While melanoma incidence and mortality (death from melanoma) are increasing worldwide, especially in fair-skinned people, fortunately the mortality rate is increasing at a slower rate than incidence (Click on Who is at Risk to learn more about skin color and other risk factors for melanoma).

Public awareness of melanoma and early detection may account for the slower rise in mortality as compared to incidence (Click on Self-Examination for a description of criteria for recognizing melanoma). Increased public awareness and early detection may explain studies showing that melanomas are being more frequently diagnosed at earlier stages of development—i.e., a decrease in the mean thickness, with an increasing proportion of thin melanomas at diagnosis (Marks R. Clin

Exp Dermatol 2000; 25:459-463). Click on Glossary for an explanation of relationship between survival rates and thickness of melanomas.

Most cases of primary melanoma, including some thick melanomas, are cured by surgical removal. However, once a melanoma has been detected and removed, the patient requires physician lifetime surveillance for new primary tumors and recurrent disease. Persons at risk for metastatic melanoma should have regularly scheduled dermatologic examinations. Chest x-ray and laboratory tests are obtained if indicated by clinical findings.

Recurrent melanoma may be:

Locally recurrent. Melanoma that develops in or near the site where the primary melanoma was completely removed is defined as a local recurrence. Recurrence is often an indication that the tumor has metastasized. Patients who have locally recurrent melanoma after the primary tumor has been removed have a 10-year survival of about 15%.

Second primary. A second primary is defined as a new melanoma that develops at a different anatomic site simultaneously or subsequent to complete removal of the primary tumor.

Recurrence at a distant site. Recurrence at a distant site is metastatic melanoma.

Local recurrence may be observed months to years after surgical removal of a melanoma.

Second primary melanoma is a finite risk for all patients who have had one primary melanoma. The risk for a second primary is higher in patients with dysplastic or atypical nevi and/or a family history of melanoma (Click on Who is at Risk for more information on melanoma risk factors). Patients at increased risk for second primary melanomas should have regularly scheduled full-body skin examinations by a dermatologist in addition to a monthly self-examination. An effective surveillance program increases the likelihood that a second primary will be detected at an early and curable stage.

First-degree blood relatives of patients who have had melanoma have an 8-fold increased risk of developing melanoma. All first-degree blood relatives of persons who have had melanoma require an examination by a dermatologist for atypical moles and early melanoma.

When a primary melanoma is thin—i.e., confined to superficial layers of skin—it is usually not in contact with lymph or blood vessels and is therefore unlikely to spread (metastasize) to lymph nodes or distant sites. As the thickness of a melanoma increases, so does its potential to metastasize.

Complete excision is usually curative for thin melanomas. Melanomas are regarded as thin if less than 1 millimeter in thickness. When regional or distant metastasis is suspected, diagnostic procedures may include laboratory tests of blood, x-rays and other radiologic tests, and biopsy of lymph nodes.

Through lymph channels the tumor cells reach regional lymph nodes:

Metastasis to regional lymph nodes is considered a risk for metastasis to distant sites (Click on Treatment for a description of lymph node biopsy in diagnosis of metastatic melanoma). Biopsy evidence of metastasis to regional lymph nodes may be an indication for surgical removal of the affected nodes. Medical treatment also may be initiated. (Click on Update 1 in the Archives for more information on chemotherapy and biotherapy). Additional diagnostic tests may be performed at regular intervals to detect any indications of metastasis to distant sites.

In its most distant spread from a primary site, melanoma may metastasize to organs in nearly every part of the body. The most frequent sites for metastasis are skin and lymph nodes. Organs metastasized (in descending order of frequency based on autopsies in large studies) are:

• Skin, subcutaneous tissue and lymph nodes 50-75%
• Lungs and mediastinum 70-87%
• Liver 54-77%
• Brain 36-54%
• Bone 23-49%
• Gastrointestinal tract 26-58%
• Heart 40-45%
• Pancreas 38-53%
• Adrenal glands 36-54%
• Kidneys 35-48%
• Thyroid 25-39%

(Meyers ML, Balch CM: Diagnosis and Treatment of Metastatic Melanoma. In: Balch CM, Houghton AN, Sober AJ, Soong S-J (Eds): Cutaneous Melanoma. St. Louis: Quality Medical Publishing, Inc.;1998:329.)

As noted by the authors referenced above, metastatic sites found at autopsy exceed the number of sites found during clinical examination. Many metastatic melanomas are "silent"—i.e., cause no symptoms. Organ failure is the usual cause of death in patients with internal metastases.

Metastasis is not a random process. Tumors do not shoot off metastatic cells in all directions to lodge indiscriminately in any tissue where they happen to land. Cancers of various types—breast cancer, pancreatic cancer, melanoma, etc.—are known to have a predilection for metastasizing to some sites more often than to others. The table above lists the "preferred" sites of melanoma.

Three hypotheses have been advanced to explain this predilection of metastases:

Metastatic tumor cells indiscriminately colonize any distant site, but multiply only in those sites that express appropriate cellular growth factors;

Metastatic cells are "glued" to specific sites by cell-specific adhesion molecules in the blood vessels of target sites; and,

Metastatic cells are selectively attracted to specific sites by organ-specific molecules—a process called chemoattraction.

A study published in March 2001 lends support to the chemoattraction hypothesis. The study shows that organ-specific chemoattractive molecules called chemokines that are released from various organs can attract circulating cancer cells to metastasize a specific site. The circulating cancer cells have distinct non-random chemical receptors for the site-specific chemokines. The authors of the study analyzed breast cancer and melanoma, both of which have metastatic predilection for lymph nodes, lung, liver and bone. The high frequency of skin metastases by melanoma was found to correlate with a skin-specific chemokine and a high level of the corresponding chemokine receptor in melanoma cells as compared to normal melanocytes.

The chemokine attractants expressed by specific organs are used by white blood cells and other cells to "home in" on specific organs to accomplish tasks such as tissue repair and fighting infection. The authors of the study speculate that cancer cells co-opted this process as a mechanism for metastasis. Reference for the study: Muller A, Homey B, Soto H et al: Involvement of chemokine receptors in breast cancer metastasis. Nature 2001; 410:50-56.

Treatment for visceral (internal organ) metastases may include selective surgical excision, chemotherapy, biotherapy and radiotherapy.

In a small percentage of metastatic melanoma cases there is no evidence of a primary lesion. A primary melanoma may have existed and spontaneously regressed, or a primary lesion may still exist in a form or internal site difficult to identify. The treatment in these cases is the same as for metastatic melanoma with a known primary.

Staging of a melanoma is an important step in planning additional diagnostic procedures and treatment. (Click on Glossary to learn more about staging). A characteristic diagnostic follow-up plan is developed for patients with localized disease, or disease spread to lymph nodes, or locally recurrent disease, or distant metastases, which includes complete history and physical examination. In addition, other tests may include periodic chest x-ray and liver function tests. Follow-up may be more frequent during the first two years after surgery, then semi-annually and annually in succeeding years if no evidence of metastatic disease is found. The frequency of examination may also depend on the presence of prominent numbers of moles or atypical moles.

Staging is also used in planning treatment, in conjunction with other information from diagnostic tests. For patients who have a high risk for developing metastatic disease, adjuvant therapy may be initiated. In patients with advanced multiple metastases, the primary goal of therapy is preservation of quality of life.

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