Proliferative inflammatory atrophy of the prostate - Implications for prostatic carcinogenesis

Proliferation in the setting of longstanding chronic inflammation appears t o predispose to carcinoma in the liver, large bowel, urinary bladder, and g astric mucosa, Focal prostatic atrophy, which is associated with chronic in flammation, is highly proliferative (Ruska et al, Am J Surg Pathol 1998, 22 :1073-1077); thus the, focus of this study was to more fully characterize t he phenotype of the atrophic cells to assess the feasibility of the proposa l that they may be targets of neoplastic transformation. The rr-class gluta thione S-transferase (GSTP1), a carcinogen-detoxifying enzyme, is not expre ssed in >90% of prostate carcinomas (CaPs), GSTP1 promoter hypermethylation , which appears to permanently silence transcription, is the most frequentl y detected genomic alteration in Cap (Lee et al, Proc Natl Acad Sci USA 199 4, 91:11733-11737; >90% of cases). In high-grade prostatic intraepithelial neoplasia (PIN), this alteration is present in at least 70% of cases (Brook s et al, Cancer Epidemiol Biomarkers Prev, 1998, 7:531-536), Although norma l-appearing prostate secretory cells rarely express GSTP1, they remain capa ble of expression, inasmuch as GSTP1 promoter hypermethylation is not detec ted in normal prostate, Fifty-five lesions from paraffin-embedded prostatec tomy specimens (n = 42) were stained for GSTP1, using immunohistochemistry. Adjacent sections were stained for p27(Kip1), Ki-67, androgen receptor (AR ), prostate-specific antigen (PSA), prostate-specific acid phosphatase (PSA P), Bcl-2, and basal cell-specific cytokeratins (34 beta E12), With normal prostate epithelium as the internal standard, staining was scored for each marker in the atrophic epithelium. The lesions showed two cell types, basal cells staining positive for 34 beta E12, and atrophic secretory type cells staining weakly negative for 34 beta E12, All lesions showed elevated leve ls of Bcl-2 in many of the secretory-type cells. All lesions had an elevate d staining index for the proliferation marker Ki-67 in the secretory layer and decreased expression of p27(Kip1), a finding reminiscent of high-grade PIN (De Marzo et al, Am J pathol 1998, 153:911-919). Consistent with partia l:secretory cell differentiation, the luminal cells showed weak to moderate staining for androgen receptor and the secretory proteins PSA and PSAP, Al l atrophic lesions showed elevated GSTP1 expression in many of the luminal secretory-type cells. Because all lesions are hyperproliferative, are assoc iated with inflammation, and have the distinct morphological appearance rec ognized as prostatic atrophy, we suggest the term "proliferative inflammato ry atrophy" (PIA), Elevated levels of GSTP1 may reflect its inducible natur e in secretory cells, possibly in response to increased electrophile or oxi dant stress. Elevated Bcl-2 expression may be responsible for the very low apoptotic rate in PIA and is consistent with the conclusion that PIA is a r egenerative lesion. We discuss our proposal to integrate the atrophy and hi gh-grade PIN hypotheses of prostate carcinogenesis by suggesting that atrop hy may give rise to carcinoma either directly, as previously postulated, or indirectly by first developing into high-grade PIN.