Conjunctival malignant melanoma is a malignant tumor originating from melanocytes of the conjunctiva. It is common in Western countries but rare in Japan. It often arises from primary acquired melanosis (PAM).
The global incidence is 0.3–0.8 per million per year, highest in Northern Europe and North America. It has been increasing over the past 50 years. In the United States, approximately 130 new cases per year are estimated, and in Europe about 320 cases 8). The age-adjusted incidence in Asians is low at 0.15 per million per year, and it is most common in Caucasians (91.2%) 1, 8).
The mean age at onset is 55–65 years, and onset under 20 years is extremely rare 1, 4, 5, 6). The 5-year disease-specific survival rate is approximately 82.9%, and 69.3% at 10 years 8).
Breakdown by origin:
Conjunctival melanoma is the only mucosal melanoma for which an association with ultraviolet exposure has been suggested, because the bulbar conjunctiva is directly exposed to UV light 4).
The incidence of conjunctival malignant melanoma is 0.3–0.8 per million per year, making it a rare disease, but it has been increasing over the past 50 years. Asians have a lower risk of developing the disease compared to Caucasians, with a reported incidence of 0.15 per million per year. Pediatric cases account for only 1% of all conjunctival melanomas, and onset under age 20 is extremely rare.
Clinically, it appears as a dark brown elevated lesion on the bulbar or palpebral conjunctiva, with abundant blood vessels feeding the tumor.
Pigmented melanoma (70%)
Predilection site: Approximately 90% occur on the bulbar conjunctiva, with 63% localized in the temporal quadrant 4, 6).
Appearance: A raised lesion that is dark brown to brownish. Accompanied by abundant feeding vessels directed toward the tumor.
Relationship with the sclera: Adhesion to the sclera may be observed. The average distance from the tumor to the corneal limbus is 2 mm, and 61% reach the limbus 2).
Amelanotic melanoma (30%)
Appearance: A pink to red mass that contains little to no pigment.
Risk of misdiagnosis: Easily misdiagnosed as squamous cell carcinoma or other red conjunctival masses 3).
Prognosis: Hypopigmented and amelanotic types may be associated with a poor prognosis.
Imaging evaluation:
Yes. About 30% of conjunctival melanomas are amelanotic, appearing as pink to red masses. Amelanotic melanoma is easily misdiagnosed because it resembles squamous cell carcinoma and other lesions, which can delay diagnosis. Pathological diagnosis by biopsy is essential for suspicious conjunctival masses.
The following factors are associated with an increased risk of metastasis and death1, 4, 5, 6, 8).
The AJCC (American Joint Committee on Cancer) staging system strongly correlates with prognosis1).
| Stage | 5-year cumulative mortality rate |
|---|---|
| cT1 | 2.5% |
| cT2 | 28.6% |
| cT3 | 31.6% |
| cT3c (orbital invasion) | 100% |
The estimated 5-year distant metastasis rate for T3 tumors is 42%, and the 5-year mortality rate is 23%1).
Lymphatic spread is the main route of metastasis. Temporal conjunctival lesions tend to metastasize to the preauricular lymph nodes, while nasal conjunctival lesions tend to metastasize to the submandibular lymph nodes. Distant metastases (hematogenous) occur in the brain, lungs, liver, skin, adrenal glands, etc.6, 1) Lymph node metastases are observed in 15–41% of cases at a median of 2.3 years after diagnosis, and systemic metastases occur in 9–25% at 3 years. Even when lymph node metastasis is not detected, distant hematogenous organ metastasis occurs in 38% of cases6).
Major poor prognostic factors include tumor thickness (especially >2 mm), lesion location (caruncle has the worst prognosis), AJCC stage, nodular morphology, lymphatic invasion, and orbital invasion. Completeness of resection also greatly affects outcomes; approximately 49.3% of incomplete resection cases recur. Sentinel lymph node positivity increases the risk of death.
A biopsy is necessary for a definitive diagnosis. Histopathologically, it consists of proliferation of cells with large nucleus-to-cytoplasm ratios, containing melanin pigment and prominent nucleoli. If melanin pigment is abundant, depigmentation of the pathological specimen is required.
Immunohistochemical staining is essential for definitive diagnosis and differential diagnosis.
| Marker | Characteristic | Notes |
|---|---|---|
| HMB-45 | Positive in melanocytic cells | Useful for diagnosis2, 8) |
| SOX10 | Positive in melanocytic cells | High sensitivity 1, 4) |
| Melan-A/MART-1 | Positive in melanocytic cells | General-purpose marker 3, 5, 6) |
| S-100 | Positive in melanocytic cells | High sensitivity but low specificity 1) |
| PRAME | Positive in melanoma, negative in nevus | Most useful differential marker 5) |
| Ki-67 | 10–15% or higher in melanoma | Proliferation index 3, 4) |
| p16 | Lost in melanoma | Retained in nevus5) |
For confirmed melanoma cases, systematic whole-body evaluation is necessary.
Surgical resection of the tumor including surrounding tissue is the mainstay. Intraoperative and postoperative topical administration of MMC or interferon alpha-2b is also effective. If the tumor is extensive with significant subconjunctival invasion, orbital exenteration may be necessary.
Surgical Therapy
Resection margin: Complete tumor resection with a 3–5 mm safety margin 4, 8)
No-touch technique: Avoid direct contact with the tumor using instruments to prevent tumor cell seeding 4, 8)
Dry technique: Resection without using irrigation fluid (BSS)
Corneal invasion: Alcohol corneal epithelial debridement + en bloc resection with a hockey knife 2)
Orbital exenteration: Indicated for extensive or recurrent cases (advanced cases)
Enucleation: Indicated for intraocular extension
Adjuvant Therapy
Cryotherapy: Applied to the resection base and margins using a double freeze-thaw technique. Elevate the conjunctiva to avoid scleral damage 3)
MMC topical chemotherapy:
IFNα-2b: Alternative to MMC that does not cause limbal stem cell deficiency 3)
Radiation therapy: Brachytherapy or external beam radiation3)
Sentinel lymph node biopsy: Considered for tumor thickness >2 mm7)
The following are used for conjunctival reconstruction after wide excision4, 5).
To prevent tumor cell seeding (local recurrence or metastasis), this technique involves excising the tumor without directly touching it with instruments and in a dry environment without using irrigation fluid (BSS). The entire tumor is removed en bloc with a 3–5 mm safety margin to reduce the risk of recurrence due to incomplete resection. It fundamentally differs from standard excision by minimizing the seeding of tumor cells onto the conjunctiva.
Conjunctival melanoma is genetically similar to cutaneous melanoma rather than uveal melanoma. The main UV-related driver mutations (C>T transitions) are BRAF, NF1, and RAS. Uveal melanoma markers (BAP1, GNAQ, GNA11, SF3B1) are confirmed negative in conjunctival melanoma1).
In a study of 101 cases by Lally et al. (2022), four high-frequency mutations were identified1).
NF1 mutation (33–50%)
Frequency: Most common mutation.
Prognosis: NF1 mutation alone is associated with low metastasis rates at 2 and 5 years.
Features: Can coexist with BRAF mutation. Often coexists with ATRX mutation8).
BRAF mutation (29–46%)
Frequency: Second most common mutation. V600E mutation accounts for 80–90%.
Distribution: Common in conjunctival melanoma (sun-exposed sites)4).
Prognosis: No significant association with metastasis or death. It is a therapeutic target for targeted therapy (BRAF inhibitors).
NRAS mutation (11–26%)
Frequency: Third most common mutation.
Prognosis: Increased risk of metastasis and death, with approximately 5-fold higher risk of death1).
Features: Mutually exclusive with BRAF mutation.
ATRX mutation (25%)
Frequency: The fourth most common mutation.
Prognosis: Similar to NF1 mutations, associated with low metastasis rates at 2 and 5 years.
Characteristics: Often coexists with NF1 mutations8).
TERT promoter mutation (c.-124C>T) affects telomerase reverse transcriptase and has been reported to be associated with metastatic conjunctival melanoma1, 8, 6). It is also detected in moderate to severe atypia of PAM (about 8%), suggesting a nature of melanoma in situ6). It has also been shown to be associated with high tumor mutational burden4). TERT mutations are found in 32–64% of conjunctival melanomas, and their association with prognosis is of interest8).
High PD-L1 expression and the presence of a transcriptional subtype rich in immune-related genes have been confirmed, providing a rationale for the use of immune checkpoint inhibitors. Data on BRAF inhibitors, MEK inhibitors, and PD-L1 inhibitors are promising but currently limited.
Chou et al. (2023) analyzed the molecular profile of a T3c conjunctival melanoma case in a 94-year-old man. They identified an NF1 mutation and a TERT promoter mutation (c.-124C>T, VAF 31.4%), with BRAF, NRAS, and cKIT all negative. The combination of NF1 mutation and NRAS negativity is considered a contributing factor to the relatively favorable course without metastasis1).
PD-1 inhibitors (pembrolizumab, nivolumab) and CTLA-4 inhibitors (ipilimumab) have been tried in metastatic and locally advanced conjunctival melanoma4, 8).
As a representative report, Sagiv et al. (2018) reported that PD-1 inhibition therapy with pembrolizumab or nivolumab was administered to 5 patients, with some achieving complete response8). A Phase 2 trial using the combination of axitinib + nivolumab (for untreated advanced or metastatic mucosal melanoma) is ongoing.
The standard regimen for systemic therapy for metastatic conjunctival melanoma has not yet been established, and careful case-by-case judgment is required.
For BRAF mutation-positive cases, BRAF inhibitor monotherapy (vemurafenib) or combination BRAF/MEK inhibitors (dabrafenib + trametinib, encorafenib + binimetinib) have been attempted 4, 8).
These drugs have been reported to reduce local tumors in some cases, but most reports are single cases or small series, and long-term outcomes are limited. The possibility of synergistic effects by simultaneously targeting the MAPK and AKT pathways is also under investigation 3).
The use of immunohistochemical panels (PRAME, p16, HMB-45, Ki-67, Cyclin D1) is enabling reclassification of lesions previously considered “indeterminate” 5). International standardization of the C-MIL (conjunctival melanocytic intraepithelial lesion) classification (WHO 5th edition, 2022) is also progressing.
Based on genetic similarities with cutaneous melanoma (BRAF, NF1, NRAS mutations, high PD-L1 expression), PD-1 inhibitors (pembrolizumab, nivolumab), CTLA-4 inhibitors, and BRAF inhibitors have been attempted in metastatic and locally advanced cases. However, large-scale clinical trials have not been conducted, and evidence is currently limited; no standard regimen has been established. There is an urgent need to accumulate large-scale data through international multicenter collaborative studies.
