Uveal Melanoma & Tumours

The uveal tract (iris, ciliary body, choroid) is the commonest site of primary intraocular malignancy in adults. Uveal melanoma dominates NEET PG questions through its classic collar-stud ultrasound silhouette, lipofuscin (orange pigment) overlay, and the perennial enucleation-versus-brachytherapy decision. This note also covers benign mimics (naevus, haemangioma) and the great impostor — choroidal metastasis.

Definition & classification

Uveal melanoma is a malignant tumour arising from melanocytes of the uveal stroma. It is the commonest primary intraocular malignancy in adults (retinoblastoma is the commonest in children; metastasis is the commonest intraocular malignancy overall across all ages).

Anatomical classification (by site of origin):

Site	Frequency	Typical presentation	Prognosis
Choroid	~80–90% (commonest)	Painless visual loss, field defect, floaters	Worst (silent, presents late)
Ciliary body	~5–10%	Sentinel dilated episcleral vessels, lens subluxation, astigmatism	Intermediate–poor (silent, large at diagnosis)
Iris	~3–10%	Visible pigmented nodule, sectoral cataract, glaucoma	Best (visible early, small)

High-yield: Iris melanoma has the best prognosis (detected early because visible); ciliary body and choroidal melanomas present late and carry a worse outlook.

Histological (Callender) classification — strongly prognostic:

Cell type	Features	Prognosis
Spindle A	Small, slender nuclei, fine chromatin, no nucleolus	Best
Spindle B	Larger nuclei, prominent nucleolus	Good
Epithelioid	Large, pleomorphic, abundant cytoplasm, prominent nucleolus, less cohesive	Worst
Mixed	Spindle + epithelioid (commonest type overall)	Intermediate

High-yield: Epithelioid cell type = worst prognosis. Mixed-cell melanoma is the most common histological type. Spindle A is the most benign.

Etiology, risk factors & pathophysiology

Uveal melanocytes are neural-crest derived. Malignant transformation is driven by characteristic mutations distinct from cutaneous melanoma.

Risk factors: fair skin, light iris colour (blue/grey), inability to tan, ocular/oculodermal melanocytosis (naevus of Ota), dysplastic naevus syndrome, BAP1 tumour predisposition syndrome, and increasing age (peak 6th decade). Unlike skin melanoma, the link with UV light is weak/unproven.

Molecular pathology (increasingly tested):

• GNAQ / GNA11 mutations — early, initiating events (mutually exclusive, in the majority of uveal melanomas).
• BAP1 loss (chromosome 3) — strongly associated with monosomy 3, epithelioid morphology, and high metastatic risk/death. Germline BAP1 mutation → BAP1 cancer syndrome (uveal & cutaneous melanoma, mesothelioma, renal cell carcinoma).
• SF3B1 mutation — intermediate, late-metastasis risk.
• EIF1AX mutation — low metastatic risk, favourable.

High-yield: Monosomy 3 and BAP1 loss are the strongest predictors of metastatic death. Gene expression profiling Class 2 = high metastatic risk; Class 1 = low risk.

Spread: Uveal melanoma metastasises haematogenously (the uvea has no lymphatics), with marked hepatotropism — the liver is the commonest and often first site of metastasis (~90% of metastatic cases). This contrasts with retinoblastoma, which spreads along the optic nerve to the CNS.

Clinical features

Choroidal melanoma

• Painless, progressive blurring or a visual field defect.
• Floaters/photopsia; metamorphopsia if macula involved.
• Fundus: elevated, dome-shaped, grey-brown/slate subretinal mass; overlying orange pigment (lipofuscin) is highly suggestive of malignancy.
• Mushroom / collar-stud shape when the tumour ruptures Bruch's membrane and balloons into the subretinal space — pathognomonic clinical and ultrasound sign.
• Secondary exudative (non-rhegmatogenous) retinal detachment, often shifting fluid.

Ciliary body melanoma

• Frequently silent until large.
• Sentinel vessels — dilated, tortuous episcleral vessels in the quadrant overlying the tumour.
• Lens indentation → astigmatism, lens subluxation, sectoral cataract.
• May erode anteriorly through iris root.

Iris melanoma

• Visible pigmented (sometimes amelanotic) iris nodule, usually inferior half.
• Distortion of pupil (corectopia), ectropion uveae, sectoral cataract.
• Secondary glaucoma (angle invasion, melanomalytic glaucoma).

High-yield: Orange pigment (lipofuscin), documented growth, subretinal fluid, thickness > 2 mm, symptoms, and margin touching the optic disc are the classic features distinguishing a small melanoma from a benign naevus. Mnemonic "To Find Small Ocular Melanoma — Doing IMaging": Thickness >2 mm, Fluid (subretinal), Symptoms, Orange pigment, Margin at disc, plus ultrasound hollowness and absence of halo/drusen.

Investigations & diagnosis

Uveal melanoma is largely a clinical + imaging diagnosis; biopsy is usually avoided to prevent tumour seeding (reserved for ambiguous cases or prognostic gene profiling).

Diagnostic flow: Dilated indirect ophthalmoscopy → B-scan ultrasonography (investigation of choice) → Fundus fluorescein angiography (FFA) ± ICG → MRI for extraocular/orbital extension → systemic metastatic work-up (liver-focused).

B-scan ultrasonography — investigation of choice:

Feature	Finding
Shape	Dome or collar-stud / mushroom
Internal reflectivity	Low to medium (acoustic hollowness)
Choroidal excavation	Present
Orbital shadowing	Present
Vascularity	Internal vascular pulsations on A-scan

High-yield: Classic B-scan triad of uveal melanoma — acoustic hollowness, choroidal excavation, and a collar-stud/mushroom shape. A-scan shows low internal reflectivity.

Fluorescein angiography: "double circulation" (simultaneous tumour and retinal vessels), late diffuse hyperfluorescence, and pinpoint leaks; not specific but supportive.

MRI: Melanin is paramagnetic → hyperintense on T1, hypointense on T2 — a useful signature and best for detecting extraocular extension.

Transillumination: Pigmented melanoma blocks light (shadow); helps differentiate from a transilluminating cyst.

Metastatic work-up: LFTs, liver ultrasound/CT, chest imaging. Because of hepatotropism, liver imaging is mandatory before and during follow-up.

High-yield: Investigation of choice for the eye = B-scan USG; for extraocular/orbital extension = MRI; for metastasis = liver imaging/LFTs.

Management & treatment of choice

Treatment is individualised by tumour size, location, visual potential, and the status of the fellow eye. The COMS (Collaborative Ocular Melanoma Study) classification guides therapy:

COMS size	Apical height	Basal diameter
Small	1–3 mm (often observed)	≤ 5 mm
Medium	2.5–10 mm	≤ 16 mm
Large	> 10 mm (or > 8 mm if near disc)	> 16 mm

Stepwise approach:

1. Small/indeterminate lesions (≈ naevus vs small melanoma): Document with photography/USG and observe for growth; treat if risk factors or growth appear.
2. Medium melanoma → globe-conserving therapy is the treatment of choice. Plaque brachytherapy (most commonly Iodine-125; Ruthenium-106 for thinner tumours) is the standard. The landmark COMS medium tumour trial showed NO difference in survival between I-125 brachytherapy and enucleation — hence eye-preserving brachytherapy is preferred.
3. Large melanoma → enucleation. COMS large tumour trial: pre-enucleation external beam radiotherapy did NOT improve survival over enucleation alone.
4. Extraocular/orbital extension → exenteration.
5. Iris melanoma: Local iridectomy / iridocyclectomy for documented, growing, localised tumours.
6. Other globe-sparing options: charged-particle (proton beam) radiotherapy, transpupillary thermotherapy (TTT) as adjunct, and local resection (endoresection/exoresection) in select cases.

High-yield (most-tested): Medium melanoma → I-125 plaque brachytherapy (survival equal to enucleation, COMS). Large melanoma → enucleation. Extraocular extension → exenteration.

Metastatic disease: Prognosis is poor (median survival months once liver metastasis appears). Tebentafusp (a gp100×CD3 bispecific T-cell engager) is the first systemic agent to show an overall-survival benefit in HLA-A*02:01-positive metastatic uveal melanoma — a newer high-yield fact. Conventional checkpoint inhibitors are far less effective than in cutaneous melanoma.

Prognosis & complications

Adverse prognostic factors: large size, ciliary body involvement, epithelioid cell type, monosomy 3 / BAP1 loss / Class 2 gene expression, extraocular extension, older age, and mitotic activity.

High-yield: Despite successful local control, ~50% of medium/large uveal melanoma patients ultimately die of (liver) metastasis — local treatment does not guarantee cure. Hence lifelong systemic surveillance.

Complications:

• Tumour: secondary exudative retinal detachment, secondary glaucoma (angle invasion, neovascular, melanomalytic), vitreous haemorrhage, cataract.
• Treatment (radiation): radiation retinopathy, optic neuropathy, cataract, neovascular glaucoma, dry eye, scleral necrosis.
• Metastatic spread to liver, lung, bone.

Other uveal tumours (key differentials)

Choroidal naevus — benign, the chief differential of small melanoma. Flat/minimally elevated (< 2 mm), uniform slate-grey, overlying drusen and a surrounding halo suggest benignity; absence of orange pigment, subretinal fluid and growth supports a naevus.

Choroidal metastasis — the commonest intraocular malignancy overall. Usually creamy-yellow, plateau-shaped, often multiple and bilateral, with high internal reflectivity on USG (vs hollow melanoma). Commonest primaries: breast (women) and lung (men); lung often presents with the ocular lesion as first sign.

Circumscribed choroidal haemangioma — benign vascular hamartoma; orange-red dome, HIGH internal reflectivity on A/B-scan, intense early FFA filling. Diffuse variant associated with Sturge–Weber syndrome.

Choroidal osteoma — young women, juxtapapillary, yellow-white with scalloped margins; CT shows calcification (bone density); USG highly reflective with shadowing.

Melanocytoma — deeply pigmented, benign, typically over the optic disc; usually static.

Lesion	Colour	USG reflectivity	Clue
Uveal melanoma	Grey-brown, orange pigment	Low (hollow)	Collar-stud, growth
Choroidal naevus	Slate-grey, flat	High	Drusen, halo, < 2 mm
Metastasis	Creamy-yellow	High	Multiple/bilateral, breast/lung
Choroidal haemangioma	Orange-red	High	Sturge–Weber (diffuse)
Choroidal osteoma	Yellow-white	Very high + shadow	CT calcification, young female

High-yield: Low/hollow reflectivity → melanoma; HIGH reflectivity → naevus, metastasis, haemangioma, osteoma. Reflectivity is the single most discriminating USG parameter.

Recently asked / exam angle

• Image-based: a fundus photo of a pigmented dome with orange pigment or a B-scan collar-stud mass → diagnosis = choroidal melanoma.
• Investigation of choice for intraocular melanoma = B-scan USG (low reflectivity, hollow, collar-stud).
• Commonest primary intraocular malignancy in adults = uveal/choroidal melanoma; commonest intraocular malignancy overall = metastasis.
• Commonest site of metastasis from uveal melanoma = liver (haematogenous, no uveal lymphatics).
• COMS-based one-liners: medium → brachytherapy (= enucleation survival); large → enucleation; pre-enucleation EBRT no benefit.
• Worst histological prognosis = epithelioid; commonest = mixed.
• Molecular: monosomy 3 / BAP1 loss / Class 2 = high metastatic risk; tebentafusp in HLA-A*02:01 metastatic disease.
• Differential reflectivity question: choroidal haemangioma & metastasis = HIGH reflectivity vs melanoma's low.
• Sentinel (episcleral) vessels → ciliary body melanoma.
• Naevus of Ota / oculodermal melanocytosis as a risk factor for uveal melanoma.

Rapid revision

• Uveal melanoma = commonest primary intraocular malignancy in adults; choroid is the commonest site (~90%).
• Mixed is the commonest cell type; epithelioid has the worst prognosis; spindle A the best.
• B-scan: collar-stud/mushroom shape, acoustic hollowness (low reflectivity), choroidal excavation = melanoma; A-scan low internal reflectivity.
• Orange pigment (lipofuscin) overlying a choroidal mass strongly suggests melanoma; drusen + halo suggest a benign naevus.
• MRI of melanin: T1 hyperintense, T2 hypointense; MRI best for extraocular extension.
• Spreads haematogenously to the LIVER (~90%) — uvea has no lymphatics; lifelong liver surveillance.
• Monosomy 3 / BAP1 loss / GEP Class 2 = high metastatic death risk; GNAQ/GNA11 are early driver mutations.
• COMS: medium → I-125 plaque brachytherapy (survival = enucleation); large → enucleation; extraocular → exenteration.
• Pre-enucleation external beam radiotherapy gives no survival benefit (COMS large trial).
• Tebentafusp improves survival in HLA-A*02:01-positive metastatic uveal melanoma.
• Sentinel episcleral vessels = ciliary body melanoma; iris melanoma = best prognosis (detected early).
• High USG reflectivity differentials: choroidal haemangioma (Sturge–Weber if diffuse), metastasis (breast/lung), choroidal osteoma (young female, CT calcification), naevus.