Giant Congenital Melanocytic Nevus Treated With Trametinib Adnan Mir, MD, PhD,a Nnenna G. Agim, MD,a Alex A. Kane, MD,b Shellie C. Josephs, MD,c Jason Y. Park, MD, PhD,d Kathleen Ludwig, MDe

Giant congenital nevi are melanocytic proliferations of the skin that may be abstract complicated by melanoma, neurocutaneous melanocytosis, pain, pruritus, and disfigurement. Current treatment options include surgical resection and medical management of associated symptoms. There is limited efficacy in these modalities. No effective pharmacologic treatments are available for the treatment of these lesions. We present the case of a 7-year-old girl with a giant congenital melanocytic nevus that had an AKAP9-BRAF fusion and was treated with trametinib, which resulted in rapid resolution of the patient’s lifelong, intractable pain and pruritus as well as dramatic improvement in the Departments of aDermatology, bPlastic Surgery, cRadiology, extent of her nevus. and dPathology, Eugene McDermott Center for Human Growth and Development, and eDivision of Pediatric Hematology and Oncology, University of Texas Southwestern Medical Center, Dallas, Texas

Congenital melanocytic nevi (CMNs) Traditional treatments of GCMNs have Dr Mir initiated the testing that led to the described are melanocytic proliferations that relied on serial surgical resection with treatment and drafted the manuscript; Drs Agim, typically present in the skin at birth skin grafting or tissue expansion and Kane, and Josephs collected data and critically fi reviewed the manuscript; Dr Park performed genetic or shortly thereafter and are classi ed advancement. However, this is of testing for the patient described in this study and primarily on the basis of size. Giant limited use in large lesions and in those critically reviewed the manuscript; Dr Ludwig congenital melanocytic nevi (GCMNs) that impinge on vital structures. The initiated therapy, coinitiated the submission of this are defined as those CMNs that are presence of activation of the MAPK manuscript, and performed the first critical review fi predicted to be $40 cm in diameter pathway has led to the suggestion that of the manuscript; and all authors approved the nal manuscript as submitted and agree to be by adulthood and that may be targeting MAP/ERK kinase (MEK), accountable for all aspects of the work. complicated by melanoma, which is a downstream target of this DOI: https://doi.org/10.1542/peds.2018-2469 neurocutaneous melanocytosis, pathway, may be a viable treatment severe pain and pruritus, option.6 No successful attempts at this Accepted for publication Oct 3, 2018 hypohidrosis, xerosis, cosmetic therapy have been reported thus far, Address correspondence to Kathleen Ludwig, MD, UT disfigurement, and social isolation. and GCMNs continue to be difficult to Southwestern Medical Center, 5323 Harry Hines Blvd, ∼ Dallas, TX 75390. E-mail: kathleen.wiertel@ There is an estimated incidence of 1 manage. utsouthwestern.edu in 20 000 to 500 000 live births.1,2 PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, GCMNs are caused by somatic 1098-4275). CASE REPORT mosaicism in melanocytic precursors. Copyright © 2019 by the American Academy of NRAS mutations can be found in 80% A 6-week-old African American girl Pediatrics to 95% of GCMNs and result in the presented with a dark brown nevus FINANCIAL DISCLOSURE: The authors have indicated activation of the mitogen-activated that covered the majority of the back they have no financial relationships relevant to this protein kinase (MAPK) and and extended onto the flanks, right article to disclose. phosphatidylinositol 3-kinase (PI3K) abdomen, buttocks, thighs, and FUNDING: No external funding. pathways, which ultimately increases suprapubic area. There were scattered POTENTIAL CONFLICT OF INTEREST: The authors have the proliferation and survival of satellite nevi on the scalp, face, indicated they have no potential conflicts of interest melanocytes.3 BRAF-activating extremities, and buttocks, with multiple to disclose. mutations (single-nucleotide hyperpigmented nail bands. Over the variants and fusions) that activate next several years, she developed To cite: Mir A, Agim NG, Kane AA, et al. Giant the MAPK pathway have also been significant, disfiguring thickening of the Congenital Melanocytic Nevus Treated With Trametinib. Pediatrics. 2019;143(3):e20182469 reported.4,5 nevus, predominantly over her back

Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 143, number 3, March 2019:e20182469 CASE REPORT FIGURE 1 Clinical images of the patient over time reveal a GCMN with progressive growth and thickening. A, The patient at age 8 months. B, The patient at age 4 years. C, The patient at age 6 years. D, Six months after the initiation of treatment with trametinib at age 7 years, there is marked improvement with a decrease in thickness, rugosity, and nodularity. and abdomen (Fig 1 A–C). She enhancement based on the MRI and activating single-nucleotide developed intractable, sleep- and enlarged inguinal lymph nodes, all of mutations in NRAS, BRAF,orPIK3CA. behavior-altering pruritus that was which were benign) as well as Because BRAF-activating fusions have only minimally responsive to topical debulking procedures. However, these been previously reported in GCMNs, steroids and systemic antihistamines, procedures provided no relief of her the residual biopsy material was also topiramate, gabapentin, pregabalin, symptoms, and the decision was tested in an extended sequencing and clonidine. MRI at age 6 years made to forgo any further surgical panel for additional activating revealed numerous T1-hyperintense intervention. Histologic evaluation of mutations, including fusions. This foci in the brain that were consistent excision specimens revealed additional testing revealed an AKAP9- with neurocutaneous melanocytosis, melanocytic proliferation with sheets BRAF fusion. Fusions with similar but the results of her neurologic of melanocytes within the dermis that break points in BRAF have been examination were normal, and she extended into the subcutis. There was reported as being constitutively had no history of seizures (Fig 2). normal maturation with smaller nests active and oncogenic, which There was marked thickening of the and melanocytes in deeper portions hyperactivates the MAPK pathway.7 dermis with invasion of the nevus of the lesion, in which cells were through the subcutaneous tissue and slightly elongated and pigmentation At 7 years of age and on the basis of into the fascia and musculature in the was denser. No mitotic activity was the AKAP9-BRAF fusion, the patient trunk and pelvis (Fig 3 A–C). identified (Fig 4). The results of was started on trametinib, an oral immunohistochemical staining for MEK inhibitor, at a dose of 0.5 mg Surgical management consisted of BRAF V600E mutation were daily. Within a month of starting the incisional biopsies of suspicious negative, and direct sequencing of medication, she was weaned off lesions (including areas of infiltrating involved tissue revealed no hydroxyzine, cetirizine, naproxen,

Downloaded from www.aappublications.org/news by guest on September 30, 2021 e2 MIR et al and near resolution of muscular invasion (Fig 3 D–F). By this time, she had a dramatic improvement in the size, texture, and thickness of her lesions (Fig 1D). Eleven months into therapy, her clinical findings and symptoms continued to improve.

DISCUSSION Activating mutations in NRAS occur in 80% to 95% of GCMNs.3 BRAF V600E mutations have also been identified in a smaller percentage of patients (∼8%) and lead to activation of the MAPK pathway, with minimal activation of PI3K.4 The activation of these signaling FIGURE 2 A, Sagittal T1-weighted image of the brain with T1 shortening in the mesial temporal lobe (marked pathways leads to melanocyte by the arrow). B, Coronal T1-weighted image of the brain with T1 shortening in the mesial temporal growth, proliferation, survival, lobe (marked by the arrow). and transformation.1 Although inhibition of the MAPK pathway has pregabalin, and clonidine. Her pain insomnia. Repeat MRI was completed been targeted in the treatment of and pruritus resolved completely. She 6 months into therapy and revealed numerous malignancies (including had no additional complaints of decreased thickening of the dermis melanoma), no reports of its successful use in the treatment of benign cellular proliferations, such as complex GCMNs and neurocutaneous melanocytosis, have been reported to date.1,6,8 Initial sequencing evaluation for single-nucleotide mutations in 25 genes (including NRAS and BRAF) revealed no mutations in biopsy samples from our patient. However, fusion analysis revealed an AKAP9- BRAF fusion that has not previously been reported in CMNs. AKAP9-BRAF fusion produces a kinase that lacks the regulatory domains of BRAF, which results in constitutive activation in a RAS-independent manner and exhibits transforming activity similar to that of BRAF V600E point mutation.5,7,9 Existing data BRAF FIGURE 3 suggest that such -activating A, Abdominal MRI reveals dermal thickening and latissimus dorsi enhancement (marked by the arrow). alterations may confer sensitivity to The arrowhead indicates the uninvolved anterior abdominal wall. B, Pelvic images reveal enlargement MEK inhibition.10 and enhancement of the inguinal lymph nodes (marked by the arrow) and marked dermal thickening (marked by the double arrow). C, Posterior dermis measuring 29 mm before treatment. D, Abdominal Trametinib is a MEK inhibitor that is MRI reveals that the dermal thickening and latissimus dorsi enhancement (marked by the arrow) are well tolerated in pediatric patients.11 fi signi cantly improved after treatment. The arrowhead indicates the uninvolved anterior abdominal Given her extreme symptoms and wall. E, Pelvic images reveal that the enlargement and enhancement of the inguinal lymph nodes (marked by the arrow) and marked dermal thickening (marked by the double arrow) are significantly lack of improvement with surgical improved after treatment. F, Posterior dermis measuring 14 mm after treatment. intervention, our patient was started

Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 143, number 3, March 2019 e3 and large/giant congenital melanocytic nevi. Pediatr Dev Pathol. 2015;18(1): 1–9 5. Ciampi R, Knauf JA, Kerler R, et al. Oncogenic AKAP9-BRAF fusion is a novel mechanism of MAPK pathway activation in thyroid cancer. J Clin Invest. 2005; 115(1):94–101 6. Küsters-Vandevelde HV, Willemsen AE, Groenen PJ, et al. Experimental treatment of NRAS-mutated FIGURE 4 neurocutaneous melanocytosis with A, Histologic analysis of a biopsy specimen that was taken before treatment with trametinib reveals MEK162, a MEK-inhibitor. Acta a deeply infiltrative intradermal proliferation of melanocytes, with relatively uniform nuclei and moderate amounts of pale-staining to lightly pigmented cytoplasm. B, No mitotic figures were Neuropathol Commun. 2014;2:41 fi identi ed within the lesion. C, Small, mature melanocytes are present at the deep border of this 4- 7. Sievert AJ, Lang SS, Boucher KL, et al. cm-thick excisional biopsy, which is just superficial to fascia. There is a conspicuous absence of subcutaneous adipose tissue, which has been replaced by nevus. Paradoxical activation and RAF inhibitor resistance of BRAF protein kinase fusions characterizing pediatric astrocytomas [published correction on this therapy and has tolerated it ABBREVIATIONS well without any detectable toxicity appears in Proc Natl Acad Sci U S A. to date. She had an excellent initial CMN: congenital 2013;110(21):8750]. Proc Natl Acad Sci – response in symptoms with melanocytic nevus USA. 2013;110(15):5957 5962 remarkable continued improvement GCMN: giant congenital 8. Holderfield M, Deuker MM, McCormick in her skin findings. Importantly, she melanocytic nevus F, McMahon M. Targeting RAF kinases has had a dramatic improvement in MAPK: mitogen-activated protein for cancer therapy: BRAF-mutated her quality of life as described kinase melanoma and beyond. Nat Rev Cancer. subjectively by her family. Her MEK: MAP/ERK kinase 2014;14(7):455–467 previous anxiety, pain, and insomnia PI3K: phosphatidylinositol 9. Kandoth C, McLellan MD, Vandin F, et al. are now resolved. 3-kinase Mutational landscape and significance Our findings reveal that patients with across 12 major cancer types. Nature. 2013;502(7471):333–339 BRAF-mutated giant congenital nevi and symptomatic neurocutaneous REFERENCES 10. Ross JS, Wang K, Chmielecki J, et al. The fi distribution of BRAF gene fusions in melanocytosis may bene tfrom 1. Meshram GG, Kaur N, Hura KS. Giant solid tumors and response to targeted therapy that is targeted at the MAPK congenital melanocytic nevi: an update therapy. Int J Cancer. 2016;138(4): pathway. Although this represents and emerging therapies. Case Rep 881–890 a small proportion of patients with Dermatol. 2018;10(1):24–28 GCMNs, it suggests that combination 2. Schaffer JV. Update on melanocytic nevi 11. Drobysheva A, Klesse LJ, Bowers DC, therapy that is used to target the PI3K in children. Clin Dermatol. 2015;33(3): et al. Targeted MAPK pathway inhibitors and MAPK pathways may be effective 368–386 in patients with disseminated pilocytic in the majority of patients whose nevi astrocytomas. J Natl Compr Canc Netw. NRAS 3. Kinsler VA, Thomas AC, Ishida M, et al. 2017;15(8):978–982 harbor mutations. Additional Multiple congenital melanocytic nevi studies will be required to determine and neurocutaneous melanosis are 12. Krengel S, Hauschild A, Schäfer T. the rates of disease- and treatment- caused by postzygotic mutations in Melanoma risk in congenital related complications in these codon 61 of NRAS [published correction melanocytic naevi: a systematic review. patients. Malignant transformation in appears in J Invest Dermatol. 2016; Br J Dermatol. 2006;155(1):1–8 large CMNs and GCMNs occurs in 2% 136(11):2326]. J Invest Dermatol. 13. Watt AJ, Kotsis SV, Chung KC. Risk of – to 3% of patients, and it remains to be 2013;133(9):2229 2236 melanoma arising in large congenital seen whether inhibition of the PI3K 4. Salgado CM, Basu D, Nikiforova M, et al. melanocytic nevi: a systematic review. and MAPK pathways affects this rate BRAF mutations are also associated Plast Reconstr Surg. 2004;113(7): of transformation.2,12,13 with neurocutaneous melanocytosis 1968–1974

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