Choroidal Melanoma

The uveal tract is the highly vascular and densely pigmented layer of the eyeball, lying between the sclera (superficial to it) and the retina (deep to it). The anterior, visible portion is the iris. This extends back into the ciliary body (at the level of the lens) and then extends round to the posterior pole. It is this fundus portion which is known as the choroid. Choroidal melanoma is the most common primary malignant intra-ocular tumour and accounts for 80% of all melanomas of the uveal tract.¹ It is also the second most common type of primary malignant melanoma in the body but, in absolute terms, it is relatively uncommon.

Primary choroidal melanoma arises from melanocytes within the choroid. It is thought to develop from pre-existing melanocytic naevi, although de novo growth may occur. The colour varies from darkly pigmented to amelanotic. It is usually dome-shaped. If it breaks through Bruch's membrane (which effectively forms a blood/neural tissue barrier between the vascular choroid and the retinal layer) as it grows, it looks like a mushroom. It can also be bilobular, multilobular and diffuse in shape. Occasionally, there may be a a number of small lesions in one or both eyes (although bilateral involvement is generally rare).

Histologically, three distinct cell types are recognised: spindle A, spindle B and epithelioid. The latter is associated with more aggressive disease and increased metastatic potential. These types of tumours tend to have a worse prognosis.

Choroidal melanomas usually cause death secondary to distant metastases rather than local spread. If the melanoma does not show extraocular extension, it can only spread haematogenously because there are no lymphatic vessels in the eye. Metastases are most commonly to the liver (this is the sole site of metastasis in 80% of cases)² but may also involve the lung, bone, skin and central nervous system. Less frequently, choroidal melanoma can metastasise locally into the orbit, the conjunctiva or the maxillo-facial bones.³

• White people of northern European descent are most often affected. Scandinavian countries have an incidence of about 7.5 cases per million population, per year.⁴
• It is rarely found among black people. Hispanics and Asians are thought to have a small risk compared to whites.
• There is a slightly higher incidence in men for all age groups, except from 20-39 years, when a small predilection exists for women.
• Incidence peaks at around 55 years of age.

Risk factors

• Light-coloured irides
• Possibly sunlight exposure
• Positive family history (although frequently absent)
• Pre-existing naevus
• Xeroderma pigmentosum

The tumour growth tends to be a silent one. In general, the further the tumour is away from the optic nerve and fovea, the less likely it is to produce symptoms. Thus, it may be asymptomatic and found incidentally during ophthalmoscopy. If it reaches a certain size or is in a sensitive location it causes visual disturbance through a variety of mechanisms (e.g. physical disruption of the retina and other processes; see 'Complications' below) and other ocular symptoms.

Ocular symptoms⁵

• Blurred vision
• A paracentral scotoma
• Painless and progressive visual field loss
• Floaters or flashes ('ball of light' slowly moving across vision)¹
• Occasionally severe ocular pain

Systemic symptoms

The tumour may have metastasised before ocular symptoms occur and a diagnosis is made (about 2% of cases). Additionally, metastases from primary non-ocular malignancy can give rise to a secondary tumour here. Therefore, there may be (in addition to or instead of ocular symptoms) a history of weight loss, fatigue, cough or change in bowel or bladder habits suggestive of systemic involvement.

Signs

• Loss of visual acuity ± visual field defects
• Occasional inflammation (marked by inflammatory cells in the vitreous)
• Usually: nodular, dome-shaped lesion on fundoscopy, occasionally: diffuse lesion growing laterally
• Varying colours but may be amelanotic (difficult to pick up)
• Occasionally: haemorrhage or hyphaema
• Advanced tumours may give rise to proptosis

Diagnosis is based on clinical findings and scan results.

• Naevus
• Melanocytoma
• Metastasis from a non-ocular tumour
• Choroidal detachment
• Intra-ocular foreign body
• Cavernous haemangioma
• Exudative retinal detachment (of other cause)
• Retinoblastoma (in a young patient particularly)
• Glaucoma
• Sarcoidosis
• Tuberculosis

Ultrasound (US) imaging can be easily carried out in the outpatient department and will give some important diagnostic clues:

• B-scan US of the eye is used to evaluate any posterior segment mass. B-scan is used to:
  • Help establish the diagnosis
  • Evaluate possible extra-ocular extension
  • Estimate tumour size for periodic observation
  • Plan treatment
• A-scan US of the eye; performing sequential scans is important in cases of diagnostic uncertainty

CT scan and MRI of the globe and orbit are more expensive than US and less sensitive, although they may be helpful in assessing extra-ocular extension. Fluorescein imaging may occasionally be useful. In a few cases, a fine needle biopsy may be performed but this has its own inherent risks; incisional biopsy should not be performed (associated with higher recurrence and metastases).¹ US scanning must be followed up by further investigations to ascertain whether this has spread or has arisen as a result of spread. These include:

• LFTs - particularly alkaline phosphatase, glutamic-oxaloacetic transaminase, lactic dehydrogenase and gamma-glutamyl transpeptidase. If these are abnormal, imaging of the liver (US or CT) is mandatory; the liver is affected in up to 90% of patients with metastases.²
• Chest X-ray to rule out lung metastases.

Choroidal melanomas may be classified according to:

• Anatomical origin - this may be anterior (e.g. ciliary body) or posterior within the choroid.
• Growth pattern - this may be elevated in to the typical dome shape or diffuse.
• Posterior location - it may be around the optic nerve, the macula or elsewhere.
• Size - this is the most common form of classification based on thickness and basal size. The tumour is termed small (< 10 mm diameter), medium (10-15 mm diameter) or large (> 15 mm diameter).¹

There are several ways to manage choroidal melanomas. Factors to take into account include:

• Visual acuity of the affected eye
• Visual acuity of the contralateral eye
• Size of the tumour
• Age and general health of the patient
• Ocular structures involved
• Presence of metastases

Choice of treatment of choroidal melanoma remains controversial. Although enucleation has been the treatment of choice in the past, research has shown that vision-sparing approaches might offer similar degrees of tumour control. A multicentre randomised trial by the Collaborative Ocular Melanoma Study (COMS) Group showed that patient survival after treatment with plaque radiotherapy is similar to enucleation for medium-sized melanoma.⁶

Non-surgical

• Observation may be acceptable for posterior uveal tumours where diagnosis is not well-established. In particular, tumours of < 2-2.5 mm in elevation and < 10 mm in diameter can be observed until growth is documented.⁷ COMS reported growth in only 31% of such tumours.¹ In this case, there will be photographic and US records of the tumour to monitor any developments.
• Laser photocoagulation and transpupillary thermotherapy are used in selected small choroidal melanomas.
• External beam irradiation using charged particles, either protons or helium ions, is a frequently used alternative method to treat medium-sized choroidal melanomas (<10 mm in height and <15 mm in diameter), although it has been used for larger tumours. It has similar indications and success rates to plaque brachytherapy.⁸

Surgical

• Block excision or sclerouvectomy, is an alternative treatment method for choroidal melanomas. It is reserved for small tumours covering less than a one third of the globe's circumference.
• Plaque brachytherapy is a widely accepted alternative to enucleation for medium-sized posterior uveal melanomas (< 10 mm in height and < 15 mm in diameter). It is associated with cataract development in up to 83% patients.⁹
• Enucleation is the classic approach to choroidal melanomas and has been the preferred treatment for large (basal diameter> 15 mm and height > 10 mm) and complicated tumours, which compromise visual function and where other therapies tend to fail. It is also advocated in blind, painful eyes with melanoma-induced neovascular glaucoma.
• Orbital exenteration is a radical treatment reserved for cases with widespread orbital extension. Patients with such advanced melanomas are likely to have extensive distant metastases and poor prognosis for survival, with or without orbital exenteration surgery.

Although undetected metastatic spread at the time of diagnosis and treatment of choroidal melanoma is a major concern in every patient, adjuvant systemic treatment is not advocated.⁴ This consensus comes from treatment trials with intra-ocular melanomas and extrapolation of the experience with cutaneous melanoma, where adjuvant treatment has shown no benefit. However, in cases where distant metastases are found during the initial systemic workup, treatment of the intra-ocular melanomas becomes palliative. Systemic chemotherapy is the primary treatment at that point.

Clearly, the most important complication of this tumour is metastasis and death. But a number of ocular problems may occur in the early stages including:

• Retinal detachment
• Choroidal neovascularisation
• Haemorrhage
• Uveitis

Occasionally, the tumour may spread anteriorly, thus affecting segments at the front of the eye and so resulting in cataract formation, ocular hypertension/hypotension or iris rubeosis. Treatment of the tumour may also lead to partial or total loss of vision in the eye.

Local tumour control can now be achieved in about 90% of cases.⁵ However, tumours are not often found early and systemic metastases occur in 40% of cases within 5 years. Approximately 30 to 50% of patients die within 10 years from diagnosis and treatment. It is usually secondary to distant metastases and the risk is greatest in larger tumours. Other features associated with an increased risk of mortality include:

• Anterior location
• Transscleral extension
• Optic nerve extension
• Lack of pigmentation
• Certain histological characteristics

A recent study has found that these patients benefit psychologically from knowing their prognosis, even if this is poor and if little can be done about it.¹⁰ All patients will need to be followed up for many years post diagnosis, even after apparently successful treatment.