Melanoma is a type of cancer arising from the melanocyte cells of the skin. The melanocytes are cells in the skin that produce the pigment melanin. Malignant melanoma develops when the melanocytes no longer respond to normal control of cellular growth and can invade other tissues locally or spread to other organs in the body (metastasis), where they compromise the function of the organ invaded.
Melanocytes are distributed in the epidermis layer of skin. The cells produce a brown pigment called melanin and are responsible for variation in skin color and the color of moles. Malignant degeneration of the melanocyte gives rise to the tumor, melanoma, of which there are four subtypes. These are: superficial spreading (the most common, accounting for 70% of melanoma cases), nodular, lentigo maligna, and acral lentiginous melanomas. Malignant melanoma can develop anywhere on the body. In men, it is most common on the trunk. In women, it is most common on the back or legs. The subtype also may influence where the tumor develops; lentigo melanoma is more common on the face, whereas acral lentiginous melanoma is more common on the palms of the hand, soles of the feet, or in the nail beds.
The melanoma tumor penetrates the skin vertically and into the dermis and subcutaneous (underthe-skin) tissues. With the exception of the nodular variety of melanoma, there is often a phase of lateral growth associated with these tumors. Since it is the vertical growth that characterizes the malignancy, the nodular variant of melanoma carries the worst prognosis. Fortunately, the superficial spreading type is most common.
The primary tumor begins in the skin, often from the melanocytes of a pre-existing mole. Once it becomes invasive, it can progress beyond the site of origin to the regional lymph nodes or travel to other organ systems in the body.
As cancer cells invade where the tumor originated, they also can work their way into blood vessels. If this occurs, it provides yet another route for the cancer to spread to other organs of the body. When the cancer spreads elsewhere in the body, it has become systemic in extent and the tumor growing elsewhere is known as a metastasis.
Untreated malignant melanoma follows a classic progression. It begins and grows locally, penetrating vertically. The malignant cells might be carried via the lymph to the regional nodes, known as regional metastasis, and can move from the lymph to the bloodstream or penetrate blood vessels, providing a route to go elsewhere in the body. When systemic disease or distant metastasis occurs, melanoma commonly involves the lung, brain, liver, or occasionally bone. The malignancy causes death when its uncontrolled growth compromises vital organ function.
In the United States, melanoma accounts for less than 2% of all skin cancers, but the majority of deaths associated with skin cancer are attributed to melanoma. Experts estimated that 91,270 new cases of melanoma may be diagnosed in 2018, with 9,320 of those cases eventually resulting in death. Of the seven most common cancers in the United States, only melanoma is becoming more common, with an annual increase of about 2% per year as of 2012. The incidence of melanoma increased 800% between 1970 and 2009 for women, and 400% for men. Melanoma affects all age groups but is more common in elderly men and is the most common cancer in young adults (25 to 29 years of age).
Sun exposure is thought to be responsible for about 86% of all cases of melanoma. The melanocytes are part of a photoprotective mechanism for skin; in response to sunlight, they produce melanin that has a protective role from the sun's ultraviolet rays. The risk of exposure likely will increase as climate change further depletes the atmospheric ozone layer, a trend already observed and likely to worsen. For Caucasians, the amount of melanin present in the skin is directly related to sun exposure. However, it is not so much the total sun exposure that seems important, rather it is the history of sunburn (especially if severe or at an early age) that correlates with the increased risk. On this basis populations of fair-skinned people living in areas of high sun exposure such as the southwest United States or Australia are subject to increased risk. Malignant melanoma also affects non-Caucasians, though sun exposure probably does not play as much a role. The most common form of melanoma in African Americans is acral lentiginous melanoma.
Having a family or personal history of melanoma or a suppressed immune system may put people at risk. Those who have fair skin that burns easily or has lots of freckles, and people with light-colored eyes and red or blond hair tend to have higher risk. Individuals with multiple nevi, or moles, are at higher risk. Nevi can appear in groups and be fleshy, brown, or black. Malignant melanoma can arise in the skin anywhere on the body. Experts estimate that 50% to 70% of all melanoma cases develop spontaneously, whereas the remainder start in a pre-existing mole.
The most common causes for developing malignant melanoma are environmental and genetic. The environmental factor is excessive sun exposure. Genetic causes are link to missing or damaged (mutated) genes. The genetic factors seldom cause melanoma on their own, but most work together with ultraviolet exposure to develop the cancer. Having a weakened immune system might make it more likely a person develops melanoma.
Melanin production in fair-skinned people is induced by sun exposure. An exposure substantial enough to result in mild sunburn will be followed by melanin producing a tan that may last a few weeks. Some fair-skinned people only burn and fail to tan. Both ultraviolet radiation and damaging oxygen radicals caused by sun exposure may damage cells, particularly their DNA. Researchers suspect that this damage induces mutations that result in the development of malignant melanoma. Though these mutations are alterations of the genome causing the melanoma, they are environmentally induced and account for sporadic or spontaneous cases of this disease.
A positive family history of one or two first-degree relatives having had melanoma substantially increases the risk on a genetic basis. A family tendency is observed in 8%–12% of patients. Dysplastic (atypical) nevus syndrome is characterized by atypical moles with bothersome clinical features in children under age ten. Such individuals have to be observed closely for the development of malignant melanoma. Chromosome 9p has been identified as being involved in familial predisposition. There are mutations in up to 50% of familial melanoma patients of the tumor-suppressing gene CDKN2A. The actual number of moles increases risk, but the size of the moles needs to be considered. Those with ten larger moles of over 1 cm (0.4 in.) are at more risk than those with a higher number (50–99) of smaller moles. Finally, when a child is born with a large congenital mole, careful observation for change is appropriate because of increased risk.
An excellent way of identifying whether a mole might be malignant is to watch for these signs:
Color variation refers to areas of light color and black scattered within the mole. Small, uniform regular lesions have less cause for concern. It is important to realize that change in skin pigment, in a mole, or the rapid development of a new one near a current one are important symptoms.
Symptoms related to the presence of regional disease are mostly those of nodules or lumps in the areas containing the lymph nodes draining the area. These lumps are found in the armpit, groin, or neck if regional nodes are involved. There is also a special type of metastasis that can occur regionally with malignant melanoma; it is known as an in-transit metastasis. If the melanoma is spreading through the lymph system, some of the tumor may grow there, resulting in a nodule part way between the primary site and the original lymph node. These in-transit metastases are seen both at the time of original examination or later after a person has received initial treatment, the latter being a type of recurrence.
Finally, in those who either are diagnosed with or progress to widespread or systemic disease, symptoms and signs are related to the affected organ. Thus neurologic problems, lung problems, or liver problems develop depending on the organ involved.
Clinical signs or symptoms observed when a physician, nurse practitioner, or physician's assistant examines the skin can indicate that a patient has malignant melanoma, but the actual diagnosis is accomplished by biopsy. A biopsy is a procedure that removes tissue to examine it under a microscope. It is important that the signs and symptoms develop a high suspicion of the diagnosis because the way the biopsy is performed for melanoma may be different than for other lesions of the skin.
It is very important for doctors to establish the exact thickness of penetration of the tumor. Any biopsy that does not remove the full vertical extent of the primary is inadequate. Therefore, if a skin lesion is suspicious, full thickness excisional biopsy is the approach recommended. Shave biopsies and biopsies that remove only a portion of the suspect area are inappropriate. Often, in an early case, the doctor removes just the suspicious lesion with minimal normal skin. If a melanoma is diagnosed, further treatment of this area will often be necessary but does not compromise outcome (prognosis). In some special areas of the body, minor modifications might be necessary in excision.
Once the diagnosis is made, careful examination of the patient for regional lymph node involvement should be done. A careful review to uncover any symptoms of widespread disease is also appropriate.
Most patients with melanoma have an early tumor, and extensive testing is not usually warranted. Routine testing in this situation involves a complete blood count, a chest x ray, and determinations of blood enzymes, including lactic dehydrogenase and alkaline phosphatase.
The treatment of malignant melanoma is primarily surgical. More effective protocols involving the medical oncologist were being developed as of 2018 for the patient with systemic disease. Radiation therapy has a limited role in the treatment of melanoma, primarily that of helping to ease the effects of metastasis to the brain or sometimes the skeleton.
The key to successful treatment is early diagnosis. Patients identified with localized, thin, small lesions (typified by superficial spreading subtype) nearly always survive. For those with advanced lesions, the outcome is poor in spite of progress in systemic therapy.
Malignant melanoma is locally staged based on the depth of penetration through the skin and ulcer formation. There are two ways of looking at the depth of penetration. The Clarke system uses the layers of the dermis and the skin appendages present at that layer to identify the depth of penetration. The Breslow system uses the absolute measurement of depth. Though useful conceptually, the Clarke system is used less frequently because skin is of different thickness in different regions of the body. The depth of penetration is much greater when the tumor reaches the subcutaneous fat when the skin involved is the back as opposed to the face. It turns out that the Breslow measurement is more reproducible and thus more useful; therefore, for purposes here, depth of penetration by absolute measurement (Breslow) is used in local staging.
Stage 0 melanoma is confined to the epidermis and has not spread. Stage I and stage II have no involvement of the regional lymph nodes and are thus localized to the site of origin. These stages are subdivided on the basis of penetration. Stage I melanomas are 2 mm thick or less and might not have ulceration. Stage II tumors are at least 1.01 mm thick and can be thicker than 4.0 mm; the tumor might have ulceration. In stage III, there is disease beyond the primary site (three or fewer nearby lymph nodes) but no distant spread. Stage III is further divided (into IIIA to IIID) based on size, spread to local skin, ulceration, and how the lymph nodes are involved. Stage IV is defined by the presence of distant metastasis.
Once the diagnosis of malignant melanoma has been established by biopsy and the stage has been identified using the results of the examination and studies, a treatment plan is developed. Melanoma is not cured unless it is diagnosed at a stage when it can be isolated and removed surgically. Considerations revolve around the extent of the local and regional nodal surgery for stages I through III. For stage IV patients, or those that are treated and then develop recurrence at distant sites, chemotherapy or immunotherapy is planned. Studies were in progress as of 2018 to improve the results from traditional chemotherapy regimens. Adjuvant therapy (auxiliary drug treatment used to make possibility of relapse less for those at high risk) is also considered.
Surgical therapy for the primary site is that of wide local removal of the skin, including subcutaneous tissue surrounding the lesion. In the past, wide excisions were large and encompassed 2 in of tissue in all directions wherever feasible. It has been shown that such wide local excisions are not necessary, and doctors seek to determine what the necessary width is. Studies from the World Health Organization Melanoma Group and by the Melanoma Intergroup Committee in the United States have provided general guidelines based on the depth of penetration of the melanoma. These guidelines and anatomic considerations need to be kept in mind by the surgeon.
Questions related to which patients should have resection of regional lymph nodes have led to an intermediary procedure known as sentinel lymph node mapping and biopsy. Intermediate thickness melanomas 1–4 mm deep (0.04–0.2 in.) may have nodal involvement even if the exam and any other studies done are normal. If a radioisotope tracer or blue dye is injected into the area of the primary tumor, very shortly it will travel to the lymph nodes draining that area. These sentinel nodes are thus identifiable and are the most likely to harbor any regional metastatic disease. If these nodes alone are biopsied and are normal, the rest of the lymph node group can be spared. If they show microscopic deposits of tumor, then the full resection of the lymph node group may be completed. This procedure allows selection of those patients with intermediate thickness melanoma who will benefit from the regional lymph node dissection.
Chemotherapy uses drugs to treat cancer. A regional form of chemotherapy called hyperthermic isolated limb perfusion involves injecting drugs directly into the arm or leg with the cancer. Several types of immunotherapy might be used to treat melanoma. The treatments help the patient's immune system fight the cancer cells. Immune checkpoint inhibitor therapy blocks proteins in T cells to help them destroy cancer cells. Interferon affects how cells divide to slow tumor growth. Interleukin-2 therapy increases growth of immune cells to help destroy cancer cells. Tumor necrosis factor therapy is a protein made in a laboratory as a treatment but was still being studied as a way to treat melanoma as of 2018. Targeted therapy fights only the cancer cells and has less effect on healthy cells. There are several types of targeted therapy used for melanoma to block signals, send a virus to the cancer cells, or block growth of blood vessels to tumors. Vaccine therapies were being studied as of 2018 to target and block melanoma. Side effects of all therapies can be severe and must be managed, but targeted therapy typically produces fewer side effects.
Some patients, such as those with IIb or stage III melanoma, are at high risk for recurrence after treatment. Although these patients are clinically free of disease after undergoing primary treatment, they are more likely to have some microscopic disease in the body that studies have not yet been able to identify. Additional treatment such as interferon alpha 2a, an agent that stimulates the immune system, might be considered.
Some researchers were investigating the reasons why melanomas are so resistant to chemotherapy. One suggestion is that the genes ordinarily responsible for apoptosis (cell self-destruction) do not function normally in melanomas. The development of new drugs to treat melanoma depends on a better understanding of the complex processes involved in apoptosis.
Though radiation therapy has a minimal role in the primary treatment of malignant melanoma, for patients who have metastatic disease, radiation may be helpful. This is true in patients who have developed tumor deposits in areas such as the brain or the bone.
Almost all patients survive stage I malignant melanoma; at five years from treatment, 99% of people with early-stage melanoma are alive. Survival drops when the lymph nodes are involved to 63%. Stage IV, or distant metastasis, has a survival rate at five years of only 20%.
For those with familial tendencies for malignant melanoma, genetic counseling may be appropriate. Psychological counseling may be appropriate for anyone having trouble coping with a potentially fatal disease. Local cancer support groups may be helpful and are often identified by contacting local hospitals or the American Cancer Society.
Clinical trials are studies of new modes of therapy in an effort to improve results of treatment. A useful resource for those wishing to find a trial related to their particular situation can be found at http://www.emergingmed.com/networks/MRF/ .
Though it is difficult to prove that sunscreens statistically reduce the frequency of malignant melanoma, many authorities recommend use as protection from ultraviolet light (considered a major factor in the development of melanoma). Avoidance of severe sunburns is recommended.
Subungual melanoma is a type of acral lentiginous melanoma that occurs in the nail beds. Any pigmented lesion in these areas needs evaluation. They are commonly mistaken for bruises or infection. What matters most is knowing they exist so that proper evaluation can be performed as early as possible.
Malignant melanoma may also involve the eye, as melanin-producing cells exist there also. Again, familiarity with these spots is important so that pigmented growths are not ignored but evaluated early.
On rare occasions, a patient comes to the doctor with regional lymph node involvement, but the primary site of the tumor cannot be identified. The primary cancer might not be producing pigment and is known as an amelanotic melanoma. Because these patients have stage III disease, they do less well as a group overall.
See also Cancer ; Skin cancer .
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Richard A. McCartney, MD
Rebecca J. Frey, PhD
Revised by Teresa G. Odle, BA, ELS