General Information About Merkel Cell Carcinoma

KEY POINTS

• Merkel cell carcinoma is a very rare disease in which malignant (cancer) cells form in the skin.
• Sun exposure and having a weak immune system can affect the risk of Merkel cell carcinoma.
• Merkel cell carcinoma usually appears as a single painless lump on sun-exposed skin.
• Tests and procedures that examine the skin are used to diagnose Merkel cell carcinoma.
• Certain factors affect prognosis (chance of recovery) and treatment options.

Merkel cell carcinoma is a very rare disease in which malignant (cancer) cells form in the skin.

Merkel cells are found in the top layer of the skin. These cells are very close to the nerve endings that receive the sensation of touch. Merkel cell carcinoma, also called neuroendocrine carcinoma of the skin or trabecular cancer, is a very rare type of skin cancer that forms when Merkel cells grow out of control. Merkel cell carcinoma starts most often in areas of skin exposed to the sun, especially the head and neck, as well as the arms, legs, and trunk.

Merkel cell carcinoma tends to grow quickly and to metastasize (spread) at an early stage. It usually spreads first to nearby lymph nodes and then may spread to lymph nodes or skin in distant parts of the body, lungs, brain, bones, or other organs.

Merkel cell carcinoma is the second most common cause of skin cancer death after melanoma.

A Merkel cell is a special type of cell found right below the epidermis (top layer of skin). These cells are very close to the nerve endings that receive the sensation of touch and may be involved in touch. The cells also contain substances that may act as hormones.

Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer. It usually develops as a single, painless, bump on sun-exposed skin. The bump may be skin-colored or red-violet, and tends to grow rapidly over weeks to months. It may spread quickly to surrounding tissues, nearby lymph nodes, or more distant parts of the body. Factors associated with developing MCC include increasing age, fair skin, a history of extensive sun exposure, chronic immune suppression, and the Merkel cell polyomavirus. This virus has been detected in about 80% of people with MCC.

Treatment may include surgery, radiation therapy, and/or chemotherapy. Treatment options and prognosis depend on the location(s) and size of the cancer, whether it has just been diagnosed or has come back (recurred), and how deeply it has grown into the skin.

Sun exposure and having a weak immune system can affect the risk of Merkel cell carcinoma.

Anything that increases your risk of getting a disease is called a risk factor. Having a risk factor does not mean that you will get cancer; not having risk factors doesn't mean that you will not get cancer. Talk with your doctor if you think you may be at risk. Risk factors for Merkel cell carcinoma include the following:

• Being exposed to a lot of natural sunlight.
• Being exposed to artificial sunlight, such as from tanning beds or psoralen and ultraviolet A (PUVA) therapy for psoriasis.
• Having an immune system weakened by disease, such as chronic lymphocytic leukemia or HIV infection.
• Taking drugs that make the immune system less active, such as after an organ transplant.
• Having a history of other types of cancer.
• Being older than 50 years, male, or White.

Cancer is caused by changes (mutations) in the DNA inside of cells. These mutations cause the cells to grow and divide into new cells, when they should not. The mutations that cause MCC are not inherited from a parent, but occur by chance during a person's lifetime (they are acquired, or somatic mutations). In many cases, it is not known what directly causes these mutations to occur. However, several factors are thought to increase the risk for mutations to occur - such as exposure to sunlight.

Merkel cell polyomavirus is frequently involved in the development of MCC and is present in about 80% of MCC tumors tested. While the majority of people have been exposed to this virus by adulthood, it appears that the virus does not cause any symptoms except in the very rare situations in which it leads to MCC.

Other risk factors that have been associated with MCC include:

• being older than age 50
• having fair skin
• having a history of extensive sun exposure
• having chronic immune suppression (e.g. organ transplantation or HIV)

Having one or more risk factors does not mean that a person will develop MCC. Most people with risk factors will not develop MCC.

MCPyV can cause Merkel cell carcinoma, a rare type of skin cancer. Most adults are infected with MCPyV, with transmission most likely occurring through casual direct (i.e., skin-to-skin) or indirect (i.e., touching a surface that an infected person has touched) contact in early childhood. The risk of Merkel cell carcinoma is greatly increased in elderly people and in younger adults with who are infected with HIV or are immunosuppressed for other reasons. Infection does not generally cause symptoms, and there are no treatments for MCPyV.

Merkel cell carcinoma usually appears as a single painless lump on sun-exposed skin.

This and other changes in the skin may be caused by Merkel cell carcinoma or by other conditions. Check with your doctor if you see changes in your skin.

Merkel cell carcinoma usually appears on sun-exposed skin as a single lump that is:

• Fast-growing.
• Painless.
• Firm and dome-shaped or raised.
• Red or violet in color.

Tests and procedures that examine the skin are used to diagnose Merkel cell carcinoma.

The following tests and procedures may be used:

• Physical exam and health history: An exam of the body to check general signs of health, including checking for signs of disease, such as lumps or anything else that seems unusual. A history of the patient’s health habits and past illnesses and treatments will also be taken.
• Full-body skin exam: A doctor or nurse checks the skin for bumps or spots that look abnormal in color, size, shape, or texture. The size, shape, and texture of the lymph nodes will also be checked.
• Skin biopsy: The removal of skin cells or tissues so they can be viewed under a microscope by a pathologist to check for signs of cancer.

KEY POINTS

• After Merkel cell carcinoma has been diagnosed, tests are done to find out if cancer cells have spread to other parts of the body.
• There are three ways that cancer spreads in the body.
• Cancer may spread from where it began to other parts of the body.
• The following stages are used for Merkel cell carcinoma:
  • Stage 0 (carcinoma in situ)
  • Stage I
  • Stage II
  • Stage III
  • Stage IV
• Merkel cell carcinoma can recur (come back) after it has been treated.

After Merkel cell carcinoma has been diagnosed, tests are done to find out if cancer cells have spread to other parts of the body.

The process used to find out if cancer has spread to other parts of the body is called staging. The information gathered from the staging process determines the stage of the disease. It is important to know the stage in order to plan treatment.

The following tests and procedures may be used in the staging process:

• CT scan (CAT scan): A procedure that makes a series of detailed pictures of areas inside the body, taken from different angles. The pictures are made by a computer linked to an x-ray machine. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. A CT scan of the chest and abdomen may be used to check for primary small cell lung cancer, or to find Merkel cell carcinoma that has spread. A CT scan of the head and neck may also be used to find Merkel cell carcinoma that has spread to the lymph nodes. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography.
• PET scan (positron emission tomography scan): A procedure to find malignant tumor cells in the body. A small amount of radioactive glucose (sugar) is injected into a vein. The PET scanner rotates around the body and makes a picture of where glucose is being used in the body. Malignant tumor cells show up brighter in the picture because they are more active and take up more glucose than normal cells do.
• Lymph node biopsy: There are several types of lymph node biopsy used to stage Merkel cell carcinoma.
  • Sentinel lymph node biopsy: The removal of the sentinel lymph node during surgery. The sentinel lymph node is the first lymph node in a group of lymph nodes to receive lymphatic drainage from the primary tumor. It is the first lymph node the cancer is likely to spread to from the primary tumor. A radioactive substance and/or blue dye is injected near the tumor. The substance or dye flows through the lymph ducts to the lymph nodes. The first lymph node to receive the substance or dye is removed. A pathologist views the tissue under a microscope to look for cancer cells. If cancer cells are not found, it may not be necessary to remove more lymph nodes. Sometimes, a sentinel lymph node is found in more than one group of nodes.

  • Lymph node dissection: A surgical procedure in which the lymph nodes are removed and a sample of tissue is checked under a microscope for signs of cancer. For a regional lymph node dissection, some of the lymph nodes in the tumor area are removed. For a radical lymph node dissection, most or all of the lymph nodes in the tumor area are removed. This procedure is also called lymphadenectomy.
  • Core needle biopsy: A procedure to remove a sample of tissue using a wide needle. A pathologist views the tissue under a microscope to look for cancer cells.
  • Fine-needle aspiration biopsy: A procedure to remove a sample of tissue using a thin needle. A pathologist views the tissue under a microscope to look for cancer cells.
• Immunohistochemistry: A laboratory test that uses antibodies to check for certain antigens (markers) in a sample of a patient’s tissue. The antibodies are usually linked to an enzyme or a fluorescent dye. After the antibodies bind to a specific antigen in the tissue sample, the enzyme or dye is activated, and the antigen can then be seen under a microscope. This type of test is used to help diagnose cancer and to help tell one type of cancer from another type of cancer.

There are three ways that cancer spreads in the body.

Cancer can spread through tissue, the lymph system, and the blood:

• Tissue. The cancer spreads from where it began by growing into nearby areas.
• Lymph system. The cancer spreads from where it began by getting into the lymph system. The cancer travels through the lymph vessels to other parts of the body.
• Blood. The cancer spreads from where it began by getting into the blood. The cancer travels through the blood vessels to other parts of the body.

Cancer may spread from where it began to other parts of the body.

When cancer spreads to another part of the body, it is called metastasis. Cancer cells break away from where they began (the primary tumor) and travel through the lymph system or blood.

• Lymph system. The cancer gets into the lymph system, travels through the lymph vessels, and forms a tumor (metastatic tumor) in another part of the body.
• Blood. The cancer gets into the blood, travels through the blood vessels, and forms a tumor (metastatic tumor) in another part of the body.

The metastatic tumor is the same type of cancer as the primary tumor. For example, if Merkel cell carcinoma spreads to the liver, the cancer cells in the liver are actually cancerous Merkel cells. The disease is metastatic Merkel cell carcinoma, not liver cancer.

The following stages are used for Merkel cell carcinoma:

Stage 0 (carcinoma in situ)

In stage 0, abnormal Merkel cells are found in the top layer of skin. These abnormal cells may become cancer and spread into nearby normal tissue.

Stage I

In stage I, the tumor is 2 centimeters or smaller.

Stage II

Stage II Merkel cell carcinoma is divided into stages IIA and IIB.

• In stage IIA, the tumor is larger than 2 centimeters.
• In stage IIB, the tumor has spread to nearby connective tissue, muscle, cartilage, or bone.

Stage III

Stage III Merkel cell carcinoma is divided into stages IIIA and IIIB.

In stage IIIA, either of the following is found:

• the tumor may be any size and may have spread to nearby connective tissue, muscle, cartilage, or bone. A lymph node cannot be felt during a physical exam but cancer is found in the lymph node by sentinel lymph node biopsy or after the lymph node is removed and checked under a microscope for signs of cancer; or
• a swollen lymph node is felt during a physical exam and/or seen on an imaging test. When the lymph node is removed and checked under a microscope for signs of cancer, cancer is found in the lymph node. The place where the cancer began is not known.

In stage IIIB, the tumor may be any size and:

• may have spread to nearby connective tissue, muscle, cartilage, or bone. A swollen lymph node is felt during a physical exam and/or seen on an imaging test. When the lymph node is removed and checked under a microscope for signs of cancer, cancer is found in the lymph node; or
• cancer is in a lymph vessel between the primary tumor and lymph nodes that are near or far away. Cancer may have spread to lymph nodes.

Stage IV

In stage IV, the tumor has spread to skin that is not close to the primary tumor or to other parts of the body, such as the liver, lung, bone, or brain.

Merkel cell carcinoma can recur (come back) after it has been treated.

The cancer may come back in the skin, lymph nodes, or other parts of the body. It is common for Merkel cell carcinoma to recur.

Treatment Option Overview

KEY POINTS

• There are different types of treatment for patients with Merkel cell carcinoma.
• Four types of standard treatment are used:
  • Surgery
  • Radiation therapy
  • Chemotherapy
  • Immunotherapy
• New types of treatment are being tested in clinical trials.
• Treatment for Merkel cell carcinoma may cause side effects.
• Patients may want to think about taking part in a clinical trial.
• Patients can enter clinical trials before, during, or after starting their cancer treatment.
• Follow-up tests may be needed.

There are different types of treatment for patients with Merkel cell carcinoma.

Different types of treatments are available for patients with Merkel cell carcinoma. Some treatments are standard (the currently used treatment), and some are being tested in clinical trials. A treatment clinical trial is a research study meant to help improve current treatments or obtain information on new treatments for patients with cancer. When clinical trials show that a new treatment is better than the standard treatment, the new treatment may become the standard treatment. Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.

Four types of standard treatment are used:

Surgery

One or more of the following surgical procedures may be used to treat Merkel cell carcinoma:

• Wide local excision: The cancer is cut from the skin along with some of the tissue around it. A sentinel lymph node biopsy may be done during the wide local excision procedure. If there is cancer in the lymph nodes, a lymph node dissection also may be done.
• Lymph node dissection: A surgical procedure in which the lymph nodes are removed and a sample of tissue is checked under a microscope for signs of cancer. For a regional lymph node dissection, some of the lymph nodes in the tumor area are removed; for a radical lymph node dissection, most or all of the lymph nodes in the tumor area are removed. This procedure is also called lymphadenectomy.

After the doctor removes all the cancer that can be seen at the time of the surgery, some patients may be given chemotherapy or radiation therapy after surgery to kill any cancer cells that are left. Treatment given after the surgery, to lower the risk that the cancer will come back, is called adjuvant therapy.

Radiation therapy

Radiation therapy is a cancer treatment that uses high-energy x-rays or other types of radiation to kill cancer cells or keep them from growing. External radiation therapy uses a machine outside the body to send radiation toward the area of the body with cancer. It is used to treat Merkel cell carcinoma, and may also be used as palliative therapy to relieve symptoms and improve quality of life.

Chemotherapy

Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping the cells from dividing. When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer cells throughout the body (systemic chemotherapy).

Immunotherapy

Immunotherapy is a treatment that uses the patient’s immune system to fight cancer. Substances made by the body or made in a laboratory are used to boost, direct, or restore the body’s natural defenses against cancer. This cancer treatment is a type of biologic therapy.

Some types of immune cells, such as T cells, and some cancer cells have certain proteins, called checkpoint proteins, on their surface that keep immune responses in check. When cancer cells have large amounts of these proteins, they will not be attacked and killed by T cells. Immune checkpoint inhibitors block these proteins and the ability of T cells to kill cancer cells is increased.

There are two types of immune checkpoint inhibitor therapy:

• PD-1 and PD-L1 inhibitor therapy: PD-1 is a protein on the surface of T cells that helps keep the body's immune responses in check. PD-L1 is a protein found on some types of cancer cells. When PD-1 attaches to PD-L1, it stops the T cell from killing the cancer cell. PD-1 and PD-L1 inhibitors keep PD-1 and PD-L1 proteins from attaching to each other. This allows the T cells to kill cancer cells. Pembrolizumab (a type of PD-1 inhibitor) and avelumab (a type of PD-L1 inhibitor) are used to treat advanced Merkel cell carcinoma. Nivolumab is a type of PD-1 inhibitor being studied to treat advanced Merkel cell carcinoma.

• CTLA-4 inhibitor therapy: CTLA-4 is a protein on the surface of T cells that helps keep the body’s immune responses in check. When CTLA-4 attaches to another protein called B7 on a cancer cell, it stops the T cell from killing the cancer cell. CTLA-4 inhibitors attach to CTLA-4 and allow the T cells to kill cancer cells. Ipilimumab is a type of CTLA-4 inhibitor being studied to treat advanced Merkel cell carcinoma.

Treatment for Merkel cell carcinoma may cause side effects.

Patients may want to think about taking part in a clinical trial.

For some patients, taking part in a clinical trial may be the best treatment choice. Clinical trials are part of the cancer research process. Clinical trials are done to find out if new cancer treatments are safe and effective or better than the standard treatment.

Many of today's standard treatments for cancer are based on earlier clinical trials. Patients who take part in a clinical trial may receive the standard treatment or be among the first to receive a new treatment.

Patients who take part in clinical trials also help improve the way cancer will be treated in the future. Even when clinical trials do not lead to effective new treatments, they often answer important questions and help move research forward.

Patients can enter clinical trials before, during, or after starting their cancer treatment.

Some clinical trials only include patients who have not yet received treatment. Other trials test treatments for patients whose cancer has not gotten better. There are also clinical trials that test new ways to stop cancer from recurring (coming back) or reduce the side effects of cancer treatment.

Clinical trials are taking place in many parts of the country. Information about clinical trials supported by NCI can be found on NCI’s clinical trials search webpage. Clinical trials supported by other organizations can be found on the ClinicalTrials.gov website.

Follow-up tests may be needed.

Some of the tests that were done to diagnose the cancer or to find out the stage of the cancer may be repeated. Some tests will be repeated in order to see how well the treatment is working. Decisions about whether to continue, change, or stop treatment may be based on the results of these tests.

Some of the tests will continue to be done from time to time after treatment has ended. The results of these tests can show if your condition has changed or if the cancer has recurred (come back). These tests are sometimes called follow-up tests or check-ups.

Treatment of Stage I and Stage II Merkel Cell Carcinoma

Treatment of stage I and stage II Merkel cell carcinoma may include the following:

• Surgery to remove the tumor, such as wide local excision with or without lymph node dissection.
• Radiation therapy after surgery.

Treatment of Stage III Merkel Cell Carcinoma

Treatment of stage III Merkel cell carcinoma may include the following:

• Wide local excision with or without lymph node dissection.
• Radiation therapy.
• Immunotherapy (immune checkpoint inhibitor therapy using pembrolizumab), for tumors that cannot be removed by surgery.
• A clinical trial of chemotherapy.
• A clinical trial of immunotherapy (nivolumab).

Treatment of Stage IV Merkel Cell Carcinoma

For information about the treatments listed below, see the Treatment Option Overview section.

Treatment of stage IV Merkel cell carcinoma may include the following:

• Immunotherapy (immune checkpoint inhibitor therapy using avelumab or pembrolizumab).
• Chemotherapy, surgery or radiation therapy as palliative treatment to relieve symptoms and improve quality of life.
• A clinical trial of immunotherapy (nivolumab and ipilimumab).

Treatment of Recurrent Merkel Cell Carcinoma

Treatment of recurrent Merkel cell carcinoma may include the following:

• Wide local excision to remove a larger area of tissue than was removed in earlier surgery. A lymph node dissection may also be done.
• Radiation therapy after surgery.
• Chemotherapy.
• Radiation therapy and/or surgery as palliative treatment to relieve symptoms and improve quality of life.

Merkel cell carcinoma (MCC) is considered an aggressive type of cancer, even more aggressive than melanoma. This means that it rapidly grows and spreads to nearby tissues or distant parts of the body (metastasizes). Estimates of the time it takes for MCC to progress from an early to advanced stage, or to cause death, is unknown because MCC is rare, the diagnosis can be difficult to make, and treatments vary. One study of 195 patients did mention that approximately two-thirds of Merkel cell carcinomas expanded in size rapidly over the course of three months.

Many factors are thought to influence the progression of MCC, including the size and location of the tumor, whether or not the tumor has spread to lymph nodes or distant sites in the body, whether the cancer regrows after treatment (a recurrence), and what types of treatments are used. Unfortunately, approximately one third of individuals affected with MCC are diagnosed when the cancer is already advanced, meaning the cancer has metastasized to the lymph nodes or farther. The advanced state at diagnosis is due to the fact that MCC can be difficult to diagnose because it appears similar to benign skin findings, is often painless, and grows so rapidly.