ORIGINAL STUDY
Congenital Melanocytic Nevus: Two Clinicopathological Forms Mario Magaña, MD,*†‡ Elizabeth Sánchez-Romero, MD,* Pablo Magaña, MD,†‡ Andrés Beck-Magaña, MD,†‡ and Mario Magaña-Lozano, MD‡
Abstract: Congenital melanocytic nevus (CMN) is a hamartomatous disease for which many attempts at classification have been proposed. This disease is relevant not only because of its functional and esthetic implications but also because it is a well-documented precursor to malignant melanoma. We performed a clinical and pathological prospective study of 200 cases of CMN and were able to identify 2 different forms of CMN, each one with biological, clinical, and histopathological features and criteria that are consistent and repeatable. We propose to name them types I and II. Type I CMN is the most common, usually, if not always, a single lesion, it consists of a plaque that involves only 1 anatomic region and does not go beyond it; type I CNM grows in proportion to the growth of the child, melanoma rarely develops from it, and when it does it usually arises at the dermoepidermal junction. Its histopathology shows cords, strands, nests, and single units of melanocytes spreading between collagen bundles only in the dermis and frequently the epidermis too, but without trespassing to the hypodermis, that is, it is superficial. Type II CMN is always made up of many lesions, one of them being very large and surrounded by many lesions; histopathologically, it involves not only the skin but also deeper structures, sometimes bone and central nervous system; therefore, it is deep; when melanoma develops, it does in the dermal component and usually from the largest plaque. This type of CMN is the one that develops neurocutaneous melanocytosis. This system is not only easy and logical but it also has biologic advantages and the clinical–pathological correlation and criteria are repeatable by clinicians and pathologists. Key Words: nevus, congenital nevus, melanocytic nevus, pigmented lesions, melanoma precursors (Am J Dermatopathol 2015;37:31–37)
INTRODUCTION Congenital melanocytic nevi (CMN) are simply melanocytic nevi that are present at birth (or appear shortly after birth).1 CMN is a hamartoma consisting mainly of From the *Hospital General de México “Eduardo Liceaga,” S.S, Mexico City, Mexico; †School of Medicine, Universidad Nacional Autónoma de México, Mexico City, Mexico; and ‡Centre for Dermatology & Dermatopathology, Mexico City, Mexico. The authors declare no conflicts of interest. Reprints: Mario Magaña, MD, Universidad Nacional Autónoma de México/ Hospital General de México “Eduardo Liceaga” S.S., Centre for Dermatology & Dermatopathology, Mexico City, Mexico (e-mail: mariomg@ dermaypatologia.com). © 2014 Lippincott Williams & Wilkins
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melanocytes in association with other normal skin elements. It is present from birth in the form of single or multiple papules, nodules, or plaques. It represents a significant and challenging problem, not only for the dermatologist but also for the pediatrician, the pathologist, and the surgeon because of its esthetic and functional implications.2–6 It is a precursor7 and occasionally also a simulator8 of malignant melanoma. The first reference for this disorder probably comes from Bateman, who in 1817 published the first atlas of dermatology entitled “Delineations of Cutaneous Diseases,” which features an impressive illustration of an infant with skin lesions highly suggestive of this disease present from birth.9 However, the first well-documented description belongs to Alibert who in his 1835 published the book “Monographie des Desmatoses” dedicated a chapter to nevi (Naeve-Naevus) and describes the case of a young woman “whose skin on the trunk was like that of a wolf.”10 It has been estimated that CMN occurs in 1 of 100 newborns according to a large multicentric series carried out in various hospitals in Latin America, a figure that coincides with that found in other countries of Europe and North America.11,12 The study of Castilla et al11 is widely accepted and consistent with congenital disorders in general. However, giant CMN is much less common with an estimated incidence of 1 in 20,000–500,000 live births.13 There is likely a genetic component in the development of the CMN, but the information so far is inconsistent. For example, in many CMN, mutations in the N-Ras gene have been shown,14 but not in the B-RAF gene, as characteristically occur in melanoma that intermittently appears on sun-exposed skin or in some acquired nevi. Some authors suggest a genotype–phenotype correlation between the size of the CMN and type of mutation.15 These mutations presumably lead to an excessive number of mutant daughter cells that migrate to the subcutaneous adipose tissue, the dermis and the epidermis, to be populated in an excessive manner, that is, the CMN substrate. Likewise, CMN has been documented in a discordant manner in identical twins.16 The familial presentation of 2 cases of giant or type II CMN has been observed.17 Therefore, a predominant polygenic inheritance pattern is proposed. What is broadly accepted in its pathogenesis is that it consists of a massive nonvascular migration of melanocytes from the neural crest along its course to the skin and intermediate tissues.18 www.amjdermatopathology.com |
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Biologically, CMN has a greater relevance because it is a precursor to melanoma, although there is a large bias in the literature with estimates of ,1% for small and medium CMN19 and from 1.25% to 5.1%20,21 for large CMN, which may not be very high but of course is higher than in the open population. A study according to lustrums demonstrates that the appearance of melanoma in CMN could occur at any time.20
Presentation of the Problem There have been many attempts at a proposed classification with the goal of understanding CMN and offering treatment for this group of patients. The attempt by Kopf et al,2 which classifies CMN as small (,1.5 cm), medium (1.6–19.9 cm), and large (20 cm or more), is one such classification. Freinkel et al4 point out that those of 120 cm2 or larger are called giant nevi and those ,11 cm2 are classified as small nevi. Illig et al5 classified them as small (up to 1.9 cm), large (2–19.9 cm), and giant (.20 cm). According to Lorentzen,22 giant nevi are considered when the lesion is greater than the patient’s palm (in the case of the face or the neck) and twice that measurement for any other anatomic region (Table 1). These and others proposals, traditional or innovative try to better understand our knowledge of CMN; however, they are based only on the clinical features and not in correlation with the histopathological structure, which is basic for the best interpretation, not only morphological but also
TABLE 1. CMN: Overview on Classification Systems Author 23
Lanier
Lorentzen22
Kopf et al2
Freinkel et al4
Illig et al5
Ruiz-Maldonado24
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Terminology Small CMN is the one that can be excised without slaps or grafts; large CMN is the one that do not fulfill the definition for small; giant is that one which involves a significant proportion of an anatomic area Giant is when the lesions are bigger than the patient’s palm for the face or the neck; and twice that measure for any other anatomic region CMN is small when it is less than 1.5 cm, medium 1.5–19.9 cm, and large 20 cm or more CMN are classified as small until 1.9 cm, large 2–19.9 cm, and giant more than 20 cm The differentiation between CMN large and small was performed because of surgical reasons, without taking in account the surface or the histologic structure and the point of division was 10 cm A CMN is small when is ,1.5 cm; medium when is 1.5–10 cm; large when is 11–20 cm, and giant when 21–30 cm G1, when 31–40 G2, and .40 cm G3
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biological, in terms of the development of melanoma in them and also as a more rationale basis for the treatment.23–26 According to our perspective, the different expressions of CMN may be reasonably grouped according to 2 types, each with its own clinical, histopathological, and prognostic characteristics with regard to the risk of developing melanoma and the susceptibility for surgical treatment.27,28 Such perspective represents the hypothesis of this work. With this hypothesis, CMN presents itself according to 2 clinical forms: type I—those lesions that usually are unique and do not overrun the anatomic segment they occupy, and type II—CMN characterized by multiple lesions, one very large lesion and others that are multiple or unable to be counted and overrun any anatomic segment.
MATERIALS AND METHODS We carried out an observational, cross-sectional, prospective clinical, and histopathological study at the Dermatology Consultation of the General Hospital of Mexico “Dr. Eduardo Liceaga” (HGMEL) and the Centre for Dermatology and Dermatopathology (CD&DP) of Mexico City. We included all patients (children or adults) who consulted for this or other reasons but who had a CMN clinically diagnosed according to the specified criteria (vide infra). Included subjects allowed and requested (with written consent) histopathological study and study of tissue samples submitted from others to our Laboratory of Dermatopathology at the CD&DP, with the clinical diagnosis of CMN and whose diagnosis was confirmed in accordance with the previously accepted criteria.1,8,25 The study period was from 2000 to 2013. Exclusion criteria included the following: nonmelanocytic nevi, acquired melanocytic nevi, and blue melanocytic nevi. Also excluded were those cases in which there was insufficient material or information to establish an adequate clinical–pathological correlation and those cases with poorly processed material of patients that refused to be included. Cases in which there was insufficient tissue for microscopic study were eliminated. For purposes of this study and according to its frequency in the population, a total of 200 cases collected during a 13-year period were considered to be a representative sample, because CMN is not an every day problem on one hand: its incidence is of 1% in new born11,12 and the estimated prevalence of “large” CMN is from 1:20,000 to 1:500,000,25 and on the other hand it is feasible to express the results in percentages. In a form especially designed for this project, registration and study period were initiated in January of 2000 for each patient with CMN who was seen at any of our Services. Special emphasis was placed on family history of CMN. Each lesion was measured, and biopsy was taken in accordance with the patient’s or parents’ request and accepted the procedure to clarify and classify the diagnosis. The study was closed on December 2013. Moreover, the same record was used for each patient with CMN who presented for consultation or until all CMN samples sent for study and diagnosis to the CD&DP Laboratory were collected. In these cases, the clinical information was obtained from histopathological study requests and, in most cases, there was communication Ó 2014 Lippincott Williams & Wilkins
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FIGURE 2. Type II CMN involving the head and anterior aspect of chest and left arm. Same patient as Figure 1.
history of the lesion having been present since birth. The topography of the lesions was documented in the following manner: head, neck, chest (anterior and posterior face), abdomen, back, upper extremity (arm, forearm, and hand), and lower extremity (thigh, leg, and foot). All biopsies obtained were studied with H&E stain under light microscopy.
RESULTS FIGURE 1. A, Type II CMN. Note a wide plaque involving the upper back, extending to the neck, head, and right extremity with many smaller plaques on the trunk. B, Type II CMN (same patient) involvement of the head and neck.
with the physician who sent the specimen. Diagnosis of CMN was established both clinically and histopathologically in accordance with the cited criteria1,8,25 and with the irrefutable Ó 2014 Lippincott Williams & Wilkins
There were 200 cases included: 68 patients were assisted clinically. We obtained skin biopsies for 40 of these patients. The mean age was 4.8 years, and there were 2 newborns of 20 and 27 days of age, and another boy of 5 months. Similarly, we gathered 132 specimens sent to our laboratory for histopathological diagnosis during the same time period. Ages ranged from 11 to 57 years with a mean age of 23 years. Overall, when combining both groups, mean age was 12 years; 44% were females and 56% were www.amjdermatopathology.com |
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FIGURE 4. Congenital type I melanocytic nevus on the forehead of a child. It is a single lesion that does not extend beyond this anatomic area. The presence of hairs is not a prognostic factor, but only designates the hamartomatous character of this nevus.
FIGURE 3. Type II CMN. A large plaque on the trunk and dozens of smaller plaques on the arm and forearm on an adult male.
characterized by a wide plaque and that surpassed more than one anatomic region. These CMN were in association with other multiple or countless smaller lesions and would be described as “a continent surrounded by islands.” The predominant topography in these cases, that is, the locations of these larger lesions, were the head (2 cases), chest–thigh– foot (1 case), lumbar (1 case), pelvis (bathing trunk area)
males. No one of these patients had a family history for CMN of any kind. Seven patients, all ,1 year of age (including the 2 newborns) had large, irregular, and asymmetric CMN
TABLE 2. Clinical and Histopathological Data of 200 Patients With CMN CMN Type II No. patients Age Family history of CMN Location
No. lesions Histopathology
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7 ,1 yr None
CMN Type I 193 11–57 yrs None
Head—2/7 Chest–thigh–foot—1/7
Head—19/55 Trunk or limbs—36/ 55 Lumbar—1/7 Trunk—15/55 Trunk-head-upper limbs—1/7 Upper limbs—11/55 Pelvis and lower limbs—2/7 Lower limbs—10/55 1 large/giant; dozens of smaller 1 per patient plaques or nodules Deep 7/7 Superficial 193/193
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FIGURE 5. Congenital type I nevus: asymmetrical single lesion that does not extend beyond the arm. Uniform color and precise boundaries with healthy skin are signs of a benign lesion. Ó 2014 Lippincott Williams & Wilkins
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FIGURE 6. CMN type I: Asymmetrical single lesion that does not extend beyond the hip region.
with lower extremities (2 cases), and trunk–neck–head– upper extremities (1 case). Multiple secondary lesions were present in diverse segments. We were able to count .300 lesions in 1 patient. In none of these 6 patients was there a family history of CMN (Figs. 1–3) (Table 2). In 193 patients, the lesions were single whose extension never extended past the anatomic region involved, that is, the cheek, the hand or forearm or thigh, etc. The topography in these patients was documented in 55 examples and predominated in the head (skull and face) with 19 cases (34.5%); the location of the rest of the cases was very diverse: trunk or limbs, but always involving only 1 anatomic segment (Figs. 4–7). The histopathology of the 7 cases in any area of the larger lesion that was biopsied showed the same changes: cords, strands, nests, sheets, and single units of melanocytes spreading between the collagen bundles not only in the dermis (also involving the adnexal structures) and epidermis but also in the fatty tissue of hypodermis, muscle, fascia, and deeper structures (Fig. 8).
FIGURE 8. Histopathology of type II CMN. Melanocytes in a wide mantle occupy the entire thickness of the skin and underlying structures: deep.
According to the 193 cases of nevi that clinically presented as sole lesions without extending beyond the anatomic zone they occupied (Figs. 4–7), histopathological findings were as follows: melanocytes in nests, rows, ropes, and mantles involving the skin from the dermal–epidermal junction to the lower portion of the reticular dermis. These were never situated deeply, and the adipose tissue and muscle were not found to be infiltrated (Fig. 9). In both types of CMN, melanocytes were able to be seen in isolated units disseminated among the collagen bundles, involving the eccrine and pilosebaceous adnexes, the hair erector muscle, and the vascular walls. The contrast between the CMN of the single lesion versus those made up by a wide lesion surrounded by countless papules, nodules, or smaller or secondary nevus plaques was highly noticeable.
DISCUSSION
We believe that the consistent finding of the CMN that clinically manifests as a single lesion (exceptionally there will
FIGURE 7. CMN type I: Asymmetrical single lesion that does not extend beyond the forehead. Ó 2014 Lippincott Williams & Wilkins
FIGURE 9. Histopathology of type I CMN showing the presence of melanocytes exclusively in the epidermis and dermis: superficial. www.amjdermatopathology.com |
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be persons who have more than one) will be defined or circumscribed to an anatomic region. CMN that extend beyond the anatomic region and are characterized by a larger lesion and multiple and numerous smaller, secondary, or “satellite” lesions have greater importance. Its definition is also histopathologically clear: in a single-lesion CMN, melanocytes do not extend beyond the dermis in its deep margins and only involve the dermis and epidermis without transcending to the hypodermis. However, in multiple-lesion CMN, the microscopic structure of massive infiltration is always constant, not only of the entire thickness of the skin (including the adipose tissue to the hypodermis) but also of the underlying structures. There are interesting aspects reported in the literature in relation to such microscopic characteristics in the CMN. In 1973, Mark et al30 observed differences between “small” and “large” CMN (in clothing). However, Ackerman et al29 in 1993 classified the histopathological characteristics of the CMN into superficial and deep. Pathologists have continued to identify superficial and deep CMNs for many years. Clinicians refer to these as “small, medium, large, and giant.” The point for discussion is how small is “small” and how large is “large,” or when giant is “giant.” In our view, it is not convenient to base this information on the metric system because a 10-mm nevus in a 3-kg newborn will measure larger when this child reaches 18 years of age and 80 kg of body weight. Naturally, the nevus will grow in proportion with the body growth. Also, it is very easy to dispel other arguments such as “the possibility of being easily resected” because it will depend on the anatomic site it occupies. It is not the same in the abdomen as in an eyelid or in the genitalia. Among other parameters, surgeon experience will also be important. The same can be said about the measurement according to the size of the patient’s hand because this does not tell us anything. Then, as the saying goes “size isn’t everything.” In view of the findings presented in this study, we believe that according to the clinical, biological, and histopathological bases, it is possible to state that there are 2 types of CMN, which we propose naming “type I” and “type II.” Type I is much more common; it is less impressive when seen and frequently the patient will say that “a certain relative has or had one” (totally subjective and uncertain assertion because melanocytic nevi are not inherited). Clinically, it manifests as a single lesion, usually 1 asymmetric plaque .6 mm in size and with limited dimensions because it does extend beyond the anatomic region it occupies. Biologically, melanoma develops much less frequently in single lesions (type I) than in giant ones (type II). Histopathologically, this nevus does not extend beyond the reticular dermis, which is consonant to the superficial denomination by Ackerman et al.29 There is a risk for developing melanoma, but we do not know the numbers because attempts at classification and numerical measurement have produced skewed statistical data; when melanoma develops in these superficial CMN it does in the dermoepidermal junction. Type II CMN is much less frequent than type I. Clinically, type II or its manifestations are dramatic and it is impossible for it to be unnoticed; it always exists as a wide plaque that extends beyond the anatomic region and is accompanied by many other smaller lesions. Histopathologically, the larger lesions are
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consonant with the denomination of deep CMN.29 Its potential for developing melanoma is undeniable. The figures in the literature are confusing, probably due to the reasons already mentioned when discussing type I CMN above, but the risk is certainly much greater for type I, and when melanoma develops it arises inside the dermis, in the mass of melanocytes. The study of CMN samples outside the clinical context led many authors to misinterpret as “small,” the secondary, or “satellite” nevi that in reality are part of the same disease, which is type II CMN. All of this caused great confusion in the literature. It has been necessary and productive to study this disorder. In conclusion, our hypothesis of CMN type I and type II will surely find a strong support on the near future development of a molecular genetics-based classification on clinical–pathological correlation. Finally, it is necessary to highlight that the CMN, as well as the Clark’s nevus, are the 2 benign melanocytic lesions accepted by a panel of experts from the US National Institutes of Health7 as melanoma precursors, and its characters continue to be a reason for study by different groups.17,18,23–35 Therefore, the therapeutic behavior of the CMN should no longer be “expectant management or observational” because it is not known at this time if the neoplastic clone will begin because there are reports that point out this time from infancy to the third age. Surgical treatment should be considered, mainly in type II CMN. However, without a doubt and unfortunately, there are patients whose treatment may be impossible; that is, when the form II of CMN arises on the head and/or neck, it may involve deeper structures, even the central nervous system, producing leptomeningeal melanocytosis (not only “melanosis”), which is the massive infiltration of melanocytes to the central nervous system. REFERENCES 1. Maize JC, Ackerman AB. Pigmented Lesions of the Skin. Philadelphia, PA: Lea & Febiger; 1987:114–130. 2. Kopf AW, Bart RS, Hennessey P. Congenital nevocytic nevi and malignant melanomas. J Am Acad Dermatol. 1979;1:123–130. 3. Rhodes AR, Melski JW. Small congenital nevocellular nevi and the risk of cutaneous melanoma. J Pediatr. 1982;100:219–224. 4. Freinkel RK, Cage GW, Caro WA, et al. Precursors to malignant melanoma. J Am Acad Dermatol. 1984;10:683–688. 5. Illig L, Weidner F, Hundeiker M, et al. Congenital nevi ,10 cm as precursors to melanoma. Arch Dermatol. 1985;121:1274–1281. 6. Alper JC. Congenital nevi. The controversy rages on. Arch Dermatol. 1985;121:734–735. 7. Precursors to malignant melanoma. National Institutes of Health Consensus Development Conference Statement, Oct. 24–26, 1983. J Am Acad Dermatol. 1984;10:683–688. 8. Ackerman AB, Cerroni L, Kerl H. Pitfalls in Histopathologic Diagnosis of Malignant Melanoma. Philadelphia, PA: Lea & Febiger; 1994:199. 9. Bateman T. Delineations of Cutaneous Diseases. London, United Kingdom: Paternoster-Row; 1817. 10. Alibert JLM. Monographie des Dermatoses. Paris, France: Germer Bailliere; 1835. 11. Castilla EE, Dutra MG, Orioli-Parreiras IM. Epidemiology of congenital pigmented nevi: I, incidence rates and relative frequencies. Br J Dermatol. 1981;104:307–315. 12. Castilla EE, Dutra MG, Orioli-Parreiras IM. Epidemiology of congenital pigmented nevi: II, risk factors. Br J Dermatol. 1981;104:421–427. 13. Warner PM, Yakuboff KP, Kagan RJ, et al. An 18-year experience in the management of congenital nevomelanocytic nevi. Ann Plast Surg. 2008; 60:283–287.
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14. Bauer J, Curtin JA, Pinkel D, et al. Congenital melanocytic nevi frequently harbor NRAS mutations but not BRAF mutations. J Invest Dermatol. 2007;127:179–182. 15. Ichii-Nakato N, Takata M, Takayanagi S, et al. High frequency of BRAFV600E mutation in acquired nevi and small congenital nevi, but low frequency of mutation in medium-sized congenital nevi. J Invest Dermatol. 2006;126:2111–2118. 16. Cantú J, Urrusti J, Hernandez RC, et al. Discordance for giant pigmented nevi in monozygotic twins. Ann Genet. l973;16:289–292. 17. De Wijn RS, ZAAl LH, Hennekam RC, et al. Familial clustering of giant congenial melanocytic nevi. J Plast Reconstr Aesthet Surg. 2010;63:906–913. 18. Alikhan A, Ibrahimi OA, Eisen DB. Congenital melanocytic nevi: where are we now? J Am Acad Dermatol. 2012;67:495–511. 19. Zaal LH, Mooi WJ, Klip H, et al. Risk of malignant transformation of congenital melanocytic nevi: a retrospective nationwide study from the Netherlands. Plast Reconstr Surg. 2005;116:1902–1909. 20. Kaplan EN. The risk of malignancy in large congenital nevi. Plast Reconstr Surg. 1974;53:421–428. 21. DeDavid M, Orlow SJ, Provost N. A study of large congenital melanocytic nevi and associated malignant melanomas: review of cases in the New York University Registry and in the world literature. J Am Acad Dermatol. 1997;36:409–416. 22. Lorentzen M. The incidence of malignant transformation in giant pigmented nevi. Scand J Plast Reconstr Surg. 1977;11:163. 23. Lanier V. Congenital nevi: clinical and pathological considers. Plast Reconsts Surg. 1976;58:48–56. 24. Ruiz-Maldonado R. Measuring congenital melanocytic nevi. Pediatr Dermatol. 2004;21:178–179.
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25. Vourc’h-Jourdain M, Martin L, Barbarot S. Large congenital melanocytic nevi: therapeutic management and melanoma risk. J Am Acad Dermatol. 2013;68:493–498. 26. Krengel S, Scope A, Dusza SW, et al. New recommendations for the categorization of cutaneous features of congenital melanocytic nevi. J Am Acad Dermatol. 2013;68:441–451. 27. Magaña GM. Nevo melanocítico congénito. Un enfoque clínico-patológico. Dermatol Rev Mex. 1991;35:292–300. 28. Magaña M, Magaña LM. Congenital melanocytic nevus is a disease with two clinicopathological forms of presentation. J Am Acad Dermatol. 2007;56:521–522. 29. Ackerman AB, Briggs P, Bravo F. Differential Diagnosis in Dermatopathology III. Philadelphia, PA: Lea & Febiger; 1993:184–187. 30. Mark GJ, Mihm MC, Liteplo MG, et al. Congenital melanocytic nevi of the small and garment type. Clinical, histological and ultrastructural studies. Hum Pathol. 1973;4:395–418. 31. Harley S, Walsh N. A new look at nevus-associated melanomas. Am J Dermatopathol. 1996;18:137–141. 32. Swerdlow AJ, English JSC, Qiao Z. The risk of melanoma in patients with congenital nevi: a cohort study. J Am Acad Dermatol. 1995;32:595–599. 33. Ibrahimi OA, Alikhan A, Eisen DB. Congenital melanocytic nevi: where are we now? J Am Acad Dermatol. 2012;67:515–527. 34. Tannous ZS, Mihm MC Jr, Sober AJ, et al. Congenital melanocytic nevi: clinical and histopathological features, risk of melanoma, and clinical management. J Am Acad Dermatol. 2005;52:197–203. 35. Bett BJ. Large or multiple cutaneous melanocytic nevi: occurrence of cutaneous melanoma in 1008 persons. J Am Acad Dermatol. 2005;52: 793–797.
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Congenital Melanocytic Nevus: Two Clinicopathological Forms Mario Magaña, MD,*†‡ Elizabeth Sánchez-Romero, MD,* Pablo Magaña, MD,†‡ Andrés Beck-Magaña, MD,†‡ and Mario Magaña-Lozano, MD‡
Abstract: Congenital melanocytic nevus (CMN) is a hamartomatous disease for which many attempts at classification have been proposed. This disease is relevant not only because of its functional and esthetic implications but also because it is a well-documented precursor to malignant melanoma. We performed a clinical and pathological prospective study of 200 cases of CMN and were able to identify 2 different forms of CMN, each one with biological, clinical, and histopathological features and criteria that are consistent and repeatable. We propose to name them types I and II. Type I CMN is the most common, usually, if not always, a single lesion, it consists of a plaque that involves only 1 anatomic region and does not go beyond it; type I CNM grows in proportion to the growth of the child, melanoma rarely develops from it, and when it does it usually arises at the dermoepidermal junction. Its histopathology shows cords, strands, nests, and single units of melanocytes spreading between collagen bundles only in the dermis and frequently the epidermis too, but without trespassing to the hypodermis, that is, it is superficial. Type II CMN is always made up of many lesions, one of them being very large and surrounded by many lesions; histopathologically, it involves not only the skin but also deeper structures, sometimes bone and central nervous system; therefore, it is deep; when melanoma develops, it does in the dermal component and usually from the largest plaque. This type of CMN is the one that develops neurocutaneous melanocytosis. This system is not only easy and logical but it also has biologic advantages and the clinical–pathological correlation and criteria are repeatable by clinicians and pathologists. Key Words: nevus, congenital nevus, melanocytic nevus, pigmented lesions, melanoma precursors (Am J Dermatopathol 2015;37:31–37)
INTRODUCTION Congenital melanocytic nevi (CMN) are simply melanocytic nevi that are present at birth (or appear shortly after birth).1 CMN is a hamartoma consisting mainly of From the *Hospital General de México “Eduardo Liceaga,” S.S, Mexico City, Mexico; †School of Medicine, Universidad Nacional Autónoma de México, Mexico City, Mexico; and ‡Centre for Dermatology & Dermatopathology, Mexico City, Mexico. The authors declare no conflicts of interest. Reprints: Mario Magaña, MD, Universidad Nacional Autónoma de México/ Hospital General de México “Eduardo Liceaga” S.S., Centre for Dermatology & Dermatopathology, Mexico City, Mexico (e-mail: mariomg@ dermaypatologia.com). © 2014 Lippincott Williams & Wilkins
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melanocytes in association with other normal skin elements. It is present from birth in the form of single or multiple papules, nodules, or plaques. It represents a significant and challenging problem, not only for the dermatologist but also for the pediatrician, the pathologist, and the surgeon because of its esthetic and functional implications.2–6 It is a precursor7 and occasionally also a simulator8 of malignant melanoma. The first reference for this disorder probably comes from Bateman, who in 1817 published the first atlas of dermatology entitled “Delineations of Cutaneous Diseases,” which features an impressive illustration of an infant with skin lesions highly suggestive of this disease present from birth.9 However, the first well-documented description belongs to Alibert who in his 1835 published the book “Monographie des Desmatoses” dedicated a chapter to nevi (Naeve-Naevus) and describes the case of a young woman “whose skin on the trunk was like that of a wolf.”10 It has been estimated that CMN occurs in 1 of 100 newborns according to a large multicentric series carried out in various hospitals in Latin America, a figure that coincides with that found in other countries of Europe and North America.11,12 The study of Castilla et al11 is widely accepted and consistent with congenital disorders in general. However, giant CMN is much less common with an estimated incidence of 1 in 20,000–500,000 live births.13 There is likely a genetic component in the development of the CMN, but the information so far is inconsistent. For example, in many CMN, mutations in the N-Ras gene have been shown,14 but not in the B-RAF gene, as characteristically occur in melanoma that intermittently appears on sun-exposed skin or in some acquired nevi. Some authors suggest a genotype–phenotype correlation between the size of the CMN and type of mutation.15 These mutations presumably lead to an excessive number of mutant daughter cells that migrate to the subcutaneous adipose tissue, the dermis and the epidermis, to be populated in an excessive manner, that is, the CMN substrate. Likewise, CMN has been documented in a discordant manner in identical twins.16 The familial presentation of 2 cases of giant or type II CMN has been observed.17 Therefore, a predominant polygenic inheritance pattern is proposed. What is broadly accepted in its pathogenesis is that it consists of a massive nonvascular migration of melanocytes from the neural crest along its course to the skin and intermediate tissues.18 www.amjdermatopathology.com |
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Biologically, CMN has a greater relevance because it is a precursor to melanoma, although there is a large bias in the literature with estimates of ,1% for small and medium CMN19 and from 1.25% to 5.1%20,21 for large CMN, which may not be very high but of course is higher than in the open population. A study according to lustrums demonstrates that the appearance of melanoma in CMN could occur at any time.20
Presentation of the Problem There have been many attempts at a proposed classification with the goal of understanding CMN and offering treatment for this group of patients. The attempt by Kopf et al,2 which classifies CMN as small (,1.5 cm), medium (1.6–19.9 cm), and large (20 cm or more), is one such classification. Freinkel et al4 point out that those of 120 cm2 or larger are called giant nevi and those ,11 cm2 are classified as small nevi. Illig et al5 classified them as small (up to 1.9 cm), large (2–19.9 cm), and giant (.20 cm). According to Lorentzen,22 giant nevi are considered when the lesion is greater than the patient’s palm (in the case of the face or the neck) and twice that measurement for any other anatomic region (Table 1). These and others proposals, traditional or innovative try to better understand our knowledge of CMN; however, they are based only on the clinical features and not in correlation with the histopathological structure, which is basic for the best interpretation, not only morphological but also
TABLE 1. CMN: Overview on Classification Systems Author 23
Lanier
Lorentzen22
Kopf et al2
Freinkel et al4
Illig et al5
Ruiz-Maldonado24
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Terminology Small CMN is the one that can be excised without slaps or grafts; large CMN is the one that do not fulfill the definition for small; giant is that one which involves a significant proportion of an anatomic area Giant is when the lesions are bigger than the patient’s palm for the face or the neck; and twice that measure for any other anatomic region CMN is small when it is less than 1.5 cm, medium 1.5–19.9 cm, and large 20 cm or more CMN are classified as small until 1.9 cm, large 2–19.9 cm, and giant more than 20 cm The differentiation between CMN large and small was performed because of surgical reasons, without taking in account the surface or the histologic structure and the point of division was 10 cm A CMN is small when is ,1.5 cm; medium when is 1.5–10 cm; large when is 11–20 cm, and giant when 21–30 cm G1, when 31–40 G2, and .40 cm G3
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biological, in terms of the development of melanoma in them and also as a more rationale basis for the treatment.23–26 According to our perspective, the different expressions of CMN may be reasonably grouped according to 2 types, each with its own clinical, histopathological, and prognostic characteristics with regard to the risk of developing melanoma and the susceptibility for surgical treatment.27,28 Such perspective represents the hypothesis of this work. With this hypothesis, CMN presents itself according to 2 clinical forms: type I—those lesions that usually are unique and do not overrun the anatomic segment they occupy, and type II—CMN characterized by multiple lesions, one very large lesion and others that are multiple or unable to be counted and overrun any anatomic segment.
MATERIALS AND METHODS We carried out an observational, cross-sectional, prospective clinical, and histopathological study at the Dermatology Consultation of the General Hospital of Mexico “Dr. Eduardo Liceaga” (HGMEL) and the Centre for Dermatology and Dermatopathology (CD&DP) of Mexico City. We included all patients (children or adults) who consulted for this or other reasons but who had a CMN clinically diagnosed according to the specified criteria (vide infra). Included subjects allowed and requested (with written consent) histopathological study and study of tissue samples submitted from others to our Laboratory of Dermatopathology at the CD&DP, with the clinical diagnosis of CMN and whose diagnosis was confirmed in accordance with the previously accepted criteria.1,8,25 The study period was from 2000 to 2013. Exclusion criteria included the following: nonmelanocytic nevi, acquired melanocytic nevi, and blue melanocytic nevi. Also excluded were those cases in which there was insufficient material or information to establish an adequate clinical–pathological correlation and those cases with poorly processed material of patients that refused to be included. Cases in which there was insufficient tissue for microscopic study were eliminated. For purposes of this study and according to its frequency in the population, a total of 200 cases collected during a 13-year period were considered to be a representative sample, because CMN is not an every day problem on one hand: its incidence is of 1% in new born11,12 and the estimated prevalence of “large” CMN is from 1:20,000 to 1:500,000,25 and on the other hand it is feasible to express the results in percentages. In a form especially designed for this project, registration and study period were initiated in January of 2000 for each patient with CMN who was seen at any of our Services. Special emphasis was placed on family history of CMN. Each lesion was measured, and biopsy was taken in accordance with the patient’s or parents’ request and accepted the procedure to clarify and classify the diagnosis. The study was closed on December 2013. Moreover, the same record was used for each patient with CMN who presented for consultation or until all CMN samples sent for study and diagnosis to the CD&DP Laboratory were collected. In these cases, the clinical information was obtained from histopathological study requests and, in most cases, there was communication Ó 2014 Lippincott Williams & Wilkins
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FIGURE 2. Type II CMN involving the head and anterior aspect of chest and left arm. Same patient as Figure 1.
history of the lesion having been present since birth. The topography of the lesions was documented in the following manner: head, neck, chest (anterior and posterior face), abdomen, back, upper extremity (arm, forearm, and hand), and lower extremity (thigh, leg, and foot). All biopsies obtained were studied with H&E stain under light microscopy.
RESULTS FIGURE 1. A, Type II CMN. Note a wide plaque involving the upper back, extending to the neck, head, and right extremity with many smaller plaques on the trunk. B, Type II CMN (same patient) involvement of the head and neck.
with the physician who sent the specimen. Diagnosis of CMN was established both clinically and histopathologically in accordance with the cited criteria1,8,25 and with the irrefutable Ó 2014 Lippincott Williams & Wilkins
There were 200 cases included: 68 patients were assisted clinically. We obtained skin biopsies for 40 of these patients. The mean age was 4.8 years, and there were 2 newborns of 20 and 27 days of age, and another boy of 5 months. Similarly, we gathered 132 specimens sent to our laboratory for histopathological diagnosis during the same time period. Ages ranged from 11 to 57 years with a mean age of 23 years. Overall, when combining both groups, mean age was 12 years; 44% were females and 56% were www.amjdermatopathology.com |
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FIGURE 4. Congenital type I melanocytic nevus on the forehead of a child. It is a single lesion that does not extend beyond this anatomic area. The presence of hairs is not a prognostic factor, but only designates the hamartomatous character of this nevus.
FIGURE 3. Type II CMN. A large plaque on the trunk and dozens of smaller plaques on the arm and forearm on an adult male.
characterized by a wide plaque and that surpassed more than one anatomic region. These CMN were in association with other multiple or countless smaller lesions and would be described as “a continent surrounded by islands.” The predominant topography in these cases, that is, the locations of these larger lesions, were the head (2 cases), chest–thigh– foot (1 case), lumbar (1 case), pelvis (bathing trunk area)
males. No one of these patients had a family history for CMN of any kind. Seven patients, all ,1 year of age (including the 2 newborns) had large, irregular, and asymmetric CMN
TABLE 2. Clinical and Histopathological Data of 200 Patients With CMN CMN Type II No. patients Age Family history of CMN Location
No. lesions Histopathology
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7 ,1 yr None
CMN Type I 193 11–57 yrs None
Head—2/7 Chest–thigh–foot—1/7
Head—19/55 Trunk or limbs—36/ 55 Lumbar—1/7 Trunk—15/55 Trunk-head-upper limbs—1/7 Upper limbs—11/55 Pelvis and lower limbs—2/7 Lower limbs—10/55 1 large/giant; dozens of smaller 1 per patient plaques or nodules Deep 7/7 Superficial 193/193
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FIGURE 5. Congenital type I nevus: asymmetrical single lesion that does not extend beyond the arm. Uniform color and precise boundaries with healthy skin are signs of a benign lesion. Ó 2014 Lippincott Williams & Wilkins
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FIGURE 6. CMN type I: Asymmetrical single lesion that does not extend beyond the hip region.
with lower extremities (2 cases), and trunk–neck–head– upper extremities (1 case). Multiple secondary lesions were present in diverse segments. We were able to count .300 lesions in 1 patient. In none of these 6 patients was there a family history of CMN (Figs. 1–3) (Table 2). In 193 patients, the lesions were single whose extension never extended past the anatomic region involved, that is, the cheek, the hand or forearm or thigh, etc. The topography in these patients was documented in 55 examples and predominated in the head (skull and face) with 19 cases (34.5%); the location of the rest of the cases was very diverse: trunk or limbs, but always involving only 1 anatomic segment (Figs. 4–7). The histopathology of the 7 cases in any area of the larger lesion that was biopsied showed the same changes: cords, strands, nests, sheets, and single units of melanocytes spreading between the collagen bundles not only in the dermis (also involving the adnexal structures) and epidermis but also in the fatty tissue of hypodermis, muscle, fascia, and deeper structures (Fig. 8).
FIGURE 8. Histopathology of type II CMN. Melanocytes in a wide mantle occupy the entire thickness of the skin and underlying structures: deep.
According to the 193 cases of nevi that clinically presented as sole lesions without extending beyond the anatomic zone they occupied (Figs. 4–7), histopathological findings were as follows: melanocytes in nests, rows, ropes, and mantles involving the skin from the dermal–epidermal junction to the lower portion of the reticular dermis. These were never situated deeply, and the adipose tissue and muscle were not found to be infiltrated (Fig. 9). In both types of CMN, melanocytes were able to be seen in isolated units disseminated among the collagen bundles, involving the eccrine and pilosebaceous adnexes, the hair erector muscle, and the vascular walls. The contrast between the CMN of the single lesion versus those made up by a wide lesion surrounded by countless papules, nodules, or smaller or secondary nevus plaques was highly noticeable.
DISCUSSION
We believe that the consistent finding of the CMN that clinically manifests as a single lesion (exceptionally there will
FIGURE 7. CMN type I: Asymmetrical single lesion that does not extend beyond the forehead. Ó 2014 Lippincott Williams & Wilkins
FIGURE 9. Histopathology of type I CMN showing the presence of melanocytes exclusively in the epidermis and dermis: superficial. www.amjdermatopathology.com |
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be persons who have more than one) will be defined or circumscribed to an anatomic region. CMN that extend beyond the anatomic region and are characterized by a larger lesion and multiple and numerous smaller, secondary, or “satellite” lesions have greater importance. Its definition is also histopathologically clear: in a single-lesion CMN, melanocytes do not extend beyond the dermis in its deep margins and only involve the dermis and epidermis without transcending to the hypodermis. However, in multiple-lesion CMN, the microscopic structure of massive infiltration is always constant, not only of the entire thickness of the skin (including the adipose tissue to the hypodermis) but also of the underlying structures. There are interesting aspects reported in the literature in relation to such microscopic characteristics in the CMN. In 1973, Mark et al30 observed differences between “small” and “large” CMN (in clothing). However, Ackerman et al29 in 1993 classified the histopathological characteristics of the CMN into superficial and deep. Pathologists have continued to identify superficial and deep CMNs for many years. Clinicians refer to these as “small, medium, large, and giant.” The point for discussion is how small is “small” and how large is “large,” or when giant is “giant.” In our view, it is not convenient to base this information on the metric system because a 10-mm nevus in a 3-kg newborn will measure larger when this child reaches 18 years of age and 80 kg of body weight. Naturally, the nevus will grow in proportion with the body growth. Also, it is very easy to dispel other arguments such as “the possibility of being easily resected” because it will depend on the anatomic site it occupies. It is not the same in the abdomen as in an eyelid or in the genitalia. Among other parameters, surgeon experience will also be important. The same can be said about the measurement according to the size of the patient’s hand because this does not tell us anything. Then, as the saying goes “size isn’t everything.” In view of the findings presented in this study, we believe that according to the clinical, biological, and histopathological bases, it is possible to state that there are 2 types of CMN, which we propose naming “type I” and “type II.” Type I is much more common; it is less impressive when seen and frequently the patient will say that “a certain relative has or had one” (totally subjective and uncertain assertion because melanocytic nevi are not inherited). Clinically, it manifests as a single lesion, usually 1 asymmetric plaque .6 mm in size and with limited dimensions because it does extend beyond the anatomic region it occupies. Biologically, melanoma develops much less frequently in single lesions (type I) than in giant ones (type II). Histopathologically, this nevus does not extend beyond the reticular dermis, which is consonant to the superficial denomination by Ackerman et al.29 There is a risk for developing melanoma, but we do not know the numbers because attempts at classification and numerical measurement have produced skewed statistical data; when melanoma develops in these superficial CMN it does in the dermoepidermal junction. Type II CMN is much less frequent than type I. Clinically, type II or its manifestations are dramatic and it is impossible for it to be unnoticed; it always exists as a wide plaque that extends beyond the anatomic region and is accompanied by many other smaller lesions. Histopathologically, the larger lesions are
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consonant with the denomination of deep CMN.29 Its potential for developing melanoma is undeniable. The figures in the literature are confusing, probably due to the reasons already mentioned when discussing type I CMN above, but the risk is certainly much greater for type I, and when melanoma develops it arises inside the dermis, in the mass of melanocytes. The study of CMN samples outside the clinical context led many authors to misinterpret as “small,” the secondary, or “satellite” nevi that in reality are part of the same disease, which is type II CMN. All of this caused great confusion in the literature. It has been necessary and productive to study this disorder. In conclusion, our hypothesis of CMN type I and type II will surely find a strong support on the near future development of a molecular genetics-based classification on clinical–pathological correlation. Finally, it is necessary to highlight that the CMN, as well as the Clark’s nevus, are the 2 benign melanocytic lesions accepted by a panel of experts from the US National Institutes of Health7 as melanoma precursors, and its characters continue to be a reason for study by different groups.17,18,23–35 Therefore, the therapeutic behavior of the CMN should no longer be “expectant management or observational” because it is not known at this time if the neoplastic clone will begin because there are reports that point out this time from infancy to the third age. Surgical treatment should be considered, mainly in type II CMN. However, without a doubt and unfortunately, there are patients whose treatment may be impossible; that is, when the form II of CMN arises on the head and/or neck, it may involve deeper structures, even the central nervous system, producing leptomeningeal melanocytosis (not only “melanosis”), which is the massive infiltration of melanocytes to the central nervous system. REFERENCES 1. Maize JC, Ackerman AB. Pigmented Lesions of the Skin. Philadelphia, PA: Lea & Febiger; 1987:114–130. 2. Kopf AW, Bart RS, Hennessey P. Congenital nevocytic nevi and malignant melanomas. J Am Acad Dermatol. 1979;1:123–130. 3. Rhodes AR, Melski JW. Small congenital nevocellular nevi and the risk of cutaneous melanoma. J Pediatr. 1982;100:219–224. 4. Freinkel RK, Cage GW, Caro WA, et al. Precursors to malignant melanoma. J Am Acad Dermatol. 1984;10:683–688. 5. Illig L, Weidner F, Hundeiker M, et al. Congenital nevi ,10 cm as precursors to melanoma. Arch Dermatol. 1985;121:1274–1281. 6. Alper JC. Congenital nevi. The controversy rages on. Arch Dermatol. 1985;121:734–735. 7. Precursors to malignant melanoma. National Institutes of Health Consensus Development Conference Statement, Oct. 24–26, 1983. J Am Acad Dermatol. 1984;10:683–688. 8. Ackerman AB, Cerroni L, Kerl H. Pitfalls in Histopathologic Diagnosis of Malignant Melanoma. Philadelphia, PA: Lea & Febiger; 1994:199. 9. Bateman T. Delineations of Cutaneous Diseases. London, United Kingdom: Paternoster-Row; 1817. 10. Alibert JLM. Monographie des Dermatoses. Paris, France: Germer Bailliere; 1835. 11. Castilla EE, Dutra MG, Orioli-Parreiras IM. Epidemiology of congenital pigmented nevi: I, incidence rates and relative frequencies. Br J Dermatol. 1981;104:307–315. 12. Castilla EE, Dutra MG, Orioli-Parreiras IM. Epidemiology of congenital pigmented nevi: II, risk factors. Br J Dermatol. 1981;104:421–427. 13. Warner PM, Yakuboff KP, Kagan RJ, et al. An 18-year experience in the management of congenital nevomelanocytic nevi. Ann Plast Surg. 2008; 60:283–287.
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14. Bauer J, Curtin JA, Pinkel D, et al. Congenital melanocytic nevi frequently harbor NRAS mutations but not BRAF mutations. J Invest Dermatol. 2007;127:179–182. 15. Ichii-Nakato N, Takata M, Takayanagi S, et al. High frequency of BRAFV600E mutation in acquired nevi and small congenital nevi, but low frequency of mutation in medium-sized congenital nevi. J Invest Dermatol. 2006;126:2111–2118. 16. Cantú J, Urrusti J, Hernandez RC, et al. Discordance for giant pigmented nevi in monozygotic twins. Ann Genet. l973;16:289–292. 17. De Wijn RS, ZAAl LH, Hennekam RC, et al. Familial clustering of giant congenial melanocytic nevi. J Plast Reconstr Aesthet Surg. 2010;63:906–913. 18. Alikhan A, Ibrahimi OA, Eisen DB. Congenital melanocytic nevi: where are we now? J Am Acad Dermatol. 2012;67:495–511. 19. Zaal LH, Mooi WJ, Klip H, et al. Risk of malignant transformation of congenital melanocytic nevi: a retrospective nationwide study from the Netherlands. Plast Reconstr Surg. 2005;116:1902–1909. 20. Kaplan EN. The risk of malignancy in large congenital nevi. Plast Reconstr Surg. 1974;53:421–428. 21. DeDavid M, Orlow SJ, Provost N. A study of large congenital melanocytic nevi and associated malignant melanomas: review of cases in the New York University Registry and in the world literature. J Am Acad Dermatol. 1997;36:409–416. 22. Lorentzen M. The incidence of malignant transformation in giant pigmented nevi. Scand J Plast Reconstr Surg. 1977;11:163. 23. Lanier V. Congenital nevi: clinical and pathological considers. Plast Reconsts Surg. 1976;58:48–56. 24. Ruiz-Maldonado R. Measuring congenital melanocytic nevi. Pediatr Dermatol. 2004;21:178–179.
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25. Vourc’h-Jourdain M, Martin L, Barbarot S. Large congenital melanocytic nevi: therapeutic management and melanoma risk. J Am Acad Dermatol. 2013;68:493–498. 26. Krengel S, Scope A, Dusza SW, et al. New recommendations for the categorization of cutaneous features of congenital melanocytic nevi. J Am Acad Dermatol. 2013;68:441–451. 27. Magaña GM. Nevo melanocítico congénito. Un enfoque clínico-patológico. Dermatol Rev Mex. 1991;35:292–300. 28. Magaña M, Magaña LM. Congenital melanocytic nevus is a disease with two clinicopathological forms of presentation. J Am Acad Dermatol. 2007;56:521–522. 29. Ackerman AB, Briggs P, Bravo F. Differential Diagnosis in Dermatopathology III. Philadelphia, PA: Lea & Febiger; 1993:184–187. 30. Mark GJ, Mihm MC, Liteplo MG, et al. Congenital melanocytic nevi of the small and garment type. Clinical, histological and ultrastructural studies. Hum Pathol. 1973;4:395–418. 31. Harley S, Walsh N. A new look at nevus-associated melanomas. Am J Dermatopathol. 1996;18:137–141. 32. Swerdlow AJ, English JSC, Qiao Z. The risk of melanoma in patients with congenital nevi: a cohort study. J Am Acad Dermatol. 1995;32:595–599. 33. Ibrahimi OA, Alikhan A, Eisen DB. Congenital melanocytic nevi: where are we now? J Am Acad Dermatol. 2012;67:515–527. 34. Tannous ZS, Mihm MC Jr, Sober AJ, et al. Congenital melanocytic nevi: clinical and histopathological features, risk of melanoma, and clinical management. J Am Acad Dermatol. 2005;52:197–203. 35. Bett BJ. Large or multiple cutaneous melanocytic nevi: occurrence of cutaneous melanoma in 1008 persons. J Am Acad Dermatol. 2005;52: 793–797.
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