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In most patients with newly diagnosed cancer, it is not hard to find the primary site . Sometimes, however, it is not clear where a cancer started, even after a physical examination, blood tests, and scans. If a cancer has spread to one or more sites but the primary site cannot be determined, it is called cancer of unknown primary ( CUP) or an occult primary cancer. This happens in a small percentage of cancer diagnoses.

Looking for the primary site

Usually, cancers are named based on their primary site, regardless of where in the body they spread. For example, lung cancer that spreads to the liver is still classified as lung cancer. It is not called liver cancer.

Finding the primary site for cancer is important because treatment is usually based on where the cancer started. This is especially important for certain cancers that respond well to specific chemotherapy, targeted therapy, immunotherapy, or hormone drugs.

• The place in the body where the cancer started is called the primary site.
• Cancer cells can then spread to other parts of the body. These are called metastatic sites.   

In most patients given a diagnosis of CUP after a complete evaluation, an anatomic primary site is never found. However, for a small percentage of patients a primary site will become evident. The cancer then is no longer considered a cancer of unknown primary. It is renamed and treated according to where it started.

Possible reasons for the difficulty in finding a primary site include:

• The primary tumor still is very small
• The body caused the primary tumor to shrink or disappear
• The primary tumor was removed during a previous surgery for another condition, such as the removal of a mole on the skin or surgery to remove the uterus, known as a hysterectomy

New molecular tests on a biopsy sample of the cancer can predict the tissue of origin (e.g., lung, breast, colon, etc.) for most CUP patients. In most of these patients, an anatomic primary site is never found, so they continue to have a CUP diagnosis. However, identifying the tissue of origin means specific treatments can be given, which has improved treatment outcomes.

Categories of cancers of unknown primary (CUP)

When first looking at the cancer cells with 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. 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 cells with a microscope and doing special tests in the lab (see Tests for a Cancer of Unknown Primary).

Cancers are classified by their primary site (where they start), the types of cells in them, how the cancer cells look under the microscope, and the results of certain lab tests on the cells. Knowing the cell type might give doctors a clue as to where the cancer started.

• When cancer cells closely look like normal cells of the organ where they start, the cancer is called well differentiated.
• When cancer cells do not look much like normal cells, the cancers are called poorly differentiated. Cancers of unknown primary are often poorly differentiated.

Carcinomas

Carcinomas begin in the epithelial cells that line the inside or outside of a body organ. The most common types are adenocarcinomas and squamous cell carcinomas.

Adenocarcinomas

These cancers develop from gland cells. They make up about 7 of 10 cases of CUP.

Poorly differentiated carcinomas

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.

Poorly differentiated malignant neoplasms

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 (lymphomas and melanomas are not considered CUPs once identified, even if the primary site is unclear). Some turn out to be carcinomas after further testing

Other cancer types

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

• 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 doesn't include all types of cancers just the most common ones.

Neuroendocrine carcinomas

These rare cancers start from cells of the diffuse neuroendocrine system. This system has cells 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.