TY - JOUR
T1 - Neuroendocrine differentiation in usual-type prostatic adenocarcinoma
T2 - Molecular characterization and clinical significance
AU - Kaur, Harsimar
AU - Samarska, Iryna
AU - Lu, Jiayun
AU - Faisal, Farzana
AU - Maughan, Benjamin L.
AU - Murali, Sanjana
AU - Asrani, Kaushal
AU - Alshalalfa, Mohamed
AU - Antonarakis, Emmanuel S.
AU - Epstein, Jonathan I.
AU - Joshu, Corinne E.
AU - Schaeffer, Edward M.
AU - Mosquera, Juan Miguel
AU - Lotan, Tamara L.
N1 - Funding Information:
This work was supported in part by the NIH/NCI Prostate SPORE P50CA58236; and the NCI Cancer Center Support Grant 5P30CA006973-52.
Funding Information:
This work was supported in part by the NIH/NCI Prostate SPORE P50CA58236; and the NCI Cancer Center Support Grant 5P30CA006973‐52.
Publisher Copyright:
© 2020 Wiley Periodicals LLC
PY - 2020/9/1
Y1 - 2020/9/1
N2 - Background: Small cell neuroendocrine (NE) carcinomas of the prostate classically lose androgen receptor (AR) expression, may harbor loss of the RB1, TP53, and PTEN tumor suppressor genes, and are associated with a poor prognosis. However usual-type adenocarcinomas may also contain areas of NE differentiation, and in this context the molecular features and biological significance are less certain. Methods: We examined the molecular phenotype and oncologic outcomes of primary prostate adenocarcinomas with ≥5% NE differentiation (≥5% chromogranin A-positive NE cells in any given tumor spot on tissue microarray) using three independent study sets: a set of tumors with paneth cell-like NE differentiation (n = 26), a retrospective case-cohort of intermediate- and high-risk patients enriched for adverse outcomes (n = 267), and primary tumors from a retrospective series of men with eventual castration-resistant metastatic prostate cancer (CRPC) treated with abiraterone or enzalutamide (n = 55). Results: Benign NE cells expressed significantly lower quantified AR levels compared with paired benign luminal cells (P <.001). Similarly, paneth-like NE carcinoma cells or carcinoma cells expressing chromogranin A expressed significantly lower quantified AR levels than paired non-NE carcinoma cells (P <.001). Quantified ERG protein expression, was also lower in chromogranin A-labeled adenocarcinoma cells compared with unlabeled cells (P <.001) and tumors with NE differentiation showed lower gene expression scores for AR activity compared with those without. Despite evidence of lower AR signaling, adenocarcinomas with NE differentiation did not differ by prevalence of TP53 missense mutations, or PTEN or RB1 loss, compared with those without NE differentiation. Finally, NE differentiation was not associated with time to metastasis in intermediate- and high-risk patients (P =.6 on multivariate analysis), nor with progression-free survival in patients with CRPC treated with abiraterone or enzalutamide (P =.9). Conclusion: NE differentiation in usual-type primary prostate adenocarcinoma is a molecularly and clinically distinct form of lineage plasticity from that occurring in small cell NE carcinoma.
AB - Background: Small cell neuroendocrine (NE) carcinomas of the prostate classically lose androgen receptor (AR) expression, may harbor loss of the RB1, TP53, and PTEN tumor suppressor genes, and are associated with a poor prognosis. However usual-type adenocarcinomas may also contain areas of NE differentiation, and in this context the molecular features and biological significance are less certain. Methods: We examined the molecular phenotype and oncologic outcomes of primary prostate adenocarcinomas with ≥5% NE differentiation (≥5% chromogranin A-positive NE cells in any given tumor spot on tissue microarray) using three independent study sets: a set of tumors with paneth cell-like NE differentiation (n = 26), a retrospective case-cohort of intermediate- and high-risk patients enriched for adverse outcomes (n = 267), and primary tumors from a retrospective series of men with eventual castration-resistant metastatic prostate cancer (CRPC) treated with abiraterone or enzalutamide (n = 55). Results: Benign NE cells expressed significantly lower quantified AR levels compared with paired benign luminal cells (P <.001). Similarly, paneth-like NE carcinoma cells or carcinoma cells expressing chromogranin A expressed significantly lower quantified AR levels than paired non-NE carcinoma cells (P <.001). Quantified ERG protein expression, was also lower in chromogranin A-labeled adenocarcinoma cells compared with unlabeled cells (P <.001) and tumors with NE differentiation showed lower gene expression scores for AR activity compared with those without. Despite evidence of lower AR signaling, adenocarcinomas with NE differentiation did not differ by prevalence of TP53 missense mutations, or PTEN or RB1 loss, compared with those without NE differentiation. Finally, NE differentiation was not associated with time to metastasis in intermediate- and high-risk patients (P =.6 on multivariate analysis), nor with progression-free survival in patients with CRPC treated with abiraterone or enzalutamide (P =.9). Conclusion: NE differentiation in usual-type primary prostate adenocarcinoma is a molecularly and clinically distinct form of lineage plasticity from that occurring in small cell NE carcinoma.
KW - androgen receptor
KW - neuroendocrine differentiation
KW - paneth cells
KW - prostate adenocarcinoma
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U2 - 10.1002/pros.24035
DO - 10.1002/pros.24035
M3 - Article
C2 - 32649013
AN - SCOPUS:85087734128
SN - 0270-4137
VL - 80
SP - 1012
EP - 1023
JO - Prostate
JF - Prostate
IS - 12
ER -
