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The test result that shows a prostate cancer has changed into a different, faster kind of cancer under hormone treatment. It is made on a biopsy, usually prompted by disease that is growing while the PSA stays flat.
This readout is about recognition rather than about the entity itself, which is a WHO tumour type with its own record. Morphology comes first: a Prostate Cancer Foundation working committee set out named categories, separating usual adenocarcinoma with neuroendocrine differentiation from small cell carcinoma, large cell neuroendocrine carcinoma and mixed neuroendocrine carcinoma with acinar adenocarcinoma, and naming the situation in which castration-resistant disease presents clinically like small cell cancer (Epstein 2014). Supporting molecular features are loss of both RB1 and TP53, which is what permits the lineage change (Ku 2017, Mu 2017), and AURKA with MYCN co-amplification, present in 40% of neuroendocrine tumours against 5% of adenocarcinomas (Beltran 2011). In 59 samples from 40 men meeting clinical aggressive variant criteria, RB1 stained in under 10% of cells in 61% and androgen receptor in 36%, and RB1 copy loss was the strongest single discriminator from unselected castration-resistant disease (Aparicio 2016). The transition is epigenetic before it is genetic, since methylation separates the two states far more sharply than mutation does (Beltran 2016), and cell-free DNA methylation discriminated the two with an area under the curve of 0.96 and 1.0 in two small cohorts (Berchuck 2022).
This is the result that changes the treatment plan most. It usually means moving from hormone treatment to chemotherapy of the kind used for small cell lung cancer, because that is what the cancer now resembles. It is found on a biopsy, which is why a repeat biopsy is sometimes asked for when scans and the PSA blood test stop agreeing with each other.
Written only from the label or guideline text cited on this page. Not medical advice; your own report and the reading your team gives it come first.
Morphological diagnosis on a biopsy of the progressing lesion, using the named categories, supported by neuroendocrine marker immunohistochemistry and by loss of androgen receptor and PSA staining; RB1 and TP53 status from sequencing raises or lowers the prior before the biopsy is taken.
“The classification system consists of: Usual prostate adenocarcinoma with NE differentiation; 2) Adenocarcinoma with Paneth cell NE differentiation; 3) Carcinoid tumor; 4) Small cell carcinoma; 5) Large cell NE carcinoma; and 5) Mixed NE carcinoma - acinar adenocarcinoma.”
Epstein et al., American Journal of Surgical Pathology 2014No approval uses this readout as a threshold. It is defined by Epstein et al., Am J Surg Pathol 2014: proposed morphologic classification of prostate cancer with neuroendocrine differentiation.
It is the right shape of answer for a transition that is epigenetic rather than genetic, and it could in principle spare the biopsy that is currently the only way to make this diagnosis.
It turned neuroendocrine transformation from a pathological curiosity into a mechanism with a genotype and a candidate intervention, and it is the reason EZH2 inhibitors are in prostate cancer trials at all.
A mechanism for the most feared form of treatment resistance in prostate cancer, and the reason combined TP53 and RB1 loss is worth knowing about before a man starts an androgen receptor drug rather than after his biopsy comes back neuroendocrine. Reversibility in the laboratory is also an argument that the switch is a target and not just a prognosis.
Treatment-emergent neuroendocrine prostate cancer is understood as lineage plasticity under androgen receptor blockade; EZH2, DLL3 and Aurora kinase are the targets under investigation.
It validates a clinical definition against a molecular one, which is unusual and useful: a man whose disease behaves like small cell carcinoma can be treated as such even when his biopsy does not look like it, because the underlying genotype is the same.
It made the reporting of these tumours mean something. The distinction it draws is the one that changes treatment: a few chromogranin-positive cells in an ordinary adenocarcinoma is not the same event as a small cell carcinoma emerging under hormonal treatment, and only the second leads to platinum and etoposide.
It was the first evidence that neuroendocrine prostate cancer is a distinct molecular disease with its own candidate drug target, and it started the programme of Aurora kinase trials in this setting, which have since disappointed.
Shares AR-V7 splice variant, AR amplification (gene and upstream enhancer), Androgen receptor signalling, Castration-resistant prostate cancer (CRPC) and the tags biomarker, resistance.
Shares Biopsy, Drug resistance (primary and acquired), Comprehensive genomic profiling, Liquid biopsy (ctDNA) and the tags biomarker, resistance.
Shares Drug resistance (primary and acquired), Comprehensive genomic profiling, Liquid biopsy (ctDNA) and the tags biomarker, resistance.
Shares the tags biomarker, resistance.
Shares the tags biomarker, resistance.
Shares the tags biomarker, resistance.
Shares Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer, SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer, Histologic transformation, Neuroendocrine and small-cell prostate cancer.
Shares AR amplification (gene and upstream enhancer), Biopsy, Androgen receptor, Metastatic castration-resistant prostate cancer and the tag biomarker.