Background
Malignant melanoma is a rare tumor during childhood and accounts for up to 0.9% of all pediatric malignancies [
1,
2]. A congenital melanocytic nevus (CMN) is clinically defined as a melanocytic lesion that is present at birth or develops during infancy from preexistent melanocytes [
3‐
5]. CMNs typically affect the trunk and proximal parts of the limbs, scalp, and neck, but might involve any other skin surface. Congenital melanocytic nevi are usually classified by size. The risk of developing melanoma over a CMN is believed to be directly proportional to the size of the nevus and varies from 2.6 to 4.9% for small and medium nevi and from 6 to 20% for giant nevi [
6]. There has been controversy about the incidence of melanoma and thus the clinical management of CMN, which is partly due to the difficulties of histological diagnosis and partly due to publishing bias towards cases of malignancy.
Giant congenital melanocytic nevus (GCMN) is usually defined as a melanocytic lesion that is present at birth and will reach a diameter of ≥20 cm in adulthood. Its incidence is estimated as < 1:20,000 newborns, of which about 6% develop melanoma at the site of the nevus. GCMN is the main risk factor for the development of melanoma in childhood. Currently, there is tremendous uncertainty regarding how GCMNs should be treated. The standard approach is based on two main considerations: (1) obtaining an acceptable cosmetic result to decrease the psychosocial inconvenience to the patient and (2) minimizing the risk of malignancy. However, there are descriptions of clinical cases where melanoma developed after the removal of a giant nevus [
7] and in old age [
8].
GCMN usually occurs sporadically [
9,
10], but rare familial cases have also been reported [
11,
12]. A report of monozygotic twins discordant for GCMN suggests that a postzygotic event might be involved [
10]. The etiology and pathogenesis of GCMN are not fully understood. Various mechanisms have been posited, such as defects in neural crest development [
13‐
15], activating mutations leading to uncontrolled melanocyte proliferation [
16,
17], cutaneous mosaicism, and paradominant inheritance [
12]. Melanoblasts originate from the neural crest cells, and their proliferation, migration, and differentiation are regulated by a complex network of interacting genes. Mutations in this network, such as in genes
MITF and
KIT and probably in the hepatocyte growth factor/c-Met signaling pathway, might deregulate the pigmentation system during embryogenesis, resulting in various congenital disorders [
12].
Another gene network that controls the proliferation of melanocytes is the RAS/RAF/MAPK signaling pathway. Various activating mutations in this pathway have been identified, which involve the genes
NRAS [
16,
18],
BRAF [
18‐
20], and
GNAQ [
21]. Postzygotic mutations in the
NRAS gene are thought to be responsible for CMN formation in 80% of cases because the same mutation is found in different cutaneous lesions from the same individual and in affected neurological and malignant tissue. The
NRAS mutations often result in an amino acid substitution in codon 61. The
BRAF V600E mutation can also be found but in no more than one lesion of the same patient and therefore cannot be assigned as causal [
22]. Additionally, mutations in
MC1R [
18,
23] and
TP53 [
18] have been identified in CMN and might be involved in its formation. The presence of
BRAF or
NRAS mutations does not confer an increased risk of malignant transformation [
21], and further mutations are required to cause melanoma formation in a CMN [
22].
Both children and adults can be affected by malignant melanoma arising in GCMN, which has a bimodal distribution with around 70% of cases occurring in childhood. Differential diagnosis should be done to distinguish between malignant and benign proliferations that may resemble malignant melanoma but usually lack progressive growth or ulceration. Benign proliferations within CMN are common and primarily arise in large or multiple nevi, although not exclusively. Knowledge of their features is helpful in monitoring for malignancy. In addition to proliferative nodules, GCMN are often associated with “satellite nevi,” which are smaller CMN that are present at birth or arise months to years later.
Only several large institutions have experience in treating children (from birth to 1 year old) with malignant melanoma. The outcomes described were linked to the stage at diagnosis and the presence of severe complications, such as neurocutaneous melanosis or melanoma in the central nervous system (CNS) [
24]. Neurocutaneous melanosis (NCM) is a rare syndrome that is characterized by benign or malignant proliferated melanocytic nodules in the CNS and is associated with the presence of congenital melanocytic lesions.
To date, no absolute guidelines to treat the GCMN have been established, and therefore, the subject remains one of the most controversial issues in dermatologic surgery and dermatologic oncology. We describe two rare cases of CMN: a case of melanoma arising in GCMN during the first month of life complicated with NCM, and another case arising in GCMN during the first 6 months of life. The clinical, pathological, and genetic characteristics of these patients are described, which provide evidence about this rare disease and generate data needed for the establishment of individual diagnostic and prognostic criteria.
Discussion
Malignant melanoma is a rare neoplasm in pediatric patients, but children with CMN have a greater risk of melanoma. The size and location of the CMN and its association with multiple satellite nevi also seem to influence malignization and melanoma development. The risk of developing melanoma over a CMN is believed to be directly proportional to the size of the nevus [
6]. According to the literature, 67% of cases have revealed primary melanoma within the nevus, with 14% showing metastatic melanoma with an unknown primary site and 8% showing extracutaneous melanoma [
26]. Cutaneous melanoma arising in the CMN usually presents as a new nodule or lump that mainly arises in the deeper dermis or subcutaneous tissue [
27,
28]. Most of the clinical reports (up to 90%) indicate malignant melanoma on the trunk [
29]. Only isolated clinical cases or small series of cases are described, which confirm the rare occurrence and necessity of accumulating data and clinical experience [
30]. Table
1 summarizes information about cutaneous melanoma cases arising in GCMN. Some of the reports contain only clinical and dermatoscopic characteristics with no detailed pathological and genetic data [
8,
30,
31].
Table 1
Clinical and genetic features of patients with congenital melanocytic naevus (CMN) and melanoma: literature data and own experience
Literature data |
Streams et al., Case 1 [ 7] | Female | 44 | Alive | Not done | Primary malignant melanoma of the left forearm underneath an intact skin graft 40 years after having had a partial excision and grafting of her GCMN | Not done | Not done |
Tchernev et al., Case 1 [ 8] | Female | 61 | Alive | Not done | Malignant melanoma of the occipital region (stage IIB) | Not done | Not done |
Lalor et al., Case 1 [ 35] | Female | 8 | Alive | Normal | Nodular melanoma on the scalp | Primary tumor | NRAS Q61R mutation |
| | 0 d | Died, 5mo | NCM | Large, multilobular, pigmented lesion covering 35% of the body, atypical melanocytic proliferation. Congenital melanoma. | Several biopsies | NRAS Wild-type, BRAF Wild-type |
Kinsler et al., Case 4 [ 22] | Male | 15, 5 | Alive, 11 mo | Normal | Cutaneous, within largest CMN on the back of the scalp and neck, metastatic to local lymph node at time of diagnosis | Cutaneous melanoma | NRAS Wild-type |
Kinsler et al., Case 10 [ 22] | Male | Not known | Death, age 2,4 years | Normal | Lymph node groin, locally recurrent despite excision, local metastasis | Not done | Not done |
Kinsler et al., Case 12 [ 22] | Female | 6,5 | Death, 6 mo | Normal | Cutaneous, within largest CMN, at the site of postnatal resection of a benign congenital nodule, metastatic to local lymph node at time of diagnosis | Cutaneous melanoma | NRAS Q61K mutation |
Maguire et al., Case 2 [ 31] | Female | 7 mo | Alive, 9 mo | Not done | Cutaneous, on the groin site. A wide local excision was done. At 16 months of age enlarged node in the groin, metastatic melanoma | Not done | Not done |
Own experience |
Case 1 | Male | 22 d | Alive | NCM | Congenital cutaneous malignant melanoma of the lumbar-sacral part | Primary tumor | NRAS Wild-type, BRAF Wild-type |
Case 2 | Male | 5 mo | Alive | Normal | Congenital cutaneous malignant melanoma of the back of the neck | Primary tumor | NRAS Q61R mutation |
We describe two cases of melanoma arising in a giant CMN as a new growing nodule and provide detailed clinical, dermatoscopic, pathological, and genetic analyses. When a diagnosis of cutaneous melanoma is suspected in a CMN patient, a biopsy should be performed (through excision if possible) with a detailed histopathological examination by at least two experts. Melanomas arising from giant congenital nevus predominantly develop from dermal melanocytes, as opposed to the melanomas emerging from small and medium nevi, which originate from the epidermis [
3].
Clark reported that diagnostic problems at the histological level are due to the complex cellular composition of some of the nodular overgrowths occurring in congenital melanocytic lesions. Four major histological patterns of proliferation have been observed in CMN at birth or in the neonatal period: 1) simulants of superficial spreading melanoma with increased numbers of large epithelioid melanocytes; 2) simulants of nodular melanoma with black nodules of epithelioid melanocytes; 3) nodular proliferative neurocristic hamartomas; and 4) biologic malignant melanomas, which are mostly characterized by small “blastic” pleomorphic melanocytes with a high mitotic rate. Clark believed that the true melanomas with metastatic potential usually develop after the neonatal period [
32]. Our cases confirm Clark’s findings because both children are now under observation without signs of disease progression despite the stage, early age of melanoma development, and subsequent surgical treatment.
Histological examination is the standard for the diagnosis of malignant melanoma and was performed in both of our cases. In the first case, the histopathology showed a nodular type of melanoma (Fig.
2a), which arose in the congenital nevus background with 1 mitosis/mm
2, ulceration (Fig.
2b), vertical growth phase, Clark invasion level 3, and Breslow thickness of 1.5 mm, without any symptoms of vessel invasion. According to immunohistochemical analysis, the tumor cells were positive for melanoma-specific markers Melan A and HMB45.
Ki67 is frequently used as an indicator of cell proliferation, and the Ki67 index of proliferation was 20–30% in tumor cells (Fig.
3). According to the literature, the Ki67 index is not a good marker for prognosis or confirming malignancy in cases of GCN burdened by melanoma. The melanoma sometimes might be a mitotically active proliferative nodule arising in a GCMN. This feature is worrisome when encountered in melanocytic lesions, but by itself, it should not trigger a diagnosis of melanoma in the absence of other histologic criteria of malignancy [
33]. We used Ki67 as an additional marker. In
Case 2, histopathology showed an epithelioid cell melanoma with 2 mitoses/mm
2, ulceration, satellites, and no vessel invasion (Fig.
6). The Breslow thickness (without satellites) was 2 mm. The tumor node (melanoma satellite) was determined in subcutaneous tissue (Fig.
6).
Molecular analysis was performed on the biopsies obtained, and several genes that might play a role in GCMN development and malignant transformation were investigated. For patient M (Case 1), we evaluated the presence of somatic and germline mutations in the BRAF, NRAS, KIT, GNAQ, GNA11, MAP2K1/2, PDGFRA, RASA1, RAC1, MET, PTEN, AKT1, TP53, and TERT genes and somatic mutations in the GNAQ and GNA11 genes. Germline mutations in the CDKN2A gene were also studied. Only non-pathogenic TP53 codon 72 Arg/Arg polymorphism was detected. For patient L (Case2), an analysis was performed to determine the somatic mutations in the BRAF, NRAS, KIT, GNAQ, GNA11, MAP2K1, and MAP2K2 genes and germline mutations in the CDKN2A gene. Ultimately, only a Q61K mutation in the NRAS gene was found.
Mutations in the
NRAS gene occur in 80–95% of giant CMNs [
10,
34] and are considered one of the causes of CMN formation [
22], although other factors are needed for malignant transformation [
21]. In both of our cases, no specific mutation was identified that could account for the melanoma. Our colleagues previously published a clinical case of an 8-year-old girl with melanoma arising within a medium-size congenital nevus with NRAS Q61K mutation (case 5, Table
1) [
35]. Kinsler et al. published the results of 25 years of experience at their center with melanoma in congenital melanocytic nevi, including the molecular characteristics of the tumor [
23]. Among 12 patients with melanoma, 6 had melanoma in CNS, 3 had an unknown melanoma site, and 3 had cutaneous melanoma (Tables
1, 4–6). There were 9 patients who developed melanoma in the first 5 years of life, and 7 patients revealed a Q61K mutation in the NRAS gene. In 3 cases of cutaneous melanoma in one patient, Q61K was found as in our Case 2. When the diagnosis of cutaneous melanoma arising in a CMN is clinically suspected, an urgent biopsy should be performed (excision if possible) with histopathological examination by at least two experts.
NRAS and
BRAF hotspot genotyping by sensitive methods are recommended to improve diagnostic accuracy and guide management.
The treatment of CMN is one of the most complicated areas of surgical and dermatologic oncology, and there are no commonly accepted standards to treat this lesion. It is not clear whether it is necessary to remove a CMN to reduce the risk of melanoma. In some reports, despite the almost complete removal of the GCN, the surgery failed to prevent the development of malignant melanoma, and the role of surgical excision of GCN remains controversial [
7,
36]. Although surgery does not reduce the risk of extracutaneous melanoma, the removal of melanocytic cells appears to reduce the risk of developing melanoma within the nevus. Some surgical options described for GCMN treatment include serial resection, skin grafts, and the use of tissue expanders [
37].
Melanomas in the GCN usually develop before puberty in the first 5 years of life, as opposed to the small and medium nevi, where it routinely occurs after puberty [
4,
5,
38].
NCM is a rare complication that worsens the prognosis of GCN patients. NCM is neuromelanosis associated with CMN, which describes melanocytic proliferation (benign or malignant and nodular or diffuse) within the leptomeninges and brain parenchyma [
4‐
6,
9‐
11]. Kadonaga described NCM and redefined it as the presence of a CMN larger than 20 cm or multiple CMN (more than three) in association with meningeal melanosis or melanoma [
39]. Our first case had NCM and malignant melanoma arising in a GCN larger than 20 cm. Malignant melanoma and NCM most often occur in patients with CMN that have a diameter > 40 cm, multiple satellite nevi, and a truncal location. Almost one-third of all patients with NCM have numerous medium-sized CMN.
For individuals at risk of NCM who are younger than 6 months old, gadolinium-enhanced screening MRI is recommended for long-term neurological observation [
4]. Patients with neuromelanosis may be symptomatic or asymptomatic. In our case, MRI revealed the presence of melanin in the structures of the brain, which was performed despite an absence of neurological symptoms. Therefore, MRI evaluation should be performed for newborns with GCN (and especially with multiple satellite nevi).
The suggested work-up for a patient with CMN and a confirmed diagnosis of melanoma is the following: (1) full blood count and lactate dehydrogenase level; (2): CNS MRI with gadolinium contrast, whole-body positron emission tomography–computed tomography scan or computed tomography scans; (3) tissue sample for histopathology,
NRAS, and
BRAF hotspot genotyping and copy-number analysis (array CGH or SNP array or FISH). The genotyping may be important to therapy strategies including use of mitogen-activated protein kinase kinase (MEK) inhibitors in NRAS-mutated tumours [
40].