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| Detailed Guide: Cancer of Unknown Primary | How Is Cancer of Unknown Primary Diagnosed? |
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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 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, 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 ascites, 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 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 may be the cause, the doctor may use different types of tests to look for the cancer:
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. They can sometimes help when looking for cancer, but other tests like 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), the barium is given as an enema before the test. Endoscopy is used more often than barium x-rays to look for CUP. X-rays of bones can help evaluate pain that might come from cancer that has spread to the bones. Computed tomography scan (CT) 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. Before any pictures are taken, you may be asked to drink 1 to 2 pints of a liquid called "oral contrast." This helps outline the intestine so that certain areas are not mistaken for tumors. You may also receive an IV (intravenous) line through which a different kind of contrast dye (IV contrast) is injected. This helps better outline structures in your body. The injection 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. 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 scan (MRI) 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). If this is severe, you may need to have the scan on an "open" MRI machine. These machines are less enclosed, but the scans may not be as good. Also, MRI machines make 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. For most ultrasound exams, 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 be useful to look at organs in the abdomen and pelvis to see if they may have been affected by cancer. Positron emission tomography scan (PET) 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 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. Endoscopy is commonly used to look at the esophagus and stomach, the large intestine, the lungs, 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 viewed under a microscope to see if cancer cells are present. Endoscopic ultrasound: This is a test is done with an ultrasound probe that is attached to an endoscope. It can be used to get pictures of the pancreas and to image tumors of the esophagus. Patients are first sedated (given medicine to make them sleepy). The probe is then passed through the mouth or nose, to 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 is a very good way to look at the pancreas. It is better than CT scans for spotting small tumors in the pancreas. If a tumor is seen, it can be biopsied during this procedure. 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). The doctor guides a catheter (a very small tube) from the end of the endoscope into the common bile duct. 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 whether or not they look like cancer. This procedure is usually done while the patient is sedated (given medicine to make them sleepy). More information about this topic can be found in our document, Endoscopy. 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.
Biopsies 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 the placement of the needle by touch. If the mass is deeper inside the body, the doctor can use an imaging test like an 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 tissue for all of the tests needed to identify some cancers of unknown primary. When that is the case, 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. A core needle biopsy removes larger pieces of tissue so it's 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 removing it 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. An incisional biopsy, like an excisional biopsy, 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. These procedures are usually done under local anesthesia (numbing medicine), with the patient 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, 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 tissue from the biopsy 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 cells' 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.
One drawback of cytogenetic testing is that it usually takes about 3 weeks to get results. This is 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 takes less time than standard cytogenetic testing. The disadvantage is that it requires that doctors have an idea of what chromosome changes they are looking for ahead of time. Molecular genetic testing Testing cancer cells' DNA using methods like 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 cancers 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. Classifying cancers of unknown primary After initial lab tests, the pathologist classifies a cancer of unknown primary into 1 of the 5 main types:
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 Cancer that has spread to neck nodes usually comes 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 like 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 a thorough breast physical exam is always done. Then diagnostic mammography (breast x-ray) and breast ultrasound are often the first tests ordered. If no tumor is found on these tests, an MRI of the breasts may be very useful. Lab tests on the tumor cells can determine if they have estrogen receptors (ER) and/or progesterone receptors (PR). These receptors are often found in breast cancers, and finding them may help confirm the diagnosis of breast cancer. The presence of these receptors is also important in planning 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, but other cancers are also possible.
Women with cancer throughout the pelvic cavity The ovaries 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. 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 eye and 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:
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: 10/15/2009 |