The Future of Treatment and Research for Giant Congenital Melanocytic Nevi

Congenital melanocytic nevi (CMN) have long posed a clinical paradox: lesions that are often benign in behavior yet burdened by a measurable risk of melanoma and significant psychosocial impact. Present at birth or emerging in early infancy, CMN vary widely in size, distribution, and long-term implications, leaving clinicians to navigate complex decisions around surveillance, intervention, and patient expectations. Management strategies have historically been driven by an urgency to mitigate melanoma risk through aggressive removal, but evolving evidence and advances in both procedural and molecular therapeutics are reshaping how dermatologists approach these lesions. This has prompted a reexamination of longstanding treatment paradigms and opening the door to more individualized, and potentially less invasive, care.

DEFINING CMN

CMN are pigmented skin lesions caused by sporadic post-zygotic somatic mutations, most commonly in NRAS, that are present at birth or appear within the first few weeks of life.¹ While they are typically benign, patients with CMN are at a higher risk of melanoma than the general population. CMN are classified by their adult size, which stratifies their melanoma risk. While small (<1.5 cm) and medium-sized (1.5-20 cm) CMN have a melanoma risk of less than 1%, large (20-40 cm) and giant (>40 cm) CMN pose a greater risk, from 1.25% to 10%.^2,3 This increased risk of melanoma is a driving force for patients seeking treatment of their CMN.⁴ The morbidity of these visually prominent nevi, particularly the large and giant congenital nevi, often causes psychosocial impact and stigmatization, leading to a greater desire for interventions to change their appearance or removal.⁵

MELANOMA RISK FOR CMN PATIENTS

We know that of those with CMN, patients with large and giant variants are at the highest risk of developing melanoma, with the greatest risk factors including that giant size and the presence of multiple CMN, commonly referred to as “satellite nevi.”² High-risk CMN may involve central nervous system tissue (termed neurocutaneous melanocytosis), and an abnormal screening MRI is the greatest predictor of melanoma in these patients. They are followed during their pediatric years for monitoring of two potential changes: the development of new skin nodules or new neurologic symptoms. As these patients move into adulthood, many are lost to follow-up or not monitored as closely. Studies have shown that the risk of melanoma extends well beyond the pediatric years. A retrospective study of an Italian cohort revealed a mean age of patients with CMN-associated melanoma to be 33 years old, ranging from 11-70 years old.⁶ Further data from the Surveillance, Epidemiology, and End Results database (SEER) suggest that only about 27% of melanomas arising in a giant pigmented nevus are diagnosed in patients under the age of 40, with a peak diagnosis age of 50-59 years old.⁷ This challenges the idea that melanoma in CMN is a predominantly pediatric concern and affirms that life-long, consistent monitoring is essential. 

REMOVAL AT ANY COST? NOT ANYMORE

For many years, surgical removal of CMN was the standard of care for both aesthetic improvement and melanoma prevention.⁸ This ideology of “removal at any cost,” especially for patients with large and giant CMN, often led to procedures with high morbidity rates at a young age. Pediatric patients were often exposed to multi-stage procedures leading to large scars in addition to hospitalizations, infections and wound healing delays.⁸ We now understand that this premise of “removal at any cost” is not only impractical but also unnecessary. Complete excision of a large or giant CMN is often technically impossible and does not impact the risk of melanoma arising in the central nervous system or viscerally. There are also reported cases of patients who underwent surgical treatment of their CMN with subsequent development of melanoma.^9,10

The REALITY OF DERMABRASION

Dermabrasion, a technique which involves the resurfacing of the top layers of the skin using a high-speed diamond burr, was once thought to be a promising treatment for the aesthetic improvement of CMNs indicated under the guise of melanoma prevention. While initial early outcomes may appear to have reduced pigment, this approach is commonly associated with prolonged wound healing, scarring, and considerable repigmentation years after the procedure. It offers no benefit in terms of melanoma prevention. For these reasons, the CMN Surgery Network does not recommend dermabrasion.⁸

A LONG LASER JOURNEY

Unlike excision and other surgical approaches, laser treatment offers a less invasive alternative for CMN and may be considered for lesions that are too large or anatomically difficult to remove surgically. Combination laser treatment with long-pulsed laser irradiation followed by simultaneous Q-switched laser treatment has been shown to reduce pigment; however, this approach requires multiple treatments and favors patients with lighter skin types.¹¹ The success of lasers in the treatment of CMN, both with ablative and pigment-specific lasers, is potentiated by the combination of surgical excision. In a study comparing laser-only treatment to combination partial surgical excision followed by laser treatment for CMNs in cosmetically sensitive areas, the laser-only patients were found to have pigment remaining, cosmetically visible depigmented marks, depressive scars, persistent erythema, or repigmentation even after several laser treatments. The combination group, on the other hand, was found to have more favorable cosmetic outcomes with fewer laser treatment sessions.¹²

Laser-treated CMN and the risk of melanoma remains controversial. In addition to the known risk associated with CMN, there is a theoretical risk of melanoma secondary to the laser treatment, although no such cases have been reported to date. Laser-induced changes in the nevus in addition to incomplete removal of nevus cells may impact clinical monitoring.¹¹ Altogether, in specific contexts, lasers may offer improvement in the cosmetic appearance of patients with CMN, though risks of other aesthetic changes and ongoing melanoma monitoring are important considerations in shared decision making.  

A SHIFT TOWARD FUTURE GENE-DRIVEN THERAPIES

As we learn more about the genetics and pathways involved in CMN pathogenesis, promising new studies and strategies are on the horizon for future care. NRAS mutations are found in a majority of giant CMNs, leading to the activation of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways.¹³ BRAF mutations, which also activate the MAPK pathway, have been reported in CMN, though not as commonly.¹⁴ The presence of these activating mutations has led to the trial of MAP/ERK kinase (MEK) inhibitors, a downstream target of the MAPK pathway, as well as BRAF-targeted therapy in the treatment of CMN. 

MEK INHIBITORS

Cases have been reported describing the use of systemic MEK inhibitors to improve symptoms and proliferation of CMN in severe presentations. A young girl with an activating BRAF mutation in her giant CMN had dramatic improvement in size, texture, thickness of her lesions, and symptoms, including pruritus, upon starting trametinib.¹⁵ Another case of a patient with a giant CMN of nevus spilus type and kaposiform lymphangiomatosis (KLA), both with NRAS mutations, saw significant improvement in the appearance of the giant CMN (fading brown macules) with oral selumetinib.¹⁶ While these case reports suggest success with use of MEK inhibitors, a senescent state of giant CMN cells may contribute to the limited efficacy of MEK inhibitors;¹⁷ this treatment has not led to “removal” of the CMN and effects on melanomagenesis require further study. 

BRAF-TARGETED THERAPY

While we know that BRAF gene rearrangements can be found in a small number of giant CMN, studies now reveal that patients with CMN harboring BRAF fusions may have distinctive tumor stroma with desmoplasia as well as numerous satellite nevi that are characterized by firmness, nodularity, and pruritus.^14,18 These distinct clinical findings may help direct genetic testing and future consideration of BRAF-targeted treatment. 

GENE SILENCING 

Because of the high prevalence of RAS gene mutations in CMN, there may be a paradigm shift of CMN treatment toward targeted gene silencing. A study by Bryant et al showed that using small interfering RNA (siRNA) targeted specifically at the mutant NRAS gene successfully silenced that gene both in vitro and in a humanized transgenic mouse.¹⁹ When compared to MEK-inhibitor trametinib, the siRNA was more successful at triggering apoptosis of the nevus cells, as opposed to just slowing down the cell growth as seen in treatment with MEK-inhibitors. This novel therapeutic approach not only highlights the potential for CMN resolution in humans and prevention of melanoma in those patients but also leads to a fundamental shift in preventative cancer therapies driven by RAS mutations.¹⁹ Many patients are optimistic for future human studies of this technology.

ANTI-BCL2 THERAPY

Giant CMN contain two distinct populations of cells, senescent and proliferative cells, and both populations express the BCL2 protein; thus, anti-BCL2 therapy has been proposed for the treatment of CMN. While not yet studied in human patients, treatment of mice with giant CMN with BCL2 inhibitor led to visible lightening of the nevus through activation of neutrophils and the host’s immune system.¹⁷

CONCLUSION

Over the past several decades, the treatment of CMN has evolved from broad, invasive procedures with high morbidity to more limited procedures, and future research may enable the use of sophisticated targeted therapies with incredible potential. The goal of modifying the appearance of CMN and managing its psychosocial impact on patients has remained constant, as has the risk of melanoma. Regardless of patient age or treatment decision, it is imperative for our patients with CMN to have ongoing regular skin surveillance with a dermatologist.

1. Moustafa D, Blundell AR, Hawryluk EB. Congenital melanocytic nevi. Curr Opin Pediatr. 2020;32(4):491-497. doi:10.1097/MOP.0000000000000924

2. Pastore LM, Valentini R, Marghoob AA. Congenital melanocytic nevi and risk of melanoma. Clin Dermatol. 2025;43(3):378-384. doi:10.1016/j.clindermatol.2024.09.004

3. 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. 2000;106(4):736-741. doi:10.1542/peds.106.4.736

4. Kinsler VA, O’Hare P, Bulstrode N, et al. Melanoma in congenital melanocytic naevi. Br J Dermatol. 2017;176(5):1131-1143. doi:10.1111/bjd.15301

5. Paller AS, Rangel SM, Chamlin SL, et al. Stigmatization and Mental Health Impact of Chronic Pediatric Skin Disorders. JAMA Dermatol. 2024;160(6):621-630. doi:10.1001/jamadermatol.2024.0594

6. Caccavale S, Calabrese G, Mattiello E, et al. Cutaneous Melanoma Arising in Congenital Melanocytic Nevus: A Retrospective Observational Study. Dermatology. 2021;237(3):473-478. doi:10.1159/000510221

7. Ugwu N, Hawryluk EB, Weiss J. Epidemiological patterns and survival outcomes in 1666 cases of malignant melanomas arising from giant pigmented nevi. J Am Acad Dermatol. 2024;91(4):727-729. doi:10.1016/j.jaad.2024.05.076

8. Ott H, Krengel S, Beck O, et al. Multidisciplinary long-term care and modern surgical treatment of congenital melanocytic nevi - recommendations by the CMN surgery network. J Dtsch Dermatol Ges. 2019;17(10):1005-1016. doi:10.1111/ddg.13951

9. Kugar M, Akhavan A, Ndem I, et al. Malignant Melanoma Arising From a Giant Congenital Melanocytic Nevus in a 3-Year Old: Review of Diagnosis and Management. J Craniofac Surg. 2021;32(4):e342-e345. doi:10.1097/SCS.0000000000007115

10. Costa BA, Zibara V, Singh V, et al. Case report: Later onset of NRAS-mutant metastatic melanoma in a patient with a partially-excised giant congenital melanocytic nevus. Front Med (Lausanne). 2022;9:1086473. Published 2022 Dec 8. doi:10.3389/fmed.2022.1086473

11. Tsai SY, Buta MR, Bojovic B, et al. Combination Laser Treatment in Procedural Management of Congenital Melanocytic Nevi. Lasers Surg Med. 2025;57(4):306-311. doi:10.1002/lsm.70007

12. Oh Y, Lee SH, Lim JM, Chung KY, Roh MR. Long-term outcomes of laser treatment for congenital melanocytic nevi. J Am Acad Dermatol. 2019;80(2):523-531.e12. doi:10.1016/j.jaad.2018.08.046

13. Charbel C, Fontaine RH, Malouf GG, et al. NRAS mutation is the sole recurrent somatic mutation in large congenital melanocytic nevi. J Invest Dermatol. 2014;134(4):1067-1074. doi:10.1038/jid.2013.429

14. Martin SB, Polubothu S, Bruzos AL, et al. Mosaic BRAF Fusions Are a Recurrent Cause of Congenital Melanocytic Nevi Targetable by MAPK Pathway Inhibition. J Invest Dermatol. 2024;144(3):593-600.e7. doi:10.1016/j.jid.2023.06.213

15. Mir A, Agim NG, Kane AA, Josephs SC, Park JY, Ludwig K. Giant Congenital Melanocytic Nevus Treated With Trametinib. Pediatrics. 2019;143(3):e20182469. doi:10.1542/peds.2018-2469

16. Berna R, Hasbun T, Adams D, Moon AT, Treat JR. Significant improvement of a nevus spilus-type congenital melanocytic nevus with oral selumetinib. Pediatr Dermatol. 2024;41(5):936-937. doi:10.1111/pde.15666

17. Wei B, Yu Q, Jin J, et al. Anti-BCL2 therapy eliminates giant congenital melanocytic nevus by senolytic and immune induction. Signal Transduct Target Ther. 2025;10(1):161. Published 2025 May 16. doi:10.1038/s41392-025-02247-2

18. Roy SF, Agim NG, Mir A, et al. Congenital melanocytic naevi initiated by BRAF fusion oncogene with firmness, pruritus and desmoplastic stroma. Br J Dermatol. 2025;193(2):232-239. doi:10.1093/bjd/ljaf061

19. Bryant D, Barberan-Martin S, Maeshima R, et al. RNA Therapy for Oncogenic NRAS-Driven Nevi Induces Apoptosis. J Invest Dermatol. 2025;145(1):122-134.e11. doi:10.1016/j.jid.2024.04.031

Tatiana F. Abrantes, MD

• Department of Dermatology
• Warren Alpert Medical School of Brown University

Providence, RI

Elena B. Hawryluk, MD, PhD

• Department of Dermatology, Massachusetts General Hospital
• Harvard Medical School

Boston, MA