Iris Melanoma

Iris melanoma is the most common primary iris tumour and accounts for approximately 5–8% of all uveal melanomas. Despite being a malignancy, it carries a substantially more favourable prognosis than its posterior uveal counterparts (choroidal or ciliary body melanoma), with a metastatic rate of approximately 3–5% at 5 years for circumscribed forms.

The tumour most commonly presents in the inferior iris, is predominantly pigmented (brown to dark brown), and is usually a circumscribed, elevated lesion with variable amounts of surface vascularity. The classical clinical challenge is distinguishing iris melanoma from the far more common benign iris naevus — a distinction that requires serial clinical observation, slit-lamp photography, and often ultrasound biomicroscopy (UBM).

A diffuse variant of iris melanoma exists — a rare but aggressive form that spreads across the entire iris without forming a discrete mass. Diffuse iris melanoma typically presents as acquired unilateral iris darkening (heterochromia), unilateral glaucoma (due to angle infiltration), and carries a substantially higher metastatic rate (~20%) compared to circumscribed melanoma.

Molecular characterisation — particularly GNAQ/GNA11 mutation status and BAP1 expression — is increasingly important for prognostication and genetic counselling. BAP1-mutated tumours carry a significantly higher risk of systemic metastasis.

Iris melanoma arises from malignant transformation of uveal melanocytes — neural crest-derived cells that populate the iris stroma during embryogenesis. Unlike cutaneous melanoma, BRAF mutations are rare; uveal melanomas have a distinct molecular profile:

• GNAQ/GNA11 mutations: Activating mutations in Gαq subunit family members (GNAQ or GNA11) occur in approximately 80–90% of uveal melanomas, including iris melanoma. These mutations constitutively activate the MAPK and PI3K/AKT pathways, driving proliferation. They are also found in benign iris naevi — so alone they do not determine malignancy.
• BAP1 mutation/deletion: BRCA1-associated protein 1 (BAP1) on chromosome 3p21 is the most clinically significant prognostic marker. BAP1 loss (by mutation or deletion of chromosome 3) is associated with epithelioid cell morphology, metastatic spread (to liver, lung, skin), and germline BAP1 mutation in familial cases (BAP1 tumour predisposition syndrome). BAP1 status is determined by immunohistochemistry on biopsy material.
• SF3B1 and EIF1AX mutations: Mutually exclusive with BAP1 loss; associated with better prognosis; typically spindle cell histology; low metastatic risk.
• UV light exposure: Epidemiological evidence suggests UV radiation contributes to uveal melanoma risk; the anterior location of the iris means it is the uveal structure most exposed to UV. Light iris colour (less UV-absorbing melanin) is a risk factor.
• Germline BAP1 mutation (familial): Autosomal dominant; predisposes to multiple malignancies including uveal melanoma, cutaneous melanoma, mesothelioma, and renal cell carcinoma (BAP1 tumour predisposition syndrome).

Malignant transformation of iris melanocytes results in uncontrolled local growth within the iris stroma. As the tumour enlarges, it may invade adjacent structures and seed cells into the aqueous humour:

• Local iris invasion: Tumour grows within the iris stroma, elevating the surface. Invasion of the iris pigment epithelium produces ectropion uveae (eversion of pigment epithelium at the pupillary margin). Anterior invasion may produce angle seeding.
• Angle seeding and glaucoma: Tumour cells shed into the aqueous circulate and deposit in the trabecular meshwork. Melanin granules from the tumour may also obstruct trabecular outflow (melanolytic glaucoma). Secondary neovascular glaucoma may develop from tumour-driven VEGF expression.
• Lens involvement: Direct contact between the tumour and the anterior lens capsule causes a focal sector cataract. Tumour cells may invade the lens if contact is prolonged.
• Extraocular extension: Tumour may extend through the sclera along emissary channels (seen on UBM as extrascleral nodule).
• Haematogenous metastasis: Unlike cutaneous melanoma, uveal melanoma (including iris) spreads exclusively haematogenously — not via the lymphatic system (the uvea has no lymphatics). The liver is the primary site of metastasis (>90% of metastatic disease). Lung, bone, and skin are secondary sites. Liver micrometastases may remain dormant for years before becoming clinically apparent.

By Morphology

By Cytology (Callender Classification)

By Size

• Small: Base <3 mm, height <1 mm; often observed; distinguish from naevus by growth documentation.
• Medium: Base 3–10 mm, height 1–3 mm; iridectomy or plaque radiotherapy.
• Large: Base >10 mm or height >3 mm; plaque radiotherapy or enucleation; ciliary body involvement likely.

• Secondary glaucoma: The most common ocular complication; three mechanisms: (1) melanolytic glaucoma from melanin granule obstruction of TM; (2) direct angle seeding by melanoma cells; (3) neovascular glaucoma from VEGF-driven iris neovascularisation. May require medical, laser, or surgical intervention.
• Hyphema: Spontaneous haemorrhage from fragile intrinsic tumour vasculature; may cloud the anterior chamber obscuring the tumour; recurrent hyphema without trauma warrants urgent iris melanoma exclusion.
• Sector cataract: Direct lens touch by the tumour causes focal lens opacity; may progress to complete cataract; cataract surgery risks disrupting tumour seeding.
• Extraocular extension: Tumour growth through scleral emissary channels to periocular tissue; visible or palpable mass in severe cases; detected by UBM (anterior) or CT/MRI orbits.
• Systemic metastasis: Haematogenous spread — primarily to liver (>90% of metastatic disease); median survival after hepatic metastasis is approximately 4–15 months without treatment; targeted therapy options are limited. Metastatic rate: ~3–5% (circumscribed), ~20% (diffuse).
• Enucleation requirements: Large tumours with uncontrollable secondary glaucoma, extensive extraocular extension, or diffuse melanoma with poor prognosis may require enucleation with profound psychological impact.

Clinical Assessment (Essential)

• Slit-lamp biomicroscopy with high magnification: Detailed characterisation of the lesion — location, size (estimate basal diameter in clock hours), height, surface morphology, colour, vascularity, relationship to angle, ectropion uveae, lens contact; red-free filter enhances vessel visualisation.
• Iris photography (serial): Standardised slit-lamp anterior segment photography at every visit — the cornerstone of melanoma vs naevus distinction. Document date, magnification, and illumination settings for valid comparison.
• IOP measurement: Asymmetric IOP or elevation in the affected eye; correlates with angle seeding.
• Gonioscopy: Essential — assess angle for melanoma seeding (pigmented clumps in TM), angle closure, and neovascularisation of the angle.

Imaging

• Ultrasound biomicroscopy (UBM — 50 MHz): Gold standard for lesion characterisation; determines: basal diameter, height, solid internal echogenicity (vs hollow in cyst), ciliary body extension, extraocular extension, angle involvement.
• Anterior segment OCT (AS-OCT): Non-contact; useful for anterior lesion topography; limited penetration depth vs UBM.
• Fluorescein angiography (FFA): Intrinsic vascularity and leakage in melanoma; absent in benign naevus; feeder vessels documented.
• B-scan ultrasound: For large lesions with possible extraocular or ciliary body extension beyond UBM field.
• CT or MRI orbits: When extraocular extension is suspected; CT chest/abdomen/pelvis for systemic staging at diagnosis of large or high-risk lesion.

Biopsy and Molecular Analysis

• Fine needle aspiration biopsy (FNAB): Transscleral or transcorneal approach; provides cytological diagnosis and material for molecular profiling (GNAQ/GNA11 mutation analysis, BAP1 immunohistochemistry, chromosome 3 status, GEP [gene expression profile]). Performed when diagnosis is uncertain or molecular prognostication is desired.
• Aqueous humour liquid biopsy: Emerging technique — tumour-derived DNA/RNA detectable in aqueous; may allow non-invasive molecular profiling.
• Systemic staging: Liver function tests (LFTs); liver ultrasound or MRI at diagnosis for large/high-risk lesions; CT PET if metastasis clinically suspected; dermatology examination.

Iris melanoma has a substantially better prognosis than posterior uveal melanoma. For circumscribed iris melanoma:

• 5-year survival: ~95%; 10-year survival: ~91%.
• Metastatic rate: ~3–5% at 5 years for circumscribed tumours — significantly lower than choroidal melanoma (~25–35%).
• Diffuse iris melanoma: ~20% 5-year metastatic rate; substantially worse prognosis.
• BAP1 mutation: Associated with higher metastatic risk regardless of tumour size or type; molecular testing increasingly guides follow-up intensity.
• Spindle cell histology: Best prognosis; epithelioid cell type confers worst prognosis (higher metastatic potential).

Local tumour control after iridectomy or plaque brachytherapy is achieved in approximately 85–95% of cases. The primary cause of tumour-related death is hepatic metastasis, which carries a median survival of 4–15 months from detection without treatment. Immunotherapy trials (pembrolizumab, ipilimumab) and MEK/AKT inhibitors are being evaluated for metastatic uveal melanoma.

Oculodermal melanocytosis confers a lifetime iris/uveal melanoma risk estimated at approximately 1 in 400; annual ophthalmic review is recommended for affected patients.