Download ATROPHY AND INFLAMMATORY LESIONS: THE OTHER SIDE …

RUOLO
DELL’INFIAMMAZIONE E
CARCINOMA PROSTATICO
Luca Cindolo
The evidence that link cancer and
inflammation
Inflammatory disease increases the risk of cancer (e.g. thyroid, bladder,
cervical, ovarian, oesophageal, gastric, intestinal)
Non-steroidal inflammatory drugs protect against some cancers (e.g. colon and
breast)
Inflammatory leucocytes, cytokines and chemokines are present in all (?)
experimental and human cancers from the earliest stages
Inflammatory pathways are downstream of oncogenic mutations (e.g. ras, myc,
RET/PTC)
Targeting cytokines, chemokines, key transcription factors of inflammation and
inflammatory cells, decreases incidence and spread of cancer (e.g. TNF-α, IL1β, NF-κB, Stats)
Infections and human cancers*
IARC Group 1 Carcinogens: “…the agent (mixture) is carcinogenic to humans…”
10 of 64 Group 1 Carcinogens are infectious agents
Epstein-Barr virus
Helicobacter pylori (infection with)
Hepatitis B virus (chronic infection with)
Hepatitis C virus (chronic infection with)
Human immunodeficiency virus type 1 (infection with)
Human papillomavirus type 16
Human papillomavirus type 18
Human T-cell lymphotropic virus type I
Opisthorchis viverrini (infection with)
Schistosoma haematobium (infection with)
*World Health Organization International Agency
for Research on Cancer (IARC); see www.iarc.fr
Infections and cancers
Klein EA, et al. Curr Opin Urol 2008,18:315–319
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NORMALITY
ABNORMALITY
?
?
NORMAL
PRECANCER
CANCER
?
NORMAL
HYPERPLASIA
DYSPLASIA
IN SITU CANCER
INVASIVE
CANCER
Open questions
• What is the border between “Normal” and
“Abnormal”?
• How long does it take for precancer to turn
into cancer?
• What is the point of no return?
• Are lesions biologically different in different
organs?
Histology is a snapshot of the disease
…
…while carcinogenesis is a dynamic process
Open questions
• What is the border between “Normal” and
“Abnormal”?
• How long does it take for precancer to turn
into cancer?
• What is the point of no return?
• Are lesions biologically different in different
organs?
Prostate Intraepithelial Neoplasia
(PIN)
Prostate epithelial cell hierarchy
Basal layer
Causes of
prostate
atrophy and
inflammation
De Marzo et al. Nature Rev Cancer 2007
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
Nelson WG et al. NEJM 2003;349:366-381
Steps to prostate cancer through
inflammation/atrophy #1
• 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
De Marzo et al. Nature Rev Cancer 2007
Steps to prostate cancer through
inflammation/atrophy #2
Klein EA, et al. Curr Opin Urol 2008,18:315–319
Inflammation and atrophy
as risk factors for CaP
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PROs
Epidemiological studies on
environmental exposures; viral/bacterial
infections ; chemoprevention trials with
NSAIDs
Morphologic transition between PAH
and PIN
PAH and CaP share the down-regulation
of known tumor suppressor genes
(NKX3.1, CDKN1B, PTEN), care-taker
genes genes (GSTP1), genes with antiviral (RNASEL) or anti-bacterial 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
Common features of atrophic lesions
• The epithelium is composed of two layers consisting of basal
cells and luminal cells
• Luminal cells are nearly flat with extremely scant cytoplasm
and sometimes dark appearance at low magnification.
• The two layers may be difficult to discriminate by standard
H&E staining.
• The basal layer can be demonstrated by staining against
basal cell specific cytokeratins (5/6, 34b12) or p63.
• The terms PIA and PAH overlap with the latter retaining a
more biological meaning.
• PAH is the only atrophic lesion correlated to the
development of CaP
Atrophy/PAH/PIN
NORMALITY
NORMAL
NORMAL
HYPERPLASIA
ABNORMALITY
PRECANCER
DYSPLASIA
CANCER
IN SITU CANCER
?
INFLAMMATION
ATROPHY
PAH
PIN
INVASIVE
CANCER
Platinum Slide Series
Relationship between age, metabolic syndrome, inflammation, hormonal alterations, and benign prostatic
hyperplasia (BPH).
CANCER
Briganti A, et al. Eur Urol Suppl 2009;13:865-871
From well-adapted to starvation and
fighting infection to poorly adapted to
overnutrition and excess inflammation
Platinum Slide Series
Schematic diagram showing some of the Serenoa repens extract (SrE) targets at the level of the prostate
cell.DHT = dihydrotestosterone; EGF = epidermal growth factor; FGF = fibroblast growth factor.
Fouad K. Habib Eur Urol Suppl 2009;13:887-893
Post-Atrophic Hyperplasia
• Acini of PAH are smalland
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