Neuroendocrine Prostate Cancer

Introduction

Carcinoma of the prostate represents the most common cancer diagnosis in American men and is the second leading cause of deaths from cancer. The large majority of prostate cancers are histologically adenocarcinomas. The development and implementation of serum prostate-specific antigen (PSA) screening among at-risk men lead to the high incidence of prostate cancers discovered in the late twentieth and early twenty-first centuries. While far more prostate carcinomas are being diagnosed at an early/localized stage in the PSA era, there is still a significant population of American men with prostate cancer who are diagnosed with advanced-stage disease or who progress following treatment.

Historically, neuroendocrine differentiation (NED) of prostate carcinoma is considered an important and largely lethal step of carcinogenesis in patients with advanced hormone refractory prostate cancer (HRPC). Indeed, NED is strongly associated with antiandrogen treatment failure, disease progression, and worsening prognosis independent of tumor stage and grade. Neuroendocrine (NE) cells appear to be a ubiquitous component of normal prostate tissue, serving a regulatory function via exocrine, endocrine, paracrine, and autocrine pathways. In its purest form, NED manifests in prostate cancer as small-cell carcinoma, a rare variant associated with extremely poor prognosis, representing at most 2% of diagnosed prostate cancers. Nevertheless, it is important to understand that to varying degrees NED is present in almost all adenocarcinomas. Decades of scientific investigation have focused on mechanisms that underpin the association of NED and prostate cancer aggressiveness, attempting to identify serum markers to detect excessive levels of NED and to pinpoint therapeutic opportunities against the disease. As such, this chapter will introduce the reader to the physiologic role of the neuroendocrine system in the development of normal prostate tissue, explain historical and current theories about NED’s part in carcinogenesis of prostate malignancy and describe therapeutic options currently available to patients with advanced prostate cancer that exhibits NED features.

Neuroendocrine cells in the healthy prostate