Ashfaq A. Marghoob (editor) - Nevogenesis ; Mechanisms and Clinical Implications of Nevus Development

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Ashfaq A. Marghoob (ed.) Nevogenesis 2012 Mechanisms and Clinical Implications of Nevus Development 10.1007/978-3-642-28397-0_1 Springer- Verlag Berlin Heidelberg 2012

1. Nevogenesis: Changing Theories

Mark E. Burnett 1

(1)

Dermatology Service, Memorial Sloan-Kettering Cancer Center, 160 East 53rd St., New York, NY 10022, USA

(2)

Memorial Sloan-Kettering Skin Cancer Center, Hauppauge, New York, USA

(3)

Department of Dermatology, Sheba Medical Center, Ramat Gan, Israel

(4)

Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

Mark E. Burnett

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Ashfaq A. Marghoob (Corresponding author)

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Alon Scope

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Abstract

The life cycle of most individual melanocytic nevi is shorter than the lifetime of the individual harboring them [13]. We are born with few or no nevi and enter old age with few or no nevi, while nevi development occurs between these two time periods (Fig. 1.1) [28]. This conception of nevogenesis appears relatively straightforward from a cross-sectional perspective, when only total nevus counts are considered.

Introduction

The life cycle of most individual melanocytic nevi is shorter than the lifetime of the individual harboring them []. This conception of nevogenesis appears relatively straightforward from a cross-sectional perspective, when only total nevus counts are considered.

Fig. 1.1

Total nevus counts take place along an arc-like trajectory over the course of ones lifetime. Usually individuals are born with no nevi, develop multiple nevi by midlife, and then lose their nevi in old age. However, the inception, growth, and involution of individual nevi can occur at any age. In other words, a child can develop a new nevus that grows and involutes within a few years. This process can also occur in adults

However, longitudinal follow-up of individual nevi has elucidated important details about the inception and growth, as well as the disappearance of nevi. The development of new nevi is a common event in youth; in fact, 75 % of children between ages 11 and 14 (5th to 8th grade) develop new nevi [].

How do nevi form and develop? Until recently, two competing theories have held sway over thought regarding inception and development of an individual nevus. Abtropfung [].

Thus, understanding how nevi arise, what determines their growth, what leads to their growth arrest or senescence, and their eventual involution, will help shed light on the genesis of melanoma. To this end, the purpose of this review is to summarize pivotal studies which have prompted a reevaluation of widely held theories of nevogenesis. Specifically, we will explain the prevailing theories of Abtropfung [], then present data from recent studies that challenge these paradigms. Finally, we will integrate these insights into contemporary hypotheses of the life cycle of nevi.

Challenge to Traditional Theories of Nevogenesis

Abtropfung and Hochsteigerung Theories of Unidirectional Melanocyte Migration

Two opposing nevogenesis theories have prevailed for decades. These theories attempt to describe the natural evolution of nevi as a process of unidirectional melanocytic migration. The first theory, put forth in 1893 by Paul Gerson Unna, is referred to as Abtropfung , literally dropping off [] dogma reinforces this position, teaching that nevus cell maturation takes place along a trajectory of downward migration, starting in the epidermis and culminating in the dermis.

Fig. 1.2

In 1893, Paul G. Unna proposed the concept of Abtropfung , according to which melanocytic nevus cells first develop and proliferate in the epidermis and subsequently drop off to the dermis over time (adapted from: Unna []). This process would lead to formation of junctional nevi with a dermoscopic reticular pattern ( a ), followed by compound ( b ), and finally dermal nevi with a dermoscopic globular pattern ( c )

Almost a century later, in 1984, Stewart F. Cramer postulated a second competing theory referred to as Hochsteigerung , literally upward climbing [). According to Cramers theory, it would follow that migration into the dermis, followed by proliferation, results in an intradermal nevus just as ascent into the epidermis would result in a junctional nevus. Migration of some melanocytes into the epidermis, while other melanocytes fail in reaching this destination and remain in the dermis, would result in a compound nevus. This process is believed to occur both during fetal development and, importantly, in the maintenance of normal skin tissue throughout postnatal life. Therefore, it stands to reason that a progression from one nevus type to another (e.g., from dermal to compound to junctional nevus) should be observable by conducting cross-sectional histopathologic analysis of nevus type by age.

Fig. 1.3

In 1984, Stewart F. Cramer put forth the theory of Hochsteigerung , which posited that inception and growth of nevi resulted from an upward migration of nevus cells along individual nerve fibers ascending through the dermis. This process would lead to the formation of dermal nevi with a dermoscopic globular pattern ( a ), followed by compound ( b ), and finally junctional nevi with a reticular dermoscopic pattern ( c ) (adapted from: Cramer [])

The Abtropfung and Hochsteigerung theories of nevogenesis are not the only theories proposed for how nevi evolve. A two-compartment theory of nevogenesis, originally hypothesized by Masson in 1951 [].

Data Challenging the Unidirectional Melanocyte Migration Theories

Evidence from Cross-Sectional Histopathologic Studies

Unnas theory of Abtropfung implies that junctional nevi would be the most prevalent nevus pattern among youth. This would be followed by the appearance of compound nevi later in life. Finally, dermal nevi should predominate in later life. In contrast, Cramers theory of Hochsteigerung suggests a predominance of dermal nevi in youth followed by a concurrent decrease in dermal nevi and increase in junctional nevi in later life. Indeed, our understanding to date of the prevalence of nevi type by age group has been largely underpinned by data gathered from cross-sectional studies.

In an attempt to correlate nevus type with age, Worret and Burgdorf published a histopathologic study in which over 3,500 melanocytic nevi from patients of all ages were evaluated []. Congenital melanocytic nevi (CMN) were excluded. The researchers found that compound nevi were very common in children and became progressively less common with age, while dermal nevi remained stable in all age groups. Furthermore, junctional nevi were not found in any of the children under the age of 10. Aside from this exception, the incidence of junctional nevi remained relatively stable across all age groups.

Another histopathologic study, conducted by Westhafer et al., also provided important data regarding the prevalence of nevi type by age. The researchers examined biopsy reports from 1,645 melanocytic lesions excised over the course of 1 year at a major medical center []. Using these data, they determined the age distributions from a total of 184 junctional nevi. Their findings demonstrate that while junctional nevi occur at all ages, peak incidence occurs between the third and fifth decades of life.

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