All About Cancer of Unknown Primary

Author: OncoLink Team
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What is a cancer of unknown primary?

Cancer can start any place in the body. Cancer can also spread to other parts of the body. When cancer spreads, the cells from both parts of the body (the first part of the body and where it has spread to) look the same under a microscope. If lung cancer spreads to the bone, a biopsy of that bone lesion will look like lung cancer cells. The pathologist will report that this cancer is a metastasis from a primary lung cancer (meaning a cancer that started in the lung but spread somewhere else). In some cases, the pathologist cannot tell which organ or body site those metastatic cells came from. When this happens, the cancer is called a "cancer of unknown primary" (CUP). CUP is a metastatic cancer that has been diagnosed by a biopsy but it is unknown where the cancer started.

A CUP can be found in any part of the body. Common sites are: lymph nodes, liver, bone, lung or lung lining (pleura), brain, abdominal cavity, adrenal gland, or skin. These are the sites that many cancers often spread, making it hard to know where the cancer started.

What causes cancer of unknown primary and am I at risk?

Each year about 32,280 new cases are diagnosed, making up 2% of new cancer diagnoses for the year. These cancers can be misdiagnosed and tend to be underreported.  Since the primary type of cancer is not known, it is hard to know what is causing these cancers. As newer diagnostic lab tests become available, it may become easier to determine where these cancers are starting. 

How can I prevent cancer of unknown primary?

There are no specific steps to preventing cancer of unknown primary. Smoking, poor diet and nutrition, obesity, and exposure to ultraviolet radiation can lead to cancer and it is best to live a healthy lifestyle.

What screening tests are used for cancer of unknown primary?

At this time, there are no screening tests approved to detect cancer of unknown primary.

What are the signs of cancer of unknown primary?

Many patients with CUP can have symptoms that are similar to patients with advanced cancer. Patients may have fatigue, weight loss, digestive symptoms (constipation, poor appetite, diarrhea), belly pain, trouble breathing, cough, night sweats, an enlarged liver, fluid in the belly, or swollen lymph nodes. 

How is cancer of unknown primary diagnosed?

Your healthcare provider will ask you questions about your health history and will do a physical exam. You may need lab tests and imaging. All men should have a prostate exam and all women should have a breast and pelvic exam. Blood tests looking for abnormalities in the blood are often done. A biopsy is needed to determine the cell type, which may help in finding the primary location. You may need further testing depending on your biopsy results.

When a biopsy of a CUP is done, a pathologist examines it under a microscope. The pathologist may determine the cancer's cell type by how it appears or by using special stains that highlight certain traits of the cell. Cell type can be classified in one of these categories:

  • Adenocarcinoma.
  • Neuroendocrine carcinoma.
  • Squamous cell carcinoma.
  • Poorly differentiated tumors.

Molecular profiling tries to find the DNA expressed in a particular tumor. Understanding the genes of a CUP can help identify its origin and guide treatment. In the past, molecular profiling was not possible because an adequate biopsy sample was hard to get. With improvements in technology, it can now be done. Studies have found gene expression assays are able to predict the tumor origin in many samples. Molecular profiling is now used in the clinical workup of CUPs, with improved patient survival.

The cell type found on biopsy determines testing and treatment decisions, as described below:


Adenocarcinomas make up about 6/10 of these cancers. Several types of cancer can be adenocarcinomas, such as colorectal, prostate, pancreatic, lung, breast, ovarian, esophageal and stomach. Knowing this can help narrow the search for the primary tumor site.

A CT scan of the abdomen can find the primary site of the tumor in some patients with adenocarcinoma. A colonoscopy may be done to look for colon cancer, particularly if the patient has had blood in the stool. Positive emission tomography (PET) imaging can be used to locate the primary tumor in some cases.PET imaging highlights tissues that use sugars rapidly. Cancers are visible by PET imaging because they metabolize sugar as they grow and divide, more so than normal tissues.

prostate specific antigen (PSA) should be ordered in men to rule out prostate cancer. If there are enlarged lymph nodes in the axillary (armpit) area, the possibility of metastatic breast cancer should be explored. Tumor markers (CEA, CA 19-9, CA-125, CA15-3) are substances that are often increased in the blood when cancer is present. For example, in colon cancer, CEA is often elevated. These markers are also often elevated in CUP and have not been found to be very helpful for finding the original site of cancer. Certain tumors can make a specific protein on their surface, which can be detected in the biopsy sample using a special test called immunohistochemistry (IHC), performed by the pathologist.

Neuroendocrine Tumors

These types of tumors are further classified as either low- or high-grade based on how the cells look under the microscope. This classification is needed for the workup and treatment of NETs. Neuroendocrine tumors can happen in many parts of the body, such as the lung, bowel, pancreas, appendix, liver, gallbladder, adrenal gland, kidney, pituitary gland, thyroid, and parathyroid.

The first step in testing a low-grade NET involves radiology tests and blood and urine tests for certain tumor markers, which can be elevated in some cancers. Eighty percent of low-grade NETs express high amounts of a protein on its surface, which binds to a hormone called somatostatin. Somatostatin can be tagged with a radioactive label, which can be visualized using a radiology scan called an octreoscan. This may find a primary site. A CT scan or MRI of the abdomen is often done because the intestinal tract is a common primary site for low-grade NETs. If these tests are unsuccessful in finding the primary site, endoscopy of the upper and lower GI tract is done, which can help in finding pancreatic NETs. If a patient presents with facial flushing and weight loss, a low-grade NET called carcinoid tumor should be suspected. Blood and urine tests for 5-hydroxyindoleacetic acid (5-HIAA) should be checked, as these are elevated in many carcinoid tumors.

High-grade neuroendocrine tumors are more aggressive and found in many sites of the body, such as the liver, bone, lung, and brain. Testing should include either an MRI or PET/CT scan of the chest, abdomen, and pelvis. Octreoscans are not useful in detecting high-grade NETs. A brain MRI is sometimes done as high-grade NETs can spread to the brain.

Squamous Cell Carcinoma

Squamous cell carcinomas (SCCs) can happen in the head and neck, lung, skin, cervix, vagina, vulva, and anus. SCCs often cause swollen lymph nodes. The location of the enlarged lymph nodes guides which diagnostic tests are done.

Head to mid-neck: A patient history may help identify a source, such as previous skin cancerA history of smoking raises the risk of head & neck cancer. A scalp and skin exam should be done along with an exam of the tongue, nose cavity, throat, and mouth with a fiberoptic camera/scope. A CT scan or MRI of the neck is also a part of the workup. If both are negative, a PET scan should be done. Without PET, almost 30% of cancers can be missed. PET scans are also able to find metastatic areas of disease. Testing for viral DNA (e.g. HPV) in the biopsy can also help find the location of the primary tumor.

Lower neck to clavicle: Enlarged SCC lymph nodes in this region are mainly due to lung or head & neck cancers. A head & neck exam may be done, along with a CT scan of the chest. If a physical exam and CT scan don’t show changes, a PET, CT scan, or a bronchoscopy may be done.

Groin: When enlarged lymph nodes are found in the groin, an exam of the genital and rectal/anal areas should be done. In women, a pelvic exam is needed. Any masses found during the physical exam should be biopsied.

Poorly Differentiated Carcinomas

These tumors are classified as poorly differentiated because they cannot be characterized under the microscope. These tumors should be well tested by the pathologist because there are many treatable cancers that can be classified as poorly differentiated. Most poorly differentiated carcinomas can be better described as melanoma, lymphoma, or sarcoma.  While the primary site of these cancers may not be found, knowing this tumor classification allows for effective treatment decisions

Testing may include CT, PET scan, or MRI of the abdomen & chest to look for a primary site or enlarged lymph nodes. Human chorionic gonadotropin (hCG) and alpha-fetal protein (AFP) should be measured using a blood test. These two markers are elevated in germ cell tumors, which are a common type of poorly differentiated carcinoma. The biopsy sample should be further tested using immunohistochemistry (IHC) tests to detect markers (substances) found on the outside of the cells of certain tumor types. For example, a subtype of melanoma has been known to express S100 protein and vimentin. Other cancers that may be classified by IHC are lymphomas and sarcomas.

How is cancer of unknown primary staged?

There is no standard staging used for cancer of unknown primary.

How is cancer of unknown primary treated?

Treatment of CUP depends on the biopsy results and the patient's site of disease.


Within adenocarcinoma, there can be specific subgroups of patients. These subgroups can guide treatment.

Women with peritoneal carcinomatosis: When cancer is found on the lining of the abdominal wall, outside of the intestinal tract, it is known as peritoneal carcinomatosisThese tumors are often similar to ovarian cancer. Treatment may include surgery, chemotherapy, and/or a clinical trial.

Women with adenocarcinoma in the axillary lymph nodes: This is most often seen in patients with breast cancer. The biopsy tests for breast cancer markers (estrogen receptor, progesterone receptors, HER2). Radiology tests (e.g. mammography, US, MRI) looking for primary breast cancer are also done. If a primary breast cancer cannot be found, the cancer may still be treated as a breast cancer with surgery, radiation, and/or chemotherapy.

Men with adenocarcinoma detected in bone metastases: Many cancers can present with bone metastases in men including lung, prostate, liver, kidney, thyroid, and colon. An elevated PSA tumor marker (blood test) may result in treating the man for prostate cancer. Without an elevated PSA, further testing may be done to find a second metastasis or the primary site to better guide treatment.

Patients with a “colon cancer profile”: Some patients may have a "colon cancer profile," which includes metastatic liver and/or peritoneal (lining of the abdomen) disease, adenocarcinoma that has qualities like colon cancer when viewed under a microscope, or colon cancer markers on tissue staining (CD20 or CDX2 positive, CD7 negative). These patients may receive a combination of chemotherapy for metastatic colon cancer, including folinic acid (supplemental vitamin), fluorouracil (chemotherapy), oxaliplatin (2nd chemotherapeutic agent), and bevacizumab (anti-VEGF).

Adenocarcinoma without a suspected primary site: If no primary site of disease is found (or strongly suspected), resection of the tumor is often performed. If resection is not an option because of the location of the disease, radiation therapy should be considered. Chemotherapy may be used after surgery.


Treatment varies based on the grade of the tumor.

Treatment of low-grade NETs of unknown primary depends on where the disease is found and the extent of the tumor. In patients with disease limited to the liver, chemoembolization can be performed. This is the delivery of chemotherapy to the tumor followed by blocking of the tumor's blood supply. Surgery may be an option in limited disease. Both targeted and chemotherapy agents and medications that target somatostatin (Octreotide) may be used to treat systemic disease.

Chemotherapy is often used to treat high-grade NETs.


The treatment for SCCs depends on the location of the enlarged lymph nodes.

Head to mid-neck: The goal is to remove or control the known cancer and to prevent the primary site from further growing or spreading. Treatment may include surgery, with or without radiation and/or chemotherapy or radiation therapy alone.

Lower neck to clavicle: If lung cancer is found on imaging or bronchoscopy, then treatment for lung cancer should be started. For non-detectable disease, treatment is similar to cancerous lymph nodes in the head to mid-neck region mentioned above.

Groin: If a primary cancer is not found, treatment is often surgical removal of cancerous lymph nodes, followed by radiation therapy.

Poorly differentiated carcinoma: If the primary source of tumor is not found, chemotherapy is given. This method of treatment is known as empiric therapy. Patients are most often started on platinum chemotherapy agents.

Clinical Trials

There are clinical research trials for most types of cancer, and each stage of the disease. Clinical trials are designed to find the value of specific treatments. Trials are often designed to treat a certain stage of cancer, either as the first form of treatment offered or as an option for treatment after other treatments have failed to work. They can be used to evaluate medications or treatments to prevent cancer, detect it earlier, or help handle side effects. Clinical trials are important in furthering our knowledge of disease. It is through clinical trials that we know what we do today, and many exciting new therapies are currently being tested. Talk to your provider about participating in clinical trials in your area. You can also explore currently open clinical trials using the OncoLink Clinical Trials Matching Service

Follow-up Care and Survivorship

After treatment is done you will be watched closely by your providers. Your provider will continually assess you and any side effects that you may have had from your treatments. It is important not to miss your appointments and to speak with your provider about any new or recurrent issues you are experiencing.

Fear of recurrence, the financial impact of cancer treatment, employment issues, and coping strategies are common emotional and practical issues experienced by cancer of unknown primary survivors. Your healthcare team can find resources for support and management of these practical and emotional challenges faced during and after cancer.

Cancer survivorship is a relatively new focus of oncology care. With almost 17 million cancer survivors in the U.S. alone, there is a need to help patients transition from active treatment to survivorship. What happens next, how do you get back to normal, what should you know and do to live healthy going forward? A survivorship care plan can be a first step in educating yourself about navigating life after cancer and helping you communicate knowledgeably with your healthcare providers. Create a survivorship care plan today on OncoLink.

Resources for More Information

Cancer of Unknown Primary Foundation

American Cancer Society

Cancer Care


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