III.1 The Life of Melanocytic Nevi

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III.1.1 Introduction

Although melanocytic nevi are very common, their histogenesis is not well understood. The origin of melanocytic nevi and their natural history is still a matter of debate. According to Unna’s “Abtropfung” theory, melanocytic nevi start in the epidermis and drop off into the dermis [1]. In contrast to the theory of “Abtrop- fung,” the theory of “Hochsteigerung” suggests that melanocytes of neural crest origin migrate up from the dermis into the epidermis [2]. It is possible that both theories are correct and that acquired and congenital melanocytic nevi are fundamentally different. Acquired melanocytic nevi may be interpreted as benign neoplasms triggered by different stimuli, one of them being exposure to UV radiation. They start as a proliferation of epidermal melanocytes, which con- secutively “drop off” into the dermis. In contrast to acquired melanocytic nevi, congenital nevi may be interpreted as hamartomas developing from neural crest cells that migrate up from the dermis into the epidermis. Unfortu- nately, the term congenital nevus has not been

The Life of Melanocytic Nevi

Harald Kittler

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Contents

III.1.1 Introduction . . . .61 III.1.2 The Life of Congenital Nevi . . . .61 III.1.3 The Life of Acquired Nevi. . . .62 III.1.4 Clark Nevi: Are They Truly Precursors

of Melanoma? . . . .64 References . . . .65

defined consistently. Most authors regard congenital nevi as melanocytic nevi that are present at birth, but in fact congenital nevi may be present but not visible at birth. Melanocytic nevi that are not visible at birth but have clinical or histopathological features of congenital nevi have been termed “tardive” congenital nevi or congenital like nevi. Sometimes it is impossible to differentiate between acquired and small congenital nevi by clinical inspection with the unaided eye or by dermoscopy in particular when anamnestic data are unavailable or unre- liable. To complicate matters further, some melanocytic nevi that were reportedly visible at birth lacked typical histopathological criteria of congenital nevi when biopsied.

All we know about the life of melanocytic nevi, no matter if acquired or congenital, is based on cross-sectional or cohort studies. At present, it is still impossible to monitor melanocytic nevi in vivo on a cellular level. In the near future new technologies, such as, for example, optical coherence tomography or confocal laser scanning microscopy (see Chap. II.1), may pro- vide new insights into the life of moles on a cellular level, but currently we are still depending on clinical examinations with the unaided eye, or on dermoscopic examinations. Most studies in this field have focused on acquired nevi and only a few studies have investigated the life of congenital nevi.

III.1.2 The Life of Congenital Nevi

Congenital nevi enlarge during infancy until they have reached a certain size, but the exact dynamic of this expansion has not been studied over long periods. Rhodes et al. monitored 41

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gion. They observed a proportionate area expansion in most cases studied, but nine congenital nevi showed a disproportionate area expansion during the first 6 months of life. In general, it can be assumed that the velocity of growth of a congenital nevus is correlated with the velocity of overall growth of the human body, which is largest during the first 6 months of age. The same factors that influence human development may also be responsible for the growth of congenital nevi. Mitotic activity of congenital nevi may be increased by stretching of human skin and/or by hormonal growth factors. Expansion of congenital nevi usually stops after the nevus has reached a certain size. Like most mammalian cells, melanocytes of congenital nevi have a protective mechanism against unlimited proliferation called senescence, which is usually driven by telomere attrition. It has been shown recently that the growth arrest of congenital nevi is induced by oncogene driven growth arrest, rather than by telomere attrition [4]. It is assumed that oncogenic mutations in BRAF, a protein kinase, trigger the induction of tumor suppressors, including p16^INK4a, and are responsible for the growth arrest of melanocytes of congenital nevi, but it is likely that other mechanisms contribute to this phenomenon as well. Whether oncogene-induced senescence is also responsible for the growth arrest of acquired nevi has yet to be determined.

III.1.3 The Life of Acquired Nevi

The life of acquired nevi has been studied in more detail than the life of congenital nevi. It has become common language to divide acquired nevi into common nevi, on one hand, and into “dysplastic” or “atypical” nevi, on the other hand. This terminology has its limitations mainly because it lacks consistent definitions of

“common “and “atypical,” and because there is only fair correlation between clinical atypia and

more common than Spitz and Reed nevi, and virtually all epidemiological studies on the dy- namics of acquired nevi deal with Clark nevi.

They appear in childhood and their number is related to genetic factors including skin type and environmental factors, chief among them being UV –exposure [5, 6]. As shown repeatedly, their number is also correlated with melanoma risk, most probably because melanoma and Clark nevi have etiological factors in common, and not because Clark nevi are precursors of melanoma.

In a cohort study of 385 individuals we observed that Clark nevi are highly active during childhood and adolescence, but usually remain static in adults [7]. One thousand six hundred twelve Clark nevi were monitored with digital dermoscopy over a median observation period of 1 year. The frequency of enlarging nevi was nearly 60% of all monitored nevi in the young- est age group (0–10 years). It declined to 12% in individuals aged 10–20 years, and finally dropped to 5% and lower in individuals older than 30 years. Although it can be expected that these numbers would be higher for longer fol- low-up periods, it confirms that the frequency of enlarging Clark nevi in adults is low, and that the velocity of growth of Clark nevi is highest in infancy and adolescence. In our experience there are some individuals that maintain a high growth activity of their Clark nevi, even after the age of 30 years. These individuals tend to have larger Clark nevi than other individuals. It would not be surprising if these patients have an increased risk for melanoma, but an epidemiological study has not been performed to address this question.

We have also discovered that Clark nevi have a specific dermoscopic appearance during the initial phase of rapid growth [7]. During this phase they usually show a peripheral rim of brown globules (Fig. III.1.1). Histopathological- ly, the globules correspond to nests of melanocytes at the dermo-epidermal junction at the

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periphery of the lesion. When the velocity of nevus growth is extremely high, these nests become confluent at the periphery, forming streaks and pseudopods, typical signs of Reed nevus, which is a type of acquired nevus that enlarges very quickly. Not all enlarging Clark nevi show a peripheral rim of globules. In the lentiginous type of Clark nevus, for example, no nests are formed at the periphery during expansion and the rim is not observed. When the globules in the periphery disappear, the nevus usually has

reached its final size. After reaching their final size, we observed that some Clark nevi become lighter and smaller (Fig. III.1.2). Whether this observed involution corresponds to “Abtrop- fung” of melanocytes into the dermis is un- known. The observation that immunosup- pressed renal transplant recipients may develop a large number of eruptive nevi with a peripheral rim of globules confirms the hypothesis that this morphological feature is a sign of nevus growth [8].

Fig. III.1.1. a–d Incipient Clark nevus in its growth phase monitored over 3 years. The peripheral rim of brown globules (corresponding to nests of melanocytes

at the dermo-epidermal junction) observed in a certain distance of the main body of the nevus is typical for enlarging Clark nevi.

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III.1.4 Clark Nevi: Are They Truly Precursors of Melanoma?

Finally, we also have to address the question as to whether Clark nevi are truly precursors of melanoma. The hypothesis of Clark was based on the assumption of stepwise tumor progression in such a way that common nevi progress to dysplastic nevi and then finally to melanoma [9]. This hypothesis of stepwise tumor progression has gained the status of a paradigm. Retro- spective studies of histopathological sections of melanoma seemingly confirmed the association between Clark nevi and melanoma, but a pro- spective cohort study to determine the risk of a Clark nevus to progress into a melanoma has never been performed [10].

In a cohort study by our group 1812 lesions thought to be Clark nevi at the patients’ first

visit were monitored with digital dermoscopy over a median observation period of 12 months [11]. All patients included in this study had multiple Clark nevi and an increased risk of developing melanoma. We observed a low frequency of changing lesions, even in this high-risk group.

Only 5% of lesions enlarged or showed other substantial changes. These lesions were excised to rule out melanoma. Histopathologically, 8 of 75 excised lesions turned out to be early melanoma. No melanoma showed remnants of a Clark nevus histopathologically. It is highly likely that all melanomas were melanomas at the patients’ first visit.

It is possible, of course, that a melanoma de- velops in a Clark nevus, but this happens very rarely. At the Department of Dermatology at the Medical University in Vienna we have monitored more than 10,000 Clark nevi over the past

Fig. III.1.2. a–d Clark nevus that has reached its final size indicated by disappearance of brown globules at the periph- ery and subsequent involution of the nevus. Observation period from a–d is 4 years.

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years, mainly in high-risk patients, and observed only three melanomas that unambigu- ously developed into a Clark nevus during fol- low-up. It seems that even in patients with multiple Clark nevi most melanomas develop de novo. This low frequency of melanomas developing in a Clark nevus does not qualify the Clark nevus as a precursor of melanoma. In that sense every melanocytic nevus would qualify as precursor lesion, including all types of congenital nevi, Spitz nevi, Reed nevi, etc. It seems that Clark nevi are no more precursors of melanoma than any other melanocytic nevus in man.

C

Core Messages

■ Congenital nevi may be interpreted as hamartomas developing from neural crest cells that migrate up from the dermis into the epidermis.

■ Congenital nevi may be present, but not visible, at birth (“tardive” congenital nevi or congenital like nevi). They enlarge during infancy and usually stop growing after they have reached a certain size.

■ Acquired melanocytic nevi, on the other hand, may be interpreted as benign neoplasms triggered by different stimuli (e.g., UV radiation), which consist of melanocytes that consecu- tively “drop off” into the dermis.

■ Acquired nevi can be divided into two groups: (a) Spitz and Reed nevi; and (b) Clark nevi, which can be further divided into common or atypical Clark nevi.

■ It seems very likely that Clark nevi are no more precursors of melanoma than any other melanocytic nevus.

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