Cancer imposes the largest worldwide burden of all diseases, accounting for an estimated 19.3 million new cancer cases and almost ten million deaths in 2020 (Sung et al., 2021). In most of the cases, the site of origin of the cancer is clear at presentation or identified soon after. However, in approximately 1–2 % of cancer cases, the site of origin cannot be detected with current diagnostic strategies, and the cancer remains of unknown primary origin (CUP) (Rassy and Pavlidis, 2019, Fizazi et al., 2015a, Kolling et al., 2019, Pavlidis and Pentheroudakis, 2012, Urban et al., 2013). The diagnosis of CUP is preferentially made when other primary cancers have been ruled out and is based on a combination of imaging techniques, as well as clinical and histopathological examination (Massard et al., 2011, van de Wouw et al., 2002). Since cancer treatment in general is based on the primary tumour, this represents a huge dilemma for both CUP patients and healthcare professionals (Kolling et al., 2019). The median survival of CUP patients ranges from three months up to five years. Most common metastatic sites include the liver, lymph nodes, lungs, and bones (Hess et al., 1999, Schroten-Loef et al., 2018, Ponce Lorenzo et al., 2007, Randen et al., 2013, Pavlidis and Fizazi, 2009, Moran et al., 2017).

Currently, there is no international consensus on the diagnostic workup for patients with CUP, which makes a reliable international comparison between CUP patient populations impossible. In addition, the lack of consensus has an impact on the quality of care provided to patients with CUP. Guidelines on CUP such as the Dutch Oncoline, as well as the English written guidelines on CUP from the European Society for Medical Oncology (ESMO), the National Comprehensive Cancer Network (NCCN), the National Institute of Health and Care Excellence (NICE), and the Spanish Society of Medical Oncology (SEOM) show overlap, but there are numerous differences in the recommended diagnostic workup (Fizazi et al., 2015a, Specialists, 2012, Ettinger, 2021, Excellence, 2010, Losa et al., 2018a). Although the NICE guideline categorizes CUP into malignancy of unknown origin (MUO), provisional CUP (pCUP), and confirmed CUP (cCUP), the diagnostic techniques used per category are not specified (Excellence, 2010).

To the best of our knowledge, no previous attempts have been made to work towards a international consensus on CUP diagnostics. In 2015, a comparison between different CUP guidelines was performed, that showed differences in imaging modalities and specific histopathological markers (Kok et al., 2015). The aim of the current study is to work towards a categorized international consensus based on the diagnostic techniques for CUP. Standardisation of diagnostic approaches will enable the international comparison of incidence, treatment, and survival rates of CUP patients. This in turn will facilitate research and ultimately improve treatment and survival of CUP patients worldwide.