What Is a Cancer of Unknown Primary? (2023)

Cancer starts when cells begin to grow out of control. Cells in nearly any part of the body can become cancer, and can spread to other areas. Cancers often spread from their primary site (the part of the body where the cancer started) to one or more metastatic sites (other parts of the body). Cancers are named based on their primary site, regardless of where in the body they spread. For example, a lung cancer that spreads to the liver is still classified as lung cancer and not as liver cancer.

Sometimes it’s not clear where a cancer may have started. When cancer is found in one or more metastatic sites but the primary site cannot be determined, it is called a cancer of unknown primary (CUP) or an occult primary cancer. This happens in a small portion of cancers.

Further tests may eventually find the primary site of some of these cancers. When this happens, they are no longer considered a cancer of unknown primary and are renamed and treated according to where they started.

As an example, a person has an enlarged lymph node on the side of their neck. When it is removed, cancer is found. But under the microscope it does not look like a cancer that normally starts in lymph nodes. At this point it might be considered a cancer of unknown primary. The way it looks under the microscope might suggest that the cancer started in the mouth, throat, or voice box (larynx). When this area is examined, a small cancer of the larynx might be found. From then on, the patient is said to have laryngeal cancer rather than a cancer of unknown primary and will get treated for that type of cancer.

In many cases, the source of the cancer is never determined. The most thorough search still might not find the primary site. Even when doctors do autopsies on people who have died of cancer of unknown primary, they are often still unable to find the site where the cancer started.

(Video) Cancer of unknown primary: how did we get here?

The main reason to look for the primary site of a CUP is to guide treatment. Since a cancer that starts in one place needs the same treatments when it spreads, knowing where a cancer started tells the doctor what types of treatments to use. This is especially important for certain cancers that respond well to specific chemotherapy or hormone drugs. When the types of cancer that respond best to treatment have been ruled out by tests, it usually becomes less important to find the exact origin or cancer type.

But even if the primary site is not known, treatment can still be successful. How the cancer cells look under the microscope, the results of lab tests, and information about which organs it has already affected can help doctors predict what kinds of treatment might be helpful.

To learn more about how cancers start and spread, see What Is Cancer?

General cancer types

Cancers are classified by their primary site. They can also be grouped by the types of cells in them, how the cancer cells look under the microscope, and on results of certain lab tests on the cells. Knowing the type of cell might give doctors a clue as to where the cancer started. When the cancer cells closely resemble normal cells of the organ where they start, the cancer is called well differentiated. When the cells do not look much like normal cells, the cancers are called poorly differentiated. Cancers of unknown primary are often poorly differentiated.


A carcinoma is a cancer that begins in the cells that line the inside or outside of a body organ. These cells are called epithelial cells. There are different types of carcinomas, depending on how the cancer cells look when seen with a microscope. The most common types are squamous cell carcinoma and adenocarcinoma.

(Video) Challenges in treating cancers of unknown primary (CUP)

Squamous cell cancers

Cancers formed by flat cells that look like cells normally found on the surface of the skin or the linings of certain organs are called squamous cell cancers or squamous cell carcinomas. Squamous cell cancers can start in the mouth, throat, esophagus, lungs, anus, cervix, vagina, and some other organs.


Cancers that develop from gland cells (cells that secrete a substance) are called adenocarcinomas. Gland cells are found in many organs of the body, including some that are not usually thought of as glands. For example, most cancers in the stomach, intestines, and colon are adenocarcinomas. About 4 of 10 lung cancers are adenocarcinomas. Adenocarcinomas can also develop in many other organs.

Other cancer types

Less common types of cancer can develop from other cell types.

(Video) CUPISCO: Identifying carcinoma of unknown primary patients according to ESMO guidelines

  • Lymphomas develop from cells of the immune system found in lymph nodes and several other organs.
  • Melanomas develop from cells that produce the skin’s tan or brown color.
  • Sarcomas develop from connective tissue cells that usually are present in tendons, ligaments, muscle, fat, bones, cartilage, and related tissues.
  • Germ cell tumors can develop in the testes (testicles) in men or the ovaries in women, or in the parts of the body where these organs developed in the fetus.

This list is not intended to include all types of cancers but merely to name the most common ones.

Broad categories of cancers of unknown primary

When first looking at the cancer cells under a microscope, doctors usually classify a cancer of unknown primary (CUP) into 1 of 5 broad categories. Many of these cancers can be better classified later on, after more extensive testing.


As noted before, these cancers develop from gland cells. They make up about 6 of 10 cases of CUP.

Poorly differentiated carcinoma

When looking at these cancers under a microscope, there is enough detail to tell that they are carcinomas, but the cells are too irregular to classify them further. These cancers make up about 3 of 10 cases of CUP. On further testing, about 10% of these turn out to be lymphoma, melanoma, or sarcoma.

Squamous cell cancer

These cancers look like the flat cells on the surface of the skin or the linings of certain organs.

(Video) ESMO 2019 Expert Video Report on Carcinoma of Unknown Primary

Poorly differentiated malignant neoplasm

These are clearly cancers, but the cells are so abnormal that the doctor can’t tell what type of cell they may have started from. Most of them turn out to be lymphomas, sarcomas, or melanomas. Some turn out to be carcinomas upon further testing.

Neuroendocrine carcinoma

These rare cancers start from cells of the diffuse neuroendocrine system. This system has cells that are like nerve cells in certain ways and like hormone-making endocrine cells in other ways. These cells do not form an actual organ like the adrenal or thyroid glands. Instead, they are scattered throughout other organs like the esophagus, stomach, pancreas, intestines, and lungs. These cancers account for a small number of CUP cases. (Some poorly differentiated cancers are found to be neuroendocrine carcinomas upon further testing.)

Even when doctors don’t know where the cancer started, they do their best to classify the type of cancer. This can help them select the best treatment. Some cancers respond very well to specific treatments, so it is very important to classify the cancer as much as possible. This is best done by looking at the cancer under a microscope and doing special tests in the lab (see Tests for a Cancer of Unknown Primary).

Other types

Lymphoma often does not have a clear primary site, but it’s not considered a CUP.

Although the primary site of a melanoma may not be clear, once a cancer is classified as a melanoma, it’s no longer called a CUP.

(Video) Metastatic Carcinoma of Unknown Prumary: Using Immunohistochemistry by Jason L. Hornick, M.D., Ph.D.


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