Abstract
Purpose
Prostatic adenocarcinoma with neuroendocrine differentiation (PaNED) is distinct from treatment-related and de-novo neuroendocrine prostate carcinomas, yet remains under-investigated in treatment-naïve patients. This study aimed to evaluate the associations of NED extent, synaptophysin intensity score (SIS), and PD-L1 expression with other histomorphological features and prognosis in treatment-naïve PaNED.
Materials and methods
Seventeen patients with PaNED diagnosed between 2014 and 2024 were retrospectively analyzed. NED was classified as diffuse (≥ 30%) or focal (< 30%), and SIS was scored as weak (+ 1), moderate (+ 2), or strong (+ 3). PD-L1 expression was assessed using tumor proportion score (TPS, cut-off ≥ 1%) and combined positive score (CPS, cut-off ≥ 10). Clinicopathological data and survival outcomes were evaluated.
Results
The mean age was 65.2 ± 6.6 years, and 47.1% (n = 8) of the cases were Grade Group 5. Diffuse NED was observed in 70.6% of cases, and strong synaptophysin expression in 35.3%. PD-L1 TPS and CPS positivity were detected in 17.6% and 35.3% of patients, respectively. Neither NED extent nor percentage was significantly associated with PD-L1 expression or prognosis. A moderate negative correlation was found between SIS and PD-L1 CPS (rho = -0.48, p = 0.051). Strong synaptophysin expression was significantly associated with shorter overall survival (p = 0.031).
Conclusions
In treatment-naïve PaNED, higher SIS was correlated with lower PD-L1 CPS values, and strong synaptophysin expression was associated with poorer survival. Assessment of SIS in morphologically suspected neuroendocrine areas may provide additional prognostic information and help predict the PD-L1 response. Larger studies are required to validate these findings.
Keywords: Prostatic adenocarcinoma, Neuroendocrine differentiation, Synaptophysin, Programmed death-ligand 1 (PD-L1), Treatment-naïve, Prognosis
Introduction
Prostatic adenocarcinoma with neuroendocrine differentiation (PaNED) is characterized by conventional adenocarcinoma cells exhibiting neuroendocrine features, such as round to oval nuclei, finely granular chromatin, and scant to moderate eosinophilic cytoplasm. These tumors often display nested, trabecular, rosette-like, or solid growth patterns. The diagnosis of NED relies on these histological features and the expression of at least one neuroendocrine immunohistochemical marker [1, 2]. The extent of NED varies among cases and may influence clinical behavior and prognosis [3].
PaNED represents a distinct entity that should be carefully distinguished from treatment-related neuroendocrine prostate carcinoma (t-NEPC). Furthermore, it requires differentiation from de-novo pure neuroendocrine carcinomas (NEPCs) to ensure accurate diagnosis and management. t-NEPC typically arises following androgen deprivation therapy (ADT) and is associated with aggressive clinical features, frequent loss of prostate-specific markers, and inactivation of tumor suppressors such as TP53 and RB1 [4, 5]. De novo pure NECs are rare but also highly aggressive, with distinct molecular and clinical characteristics [1, 6].
Current management of prostate cancer involves various treatment lines, including androgen deprivation therapy (ADT), chemotherapy, and androgen-receptor-axis-targeted (ARAT) agents. However, the optimal therapeutic choice remains challenging due to the lack of robust predictive biomarkers. Recent systematic reviews have highlighted the importance of identifying novel tools and markers to predict response to therapies in genitourinary malignancies, emphasizing that clinical features alone may not be sufficient for personalized treatment strategies [7, 8].
Despite increasing recognition of NED in prostate cancer, the clinicopathological and prognostic features of treatment-naïve PaNED remain poorly defined. In particular, the relationships between histomorphological features, programmed death-ligand 1 (PD-L1) expression, and clinical outcomes in this group are unclear. Clarifying these associations may improve diagnostic accuracy, risk stratification, and therapeutic decision-making.
To the best of our knowledge, this is one of the few studies specifically focusing on the intensity of synaptophysin expression rather than extent alone in a strictly treatment-naïve cohort, providing novel insights into the intrinsic biology of these tumors independent of therapy-induced changes. This study aimed to investigate the associations between histomorphological findings, PD-L1 expression, and prognostic parameters in a cohort of treatment-naïve patients with PaNED.
Materials and methods
Study design and ethical approval
This single-center, retrospective, observational study was conducted in accordance with the Declaration of Helsinki and was approved by the Umraniye Training and Research Hospital Ethics Committee, University of Health Sciences, Istanbul, Turkey (approval number: B.10.1.TKH.4.34.H.GP.0.01/179). The requirement for written informed consent to participate was waived by the ethics committee due to the retrospective design of the study and the use of anonymized archival data. The study was reported in compliance with the STROBE guidelines for cohort studies.
Case selection
Seventeen cases of treatment-naïve PaNED diagnosed between June 2014 and June 2024 were included in the study. The inclusion criteria were: (1) histologically confirmed diagnosis of prostatic adenocarcinoma with neuroendocrine differentiation, and (2) no history of prior systemic therapy, hormonal therapy, or radiotherapy (treatment-naïve status) at the time of diagnosis.
The exclusion criteria were: (1) patients with missing clinical follow-up data preventing accurate survival analysis, and (2) cases with insufficient formalin-fixed paraffin-embedded (FFPE) tissue blocks to perform the required immunohistochemical studies. Demographic and clinical data were retrieved from the hospital database.
Histopathological and immunohistochemical evaluation
All hematoxylin and eosin (H&E)-stained slides and immunohistochemical preparations were independently reviewed by two pathologists. PaNED was defined using morphological and immunohistochemical criteria. The extent of NED was calculated as the ratio of the NED area to the total tumor area. According to recent literature, a 30% threshold is commonly used to define mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs), particularly in colorectal tumors [9]. we classified cases into two groups: “focal” (cases with < 30% NED) and “diffuse” (cases with ≥ 30% NED).
Immunohistochemical staining was performed for Synaptophysin (clone SY38, 1:100 dilution, Ventana) and PD-L1 (clone 22C3, 1:50 dilution, Leica). Synaptophysin intensity was graded as weak (1+), moderate (2+), or strong (3+). PD-L1 expression was assessed using standard criteria; the Tumor Proportion Score (TPS), defined as the percentage of positive tumor cells (cut-off ≥ 1%), and the Combined Positive Score (CPS), representing the ratio of positive tumor and immune cells to total tumor cells (cut-off ≥ 10). Necrotic areas were excluded from all evaluations.
Statistical analysis
All statistical analyses were performed using IBM SPSS Statistics for Mac (version 27.0, IBM Corp., Armonk, NY, USA). Normality was assessed with the Shapiro-Wilk test and histograms. Categorical variables were reported as counts and percentages; continuous variables as median (IQR) or mean ± SD. Due to small sample size, non-parametric tests were used; Fisher’s exact test for categorical variables, Mann-Whitney U test for continuous variables, and Spearman’s rank correlation for SIS and PD-L1 CPS. Overall survival (OS) was calculated from surgery to death or last follow-up, with Kaplan-Meier curves and log-rank test for group comparisons. Two-tailed p-values < 0.05 were considered significant.
Results
Patient characteristics and histological findings
The mean age of the cohort was 65.2 ± 6.6 years. Radical prostatectomy was performed in 58.8% of patients, and Grade Group 5 (GG5) was observed in 47.1%. The mean percentage of NED was 42.6 ± 24.5% (range, 10–80%), with diffuse NED present in 70.6% of cases. SIS was weak in 17.6%, moderate in 47.1%, and strong in 35.3% of cases. Representative sections of NED and SIS are shown in Fig. 1. PD-L1 TPS positivity was found in 17.6% of cases, and CPS positivity in 35.3% (Fig. 2).
Fig. 1.
Representative images of NED and synaptophysin intensity in PaNED. A Focal NED, 100x. B-C Diffuse NED, 400x. D Weak synaptophysin intensity (SIS 1+), 400x. E Moderate synaptophysin intensity (SIS 2+), 400x. F Strong synaptophysin intensity (SIS 3+), 400x
Fig. 2.
PD-L1 expression in PaNED. A TPS positivity, 400x. B CPS positivity, 400x
During a mean follow-up of 55.2 ± 33 months, metastatic disease was present in 41.2% of patients, and the overall mortality rate was 29.4%. Detailed demographic and clinicopathological characteristics are presented in Table 1.
Table 1.
Demographic and clinicopathological characteristics
| Specimen type, n (%) | |
|---|---|
| RRP | 10 (58.8) |
| TRUS | 6 (35.3) |
| TUR | 1 (5.9) |
| Age (mean ± SD), years | 65.2 ± 6.6 |
| Tumor volume (%) (median, IQR) | 33.5 (30.2) |
| Preoperative PSA (ng/mL) (median, IQR) | 11.5 (47.5) |
| GG, n (%) | |
| GG2 | 1 (5.9) |
| GG3 | 4 (23.5) |
| GG4 | 4 (23.5) |
| GG5 | 8 (47.1) |
| Lymphovascular invasion, n (%) | 6 (35.3) |
| Perineural invasion, n (%) | 12 (70.6) |
| NED, n (%) | |
| focal | 5 (29.4) |
| diffuse | 12 (70.6) |
| SIS, n (%) | |
| weak | 3 (17.6) |
| moderate | 8 (47.1) |
| strong | 6 (35.3) |
| Metastasis, n (%) | 7 (41.2) |
| Follow-up duration (months, mean ± SD) | 55.2 ± 33 |
| Death during follow-up, n (%) | 5 (29.4) |
Abbreviations: RRP Robotic Radical prostatectomy, TRUS Transrectal ultrasound-guided biopsy, TUR Transurethral resection, SD Standard deviation, IQR Interquartile range, PSA Prostate-specific antigen, GG Grade group, NED Neuroendocrine differentiaton, SIS Synaptophysin intensity score
Association of SIS and NED with PD-L1 expression
The relationships between SIS, NED extent, and PD-L1 expression are summarized in Table 2. No significant differences were found between SIS groups regarding PD-L1 TPS or CPS positivity. There was a moderate negative correlation trend between SIS and PD-L1 CPS (Spearman’s rho = -0.481, p = 0.051), indicating a borderline significant tendency where tumors with strong synaptophysin staining intensity exhibited lower PD-L1 CPS values. The extent and percentage of NED were not significantly associated with PD-L1 status or other histomorphological parameters.
Table 2.
Association of SIS and NED with PD-L1 expression
| PD-L1 TPS | PD-L1 TPS (%) | PD-L1 CPS | PD-L1 CPS (value) | ||||||
|---|---|---|---|---|---|---|---|---|---|
| Positive n(%) |
p | Mean ± SD | p | Positive n(%) |
p | Mean ± SD | p | ||
| SIS | 0.241¹ | 0.1752 | 0.071¹ | 0.0872 0.0513 | |||||
| weak | 0 (0.0) | 0 (0.0) | 2 (33.3) | 15 ± 5 | |||||
| moderate | 3 (100) | 3.33 ± 1.25 | 4 (66.7) | 31.25 ± 20.12 | |||||
| strong | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | |||||
| NED | 1.0004 | 0.6765 | 1.0005 | 0.9825 | |||||
| focal | 1 (33.3) | 5 | 2 (33.3) | 30 ± 10 | |||||
| diffuse | 2 (66.7) | 2.5 ± 0.5 | 4 (66.7) | 23.75 ± 21.05 | |||||
Abbreviations: SIS Synaptophysin intensity score, NED Neuroendocrine differentiation, TPS tumor proportion score, CPS combined positive score, SD Standard deviation
¹Fisher-Freeman-Halton exact, ²Kruskal- Wallis H, 3Spearman correlation, 4Fisher’s exact, 5Mann- Whitney U
Association of clinicopathological parameters with PD-L1 expression
The relationship between other clinicopathological parameters and PD-L1 expression was examined. No statistically significant association was found between grade group, tumor volume, PD-L1 TPS or CPS positivity, TPS percentage, or CPS value.
Prognostic parameters and survival analysis
No significant associations were found between NED group, SIS, PD-L1 TPS or CPS positivity, and presence of metastasis (p = 0.338, 0.377, 1.000, and 1.000, respectively). Similarly, PD-L1 TPS percentage and CPS value were not significantly related to metastasis (p = 0.691 and 0.280). Lymphovascular invasion (LVI) and perineural invasion (PNI) also showed no significant associations with NED group, SIS, or PD-L1 status.
OS was analyzed by SIS, NED, and PD-L1 expression using Kaplan–Meier and log-rank tests. Survival differed significantly between SIS groups; the p-value of 0.031 explicitly indicates a significant correlation between strong synaptophysin expression and shorter OS compared to weak or moderate expression. Five-year survival rates were 100% (weak), 87.5% (moderate), and 33.3% (strong). Median survival in the strong-staining group was 26 months, while median survival was not reached in the other groups. This finding aligns with previous studies suggesting that intense neuroendocrine marker expression is often associated with a more aggressive clinical course and poorer outcomes [10, 11]. Mean survival times for focal and diffuse NED groups were similar (85.4 vs. 84.8 months; p = 0.463) (Fig. 3A and B).
Fig. 3.
Kaplan-Meier survival curves for OS in PaNED. A OS by SIS; patients with strong synaptophysin expression had significantly shorter OS than those with weak or moderate expression (p = 0.031). B OS according to the extent of NED (focal vs. diffuse); no significant difference was observed. C OS by TPS status; no significant difference was observed. D OS by CPS status; no significant difference was observed
Survival was compared between PD-L1 TPS and CPS positive and negative groups. No significant differences were found (p = 0.841 for TPS, p = 0.540 for CPS) (Fig. 3C and D). Mean survival times were 92.0 months (TPS-negative) vs. 63.7 months (TPS-positive), and 85.9 months (CPS-negative) vs. 78.3 months (CPS-positive).
Discussion
This study examined the relationship between NED, SIS, and PD-L1 expression in treatment-naïve PaNED. While NED extent was not linked to adverse pathology or survival, strong SIS was associated with poorer OS. PD-L1 expression was generally low and not significantly related to outcomes, though a trend toward moderate negative correlation with SIS was noted. These findings indicate a complex relationship between neuroendocrine features and immune checkpoint expression, warranting further research.
PaNED is relatively understudied, and its biological and clinical significance remains unclear [12]. The clinicopathological and prognostic roles of NED and immune checkpoint expression in treatment-naïve prostatic adenocarcinoma are not well defined. While t-NEPC or de novo NEPC are linked to aggressive disease and poor prognosis [13, 14], most studies report that neuroendocrine features in conventional prostatic adenocarcinoma do not independently predict outcomes [15].
The prognostic value of NED extent in prostatic adenocarcinoma is controversial. Some studies link diffuse NED to more aggressive behavior, while others find no outcome differences between focal and diffuse patterns [16, 17]. Prognosis may depend more on molecular alterations, such as RB1 and TP53 loss, than on NED extent alone [11]. In our cohort, NED extent was not associated with adverse pathology or survival, suggesting it is not a reliable prognostic factor. Additionally, no standard cutoff distinguishes focal from diffuse NED in prostate cancer.
Our results indicate that synaptophysin intensity, rather than NED extent, is a more relevant prognostic factor. This finding resonates with recent literature emphasizing that intense neuroendocrine marker expression often signals a transition toward a more aggressive phenotype, characterized by treatment resistance and poorer survival outcomes [5, 10, 16, 18]. While these aggressive traits are typically associated with t-NEPC, our data suggest that strong synaptophysin intensity in treatment-naïve cases may serve as an early indicator of intrinsic biological aggression, potentially predating the full development of a neuroendocrine carcinoma phenotype [13, 14, 19].
The prognostic or predictive value of PD-L1 in prostate cancer remains unclear. In our study, PD-L1 expression (both TPS and CPS) was low and did not correlate with OS or adverse pathology, consistent with previous reports showing minimal PD-L1 expression in prostate cancer [20, 21]. Thus, PD-L1 is not a reliable biomarker for immunotherapy selection in this setting [22]. The immune microenvironment in PaNED is heterogeneous, and the relationship between PD-L1 and synaptophysin intensity is unclear. Although we observed a trend toward lower PD-L1 CPS in cases with strong synaptophysin staining, this was not statistically significant, likely reflecting the complex tumor microenvironment and limitations of current scoring methods [23–25]. This observation aligns with the broader challenges in prostate cancer management, where therapeutic resistance and tumor heterogeneity often limit the efficacy of systemic approaches. As highlighted in recent literature, the biological complexity of prostate cancer variants—ranging from oligometastatic disease to aggressive neuroendocrine forms—requires a nuanced understanding of tumor biology beyond single biomarkers [26]. Therefore, the low PD-L1 expression observed in our cohort may reflect intrinsic immune evasion mechanisms that are distinct from the classic PD-1/PD-L1 axis, contributing to the therapeutic refractoriness often seen in these tumors.
Our findings suggest two main clinical implications. First, incorporating the assessment of synaptophysin intensity into routine pathological reporting for PaNED could refine risk stratification, helping clinicians identify patients who may require closer surveillance or early molecular profiling [13, 19]. Second, the consistently low PD-L1 expression observed in our cohort further supports the limited utility of PD-L1 as a biomarker for immunotherapy selection in prostate cancer, in contrast to its established role in other solid tumors [21]. Thus, risk stratification in PaNED should include qualitative, molecular, and immunophenotypic features, not just quantitative measures [27].
Limitations of this study include the small sample size, single-center retrospective design, and absence of molecular profiling or RB1/TP53 assessment, all of which may limit generalizability and risk stratification. Additionally, reliance on a single neuroendocrine marker may not fully capture the heterogeneity of NED. A key strength of this study is the exclusive inclusion of treatment-naïve cases, which provides clearer insight into intrinsic tumor biology. Furthermore, the integration of clinicopathological, immunophenotypic, and survival data enhances the robustness of the prognostic analysis [28].
Conclusion
This study demonstrates the heterogeneity of NED in treatment-naïve prostatic adenocarcinoma. While NED extent does not predict outcomes, strong synaptophysin expression is linked to poorer survival, highlighting the value of qualitative neuroendocrine assessment. The negative correlation between SIS and PD-L1 CPS suggests higher neuroendocrine marker expression may be associated with lower immune checkpoint activity. These results support integrated diagnostic and prognostic strategies combining immunophenotypic, molecular, and clinical data in PaNED. Future research should focus on elucidating the molecular drivers underlying high synaptophysin intensity and exploring whether this subgroup could benefit from early, targeted therapeutic interventions or intensified surveillance protocols.
Summary
In prostate cancer with neuroendocrine features, strong synaptophysin staining is linked to shorter survival. Assessing this marker may help identify patients at higher risk and guide more effective treatment choices.
Acknowledgements
None.
Abbreviations
- ADT
Androgen deprivation therapy
- CPS
Combined positive score
- GG
Grade group
- H&E
Hematoxylin and eosin
- IQR
Interquartile range
- LVI
Lymphovascular invasion
- MiNEN
Mixed neuroendocrine-non-neuroendocrine neoplasm
- NED
Neuroendocrine differentiation
- NEPC
Neuroendocrine prostate carcinoma
- OS
Overall survival
- PaNED
Prostatic adenocarcinoma with neuroendocrine differentiation
- PD-L1
Programmed death-ligand 1
- PNI
Perineural invasion
- PSA
Prostate-specific antigen
- RRP
Robotic radical prostatectomy
- SD
Standard deviation
- SIS
Synaptophysin intensity score
- STROBE
Strengthening the Reporting of Observational Studies in Epidemiology
- TPS
Tumor proportion score
- TRUS
Transrectal ultrasound-guided biopsy
- TUR
Transurethral resection
Authors’ contributions
IT conceived and designed the study, performed the histopathological evaluation, collected clinicopathological data, and drafted the manuscript. OS contributed to the pathological review and data collection. IGB contributed to the pathological assessment and interpretation of immunohistochemical findings. NMS collected and interpreted the urological and clinical data. MO contributed to the acquisition and interpretation of oncological data. All authors contributed to data interpretation, critically revised the manuscript for important intellectual content, and approved the final version of the manuscript.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Data availability
The datasets generated and/or analysed during the current study are not publicly available due to institutional and national data protection regulations but are available from the corresponding author on reasonable request.
Declarations
Ethics approval and consent to participate
This study was conducted in line with the principles of the Declaration of Helsinki. The study protocol was approved by the Umraniye Training and Research Hospital Ethics Committee, University of Health Sciences, Istanbul, Turkey (approval number: B.10.1.TKH.4.34.H.GP.0.01/179). Given the retrospective design of the study and the use of anonymized archival data, the requirement for written informed consent to participate was waived by the ethics committee.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets generated and/or analysed during the current study are not publicly available due to institutional and national data protection regulations but are available from the corresponding author on reasonable request.