Skin Cancer Melanoma

Melanoma. Source: CDC

Author: Dr Mohammed Kashani-Sabet University of California San francisco 2008-07-21

Melanoma is a cancer of pigment-producing cells known as melanocytes. Melanocytes are developmentally part of the nervous system, and migrate to the skin and other organs, where their chief role is the production of the pigment known as melanin. Melanin is in turn responsible for protecting various tissues from the effects of ultraviolet (UV) light (sunlight). Freckles develop when there is an excess of pigment produced by melanocytes (without an increase in the number of melanocytes). Moles (also known as nevi) develop when there is a growth or increase in the number of benign melanocytes (with or without excess pigment). Melanomas are produced when abnormal, cancerous melanocytes grow (with or without excess pigment production). Melanoma is most commonly encountered on the skin (over 90% of the cases) but can be detected anywhere that normal melanocytes are found, such as inside the mouth and nose, in the anal or genital tract, in the eye, lymph nodes, and the lining of the brain.

Epidemiology: Melanoma’s Prevalence and Effect on the United States Population

In 2007, melanoma was the seventh most-common cancer in the United States. Many studies have shown that the number of melanoma cases seen annually (known as incidence) is increasing at a faster pace than any other cancer. In the year 2007, an estimated 59,940 invasive melanomas were diagnosed in the United States, with 56% of the melanomas detected in men. The average age of a patient with a newly diagnosed melanoma is somewhere in their fifties. However, melanoma appears to be occurring more frequently both in younger and older people.
In 2007, there were an estimated 8,110 deaths due to melanoma, with the majority of these deaths in men. The mortality rate from melanoma has actually decreased over the last fifty years, in large part due to earlier diagnosis. As a result, more than 90% of individuals with melanoma are alive five years after their diagnosis, which is a significant improvement over what was seen twenty years ago.

Risk Factors

Several risk factors have been described for melanoma. Persons with red or blond hair and blue eyes are at a higher risk for developing melanoma. Caucasians with a large number of moles are also at a higher risk for developing melanoma. In additions, persons who have irregular moles (called dysplastic nevi by some experts) are at a higher risk for developing melanoma. However, melanomas may occur in a new spot that did not have a pre-existing mole in it. As a result, individuals with a large number of moles are monitored very carefully for changes in their moles or new moles that are suspicious for melanoma so that they can be removed at the earliest possible time. Some physicians use photography as a tool to follow moles; others use a hand-held instrument called a dermatoscope that (in experienced hands) can allow the physician to see the pigment pattern of an individual mole to help make the decision whether to remove the mole or not.
Other than the above-mentioned factors, specific factors in the individual’s history can contribute to one’s risk of developing melanoma. Having had one melanoma (or different kind of skin cancer) increases the risk of another primary skin melanoma, and this usually occurs within five years of the initial melanoma diagnosis, though it can occur later than that. Having someone in the family with melanoma also increases one’s risk for developing melanoma. It is estimated that 5-10% of melanomas may occur because of some inherited predisposition to it, and many studies have tried to identify mutations in genes that may increase one’s risk for melanoma. So far, the best characterized familial gene for melanoma is the CDKN2A gene (also known as p16). However, at the current time, genetic testing for melanoma is still considered largely experimental and should be performed at experienced centers after thorough counseling of the pros and cons of such testing have been explained to the individual.
Finally, there is an important though imperfect relationship between sun exposure and melanoma. Numerous studies have clearly shown an increased risk of developing melanoma in people who tan poorly or burn easily, or who have had multiple (usually blistering) sunburns. Early on, these studies showed the importance of sunburns in childhood and adolescence. More recent evidence points to the additional importance of cumulative sun exposure, especially with the aging population of some Western countries such as the United States. However, individuals do not always develop their melanomas where they had their most severe burns, so the exact relationship between sun exposure and the development of a given melanoma may be uncertain.
In general, while a single risk factor may increase the risk for developing melanoma to a small extent, having multiple risk factors in the same individual or family can greatly increase the risk for melanoma, requiring a customized approach to skin checks for each individual at risk for melanoma.

Signs and Symptoms

The most common appearance of a skin melanoma is a changing, irregular appearing growth or dark spot. While most melanomas produce pigment and tend to look dark, melanomas can also appear with little or no visible pigment (known as amelanotic melanoma). However, amelanotic melanomas still produce melanin at the cellular level that may not be detected by the naked eye. Melanoma has been broken down into several different types based on clinical appearance as well as features seen under the microscope (histopathological features) (see photographs).
The most common type of melanoma is called superficial spreading melanoma, in which early on the growth is flat and outward on the surface of the skin (like spokes on a wheel, known as the radial growth phase). This phase may last for months or even years. Eventually, the melanoma begins to grow inward into the skin, which can have the appearance of a bump above the skin (called the vertical growth phase). Superficial spreading melanomas can be detected using the “ABCDE” abbreviation, where A stands for asymmetry, B border irregularity, C color variation, D diameter enlargement, and E evolution or change in the spot.
Nodular melanomas are the next most common type of melanoma, and grow as a lump or bump (with or without noticeable pigment) directly into the skin without an obvious flat phase.
Acral lentiginous melanomas appear in areas of skin without hair, including the palms, soles, and underneath the nail. Melanomas on the palms and soles usually appear as darker spots, but melanomas in the nail can look like red bumps and be mistaken for a fungus infection.
Lentigo maligna melanomas can look like a dark freckle that is growing, and occur as a result of chronic sun exposure. They are usually seen in areas such as the scalp, face, neck, and arms with signs of sun damage.
Desmoplastic melanomas are a type of melanoma that is being seen more frequently recently. These melanomas tend to start in the same regions as lentigo maligna melanomas, but they usually do not produce a lot of pigment and can have a deceiving appearance that does not look like an ordinary melanoma. Desmoplastic melanomas usually show up as a reddish or flesh-colored lump or bump and can be mistaken for a cyst or scar.
Most skin melanomas do not have any associated symptoms early in their development, but itching, bleeding, and pain can eventually develop. Melanomas in the eye can cause pain or vision problems (like blurry vision, double vision, or partial or complete loss of vision).

Diagnosis

Melanoma is usually diagnosed when a suspected growth is removed (or biopsied) by a physician, usually a primary care doctor, dermatologist, or surgeon. Different biopsy techniques can be used that will be reviewed here:

1. Excisional biopsy

This type of biopsy attempts to remove the growth in its entirety. In general this is the best approach because it allows the pathologist who reviews the tissue to examine the entire growth. Depending on the size and the location of the growth, an excisional biopsy can be performed using a number of different techniques, including: (i) elliptical excision, in which the growth is removed by cutting around it with a scalpel and sewing the skin together; (ii) punch biopsy, in which a cylindrical instrument (called a punch) is used to remove the mole and a small area of normal skin around it; and (iii) shave biopsy, in which a scalpel alone is used to get underneath the growth. Elliptical and punch biopsies require sutures, whereas shave biopsies do not. However, shave biopsies may not always remove the entire growth, so they should be performed by experienced health care professionals when a melanoma is suspected.

2. Incisional biopsy

This type of biopsy attempts to remove a piece of the growth. This is usually not the preferred approach but sometimes has to be used if the suspected melanoma is unusually large, in a sensitive location (such as the face), or in which complete removal would require drastic surgery. For incisional biopsies, the same three approaches described for excisional biopsies would typically be used.
Once the biopsy is performed, it is sent to a pathology laboratory for review by a pathologist, who makes the final diagnosis. For a suspected eye melanoma, the diagnosis is made on clinical examination of the growth in the eye by an experienced ophthalmologist, and a biopsy is not usually performed. When melanoma appears in unusual locations such as the lymph nodes or internal organs, a partial biopsy of the involved area or complete removal of the growth is performed to make the diagnosis.

Patterns of Spread

Skin melanoma is unusual in its ability to spread to potentially any organ. The most common areas that skin melanomas usually spread to are the skin or lymph nodes. Melanomas spreading to the skin usually show up as lumps or bumps near the original scar or somewhere between the original scar and the lymph node region draining that area. These growths are called satellites or in-transit metastases. Melanomas spreading to the lymph nodes show up as a lump or bump underneath the skin in a lymph node area (for example, for a melanoma on the leg, the most common lymph node area would be in the groin, whereas for a melanoma on the arm, the most common lymph node area would be in the armpit region; melanomas on the face, ears, and scalp can spread to lymph nodes in the head and neck region). Both of these phenomena are a sign that the melanoma has entered the lymphatic system.
Melanoma can also spread through the bloodstream, either directly from the skin or after spreading to a lymph node. The most common internal organs that melanoma can spread to include the lungs, liver, and brain, but melanoma can also be seen in the small bowel, adrenal gland, spleen, and internal lymph nodes. Melanomas in the eye do not spread to lymph nodes, but tend to involve the liver before other organs are affected.

Staging: Identifying the Seriousness of the Melanoma

Once a diagnosis of melanoma is made, the potential seriousness of the melanoma is determined using a number of prognostic factors. In general, the most important determinant of the prognosis of a skin melanoma is the depth of penetration into the skin. Areas potentially involved by skin melanomas are composed of three major layers: the epidermis, the dermis, and the fat. The earliest stage of a melanoma is called a melanoma in situ, which involves only the epidermis and does not show any involvement (or invasion) into the dermis. This is by definition a non-invasive stage of melanoma that is usually associated with an excellent prognosis once it is completely removed by surgery.
Once a melanoma moves beyond the epidermis to involve the dermis, it is called an invasive melanoma. For an invasive melanoma, the most important factor to determine prognosis is the vertical thickness in millimeters (also called the Breslow thickness) measured by a ruler under the microscope from the top of the melanoma (even if it is raised above the skin) to its base underneath the skin. Currently, four breakpoints for tumor thickness have been entered into the staging classification for melanoma:

(1) Melanomas less than or equal to 1.0 mm (called T1).
(2) Melanomas greater than 1.0 mm but less than or equal to 2.0 mm (called T2).
(3) Melanomas greater than 2.0 mm but less than equal or 4.0 mm (called T3).
(4) Melanomas greater than 4.0 mm (called T4).

Using this measurement, melanomas under 1.0 mm are usually considered thin, melanomas from 1.0-4.0 mm in the intermediate range, and melanomas over 4.0 mm usually considered thick.
Another measurement that is frequently used is the Clark level, which measures the anatomic depth of the penetration of the melanoma into the skin. Clark level is separate from the stage (discussed below), but since Roman numerals are used to record both pieces of information, patients and physicians sometimes can mistake one for the other, thereby causing significant confusion and anxiety. The Clark levels refer to the following:

Clark level I - melanoma confined to the epidermis (i.e., melanoma in situ).
Clark level II - melanoma extending to the top part of the dermis, known as the papillary dermis.
Clark level III - melanoma extending to the border of the papillary and the reticular dermis.
Clark level IV - melanoma extending to the bottom part of the dermis, known as the reticular dermis.
Clark level V - melanoma extending beyond the dermis into the fatty tissue.
Clark level II and III melanomas are generally considered superficial, whereas melanomas invading into level IV and V are considered deep.

Recently, a phenomenon called ulceration has also been included in the staging classification for melanoma. Ulceration is a break in the area of the epidermis affected by the melanoma; the pathologist measures the ulceration by looking under the microscope. A bleeding melanoma can sometimes alert the physician to the presence of ulceration, although this is a measurement that has to be made by the pathologist. Studies have shown that the risk of recurrence for an ulcerated melanoma is higher than a melanoma of the same thickness without ulceration.

The current staging classification for melanoma appears in Table 1. Melanoma confined to the skin occupies stages IA through IIC, with the advancing stages accounting for thicker or ulcerated tumors. Stage III melanoma encompasses cases that involve the lymph nodes, or that show up with satellites/in-transit metastases. Stage III melanoma is currently broken down into three substages, based on the following factors: number of lymph nodes involved by the melanoma; whether the lymph node involvement was microscopic (observed only under the microscope) or could be felt clinically (macroscopic); whether the primary melanoma had ulceration; and whether satellites/in-transit metastases were present with or without lymph node involvement. Stage IV melanoma refers to melanoma involving any area beyond the regional lymph nodes, including distant skin and lymph nodes, lungs, and internal organs.

Treatment of Melanoma

Surgery

Surgical removal of skin melanoma is the most important initial treatment for melanoma. Following the initial biopsy, every melanoma undergoes a further surgery (called re-excision or wide excision) to remove the skin around the original site of the tumor in order to ensure complete removal and to reduce the risk of regrowth (recurrence) of the tumor at that site. The amount of skin to be removed (called the re-excision margin) depends on the thickness of the melanoma, with increasing margins for increasing categories of thickness, from five millimeters on either side of the scar for melanoma in situ to potentially two centimeters on either side for melanoma over four millimeters thick. However, it is important to note that the surgical approach to every melanoma should be customized based on the specific details of the patient and the melanoma, location of the melanoma, and how the resultant wound would be repaired. A simple excision of a melanoma can usually be accomplished by sewing the skin together, resulting in a linear scar. Wider margins of excision can require more complex ways of closing the wound, including skin grafts (in which skin is taken from another area of the body to cover the wound) or flaps (in which nearby tissue is moved over to cover the wound). In most instances, wide excision alone can be performed under local anesthesia in the physician’s office.

The other important use of surgery for melanoma is removal of the regional lymph nodes to identify whether melanoma has spread. Initially, the physician evaluating the patient with a skin melanoma will feel the lymph nodes to determine whether there are any enlarged lymph nodes, which can undergo biopsy directly. In most patients with primary melanoma, no lymph nodes can be felt, so the question is whether melanoma has spread to lymph nodes microscopically. To date, only lymph node surgery can determine whether this has occurred. Historically, this was accomplished by complete removal of all of the lymph nodes of the suspected region, called elective lymph node dissection (ELND), which could require radical surgery. Recently, a technique called sentinel lymph node biopsy (SLNB) has largely replaced ELND to evaluate the regional lymph nodes. The sentinel node(s) is considered to be the first lymph node that the cancer cells encounter as they travel along the lymphatic vessels. In this technique, usually a blue dye and a radioactive tracer are injected at the site of the tumor (or where the tumor used to be before its removal by biopsy) at the time of the re-excision. After injecting the dye and tracer, a nuclear medicine scan is performed to identify the sentinel lymph node, which shows uptake of the tracer on the scan. If the sentinel node has tumor cells in it (“positive” lymph node”), the current practice is to remove other lymph nodes in the area. In general, lymph node surgery requires general anesthesia, although the SLNB procedure can be performed without staying in the hospital.

Recent studies have shown that patients with an involved (or “positive”) sentinel lymph node have a higher risk of recurrence than those who have a negative sentinel node. Following the removal of any involved regional lymph nodes, patients can be considered for further treatment to lower the risk of melanoma recurrence, called adjuvant therapy (see below). Another major benefit of the procedure is preventing extensive surgery on regional lymph nodes when the sentinel node is negative. Whether removing the lymph nodes prolongs survival of patients with melanoma is still being studied.
When melanoma has spread beyond the regional lymph nodes, surgery can still be important in specific situations either to establish the diagnosis, remove all evidence of the tumor, or control symptoms produced by the tumor.

Systemic Treatments for Melanoma

Systemic treatments refer to treatments that treat the entire individual (usually given either orally or by injection) to treat all sites of involvement by the cancer. In melanoma, there are two settings in which systemic therapy is usually considered: (i) in the adjuvant setting, that is following removal of all known sites of melanoma, systemic therapy is performed in order to lower the risk of recurrence; and (ii) in the metastatic setting, when melanoma has spread to distant sites (stage IV melanoma) that cannot be treated with local treatments (such as surgery or radiation). These two settings will be considered separately.

1. Adjuvant Therapy for Melanoma

Melanoma that is considered to be at a high risk for recurrence despite surgical removal would be the appropriate time to consider adjuvant (or adjunctive) treatments. Three situations in which adjuvant therapy has been examined for melanoma have included primary skin melanoma, melanoma spreading to the regional lymph nodes, and melanoma spreading to limited distant sites, all following surgery to remove all known site(s) of melanoma involvement.
When adjuvant therapy is being evaluated, because no obvious or detectable evidence of the cancer remains the treatment has to be shown to prolong either the time to relapse (known as relapse-free survival) or the time to death (known as overall survival) or both when compared with either no treatment, placebo, or a treatment that is known to be effective. Currently, the only adjunctive treatment approved by the United States Food and Drug Administration (FDA) is interferon alpha 2b (IFN). Prior to the approval of IFN, over the last thirty years, numerous studies testing a variety of different experimental treatments had been performed in the adjuvant setting, with no studies showing benefit in survival. IFN is a naturally occurring protein that attempts to boost the immune system (also known as immunotherapy) to better recognize and eradicate the cancer. IFN was compared with no treatment in a multi-center clinical trial in two groups of patients: those with a thick melanoma (greater than 4.0 mm) or those with melanoma involving the lymph nodes. In this study, a high-dose, one-year program of IFN was tested, and was found to prolong both relapse-free survival and overall survival, resulting in FDA approval for the treatment of high-risk melanoma. The IFN program is an intensive therapy with numerous side effects (including but not limited to fatigue, depression, and flu-like reactions such as fever, chills, headaches, muscle and joint aches,) that most patients in the trial were able to tolerate, though reducing the dose of IFN may be required in a sizable number of patients. Additional trials of IFN have shown confusing (and at times conflicting) results, making it difficult to be sure about the exact amount of benefit gained by doing the treatment. Patients who are a candidate for IFN treatment should have a thorough discussion with their physician regarding the pros and cons of this treatment as well as alternative treatments, when available.
Given that IFN is an intensive therapy with an apparently modest benefit, other adjunctive treatments have been explored to see if they can be as or more effective, possibly with fewer side effects. Most of these treatments try to boost the immune system in different ways from IFN, and many of these studies have tested various vaccines. Melanoma vaccines are different from vaccines used for infectious diseases. Melanoma vaccines usually consist of melanoma cells (or pieces of proteins inside melanoma cells) that have been modified in various ways and are given to patients in attempts to better alert the immune system to the presence of melanoma cells. Most vaccine treatments do not have severe side effects, making them very attractive potential alternatives to IFN. However, so far, despite many studies conducted over the last twenty years (including a number of recently completed phase III trials), no melanoma vaccine has been shown to prolong survival, and none has been approved by the FDA.

2. Systemic Treatments for Stage IV Melanoma

Stage IV melanoma is a serious, life-threatening condition. When melanoma has spread to more than a limited number of sites, systemic treatments need to be considered in order to shrink the known tumors, prevent new tumors from developing and, hopefully, prolong the patient’s survival. Unfortunately, treatments for stage IV melanoma are not optimal at the current time, since no treatment has been conclusively and consistently shown to prolong survival in this situation. One problem is that many chemotherapy drugs, which are used to treat other cancers, are not as effective in treating melanoma. Nevertheless, a number of treatment options exist for patients with stage IV melanoma, and these treatments can sometimes benefit certain groups of patients. In addition, many more (currently experimental) treatments are being developed and tested, with the hopes that better and more effective treatments will soon be available to treat stage IV melanoma.
Two treatments have been approved by the FDA for stage IV melanoma: dacarbazine (also known as DTIC) and interleukin-2 (IL-2). DTIC is a chemotherapy drug that has been available for over thirty years to treat melanoma. It is associated with few cures, but it can shrink melanoma tumors in a small percentage of patients and control their symptoms. It is given by a simple intravenous injection in the doctor’s office and usually does not cause serious side effects. A frequently used alternative to DTIC is a drug known as temozolomide, which is chemically similar to DTIC and with similar effectiveness. Temozolomide is available as a pill and is approved by the FDA for the treatment of brain tumors, but not melanoma.
IL-2, another protein that boosts the immune system, is used to treat melanoma. IL-2 is a highly intensive treatment with serious side effects that require hospitalization and should be performed in hospitals with adequate experience in doing the treatment. IL-2 was approved by the FDA because it caused a complete regression of all evidence of the cancer in a small percentage of patients.
Other approaches that have been tested include combining chemotherapy drugs together, and combining chemotherapy and immunotherapy (sometimes referred to as biochemotherapy). At the current time, many clinical trials are examining a number of experimental drugs for their effectiveness against melanoma. Some of these drugs are in the final phase (phase III) of testing in order to obtain FDA approval. While these drugs appear to work in different ways, most of these experimental approaches are either trying to make chemotherapy more effective (that is, make the cancer more receptive to the effects of chemotherapy) or to test new chemotherapy or immunotherapy drugs.

3. Radiation Treatment

Radiation therapy can be used to treat melanoma that grows uncontrollably in specific areas that cannot be treated adequately by surgery alone. Radiation treatments are most commonly used to treat melanoma growing in lymph nodes (following surgery), the spine or the brain. Radiation therapy is also the preferred treatment for a primary melanoma in the eye.

References

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Table 1. American Joint Commission on Cancer Staging for Cutaneous Melanoma

Stage Criteria
IA Localized melanomas < 1.0 mm thick without ulceration and Clark level II/III (T1a, N0, M0)
IB Localized melanomas < 1.0 mm thick with ulceration or Clark level IV/V (T1b, N0, M0) OR localized melanomas 1.01- 2.0 mm thick without ulceration (T2a, N0, M0)
IIA Localized melanomas 1.01- 2.0 mm thick with ulceration (T2b, N0, M0) OR localized melanomas 2.01-4.0 mm thick without ulceration (T3a, N0, M0)
IIB

IIC Localized melanomas 2.01- 4.0 mm thick with ulceration (T3b, N0, M0) OR localized melanomas > 4.0 mm thick without ulceration (T4a, N0, M0)
Localized melanomas > 4.0 mm thick with ulceration (T4b, N0, M0)

IIIA-C Nodal metastases depending on number of lymph nodes involved, presence of ulceration and/or in-transit metastases
IV Any patient with distant metastases (any T, any N, any M1)