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Clinical Review State of the Art Review

Cancer of unknown primary

BMJ 2020; 371 doi: (Published 07 December 2020) Cite this as: BMJ 2020;371:m4050
  1. Michael S Lee, assistant professor1,
  2. Hanna K Sanoff, associate professor2
  1. 1Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
  2. 2Division of Hematology/Oncology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
  1. Correspondence to: M S Lee mslee2{at}


Cancers of unknown primary (CUPs) are histologically confirmed, metastatic malignancies with a primary tumor site that is unidentifiable on the basis of standard evaluation and imaging studies. CUP comprises 2-5% of all diagnosed cancers worldwide and is characterized by early and aggressive metastasis. Current standard evaluation of CUP requires histopathologic evaluation and identification of favorable risk subtypes that can be more definitively treated or have superior outcomes. Current standard treatment of the unfavorable risk subtype requires assessment of prognosis and consideration of empiric chemotherapy. The use of molecular tissue of origin tests to identify the likely primary tumor site has been extensively studied, and here we review the rationale and the evidence for and against the use of such tests in the assessment of CUPs. The expanding use of next generation sequencing in advanced cancers offers the potential to identify a subgroup of patients who have actionable genomic aberrations and may allow for further personalization of therapy.


  • Series explanation: State of the Art Reviews are commissioned on the basis of their relevance to academics and specialists in the US and internationally. For this reason they are written predominantly by US authors

  • Contributors: Both authors contributed to the planning, conduct, and reporting of the work in the article, and both are responsible for the overall content as guarantors.

  • Competing interests: We have read and understood the BMJ policy on declaration of interests and declare the following interests: MSL has received consulting fees from AstraZeneca, Bayer, and Genentech/Roche and research grants from Genentech/Roche, Pfizer, Amgen, Bristol-Myers Squibb, EMD Serono, and Exelixis; HKS has received research grants from Bayer, Merck, and Precision Biologics.

  • Patient involvement: No patients were asked for input in the creation of this article.

  • Provenance and peer review: Commissioned; externally peer reviewed.

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