Before CUP is diagnosed, you will usually see your GP, who will examine you, send you for tests and refer you to a specialist doctor. The specialist will ask you about your general health and any previous medical problems.

At first, the aim of the tests is to work out whether you have primary or secondary cancer. If the tests show that the cancer is secondary, you will have several different tests to try to find the primary cancer. The tests you have will vary depending on your general health, your symptoms, the location of the secondary cancer and the suspected location of the primary cancer.

Tests used to find where the cancer started

• Blood and urine tests – These tests look for abnormal cells and measure the levels of certain chemicals called tumour markers. 
• Biopsy – In this procedure, a sample of tissue is removed from a secondary tumour or an enlarged lymph node and sent to a laboratory for examination. 
• Endoscopy – This procedure uses an instrument called an endoscope to look inside the body and remove small tissue samples. 
• Imaging tests – X-rays, ultrasounds, and CT, PET-CT, MRI and bone scans create images of the inside of the body.

If these tests find where the cancer started, the cancer is no longer an unknown primary. It will then be treated like the primary cancer type.

Blood and urine tests

A complete blood count checks the levels of red blood cells, white blood cells and platelets. Blood may also be tested to see how well the kidneys or liver are working. Urine may be tested for the presence of any abnormal cells or bleeding that may be coming from the bladder or kidneys. In some cases, blood and urine may also be tested for the presence of an abnormal protein that might help diagnosis a blood cancer called myeloma.

Tumour markers are chemicals made by some cancer cells. They are found in the blood, urine or other body fluids of some people with cancer. Tumour markers include:

• prostate specific antigen (PSA) – high PSA levels may indicate prostate cancer
• alpha-fetoprotein (AFP) – high AFP levels may be a sign of testicular or liver cancer
• human chorionic gonadotropin (HCG) – high levels of HCG can suggest testicular cancer or a rare type of ovarian cancer
• carcinoembryonic antigen (CEA) – may be raised in people who have bowel cancer. Other cancers that may have high CEA levels include lung, pancreatic, stomach, ovarian, breast, thyroid and liver
• cancers cancer antigen 125 (CA125) – CA125 levels may be raised in women with ovarian, endometrial, fallopian tube or peritoneal cancers
• cancer antigen 19-9 (CA 19-9) – may be raised in pancreatic, stomach, bile duct, gall bladder or ovarian cancers
• cancer antigen 153 (CA15-3) – may be raised in women with breast cancer.

Biopsy

A biopsy is the removal of a tissue sample for examination in a laboratory. It is usually the most important test in the diagnosis of CUP because it can show what type of cell has changed. This can indicate where in the body the cancer may have started.

The tissue sample is often removed under local anaesthetic, but it may sometimes be removed under general anaesthetic. You may have one of the following procedures:

• fine needle aspiration – removes cells using a thin needle
• core biopsy – removes tissue using a wide needle
• incisional biopsy – cuts out only part of a tumour
• excisional biopsy – cuts out the whole tumour.

The biopsy sample is sent to a laboratory, where a pathologist uses a series of stains on the sample. This is called immunohistochemistry. These stains may show specific changes in the cells or highlight proteins (antigens) that are linked to various types of cancer.

A biopsy sample can also be tested for genes or proteins that are more commonly seen in specific types of cancer. These may include cytogenetic tests, genomic testing or gene expression-based profiling. These tests are usually part of research projects, and it is not yet clear how useful they are for people with CUP.

A biopsy may not be helpful if the cancer is too difficult to reach or you're too unwell for the procedure.

Endoscopy

This procedure is used to look inside the body for any abnormal areas. A thin, flexible tube with a light and camera on the end, called an endoscope, is inserted through a natural opening (such as the mouth, anus or vagina) or through a small cut made by the surgeon. The endoscope has a small cutting instrument on the end so a biopsy can be taken at the same time if something suspicious is seen. The most common types of endoscopies are listed below.

Imaging tests

X-ray

• This test creates pictures of the inside of the body.
• X-rays may be taken of the chest and other parts of the body.
• For some types of x-rays, a dye (contrast) is used to improve the image.
• This test is painless, and the dose of radiation is small and will not make you radioactive.
• A mammogram is a low-dose x-ray of the breast. The breast is positioned against an x-ray plate and gently but firmly compressed with a clear plastic plate. This test can be uncomfortable but usually only takes 10–30 minutes.

Ultrasound

• This test uses soundwaves to build up a picture of your body.
• A device is placed on or in your body. It sends out soundwaves that echo when they meet something dense, like a tumour. The images are projected onto a computer screen.
• The device may be a small, handheld device (transducer) that is passed over part of your body, such as your abdomen. It may also be a probe that is inserted into part of your body, such as the vagina or rectum.
• An ultrasound takes 10–20 minutes. While it is usually painless, it can be uncomfortable.

CT scan

• Computerised tomography scan.
• This test uses x-ray beams to produce detailed pictures of the inside of the body.
• Before the scan, you may be given a drink or an injection of a dye (called the contrast) to make the pictures clearer. The dye may make you feel hot all over for a few minutes and cause a strange taste in your mouth.
• The dye can cause allergies in some people. If you've had a reaction to dyes during a previous scan, let your medical team know.
• You lie on a table that moves in and out of the scanner, which is large and round like a doughnut. The scan can take up to 30 minutes.

PET-CT scan

• Positron emission tomography scan, combined with a CT scan.
• The PET scan uses low-dose radioactive glucose to measure cell activity in different parts of the body.
• A sample of your blood is taken and mixed with the low-dose radioactive glucose before it is reinjected into a vein. You wait 30–90 minutes for the solution to circulate through your body.
• You then have a CT scan. Cancer cells generally use more glucose than the surrounding tissue does, so any areas of cancer light up on the scan.

Bone scan

• This test shows any abnormal areas of the bones.
• A small amount of a radioactive dye is injected into a vein, usually in the arm.
• You wait 2–3 hours to allow the dye to circulate and be absorbed by your body.
• A scan of your whole body is then taken and any abnormal areas show up as highlighted areas, which are known as hot spots.
• This scan is painless and will not make you radioactive.

MRI scan

• Magnetic resonance imaging scan.
• This uses a magnet and radio waves to take detailed pictures of an area of the body.
• Dye (contrast) may be injected into a vein before the scan to make the images clearer.
• You lie on a table that slides into a narrow metal cylinder that is open at both ends. The cylinder makes some people anxious, but you can ask for a mild sedative beforehand to help you relax. The scan is also noisy, so you will probably be given earplugs or headphones to help block the sound.
• People with some types of pacemakers or other metallic objects cannot have an MRI.

Staging is a way to describe the spread of cancer. However, CUP cannot be given a stage because the primary cancer is not known and the cancer has already spread to other parts of the body when it is found.

Prognosis

Prognosis means the expected outcome of a disease. You may wish to discuss your prognosis and treatment options with your doctor, but it is not possible for any doctor to predict the exact course of your disease.

To work out your prognosis, your doctor will consider test results, the type of CUP you have, the rate and depth of tumour growth, how well you respond to treatment, and other factors such as your age, fitness and medical history.

Although most cases of CUP can't be cured, treatment can keep some cancers under control for months or years. For example, some people with a localised deposit of CUP (e.g. in a lymph node in the neck) are able to achieve long-term control, or sometimes even a cure, with surgery or high-dose chemoradiation (a combination of chemotherapy and radiation therapy).

Whatever the prognosis, palliative treatment can relieve symptoms such as pain to improve quality of life. It can be used at any stage of advanced cancer.

Key points

• Several different tests are used to try to identify the primary cancer.
• The type of tests you have will depend on your general health, the location of the secondary cancer, and the presumed location of the primary cancer.
• Blood tests can check your general health, examine the number and type of blood cells, and measure the levels of tumour markers. Urine may also be tested to check for abnormal cells.
• Taking a tissue sample (biopsy) is the main test for CUP. There are a few ways of doing a biopsy. The doctor may use a needle to take out the tissue (fine needle aspiration or core biopsy). Other options involve surgically removing the sample (incisional or excisional biopsy).
• An endoscopy is another way to look inside the body and remove small tissue samples. This procedure uses a thin, flexible tube called an endoscope. Different types of endoscopies are known by different names, for example, a colonoscopy checks the colon (large bowel).
• Imaging scans such as x-rays, ultrasounds, MRI, CT, PET-CT and bone scans may be used to create pictures of the inside of the body.
• If any of these tests find where the cancer started, the cancer is no longer an unknown primary and is treated according to the primary cancer type.
• Your doctor may talk to you about your prognosis. This is a general prediction about what may happen to you, but no-one can predict the exact course of your illness.

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