Uveal
melanoma threatens the patient with visual deficit, loss of the eye and
metastatic death. A healthy controversy surrounds most aspects of care,
which continue to evolve.
Diagnosis
Almost
all intraocular melanomas can readily be diagnosed by ophthalmoscopy or
bio-microscopy; however, the examiner must be aware of every condition
that might resemble melanoma and should also be able to recognise any clinical
variation of each condition. Some tumours, such as suspicious naevi and
melanocytomas, demand life-long monitoring, aided by baseline colour photographs
with which ophthalmoscopic appearances can be compared.
Ultrasonography
is useful for measuring tumour dimensions, detecting extraocular extension,
and demonstrating whether a tumour is solid or cystic. Special expertise
is required to distinguish melanoma from other tumours, according to internal
reflectivity. When measuring thickness, care should be taken to measure
the thickest part of the tumour, identifying the deep scleral surface,
taking account of overlying retinal detachment, and avoiding an oblique
cut, which would result in over-estimation. Angiography, computerised tomography,
and magnetic resonance imaging are rarely helpful and can be confusing.
Occasionally, biopsy is needed to determine the primary source of a metastasis
or to exclude melanoma. Both fine needle aspiration biopsy and trans-scleral
incisional biopsy require the involvement of a highly skilled cytologist
or pathologist.
Systemic
investigation
Patients
with suspected melanoma require a full systematic history, complete medical
examination, full blood count, serum biochemistry and liver function tests.
If these give rise to any suspicion of extraocular malignancy then further
investigations are performed as appropriate. There is debate as to whether
pre-operative liver scans should be performed routinely or only if there
is an increased chance of metastatic disease (ie, tumour diameter >17mm
or extraocular extension.)
Ocular
treatment
Plaque
radiotherapy is the first choice of treatment in most centres. The ruthenium
applicator is effective for tumours up to 5.5mm thick. Iodine plaques destroy
tumours up to 9mm thick but are more likely to cause radiational side-effects.
Proton
beam radiotherapy is relatively expensive. It requires suturing of tantalum
markers to sclera, treatment planning at Clatterbridge Centre for Oncology
(Wirral) two weeks later, and a four-day course of radiotherapy at Clatterbridge
after another fortnight. Unlike plaque treatment, proton beam radiotherapy
often damages superficial tissues, causing permanent discomfort. It is
therefore reserved for some small, posterior melanomas that are difficult
to treat with plaque. Some centres select proton beam radiotherapy for
large tumours, accepting the high incidence of persistent exudative retinal
detachment and neovascular glaucoma. Proton beam radiotherapy has been
applied to iris tumours, as an alternative to local resection, with encouraging
initial results (Damato et al, unpublished data).
Trans-scleral
local resection of choroidal and ciliary body melanomas is technically
difficult and requires hypotensive anaesthesia to lower the systemic blood
pressure to 44 mm Hg. Local tumour recurrence has become less of a problem
since the introduction of adjunctive plaque radiotherapy, but about 25%
of all patients require subsequent vitreoretinal surgery. For these reasons,
resection is performed only in a few centres, where it is reserved for
tumours deemed too large for radiotherapy.
Photocoagulation
using argon, xenon or krypton applications has largely been superseded
by low-energy, long exposure trans-pupillary thermotherapy delivered with
a 3 mm diode laser. Some centres would rely entirely on trans-pupillary
thermotherapy to destroy a juxtapapillary tumour; however, such a policy
is opposed by those who have seen patients return with orbital recurrence
many years after apparently successful photocoagulation. Long-term studies
are required to determine (1) whether phototherapy is indeed as effective
as is suggested by early results and, (2) whether it can safely be used
to reduce radiational safety margins and tumour dose when administering
plaque or proton beam radiotherapy.
Trans-retinal
'endoresection' has been developed for small, juxtapapillary melanomas
as a means of avoiding radiational complications. It is controversial because
of fears about tumour seeding. Although this complication has not yet occurred
in a series of more than 50 primary endoresections, initial phototherapy
is now administered as a precaution. The main complications are silicone
cataract and retinal detachment, mostly cause by entry-site tears. Further
studies are needed to determine the scope of endoresection.
Enucleation
is indicated when none of the methods above can conserve what the patient
considers to be a useful eye. It is performed in the standard fashion,
with an orbital implant. Pre-enucleation radiotherapy is now known to be
useless. If there is extra-ocular extension the patient is either monitored
or given prophylactic external beam radiotherapy, according to individual
preference.
Non-treatment
is not advised, unless the patient is moribund, because (1) an opportunity
for preventing metastatic disease might be missed, (2) the eye might become
acutely painful, necessitating urgent enucleation, perhaps when the patient
is unfit for general anaesthesia, and (3) the scope for preserving vision
might diminish.
Factors
reducing the chances of ocular retention include: (1) tumour diameter >
15 mm; (2) thickness > 5.5 mm; (3) posterior margin < 1 mm from disc;
(4) involvement of more than a third of ciliary body, iris, or angle; (5)
retinal perforation; (6) extraocular extension; and (7) diffuse spread.
Good visual acuity can be expected if the tumour does not extend within
3 mm of fovea and if pre-operative acuity is normal.
Management
of systemic disease
The most
valuable predictive factors for metastatic death are (1) intra-tumoral
chromosomal abnormality, such as monosomy 3, (2) large basal tumour diameter
(i.e., > 15 mm), (3) epithelioid cells, (4) closed vascular loops, and
(5) old age (i.e., > 60 years) at treatment. These allow patients with
approximately an 80% chance of surviving 10-15 years to be distinguished
from those with only a 30% chance of surviving five years.
Metastatic
disease usually presents with hepatic problems and is invariably fatal.
Chemotherapy for established disease only rarely prolongs life significantly,
whether delivered systemically or by hepatic perfusion. Partial hepatectomy
can be beneficial in the few patients having only a few metastases.
It
is not yet known whether screening for metastatic disease should be recommended
to all patients or just high risk cases or not at all.
Interferon-alpha,
vaccination, and intra-hepatic chemotherapy are under investigation as
adjuvant therapies aimed at preventing any micro-metastases from developing
into clinical disease.
The
European Organisation for Research and Treatment of Cancer (EORTC) has
established the Ophthalmic Oncology Group so that these questions can be
addressed by multi-centre studies.
Ocular
Oncology Centres
A few
ocular oncology centres exist around Britain. Some (i.e., in Glasgow, Liverpool,
London and Sheffield) are funded supra-regionally, removing financial obstacles
imposed by the extra-contractual referral system. The routine treatment
of many patients at specialist units allows patients to be managed by multi-disciplinary
teams, enables investment in special equipment, and enhances opportunities
for research and teaching. It also becomes easier to address psychological
problems, for example, by providing expert counselling, getting patients
in touch with others who have had a similar experience, and providing a
telephone help-line.
Shared
Care
Special
precautions are necessary when referring a patient to an oncology centre.
The patient should be informed of the suspected diagnosis and advised to
get in touch if an appointment letter is not received within a specified
time. The referral should not be delayed unduly because investigations
are being performed.
When
monitoring is required, some oncologists alternate visits with the referring
ophthalmologist to facilitate the eventual discharge of the patient from
the oncology centre. For this strategy to work, referring ophthalmologists
and other associates need to be kept informed on the patient's progress,
reassured about signs that might cause undue concern, and alerted to any
problems that can arise. Conversely, the referring ophthalmologist should
develop the habit of sending the oncologist a copy of the GP letter after
each visit, explicitly stating the visual acuity in each eye and mentioning
any ocular or systemic conditions that develop. This would facilitate audit,
which forms an essential part of ocular oncology.
Conclusions
Many patients
with uveal melanoma have a reasonable chance of surviving and retaining
the eye with good vision. Sadly all too often, they are referred with a
large tumour, usually because their condition was missed when they presented
with blurred vision, metamorphopsia, or photopsia. Ophthalmologists should
teach optometrists and general practitioners not to assume that such symptoms
are due to cataract or macular degeneration without performing full ophthalmoscopy
with mydriasis. Such simple measures might do more to prevent visual loss
and metastasis than any marvellous developments in microsurgery, immunotherapy
or chemotherapy.
Bertil
Damato PhD FRCOphth,
Ocular
Oncology Centre,
St
Paul's Eye Unit,
Royal
Liverpool University Hospital,
Prescot
St,
Liverpool
L7
8XP
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Leyvraz S, Spataro V, Bauer J, et al. Treatment of ocular melanoma metastatic
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