In metastatic cancer with an unknown primary site, finding the primary site is imperative to permit planning of treatment as soon as possible. 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.
Communication with the pathologist is essential for identification of the primary pathology. 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. Clinical reassessment of the patient, including close questioning about signs and symptoms, may bring to light previously unreported issues that may help guide diagnosis.
In spite of the increasing sophistication in the diagnostic workup for malignancies, detailed investigations fail to reveal a primary site of origin for a subset of patients with metastatic cancer. This is often referred to as carcinoma of unknown primary origin (CUP) or occult primary malignancy. 
The American Cancer Society estimates that 34,170 persons (17,810 males; 16,360 females) will be diagnosed with cancers of unspecified primary sites in the United States in 2016.  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 42,700 in 2016 (23,900 males; 18,800 females).  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.
The exact incidence of cancer of unknown primary origin in the United States is not precisely known. It is almost certainly underreported, and its true incidence is most probably between 2% and 6%. In 15-25% of cases, the primary site cannot be identified even on postmortem examination. The inability to identify a primary site of cancer poses many challenges, since the primary site of cancer usually dictates the treatment, expected outcome, and overall prognosis. The diagnosis of carcinoma of unknown primary 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.
Cancer of unknown primary origin represents 2-6% of all cancers diagnosed in the United States, and for for 2-9% of cancers diagnosed worldwide.
Median survival ranges from 11 weeks to 11 months.  The 5-year overall survival rate is about 11%.
Sex- and Age-related Demographics
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 on presentation for both men and women ranges from 59-66 years.
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