Tests and Investigations for CUP

This page provides information on the types of tests and investigations that may be required leading to a diagnosis of MUO/CUP. These will vary depending on the symptoms and the results of other tests. This section also explains the role of a pathologist and the broader role of genomics in helping diagnose CUP or a primary cancer.

Health History and Physical Exam

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Your doctor will conduct a physical examination of your body. Your doctor will pay particular attention to the areas of your body where you are experiencing symptoms, which will be guiding the exam. This can include looking for lumps on your body, feeling for swollen lymph nodes or anything that might be unusual.

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Your doctor will also have a discussion with you about your health history and your family history. This can include:

current or past health issues
past history of cancer in you or your family
risk factors for cancer such as smoking, drinking or exposure to certain chemicals (e.g. asbestos)
family history of cancer
current medications, vitamins and supplements
any other treatments being recieved

Biopsy

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A biopsy is a procedure to obtain a small amount of tissue for testing, with the overall purpose of identifying the type of cancer and, if possible, the original location of the cancer. This may help to guide your doctors in making a diagnosis and choosing the best treatment option. However, if the cancer is too hard to reach or if you are too unwell for the procedure, your doctor might decide against performing a biopsy.

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There are multiple ways to obtain a tissue sample and the method used will depend on the type of mass and location in the body. Depending on the method, you will have local anaesthesia to numb the area or general anaesthesia to make you unconscious during the procedure.

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Fine needle aspiration cytology – removes cells or fluid using a thin needle
Core biopsy – removes tissue using a hollow needle
Incisional biopsy – only cuts out part of the tumour
Excisional biopsy – cuts out the whole tumour

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Role of the Pathologist in diagnosing CUP

After you have a biopsy, it will be sent to a laboratory for testing. The sample of tissue will be looked at under a microscope by a specialist doctor called a pathologist. A pathologist is a doctor specialising in the diagnosis of disease based on examination of tissues and fluids removed from the body. Upon examination, the pathologist determines if the tissue sample contains normal, pre-cancerous or cancerous cells and then writes a report on their findings (pathology report).

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The pathologist will try and identify the type of cancer present in the biopsy, determine the original location of the cancer, and provide information that may help to identify the best treatment option. This helps to guide the clinical team in making a diagnosis and choosing the best treatment. Cancer changes the appearance of healthy cells, making them look abnormal. Pathologists can also identify which cells do not belong in the tissue or organ that it has spread to and are able to identify it as a secondary cancer. However, in MUO or CUP, the primary cancer is not easily recognisable. These cells may have become so abnormal that it is difficult to identify where they came from. These cells are called poorly differentiated or undifferentiated.

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Further testing may be required, such as immunohistochemistry, where the pathologist uses special stains to locate specific proteins that are linked to known cancer types (e.g., adenocarcinoma, squamous cell carcinoma).

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Watch and listen to a medical pathologist share her expert insights about the role of a pathologist in diagnosing CUP.

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Imaging Tests

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Depending on your situation, your doctor might recommend additional scans. You will need to inform the doctor before having any scans if you have any allergies or past reactions, chronic conditions such as diabetes, or are pregnant or breastfeeding.

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X-ray

How it works	X-rays deliver low-energy beams of radiation to create images of parts of the body to produce the pictures. X-ray beams are absorbed differently by structures in the body, such as bones that absorb radiation easily (appearing white in the picture) or soft tissues like organs that don’t absorb radiation as easily and will appear gray.
How long	10-30 minutes.
What happens	Some x-rays use dye (contrast) to improve the image and make certain structures easier to see. Depending on what part of the body is being x-rayed, you might be asked to lie, sit or stand. You will hold still in front of or on a machine while the images are taken.
Special notes	The procedure is painless with only a small dose of radiation. The contrast dye is generally very safe and reactions are uncommon; however, people with diabetes and kidney disease should inform their doctor as they will have a slightly greater risk of reaction.

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Mammogram

How it works	An x-ray machine that is designed only for mammograms will use low-dose x-ray beams to create an image of the inside of the breast.
How long	10-30 minutes.
What happens	You will stand in front of an x-ray machine that is specially designed for mammograms. Your breast is placed between two x-ray plates, one at a time, which will press together firmly to spread the tissue so a clear image can be taken. This also prevents movement so the image does not become blurred. Usually two different views are taken of each breast. During the brief period when you are exposed to the x-ray beams, you will be asked to stand still and hold your breath.
Special notes	The procedure can be uncomfortable when the x-ray plates are pressed together. If the discomfort becomes too much, notify the technologist (the person performing the procedure). You should notify your doctor if you are pregnant (or believe you are) or breastfeeding.

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Ultrasound

How it works	An ultrasound is a generally non-invasive imaging test that uses soundwaves to create a picture of the inside of the body. These soundwaves echo when they meet something solid, such as an organ or tumour and a computer will create the image.
How long	10-20 minutes.
What happens	A gel is spread on your skin in the required area and a handheld device called a transducer will pass across the surface. The transducer produces high-frequency sound waves which pass through the gel and into your body. The soundwaves bounce off structures in the body and back to the transducer, converting them into an image. Some transducers are wands that can be inserted into a body cavity.
Special notes	The procedure is usually painless, but it can be uncomfortable when a transducer is inserted into a body cavity. The soundwaves produced during an ultrasound will not be able to be heard.

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CT scan (computerised tomography scan)

How it works	A CT scan uses x-ray beams and a computer to create detailed pictures of the inside of the body. The scanner is large and shaped like a doughnut. CT scans will provide more detail than an x-ray as it takes dozens to hundreds of images of your body. This provides a clearer image of soft tissues in the body, which don’t always show up on a regular x-ray, and also shows organs and other structures that overlap or are hidden.
How long	30-60 minutes (mostly due to preparation).
What happens	Before the scan, you may be given a drink or injected with a dye (contrast) to highlight certain structures in your body. This will make the images clearer. You will usually lie still on a table that moves into the scanner. It is important to lie still as movement could cause blurry or less clear images.
Special notes	The procedure is painless; however, the dye can make you feel hot or flushed and leave a bitter taste in your mouth. There is a small risk of having an allergy-like reaction to the dye, such as a rash, itchiness, nausea, sweating or difficulty breathing. If you know that you have an allergy to the dye or contrast, or if you are diabetic or have some known kidney issue, inform your doctor. You should also notify your doctor if you are pregnant (or think you may be) as CT scans use slightly higher levels of radiation than x-rays.

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PET scan (positron emission tomography scan)

How it works	PET scans use a low-dose radioactive solution to measure cell activity in different parts of the body. The one most commonly used is fluorodeoxyglucose (FDG) which is a simple sugar (glucose) that has been made radioactive. This means that it will give off energy in the body to be seen by the scanner. Cancer cells grow quickly, and as such, need a lot of energy (or a lot of sugar). The increased amount of sugar needed in these areas will show up as “hot spots”.
How long	About 2 hours.
What happens	You will be asked to remove anything metal from your body as it interferes with the images of the scanner. You are injected in the arm with a small amount of the radioactive solution and wait 30-90 minutes to allow the solution to spread through your body. You will be lying down, usually on your back, on a couch while it moves backwards and forwards in the scanner. The scanner is large and doughnut shaped. As you move through the scanner, it will take pictures of your body.
Special notes	You need to notify your doctor if you are pregnant or have any possibility of being so or are breastfeeding. The specialist will also tell you to avoid children and pregnant women for a few hours after the scan. It is very rare to have an allergic reaction to the radioactive solution. The solution will leave your body in your urine within a few hours.

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PET-CT Scan

How it works	This test combines both a PET scan and a CT scan and will provide more detailed information about the cancer. See above for information about PET scans and CT scans.
How long	About 2 hours.

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Bone scan

How it works	A bone scan will look for changes in your bones, using a radioactive tracer (dye) injected into your bloodstream. It can look at one particular joint or bone, but it is more usual for the entire body to be scanned for cancer patients.
How long	The test takes between 30-60 minutes, but you will be required to be at the hospital for several hours.
What happens	You are injected in the arm with a small amount of radioactive dye. You will then wait 2–3 hours for it to move through your bloodstream and collect in your bones. The dye tends to collect more in areas where the bone is breaking down or repairing itself and will appear darker on the scan than the other bones. You will lie down on a couch and must keep very still while going through the scanner. A large camera connected to an arm-like device will scan you and pick up on the radioactivity.
Special notes	If you are pregnant or breastfeeding, notify your doctor and the specialist conducting the scan. The dye leaves your body through your urine after a few hours and you will be told to avoid children and pregnant women for a number of hours.

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MRI scan (magnetic resonance imaging scan)

How it works	An MRI scan uses a magnet and radio waves to take detailed pictures of a particular area inside your body.
How long	30-90 minutes.
What happens	You may be injected with a dye (contrast) depending on the scan you are getting to help the tissues show up clearer on the image. You will lie down on a table and be given earplugs or headphones as the MRI scanner is very noisy. You will also be given a buzzer so you can talk to the specialist who is in a different room whenever you press the button. The scanner is a narrow metal cylinder that is open at both ends. During the scan, the table will move in and out of the tunnel. Depending on the scan, you might have leads (wires or stickers) placed on your chest to monitor your heartbeat, a plastic tube attached to your finger to monitor your breathing, or a needle inserted into a vein if any medicine is needed. The part of the body that is being scanned will be gently secured so that the images collected are clear.
Special notes	If you might be pregnant, have kidney problems or do not like closed spaces, you should talk to your doctor. If you feel anxious in closed spaces, the doctor may give you some medicine to keep you calm. If there are any metallic objects in your body, such as a pacemaker, you will not be able to have an MRI – notify your doctor. An allergic reaction to the dye (contrast) is very rare, but any reactions are usually mild.

[Adapted from Cancer Council Australia. Understanding Cancer of Unknown Primary. IVE Group; 2022]

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Further information about about Medical Procedures:

Procedures | healthdirect

Blood, Urine & Tumour Marker Tests

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Blood tests check the number of white blood cells, red blood cells and platelets in your blood. This is usually referred to as a complete blood count (CBC), full blood count (FBC), or full blood examination (FBE). They can also check the health of your kidneys and your liver.
Urine tests assess the health of the kidneys and the bladder by looking for any blood or abnormal cells that are present. In some cases, blood and urine tests may also be able to focus on a protein that could help diagnose a blood cancer called myeloma.
Tumour markers might suggest certain types of cancer. Cancers can release certain chemicals into the body called tumour markers that can be produced by one or several types of cancer. High levels can be found in the blood, urine or other bodily fluids of some people with cancer.

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Tumour Marker		Types of Cancer
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, gallbladder, and ovarian cancers
Cancer antigen 15-3	CA 15-3	Breast cancer

Additional Tests

Your doctor will only recommend additional tests (such as an endoscopy) if they are appropriate and may help locate the primary cancer. This will be based on your individual situation, such as your presenting symptoms and results of previous tests.

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Endoscopy

An endoscopy is a procedure that uses an endoscope (a thin, flexible tube with a light and camera on the end) to look inside the body for any abnormalities. The endoscope is inserted through a natural opening (such as the mouth) or through a small cut made by a surgeon. The endoscope can also be used to take a biopsy if your doctor notices anything suspicious. The most common endoscopies performed for CUP include gastroscopy and colonoscopy.

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Endoscopy Type	What is checked
Bronchoscopy or endobronchial ultrasound (EBUS)	Lungs or respiratory tract (airways)
Colonoscopy	Colon (large bowel)
Cystoscopy	Bladder
Gastroscopy	Oesophagus, stomach and first part of the small bowel
Hysteroscopy	Vagina and cervix
Laparoscopy	Abdominal cavity, liver, bowel, uterus and ovaries
Laryngoscopy	Larynx (voice box)
Sigmoidoscopy	Lower part of the colon (large bowel)
Thoracoscopy	Lungs

Genomic Testing

The Role of Genomic Testing in CUP

Watch and listen to genomic experts share their insights about genomic testing for CUP patients.

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Specialised tests can be performed on a biopsy, including Genomic Testing which involves looking at the genes of the cell and changes that might be causing the cancer to grow. Sometimes this testing is done on a blood test or 'liquid biopsy' from which fragments of circulating DNA from cancers may be identified and analysed. You may be able to access genomic testing for free through clinical trials and other research studies, which should be discussed with your doctor.
Genomics is the study of DNA and genes (the genetic blueprint of the cell), and of the changes that can occur to the genome during disease development, such as cancer. In contrast, the term “genetics” is more often used to describe pre-existing variations in the DNA code of an individual that predispose that person developing a disease such as cancer. These genetic DNA variants are typically passed down through generations leading to an increased risk of cancer within families and earlier onset of disease.
Cancer describes a group of diseases where DNA changes (mutations) are detected in the cancer genes of specific cells, which causes those cells to “go rogue”. This means that cancer cells start to act on their own, outside of the normal rules governed by the human body. When cells “go rogue”, they develop some common characteristics, including uncontrolled cell growth and replication leading to development of a tumour in an organ – this is referred to as the primary cancer site. Later stages of cancer development involve spread of cancer cells into neighbouring tissues and then eventual spread (metastasis) to other parts of the body, sometimes very far away from where the cancer began. In CUP, a metastasised tumour can be detected but the primary tumour where the disease originally developed remains undetected or is not clear.
New technologies in genomic testing continue to be developed to try and help clinicians identify the likely primary cancer for CUP patients and determine how best to treat the disease. Genomics can provide important clues about where a cancer has come from, what is driving its growth and whether it may respond to different forms of therapy.
When the primary source of a tumour is unknown (i.e., with CUP), treatments may be less successful because they are not targeting a specific type of cancer. Researchers are studying patients’ genomics and their cancers’ DNA, to help find out where an unknown cancer started. In some cases, this genomic information can also find a weakness that the cancer has to a particular treatment. This allows treatment to be person-specific rather than a one-size-fits-all approach.
Over the past 20 years, cancer researchers have studied thousands of cancer tissue samples, which has led to a much better understanding of what genomic changes make cancer cells “go rogue”. This research has led to the identification of “genomic portraits” of different cancer types. These genomic portraits can be used as a “line-up of usual suspects”, to identify an unknown tumour based upon its genomic “look-a-like” portrait. Early work in this area involved measuring the gene activity rather than looking for DNA mutations in those genes, but both approaches can be effective.
Genomic testing involves analysing DNA +/- RNA from a tumour and/or blood sample. This process can take several weeks as there are many complex steps involved. Sometimes, testing may fail if there are very few tumour cells in the sample. The cost of genomic testing is not yet covered by Medicare, but you may be able to access genomic testing for free through clinical trials and other research studies. Discuss this with your doctor.

DNA sequencers (molecular genetic tool) analyse or "read" the genetic code, using DNA taken from a blood or tissue sample, to identify genetic changes associated with known cancer types.

What else can I read about diagnosis?

Here are the links to other information pages to learn more about different aspects of diagnosis. You may also use the quick links on the right side of the page to navigate.

How is CUP Diagnosed?

Patient Journey: What to Expect

Your Healthcare Team

Questions to Ask Your Doctor