CLASSIFICATION OF DIABETIC RETINOPATHY

The initial clinical features of diabetic retinopathy are microaneurysms, small retinal haemorrhages and small areas of capillary closure (Table 15.1). Visual acuity is commonly normal at this stage, although subclinical changes in colour vision and contrast sensitivity might be found. This is followed by vascular leakage, hard exudate and cotton-wool spots. Retinopathy may progress to compromise vision in two ways: (1) maculopathy develops with oedema, lipid exudation or ischaemia, or (2) a proliferative retinopathy occurs, in which retinal hypoxia and neovascularization predominate and reduce vision by vitreous haemorrhage or traction retinal detachment. Not uncommonly, both mechanisms coexist in the same patient. Diabetic retinopathy is staged by its clinical features. Maculopathy is classified by extent as focal or diffuse, and by mechanism as exudative, ischaemic or mixed.

Table 15.1 Classification of diabetic retinopathy

Fig. 15.5 A flow diagram illustrates the concept of progression from initial nonproliferative or ‘background’ retinopathy to visual loss from maculopathy or proliferative retinopathy.

NATURAL HISTORY

Visual loss is a late event in diabetic retinopathy. Retinopathy normally develops many years after the onset of diabetes, although in some adults it may be the first presenting sign of the disease. About 25 per cent of type I diabetics have some retinopathy after 10 years of disease, whereas type II diabetics seem to develop retinopathy earlier with significant numbers being affected by 5 years after diagnosis and 50 per cent by 10 years. Diabetics lose vision as a result of either maculopathy or proliferative retinopathy. In general, type I diabetics are more likely to have proliferative retinopathy whereas type II diabetics are more likely to have maculopathy. More than 80 per cent of visual loss in diabetics is due to maculopathy, due in part to the 10-fold greater number of type II patients. These patients lose central vision but retain navigating sight. Proliferative retinopathy is much more serious as about 70 per cent of these eyes would be totally blind within 5 years from vitreous haemorrhage and retinal traction detachment if left untreated.

Risk factors for the progression of retinopathy are the duration of diabetes and the type (type I is worse than type II). Recent clinical trials have shown that meticulous long-term glycaemic and blood pressure control retards the onset and progression of diabetic retinopathy. Tightening poor glycaemic control may, however, initially markedly worsen retinopathy and cause neovascularization, possibly because initiating good control lowers retinal blood flow and exacerbates ischaemia. Careful monitoring of diabetic retinopathy when altering glycaemic control is therefore critical. Pregnancy, renal disease and cataract surgery may worsen the retinopathy whereas high myopia, optic atrophy, glaucoma, central retinal artery occlusion and carotid artery stenosis appear to protect, possibly by reducing retinal metabolic demand (Table 15.2). Diabetic retinopathy is not seen before puberty.

Table 15.2 Risk and protective factors for progression of retinopathy

MILD AND MODERATE NONPROLIFERATIVE DIABETIC RETINOPATHY (NPDR)

Previously termed ‘background’, this is the commonest form of diabetic retinopathy. Microaneurysms, dot haemorrhages (indistinguishable from microaneurysms without fluorescein angiography) and small, deep, blotchy haemorrhages are seen in the posterior pole and become more numerous as the retinopathy progresses. Initially, NPDR tends to be most prominent in the retina temporal to the macula, possibly because this is a watershed area in the retinal circulation. Splinter haemorrhages are a feature of combined hypertensive–diabetic retinopathy. Small focal areas of closure in the capillary bed are common. Hard exudates appear in relationship to focal vascular leakage, and the occasional cotton-wool spot may be seen. Fluorescein angiography shows more extensive changes than can be seen ophthalmoscopically.

Fig. 15.6 This patient shows the typical changes of early retinopathy with scattered microaneurysms, blot haemorrhages and hard exudates and cotton-wool spots in the posterior pole. The macula and visual acuity are normal. The retinopathy can fluctuate, improving or deteriorating over a period of time. Fluorescein angiography demonstrates extensive microvascular changes throughout the posterior pole with scattered microaneurysms and minimal vascular leakage. Many more microaneurysms are visible that can be seen clinically. Although in some areas capillary patterns around the macula are irregular and show minor areas of capillary closure, they are, in the main, complete.

Fig. 15.7 With early retinopathy, the retina temporal to the macula is often susceptible to earlier and more pronounced changes; elsewhere in the posterior pole of this patient, retinopathy is comparatively sparse.

Fig. 15.8 These patients show a more marked nonproliferative retinopathy.

Fig. 15.9 Background retinopathy appearances can fluctuate and do not progress relentlessly. These photographs were taken 18 months apart. The later photograph (top right) shows that the exudates temporal to the macula have been absorbed spontaneously and new exudate has appeared inferior to the macula. Comparison of angiograms from the same patient shows there has been a considerable change in the pattern of the microaneurysms. New microaneurysms have formed and others, on the temporal side of the macula in particular, have disappeared over the same period of time.

SEVERE NONPROLIFERATIVE DIABETIC RETINOPATHY

Previously the stage between background and proliferative retinopathy was called ‘preproliferative diabetic retinopathy’, but is now termed severe or very severe nonproliferative diabetic retinopathy. These patients have a substantial risk of progressing to proliferative diabetic retinopathy (PDR). Severe or very severe NPDR is characterized by signs of marked retinal hypoxia such as cotton-wool spots, capillary nonperfusion, numerous intraretinal haemorrhages, venous beading and loops, and intraretinal microvascular abnormalities (IRMAs). Cotton-wool spots have often been considered the hallmark of preproliferative diabetic retinopathy, but the Early Treatment Diabetic Retinopathy Study (ETDRS) found that IRMAs, venous changes and many deep haemorrhages were more predictive of imminent PDR. The retinopathy is defined as severe when one of the following signs is present and as very severe when two of the signs are present: (1) deep haemorrhages in four quadrants, (2) venous abnormalities in two or more quadrants, and (3) IRMAs in one or more quadrants.

Fig. 15.10 Numerous cotton-wool spots, which persist for longer in diabetes (up to 3 months) than with other causes indicate marked retinal ischaemia, as confirmed on angiography.

Fig. 15.11 Areas of intraretinal microvascular abnormalities (IRMAs) with dilated tortuous veins along the inferior temporal arcade are seen in this patient. IRMAs represent intraretinal neovascularization and are found at the border of areas of nonperfusion. They are entirely intraretinal and do not leak fluorescein. As they are associated with nonperfusion it is not surprising that they are associated with an increased risk of PDR.

Fig. 15.12 Areas of nonperfusion can often be recognized ophthalmoscopically by their flat featureless appearance and relative absence of microvascular changes.

Fig. 15.13 Blotchy, deep, retinal cluster haemorrhages are a feature of nonperfusion.

Fig. 15.14 Venous beading is seen where a vein traverses an area of capillary nonperfusion.

Fig. 15.15 This patient shows an extensive venous loop or ‘omega anomaly’. There is early neovascularization on the disc and deep cluster haemorrhages temporal to the macula.

PROLIFERATIVE DIABETIC RETINOPATHY (PDR)

This tends to occur in diabetics who have evidence of other diabetic complications with renal, vascular and neurological complications. The prognosis of these patients has improved considerably in recent years with better medical management.

The stimulus for neovascularization, as in other neovascular retinopathies, appears to be retinal hypoxia from extensive areas of retinal capillary closure. This leads to a reduction of the increased retinal blood flow which is a feature of nonproliferative retinopathy. Neovascularization starts to appear from the capillaries on the venous side of the circulation on either the optic disc or retina, usually at the junction of normal and hypoxic retina. At first the new vessels lie as vascular membranes flat on the retinal surface, but induced changes in the vitreous gel cause the gel to collapse and detach from the retina. New vessels that have penetrated the internal limiting membrane are dragged forwards on the posterior hyaloid face which acts as a scaffold for further proliferation. The neovascular tissue proliferates on the posterior hyaloid face but does not penetrate the vitreous gel.

In common with neovascularization elsewhere in the eye these vessels have fenestrated endothelial cell junctions and tend to leak, while minor trauma and vitreous traction causes them to tear and bleed to cloud the ocular media. Subsequent formation of fibrous tissue produces traction bands between the retina and posterior vitreous face; these eventually contract and detach the retina (see Ch. 12).

Clinically PDR is categorized by the location of neovascularization, either on the optic disc (NVD) or elsewhere (NVE), and by the presence of preretinal or vitreous haemorrhage and fibrosis with retinal traction. Advanced diabetic eye disease is characterized by vitreous haemorrhage and tractional retinal detachment (see Ch. 12).

Fig. 15.16 This patient was a longstanding diabetic with renal failure and poor vision (CF) in each eye. A composite mount of the fluorescein angiogram of the right eye shows gross retinal capillary closure and demonstrates how neovascularization tends to arise on the retina at the border zone of the perfused and ischaemic areas. This eye later developed rubeotic glaucoma.

Fig. 15.17 Retinal neovascularization begins as fine thready vessels that are difficult to see, usually adjacent to a vein. Angiography shows them more clearly because of their leakage.

Fig. 15.18 More advanced changes are seen in these patients. Peripheral neovascular tissue is initially seen as a flat neovascular fan; in more marked cases there is accompanying fibrous and retinal traction.

Fig. 15.19 Neovascularization on the optic disc carries a more serious visual prognosis than peripheral new vessel formation, and it is therefore essential to detect this early. In common with all neovascular tissue, neovascularization leaks intensely on angiography; this sign can, therefore, be very helpful in early diagnosis.

Fig. 15.20 Neovascularization starts as fine, flat, thready vessels on the disc that do not have a normal anatomical distribution. With time it increases in extent and severity and with collapse of the vitreous gel is pulled forwards on the posterior hyaloid face.

Fig. 15.21 This optic disc shows a prominent neovascular fan which has been pulled forwards by the detached vitreous gel; the vessels can be seen multiplying on the retrohyaloid face. Movements of the gel with ocular movement will put traction on these delicate vessels producing haemorrhage.

Fig. 15.22 Histological examination shows vascularized fibroglial tissue extending from the disc and adherent to the vitreous; note that the neovascularization does not invade the gel.

Fig. 15.23 Preretinal and vitreous haemorrhages are a serious complication of neovascularization both on the optic disc and in the peripheral retina.

Fig. 15.24 This patient has marked neovascularization on the optic disc and along the inferior temporal arcade. Vitreoretinal adhesions along the temporal vascular arcades are very common in diabetes. Here localized fibrotic changes have produced traction on the retina and distortion of the macula. If untreated the natural history would be of further fibrotic tissue formation and traction, progressing to localized or general traction detachment of the retina.

Fig. 15.25 In advanced cases vision is lost as a result of a combination of vitreous haemorrhage and traction detachment. In a few patients, the retinopathy ‘burns out’ before this final stage and leaves inactive fibrotic tissue with varying distortion of the retinal architecture. This patient, who never had photocoagulation, was left with visual acuities of hand movements and 20/60.

DIABETIC MACULOPATHY

Diabetic maculopathy is the leading cause of blindness in diabetic patients, especially noninsulin-dependent (type II) diabetics. It results from lipid exudation, oedema and ischaemia, frequently in combination. The ETDRS used the term ‘clinically significant macular oedema’ (CSMO) for the following signs: retinal thickening (i.e. oedema) at or within 500μm of the foveal centre, hard exudates at or within 500μm of the foveal centre if associated with thickened adjacent retina or a zone of retinal thickening covering at least one disc diameter (1500μm) within one disc diameter of the foveal centre. Retinal thickening can be satisfactorily assessed only by stereo-biomicroscopy; optical coherence tomography (OCT) (see Chs 1 and 12) has an increasing role in objectively assessing retinal thickness and the response to treatment.

Fig. 15.26 Lipid exudation into the macula originates from a leaking vascular anomaly, usually a microaneurysm or area of capillary closure, and spreads linearly in Henlé’s fibre layer. It is accompanied by oedema and thickening of the macula. Red-free photography shows lipid and vessels more clearly and the angiogram shows that the leak originates from a microaneurysm surrounded by a small area of capillary closure.

Fig. 15.27 Circinate patterns of exudate form around leaking foci in more established cases. The angiogram shows the vascular abnormalities in the centre of these lesions.

Fig. 15.28 Advanced exudative maculopathy results from prolonged and untreated deposition of lipid within the macula. Circinate exudates coalesce to produce massive plaques and although these will absorb if the sources of vascular leakage are destroyed by photocoagulation neuronal destruction has occurred to such an extent that vision rarely improves.

Fig. 15.29 Purely oedematous types of maculopathy are less common. Vascular changes produce macular oedema with relatively little haemorrhage or exudation. These maculas have a thickened, rather amorphous, appearance and cystoid spaces are sometimes visible. These changes are best appreciated by stereoscopic examination. Visual impairment is usually severe. Characteristically on angiography these individuals show diffuse capillary dilatation over the whole posterior pole with relatively few focal changes. Later phases show massive vascular leakage.

Fig. 15.30 Diabetic retinopathy can progress dramatically during pregnancy to maculopathy or proliferative disease. This patient had a background retinopathy before her pregnancy but developed marked macular oedema so that acuity had fallen to 20/80 by 36 weeks when labour was induced. At 3 weeks postdelivery (right) the oedema had resolved spontaneously and acuity improved to 20/30.

Fig. 15.31 With ischaemic maculopathy capillary closure produces deep intraretinal haemorrhage, oedema and ischaemia. Exudates are comparatively sparse but may surround the central disturbance. The angiogram shows loss of the macular capillary circulation but the patient still maintained an acuity of 20/80.

Fig. 15.32 This series of angiograms shows three patients with increasing extensiveness of capillary closure and macular ischaemia. Visual acuity is usually extremely poor and there is a high risk of progression to proliferative retinopathy.

DIABETIC PAPILLOPATHY

Fig. 15.33 This is an uncommon condition usually presenting with unilateral or bilateral optic disc swelling in a young adult diabetic. It is often associated with signs of a mild optic neuropathy and only mild or moderate retinopathy. The aetiology is thought to be ischaemic small vessel disease. The visual prognosis is generally good, with resolution without treatment.

MANAGEMENT OF DIABETIC RETINOPATHY

Many clinical studies have helped guide the management of diabetic retinopathy. Rigorous control of systemic hypertension has been shown to improve retinopathy and blood pressure monitoring is essential for all diabetics. Mild or severe NPDR without clinically significant macula oedema does not require laser treatment. Exudative maculopathy with hard exudation responds well to focal laser treatment of the leaking vessels. Generalized macular oedema is more difficult to treat; grid laser photocoagulation has been shown to be helpful. Ischaemic maculopathy cannot be treated. The ETDRS did not find aspirin (650 mg daily) to benefit or harm diabetic retinopathy and thus aspirin can be safely used if needed for other reasons. The study also found that hyperlipidaemia was associated with a higher incidence of hard exudates indicating that good serum lipid control is beneficial.

All eyes with neovascularization require panretinal photocoagulation. This reduces the risk of severe visual loss by 50 per cent at 2 years and 70 per cent at 5 years. Some ophthalmologists also treat all eyes with high-risk NPDR, particularly if follow-up is difficult; others prefer to observe until signs of neovascularization appear. The ETDRS showed that not all eyes with PDR require urgent panretinal photocoagulation. Eyes were shown to have ‘high-risk characteristics’ if they showed signs of NVD larger than one-third of a disc area, NVD with vitreous or preretinal haemorrhage, or NVE exceeding half a disc diameter with vitreous or preretinal haemorrhage. Those eyes with concomitant macular oedema or exudates should receive additional focal laser therapy.

Fig. 15.34 Proliferative retinopathy requires treatment by panretinal photocoagulation. By sparing the macular area panretinal photocoagulation does not affect visual acuity. Some 2000 burns are usually given to the equatorial retina, normally in one or two treatments, to produce regression of optic disc neovascularization within a few weeks. A few patients require much more treatment and all patients need to be followed up carefully with further treatment if neovascularization reappears. After panretinal photocoagulation visual disability is surprisingly slight. Preservation of the inner nerve fibre layer avoids the production of arcuate field loss and patients normally notice only marginal constriction of their visual field and sometimes a reduction in their visual performance in the dark. It is essential that patients are counselled about the effect of panretinal photocoagulation on their ability to drive especially on the right.

Fig. 15.35 The histology of a laser burn shows that there is atrophy of the retinal pigment epithelium (RPE) and photoreceptors in the area of the burn. The energy is taken up in the RPE and, provided the amount of energy is restricted, the thermal injury is localized and the inner nerve fibre layer spared. Damage to this layer would result in nerve fibre damage and visual field defects.

By courtesy of Professor J Marshall.

Fig. 15.36 In practice, the burns must be of sufficient intensity to produce a soft white reaction in the retinal pigment epithelium; a dense white reaction indicates damage to the inner retina. Within a few days the burns become pigmented atrophic scars (middle). Photocoagulation that is excessive leads to damage of the RPE and subsequent atrophy (right), causing peripheral field constriction and night blindness.

Fig. 15.37 The efficiency of panretinal photocoagulation is demonstrated by this patient who participated with informed consent in a controlled trial of panretinal photocoagulation in the early 1970 s. (Left pair) Early neovascularization is seen on each optic disc, confirmed by the presence of leakage on the fluorescein angiogram. The right eye was treated with xenon arc photocoagulation and the left remained untreated as a control eye. (Right pair) Fifteen months after panretinal photocoagulation to the right eye, the new vessels on the optic disc have regressed and marked chorioretinal scars can be seen from the photocoagulation (excessive treatment by present standards). Visual acuity remained normal in this eye, with loss of peripheral visual field and night blindness. In contrast the left deteriorated to perception of light with a marked neovascular membrane arising from the optic disc with total traction retinal detachment. This eye now has a substantial risk of developing rubeotic glaucoma.

Fig. 15.38 Exudative maculopathy is treated by obliterating the leaking microvascular abnormalities that produce the hard exudate. These can often be identified clinically without the need for routine fluorescein angiography. Absorption of hard exudates takes several weeks, depending on their extent.

Fig. 15.39 Fundus appearance (left) before and (middle) after laser photocoagulation. Before treatment, early deposition of hard exudate can be seen in the macular area. Eight weeks after treatment the exudate is in the process of being absorbed; 1 month later it has disappeared and the scars in the retinal pigment epithelium from the photocoagulation can be seen. Such treatment does not produce any visual impairment as long as the burns are outside the foveal avascular zone and of sufficiently low intensity to protect the overlying retinal nerve fibres.

Fig. 15.40 Macular oedema is treated by putting a grid of gentle photocoagulation over the macular area, taking care to avoid the fovea. Some 12 weeks after treatment the oedema has considerably resolved.

RACEMOSE MALFORMATIONS

These are thought to be developmental rather than genetic in origin. Rarely, retinal arteriovenous malformations or anastomoses can be associated with intracranial vascular abnormalities (Wyburn–Mason syndrome). Sturge–Weber syndrome affects the choroidal vessels rather than the retinal circulation (see Ch. 9). Visual loss from vascular leakage, accumulation of hard exudates or haemorrhage is rare.

Fig. 15.51 Arterial loops can be seen projecting forwards from the disc. They occasionally undergo torsion, causing retinal infarction.

Fig. 15.52 Small localized vascular abnormalities may be discovered as an incidental finding on routine examination. This patient has a small arteriovenous malformation adjacent to the optic disc.

Fig. 15.53 Larger arteriovenous malformations have a dramatic fundal appearance. They are normally totally static, but visual acuity will be affected if the macula is involved, as in this patient.

CAVERNOUS HAEMANGIOMA

Fig. 15.54 Cavernous haemangioma of the retina is a rare benign lesion. It consists of isolated clusters of dilated blood vessels within a fibrous matrix. The lesions do not progress or generally cause symptoms and are not associated with any systemic vascular disease. Well documented cases have been shown to remain unchanged over many years. The fluorescein angiogram shows that the dilatations fill with dye in the late venous phase, often with a fluid level from the stagnant circulation (fluorescein on top of the stagnant red blood cells), but with no vascular leakage.

VON HIPPEL–LINDAU DISEASE

This is a dominantly inherited disease with variable penetrance. Characteristic retinal haemangioblastomas are associated with similar lesions in the cerebellum, renal carcinoma and phaeochromocytomas, as well as renal and pancreatic cysts. Patients require lifelong screening with magnetic resonance imaging (MRI) to detect intracranial lesions, and renal ultrasonography to detect renal carcinoma and biochemistry for phaeochromocytomas. Genetic counselling of affected families is important. The gene has been identified and characterized as a tumour suppressor gene on the short arm of chromosome 3.

Retinal haemangioblastomas are the commonest manifestation of the syndrome; they can occur at any age but most present around 20–30 years of age. They are frequently bilateral and may be multiple in the same eye. About 70 per cent of patients who carry the gene will have developed them by the age of 60 years. Retinal haemangioblastomas have a progressive course of enlargement and leakage or rupture to produce lipid exudation or vitreous haemorrhage with significant ocular morbidity. In view of the complications these lesions should be treated with photocoagulation or cryotherapy, and the patient must be observed constantly as, with time, new lesions may develop. Photodynamic therapy has a potential therapeutic role.

Fig. 15.55 Early tumours are seen in the peripheral retina as red or yellowish bulbous vascular lesions with enlarged feeder vessels. Fluorescein angiography can be very helpful in detecting early lesions which are easily obliterated by photocoagulation.

Fig. 15.56 These tumours can reach dramatic proportions. Fluorescein angiography demonstrates the feeder vessels and the large leaking tumour. A shallow retinal serous detachment may occur around large tumours.

Fig. 15.57 This patient has a haemangioblastoma within the optic disc.

By courtesy of Dr A Webster

COATS’ DISEASE, LEBER’S MILIARY ANEURYSMS AND PARAFOVEAL TELANGIECTASIA

Many retinal specialists consider Coats’ disease, Leber’s miliary aneurysms and parafoveal telangiectasia to be variations of the same disease spectrum but affecting different age groups. The aetiology is unknown, but, in some patients at least the pathology appears to be related to somatic expression of the dominant X-linked gene for Norrie’s disease.

Coats’ disease usually presents in boys aged 8–10 years as a uniocular disease in which saccular aneurysmal malformations produce massive subretinal exudation and visual loss. In childhood, Coats’ disease must be distinguished from retinoblastoma or toxocariasis.

Similar vascular lesions are described as Leber’s miliary aneurysms when they present in young adults, usually with less telangiectasia, retinal exudation and destruction.

Parafoveal telangiectasis usually presents as macular oedema or exudates in middle age associated with aneurysmal and coarse ectatic dilated parafoveal capillaries. Telangiectasia may be present in the peripheral fundus. Patients with macular oedema and exudates sometimes benefit from laser treatment although spontaneous resolution may also occur.

Fig. 15.58 This boy has massive subretinal exudates associated with a localized area of vascular malformation, which leaks in the later phase of the angiogram.

Fig. 15.59 Massive subretinal lipid exudate and serous retinal detachment in a young boy with Coats’ disease can simulate a retinoblastoma. Apart from the difference in age of presentation, the differential diagnosis is aided by demonstrating the vascular anomalies and the yellowish-green lipid exudate, in contrast to the white or pink fleshy appearance of retinoblastoma.

Fig. 15.60 Lipid-containing exudate fills the subretinal space and the retina is totally detached. Histological examination shows telangiectatic vessels in the retina and proteinaceous and lipid-containing exudate in the retina and subretinal space.

Fig. 15.61 Peripheral miliary aneurysms in another patient. Fluorescein angiography demonstrates the saccular vascular dilatation accompanied by coarseness and closure of the capillary bed. Massive leakage of dye occurs in the late phases, although some degree of capillary closure occurs retinal neovascularization is not seen.

Fig. 15.62 Parafoveal telangiectasia presents with distortion, macular oedema and serous retinal detachment in this middle-aged man, who presented with visual blurring in the right eye. Fluorescein angiography in the early phases demonstrates dilated telangiectatic capillaries adjacent to the macula; these leak slowly as the angiogram progresses. Such patients require a careful examination of the peripheral retina for occult vascular abnormalities. Patients can be helped by photocoagulation to the abnormal vascular tissue.

PATHOLOGY

Retinoblastomas are derived from totipotent germinal retinoblasts or possible photoreceptor progenitor cells. They show varying degrees of differentiation ranging from anaplasia to the formation of rosette- and fleurette-shaped structures which represent an attempt at differentiation into photoreceptors. Necrosis and calcification are common findings. Extraocular extension occurs mainly by infiltration of the optic nerve spread into the brain but there may also be infiltration of the orbit. Blood-borne metastases may develop in the lungs and in bone.

Patients are best managed by those with special experience of retinoblastomas. Small intraocular tumours can by treated conservatively by localized photocoagulation, cryotherapy or radiotherapy to preserve vision but large tumours or those with suspected optic nerve involvement necessitate enucleation. It is essential at enucleation to remove as much optic nerve as possible and to examine transverse sections of the nerve to ensure that the residual nerve is free from tumour. Patients in whom retinoblastoma has spread outside the eye have a very poor prognosis.

Fig. 15.70 Section of an enucleated eye showing both endophytic and exophytic growth of tumour.

Fig. 15.71 Optic nerve invasion by retinoblastoma: longitudinal section (left) and transverse section (right).

Fig. 15.72 Many retinoblastomas are undifferentiated but some show differentiation as a primitive attempt to form photoreceptor cells. This is exemplified by Flexner–Wintersteiner rosettes (left) and fleurettes (right).