Merkel Cell Carcinoma

General Information About Merkel Cell Carcinoma

Key Points for This Section

  • 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 developing 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 detect (find) and 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.

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Anatomy of the skin, showing the epidermis, dermis, and subcutaneous tissue. Merkel cells are in the layer of basal cells at the deepest part of the epidermis and are connected to nerves.

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.

Sun exposure and having a weak immune system can affect the risk of developing 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. People who think they may be at risk should discuss this with their doctor. 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.

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. Other conditions may cause the same symptoms. A doctor should be consulted if changes in the skin are seen.

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 detect (find) and diagnose Merkel cell carcinoma.

The following tests and procedures may be used:

  • Physical exam and 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.
  • Biopsy: The removal of cells or tissues so they can be viewed under a microscope by a pathologist to check for signs of cancer.

Certain factors affect prognosis (chance of recovery) and treatment options.

The prognosis (chance of recovery) and treatment options depend on the following:

  • The stage of the cancer (the size of the tumor and whether it has spread to the lymph nodes or other parts of the body).
  • Where the cancer is in the body.
  • Whether the cancer has just been diagnosed or has recurred (come back).
  • The patient’s age and general health.

Prognosis also depends on how deeply the tumor has grown into the skin.

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Stages of Merkel Cell Carcinoma

Key Points for This Section

  • 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.
  • The following stages are used for Merkel cell carcinoma:
  • Stage 0 (carcinoma in situ)
  • Stage IA
  • Stage IB
  • Stage IIA
  • Stage IIB
  • Stage IIC
  • Stage IIIA
  • Stage IIIB
  • Stage IV

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.
  • MRI (magnetic resonance imaging): A procedure that uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas inside the body. This procedure is also called nuclear magnetic resonance imaging (NMRI).
  • 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.
  • Octreotide scan: A type of radionuclide scan used to find carcinomas and other types of tumors. A small amount of radioactive octreotide (a hormone that attaches to carcinoid tumors) is injected into a vein and travels through the bloodstream. The radioactive octreotide attaches to the tumor and a special camera that detects radioactivity is used to show where the tumor cells are in the body.
  • Lymph node biopsy: There are two main 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 to receive lymphatic drainage from a tumor. It is the first lymph node the cancer is likely to spread to from the 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.
      Enlarge
      Sentinel lymph node biopsy of the skin. A radioactive substance and/or blue dye is injected near the tumor (first panel). The injected material is detected visually and/or with a probe that detects radioactivity (middle panel). The sentinel nodes (the first lymph nodes to take up the material) are removed and checked for cancer cells (last panel).
    • 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.

There are three ways that cancer spreads in the body.

The three ways that cancer spreads in the body are:

  • Through tissue. Cancer invades the surrounding normal tissue.
  • Through the lymph system. Cancer invades the lymph system and travels through the lymph vessels to other places in the body.
  • Through the blood. Cancer invades the veins and capillaries and travels through the blood to other places in the body.

When cancer cells break away from the primary (original) tumor and travel through the lymph or blood to other places in the body, another (secondary) tumor may form. This process is called metastasis. The secondary (metastatic) tumor is the same type of cancer as the primary tumor. For example, if breast cancer spreads to the bones, the cancer cells in the bones are actually breast cancer cells. The disease is metastatic breast cancer, not bone cancer.

The following stages are used for Merkel cell carcinoma:

Enlarge
Pea, peanut, walnut, and lime show tumor sizes.

Stage 0 (carcinoma in situ)

In stage 0, the tumor is a group of abnormal cells that remain in the place where they first formed and have not spread. These abnormal cells may become cancer and spread to lymph nodes or distant parts of the body.

Stage IA

In stage IA, the tumor is 2 centimeters or smaller at its widest point and no cancer is found when the lymph nodes are checked under a microscope.

Stage IB

In stage IB, the tumor is 2 centimeters or smaller at its widest point and no swollen lymph nodes are found by a physical exam or imaging tests.

Stage IIA

In stage IIA, the tumor is larger than 2 centimeters and no cancer is found when the lymph nodes are checked under a microscope.

Stage IIB

In stage IIB, the tumor is larger than 2 centimeters and no swollen lymph nodes are found by a physical exam or imaging tests.

Stage IIC

In stage IIC, the tumor may be any size and has spread to nearby bone, muscle, connective tissue, or cartilage. It has not spread to lymph nodes or distant parts of the body.

Stage IIIA

In stage IIIA, the tumor may be any size and may have spread to nearby bone, muscle, connective tissue, or cartilage. Cancer is found in the lymph nodes when they are checked under a microscope.

Stage IIIB

In stage IIIB, the tumor may be any size and may have spread to nearby bone, muscle, connective tissue, or cartilage. Cancer has spread to the lymph nodes near the tumor and is found by a physical exam or imaging test. The lymph nodes are removed and cancer is found in the lymph nodes when they are checked under a microscope. There may also be a second tumor, which is either:

  • Between the primary tumor and nearby lymph nodes; or
  • Farther away from the center of the body than the primary tumor is.

Stage IV

In stage IV, the tumor may be any size and has spread to distant parts of the body, such as the liver, lung, bone, or brain.

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Recurrent Merkel Cell Carcinoma

Recurrent Merkel cell carcinoma is cancer that has recurred (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.

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Treatment Option Overview

Key Points for This Section

  • There are different types of treatment for patients with Merkel cell carcinoma.
  • Three types of standard treatment are used:
    • Surgery
    • Radiation therapy
    • Chemotherapy
  • New types of treatment are being tested in clinical trials.
  • 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.

Three 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.

Even if 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. There are two types of radiation therapy. External radiation therapy uses a machine outside the body to send radiation toward the cancer. Internal radiation therapy uses a radioactive substance sealed in needles, seeds, wires, or catheters that are placed directly into or near the cancer. The way the radiation therapy is given depends on the type and stage of the cancer being treated.

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). When chemotherapy is placed directly into the cerebrospinal fluid, an organ, or a body cavity such as the abdomen, the drugs mainly affect cancer cells in those areas (regional chemotherapy). The way the chemotherapy is given depends on the type and stage of the cancer being treated.

New types of treatment are being tested in clinical trials.

Information about clinical trials is available from the NCI Web site.

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. See the Treatment Options section that follows for links to current treatment clinical trials. These have been retrieved from NCI’s listing of clinical trials.

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. This is sometimes called re-staging.

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.

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Treatment Options by Stage

A link to a list of current clinical trials is included for each treatment section. For some types or stages of cancer, there may not be any trials listed. Check with your doctor for clinical trials that are not listed here but may be right for you.

Stage I and Stage II Merkel Cell CarcinomaTreatment 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.
  • A clinical trial of a new treatment.

Check for U.S. clinical trials from NCI’s PDQ Cancer Clinical Trials Registry that are now accepting patients with stage I neuroendocrine carcinoma of the skin. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. General information about clinical trials is available from the NCI Web site.

Stage III Merkel Cell CarcinomaTreatment of stage III Merkel cell carcinoma may include the following:

  • Wide local excision with or without lymph node dissection.
  • Radiation therapy.
  • A clinical trial of chemotherapy.

Check for U.S. clinical trials from NCI’s PDQ Cancer Clinical Trials Registry that are now accepting patients with stage III neuroendocrine carcinoma of the skin. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. General information about clinical trials is available from the NCI Web site.

Stage IV Merkel Cell CarcinomaTreatment of stage IV Merkel cell carcinoma may include the following as palliative treatment to relieve symptoms and improve quality of life:

  • Chemotherapy.
  • Surgery.
  • Radiation therapy.
  • A clinical trial of a new treatment.

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Treatment Options for 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.

Check for U.S. clinical trials from NCI’s PDQ Cancer Clinical Trials Registry that are now accepting patients with recurrent neuroendocrine carcinoma of the skin. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. General information about clinical trials is available from the NCI Web site.

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To Learn More About Merkel Cell Carcinoma

For more information from the National Cancer Institute about Merkel cell carcinoma, see the following:

  • Skin Cancer Home Page
  • Skin Cancer Prevention
  • Skin Cancer Screening
  • Sentinel Lymph Node Biopsy: Questions and Answers

For general cancer information and other resources from the National Cancer Institute, see the following:

  • What You Need to Know About™ Cancer – An Overview
  • Understanding Cancer Series: Cancer
  • Cancer Staging
  • Chemotherapy and You: Support for People With Cancer
  • Radiation Therapy and You: Support for People With Cancer
  • Coping with Cancer: Supportive and Palliative Care
  • Cancer Library
  • Information For Survivors/Caregivers/Advocates

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Get More Information From NCI

Call 1-800-4-CANCER

For more information, U.S. residents may call the National Cancer Institute’s (NCI’s) Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237) Monday through Friday from 8:00 a.m. to 8:00 p.m., Eastern Time. A trained Cancer Information Specialist is available to answer your questions.

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The NCI’s LiveHelp® online chat service provides Internet users with the ability to chat online with an Information Specialist. The service is available from 8:00 a.m. to 11:00 p.m. Eastern time, Monday through Friday. Information Specialists can help Internet users find information on NCI Web sites and answer questions about cancer.

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For more information from the NCI, please write to this address:

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Search the NCI Web site

The NCI Web site provides online access to information on cancer, clinical trials, and other Web sites and organizations that offer support and resources for cancer patients and their families. For a quick search, use the search box in the upper right corner of each Web page. The results for a wide range of search terms will include a list of “Best Bets,” editorially chosen Web pages that are most closely related to the search term entered.

There are also many other places to get materials and information about cancer treatment and services. Hospitals in your area may have information about local and regional agencies that have information on finances, getting to and from treatment, receiving care at home, and dealing with problems related to cancer treatment.

Find Publications

The NCI has booklets and other materials for patients, health professionals, and the public. These publications discuss types of cancer, methods of cancer treatment, coping with cancer, and clinical trials. Some publications provide information on tests for cancer, cancer causes and prevention, cancer statistics, and NCI research activities. NCI materials on these and other topics may be ordered online or printed directly from the NCI Publications Locator. These materials can also be ordered by telephone from the Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237).

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Changes to This Summary (09/23/2010)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Editorial changes were made to this summary.

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About PDQ

PDQ is a comprehensive cancer database available on NCI’s Web site.

PDQ is the National Cancer Institute’s (NCI’s) comprehensive cancer information database. Most of the information contained in PDQ is available online at NCI’s Web site. PDQ is provided as a service of the NCI. The NCI is part of the National Institutes of Health, the federal government’s focal point for biomedical research.

PDQ contains cancer information summaries.

The PDQ database contains summaries of the latest published information on cancer prevention, detection, genetics, treatment, supportive care, and complementary and alternative medicine. Most summaries are available in two versions. The health professional versions provide detailed information written in technical language. The patient versions are written in easy-to-understand, nontechnical language. Both versions provide current and accurate cancer information.

The PDQ cancer information summaries are developed by cancer experts and reviewed regularly.

Editorial Boards made up of experts in oncology and related specialties are responsible for writing and maintaining the cancer information summaries. The summaries are reviewed regularly and changes are made as new information becomes available. The date on each summary (“Date Last Modified”) indicates the time of the most recent change.

PDQ also contains information on clinical trials.

A clinical trial is a study to answer a scientific question, such as whether one treatment is better than another. Trials are based on past studies and what has been learned in the laboratory. Each trial answers certain scientific questions in order to find new and better ways to help cancer patients. During treatment clinical trials, information is collected about the effects of a new treatment and how well it works. If a clinical trial shows that a new treatment is better than one currently being used, the new treatment may become “standard.” 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.

Listings of clinical trials are included in PDQ and are available online at NCI’s Web site. Descriptions of the trials are available in health professional and patient versions. Many cancer doctors who take part in clinical trials are also listed in PDQ. For more information, call the Cancer Information Service 1-800-4-CANCER (1-800-422-6237).

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General Information About Merkel Cell Carcinoma

Epidemiology/Etiology
Clinical Presentation
Initial Clinical Evaluation
Initial Staging Results
Clinical Progression
Potential Prognostic Factors
Prognosis

Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Merkel cell carcinoma (MCC) was originally described by Toker in 1972 as trabecular carcinoma of the skin.[1] Other names include Toker tumor, primary small cell carcinoma of the skin, primary cutaneous neuroendocrine tumor, and malignant trichodiscoma.[2]

MCC is an aggressive neuroendocrine carcinoma arising in the dermoepidermal junction (see Figure 1). Although the exact origin and function of the Merkel cell remains under investigation, it is thought to have features of both epithelial and neuroendocrine origin and arise in cells with touch-sensitivity function (mechanoreceptors).[3-8]

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Figure 1. Merkel Cell Anatomy.

Epidemiology/Etiology

In Surveillance, Epidemiology and End Results (SEER) Program data from 1986 to 2001, the age-adjusted U.S. annual incidence of MCC tripled from 0.15 to 0.44 per 100,000, an increase of 8.08% per year. Although this rate of increase is faster than any other skin cancer including melanoma, the absolute number of U.S. cases per year is small. About 1,500 new cases of MCC were expected in the United States in 2007.[9-14]

MCC incidence increases progressively with age. There are few cases in patients younger than 50 years, and the median age at diagnosis is about 65 years (see Figure 2).[10,15] Incidence is considerably greater in whites than blacks and slightly greater in males than females.[9-12,14]

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Figure 2. Frequency of MCC by age and sex of men (square) and women (circle). Reprinted from Journal of the American Academy of Dermatology, 49 (5), Agelli M and Clegg L, Epidemiology of primary Merkel cell carcinoma in the United States, pp. 832–41, Copyright (2003), with permission from Elsevier.

The apparent increase in incidence may reflect an actual increase and/or more accurate diagnostic pathology tools, improved clinical awareness of MCC, an aging population, increased sun exposure in susceptible populations, and improved registry tools.

MCC occurs most frequently in sun-exposed areas of skin, particularly the head and neck, followed by the extremities, and then the trunk.[3,12,16] Incidence has been reported to be greater in geographic regions with higher levels of ultraviolet B sunlight.[12]

A 2009 review of 3,804 MCC cases from the SEER Program database from 1973–2000 tabulated the ten most common sites of MCC (see Table 1).[14]

Anatomic Site Cases (%)
Skin, face 1,041 (26.9)
Skin of upper limb and shoulder 853 (22.0)
Skin of lower limb and hip 578 (14.9)
Skin of trunk 410 (10.6)
Skin of scalp and neck 348 (9.0)
Skin, NOS 234 (6.0)
External ear 120 (3.1)
Eyelid 98 (2.5)
Skin of lip 91 (2.4)
Unknown primary site 31 (0.8)
Total 3,804 (98.3)

 

NOS = not otherwise specified
aAlbores-Saavedra J et al: Merkel cell carcinoma demographics, morphology, and survival based on 3,870 cases: A population-based study. J Cutan Pathol. Reprinted with permission © 2009. Published by Wiley-Blackwell. All rights reserved.[14]

 

In various cases series, up to 97% of MCCs arise in skin. Primaries in other sites were very rare, as are MCCs from unknown primary sites.[14]

SEER registry data have also shown excess risk of MCC as a first or second cancer in patients with several primary cancers.[17] Increased incidence of MCC has also been seen in people treated heavily with methoxsalen (psoralen) and ultraviolet A (PUVA) for psoriasis (3 of 1,380 patients, 0.2%), and those with chronic immune suppression, especially from chronic lymphocytic leukemia, human immunodeficiency virus, and prior solid organ transplant.[12,18]

In 2008, a novel polyomavirus (Merkel cell polyoma virus, MCPyV) was first reported in MCC tumor specimens [19], a finding subsequently confirmed in other laboratories.[20-22] High levels of viral DNA and clonal integration of the virus in MCC tumors has also been reported.[23] However, the significance of the new MCPyV findings remains uncertain. MCPyV has been detected at very low levels in normal skin distant from the MCC primary, in a significant percentage of patients with non-MCC cutaneous disorders, in normal appearing skin in healthy individuals, and in nonmelanoma skin cancers in immune-suppressed individuals. [8,24-26]

Although no unique marker for MCC has been identified, a variety of molecular and cytogenetic markers of MCC have been reported.[5,8,13]

Clinical Presentation

MCC usually presents as a painless, indurated, solitary dermal nodule with a slightly erythematous to deeply violaceous color, and rarely, an ulcer. MCC can infiltrate locally via dermal lymphatics, resulting in multiple satellite lesions. Because of its nonspecific clinical appearance, MCC is rarely suspected prior to biopsy.[3]. Photographs of MCC skin lesions illustrate its clinical variability.[27]

A mnemonic [16] summarizing typical clinical characteristics of MCC has been proposed:

AEIOU

  • A=Asymptomatic.
  • E=Expanding rapidly.
  • I=Immune suppressed.
  • O=Older than 50 years.
  • U=UV-exposed skin.

Not all patients have every element in this mnemonic; however, in this study, 89% of patients met three or more criteria, 52% met four or more criteria, and 7% met all five criteria.[16]

Initial Clinical Evaluation

Because local-regional spread is common, newly diagnosed MCC patients require a careful clinical examination that includes looking for satellite lesions and regional nodal involvement.

An imaging work-up should be tailored to the clinical presentation as well as any relevant signs and symptoms. There has been no systematic study of the optimal imaging work-up for newly diagnosed patients, and it is not clear if all newly diagnosed patients, especially those with the smallest primaries, benefit from a detailed imaging work-up.

If an imaging work-up is performed, it may include a computed tomography (CT) scan of the chest and abdomen to rule out primary small cell lung cancer as well as distant and regional metastases. Imaging studies designed to evaluate suspicious signs and symptoms may also be recommended. In one series, CT scans had an 80% false-negative rate for regional metastases.[28] Head and neck presentations may require additional imaging. Magnetic resonance imaging has been used to evaluate MCC but has not been studied systematically.[29] Fluorodeoxyglucose-positron emission tomography results have been reported only in selected cases.[30,31] Routine blood work as a baseline has been recommended but has not been studied systematically. There are no known circulating tumor markers specifically for MCC.

Initial Staging Results

The results of initial clinical staging of MCC vary widely in the literature, based on retrospective case series reported over decades. In 2009, 3,870 MCC cases were reported from the SEER Program registry. For invasive cancers, 48.6% were localized, 31.1% were regional, and 8.2% were distant.[14]

MCC that presents in regional nodes without an identifiable primary lesion is found in a minority of patients, with the percent of these cases varying among the reported series. Tumors without an identifiable primary lesion have been attributed to either spontaneous regression of the primary or metastatic neuroendocrine carcinoma from a clinically occult site.[6,14,16,32,33]

Clinical Progression

In a review of patients from 18 case series, 279 of 926 patients (30.1%) developed local recurrence during follow-up, excluding those presenting with distant metastatic disease. These events have been typically attributed to inadequate surgical margins and/or a lack of adjuvant radiation therapy. In addition, 545 of 982 patients (55.5%) had lymph node metastases at diagnosis or during follow-up.[6]

In the same review of 18 case series, the most common sites of distant metastases were distant lymph nodes (60.1%), distant skin (30.3%), lung (23.4%), central nervous system (18.4%), and bone (15.2%).[6] Many other sites of disease have also been reported, and the distribution of metastatic sites varies among case series.

In one series of 237 patients presenting with local or regional disease, the median time-to-recurrence was 9 months (range, 2–70 months). Ninety-one percent of recurrences occurred within 2 years of diagnosis.[34]

Potential Prognostic Factors

The extent of disease at presentation appears to provide the most useful estimate of prognosis.[5]

Diagnostic procedures, such as sentinel lymph node biopsy, may help distinguish between local and regional disease at presentation. One-third of patients who lack clinically palpable or radiologically visible nodes will have microscopically evident regional disease.[28] The likelihood is that nodal positivity may be substantially lower among patients with small tumors (e.g., ≤1.0 cm).[35]

Many retrospective studies have evaluated the relationship of a wide variety of biological and histological factors to survival and local-regional control.[5,6,14,28,34,36-45][Level of evidence: 3iiiDiii] Many of these reports are confounded by small numbers, potential selection bias, referral bias, short follow-up, no uniform clinical protocol for both staging and treatment, and are underpowered to detect modest differences.

A large, single-institution retrospective study of 156 MCC patients, with a median follow-up of 51 months (range 2–224 months), evaluated histologic factors potentially associated with prognosis.[45][Level of evidence: 3iiiB] Although this report is subject to potential selection and referral bias, both univariate and multivariate analyses demonstrated a relationship between improved cause-specific survival and circumscribed growth pattern versus infiltrative pattern, shallow-tumor depth versus deep-tumor depth, and absence of lymphovascular invasion versus presence of lymphovascular invasion. Adoption of these findings into a global prognostic algorithm awaits independent confirmation by adequately powered studies.

A 2009 study investigated whether the presence of newly identified MCPyV in MCC tumor specimens influenced clinical outcome among 114 Finnish patients with MCC. In this small study, patients whose tumors were MCPyV+ appeared to have better survival than patients whose tumors were MCPyV-.[46][Level of evidence: 3iiiDiii]

Prognosis

The bulk of MCC literature is from small case series, which are subject to many confounding factors (such as those listed above in the Prognostic Factors section). For this reason, the relapse and survival rates reported by stage vary widely in the literature. In general, lower-stage disease is associated with better overall survival.[47]

Outcomes from patients presenting with small volume local disease and pathologically confirmed cancer-negative lymph nodes report a cause-specific 5-year survival exceeding 90% in one report.[34,45][Level of evidence: 3iiiDiii]

A tabular summary of treatment results of MCC from 12 series illustrates the difficulty in comparing outcome data among series.[5]

Using the SEER Program registry MCC staging system adopted in 1973, MCC survival data (1973–2006) by stage is summarized below:[14]

Enlarge
Figure 3. Relative ten-year survival rates for Merkel Cell Carcinoma by stage (SEER 1973–2006). Albores-Saavedra J et al: Merkel cell carcinoma demographics, morphology, and survival based on 3,870 cases: A population-based study. J Cutan Pathol. Reprinted with permission © 2009. Published by Wiley-Blackwell. All rights reserved.

References

  1. Toker C: Trabecular carcinoma of the skin. Arch Dermatol 105 (1): 107-10, 1972.  [PUBMED Abstract]
  2. Schwartz RA, Lambert WC: The Merkel cell carcinoma: a 50-year retrospect. J Surg Oncol 89 (1): 5, 2005.  [PUBMED Abstract]
  3. Nghiem P, McKee PH, Haynes HA: Merkel cell (cutaneous neuroendocrine) carcinoma. In: Sober AJ, Haluska FG, eds.: Skin Cancer. Hamilton, Ontario: BC Decker Inc., 2001., pp 127-141.
  4. Nghiem P, James N: Merkel cell carcinoma. In: Wolff K, Goldsmith LA, Katz SI, et al., eds.: Fitzpatrick’s Dermatology in General Medicine. 7th ed. New York, NY: McGraw-Hill , 2008, pp 1087-94.
  5. Eng TY, Boersma MG, Fuller CD, et al.: A comprehensive review of the treatment of Merkel cell carcinoma. Am J Clin Oncol 30 (6): 624-36, 2007.  [PUBMED Abstract]
  6. Medina-Franco H, Urist MM, Fiveash J, et al.: Multimodality treatment of Merkel cell carcinoma: case series and literature review of 1024 cases. Ann Surg Oncol 8 (3): 204-8, 2001.  [PUBMED Abstract]
  7. Busse PM, Clark JR, Muse VV, et al.: Case records of the Massachusetts General Hospital. Case 19-2008. A 63-year-old HIV-positive man with cutaneous Merkel-cell carcinoma. N Engl J Med 358 (25): 2717-23, 2008.  [PUBMED Abstract]
  8. Rockville Merkel Cell Carcinoma Group.: Merkel cell carcinoma: recent progress and current priorities on etiology, pathogenesis, and clinical management. J Clin Oncol 27 (24): 4021-6, 2009.  [PUBMED Abstract]
  9. Hodgson NC: Merkel cell carcinoma: changing incidence trends. J Surg Oncol 89 (1): 1-4, 2005.  [PUBMED Abstract]
  10. Agelli M, Clegg LX: Epidemiology of primary Merkel cell carcinoma in the United States. J Am Acad Dermatol 49 (5): 832-41, 2003.  [PUBMED Abstract]
  11. Young JL, Ward KC, Ries LAG: Cancer of rare sites. In: Ries LAG, Young JL, Keel GE, et al., eds.: SEER Survival Monograph: Cancer Survival Among Adults: U. S. SEER Program, 1988-2001, Patient and Tumor Characteristics. Bethesda, MD: National Cancer Institute, 2007. NIH Pub. No. 07-6215, pp 251-61.
  12. Miller RW, Rabkin CS: Merkel cell carcinoma and melanoma: etiological similarities and differences. Cancer Epidemiol Biomarkers Prev 8 (2): 153-8, 1999.  [PUBMED Abstract]
  13. Lemos B, Nghiem P: Merkel cell carcinoma: more deaths but still no pathway to blame. J Invest Dermatol 127 (9): 2100-3, 2007.  [PUBMED Abstract]
  14. Albores-Saavedra J, Batich K, Chable-Montero F, et al.: Merkel cell carcinoma demographics, morphology, and survival based on 3870 cases: a population based study. J Cutan Pathol : , 2009.  [PUBMED Abstract]
  15. Journal of the American Academy of Dermatology. Elsevier, Oxford, UK. Also available online. Last accessed November 30, 2009.
  16. Heath M, Jaimes N, Lemos B, et al.: Clinical characteristics of Merkel cell carcinoma at diagnosis in 195 patients: the AEIOU features. J Am Acad Dermatol 58 (3): 375-81, 2008.  [PUBMED Abstract]
  17. Howard RA, Dores GM, Curtis RE, et al.: Merkel cell carcinoma and multiple primary cancers. Cancer Epidemiol Biomarkers Prev 15 (8): 1545-9, 2006.  [PUBMED Abstract]
  18. Lunder EJ, Stern RS: Merkel-cell carcinomas in patients treated with methoxsalen and ultraviolet A radiation. N Engl J Med 339 (17): 1247-8, 1998.  [PUBMED Abstract]
  19. Feng H, Shuda M, Chang Y, et al.: Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science 319 (5866): 1096-100, 2008.  [PUBMED Abstract]
  20. Garneski KM, Warcola AH, Feng Q, et al.: Merkel cell polyomavirus is more frequently present in North American than Australian Merkel cell carcinoma tumors. J Invest Dermatol 129 (1): 246-8, 2009.  [PUBMED Abstract]
  21. Becker JC, Houben R, Ugurel S, et al.: MC polyomavirus is frequently present in Merkel cell carcinoma of European patients. J Invest Dermatol 129 (1): 248-50, 2009.  [PUBMED Abstract]
  22. Kassem A, Schöpflin A, Diaz C, et al.: Frequent detection of Merkel cell polyomavirus in human Merkel cell carcinomas and identification of a unique deletion in the VP1 gene. Cancer Res 68 (13): 5009-13, 2008.  [PUBMED Abstract]
  23. Houben R, Schrama D, Becker JC: Molecular pathogenesis of Merkel cell carcinoma. Exp Dermatol 18 (3): 193-8, 2009.  [PUBMED Abstract]
  24. Andres C, Belloni B, Puchta U, et al.: Prevalence of MCPyV in Merkel cell carcinoma and non-MCC tumors. J Cutan Pathol : , 2009.  [PUBMED Abstract]
  25. Kassem A, Technau K, Kurz AK, et al.: Merkel cell polyomavirus sequences are frequently detected in nonmelanoma skin cancer of immunosuppressed patients. Int J Cancer 125 (2): 356-61, 2009.  [PUBMED Abstract]
  26. Foulongne V, Dereure O, Kluger N, et al.: Merkel cell polyomavirus DNA detection in lesional and nonlesional skin from patients with Merkel cell carcinoma or other skin diseases. Br J Dermatol 162 (1): 59-63, 2010.  [PUBMED Abstract]
  27. Seattle Cancer Care Alliance.: Merkel Cell Carcinoma Information for Patients and Their Physicians: Clinical Photos/Images. Seattle, Wa: Seattle Cancer Care Alliance Skin Oncology Clinic, 2009. Available online. Last accessed March 13, 2009.
  28. Gupta SG, Wang LC, Peñas PF, et al.: Sentinel lymph node biopsy for evaluation and treatment of patients with Merkel cell carcinoma: The Dana-Farber experience and meta-analysis of the literature. Arch Dermatol 142 (6): 685-90, 2006.  [PUBMED Abstract]
  29. Anderson SE, Beer KT, Banic A, et al.: MRI of merkel cell carcinoma: histologic correlation and review of the literature. AJR Am J Roentgenol 185 (6): 1441-8, 2005.  [PUBMED Abstract]
  30. Iagaru A, Quon A, McDougall IR, et al.: Merkel cell carcinoma: Is there a role for 2-deoxy-2-[f-18]fluoro-D-glucose-positron emission tomography/computed tomography? Mol Imaging Biol 8 (4): 212-7, 2006 Jul-Aug.  [PUBMED Abstract]
  31. Belhocine T, Pierard GE, Frühling J, et al.: Clinical added-value of 18FDG PET in neuroendocrine-merkel cell carcinoma. Oncol Rep 16 (2): 347-52, 2006.  [PUBMED Abstract]
  32. Missotten GS, de Wolff-Rouendaal D, de Keizer RJ: Merkel cell carcinoma of the eyelid review of the literature and report of patients with Merkel cell carcinoma showing spontaneous regression. Ophthalmology 115 (1): 195-201, 2008.  [PUBMED Abstract]
  33. Richetta AG, Mancini M, Torroni A, et al.: Total spontaneous regression of advanced merkel cell carcinoma after biopsy: review and a new case. Dermatol Surg 34 (6): 815-22, 2008.  [PUBMED Abstract]
  34. Allen PJ, Bowne WB, Jaques DP, et al.: Merkel cell carcinoma: prognosis and treatment of patients from a single institution. J Clin Oncol 23 (10): 2300-9, 2005.  [PUBMED Abstract]
  35. Stokes JB, Graw KS, Dengel LT, et al.: Patients with Merkel cell carcinoma tumors < or = 1.0 cm in diameter are unlikely to harbor regional lymph node metastasis. J Clin Oncol 27 (23): 3772-7, 2009.  [PUBMED Abstract]
  36. Jabbour J, Cumming R, Scolyer RA, et al.: Merkel cell carcinoma: assessing the effect of wide local excision, lymph node dissection, and radiotherapy on recurrence and survival in early-stage disease–results from a review of 82 consecutive cases diagnosed between 1992 and 2004. Ann Surg Oncol 14 (6): 1943-52, 2007.  [PUBMED Abstract]
  37. Henness S, Vereecken P: Management of Merkel tumours: an evidence-based review. Curr Opin Oncol 20 (3): 280-6, 2008.  [PUBMED Abstract]
  38. Skelton HG, Smith KJ, Hitchcock CL, et al.: Merkel cell carcinoma: analysis of clinical, histologic, and immunohistologic features of 132 cases with relation to survival. J Am Acad Dermatol 37 (5 Pt 1): 734-9, 1997.  [PUBMED Abstract]
  39. Sandel HD 4th, Day T, Richardson MS, et al.: Merkel cell carcinoma: does tumor size or depth of invasion correlate with recurrence, metastasis, or patient survival? Laryngoscope 116 (5): 791-5, 2006.  [PUBMED Abstract]
  40. Llombart B, Monteagudo C, López-Guerrero JA, et al.: Clinicopathological and immunohistochemical analysis of 20 cases of Merkel cell carcinoma in search of prognostic markers. Histopathology 46 (6): 622-34, 2005.  [PUBMED Abstract]
  41. Senchenkov A, Barnes SA, Moran SL: Predictors of survival and recurrence in the surgical treatment of merkel cell carcinoma of the extremities. J Surg Oncol 95 (3): 229-34, 2007.  [PUBMED Abstract]
  42. Goldberg SR, Neifeld JP, Frable WJ: Prognostic value of tumor thickness in patients with Merkel cell carcinoma. J Surg Oncol 95 (8): 618-22, 2007.  [PUBMED Abstract]
  43. Heath ML, Nghiem P: Merkel cell carcinoma: if no breslow, then what? J Surg Oncol 95 (8): 614-5, 2007.  [PUBMED Abstract]
  44. Tai P: Merkel cell cancer: update on biology and treatment. Curr Opin Oncol 20 (2): 196-200, 2008.  [PUBMED Abstract]
  45. Andea AA, Coit DG, Amin B, et al.: Merkel cell carcinoma: histologic features and prognosis. Cancer 113 (9): 2549-58, 2008.  [PUBMED Abstract]
  46. Sihto H, Kukko H, Koljonen V, et al.: Clinical factors associated with Merkel cell polyomavirus infection in Merkel cell carcinoma. J Natl Cancer Inst 101 (13): 938-45, 2009.  [PUBMED Abstract]
  47. Eng TY, Boersma MG, Fuller CD, et al.: Treatment of merkel cell carcinoma. Am J Clin Oncol 27 (5): 510-5, 2004.  [PUBMED Abstract]