Cancers of unknown primary are usually found as the result of signs or symptoms a person is having.

Signs and symptoms of a cancer of unknown primary

The signs and symptoms of a cancer of unknown primary (CUP) vary depending on which organs it has spread to. It's important to note that none of the symptoms listed below are caused only by CUP. In fact, they are more likely to be caused by something other than cancer. Still, if you have symptoms that suggest that something abnormal may be going on, consult a doctor so that the cause can be evaluated and treated, if needed.

Some possible symptoms of CUP include:

Swollen, firm, non-tender lymph nodes

Normal lymph nodes are bean-sized collections of immune system cells located throughout the body that are important in fighting infections. Cancers often spread to the lymph nodes, which become swollen and firmer. A person may notice an abnormal lymph node as a lump under the skin on the side of the neck, above the collarbone, under the arms, or in the groin area. Sometimes, a doctor notices them first during a routine checkup.

A mass in the abdomen that can be felt or causes a feeling of "fullness"

This can be caused by cancer growing in the liver or less often, the spleen. Sometimes the cancer cells grow on the surface of many organs in the abdomen. This may cause the buildup of fluid inside the abdomen.

Shortness of breath

This symptom may be caused by cancer that has spread to the lungs or by the buildup of fluid and cancer cells in the space around the lungs.

Pain in the chest or abdomen

This may be caused by cancer growth around nerves or by tumors that press against internal organs.

Bone pain

Cancer that has spread to the bones can sometimes cause severe pain. The bones may be weakened by the cancer's spread, and bones can break from minor injuries or even the normal stress of supporting the body's weight.

Skin tumors

Some cancers that start in internal organs can spread through the bloodstream to the skin. Because bumps in the skin are easily seen, skin metastases are sometimes the first sign of spread from a CUP.

Weakness, fatigue, poor appetite, and weight loss

These symptoms are often seen with more advanced cancers. They may occur because the cancer has spread to specific organs or systems such as the bone marrow or digestive system. Some cancers also release substances into the bloodstream that can affect metabolism and cause these problems.

This is by no means a complete list of symptoms that might be caused by CUPs. Again, most of the symptoms above are more likely to be caused by conditions other than cancer, Still, if you have any of these problems, it's important to see your doctor right away so the cause can be found and treated, if needed.

Medical history and physical exam

If you have any signs or symptoms that suggest you might have cancer, your doctor will want to take a complete medical history to check for symptoms and risk factors, including your family history. This will be followed by a physical exam, with special attention paid to any parts of the body where there are symptoms.

Approach to diagnosing a cancer of unknown primary

If your symptoms and the results of your physical exam suggest cancer may be the cause, the doctor may use different types of tests to look for the cancer:

• imaging tests such as x-rays, ultrasound, or CT (computed tomography) or MRI (magnetic resonance imaging) scans
• endoscopy exams, in which organs are looked at through a lighted tube placed into a body opening such as the mouth, nose, or anus
• blood tests
• biopsies, in which samples of tissue or cells are removed and looked at under a microscope or tested in the lab

Imaging tests and endoscopy exams

Imaging tests use sound waves, x-rays, magnetic fields, or radioactive substances to create pictures of the inside of your body. Imaging tests may be done for a number of reasons, including to help find out whether a suspicious area might be cancerous, to learn how far cancer may have spread, and to help determine if treatment has been effective.

X-rays

X-rays are tests that use low doses of radiation to help doctors see bones and some aspects of certain organs. While they can sometimes be helpful when looking for cancer, other tests such as CT and MRI scans often provide better views of soft tissues in the body.

A chest x-ray is a simple test that allows the doctor to look at the lungs, heart, and bones of the upper body. It can help show if the cancer may have started in the lung or has spread to the lung. The test can be done in a doctor's office or any outpatient facility.

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. A liquid contrast material called barium can help outline the organs on the x-rays. You will be asked to drink it before the x-rays if the esophagus and stomach are being looked at (an upper GI series). If the large intestine is to be looked at (a lower GI series), then the barium will be given as an enema before the test.

X-rays of bones can help evaluate pain that might come from cancer that has spread to the bones.

Computed tomography (CT) scan

The CT scan is an x-ray test that can produce detailed cross-sectional images of parts of your body. Instead of taking one picture, like a regular x-ray, a CT scanner takes many pictures as it rotates around you while you lie on a table. A computer then combines these pictures into images of slices of the part of the body being studied. Unlike a regular x-ray, a CT scan creates detailed images of the soft tissues in the body.

You may receive an injection of a contrast dye through an IV (intravenous) line. This helps better outline any tumors that are present. The contrast may cause some flushing (a feeling of warmth, especially in the face). Some people are allergic and get hives. Rarely, more serious reactions like trouble breathing or low blood pressure can occur. Be sure to tell the doctor if you have ever had a reaction to any contrast material used for x-rays. The contrast can also sometimes affect the kidneys, so usually a blood test to check kidney function is done before the contrast is given.

CT scans take longer than regular x-rays. You will need to lie still on a table while they are being done. During the test, the table moves in and out of the scanner, a ring-shaped machine that completely surrounds the table. Some people feel a bit confined by the ring they have to lie in while the pictures are being taken.

In recent years, spiral CT (also known as helical CT) has become available in many medical centers. This type of CT scan uses a faster machine. The scanner part of the machine rotates around the body continuously, allowing images to be collected much more quickly than with a standard CT. This lowers the chance of blurred images occurring as a result of motion. It also lowers the dose of radiation received during the test. The biggest advantage may be that the image slices are thinner, which yields more detailed pictures and allows doctors to look at suspicious areas from different angles.

CT-guided needle biopsy: CT scans can also be used to guide a biopsy needle precisely into a tumor. For this procedure, the patient remains on the CT scanning table while a radiologist advances a biopsy needle through the skin and toward the mass. CT scans are repeated until the doctors are sure that the needle is within the mass. A fine needle biopsy sample (tiny fragment of tissue) or a core needle biopsy sample (a thin cylinder of tissue about 1/2-inch long and less than 1/8-inch in diameter) is then removed and looked at under a microscope.

Magnetic resonance imaging (MRI) scan

MRI scans provide detailed images of soft tissues in the body, especially the brain and spinal cord. They are often useful in looking at cancers. But MRI scans use radio waves and strong magnets instead of x-rays, so there is no radiation involved. The energy from the radio waves is absorbed by the body and then released in a pattern formed by the type of body tissue and by certain diseases. A computer translates the pattern into a very detailed image of parts of the body. A contrast material called gadolinium may be injected into a vein before the scan to better see details, but contrast is needed less often than with a CT scan.

MRI scans are a little more uncomfortable than CT scans. First, they take longer -- often up to an hour. Second, you have to lie inside a narrow tube, which is confining and can upset people with claustrophobia (a fear of enclosed spaces). Newer, "open" MRI machines can sometimes help with this if needed. The machine also makes buzzing and clicking noises that you may find disturbing. Some centers provide headphones with music to block this out.

Ultrasound

Ultrasound uses sound waves whose echoes produce a picture of internal organs or masses. A small microphone-like instrument called a transducer emits sound waves and picks up the echoes as they bounce off body tissues. The echoes are converted by a computer into a black and white image that is displayed on a computer screen.

Ultrasound is a fairly quick and easy procedure that doesn't use radiation, which is why it is often one of the first tests done if an internal mass is suspected. To have an ultrasound exam, you simply lie on a table and a technician moves the transducer on the skin over the part of the body being examined. Usually, the skin is lubricated with gel first.

Ultrasound can help show which organs in the abdomen may have been affected by cancer, but it is not useful for looking inside the chest (because the ribs block the sound waves).

Positron emission tomography (PET) scan

PET scans inject glucose (a form of sugar) that contains a radioactive atom into the blood. The amount of radioactivity used is very low. Because cancer cells in the body are growing rapidly, they absorb large amounts of the radioactive sugar. A special camera can then create a picture of areas of radioactivity in the body. The picture is not finely detailed like a CT or MRI scan, but it can provide helpful information about the whole body.

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 somewhere in your head or neck. It can also help tell whether an abnormal area on a chest x-ray is cancer. PET scans are also useful when your doctor thinks the cancer has spread, but doesn't know where.

Some newer machines are able to perform both a PET and CT scan at the same time (PET/CT scan). This allows the doctor to compare areas of higher radioactivity on the PET with the appearance of that area on the CT.

Endoscopy

Endoscopy is a medical procedure in which tube-like instruments (called endoscopes) are used to look inside of the body. Some endoscopes are hollow, allowing the doctor to see directly into the body, while others use fiber optics (flexible glass or plastic fibers that transmit light). Still others have a small video camera on the end for viewing.

Endoscopes are named for the part of the body they examine. For example, an endoscope that looks at the main airways in the lungs is called a bronchoscope and the procedure is called a bronchoscopy.

Depending on the area of the body being looked at, the endoscope may be inserted through an opening like the mouth, nose, or anus. Usually this is done after you have been sedated (made sleepy) and is painless. In some cases, the endoscope is inserted through a small skin incision, which may require that you are under general anesthesia (asleep).

Your doctor may recommend endoscopy if he or she thinks your cancer may have started in an organ such as your intestine, lung, or larynx (voice box). 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 viewed under a microscope to see if cancer cells are present.

Blood tests

If signs and symptoms suggest you may have cancer, blood tests will probably be done to examine the number and type of blood cells and to measure levels of certain blood chemicals.

Blood cell counts: Lower than normal numbers of different blood cell types may suggest that a CUP has spread to bones and replaced much of the normal bone marrow, where new blood cells are made.

Anemia (lower than normal numbers of red blood cells) might also mean there is intestinal bleeding caused by the cancer. This could point to somewhere in the intestine as the site of its origin.

Blood chemistry tests: Tests of chemical levels in the blood can show how well certain organs are functioning, and in some cases they may give a clue as to where cancer may be found in the body.

For example, abnormal liver function tests in a person with CUP may suggest cancer is in the liver. The cancer may have started in the liver or may have spread from another part of the body. Other blood tests can tell how well the kidneys are working and whether or not cancer may have invaded the bones.

Serum tumor markers: Some types of cancer release certain substances into the bloodstream. Testing for these substances in the blood can sometimes provide valuable clues about the origin of the cancer.

• prostate-specific antigen (PSA): A high PSA level in a man suggests that a CUP may have started in the prostate gland.

• CA-125: A high CA-125 level in a woman suggests ovarian cancer may be the cause.

• human chorionic gonadotropin (HCG): High levels of HCG suggest a germ cell tumor, a type of cancer that can begin in the testicles, ovaries, the mediastinum (area between the lungs), or the retroperitoneum (area behind the intestines).

• alpha-fetoprotein (AFP): This substance is produced by some germ cell tumors as well as by some cancers that start in the liver.

Biopsies

Although physical exams, imaging tests, and blood tests can sometimes strongly suggest a cancer diagnosis, in most cases a biopsy (removing some of the tumor for viewing under a microscope and other lab testing) is needed to confirm that cancer is indeed present. Different types of biopsies may be done depending on where a suspected tumor is located.

Fine needle aspiration (FNA) biopsy: In an FNA biopsy, the doctor uses a thin, hollow needle attached to a syringe to aspirate (withdraw) a few drops of fluid containing cells and tiny fragments of tissue. Local anesthetic (numbing medication) may be used on the skin where the needle will be inserted.

If a lymph node or tumor is near the skin's surface, the doctor can guide placement of the needle by touch. If the mass is deeper inside the body, the doctor can use an imaging test such as ultrasound or a CT scan to guide the placement of a longer needle.

FNA biopsies are quick, cause little discomfort, have few complications, and are useful in determining if a lump is cancerous. But in many cases, an FNA biopsy will not remove enough of a sample for all of the tests needed to identify some cancers of unknown primary, so other types of biopsies may be needed.

Core needle biopsy: A core biopsy uses a slightly larger needle to remove more tissue -- usually one or more cylinders of tissue about 1/16-inch across and 1/2- to 1-inch long. Like FNA biopsies, core biopsies can be done by touch or guided by imaging tests, depending on the tumor's location. They are usually done with local anesthesia (where you are awake but the area is numbed) in an outpatient setting.

Because it removes larger pieces of tissue, a core needle biopsy is more likely than an FNA biopsy to provide a clear diagnosis.

Excisional biopsy: During an excisional biopsy, a surgeon cuts through the skin to remove the entire tumor nodule or lymph node. Doctors often prefer this type of biopsy for a CUP because it allows them to get as much tissue as possible to help make the right diagnosis.

If the node or tumor is near the skin surface, this is a simple operation that can usually be done with local anesthesia. If the node or tumor nodule is inside the chest or abdomen, general anesthesia is needed (the patient is asleep). If a tumor is deep inside the body and its removal would require major surgery, doctors often try a fine needle or core needle biopsy first.

Incisional biopsy: This procedure is similar to an excisional biopsy except that it removes only a part of the tumor or mass. It is useful in sampling large tumors, when removing the entire mass might cause serious complications, side effects, or the need for a prolonged recovery. As with excisional biopsy, it can often be done with local anesthesia if the tumor is near the surface, but it requires general anesthesia if the tumor is deeper in the body.

Thoracentesis or paracentesis: In patients who have large amounts of fluid inside the chest (known as a pleural effusion) or abdomen (ascites), samples of the fluid 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, if so, to determine the type of cancer that is present. Thoracentesis is the medical term for removing fluid from the chest cavity. Paracentesis refers to removing fluid from the abdomen.

Bone marrow aspiration and biopsy: These tests may be done to see if cancer has spread to the bone marrow, the soft inner part of certain bones where new blood cells are made.

A bone marrow aspiration and biopsy are usually done at the same time. In most cases the samples are taken from the back of the pelvic (hip) bone.

For a bone marrow aspiration, you lie on a table (on your side or belly). After cleaning the area, the skin over the hip and the surface of the bone are numbed with local anesthetic, which may cause a brief stinging or burning sensation. A thin, hollow needle is then inserted into the bone and a syringe is used to suck out a small amount of liquid bone marrow. Even with the anesthetic, most patients still have some brief pain when the marrow is removed.

A bone marrow biopsy is usually done just after the aspiration. A small piece of bone and marrow (about 1/16 inch in diameter and 1/2 inch long) is removed with a slightly larger needle that is twisted as it is pushed down into the bone. The biopsy may also cause some brief pain. Once the biopsy is done, pressure will be applied to the site to help stop any bleeding.

Samples from the bone marrow are sent to a pathology lab, where they are looked at and tested for cancer cells.

Lab tests of biopsy samples

All biopsy samples are first looked at under a microscope by a pathologist, a doctor who has special training in laboratory diagnosis of cancers. How the cancer looks under the microscope will often provide clues to its origin. If the diagnosis isn't clear, then further testing might help.

Immunohistochemistry

For this test, very thin slices of the sample are attached to glass microscope slides. The samples are then treated with special proteins (antibodies) designed to attach only to a specific substance found in certain cancer cells. If the patient's cancer contains that substance, the antibody will attach to the cells. Chemicals are then added so that antibodies attached to the cells change color. The doctor who views the sample under a microscope can see this color change. Doctors often need to use many different antibodies to try to determine what type of cancer is on the slides.

Flow cytometry

In flow cytometry, cells from a biopsy sample are treated with special antibodies, each of which sticks only to certain types of cells. The cells are then passed in front of a laser beam. If the antibodies have stuck to the cells, the laser causes them to give off a colored light that is measured and analyzed by a computer. This test is probably most useful in helping to determine whether cancer in a lymph node is a lymphoma or some other cancer. It also can help determine the exact type of lymphoma so doctors can select the best treatment.

Cytogenetic testing

Cytogenetic tests look at a cell's chromosomes (pieces of DNA) under a microscope to find any changes. Normal human cells contain 46 chromosomes. Some types of cancer have characteristic abnormalities in their chromosomes. Finding these changes helps identify certain types of cancer. Several types of chromosome changes can be found in cancer cells.

• A translocation means a part of one chromosome has broken off and is now located on another chromosome.

• An inversion means that part of a chromosome is upside down (now in reverse order) but still attached to the chromosome where it originated.

• A deletion indicates part of a chromosome has been lost.

• An addition happens when all or part of a chromosome has been duplicated and too many copies of it are found within the cell.

One drawback of cytogenetic testing is that it usually takes about 3 weeks because the cancer cells must grow in lab dishes for about 2 weeks before their chromosomes are ready to be viewed under the microscope. A newer form of cytogenetic testing is called fluorescence in situ hybridization (FISH). FISH uses special fluorescent dyes to recognize specific chromosome changes in certain types of cancer. An advantage of FISH is that it can be done much more quickly than standard cytogenetic testing, although it requires that doctors have an idea of what chromosome changes they are looking for ahead of time.

Molecular genetic testing

Tests of the cancer cells' DNA by methods such as polymerase chain reaction (PCR) can find some chromosome changes that can't be seen under a microscope in cytogenetic tests. PCR testing can find some translocations involving parts of chromosomes too small to be seen with usual cytogenetic testing, but like FISH it requires that the doctors know what they are looking for. This sophisticated testing is not needed in most cases, but it is sometimes helpful in classifying some cancers when other tests have not provided clues regarding their origin.

Gene expression profiling

With advances in technology, some newer lab tests are able to look at the activity of many genes in the cancer cells at the same time. By comparing the pattern of gene activity in the CUP sample to the patterns of activity seen with known types of cancer, doctors can sometimes get a better idea of where a cancer started. For more on this topic, see the section, "What's new in research and treatment for cancer of unknown primary?"

Electron microscopy

Most microscopes use a beam of ordinary light to view specimens. A much more complex, larger, and more expensive instrument called an electron microscope uses beams of electrons. The electron microscope's magnifying power is hundreds of times greater than that of an ordinary light microscope. This sometimes helps find very tiny details of cancer cell structure that can provide clues to the tumor type or origin.

Using the results of these tests, the appearance of the cancer under the microscope, the location of its metastasis, and other information about the patient (age, gender, etc.), it is often possible to find the source of the cancer or to classify the cancer in a way that can help guide treatment.

Classification of cancers of unknown primary

After initial lab tests, the pathologist classifies a cancer of unknown primary into 1 of the 5 main types:

• squamous cell carcinoma
• adenocarcinoma
• poorly differentiated carcinoma
• neuroendocrine carcinoma
• poorly differentiated malignant neoplasm

Based on the classification and the location of the metastatic cancer, doctors decide which additional tests should be done. For example, a poorly differentiated malignant neoplasm may be tested further to try to classify it more precisely as a melanoma, lymphoma, sarcoma, small cell carcinoma, germ cell tumor, etc.

Some of the more common ways in which cancer of unknown primary may appear are listed below, along with a brief description of what testing may be done.

Squamous cell carcinoma in lymph nodes in the neck

Metastases to neck nodes usually come from cancers of the mouth, throat, sinuses, larynx (voice box), or lung. Tests will be done to look at these areas thoroughly for signs of where the cancer may have started.

The base of the tongue, the throat, and the larynx are deep inside the neck and not easily seen. Indirect pharyngoscopy and laryngoscopy use small mirrors to look at these areas. A fiber optic laryngoscope (a flexible, lighted, tube inserted through the mouth or nose) can be used to look deeper in the throat, if needed.

If the cancer is likely to have started in the head and neck area, the mouth, throat, larynx, esophagus (tube that connects the mouth to the stomach), trachea (wind pipe), and bronchi (tubes leading from the trachea to the lungs) will be examined very thoroughly. This exam, called panendoscopy, is done in the operating room while the patient is under general anesthesia (asleep).

Imaging tests such as CT or MRI scans of the sinuses and neck area may be used to look for small cancers that may have already spread to lymph nodes in the neck. A PET scan (or combined PET/CT scan) may be done as well.

A chest CT scan and bronchoscopy (viewing the air passages through a flexible lighted tube) are often recommended to find suspected lung cancers that may have been missed by a routine chest x-ray.

Women with adenocarcinoma in lymph nodes under the arm

In women, cancer that has spread to underarm nodes is most likely to have started in the breast, so diagnostic mammography (breast x-ray) and a thorough breast physical exam is always done. An MRI of the breasts can be very useful in many cases.

Lab tests on the tumor cells can determine if they have estrogen receptors (ER) and/or progesterone receptors (PR). These receptors are typically found in breast cancers. This finding may help confirm the diagnosis and also help plan treatment, as cancers containing these receptors are likely to respond to hormone therapy.

Cancer in lymph nodes in the groin

The most likely starting places of these cancers are the vulva, vagina, cervix, penis, skin of the legs, anus, rectum, or bladder, although other cancers are also possible.

• In women, a Pap test and exam of the vulva, vagina, and cervix are recommended. A CA-125 blood test may be done to see if ovarian cancer might be the source.

• In men, the penis and scrotum should be carefully examined. A blood test for prostate-specific antigen (PSA) can help tell if the cancer may have started in the prostate.

• In men and women, a proctoscopy (exam of the anus and the rectum through a lighted tube), skin exam, microscopic exam of urine, and abdominal and pelvic CT scans may be useful. If they are having urinary symptoms, an exam of the bladder (cystoscopy) may be done as well.

Women with cancer throughout the pelvic cavity

The ovaries are the most likely source of a cancer that has spread in this way, although cancers from the breast, lung, or digestive tract can also spread here. Tests for CA-125 in the blood and tumor samples are positive in most ovarian cancers, and can be used to help determine whether the primary tumor is likely to be in the ovaries or some other organ. CT scans of the abdomen and pelvis are also usually done.

Sometimes cancer that starts in the peritoneum (lining of the pelvis) looks and behaves like a cancer that started in the ovary. This is called primary peritoneal carcinomatosis. It is treated like ovarian cancer.

Cancer in the retroperitoneum (back of the abdomen) or mediastinum (middle of the chest)

Germ cell tumors are one of the types of cancer that can start in these locations, especially in younger people. Most germ cell tumors develop from germ cells in the gonads (testicles or ovaries), but these cancers can sometimes start in other parts of the body.

Results of blood tests and immunohistochemical tests for alpha-fetoprotein (AFP) and human chorionic gonadotropin (HCG) are often positive in germ cell tumors. Cytogenetic studies may also find chromosomal changes that support a diagnosis of germ cell tumor.

In younger men with abnormal levels of AFP and/or HCG, ultrasound of the scrotum may be done to see if the cancer may have started in the testicles.

CT scans of the chest, abdomen, and pelvis are typically used to try to exclude other types of cancers (such as lung cancer). In women, tests may be done to see if the cancer started in the breast or ovaries.

It is important to identify germ cell tumors because they often respond well to certain combinations of chemotherapy drugs with good outcomes and sometimes, cures.

Melanoma in lymph nodes only

A thorough exam of the skin, nails, and other body surfaces such as the inside of the mouth is needed to look for the primary melanoma. Some primary melanomas that have already spread may be quite small or may look like ordinary moles to the untrained examiner. Rarely, primary melanomas go away on their own without treatment after spreading, leaving behind only an area of slightly lighter colored skin.

Treatment of melanoma depends on whether it has spread only to lymph nodes or whether internal organs are also involved. Chest x-rays, CT scans of the head and abdomen, and blood tests are usually done to see if cancer can be found anywhere else in the body.

Cancer in other locations

The main goal in trying to determine the source of a CUP is to see if you have a cancer that may respond well to specific treatments. Some of the most important cancers to identify include thyroid, breast, and prostate cancers:

• Immunohistochemical tests for thyroglobulin can identify many thyroid cancers, which are often effectively treated with radioactive iodine injections.

• Lab tests can help identify breast cancers containing estrogen receptors (ER) and progesterone receptors (PR), and these cancers can be treated with hormonal therapy.

• Hormonal therapy is also used for prostate cancers, which can be identified by blood tests and immunohistochemical tests for prostate-specific antigen (PSA).

A type of poorly differentiated malignant neoplasm called small cell carcinoma or poorly differentiated neuroendocrine carcinoma can develop in the lungs and, less often, in other organs. Some of these cancers usually respond to certain chemotherapy combinations, although they are likely to come back (recur) at a later time.

Last Medical Review: 10/28/2008
Last Revised: 10/28/2008