What Is Melanoma?

Malignant melanomas are cancers involving specialized cells called melanocytes. Melanocytes have the unique ability to produce the pigment melanin and can be found in the skin, mucous membranes, eye, adrenal gland, and brain. Melanomas have a peculiar tendency to spread to distant sites (metastasize) at an early stage of growth and to grow in an uncontrolled fashion at the new site. This results in organ damage and ultimately death. When melanoma spreads from its original site, it is referred to as metastatic melanoma. The incidence of this type of cancer has recently been rising and it is the single most common cause of death from any skin disease. Like most cancers, the cause of melanoma involves an interplay between genetic and environmental factors.

What Causes Melanoma?

Like most cancers, the cause of melanoma involves interplay between genetic and environmental factors. It is generally agreed that ultraviolet-light-induced mutations in melanocytes is the single most important environmental factor in the induction of cutaneous melanomas. The fact that these cancers are difficult to produce experimentally as well as their appearance in areas of the body in which no light exposure occurs has fueled some controversy as to causation. Melanomas tend to occur on sun-exposed skin in fair-skinned individuals. On the other hand, there is a correlation between exposure to sunlight as defined by the earth's latitude and the incidence of melanoma. For example, melanoma is much more common in sunny areas, such as Arizona, than in Seattle. About 20% of melanomas are produced by heritable genetic mutations. Some of these genes have been identified. The remainder seem to be due to ultraviolet light-induced changes in genes (mutational events).

What Are Symptoms and Signs of Melanoma?

Melanomas most often arise on normal skin, but they may also occasionally occur in conjunction with a benign nevus (beauty mark or birthmark). The identification of potentially malignant pigmented lesions is best remembered by using the first five letters of the alphabet as follows:

• A for asymmetry
• B for border irregularity
• C for color multiplicity
• D for diameter greater than ¼ inch
• E for evolution (change) in the size and/or shape

Melanomas may ulcerate and bleed and occasionally cause these lesions to itch or burn. In summary, melanomas are most often pigmented, asymmetric with respect to color and shape, and tend to enlarge or change over time. The presence or absence of hair follicles is of no significance. The appearance of these cancers has resulted in a number of terms that are somewhat confusing and have limited clinical significance. They include superficial spreading melanoma, nodular melanoma, melanoma in situ, acro-lentiginous melanoma, and lentigo maligna melanoma.

Metastatic melanoma produces effects depending on the affected organ. In the brain, it can cause headaches and seizures. In the lungs, it causes shortness of breath and malaise. In the bones, it causes bone pain and fractures. It can affect any area of the body. Although rare, melanomas can arise in tissue other than the skin at any site that contains melanocytes. This includes the eye (uveal melanomas), mucosa (genital or oral tissues), and in the brain.

What Are Risk Factors for Melanoma?

• Having fair skin
• Living closer to the equator
• Having a large number of nevi (moles)
• Having a personal or family history of melanoma
• "Dysplastic nevus syndrome," is characterized by an inherited predisposition to develop numerous, large irregularly pigmented moles
• The presence of a very large congenital (present at birth) mole (bathing trunk congenital nevus)

When Should Someone Seek Medical Care for Suspicious Skin Lesions?

There are many kinds of benign pigmented lesions normally found on the skin. Some are present from the time of birth (congenital) while others develop after birth. Commonly, these are referred to as "moles." In younger patients, most pigmented lesions are melanocytic nevi composed of benign melanocytes growing in nests or clumps within the skin. The average number of these lesions is 30-35 per person in light-skinned races. It is not uncommon for such lesions to continue to arise until 35 years of age. Older individuals predominantly have non-melanocytic pigmented lesions called seborrheic keratoses, which arise in the most superficial layer of the skin and tend to continue to appear during adult life. Lentigines and freckles are other benign lentiginous lesions that can be confused with melanoma. Distinguishing these benign lesions from more ominous ones may be difficult. Any asymmetrical (color or border), changing lesion, especially if it is bleeding or irritated, or symptomatic, should be examined by a physician. Regular self-examination or examination by a significant other can be a valuable asset in early detection.

What Specialties of Doctors Treat and Diagnose Melanoma?

Primary localized melanoma is frequently diagnosed and treated by dermatologists, plastic surgeons, and occasionally primary-care physicians. If the melanoma is more advanced or invasive or shows signs of potential metastasis, physicians who specialize in treating advanced cancer (surgical and/or medical oncologists) are consulted.

How Do Specialists Diagnose Melanoma?

The diagnosis of melanoma is suspected when a skin lesion exhibits some or all of the criteria described in the symptoms and signs section above. Melanomas may develop on any area of the skin, including the palms, soles, scalp, and under fingernails.

Recently, handheld devices have been developed, utilizing magnification and polarized light, which can enhance the detection of dangerous pigmented lesions (dermoscopy). Suspicious lesions are surgically removed by the physician in their entirety, if possible, and submitted to a pathologist who is an expert in the microscopic interpretation of skin disease. The diagnosis is made when the pathologist identifies certain microscopic features. Occasionally, certain lesions may not exhibit sufficient criteria to qualify as melanomas but maybe "borderline" lesions. Then the pathologist may suggest that such worrisome lesions be re-excised with a margin of normal tissue surrounding the excision site.

If the diagnosis of melanoma is made, the pathologist will also describe its thickness in millimeters, how deep it has penetrated into the skin, if there is any invasion of nerves or blood vessels, and estimate its mitotic activity. New molecular testing of melanoma gene expression (DecisionDx-Melanoma) that can aid in the identification of tumors likely to metastasize early is now available. These tests could help to guide treatment options.

What Are Melanoma Survival Rates?

The 10-year melanoma survival rates, according to the stage, are as follows:

• Stage I: 85%-96%
• Stage II: 57%-67%
• Stage III: 24%-68%
• Stage IV: 10%-15%

How Do Doctors Determine the Stage of a Melanoma? What Are Treatments for Melanoma?

The treatment of melanoma is dependent on the stage of the disease at the time of diagnosis. Staging is a technique often used to categorize various kinds of cancer according to the extent of cancer in the hope that this will help the doctor to predict the behavior of the disease and select the best treatment.

Stage 0: These are melanomas that are confined solely within the epidermis and have not penetrated below the basement membrane -- so-called "melanoma in situ" or lentigo maligna. Thin tumors of this type ought to be excised with surrounding margins of normal skin of about 1 cm if possible. Occasionally, it may be difficult to visually estimate the extent of this type of tumor. Some dermatologic surgeons advocate the use of micrographic surgery with frozen section control (Mohs surgery) utilizing special stains to assure complete removal of tumors with indistinct margins.

Stage 1: These melanomas (lesions ≤1 mm thick) have not metastasized. Stage 1 melanomas generally only require surgical removal of the tumor with a 2 cm margin of normal tissue. If the tumor has ulcerated or if the cells are dividing rapidly, pathologically the tumor may be classified as stage IB.

Stage II: These are melanoma tumors that are 1-2 mm and may be ulcerated but without evidence of spread beyond the primary lesion.

Stage III: These are melanoma tumors of any thickness that have spread locally to adjacent skin or to local draining lymph nodes.

Stage IV: These are melanoma tumors that have spread to distant sites.

Thicker tumors or tumors that appear to have spread to other parts of the body have a much poorer prognosis. For melanomas of intermediate thickness (generally ≥ 1mm) with no evidence of metastatic spread, a technique called sentinel lymph node biopsy has been developed, which is useful in predicting the progression of the disease. This is performed by injecting a radioactive tracer and/or a dye at the site of the tumor and tracing it to the local lymph nodes that drain the site of cancer. Once identified, these lymph nodes are removed and examined by the pathologist to determine if they have been invaded by melanoma. The lack of invasion is a good sign. It is often desirable to submit portions of the melanoma for genetic testing to determine if it possesses one or more mutations that may render it susceptible to certain drugs. For example, mutations in BRAF and MEK, two important genes in the MAPK/ERK pathway (controls cellular proliferation), are often susceptible to drugs that inhibit these pathways. For patients whose tumors do not contain these two mutated genes, advances in immunotherapy, in particular the inhibitors targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed death ligand 1 (PD-L1) have shown substantial promise in prolonging life.

Once melanoma has metastasized to draining regional lymph nodes or to more distant sites, treatment options become more complicated, and good outcomes become less common. Such treatments for metastatic melanoma include the following:

Regional lymph node dissection does not seem to significantly decrease the mortality rate due to melanoma, but it may offer palliative effects.

Peginterferon alpha 2-b (Sylatron) seems to prolong melanoma-free periods but does not prolong overall survival.

Aldesleukin is a genetically engineered protein (IL-2) approved for the treatment of advanced metastatic melanoma in 1998. It has been supplanted by more effective immunotherapies listed below.

Radiation therapy is useful for the palliation of brain and bone metastasis.

Newer local and systemic options:

T-VEC (Imlygic) received FDA approval in 2015 is a genetically modified type 1 herpes simplex virus designed to replicate within tumors, causing tumors to rupture (cell death). It seems useful in treating local metastatic lesions, especially in the skin, but there is no convincing evidence that it has much effect on distant metastasis to important organs.

The Ipi + Nivo (Ipilimumab + Nivolumab) combination is a checkpoint inhibitor that received FDA approval in 2015 based on improved response rates and progression-free survival in previously treated patients. Nivolumab (Opdivo) was approved in 2015 as first-line therapy for melanoma patients who do not have a positive BRAF V600 mutation. They work by blocking the melanoma cell's ability to suppress the patient's lymphocytic immune response.

Pembrolizumab (Keytruda) another checkpoint inhibitor received approval in 2014 for demonstrating responses in patients whose disease has progressed following ipilimumab and, if BRAF V600 mutation-positive, also a BRAF inhibitor.

Ipilimumab (Yervoy), a T lymphocytes stimulator, was approved in 2011 and produced improvement in overall survival in patients with either previously treated or untreated advanced melanoma.

Vemurafenib and dabrafenib in combination were shown to achieve a high rapid tumor response rate (roughly 50%) in patients carrying the BRAF V600E mutation and a substantial improvement in overall survival.

Cobimetinib (Cotellic) and vemurafenib (Zelboraf) may treat people with BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma.

Trametinib (Mekinist) and dabrafenib (Tafinlar) treat patients with advanced melanoma BRAF V600E or V600K mutation that is unresectable or metastatic.

These new adjuvant immuno-stimulating therapies are being actively studied in clinical trials. They are associated with a number of serious side effects that may limit to some extent the wide application. This is just a fraction of the available drug options for the treatment of metastatic melanoma. The choice of the best option requires consultation with an experienced medical oncologist.

Melanoma Follow-up

Once melanoma has been diagnosed and treated, it is important for the patient to be seen regularly by a physician. This is for:

monitoring the patient for metastatic melanoma;
• monitoring for new melanomas;
• various diagnostic modalities are used to monitor the progress of metastatic melanoma, including chest X-ray, CT scan, MRI scan, PET scan;
• biopsy of any suspicious cutaneous masses.

What Is the Prognosis of Melanoma?

Prognosis is most closely related to the thickness of the melanoma as measured by the pathologist. Other factors of importance include:

• the anatomic depth of penetration,
• ulceration,
• mitotic activity (rate of cell dividing),
• gene expression studies,
• stage of melanoma.

This is why it is of great importance to remove the entire melanoma at its earliest stage to preclude the possibility of metastatic spread, as well as determining the accurate thickness of the tumor.

In addition, new genetic tests are available that can help predict a particular tumor's sensitivity to a variety of drug regimens. For example, patients whose melanoma expresses a BRAF mutation are likely to respond to vemurafenib and dabrafenib with a substantial prolongation of overall survival. Other mutations signify that other drugs are more likely to be effective.

Is It Possible to Prevent Melanoma?

There is general agreement that ultraviolet light is the major environmental cause of most cutaneous melanomas.

Avoiding ultraviolet light exposure by eliminating sunbathing (for cosmetic purposes, including artificial tanning), wearing appropriate clothing, and using effective sunscreens are prudent methods to prevent melanomas, as well as most other sorts of skin cancer and photoaging. Concerns about vitamin D deficiency are overcome by taking supplements containing at least 1,000 IU of vitamin D per day.