De novo neuroendocrine transdifferentiation in primary prostate cancer-a phenotype associated with advanced clinico-pathologic features and aggressive outcome.

Neuroendocrine transdifferentiation of high-grade prostate cancer (PCA-NT) comprises a morphologic and immunophenotypic transition from conventional adenocarcinoma towards high-grade neuroendocrine/small cell carcinoma. This phenomenon is frequently observed post androgen deprivation and/or radiotherapy, but de novo instances are increasingly recognized. Herein, we report a series of de novo PCA-NT focusing on characteristic morphologic, immunophenotypic and clinical features. Treatment naïve PCA-NT were identified. IHC for PSA, NKX3.1, Chromogranin, Synaptophysin, Cyclin D1, RB and Ki67 were performed. Radiology, treatment and follow-up data were reviewed. Sixteen patients were included. Apart from focal areas of high-grade prostate cancer with acinar features (reminiscent of Grade Group 5 disease), extensive areas with sheets of cells with deep amphophilic/basophilic cytoplasm, enlarged, hyperchromatic nuclei with granular chromatin and inconspicuous to prominent nucleoli with high mitotic activity were identified. Immunohistochemistry showed patchy NKX3.1, patchy PSA, variable Synaptophysin and Chromogranin; RB and CyclinD1 showed loss of expression. Ki67 showed high proliferative index, in most cases. Adverse radiologic findings and metastases were documented in most cases. Two patients died of disease. De novo PCA-NT exhibits high-grade nuclei, high mitotic activity, reduced PSA expression with high Ki67 and functional inactivation of RB1 pathway, suggesting transition from androgen-driven to proliferation-driven phenotype. Most cases presented at advanced stage with adverse radiological findings, metastasis at time of diagnosis, and high mortality. In light of their prognostic and therapeutic implications, pathologists may need to maintain a sensitive threshold for performing immunostains-in particular, Ki67 and CyclinD1-when presented with such cases in their day to day clinical practice.