Eyelid malignant melanoma is a tumor arising from malignant proliferation of melanocytes in the eyelid skin. It may occur de novo or develop from a pre-existing nevus. Compound nevi and junctional nevi of the eyelid skin carry a risk of malignant transformation, albeit rare, so complete excision is recommended while monitoring the course.
It is a rare disease, accounting for less than 1% of all cutaneous malignant melanomas, less than 7% of head and neck melanomas, and about 1% of all malignant eyelid tumors. The peak incidence of head and neck melanoma is between 50 and 80 years of age, about 20 years later than cutaneous melanoma at other sites. The most common site is the lower eyelid, occurring about 2.6 times more frequently than the upper eyelid. The incidence tends to be slightly lower in East Asians compared to Western populations.
Evaluation based on the ABCDE criteria—Asymmetry in color, Border irregularity, Color variation, Diameter (longest diameter ≥7 mm), and Elevation or change—is fundamental to the examination. Pigmented lesions with a longest diameter of 7 mm or more are considered an indication for referral to an ophthalmologist.
The lower eyelid is affected about 2.6 times more frequently than the upper eyelid. This is thought to be related to the lower eyelid being more exposed to ultraviolet radiation.
The ABCDE criteria are used to evaluate suspicious lesions.
As common danger signs for eyelid malignancies, pay attention to the following 7 items.
Lesions show a wide spectrum from flat brown patches to nodular elevated lesions. They may lack pigment as amelanotic melanoma, making detection difficult in fair-skinned individuals. Erythema, scales, and irregular borders are clues, and dermoscopic evaluation is useful.
Examination must always include palpation of regional lymph nodes.
The diagnosis of eyelid skin malignant melanoma is suspected clinically and confirmed histologically. If it is difficult to distinguish between benign and malignant, incisional biopsy may be performed followed by radical resection. Intraoperative frozen section is used to check for tumor cells at the resection margin, and final confirmation is always made with permanent sections. Preoperative head and neck CT/MRI is performed to check for metastasis.
| Marker | Sensitivity | Specificity |
|---|---|---|
| S100 | 97–100% | 75–87% |
| MelanA/MART-1 | 75–92% | 95–100% |
| HMB-45 | 69–93% | Approximately 97% |
S100 is the most sensitive, but its specificity is limited because it also stains Schwann cells, myoepithelial cells, and adipocytes. MelanA/MART-1 has high specificity. HMB-45 is a marker for the premelanosomal glycoprotein gp100.
Indications for sentinel lymph node biopsy based on the National Comprehensive Cancer Network (NCCN) guidelines (version 2.2023)1):
Main diseases to consider in the differential diagnosis of eyelid malignant melanoma:
It is not necessarily required for all cases. The NCCN guidelines do not recommend sentinel lymph node biopsy for melanomas less than 0.8 mm thick without ulceration. It should be actively considered for melanomas thicker than 1.0 mm or with ulceration.
Stage 0 (in situ)
Mohs micrographic surgery: Recommended treatment for in situ melanoma. Recurrence rate 0–3.6%, superior to surgical excision (6–20%).
MART1 immunostaining: Improves detection of melanoma in frozen sections, enabling Mohs excision in one day.
Paraffin-embedded sections: Gold standard for evaluating melanocytic lesions.
Stage IA–II
Wide local excision: 10 mm margin is standard (Stage 0/IA/IB, thickness <0.8 mm).
Thick tumors: For thickness >2.0 mm, ensure a 20 mm margin.
Sentinel lymph node biopsy: Consider individually. If positive, complete lymph node dissection.
In eyelid malignant melanoma (and sebaceous carcinoma), even with a safety margin of 3–5 mm or more, skip lesions may be scattered. After confirming the absence of tumor cells at the resection margin by intraoperative frozen section, reconstruct the defect. However, frozen section diagnosis is not final; always reconfirm with permanent sections. If the patient cannot tolerate radical resection due to poor general condition or advanced age, consider radiation therapy.
After surgery, regular imaging examinations are performed not only to check for local recurrence but also for systemic metastasis (hematogenous metastasis to the lungs, liver, etc.).
Recommended margins by stage according to NCCN guidelines1):
| Stage | Recommended margin |
|---|---|
| Stage 0–IB (<0.8mm) | 10mm |
| Stage II (>2.0mm) | 20mm |
Patients with positive sentinel lymph node biopsy or stage III disease undergo excision and complete lymph node dissection, followed by consideration of observation, clinical trials, or adjuvant interferon-alpha therapy. Radiation therapy to the lymph node basin may also be considered for some patients.
Patients with stage IV disease undergo biopsy for genetic testing, lactate dehydrogenase (LDH) measurement, and imaging.
Immune checkpoint inhibitors such as pembrolizumab (anti-PD-1 antibody) and nivolumab (anti-PD-1 antibody) have shown efficacy in some cases of locally advanced and metastatic eyelid melanoma and may be used as first-line therapy, neoadjuvant therapy, or palliative care1).
Mohs micrographic surgery is recommended for melanoma in situ (stage 0). Recurrence rates are 0–3.6% with Mohs surgery and 6–20% with conventional surgical excision, showing Mohs surgery is superior. However, paraffin-embedded sections remain the gold standard for melanocyte evaluation.
Malignant transformation of normal melanocytes occurs through the accumulation of genetic and molecular changes. Eyelid skin is a site of ultraviolet exposure, and UVB-induced DNA damage contributes to development. Chromosomes frequently altered include 1, 6, 7, 9–11, 17, and 20.
Activation of the MAPK pathway (RAS-RAF-MEK-ERK) plays a central role, inducing cell proliferation and survival. Additionally, dysregulation of apoptosis pathways involving tumor suppressor genes such as CDKN2A, TP53 (p53), and PTEN contributes to pathogenesis.
The progression of malignant melanoma occurs in two phases.
Lentigo Maligna Type
Lentigo maligna melanoma: The most common subtype on the eyelid. Arises from sun-damaged skin. Characterized by atypical spindle-shaped melanocytes at the basal epidermis with pagetoid spread.
Superficial Spreading Type
Superficial spreading melanoma: Characterized by epithelioid cells scattered throughout the epidermis, sometimes with vertical growth.
Nodular Type
Nodular melanoma: Mainly vertical growth pattern. Composed of epithelioid cells. Shows early deep invasion and poor prognosis.
Acral lentiginous
Acral lentiginous melanoma: Occurs on palms, soles, subungual areas, and oral mucosa. Characterized by proliferation of atypical melanocytes at the dermal-epidermal junction.
Anti-PD-1 antibodies such as pembrolizumab and nivolumab have shown good efficacy in some cases of locally advanced or metastatic eyelid melanoma. Their use as first-line therapy, neoadjuvant therapy, and palliative care is being considered.
Tumor thickness, ulceration, and mitotic rate are major prognostic factors. The 10-year survival rate is reported as 93% for stage IA, 39% for stage IIC, approximately 68% for stage IIIA, 24% for stage IIIC, and 10–15% for stage IV.
