Original Article Prognostic significance of neuroendocrine differentiation, proliferation activity and androgen receptor expression in prostate cancer Naoki Segawa, 1 Ichiro Mori, 2 Hirotoshi Utsunomiya, 2 Misa Nakamura, 2 Yasushi Nakamura, 2 Liang Shan, 2 Kennichi Kakudo 2 and Yoji Katsuoka 1 1 Department of Urology, Osaka Medical College, Takatsuki and 2 Department of Pathology, Wakayama Medical College, Wakayama, Japan cancer has prognostic value for patients undergoing hor- monal therapy. Several research groups have demonstrated this value, 2–5 however, some have failed to. 6 In addition to AR expression, the proliferation activity and neuroendocrine (NE) differentiation of the tumor cells have also been suggested to be useful as prognostic indicators by some researchers. In particular, NE differentiation has been considered to enhance tumor-cell proliferation. In this study, we investigated the prognostic value of NE differentiation, tumor-cell proliferation activity and AR expression, and the relationship among them, in untreated prostate cancer. MATERIALS AND METHODS Cases Forty-two prostate adenocarcinomas from 42 individuals were included in this study. They were collected from January 1994 to March 1999 in the Urological Department, Osaka Medical College. In 17 cases, the core needle biopsy materi- als were available, in six cases, the radical prostatectomy materials were available and in 19 cases, the transurethral resection (TUR) materials were available. The mean age of the patients was 70.1 years (range: 55–91 years). The follow- up period varied from 1 to 133 months, with a mean of 30.4 months. None of the patients had received neo-adjuvant hormonal therapy before the materials were collected. Pro- gression of the tumor was defined as appearance of distant metastases by chest X-ray and bone scans, and abnormal, increased levels of serum prostate-specific antigen (PSA). Histological study The nuclear grade and glandular differentiation of the tumors were determined by two investigators, according to the Pathology International 2001; 51: 452–459 Androgen, acting via the androgen receptor (AR), is associ- ated with the development and progression of prostate cancer. Anti-androgen therapy is widely used to manage prostate cancer. However, the conversion of the tumor from a hormone-sensitive to a hormone-insensitive status causes such therapy to fail. Several mechanisms have now been put forward for this conversion, including neuroen- docrine (NE) differentiation of the tumor cells. In this study, we evaluated the prognostic significance of tumor-cell proliferation activity, NE differentiation and AR expression. Formalin-fixed, paraffin-embedded sections were prepared from 42 patients with adenocarcinoma of the prostate. Using antibodies to AR, the Ki-67 antigen (MIB-1), chromogranin A and synaptophysin, immunohistochemical expression of AR, tumor proliferation activity and NE differentiation were analyzed. Our study revealed that AR expression was significantly lower in adenocarcinoma (52.2 ± 27.1%) than in non-tumorous prostate tissue (68.3 ± 18.3%; P < 0.001). NE differentiation was found in 50% of the tumors, which was correlated with the Gleason score (P < 0.05). An univari- ate analysis revealed a significant correlation between progression-free survival with both AR expression (P < 0.01) and proliferation activity (P < 0.001). NE differentiation was not a prognostic factor in this study. Key words: adenocarcinoma, androgen receptor, immunohisto- chemistry, neuroendocrine differentiation, proliferation activity, prostate Prostate cancer is the most common malignancy in men and the second leading cause of cancer-related death in Western countries. 1 Anti-androgen therapy is now widely used to manage prostate cancer because of the tumor’s necessity for androgen. Because androgen acts via the androgen receptor (AR), the level of expression of AR in untreated prostate Correspondence: Naoki Segawa, MD, Department of Urology, Osaka Medical College, 2-7 Daigaku-cho, Takatsuki City 869-8686, Japan. Email: uro009@poh.osaka-med.ac.jp Received 22 September 2000. Accepted for publication 9 Febru- ary 2001.