AbstractBACKGROUNDHigh grade prostatic intraepithelial neoplasia (HGPIN) is a putative pre‐malignant lesion of the prostate. While apolipoprotein‐D (Apo‐D), an androgen‐regulated hydrophobic transporter protein, is expressed in prostate tumors, its expression in HGPIN is unknown.METHODSImmunoreactivity for Apo‐D and another androgen‐regulated protein, prostate specific antigen (PSA), was investigated in 64 radical prostatectomy tissues by video image analysis.RESULTSEighty two percent of prostatectomy specimens demonstrated moderate to strong Apo‐D immunoreactivity in areas of HGPIN. In comparison, weak Apo‐D immunoreactivity was observed in non‐malignant areas in only 24% of specimens. The median (range) percentage cellular area of HGPIN immunopositive for Apo‐D (9.7%, 0–42.9), and the cellular concentration of Apo‐D (MIOD 3.1, 0–13.3), were intermediate between that of normal (area 0%, 0–53.5%, MIOD 0, 0–12.6) and early stage prostate cancer tissues (area 29.2%, 0–90.8%, MIOD 6.7, 0–28.1). This increase in Apo‐D expression from non‐malignant, through HGPIN to prostate cancer was statistically significant (P < 0.001), and contrasted with the decrease observed in PSA staining between adjacent areas of normal glands, HGPIN, and cancer (P = 0.026).CONCLUSIONSThe presence of high levels of immunoreactive Apo‐D in HGPIN and prostate cancer, but not in non‐malignant epithelial cells, is consistent with HGPIN being an intermediate lesion in the transition to prostate cancer, and suggests that cellular Apo‐D expression is a marker of malignant transformation of the prostate. © 2003 Wiley‐Liss, Inc.