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Peer-reviewedCC BYThe oncologist

Non-conventional histologies of prostate cancer: from morphology to biology-driven precision oncology.

  • Fabiano Flauto1
  • Giuseppe Neola1,2
  • Alessia Cimadamore3
  • Michele Maffezzoli4
  • Akash Maniam2
  • Sarah Scagliarini5
  • Fabio Calabrò6
  • Luigi Formisano1
  • Pasquale Rescigno7
  • Giuseppe Luigi Banna2
7 affiliations
  1. 1Department of Clinical Medicine and Surgery, Federico II University, Naples, 80131, Italy.
  2. 2Portsmouth Hospitals University NHS Trust, Portsmouth, PO6 3LY, United Kingdom.
  3. 3Department of Medicine, Institute of Pathological Anatomy, University of Udine, Udine, 33100, Italy.
  4. 4Department of Medicine and Surgery, University Hospital of Parma-Medical Oncology Unit, University of Parma, Parma, 43126, Italy.
  5. 5UOC di Oncologia, Azienda Ospedaliera di Rilievo Nazionale Cardarelli di Napoli, Naples, 80131, Italy.
  6. 6Medical Oncology 1, IRCCS Regina Elena National Cancer Institute, Rome, 00128, Italy.
  7. 7Translational & Clinical Research Institute, Centre for Cancer, Newcastle University, Newcastle Upon Tyne, NE2 4HH, United Kingdom.
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Abstract

Non-conventional prostate cancer histologies represent a small but clinically significant subset characterized by aggressive behavior, atypical biomarker profiles, and reduced dependence on androgen receptor signaling. Evidence indicates these histologies reflect dynamic biological states driven by genomic instability, lineage plasticity, and therapeutic selection rather than static morphologic entities, with several morphologies acting as accessible, if imperfect, surrogates for actionable alterations. We performed a translational narrative review integrating anatomic pathology, genomic and epigenomic biology, and biomarker-selected therapy, searching PubMed/MEDLINE, Embase, Cochrane CENTRAL, the ASCO Meeting Library, ESMO publications, and APCCC through May 2026, spanning neuroendocrine, ductal, intraductal, cribriform, adenosquamous, sarcomatoid, adenoid cystic, signet ring cell, and mucinous subtypes. These histologies are individually uncommon but are consistently associated with advanced stage and inferior survival. Neuroendocrine prostate cancer is the most aggressive phenotype and a major mechanism of resistance to AR-directed therapy, driven by combined RB1 and TP53 loss, epigenetic reprogramming, and lineage plasticity, and marked by DLL3 expression. Cribriform and intraductal carcinoma are often enriched for BRCA2 and DNA-repair deficiency, whereas ductal differentiation is associated with mismatch-repair deficiency in a subset, with implications for PARP inhibition and checkpoint blockade. Emerging strategies include platinum-based chemoimmunotherapy and investigational lineage-directed agents targeting DLL3, STEAP1, KLK2, and TROP-2, alongside radioligands. These histologies are best viewed as biologically distinct, evolving disease states. By integrating pathology, molecular biology, and biomarker-selected therapy into one translational pathway, this review reframes non-conventional histology as a prompt for early molecular characterization and adaptive, biology-driven treatment.

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Cite

BibTeXRIS
BibTeX
@article{flauto2026nonconventional,
  title = {{Non-conventional histologies of prostate cancer: from morphology to biology-driven precision oncology.}},
  author = {Fabiano Flauto and Giuseppe Neola and Alessia Cimadamore and Michele Maffezzoli and Akash Maniam and Sarah Scagliarini and Fabio Calabrò and Luigi Formisano and Pasquale Rescigno and Giuseppe Luigi Banna},
  journal = {The oncologist},
  year = {2026},
  month = oct,
  doi = {10.1093/oncolo/oyag391},
  url = {https://europepmc.org/article/MED/42832307},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Non-conventional histologies of prostate cancer: from morphology to biology-driven precision oncology.
AU  - Fabiano Flauto
AU  - Giuseppe Neola
AU  - Alessia Cimadamore
AU  - Michele Maffezzoli
AU  - Akash Maniam
AU  - Sarah Scagliarini
AU  - Fabio Calabrò
AU  - Luigi Formisano
AU  - Pasquale Rescigno
AU  - Giuseppe Luigi Banna
PY  - 2026
DA  - 2026/10/01
JO  - The oncologist
DO  - 10.1093/oncolo/oyag391
UR  - https://europepmc.org/article/MED/42832307
AB  - Non-conventional prostate cancer histologies represent a small but clinically significant subset characterized by aggressive behavior, atypical biomarker profiles, and reduced dependence on androgen receptor signaling. Evidence indicates these histologies reflect dynamic biological states driven by genomic instability, lineage plasticity, and therapeutic selection rather than static morphologic entities, with several morphologies acting as accessible, if imperfect, surrogates for actionable alterations. We performed a translational narrative review integrating anatomic pathology, genomic and epigenomic biology, and biomarker-selected therapy, searching PubMed/MEDLINE, Embase, Cochrane CENTRAL, the ASCO Meeting Library, ESMO publications, and APCCC through May 2026, spanning neuroendocrine, ductal, intraductal, cribriform, adenosquamous, sarcomatoid, adenoid cystic, signet ring cell, and mucinous subtypes. These histologies are individually uncommon but are consistently associated with advanced stage and inferior survival. Neuroendocrine prostate cancer is the most aggressive phenotype and a major mechanism of resistance to AR-directed therapy, driven by combined RB1 and TP53 loss, epigenetic reprogramming, and lineage plasticity, and marked by DLL3 expression. Cribriform and intraductal carcinoma are often enriched for BRCA2 and DNA-repair deficiency, whereas ductal differentiation is associated with mismatch-repair deficiency in a subset, with implications for PARP inhibition and checkpoint blockade. Emerging strategies include platinum-based chemoimmunotherapy and investigational lineage-directed agents targeting DLL3, STEAP1, KLK2, and TROP-2, alongside radioligands. These histologies are best viewed as biologically distinct, evolving disease states. By integrating pathology, molecular biology, and biomarker-selected therapy into one translational pathway, this review reframes non-conventional histology as a prompt for early molecular characterization and adaptive, biology-driven treatment.
SN  - 1083-7159
SN  - 1549-490X
ER  -