Diagnosis of cancer of unknown primary

Cancer of unknown primary (CUP) means that cancer has already spread, or metastasized, to other parts of the body, but doctors don’t know where it started (called the primary site). So the focus of diagnosis is finding out the type of CUP, the primary site and all the places the cancer has spread. The process of diagnosis may seem long and frustrating. It’s normal to worry, but try to remember that knowing where your cancer started can help your healthcare team decide on the best treatment options for you.

An important early step in diagnosis is to try to find out the type of CUP. Different types of cells are found in different parts of the body. A pathologist will look at the cancer cells to try to identify the type of cell they started from. This can give the healthcare team clues to where the primary site might be.

Understanding how cancer spreads also helps the healthcare team find out where CUP started. Some types of cancer spread in a predictable way from one part of the body to another. So the healthcare team will check if the CUP is a type of cancer that they know usually spreads to the organ or tissue where the CUP was found. Sometimes the symptoms that CUP causes can also help doctors decide where to look for the primary site.

In most cases, doctors can eventually find the primary site. Once they identify the primary site, the cancer is treated like the type of cancer that was found.

Sometimes doctors can’t identify the primary site. This may be because the original tumour is very small and hard to find. In some cases, the body’s immune system may have destroyed the original tumour after the cancer spread. In these cases, a person is diagnosed with CUP.

Some people with CUP are very ill when they are diagnosed. In these cases, looking for the primary cancer isn’t helpful because finding it wouldn’t affect care or treatment. As a result, doctors will only do diagnostic testing if they think it will help them treat the disease.

The following tests are commonly used to try to find the primary site. After a health history, physical exam and basic imaging with CT scan, a biopsy is done. The results of these tests will help the healthcare team decide what other tests you may have. Your doctor may also order other tests to check your general health and to help plan your treatment.

Your health history is a record of your symptoms, risk factors and all the medical events and problems you have had in the past. In taking a health history, your doctor will ask questions about a personal history of:

• cancer
• any abnormal tissue that doctors removed or that disappeared on its own
• general risk factors for cancer such as smoking
• any occupational or environmental exposure to substances that are known to cause cancer

Your doctor may also ask about a family history of:

• any type of cancer
• risk factors for cancer

A physical exam allows your doctor to look for any signs that can help them identify where the cancer started. During a physical exam, your doctor may:

• examine the head and neck, including the skin, scalp, ears, nose, mouth and throat
• feel the neck and area above the collarbone for swelling or enlarged lymph nodes
• listen to the lungs using a stethoscope
• tap the chest to hear percussion sounds
• look at the movement of the chest during breathing
• feel the abdomen for any swelling or a lump
• feel for swelling in the groin
• do a clinical breast exam (CBE) and feel for swelling in the axilla
• do a digital rectal exam (DRE)
• do a pelvic exam
• examine the skin for moles, freckles, birthmarks or spots

Find out more about physical examination, clinical breast exam (CBE), digital rectal examination (DRE) and pelvic exam.

During a biopsy, the doctor removes tissues or cells from the body so they can be tested in a lab. The report from the lab will confirm whether or not cancer cells are present in the sample.

In the case of CUP, this biopsy tells doctors that there is cancer present, but they can’t tell what kind of cancer it is. More biopsies may be done in some cases to try to find the primary site. These biopsy samples may be collected during an endoscopy. They may also be collected using paracentesis or thoracentesis.

Paracentesis may be done if you have a buildup of fluid in the abdomen (called ascites), which can be caused by cancer in the abdomen or pelvis. The doctor passes a needle through the skin and into the abdominal cavity or peritoneum. The doctor then uses the needle to remove fluid from the abdomen.

Thoracentesis may be done of you have fluid around the lungs (called pleural effusion), which can be caused by cancer in a lung. The doctor passes a needle through the skin and between the ribs into the space between the lungs and the wall of the chest (called the pleural cavity). The doctor then uses the needle to remove fluid from the pleural cavity.

Find out more about biopsy, paracentesis and thoracentesis.

Different types of cancer cells may look the same, but they don’t always behave the same. The best way to tell different cancer cells apart is to look for the special markers or molecules on them. These markers can’t be seen under a microscope, so the pathologist has to use a special technique to make them visible.

Immunohistochemistry is a type of cell and tissue study. It uses chemicals to stain antibodies, which are proteins that match up with and attach to markers on the cancer cells. The stain helps the pathologist see the antibodies under a microscope. This helps the pathologist identify the type of cancer cell and how it may behave.

Immunochemistry is an important part of diagnosis for CUP. It can help doctors identify the primary site and how aggressively the cancer behaves. This information helps doctors decide on the best treatment options and make a prognosis.

Find out more about cell and tissue studies.

Tumour markers are substances in the blood that may mean cancer is present. Tumour marker tests are generally used to check your response to cancer treatment. They can also be used to help find the primary tumour in a person with CUP and can guide which other tests may be done.

The tumour markers that may be measured for CUP are:

Alpha-fetoprotein (AFP) and human chorionic gonadotrophin (HCG or b-HCG) levels may be high in people who have metastatic germ cell tumours (testicular cancer or ovarian cancer). It can also be elevated in cancer that starts in the liver (hepatocellular carcinoma).

Cancer antigen 125 (CA125) may be higher than normal in people with metastatic ovarian cancer.

Prostate-specific antigen (PSA) levels may be high in people with metastatic prostate cancer.

Carbohydrate antigen 19-9 (CA19-9) levels may be high if there is pancreatic, liver, gallbladder or bile duct cancer.

Carcinoembryonic antigen (CEA) levels may be higher than normal in people with a type squamous cell of carcinoma of unknown primary.

Find out more about tumour marker tests.

Blood chemistry tests measure certain chemicals in the blood. They show how well certain organs are functioning and can help find abnormalities.

Alkaline phosphatise (ALP), alanine aminotransferase (ALT), aspartate transaminase (AST) and lactate dehydrogenase (LDH) may be measured to check liver function. Higher levels of these chemicals may mean that cancer started in or has spread to the liver.

Creatinine and blood urea nitrogen (BUN) may be measured to check kidney function.

Doctors may order other blood chemistry tests based on the results of other diagnostic tests and where they think the primary site might be.

Find out more about blood chemistry tests.

A stool test examines the stool (feces). Stool tests may be used to look for blood from a tumour in the colon or other parts of the gastrointestinal tract. It may be done if doctors think the primary site is in the colon.

Find out more about a stool test.

A CBC measures the number and quality of white blood cells, red blood cells and platelets. A CBC is done to check your general health.

A low red blood cell count (called anemia) can develop if cancer in the stomach or intestine causes long-term, or chronic, bleeding. Low numbers of different types of blood cells may mean that cancer has spread to the bones and is affecting the bone marrow.

Find out more about complete blood count (CBC).

A computed tomography (CT) scan uses special x-ray equipment to make 3-D and cross-sectional images of organs, tissues, bones and blood vessels inside the body. A computer turns the images into detailed pictures.

A CT scan is used to look at the head and neck, chest, abdomen and pelvis for any evidence of the primary site. Doctors will use other tests, such as a biopsy, to examine any abnormal areas found with a CT scan.

Find out more about CT scan.

Mammography uses x-rays to get a clear picture of the soft tissues inside the breast. Diagnostic mammography may be done if a person who was assigned female at birth has CUP in the lymph nodes under the arm (called the axilla) and the doctor thinks that the original tumour might be a breast cancer.

Find out more about mammography.

Magnetic resonance imaging (MRI) uses powerful magnetic forces and radiofrequency waves to make cross-sectional images of organs, tissues, bones and blood vessels. A computer turns the images into 3D pictures.

In some cases with CUP, an MRI may be done to look for a breast cancer if it doesn’t show up with mammography. This is usually done in people who were assigned female at birth who have a lump in the axilla or sometimes done if there are other reasons why breast cancer may be a likely diagnosis.

Find out more about MRI.

A bone scan uses bone-seeking radioactive materials (called radiopharmaceuticals) and a computer to create a picture of the bones. It is used to find out what is causing bone pain and to see if cancer has spread to the bone.

Find out more about bone scan.

An ultrasound uses high-frequency sound waves to make images of structures in the body. It may be used to examine the testicles in people who were assigned male at birth who have high levels of AFP or HCG tumour markers. It may also be used to examine the breasts of people who were assigned female at birth with CUP in the lymph nodes under the arm (axilla) if the doctor thinks a breast cancer could be the primary site.

Find out more about ultrasound.

An endoscopy allows a doctor to look inside the body cavities using a tube with a light and lens on the end (called an endoscope). During an endoscopy, the doctor can also take samples from any abnormal areas. A pathologist examines the samples to see if it is cancer, which can help the healthcare team identify the primary site.

The type of endoscopy done will depend on:

• the type of CUP, including immunohistochemistry test results
• results of imaging, tumour marker, blood chemistry, or stool tests
• what the doctor found during a physical exam
• your health history

The following are some of the different types of endoscopy that may be used to help find the primary site:

Bronchoscopy is used to look at the airways in the lungs.

Colonoscopy is used to look at the lining of the entire rectum and colon. It is done if doctors think a tumour is in the colon or rectum.

Cystoscopy is used to look at the bladder and urethra.

Endoscopic retrograde cholangiopancreatography (ERCP) combines the use of an endoscope and x-rays to look at the ducts that drain the pancreas, liver and gallbladder.

Panendoscopy combines nasophyngoscopy, laryngoscopy, bronchoscopy and esophagoscopy. It is used to look at the pharynx (throat), larynx (voice box), esophagus, trachea (windpipe) and bronchi (the tubes, or airways, that carry air in and out of the lungs).

Find out more about endoscopy.

A positron emission tomography (PET) scan uses radioactive materials called radiopharmaceuticals to look for changes in the metabolic activity of body tissues. A computer analyzes the radioactive patterns and makes 3-D colour images of the area being scanned.

A PET scan is not used very often to try to find the primary site in people with CUP. In rare cases, doctors may use a PET scan to guide them during a biopsy in parts of the head or neck.

Find out more about PET scan.

To make the decisions that are right for you, ask your healthcare team questions about diagnosis.