Neuroendocrine Differentiation in Hormone Refractory Prostate Cancer Following Androgen Deprivation Therapy
Introduction
Prostate carcinoma, even at later stages, responds to primary androgen deprivation therapy (either surgical or medical castration) with a response rate of more than 80% [1]. However, more than half of these cancers progress to a hormone-independent status within 16 to 18 months [2]. The elucidation of this conversion from hormone-sensitive status to hormone-insensitive is currently one of the most critical tasks in prostate cancer. A better understanding of the mechanisms of resistance to hormone therapy following androgen deprivation may eventually facilitate the clinical manipulation of such hormone refractory prostate cancer (HRPC) and result in greater survival.
Recently, changes in the differentiation pathway in prostate cancer have been increasingly demonstrated, particularly neuroendocrine (NE) cells as a mechanism in the development of resistance to androgen deprivation therapy [3]. NE cells comprise a highly specialized cell population, containing neurosecretory granules rich in various peptide hormones and biogenic amines such as calcitonin [4], parathyroid hormone-related protein [5], chromogranin A (CgA) [6], [7], serotonin [8], bombesin [9], vascular endothelial growth factors [10] and somatostatin [11]. Approximately 10% of prostatic carcinomas reveal extensive and multifocal NE features by using the endocrine marker CgA [3], [12], [13]. These cancer cells with NE differentiation have been shown to be more abundant after androgen deprivation therapy [6], [14]. Recent studies have indicated that all NE cells in malignant prostatic tissues had no androgen receptors [15], [16], and NE differentiation has been suggested to be associated with HRPC [17]. These previous immunohistochemical studies were performed using radical prostatectomy specimens obtained from early stage patients with or without hormone therapy, or TUR specimens from patients with relatively early progression after androgen ablation therapy, and did not involve substantial hormone refractory prostate cancer specimens such as autopsy specimens obtained from patients whose cause of death was HRPC following hormone treatment. In the current study we confirmed whether NE differentiation status in prostate cancer is substantially associated with HRPC after androgen deprivation therapy based on the comparison between radical prostatectomy and autopsy specimens obtained from HRPC patients.
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Patients
Seventy-two patients with prostate cancer that underwent radical prostatectomy between 1992 and 2001 and 21 patients that died from hormone refractory prostate cancer after androgen deprivation therapies in our university hospital between 1983 and 2001 were included in this study. Patient characteristics are found in Table 1. Patients were classified into 3 arms based on different treatments: Group 1 consists of 38 patients who received radical prostatectomy with no neoadjuvant therapy; Group
Results
Most specimens obtained from patients who underwent neoadjuvant hormone therapy and all autopsy specimens showed morphological changes such as atrophy and squamous metaplasia of the non-neoplastic ducts and acini, and cytoplasmic vacuolization, nuclear pyknosis, and fibrosis of the tumor tissue. With respect to morphological features in the immunoreactive neoplastic cells, the highest concentration of NE differentiation appeared in sparse staining or occasional individual positive cells in
Discussion
Increasing attention has been given to NE differentiation in prostate cancer because of its prognostic and therapeutic implications. Serum CgA as a NE differentiation marker has been proposed as an indicator of advanced prostate cancer in some patients who do not have elevated serum PSA [20], [21]. With respect to the correlation between NE differentiation based on immunohistochemical analysis and serum PSA, Deftos et al. [22] measured serum CgA and PSA, and conducted immunohistochemical
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