Specificities of small cell neuroendocrine prostate cancer: Adverse prognostic value of TTF1 expression.

Objectives: To determine whether small cell neuroendocrine prostate cancers (NEPCa) emerging after anti-androgen treatments are different from the rarest cases diagnosed de novo, and to identify effective predictive markers.

Material And Methods: The expression of neuroendocrine markers, androgen receptor (AR) and androgen-regulated genes, as well as markers of aggressiveness, were analyzed by immunohistochemistry on a tissue microarray containing samples of 30 sNEPCa, either pure or admixed with conventional PCa, and including 14 cases diagnosed de novo and 16 cases subsequent to prior androgen deprivation.

Results: Chromogranin A is a better marker of NE differentiation than synaptophysin in post-treatment NEPCa, with 94% and 44% of positive tumors, respectively, while both markers are equally expressed in de novo cases. Despite the acquisition of a NE phenotype, more than half of NEPCa expressed AR and the androgen-regulated gene NKX3.1, more frequently in cases admixed with conventional PCa. TTF1 staining, present in half of NEPCa, was associated with loss of androgen-regulated genes and with markers of aggressiveness, including increased proliferation, Zeb1 expression and PTEN loss. In multivariate analysis, only TTF1 expression was significantly associated with shorter overall survival.

Conclusion: These results suggest the persistence of androgen signaling in a number of NEPCa cases, and the interest of TTF1 staining as a predictive biomarker.