Signs and Symptoms of Cancer of Unknown Primary

The signs and symptoms of a cancer of unknown primary vary depending on which organs it has spread to. They include:

Swollen, firm, nontender lymph nodes: Normal lymph nodes are bean-sized collections of immune system cells that are important in fighting infections. Cancers often spread to the lymph nodes, which become swollen and firmer. Patients themselves usually notice spread of cancer to lymph nodes on the sides of the neck, above the collarbone, under the arms, or in the groin area. Sometimes, the doctor notices them first during a routine checkup.

A mass in the abdomen that can be felt or produces a feeling of "fullness": This is often 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 accumulation of fluid inside the abdomen called ascites.

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

Pain in the chest or abdomen: This may be due to cancer growth around nerves or to tumors that press against internal organs.

Bone pain: When cancer has spread to your bones, the pain may be severe. Your 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 cancer of unknown origin.

Weakness, fatigue, poor appetite, and weight loss: These generalized symptoms may occur because the cancer has spread to specific organs or systems such as the bone marrow or digestive system. Also, some cancers release substances into the bloodstream that affect metabolism and cause these problems.

General Approach to Diagnosis of Cancer of Unknown Primary

The doctor’s first step in evaluating a person with cancer is to take a medical history (interview to ask about symptoms and risk factors) and a general physical exam. In many cases, these simple steps will reveal, or at least strongly suggest, the source of the cancer. The doctor will also ask if there is a family history of cancer. If there is, this might suggest the origin of the cancer.

If your symptoms and general physical exam strongly suggest cancer and the source is not apparent, the doctor may use imaging tests, specialized blood tests, and endoscopic exams (viewing organs through a lighted tube placed into the mouth, nose, or anus) to look for the primary site of the cancer.

A biopsy (sample of tissue or cells) will be taken for routine study under the microscope and, perhaps, by other specialized lab tests. The biopsy is the most important test. Before any other tests are done, the diagnosis of cancer must be confirmed.

Types of Biopsies

Fine needle aspiration (FNA) biopsy: The doctor places a thin needle into the tumor and aspirates (withdraws) 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, a radiologist can use imaging tests such as a CT scan to guide 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 often, a FNA biopsy will not remove enough tissue for all of the tests needed to identify or clarify some cancers of unknown primary, so other types of biopsies are sometimes needed.

Core needle biopsy: The core biopsy needle is slightly wider than the FNA needle and it removes more tissue, usually one or more cylinders of tissue about 1/16-inch across and one-half inch to 1 inch long. Core biopsies can be done by touch or guided by imaging tests, depending on the tumor's location.

Excisional biopsy: This is often the best approach for a CUP, because it is important to get as much information as possible to make the right diagnosis. A surgeon cuts through the skin to remove the entire tumor nodule or lymph node being examined. If the node or tumor is near the skin surface, this is a simple operation that can 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 prolonged recovery.

Blood Tests

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

Blood cell counts and blood cell examination: Changes in the numbers of different blood cell types may suggest that a CUP has spread to bones and replaced much of the normal blood-producing marrow cells. If there is anemia (lower than normal amount of red blood cells), that might mean there is intestinal bleeding caused by the cancer and point to somewhere in the intestine as the site of its origin.

Liver function tests: Abnormal liver function tests in a person with CUP suggest cancer may be present in the liver. The cancer may have started in the liver or may have spread from another part of the body. Hepatitis virus infection can cause liver cancer. A test for hepatitis B and C viruses might be helpful. If the test shows that you have the virus doctors would suspect that the cancer may have started in the liver

Serum tumor markers: Some types of cancer release certain substances into the bloodstream. If these substances are present in blood samples of CUP patients, they can provide valuable clues to the origin of the cancer. For example, high prostate-specific antigen (PSA) levels suggest that a CUP started in the prostate gland. High CA-125 levels suggest ovarian cancer. High levels of human chorionic gonadotropin (HCG) suggest a germ cell tumor, a type of cancer that can begin in the testicles, ovaries, the mediastinum (area in front of the heart and behind the breastbone), or the retroperitoneum (area behind the intestines). Alpha-fetoprotein (AFP) is produced by some germ cell tumors as well as by hepatocellular carcinoma (liver cancer).

Paracentesis or thoracentesis: In patients with a collection of fluid inside the abdomen (ascites) or fluid in the chest (pleural effusion), samples of the fluid can be removed through a needle for examination under the microscope. Paracentesis is the medical term for removing abdominal fluid. Thoracentesis refers to removing fluid from the chest cavity. These procedures are done to see if the fluid contains cancer cells and, if so, to determine the type of cancer that is present.

Bone marrow aspiration and biopsy: In bone marrow aspiration, a needle and syringe are used to remove small amounts of liquid bone marrow. For a bone marrow biopsy, a larger needle is used to remove a cylinder of bone and marrow, about 1/16-inch across and 1-inch long. Both samples are usually taken from marrow at the back of the pelvis after numbing the area with a local anesthetic.

Lab Tests Used to Analyze Biopsy Samples

All biopsy samples are examined 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 site of origin. If this doesnÂ’t help, then further testing described below might help.

Immunohistochemistry: As with routine biopsy sample processing, very thin slices of the sample are attached to a glass microscope slide. The tissue slice is then treated with a special antibody designed to recognize a specific substance present only in some types of cancer cells. If the patient's cancer contains that substance, the antibody will attach to the cells. Chemicals are added next so that antibodies attached to the cell change color. The doctor who views the sample under a microscope can see this color change.

Hundreds of antibodies are used for immunohistochemical tests by laboratories at cancer centers. Some antibodies are quite specific, meaning that they react only with one type of cancer. For example, some react only with melanomas, others with lymphomas, etc. Others may react with a few types of cancer, so tests with several antibodies are used to make a decision about where the cancer started. Using the results of these tests, the cancer's appearance after routine processing, 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.

Electron microscopy: The typical medical lab microscope uses 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 provide clues to the tumor type or origin.

Flow cytometry: Cells from a biopsy sample are treated with special laboratory antibodies and passed in front of a laser beam. Each antibody sticks only to certain types of cells. If the sample contains those cells, the laser light causes them to give off a different colored light that is measured and analyzed by a computer. This test can help 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.

Cytogenetics: Normal human cells contain 46 chromosomes, pieces of DNA and protein that control cell growth and metabolism. Some types of cancer have characteristic abnormalities of their chromosomes. Recognizing these changes helps in identifying 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.

Cytogenetic testing usually takes about 3 weeks, because the cancer cells must grow in laboratory dishes for about 2 weeks before their chromosomes are ready to be viewed under the microscope.

Molecular genetic testing: Tests of the cancer cellsÂ’ DNA by methods such as polymerase chain reaction (PCR) can find many translocations that are visible under a microscope in cytogenetic tests. DNA tests can also find some translocations involving parts of chromosomes too small to be seen with usual cytogenetic testing under a microscope. This sophisticated testing is not needed in most cases of cancer, but it is sometimes helpful in classifying some cancers when other tests have not provided clues regarding their origin.

Imaging Studies

Imaging studies are ways of producing pictures of the inside of the body. These include:

Chest x-ray: This is a simple test that allows the doctor to look at the lungs, heart, and bones of the upper body. It can show if the cancer started in the lung or has spread to the lung. The test can be done in a doctorÂ’s office or any outpatient facility.

Computed tomography (CT): The CT scan is an x-ray procedure that produces detailed cross-sectional images of your body. Instead of taking one picture as does a conventional x-ray, a CT scanner takes many pictures as it rotates around you. A computer then combines these pictures into an image of a slice of your body. The machine takes pictures of multiple slices of the part of your body that is being studied. This test is very useful in identifying many types of liver tumors.

Often after the first set of pictures is taken you will receive an intravenous (IV) injection of a "dye" or contrast agent that helps better outline structures in your body. A second set of pictures is then taken. This is a very useful test for seeing cancers.

CT scans take longer than regular x-rays and you need to lie quietly on a table while they are being done. But just like other computerized devices, they are getting faster and your scan might be pleasantly short. Also, you might feel a bit confined by the tube you lie within while the pictures are being taken.

You will need to have an IV through which the contrast dye is injected. Some people experience a flushed feeling from the dye or are allergic and get hives, or, rarely, more serious reactions like trouble breathing and low blood pressure can occur. Be sure to tell your doctor if you have ever had a reaction to any contrast material used for x-rays.

Magnetic resonance imaging (MRI): MRI scans use radio waves and strong magnets instead of x-rays. The energy from the radio waves is absorbed and then released in a pattern formed by the type of tissue and by certain diseases. A computer translates the pattern of radio waves given off by the tissues into a very detailed image of parts of the body. Not only does this produce cross-sectional slices of the body like a CT scanner, it can also produce lengthwise slices of your body. A contrast material might be injected just as with CT scans. MRI scans are very useful in looking at cancers. Sometimes they can tell a benign tumor from a malignant one.

MRI scans take longer than CT scans – often up to an hour. Also, you have to be placed inside a tube, which is confining and can upset people with claustrophobia (fear of enclosed spaces). Finally, the machine gives off a thumping noise. Some places provide headphones with music to block out the noise.

Ultrasound: This test uses sound waves (like sonar) to produce images of internal organs. It can help to show which organs have been affected by a cancer of unknown primary (CUP) and, rarely, can help find the cancer's origin.

Positron emission tomography (PET): Positron emission tomography (PET) uses glucose (a form of sugar) that contains a radioactive atom. Cancer cells in the body absorb large amounts of the radioactive sugar and a special camera can detect the radioactivity. This 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 is also helpful in telling whether a shadow on your chest x-ray is cancer. PET scans are also useful when your doctor thinks the cancer has spread, but doesn’t know where. PET scans can be used instead of several different x-rays because they scan your whole body. Newer devices combine a CT scan and a PET scan to even better pinpoint the tumor.

X-rays of the gastrointestinal tract: Sometimes, your doctor may suspect your cancer came from somewhere in your intestinal tract, such as your esophagus, stomach, or large intestine and will x-ray those organs. You will be given a contrast agent that outlines these organs. This is usually a suspension of barium and you will either drink it or it will be given through your rectum as an enema.

Endoscopy: Using a medical instrument called an endoscope, your doctor can look directly inside your body. If your doctor thinks your cancer started in an internal organ such as your intestine, your lung, or your larynx, you may undergo endoscopy, where a specialist in this procedure will look at one of those organs. Usually this procedure is done after you have been sedated (made sleepy) and it is painless.

Diagnostic Strategy for Cancer of Unknown Primary

The pathologist will classify your cancer as 1 of the 3 main types of CUP:

• squamous cell carcinoma
• adenocarcinoma
• poorly differentiated malignant neoplasm

Based on this classification and the location of the metastatic cancer, doctors will decide which additional tests should be done. In many cases, a poorly differentiated malignant neoplasm will undergo additional laboratory testing to classify it more precisely as a melanoma, lymphoma, sarcoma, small cell carcinoma, germ cell tumor, etc.

Carcinoma (not lymphoma, melanoma, etc.) in lymph nodes in the neck: Metastases to neck nodes usually come from cancers of the mouth, throat, sinuses, larynx, or lung. If it is an adenocarcinoma, it may come from the lung. Tests to find cancers of these sites are needed.

The base of the tongue, the throat, and the larynx are deep inside the neck and not easily seen. Fiberoptic laryngoscopes (flexible, lighted, tubes inserted through the mouth or nose) and mirrors are often used to examine these areas. Indirect pharyngoscopy and laryngoscopy use small mirrors to look at the pharynx, base of tongue, and larynx.

If the suspicion of a cancer in the head and neck is very high, the oral cavity, oropharynx (part of the throat just behind the mouth), larynx (voice box), esophagus (muscular tube that connects the mouth to the stomach), and the trachea (wind pipe) and bronchi (breathing passageways that lead to the lungs) will be examined very thoroughly. This exam, called panendoscopy, is done in the operating room with the patient under general anesthesia (asleep).

Imaging tests such as CT and MRI scans of the sinuses and neck area are also used to find small cancers that may have already spread to lymph nodes in the neck. 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 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. Tests to determine whether estrogen receptors (ER) and progesterone receptors (PR) are present in the tumor will help if they are present. These may help confirm the diagnosis and also help in planning treatment and should be performed on the lymph node specimen. These receptors are typically found in breast cancers. In men, a small cancer of the breast may rarely be responsible for underarm lymph nodes spread. In general, women with this problem have a very good outlook.  

Cancer in groin lymph nodes: The likely sources of these metastases include cancers of the vulva, vagina, cervix, penis, skin of the legs, anus, rectum, or bladder. If the cancer is squamous cell, the outlook is fairly good. 

• In women, a Pap test and exam of the vulva, vagina, and cervix are recommended.

• In men, the penis should be carefully examined.

• In both men and women, an exam of the anus and a proctoscopy (examining the rectum through a lighted tube), skin exam, microscopic exam of urine, and pelvic CT scans may be useful.

Women with cancer throughout the pelvic cavity: The ovaries are the most likely source of a cancer that has spread in this way. Serum tests and immunohistochemical tests for CA-125 (positive in most ovarian cancers), as well as CT scans of the abdomen and pelvis, are recommended to help determine whether the primary tumor is likely to be in the ovaries or some other organ. Sometimes the cancer arising 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 and responds well to treatment.

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. Most germ cell tumors develop from germ cells in the gonads (testes or ovaries), but these cancers can sometimes start in other parts of the body.

CT scans of the chest and abdomen are used to try to exclude other types of cancers. Serum tests and immunohistochemical tests for alpha-fetoprotein (AFP) and human chorionic gonadotropin (HCG) are often positive in germ cell tumors.

Cytogenetic studies may find chromosomal changes that support a diagnosis of germ cell tumor. 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.

Cancer in other locations: The main goal is to see if you have a cancer that may respond well to specific treatments. Immunohistochemical tests for thyroglobulin can identify many thyroid cancers, which are often effectively treated with radioactive iodine injections. Other immunohistochemical 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 serum 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 several other organs. Some of these cancers respond to certain chemotherapy combinations.

Melanoma in lymph nodes only: A thorough skin exam should be done to look for the primary melanoma. Some primary melanomas that have already metastasized may be quite small or may resemble ordinary moles to the untrained examiner.

Rarely, primary melanomas disappear on their own without treatment after metastasizing, leaving behind only an area of slightly lighter colored skin. Some patients may not recall that a doctor had previously removed a primary melanoma, so it is important to specifically ask about any skin surgery and to look carefully for any small scars on the skin.

Treatment of metastatic 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 that might suggest liver metastases are usually done.