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Medically reviewed by Dr. C.H. Weaver M.D. Medical Editor 6/2021

Carcinoma of unknown primary (CUP) is a rare disease in which cancer cells are found in the body but the place the cancer began is not known. Cancer can form in any tissue of the body. The primary cancer (the cancer that first formed) can spread to other parts of the body. This process is called metastasis. Cancers historically have been named based on their primary site of origin, regardless of where in the body they have spread. For example, a breast cancer that spreads to the liver is still classified as breast cancer and not as liver cancer.

Sometimes it’s not clear where a cancer may have started. When cancer is found in one or more metastatic sites but the primary site cannot be determined, it is called a CUP. In many cases, the source of the cancer is never determined. Even the most thorough search may not find the primary site.

The main reason to look for the primary site of a CUP is to guide treatment. Since a cancer that starts in one place needs the same treatments when it spreads, knowing where a cancer started tells the doctor what types of treatments to use. This is especially important for certain cancers that respond well to specific chemotherapy or hormone drugs. When the types of cancer with the best hope for responding to treatment have been ruled out by certain tests, it usually becomes less important to find the exact origin or cancer type.

But even if the primary site is not known, treatment can still be successful. How the cancer looks under the microscope, the results of lab and genomic tests, and information about which organs it has already affected can help doctors predict what kinds of treatment might be helpful.1,2

Results of a recent clinical study suggest that a liquid biopsy to perform genomic analyses is feasible and that most patients with a CUP will have a unique genetic profile that can be treated with currently available precision cancer medicines.3

Signs and Symptoms of Carcinoma of Unknown Primary

The signs and symptoms of CUP are different, depending on where the cancer has spread in the body. Signs and symptoms may be caused by CUP or by other conditions. Check with your doctor if you have any of the following:

  • Lump or thickening in any part of the body.
  • Fever for no known reason that does not go away.
  • Night sweats.
  • Unexplained weight loss.
  • Pain that is in one part of the body and does not go away.
  • A cough that does not go away or hoarseness in the voice.
  • Change in bowel or bladder habits, such as constipation, diarrhea, or increased frequency of urination.
  • Unusual bleeding or discharge.

Diagnosis & Tests of Carcinoma of Unknown Primary

Diagnostic tests are done to find where the primary cancer began and to get information about where the cancer has spread. When tests are able to find the source of the primary cancer, the cancer is no longer considered a CUP and treatment is based on the type of primary cancer.

Liquid Biopsies Find Distinct Genomic Profiles in Many Patients with Carcinoma of Unknown Primary

New research suggests that a simple blood test to evaluate circulating tumor DNA (ctDNA) can correctly identify distinct genomic profiles with potentially treatable targetable alterations in patients with CUP.[1] Using liquid biopsies collected from 442 patients with CUP researchers found that a total of 66 percent of patients had at least one characterized genetic mutation and 44 percent had two or more. Among CUP patients found to have at least one characterized alteration, 99.7 percent of patients had a treatable genetic mutation with a currently available precision cancer medicine.1

Other Diagnostic Tests

  • A thorough physical exam of the body to check general signs of health, including checking for signs of disease, such as lumps or anything else that seems unusual. A history of the patient’s health habits and past illnesses and treatments will also be taken.
  • Urinalysis is a test to check the color of urine and its contents.
  • Blood chemistry is checked to measure the amounts of certain substances released into the blood by organs and tissues in the body. An unusual (higher or lower than normal) amount of a substance can be a sign of disease.
  • A complete blood count evaluates a sample of blood to check for abnormalities in the appearance and the number of red blood cells, white blood cells and platelets.
  • Tumor Markers in a sample of blood, urine, or tissue can be checked to measure the amounts of certain substances made by organs, tissues, or cancer cells in the body that are know to be linked to specific types of cancer when found in increased levels in the body. The blood may be checked for the levels of CA-125 CEA alpha-fetoprotein (AFP) beta human chorionic gonadotropin (β-hCG) prostate-specific antigen (PSA).
  • A test to check stool (solid waste) for blood is performed because blood in the stool may be a sign of colorectal cancer.

The most important test in evaluating for a CUP is a biopsy. During a biopsy some or all of the tissue is removed and sent to a pathologist for evaluation under a microscope.

The cells in the body have a certain look that depends on the type of tissue they come from. For example, a sample of cancer tissue taken from the liver is expected to be made up of liver cells. However, if the sample of tissue is a different type of cell (not made up of colon cells), it is likely that the cells have spread to the colon from another part of the body.

Liquid Biopsy

A liquid biopsy is performed by testing a sample of blood for the presence of circulating cancer cells, known as circulating tumor and for cell-free tumor DNA (cfDNA), which are fragments of DNA shed by cancer cells into a patient’s bloodstream.

Because cancer cells are constantly “shedding” parts of their DNA, specific genetic mutations (alterations) within these pieces of DNA can provide invaluable information to healthcare providers and ultimately help guide optimal treatment options for each patient.

Importantly, the bits of cf DNA obtained from a liquid biopsy can provide information to healthcare providers to identify which mutations are present specific to the DNA mutations of the cancer cells that can be treated with targeted precision cancer medicines.

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The following tests and procedures may be done to find where the cancer first began:

Computed Tomography (CT) Scan: A CT scan is a technique for imaging body tissues and organs, during which X-ray transmissions are converted to detailed images, using a computer to synthesize X-ray data. A CT scan is conducted with a large machine positioned outside the body that can rotate to capture detailed images of the organs and tissues inside the body. This method is more sensitive and precise than an X-ray.

Magnetic Resonance Imaging (MRI): MRI uses a magnetic field rather than X-rays, and can often distinguish more accurately between healthy and diseased tissue. MRI gives better pictures of tumors located near bone than CT, does not use radiation as CT does, and provides pictures from various angles that enable doctors to construct a three-dimensional image of the tumor.

Positron emission tomography (PET): Positron emission tomography (PET) scanning has been used to improve the detection of cancer in lymph nodes. One characteristic of living tissue is the metabolism of sugar. Prior to a PET scan, a substance containing a type of sugar attached to a radioactive isotope (a molecule that spontaneously emits radiation) is injected into the patient’s vein. The cancer cells “take up” the sugar and attached isotope, which emits positively charged, low energy radiation (positrons). The positrons react with electrons in the cancer cells, which creates the production of gamma rays. The gamma rays are then detected by the PET machine, which transforms the information into a picture. If no gamma rays are detected in the scanned area, it is unlikely that the mass in question contains living cancer cells.

Bone Scan: A bone scan is used to determine whether cancer has spread to the bones. Prior to a bone scan, a surgeon injects a small amount of radioactive substance into a vein. This substance travels through the bloodstream and collects in areas of abnormal bone growth. An instrument called a scanner measures the radioactivity levels in these areas and records them on x-ray film.

Mammogram: An x-ray of the breast.

Colonoscopy: lets your doctor examine the lining of your large intestine (colon) for abnormalities by inserting a thin flexible tube, as thick as your finger, into your anus and slowly advancing it into the rectum and colon. This instrument, called a colonoscope, has its own lens and light source and it allows your doctor to view images on a video monitor.

Endoscopy: lets your doctor examine the lining of the upper portion of the gastrointestinal tract which includes the esophagus, stomach and duodenum.

Treatment of Cancer of Unknown Primary

If following the evaluation to find the primary site of origin it remains unknown or undiscovered, then a cancer of unknown primary’s treatment can be based on the histology of the cancer (e.g., adenocarcinoma, squamous cell or mesenchymal) or biomarkers identified with the liquid biopsy.1

Surgery, radiation, chemotherapy and precision cancer medicines all are used to treat a CUP depending on the location of the cancer. Even when the cancer is unlikely to be cured, treatment may help the patient live longer or improve the patient’s quality of life. The chemotherapy combination of carboplatin and paclitaxel is often used and the response to treatment is modest with an overall survival of only six to eight months.2

Liquid Biopsies Find Distinct Genomic Profiles in Many Patients with Carcinoma of Unknown Primary

New research suggests that a simple blood test to evaluate circulating tumor DNA (ctDNA) can correctly identify distinct genomic profiles with potentially treatable targetable alterations in patients with CUP.3

Liquid Biopsy and Precision Cancer Medicines

A liquid biopsy with ctDNA evaluation can identify a unique genetic profile that can be treated with currently available precision cancer medicines in a majority of patients with CUP.

Precision cancer medicines are designed to target unique genomic alterations in the cancers DNA that are driving that specific with targeted drugs and immunotherapies engineered to directly attack the cancer cells specific abnormalities, leaving normal cells largely unharmed.

In recent years precision cancer medicine has led to improved treatments for melanoma, lung, colon, breast, and other cancer types. Recently the first “tissue agnostic” approval of a precision cancer medicine was given to Keytruda (pembrolizumab) meaning the actual characteristics of the cancer that determine whether Keytruda is indicated, not the physical location of the cancer were sufficient to direct treatment.2


  1. Stella, GM; Senetta, R; Cassenti, A; Ronco, M; Cassoni, P (24 January 2012). “Cancers of unknown primary origin: current perspectives and future therapeutic strategies”. Journal of translational medicine. 10: 12.
  2. National Institute for Health and Clinical Excellence. Clinical guideline 104: Metastatic malignant disease of unknown primary origin. London, 2010.