Background: Although the incidence of Cancer of Unknown Primary (CUP) is estimated to be 1–2 % of all cancers worldwide, no international standards for diagnostic workup are yet established. Such an international guideline would facilitate international comparison, provide adequate incidence and survival rates, and ultimately improve care of patients with CUP. Methods: Participants for a four round modified Delphi study were selected via a CUP literature search in PubMed and an international network of cancer researchers. A total of 90 CUP experts were invited, and 34 experts from 15 countries over four continents completed all Delphi survey rounds. Findings: The Delphi procedure resulted in a multi-layer CUP classification for the diagnostic workup. Initial diagnostic workup should at least consist of history and physical examination, full blood count, analysis of serum markers, a biopsy of the most accessible lesion, a CT scan of chest/abdomen/pelvis, and immunohistochemical testing. Additionally, the expert panel agreed on the need of an ideal diagnostic lead time for CUP patients. There was no full consensus on the place in diagnostic workup of symptom-guided MRI or ultrasound, a PET/CT scan, targeted gene panels, immunohistochemical markers, and whole genome sequencing. Interpretation: Consensus was reached on the contents of the first diagnostic layer of a multi-layer CUP classification. This is a first step towards full consensus on CUP diagnostics, that should also include supplementary and advanced diagnostics.
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