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Year : 2021  |  Volume : 64  |  Issue : 2  |  Page : 402-405
NRAS mutant melanoma arising in a giant congenital melanocytic nevus in an infant

1 Department of Pathology, Institute of Post Graduate Medical Education and Research, Kolkata, West Bengal, India
2 Department of Molecular Genetics, Tata Medical Center, Kolkata, West Bengal, India

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Date of Submission16-Jan-2020
Date of Decision05-Feb-2020
Date of Acceptance09-Mar-2020
Date of Web Publication9-Apr-2021


Pediatric melanomas are uncommon and sometimes arise in the background of giant congenital melanocytic nevus (GCMN). A 1-year-old girl was born with GCMN affecting her left half of the face and smaller nodules affecting trunk, hands, and feet. She developed an ulcerated lesion on the left temporoparietal scalp. The lesion showed features of GCMN along with large nests of a tumor composed of round cells with a vesicular nucleus, prominent nucleolus, plentiful mitoses, and areas of necrosis. Immunostaining for desmin, LCA, CD 20, CD 34, CD 99, BCL-2, and FLI1 was negative. Tumor cells showed immunopositivity for S-100 and HMB-45 confirming the diagnosis of melanoma. Immunostaining for BRAF V600E was negative; however, NRAS mutation was detected on next-generation sequencing. Unlike adult melanomas BRAF mutations are rare but NRAS mutations have been reported in pediatric melanomas. Adjunctive molecular testing will be important to understand the genetic basis of this disease and future targeted therapy.

Keywords: Giant congenital melanocytic nevus, malignant melanoma, NRAS gene

How to cite this article:
Bansal N, Das M, Chatterjee U, Mallick MG, Arora N, Mishra DK. NRAS mutant melanoma arising in a giant congenital melanocytic nevus in an infant. Indian J Pathol Microbiol 2021;64:402-5

How to cite this URL:
Bansal N, Das M, Chatterjee U, Mallick MG, Arora N, Mishra DK. NRAS mutant melanoma arising in a giant congenital melanocytic nevus in an infant. Indian J Pathol Microbiol [serial online] 2021 [cited 2021 May 8];64:402-5. Available from: https://www.ijpmonline.org/text.asp?2021/64/2/402/313285

   Introduction Top

Pediatric melanomas are rare and account for <1% of all melanomas. The three most common subtypes of pediatric melanoma are spitzoid melanoma, melanoma arising in giant congenital melanocytic nevus (GCMN), and conventional (adult type) melanoma. GCMN affects <0.1% of newborns. Although the risk of malignant transformation in a congenital melanocytic nevus is estimated to be <1% this risk varies depending upon the size.[1] The genetic alteration in pediatric melanoma is different from that in adults as the genetic pathways involved in the two are different. The genotyping is important for target-based chemotherapies. Unlike adult melanoma BRAF mutation is uncommon, however, NRAS mutations are more frequent in childhood melanomas.[2],[3]

Herein, we describe a case of melanoma arising in GCMN in an infant along with its genetic alterations.

   Case Report Top

A 1-year-old girl came with GCMN affecting left half of her face and nape along with smaller nodules affecting trunk, hands, and feet. There was a raised, ulcerated patch over the left temporoparietal scalp [Figure 1]a and [Figure 1]b. MRI brain was unremarkable. The mass was excised and showed features of GCMN along with large nests of round cells with a vesicular nucleus, prominent nucleolus, plentiful mitoses and necrosis, and morphologically resembling small round cell tumor of childhood. There was no definite pigment identified in the tumor cells. The tumor involved the entire dermis [Figure 2]a,[Figure 2]b,[Figure 2]c,[Figure 2]d. The tumor cells were negative for LCA, desmin, myogenin, CD 99, BCL-2, FLI 1 and CD 34 ruling out lymphoma, rhabdomyosarcoma, PNET, and synovial sarcoma. The tumor cells were strongly positive for S-100 and HMB-45 confirming the diagnosis of melanoma [Figure 3]a,[Figure 3]b,[Figure 3]c,[Figure 3]d. IHC for BRAF V 600E was negative [Figure 3]d. Subsequently, a missense mutation in exon 3 of the NRAS gene was detected by next-generation sequencing. A second surgery to excise the contiguous mass was being planned; however, the child passed away 3 weeks post-operation due to septicemia.
Figure 1: (a) GCMN affecting the left half of the face and the nape of the neck with areas of ulceration. (b) Satellite nodules affecting trunk and feet

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Figure 2: (a) Low power (10×) of GCMN (inset showing high power). (b) Scan power (4×) view of GCMN with the underlying tumor. (c) Tumor involving entire dermis, low power (10×) (d) High power (40×) showing tumor composed of round cells with vesicular nuclei, prominent nucleoli, and plentiful mitoses morphologically resembling small round tumor of childhood. The arrows highlight mitotic figures. (H and E stains)

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Figure 3: (a and b) showing positivity for S-100 and HMB-45, respectively (inset shows high power image). (c and d) showing negativity for Desmin and BRAF respectively (inset showing positive control for BRAF)

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   Discussion Top

Malignant melanoma is a rare tumor of childhood and children with congenital melanocytic nevus (CMN) have a greater risk of developing melanomas. CMN affects approximately 1% of newborns. They are classified according to their size as small (<1.5 cm), medium (1.5–19.9 cm) and large/giant (>20 cm).[4],[5] Attempts to classify CMN according to their size stems mainly from the fact that the risk of complications is proportional to the diameter of the nevus.[1] The risk varies from 2.6 to 4.9% for small and medium nevi and 6 to 20% for the GCMN.[6] Most of the malignant melanomas arising in a background of GCMN are reported in the trunk, followed by the limbs, head, and neck region.[7] GCMN can be further complicated by the presence of neurological abnormalities such as melanosis of the brain parenchyma and leptomeninges, neurocongenital melanosis, seizures, hydrocephalus, developmental delay, or behavioral abnormalities.[8],[9] MRI is the best predictor of neurodevelopmental anomalies.

Pediatric melanoma is subclassified into three main categories: conventional (adult type) melanoma (CM), melanoma arising in GCMN, and spitzoid melanoma. Differentiating between these subtypes is important because each subtype has different risk factors, histological findings, and treatment options. In childhood, most reported melanomas are spitzoid whereas melanomas arising in a congenital nevus are uncommon.

A diagnosis of spitzoid melanoma is supported by typical spitzoid cytomorphological features such as the presence of cells with abundant eosinophilic cytoplasm and a high degree of nuclear atypia along with other features such as ulceration, brisk mitotic activity, and poor maturation.

The melanomas arising in GCMN often show undifferentiated "blastic" morphology resembling lymphoblasts, rhabdomyoblasts, or other small round cell tumors, containing little or no melanin, while others comprised large epithelioid cells similar to usual melanoma. The round cell and undifferentiated blastic morphology like our case must be differentiated from other common round cell tumors of childhood i.e., Ewing's sarcoma/PNET, rhabdomyosarcoma of head and neck region, especially alveolar variety, lymphoma, and poorly differentiated synovial sarcoma. Hence, an extended panel of IHC is useful to differentiate these tumors from melanomas.

The histological distinction of melanoma arising in giant congenital nevi from proliferative nodules which are benign masses can be challenging.[10],[11] The presence of high-grade nuclear atypia, high mitotic activity, ulceration, and zones of necrosis can be useful morphological features to differentiate between the two.

The genetic pathways involved in adult and childhood melanomas are different. The most common mutations in adult melanomas are in TERT promoter region (92%) followed by a mutation in BRAFV600E in 87% cases and mutations in CDKN2A in 40% cases.[3],[12],[13],[14] Whereas in GCMN the initiating somatic mutations involve NRASQ61K and NRASQ61R in 80% cases.[15] Mutations of BRAFV600E are less common, occurring in only 5–15% of cases of congenital nevi.[15] The genomic alterations of 3 common subtypes of melanomas are summarized in [Table 1].
Table 1: Summary of genomic alterations in melanoma[12],[13],[14],[15]

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BRAF mutations in congenital melanomas only affect the mitogen-activated protein kinase pathway and require a supplementary PTEN mutation to result in melanoma.[3] Since NRAS affects both the mitogen-activated protein kinase and the phosphatidylinositol 3 kinase (PI3K)/AKT pathway, NRAS mutation in CMN can lead to malignancy without a PTEN mutation.[3] Based on these, different treatment options can be approached by inhibiting the specific downstream signalling molecules or a combination of molecules. The most common targeted therapy used is MEK inhibitors such as binimetinib, trametinib, and selumetinib.

   Conclusion Top

A rare case of melanoma arising in GCMN in an infant has been reported in the present study. Histologically, it must be distinguished from small round cell tumors of childhood. These cases frequently show activating mutation in NRAS gene. Therefore, adjunctive molecular analysis is important to understand the genetic basis of the disease and guide management.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

   References Top

Krengel S, Hauschild A, Schafer T. Melanoma risk in congenital melanocytic naevi: A systematic review. Br J Dermatol 2006;155:1-8.  Back to cited text no. 1
Dessars B, De Raeve LE, EI Housni H, Debouck CJ, Sidon PJ, Morandini R, et al. Chromosomal translocations as a mechanism of BRAF activation in two cases of large congenital melanocytic nevi. J Invest Dermatol 2007;127:1468-70.  Back to cited text no. 2
Lu C, Zhang J, Nagahawatte P, Easton J, Lee S, Liu Z, et al. The genomic landscape of childhood and adolescent melanoma. J Invest Dermatol 2015;135:816-23.  Back to cited text no. 3
Kopf AW, Bart RS, Hennessey P. Congenital nevocytic nevi and malignant melanomas. J Am Acad Dermatol 1979;1:123-30.  Back to cited text no. 4
Alikhan A, Ibrahimi OA, Eisen DB. Congenital melanocytic nevi: Where are we now? Part I. Clinical presentation, epidemiology, pathogenesis, histology, malignant transformation, and neurocutaneous melanosis. J Am Acad Dermatol 2012;67:495 e1-17.  Back to cited text no. 5
Khashashneh I, Shatnawi M, Tawalbeh A, Alhaji M, Rajjal M. Giant congenital hairy nevus on the scalp. Sudan J Med Sci 2008;3:343-7.  Back to cited text no. 6
Hale EK, Stein J, Ben-Porat L, Panageas KS, Eichenbaum MS, Marghoob AA, et al. Association of melanoma and neurocutaneous melanocytosis with large congenital melanocytic naevi-results from the NYU-LCMN registry. Br J Dermatol 2005;152:512-7.  Back to cited text no. 7
Kinsler VA, Chong WK, Aylett SE, Atherton DJ. Complications of congenital melanocytic naevi in children: Analysis of 16 years'experience and clinical practice. Br J Dermatol 2008; 159:907-14.  Back to cited text no. 8
Ramaswamy V, Delaney H, Haque S, Marghoob A, Khakoo Y. Spectrum of central nervous system abnormalities in neurocutaneous melanocytosis. Dev Med Child Neurol 2012;54:563-8.  Back to cited text no. 9
Bastian BC, Xiong J, Frieden IJ, Williams ML, Chou P, Busam K, et al. Genetic changes in neoplasms arising in congenital melanocytic nevi: differences between nodular proliferations and melanomas. Am J Pathol. 2002;161:1163-9.  Back to cited text no. 10
Aoyagi S, Akiyama M, Mashiko M, Shibaki A, Shimizu H. Extensive proliferative nodules in a case of giant congenital naevus. Clin Exp Dermatol 2008;33:125-7.  Back to cited text no. 11
Davar D, Lin Y, Kirkwood JM. Unfolding the mutational landscape of human melanoma. J Invest Dermatol 2015;135:659-62.  Back to cited text no. 12
Aoude LG, Wadt KA, Pritchard AL, Hayward NK. Genetics of familial melanoma: 20 years after CDKN2A. Pigment Cell Melanoma Res 2015;28:148-60.  Back to cited text no. 13
Soura E, Eliades PJ, Shannon K, Stratigos AJ, Tsao H. Hereditary melanoma: Update on syndromes and management: Genetics of familial atypical multiple mole melanoma syndrome. J Am Acad Dermatol 2016;74:395-7.  Back to cited text no. 14
Yang C, Gru AA, Dehner LP. Common and not so common melanocytic lesions in children and adolescents. Pediatr Dev Pathol 2018;21:252-70.  Back to cited text no. 15

Correspondence Address:
Uttara Chatterjee
Department of Pathology, Institute of Post Graduate Medical Education and Research, Kolkata, West Bengal
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/IJPM.IJPM_38_20

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  [Figure 1], [Figure 2], [Figure 3]

  [Table 1]


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