Malignant melanoma is a type of skin cancer that originates in melanocytes. Although these pigment-producing cells are found primarily in the basal layer of the skin, they are also located in the GI tract, eyes, ears, and the oral and genital mucosal membranes.1

Melanoma is the leading cause of skin-cancer-related death worldwide.1 In the United States, melanoma is the fifth most common cancer in men and the sixth most common cancer in women.2,3 It is projected that 1 in 52 Americans will develop cutaneous malignant melanoma at some point.4 Melanoma incidence is increasing worldwide faster than any other neoplasm outside of lung cancer in women.5 This continuing rise in incidence is becoming a public-health crisis that mandates early recognition of suspicious lesions.

Early detection of melanoma is critical to patient prognosis and survival.5 A recent study on the evidence-based staging system for melanoma found that tumor thickness and ulceration were two of the most powerful independent predictors of survival in cases of localized disease.6 Earlier detection has boosted the five-year survival rate for invasive melanoma from 82.6% of cases diagnosed between 1975 and 1979 to 93.1% of cases diagnosed in 2002.7

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Nevertheless, invasive melanoma remains very difficult to treat, with no proven therapy plan and poor long-term prognosis. Early detection and diagnosis of melanoma before metastasis is critical to improving patient outcomes.5 Primary-care clinicians are often the first line of defense against melanoma and must be educated in the correct identification of cancerous lesions. 

Identifying at risk patients 

Personal history. One of the most significant contributors to the development of melanoma is sunlight exposure, particularly exposure to UVB radiation (Table 1).8 UVB radiation is most notably a risk in those with phenotypic susceptibility (Table 2). A history of sunburns and excessive sun exposure in young children dramatically increases the risk of developing melanoma. The risk of melanoma in people with a history of sunburn is twice that of those who have never sunburned.5

In addition to a history of UV exposure and multiple sunburns, a personal history of melanoma or dysplastic nevi is highly predictive of melanoma risk. Personal history of other associated diseases, including pancreatic cancer, retinoblastoma, Li-Fraumeni or xeroderma pigmentosa, are also associated with increased risk of developing melanoma.5,9

Phenotypic features. The presence of certain phenotypic characteristics approximately doubles the risk of developing melanoma and include fair complexion, blue or green eye color, light or red hair color, presence of freckles, location of nevi and an inability to tan.5,8,9 One possible mechanism for this risk is a variation in the melanocortin-1 receptor, resulting in the development of sporadic cutaneous melanomas. 

The risk of developing melanoma has also been directly correlated with the total number of benign nevi on the body. Individuals with 11 to 25 nevi are approximately 1.5 times more likely to develop melanoma than are those with fewer than 10 nevi. This risk doubles with every increase of 25 nevi. Dysplastic nevi also significantly increase the risk of developing melanoma.5

Family history. Genetics have also been shown to have a clear role in the development of melanoma and may explain the variations in age- and gender-specific incidence rates (Table 3).8 A family history of melanoma is one of the strongest predictive factors for the development of the disease.

Persons with a first-degree relative with melanoma have twice the risk of developing melanoma than those without a positive family history. Several genetic conditions — including dysplastic nevus syndrome or familial atypical multiple mole and melanoma (FAMMM) syndrome — have been found to significantly increase the risk of developing melanoma.

FAMMM syndrome should be suspected when a family history of pancreatic cancer or astrocytoma is present. Patients with FAMMM syndrome may present at a younger age (<40 years), have multiple primary melanomas or have a history of dysplastic nevi. History of other familial cancer syndromes, including familial retinoblastoma, Li-Fraumeni syndrome and Lynch syndrome type II, also increases an individual’s melanoma risk.5

Family history of breast cancer and nonmelanoma skin cancers also raises the risk of developing melanoma.9 Patients without a family history of melanoma may still have a genetic predisposition to the disease from a new mutation to the CDKN2A gene or the CDK4 gene.5


The ABCD(E)s of melanoma. The original ABCD criteria (Asymmetry, Border irregularity, uneven Color, and Diameter >6 mm) was devised in 1985 to provide primary-care practitioners and the general public with an easy-to-remember algorithm to aid in the early diagnosis of malignant melanoma.10

Prior to the addition of the final criterion (E [Evolution]), the specificity was 75% and sensitivity was 84% with a diagnostic accuracy of 76%.7 Assessing for evolving lesions optimizes diagnostic sensitivity and specificity.11Table 4 lists the sensitivity and specificity for each criterion.11

Benign pigmented lesions are characteristically small, round and symmetric with regular borders and uniform pigmentation. Lesions demonstrating characteristics of malignancy are described as large (>6 mm) and asymmetrical lesions, with grossly irregular borders and variant pigmentation ranging from tan to black.12 These clinical features led to the development of the ABCDs of diagnosing melanoma.

Evaluating the diameter criterion. There has been some debate regarding the diameter criterion, as the incidence of small-diameter (<6 mm) malignant melanomas has increased. Small melanomas comprise 3% to 14% of all invasive melanomas and rarely result in metastasis and death.13 Researchers have concluded that although the incidence of small-diameter melanomas may be on the rise, there is currently not enough evidence to revise the criteria.10,13 Specifically, the percentage of small-diameter lesions that are melanoma compared with those that are benign pigmented lesions must be more thoroughly investigated.10

Evolving lesions. A history of change in a preexisting nevus or the growth of a new nevus in at-risk patients may signal malignancy. Change noted in a preexisting nevus occurs at a higher frequency in malignant lesions than in benign lesions. Studies have indicated that growing melanomas tend to exhibit observable changes in a three-to-six-month period. These alterations include changes in lesion size, shape, color, elevation, and such symptoms as itching or bleeding.

The addition of evolution to the established ABCD criteria for the detection of melanoma has increased both the sensitivity and the specificity of the guidelines and has significantly enhanced the ability of clinicians to diagnose melanoma earlier. This development is particularly important for the diagnosis of nodular melanoma, which frequently presents at advanced stages.

In one study, lesion change was associated with 78% of nodular melanomas and 71% of superficial spreading melanomas.14 Evolution has been found to have the highest specificity and sensitivity of all diagnostic criteria, at 90% and 84%, respectively.11

The “ugly duckling.” An outlier nevus that does not match the patient’s other nevi is often identified as the “ugly duckling” sign. The term was coined by researchers describing the clinical manifestation of melanoma in two different patients. One case of melanoma presented as a brown-black lesion in an individual with mainly red-brown nevi, while the other melanoma presented as a uniformly dark lesion in a patient whose nevi predominately displayed multiple pigments and irregular borders.

The investigators’ observations led to the conclusion that the ugly-duckling nevus can be described as atypical in a patient with multiple typical nevi, or as typical in a patient with multiple atypical nevi. Several clinical studies have demonstrated the efficacy of this method in differentiating cases of melanoma from benign nevi.14,15 One such study described a 100% positive identification of melanoma and a 2.1% false-positive finding of benign lesions, making the sensitivity of the ugly duckling sign for melanoma 90%.15 The ugly duckling sign is highly sensitive in the detection of melanoma even among non-dermatologists, thereby improving the early detection rate of melanoma and patient prognosis.14,15 

The gold standard in diagnosis

Skin biopsy followed by histopathologic examination remains the gold standard in diagnosing melanoma.14 Current guidelines recommend full-thickness excisional biopsy of lesions clinically suspected of melanoma with a margin of 1 mm to 2 mm. Full-thickness excisional biopsy allows complete histopathologic assessment, providing more accurate diagnosis and staging of the tumor.16

Partial biopsies using the punch or shave techniques result in a higher frequency of misdiagnosis and microstaging inaccuracy through unrepresentative tissue sampling.17 Microstaging inaccuracy is attributable to the increased possibility of transecting the base of the lesion, resulting in an inconclusive Breslow depth. In one study, inaccurate staging was observed in 34% of punch biopsies, 19% of shave biopsies and 9.1% of excisional biopsies.17