The first accredited report of melanoma is found in the writings of Hippocrates (born c. 460 BC), where he described “fatal black tumors with metastases.” Paleopathologists discovered diffuse bony metastases and round melanotic masses in the skin of Peruvian mummies of the fourth century BC (1
). However, it was not until 1806, when René Laennec described “la melanose” to the Faculté de Médecine in Paris, that the disease was characterized in detail and named (2
). General practitioner William Norris suggested that melanoma may be hereditary in an 1820 manuscript describing a family with numerous moles and several family members with metastatic lesions (3
). Molecular insights over the past 20 years have confirmed Norris’s theory of a significant genetic contribution to the etiology of melanoma.
Melanoma develops from the malignant transformation of melanocytes, the pigment-producing cells that reside in the basal epidermal layer in human skin (Figure ). Recognized as the most common fatal skin cancer, melanoma incidence has increased 15-fold in the past 40 years in the United States, a rate more rapid than that described for any other malignancy (4
). Every hour, an American will die from melanoma (5
), and it remains one of the most common types of cancer among young adults (6
). Furthermore, according to US statistics for 1973–1997, the increase in the mortality rate for melanoma in individuals 65 years of age and older, especially men, was the second highest among all cancers (4
Figure 1 Phases of histologic progression of melanocyte transformation. H&E-stained histologic sections and corresponding pictorial representation. (A) Normal skin. There is even distribution of normal dendritic melanocytes in the basal epithelial layer. (more ...)
As in many cancers, both genetic predisposition and exposure to environmental agents are risk factors for melanoma development. Case-control studies have identified several risk factors in populations susceptible to developing melanoma (7
). Melanoma primarily affects fair-haired and fair-skinned individuals, and those who burn easily or have a history of severe sunburn are at higher risk than their darkly pigmented, age-matched controls. The UV component of sunlight causes skin damage and increases the risk for skin cancers such as melanoma. It appears that melanoma risk is typically associated with intermittent, intense sun exposure rather than cumulative sun exposure (an exception is lentigo maligna melanoma). The exact mechanism and wavelengths of UV light that are the most critical remain controversial, but both UV-A (wavelength 320–400 nm) and UV-B (290–320 nm) have been implicated (4
). This is in contrast to the nonmelanoma skin cancers, basal cell carcinoma and squamous cell carcinoma, which arise from epidermal keratinocytes and are more strongly associated with cumulative sun exposure. Melanoma incidence in fair-skinned people is inversely related to latitude of residence, with the highest incidence found in Australia, which supports the role of UV-induced damage in melanoma pathogenesis (9
). In the 1920s, women’s fashions became more revealing, and French fashion designer Coco Chanel, who developed a suntan when cruising from Paris to Cannes, is credited with initiating the modern sunbathing trend (10
). As our social dress has moved from petticoat and parasol or topcoat and hat to tank top and sunglasses, the incidence of skin cancers, including melanoma, has increased significantly.
Family history of melanoma, increased numbers of both common and dysplastic moles, and a tendency to freckle also increase risk (11
). Ten percent of melanoma patients have an affected relative. In a small number of cases, melanomas occur in the setting of the familial atypical multiple mole and melanoma syndrome, also referred to as the dysplastic nevus syndrome (DNS) (12
). DNS-affected kindreds develop many atypical moles (dysplastic nevi) at a young age and acquire melanoma with a higher penetrance and earlier onset than are typical of sporadic melanoma. Some evidence suggests that dysplastic nevi may be melanoma precursors in a subset of cases; however, this correlation is controversial and difficult to clearly document (4
). More than 50% of melanomas likely arise de novo without a precursor lesion.
Cutaneous melanoma can be subdivided into several subtypes, primarily based on anatomic location and patterns of growth (see Table for key clinical features of subtypes; reviewed in ref. 4
). The majority of melanoma subtypes are observed to progress through distinct histologic phases (Figure ). As melanomas progress from the radial growth phase (RGP) to the vertical growth phase (VGP), treatment options, cure rates, and survival rates decrease dramatically. Most melanoma subtypes demonstrate a slow RGP restricted to the epidermis, followed by a potentially more rapid VGP (14
). RGP melanoma cells extend upward into the epidermis (pagetoid spread) but remain in situ and lack the capacity to invade the dermis and metastasize. RGP melanoma is generally cured by excisional surgery. VGP melanoma invades the dermis and deeper structures and is metastatically competent (15
Clinical classification of melanoma
Melanoma can be further classified into clinical stages according to significant prognostic factors, and this staging system was recently revised by the American Joint Committee on Cancer (AJCC) (see Staging for cutaneous melanoma
; a complete staging system is summarized in ref. 17
). The AJCC prognostic indicators were confirmed by analysis of outcomes in over 17,000 patients. In the absence of known distant metastasis, the most important prognostic indicator is regional lymph node involvement. However, the majority of melanoma patients present with clinically normal lymph nodes. Thus, in clinically node-negative patients, the microscopic degree of invasion of melanoma is of importance in predicting outcome. There are 2 systems described for microscopic staging of primary cutaneous melanoma, Clark level and Breslow thickness (4
). Clark levels classify melanoma according to anatomic landmarks in the epidermis, dermis, and fat (18
). While this system correlates with prognosis, an inherent concern with Clark microscopic staging is that the thickness of the skin, and thus the location of these defined landmarks, varies in different parts of the body. Breslow thickness is a measure of the absolute thickness of the tumor from the granular layer (the most superficial nucleated layer of the epidermis) to the deepest contiguous tumor cell at the base of the lesion (19
). Breslow thickness has strong prognostic value in those with nonmetastatic melanoma. The presence of regional lymph node metastasis is a concerning sign regardless of the microscopic stage of the primary lesion. However, there is a direct relationship between the thickness of the primary lesion and the likelihood of microscopic nodal involvement in individuals with clinically normal nodes.
Melanoma prognosis also worsens with the histologic findings of ulceration, high tumor cell mitotic rate, sparse lymphocytic host response, vascular invasion, and histologic signs of tumor regression (17
). Increasing age, male sex, and tumor location on the trunk, head, or neck also worsen prognosis. The expression of the cellular marker and melanocyte-specific protein, melastatin, in melanoma cells appears to be inversely proportional to metastasis and was correlated with prolonged disease-free survival in a study of 150 patients with localized disease (21
). The presence of tumor-infiltrating T lymphocytes in the VGP of primary melanomas correlates with decreased recurrence and reduced mortality (20
). Tumor immunity (host immune response to a tumor) has potential to be exploited for therapeutic use (23
Once metastasis to lymph nodes occurs, the 5-year survival ranges from 13% to 69%, depending on the number of lymph nodes affected and tumor burden (17
). With visceral metastasis, the 5-year survival drops to approximately 6%, and the median survival from time of diagnosis is 7.5 months (25
). The management of patients with clinically normal lymph nodes remains controversial. Elective node dissection has been replaced by sentinel lymph node biopsy (SLNB). In this method, lymphatic mapping is done to find the primary (or sentinel) draining lymph node or nodes, and histologic analysis is performed to assist with determining prognosis and staging. Currently, SLNB remains a diagnostic procedure, as it is unclear whether SLNB improves survival. SLNB’s impact on survival is the subject of a large, randomized study, the Multicenter Selective Lymphadenectomy Trial (26
). Unfortunately, there are no treatment options currently available that have been shown to increase life expectancy once melanoma spreads to regions beyond which it can be cured by local surgical excision.
Because there is no effective therapy for widely metastatic melanoma, the general public and primary care physicians must be aware of the classic clinical signs of melanoma in order to reduce mortality by detecting the disease in the early stages. These signs include change in color, recent enlargement, nodularity, irregular borders, and bleeding. Cardinal signs of melanoma are sometimes referred to by the mnemonic ABCDEs (asymmetry, border irregularity, color, diameter, elevation).
Histologic diagnosis of melanoma depends on a combination of certain characteristic architectural features and cellular atypia (reviewed in ref. 27
). The discovery of histologic markers unique to melanocytes or melanoma, such as differentiation antigen melanoma antigen recognized by T cells 1 (MART-1), also known as Melan-A, and human melanoma, black-45 (HMB-45), has aided melanoma diagnosis, but there is no marker that is 100% specific or sensitive (28
). Thus, fulfillment of histopathologic criteria (reviewed in ref. 4
), combined with multiple positive histologic markers, provides the most reliable method of diagnosis.
Cancers such as melanoma arise due to accumulation of mutations in genes critical for cell proliferation, differentiation, and cell death (30
). In addition, cancer cells acquire the ability to initiate and sustain angiogenesis, invade across tissue planes, and metastasize. The clinical and histologic progression observed in the growth phases of melanoma (Figure ) is hypothesized to correspond to the accumulation of these genetic mutations (14
). In order to develop treatments for advanced disease and to increase survival from metastatic melanoma, it is critical to understand the genetic changes leading to each progressive step of the cancer, especially the transition from RGP to VGP. Furthermore, an understanding of the changes that permit invasion through the epidermal basement membrane and thus allow for subsequent metastasis will permit the rational design of treatments for early stages of melanoma and potentially the design of chemopreventive treatments for patients with premalignant lesions or who are at high risk for melanoma development. In addition, an understanding of tumor biology and immunology will aid in the rational design of biochemotherapy and immunotherapy agents for more advanced stages of disease. Mutations observed in human melanoma patients provide starting points for a genetic analysis of melanoma.