Neuroendocrine Differentiation in Prostatic Carcinoma Focal neuroendocrine differentiation is present in virtually all prostate cancers but is prominent in only 5-10%. This neuroendocrine differentiation is a recapitulation of normal differentiation pathways, albeit in caricature. Some carcinomas are completely differentiated along neuroendocrine lines, most notably some small cell carcinomas which are relatively rare. Neuroendocrine differentiation may increase with androgen deprivation and neuroendocrine factors appear to be paticularly active in androgen independent prostate cancer. Interestingly, neuroendocrine cells, both benign and malignant, do not express androgen receptor, in contrast to non-neuroendocrine prostate cancer cells, which usually express the androgen receptor. Possible Mechanisms of Increased Neuroendocrine Activity in Prostate Cancer Increased Neuroendocrine Secretory Products Increased Neuroendocrine Receptors Decreased Neutral Endopeptidase 24.11 Increased Peptidylglycine Alpha-amidating Monooxygenase Increased Prohormone Convertases Decreased PSA (PSA cleaves PTHrP) Chromogranin A, as well as other neuroendocrine secretory products, have been used as serum markers to follow the course of the disease, particularly in androgen independent, PSA negative, prostate cancer. Experimental evidence suggests that neuroendocrine factors induce proliferation and bcl-2 (an anti-apoptosis factor) expression in adjacent non-neuroendocrine prostate cancer cells. Neuroendocrine factors may also contribute to tumor invasiveness and angiogenesis (VEGF is produced mainly in neuroendocrine cells). Neuroendocrine differentiation may be an independent prognostic factor, especially in androgen independent cancer. Figure 11: Moderately differentiated adenocarcinoma with focal neuroendocrine differentiation (Chromogranin A immunocytochemistry). Figure 12: Another higher grade prostatic adenocarcinoma with clonal-like proliferation of prostatic neuroendocrine cells (Serotonin immunocytochemistry). Figure 13: Electron photomicrograph of neoplastic neuroendocrine cells in carcinoma from Figure 12. Figure 14: Small cell carcinoma of the prostate. Figure 15: Same small cell carcinoma of the prostate as Figure 14, showing strong staining for chromogranin A (chromogranin A immunocytochemistry). Figure 16: Hypothetical schematic composite diagram of prostate cancer with focal neuroendocrine differentiation (triangular cells) showing potential neuroendocrine products with known receptors, pathways of neuroendocrine activation, and neuroendocrine action. Androgen receptor (AR) is expressed in non-neuroendocrine cells but not neuroendocrine cells. The enzymes which cleave neuropeptides such as neutral endopeptidase 24.11 (NEP) and prostatic specific antigen (PSA) may decrease and those that activate neuropeptides such as peptidylglycine alpha-amidating monooxygenase (PAM) and prohormone convertase may increase, particularly in the androgen independent state. Bcl-2 expression and proliferative activity is increased in the non-neuroendocrine cells in the vicinity of neuroendocrine cells. Survivin is expressed in neuroendocrine cells. Vascular endothelial growth factor (VEGF) stimulates neovascularization. Chromogranin is a good serum marker for neuroendocrine differentiation. Figure 17: Hypothesis relating to increase of neuroendocrine cells and increase in neuroendocrine activity in androgen deprived and particularly, androgen independent cancer compared to androgen dependent cancer. Left panel shows neuroendocrine cells with a maintenance role similar to role in normal prostate. Middle panel shows maintenance of androgen sensitive (but not dependent) cells with a relative increase in neuroendocrine cell number (middle). Right hand panel shows relative increase of neuroendocrine cells and, in particular, an increase in neuroendocrine activity (increased neuroendocrine secretions, neuroendocrine receptors and activation of neuropeptides).