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Cancer of Unknown Primary: Diagnosis 

How is cancer of unknown primary diagnosed?

Cancer of unknown primary (CUP) is cancer that's found after it has spread (metastasized) to another part of the body. 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. This is the place the cancer first started. Diagnosing CUP starts with your healthcare provider asking you questions. You'll be asked about your about your health history, your symptoms, risk factors, and family history of disease. Your healthcare provider will also do a physical exam.

What tests might I need?

Tests help your healthcare providers learn more about the cancer. They can help show where the cancer has spread throughout your body. The tests you get depend on where the CUP is found.

Tests are used to help your healthcare providers find out where the cancer first started. The test results help your healthcare providers decide the best ways to treat the cancer.

You may have 1 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 you have certain markers, 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 be linked with certain types of cancer. These tests may also be used to check if cancer has spread to your bones or 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 a tumor in your lungs or chest. It might show enlarged lymph nodes in your chest. An x-ray takes a few minutes, and doesn’t hurt.

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 ring-shaped CT scanner. A CT scan is painless. You may be asked to hold your breath a few times during the scan.

You may need to drink a contrast dye 4 to 6 hours before the scan. The dye helps certain parts of your body show up more clearly. It will pass through your body and come out in your bowel movements. A dye might also be put into your blood through a vein. When the dye is injected, you may have a warm flush feeling spread 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 might need 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, a mildly radioactive form of sugar (glucose) is put into your blood. 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 sugar used. This may cause nausea, a headache, or vomiting. Some newer machines can do PET and CT scans at the same time. This way the areas that show up on the PET scan can be compared with the more detailed CT scan images.


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

During the test, you’ll lie still on a narrow table that slides into a long, tube-like scanner. If you’re claustrophobic, you may need a sedative before the test. This test may last an hour or more. An MRI test is painless, but it’s noisy. You can ask for earphones or earplugs.

Bone scans

Bone scans use a radioactive dye that’s injected into a vein. The dye will travel to and be taken up by your bones. Cancers cells in bone take up the dye differently than normal bone. These spots can be seen on the scan.


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 tiny pieces of tissue, called samples, from your body. If fluid has collected where it shouldn't, like in the space around your lung, if can be taken out, too. A pathologist tests the tissue or fluid for signs of cancer. The way the cells look and results of lab tests that are done can help healthcare providers tell where the cancer started. Special stains done on the tissue can sometimes help, too.

During a biopsy, your healthcare provider removes tissue or fluid samples from areas that might be cancer, such as swollen lymph nodes. There are several types of biopsies that can be used. Many times, a biopsy is the only way to know if a person has cancer. It's also an important part of figuring out where the cancer started.

Fine needle aspiration

A very thin needle is used to remove some fluid or a small amount of tissue from the tumor.

Core needle biopsy

More tissue can be taken out in this test. The needle is wider than the needle used in a fine needle aspiration.

Paracentesis or thoracentesis

For paracentesis, a long, thin needle is used to remove fluid from your abdomen (belly). For thoracentesis, a needle is used to remove fluid from the area around your lungs. Ultrasound may be used to guide the needle to the right place.

Bone marrow aspiration/biopsy

A special needle is used to remove a small amount of bone marrow fluid (aspiration) and a piece of bone tissue (biopsy). It’s normally taken from the back of your pelvis bone.

Excisional biopsy

In this case, the whole tumor is taken out in 1 piece. Lymph nodes that could contain cancer may also be removed.

Incisional biopsy

Only a part of the tumor is taken out for this type of biopsy. This method is used if the tumor is so large that removing the whole tumor may cause problems.

Diagnostic pathology tests

The pathologist uses a range of lab tests to look for signs of cancer and find the source. Sometimes, the tissue samples are stained with special dyes 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.

The pathologist may also look at the sample under an electron microscope. This can show more details that give clues about what kind of cells the cancer started in.

You may also have molecular tests. These tests look for genes in the cells that may have problems (they may be changed or mutated). Different gene mutations can lead to different kinds of cancers.

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

Getting your test results

When your healthcare provider has the results of your tests and biopsy, he or she will contact you. If the primary site, or the place the cancer started, cannot be found after many tests, you may be diagnosed with cancer of unknown primary. A pathologist will review the biopsy samples. He or she will then classify the cancer as 1 of these 5 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 isn't known. 

Your healthcare provider may repeat a physical exam and maybe some tests. A second pathologist might look at the biopsy samples. Sometimes, as time passes, a small hidden primary tumor may grow large enough to be found. This can 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 advice to get ready for the tests. Ask questions and talk about any concerns you have.

Online Medical Reviewer: Kimberly Stump-Sutliff RN MSN AOCNS
Online Medical Reviewer: Lu Cunningham
Online Medical Reviewer: Richard LoCicero MD
Date Last Reviewed: 3/1/2019
© 2021 The StayWell Company, LLC. All rights reserved. This information is not intended as a substitute for professional medical care. Always follow your healthcare provider's instructions.
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