Malignant Neoplasm of Unknown Primary Site

When cancer spreads through the body but doctors cannot find where it first started, this creates a challenging medical puzzle that requires careful testing and specialized care to guide treatment decisions.

Table of contents

• What Is Cancer of Unknown Primary?
• Why the Primary Cancer May Not Be Found
• Signs and Symptoms
• Diagnosis and Testing
• Outlook and Survival
• Treatment Options

carcinoma of unknown primary, CUP, cancer of unknown primary, occult primary tumor, occult primary cancer, malignancy of unknown primary origin, MUO

What Is Cancer of Unknown Primary?

Carcinoma of unknown primary (CUP) is a rare disease in which malignant (cancer) cells are found in the body but doctors cannot find where the cancer began. The word “malignant” means the cells can grow uncontrollably and spread to other parts of the body.^[1]

Cancer can form in any tissue of the body. When cancer spreads from where it started to other parts of the body, this process is called metastasis. The place where cancer first formed is called the primary cancer or primary tumor. The cancer that has spread is called secondary cancer or metastatic cancer.^[1]

Normally, doctors can find the primary cancer relatively easily. Cancer cells usually look like the cells from the tissue where the cancer began. For example, breast cancer cells that spread to the lung still look like breast cancer cells under a microscope.^[1]

Sometimes doctors find cancer that has spread to one or more parts of the body, but despite several tests, they cannot find where in the body the cancer first began to grow. When tests are able to find the primary cancer, it is no longer considered CUP and treatment is based on the type of primary cancer that was found.^[1]

With modern testing methods including advanced imaging and genetic testing, less than 1% of new cancer diagnoses are designated as CUP. Most cases of CUP are adenocarcinomas (cancers that start in gland cells) or undifferentiated tumors (cancer cells that do not look like any particular type of normal cell). Less commonly, CUP can be squamous cell carcinomas, melanomas, sarcomas, germ cell tumors, or neuroendocrine tumors.^[3]

Why the Primary Cancer May Not Be Found

There are several reasons why doctors may not be able to find the primary cancer, though they don’t always know for certain why this happens.^[1]

The primary cancer may be very small and grow slowly, making it too small to be detected by imaging tests or to cause symptoms. In some cases, your body’s immune system may have successfully attacked and destroyed the original primary cancer, while the secondary cancer continues growing. This is not common, but it can happen.^[1][4]

Sometimes the primary cancer was removed during surgery done for another medical condition, and doctors didn’t know cancer had formed. For example, a uterus with cancer may have been removed during a hysterectomy performed to treat a serious infection.^[1]

In some patients, the primary site cannot be identified even when doctors examine the body after death.^[3]

Signs and Symptoms

The signs and symptoms of CUP are different depending on where the cancer has spread in the body. Sometimes CUP does not cause any signs or symptoms at all.^[1]

Any change in your body that doesn’t go away or gets worse is a reason to talk to a healthcare provider. Common symptoms that cancer can cause include:^[1][2][5]

• A lump or thickening in any part of the body
• Pain in one part of the body that does not go away
• A cough that does not go away or hoarseness in the voice
• Changes in bowel or bladder habits, such as constipation, diarrhea, or frequent urination
• Unusual bleeding or discharge
• Fever for no known reason that does not go away
• Drenching night sweats
• Weight loss for no known reason or loss of appetite
• Feeling very tired
• Nausea and vomiting
• Swelling of the belly
• Swollen lymph nodes in your collarbone, neck, groin, or under your arms

These symptoms may be caused by CUP or by other conditions. You should check with your doctor if you have any of these symptoms.^[1]

Diagnosis and Testing

Because the place where the cancer started is not known, many tests and procedures may be done to search for the primary cancer. The process of diagnosis may seem long and frustrating, but understanding where your cancer started can help your healthcare team decide on the best treatment options for you.^[7]

Initial Evaluation

Your doctor will start by doing a physical examination to look for any signs of cancer. They will check for lumps, swollen lymph nodes, and anything else that seems unusual. Your doctor will ask about your symptoms, your current health, your health history, and your family’s health history. They may also ask about risk factors for cancer such as smoking or exposure to substances that are known to cause cancer.^[1][7]

Initial tests may include blood tests such as a complete blood count, basic metabolic panel, and tests to check how well your organs are working. Your doctor may also do a fecal occult blood test to check for hidden blood in stool or a urinalysis to check your urine.^[5]

Biopsy

If tests show there may be cancer, a biopsy is done. A biopsy is a procedure to remove a sample of tissue for testing in a laboratory. A medical pathologist will examine the tissue samples under a microscope to look for cancer cells.^[1][5]

The pathologist plays a central role in evaluating CUP. They will use several techniques including examining the tissue structure, special staining methods called immunohistochemistry, and genetic testing to try to determine what type of cells the cancer started from. This can give the healthcare team important clues about where the primary cancer might be.^[18]

Advanced tests may be done on the tissue sample, such as gene expression profiling or next-generation sequencing. These tests look for specific proteins or gene changes on the surface of cancer cells that may help identify where the cancer started or which treatments might work best.^[16][18]

Imaging Tests

Imaging tests create pictures of the inside of the body. They can show the location and size of the cancer and help doctors search for where the cancer may have started. Imaging tests used to diagnose CUP may include:^[11][23]

• Computerized tomography (CT) scan: Uses X-rays to create detailed cross-sectional images of your body
• Magnetic resonance imaging (MRI): Uses magnets and radio waves to create detailed images of soft tissues in your body
• Positron emission tomography (PET) scan: Uses a small amount of radioactive material to look for areas of cancer throughout the body
• Ultrasound: Uses sound waves to create pictures of organs and tissues

Other Tests

Depending on your symptoms and the results of other tests, your doctor may recommend additional procedures such as endoscopy (using a thin tube with a camera to look inside your body), colonoscopy, or specialized tests to check specific organs.^[5][7]

Blood tests called tumor marker tests may be done to look for substances that certain kinds of cancer release into the blood. These can provide clues about which type of cancer might be present.^[11][23]

Outlook and Survival

The prognosis for patients with CUP is generally poor because the cancer has already spread from one part of the body to another. Approximately 30% of patients are alive at 1 year.^[3]

CUP represents a diverse group of diseases, and your individual outlook depends on several factors. Some patients have what doctors call favorable-risk CUP, which has a better prognosis, while others have poor-risk CUP.^[22]

Factors That Affect Outlook

Several characteristics can influence your prognosis:^[3][22]

The type of cancer cells under the microscope makes a difference. Adenocarcinoma or undifferentiated carcinoma generally has a worse outlook than neuroendocrine tumors.

Where the cancer is found matters. Cancer found only in lymph nodes tends to have a better outlook than cancer that has spread to organs like the liver or adrenal glands. If cancer is found in only one lymph node or one organ, the outlook is generally better than if it is found in multiple places.

Your overall health and ability to perform daily activities (called performance status by doctors) is important. People who can carry out normal activities have a better prognosis than those who need significant assistance.^[22]

Blood test results, specifically the level of an enzyme called lactate dehydrogenase (LDH), can provide prognostic information. People with normal LDH levels have a better prognosis than those with high levels.^[3][22]

Age also plays a role, with younger patients generally having better outcomes than older patients.^[3]

Modern testing methods can identify targeted therapies for some patients, which may result in a much better prognosis than traditional treatments.^[3]

Treatment Options

Although doctors can’t cure most cases of CUP because the cancer has already spread, treatment can control it, relieve symptoms, and give you a good quality of life. Your healthcare team will work to develop a treatment plan based on what they learn about your cancer, even when they can’t find the primary tumor.^[16]

The treatment you receive depends on several factors including where the cancer is found in your body, what type of cells are involved, how many places the cancer has spread to, your overall health, and what you prefer.^[17]

Chemotherapy

Chemotherapy uses anti-cancer drugs to destroy cancer cells. The drugs circulate throughout the body in the bloodstream. You often receive a combination of 2 or 3 chemotherapy drugs. Chemotherapy is the most common treatment for CUP.^[16][17]

Targeted Therapy and Immunotherapy

If special tests on your tissue sample find certain proteins or gene changes, you may be able to have treatment with a targeted cancer drug. These drugs target specific differences between cancer cells and normal cells that help them grow and survive.^[16]

Immunotherapy uses your body’s own immune system to fight cancer. Your doctor will tell you if these treatments are possible for your situation, which may include participation in a clinical trial.^[16]

Radiation Therapy

Radiotherapy uses high-energy rays to kill cancer cells. You might have radiotherapy to help treat symptoms caused by the cancer, such as pain. This is called palliative radiotherapy. Very occasionally, you may have radiotherapy to try to cure the cancer, for example, if you only have cancer in the lymph nodes in one area such as the neck.^[16][17]

Surgery

Surgery is not often used to treat CUP because the position of the primary cancer is not known and doctors usually cannot remove all the secondary cancers. However, surgery may be offered in specific situations.^[16]

If tests show that cancer has spread to lymph nodes in the head and neck area or groin, and this is the only place where cancer is found, you may have surgery to remove the lymph nodes. This type of surgery is called lymph node dissection. This can cure some people with CUP if this is the only place where the cancer is. You often have radiotherapy to the area after this operation.^[16]

Surgery may also be suggested to relieve symptoms such as bleeding or blockages in the body caused by CUP.^[16]

Supportive Care

Your doctor may suggest holding off treatment for a while if you don’t have many symptoms. Treatment to help control symptoms and maintain quality of life is an important part of care for CUP.^[16]

Finding out that your cancer cannot be cured can be very difficult. It may help to talk to a close friend or relative about how you feel, or you can reach out to cancer support organizations for assistance.^[16]