Ординатура / Офтальмология / Английские материалы / Clinical Ophthalmology A Systematic Approach 7th Edition_Kanski, Bowling_2011

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Fig. 12.25 Imaging in choroidal melanoma. (A) FA early phase of a ‘collar-stud’ tumour shows a ‘dual circulation’; (B) B-scan of a dome-shaped tumour shows choroidal excavation; (C) B-scan of a ‘collar-stud’ tumour; (D) T1-weighted MRshows a choroidal melanoma (white arrow) and extraocular extension (black arrow)

(Courtesy of B Damato – figs A and B; S Milewski – fig. C; M Karolczak-Kulesza – fig. D)

Systemic investigations

Systemic investigation is aimed at the following:

1Excluding a metastasis to the choroid, most frequently from the lung in both sexes and from the breast in women. Occasionally, the primary site is the kidney or gastrointestinal tract.

2Detecting possible metastatic spread from the choroid because of large tumour size (e.g. basal diameter > 16 mm) and if there is clinical suspicion of metastatic spread. Hepatic involvement can be detected by ultrasonography and elevated lactate dehydrogenase, gamma-glutamyl transpeptidase and alkaline phosphatase levels. Chest radiography rarely shows lung secondaries in the absence of liver metastases. Only about 1–2% of patients have detectable metastases at the time of presentation.

Principles of treatment

Treatment is performed to avoid the development of a painful and unsightly eye, preferably conserving as much useful vision as possible. Since it is not known when metastasis occurs it is uncertain as to whether or not ocular treatment influences survival. Theoretically the smaller the tumour the greater the opportunity for preventing metastasis and therefore the more urgent is the need for treatment.

Management should be tailored to the individual patient taking the following factors into consideration:

•Size, location and extent of the tumour together with effects on vision.

•State of the fellow eye.

•General health and age of the patient.

•The patient's wishes and fears.

Treatment may not be required in the following cases:

•If the tumour is slow-growing and present in the only seeing eye of a very elderly or chronically ill patient.

•If it is not possible to determine clinically whether a tumour is a small melanoma or a large naevus. In this case the lesion is observed and treatment is administered only if growth is documented by sequential ultrasonography or photography.

Brachytherapy

Brachytherapy (episcleral plaque radiotherapy) with ruthenium-106 or an iodine-125 applicator (Fig. 12.26A) is usually the treatment of first choice because it is relatively straightforward and effective.

1Indications are tumours less than 20 mm in basal diameter in which there is a reasonable chance of salvaging vision. It is possible to treat tumours up to 5 mm thick with a ruthenium plaque and up to 10 mm thick with an iodine plaque. Supplemental transpupillary thermotherapy may be required to sterilize the tumour or to reduce exudation.

2Technique

a The tumour is localized by transillumination or binocular indirect ophthalmoscopy.

bA template consisting of a transparent plastic dummy or metal ring with eyelets is sutured to the sclera with a releasable bow.

cOnce it has been established that the template is correctly positioned, the sutures are loosened and used to secure the

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radioactive plaque.

dThe plaque is removed once the appropriate dose has been delivered, usually within 3–7 days. At least 80 Gy should be delivered to the tumour apex. Tumour regression starts about 1–2 months after treatment and continues for several years, leaving a flat or dome-shaped pigmented scar.

3Tumour response is usually gradual. Amelanotic tumours tend to become more pigmented as they regress (Fig. 12.26B and C).

4Complications depend on the size of the tumour and its distance from optic nerve and fovea. Problems from excessive irradiation include cataract, papillopathy (with or without disc neovascularization) and maculopathy. The irradiated tumour can also cause macular oedema, retinal hard exudates, serous retinal detachment, rubeosis and neovascular glaucoma (‘toxic tumour syndrome’).

5Survival is similar to that following enucleation for comparable tumours.

Fig. 12.26 Brachytherapy for choroidal melanoma. (A) Placement of plaque; (B) amelanotic tumour prior to treatment; (C) pigmentation following treatment

(Courtesy of C Barry)

External beam radiotherapy

Irradiation with charged particles such as protons achieves a high dose in the tumour with a relatively small dose in the superficial tissues.

1Indications are tumours unsuitable for brachytherapy either because of large size or posterior location making positioning of a plaque unreliable.

2Technique

aRadio-opaque tantalum markers are sutured to the sclera and used to locate the tumour radiographically.

b The patient is seated in a mechanized chair with the head immobilized.

cThe patient directs gaze at an adjustable fixation target.

dFour fractions of radiotherapy are delivered over 4 consecutive days.

3Tumour regression is slower than with brachytherapy and choroidal atrophy around the base of the tumour takes longer to develop.

4Complications involving intraocular structures are similar to brachytherapy. Extraocular complications include loss of lashes, eyelid depigmentation, canaliculitis with epiphora, conjunctival keratinization and keratitis.

5Survival results are similar to those following brachytherapy or enucleation.

Stereotactic radiotherapy

Radiation is focused on the tumour by aiming multiple, highly collimated beams from different directions, either concurrently or sequentially, so that only the tumour receives a high dose of radiation. This is still a new technique, which is gaining in popularity in centres where proton

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beam radiotherapy is not available. The indications, contraindications and complications of these two methods are likely to be similar.

Transpupillary thermotherapy

Transpupillary thermotherapy (TTT) uses an infrared laser beam to induce tumour cell death by hyperthermia but not coagulation. It is a useful adjunct to radiotherapy.

1Indications

•Small, pigmented choroidal tumour when differentiation between naevus and melanoma is not possible and when radiotherapy is considered unsuitable.

•Small choroidal melanoma when radiotherapy is inappropriate because of poor general health or reduced life expectancy.

•After radiotherapy, as a treatment for exudation threatening vision.

2Technique

aOverlapping one-minute applications of a 3 mm diode laser beam are applied all over the tumour surface, adjusting the power so that retinal blanching does not develop before 45 seconds.

bA 2 mm rim of surrounding choroid is treated to prevent marginal recurrence.

c Adjunctive plaque radiotherapy is administered, if possible, to prevent recurrence from deep intrascleral deposits.

dThe treatment is repeated if there is residual tumour after six months.

3Tumour response is gradual, with the lesion first becoming darker and flatter, eventually disappearing to leave bare sclera.

4Complications include retinal traction, retinal tear formation with rhegmatogenous detachment, vascular occlusion, neovascularization and iris burns, which can be associated with lens opacities. Local recurrence is common, especially if the tumour is thick, amelanotic or involving the disc margin.

Trans-scleral choroidectomy

Choroidectomy is a difficult procedure and is therefore not performed widely. It may be indicated for carefully selected tumours that that are too thick for radiotherapy but usually less than 16 mm in diameter. Complications include retinal detachment, ocular hypotony, wound dehiscence and local tumour recurrence.

Enucleation

1Indications for excision of the globe are large tumour size, optic disc invasion, extensive involvement of the ciliary body or angle, irreversible loss of useful vision, and poor motivation to keep the eye.

2Technique is the same as for other conditions, using the surgeon's preferred orbital implant. It is essential to perform ophthalmoscopy after draping the patient to ensure that the correct eye is treated.

3Complications are the same as with enucleation for other conditions. Orbital recurrence is rare if there is no extraocular tumour spread or if any such extension is completely excised.

Differential diagnosis

The following conditions should be considered in the differential diagnosis of atypical cases:

1Pigmented lesions

•Large naevus usually shows numerous surface drusen, without serous retinal detachment and little if any orange pigment.

•Melanocytoma is deeply pigmented and usually located at the optic disc.

•Congenital hypertrophy of the RPE is flat and has a well-defined margin.

•Haemorrhage in the subretinal space or suprachoroidal space as from choroidal neovascularization or retinal artery macroaneurysm.

•Metastatic cutaneous melanoma has a smooth surface, a light brown colour, indistinct margins, extensive retinal detachment and often a past history of malignancy.

2Non-pigmented lesions

•Circumscribed choroidal haemangioma is typically posterior, pink, dome-shaped, and has a smooth surface.

•Metastasis is often associated with exudative retinal detachment.

•Solitary choroidal granulomas associated with sarcoidosis or tuberculosis.

•Posterior scleritis, which can present with a large elevated lesion, but in contrast to melanoma pain is a common feature.

•Large elevated disciform lesion, which can be eccentrically located, usually in the temporal pre-equatorial region, and are usually associated with hard exudates and fresh haemorrhages, both of which rarely accompany a melanoma.

•Prominent vortex vein ampulla is characterized by a small, smooth, brown, dome-shaped lesion, which disappears on exerting pressure on the eye.

Circumscribed choroidal haemangioma

A circumscribed choroidal haemangioma is not associated with systemic disease. It may be dormant throughout life or may give rise to symptoms, usually as a result of exudative retinal detachment. Slight progressive enlargement can occur over many years.

Diagnosis

1 Histology shows a mass within the choroid composed of varying-sized vascular channels (Fig. 12.27A).

2Presentation is in the 2nd–4th decades in one of the following ways:

•Unilateral blurring of central vision, visual field defect or metamorphopsia.

•Hypermetropia may occur if the retina is elevated by tumour or fluid.

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• Asymptomatic with normal visual acuity, as an incidental finding.

3Signs

•An oval orange mass at the posterior pole with indistinct margins that blend with the surrounding choroid (Fig. 12.27B).

•Subretinal fluid is usually present in symptomatic cases.

•The median base diameter of the lesion is 6 mm and the median thickness 3 mm.

•Complications include surface fibrous metaplasia, cystoid retinal degeneration, RPE degeneration and subretinal fibrosis.

4FA reveals rapid, spotty hyperfluorescence in the pre-arterial or early arterial phase (Fig. 12.27C) and diffuse intense late hyperfluorescence.

5ICGA shows hyperfluorescence in the early frames (Fig. 12.27D) and hypofluorescence (‘washout’) at 20 minutes.

6US shows an acoustically solid lesion with a sharp anterior surface, without choroidal excavation and orbital shadowing (Fig. 12.27E).

7MR shows that the tumour is isoor hyperintense to the vitreous in T1-weighted images and isointense in T2-weighted images, with marked enhancement by gadolinium.

Fig. 12.27 Circumscribed choroidal haemangioma. (A) Histology shows varying-sized congested vascular channels forming a mass within the choroid; (B) clinical appearance; (C) FA early phase shows hyperfluorescence; (D) ICGA shows early hyperfluorescence; (E) B-scan shows an acoustically solid lesion with a sharp anterior surface and high internal reflectivity but without choroidal excavation and orbital shadowing; (F) surface fibrous metaplasia

(Courtesy of J Harry – fig. A; P Gili – figs B, C and D; B Damato – figs E and F)

Treatment

The following may be used to treat vision-threatening tumours.

1Photodynamic therapy (PDT) using the same method as for choroidal neovascularization. The treatment may need to be repeated after a few months if subretinal fluid persists.

2TTT for lesions not involving the macula, though this causes peripheral visual field loss.

3Radiotherapy may involve lens-sparing external beam irradiation, proton beam radiotherapy or plaque brachytherapy. Only a low dose of radiotherapy is needed, but even this can cause collateral damage to normal tissues.

4Intravitreal anti-VEGF therapy shows promise.

Differential diagnosis

1 Amelanotic choroidal melanoma has a yellow-tan colour, often with subtle intrinsic darker pigment.

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2Choroidal metastasis is usually creamy-yellow and may be multifocal. However, metastatic deposits from carcinoid tumour, renal cell carcinoma and thyroid carcinoma may appear orange, similar to a haemangioma.

3RPE detachment is acoustically hollow and shows a distinct pattern on FA.

4Posterior scleritis is associated with pain and has different ultrasonographic features, including scleral thickening and episcleral oedema.

Diffuse choroidal haemangioma

Diffuse choroidal haemangioma usually affects over half of the choroid and enlarges very slowly. It occurs almost exclusively in patients with the Sturge–Weber syndrome ipsilateral to the naevus flammeus (see Ch. 1).

1Presentation is usually in the 2nd decade despite the fact that the tumour is present at birth.

2Signs

•The fundus has a diffuse deep-red ‘tomato ketchup’ colour that is most marked at the posterior pole (Fig. 12.28A).

•Localized areas of thickening, simulating a circumscribed haemangioma, may be present within the diffuse lesion.

3US shows diffuse choroidal thickening (Fig. 12.28B)

4Complications include secondary retinal cystoid degeneration and exudative retinal detachment. Neovascular glaucoma can result if exudative retinal detachment is not treated.

5Treatment of vision-threatening cases involves low-dose radiotherapy or PDT.

Fig. 12.28 (A) Diffuse choroidal haemangioma; (B) B-scan shows diffuse choroidal thickening

(Courtesy of B Damato – fig. B)

Optic disc melanocytoma

Melanocytoma (magnocellular naevus) is a rare, distinctive, unilateral, heavily pigmented congenital hamartoma which is seen most frequently in the optic nerve head but which can rarely arise anywhere in the uvea. In contrast to choroidal melanoma, melanocytomas are relatively more common in dark-skinned individuals and have a female predominance. In most cases the tumour is stationary with little tendency to change.

1 Histology shows, large, deeply pigmented polyhedral or spindle cells with small nuclei (Fig. 12.29A).

2Presentation. Most cases are asymptomatic and the condition is detected on routine ophthalmoscopy (mean age 50 years).

3Signs

•A dark brown or black, flat or slightly elevated lesion with feathery edges that may extend over the edge of the disc (Fig.

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12.29B).

•Occasionally a large tumour occupies most of the disc surface and may lead to pigment dispersion into the vitreous (Fig. 12.29C).

•An afferent pupillary conduction defect may be present, even if visual acuity is good.

4FA shows dense persistent hypofluorescence in all phases of the angiogram due to blockage (Fig. 12.29D).

5Complications, which are rare, include malignant transformation, spontaneous tumour necrosis, optic nerve compression and retinal vein obstruction.

6Treatment is not required except in the very rare event of malignant transformation.

Fig. 12.29 Melanocytoma. (A) Histology shows heavily pigmented polyhedral cells; (B) relatively flat tumour; (C) large elevated tumour; (D) FA shows hypofluorescence of deeper disc vessels due to blockage

(Courtesy of B Damato – fig. A; P Gili – fig. B)

Choroidal osteoma

Choroidal osteoma is a very rare benign, slow-growing, ossifying tumour which has a very strong female preponderance. Both eyes are affected in about 25% of cases but not usually simultaneously.

Diagnosis

1Histology shows mature cancellous bone, which causes overlying RPE atrophy.

2Presentation is in the 2nd–3rd decades with gradual visual impairment if the macula is involved by the tumour itself or by secondary choroidal neovascularization.

3Signs

•A yellow-white flat or minimally elevated lesion with well-defined, scalloped margins near the disc or at the posterior pole (Fig. 12.30A).

•Slow growth may occur over several years and long-standing cases may develop RPE changes (Fig. 12.30B).

•Spontaneous resorption and decalcification may rarely occur.

•Prognosis is poor if the lesion involves the fovea.

4FA manifests early, irregular, diffuse mottled hyperfluorescence and late staining (Fig. 12.30C); choroidal neovascularization may be evident.

5 ICGA shows early hypofluorescence (Fig. 12.30D) and late staining. The tumour appears larger than on ophthalmoscopy.

6US shows a highly reflective anterior surface and orbital shadowing (Fig. 12.30E).

7 CT demonstrates a dense plaque-like opacity at the level of the choroid (Fig. 12.30F).

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Fig. 12.30 Choroidal osteoma. (A) Early juxtapapillary lesion; (B) long-standing tumour with overlying RPEchanges; (C) FA late phase shows mottled hyperfluorescence; (D) ICGA early phase shows hypofluorescence; (E) B-scan shows a highly reflective anterior surface and orbital shadowing; (F) axial CT demonstrates bilateral lesions that have the same consistency as bone

(Courtesy P Gili – figs C and D)

Differential diagnosis

1Choroidal metastasis, which may also be bilateral, but typically affects an older age group.

2 Amelanotic choroidal naevus or melanoma does not cause such extensive orbital shadowing.

3Osseous metaplasia, which may occur in association with choroidal haemangiomas.

4Sclerochoroidal calcification is an uncommon condition characterized by multifocal geographical yellow-white fundus lesions which are usually found in both eyes of older adults (see Fig. 8.21A).

Metastatic tumours

The choroid is by far the most common site for uveal metastases accounting for about 90%, followed by the iris and ciliary body. The most frequent primary site is the breast and bronchus. A choroidal secondary may be the initial presentation of a bronchial carcinoma, whereas a past history of breast cancer is the rule in patients with breast secondaries. Other less common primary sites include the gastrointestinal tract, kidney and skin melanoma. The prostate is, however, an extremely rare primary site. Patient survival is generally poor, with a median of 8–12 months.

Diagnosis

1Presentation is usually with visual impairment although metastases may be asymptomatic if located away from the macula.

2Signs

•A fast-growing creamy-white placoid lesion with indistinct margins most frequently located at the posterior pole (Fig. 12.31A) that may occasionally exhibit black pigment clumps on its surface (Fig. 12.31B).

•In some cases the deposits are globular in shape and may mimic an amelanotic melanoma (Fig. 12.31C) although they never exhibit a ‘mushroom’ configuration.

•The deposits are multifocal (Fig. 12.31D) in about 30% of patients and both eyes are involved in 10–30% of cases.

•Secondary exudative retinal detachment is frequent and may occur in eyes with relatively small deposits (Fig. 12.31E).

3US may be useful in detecting a deposit, particularly in eyes with secondary exudative retinal detachment. A placoid tumour shows diffuse choroidal thickening (Fig. 12.31F). A dome-shaped lesion shows moderately high internal acoustic reflectivity throughout the tumour which is suggestive but not pathognomonic.

4FA shows early hypofluorescence and diffuse late staining but in contrast with choroidal melanomas a ‘dual circulation’ is not seen.

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5ICGA usually shows hypofluorescence through the study and may show subtle deposits not evident on FA.

6Biopsy by fine needle aspiration or using a 25-gauge vitrectomy system may be appropriate when the primary site is unknown.

Fig. 12.31 Choroidal metastasis. (A) Small placoid deposit; (B) secondary pigment clumps on the surface of a large deposit; (C) large dome-shaped deposit; (D) multiple deposits; (E) deposits above the disc and in the temporal fundus with shallow inferior retinal detachment; (F) B-scan of a placoid lesion

(Courtesy of C Barry – figs A and E; B Damato – fig. B)

Systemic investigations

Systemic investigations are aimed at locating the primary tumour, if unknown, and other metastatic sites. This may include the following:

•Full history and physical examination.

•Mammography in females.

•Chest radiography and sputum cytology.

•Serum biochemistry, including alkaline phosphatase.

•Abdominal or whole body scans.

•Faecal occult blood.

•Urinalysis for red blood cells.

Management

1 Observation, if the patient is asymptomatic or receiving systemic chemotherapy.

2Radiotherapy, either external beam or brachytherapy.

3TTT is useful for small tumours with minimal subretinal fluid.

4Systemic therapy for the primary tumour may also be beneficial for choroidal metastases.

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Neural retinal tumours

Retinoblastoma

Retinoblastoma is the most common primary intraocular malignancy of childhood and accounts for about 3% of all childhood cancers. Even so, it is rare, occurring in about 1 : 17 000 live births.

Pathology

1Histology. The tumour is composed of small basophilic cells (retinoblasts) with large hyperchromatic nuclei and scanty cytoplasm. Many retinoblastomas are undifferentiated (Fig. 12.32A) but varying degrees of differentiation are characterized by the formation of rosettes, of which there are three types:

aFlexner–Wintersteiner rosettes consist of a central lumen surrounded by tall columnar cells. The nuclei of the cells lie away from the lumen (Fig. 12.32B).

bHomer–Wright rosettes ('pseudorosettes’) have no lumen and the cells form around a tangled mass of eosinophilic processes.

cFleurettes are foci of tumour cells which exhibit photoreceptor differentiation. Clusters of cells with long cytoplasmic processes project through a fenestrated membrane and the appearance resembles a bouquet of flowers (Fig. 12.32C).

2Patterns of tumour spread

aGrowth pattern may be endophytic (into the vitreous), with seeding of tumour cells throughout the eye or exophytic (into the subretinal space), causing retinal detachment (Fig. 12.32D).

b Optic nerve invasion, with spread of tumour along the subarachnoid space to the brain (Fig. 12.32E). c Diffuse infiltration of the retina, without exophytic or endophytic growth.

dMetastatic spread is to regional nodes, lung, brain and bone.

Fig. 12.32 Pathology of retinoblastoma: (A) Undifferentiated tumour; (B) well-differentiated tumour shows abundant Flexner-Wintersteiner rosettes; (C) fleurettes;

(D) whole eye section shows a mixed endophytic (into the vitreous) and exophytic (into the subretinal space) growth pattern; (E) transverse section of the cut end

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of the optic nerve with an area of tumour infiltration

(Courtesy of J Harry and G Misson, from Clinical Ophthalmic Pathology, Butterworth-Heinemann 2001 – fig. A; courtesy of J Harry – figs B, C, D and E)

In both heritable and non-heritable retinoblastoma (see below), the risk of metastatic disease is greater if the tumour is advanced, and if there is retrolaminar optic nerve invasion, massive choroidal invasion, anterior chamber involvement and orbital spread. Repeated recurrences after conservative treatment also indicate an increased risk of metastasis.

Genetics

Retinoblastoma results from malignant transformation of primitive retinal cells before final differentiation. Because these cells disappear within the first few years of life, the tumour is seldom seen after 3 years of age. Retinoblastoma may be heritable or non-heritable. The gene predisposing to retinoblastoma (RB1) is at 13q14.

1Heritable (germline) retinoblastoma accounts for 40%. An association with advanced paternal age suggests that in some patients the mutation has occurred in the father's sperm. In heritable retinoblastoma one allele of RB1 (a tumour suppressor gene) is mutated in all body cells. When a further mutagenic event ('second hit’) affects the second allele, the cell undergoes malignant transformation. Because all the retinal precursor cells contain the initial mutation, these children develop bilateral and multifocal tumours. Heritable retinoblastoma patients also have a predisposition to nonocular cancers, most notably pineal or suprasellar primitive neuroectodermal tumour (PNET; also known as pinealoblastoma and trilateral retinoblastoma), which occurs in about 3%. Second malignant neoplasms include osteosarcoma, melanoma, and malignancies of the brain and lung, each of these tumours tending to occur in a particular age group. The risk of second malignancy is about 6% but this increases five-fold if external beam irradiation has been used to treat the original tumour, the second tumour tending to arise within the irradiated field.

•The mutation is transmitted in 50% but because of incomplete penetrance only 40% of offspring will be affected.

•If a child has heritable retinoblastoma, the risk to siblings is 2% if the parents are healthy, and 40% if a parent is affected.

•About 15% of patients with hereditary retinoblastoma manifest unilateral involvement.

2Non-heritable (somatic) retinoblastoma accounts for 60% of cases. The tumour is unilateral, not transmissible and does not predispose the patient to second nonocular cancers. If a patient has a solitary retinoblastoma and no positive family history, this is probably but not definitely non-heritable so that the risk in each sibling and offspring is about 1%.

Siblings at risk of retinoblastoma should be screened by prenatal ultrasonography, and by ophthalmoscopy soon after birth and then regularly until the age of 4 or 5 years.

Presentation

Presentation is within the first year of life in bilateral cases and around 2 years of age if the tumour is unilateral.

•Leukocoria (white pupillary reflex – Fig. 12.33A) is the commonest presentation (60%) and may first be noticed in family photographs.

•Strabismus is the second most common (20%); fundus examination is therefore mandatory in all cases of childhood strabismus.

•Secondary glaucoma which is occasionally associated with buphthalmos (Fig. 12.33B).

•Diffuse retinoblastoma invading the anterior segment tends to present in older children. It may cause a red eye due to tumourinduced uveitis and iris nodules which may be associated with pseudohypopyon (Fig. 12.33D). It is therefore important to consider retinoblastoma in the differential diagnosis of unusual chronic uveitis in children.

•Orbital inflammation (Fig. 12.33E) mimicking orbital or preseptal cellulitis may occur with necrotic tumours. It does not necessarily imply extraocular extension and the exact mechanism is not known.

•Orbital invasion with proptosis and bony involvement may occur in neglected cases (Fig. 12.33F).

•Metastatic disease involving regional lymph nodes and brain before the detection of ocular involvement is rare.

•Raised intracranial pressure due to ‘trilateral retinoblastoma’ before the diagnosis of ocular involvement is very rare.

•Routine examination of a patient known to be at risk.

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