Introduction
Melanoma is a skin cancer originating from melanocytes that are most commonly located in the skin. Melanoma can less commonly also arise from the eye or mucosal surfaces of the head and neck, urogenital tract, and gastrointestinal surfaces.1 Melanoma is responsible for more than 90% of deaths related to skin cancer, with incidence increasing by 270% from 1973 to 2002 in the United States.2,3
Epidemiology
The incidence of melanoma has been increasing steadily by 3%â4% annually.2 The estimated current lifetime risk of melanoma in the United States is 1 in 63, with an incidence rate of 20.1 per 100,000 persons for the period between 2003 and 2007. This compares to 41.1â55.8 per 100,000 persons in Australia.3 This increased incidence over the past five decades has been attributed to multiple factors, including increased exposure to ultraviolet (UV) radiation from sun or tanning bed use and enhanced screening leading to increased diagnosis.2 Melanoma tends to affect middle-aged adults, with a median age of 57 years at diagnosis. In young adults (<55 years), it is more common in females, representing the sixth most common cancer in women, while for adults over the age of 55 years, it is seen more commonly in males, constituting the fifth most common cancer in men.3,4
Pathogenesis and Risk Factors
Melanoma is a multifactorial disease that results from the interaction of environmental factors in genetically predisposed individuals.3 It is associated with a high somatic mutation burden when compared to many other human cancers. However, most of these mutations eventually lead to activation of two main pathways: The mitogen-activated protein kinase (MAPK) and the phosphoinositol-3 kinase (PI3K/AKT) pathways. MAPK is responsible for cellular proliferation, differentiation, and survival, while PI3K is responsible for cellular homeostasis. Approximately 90% of all melanomas show MAPK pathway activation. The most common mutation in the MAPK pathway is a mutation in the BRAF gene, with 80%â90% of the mutations being a missense mutation resulting in valine to glutamate substitution (V600E). This mutation is found in ~40%â60% of melanomas arising in intermittently sun-exposed skin. The second most common mutation in the MAPK pathway is an activating mutation in NRAS found in 15%â30% of melanomas, followed by neurofibromin 1 (NF1) tumor-suppressor gene mutation, present in 10%â15% of melanomas. However, NF1 mutations are usually associated with chronic sun exposure.4 The receptor tyrosine kinase KIT mutations are found in 2%â8% of melanomas and are usually present in acral melanomas and in melanomas arising from intermittent sun exposure. A number of other gene mutations are involved in melanoma development; some examples include telomerase reverse transcriptase (TERT) promoter mutations, cyclin-dependent kinase inhibitor-2A (CDKN2A) mutations, and phosphatase and tensin homolog (PTEN) mutations.4
The most important environmental risk factor for the development of melanoma is UV radiation from sun light.3,4 Specifically, intense intermittent sun exposure (sun burns) carries a higher melanoma risk when compared with chronic continuous exposure. Other risk factors include fair skin type, red hair, blue eyes, numerous freckles, UV-A exposure (therapeutic or tanning bed use), immune suppression, multiple melanocytic nevi, and a personal or family history of melanoma.3,4 The white population has a tenfold higher risk of developing cutaneous melanoma when compared with people of color (Black, Asian, or Hispanics). However, the rate of acral melanoma, which is not correlated with UV damage, is equal between Whites and Blacks (though it is the most common subtype of melanoma in the Black population). In the case of non-cutaneous melanomas (i.e., mucosal melanoma), although higher numbers are detected in the white population, they make up a higher proportion of melanoma subtype in patients of color compared to Whites.5 There is a sevenfold increased risk of melanoma in patients with more than 100 melanocytic nevi, 32-fold increased risk with more than 10 atypical nevi, and 2%â5% increased risk with large congenital nevi (>20 cm in size). Despite this, only 25%â30% of melanomas arise from preexisting nevi, with the vast majority occurring de novo on normal skin.3,4,6, 7, 8 Familial cases are rare and are usually related to mutations in CDKN2A or cyclin-dependent kinase-4 (CDK4).3,4
Clinical Presentation and Histological Subtypes
Melanoma presents classically as a changing brown, black, or pink pigmented skin lesion. If left untreated, it can ulcerate and/or bleed. The education campaigns targeted for early melanoma recognition by physicians and the public launched the âABCDâ criteria in 1985, with subsequent addition of the letter âEâ. They stand for Asymmetry, Border irregularity, Color variation, Diameter > 6 mm, and Evolution. This can help patients considerably during regular self-skin exams, which has a sensitivity of 57%â90% for melanoma detection. Dermatoscopic findings of an atypical pigment network, irregular dots/globules/streaks, regression, or blue-white veil raise the suspicion of melanoma.3 Melanomas are most commonly located on the back of men and the legs of women. The mortality rate of melanoma showed an initial increase of 1.4% annually between 1977 and 1990. However, a downtrend of 0.3% annually was subsequently observed for the period between 1990 and 2002.3
Historically, cutaneous melanomas were divided into several subtypes based on clinical factors or histopathological growth patterns. Superficial spreading melanoma accounts for 70% of cases with an early radial growth phase in the epidermis followed by a vertical growth phase in the dermis. Nodular melanoma, which accounts for 5% of cases, presents as a rapidly growing, often ulcerating, brown-black nodule which has a vertical growth pattern from the outset with no radial growth pattern. Nodular melanoma is associated with an aggressive biological behavior. Lentigo maligna melanoma accounts for 4%â15% of melanomas arising in chronically sun-exposed areas (head and neck). This subtype has a very prolonged radial growth phase with slow growth over years before invading the papillary dermis. Acral lentiginous melanoma accounts for 5% of cases in Whites but represents the most common subtype of melanoma in people of color. This subtype arises on the palms, soles, digits, and nails. Desmoplastic melanoma typically appears as a pink or pale scar-like papule that is characterized histologically by an infiltrative growth pattern and frequent perineural invasion. The term amelanotic melanoma is often used to describe melanomas lacking dark brown-black pigmentation on clinical exam, but does not specify any histological or clinical subtype.3,9 These clinicopathological descriptive subtypes of melanoma are slowly being phased out in favor of a molecular description for melanoma, for example, BRAF-positive melanoma and c-KIT-positive melanoma. The latter subclassification provides more valuable information regarding the origin of the cancer and the possible therapeutic options, which is more meaningful in clinical practice.10
Treatment and Prognosis
Most cases of melanoma are diagnosed early, and therefore, surgical excision is usually the first-line treatment for achieving cure in the majority of cases. Some cases, however, subsequently relapse with local recurrence or regional/distant metastasis. Approximately 10% of melanoma cases present with unresectable disease due to regional or metastatic disease at the time of diagnosis.4 The National Comprehensive Cancer Network (NCCN) recommends wide local excision of melanomas with 1 cm margins if the primary tumor is equal to or less than 1 mm in thickness, 1â2 cm margins if the primary tumor is >1â2 mm in thickness, and 2 cm margins for all melanomas thicker than 2 mm. The addition of sentinel lymph node biopsy (SLNB) is recommended for tumors equal to or more than 0.8 mm in thickness or for tumors less than 0.8 mm in thickness if ulceration is noticed on histopathology.11,12
Until recently, treatment of metastatic melanoma was mostly palliative with chemotherapy and/or radiation. Since 2011, the approval of several targeted therapies and immune checkpoint inhibitors has revolutionized the field of melanoma therapeutics and significantly improved the survival of metastatic melanoma patients.13 Agents used for targeted therapy include BRAF inhibitors (e.g., dabrafenib) and MEK inhibitors (e.g., trametinib). Immune checkpoint inhibitor therapeutic agents include cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) inhibitors (e.g., ipilimumab) and programmed cell death 1 (PD-1) inhibitors (e.g., pembrolizumab).4 Other recently approved modalities include Talimogene Laherparepvec (T-VEC), which is a modified oncolytic herpes simplex virus type 1...