Dysplastic nevus syndrome

Key points at a glance

Key points about this condition

• Dysplastic nevus syndrome is characterized by multiple atypical melanocytic nevi and increases the risk of skin and ocular melanoma.
• Familial atypical multiple mole melanoma (FAMMM) syndrome is inherited in an autosomal dominant pattern and is associated with CDKN2A gene mutations.
• Dysplastic nevi are usually benign, but they serve as a marker of increased melanoma susceptibility.
• The risk of melanoma in people with dysplastic nevus syndrome can be up to 150 times higher than in the general population.
• Management centers on regular full-body skin examinations and eye examinations for surveillance and early detection.
• Follow-up with ABCDE criteria and total body mapping is recommended.
• The genetic backgrounds of ocular melanoma and skin melanoma are largely different, but shared risk factors also exist.

1. What is dysplastic nevus syndrome?

Dysplastic nevus syndrome (DNS) is a condition characterized by multiple atypical melanocytic nevi and is associated with an increased risk of skin and potential ocular melanoma. It may occur sporadically or as familial atypical multiple mole melanoma (FAMMM) syndrome with an autosomal dominant pattern of inheritance.

Uveal melanoma is the most common primary intraocular malignant tumor in adults, with an annual incidence of about 5 cases per million. The risk of skin melanoma in patients with dysplastic nevus syndrome is up to 150 times higher than in the general population³⁾.

Dysplastic nevi themselves are generally benign lesions, but they are thought to function more as a marker of increased melanoma susceptibility rather than as a direct precursor. Most melanomas arise de novo (newly), not from existing atypical nevi.

Q Do all dysplastic nevi become malignant?

A

No. Most dysplastic nevi remain benign. Many melanomas arise de novo rather than from existing nevi. However, because patients with dysplastic nevus syndrome have a markedly higher risk of developing melanoma (up to 150 times)³⁾, regular skin and eye examinations are essential.

2. Main symptoms and clinical findings

Subjective symptoms

Dysplastic nevi themselves are usually asymptomatic. The following changes may suggest malignant transformation.

• Change in an existing lesion: changes in size, shape, or color.
• Rapid growth: appearance of a new lesion.
• Bleeding and ulceration: bleeding from the lesion or crusting.
• Itching and pain: rare, but can be a sign of malignant transformation.

In uveal melanoma, blurred vision, flashes of light, and floaters may occur, but in the early stages it is often asymptomatic.

Clinical findings (findings confirmed by the doctor during examination)

Features of dysplastic nevus

Evaluated using the ABCDE criteria.

• A (asymmetry): The shape is asymmetrical on both sides.
• B (border irregularity): The edges are jagged and unclear.
• C (color variegation): Multiple colors (brown, black, red, white) are mixed together.
• D (diameter): More than 5 mm.
• E (evolution): Changes over time.

Ophthalmic findings

A comprehensive ophthalmic evaluation is needed, especially in high-risk patients. For monitoring choroidal nevus, “To Find Small Ocular Melanoma Using Helpful Hints Daily” is used. Malignant transformation is suspected when three or more of the following are present: thickness >2 mm, subretinal fluid, orange pigment (lipofuscin), proximity to the optic disc, internal hypoechogenicity on ultrasound, absence of halo, and absence of drusen.

3. Causes and risk factors

Genetic factors

• CDKN2A gene mutation: The most common in FAMMM syndrome. It encodes two tumor suppressor proteins, p16INK4A and p14ARF¹⁾.
• p16INK4A mutation: also increases the risk of pancreatic cancer (17% by age 75)¹⁾.
• p14ARF mutation: rarer, and associations with nervous system tumors have also been reported¹⁾.

Bray et al. (2025) reported a 56-year-old woman with a CDKN2A p14ARF mutation. She had a five-generation family history of melanoma and had developed melanoma three times, along with multiple dysplastic nevi. NCCN guidelines recommend skin examinations every six months, total-body photography, and dermoscopy¹⁾.

Environmental factors

UV exposure is an established risk factor for cutaneous melanoma, but its contribution to ocular melanoma is limited.

Phenotypic risk factors

Fair skin, freckles, and light-colored eyes and hair are associated with risk for both DNS and ocular melanoma.

Prevention and daily care

Regular reapplication of broad-spectrum sunscreen, especially sun protection in childhood, is important. If there is a family history of melanoma, consider genetic counseling.

4. Diagnosis and testing

The diagnosis of dysplastic nevus syndrome is mainly clinical and combines the following tests.

• ABCDE criteria: screening for atypical nevi.
• Dermoscopy: improves the accuracy of distinguishing benign dysplastic nevi from melanoma.
• Total body mapping: digital photographic documentation of the entire body. 34–61% of melanomas in patients with dysplastic nevus syndrome are detected only during follow-up with total body mapping ³⁾.
• Skin biopsy: definitive diagnosis. Breslow thickness (depth of invasion) is the strongest predictor of metastatic potential and survival.
• Dilated fundus examination: screening for choroidal nevi. Optical coherence tomography (OCT), ultrasound, and fundus autofluorescence are used as adjuncts.
• Genetic testing: when there is a strong family history, germline testing for CDKN2A and CDK4 mutations is useful ¹⁾.

Histopathological features

Dysplastic nevi are defined by four main features.

• Lentiginous melanocytic proliferation: proliferation of atypical melanocytes along the basal layer of the epidermis.
• Cytologic atypia: abnormalities in nuclear size, shape, and chromatin pattern.
• Laminated and concentric fibroplasia: fibrosis of the dermal papillae.
• Architectural disorder: irregular nest formation and bridging of epidermal rete ridges.

Costa et al. (2023) examined collagen texture and PRAME expression in 56 lesions from patients with dysplastic nevus syndrome, showing that high-grade dysplastic nevi had greater collagen organization than low-grade lesions, and that patients with a history of melanoma had significantly higher collagen density. PRAME was rarely overexpressed in dysplastic nevi ²⁾.

5. Standard treatment

Monitoring and follow-up

There is no established drug therapy, and management focuses on monitoring, early detection, patient education, and risk reduction.

• Dermatology follow-up: Full-body skin examination every six months in FAMMM syndrome¹⁾.
• Ophthalmology follow-up: Regular dilated examinations. Monitoring with OCT and ultrasound.
• Whole-body photographic documentation: A combination of digital photography and dermoscopy³⁾.

Surgical intervention

Used for lesions that threaten visual function or show malignant transformation.

Treatment considerations

In patients with dysplastic nevus syndrome, there may be more than 100 nevi, and removing all of them is not practical. Selectively biopsy lesions that show change by ABCDE criteria or have suspicious dermoscopic findings.

Q Which lesions should be biopsied?

A

Lesions that show change by the ABCDE criteria (especially E: evolution), newly enlarging lesions, lesions with bleeding or ulceration, and lesions that show atypical patterns on dermoscopy are candidates for biopsy. Because 34–61% of melanomas in patients with dysplastic nevus syndrome are found only during follow-up with total-body photography³⁾, regular digital recording of all lesions is important.

6. Pathophysiology and detailed pathogenesis

The molecular basis of dysplastic nevus syndrome is understood mainly through the CDKN2A gene.

The CDKN2A gene has four exons (1a, 1b, 2, 3) and, through alternative splicing, encodes two different tumor-suppressor proteins¹⁾.

• p16INK4A (exons 1a, 2, 3): inhibits CDK4/6 and promotes G1-phase arrest through the Rb pathway.
• p14ARF (exons 1b, 2, 3): inhibits MDM2 and helps stabilize p53, supporting tumor-suppressor function.

Loss of cell-cycle control and increased melanocyte survival caused by CDKN2A mutations lead to greater susceptibility to melanoma.

The pathophysiology of ocular melanoma (uveal melanoma) is different, with early activating mutations in GNAQ/GNA11 and secondary loss of BAP1 playing central roles. The two diseases have different molecular drivers, but share convergent mechanisms of disrupted cell-cycle regulation and impaired DNA repair.

---

7. Latest research and future directions (research-stage reports)

For patients: Please read

The following content is still in the research stage or under clinical trial and is not standard treatment available at ordinary hospitals. It is reference information for specialists about future medical advances.

Clinical phenotype of CDKN2A p14ARF

Bray et al. (2025) reported a patient with only a CDKN2A p14ARF mutation (p16INK4A was normal) and confirmed that deletion of exon 1b causes loss of the p14ARF tumor suppressor protein¹⁾. NCCN guidelines also recommend surveillance with brain MRI and whole-body MRI for carriers of p14ARF mutations.

PRAME biomarker

In the study by Costa et al. (2023), PRAME was barely expressed in dysplastic nevi, showing its usefulness as a marker to distinguish melanoma from dysplastic nevi²⁾. Only 5 of 24 high-grade dysplastic nevi showed focal expression.

Early detection through total body photography

In patients with dysplastic nevus syndrome who had 645 melanocytic lesions, follow-up with total body photography led to the early diagnosis of three new melanomas (1 superficial spreading melanoma and 2 in situ melanomas)³⁾. It was shown that TBM including all pigmented lesions contributes to improved diagnostic accuracy.

---

8. References

1. Bray JK, Thurman SA, Riegert-Johnson D, Muthusamy K, Sluzevich J. A case of hereditary CDKN2A p14ARF melanoma and dysplastic nevi. JAAD case reports. 2025;61:12-14. doi:10.1016/j.jdcr.2025.04.026. PMID:40530172; PMCID:PMC12173685.
2. Costa PRM, Vieira-Damiani G, Stelini RF, Ferreira LÁ, Cintra ML, Teixeira F.. The texture of collagen and immunoexpression of PRAME in dysplastic nevus syndrome lesions: relationship with melanoma. An Bras Dermatol. 2023;98(1):128-130. doi:10.1016/j.abd.2022.02.002. PMID:36369201; PMCID:PMC9837641.
3. Abrahão-Machado LF, et al. Synchronous and metachronous melanomas diagnosed at early stages in a patient with dysplastic nevus syndrome. An Bras Dermatol. 2023;98(4):556-558.