- Email: [email protected]
Histologic features of scalp melanocytic nevi
DERMATOPATHOLOGY
Histologic features of scalp melanocytic nevi Kristopher R. Fisher, MD,a John C. Maize, Jr, MD,a,b and John C. Maize, Sr, MDa,b Charleston and Mount Pleasant, South Carolina Background: The scalp has been proposed as an anatomic site that harbors melanocytic nevi with distinctive histologic attributes, so-called ‘‘special-site’’ nevi, similar to nevi on the breast and genitalia. However, detailed studies are lacking. Objective: We sought to better delineate the features of scalp melanocytic nevi, particularly lesions that may qualify as special-site nevi. Methods: The histologic features of 365 total melanocytic nevi of the scalp were studied from 322 patients over a consecutive period of 18 months from July 2007 through January 2009. Results: A total of 56 nevi with characteristic features were identified. The most common features were: (1) random melanocytes containing large nuclei (92.9%) and abundant pale cytoplasm with dusty melanin granules (96.4%); (2) large nests (76.8%) situated along the sides of rete and between rete ridges (85.7%); (3) nests of poorly cohesive melanocytes (82.1%); (4) overlap features with Clark nevi (75.0%); and (5) overlap features with superficial congenital nevi (50.0%). Pagetoid spread (14.3%), asymmetry (23.2%), and poor lateral demarcation (16.1%) were less common. These 56 lesions predominated in the first 2 decades of life and were not observed after age 35 years. Limitations: Lack of long-term clinical follow-up of patients is a limitation; however, no recurrences or malignancies from these patients’ scalps were submitted in the time period ( $ 3 years) since the initial biopsies. Conclusion: A special site scalp nevus is recognizable amongst scalp melanocytic nevi, and this lesion is more common in younger patients. Familiarization of its features should assist in the diagnosis and management of scalp melanocytic lesions. ( J Am Acad Dermatol 2013;68:466-72.) Key words: children; histology; melanoma; nevus; scalp; special site.
elanocytic nevi in certain anatomic locations may exhibit distinctive histologic features, some of which are concerning because they can simulate features of melanoma. Such lesions have been termed ‘‘nevi of special sites,’’ ‘‘nevi with site-related atypia,’’ or ‘‘specific-site nevi.’’1,2 The importance of identifying these lesions lies in their benign biologic behavior despite worrisome histologic attributes. Anatomic locations reported as special sites include the genitalia,3-6 breast,7 ear,8,9 flexural regions,5 acral locations,10
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and conjunctiva.11 It has been proposed that nevi from the scalp share histologic attributes with other special-site nevi.12,13 We characterized a series of consecutive scalp nevi submitted to our laboratory in the attempt to better illustrate and define their distinctive histologic features. Special-site features in scalp nevi have been posited to present more commonly in certain age groups, particularly adolescents and young adults.12,13 Therefore, we also attempted to correlate patient age
From the Medical University of South Carolina, Charleston,a and Dermpath Diagnostics, Maize Center for Dermatopathology, Mount Pleasant.b Funding sources: None. Conflicts of interest: None declared. Previously presented in poster format entitled ‘‘Histologic Features of Scalp Melanocytic Nevi’’ at the 70th Annual Meeting of the American Academy of Dermatology, in San Diego, CA, March 16-20, 2012.
Reprint requests: Kristopher R. Fisher, MD, 930 Madison Avenue, Suite 890, Memphis, TN 38103. E-mail: fisher_kristopher@ yahoo.com. Published online December 26, 2012. 0190-9622/$36.00 Ó 2012 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2012.10.046
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with the histologic patterns observed in these lesions.
defined as loosely aggregated collections of melanocytes, similar to the previously described ‘‘nested and dyshesive’’ pattern in other special-site nevi.3,5 Nests were considered large if their size approxiMETHODS mated or exceeded the volume of 2 rete ridges. In all, 365 total melanocytic nevi of the scalp were Superficial congenital pattern was defined as an studied from 322 patients over a consecutive period angiocentric and adnexocentric distribution of melof 18 months from July 2007 through January 2009. anocytes with splaying foAges of patients ranged from cally between collagen 2 to 81 years, with a mean CAPSULE SUMMARY bundles in the upper half of age of 33.7 years. Age ranges the reticular dermis.14 were divided by decade to The scalp may represent a special site, Because many lesions exfacilitate study of lesions in where histologic features of nevi overlap hibited at least 1 feature chardifferent age groups. No sigwith melanoma despite their benign acteristic of Clark nevus, we nificant gender differences nature. classified each nevus as: (1) were present in any age We studied 365 consecutive scalp nevi predominantly special-site group from 0 to 79 years and identified 56 lesions that showed nevus; (2) predominantly (only 1 lesion was present predominant features of special-site nevi. Clark nevus; or (3) other in the $ 80-year age group). These lesions were more common in the common nevus. Lesions We excluded common and first 2 decades of life and were not were classified as predomicellular blue nevi, combined observed after age 35 years. nantly special-site nevi if nevi, deep penetrating nevi, they exhibited mostly feaand Spitz nevi. Lesions were Familiarization with these scalp nevi will tures commonly ascribed to excluded from the study if avoid overaggressive management of nevi on special sites: nests they contained features conthese lesions, particularly in young positioned along the sides cerning for evolution to melchildren. and between rete ridges, anoma in situ. In addition, pagetoid scatter, asymmetry, because our goal was to obpoor circumscription, and large junctional nests with serve and describe the features of a stereotypical poor cellular cohesion. Lesions were classified as special-site scalp nevus, we also excluded indeterpredominantly Clark nevi if they shared more feaminate lesions or Clark nevi with unusual features. tures of that nevus. Clark nevus was defined as a Nevi were assessed for the following features: (1) junctional or compound melanocytic nevus mostly symmetry; (2) lateral demarcation/circumscription; confined to the papillary dermis with nests often (3) growth patternepredominantly nested or prespaced unevenly along the dermoepidermal junction dominantly lentiginous; (4) superficial congenital and extending laterally at least 3 rete past the dermal pattern; (5) presence of inflammation; (6) papillary component; nests often oriented parallel to the skin dermal fibroplasia; (7) bridging of nests between rete surface and bridging rete; and with scattered cytoridges; (8) random large melanocyte nuclei; (9) logically atypical melanocytes, papillary dermal firandom melanocyte nuclear hyperchromasia; (10) brosis, and a patchy lymphomononuclear cell melanocytes containing pale cytoplasm with fine infiltrate in the papillary dermis.15,16 Nevi were dusty melanin granules; (11) nests positioned along classified as other common nevi if they exhibited the sides and between rete ridges; (12) pagetoid mostly features of common acquired compound or scatter; (13) poor melanocytic cellular cohesion; and intradermal nevi, often of Unna or Miescher (14) large nests. Rather than evaluating melanocyte type.17,18 Special-site nevi and Clark nevi were comatypia unqualified, we focused specifically on the 2 pared, and Fisher exact test was used to determine most prominent aspects of melanocyte atypia in statistically significant differences. Finally, lesion these lesions, studying each component separately: type was compared across age groups to analyze nucleomegaly and nuclear hyperchromasia. any trends in lesion presentation with patient age. Melanocyte nuclei were considered large if their size was greater than adjacent keratinocyte nuclei. RESULTS Melanocyte nuclei were considered hyperchromatic Of 365 melanocytic nevi, 56 were identified that if their chromatin stained more darkly with hemashared most histologic characteristics described in toxylin than adjacent keratinocyte nuclei. Pagetoid other special-site nevi. These lesions contained scatter was deemed present if intraepidermal melamelanocytes arranged in a nested, rather than nocytes were located above the basal layer over an lentiginous growth pattern (98.2%). These nests expanse of 3 rete ridges.9 Poor cellular cohesion was d
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Table I. Histologic features of scalp nevi Special-site nevi (n = 56)
Predominantly nested growth pattern Pale cytoplasm with dusty melanin Random melanocyte nucleomegaly Lateral extension of junctional component Nests positioned at sides and between rete Poor cellular cohesion Large nests Fibroplasia Bridging between rete Presence of inflammation Superficial congenital pattern Random melanocyte nuclear hyperchromasia Asymmetry Poor lateral demarcation Pagetoid migration
98.2% 96.4% 92.9% 87.5% 85.7% 82.1% 76.8% 75.0% 75.0% 62.5% 50.0% 44.6% 23.2% 16.1% 14.3%
(55/56) (54/56) (52/56) (49/56) (48/56) (46/56) (43/56) (42/56) (42/56) (35/56) (28/56) (25/56) (13/56) (9/56) (8/56)
Clark nevi (n = 61)
67.2% 73.8% 82.0% 70.5% 14.8% 41.0% 16.4% 95.1% 93.4% 88.5% 16.4% 23.0% 16.4% 32.8% 11.5%
(41/61)* (45/61)* (50/61) (43/61)* (9/61)* (25/61)* (10/61)* (58/61)* (57/61)* (54/61)* (10/61)* (14/61)* (10/61) (20/61) (7/61)
Other common nevi (n = 248)
97.6% 6.5% 4.0% 3.2% 2.0% 3.6% 9.3% 5.6% 4.8% 6.9% 41.9% 1.2% 7.7% 2.8% 1.2%
(242/248) (16/248)* (10/248)* (8/248)* (5/248)* (9/248)* (23/248)* (14/248)* (12/248)* (17/248)* (104/248) (3/248)* (19/248)* (7/248)* (3/248)*
*Statistical significant difference (P \ .05) when comparing value with special-site nevus value.
were often large (76.8%) and situated not only at rete tips, but also along their sides and between rete ridges (85.7%). Frequently, these nests were composed of loosely adherent melanocytes, similar to the previously described ‘‘nested and dyshesive’’ pattern (82.1%).3,5 Individual melanocytes commonly contained large nuclei (92.9%) and abundant pale cytoplasm with dusty melanin granules (96.4%). Overlap with stereotypical features of Clark nevus were frequent, including papillary dermal fibroplasia (75.0%), nests that bridged adjacent rete (75.0%), and lateral extension of the epidermal component past the dermal component (87.5%). Fifty percent of lesions also contained features of superficial congenital nevi, such as adnexocentricity and splaying of melanocytes between collagen fibers of the reticular dermis. This number could likely have been greater if not for frequent superficial sampling, not allowing for inspection of adnexal structures or the reticular dermis. Pagetoid spread (14.3%), asymmetry (23.2%), and poor lateral demarcation (16.1%) were less common. Although we were unable to obtain long-term clinical follow-up for the majority of these lesions, we served as the exclusive dermatopathology providers to the submitting dermatologists during the 3 to 4 years since their initial biopsies, and no recurrences or melanomas from these patients’ scalps were submitted. We also identified nevi that contained some special-site attributes, but for which features were otherwise predominantly those of Clark nevi. A total of 61 such lesions were identified. As opposed to special-site nevi, these lesions were more likely to contain a prominent lentiginous growth pattern of
Fig 1. Special-site/other common nevi versus age.
melanocytes (32.8% vs 1.8%, P\.05) and less likely to contain large nests (16.4% vs 76.8%, P \ .05). Nests were more frequently restricted to rete tips, rather than located between and at the sides of rete ridges (85.2% vs 14.3%, P \ .05). Also, the predominantly Clark nevi were less likely to contain features of superficial congenital nevus (16.4% vs 50.0%, P\.05), less likely to exhibit poor melanocyte cohesion (41.0% vs 82.1%, P \.05), and more likely to display a patchy lymphocytic infiltrate in the superficial dermis (88.5% vs 62.5%, P \ .05). The complete histologic findings of all nevi are available in Table I. We compared the ages of patients who presented with various nevi types (Figs 1 and 2). More specialsite nevi than Clark nevi presented in prepubescent children. As opposed to the histologic features common in Clark nevi, features of special-site nevi were not common after age 30 years, and were not observed at all after age 35 years.
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Fig 2. Special-site/Clark nevi versus age.
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Fig 4. Predominantly nested pattern, with nests of various size and shape within epidermis and superficial congenital features within dermis. (Hematoxylin-eosin stain; original magnification: 3100.)
Fig 3. Well-circumscribed proliferation of large nests positioned along sides and between rete ridges, with prominent adnexal involvement. (Hematoxylin-eosin stain; original magnification: 340.)
DISCUSSION Our study has identified a subset of scalp melanocytic nevi that contain particular features common to other special-site nevi. The prototypical specialsite scalp nevus is one that contains poorly cohesive melanocytes arranged in large nests positioned both along the sides of rete and between rete ridges, housing random melanocytes with large nuclei and abundant pale cytoplasm, and exhibiting adnexocentricity and splaying of melanocytes through the reticular dermis (Figs 3 to 8). Overlap features with Clark nevienests that bridge rete, lateral extension past the dermal component, and papillary dermal fibroplasiaewere also common to these lesions (Figs 9 and 10). We did not, however, classify all Clark nevi on the scalp as special-site nevi. In our analysis, we reserved the diagnosis of Clark nevus to those lesions that displayed predominant features of that nevus. Fabrizi et al12 previously identified 4 cases, all on the scalp of teenagers, called ‘‘atypical nevi of the scalp’’ by the authors. The most striking features in those lesions were large bizarrely shaped nests scattered along the junction with follicular involvement. Our study supports those findings. However, unlike that previous work, the majority of lesions in our study were symmetric, well-circumscribed, and
Fig 5. Large nests at various positions along rete ridges. Note mild clefting around nests, focal bridging between rete tips, and mild papillary dermal fibroplasia. (Hematoxylin-eosin stain; original magnification: 3100.)
Fig 6. Nests with prominent clefting and poor cellular cohesion. Random individual melanocytes contain large nuclei, and many contain abundant pale cytoplasm. (Hematoxylin-eosin stain; original magnification: 3200.)
without significant pagetoid scatter of melanocytes. Fabrizi et al12 emphasized that atypical nevi on the scalp were observed in adolescents, but not adults or younger children. In this regard, our findings also differ. We agree that these features are not commonly
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Fig 7. Individual melanocytes contain large nuclei with abundant pale cytoplasm with dusty melanin granules. (Hematoxylin-eosin stain; original magnification: 3200.)
Fig 8. Poor cellular cohesion with hyperchromatic nuclei. (Hematoxylin-eosin stain; original magnification: 3200.)
Fig 9. Predominantly nested neoplasm with large expansive nests within epidermis and melanocytes arranged around adnexal structures with splaying into reticular dermis. Overlap features of Clark nevus include bridging between rete and papillary dermal fibroplasia. (Hematoxylin-eosin stain; original magnification: 3100.)
recognized after the age of 30 years, but we did identify 9 of 56 lesions in the 20- to 30-year-old age group. In addition, lesions with special-site features were commonly detected in prepubescent children. As seen in Fig 2, special-site nevi on the scalp typically appeared at an earlier age than Clark nevi and other common nevi.
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Fig 10. Clarkoid edge with lateral extension past dermal component, papillary dermal fibroplasia and focal bridging. Prominent adnexal involvement. Center portion of this lesion is pictured in Fig 5. (Hematoxylin-eosin stain; original magnification: 3100.)
The age distribution of special-site features has particular relevance to the management of scalp nevi in children. Although most Clark dysplastic nevi arise in adolescence and around the time of puberty,19 Tucker et al20 suggested that one of the first locations of Clark dysplastic nevi (in patients with true familial mole melanoma syndrome) may be the scalp, presenting as early as age 5 to 9 years. In addition, Fernandez et al21 determined that a higher percentage of nevi located on the scalp of children (age \12 years) were dysplastic, compared with those located on the trunk and extremities. This makes the discrimination of Clark dysplastic nevi from special-site nevi relevant. Management of Clark dysplastic nevi in children, particularly on the scalp, has been the focus of debate, with various degrees of importance ascribed to dysplastic features in childhood nevi.19 For example, some experts advocate excision of scalp nevi in patients who present with dysplastic features, as these lesions cannot be easily followed because of hair coverage.19 Although we view a solitary Clark nevus as simply another type of common acquired nevus, we recognize that opinions differ on the biologic significance of dysplasia within a single lesion. However, as opposed to Clark dysplastic nevi, there is no evidence to date to warrant malignant connotations whatsoever to special-site nevi. These lesions, as described on the genitalia, ear, breast, and acral and flexural areas3-10 are of interest because of their overlap features with melanoma, but are otherwise histologic curiosities, imparting no different biologic significance than other common nevi. Therefore, distinction from both melanoma and Clark dysplastic nevi makes it clear to clinicians (who may have various views on the biologic importance of dysplasia) that the special-site scalp nevus probably shares the biologic behavior of other special-site nevi.
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Evaluation of scalp nevi constitutes a significant subset of referrals to pediatric dermatologists.22 Presumably, recommendations by dermatopathologists for re-excision of these lesions, or even misdiagnosis as melanoma, could contribute to further scalp surgery, leading to unsightly scars and permanent alopecia. Scalp nevi in children usually evolve in a benign fashion not supportive of excisional biopsies.23 A subset of patterned nevieeclipse and cockade nevi24,25erepresent around one fourth of childhood scalp nevi26 and also do not warrant excision.22 These findings, along with our current study, should help dermatologists and dermatopathologists identify morphologic features of scalp nevi in children. Despite the evidence above, we do not underestimate the seriousness of scalp melanocytic lesions. The presence of scalp nevi in children may be a harbinger of an above-average total number of nevi on the entire body,27 which in turn places one at higher risk for melanoma based on melanocyte burden.28-31 Similarly, some epidemiologic studies have correlated the presence of scalp nevi to higher risk of melanoma (at other sites) overall.30,31 Childhood melanomas on the head/neck have been associated with a lower survival than melanomas on other anatomic sites32,33; one European study linked lower survival specifically to the scalp.34 Not all studies in children have shown similar results.35 Although the relationship between anatomic site and prognosis of melanoma has been debated for years, epidemiologic evidence is mounting to suggest worse survival of scalp/neck melanoma versus other anatomic sites after controlling for age, Breslow thickness, gender, and ulceration.36 Therefore, we believe that better characterization of scalp nevi is important to prevent both underdiagnosis and overdiagnosis of melanoma. We did not recognize special-site features in any lesion after the age of 35 years. The influence of trauma, hormones, and regional anatomy have all been proposed as contributing factors to unusual features in nevi.1 In our study, age clearly influenced the histologic features of scalp nevi. To this end, scalp lesions exhibiting expansive nests of poorly cohesive melanocytes containing large hyperchromatic nuclei should probably trigger more concern when detected after age 30 years.
CONCLUSION We herein describe a subset of scalp melanocytic nevi with histologic features that are particular to that site, similar to other special-site nevi. These particular histologic features are more prominent in patients of younger ages, similar to results of previous studies.12,13 We propose that these nevi share histologic features with both superficial congenital and
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Clark nevi, but are not equivalent to Clark nevi, and commonly present in prepubescent children and adolescents. Because of the overlap features with superficial congenital nevi, we cannot exclude the possibility that these lesions represent a type of small congenital nevus. Familiarization of these lesions by dermatopathologists and dermatologists should aid in the management of melanocytic lesions on the scalp. REFERENCES 1. Hosler GA, Moresi JM, Barrett TL. Nevi with site-related atypia: a review of melanocytic nevi with atypical histologic features based on anatomic site. J Cutan Pathol 2008;35:889-98. 2. Elder DE. Precursors to melanoma and their mimics: nevi of special sites. Mod Pathol 2006;19:S4-20. 3. Clark WH Jr, Hood AF, Tucker MA, Jampel RM. Atypical melanocytic nevi of the genital type with a discussion of reciprocal parenchymal-stromal interactions in the biology of neoplasia. Hum Pathol 1998;29:S1-24. 4. Gleason BC, Hirsch MS, Nucci MR, Schmidt BA, Zembowicz A, Mihm MC Jr, et al. Atypical genital nevi: a clinicopathologic analysis of 56 cases. Am J Surg Pathol 2008;32:51-7. 5. Rongioletti F, Ball RA, Marcus R, Barnhill RL. Histopathologic features of flexural melanocytic nevi: a study of 40 cases. J Cutan Pathol 2000;27:215-7. 6. Christensen WN, Friedman KJ, Woodruff JD, Hood AF. Histologic characteristics of vulvar nevocellular nevi. J Cutan Pathol 1987;14:87-91. 7. Rongioletti F, Urso C, Batolo D, Chimenti S, Fanti PA, Filotico R, et al. Melanocytic nevi of the breast: a histologic case-control study. J Cutan Pathol 2004;31:137-40. 8. Lazova R, Lester B, Glusac EJ, Handerson T, McNiff J. The characteristic histopathologic features of nevi on and around the ear. J Cutan Pathol 2005;32:40-4. 9. Saad AG, Patel S, Mutasim DF. Melanocytic nevi of the auricular region: histologic characteristics and diagnostic difficulties. Am J Dermatopathol 2005;27:111-5. 10. Boyd AS, Rapini RP. Acral melanocytic neoplasms: a histologic analysis of 158 lesions. J Am Acad Dermatol 1994;31:740-5. 11. Massi G, LeBoit PE. Histological diagnosis of nevi and melanoma. Germany: Springer/Steinkopff Verlag Darmstadt; 2004. pp. 337-46. 12. Fabrizi G, Pagliarello C, Parente P, Massi G. Atypical nevi of the scalp in adolescents. J Cutan Pathol 2007;34:365-9. 13. Perry B, Ruben B. Nevi on the scalp: ‘‘special’’ not only in children but in young adults as well. Abstract presented at: 45th American Society of Dermatopathology Annual Meeting; October 16-19, 2008; San Francisco, CA. 14. Maize JC, Ackerman AB. Pigmented lesions of the skin. Philadelphia: Lea and Febiger; 1987. pp. 114-23. 15. Clark WH Jr, Reimer RR, Greene MH, Ainsworth AM, Mastrangelo MJ. Origin of familial melanomas from heritable melanocytic lesions: ‘‘the B-K mole syndrome.’’ Arch Dermatol 1978; 114:732-8. 16. Metcalf JS, Maize JC. Clark’s nevus. Semin Cutan Med Surg 1999;18:43-6. 17. Yus ES, del Cerro M, Simon RS, Herrera M, Rueda M. Unna’s and Miescher’s nevi: two different types of intradermal nevus; hypothesis concerning their histogenesis. Am J Dermatopathol 2007;29:141-51. 18. Ackerman AB, Magana-Garcia M. Naming acquired melanocytic nevi: Unna’s, Miescher’s, Spitz’s, Clark’s. Am J Dermatopathol 1990;12:193-209.
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19. Rothman KF, Esterly NB. Dysplastic nevi in children: special symposium. Pediatr Dermatol 1990;7:218-34. 20. Tucker MA, Greene MH, Clark WH Jr, Kraemer KH, Fraser MC, Elder DE. Dysplastic nevi on the scalp of prepubertal children from melanoma-prone families. J Pediatr 1983;103:65-9. 21. Fernandez M, Raimer SS, Sanchez RL. Dysplastic nevi of the scalp and forehead in children. Pediatr Dermatol 2001;18:5-8. 22. Kessides MC, Puttgen KB, Cohen BA. No biopsy needed for eclipse and cockade nevi found on the scalps of children. Arch Dermatol 2009;145:1334-6. 23. Gupta M, Berk DR, Gray C, Cornelius LA, Bayliss SJ. Morphologic features and natural history of scalp nevi in children. Arch Dermatol 2010;146:506-11. 24. Schaffer JV, Glusac E, Bolognia JL. Eclipse nevusetan center with stellate brown rim. Br J Dermatol 2001;145:1023-6. 25. Happle R. Cockade nevus: unusual variation of nevus cell nevus [in German]. Hautarzt 1974;25:594-6. 26. Tcheung WJ, Bellet JS, Prose NS, Cyr DD, Nelson KC. Clinical and dermoscopic features of 88 scalp nevi in 39 children. Br J Dermatol 2011;165:137-43. 27. Aguilera P, Puig S, Guilabert A, Julia M, Romero D, Vicente A, et al. Prevalence study of nevi in children from Barcelona: dermoscopy, constitutional and environmental factors. Dermatology 2009;218:203-14. 28. Holly EA, Kelly JW, Shpall SN, Chiu S-H. Number of melanocytic nevi as a major risk factor for malignant melanoma. J Am Acad Dermatol 1987;17:459-68.
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29. Bauer J, Garbe C. Acquired melanocytic nevi as risk factor for melanoma development: a comprehensive review of epidemiological data. Pigment Cell Res 2003;16:297-306. 30. Swerdlow AJ, English J, MacKie RM, O’Doherty CJ, Hunter JA, Clark J, et al. Benign melanocytic nevi as a risk factor for malignant melanoma. Br Med J (Clin Res Ed) 1986;292:1555-9. 31. Bataille V, Newton Bishop JA, Sasieni P, Swerdlow AJ, Pinney E, Griffiths K, et al. Risk of cutaneous melanoma in relation to the numbers, types and sites of nevi: a case-control study. Br J Cancer 1996;73:1605-11. 32. Barnhill RL, Flotte TJ, Fleischli M, Perez-Atayde A. Cutaneous melanoma and atypical Spitz tumors in childhood. Cancer 1995;76:1833-45. 33. Strouse JJ, Fears TR, Tucker MA, Wayne AS. Pediatric melanoma: risk factor and survival analysis of the Surveillance, Epidemiology and End Results database. J Clin Oncol 2005;23: 4735-41. 34. Conti EMS, Cercato MC, Gatta G, Ramazzotti V, Roscioni S. Childhood melanoma in Europe since 1978: a population-based survival study. Eur J Cancer 2001;37:780-4. 35. Paradela S, Fonseca E, Prieto VG. Melanoma in children. Arch Pathol Lab Med 2011;135:307-16. 36. Lachiewicz AM, Berwick M, Wiggins CL, Thomas NE. Survival differences between patients with scalp or neck melanoma and those with melanoma of other sites in the Surveillance, Epidemiology, and End Results (SEER) program. Arch Dermatol 2008;144:515-21.
Histologic features of scalp melanocytic nevi Kristopher R. Fisher, MD,a John C. Maize, Jr, MD,a,b and John C. Maize, Sr, MDa,b Charleston and Mount Pleasant, South Carolina Background: The scalp has been proposed as an anatomic site that harbors melanocytic nevi with distinctive histologic attributes, so-called ‘‘special-site’’ nevi, similar to nevi on the breast and genitalia. However, detailed studies are lacking. Objective: We sought to better delineate the features of scalp melanocytic nevi, particularly lesions that may qualify as special-site nevi. Methods: The histologic features of 365 total melanocytic nevi of the scalp were studied from 322 patients over a consecutive period of 18 months from July 2007 through January 2009. Results: A total of 56 nevi with characteristic features were identified. The most common features were: (1) random melanocytes containing large nuclei (92.9%) and abundant pale cytoplasm with dusty melanin granules (96.4%); (2) large nests (76.8%) situated along the sides of rete and between rete ridges (85.7%); (3) nests of poorly cohesive melanocytes (82.1%); (4) overlap features with Clark nevi (75.0%); and (5) overlap features with superficial congenital nevi (50.0%). Pagetoid spread (14.3%), asymmetry (23.2%), and poor lateral demarcation (16.1%) were less common. These 56 lesions predominated in the first 2 decades of life and were not observed after age 35 years. Limitations: Lack of long-term clinical follow-up of patients is a limitation; however, no recurrences or malignancies from these patients’ scalps were submitted in the time period ( $ 3 years) since the initial biopsies. Conclusion: A special site scalp nevus is recognizable amongst scalp melanocytic nevi, and this lesion is more common in younger patients. Familiarization of its features should assist in the diagnosis and management of scalp melanocytic lesions. ( J Am Acad Dermatol 2013;68:466-72.) Key words: children; histology; melanoma; nevus; scalp; special site.
elanocytic nevi in certain anatomic locations may exhibit distinctive histologic features, some of which are concerning because they can simulate features of melanoma. Such lesions have been termed ‘‘nevi of special sites,’’ ‘‘nevi with site-related atypia,’’ or ‘‘specific-site nevi.’’1,2 The importance of identifying these lesions lies in their benign biologic behavior despite worrisome histologic attributes. Anatomic locations reported as special sites include the genitalia,3-6 breast,7 ear,8,9 flexural regions,5 acral locations,10
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and conjunctiva.11 It has been proposed that nevi from the scalp share histologic attributes with other special-site nevi.12,13 We characterized a series of consecutive scalp nevi submitted to our laboratory in the attempt to better illustrate and define their distinctive histologic features. Special-site features in scalp nevi have been posited to present more commonly in certain age groups, particularly adolescents and young adults.12,13 Therefore, we also attempted to correlate patient age
From the Medical University of South Carolina, Charleston,a and Dermpath Diagnostics, Maize Center for Dermatopathology, Mount Pleasant.b Funding sources: None. Conflicts of interest: None declared. Previously presented in poster format entitled ‘‘Histologic Features of Scalp Melanocytic Nevi’’ at the 70th Annual Meeting of the American Academy of Dermatology, in San Diego, CA, March 16-20, 2012.
Reprint requests: Kristopher R. Fisher, MD, 930 Madison Avenue, Suite 890, Memphis, TN 38103. E-mail: fisher_kristopher@ yahoo.com. Published online December 26, 2012. 0190-9622/$36.00 Ó 2012 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2012.10.046
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with the histologic patterns observed in these lesions.
defined as loosely aggregated collections of melanocytes, similar to the previously described ‘‘nested and dyshesive’’ pattern in other special-site nevi.3,5 Nests were considered large if their size approxiMETHODS mated or exceeded the volume of 2 rete ridges. In all, 365 total melanocytic nevi of the scalp were Superficial congenital pattern was defined as an studied from 322 patients over a consecutive period angiocentric and adnexocentric distribution of melof 18 months from July 2007 through January 2009. anocytes with splaying foAges of patients ranged from cally between collagen 2 to 81 years, with a mean CAPSULE SUMMARY bundles in the upper half of age of 33.7 years. Age ranges the reticular dermis.14 were divided by decade to The scalp may represent a special site, Because many lesions exfacilitate study of lesions in where histologic features of nevi overlap hibited at least 1 feature chardifferent age groups. No sigwith melanoma despite their benign acteristic of Clark nevus, we nificant gender differences nature. classified each nevus as: (1) were present in any age We studied 365 consecutive scalp nevi predominantly special-site group from 0 to 79 years and identified 56 lesions that showed nevus; (2) predominantly (only 1 lesion was present predominant features of special-site nevi. Clark nevus; or (3) other in the $ 80-year age group). These lesions were more common in the common nevus. Lesions We excluded common and first 2 decades of life and were not were classified as predomicellular blue nevi, combined observed after age 35 years. nantly special-site nevi if nevi, deep penetrating nevi, they exhibited mostly feaand Spitz nevi. Lesions were Familiarization with these scalp nevi will tures commonly ascribed to excluded from the study if avoid overaggressive management of nevi on special sites: nests they contained features conthese lesions, particularly in young positioned along the sides cerning for evolution to melchildren. and between rete ridges, anoma in situ. In addition, pagetoid scatter, asymmetry, because our goal was to obpoor circumscription, and large junctional nests with serve and describe the features of a stereotypical poor cellular cohesion. Lesions were classified as special-site scalp nevus, we also excluded indeterpredominantly Clark nevi if they shared more feaminate lesions or Clark nevi with unusual features. tures of that nevus. Clark nevus was defined as a Nevi were assessed for the following features: (1) junctional or compound melanocytic nevus mostly symmetry; (2) lateral demarcation/circumscription; confined to the papillary dermis with nests often (3) growth patternepredominantly nested or prespaced unevenly along the dermoepidermal junction dominantly lentiginous; (4) superficial congenital and extending laterally at least 3 rete past the dermal pattern; (5) presence of inflammation; (6) papillary component; nests often oriented parallel to the skin dermal fibroplasia; (7) bridging of nests between rete surface and bridging rete; and with scattered cytoridges; (8) random large melanocyte nuclei; (9) logically atypical melanocytes, papillary dermal firandom melanocyte nuclear hyperchromasia; (10) brosis, and a patchy lymphomononuclear cell melanocytes containing pale cytoplasm with fine infiltrate in the papillary dermis.15,16 Nevi were dusty melanin granules; (11) nests positioned along classified as other common nevi if they exhibited the sides and between rete ridges; (12) pagetoid mostly features of common acquired compound or scatter; (13) poor melanocytic cellular cohesion; and intradermal nevi, often of Unna or Miescher (14) large nests. Rather than evaluating melanocyte type.17,18 Special-site nevi and Clark nevi were comatypia unqualified, we focused specifically on the 2 pared, and Fisher exact test was used to determine most prominent aspects of melanocyte atypia in statistically significant differences. Finally, lesion these lesions, studying each component separately: type was compared across age groups to analyze nucleomegaly and nuclear hyperchromasia. any trends in lesion presentation with patient age. Melanocyte nuclei were considered large if their size was greater than adjacent keratinocyte nuclei. RESULTS Melanocyte nuclei were considered hyperchromatic Of 365 melanocytic nevi, 56 were identified that if their chromatin stained more darkly with hemashared most histologic characteristics described in toxylin than adjacent keratinocyte nuclei. Pagetoid other special-site nevi. These lesions contained scatter was deemed present if intraepidermal melamelanocytes arranged in a nested, rather than nocytes were located above the basal layer over an lentiginous growth pattern (98.2%). These nests expanse of 3 rete ridges.9 Poor cellular cohesion was d
d
d
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Table I. Histologic features of scalp nevi Special-site nevi (n = 56)
Predominantly nested growth pattern Pale cytoplasm with dusty melanin Random melanocyte nucleomegaly Lateral extension of junctional component Nests positioned at sides and between rete Poor cellular cohesion Large nests Fibroplasia Bridging between rete Presence of inflammation Superficial congenital pattern Random melanocyte nuclear hyperchromasia Asymmetry Poor lateral demarcation Pagetoid migration
98.2% 96.4% 92.9% 87.5% 85.7% 82.1% 76.8% 75.0% 75.0% 62.5% 50.0% 44.6% 23.2% 16.1% 14.3%
(55/56) (54/56) (52/56) (49/56) (48/56) (46/56) (43/56) (42/56) (42/56) (35/56) (28/56) (25/56) (13/56) (9/56) (8/56)
Clark nevi (n = 61)
67.2% 73.8% 82.0% 70.5% 14.8% 41.0% 16.4% 95.1% 93.4% 88.5% 16.4% 23.0% 16.4% 32.8% 11.5%
(41/61)* (45/61)* (50/61) (43/61)* (9/61)* (25/61)* (10/61)* (58/61)* (57/61)* (54/61)* (10/61)* (14/61)* (10/61) (20/61) (7/61)
Other common nevi (n = 248)
97.6% 6.5% 4.0% 3.2% 2.0% 3.6% 9.3% 5.6% 4.8% 6.9% 41.9% 1.2% 7.7% 2.8% 1.2%
(242/248) (16/248)* (10/248)* (8/248)* (5/248)* (9/248)* (23/248)* (14/248)* (12/248)* (17/248)* (104/248) (3/248)* (19/248)* (7/248)* (3/248)*
*Statistical significant difference (P \ .05) when comparing value with special-site nevus value.
were often large (76.8%) and situated not only at rete tips, but also along their sides and between rete ridges (85.7%). Frequently, these nests were composed of loosely adherent melanocytes, similar to the previously described ‘‘nested and dyshesive’’ pattern (82.1%).3,5 Individual melanocytes commonly contained large nuclei (92.9%) and abundant pale cytoplasm with dusty melanin granules (96.4%). Overlap with stereotypical features of Clark nevus were frequent, including papillary dermal fibroplasia (75.0%), nests that bridged adjacent rete (75.0%), and lateral extension of the epidermal component past the dermal component (87.5%). Fifty percent of lesions also contained features of superficial congenital nevi, such as adnexocentricity and splaying of melanocytes between collagen fibers of the reticular dermis. This number could likely have been greater if not for frequent superficial sampling, not allowing for inspection of adnexal structures or the reticular dermis. Pagetoid spread (14.3%), asymmetry (23.2%), and poor lateral demarcation (16.1%) were less common. Although we were unable to obtain long-term clinical follow-up for the majority of these lesions, we served as the exclusive dermatopathology providers to the submitting dermatologists during the 3 to 4 years since their initial biopsies, and no recurrences or melanomas from these patients’ scalps were submitted. We also identified nevi that contained some special-site attributes, but for which features were otherwise predominantly those of Clark nevi. A total of 61 such lesions were identified. As opposed to special-site nevi, these lesions were more likely to contain a prominent lentiginous growth pattern of
Fig 1. Special-site/other common nevi versus age.
melanocytes (32.8% vs 1.8%, P\.05) and less likely to contain large nests (16.4% vs 76.8%, P \ .05). Nests were more frequently restricted to rete tips, rather than located between and at the sides of rete ridges (85.2% vs 14.3%, P \ .05). Also, the predominantly Clark nevi were less likely to contain features of superficial congenital nevus (16.4% vs 50.0%, P\.05), less likely to exhibit poor melanocyte cohesion (41.0% vs 82.1%, P \.05), and more likely to display a patchy lymphocytic infiltrate in the superficial dermis (88.5% vs 62.5%, P \ .05). The complete histologic findings of all nevi are available in Table I. We compared the ages of patients who presented with various nevi types (Figs 1 and 2). More specialsite nevi than Clark nevi presented in prepubescent children. As opposed to the histologic features common in Clark nevi, features of special-site nevi were not common after age 30 years, and were not observed at all after age 35 years.
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Fig 2. Special-site/Clark nevi versus age.
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Fig 4. Predominantly nested pattern, with nests of various size and shape within epidermis and superficial congenital features within dermis. (Hematoxylin-eosin stain; original magnification: 3100.)
Fig 3. Well-circumscribed proliferation of large nests positioned along sides and between rete ridges, with prominent adnexal involvement. (Hematoxylin-eosin stain; original magnification: 340.)
DISCUSSION Our study has identified a subset of scalp melanocytic nevi that contain particular features common to other special-site nevi. The prototypical specialsite scalp nevus is one that contains poorly cohesive melanocytes arranged in large nests positioned both along the sides of rete and between rete ridges, housing random melanocytes with large nuclei and abundant pale cytoplasm, and exhibiting adnexocentricity and splaying of melanocytes through the reticular dermis (Figs 3 to 8). Overlap features with Clark nevienests that bridge rete, lateral extension past the dermal component, and papillary dermal fibroplasiaewere also common to these lesions (Figs 9 and 10). We did not, however, classify all Clark nevi on the scalp as special-site nevi. In our analysis, we reserved the diagnosis of Clark nevus to those lesions that displayed predominant features of that nevus. Fabrizi et al12 previously identified 4 cases, all on the scalp of teenagers, called ‘‘atypical nevi of the scalp’’ by the authors. The most striking features in those lesions were large bizarrely shaped nests scattered along the junction with follicular involvement. Our study supports those findings. However, unlike that previous work, the majority of lesions in our study were symmetric, well-circumscribed, and
Fig 5. Large nests at various positions along rete ridges. Note mild clefting around nests, focal bridging between rete tips, and mild papillary dermal fibroplasia. (Hematoxylin-eosin stain; original magnification: 3100.)
Fig 6. Nests with prominent clefting and poor cellular cohesion. Random individual melanocytes contain large nuclei, and many contain abundant pale cytoplasm. (Hematoxylin-eosin stain; original magnification: 3200.)
without significant pagetoid scatter of melanocytes. Fabrizi et al12 emphasized that atypical nevi on the scalp were observed in adolescents, but not adults or younger children. In this regard, our findings also differ. We agree that these features are not commonly
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Fig 7. Individual melanocytes contain large nuclei with abundant pale cytoplasm with dusty melanin granules. (Hematoxylin-eosin stain; original magnification: 3200.)
Fig 8. Poor cellular cohesion with hyperchromatic nuclei. (Hematoxylin-eosin stain; original magnification: 3200.)
Fig 9. Predominantly nested neoplasm with large expansive nests within epidermis and melanocytes arranged around adnexal structures with splaying into reticular dermis. Overlap features of Clark nevus include bridging between rete and papillary dermal fibroplasia. (Hematoxylin-eosin stain; original magnification: 3100.)
recognized after the age of 30 years, but we did identify 9 of 56 lesions in the 20- to 30-year-old age group. In addition, lesions with special-site features were commonly detected in prepubescent children. As seen in Fig 2, special-site nevi on the scalp typically appeared at an earlier age than Clark nevi and other common nevi.
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Fig 10. Clarkoid edge with lateral extension past dermal component, papillary dermal fibroplasia and focal bridging. Prominent adnexal involvement. Center portion of this lesion is pictured in Fig 5. (Hematoxylin-eosin stain; original magnification: 3100.)
The age distribution of special-site features has particular relevance to the management of scalp nevi in children. Although most Clark dysplastic nevi arise in adolescence and around the time of puberty,19 Tucker et al20 suggested that one of the first locations of Clark dysplastic nevi (in patients with true familial mole melanoma syndrome) may be the scalp, presenting as early as age 5 to 9 years. In addition, Fernandez et al21 determined that a higher percentage of nevi located on the scalp of children (age \12 years) were dysplastic, compared with those located on the trunk and extremities. This makes the discrimination of Clark dysplastic nevi from special-site nevi relevant. Management of Clark dysplastic nevi in children, particularly on the scalp, has been the focus of debate, with various degrees of importance ascribed to dysplastic features in childhood nevi.19 For example, some experts advocate excision of scalp nevi in patients who present with dysplastic features, as these lesions cannot be easily followed because of hair coverage.19 Although we view a solitary Clark nevus as simply another type of common acquired nevus, we recognize that opinions differ on the biologic significance of dysplasia within a single lesion. However, as opposed to Clark dysplastic nevi, there is no evidence to date to warrant malignant connotations whatsoever to special-site nevi. These lesions, as described on the genitalia, ear, breast, and acral and flexural areas3-10 are of interest because of their overlap features with melanoma, but are otherwise histologic curiosities, imparting no different biologic significance than other common nevi. Therefore, distinction from both melanoma and Clark dysplastic nevi makes it clear to clinicians (who may have various views on the biologic importance of dysplasia) that the special-site scalp nevus probably shares the biologic behavior of other special-site nevi.
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Evaluation of scalp nevi constitutes a significant subset of referrals to pediatric dermatologists.22 Presumably, recommendations by dermatopathologists for re-excision of these lesions, or even misdiagnosis as melanoma, could contribute to further scalp surgery, leading to unsightly scars and permanent alopecia. Scalp nevi in children usually evolve in a benign fashion not supportive of excisional biopsies.23 A subset of patterned nevieeclipse and cockade nevi24,25erepresent around one fourth of childhood scalp nevi26 and also do not warrant excision.22 These findings, along with our current study, should help dermatologists and dermatopathologists identify morphologic features of scalp nevi in children. Despite the evidence above, we do not underestimate the seriousness of scalp melanocytic lesions. The presence of scalp nevi in children may be a harbinger of an above-average total number of nevi on the entire body,27 which in turn places one at higher risk for melanoma based on melanocyte burden.28-31 Similarly, some epidemiologic studies have correlated the presence of scalp nevi to higher risk of melanoma (at other sites) overall.30,31 Childhood melanomas on the head/neck have been associated with a lower survival than melanomas on other anatomic sites32,33; one European study linked lower survival specifically to the scalp.34 Not all studies in children have shown similar results.35 Although the relationship between anatomic site and prognosis of melanoma has been debated for years, epidemiologic evidence is mounting to suggest worse survival of scalp/neck melanoma versus other anatomic sites after controlling for age, Breslow thickness, gender, and ulceration.36 Therefore, we believe that better characterization of scalp nevi is important to prevent both underdiagnosis and overdiagnosis of melanoma. We did not recognize special-site features in any lesion after the age of 35 years. The influence of trauma, hormones, and regional anatomy have all been proposed as contributing factors to unusual features in nevi.1 In our study, age clearly influenced the histologic features of scalp nevi. To this end, scalp lesions exhibiting expansive nests of poorly cohesive melanocytes containing large hyperchromatic nuclei should probably trigger more concern when detected after age 30 years.
CONCLUSION We herein describe a subset of scalp melanocytic nevi with histologic features that are particular to that site, similar to other special-site nevi. These particular histologic features are more prominent in patients of younger ages, similar to results of previous studies.12,13 We propose that these nevi share histologic features with both superficial congenital and
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Clark nevi, but are not equivalent to Clark nevi, and commonly present in prepubescent children and adolescents. Because of the overlap features with superficial congenital nevi, we cannot exclude the possibility that these lesions represent a type of small congenital nevus. Familiarization of these lesions by dermatopathologists and dermatologists should aid in the management of melanocytic lesions on the scalp. REFERENCES 1. Hosler GA, Moresi JM, Barrett TL. Nevi with site-related atypia: a review of melanocytic nevi with atypical histologic features based on anatomic site. J Cutan Pathol 2008;35:889-98. 2. Elder DE. Precursors to melanoma and their mimics: nevi of special sites. Mod Pathol 2006;19:S4-20. 3. Clark WH Jr, Hood AF, Tucker MA, Jampel RM. Atypical melanocytic nevi of the genital type with a discussion of reciprocal parenchymal-stromal interactions in the biology of neoplasia. Hum Pathol 1998;29:S1-24. 4. Gleason BC, Hirsch MS, Nucci MR, Schmidt BA, Zembowicz A, Mihm MC Jr, et al. Atypical genital nevi: a clinicopathologic analysis of 56 cases. Am J Surg Pathol 2008;32:51-7. 5. Rongioletti F, Ball RA, Marcus R, Barnhill RL. Histopathologic features of flexural melanocytic nevi: a study of 40 cases. J Cutan Pathol 2000;27:215-7. 6. Christensen WN, Friedman KJ, Woodruff JD, Hood AF. Histologic characteristics of vulvar nevocellular nevi. J Cutan Pathol 1987;14:87-91. 7. Rongioletti F, Urso C, Batolo D, Chimenti S, Fanti PA, Filotico R, et al. Melanocytic nevi of the breast: a histologic case-control study. J Cutan Pathol 2004;31:137-40. 8. Lazova R, Lester B, Glusac EJ, Handerson T, McNiff J. The characteristic histopathologic features of nevi on and around the ear. J Cutan Pathol 2005;32:40-4. 9. Saad AG, Patel S, Mutasim DF. Melanocytic nevi of the auricular region: histologic characteristics and diagnostic difficulties. Am J Dermatopathol 2005;27:111-5. 10. Boyd AS, Rapini RP. Acral melanocytic neoplasms: a histologic analysis of 158 lesions. J Am Acad Dermatol 1994;31:740-5. 11. Massi G, LeBoit PE. Histological diagnosis of nevi and melanoma. Germany: Springer/Steinkopff Verlag Darmstadt; 2004. pp. 337-46. 12. Fabrizi G, Pagliarello C, Parente P, Massi G. Atypical nevi of the scalp in adolescents. J Cutan Pathol 2007;34:365-9. 13. Perry B, Ruben B. Nevi on the scalp: ‘‘special’’ not only in children but in young adults as well. Abstract presented at: 45th American Society of Dermatopathology Annual Meeting; October 16-19, 2008; San Francisco, CA. 14. Maize JC, Ackerman AB. Pigmented lesions of the skin. Philadelphia: Lea and Febiger; 1987. pp. 114-23. 15. Clark WH Jr, Reimer RR, Greene MH, Ainsworth AM, Mastrangelo MJ. Origin of familial melanomas from heritable melanocytic lesions: ‘‘the B-K mole syndrome.’’ Arch Dermatol 1978; 114:732-8. 16. Metcalf JS, Maize JC. Clark’s nevus. Semin Cutan Med Surg 1999;18:43-6. 17. Yus ES, del Cerro M, Simon RS, Herrera M, Rueda M. Unna’s and Miescher’s nevi: two different types of intradermal nevus; hypothesis concerning their histogenesis. Am J Dermatopathol 2007;29:141-51. 18. Ackerman AB, Magana-Garcia M. Naming acquired melanocytic nevi: Unna’s, Miescher’s, Spitz’s, Clark’s. Am J Dermatopathol 1990;12:193-209.
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19. Rothman KF, Esterly NB. Dysplastic nevi in children: special symposium. Pediatr Dermatol 1990;7:218-34. 20. Tucker MA, Greene MH, Clark WH Jr, Kraemer KH, Fraser MC, Elder DE. Dysplastic nevi on the scalp of prepubertal children from melanoma-prone families. J Pediatr 1983;103:65-9. 21. Fernandez M, Raimer SS, Sanchez RL. Dysplastic nevi of the scalp and forehead in children. Pediatr Dermatol 2001;18:5-8. 22. Kessides MC, Puttgen KB, Cohen BA. No biopsy needed for eclipse and cockade nevi found on the scalps of children. Arch Dermatol 2009;145:1334-6. 23. Gupta M, Berk DR, Gray C, Cornelius LA, Bayliss SJ. Morphologic features and natural history of scalp nevi in children. Arch Dermatol 2010;146:506-11. 24. Schaffer JV, Glusac E, Bolognia JL. Eclipse nevusetan center with stellate brown rim. Br J Dermatol 2001;145:1023-6. 25. Happle R. Cockade nevus: unusual variation of nevus cell nevus [in German]. Hautarzt 1974;25:594-6. 26. Tcheung WJ, Bellet JS, Prose NS, Cyr DD, Nelson KC. Clinical and dermoscopic features of 88 scalp nevi in 39 children. Br J Dermatol 2011;165:137-43. 27. Aguilera P, Puig S, Guilabert A, Julia M, Romero D, Vicente A, et al. Prevalence study of nevi in children from Barcelona: dermoscopy, constitutional and environmental factors. Dermatology 2009;218:203-14. 28. Holly EA, Kelly JW, Shpall SN, Chiu S-H. Number of melanocytic nevi as a major risk factor for malignant melanoma. J Am Acad Dermatol 1987;17:459-68.
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29. Bauer J, Garbe C. Acquired melanocytic nevi as risk factor for melanoma development: a comprehensive review of epidemiological data. Pigment Cell Res 2003;16:297-306. 30. Swerdlow AJ, English J, MacKie RM, O’Doherty CJ, Hunter JA, Clark J, et al. Benign melanocytic nevi as a risk factor for malignant melanoma. Br Med J (Clin Res Ed) 1986;292:1555-9. 31. Bataille V, Newton Bishop JA, Sasieni P, Swerdlow AJ, Pinney E, Griffiths K, et al. Risk of cutaneous melanoma in relation to the numbers, types and sites of nevi: a case-control study. Br J Cancer 1996;73:1605-11. 32. Barnhill RL, Flotte TJ, Fleischli M, Perez-Atayde A. Cutaneous melanoma and atypical Spitz tumors in childhood. Cancer 1995;76:1833-45. 33. Strouse JJ, Fears TR, Tucker MA, Wayne AS. Pediatric melanoma: risk factor and survival analysis of the Surveillance, Epidemiology and End Results database. J Clin Oncol 2005;23: 4735-41. 34. Conti EMS, Cercato MC, Gatta G, Ramazzotti V, Roscioni S. Childhood melanoma in Europe since 1978: a population-based survival study. Eur J Cancer 2001;37:780-4. 35. Paradela S, Fonseca E, Prieto VG. Melanoma in children. Arch Pathol Lab Med 2011;135:307-16. 36. Lachiewicz AM, Berwick M, Wiggins CL, Thomas NE. Survival differences between patients with scalp or neck melanoma and those with melanoma of other sites in the Surveillance, Epidemiology, and End Results (SEER) program. Arch Dermatol 2008;144:515-21.