ing the study period. The subjects with BA x-rays re- mens, what role BA radiographs play during rou- ceived more GH injections and had more frequent tine clinical practice has been questioned. These visits documented in the NCGS database than did the data from the NCGS support the notion that not cohort with no BA measurements. This would suggest only do pediatric endocrinologists find it of value that NCGS investigators find it of value to obtain BA to obtain BA determinations at enrollment, but that measurements in most subjects. Although the slightly they also find it beneficial to assess serially skeletal improved height SDS and height age outcomes during development. BA assessment should be considered treatment of the subjects with BA readings might be an important component of the follow-up of pa- attributed to their older age and pubertal status, there tients treated with GH. still remains the suggestion that somehow radiographs are used by the NCGS investigators to maximize GH ACKNOWLEDGMENTS therapy. Because final height data were not yet avail- Supported by an educational grant from Genentech, Inc, South able, it is possible that by assessing skeletal maturation San Francisco. at frequent intervals, GH treatment might be extended We thank Kevin Connelly for analysis and programming sup- longer, other agents (such as sex steroids or luteinizing port, and Sandra Blethen, MD, PhD, and Jim Frane, PhD, for releasing hormone analogues) might be added more helpful suggestions. often and in a more efficacious manner, or, because of more frequent visits, subjects might be more compliant REFERENCES with treatment regimens, all which would ultimately 1. Gruelich WW, Pyle SI. Radiographic Atlas of Skeletal Development of the improve the outcome of the cohort followed with BA Hand and Wrist. Stanford, CA: Stanford University Press; 1993 2. Buchlis JG, Irizarry L, Crotzer BC, Shine BJ, Allen L, Macgillivray MH. radiographs. Comparison of final heights of growth hormone-treated vs untreated The conclusion of this study, that it is important to children with idiopathic growth failure. J Clin Endocrinol Metab. 1998; follow BA x-rays for the pediatric endocrinologist, is 83:1075–1079 supported by the survey of GH treatment practices that 3. Coutant R, Carel J-C, Letrait M. Short stature associated with intrauter- was conducted by Wyatt et al6 in 1993 and reported in ine growth retardation: final height of untreated and growth hormone- treated children. J Clin Endocrinol Metab. 1998;83:1070–1074 1995. Of the 251 pediatric endocrinologists surveyed, 4. Balducci R, Toscano V, Mangiantini A, et al. Adult height in short BA determinations were used by 60% of them to de- normal adolescent girls treated with gonadotropin-releasing hormone termine who should start GH treatment, and BA delay analog and growth hormone. J Clin Endocrinol Metab. 1995;80:3596–3600 was ranked 5 of 14 on the scale of auxologic and labo- 5. Rosenfeld RO, Frane J, Affie KM, et al. Six-year results of a randomized, prospective trial of human growth hormone and oxandrolone in Turner ratory criteria used to initiate GH. These findings were syndrome. J Pediatr. 1992;121:49–55 similar to the percentages of those who ranked obtain- 6. Wyatt DT, Mark D, Slyper A. Survey of growth hormone treatment ing a BA determination as an important criterion to practices by 251 pediatric endocrinologists. J Clin Endocrinol Metab. discontinue GH. Again, 61% of those surveyed stated 1995;80:3292–3297 that BA was important, and they ranked it 5 of 14 in 7. Hopwood NJ, Hintz RL, Oertner JM, et al. Growth response of children with non-growth-hormone deficiency and marked short stature during criteria used to stop GH therapy. three years of growth hormone therapy. J Pediatr. 1993;123:215–222 There is no doubt that assessment of skeletal 8. Plotnick L, Attie KM, Blethen SL, Sy JP. Growth hormone treatment of maturation is at the foundation of research per- girls with Turner syndrome: the National Cooperative Growth Study formed evaluating GH treatment.7–9 Although BA experience. Pediatrics. 1998;102:479–481 9. August GP, Julius JR, Blethen SL. Adult height in children with growth radiographs are used to distinguish benefit from hormone deficiency who are treated with biosynthetic growth hormone: harm during studies of GH efficacy in novel clin- the National Cooperative Growth Study experience. Pediatrics. 1998;102: ical situations and in innovative therapeutic regi- 512–516

The Physiology of Pigmented Nevi

Jay Kincannon, MD, and Christine Boutzale, BS

ABSTRACT. Melanocytes are pigment-producing cells nosomes. Within the melanocyte, tyrosine is converted to derived from the neural crest. These specialized exocrine dopa, and then dopaquinone via the bifunctional enzyme cells produce melanin, which is packaged and dispersed tyrosinase. Dopaquinone is oxidized further to form the to neighboring keratinocytes in organelles called mela- pigment melanin. Each epidermal melanocyte secretes melanosomes to approximately 36 adjacent keratino- From the Department of Pediatric Dermatology, University of Arkansas for cytes, forming an epidermal melanin unit. Genetically Medical Sciences, Little Rock, Arkansas. programmed constitutive skin color is determined by the Presented in part at the National Cooperative Growth Study Twelfth An- amount of cutaneous melanin pigmentation. nual Investigator’s Meeting; October 8–11, 1998; New Orleans, LA. The common mole or acquired melanocytic nevus Received for publication May 13, 1999; accepted Jun 22, 1999. (AMN) is a collection of nevomelanocytes grouped into Reprint requests to (J.K.) Arkansas Children’s Hospital, 800 Marshall St, Little Rock, AR 72202-3591. E-mail: [email protected] nests located in the epidermis (junctional nevus), dermis PEDIATRICS (ISSN 0031 4005). Copyright © 1999 by the American Acad- (dermal nevus), or both (compound nevus). It is hypoth- emy of Pediatrics. esized that nevomelanocytes are derived from either epi-

1042 SUPPLEMENT Downloaded from www.aappublications.org/news by guest on September 30, 2021 dermal melanoblasts or dermal Schwann cells. AMN first pathway. What is known as a premelanosome is appear at ϳ1 year of age, peaking in number during the formed in the smooth endoplasmic reticulum, second or third decades of life, and disappearing by the whereas the rough endoplasmic reticulum is pro- seventh to ninth decades. AMN may appear suddenly or ducing the copper-containing oxidase known as become more prominent in response to sun exposure, tyrosinase. Final maturation occurs in the Golgi cortisone and corticotropin, blistering diseases, chemo- apparatus as tyrosinase is transported by coated therapy, immunosuppression, and other factors that are not well-defined. Reports of AMN increasing in size and vesicles to the premelanosome. There it catalyzes darkening in color during puberty and pregnancy have the conversion of tyrosine to dopa and then dopa- been reported but not quantitated systematically. quinone, which is oxidized further to form the Pediatrics 1999;104:1042–1045; melanocytes, keratino- pigment melanin. cytes, acquired melanocytic nevi. Eumelanin is a black–brown pigment, whereas pheomelanins are pigments that contribute primarily ABBREVIATIONS. AMN, acquired melanocytic nevus; CMN, to hair color. The biochemical pathway for the pro- congenital melanocytic nevus. duction of pheomelanin varies somewhat to yield a more yellow–red color.

he incidence of malignant melanoma is in- BIOLOGY OF PIGMENTED NEVI creasing within the population. Risk factors for Melanotic nevi, or moles, are quite common. Usu- Tthe development of cutaneous melanoma in- ally brown, they vary in shape and size, and can be clude: 1) a new or changing mole; 2) adulthood (15 found anywhere on the skin. A pigmented nevus is a years or older); 3) family history of melanoma; 4) benign proliferation of cells with melanocytic differ- dysplastic nevus syndrome; 5) large congenital ne- entiation. These cells can be formed from either pre- Ͼ vus ( 20 cm); 6) several nevi; 7) white race; 8) severe existing melanocytes or cells called nevomelano- childhood sunburns; and 9) immunosuppression. cytes. The origin of the nevomelanocyte is the nevomelanoblast. Embryologically, nevomelano- BIOLOGY OF MELANOCYTES blasts are melanocytes within the neural crest.1 The Melanin, the skin pigment that is the primary de- cells migrate to the epidermis and dermis, where terminant of skin color, is produced by melanocytes, they differentiate into nevomelanocytes. One hy- which make up ϳ15% of the basal layer of sun- pothesis is that the nevomelanoblasts in the upper exposed skin and 6% of unexposed skin. In its pri- dermis and epidermis are derived from epidermal mary role of absorbing ultraviolet light, melanin is melanocytes, whereas those in the lower dermis are deposited in keratinocytes of the interfollicular epi- from Schwann cells of nerves. For a melanocyte to dermis, thus protecting the genome of the dividing express a normal morphology, it must be located in basal keratinocytes and melanocytes. The melano- the basement membrane zone. Recent studies show somes are located supranuclearly in the melanocytes that when melanocytes migrate to other locations, before being distributed throughout the cell to pro- they lose dendrite expression, decrease production of vide maximal protection from damaging ultraviolet melanin and enzymes such as tyrosinase, and mor- light. Melanin also has been shown to be a free phologically begin to resemble Schwann cells.4 These oxygen–radical scavenger, protecting the metaboli- cells become round instead of dendritic, and store cally active keratinocyte from any free radicals that rather than transfer the melanin they produce. Mela- are generated. nocytic nevi and nevomelanocytic nevi are of impor- Embryologically, melanocytes are cells that tance because histologically, they can resemble mel- emigrate from the lateral ridges of the neural plate as anomas, or malignant proliferation of cells with the ridges join to form the neural tube. Using HMB- melanocytic lineage. It is important to distinguish 45, a monoclonal antibody, melanoblasts have been both with certainty for the purpose of appropriate identified in fetal skin at ϳ7 weeks of gestation.1 At treatment. 15 to 16 weeks of gestation, melanin synthesis begins, followed shortly by melanosome transfer at ϳ20 CLASSIFICATION OF NEVI weeks.2 The cells then migrate to the basal layer of The common mole or AMN consists of nests of the dermal–epidermal junction. melanocytes, as opposed to normal melanocytes One melanocyte provides pigment to approxi- placed singly along the basement membrane. These mately 36 keratinocytes, forming what is known as nests are divided for classification purposes into an epidermal melanin unit. The pigment is formed, three groups by location. Those along the dermal– packaged into vesicles, and transferred to keratino- epidermal junction are called junctional nevi. Those cytes via dendrites. The outcome of pigment transfer in the dermal–epidermal junction and the dermis are from melanocytes to keratinocytes differs among compound nevi. Those only in the papillary and races. In black skin, melanosomes are dispersed in- reticular dermis are intradermal nevi. Nevi increase dividually, whereas in white skin, the melanosomes in frequency with age until middle age, when they are in clusters with a surrounding membrane.3 This reach a plateau in frequency and begin to migrate pattern of distribution affects the absorption and lower in the dermis and involute spontaneously. reflection of light, accounting for the major difference Nevi also are classified by the age at which they in skin color among the races. occur. Congenital nevi are present within the first 6 Melanin production begins as one process that months of life. Acquired nevi arise later in life. This ends with two distinct options for completing the distinction is significant because congenital nevi are

Downloaded from www.aappublications.org/news by guest on September 30, 2021 SUPPLEMENT 1043 apparently more likely to become malignant than 1% to 2% of newborns at birth. The clinical appear- their acquired counterparts.5 ance of CMN can be varied, but typically appear as a A third classification of nevi, particularly with re- sharply demarcated plaque with or without coarse gard to congenital nevi, is based on the size of the hairs. They are light or dark brown and are solitary lesion. Small nevi are Ͻ1.5 cm in diameter, medium- in 95% of cases (except with giant CMN, in which size nevi range from 1.5 to 19.9 cm in diameter, and satellite nevi exist). The cells in this nevus type often giant nevi are Ն20 cm in diameter.6 are clustered at the dermal–epidermal junction. Histologically, nevi are classified generally as hav- These cells go deeper into the dermis than do ac- ing atypical cells, as in dysplastic nevi, or normal quired nevi, and therefore tend to have more neural cytology, as in the common nevus. differentiation. The cells of congenital nevi also are Any additional features associated with the nevus, more likely to invade blood vessels, nerves, and erec- such as other prevalent cell types or tissue types, also tor pili muscles. Clinically, they can be Ͻ1.5 cm for are used to further distinguish among types of nevi. the smallest type. Alternatively, a giant congenital One example is the halo nevus. Clinically, halo nevi nevus can cover the scalp, a limb, or the entire back. are described as a pigmented macule with surround- Giant nevi have an increased risk of melanoma and ing depigmentation. Histologically, they have a lym- have been associated with meningeal melanocytosis.9 phocytic infiltrate. Another variant of the melanocytic nevus is the Clearly, many variants of nevi exist, but this dis- blue nevus. Distinguished by its typical bluish–black cussion centers primarily on the clinical morphology or blue–gray color, it consists of cells deep in the of the various types of AMN. There are five types of dermis. This nevus owes its unique color to the abun- AMN based on gross appearance. They can be flat, dance of melanin transmitting from the deep location slightly elevated, papillomatous, dome-shaped, or offset by the color of the normal surrounding skin. pedunculated, and are associated more commonly Three types have been described. They are the cellu- with phenotypes such as blue or green eye color and lar blue nevus, the common blue nevus, and the blond, light brown, or red hair.7,8 Children are more combined blue nevus-nevomelanocytic nevus. likely to have nevi if their mother has numerous nevi The common blue nevus is smaller, less raised, and or if they have a family history of melanoma.8 AMN less locally aggressive than is the cellular variety. show a fairly consistent progression of growth. Ini- Approximately half of the common blue nevi are tially, the cells typically proliferate at the dermal– solitary and located on the dorsal aspects of the epidermal junction. With time, they begin also to hands and feet. The cellular nevi more often are involve the upper dermis. This compound stage found on the sacrum or buttock and can be associ- eventually will lose its junctional component, leaving ated with benign lymph node metastasis. The com- only an interdermal nevus in the final stage. pound blue nevi are often first thought to be mela- Clinically, these nevi are round, brown, or black, nomas because of their often irregular, elevated flat, or slightly raised. The skin creases are preserved. surface. Blue nevi are most commonly acquired, al- A striated pattern in the skin may be noted, which beit at an early age. As with other melanocytes situ- reflects the histologic picture of melanocytes involv- ated deep within the dermis, the cells of the blue ing the rete ridges. Cytologically, the cells are fairly nevus resemble Schwann cells. bland. Clinically, compound nevi also are similar to junc- FACTORS AFFECTING GROWTH OF NEVI tional nevi in that they are of uniform color and often It has been suggested that physiologic conditions, are described as macules. They can also present as such as pregnancy, puberty, or systemic corticoste- verrucal papules. Histologically, compound nevi roids,10 and human growth hormone therapy11 pro- consist of nests of melanocytes as well, but are lo- duce changes in nevi. However, it is not clear exactly cated in the dermis and are either spindled or neu- how much change can be attributed to these condi- rally differentiated. Also consistent with junctional tions. Sun exposure and blistering disease also can nevi is the appearance of the epidermis, with slightly cause nevi to become increasingly pigmented. Sun increased numbers of enlarged melanocytes between can induce the junctional component to proliferate. If nests of nevomelanocytes. In nevi that are com- one of these factors is suspected to account for pig- pletely benign, the junctional component usually ex- ment change in a particular nevus, all nevi should be tends to approximately the same depth as the dermal affected. If only one nevus has changed, a biopsy component. should be performed to check for malignant trans- Intradermal nevi, as the name implies, are located formation. Recent change of any parameter of a ne- in the dermis and have no junctional component. vus, such as color, shape, or size, should be evalu- Clinically, they appear the least pigmented of the ated, as should any new onset of pain, pruritus, three classes because the deeper into the dermis the ulceration, or bleeding. A biopsy of the lesion is the melanocytes are clustered, the less pigment is seen at recommended measure at this time for diagnostic the surface of the skin. These cells are smaller than and possible therapeutic purposes. their more superficial counterparts, have less intra- cellular pigment, and display rare mitotic figures. If MELANOMA any pleomorphism is observed, the clinician should Melanoma is of increasing concern, as its fre- initiate additional investigation because this could quency within the population is increasing. Skin ex- indicate developing melanoma. aminations are important, especially for patients Congenital melanocytic nevi (CMN) are present in with risk factors. Some common risk factors are

1044 SUPPLEMENT Downloaded from www.aappublications.org/news by guest on September 30, 2021 adulthood, a new or changing mole, numerous nevi, ACKNOWLEDGMENT light skin color, a family history of melanoma, dys- Supported by an educational grant from Genentech, Inc, South plastic nevus syndrome, giant congenital nevus, se- San Francisco, CA. vere childhood sunburns, and immunosuppres- sion.12 REFERENCES An important characteristic of melanoma is its 1. Holbrook KA, Underwood RA, Vogel AM, Gown AM, Kimball H. The overall asymmetry in contrast to the typical symme- appearance, density and distribution of melanocytes in human embry- try of benign lesions. Also, the size of the lesion is onic and fetal skin revealed by the anti-melanoma monoclonal anti- body, HMB-45. Anat Embryol (Berl). 1989;180:443–455 important to note. The larger a pigmented lesion is 2. Zimmermann AA, Cornbleet T. The development of epidermal pigmen- over 5 or 6 mm across, the more likely it is to display tation in the Negro fetus. J Invest Dermatol. 1948;11:383–395 atypia in its cells. Both the length and width of 3. Szab-G, Gerald AB, Pathak MA, Fitzpatrick TB. Racial differences in the lesions should be measured. Melanoma usually has a fate of melanosomes in human epidermis. Nature. 1969;222:1081–1082 more irregular, notched, or scalloped border. Raised 4. Cramer SF. The origin of epidermal melanocytes. Implications for the histogenesis of nevi and melanomas. Arch Pathol Lab Med. 1991;115:115–119 lesions and lesions with increased surface markings 5. Cochran AJ, Bailly C, Paul E, Remotti F. Melanocytic Tumors: A Guide to as viewed by tangential lighting are at increased risk Diagnosis. Philadelphia, PA: Lippincott–Raven; 1997:68 for malignant transformation. 6. Rhodes AR. Melanocytic precursors of cutaneous melanoma: estimated risks and guidelines for management. Med Clin North Am. 1986;70:337 CONCLUSION 7. Sigg C, Pelloni F. Frequency of acquired melanonevocytic nevi and their relationship to skin complexion in 939 schoolchildren. Dermatologica. Many factors influence the clinical appearance of 1989;179:123–128 AMN, including sun exposure, pregnancy, puberty, 8. Green A, Sisking V, Hansen M-E, Hanson L, Leech P. Melanocytic nevi in and immunosuppression. Growth hormone has been schoolchildren in Queensland. J Am Acad Dermatol. 1989;20:1054–1060 ␾ implicated as a possible factor contributing to 9. Cordoba A, Tun˜on T, Vasquez JJ. Melanocitoma men nego: pre- sentaci-n de un caso y revisi-n de la literatura [in Spanish]. Arch Neu- changes seen in AMN; however, there are no current robiol. 1989;53:93–99 data suggesting that growth hormone is at all in- 10. Goldman L, Richfield DF. Effect of corticotropin and cortisone on volved in malignant transformation of these nevi development and progress of pigmented nevi. JAMA. 1951;147:941–943 into melanoma. At present, the most effective means 11. Bourguignon J-P, Pie´ard GE, Ernould C, et al. Effects of human growth hormone therapy on melanocytic naevi. Lancet. 1993;341:1505–1506 of prevention and early detection of melanoma in- 12. Rhodes AR, Weinstock MA, Fitzpatrick TB, Mihm MC, Sober AJ. Risk clude routine skin evaluation, sun avoidance during factors for cutaneous melanomas: a practical method for recognizing peak hours, and use of sunscreen. predisposed individuals. JAMA. 1987;258:3146–3154

Melanocytic Nevi in Children Treated With Growth Hormone

David Wyatt, MD

ABSTRACT. There is concern that growth hormone nevi count or the risk of skin cancer. Pediatrics 1999; (GH) therapy may influence the growth of melanocytic 104:1045–1049; aquired melanocytic nevi, growth hor- nevi. In a review of the experience of the National mone, melanoma, Noonan syndrome, Turner syndrome. Cooperative Growth Study, we found no excess of skin cancer in children who were treated with GH. We also reviewed our experience in 90 children with GH defi- ABBREVIATIONS. GH, growth hormone; AMN, acquired mela- ciency and 24 with Turner syndrome. We found no nocytic nevi; GHD, growth hormone deficiency; NCGS, National difference in the nevi count between control subjects Cooperative Growth Study; SCI, skin color index. and children with GH deficiency, even after many years of GH therapy. Nor was there any relation be- tween the duration of therapy and the nevi count. rowth hormone (GH) therapy has been re- Children with Turner syndrome had more nevi, but ported to have a reversible stimulatory effect there was no relation to the duration of GH therapy. on the size of acquired melanocytic nevi These findings and the absence of a greater frequency G (AMN) in children with isolated GH deficiency of skin cancer in acromegaly are reassuring. It is un- 1 likely that GH therapy has a significant influence on (GHD) and with Turner syndrome. Recent reviews of safety issues in the use of GH have reflected the concern that it may influence mole growth.2,3 How- From the Department of Pediatrics, Medical College of Wisconsin, Milwau- ever, increased AMN count rather than size is a kee, Wisconsin. known risk factor for melanoma.4 Furthermore, ac- Presented in part at the National Cooperative Growth Study Twelfth An- nual Investigators Meeting; October 8–11, 1998; New Orleans, LA. romegaly, a condition of chronic GH excess, is not 5–13 Received for publication May 13, 1999; accepted Jun 22, 1999. associated with an increased risk of skin cancer. It Address correspondence to Dr Wyatt, Department of Pediatrics, Medical is believed generally that the number of AMN is College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226. greater in Turner syndrome,14 but there does not E-mail: [email protected] PEDIATRICS (ISSN 0031 4005). Copyright © 1999 by the American Acad- appear to be an increased risk of melanoma in this emy of Pediatrics. condition either. It is not known whether GH ther-

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Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/104/Supplement_5/1042 References This article cites 11 articles, 0 of which you can access for free at: http://pediatrics.aappublications.org/content/104/Supplement_5/1042 #BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Growth/Development Milestones http://www.aappublications.org/cgi/collection/growth:development_ milestones_sub Endocrinology http://www.aappublications.org/cgi/collection/endocrinology_sub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml

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Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. Pediatrics is owned, published, and trademarked by the American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 1999 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

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