Conjunctival melanoma
Ocular surface melanoma; melanoma of bulbar / palpebral / forniceal conjunctiva
Conjunctival melanoma is a rare melanoma of the ocular surface that, unlike uveal melanoma, shares the molecular biology and metastatic patterns of cutaneous melanoma — driven by BRAF, NRAS, KIT and NF1 mutations and metastasising preferentially to lymph nodes, lung and brain rather than to liver. Approximately 75% arise within a field of pre-existing primary acquired melanosis with atypia (PAM with atypia / conjunctival melanoma in situ); the remainder arise de novo or from a conjunctival naevus. Reported incidence in Western registries is approximately 0.3–0.8 per million per year. Treatment is delivered by an ophthalmic oncology service through wide local excision with cryotherapy ("no-touch" technique), adjuvant topical mitomycin C and plaque brachytherapy where indicated. Local recurrence and regional / distant metastasis are substantial concerns, with 10-year mortality around 25–30%.
Precursor — primary acquired melanosis (PAM)
- PAM is a unilateral, flat, brown patch on the conjunctiva that appears in middle age.
- Sub-classified histologically:
- PAM without atypia — benign; very low malignant potential.
- PAM with atypia (conjunctival melanoma in situ) — substantial progression to invasive melanoma; up to 50% over time with severe atypia (markedly lower with mild atypia).
- Surveillance and lesional biopsy of any change in pigmentation, thickness or vascularity.
Clinical features
- Pigmented (most), partly pigmented or amelanotic vascularised nodule or plaque on the bulbar (most common), forniceal, palpebral or caruncular conjunctiva.
- Median age 60; M:F roughly equal; predominantly white populations.
- Risk factors: PAM with atypia, conjunctival naevi (rare), UV exposure, fair skin.
- Differential: PAM without atypia, conjunctival naevus, racial conjunctival melanosis (bilateral), foreign-body pigment, ocular surface squamous neoplasia, tarsal cyst.
Genetics & molecular
- Driver mutations more closely resemble cutaneous melanoma than uveal melanoma:
- BRAF V600E in ~30%.
- NRAS in ~20%.
- NF1 in ~15%.
- KIT mutations in some (similar to mucosal/acral melanomas).
- UV mutational signature in lesions on sun-exposed bulbar conjunctiva.
- Distinct from uveal melanoma (GNAQ/GNA11-driven, hepatic-tropic).
Management
- Refer urgently to an ophthalmic oncology centre (in the UK: Liverpool Ocular Oncology Centre, Sheffield, Moorfields, Royal Hallamshire).
- Local treatment:
- Wide local excision with the "no-touch" technique (avoid disturbing the lesion to prevent seeding) and 2–4 mm conjunctival margins (operator preference within range), with double-freeze-thaw cryotherapy to the cut edges.
- Adjuvant double-freeze-thaw cryotherapy to the conjunctival margins and base.
- Topical mitomycin C 0.04% — adjuvant for diffuse PAM with atypia.
- Plaque brachytherapy (ruthenium-106) for deep or recurrent lesions.
- Orbital exenteration for advanced disease (rarely needed).
- Staging:
- AJCC 8 staging system for conjunctival melanoma.
- Sentinel lymph node biopsy considered for thick / ulcerated lesions.
- CT chest/abdomen/pelvis ± brain MRI; PET-CT in selected cases.
- Metastatic disease:
- Anti-PD-1 immunotherapy (pembrolizumab, nivolumab); combination ipilimumab + nivolumab.
- BRAF / MEK inhibitor combination for BRAF V600E-mutant disease.
- Response rates approach those for cutaneous melanoma (much higher than for uveal melanoma).
Prognosis
Local recurrence ~30–50% at 10 years (lower with no-touch surgery, cryotherapy and mitomycin); regional / distant metastasis ~25%; 10-year mortality ~25–30%. Adverse factors: forniceal, palpebral or caruncular site (versus bulbar); thickness >2 mm; ulceration; multifocality; incomplete excision; lymphovascular invasion. Long-term ophthalmology and oncology surveillance is essential.
References
- Shields CL et al. Conjunctival melanoma — outcomes based on tumor origin in 382 consecutive cases. Ophthalmology; 2011.
- Wong JR et al. Management of conjunctival melanoma in 2019. Curr Opin Ophthalmol; 2019.
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