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How is cancer of unknown primary diagnosed?

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

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, more tests will be done to try to find the primary cancer. The tests you have will depend on your health and symptoms, the location of the secondary cancer and the suspected location of the primary cancer.

If the tests find where the cancer started, the cancer is no longer an unknown primary. It will then be treated like the primary cancer type. For example, bowel cancer that has spread to the liver will be given the treatment for advanced bowel cancer.

A complete blood count is a test that 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 to look for 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 a protein that might help diagnose a blood cancer called myeloma.

Tumour markers are chemicals made by some cancer cells, and high levels are found in the blood, urine or other body fluids of some people with cancer. Markers that may suggest certain types of cancer include:

  • prostate specific antigen (PSA) – prostate cancer
  • alpha-fetoprotein (AFP) – testicular and liver cancers
  • human chorionic gonadotropin (HCG) – testicular cancer and a rare type of ovarian cancer
  • carcinoembryonic antigen (CEA) – bowel, lung, pancreatic, stomach, ovarian, breast, thyroid and liver cancers
  • cancer antigen 125 (CA125) – ovarian, endometrial, fallopian tube and peritoneal cancers
  • cancer antigen 19-9 (CA 19-9) – pancreatic, stomach, bile duct, gall bladder and ovarian cancers
  • cancer antigen 15-3 (CA15-3) – breast cancer.

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 point to where in the body the cancer may have started. 

For a biopsy, you will usually have a local anaesthetic to numb the area, but in some cases, you may need a general anaesthetic, which makes you unconscious.

There are different ways to remove a biopsy sample. 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.

You might not have a biopsy if the cancer is too hard to reach or if you are too unwell for the procedure.

Tests on the biopsy

If you have a biopsy, the sample will be sent to a laboratory, where a pathologist uses a series of stains on the sample. These stains may show changes in the cells or highlight proteins that are linked to various types of cancer.

In some cases, more specialised tests are done on the biopsy sample. These may include a genomic panel, a series of tests that looks for patterns of abnormalities within the cancer cells. The results may suggest what the primary cancer is most likely to be and which targeted therapy or  immunotherapy drugs may be helpful. This more extensive testing is usually part of research projects and it is not yet clear how useful it is for people with CUP. You can ask your cancer specialists for more information about these specialised tests.

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) or through a small cut made by the surgeon. Your doctor can also use the endoscope to take a biopsy at the same time if they see something suspicious. The most common types of endoscopies are:

  • bronchoscopy or endobronchial ultrasound (EBUS) – lungs or respiratory tract (airways); tube inserted through the mouth or nose.
  • colonoscopy – colon (large bowel); tube inserted through the anus.
  • cystoscopy – bladder; tube inserted through the urethra.
  • gastroscopy – stomach and first part of the small bowel; tube inserted through the mouth.
  • hysteroscopy – uterus (womb); tube inserted through the vagina.
  • laparoscopy – stomach, liver, uterus; tube inserted through small cuts in the abdomen.
  • laryngoscopy – larynx (voice box); tube inserted through the mouth.
  • sigmoidoscopy – lower part of the colon (large bowel); tube inserted through the anus.
  • thoracoscopy – lungs; tube inserted through a small cut in the chest.

Imaging tests are scans that create images of the inside of your body and provide different types of information. Your doctors will recommend the most useful scans for your situation.

  • x-ray – uses low-level radiation to create images of parts of the body, such as bones and chest
  • mammogram – uses a low-dose x-ray to create an image of the inside of the breast
  • ultrasound – uses soundwaves to build up a picture of your body
  • CT scan (computerised tomography scan) – uses multiple x-ray beams to produce detailed pictures of the inside of the body, showing blood vessels, soft tissue and bone all at once
  • PET–CT scan (positron emission tomography scan with CT scan) – a PET scan uses a low-dose radioactive glucose solution to measure cell activity in different parts of the body; combined with a CT scan
  • bone scan – uses radioactive dye to show any abnormal areas of the bones
  • MRI scan (magnetic resonance imaging scan) – uses a magnet and radio waves to take detailed pictures of an area of the body.

This information is reviewed by

This information was last updated June 2020 by the following expert content reviewers: Prof Linda Mileshkin, Medical Oncologist, Clinical Researcher, Peter MacCallum Cancer Centre, VIC; Christine Bradfield, Consumer; Cindy Bryant, Consumer; Dr Maria Cigolini, Head, Department of Palliative Medicine, Royal Prince Alfred Hospital, and Clinical Lecturer, The University of Sydney, NSW; Mary Duffy, Advanced Practice Nurse and Nurse Coordinator, Lung Service, Peter MacCallum Cancer Centre, VIC; Karen Hall, 13 11 20 Consultant, Cancer Council SA; Dr Andrew Oar, Radiation Oncologist, Icon Cancer Centre, Gold Coast University Hospital, QLD; Dr Siobhan O’Neill, Medical Oncologist, Nelune Comprehensive Cancer Centre, NSW; Prof Penelope Schofield, Department of Psychological Sciences and the Iverson Health Innovation Research Institute, Swinburne University of Technology, and Head, Behavioural Science in Cancer, Peter MacCallum Cancer Centre, VIC; Frank Stoss, Consumer.