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. 2025 Aug 1;98(1172):1209-1226.
doi: 10.1093/bjr/tqaf039.

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

Sajjad Rostami  1   2 , Hannah W Stutterheim  1 , Olga Maxouri  1   2 , Jeroen R J Willemse  1   2 , Diana Ivonne Rodríguez Sánchez  1   2 , Winnie Schats  3 , Larissa W van Golen  4 , Marieke A Vollebergh  5 , Zing Cheung  4 , Wouter V Vogel  4   6 , Serena Marchetti  7 , Petur Snaebjornsson  8   9 , Max J Lahaye  1   2 , Doenja M J Lambregts  1   2 , Zuhir Bodalal  1   2 , Regina G H Beets-Tan  2   10   11
Affiliations

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

Sajjad Rostami et al. Br J Radiol. .

Abstract

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.

Keywords: CT; FAPI; FDG; MRI; PET; artificial intelligence; cancer of unknown primary; medical imaging; radiomics.

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Conflict of interest statement

The authors have no relevant conflicts of interest to declare.

Figures

Figure 1.
Figure 1.
PRISMA flowchart for the study inclusion process. This flowchart depicts the process of identifying, screening, and selecting studies for inclusion in this systematic review.
Figure 2.
Figure 2.
Graphical overview of the study characteristics. (A) Proportional representation of the included studies across 2D imaging, 3D imaging and emerging technologies. (B) Quantitative distribution of studies per modality (PET, MRI, CT, and others). (C) Histogram illustrating the distribution of study sample sizes of the included studies. (D) Percentage of prospective versus retrospective studies within the total 140 publications.
Figure 3.
Figure 3.
Risk of bias and applicability concerns. A summary of the risk of bias, applicability concerns, and quality assessment of the 137 included studies evaluated via the QUADAS-2 tool.
Figure 4.
Figure 4.
Timeline of the evolution of medical imaging in regard to cancer of unknown primary. This timeline showcases the key milestones in imaging technologies and their implications for cancer of unknown primary.
See this image and copyright information in PMC

References

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