Treatment-Emergent Neuroendocrine Prostate Cancer: A Clinicopathological and Immunohistochemical Analysis of 94 Cases

Abstract

Purpose: This study aimed to evaluate the pathological characteristics, immunophenotype, and prognosis of treatment-emergent neuroendocrine prostate cancer (T-NEPC).

Materials and methods: We collected 231 repeated biopsy specimens of castration-resistant prostate cancer (CRPC) cases between 2008 and 2019. We used histopathological and immunohistochemical evaluations of Synaptophysin (SYN), ChromograninA (CgA), CD56, androgen receptor (AR), and prostate-specific antigen (PSA) to screen out T-NEPC cases. Multivariate analyses were performed to identify factors in the prognosis of T-NEPC. Further, the results were verified in the Surveillance, Epidemiology, and End Results (SEER) program.

Results: Among the 231 CRPC cases, 94 (40.7%) cases were T-NEPC. T-NEPC were more likely to present with negative immunohistochemistry for AR (30.9%) and PSA (47.9%) than that of CRPC (8.8% and 17.5%, respectively). Kaplan-Meier analysis revealed that patients with T-NEPC (median overall survival [OS]: 17.6 months, 95% CI: 15.3-19.9 months) had significantly worse survival compared with usual CRPC patients (median OS: 23.6 months, 95% CI: 21.3-25.9 months, log-rank P = 0.001), especially in metastasis cases (median OS: 15.7 months, 95% CI: 13.3-18.0 months) and patients with small cell carcinoma component (median OS: 9.7 months, 95% CI: 8.2-11.2 months). Prostate adenocarcinoma with diffuse NE differentiation (median OS: 18.8 months, 95% CI: 15.3-22.3 months) had poor outcome than those with usual CRPC (P = 0.027), while there was no significant change in the focal NE differentiation (median OS: 22.9 months, 95% CI: 18.1-27.7 months, P = 0.136). In the unadjusted model, an excess risk of overall death was observed in T-NEPC with PSA negative (HR = 2.86, 95% CI = 1.39-6.73). Among 476 NEPC cases in the SEER database from 2004 to 2017, we observed a higher hazard of overall death in patients aged 65 years and older (HR = 1.35, 95% CI = 1.08-1.69), patients with PSA ≤ 2.5 ng/ml (HR = 1.90, 95%CI = 1.44-2.52), patients with PSA 2.6-4.0 ng/ml (HR = 2.03, 95%CI = 1.38-2.99), stage IV tumor (HR = 2.13, 95%CI = 1.47-3.08) and other races (HR = 1.85, 95%CI = 1.17-2.94) in total NEPC, adjusting for confounders. Similar hazard ratios were observed in pure NEPC, while there was no significant results among prostate adenocarcinoma with NE differentiation tumors.

Conclusion: T-NEPC was associated with an unfavorable prognosis, negative immunohistochemistry for PSA in T-NEPC and serum PSA level ≤ 4 ng/ml had a worse prognosis. Urologists and pathologists should recognize the importance of the second biopsy in CRPC to avoid unnecessary diagnosis and treatment delays.

Keywords: SEER program; castration-resistant prostate cancer; immunohistochemistry; small cell carcinoma; treatment-emergent neuroendocrine prostate cancer.

Figure 1

Flowchart of eligible individuals, surveillance, epidemiology, and end results (SEER) 18 registries, 2004–2017.

Figure 2

The histomorphology and immunohistochemistry of prostate adenocarcinoma with focal/diffuse increased neuroendocrine differentiation. (A) Prostate adenocarcinoma with focal increased neuroendocrine differentiation, the tumor cells show androgen receptor (AR) (B) and prostate-specific antigen (PSA) (C) positive, and focal express CD56 (D), Syn (E), and CgA (F); (G) prostate adenocarcinoma with diffuse neuroendocrine differentiation, the tumor cells show AR (H) and PSA (I) positive, and negative express CD56 (J), but Syn (K), and CgA (L) diffuse positive; (M) prostate adenocarcinoma with diffuse neuroendocrine differentiation, the tumor cells show AR (N) and PSA (O) negative, and diffuse express CD56 (P), Syn (Q) and CgA (R).

Figure 3

The histomorphology and immunohistochemistry of prostate highly differentiated neuroendocrine cancer and poorly differentiated neuroendocrine carcinoma. (A) Highly differentiated neuroendocrine cancer, the tumor cells show androgen receptor (AR) (B) and prostate-specific antigen (PSA) (C) negative, and diffuse express CD56 (D), Syn (E), and CgA (F); (G) Prostate large-cell neuroendocrine carcinoma, the tumor cells show AR (H) positive, and negative express PSA (I), diffuse express CD56 (J), Syn (K), and CgA (L); (M) Prostate small-cell carcinoma, the tumor cells show AR (N) and PSA (O) negative, and diffuse express CD56 (P), Syn (Q) and CgA (R).

Figure 4

Overall survival (OS) from diagnosis of castration-resistant prostate cancer (CRPC) and treatment-emergent neuroendocrine prostate cancer (T-NEPC) in a cohort of patients with CRPC and T-NEPC. (A) OS in CRPC versus T-NEPC; (B) OS in T-NEPC patients with metastasis versus without metastasis; (C) OS in T-NEPC patients with small cell carcinoma component versus without small cell carcinoma component; (D) OS in patients with focal NE differentiation versus diffuse NE differentiation; (E) OS in patients with diffuse NE differentiation versus usual CRPC; (F) OS in patients with focal NE differentiation versus usual CRPC.