Oncologist-approved cancer information from the American Society of Clinical Oncology
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Unknown Primary

This section has been reviewed and approved by the Cancer.Net Editorial Board, 4/2013
Diagnosis

ON THIS PAGE: You will find a list of the common tests, procedures, and scans that doctors can use to find out what’s wrong and identify the cause of the problem. To see other pages in this guide, use the colored boxes on the right side of your screen, or click “Next” at the bottom

By definition, CUP is found after it has spread from where it started. Doctors use many tests to try to find the primary site. Some tests may also determine which treatments may be the most effective. For most types of cancer, a biopsy is the only way to make a definitive diagnosis of cancer. Imaging tests will likely be used to look for other areas where the cancer has spread. This list describes options for diagnosing CUP and trying to find the original site it began, and not all tests listed will be used for every person.

A biopsy is the removal of a small amount of tissue for examination under a microscope. Other tests can suggest that cancer is present, but only a biopsy can make a definite diagnosis. The sample removed during the biopsy is analyzed by a pathologist (a doctor who specializes in interpreting laboratory tests and evaluating cells, tissues, and organs to diagnose disease; see below). The type of biopsy performed will depend on the location of the cancer. In another article on Cancer.Net, learn more about what to expect when having a biopsy.

Evaluation by a pathologist

A pathologist diagnoses cancer by looking at the sample of the tumor from the biopsy. The results of the initial biopsy gives important information and helps doctors plan additional testing.

It may also be recommended that additional laboratory tests should be run on a tumor sample to identify specific genes, proteins, and other factors unique to the tumor. This is called molecular testing or profiling of the tumor. Results of these tests may help decide which treatment options may work well and be valuable in helping to predict where the cancer began. More information is provided below.

Most people with CUP have one of these four different types of tumors:

Adenocarcinoma. Nearly 60% of people with CUP have adenocarcinoma. Adenocarcinoma can begin in the glandular tissue of most internal organs (for example, lung, stomach, pancreas, colon, ovary, and breast). Because of this, when adenocarcinoma is found in a metastatic site, it is extremely difficult for the pathologist to tell where it began. Additional diagnostic tests on the biopsy samples, called immunohistochemical (IHC) tests, usually narrow the possibilities. A molecular tumor profiling assay, discussed further in the Treatment Options and Latest Research sections, may be able to predict where the cancer began.

Poorly differentiated carcinoma. Nearly 20% to 30% of people with CUP have poorly differentiated carcinomas. These cancers need extra tests by the pathologist, since some very treatable cancers may initially be diagnosed as poorly differentiated carcinoma. If testing finds that the cancer is lymphoma, germ cell carcinoma, or neuroendocrine carcinoma, effective treatments are often available. When additional testing does not identify more specific tumor types, some patients with poorly differentiated carcinoma may still be treated successfully with chemotherapy (see Treatment Options).

Squamous cell carcinoma. Nearly 5% to 10% of people with CUP have squamous cell carcinoma. Effective treatments are available for this type of tumor if it has certain characteristics. For instance, if squamous cell carcinoma is found in the cervical (neck) lymph nodes, the primary site is often in the head and neck area. If it is found in the inguinal (groin) lymph nodes, the primary site may be in the vulva, vagina, cervix, anus, or bladder. A careful search is important, particularly since most of these cancers can often be treated successfully.

Neuroendocrine carcinoma. Nearly 1% to 5% of people with CUP have neuroendocrine carcinoma. These cancers are being found more often with IHC tests (see above). Some of these tumors are aggressive and fast-growing, but combination chemotherapy (see Treatment Options) may be effective. Others are very slow-growing, and patients sometimes live for several years even without treatment.

Evaluation by an oncologist (called clinical evaluation)


Once CUP is diagnosed, an oncologist (a doctor who specializes in treating people with cancer) will do more tests to search for the primary site and to find out how far the cancer has spread. However, for most patients with CUP, the primary site is not found even after extensive evaluation. For this reason, several diagnostic tests may be done to evaluate specific signs and symptoms, including the following:

Medical history. The doctor will ask detailed questions about previous illnesses, surgeries, and medications. The doctors can help more if they also know as much information as possible about smoking history, drug use, previous moles or benign (noncancerous) tumors, and any exposure to radiation, asbestos, or other chemicals known to be dangerous. A complete family medical history may also provide your doctor with important clues, especially if one or more siblings, parents, or grandparents have had breast, ovarian, or colorectal cancer.

Physical examination. The doctor will do a thorough physical examination of the entire body, including lymph nodes, pelvis, breasts, rectum, and genitals.

Urine and blood tests. These tests can find certain tumor markers and proteins that may help determine where the cancer began. Tumor markers are substances found at higher than normal levels in the blood, urine, or body tissues of some people with cancer. Tumor markers are made either by the tumor or by the body as a result of cancer or other conditions. For example, patients who have cancer in the neck lymph nodes and the Epstein-Barr virus (EBV) may have nasopharyngeal cancer. Also, high levels of the proteins human chorionic gonadotropin (HCG) and alpha-fetoprotein (AFP) may mean a young man with poorly differentiated carcinoma has a germ cell tumor.

X-ray. An x-ray is a way to create a picture of the structures inside of the body using a small amount of radiation.

Computed tomography (CT or CAT) scan of the chest and abdomen. A CT scan helps doctors determine the location of the cancer and where it has spread. A CT scan creates a three-dimensional picture of the inside of the body with an x-ray machine. A computer then combines these images into a detailed, cross-sectional view that shows any abnormalities or tumors. A CT scan can also be used to measure the tumor’s size. Sometimes, a contrast medium (a special dye) is injected into a patient’s vein or given orally (by mouth) to provide better detail.  The CT scan can show cancer in the abdomen and chest.

Positron emission tomography (PET) scan. A PET scan is a way to create pictures of organs and tissues inside the body. A small amount of a radioactive substance is injected into a patient’s body. This substance is absorbed mainly by organs and tissues that use the most energy. Because cancer tends to use energy actively, it absorbs more of the radioactive substance. A scanner then detects this substance to produce images of the inside of the body.

PET scans have proven useful for finding a primary site in 20% to 30% of patients with CUP. For this reason, the PET scan is now considered a routine part of the initial evaluation. Even when a primary site is not found, a PET scan can sometimes provide information that is useful in planning treatment. For example, for patients who have one area of cancer where local treatment (surgery or radiation therapy) is being considered, a PET scan can make sure that no other parts of the body have cancer. Using PET and CT scans together, called an integrated PET-CT scan, provides more detailed and specific information than either test alone.

Magnetic resonance imaging (MRI). An MRI uses magnetic fields, not x-rays, to produce detailed images of the body. A contrast medium (a special dye) may be injected into a patient’s vein or given orally (by mouth) to create a clearer picture. In some parts of the body, especially the brain and spinal column, MRI provides more information than the CT scan. In addition, women with cancer in the axillary lymph nodes (under the arm) should have a breast MRI scan, since this test can sometimes find a small breast cancer that cannot be seen on a mammogram (x-ray of the breast; see below).

Endoscopy. This test allows the doctor to see inside the body with a thin, lighted, flexible tube called an endoscope. The person may be sedated as the tube is inserted through the mouth, down the esophagus, and into the stomach and small bowel. Similar procedures are named according to the part of the body being looked at. For example, a bronchoscopy allows doctors to look inside the bronchial tubes (lungs), and a colonoscopy allows doctors to look inside the colon and rectum. Endoscopy is used for patients with CUP to evaluate the specific symptoms. For instance, patients with squamous cell carcinoma in the neck lymph nodes should always have a complete endoscopy of the nasopharynx, throat, and larynx (voice box) to search for a primary tumor.

Prostate-specific antigen (PSA) test. Prostate-specific antigen (a type of protein released by prostate tissue) is a substance found in a man's blood when there is abnormal activity in the prostate, including prostate cancer, benign prostatic hyperplasia (BPH), or prostatitis (inflammation of the prostate). Men who are experiencing bone pain or have metastasis found in their bones will have a PSA test. A PSA test detects higher than normal levels of PSA, which may mean a man has prostate cancer.

Mammogram. Women may receive a mammogram, especially if they have cancer in the axillary lymph nodes or other areas that might suggest metastatic breast cancer (for example, fluid around the lungs or cancer that has spread to the bone).

Planning treatment after diagnostic evaluations

After these diagnostic tests are done, your doctor will review all of the results with you. Answers to the following questions are essential in helping doctors plan treatment:

  • Was the primary site found during clinical and imaging testing? If so, treatment should follow guidelines for an advanced (metastatic) tumor of that primary tumor.
  • Did the pathologist identify a specific tumor type (for example, lymphoma or germ cell tumor) or a primary tumor? If so, treatment should follow guidelines for the specific tumor type.
  • If no primary site was found, does this CUP fit into any of the subgroups for which specific treatment is recommended (see Treatment Options)?
  • If no primary site was found and this CUP does not fit any of the specific subgroups, will treatment be beneficial? If so, should treatment be based on the tumor type predicted by molecular tumor profiling, or should it be with an empiric (general) chemotherapy program? The chance of chemotherapy being effective depends on the location of the tumor, number of tumors involved, and the person's overall health (see Treatment Options).

Choose “Next” (below, right) to continue reading this guide to learn about the different stages for this type of cancer. Or, use the colored boxes located on the right side of your screen to visit any section.

© 2005-2014 American Society of Clinical Oncology (ASCO). All rights reserved worldwide.

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