Tests for Cancer of Unknown Primary

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