Giant congenital melanocytic naevus with a novel CUX1–BRAF fusion mutation treated with trametinib

Dear Editor, Giant congenital melanocytic naevi (GCMN) are rare, large melanocytic proliferations, caused by genetic mutations that interfere with the normal proliferation, differentiation and migration of melanoblasts.1 Apart from cosmetic disfigurement, these naevi may be complicated with pain, pruritus, neurocutaneous melanosis and higher risk of melanoma.1 Somatic mutations mainly in NRAS but also in BRAF and in other genes have been described in GCMN.2–4 Both NRAS and BRAF mutations activate the mitogen‐activated protein kinase (MAPK) pathway, which increases proliferation and survival of melanocytes. A 4‐year‐old girl with a GCMN in a bathing trunk distribution presented with a rapidly growing right flank mass accompanied by recent swelling of the inguinal area, perianal and genital pruritus, and pain. Physical examination revealed a large brown plaque affecting the lower trunk, buttocks, genital and inguinal areas with rough consistency, covered with fine hair. Multiple accompanying smaller naevi over the trunk and extremities were observed. A 4‐cm round mass was noted in the right flank area, as well as inguinal lymphadenopathy and genital swelling (Figure 1a,b). Imaging studies demonstrated enlargement of right inguinal lymph nodes (LN) coalescing to a 5‐cm mass with swelling of the perineum, and retroperitoneal lymphadenopathy along the iliac chain without involvement of the spinal canal. Positron emission tomography‐computed tomography revealed an excessive metabolic activity in the right flank mass while only a mild signal in the inguinal LN (Figure 1d‐I). At that point, excision of the right flank mass was performed. Histopathological findings showed epithelioid melanocytes with significant atypia, mitotic figures (8–12 per mm2), hypercellularity and abrupt margins between the tumour nodule and surrounding naevus. The tumour abuts the deep margin focally in the centre of the specimen. The findings were nonconclusive for either an atypical proliferative nodule or transformation to melanoma. Clinical and radiological findings of the giant congenital melanocytic naevus (GCMN) before and after commencement of trametinib. Bathing trunk GCMN with a 4‐cm nodule that rapidly evolved with the appearance of inguinal and genital swelling. (a) Back and (b) front. Clinical improvement in GCMN following 16 months of treatment with trametinib. (c) Back: note that the right flank nodule was excised. Notable diffuse fading of GCMN hyperpigmentation and improvement in overall swelling and skin induration. (d) Improvement of imaging under MEK inhibitor treatment (d‐I) Highly increased uptake presented in positron emission tomography‐computed tomography (PET‐CT) in the right flank and increased uptake in inguinal lymph nodes at patient presentation. (d‐II) PET‐CT 6 months after initiation of trametinib treatment showing decreased swelling and induration, resolution of enlarged lymph nodes and no sites with increased uptake. Biopsy of the suspected inguinal LN demonstrated small naevus cells without atypia. Next‐generation sequencing of DNA extracted from the mass for melanoma mutational hot spots, including BRAF, NRAS, KRAS, was negative. However, comprehensive genomic profiling (FoundationOne® Heme) performed on DNA extracted from the GCMN was positive for a novel fusion mutation of CUX1–BRAF. Although this fusion has not been functionally characterized, other fusions with similar breakpoints in BRAF have been reported as constitutively active, causing hyperactivation of the MAPK pathway,5 therefore supporting the notion that this mutation is driving the GCMN in our patient. Following the surgical procedures, the patient still reported intractable perianal–genital pain and pruritus persisted. As an attempt to suppress melanocytic proliferation in the GCMN and thus improve the patient’s symptoms, we initiated trametinib treatment [MAPK kinase enzyme (MEK) inhibitor] at a dose of 0·6 mg daily. Two weeks after initiation of treatment, the patient reported a significant improvement in pain and pruritus. Currently, 22 months under treatment with trametinib, clinical improvement continues. Pain and pruritus have resolved and swelling has improved. Mild fading of hyperpigmentation has been observed in the GCMN (Figure 1c). Repeated imaging demonstrated improvement in oedema of the entire naevus, normalization of lymphadenopathy, and no new suspicious foci with excessive metabolic activity (Figure 1d‐II). The patient had mild elevation of liver function tests (aspartate aminotransferase up to 59 U L–1, normal ≤34 U L–1), which has been stable under recurrent monitoring. Mild elevation of creatinine phosphokinase (338 U L–1, normal ≤145 U L–1) and mild scalp hair loss were also noted. All abovementioned abnormalities are known adverse effects of trametinib. The presence of a GCMN can have a dramatic effect on a patient’s life, with associated higher risk of neurological complications, malignancy, cosmetic effect and more.1 As already mentioned, GCMN result from postzygotic activating mutations in the MAPK pathway, interfering with the normal proliferation, differentiation and migration of melanoblasts and melanocytes.2–4 The possibility of using MEK inhibitor treatment in selected GCMN cases has been suggested previously,6 but to our knowledge, only one patient with GCMN (due to a AKAP9–BRAF fusion mutation) was treated with a MEK inhibitor, with encouraging results.7 Our patient presented with a novel BRAF mutation (CUX1–BRAF), which has not been reported previously in GCMN. Previous data imply a connection of this mutation to malignancy development,8 possibly via loss of the regulatory domain of BRAF. Hence, these alterations might be sensitive to MEK inhibition. Initiation of trametinib treatment in our patient brought a rapid improvement of pain and pruritus, as well as gradual resolution of objective findings, such as oedema and pigmentation of the naevus. Our findings show that patients with BRAF‐mutated GCMN can benefit from MEK inhibitor treatment. Data are available only on request due to privacy/ethical restrictions. Further investigations regarding the long‐term effect of this treatment, as well as its effect on the risk of melanoma development in GCMN, are warranted. Vered Molho‐Pessach: Conceptualization (lead); data curation (lead); formal analysis (lead); investigation (equal); writing – original draft (lead); writing – review and editing (lead). Stav Hartshtark: Data curation (lead); formal analysis (equal); investigation (equal); validation (equal); visualization (equal); writing – review and editing (equal). Sharon Merims: Conceptualization (equal); data curation (equal); investigation (equal); validation (equal); visualization (equal). Michal Lotem: Formal analysis (equal); investigation (equal); validation (equal); visualization (equal). Nadia Caplan: Investigation (equal); visualization (equal). Hila Alfassi: Validation (equal); writing – review and editing (equal). Alexander Maly: Conceptualization (equal); data curation (equal); formal analysis (equal); validation (equal); visualization (equal). Gal Goldstein: Conceptualization (equal); data curation (equal); formal analysis (equal); investigation (equal); supervision (equal); validation (equal); visualization (equal); writing – review and editing (equal). Rakefet Sidlik Muskatel: Conceptualization (lead); data curation (lead); formal analysis (lead); investigation (lead); resources (lead); supervision (lead); writing – original draft (lead); writing – review and editing (lead).