Unknown Primary: Diagnosis

Approved by the Cancer.Net Editorial Board, 03/2014

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, use the menu on the side of your screen.

By definition, CUP is found after it has spread to another part of the body through a process known as metastasis. Therefore, doctors use many tests to try to find the primary site. Some tests may also determine which treatments may be most effective. For most types of cancer, a biopsy is the only way to make a definitive diagnosis of cancer. Imaging tests are usually 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 where it began. 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 (see below). A pathologist is a doctor who specializes in interpreting laboratory tests and evaluating cells, tissues, and organs to diagnose disease. Careful evaluation and testing of the tumor tissue removed during a biopsy can sometimes give clues about where the tumor began.

The type of biopsy performed will depend on the location of the cancer. Learn more about what to expect when having a biopsy in this separate article on Cancer.Net.

Evaluation by a pathologist

A pathologist diagnoses cancer by looking at the sample of the tumor collected during a biopsy. The pathologist can sometimes predict the primary site of the tumor based on the microscopic appearance of the tumor biopsy or based on the results of special stains, known as immunohistochemical (IHC) stains, that are part of the standard pathologic evaluation. These results, which are often presented in a pathology report, give important information about the cancer and help doctors plan additional testing.

When such a prediction is not possible, an additional test called molecular tumor profiling should be considered. This new diagnostic test can accurately predict the site where the tumor began in most patients with CUP and is frequently useful in directing treatment. More information is provided below.

Evaluation by an oncologist (called clinical evaluation)

Once CUP is diagnosed, an oncologist, which is a doctor who specializes in treating people with cancer, will do more tests to search for the primary site and 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:

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 the 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. For CUP, a CT scan can show cancer in the abdomen and chest. A CT scan can also be used to measure the tumor’s size. Sometimes, a special dye called a contrast medium is given before the scan to provide better detail on the image. This dye can be injected into a patient’s vein or given as a pill to swallow.

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 sugar substance is injected into the patient’s body. This sugar substance is taken up by cells 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 sometimes provides 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. MRI can also be used to measure the tumor’s size. A special dye called a contrast medium is given before the scan to create a clearer picture. This dye can be injected into a patient’s vein or given as a pill to swallow. 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. Sedation is giving medication to become more relaxed, calm, or sleepy.

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 specific symptoms. For example, 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 (PSA) is a protein released by prostate tissue. A PSA test detects higher than normal levels of PSA in a man’s blood, which may mean a man has prostate cancer or a noncancerous condition, such as benign prostatic hyperplasia (BPH) or prostatitis (inflammation of the prostate). Men who are experiencing bone pain or have cancer found in their bones will have a PSA test.

Mammography. Women may receive a mammogram, especially if they have cancer in the axillary lymph nodes, cancer found in other areas that might suggest metastatic breast cancer, such as cancer in the bone, or fluid around the lungs.

After diagnostic tests are done, your doctor will review all of the results with you. These results will help determine the type of tumor and guide the development of your individual treatment plan.

The next section helps explain the different types of CUP tumors that may be diagnosed. Use the menu on the side of your screen to select Subtypes, or you can select another section, to continue reading this guide.