Prostate cancer is the most frequently diagnosed malignancy in men. An early diagnosis of neuroendocrine differentiation in prostate cancer is particularly important to indicate/modulate the most appropriate therapy. Several clinical studies tried to correlate serum markers and neuroendocrine differentiation in PCa, but none of the markers investigated have been found to be sufficiently accurate to enter routine clinical practice. Our investigation has been performed by clinical staging (E-E), IHC and confocal microscopy analyses on 200 prostate biopsy provided by the Pathologic Anatomy Unit of Annunziata Hospital, Cosenza, Italy. Clinical evaluation of oncological patients was then performed before and after anti-androgen therapy. The second clinical evaluation revealed that some patients did not respond to anti-androgen therapy even if they were in the early stage of the disease; on the contrary, other patients, in an advanced stage of disease, have responded well to treatment. Hence we performed IHC and IF techniques revealing that in these cases CgA expression showed an unusual localization pattern whereas the expression of androgen receptor showed a typical expression pattern. Our results suggest that, in prostate adenocarcinoma, clinical staging, immunohistochemistry and immunofluorescence detection of both AR and CgA represent the most reliable prognostic and predictor clinical indicators.