# Neuroendocrine differentiation in prostate cancer

Source: https://onco.cc/terms/neuroendocrine-differentiation/  
OnCo record `neuroendocrine-differentiation` (Term). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Prostate cancer cells that have taken on the look and the markers of nerve-and-hormone cells. A trace of it is present in almost every prostate cancer and means nothing; a tumour made mostly of it is a different and much more serious disease, and it usually appears after years of hormone treatment.

## Summary

Neuroendocrine differentiation describes prostate cancer cells expressing neuroendocrine markers, principally chromogranin A, synaptophysin and CD56, with or without the morphology to match. It is a spectrum rather than a category, which is why the word appears in so many contexts with so many meanings. The Prostate Cancer Foundation working committee set out the range in a classification with six named entries: usual prostate adenocarcinoma with neuroendocrine differentiation; adenocarcinoma with Paneth cell neuroendocrine differentiation; carcinoid tumour; small cell carcinoma; large cell neuroendocrine carcinoma; and mixed neuroendocrine carcinoma with acinar adenocarcinoma, alongside two clinical descriptions, prostate carcinoma with overlapping features of small cell carcinoma and acinar adenocarcinoma, and castration-resistant prostate cancer with a small cell cancer-like clinical presentation.

The practical rule in a United Kingdom report is that scattered marker positivity in an ordinary adenocarcinoma is not looked for and does not change anything. The Royal College of Pathologists dataset does not ask for routine synaptophysin and chromogranin staining of ordinary prostate adenocarcinoma, because almost all of them show some neuroendocrine differentiation and the evidence that finding it changes treatment or prognosis is insufficient; the stains are for tumours that already look neuroendocrine down the microscope. Neuroendocrine carcinomas are not Gleason graded.

The form that matters is treatment-related. The WHO fifth edition gives treatment-related neuroendocrine prostatic carcinoma its own section in the prostate chapter rather than folding it into the classification's neuroendocrine chapter, and defines it as tumours demonstrating complete neuroendocrine differentiation, or partial neuroendocrine differentiation with adenocarcinoma, following androgen deprivation therapy, covering both the primary and its metastases. It is found in 10.5 to 17 percent of people with metastatic castration-resistant prostate cancer treated with androgen receptor signalling inhibitors, and the evidence is that it arises by transformation of an existing adenocarcinoma rather than from resident neuroendocrine cells, which is what lineage plasticity means in this disease. PSA and NKX3.1 are usually lost, which is why the blood test can stay reassuringly low while the disease advances, and why an unexplained clinical deterioration with a flat prostate-specific antigen is the situation in which a biopsy is worth taking.

## Fields

- Kind: Term
- Last checked: 2026-09-25
- Also known as: NED; neuroendocrine differentiation; treatment-emergent neuroendocrine differentiation; Paneth cell-like change; chromogranin positive prostate cancer; synaptophysin positive prostate cancer
- Tags: gu; prostate-glossary

## Notes

- A trace is not a diagnosis. Almost all prostate adenocarcinomas contain some cells with neuroendocrine features, and that is why the United Kingdom dataset does not ask for the stains routinely. A report mentioning focal chromogranin positivity in an otherwise ordinary adenocarcinoma is describing a common finding, not a change of disease.
- Three words that are often run together and are not the same. Neuroendocrine differentiation is a marker and morphology finding on a spectrum. Lineage plasticity is the mechanism by which an androgen receptor-dependent luminal cell becomes androgen receptor-independent. Treatment-related neuroendocrine prostatic carcinoma is the WHO entity at the far end of the spectrum, with its own page here.
- Why the PSA misleads here. These tumours usually lose PSA and NKX3.1 expression, so a man whose disease is transforming can have a stable or falling prostate-specific antigen while his scans and his symptoms worsen. Discordance between the blood test and the clinical picture is the trigger to look, not reassurance.

## Sources

- Epstein et al., American Journal of Surgical Pathology 2014: proposed morphologic classification of prostate cancer with neuroendocrine differentiation: https://doi.org/10.1097/pas.0000000000000208
- Kench et al., Histopathology 2022: WHO Classification of Tumours fifth edition, evolving issues in the classification, diagnosis and prognostication of prostate cancer: https://doi.org/10.1111/his.14711
- WHO Classification of Tumours, 5th edition: tumours of the prostate (IARC, 2022): https://tumourclassification.iarc.who.int/chapters/36
- Royal College of Pathologists G084: dataset for histopathology reports for prostatic carcinoma, version 4, October 2024: https://www.rcpath.org/static/8cc88604-2c8d-4df4-a99542df41c102af/G084-dataset-for-histopathology-reports-for-prostatic-carcinoma.pdf

## Connected records

- terms: [Acinar adenocarcinoma of the prostate](https://onco.cc/terms/prostate-acinar-adenocarcinoma/), [AR-V7 splice variant](https://onco.cc/terms/ar-v7/), [Castration-resistant prostate cancer (CRPC)](https://onco.cc/terms/castration-resistance/), [Gleason score / Grade Group](https://onco.cc/terms/gleason-grade-group/), [Histologic transformation](https://onco.cc/terms/histologic-transformation/), [Immunohistochemistry (IHC)](https://onco.cc/terms/ihc/), [PSA (prostate-specific antigen)](https://onco.cc/terms/psa/)
- cancers: [Metastatic castration-resistant prostate cancer](https://onco.cc/cancers/prostate-mcrpc/), [Neuroendocrine and small-cell prostate cancer](https://onco.cc/cancers/prostate-nepc/), [Prostate cancer](https://onco.cc/cancers/prostate/)
- key papers: [AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer](https://onco.cc/key-papers/paper-antonarakis-ar-v7-resistance-nejm-2014/), [Clinical and genomic characterisation of treatment-emergent small-cell neuroendocrine prostate cancer](https://onco.cc/key-papers/paper-aggarwal-t-sccpc-jco-2018/), [Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer](https://onco.cc/key-papers/paper-beltran-nepc-divergent-evolution-nat-med-2016/), [SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer](https://onco.cc/key-papers/paper-mu-sox2-lineage-plasticity-science-2017/)
- ideas: [Watch for the cancer changing cell type before the biopsy says neuroendocrine, and act on it](https://onco.cc/ideas/idea-prostate-plasticity-surveillance-before-it-is-neuroendocrine/)
- fronts: [Diagnostics & Biomarkers](https://onco.cc/fronts/diagnostics/), [Hormonal Therapy](https://onco.cc/fronts/hormonal/), [Targeted Therapy](https://onco.cc/fronts/targeted-therapy/)
- technologies: [Liquid biopsy (ctDNA)](https://onco.cc/technologies/liquid-biopsy/)
- targets: [Androgen receptor](https://onco.cc/targets/androgen-receptor/), [RB1](https://onco.cc/targets/rb1/), [TP53](https://onco.cc/targets/tp53/)
- pathways: [Lineage plasticity & neuroendocrine transformation](https://onco.cc/pathways/lineage-plasticity-neuroendocrine/)
- bottlenecks: [Acquired resistance to every therapy](https://onco.cc/bottlenecks/b-resistance/), [Rare and paediatric cancers without markets](https://onco.cc/bottlenecks/b-rare-cancers/), [Tumour heterogeneity and clonal evolution](https://onco.cc/bottlenecks/b-tumor-heterogeneity/)

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