What Is Melanoma? - Types, Causes & Risk Factors

Key Points

• Melanoma is one of the most aggressive forms of skin cancer
• Genetics and sun exposure can increase the risk of melanoma development
• Acral lentiginous melanoma can occur on non-sun exposed areas of the body, such as nailbeds, palms, and soles

Dermatologists and other providers always recommend sunscreen to help protect against skin cancer. While it is true that skin cancer can result from excess sun exposure, skin cancer can also arise on areas of the body not directly exposed to the sun.

What is Melanoma?

Melanoma, also referred to as malignant melanoma and cutaneous melanoma, is one of the most aggressive forms of skin cancer and one of the leading causes of cancer related mortality due to its ability to metastasize to other locations.^[1] Melanoma skin cancer consists of 4–5% of all skin cancers, and contributes to 71–80% of skin cancer deaths.^[1,2] 

Cutaneous melanoma arises from melanocytes. In the skin, these cells are present in the stratum basale layer of the epidermis. One of the important functions of melanocytes is to produce melanin (pigment). Melanin is produced in response to UV light and functions to serve as a protective shield against UV radiation from the sun to prevent further DNA damage.^[2] This is why individuals may experience skin darkening or a tan after sun exposure.

Melanoma occurs when melanocytes stop functioning properly. This could be due to genetic mutations or DNA damage to the cells from sun exposure.

Types of melanoma

There are four major subtypes of cutaneous malignant melanoma:^[3]

• Superficial spreading melanoma (SSM): is the most common subtype, accounting for approximately 70% of cases. Commonly presents on the trunk.
• Nodular melanoma (NM): accounts for 15% of melanomas.
• Lentigo maligna melanoma (LMM): accounts for 13% of melanomas that arise from lentigos (sun spots). Associated with chronic sun exposure in individuals with fair-skin.
• Acral lentiginous melanoma (ALM):accounts for 2-3% of all melanomas and is predominantly found on the nailbeds, palms, and soles. 

While acral lentiginous melanoma accounts for the least common subtype of melanoma, it can be the most dangerous given its presentation in non-sun exposed locations causing a delayed diagnosis.

Causes of Melanoma

It’s true that excess sun exposure is one of the leading causes of skin cancer. However, there is a misconception that ultraviolet radiation from the sun is the only cause of skin cancer.

The risks of melanoma include both environmental risk factors i.e. ultraviolet light exposure as well as genetic risk factors (individual susceptibility):^[2]

1. Environmental - Intermittent or chronic sun exposure and multiple sun burns during childhood
2. Genetic - Ability to develop multiple melanocytic nevi (moles), family history of melanoma, and fairness of skin, light hair color, and light eyes

Environmental risk factors

Like other types of skin cancer, ultraviolet (UV) light radiation from the sun is the main environmental factor that causes melanoma.^[4] In fact, an estimated 65% of melanoma is due to sun exposure.^[5]

When the skin is exposed to UV light it can affect a variety of internal processes that can contribute to the development of skin cancer:^[2]

• Damage DNA by creating mutations, deletions, and duplications
• Cell and tissue dysregulation, such as cause a mole growing rapidly or melanocytes (pigment cells) invading surrounding tissues
• Affect expression of oncogenes and tumor suppressor genes 

A history of sunburns in childhood and adolescence is associated with the highest risk of developing melanoma. Those who experience more than five severe sunburns have a 2-fold increased risk in the development of melanoma.^[4]

Cutaneous melanoma can be classified by its origin from chronic or intermittent sun exposure:^[5]

• Intermittent and intense exposure: associated with a history of severe sunburns and arise in younger populations (<55). Melanoma may present on less sun exposed areas such as the trunk.
• Chronic exposure: usually appear in older individuals (>55) on areas of the head, neck, and upper extremities. These individuals may also have other skin manifestations such as actinic keratosis, sun spots, and signs of premature aging.

Not only does natural light from the sun increase the risk of melanoma, but artificial lighting from tanning beds have demonstrated a positive correlation between the risk of developing melanoma and the amount of sunbed usage by up to 75%.^[4]

Genetic risk factors

In addition to UV light, genetics also play a significant role in the development of melanoma, particularly in the Caucasian population. In fact, every year there is a 3–6% rise in new melanoma cases observed within Caucasians.^[2] The lack of cutaneous melanin (pigment), a protective factor against UV damage, is likely one the main contributing factors that renders this population more susceptible to melanoma.

Phenotypic (personal) characteristics that may predispose individuals to melanoma include:^[1]

• Red or blond hair
• Blue or green eyes
• Fair skin with low tanning ability
• Freckles and multiple melanocytic nevi (>100)
• Five or more atypical nevi diagnosed by biopsy

One of the biggest risk factors for cutaneous melanoma is the presence of moles (nevi). In fact, approximately 25% of melanoma cases arise from a pre-existing mole.^[4] However, not only is the total number of nevi an associated risk factor, but the size and type of nevi are also independent risk factors for the development of melanoma.

Another important genetic risk factor to consider is family history. There is an approximate 2-fold increased risk of developing melanoma if there is a positive family history in a first degree relative.^[6]

Melanoma in Non-Sun Exposed Areas

While UV light can significantly increase the risk of skin cancer, some types of melanoma can occur on areas of the body not directly exposed to the sun, such as soles of feet, palms of hands, and even the skin under the nail bed. This type of melanoma is referred to as acral lentiginous melanoma (ALM).

The word “acral” refers to the association of melanoma on the palms and soles, and “lentiginous” means that the melanocytic lesion is darker in comparison to the surrounding skin. This contrast in color and presentation on the body are two of the most prominent identifying factors of ALM.

Interestingly, melanin does not appear to be a protective factor in this subtype of melanoma. While all races and ethnicities can be affected, studies have shown that populations with an increased abundance of natural melanin, such as Asians, Middle Easterners, and Africans are more susceptible to ALM compared to Caucasian populations.^[7]

Risk factors

The atypical presentation of this subtype of melanoma on areas of the body not excessively exposed to sun suggests an etiology different to that of other types of skin cancers. However, studies have shown that sun exposure may still present as a risk factor for developing ALM.

A case control study of 275 melanomas diagnosed on the palms of hands and soles of feet identified several risk factors:^[7]

• Sun exposure: despite the minimal sun exposure to the soles of feet and palms of hands, increased UV light can increase the risk of ALM. Sun light may also influence mole development, another risk factor.
• Moles: specifically, on the soles of feet have been associated with an increased risk of ALM.
• Trauma: some studies suggest that trauma to the foot may be associated with the development of ALM. However, studies could not conclude if ALM developed at the original site of trauma.

Similar to other subtypes of melanoma, inherited gene mutations may also increase the risk of developing ALM.^[8] The most common gene mutations identified are BRAF, NRAS, NF1, GNAQ, and KIT, with BRAF V600E mutation being the most commonly detected mutation in ALM.**

**citation: https://www.sciencedirect.com/science/article/pii/S0022202X17332256

Warning signs

Similar to other variants of melanoma, ALM will typically present as a darkened spot on the skin surrounded by skin that remains the skins natural pigment. However, they may not be as obvious as other types of melanoma due to the presenting locations (i.e. bottom of the foot). Therefore, it is important to be able to recognize warning signs of ALM:^[9]

• A new longitudinal darkened streak along the nailbed. This can progress to splitting and destruction of the nail bed
• Appearance of new moles or growths on soles of feet or palms of hands
• Preexisting moles or growths changing shape or color
• Thickening or elevation of a new or existing mole
• Ulcerations of non-healing wounds within a mole

ALM is associated with a poor prognosis most commonly due to a delayed diagnosis, because of ALM’s inherent atypical presentation. The ability to identify these warning signs may improve the outcomes of individuals diagnosed with ALM.

Diagnosis of Melanoma

If a mole or other skin lesions look abnormal, a biopsy is often performed to confirm the diagnosis of melanoma. Either a portion or the entire skin lesion is removed and sent to be analyzed under the microscope. The depth of the pigmented lesion is a crucial factor to consider for melanoma, as this can indicate the risk of metastasis. Melanomas are measured using Breslow’s Depth, a critical measurement of how deep melanoma has invaded the skin. Determining the depth of melanoma is crucial because it is important when considering future treatment and severity of the melanoma.

ABCDEF rule

To identify an abnormal mole, the ABCDEF rule is particularly beneficial:^[10]

• A for Asymmetry: half of the mole does not match the other half
• B for Border: irregular with edges often ragged, notched or blurred
• C for Color: uneven, with varying shades of colors
• D for Diameter: an increase in size to about ¼-inch or 6mm wide
• E for Evolving: changes over the past few weeks to months
• F for Funny looking: also known as the “ugly duckling sign,” refers to a mole that doesn’t look the same as the others

Any changes in size, shape, color, or any new symptom such as bleeding, itching, or crusting warrants an evaluation by a dermatologist and possibly a biopsy.

Treatment of Melanoma

There are several treatment options for melanoma. The treatment ultimately depends on a few factors:

• The size and depth of the lesion
• The location of the lesion on the body
• If the cancer has metastasized internally 

Ultimately, surgery is the mainstay of treatment for melanoma. This surgery is generally done as an outpatient procedure under local anesthesia. The site of the melanocytic lesion is then cut out along with a small amount of normal skin at the edges. This is referred to as a wide local excision, as margins around the melanocytic lesion also need to be removed to ensure complete removal of the cancer. The margins vary depending on histopathologic features including Breslow’s depth. 

The excised sample is sent to pathology where it will be examined under a microscope to assess for any cancerous cells that may have been left behind or present within the margins. There are specific features a pathologist looks for when evaluating a melanoma specimen, such as pagetoid spread of melanocytes, nests of melanocytes with variable size and shape, melanocytes within lymphovascular spaces, deep and atypical mitoses along with inflammation, regression, and ulceration. A thorough evaluation ensures complete excision of cancerous cells.

Aside from surgical excisions, there are other treatment options for melanoma. These are determined by TNM staging (Tumor, Nodes, Metastasis). Examples include immunotherapy, chemotherapy, and radiation therapy. If diagnosed with melanoma, treatment options will be evaluated and explained by your dermatologist. However, surgery is the most common and has a high cure rate.

Prevention of Melanoma

It is difficult to alter genetic factors that may contribute to melanoma, such as skin type and the presence of moles. However, there are several lifestyle modifications that can help reduce the development of melanoma:

• Avoid excess sun exposure and tanning beds
• Apply sunscreen daily and reapply every two hours especially when spending time outdoors in direct sunlight
• Wear protective clothing when in the sun, such as a wide brimmed hat, tight knit clothing, and sunglasses
• Regularly receive a full body skin exam by a dermatology trained professional to assess for abnormal lesions. At the minimum, full body exam should be once a year, however, this can vary, and your dermatologist will consult with you about your specific full body screening intervals.

A personal history of melanoma increases the risk of developing a second melanoma by 5-8%.^[1] In order to prevent a reoccurrence or diagnose another melanoma before it metastasizes, it is important to have regular checkups performed by a dermatologist. 

Practical Tips

• A mole changing in color, shape, or size should be examined by a dermatology trained professional.
• Those with a family history of melanoma or who have many moles should be regularly seen by a dermatologist for yearly skin exams.
• Checking the soles of feet, between the toes, palms of hands, and nail bed is important for prompt diagnosis of acral lentiginous melanoma.