All About Cancer of Unknown Primary
What is a cancer of unknown primary (CUP)?
Cancer can start anywhere in the body. Where the cancer starts is called the primary cancer site. Cancer can also spread (metastasize) to other parts of the body. When cancer spreads, the cells look like cancer cells from the primary site. If lung cancer spreads to the bone, a biopsy of the bone will have cells in it that look like the lung cancer cells. This cancer is a metastasis from a primary lung cancer.
In some cases, it is not known where the metastatic cells came from. When this happens, the cancer is called a "cancer of unknown primary" (CUP). CUP can also be called “occult primary tumor.” CUP is a metastatic cancer that is diagnosed with a biopsy, but it is unknown where the cancer started.
There are 4 major types of CUP:
- Adenocarcinoma: These make up about 60% of CUP cases. A few types of cancer can be adenocarcinomas, such as colorectal, prostate, pancreatic, lung, breast, ovarian, esophageal and stomach.
- Neuroendocrine Carcinomas (Neuroendocrine tumor/NET): These types of tumors are 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.
- 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.
- Poorly Differentiated Carcinomas: These tumors are called “poorly differentiated” because the cells cannot be classified by looking at them under a microscope. 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 can help with treatment decisions.
The type is determined with a biopsy. Knowing the type of CUP can help guide your treatment plan.
Why is the primary cancer unable to be found?
There are a few reasons why the primary tumor may not be found:
- The primary cancer is very small and slow growing. The metastatic cells may grow faster or cause more symptoms than the primary tumor.
- The primary cancer was removed unknowingly during surgery for something else.
- Your immune system has already killed the primary cancer cells.
Your provider may have other thoughts about why the primary tumor cannot be found.
What are the signs of cancer of unknown primary?
Many patients with CUP have symptoms of advanced (metastatic) cancer. You may have fatigue, weight loss, problems with digesting food (constipation, poor appetite, diarrhea), belly pain, trouble breathing, cough, night sweats, an enlarged liver, fluid in the belly, or swollen lymph nodes. It depends where the cancer is in your body.
How is cancer of unknown primary diagnosed?
Your provider will ask you questions about your health history and will do a physical exam. You may need lab tests and imaging. Blood tests may look at how your organs are working and also look for certain tumor markers. Imaging tests may include x-rays, CTs, MRIs, PET scans, procedures done with scopes, and ultrasounds. You may also have a biopsy to look at the cells and to see what type they are. Your provider will talk to you about what tests you will need to have done.
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 for CUP depends on many factors, like your cancer stage, age, overall health, and testing results, especially the results of your biopsy. Your treatment may include some or all of the following:
- Radiation Therapy.
- Hormone Therapy.
- Other Medications and Treatments.
- Clinical Trials.
Surgery is used to remove as much of the cancer as possible, called a resection. Surgery may also be done to remove lymph nodes affected by the cancer. You may receive chemotherapy or radiation therapy before or after surgery. Talk with your provider about your treatment options, including whether surgery is part of your plan.
Chemotherapy is the use of anti-cancer medicines that go through your whole body to kill cancer cells. These medicines may be given through a vein (IV, intravenously) or by mouth. Chemotherapy is used often for CUP because it can attack cancer cells in many parts of your body.
Chemotherapy can also be put into certain organs or parts of the body being affected. If cancer is only in your liver, chemoembolization can be done. This is the delivery of chemotherapy to the tumor followed by blocking of the tumor's blood supply.
Talk with your provider about which chemotherapies will be a part of your treatment for CUP and how they will be given.
Radiation therapy uses high-energy x-rays to kill cancer cells. It can be used in a few ways. It can be used to treat the cancer itself. If you can’t have surgery because of where the metastatic tumor is, or because of other health problems, radiation can be used with or without chemotherapy to try to shrink the tumor. Radiation can also be used to treat lymph nodes that have cancer in them.
Some types of cancer need sex hormones to grow and divide. If prostate cancer is suspected, hormone therapy may be used to lower androgen levels or to block androgen in your body, which slows or stops the cancer from growing. Some breast cancers are hormone receptor-positive, meaning their cells have receptors for estrogen (ER-positive cancers) and/or progesterone (PR-positive cancers), which help the cancer cells grow and spread. Hormone therapy for breast cancer slows or stops estrogen and/or progesterone so that the cancer stops growing.
Other Medications and Treatments
Medications that target somatostatin (Octreotide) may be used to treat some CUPs. Octreotide is a hormone in your body. Carcinoid and neuroendocrine tumors cause the body to make too much of certain hormones. Octreotide works to reduce the production of these hormones and decrease symptoms the tumor may cause.
If the cancer has spread to your bones, medications called bisphosphonates may be used. Bisphosphonates can help bones affected by cancer by helping them hold on to calcium, making them stronger. This slows down bone damage caused by the cancer, lowers high blood calcium levels (hypercalcemia), and lessens the risk of fracture.
Targeted therapy may be used to treat CUP. Targeted therapies target genes and proteins that control how cancer cells grow, divide, and spread. This slows down or kills the cancer cells. Your tumor will be checked for these genes and proteins before treatment. The medication denosumab (Xgeva®) is a targeted therapy used to prevent further bone damage from cancer cells. By targeting a protein called RANKL, denosumab stops the breakdown of bone and lowers the chance of a fracture in the affected bone.
Your quality of life is very important and sometimes treatment like chemotherapy, radiation, surgery, and other treatments can be used to lessen symptoms or side effects that you may have. Treatments used to help you live a better life, rather than cure your cancer, are called palliative treatment. Palliative treatment can be used to manage pain, nutrition issues, and other side effects.
You may be offered a clinical trial as part of your treatment plan. To find out more about current clinical trials, visit the OncoLink Clinical Trials Matching Service.
Making Treatment Decisions
Your care team will make sure you are included in choosing your treatment plan. This can be overwhelming as you may be given a few options to choose from. It feels like an emergency, but you can take a few weeks to meet with different providers and think about your options and what is best for you. This is a personal decision. Friends and family can help you talk through the options and the pros and cons of each, but they cannot make the decision for you. You need to be comfortable with your decision – this will help you move on to the next steps. If you ever have any questions or concerns, be sure to call your team.
Resources for More Information
Cancer of Unknown Primary Foundation
American Cancer Society
Nactional Cancer Institute (NCI)
American Cancer Society. 2021. Cancer of Unknown Primary. Taken from https://www.cancer.org/cancer/cancer-unknown-primary.htm
American Cancer Society. 2023. Hormone therapy for breast cancer. Taken from https://www.cancer.org/cancer/types/breast-cancer/treatment/hormone-therapy-for-breast-cancer.html
American Cancer Society. 2018. What is a cancer of unknown primary? Taken from https://www.cancer.org/cancer/types/cancer-unknown-primary/about/cancer-of-unknown-primary.html
Hainsorth, J.D. & Greco, F.E. 2022. Adenocarcinoma of unknown primary site. Taken from https://www.uptodate.com/contents/adenocarcinoma-of-unknown-primary-site
Mayordomo JI et al. Neoplasms of unknown primary site: A clinicopathological study of autopsied patients. Tumori 1993;79(5):321-324.
National Institute of Health. National Cancer Institute. Carcinoma of unknown primary treatment (PDQ®). 2021. Found at: https://www.cancer.gov/types/unknown-primary/patient/unknown-primary-treatment-pdq#:~:text=chance%20of%20recovery).-,Carcinoma%20of%20unknown%20primary%20(CUP)%20is%20a%20rare%20disease%20in,This%20process%20is%20called%20metastasis
Qaseem, A., Usman, N., Jayaraj, J. S., Janapala, R. N., & Kashif, T. (2019). Cancer of Unknown Primary: A Review on Clinical Guidelines in the Development and Targeted Management of Patients with the Unknown Primary Site. Cureus, 11(9), e5552. https://doi.org/10.7759/cureus.5552
Seve P et al. The role of 2-deoxy-2-[F-18]fluoro-D-glucose positron emission tomography in disseminated carcinoma of unknown primary site. Cancer. 2007;109(2):292.
Varadhachary G. R. (2007). Carcinoma of unknown primary origin. Gastrointestinal cancer research : GCR, 1(6), 229–235.
Yabuki K et al. Role of 18F-FDG PET in detecting primary site in the patient with primary unknown carcinoma. Eur Arch Otorhinolaryngol. 2010;267(11):1785.