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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 • • • • 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 • • • • • • 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 • • • • 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 • Sweden Sabina Davidsson Ove Andren Swen-Olof Andersson Katja Fall • Ireland Stephen Finn Richie Flavin John O’Leary • Italy Enrico Bollito the GIUP group