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Overview of the classification and management of cancers of unknown primary site

John D Hainsworth, MD
F Anthony Greco, MD
Section Editor
George P Canellos, MD
Deputy Editor
Sadhna R Vora, MD


Cancer of unknown primary site (CUP) is a relatively common clinical entity, accounting for 4 to 5 percent of all invasive cancers [1]. Within this category, tumors from many primary sites with varying biology are represented. This heterogeneity has made the design and interpretation of clinical studies difficult.

Patients with CUPs typically present with symptoms referable to metastases. The initial work-up, including physical examination, laboratory studies, and imaging procedures, often fails to identify the primary site.

Patients are initially placed into one of four categories based upon the light microscopic examination of the initial biopsy. This classification is then used to guide further evaluation:


Squamous cell carcinoma (SCC)

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Literature review current through: Nov 2017. | This topic last updated: Jun 05, 2017.
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  1. Greco FA, Hainsworth JD. Cancer of unknown primary site. In: Cancer: Principles and Practice of Oncology, DeVita VT Jr, Hellman S, Rosenberg SA (Eds), JB Lippincott, Philadelphia 2011. p.2033.
  2. Pentheroudakis G, Golfinopoulos V, Pavlidis N. Switching benchmarks in cancer of unknown primary: from autopsy to microarray. Eur J Cancer 2007; 43:2026.
  3. Nystrom JS, Weiner JM, Heffelfinger-Juttner J, et al. Metastatic and histologic presentations in unknown primary cancer. Semin Oncol 1977; 4:53.
  4. Karsell PR, Sheedy PF 2nd, O'Connell MJ. Computed tomography in search of cancer of unknown origin. JAMA 1982; 248:340.
  5. McMillan JH, Levine E, Stephens RH. Computed tomography in the evaluation of metastatic adenocarcinoma from an unknown primary site. A retrospective study. Radiology 1982; 143:143.
  6. Rades D, Kühnel G, Wildfang I, et al. Localised disease in cancer of unknown primary (CUP): the value of positron emission tomography (PET) for individual therapeutic management. Ann Oncol 2001; 12:1605.
  7. Rusthoven KE, Koshy M, Paulino AC. The role of fluorodeoxyglucose positron emission tomography in cervical lymph node metastases from an unknown primary tumor. Cancer 2004; 101:2641.
  8. Møller AK, Loft A, Berthelsen AK, et al. A prospective comparison of 18F-FDG PET/CT and CT as diagnostic tools to identify the primary tumor site in patients with extracervical carcinoma of unknown primary site. Oncologist 2012; 17:1146.
  9. Hainsworth JD, Johnson DH, Greco FA. Poorly differentiated neuroendocrine carcinoma of unknown primary site. A newly recognized clinicopathologic entity. Ann Intern Med 1988; 109:364.
  10. Greco FA, Pavlidis N. Treatment for patients with unknown primary carcinoma and unfavorable prognostic factors. Semin Oncol 2009; 36:65.
  11. Altman E, Cadman E. An analysis of 1539 patients with cancer of unknown primary site. Cancer 1986; 57:120.
  12. Muir C. Cancer of unknown primary site. Cancer 1995; 75:353.
  13. Riihimäki M, Hemminki A, Sundquist K, Hemminki K. Time trends in survival from cancer of unknown primary: small steps forward. Eur J Cancer 2013; 49:2403.
  14. Hainsworth JD, Greco FA. Gene expression profiling in patients with carcinoma of unknown primary site: from translational research to standard of care. Virchows Arch 2014; 464:393.
  15. Hainsworth JD, Rubin MS, Spigel DR, et al. Molecular gene expression profiling to predict the tissue of origin and direct site-specific therapy in patients with carcinoma of unknown primary site: a prospective trial of the Sarah Cannon research institute. J Clin Oncol 2013; 31:217.
  16. Moran S, Martínez-Cardús A, Sayols S, et al. Epigenetic profiling to classify cancer of unknown primary: a multicentre, retrospective analysis. Lancet Oncol 2016; 17:1386.
  17. Yoon HH, Foster NR, Meyers JP, et al. Gene expression profiling identifies responsive patients with cancer of unknown primary treated with carboplatin, paclitaxel, and everolimus: NCCTG N0871 (alliance). Ann Oncol 2016; 27:339.