Proliferative inflammatory atrophy of the prostate: implications for prostatic carcinogenesis

Abstract

Proliferation in the setting of longstanding chronic inflammation appears to predispose to carcinoma in the liver, large bowel, urinary bladder, and gastric mucosa. Focal prostatic atrophy, which is associated with chronic inflammation, 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 the phenotype of the atrophic cells to assess the feasibility of the proposal that they may be targets of neoplastic transformation. The pi-class glutathione S-transferase (GSTP1), a carcinogen-detoxifying enzyme, is not expressed in >90% of prostate carcinomas (CaPs). GSTP1 promoter hypermethylation, which appears to permanently silence transcription, is the most frequently detected genomic alteration in CaP (Lee et al, Proc Natl Acad Sci USA 1994, 91:11733-11737; >90% of cases). In high-grade prostatic intraepithelial neoplasia (PIN), this alteration is present in at least 70% of cases (Brooks et al, Cancer Epidemiol Biomarkers Prev, 1998, 7:531-536). Although normal-appearing prostate secretory cells rarely express GSTP1, they remain capable of expression, inasmuch as GSTP1 promoter hypermethylation is not detected in normal prostate. Fifty-five lesions from paraffin-embedded prostatectomy 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 (PSAP), Bcl-2, and basal cell-specific cytokeratins (34betaE12). 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 34betaE12, and atrophic secretory-type cells staining weakly negative for 34betaE12. All lesions showed elevated levels of Bcl-2 in many of the secretory-type cells. All lesions had an elevated 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 partial secretory cell differentiation, the luminal cells showed weak to moderate staining for androgen receptor and the secretory proteins PSA and PSAP. All atrophic lesions showed elevated GSTP1 expression in many of the luminal secretory-type cells. Because all lesions are hyperproliferative, are associated with inflammation, and have the distinct morphological appearance recognized as prostatic atrophy, we suggest the term "proliferative inflammatory atrophy" (PIA). Elevated levels of GSTP1 may reflect its inducible nature in secretory cells, possibly in response to increased electrophile or oxidant 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 regenerative lesion. We discuss our proposal to integrate the atrophy and high-grade PIN hypotheses of prostate carcinogenesis by suggesting that atrophy may give rise to carcinoma either directly, as previously postulated, or indirectly by first developing into high-grade PIN.

Figure 1.

Proliferative inflammatory atrophy (PIA) of the prostate. A: Low-magnification view of a focus of PIA (outlined area) occurring adjacent to benign normal appearing glands (lower right). Arrows indicate collections of chronic inflammatory cells (predominantly lymphocytes). This lesion was classified as having marked chronic inflammation. H&E, ×40. B: Section adjacent to that shown in A, stained with anti-GSTP1 polyclonal antibody. Immunoperoxidase, ×40.

Figure 2.

Two cell layers in PIA. Medium-power view of section of PIA stained with the 34BE12 monoclonal antibody against basal cells. Arrows indicate atrophic secretory-type cells in the gland lumen. Arrowheads indicate basal cells. Inset: Higher power view of boxed area. Immunoperoxidase, ×200. Inset, ×400.

Figure 3.

Expression of markers of proliferation and differentiation in PIA. A: Increased expression of proliferation associated marker, Ki-67, in secretory-type cells. B: Decreased expression of cyclin-dependent kinase inhibitor p27^kip1 in secretory-type cells. C: Expression of PSA in secretory-type cells. A–C: Immunoperoxidase, ×200. Arrows indicate luminal cells.

Figure 4.

Expression of androgen receptors and Bcl-2 in PIA. A: Medium-power view of AR expression in PIA. B: Adjacent section showing expression of Bcl-2. The solid line demarcates a single acinus with heterogeneous staining. Arrowheads indicate weak staining for AR but strong staining for Bcl-2. Immunoperoxidase, ×100.

Figure 5.

Heterogeneity of expression of GSTP1 in PIA. Note areas of positive staining intermixed with areas of negative staining for GSTP1. The inset is a higher power view from the boxed area, showing the border zone between these areas. This lesion was classified as having mild chronic inflammation. Immunoperoxidase, ×100. Inset: Arrow indicates an atrophic secretory cell staining negatively, and the arrowhead indicates a nearby atrophic secretory cell staining positively. Magnification, ×400.