Atypical Mole

Etiology

The etiology of atypical moles is not well-characterized scientifically. Predisposing factors are a combination of genetic (internal) and environmental (external) factors. 

Their presence is associated with specific genetic characteristics, including fair skin, lighter (blond) hair color, lighter shades of eye color, freckling propensity, and sun sensitivity. In particular, epidemiological studies have demonstrated a higher incidence of atypical moles in those with a history of increased ultraviolet (UV) sunlight exposure.[3][4]

Nevi have been linked genetically to several chromosomal loci. Genome-wide studies have demonstrated that the presence of IRF4, PLA2G6, and MTAP are widely associated with melanocytic nevi count.[5] Clark proposed a sequential progression model, whereby atypical moles are the intermediate stage between banal nevi and the development of melanoma, a model still favored by some Dermatologists. However, there is limited evidence of common genetic mutations between atypical moles and melanoma, for example, CDKN2A is expressed by the vast majority of familial melanoma patients, but not commonly in those with atypical moles. Additionally, since 75% of melanomas arise de novo, there are further questions regarding the validity of this hypothesis.

Epidemiology

Atypical moles have an extensive geographic distribution globally and are slightly more common in males compared to females. Global prevalence is in the range of 2% to 18%, displaying a higher incidence in European populations (7% to 24%) and fair-skinned individuals. Some notable exceptions to this exist, including the Japanese population, where the incidence of atypical moles is low despite a light-skinned phenotype. Pediatric incidence is also low. 

Lifetime melanoma risk to individuals in the United States is less than 1% but is significantly greater in those with atypical moles, considered to be greater than 10%. The risk of malignant transformation in common moles to melanoma amongst the population of the United States is about 1:30,000 in males and 1:40,000 in females.[6] Common benign moles do not frequently develop into atypical moles; 75% of atypical moles develop de novo, without any history of a pre-existing mole at the affected site.

Those at higher risk include patients with familial atypical multiple-mole melanoma syndrome (FAMMM) who have a near 100% lifetime risk of atypical mole transformation to melanoma in situ.[7]

Pathophysiology

The pathophysiology of atypical moles is poorly understood, but it is generally accepted that its pathogenesis is a complex interaction of environmental and genetic factors.

Genetic alterations known to contribute to the pathogenesis of atypical moles include allelic loss of specific chromosomal regions, including 9p21-22 and 1p36. Additionally, mutations in the tumor suppressor melastatin and protooncogenes BRAF and CDK4 have a direct correlation with pathogenesis. DNA mismatch repair mechanisms contribute to melanocytic cellular atypia of these moles, through excessive telomerase activity, as measured by Ki-67 and cyclin D1.[8]

Atypical moles often do not display the CDKN2A mutation that is common in melanomas.

Histopathology

There are specific histological criteria that are common among atypical moles, which may be split into architectural and cytological features. 

The majority of dysplastic nevi are compound, and the remainder junctional. Architectural features include lentiginous melanocytic proliferation, disordered junctional nesting, reduced cohesion between cells with junctional nests, and the "shoulder phenomenon" (where the junctional component extends beyond the intradermal component and diminishes without clear demarcation). Nuclear atypia is the key cytological feature, but atypical moles may also display a spindled or epithelioid cell pattern, large melanin granules, and abundant pale or dusky cytoplasm.[9]

Additionally, host response features may be noted. These include lymphocytic infiltrates, dermal fibroplasia, and prominent vascularity. 

Atypical moles may be graded as to their degree of cytologic atypia, although there is considerable interobserver variability. Mildly dysplastic moles may be difficult to distinguish from moles without atypia reliably. In the same respect, severely atypical moles may be difficult to distinguish from melanoma.

The most common dilemma during the diagnosis of an atypical mole is the lack of universal histopathologic features or pathognomonic features. Consequently, the terms MELTUMP (melanocytic tumor of uncertain malignancy potential) and SAMPUS (superficial atypical melanocytic proliferation of unknown significance) can be used to describe lesions where the diagnosis of an atypical mole is possible but not felt to be sufficiently certain.[10]

History and Physical

Atypical moles may have different morphological appearances ranging from flat to mildly elevated or even papilloma-like pigmented lesions. Although atypical moles are commonly present in sun-exposed areas, they are most abundant in the trunk area for males and calves for females. The identification of atypical moles during physical examination usually follows the 'ABCDE' guidelines for melanoma.[11]

That system refers to asymmetry, irregularity of the nevus border, color variegation, a relatively large diameter (greater than 6 m), and the evolution of the lesion. Most atypical moles appear during childhood and early adolescence. Atypical moles rarely develop in those over the age of 60; the development of atypical moles in elderly patients is often regarded as an early sign of melanoma in situ or nevoid lentigo maligna.[12]

There are five clinical subtypes of atypical moles:

• Fried-egg subtype: the lesion has a raised central portion, with dark brown pigmentation. This is surrounded by a macular and ill-defined area of lighter brown pigmentation. 
• Lentiginous subtype: the lesion has an entirely flat surface with a brown or dark brown pigmentation. 
• Seborrheic keratosis-like subtype: the lesion has a dark brown pigmentation with a rough verrucous surface resembling seborrheic keratosis. 
• Targeted subtype: the lesion has a central annular zone with variable pigmentation.
• Erythematous subtype: the lesion has a characteristic pink pigmentation and exhibits few pigmentation remnants.

The number of atypical moles varies amongst individuals. In cases where patients have more than 100 lesions, a diagnosis of dysplastic nevus syndrome must be considered. Dysplastic nevus syndrome can be sporadic or familial. Diagnostic criteria include the presence of at least 100 atypical moles with a diameter that of greater than 8 mm.[13]

Evaluation

A full evaluation of suspected atypical moles can only be performed after complete excision since this facilitates full histological analysis.

Excision biopsy is generally considered to be the most appropriate method of assessment, since incision biopsy can miss areas of melanoma in situ lying within a specific area of the lesion, resulting in an incomplete picture of the lesion's microscopic features.[14] Removing atypical moles is not an entirely preventative measure; in terms of preventing progression to melanoma in situ, those with numerous atypical moles remain at risk of developing melanoma, and vigilant self-monitoring is recommended. 

Dermoscopy may be used to evaluate the pigmentation patterns and secondary features of suspicious skin lesions. There are not presently any widely agreed criteria to distinguish atypical moles from melanoma in situ.[13] However, atypical moles can be classified into subtypes based on dermoscopy:[15]

• Reticular subtype: the most common subtype, characterized by a prominent network of dark brown lines, distributed relatively evenly throughout the lesion and fading gradually towards the peripheral borders.
• Globular subtype: characterized by a globular speckled pattern, consisting of several dots distributed throughout the lesion. 
• Homogenous subtype: the rarest subtype, characterized by variegated brown pigmentation, present throughout the lesion.
• Mixed: lesions displaying a combination of reticular and globular features. Clinicians should evaluate lesions that display characteristics of multiples subtypes particularly carefully since this may be more in keeping with a diagnosis of melanoma in situ.[16]

Treatment / Management

There is no known preventative method for the development of atypical moles, but those with a history of atypical moles should be especially vigilant in wearing high factor sun protection.[17] However, regular skin checks by a suitable healthcare practitioner to examine any concerning lesions and assess changes within preexisting moles are considered the most effective means by which malignant transformations can be detected promptly.(B3)

The management of atypical moles is controversial amongst dermatologists. Excision biopsy is usually performed when there is any clinical concern regarding atypical moles which have developed de novo, or where morphological changes are noted in pre-existing atypical moles. More than half of physicians surveyed by the American Academy of Dermatology reported that it is their practice to re-excise atypical moles when margins are not complete, or lesions recur. Reexcision of positive margins is based on the principle that the recurrence of an excised lesions along a biopsy scar may become indistinguishable from melanoma, known as the 'pseudo-melanoma' phenomenon.[18] However, there is substantial evidence that the majority of atypical moles need not be re-excised.

Exceptions include instances where there is concern that the clinical examination is not in keeping with the histology, there is severe atypia, or histological examination cannot differentiate the lesion from melanoma. In these cases, the lesion should be treated in line with guidelines for the management of melanoma and re-excised with appropriate margins.[17](B3)

Differential Diagnosis

The key differential diagnosis for atypical moles is melanoma (often the superficial spreading subtype). While dermoscopy is considered a useful tool to differentiate superficial spreading melanoma and atypical moles, where there is clinical concern or uncertainty in the differential diagnosis, lesions must be managed in line with guidelines for the treatment of melanomas.

Congenital nevi usually present with a larger diameter and prominent hairs which are absent in atypical moles. Although seborrheic keratosis may cause some confusion during the diagnosis, the dull surface and hyperkeratosis should facilitate clinical differentiation in the vast majority of cases.[10]

Complications

A significant minority of atypical moles evolve into melanoma; indeed, it is for this reason that they are clinically significant lesions.

Additionally, the lifetime melanoma risk to individuals in the United States is less than 1% but is significantly greater in those with atypical moles, greater than 10%. The risk of malignant transformation in common moles to melanoma amongst the population of the United States is about 1:30,000 in males, and 1:40,000 in females.[6] Common benign moles do not frequently develop into atypical moles; 75% of atypical moles develop de novo, without any history of a pre-existing mole at the affected site.

Those at higher risk include patients with familial atypical multiple-mole melanoma syndrome (FAMMM) who have a near 100% lifetime risk of atypical mole transformation to melanoma in situ.[7]