Principles for Melanoma Diagnosis Learned From the Study of Nevi in Children (SONIC)

Alon Scope, MD
Medical Screening Institute
Sheba Medical Center and
Sackler School of Medicine
Tel Aviv University, Israel

Dermatology Service, Department of Medicine,
Memorial Sloan Kettering Cancer Center, New York City

 

Cutaneous melanoma is a potentially lethal disease that offers a unique chance for early detection and cure like no other cancer. The late Bernard Ackerman, MD, spelled out the goal of early melanoma detection succinctly in his aptly titled 1985 paper, “No One Should Die of Malignant Melanoma.”¹

To achieve early detection, clinicians have proposed multiple clinical strategies, including the ABCDE early recognition criteria [A (asymmetry), B (border irregularity), C (color variegation), D (diameter >6 mm), E (“evolving”)²] and the “ugly duckling” sign. The latter highlights that melanoma can be an outlier lesion, differing in size, color and pattern from the patient’s benign nevi, which often appear similar to one another.³

Physicians have also improved diagnostic accuracy by incorporating imaging technologies in clinical practice. Dermoscopy enables evaluation, at higher magnification, of subsurface patterns and structures that are not visible to the naked eye; dermoscopic digital monitoring allows short-term follow-up of the dermoscopic pattern of melanocytic lesions for stability versus change over time. Total-body photography also assists in long-term monitoring, whereby a melanoma can be detected as a new or changing lesion among the patient’s host of stable benign nevi.

Despite all these diagnostic techniques, some melanomas elude diagnosis; not only very early or small-diameter melanomas, but also nodular, amelanotic and nevoid melanomas, as well as those arising on sun-damaged skin. Difficult-to-diagnose melanomas need to be differentiated from the patient’s benign nevi. In such scenarios, physicians may glean subtle diagnostic clues from the clinical context, taking into account different patient-related factors.⁴

For the most part, a patient’s nevi abide by “rules” — their morphology and biological behavior depend on the patient’s demographic, phenotypic, genetic and environmental factors. If we decipher these rules that govern the morphology of nevi, we may be able to detect an otherwise difficult-to-diagnose melanoma that is breaking these rules.

The Importance of Childhood Nevi

Melanocytic nevi are a strong phenotypic marker of cutaneous melanoma risk.⁵ Nevi frequently develop in the first two decades of life, making this a prime period for studying when, where and how nevi should appear. The Study of Nevi in Children (SONIC), a population-based study centered in Framingham, Massachusetts, has documented the morphology of nevi and their evolution over time during childhood and adolescence. We accrued participants at ages 11 to 14 from all schools in the Framingham district and followed a subset of their nevi, using clinical and dermoscopic imaging, until age 17. By administering questionnaires to participants and their parents and conducting on-site skin examinations, we collected demographic, clinical, phenotypic and environmental exposure data.⁶

Here, we offer examples of nevus rules that we established from the SONIC project and from other studies of nevi, and the implications for detecting a melanoma that is breaking these rules.⁷ Obviously, there are exceptions; not every lesion that deviates from the expected pattern is an obligatory melanoma. Nonetheless, a deviant lesion should be approached judiciously to exclude melanoma.

Rule: The pattern of nevi depends on the patient’s age

Multiple studies have shown a major shift in the predominant dermoscopic pattern of nevi from childhood to adulthood.⁸ The most frequent dermoscopic nevus pattern in children is the globular type (Figure 1A), and the most frequent pattern in adults is the reticular type (Figure 1B). In the SONIC cohort, at age 11, 34 percent of back nevi were globular, while only 11 percent were reticular.⁹ During follow-up from age 11 to age 17, we observed a gradual decline in the percentage of globular nevi and an increase in that of reticular nevi. This pattern shift was not due to change within individual nevi, but the appearance of more nevi with reticular patterns; at age 17, of new back nevi, 44 percent were reticular and only 16 percent were globular (unpublished data). This globular to reticular pattern shift continues into adulthood; in patients in their fourth decade, 61 percent of trunk nevi were reticular, while only 20 percent were globular.⁸

Another dermoscopic pattern of nevi that is highly age-dependent is the “peripheral rim of globules” (PRG) pattern (Figure 1E); this pattern signifies a growing nevus.¹⁰ When the nevus ceases to grow, the peripheral rim of globules disappears and the nevus assumes one of the other patterns (e.g., reticular pattern). In the second decade, PRG nevi were observed in 3 percent of back nevi among SONIC participants¹⁰ and in 5 percent of trunk nevi among adolescent patients visiting pigmented lesion clinics.⁸ Notably, the frequency of PRG pattern rapidly declines with age — these lesions are seen in 1.5 percent of trunk nevi in the fourth decade, and in <1 percent of patients >50 years old.⁸

 

Significance for melanoma diagnosis

A new nevus with a globular dermoscopic pattern in an elderly patient is uncommon. Notably, a recently described subtype of melanoma termed “nested melanoma of the elderly”¹¹ can be recognized as a lesion with a diffuse globular pattern appearing in a patient at the “wrong age.” Furthermore, melanomas that display a predominantly globular dermoscopic pattern have been shown to grow faster than melanomas that show a predominantly reticular pattern.¹² Finally, pigmented lesions that show a PRG pattern in a patient >50 years old should raise suspicion for melanoma.

Rule: The pattern of nevi depends on body site

In SONIC, we observed that the size and dermoscopic pattern of nevi depends on the anatomic site of the nevi.^6,13 First, nevi on the upper trunk tend to be larger in diameter and show a globular dermoscopic pattern (Figure 2A), whereas nevi on the lower trunk and extremities become increasingly smaller and tend to be more frequently reticular in dermoscopic pattern (Figure 2B). Second, nevi with a PRG pattern are very rare on the legs. Third, nevi with a complex dermoscopic pattern (Figure 1D), showing both globular and reticular components, occur more frequently on the trunk than on the extremities (Figure 2C).

 

Some exceptions exist; for example, a congenital (“birthmark”) nevus that is located on the lower extremities may be the patient’s largest mole; patients with the so-called “atypical nevus phenotype,” who have a high nevus count and large nevi (>5 mm in diameter), may show nevi with a complex pattern on the extremities as well as on the trunk.

Significance for melanoma diagnosis

(Figures 3A-3B): An example of a suspect lesion breaking the anatomic site rules would be an acquired, singular pigmented lesion on the lower extremities of an adult that is larger in diameter than the patient’s trunk nevi, and/or shows a globular, complex or PRG dermoscopic pattern.

 

Rule: The pattern of nevi depends on the patient’s skin color

In SONIC and in other studies, a predictable association has been observed between a patient’s skin color and the dermoscopic pattern and size of nevi.^6,14 Participants with darker skin tend to have nevi that are smaller in diameter and reticular in dermoscopic pattern; in contrast, participants with fair skin more frequently harbor larger nevi with a globular or complex dermoscopic pattern. Another subset of nevi are those that lack a specific dermoscopic pattern (termed “structureless” or “homogeneous” nevi, Figure 1C): Structureless, light-colored nevi are more frequent among fair-skinned participants. Skin color has been associated with germline variations in the gene for melanocortin-1 receptor (MC1R); indeed, individuals who harbor a mutation in MC1R, which is associated with fair phenotype and red hair color, show structureless nevi more frequently, whereas those with MC1R variants associated with darker skin type tend to show nevi with a reticular pattern.¹⁵

Significance for melanoma diagnosis

An outlier, darkly pigmented lesion in an individual with a fair-skinned phenotype should raise suspicion for melanoma (Figure 3C). In addition, individuals with very fair skin, particularly those with an MC1R mutation associated with red hair color, may pose a particular challenge for melanoma diagnosis.¹⁶ While their nevi tend to appear lightly pigmented and structureless under dermoscopy, a melanoma in such a patient may also lack pigment (termed “amelanotic melanoma”) and display a structureless dermoscopic pattern. Hence, these very fair patients may benefit from closer surveillance using total-body photography to detect melanoma as a new or changing lesion.

Rule: Change in nevi is frequent in childhood

Among SONIC participants, we frequently saw newly appearing, changing and disappearing nevi.^9,17 Between ages 11 and 14, 75 percent of participants developed new nevi, while 28 percent had at least one nevus that disappeared. Of the new nevi detected at age 14, only half were stable over the next three years, while 43 percent increased in size and 5 percent disappeared. Disappearing nevi often gradually faded in color and/or shrank in diameter. Children with the highest baseline nevus counts were also those with the highest nevus volatility, i.e., with a proclivity for new, changing and disappearing nevi. We also observed that among children with many nevi, a history of sunburn could be associated with a greater increase in number of nevi.¹⁵

Significance for melanoma diagnosis

Use of total-body photography in children and adolescents to identify suspicious lesions based on change is likely to have poor specificity for the diagnosis of melanoma. The infrequency of melanoma, taken together with the high nevus volatility in the first two decades of life, make the use of total-body photography a less effective strategy for melanoma detection than in adults.

Rule: Melanoma risk is related to the patient’s nevus phenotype

Having numerous nevi and large nevi (>5 mm in diameter) is associated with a high-risk phenotype for developing melanoma.⁵ In SONIC, we found that children harboring more nevi than their peers at age 14 were those most likely to develop a high-risk nevus phenotype at age 17.¹⁸ Individuals whose nevi showed greater variability in dermoscopic patterns (i.e., co-occurrence of nevi with globular, reticular and complex patterns) were also more likely to develop a high-risk nevus phenotype.¹⁸

Across SONIC studies, we have shown that subsets of nevi that can be recognized by their dermoscopic patterns (e.g., reticular nevi and globular nevi) are biologically distinct. As previously noted, globular and reticular nevi differ in their associations with the patient’s age and skin color, as well as in their predilection for different body sites.⁶ Furthermore, we have shown in a convenience sample from adult patients that these subsets of nevi also differ in their genetic profile — globular nevi are associated with BRAF V600E mutation, which is also frequently observed in melanoma, whereas reticular nevi are mostly BRAF-mutation-negative.¹⁹

Relevance for melanoma diagnosis

Interestingly, in a pilot case-control study, we found that patients with melanoma more frequently harbored nevi with a complex (reticular-globular) pattern (Figure 1D), compared to patients without melanoma. We are currently expanding this study, to better characterize nevus phenotypes that herald a heightened melanoma risk.

Conclusions

We have gained important insights about the expected morphology and host associations of childhood nevi from SONIC and other studies. A comprehensive understanding of the rules by which nevi abide may help in the early detection of melanomas that break these rules. In addition, to inform melanoma prevention and screening efforts, we need to better stratify patients based on their melanoma risk. A thorough understanding of nevogenesis and of nevus phenotypes may improve our ability to predict patients’ melanoma risk.

References

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The author gratefully acknowledges the grant support of the National Institutes of Health for the SONIC study.