Congenital melanocytic nevus

Congenital Melanocytic Nevus – 216.9

Are You Confident of the Diagnosis?

What you should be alert for in the history

The diagnosis of a congenital melanocytic nevus (CMN) is usually straightforward. They usually present at birth as a well-demarcated pigmented macule, patch, papule or plaque (Figure 1), although on occasion they may not be clinically evident until 1-2 years of age. Most CMN remain relatively stable in appearance; CMN will grow during childhood in dimensions proportionate to the growth of the child. The development of focal changes in pigmentation, a new papular or nodular component, symptoms such as pain or itching, or signs such as bleeding or ulceration warrant further attention.

Characteristic findings on physical examination
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Although typically uniform in color, in larger CMN there may be areas of variability in pigmentation. Associated hypertrichosis is not uncommon, especially in larger CMN. Focal proliferations may also be noted as a papular or nodular component.

Congenital melanocytic nevi are classified into three categories as defined by the maximal diameter of the nevus in the adult. The classifications are as follows:

Small: < 1.5 cm

Intermediate: 1.5-19.9 cm

Large: 20-49.9 cm

Giant: > 50 cm

Many children with a large or giant CMN will also present with numerous smaller congenital melanocytic nevi, known as satellite nevi, scattered on the head, neck, torso and extremities (Figure 2). In addition, there is a rare entity called multiple congential melanocytic nevi (MCMN) in which numerous small and intermediate-sized CMN are present at birth in the absence of a large or giant CMN. In the neonate or young infant, a congenital nevus larger than 6 cm on the body or 9 cm on the head will likely reach a maximal diameter of at least 20 cm once the child grows into an adult.

Large congenital melanocytic nevus with satellite nevi.

Recently, a new classification system was proposed by Krengel, et al that includes additional size classifications, location, number of satellite nevi, and additional morphologic characteristics (color heterogeneity, surface rugosity, presence of dermal or subcutaneous nodules, and hypertrichosis).

Small: < 1.5 cm

Medium

M1: 1.5 – 10 cm

M2: >10 – 20 cm

Large

L1: >20 – 30 cm

L2: >30 – 40 cm

Giant

G1: >40 – 60 cm

G2: > 60 cm

Expected results of diagnostic studies

On histology, small and intermediate-sized CMN may demonstrate junctional, compound, or dermal involvement (Figure 3) . They may be indistinguishable from acquired melanocytic nevi. Histologic features that may differentiate congenital melanocytic nevi from acquired melanocytic nevi include the presence of melanocytes around and within hair follicles, eccrine glands, and sebaceous glands or closely approximating blood vessels and nerves; melanocytes extending in rows between collagen bundles; or extension of melanocytes into the deep dermis and subcutis. Nevus cells stain positively with the melanocytic markers S-100, HMB-45, and Melan-A.

Typical histology of a congenital melanocytic nevus.

Large congenital melanocytic nevi are compound or dermal melanocytic proliferations. Histologically, in addition to the features noted above, large CMN may manifest neurotization or features resembling a common or cellular blue nevus.

Diagnosis confirmation

The differential diagnosis of a congenital melanocytic nevus includes cafe-au-lait macule, smooth muscle hamartoma, solitary mastocytoma, and epidermal nevus. Cafe-au-lait are generally lighter in color than CMN and sometimes have a more irregular and ill-defined border. Mastocytomas can often be differentiated clinically by elicitation of a positive Darier sign with firm stroking, which causes pressure-induced degranulation of mast cells and a resultant wheal and flare response. Epidermal nevi typically have a more verrucous appearance and often follow Blaschko’s lines of embryonic migration.

In older children, adolescents and adults in whom it is unclear whether the nevus was present at birth, the differential diagnosis also includes other melanocytic lesions, including an acquired melanocytic nevus, a pigmented Spitz nevus or pigmented spindled cell nevus, a nevus spilus, and malignant melanoma, which is very rare in children.

A CMN may be difficult to differentiate clinically from other melanocytic neoplasms; the use of dermoscopy may be helpful. Congenital melanocytic nevi typically demonstrate a globular or cobblestone pigment network with a regular distribution of pigmented dots and globules, while acquired melanocytic nevi may demonstrate a predominantly reticular pigment network, a globular pigment network, or features of both. Pigmented Spitz nevi usually display a characteristic symmetric starburst pattern to the pigment network. The dermoscopic features of malignant melanoma are variable but may demonstrate an atypical pigment network, irregular pigment streaks, irregular dots and globules, and blue-white structures.

Who is at Risk for Developing this Disease?

Congenital melanocytic nevi are present in about 1-2% of the general population. They are seen slightly more frequently in African-American neonates as opposed to Caucasians. CMN occur sporadically with no known genetic predisposition.

The overwhelming majority of CMN are less than 4 cm in diameter. Large CMN are extremely rare and occur with an estimated frequency of 1:20,000 neonates, and giant CMN in 1:50,000 neonates.

What is the Cause of the Disease?

Pathophysiology

Little is known about the pathophysiology of congenital melanocytic nevi. They are believed to occur as a result of aberrant proliferation and migration of neural crest-derived melanoblasts involving the skin and leptomeninges during the first and second trimesters of gestation.

Some studies have suggested that CMN have a high frequency of NRAS mutations (70-81%; large CMN). Small and intermediate-sized CMN have been reported to have a high frequency of BRAF mutations (70% in small CMN and 30% in intermediate CMN) and a lower frequency of NRAS mutations (14-56%).

NRAS Q61 mutations have been reported to occur in the majority of large and giant CMN. One study reported NRAS Q61 in 94% of large CMN; BRAF mutations were noted in on 5% of large CMN and 11% of giant CMN. NRAS mutations are also associated with the phenotype of multiple CMN and neurocutaneous melanosis.

Systemic Implications and Complications

The risk of malignant melanoma arising within a congenital melanocytic nevus is established most clearly for patients with large CMN, in whom the risk is about 2.5% over lifetime, although prospective studies on large cohorts of patients with large CMN indicate that at least half of melanomas associated with a large CMN have developed within the first 3-5 years of life. Melanoma arising within a large CMN has been reported in infants.

The risk of melanoma is highest in those persons with large CMN involving the trunk and those with numerous satellite nevi. The risk of malignant melanoma arising in small and intermediate-size congenital melanocytic nevi is unknown but appears very low. Several retrospective studies of melanoma in children and adolescents have documented the presence of an associated CMN in only 4.4-6.7% of cases.

The presence of a large CMN involving the posterior axis, in particular when associated with more than 20 satellite nevi or the presence of multiple small and intermediate-sized CMN in the absence of a large CMN (MCMN) is also associated with a risk for neurocutaneous melanosis (NCM), which is defined by the presence of excessive proliferation of melanocytes within the central nervous system, including the brain parenchyma and/or leptomeninges. The diagnostic criteria for NCM as established by Kadonaga and Frieden (1991) are as follows:

the presence of a large (> 20 cm) CMN or multiple (> 3) CMN in association with histologic confirmation of leptomeningeal melanocytosis or CNS melanoma
absence of cutaneous melanoma unless there is no evidence of CNS melanoma
absence of meningeal melanoma, unless there is no evidence of cutaneous melanoma

A provisional diagnosis of NCM is made if the above criteria are met in the absence of histologic confirmation of leptomeningeal melanocytosis. As imaging of the neuroaxis has become more common in infants and children at risk for NCM, it has become apparent that a significant number of at risk patients may demonstrate focal abnormal findings on magnetic resonance imaging (MRI) of the brain and spinal cord, yet remain asymptomatic.

Signs and symptoms of NCM may include signs of increased intracranial pressure, including headache, seizures, hydrocephalus, and cranial nerve palsies. Developmental delays may also occur. Most symptomatic children present within the first 5 years of life, although delayed presentation in adolescence and adulthood have been reported.

The prognosis of symptomatic NCM is poor. Neurologic symptoms often progress rapidly and lead to death within several months to years. Primary CNS melanoma occurs in about 65% of patients in the first few years of life and is uniformly fatal.

Treatment Options

Treatment options are summarized in Table I.

Table I.

Medical Treatment	Surgical Procedures	Physical Modalities
	Partial or complete excision with closure by split- or full-thickness skin graft, direct advancement flap, skin substitute, or free tissue transfer, if necessary; larger nevi may require use of staged excision or tissue expansion	Not applicable
	Chemical peel (phenol)
	Dermabrasion
	Curettage
	Laser ablation (modalities which have been used include carbon dioxide, alexandrite, Q-switched ruby, and erbium:YAG)

Optimal Therapeutic Approach for this Disease

In general, prophylactic excision of most small and intermediate-sized CMN is not warranted due to the exceedingly low risk of malignant melanoma. In certain circumstances, such as in children with CMN in areas that preclude routine self-examination such as the scalp, excision may be considered when the child is either old enough to tolerate the procedure without the need for general anesthesia, if possible, or if the child requires anesthesia or sedation for another procedure and excision can be reasonably performed at the same time. Children and their caregivers should understand that surgery will result in a permanent scar.

Any CMN with a documented change in appearance or in which pain, bleeding, or crusting develops should be biopsied or excised.

Use of non-excisional treatments for CMN are controversial due to concerns regarding the inability to provide a histologic diagnosis due to tissue destruction and the incomplete removal of the total melanocyte burden due to limitations with regards to depth of treatment; only the most superficial portion of the CMN is targeted during these treatments.

Non-excisional methods include laser ablation, curettage, dermabrasion, and chemical peels. Multiple laser modalities, including carbon dioxide, argon, erbium:YAG laser, Q-switched ruby laser, and the alexandrite laser have been used in an attempt to minimize the appearance of congenital melanocytic nevi.

Recurrence of pigmentation is common and scarring is possible with use of the higher fluences often required; therefore treatment of CMN with laser ablation is not recommended. The use of lasers to treat melanocytic lesions in general is also controversial due to concerns regarding the potential for promotion of tumorigenesis via the laser fluence.

Dermabrasion and phenol chemical peels have been used in some centers to minimize the appearance of CMN in areas not amenable to surgical excision; results are variable and there is a significant risk of scarring.

Surgical treatment of large congenital melanocytic nevi is controversial. Although partial or complete excision, when possible, does appear to reduce the risk of cutaneous melanoma by about 90%, cases of melanoma have been reported in patients who have been treated previously with excision or other surgical techniques such as dermabrasion. In addition, in those patients with neurocutaneous melanosis, the excision of the CMN in no way modifies the risk for primary CNS melanoma.

Some experts caution that surgical intervention for large CMN with surgical procedures such as excision and grafting, laser ablation, dermabrasion, and chemical peels may not only prevent the detection of melanoma within the treated areas but may in fact increase the risk of malignant degeneration by altering the biological behavior of residual melanocytes. The development of increased pigmentation involving the borders of areas previously resected and grafted as well as within residual nevus has been documented.

Due to the large size of large CMN, complete excision is usually not feasible, and the risk of scarring and surgical complications is significant. Use of staged excisions, free tissue transfer, direct advancement flaps, skin substitutes, and/or tissue expanders are often required. Use of surgical curettage in neonates has been suggested as a method to debulk large CMN but carries a risk of scarring and recurrence is the rule.

Patient Management

All patients with a congenital melanocytic nevus should be educated on the importance of sun protective measures, including the use of sunscreen, sun protective clothing, and avoidance of excess sun exposure. The routine use of broad-spectrum sunscreens that provide protection against ultraviolet A (UVA) and UVB should be encouraged.

In infants and in children and adults with sensitive skin, use of sunscreens containing zinc oxide and titanium dioxide are recommended as these ingredients block both UVA and UVB and are generally least likely to be irritating. Other broad-spectrum agents include oxybenzone, avobenzone and (ecamsule) Mexoryl SX.

Patients and caregivers should be encouraged to monitor the congenital nevus as well as all of their other nevi through regular self-examination for changes in the appearance of their nevi. In general, the ABCDE guidelines are helpful in understanding which changes are potentially significant: asymmetry; (irregular) borders; color (2 or more colors or shades of brown); diameter (> 6 mm or the size of a pencil eraser); and evolution, enlargement, or elevation of any part of the mole. In addition, symptoms such as bleeding, crusting, or pain should be noted.

The use of photodocumentation with a digital camera of sufficient resolution is exceedingly helpful for both patients and caregivers as well as clinicians, and photodermoscopy may be used for additional monitoring. Areas of documented clinical change, either by history or clinical examination, should warrant consideration for a skin biopsy.

Neonates and young infants with large CMN, particularly involving the posterior axis in association with multiple satellite nevi, should be evaluated for neurocutaneous melanosis. Screening of at-risk patients ideally should occur before 4-6 months of age and should include measurement of head circumference and unenhanced MRI of the brain and spinal cord.

MRI findings suggestive of NCM include focal T1 shortening, which is an indication of increased melanization, involving the anterior temporal lobes, amygdala, cerebellum, thalamus, and/or base of the frontal lobe, areas which correlate with the normal distribution of melanocytes within the CNS. The presence of diffuse leptomeningeal enhancement on post-gadolinium T1-weighted images is less common but more likely to be associated with symptomatic NCM.

The treatment of symptomatic NCM is palliative, including placement of a ventricular shunt if hydrocephalus is present, use of enteral or parenteral nutritional support, and initiation of antiepileptic medications to treat associated seizures. Use of chemotherapy and/or radiation therapy has no demonstrated clinical benefit, although with the emerging use of targeted therapies, it is possible that treatment may become available in the future.

Unusual Clinical Scenarios to Consider in Patient Management

Patients with large CMN may also develop benign melanocytic proliferations that can histologically and clinically mimic malignant melanoma. These proliferative nodules may appear as either relatively stable small dermal papules or nodules or as rapidly proliferating tumors that may ulcerate. These nodules not uncommonly mimic melanoma histologically.

Differentiating features include lack of significant number of mitoses and the presence of maturation of epitheloid melanocytes despite an atypical histology. The presence of aneuploidy as opposed to specific chromosomal aberrations may also help to distinguish proliferative nodules from malignant melanoma. Proliferative nodules have a benign clinical course often with spontaneous involution.

What is the Evidence?

Agero, AL, Benvenuto-Andrade, C, Dusza, SW, Halpern, AC, Marghoob, AA. “Asymptomatic neurocutaneous melanocytosis in patients with large congenital melanocytic nevi: a study of cases from an Internet-based registry”. J Am Acad Dermatol. vol. 53. 2005 Dec. pp. 959-65. (Large cohort study of patients with large CMN identified through use of internet-based registry; self-reported prevalence of asymptomatic NCM was 4.8%, lower than reported in other studies, possibly as a result of ascertainment bias.)

Arneja, JS, Gosain, AK. “Giant congenital melanocytic nevi of the trunk and an algorithm for treatment”. J Craniofac Surg. vol. 16. 2005 Sep. pp. 886-93. (Excellent overview of surgical and nonsurgical treatment options for large CMN.)

Bett, BJ. “Large or multiple congenital melanocytic nevi: occurrence of cutaneous melanoma in 1008 persons”. J Am Acad Dermatol. vol. 52. 2005 May. pp. 793-7. (Using data obtained from a patient support group, the authors reported the development of cutaneous melanoma in 2.9% of patients with a large CMN involving the torso, 0.3% of patients with a large CMN involving an extremity, and 6.7% of patients with multiple CMN.)

Bittencourt, FV, Marghoob, AA, Kopf, AW, Koenig, KL, Bart, RS. “Large congenital melanocytic nevi and the risk for development of malignant melanoma and neurocutaneous melanocytosis”. Pediatrics. vol. 106. 2000 Oct. pp. 736-41. (A prospective study of patients enrolled in the NYU Registry of Large CMN with regard to the development of melanoma and NCM.)

Charbel, C, Fontaine, RH, Malouf, GG, Picard, A, Kadlub, N, El-Murr, N, How-Kit, A, Su, X, Coulomb-L’Hermine, A, Tost, J, Mourah, S, Aractingi, S, Guégan, S. “NRAS mutation is the sole recurrent somatic mutation in large congenital melanocytic nevi”. J Invest Dermatol. vol. 134. 2014 Apr. pp. 1067-74. (Evaluation of NRAS mutations and exome sequencing in large CMN.)

Hale, EK, Stein, J, Ben-Porat, L, Panageas, KS, Eichenbaum, MS, Marghoob, AA. “Association of melanoma and neurocutaneous melanocytosis with large congenital melanocytic naevi–results from the NYU-LCMN registry”. Br J Dermatol. vol. 152. 2005 Mar. pp. 512-7. (Using data from the NYU Registry of Large CMN, the authors determined the association between the risk of NCM and the presence of increasing numbers of satellite nevi and increasing size of the large CMN.)

Kadonaga, JN, Frieden, IJ. “Neurocutaneous melanosis: definition and review of the literature”. J Am Acad Dermatol. vol. 24. 1991 May. pp. 747-55. (Sentinel paper defining NCM, including clinical features, risk factors, and association with primary CNS melanoma.)

Kinsler, VA, Thomas, AC, Ishida, M, Bulstrode, NW, Loughlin, S, Hing, S, Chalker, J, McKenzie, K, Abu-Amero, S, Slater, O, Chanudet, E, Palmer, R, Morrogh, D, Stanier, P, Healy, E, Sebire, NJ, Moore, GE. “Multiple congenital melanocytic nevi and neurocutaneous melanosis are caused by postzygotic mutations in codon 61 of NRAS”. J Invest Dermatol. vol. 133. 2013 Sep. pp. 2229-36. (NRAS Q61 mutations were noted in 12 of 15 patients with multiple CMN and neurocutaneous melanosis.)

Krengel, S, Scope, A, Dusza, SW, Vonthein, R, Marghoob, AA. “New recommendations for the categorization of cutaneous features of congenital melanocytic nevi”. J Am Acad Dermatol. vol. 68. 2013 Mar. pp. 441-51.

Leech, SN, Bell, H, Leonard, N, Jones, SL, Geurin, D, McKee, PH. “Neonatal giant congenital nevi with proliferative nodules: a clinicopathologic study and literature review of neonatal melanoma”. Arch Dermatol. vol. 140. 2004 Jan. pp. 83-8. (Small case series and review of the literature on proliferative nodules arising in large CMN.)

Marghoob, AA, Agero, AL, Benvenuto-Andrade, C, Dusza, SW. “Large congenital melanocytic nevi, risk of cutaneous melanoma, and prophylactic surgery”. J Am Acad Dermatol. vol. 54. 2006 May. pp. 868-70. (Meta-analysis of data from several studies suggesting a decreased risk of cutaneous melanoma in patients with LCMN undergoing prophylactic partial or complete surgical excision.)

Marghoob, AA, Dusza, S, Oliveria, S, Halpern, AC. “Number of satellite nevi as a correlate for neurocutaneous melanocytosis in patients with large congenital melanocytic nevi”. Arch Dermatol. vol. 140. 2004 Feb. pp. 171-5. (Using data from an internet-based patient support group, the authors identify number of satellite nevi as the most significant risk factor for the development of NCM.)

Salgado, CM, Basu, D, Nikiforova, M, Bauer, BS, Johnson, D, Rundell, V, Grunwaldt, LJ, Reyes-Múgica, M. “BRAF mutations are also associated with neurocutaneous melanocytosis and large/giant congenital melanocytic nevi”. Pediatr Dev Pathol. vol. 18. 2015 Jan-Feb. pp. 1-9. (Small case series evaluating the prevalence of mutations of BRAF and NRAS in CMN.)

Tannous, ZS, Mihm, MC, Sober, AJ, Duncan, LM. “Congenital melanocytic nevi: clinical and histopathologic features, risk of melanoma, and clinical management”. J Am Acad Dermatol. vol. 52. 2005 Feb. pp. 197-203. (Overview of the risk of melanoma and NCM in patients with large CMN and management strategy for the care of these patients.)

Yélamos, O, Arva, NC, Obregon, R, Yazdan, P, Wagner, A, Guitart, J, Gerami, P. “A comparative study of proliferative nodules and lethal melanomas in congenital nevi from children”. Am J Surg Pathol. vol. 39. 2015 Mar. pp. 405-15. (Comparison of the histopathology and genomic features of proliferative nodules and malignant melanoma arising within a congenital melanocytic nevus.)

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