Neuroendocrine differentiation

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Neuroendocrine differentiation refers to prostate cancers that have a noticeable population of neuroendocrine cells. These include true neuroendocrine cancers such as small cell carcinoma and carcinoid tumors, and prostate adenocarcinoma that shows neuroendocrine features in some areas.

Neuroendocrine cells are part of a diffuse neuroendocrine system found throughout the body. In the prostate they are present in all regions, especially near ducts, and come in two shapes: open type with extensions toward the lumen, and closed type with dendrite-like connections between cells.

These cells secrete many peptides and hormones, including serotonin, chromogranin A, synaptophysin, and neuron-specific enolase (NSE), which are common markers for identifying them. They can also produce calcitonin and other peptides such as CGRP, bombesin/GRP, VIP, somatostatin, neurotensin, and others. How their secretion is controlled is not fully understood and may involve endocrine, paracrine, autocrine, or neural signals.

The origin of these cells is not clear. They may arise from a different precursor than other prostate epithelial cells, possibly a separate neurogenic lineage.

In prostate cancer, a key area of study is focal neuroendocrine differentiation, where a standard prostate adenocarcinoma contains neuroendocrine foci. By contrast, small cell carcinoma of the prostate shows a universal neuroendocrine phenotype, with nearly all tumor cells displaying these features.

Castration experiments in mice show that loss of androgen signaling can cause tumor regression and a drop in androgen receptor expression, while neuroendocrine tumor cells increase and form dispersed islets within the tumor.

Immunohistochemistry helps identify neuroendocrine differentiation. Chromogranin A is the most common and reliable marker, with synaptophysin and NSE also used. In many neuroendocrine tumor cells, calcitonin, neurotensin, serotonin, human chorionic gonadotropin (hCG), VIP, and bombesin/GRP are frequently found.

Neuroendocrine tumor cells typically express luminal-type cytokeratins but lack basal markers such as high molecular weight cytokeratin and p63. They are usually negative for androgen receptor (AR) and prostate-specific antigen (PSA) but positive for prostate acid phosphatase (PAP). Ki-67, a proliferation marker, is generally low in neuroendocrine cells, though neighboring non-neuroendocrine tumor cells may show higher Ki-67.

Compared with normal prostatic neuroendocrine cells, tumor neuroendocrine cells express AMACR (alpha-methylacyl-CoA racemase), a marker linked to prostate cancer.

Small cell carcinoma of the prostate is an aggressive form with a broad neuroendocrine profile, often positive for TTF-1, CD56, chromogranin A, synaptophysin, NSE, calcitonin, and bombesin/GRP, and typically lacking AR and PSA.

In summary, prostate cancers with notable neuroendocrine differentiation are thought to be less differentiated, more aggressive, and more resistant to hormone therapy.