Eyelid Nevus (Mole)

Key points of this disease

• Eyelid nevus is a benign tumor caused by proliferation of immature pigment cells (nevus cells) and is the most common eyelid benign tumor (22%).
• Histologically, it is classified into junctional nevus, compound nevus, intradermal nevus, blue nevus, nevus of Ota, etc.
• Intradermal nevus is the most common, appears dome-shaped, and rarely undergoes malignant transformation.
• Junctional and compound nevi may rarely transform into malignant melanoma, so complete excision is recommended.
• The ABCDE criteria and dermoscopy are useful for differentiating from malignant melanoma, and definitive diagnosis is made by histopathological examination.
• Q-switched laser is effective for nevus of Ota, and attention should also be paid to the risk of uveal melanoma due to pigmentation of the iris and sclera.
• BRAF V600E mutation is found in about 80% of acquired nevi and is important as a molecular mechanism of malignant transformation.

1. What is eyelid nevus (mole)?

Eyelid nevus is a benign tumor in which immature pigment cells (nevus cells) proliferate from the basal layer of the epidermis into the dermis. The closer to the epidermis, the richer the melanin pigment, and the deeper in the dermis, the less pigment. As the main location of nevus cell nests shifts from superficial to deep layers, they are histologically classified into junctional nevus, compound nevus, and intradermal nevus.

Epidemiology

It is the most common eyelid benign tumor by pathological diagnosis, accounting for 14 out of 64 eyes (22%). Many are present from childhood, and history taking is helpful for diagnosis. Among subtypes, intradermal nevus is the most common. The average number of common skin nevi per person is 10 to 40¹⁾. Nevus of Ota is relatively common in Asians, with a reported frequency of 0.1 to 0.6%²⁾.

Classification

The main histological subtypes of nevi occurring on the eyelid are shown below.

Junctional nevus: Occurs in the deep layer of the epidermis at the junction with the dermis. It is a well-defined, flat tumor containing abundant pigment, presenting a strong brown to black color. It may become malignant.

Intradermal nevus: Occurs within the dermis and is the most frequent type. It often presents as raised or nodular lesions with little brown pigmentation. It may have hair. Malignant transformation is extremely rare.

Compound nevus: Has characteristics of both junctional and intradermal nevi, with variable color. It may become malignant.

Blue nevus: Contains melanocytes in the dermis and presents a blue to blue-brown color.

Nevus of Ota: A blue nevus that occurs diffusely in the area of the first and second branches of the trigeminal nerve. It often causes pigmentation of the sclera and iris. It is more common in women and appears unilaterally.

Q Can eyelid nevi be left untreated?

A

It depends on the subtype. Intradermal nevi do not become malignant, so observation is possible if there are no cosmetic concerns. However, if rapid growth, color change, bleeding, or itching occurs, consult an ophthalmologist. Junctional and compound nevi rarely transform into malignant melanoma, so consider complete excision along with observation.

2. Main symptoms and clinical findings

Congenital pigmented nevus extensively covering the right upper eyelid (preoperative appearance). A well-defined, black-brown raised lesion is seen over the entire eyelid.

Chauhan DS, Guruprasad Y. Congenital Melanocytic Nevus of Upper Eyelid. J Cutan Aesthet Surg. 2011;4(1):61-63. Figure 1a. PMCID: PMC3081491. License: CC BY.

Preoperative photograph of a congenital pigmented nevus spreading over the right upper eyelid, showing a black-brown, well-defined raised lesion occupying the entire eyelid. This corresponds to the clinical picture of eyelid nevus discussed in the section “Main symptoms and clinical findings.”

Subjective symptoms

Most eyelid nevi are asymptomatic. The main complaint is cosmetic (pigmented raised lesion on the face), and pain or visual impairment is usually absent. Patients are often aware of the mass since childhood, and history taking is a clue to diagnosis.

Clinical findings

They commonly occur at the eyelid margin between the eyelashes, but may also develop near the lacrimal punctum. Among nevi, intradermal nevus is the most common, where nevus cells in the dermis proliferate and push the epidermis upward in a dome shape. Compound nevi present as brown raised tumors, while junctional nevi present as black flat lesions. Color tends to be darker (black) in superficial layers and lighter in deeper layers.

The clinical features of each subtype are shown below.

Intradermal Nevus

Appearance: Dome-shaped or nodular raised lesion. Little pigment, often flesh-colored to light brown.

Features: May have hair. Often noticed since childhood.

Risk of malignancy: Almost none.

Compound and Junctional Nevus

Appearance: Compound nevus is a brown raised mass. Junctional nevus is black and flat.

Features: Rich in pigment, often black to dark brown. Relatively clear borders.

Risk of malignancy: Rarely transforms into malignant melanoma.

Nevus of Ota

Appearance: Diffuse bluish-gray to bluish-brown pigmentation in the distribution of the first and second branches of the trigeminal nerve.

Features: Pigmentation also in the sclera and iris. More common in women, unilateral. Congenital or adolescent onset.

Risk of malignancy: Risk of uveal melanoma has been reported.

Q Is the risk of glaucoma high with nevus of Ota?

A

Nevus of Ota may involve pigmentation of the iris and sclera, and an increased risk of pigmentary glaucoma (melanocytic glaucoma) has been noted. Additionally, an association between nevus of Ota and uveal malignant melanoma has been reported⁹⁾, and regular ophthalmologic follow-up is recommended.

3. Causes and Risk Factors

The following factors are involved in the development of eyelid nevus.

• Genetic predisposition: Melanocyte precursor cells that migrate from the neural crest become the origin of nevus cells. Genetic background is known to be involved in the increase of acquired nevi ¹⁾.
• Ultraviolet exposure: Ultraviolet light has been reported as a factor in the increase of acquired nevi ¹⁾.
• Congenital factors: Nevus of Ota is congenital, and pigmentation in the trigeminal nerve area is observed from birth or adolescence.
• Warning signs of malignant transformation: Junctional and compound nevi rarely transform into malignant melanoma. Evaluation using the ABCDE criteria (Asymmetry, Border irregularity, Color variation, Diameter >6 mm, Evolution) is important ³⁾.

When to see a doctor

If a mole on the eyelid rapidly enlarges, changes color, or develops bleeding or erosion, please see an ophthalmologist as it may indicate malignancy. Early consultation is especially important if asymmetry, irregular borders, or uneven color are observed.

4. Diagnosis and examination methods

Diagnostic approach

The following information is important in the diagnosis of eyelid nevus.

• Medical history: Presence since childhood is important information suggesting benignity.
• Visual assessment of the tumor: Systematically evaluate color, shape, size, and growth rate.
• Differentiation from malignant melanoma using ABCDE criteria ³⁾:
  • A (Asymmetry): Asymmetry
  • B (Border): Irregular border
  • C (Color): Color variation
  • D (Diameter): Diameter >6 mm
  • E (Evolution): Change in shape, color, or size
• Dermoscopy: A uniform pigment pattern suggests benignity. Pigment network, dotted globules, and uniform color are characteristic findings of benign nevi ⁴⁾.
• Histopathological examination: Essential for definitive diagnosis. All excised specimens must be submitted for pathology.

Differential Diagnosis

The main diseases that require differentiation from eyelid nevus are listed below.

Differential Diagnosis	Key Differentiating Features
Malignant melanoma	Color variation, irregular borders, rapid change, meets ABCDE criteria
Basal cell carcinoma	Central ulceration, pearly luster, rapid growth
Seborrheic keratosis	Surface hyperkeratosis/verrucous, elderly
Blue nevus	Bluish color, deep dermis
Hemangioma	Red color, blanches with pressure

Q How to differentiate from malignant melanoma?

A

For clinical differentiation, the ABCDE criteria (asymmetry, border irregularity, color variegation, diameter >6 mm, evolution) are useful. If dermoscopy shows an atypical pattern, malignancy should be suspected ^3,4). Lesions present since childhood are likely benign (history is important). Definitive diagnosis is made by histopathological examination. If rapid change occurs, excisional biopsy should be performed without hesitation.

5. Standard Treatment

Treatment of eyelid nevus is determined based on subtype and risk of malignant transformation. Treatment strategies by subtype are shown in the table below.

Subtype	Treatment	Malignant risk
Intradermal nevus	Shaving (open treatment) if cosmetic concern	Almost none
Compound nevus	Complete excision recommended	Rarely malignant melanoma
Junctional nevus	Complete excision recommended	Rarely malignant melanoma
Blue nevus	Observation or excision	Extremely rare
Nevus of Ota	Q-switched laser	Reports of uveal melanoma

Details by subtype

Treatment of intradermal nevus: Since it does not become malignant, surgery is indicated only if the patient desires removal for cosmetic reasons. Often, patients have lived with the nevus as part of their face since childhood and may have little desire for removal. The common surgical technique is partial excision (shaving) of the raised portion, leaving an open wound (open treatment).

Treatment of compound nevus and junctional nevus: Because there is a risk of transformation into malignant melanoma, albeit rare, complete excision is recommended while monitoring the condition. The excised specimen must always be sent for histopathological examination.

Treatment of nevus of Ota: Q-switched ruby laser and Q-switched alexandrite laser have been reported to be effective ⁵⁾. Laser irradiation selectively destroys dermal melanocytes and improves pigmentation. Multiple sessions are often required.

Treatment of congenital giant pigmented nevus: Staged excision and tissue expansion techniques are used ⁶⁾. When the eyelid is involved, reconstructive surgery becomes complex, so management at a specialized facility is recommended.

Precautions in treatment

• For compound nevi and junctional nevi, partial shaving for cosmetic purposes may leave nevus cells at the margins. Complete excision is recommended.
• All excised specimens should be submitted for histopathological examination to confirm the subtype and assess for malignant transformation.
• When performing Q-switched laser for nevus of Ota, consider the effects on the iris and sclera and the need for long-term ophthalmological follow-up.

Q Is laser treatment effective for moles on the eyelids?

A

For nevus of Ota, Q-switched ruby laser and Q-switched alexandrite laser are considered effective, and multiple sessions can improve pigmentation ⁵⁾. For common intradermal nevi, compound nevi, and junctional nevi, excision (shaving or complete excision) is the standard treatment, and laser is not the first choice.

6. Pathophysiology and Detailed Pathogenesis

Origin and Histological Features of Nevus Cells

Nevus cells are immature pigment cells originating from melanocyte precursors that migrated from the neural crest ¹⁾. The histological subtype is determined by the depth of the nevus cell nests. If the nests are localized in the epidermal basal layer, it is a junctional nevus; if in the dermis, an intradermal nevus; and if spanning both, a compound nevus. Cells in superficial layers are rich in melanin, while those in deeper layers have less pigment. This pigment gradient accounts for the differences in macroscopic color among subtypes.

Molecular Mechanisms of Malignant Transformation

Approximately 80% of acquired nevi harbor BRAF V600E mutations ⁷⁾. BRAF mutations activate cell proliferation signals (MAPK pathway), but alone they do not lead to malignancy and often cause oncogene-induced senescence. Transformation to malignant melanoma occurs when additional mutations such as TERT promoter mutations or CDKN2A deletions accumulate alongside BRAF mutations ⁷⁾. The estimated risk of a common mole transforming into malignant melanoma is less than 0.0005% per mole per year, which is extremely low ¹⁾.

Pathology of Nevus of Ota

Nevus of Ota results from hyperplasia of dermal melanocytes. Proliferation of melanocytes scattered in the dermis of the first and second branches of the trigeminal nerve leads to blue to blue-gray pigmentation. Pigmentation may occur not only on the eyelid skin but also on the sclera, iris, and fundus. In Caucasian patients with oculodermal melanocytosis, the lifetime incidence of uveal melanoma is reported to be significantly higher ⁹⁾, and regular fundus and intraocular pressure examinations are recommended.

7. Latest Research and Future Perspectives

For Patients: Please Read Carefully

The following content is currently under research or in clinical trials and is not standard treatment available at general hospitals. It is reference information for professionals regarding future medical developments.

AI Image Diagnosis for Benign and Malignant Differentiation

Deep learning-based image diagnosis systems for skin tumors have been developed, and classification accuracy at the level of a dermatologist has been reported ⁸⁾. Combining with dermoscopic images is expected to further improve the accuracy of differentiating nevi from malignant melanoma. Application to the eyelid area remains a future challenge.

Application of Tissue Expanders to Congenital Giant Pigmented Nevi

A systematic review of staged excision using tissue expanders for congenital giant pigmented nevi has reported improvements in functional and cosmetic reconstruction ⁶⁾. In cases involving the eyelid, technical refinements are progressing to minimize impact on visual function while performing excision and reconstruction.

Association Between Nevus of Ota and Uveal Melanoma

A study of white patients with oculodermal melanocytosis reported a lifetime incidence of uveal melanoma of approximately 1 in 400, suggesting the usefulness of regular fundus examinations in patients with nevus of Ota ⁹⁾.

8. References

1. Tsao H, Bevona C, Goggins W, et al. The transformation rate of moles (melanocytic nevi) into cutaneous melanoma. Arch Dermatol. 2003;139(3):282-288.

2. Hidano A, Kajima H, Ikeda S, et al. Natural history of nevus of Ota. Arch Dermatol. 1967;95(2):187-195.

3. Abbasi NR, Shaw HM, Rigel DS, et al. Early diagnosis of cutaneous melanoma: revisiting the ABCD criteria. JAMA. 2004;292(22):2771-2776.

4. Argenziano G, Soyer HP, Chimenti S, et al. Dermoscopy of pigmented skin lesions: results of a consensus meeting. J Am Acad Dermatol. 2003;48(5):679-693.

5. Chan HH, Kono T. The use of lasers and intense pulsed light sources for the treatment of pigmentary lesions. Skin Therapy Lett. 2004;9(8):5-7.

6. Kishi K, Matsuda N, Kubota Y, et al. Systematic review: staged excision and tissue expansion for giant congenital melanocytic nevi. J Plast Reconstr Aesthet Surg. 2022;75(1):1-15.

7. Shain AH, Yeh I, Kovalyshyn I, et al. The genetic evolution of melanoma from precursor lesions. N Engl J Med. 2015;373(20):1926-1936.

8. Esteva A, Kuprel B, Novoa RA, et al. Dermatologist-level classification of skin cancer with deep neural networks. Nature. 2017;542(7639):115-118.

9. Singh AD, De Potter P, Fijal BA, et al. Lifetime prevalence of uveal melanoma in white patients with oculo(dermal) melanocytosis. Ophthalmology. 1998;105(1):195-198.