The Role of PET Tracers in Small-Cell Prostate Cancer (SCPC): An Overview in Clinical and Preclinical Settings

Small-cell prostate cancer (SCPC) is a rare, aggressive variant of prostate cancer with poor prognosis, arising "de novo" or through lineage plasticity from conventional adenocarcinoma under androgen receptor-targeted therapies. Characterized by low PSA levels despite high tumor burden and visceral metastases, SCPC poses diagnostic challenges with conventional and PSMA-targeted imaging due to variable tracer uptake. This narrative review aims to evaluate the role of PET/CT tracers in clinical and preclinical settings for SCPC diagnosis, staging, and management.

A systematic literature search was conducted on PubMed and Scopus up to December 2025 using terms "PET OR positron emission tomography AND prostate OR prostatic AND small-cell NOT non-small-cell". Eight studies (five clinical, three preclinical) on the role of PET/CT imaging in SCPC were included and analyzed for study design, population, tracers, and findings, with comparative evaluation of diagnostic performance across PET tracers.

Clinical studies showed that ¹¹C-choline detects progression at low PSA but misses SCPC; ¹⁸F-FDG exhibited a high SUVmax value for distinguishing SCPC from adenocarcinomas with neuroendocrine differentiation, predicting poor survival; ⁶⁸Ga-DOTATATE identified NEPC/SCPC with promising prognostic/therapeutic value for selected cases. Preclinical models evaluated ⁸⁹Zr-tracers targeting DLL3 or CDCP1 (an antigen expressed in aggressive neuroendocrine tumours) and ¹⁸F-BnTP (a target of mitochondrial activity) in SCPC subtypes, focusing on translational imaging.

From this review, although still based on limited literature evidence and mostly derived from retrospective and small SCPC sub-cohorts,¹⁸F-FDG PET/CT currently appears as the most reliable tracer for SCPC, aiding tumor detection and prognostication when PSMA/choline imaging fails. In the preclinical setting, DLL3/CDCP1-targeted agents emerge as promising theranostics tools. Multimodal imaging approach and prospective trials are needed for standardization and patient-based SCPC management.