Metastatic Cancer With Unknown Primary Site

Updated: May 07, 2019
  • Author: Winston W Tan, MD, FACP; Chief Editor: Wafik S El-Deiry, MD, PhD  more...
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Practice Essentials

In metastatic cancer, the primary site of the cancer usually dictates the treatment, expected outcome, and overall prognosis. Consequently, in patients who present with metastatic cancer without a known primary site, the search for the primary site has high priority. Examination of an additional tissue sample very often proves helpful in this diagnostic process, and is often done if the initial biopsy result is equivocal.

Special stains and genomic and proteomic testing can be done with a clear plan of action. If those do not yield a diagnosis, the pattern of organ system involvement and the cytologic diagnosis may help in identifying the primary site. Clinical reassessment of the patient, including close questioning about signs and symptoms, may bring to light previously unreported issues that may help guide diagnosis. If a closed biopsy using ultrasound or CT guidance is equivocal, an open biopsy may sometimes be necessary. Liquid biopsy has overcome the many limitations of tumor biopsy, but its exact place in the spectrum of testing in cancer of unknown primary is still being studied. [1]

Despite the increasing sophistication in the diagnostic workup for malignancies, detailed investigations fail to reveal a primary site of origin in a small percentage m of patients with metastatic cancer. This is often referred to as carcinoma of unknown primary origin (CUP) or occult primary malignancy. [2]  In 15-25% of cases of CUP, the primary site cannot be identified even on postmortem examination. The diagnosis of CUP thus generates anxiety among patients and caregivers, who may feel that the evaluation has been incomplete.



Cancers are thought to arise from a single cell that escapes the controls of normal cell replication, forms a tumor at the site of origin, and ultimately metastasizes to other organs. In some cases, the original tumor may remain small or undetectable at the time of metastasis, leading to the clinical presentation of cancer of unknown primary origin. Whether a specific genetic or mutational factor plays a role in cancer of unknown primary origin remains uncertain.



The exact incidence of cancer of unknown primary origin is not precisely known. It is almost certainly underreported, and its true incidence is most probably from 2% to 6% of all cancers diagnosed in the United States, and 2-9% of cancers diagnosed worldwide.

The American Cancer Society estimates that 31,480 persons (16,750 males; 14,730 females) will be diagnosed with cancers of unspecified primary sites in the United States in 2019. [3]  This would suggest that cancer of unknown primary origin constitutes about 2% of all cancers diagnosed in the United States. However, deaths due to cancer of unknown primary site are estimated to be 45,140 in 2019 (24,240 males; 20,900 females). [3]  This discrepancy between incidence and mortality is believed to be due to a lack of specificity in the listing of cause of death on death certificates.

Most series reporting on or reviewing cancer of unknown primary origin patient groups give an approximate equal incidence for men and women. The median age at presentation for both men and women ranges from 59-66 years.



Median survival in patients with cancer of unknown primary origin ranges from 11 weeks to 11 months. [4] The 5-year overall survival rate is about 11%. In those with multiple organ involvement and poor performance status, the median survival is only 3-4 months; the 1-year survival rate is less than 15%, with a 5-year survival of 5-10%. Factors associated with a poor prognosis include the following:

  • Male sex
  • Multiple brain metastases
  • Pleural/lung involvement
  • Liver involvement
  • Adrenal involvement
  • Adenocarcinoma histology

In contrast, lymph node involvement and neuroendocrine histology are associated with a longer survival.


Patient Education

Communication between the clinician and the patient is paramount to optimal patient care. Patients and caregivers should be informed at each step of assessment and treatment. Patients should understand the goal of treatment, whether it is curative or palliative in nature. This should be defined upfront, although it can change as the patient responds or fails to respond to treatment