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For years, emphasis has been placed on finding the tissue-of-origin, but the lack of conclusive evidence and evolving cancer classification paradigms have renewed debate about its clinical relevance across CUP and 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\nCancer of unknown primary: the hunt for its elusive tissue-oforigin – is it time to call off the search?  \n 1,2, Claire Mitchell1, Natalie Cook 1,2 1,2,3 ✉  \nLaura Spurgeon  and Alicia-Marie Conway  \n© The Author(s) 2025  \n|  |  |  |\n| --- | --- | --- |\n|  | Cancer of Unknown Primary (CUP) is an heterogenous group of metastatic cancers, for which the primary site cannot be identified despite thorough diagnostic work-up. Whilst it is a relatively rare entity, its aggressive nature, together with the paucity of effective treatments, mean it has a disproportionately high mortality rate. Advances in genomic profiling have driven research in the area, but despite this, therapeutic options and prognosis remain poor. For many years, the primary focus in CUP has been improving identification of the tissue-of-origin (TOO), with the hope that site-specific therapy will improve survival outcomes. However, the lack of conclusive evidence to support this, as well as an emerging paradigm shift in how cancers should be classified, has reignited the debate surrounding the importance of TOO. Here, we provide a comprehensive review of the ongoing relevance of TOO, within |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n| both the CUP and wider oncology landscape. |  |  |\n|  | British Journal of Cancer (2025) 133:733–742; [https://doi.org/10.1038/s41416-025-03073-7](https://doi.org/10.1038/s41416-025-03073-7) |  |\n|  |  |  |\n\nBACKGROUND  \nOver 8500 cases of Cancer of Unknown Primary (CUP) are diagnosed each year in the UK, whilst it accounts for 2–5% of all new cancer diagnoses worldwide [1, 2]. Although its incidence is declining, likely due to advances in diagnostic techniques identifying primary sites, it remains the sixth leading cause of cancer-related death in the UK [3], and at least fourth globally [4] . Patients presenting with disseminated disease undergo extensive investigations to determine the tissue-of-origin (TOO) if a primary site is not readily identifiable. This initial presentation, termed malignancy of unknown origin (MUO), represents 10–15% of all new cancer diagnoses in the UK [5] . For most patients with MUO, a primary site is identified or strongly suspected after appropriate investigations; for the remaining third, a diagnosis of confirmed CUP is made [6] . Determining TOO requires adequate pathological examination of the tumour tissue; guidelines recommend a stepwise approach, including morphological assessment and appropriate immunohistochemistry (IHC) for undifferentiated neoplasms and cells with unclear lineage [7, 8] . Once carcinoma has been confirmed and other treatable malignancies excluded (such as lymphoma and sarcoma), further IHC can be applied to delineate TOO [8]. Whilst IHC using tissue obtained from both primary and metastatic sites can be highly accurate at determining TOO, when obtained from metastatic lesions alone, the accuracy falls significantly [9] . Given biopsies in CUP are nearly always from metastatic sites and are typically poorly-differentiated, identifying TOO using standard-of-care (SoC) IHC remains challenging.  \nESMO guidelines recommend clinical work-up to help determine TOO, incorporating mandatory assessments and optional investigations, which may be indicated depending on the pattern of disease, sex, and suspected primary (Table 1) [10] . If a primary site is not identified during diagnostic work-up, patients are treated as confirmed CUP, subsequently classified into favourable and poor-risk (previously unfavourable) subtypes to guide management and prognostication. Those with favourable disease have an Eastern Cooperative Oncology Group performance status 0–1, lactate dehydrogenase within normal limits, and either low volume, predominantly nodal disease, or radiological and/or histological features aligning with a primary site. These patients account","cbCaio13i3uQDlad","https://ap.wps.com/l/cbCaio13i3uQDlad","pdf",1244882,"English","# Background\n## Diagnostic work-up and tissue-of-origin identification\n## Risk stratification and treatment implications\n# Prognosis and standard-of-care treatment","[{\"question\":\"What is Cancer of Unknown Primary (CUP)?\",\"answer\":\"CUP refers to metastatic cancers where the primary site cannot be identified even after a thorough diagnostic work-up.\"},{\"question\":\"Why is determining the tissue-of-origin (TOO) important in CUP?\",\"answer\":\"TOO identification has been pursued with the hope that site-specific therapy could improve survival, but evidence remains inconclusive and debate continues.\"},{\"question\":\"How are CUP patients typically managed when the primary site is not identified?\",\"answer\":\"Patients are treated as confirmed CUP and classified into favourable or poor-risk subtypes to guide management and prognostication, with poor-risk cases showing limited response to standard treatments.\"}]","Molecular Diagnostics - Cancer of unknown primary - the hunt for its elusive tissue-of-origin – is it time to call off the search? | PDF",1790192972,25]