BRAFV600E mutation in high-grade dysplastic nevi: contributions to the distinction from early melanomas^☆

Dear Editor,

Individuals with multiple dysplastic nevi (DN) are at increased risk for the development of cutaneous melanoma (CM).¹ Their follow-up is essential. Also, it is possible that DN falls within an intermediate stage in CM progression.² The distinction between DN and CM may be challenging, particularly in the presence of pronounced cytoarchitec-tural atypia, the so-called high-grade dysplastic nevi (HDN).¹ Indeed, some excised lesions diagnosed as HDN could actually correspond to early-stage melanomas. Molecular markers have been investigated as auxiliary tools in dis-tinguishing between benign and malignant lesions.³,⁴ The BRAFV600E mutation promotes continuous stimulation of cell proliferation and survival. It is a common early event in melanocytogenesis, identified in up to 80% of acquired melanocytic nevi and in about 50% of CMs, particularly those in the vertical growth phase. However, the BRAFV600E muta-tion alone does not determine malignancy, as it induces a state of oncogenic senescence characterized by cell cycle arrest and blockage of tumor progression. For malig-nant transformation to occur, additional genetic events are required.³,⁵

The BRAFV600E mutation is found in only 6% of intraepi-dermal CMs.⁵ Thus, detecting the mutation in lesions with marked atypia, but without dermal invasion, would favor HDN and could be an auxiliary tool in the differential diag-nosis between HDN and incipient CM. We studied the rate of BRAFV600E gene mutations in a sample of lesions with a histopathological diagnosis of HDN, excised from individuals with dysplastic nevus syndrome.

From the archives of the Pathology Laboratory, all histopathological specimens diagnosed as DN, between 1994 and 2022, were retrieved. Clinical data from patients with DN syndrome were compiled. Two pathologists reviewed the histological sections. The following exclusion criteria were applied: 1) Samples from patients who had fewer than 3 nevi removed at the service; 2) Samples in which histopathological review raised doubts about differential diagnosis between HDN and CM; 3) Patients diagnosed with any genodermatosis. The selected specimens were those which presented: 1) Epidermal hyperplasia with a degree of irregularity and asymmetry; 2) Larger clusters of melanocytes at the dermoepidermal junction or more lentiginous areas; 3) Irregularities in the size, spacing, and polarity of melanocyte clusters and greater asym-metry in their distribution; 4) Uniform, fine (‘‘dusty’’) melanin pigment in the cytoplasm in some areas; 5) More pronounced and continuous cytological atypia, and 6) Asym-metry regarding hypervascularization, lymphoid infiltrate, and melanophages beneath the epidermis (Fig. 1).

Fig. 1
Junctional dysplastic melanocytic nevus with marked cytoarchitectural disorder. Hematoxylin & eosin, ×40 (A) and ×400 (B).

After applying the exclusion criteria, 25 HDN (9 patients, 5 male, 4 female) were included. Five 10 µ,m-thick lesions’ sections were cut with sterile blades and stored in 1.5 mL polypropylene tubes. DNA extraction was per-formed using the QIAamp DNA FFPE Tissue Kit (Qiagen, Germany), according to the manufacturer’s protocol. The BRAFV600E mutation was screened by digital PCR using the QuantStudio 3D platform (Applied Biosystems, USA) and the TaqMan^TM Liquid Biopsy dPCR Assay Hs000000004 rm; BRAF 476 (Applied Biosystems, USA).

Of the 25 HDN, 17 (68%) carried the BRAF mutation and 8 (32%) did not. All patients were white, and the mean age at diagnosis of the first DN was 27.8 years. Tables 1 and 2 show clinical data of patients and the lesions’ topography. All patients had at least one HDN with the BRAFV600E muta-tion, and 5 patients also had HDN without the mutation.

Table 1
Clinical data of the patients and number of HDNs.

Patient	Sex	Agea	Personal history of melanoma	Family history of melanoma	Personal and family history of melanoma	Total number of HGDNs	HDNs with mutation	HDNs without mutation
1	M	22	Yes	Yes (sister)	Yes	10	7	3
2	M	15	Yes	No	No	3	2	1
3	M	27	No	No	No	2	1	1
4	F	22	Yes	Yes (mother)	Yes	1	1	0
5	F	24	Yes	No	No	3	1	2
6	M	27	Yes	Yes (uncle)	Yes	1	1	0
7	F	45	Yes	No	No	1	1	0
8	F	24	Yes	Yes	Yes	1	1	0
9	M	45	Yes	No	No	3	2	1

• ^a
  Age at diagnosis of the first dysplastic nevus.

Table 2
Dysplastic nevi with more pronounced cytoarchi-tectural atypia (n = 25): lesion topography.

Axial lesions	15 (60%)
Limb lesions	9 (36 %)
Lesion with unspecified location	1 (4 %)

Our results reflect the described higher prevalence of DNs in young, fair-skinned individuals, developing in photo-exposed areas, especially the trunk.⁴ The BRAFV600E mutation rate was similar to that described for DN in gen-eral (70%-80%), and much higher than that in early-stage melanomas (5%-10%).³,⁵

Interestingly, only one of the nine patients had no per-sonal history of melanoma. There is an association between multiple DNs and higher melanoma risk, although the chance of transformation for an isolated DN is low. This risk can be over 1200 times higher when there is a personal and family history of melanoma.²

Studies suggest that the absence of this mutation may be associated with more aggressive genetic alterations, such as NRAS and TERT mutations and CDKN2A deletions, indi-cating a molecular profile closer to incipient melanoma.⁶ This hypothesis highlights the importance of considering BRAFV600E-negative HDN as potentially higher-risk lesions.

Saroufim et al. reported a high prevalence of somatic BRAF mutations in dysplastic nevi, supporting the concept that BRAF activation represents an early event in melanocytic tumorigenesis. In addition, the observation of discordant BRAF mutational status among multiple dysplas-tic nevi within the same individual suggests that these mutations are independent somatic events rather than reflecting a constitutional predisposition, likely influenced by local environmental factors.⁷

There is still controversy regarding the follow-up of patients with a diagnosis of DN, because of the difficulty in distinguishing HDN from intraepidermal melanoma.⁸ In a multicenter study with 438 individuals, patients with two or more DN presented a significantly higher risk of developing melanoma in areas different from the DN biopsy. Therefore, regular full-body skin screening is important.⁹

This study has some limitations that should be acknowl-edged. The size of the study, determined by the number of included patients and analyzed dysplastic nevi, limits the generalizability of the findings. In addition, the absence of melanoma samples precludes direct diagnostic comparisons. Laser capture microdissection was not performed.

Overall, the integration of molecular, histopathological, and clinical data is essential for improving risk stratification and the management of high-grade dysplastic nevi.

• ☆
  Study conducted at the Medical Sciences School, Universidade Estadual de Campinas, Campinas, SP, Brazil.
• Financial support
  None declared.

Research data availability

The entire dataset supporting the results of this study was published in this article.

References

• ¹ Rezze GG, Leon A, Duprat J. Dysplastic nevus (atypical nevus). An Bras Dermatol. 2010;85:863-71.
• ² Lachiewicz AM, Berwick M, Wiggins CL, Thomas NE. Epidemio-logic support for melanoma heterogeneity using the surveillance, epidemiology, and end results program. J Am Acad Dermatol. 2008;58:719-28.
• ³ Shain AH, Bastian BC. From melanocytes to melanomas. Nat Rev Cancer. 2016;16:345-58.
• ⁴ Friedman RJ, Farber MJ, Warycha MA, Papathasis N, Miller MK, Heilman ER. The ‘‘dysplastic’’ nevus. Clin Dermatol. 2009;27:103-15.
• ⁵ Pollock PM, Harper UL, Hansen KS, Yudt LM, Stark M, Robbins CM, et al. High frequency of BRAF mutations in nevi. Nat Genet. 2003;33:19-20.
• ⁶ Shain AH, Yeh I, Kovalyshyn I, Sriharan A, Talevich E, Gagnon A, et al. The genetic evolution of Melanoma from precursor lesions. N Engl J Med. 2015;373:1926-36.
• ⁷ Saroufim M, Novy M, Taraif S, Habib RH, Loya A, Rauscher B, et al. BRAF mutational epidemiology in dysplastic nevi: does dif-ferent solar UV radiation exposure matter? J Eur Acad Dermatol Venereol. 2014;28:615-25.
• ⁸ Briatico G, Argenziano G. Dysplastic Nevus or Melanoma? a com-mentary on the ‘‘patient and doctor anecdotal observations’’ article. Int J Dermatol. 2025;64:1155-6.
• ⁹ Kim CC, Berry EG, Marchetti MA, Swetter SM, Lim G, Grossman D, et al. Risk of subsequent cutaneous Melanoma in moderately dysplastic nevi excisionally biopsied but with positive histologic margins. JAMA Dermatol. 2018;154:1401-8.

Edited by

• Editor
  Hiram Larangeira de Almeida Jr

Publication Dates

• Publication in this collection
  24 Aug 2026
• Date of issue
  2026

History

• Received
  18 Nov 2025
• Accepted
  19 Jan 2026
• Published
  16 June 2026