Cancer of Unknown Primary: Diagnosis

How is cancer of unknown primary diagnosed?

If your healthcare provider thinks you might have cancer of unknown primary (CUP), you will need certain exams and tests to be sure. These tests will be used to try to find the primary site—the place the cancer started. Diagnosing CUP starts with your healthcare provider asking you questions. He or she will ask you about your health history, your symptoms, risk factors, and family history of disease. Your healthcare provider will also give you a physical exam.

What tests might I need?

Tests help your healthcare providers learn more about the cancer. Tests may be able to tell if and where the cancer has spread throughout your body. They can also help your healthcare providers find out where the cancer first started. The tests you have depend on where the CUP is found. The test results help your healthcare providers decide the best ways to treat the cancer.

You may have one or more of these tests to look for the primary site and spread of CUP:

  • Urine and blood tests

  • Imaging tests

  • Biopsy

Urine and blood tests

Some types of cancer make and release certain substances in your blood and urine. These substances are called tumor markers. If any of these markers is present, your healthcare provider may be able to tell what kind of cancer you have. For instance, a man may have high prostate-specific antigen (PSA) levels in his blood. This may mean the cancer started in his prostate gland.

A complete blood count (CBC) and blood chemistry test can show signs that may linked with certain types of cancer. These tests may also be used to check if cancer has spread to your bones and bone marrow cells.

Imaging tests

Chest X-rays

Your healthcare provider may do chest x-rays to look for changes in your lungs. This may show cancer in your lungs or chest. An X-ray uses a small amount of radiation to make an image of organs and bones inside your body. The test can show enlarged lymph nodes in your chest. An x-ray takes a few minutes, and doesn’t cause pain.

CT scans

CT scans use a series of X-rays and a computer to make detailed images of the inside of your body. During the test, you lie still on a table as it slides into a CT scanner. A CT scan is painless. You may be asked to hold your breath one or more times during the scan.

You may be asked to drink a contrast dye 4 to 6 hours before the scan. Then you may be asked not to eat anything until a second set of pictures is taken. The dye shows your healthcare provider certain parts of your body more clearly. The dye will pass through your body and exit through your bowel movements. You may receive dye into a vein as well. When the dye is injected, you may have a warm feeling from your chest to your groin.

Tell your healthcare provider if you’ve ever had a reaction to contrast dye. This includes hives, trouble breathing, or becoming suddenly hot. You can receive special medicines before the test to help prevent a reaction.

PET (positron emission tomography) scans

PET scans can look for cancer cells throughout your entire body. For this test, you either swallow or are injected with a mildly radioactive substance. This is usually a form of sugar (glucose). The PET scan will show where in your body the glucose is being used the most. This helps find active cells that are dividing quickly, such as cancer cells.

You’ll lie still on a table that is pushed into the PET scanner. It will rotate around you and take pictures. Other than the injection, a PET scan is painless. Some people are sensitive to the substance. This may cause nausea, a headache, or vomiting. Some newer machines can do PET and CT scans at the same time. So, the areas that show up on the PET scan can be compared with the more detailed image of the CT scan.


A MRI uses radio waves, large magnets, and a computer to create detailed images of your body. An MRI can show if cancer has spread to your spine or brain.

During the test, you’ll lie still on a table as it passes into a scanner tube. If you’re claustrophobic, you may receive a sedative before the test. The scanner takes 2 to 15 minutes to create an image. You may need more than one set of images. The test may last an hour or more. An MRI test is painless, but it’s noisy. You can bring earphones and an MP3 device, or ask for earplugs.

Bone scans

Bone scans use a radioactive dye that’s injected into your veins. The dye will travel to and be taken up by your bones. Cancerous growths in bone take up the dye differently than normal bone.


Endoscopy is when a long, narrow tube with a light and a camera on the end is used to look inside your body. This tube may be put into a natural body opening, such as your mouth to look at your stomach, breathing tubes, or lungs. Or it may be put in your anus to look at your rectum and colon.


A mammogram looks for tumors in your breast. You may have this test if cancer is found in lymph nodes in your armpit.


A biopsy is a test to take small pieces of tissue from your body. The tissue is then looked at with a microscope. The way the cells look and results of lab tests that are done on the cells can help healthcare providers tell where the cancer started. Special stains done with the tissue can sometimes help, too.

During a biopsy, your healthcare provider removes tissue samples from areas that might be cancer, such as swollen lymph nodes. There are several types of biopsies done to try to find out where the cancer started.

Fine needle aspiration

Your healthcare provider uses a very thin needle to remove some fluid or a small amount of tissue from the tumor.

Core needle biopsy

Your healthcare provider can remove more tissue in this test. The needle is wider than the one used in a fine needle aspiration.

Paracentesis or thoracentesis

For paracentesis, your healthcare provider uses a needle to remove fluid from your abdomen. For thoracentesis, he or she uses a needle to remove fluid from the area around your lungs. A doctor who checks tissues (pathologist) can tell if the fluid contains cancer cells.

Bone marrow aspiration/biopsy

Your healthcare provider will remove a small amount of bone marrow fluid and a piece of bone tissue. He or she uses a special needle to take these samples. It’s normally taken from the back of your hip bone.

Excisional biopsy

A surgeon removes the whole tumor in one piece. Lymph nodes that could contain cancer may also be removed. A pathologist checks the tissue for signs of cancer.

Incisional biopsy

The surgeon takes out only a part of the tumor. This method is used if the tumor is so large that removing the whole tumor may cause problems. A pathologist checks the tissue for signs of cancer.

Diagnostic pathology tests

The pathologist uses a range of tests to help find signs of cancer and find the source. He or she stains the tissue samples to find tumors. These include sarcomas, melanomas, and lymphomas. Other stains help find tumors or cells that may have come from the testicle, prostate, breast, thyroid gland, or colon.

Your pathologist may also view the sample under an electron microscope. This special microscope can show more details that give clues about the origin of the cells.

Your healthcare provider may also order specialized molecular tests. These tests look for any genes that may have problems. Different damaged genes may lead to different kinds of tumors.

Other tests may be used, too. This depends on the symptoms you have and the results of these tests.

Getting your test results

When your healthcare provider has the results of your tests and biopsy, he or she will contact you. If he or she still cannot find the primary site of the cancer after many tests, you may be diagnosed with cancer of unknown primary. A pathologist will review the biopsy samples. He or she will likely classify the cancer as one of these five most common types:

  • Squamous cell carcinoma

  • Adenocarcinoma

  • Poorly differentiated carcinoma

  • Neuroendocrine carcinoma

  • Poorly differentiated malignant neoplasm

This classification will help your healthcare provider decide a treatment plan, even if the original site of the cancer stays unknown. 

Your healthcare provider will repeat a physical exam and maybe some tests. A second pathologist will look at the biopsy samples. Sometimes, as time passes, a small hidden primary tumor may grow large enough to be found. This may help the doctors reclassify the CUP.

Working with your healthcare provider

Your healthcare provider will talk with you about which tests you'll have. Make sure to follow his or her orders to get ready for the tests. Ask questions and talk about any concerns you have.