CUP syndrome

In this section you can find useful information to learn more about the basics of CUP (cancer of unknown primary) including epidemiology, pathogenesis, diagnostic work-up and therapeutic options.



CUP (cancer of unknown primary) syndrome is defined as a histologically and clinically verified cancer for which only metastases can be found at the time of diagnosis, but no primary tumour is detectable.


1. Krämer A et al., Annals of Oncology 2022/ 

2. Stella GM et al. J Transl Med 2012; 10: 12.


CUP syndrome accounts for approximately 3–5% of all cancer cases.


1. Krämer A et al., Annals of Oncology 2022/  

2. Stella GM et al. J Transl Med 2012; 10: 12.



How might CUP develop?


There are various hypotheses on aetiology and pathogenesis. One tentative explanation for CUP is the “stem cell theory” of cancer.1-3 Asynchronous division of the premalignantly or malignantly transformed stem cells may produce daughter cells that do not grow locally but are able to metastasise. Given the favourable microenvironment of these metastases, these may spread to another site, even though no tumour develops in the tissue of origin.4 This hypothesis is supported by tumour genomics, with clonal evolution documented in various cancers (e.g., lung cancer).5


1. Aktipis CA et al. Nat Rev Cancer 2013; 13: 883–92.

2. Visvader JE. Nature 2011; 469: 314–22.

3. Lee G et al. J Stem Cell Res Ther 2016; 6: 363.

4. López-Lázaro M. Oncoscience 2015; 2: 467–75.


What are the potential risk factors for CUP?


Potential risk factors that support the development of CUP syndrome include:

  • Diabetes mellitus
  • Smoking
  • Obesity
  • A positive family history of cancer


1. Mnatsakanyan E et al. Cancer causes & control 2014; 25: 747–57.

2. Robert Koch Institut (2016) GEKID Publication. Available at: (last accessed March 2019).

3. Hemminki K et al. Int J Cancer 2015; 136: 246–47.


1. Unknown Primary: Symptoms and Signs. Available at: (last accessed March 2019).
2. Mayo Clinic Carcinoma of unknown primary. Available at: (last accessed March 2019).
3. The University of Texas MD Anderson Cancer Center. Cancer of Unknown Primary. Available at: (last accessed March 2019).
4. Stella GM et al. J Transl Med 2012; 10: 12.
5. Pavlidis N and Pentheroudakis G. Lancet 2012; 379: 1428–35.
6. Ettinger DS et al. NCCN Guidelines version 2.2019.


  1. Krämer A et al., Annals of Oncology 2022/
  2. Frampton GM et al. Nat biotechnol 2013; 31: 1023–31.
  3. He J et al. Blood 2016; 127: 3004–14.
  4. Gagan J and van Allen EM. Genome Med 2015; 7: 80.
  5. Rozenblum AB et al. J Thorac Oncol 2017; 12: 258–68.
  6. Suh JH et al. Oncologist 2016; 21: 684–91.
  7. NCCN Clinical Practice Guidelines in Oncology.
    Non-Small Lung Cancer. V.2.2019. Available at:
    (last accessed March 2019).
  8. Chung J et al. Case Report Oncol 2014; 7: 628–82.


1. Krämer A et al., Annals of Oncology 2022/
2. Greco FA and Hainsworth JD (2011) Cancer of unknown primary site, DeVita VT Jr., Hellman S, Rosenberg SA (eds) Cancer: Principles and Practice of Oncology (9th ed) Philadelphia, PA, JB Lippincott: 2033–51.


1. Fizazi K et al. Ann Oncol 2015; (26 suppl 5): v133–8.
2. Hainsworth JD and Greco FA. ASCO educational book 2018.
3. Moran S et al. Lancet Oncol 2016; 17: 1386–95.
4. Greco FA et al. Ann Oncol 2012; 23: 298–304.
5. Ross JS et al. JAMA Oncol 2015; 1: 40–9.
6. Subbiah IM et al. Oncoscience 2017; 4: 47–56.
7. Varghese AM et al. Ann Oncol 2017; 28: 3015–21.
8. Kato S et al. Cancer Res 2017; 77: 4238–46.
9. Krämer A et al. J Clin Oncol 2018; 36: 15_suppl e24162.

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