement of
the involved acini, but requires
distinct cytologic features
• The luminal cells contain less
cytoplasm than normal, but not
so little as in the other
subtypes of atrophy, and the
cytoplasm in many of the cells
must be clear.
• Partial atrophy may show
moderate nucleolar
enlargement and a “pseudoinfiltrative” pattern which can
lead to diagnostic confusion
withCaP
Post-Atrophic Hyperplasia
• Acini of PAH are small and
arranged in a lobular
distribution around a dilated
‘‘feeder’’ duct, similarly to
breast lobules
• The number of acini per unit
area is increased compared to
the normal epithelium but It’s
debated if there is actual
“hyperplasia”
• Possible moderate nucleolar
enlargement can lead to
diagnostic confusion with CaP
• Most of the lesions contain at
least some chronic (rarely
acute) inflammatory cells
• This is the only lesion that has
been related to CaP
Basal layer in PAH
Squamous metaplasia
From De Marzo et al. Nature Rev Cancer April 2007
Diagnostic reproducibility is
“the” issue
Study of diagnostic concordance
on atrophic lesions among
Italian pathologists
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In collaboration with GIUP
Selection of 120 cases (biopsies, RP, TURPS)
Preparation of 5 slide sets
Blind histological evaluation by 15 dedicated GU
pathologists and 15 general histopathologists
• Statistical analysis of inter-rater concordance (kappa
coefficient) among pathologists on the diagnosis of
PAH and the type and extent of inflammation
• Results expected by September 2012
OR1 (95% CI)
OR2 (95% CI)
Marker
Mean CD4+
1.01 (1.00-1.02)
1.01 (0.99-1.03)
Mean CD8+
1.00 (0.98-1.01)
1.00 (0.98-1.02)
Mean CD4+/Foxp3+
1.13 (1.06-1.20)
1.12 (1.02-1.23)
Sabina Davidsson unpublished data
Take home messages
• Inflammation is possibly a driver condition of
lethal prostate cancer rather than a simple
bystander
• PAH is a “sentinel” histological lesion,
possibly precursor of PIN
• Both Inflammation and PAH it should be
recorded in the pathology reports
• Satisfactory diagnostic concordance among
pathologists should lead to histopathological
guidelines on the reporting of these lesions
• Harvard
Massimo Loda
Lorelei Mucci
Meir Stampfer
Jennifer Rider
Neil Martin
Chris Sweeney
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Sweden
Sabina Davidsson
Ove Andren
Swen-Olof Andersson
Katja Fall
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Ireland
Stephen Finn
Richie Flavin
John O’Leary
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Italy
Enrico Bollito
the GIUP group