Survival rates tell you what portion of people with the same type an dstage of cancer are still alive a certain amount of time (usually 5 years) after they were diagnosed. They can't tell you how long you will live, but they may help give you a better understanding about how likely it is that your treatment will be successful.

Cancer of unknown primary (CUP) includes many different cancer types, so it’s hard to provide meaningful survival statistics for these cancers as a group. In general, these are difficult cancers for several reasons:

• When they are first diagnosed, these cancers have already spread beyond the site where they started. This means that the types of treatments that are most likely to be successful, such as surgery or radiation therapy, are not likely to result in a cure in most cases.
• Because the exact type of cancer is not known, it’s harder for doctors to know what treatment is most likely to help the patient.
• Many CUPs are fast-growing and/or fast-spreading cancers.

When all types of CUP are included, the average survival time is about 9 to 12 months after diagnosis. But this can vary widely depending on many factors, including the cancer cell type, where the cancer is found, how far the cancer has spread, a person’s general health, the treatments received, and how well the cancer responds to treatment.

Survival statistics can sometimes be useful as a general guide, but they may not accurately represent any one person’s prognosis (outlook). This is because survival rates are often based on previous outcomes of large numbers of people who had the disease, but they can’t predict what will happen in any particular person’s case. Your doctor can tell you how these numbers may apply to you, as he or she is familiar with your particular situation.

Research into the causes, diagnosis, and treatment of cancer is being done at many cancer research centers. Scientists are making progress in understanding how changes in a person’s DNA can cause normal cells to develop into cancer. A greater understanding of the gene changes that can occur in cancer is providing insight into why these cells become abnormal. Some of these advances may lead to better diagnosis and treatment of cancer of unknown primary (CUP).

Diagnosis

It’s important that doctors are able to identify the origin of cancers of unknown primary so that the most effective treatments can be used. Immunohistochemistry and other lab tests can be very helpful in this regard, but they are not yet able to tell where all CUPs have started. Newer lab tests now becoming available, and others being studied, will help classify CUP more precisely and predict a patient’s prognosis and response to treatment.

Hopefully at some point in the future, the number of cancers of unknown primary will drop dramatically, as doctors will be able to test tumor samples and determine what types of cancer they are.

Treatment

Because CUP represents a number of different types of cancer, it’s unlikely that a single treatment breakthrough will benefit all people with CUP. Still, progress in treating some of the more common types of cancer is likely to benefit people with CUP as well, especially if the cancers can be classified more accurately.

As researchers have come to understand the genetic changes that cause these tumors, they’ve been able to use newer treatments to target these changes. Some of these newer drugs are called targeted therapies. These drugs have more selective effects than chemotherapy (chemo). Some of them, such as bevacizumab (Avastin^®) and erlotinib (Tarceva^®), are available to treat other cancers and have shown some activity in CUP.

Recent studies have found that cancers starting in each organ are not all the same. They can have different changes in their most important molecules and respond differently to treatments.

As targeted treatments are found for more of the specific molecular changes in cancer cells, knowing the origin of a cancer may become less important. Instead, detailed information about changes in the cancer cells’ DNA and RNA may become more important in choosing the treatments most likely to help individual patients.

Cancer cells from CUP are sometimes tested in a lab to try to see which chemo drugs will be likely to work. Unfortunately, these tests don’t always do a good job of predicting the right chemo drugs to use and don't always tell which are most effective. Many doctors don’t find them very helpful.

Many patients with cancer of unknown primary face a serious prognosis, so the need for advances in treatment is obvious. Clinical trials of new treatments are essential if progress is to occur. Some of these trials are testing new chemo drugs, new drug combinations, and new ways to give these drugs. Other clinical trials are studying new approaches to treatment, such as biological therapy, immunotherapy, and gene therapy. Because CUP is many types of cancers, progress against CUP is likely to depend on continued progress toward understanding the molecular basis of all cancers.

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

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 that will pay special attention 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, the doctor may use the following different types of tests to look for cancer, see what kind it is, and find out where it is located (and where it might have started):

• Imaging tests such as x-rays, ultrasound, or CT (computed tomography) or MRI (magnetic resonance imaging) scans
• Endoscopy exams to look at organs through a lighted tube placed into a body opening such as the mouth, nose, or anus
• Blood tests
• Biopsies to remove samples of tissues or cells and look at them with a microscope or test them in the lab

Imaging tests

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 look more closely at an abnormal area that might be a cancer
• To learn how far cancer may have spread
• To try to see where a cancer has started
• To help determine if treatment has been effective

Somatostatin receptor scintigraphy

Somatostatin receptor scintigraphy (SRS) an imaging test also known as OctreoScan, can be very helpful in diagnosing neuroendocrine tumors (NETs), including neuroendocrine carcinomas that may be suspected if you have a CUP. SRS uses a hormone-like substance called octreotide that has been bound to radioactive indium-111. A small amount of octreotide is injected into a vein and attaches to proteins on the tumor cells of many NETs. A special camera is then used to show where the radioactivity has collected in the body. Additional scans may be done on the following few days as well. This test is useful not only in finding some NETs, but also with determining treatment. If a tumor is seen on SRS, it is likely to respond to treatment with certain drugs.

Endoscopy

For endoscopy, the doctor puts a flexible lighted tube (endoscope) with a tiny video camera on the end into the body. 

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. The endoscope used to look at the inside of the colon is called a colonoscope.

Common types of endoscopy include:

• Laryngoscopy to look at the larynx (voice box)
• Esophagogastroduodenoscopy (EGD, also called upper endoscopy) to look at the esophagus (the tube that connects the throat to the stomach), the stomach, and the duodenum (the first part of the small intestine)
• Bronchoscopy to look at the lungs
• Colonoscopy to look at the large intestine (colon)
• Cystoscopy to look at the bladder

Endoscopy is commonly used to look at the esophagus and stomach, the large intestine, the lungs, and the throat and 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 looked at under a microscope to see if cancer cells are present.

Endoscopic ultrasound: This test is done with an ultrasound probe attached to an endoscope. It’s most often used to get pictures of the pancreas and tumors of the esophagus. In the esophagus it can be used to look closer at any tumors present. When there are no esophagus tumors, the endoscope travels through the esophagus and the stomach, and into the first part of the small intestine. The probe can then be pointed toward the pancreas, which sits next to the small intestine. The probe is on the tip of the endoscope, so it’s a very good way to look at the pancreas. It’s better than CT scans for spotting small tumors in the pancreas. If a tumor is seen, it can be biopsied during this procedure.

A form of endoscopic ultrasound also can be used to look more closely at tumors of the rectum. For this procedure, the endoscope is passed through the anus and into the rectum.

Endoscopic retrograde pancreatography (ERCP): For this procedure, the endoscope is passed down the patient’s throat, through the esophagus and stomach, and into the first part of the small intestine. The doctor can see through the endoscope to find the ampulla of Vater (the place where the common bile duct is connected to the small intestine). A small amount of dye (contrast material) is then injected through the tube into the common bile duct and x-rays are taken. This dye helps outline the bile duct and pancreatic duct. The x-ray images can show narrowing or blockage of these ducts that might be due to pancreatic cancer. The doctor doing this test can also put a small brush through the tube to remove cells to view under a microscope to see if they look like cancer.

More information about these tests can be found in Endoscopy.

Blood tests

If signs and symptoms suggest you might 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.

Complete blood count

The complete blood count (CBC) can tell if you have a low blood count (red blood cells, white blood cells, or platelets). 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’s stomach or intestinal bleeding caused by the cancer. This could point to somewhere in the stomach or 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 might 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 has have invaded the bones.

Serum tumor markers

Some types of cancer release certain substances into the bloodstream that are known as tumor markers. There are many different tumor markers, but only a few of them are helpful in figuring out the origin of a cancer, such as:

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

• 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.
• Chromogranin A (CgA): CgA levels can go up with neuroendocrine cancers.

Other tumor markers that may be helpful include:

• CA-125: A high CA-125 level in a woman suggests ovarian, fallopian tube, or primary peritoneal cancer may be the cause.
• CA 19-9: High levels of this tumor marker suggest that the cancer started in the pancreas or bile ducts.

There are many other tumor markers, but they are less useful in patients with CUP because their levels go up with many different cancers. For example, carcinoembryonic antigen (CEA) can go up in the presence of an adenocarcinoma of any source. Cancers of the colon, lung, ovaries, pancreas, stomach and many others can be adenocarcinomas and cause the CEA level to rise.

Biopsies

Physical exams, imaging tests, and blood tests can sometimes strongly suggest a cancer is present, but in most cases a biopsy (removing some of the tumor for viewing under a microscope and other lab testing) is needed to know for certain that cancer is present. A biopsy is also usually needed to tell what kind of cancer it is (like adenocarcinoma or squamous cell carcinoma) and can give clues about where the cancer started. A biopsy is needed to diagnose CUP.

Different types of biopsies may be done depending on where a suspected tumor is located.

• Needle biopsy
• Core needle biopsy
• Surgical biopsy
• Endoscopic biopsy

For more detailed information about biopsies see Types of Biopsies Used to Look for Cancer.

Thoracentesis or paracentesis

If you have have large amounts of fluid inside your chest in the area around your lungs (known as a pleural effusion) or in your abdomen (ascites), samples of the fluid can be removed with a long, hollow needle. Ultrasound often is used to guide the 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. These procedures are usually done under local anesthesia (numbing medicine), with you awake.

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, a thin, hollow needle is inserted into the bone and a syringe is used to suck out a small amount of liquid bone marrow. 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. 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 with a microscope by a pathologist, a doctor who has special training in laboratory diagnosis of cancers. How the cancer cells look will often provide clues to where it started. If the diagnosis isn’t clear, then further testing might help.

Immunohistochemistry

For this lab test, a part of the biopsy sample is treated with man-made 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 cells with antibodies attached to them change color. The doctor who looks at 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 may help identify some types of cancer. Several types of chromosome changes can be found in cancer cells. With this type of testing, the doctor needs to know what abnormalities to look for. Cytogenetic tests are not being used much in people with CUP since immunohistochemistry tests are becoming more advanced in identifying cell changes that may be related to certain cancers.

Molecular genetic testing

Sometimes, testing cancer cells’ DNA using methods like polymerase chain reaction (PCR) can find some genes and chromosome changes that can’t be seen under a microscope if a cytogenetic test is used. PCR testing also requires that the doctors know what they are looking for. It can also be used to look for certain viruses. For example, it can be used to find the Epstein-Barr virus. Finding this virus in cancer cells from an enlarged neck lymph node can mean that it’s a nasopharyngeal cancer.

This type of testing is not needed in most cases, but it’s 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. These tests can sometimes help your doctor discover where the cancer may have started, but so far, they haven’t been linked to better outcomes in patients.

Electron microscopy

An electron microscope uses beams of electrons that may help find very tiny details of cancer cell structure that can provide clues to the tumor type or origin.

This technique is not used often for CUP due to the more sophisticated tests already discussed, but it might help find the source of the cancer or classify the cancer in a way that can help guide treatment.

Classifying 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

The signs and symptoms of a cancer of unknown primary vary depending on which organs it has spread to. It’s important to note that none of the symptoms listed below is 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, see 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 might notice a lump (enlarged lymph node) 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 a feeling of “fullness”

A mass is an abnormal area such as a swelling or firm area that can be caused by a tumor. 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 ascites, the buildup of fluid inside the abdomen. The fluid buildup can swell the abdomen. It can sometimes lead to a feeling of fullness or bloating.

Shortness of breath

This symptom may be caused by cancer that has spread to the lungs or by the build-up of fluid and cancer cells in the space around the lungs (a pleural effusion).

Pain in the chest or abdomen

This may be caused by cancer growing around nerves or by tumors pressing against internal organs.

Bone pain

Cancer that has spread to the bones can sometimes cause severe pain. Common areas of pain include the back and the legs and hips, but any bone can be affected. The bones may be weakened by the cancer’s spread, and can break from minor injuries or even the normal stress of supporting the body’s weight. This can lead to a sudden severe pain or worsening of pain that was already there.

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.

Low red blood cell counts (anemia)

Cancer that started in the gastrointestinal system (such as esophagus, stomach, small intestines, or colon) can bleed. Often this occurs at a slow rate, so that the blood isn’t visible in the stool. Eventually, this can lead to low red blood cell counts.

Red blood cell counts can also become low if the cancer spreads to the bone marrow and crowds out the normal blood forming cells.

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.

Cancer survivors can be affected by a number of health problems, but often their greatest concern is facing cancer again. If a cancer comes back after treatment it is called a recurrence. But some cancer survivors may develop a new, unrelated cancer later. This is called a second cancer. No matter what type of cancer you have had, it is still possible to get another (new) cancer, even after being treated for and surviving the first.

In fact, certain types of cancer and cancer treatments can be linked to a higher risk of certain second cancers. Since the location where a cancer of unknown primary started is not known, survivors of cancer of unknown primary can get any type of second cancer.

Follow-up after treatment

After completing treatment for cancer, you should still see your doctor regularly and may have tests to look for signs the cancer has come back or spread. Experts do not recommend any additional testing to look for second cancers in patients without symptoms. Let your doctor know about any new symptoms or problems, because they could be caused by the cancer coming back or by a new disease or second cancer.

Survivors of cancer of unknown primary should follow the  and stay away from tobacco products. Smoking increases the risk of many cancers.American Cancer Society guidelines for the early detection of cancer

To help maintain good health, survivors should also:

• Get to and stay at a healthy weight
• Adopt a physically active lifestyle
• Eat a healthy diet, with an emphasis on plant foods
• Limit alcohol to no more than 1 drink per day if you're a woman or 2 per day if you're a man

These steps may also lower the risk of some cancers.

See Second Cancers in Adults for more information about causes of second cancers.

The exact number of cancers of unknown primary (CUP) diagnosed each year is unknown, because some cancers start out being diagnosed as unknown primary, but the primary site is found later. Still, the American Cancer Society estimates that about 31,810 cases of cancer of unknown primary will be diagnosed in 2018 in the United States. This number represents about 2% of all cancers. As more sophisticated lab tests become available to determine where a cancer started, the number of cancers of unknown primary may go down.

Visit the American Cancer Society’s Cancer Statistics Center for more key statistics.

A risk factor is anything that affects a person’s chance of getting a disease such as cancer. Different cancers have different risk factors. Some risk factors, like smoking, can be changed. Others, like a person's age or family history, can't be changed.

But having a risk factor, or even several, does not mean that a person will get the disease, and many people get cancer without having any known risk factors.

Since the exact type of cancer is not known, it’s hard to identify factors that might affect risk for cancer of unknown primary (CUP). These cancers are also a very diverse group, making this issue even more complicated. But there is research that provides some information about CUP risk factors.

Smoking is probably an important risk factor for CUP. More than half of patients with CUP have a history of smoking. When autopsy studies are done, many cancers of unknown primary are found to have started in the pancreas, lungs, kidneys, throat, larynx, or esophagus. Smoking increases the risk for all of these cancers.

Some other cancers of unknown primary are eventually found to have started in the stomach, colon, rectum, or ovaries. Diet, nutrition, and weight are factors that have been linked to these cancers. For more information, see the specific type of cancer.

Melanoma (an aggressive type of skin cancer) is another source of cancer of unknown primary. An important melanoma risk factor is exposure to ultraviolet radiation in sunlight.

Overall, however, there are no factors that specifically increase the risk of cancer of unknown primary. Even in people who may have one or more of the risk factors above, it’s not possible to know for sure if these factors contributed to the cancer.

Cancers of unknown primary (CUP) include a variety of cancers, which may each have a number of different causes. This is why it’s hard to assign a particular cause to CUP.

Cancer is the result of changes in a cell’s DNA. In recent years, scientists have made great progress in learning how certain changes in DNA can cause normal cells to become cancerous. DNA is the chemical in each of our cells that makes up our genes, which control how our cells function. We usually look like our parents because they are the source of our DNA. But DNA affects more than how we look.

Some genes control when our cells grow anddivide into new cells:

• Certain genes that help cells grow and divide are called oncogenes.
• Genes that help keep cell division under control or cause cells to die at the right time are called tumor suppressor genes.

Cancers can be caused by DNA changes that turn on oncogenes or turn off tumor suppressor genes.

Most of the DNA changes related to CUP probably occur during a person’s lifetime rather than having been inherited before birth. These are called acquired or sporadic mutations. These kinds of mutations may sometimes result from known exposures such as tobacco smoke, ultraviolet light, radiation, or certain cancer-causing chemicals, but often they occur for no apparent reason.

As scientists learn more about how cancers develop, they are also beginning to understand why some cancers tend to grow and spread so quickly that they are diagnosed as cancers of unknown primary.

Cancer of unknown primary (CUP) represents a number of different cancers, so there is no known way to prevent it. Still, certain lifestyle changes may reduce the risk of many types of cancer. This might in turn reduce a person’s risk of CUP.

Smoking is one of the most significant risk factors that a person can control, and is thought to be directly related to deaths from cancer. Quitting or never starting reduces the risk of cancers of many types, including those of unknown primary. Please call us if you need help quitting tobacco. This, and a lot more information about tobacco, can be read online or mailed to you.

Factors linked with body weight, physical activity, and nutrition are also known to affect the risk for different types of cancers and deaths related to cancer. Staying at a healthy weight throughout life, being physically active, eating a healthy diet with an emphasis on plant-based foods, and limiting alcohol intake can all help reduce your risk of cancer.

Because the exact type and the origin of a CUP are unknown, it’s not possible to say how any particular case might have been prevented. It is important to realize that many people with cancer have no apparent risk factors, and there’s nothing they could have done to avoid the disease.

Cancers of unknown primary (CUP) have always spread outside the organ they started in by the time they are diagnosed. If they had been found early, we would know where they started and they would not be classified as a cancer of unknown primary.

Screening tests

The American Cancer Society has specific recommendations about tests that may help detect breast, prostate, cervical, and colorectal cancers early, before they cause any symptoms.

But these cancers account for a fairly small portion of cancers of unknown primary. No screening tests have been proven to be effective in the early detection of many of the cancers that are likely to be diagnosed as cancer of unknown primary, such as pancreatic, stomach, and kidney cancers.