Unknown Primary: Diagnosis

Approved by the Cancer.Net Editorial Board, 02/2019

ON THIS PAGE: You will find a list of common tests, procedures, and scans that doctors use to find the cause of a medical problem. Use the menu to see other pages.

By its very nature, CUP is found after it has spread to another part of the body from where it started, which is called metastasis. Therefore, doctors use many tests to try to find where in the body the cancer began, called the primary site. Some tests may also determine which treatments may be most effective.

This section describes options for diagnosing CUP and trying to find the primary site. Not all tests listed below will be used for every person. Your doctor may consider these factors when choosing a diagnostic test: 

  • The type of cancer suspected

  • Your signs and symptoms

  • Your age and general health

  • The results of earlier medical tests

In addition to a physical examination, the following tests may be used to diagnose CUP.


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 the examination of a biopsy specimen by a pathologist can make a definite diagnosis. 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 to where the tumor began.

Evaluation by a pathologist

A pathologist diagnoses cancer by looking at the tumor sample collected during a biopsy. The pathologist can sometimes predict the primary site of the tumor based on the appearance of the tumor cells under a microscope 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 predicting the location of the primary site is not possible, an additional test called a molecular cancer classifier assay may be considered. For this test, the pathologist uses tumor tissue collected during the biopsy. This new diagnostic test can accurately predict the site where the tumor began in many patients with CUP, using a technique called gene expression profiling. The results of this new diagnostic test are often useful in helping choose treatment options. Learn more about gene expression profiling in the Types of Treatment and Latest Research sections.

Evaluation by an oncologist

Before CUP can be diagnosed, a number of tests need to be performed to search for a primary site.  This is called a clinical evaluation, and is usually conducted by an oncologist. An oncologist is a doctor who specializes in treating people with cancer.

The following diagnostic tests may be included in the evaluation: 

  • Medical history. The doctor will ask detailed questions about previous illnesses, surgeries, and medications. Doctors are able to 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 give your doctor important clues, especially if 1 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 indicate 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 takes pictures of the inside of the body using x-rays taken from different angles. A computer combines these picutres into a detailed, 3-dimensional or 3-D view that shows any abnormalities or tumors. A CT scan can show cancer in the abdomen and chest, and sometimes can lead to the identification of the primary site. 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 or liquid to swallow.

  • Positron emission tomography (PET) or PET-CT scan. A PET scan is usually combined with a CT scan (see above), called a PET-CT scan. However, you may hear your doctor refer to this procedure just as a 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.

    For most patients with CUP, a PET scan is not included in the initial evaluation because it does not improve the ability to locate the primary site when compared to CT scanning alone. However, a PET scan may provide valuable information in specific situations. Patients with CUP who have 1 area of cancer where local treatment, such as surgery or radiation therapy, is being considered should have a PET scan to make sure that no other parts of the body have cancer. For people with squamous cell carcinoma involving lymph nodes in the neck (see the Subtypes section), a PET-CT scan is often useful in identifying a primary site in the head and neck area.

  • Magnetic resonance imaging (MRI). An MRI uses magnetic fields, not x-rays, to produce detailed images of the body. 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 or liquid to swallow. In most situations, an MRI scan provides the same type of information as described above for the CT scan.  However, in some parts of the body, especially the brain and spinal column, MRI provides more information than CT scans. In addition, women with cancer in the axillary lymph nodes, located under the arm, should have a breast MRI, since this test can sometimes find a small breast cancer that cannot be seen on a mammogram (see below).

  • Endoscopy. An endoscopy 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.

    Endoscopy 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 substance released by prostate tissue. A PSA test finds 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 with CUP should have their PSA level measured, since higher-than-normal levels usually identify the prostate as the primary site.

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

If these diagnostic tests identify a primary site, then CUP is not the diagnosis, and treatment should follow guidelines for the tumor type identified. If these tests are unsuccessful in identifying a primary site, the diagnosis of CUP is made. At this point, further X-rays or clinical tests are unlikely to identify the primary site, and treatment for CUP should be considered.

The next section in this guide is Subtypes. It describes the different CUP tumors that may be diagnosed. Use the menu to choose a different section to read in this guide.