How is cancer of unknown primary found?

Cancer of unknown primary (CUP) has always spread beyond the place where it started by the time it is found. If it had been found early, it would not be a cancer of unknown primary.

Some cancers can be found early, before they cause symptoms, using screening tests. The American Cancer Society has guidelines about tests that may help find breast, prostate, cervical, and colorectal cancers early, before they cause any symptoms. If people follow these guidelines, some of these cancers could be found early. But many cases of CUP are caused by other types of cancer. There are still no screening tests to find many of the types of cancer that are likely to spread quickly and cause CUP.

Signs and symptoms of cancer of unknown primary

Cancers of unknown primary are most often found because of signs or symptoms a person is having. The symptoms of CUP depend on which organs the cancer has spread to. Symptoms can include those listed below, but keep in mind that these problems are more likely to be caused by something other than cancer.

• Swollen, firm, non-tender lymph nodes. Lymph nodes are bean-sized collections of immune system cells that help fight infections. Cancer often spreads to lymph nodes, which may be felt as a lump under the skin on the side of the neck, above the collarbone, under the arms, or in the groin. Sometimes a doctor notices them first during a routine check-up.
• A mass (a swelling or firm area that can be caused by a tumor) in the belly (abdomen) that can be felt or that causes a feeling of fullness
• Shortness of breath if the cancer has spread to the lungs or because of fluid and cancer cells around the lungs
• Pain in the chest or belly (abdomen) from cancer growing around nerves or pressing against organs
• Bone pain. The bones may be weakened by the cancer’s spread.
• Skin tumors. Because bumps in the skin are easy to see, skin tumors are sometimes the first sign of spread from a CUP.
• Weakness, tiredness, poor appetite, and weight loss can be symptoms of cancer that has spread

This is not a complete list of symptoms that might be caused by CUP. Most often, these symptoms are caused by something else. But if you have any of these problems, you should see a doctor right away.

If your doctor suspects cancer

To try to find the place where the cancer started and to see what kind it is, the doctor will first ask questions about your health and do a physical exam. Sometimes these simple steps can suggest the source of the cancer. If not, other tests such as imaging scans and blood tests might help narrow the search.

A biopsy (taking a sample of tissue to be looked at under a microscope) will be done to confirm that you have cancer. If you do, the doctor will use different tests to try to find the place where the cancer started. A few of these tests, including different types of biopsies, are briefly described below. But tracking down the place where the cancer started can be a complex process, and your doctor might use other tests that are not listed here. You should talk to your doctor about the purpose and details of any tests that will be done.

Imaging studies

Imaging studies are ways of taking pictures of the inside of the body. These tests may be done for a number of reasons:

• To help find out whether an area of concern is cancer
• To try to find out where it started
• To learn how far cancer may have spread
• To help find out if treatment is working

The tests could include the following:

X-ray: x-rays can help doctors see bones and certain organs. While they can sometimes be helpful when looking for cancer, other tests such as CT and MRI scans often give better pictures of soft tissues in the body.

A chest x-ray is a simple test that lets the doctor to look at the lungs, heart, and bones of the upper body. It can help show if the cancer started in the lung or has spread to the lung. If your doctor suspects your cancer came from somewhere in your digestive tract, such as your esophagus, stomach, or large intestine, he or she may x-ray these organs.

CT scan (computed tomography): A CT or CAT scan uses x-rays to take many pictures of the body that are then combined by a computer to give a detailed picture.

A CT scanner has been described as a large donut, with a narrow table in the middle “hole.” You will need to lie still on the table while the scan is being done. CT scans take longer than regular x-rays, and you might feel a bit confined by the ring while the pictures are being taken.

Before any pictures are taken, you may need to drink a liquid called oral contrast to outline the intestines so that they are not mistaken for tumors. You may also be given a contrast dye through an IV line. The dye helps to better outline organs inside the body. The dye may cause some flushing (a feeling of warmth, often in the face). Some people are allergic and get hives. Rarely, problems like trouble breathing or low blood pressure can happen. Be sure to tell the doctor if you have ever had a problem from any contrast dyes used for x-rays. CT scans can also be used to guide a biopsy needle (see below) into a tumor.

MRI scan (magnetic resonance imaging): MRIs show a cross-section of the body in more detail. They are often useful in looking at cancers. MRIs use radio waves and strong magnets instead of x-rays to take pictures. MRI scans take longer than CT scans -- often up to an hour. And you have to lie inside a narrow tube, which can upset people with a fear of enclosed spaces. Special, “open” MRI machines can sometimes help with this if needed. The machine also makes buzzing and clicking noises. Some centers can give headphones with music to block this noise out.

Ultrasound: An ultrasound uses sound waves to make a picture of the inside of the body. It can help show which organs the cancer has affected. It is fairly quick. Most often for this test you lie on a table. A technician puts gel on your skin and moves a small “wand” on the skin over the part of the body being checked. Ultrasound can be useful to look at organs in the belly (abdomen) and pelvis.

PET scan (positron emission tomography): PET scans use a form of sugar that contains a radioactive atom. Cancer cells in the body absorb large amounts of the sugar and a special camera can spot the radioactivity. A PET scan can be useful if you have cancer in lymph nodes in your neck. It may be able to find the source of the cancer if it is somewhere in your head or neck. It is also helpful in telling whether a shadow on your chest x-ray is cancer. PET scans are useful when your doctor thinks the cancer has spread but doesn’t know where. Some machines can do both a PET and CT scan at the same time.

SRS (somatostatin receptor scintigraphy): SRS, also known as OctreoScan, can be very helpful in finding neuroendocrine tumors (NETs). To do this test, a small amount of a substance called octreotide that contains a radioactive atom is put into into a vein. It travels through the blood and is drawn to neuroendocrine tumors (NETs). About 4 hours later, a special camera can be used to show where the radioactivity is in the body. More scans may be done on the next few days as well. This test is useful not only in finding some NETs, but also with helping to choose treatment. If a tumor is seen on SRS, it is likely to respond to treatment with certain drugs.

Endoscopy: Using a special thin, lighted, flexible tube called an endoscope, a doctor can look inside certain parts of the body. If your doctor thinks your cancer started in an organ such as your lung or intestine, you might have this test. Based on the place in the body being looked at, the endoscope may be put in through your mouth, nose, or anus. This is most often done after you have been sedated (given drugs to make you sleepy) and is often painless. If something suspicious is seen during the exam, biopsy samples may be removed with special tools used through the endoscope. The samples will then be looked at under a microscope to see if cancer cells are present.

To learn more, please see our document, Endoscopy.

Blood tests

If it looks like you might have cancer, blood tests will be done to find out the number and type of blood cells and to measure levels of certain chemicals in the blood.

Complete blood cell count (CBC): Lower than normal numbers of different blood cell types could suggest that the cancer has spread to bones and replaced much of the normal bone marrow, where new blood cells are made. Lower than normal numbers of red blood cells (anemia) might mean there is intestinal bleeding caused by the cancer. This could point to the intestine as the place where the cancer started.

Blood chemistry tests: Tests of chemicals in the blood can show how well certain organs are working. In some cases the tests may give clues as to where cancer may be found in the body.

Serum tumor markers: Some types of cancer release certain substances into the bloodstream. These are known as tumor markers. Testing for these substances might provide useful clues about the place where the cancer started.

More details about tumor markers can be found in our document Tumor Markers.

Biopsies

Although physical exams and other tests can strongly suggest that you have cancer, in most cases a biopsy is needed to confirm that cancer is present. A biopsy is often needed to tell what kind of cancer it is (like adenocarcinoma or squamous cell carcinoma) and can give clues about where the cancer started. The biopsy involves taking out some of the tumor and looking at it under a microscope. Different types of biopsies may be done based on where the tumor is found.

Fine needle aspiration (FNA) biopsy: For this test, the doctor first numbs the skin and then uses a very thin, hollow needle to draw up a small amount of tissue from the tumor. If a lymph node or tumor is near the skin’s surface, the doctor can guide the placement of the needle by touch. But if the mass is deeper inside the body, the doctor can use an ultrasound or a CT scan to guide the placement of a longer needle. FNA biopsies are quick and seldom cause problems. A drawback is that in some cases not enough tissue can be removed. When that is the case, other types of biopsies may be needed.

Core needle biopsy: The core biopsy needle is slightly larger than the FNA needle and it removes more tissue. It can be done the same way as a FNA. Because it removes larger pieces of tissue, a core needle biopsy is more likely than an FNA biopsy to provide a clear answer.

Excisional biopsy: In this biopsy, the surgeon removes the whole lymph node or tumor. If the node is near the skin’s surface, this is a simple operation that can be done after numbing the skin. If the node is inside the chest or belly (abdomen), then you will need deep sedation or general anesthesia (you would be asleep). Doctors often prefer this type of biopsy for a CUP because it allows them to get as much tissue as they can to help make the right diagnosis.

Sometimes this type of biopsy can be done using a laparoscope. A laparoscope is a thin, lighted tube that is put in through a small cut in the belly. It is used to look at the contents of the abdomen and guide instruments during surgery. This approach means that only a few small cuts (incisions) are needed. Recovery time is often shorter than with regular, open surgery. (Thoracoscopy is like laparoscopy, but is used for surgery of the chest.)

Incisional biopsy: This method is like the excisional biopsy except that only part of the tumor or lymph node is removed. It might be used to look at part of a large tumor.

Fluid removal: If a person has large amounts of fluid inside the chest or belly (abdomen), samples can be removed with a long, hollow needle. The fluid is then looked at under a microscope to see if it contains cancer cells and what type they are. Thoracentesis is the medical term for taking out fluid from the chest cavity. Paracentesis refers to removing fluid from the belly. These tests are most often done with numbing medicine while the patient is awake.

Bone marrow aspiration and biopsy: This test is used to see whether cancer has spread to the bone marrow (the thick liquid in the center of large bones). A needle is used to remove a small amount of liquid bone marrow, or a larger needle is used to remove both a cylinder of bone and some marrow. Samples are most often taken from the back of the hip bone after numbing the area. The biopsy may cause some brief pain.

A doctor with special training looks at all of the biopsy samples under a microscope. This can help find the place where the cancer started or help in putting it into one of the major groups in order to guide treatment. Other tests, like those that follow, may also be done.

Lab tests of biopsy samples

There are a number of lab tests that can be done to try to pinpoint the source of the cancer or to tell more about the type of cancer cells found. Some of these tests involve treating tissue samples with antibodies or special chemicals. Other methods make use of a powerful microscope. Still others involve a careful study of cancer cells to spot changes in the DNA. Ask your doctor or nurse to explain any tests you are having.

Putting it all together

After looking at the results of all the tests, the doctor will place the CUP in one of these 5 groups:

• Squamous cell carcinoma
• Adenocarcinoma
• Poorly differentiated carcinoma
• Neuroendocrine carcinoma
• Poorly differentiated malignant neoplasm

Based on this grouping and on the place where the cancer was found, doctors decide what other tests need to be needed in order to better classify the cancer and decide on the best treatment plan. Feel free to ask your doctor about any tests you will be having and what they hope to learn from these tests.

Some of the more common ways in which CUP may appear

Cancer in lymph nodes in the neck: Spread to nodes in the neck often comes from cancers of the mouth, throat, sinuses, salivary glands, larynx (voice box), thyroid, or lung. Tests will be done to look at these areas thoroughly for signs of where the cancer may have started.

Women with adenocarcinoma in lymph nodes under the arm: In women, cancer that has spread to underarm nodes is likely to have started in the breast, so a mammogram and a thorough breast physical exam are always done. An MRI of the breasts can be very useful in many cases. Lab tests on the tumor cells can tell if they have estrogen receptors (ER) or progesterone receptors (PR). The presence of these receptors is also important in planning treatment, as cancers with these receptors are likely to respond to hormone treatment.

If the finding of breast cancer cannot be confirmed, tests to look for lung cancer may be done. Lung cancer is the most common cause of cancer spread to underarm lymph nodes in men and can also be the cause in women.

Cancer in groin lymph nodes: The likely sources of these metastases include cancers of the vulva, vagina, cervix, penis, skin of the legs, anus, rectum, bladder, and others. Tests for these cancers will be done.

Women with cancer throughout the pelvic cavity: The ovaries and fallopian tubes are the most likely source of a cancer that has spread in this way. But cancers from the breast, lung, or digestive tract can also spread here.

Cancer in the back of the belly (abdomen) or the middle of the chest: Germ cell tumors are one of the types of cancer that can start in these places. Most germ cell tumors start from germ cells (sperm or eggs) in the testes or ovaries, so these will be checked for cancer. It is important to spot germ cell tumors because they often respond well to certain kinds of chemotherapy drugs with good outcomes and sometimes, cures.

Melanoma in lymph nodes only: A complete skin exam should be done to look for the primary melanoma. Some that have already spread might be quite small or may look like simple moles to someone without training. Other tests are often done to see if cancer can be found elsewhere in the body.

Cancer in other places: The main goal in trying to find out where cancer started is to see if you have a cancer that may respond well to certain treatments.