Metastatic Cancer With Unknown Primary Site

Updated: Jul 28, 2023
  • 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. This search is best conducted by a multidisciplinary team, consisting at a minimum of clinicians, radiologist, internist, radiation oncologist, and pathologist for resolving the most challenging cases.

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 minority 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.

CUP is characterized by an aggressive course and resistance to conventional chemotherapy. [3]  Nevertheless, a precise pathologic diagnosis with next-generation sequencing may identify targetable mutations and help guide therapy. For example, in patients whose tumors are found to have high microsatellite instability/deficient mismatch repair (MSI-H/dMMR), treatment with an immune checkpoint inhibitor (programmed cell death inhibitor) may significantly improve survival.



Two main hypotheses have been proposed to explain metastatic cancer with an unknown primary (CUP). [4] One is that a single cell escapes the controls of normal cell replication, forms a tumor at the site of origin, and the tumor cells ultimately metastasize to other organs, but the original tumor is too small to be detected at the time of metastasis. A primary tumor can be found at autopsy in as many as 50–80% of CUP cases. [5]

The second hypothesis, termed true CUP or genuine CUP, is that the primary lesion undergoes early regression while the metastases evolve independently, under the selection pressure of the immune system and their microenvironment. This process results in heterogeneous and genetically diverse tumors that are aggressive and resistant to therapy. Thus, regardless of their cell of origin, CUPs share similarities and can be considered a specific entity. [4, 5]



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 32,590 persons (16,810 males; 15,780 females) will be diagnosed with cancers of unspecified primary sites in the United States in 2023. [6]  This would suggest that cancer of unknown primary origin constitutes less than 2% of all cancers diagnosed in the United States. However, deaths due to cancer of unknown primary site are estimated to be 48,160 in 2023 (26,130 males; 22,030 females). [6]  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. [7] 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

Approximately 15-20% of patients with CUP have a favorable prognosis. In these cases, treatment corresponds to that of the equivalent known primary tumor (see Guidelines). Favorable-risk CUPs are as follows [4] :

  • Single metastatic deposit or oligometastatic disease amenable to local ablative treatment
  • In women, isolated axillary nodal metastases
  • In women, peritoneal adenocarcinomatosis of a serous papillary histologic type
  • In men, blastic bone metastases or IHC/serum prostate-specific antigen (PSA) expression
  • Squamous cell carcinoma involving non-supraclavicular cervical lymph nodes (head-and-neck)
  • Adenocarcinoma with a colorectal immunohistochemical (CK7-negative, CK20-positive, CDX2-positive) or molecular profile
  • Carcinoma with a renal-cell histologic and immunohistochemical profile

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