Review article
Prognostic effect of neuroendocrine differentiation in prostate cancer: A critical review

https://doi.org/10.1016/j.urolonc.2014.08.007Get rights and content

Abstract

Background

The multiple pathways that are involved in neuroendocrine differentiation (NED) in prostate cancer (PCa) are poorly elucidated. Evidence suggests that several environmental triggers induce NED leading to the adaptation of PCa to its close environment to maintain cell proliferation. Nevertheless, there is conflicting evidence regarding the prognostic role of NED in PCa.

Methods

In this review, we aimed to summarize all available data about NED and to assess the prognostic role of NED in disease progression and therapy resistance, and its role in routine clinical practice. This review was based on articles found through a PubMed literature search between 1993 and 2013. The study outcome measure was the effect of NED on oncologic outcomes at each PCa stage.

Results

In total, 59 articles reporting on the effect of NED on oncologic outcomes have been selected. In clinical practice, immunostaining for NED markers could have interesting predictive value for assessing the oncologic outcomes in patients receiving androgen-deprivation therapy. Thus, patients with high NED burden may be candidates for more aggressive treatment strategies targeting NED pathways. Conversely, strong evidence is lacking concerning its potential independent prognostic value in hormone-naïve PCa.

Conclusions

Current published data are not sufficient to recommend the use of NE markers in routine practice, particularly at early PCa stage.

Introduction

Neuroendocrine differentiation (NED) is commonly present in the prostate gland, and its mechanisms have been studied extensively in the literature [1], [2]. Nevertheless, multiple pathways are involved in the NED phenomenon and remain still unclear. Evidence suggests that several environmental triggers induce NED in prostate cancer (PCa), leading to the adaptation of PCa to its close environment to maintain cell proliferation. Thus, NED, an androgen-independent phenomenon, allows tumor cell growth under androgen-deprivation therapy (ADT) and may represent a viable option to escape hormone therapy and, thus, to contribute to cancer progression, mainly at castration-resistant stage. The functional network between adenocarcinoma cells and neuroendocrine (NE) cells may play an important role and may be the key mechanism in therapy and castration resistance, leading to disease progression.

In this review, we aimed to summarize all available data about NED and to assess the potential prognostic role of such differentiation in disease progression and therapy resistance and its role in routine clinical practice.

Section snippets

Methods

This review is based on articles found through a PubMed literature search between January 1, 1993 and December 31, 2013, using the following search terms: neuroendocrine differentiation, prostate cancer, ionizing radiation, androgen-deprivation therapy, chemotherapy, prognosis, immunohistochemistry, radical prostatectomy, and androgen therapy. The search terms were used one at a time and simultaneously in various combinations. Eventually, 1,270 articles were selected. Case reports, letters, or

Nonmalignant prostate gland

NE cells are present in normal prostate gland and were originally described by Pretl in 1944 [3], [4]. They represent the third type of epithelial cell in the prostate gland after basal and exocrine secretory cells and account for<1% of all normal prostate cells. The role of NE cells is to regulate the cell growth and secretory activity via a paracrine mechanism [5]. However, the exact pathways underlying this regulation, as well the exact origin (neurogenic or stem cell origin) of these NE

Conclusions

Evidence contributes that NED in PCa that bears witness of the PCa adaptation to an androgen-deprived environment contribute to cancer progression. In clinical practice, immunostaining for NE markers could have interesting predictive value for assessing the oncologic outcomes in patients at castration-resistant stage and might promote more aggressive treatment strategies targeting NED pathways. Conversely, strong evidence is lacking concerning its potential independent prognostic value in

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