Imaging of cancer of unknown primary: a systematic literature review of the past, present, and future

Objectives To evaluate the evolution and current diagnostic capabilities of medical imaging in cancer of unknown primary (CUP) and explore promising technologies for enhancing diagnostic precision.Methods A comprehensive literature search was conducted across MEDLINE, Embase, and Scopus in March 2023 (updated in August 2024) to identify original articles focusing on CUP imaging. Two reviewers independently selected articles and extracted data. Quality assessment was performed using QUADAS-2 and Radiomics Quality Score. Given the variability in study designs, imaging techniques, and reported outcomes, a narrative synthesis was performed. Subgroup analyses compared detection rates across modalities.Results From 4760 de-duplicated search results, 140 original articles were included. Early CUP imaging relied on 2D modalities with notable diagnostic limitations. Modern 3D modalities have risen in prominence, though mammography and ultrasound remain in CUP guidelines. Implementing CT and MRI significantly improved primary tumour detection and disease characterization. CT is fundamental for CUP evaluation, and MRI offers superior soft tissue resolution, effective for detecting occult breast cancer, head and neck primaries, and suspected abdominopelvic neoplasms. FDG-PET/CT showed varying primary detection capabilities, adding value in identifying lesions/metastases missed by other modalities, essential for confirming locoregional treatment strategies. Emerging technologies for CUP imaging include whole-body MRI, FAPI-PET/CT, and AI/radiomics.Conclusions Advancements in imaging have improved the diagnostic workup for CUP. Innovative approaches show potential for further improvement in diagnostic accuracy.Advances in knowledge This study provides a comprehensive overview of CUP imaging and introduces emerging modalities that could boost diagnostic accuracy.Prospero registration CRD42023453393.