Chapter 12 Ocular Tumours

BENIGN EPIBULBAR TUMOURS 476

Conjunctival naevus 476

Conjunctival papilloma 476

Dermoid 476

Dermolipoma 479

Pyogenic granuloma 480

Conjunctival epithelial melanosis 480

Miscellaneous tumours 481

MALIGNANT AND PREMALIGNANT EPIBULBAR TUMOURS 481

Primary acquired melanosis 481

Melanoma 482

Ocular surface squamous neoplasia 483

Lymphoproliferative lesions 486

Kaposi sarcoma 486

IRIS TUMOURS 486

Iris naevus 486

Iris melanoma 486

Metastatic tumours 488

Miscellaneous tumours 488

IRIS CYSTS 488

Primary 488

Secondary 492

CILIARY BODY TUMOURS 492

Ciliary body melanoma 492

Medulloepithelioma 495

TUMOURS OF THE CHOROID 496

Choroidal naevus 496

Choroidal melanoma 496

Circumscribed choroidal haemangioma 504

Diffuse choroidal haemangioma 504

Optic disc melanocytoma 504

Choroidal osteoma 506

Metastatic tumours 506

NEURAL RETINAL TUMOURS 510

Retinoblastoma 510

Astrocytoma 517

VASCULAR RETINAL TUMOURS 520

Capillary haemangioma 520

Cavernous haemangioma 523

Racemose haemangioma 523

Vasoproliferative tumour 524

PRIMARY INTRAOCULAR LYMPHOMA 525

TUMOURS OF THE RETINAL PIGMENT EPITHELIUM 527

Typical congenital hypertrophy of the RPE 527

Atypical congenital hypertrophy of the RPE 527

Combined hamartoma of the retina and RPE 527

Congenital hamartoma of the RPE 528

PARANEOPLASTIC SYNDROMES 529

Bilateral diffuse uveal melanocytic proliferation 529

Cancer-associated retinopathy 531

Melanoma-associated retinopathy 531

Page 476

Benign epibulbar tumours

Conjunctival naevus

A conjunctival naevus is the most common melanocytic conjunctival tumour. The overall risk of malignant transformation is about 1%.

1 Histology is similar to cutaneous naevi except that there is no dermis so that subepithelial and stromal replaces dermal in the nomenclature.

a Junctional naevi are uncommon and are characterized by nests of naevus cells at the epithelial–subepithelial junction (Fig. 12.1A).

b Compound naevi are characterized by the presence of naevus cells at the epithelial–subepithelial junction and within the subepithelial stroma, with downward proliferation of surface epithelium containing goblet cells (Fig. 12.1B).

c Subepithelial lesions are confined entirely beneath the epithelium.

2 Presentation is usually during the 1st–2nd decades.

3 Signs

• Solitary, unilateral, discrete, slightly elevated, pigmented intraepithelial bulbar lesion of variable size, most frequently in the juxtalimbal area (Fig. 12.2C).

• The extent of pigmentation is variable and some may be virtually non-pigmented (Fig. 12.2D).

• Cystic spaces within the naevus are frequent (Fig. 12.2E).

• The second most frequent locations are the plica and caruncle (Fig. 12.2F).

• In children and adolescents the lesion may become pink and congested.

4 Signs of potential malignancy

• An unusual site such as palpebral or forniceal conjunctiva.

• Prominent feeder vessels.

• Sudden growth or increase in pigmentation.

• Development after the 2nd decade.

5 Treatment by excision is indicated mainly for cosmetic reasons. Less common indications include irritation and suspicion of malignant transformation.

Fig. 12.1 Conjunctival naevus. (A) Histology of a junctional naevus shows nests of naevus cells at the epithelial/subepithelial junction; (B) histology of a compound naevus shows naevus cells at the epithelial/subepithelial junction and within the stroma, and downward proliferation of surface epithelium containing goblet cells (evident as clear spaces); (C) pigmented juxtalimbal naevus; (D) lightly pigmented juxtalimbal naevus; (E) naevus with cystic spaces; (F) naevus involving the caruncle

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

Fig. 12.2 Conjunctival papilloma. (A) Histology shows irregular proliferation of stratified squamous epithelium containing goblet cells, overlying a fibrovascular core; (B) small juxtalimbal and forniceal papillomas; (C) papillomas involving the plica and caruncle; (D) confluent papillomas; (E) large multiple papillomas interfering with eyelid closure; (F) large sessile papilloma encroaching onto the cornea

(Courtesy of J Harry – fig. A; U Raina – fig. B; R Bates – figs D and E)

Conjunctival papilloma

Conjunctival papillomas in childhood are caused by infection with human papillomavirus (types 6, 11 and 16) by mother-to-infant transmission at birth through an infected vagina. Adult papillomas are not infectious.

1 Histology shows a fibrovascular core covered by irregular proliferation of non-keratinized, stratified squamous epithelium containing goblet cells (Fig. 12.2A).

2 Signs

• Sessile or pedunculated lesions most frequently located in the juxtalimbal area, fornix (Fig. 12.2B) or the caruncle (Fig. 12.2C).

• The lesions are usually solitary but may be multiple and occasionally bilateral, and may become confluent (Fig. 12.2D).

• Large pedunculated lesions may cause irritation and interfere with lid closure (Fig. 12.2E).

• Occasionally they may involve a large area and encroach onto the cornea (Fig. 12.2F).

3 Treatment of small lesions may not be required because they often resolve spontaneously. Large lesions are treated by excision and cryotherapy to the base and surrounding area. Treatment options for recurrences include subconjunctival alpha-interferon, carbon dioxide laser vaporization, topical mitomycin C and oral cimetidine (Tagamet).

Dermoid

Diagnosis

1 Histology shows a solid mass of collagenous tissue containing dermal elements covered by stratified squamous epithelium (Fig. 12.3A).

2 Presentation is in early childhood.

3 Signs

• Smooth, soft, yellowish, subconjunctival masses most frequently located at the inferotemporal limbus and showing protruding hair (Fig. 12.3B).

• Occasionally the lesions are very large and may virtually encircle the limbus (complex dermoid – Fig. 12.3C).

4 Treatment is indicated for cosmetic reasons, chronic irritation, dellen formation and amblyopia from astigmatism or involvement of the visual axis. Small lesions can be excised although large lesions may require lamellar keratosclerectomy.

Fig. 12.3 Dermoid. (A) Histology shows a solid mass of collagenous tissue containing dermal elements and covered by stratified squamous epithelium; (B) typical dermoid with protruding hair; (C) complex choristoma; (D) dermoids in a patient with Goldenhar syndrome

(Courtesy of J Harry and G Misson, from Clinical Ophthalmic Pathology, Butterworth-Heinemann 2001 – fig. A)

Systemic associations

Systemic associations include Goldenhar syndrome (see below), and less commonly Treacher Collins syndrome (see Ch. 1) and naevus sebaceus of Jadassohn (see below).

1 Goldenhar syndrome (oculoauriculovertebral spectrum) is usually sporadic. It is thought that hemifacial microsomia and Goldenhar syndrome are part of the same spectrum of anomaly.

a Systemic features

• Hypoplasia of the malar, maxillary and mandibular regions (Fig. 12.3D).

• Macrostomia and microtia.

• Preauricular and facial skin tags.

• Some patients manifest severe asymmetrical facial clefting.

• Hemivertebrae, usually cervical.

• Incidence of mental handicap increases with presence of microphthalmos.

• Other features include cardiac, renal and CNS anomalies.

b Ocular features, apart from dermoids, include upper lid notching or coloboma (Fig. 3.15D), microphthalmos and disc coloboma.

Page 477

Page 478

Page 479

2 Linear naevus sebaceus of Jadassohn

a Systemic features, apart from dermoids, include warty or scaly cutaneous lesions, infantile spasms, CNS anomalies and developmental delay.

b Ocular features, apart from dermoids, include ptosis, cloudy cornea, lid colobomas, fundus colobomas and microphthalmos.

Dermolipoma

1 Histology is similar to solid dermoids but also shows fatty tissue.

2 Presentation is in adult life although the lesion is congenital.

3 Signs. Soft, movable, yellowish-tan subconjunctival mass located near the outer canthus (Fig. 12.4A). The surface is usually keratinized and may have hairs, reflecting its origin from ectopic skin. Occasionally the lesion may extend into the orbit or anteriorly towards the limbus.

4 Treatment should be avoided because surgery may be complicated by scarring, ptosis, dry eye and ocular motility problems. However, if they are particularly unsightly, then debulking the anterior portion may improve cosmesis without compromising ocular motility.

5 Differential diagnosis

• Orbital fat prolapse, which has a normal conjunctival surface. It is also more mobile and softer (Fig. 12.4B) and can be reposited into the orbit with pressure.

• Orbital lobe of the lacrimal gland and lymphoma.

Page 480

Fig. 12.4 (A) Dermolipoma; (B) orbital fat prolapse for comparison

(Courtesy of A Pearson)

Pyogenic granuloma

1 Pathogenesis. A pyogenic granuloma is a fibrovascular proliferation in response to a tissue insult involving the conjunctiva such as surgery, trauma and less frequently inflammation. Spontaneous lesions are rare.

2 Histology shows granulation tissue, chronic inflammation and proliferation of small blood vessels, similar to a cutaneous pyogenic granuloma. The term pyogenic granuloma is a misnomer because the lesion is neither pyogenic nor granulomatous.

3 Presentation is a few weeks after surgery for chalazion, strabismus or enucleation.

4 Signs. A fast-growing, pink, fleshy, vascularized conjunctival mass near the conjunctival wound (Fig. 12.5A and B) that bleeds easily.

5 Treatment with topical steroids is usually successful; resistant cases require excision.

6 Differential diagnosis includes suture granuloma, vascular tumour, and Tenon granuloma or cyst.

Fig. 12.5 Pyogenic granuloma. (A) Following excision of pterygium; (B) following removal of a meibomian cyst

Conjunctival epithelial melanosis

Page 481

Conjunctival (racial) epithelial melanosis is a benign condition due to increased melanin production. It is often seen in dark-skinned individuals. Both eyes are affected but the intensity may be asymmetrical.

1 Presentation is during the first few years of life. The melanosis becomes static by early adulthood.

2 Signs

• Areas of flat, patchy, brownish pigmentation scattered throughout the conjunctiva but more intense at the limbus (Fig. 12.6A).

• The lesions may be more intense around the perforating branches of the anterior ciliary vessels or around an intrascleral nerve as it enters the sclera (Axenfeld loop – Fig. 12.6B).

• With the slit lamp the pigmentation is seen to be within the epithelium and therefore moves freely over the surface of the globe.

Fig. 12.6 Epithelial (racial) melanosis. (A) Juxtalimbal involvement; (B) Axenfeld loops

Miscellaneous tumours

1 Episcleral haemangioma or telangiectasia may be associated with Sturge–Weber syndrome (Fig. 12.7A).

2 Reactive pseudoepitheliomatous hyperplasia is a rapidly-growing, white, hyperkeratotic, juxtalimbal nodule which develops secondary to irritation (Fig. 12.7B).

3 Benign hereditary intraepithelial dyskeratosis is a rare bilateral juxtalimbal hyperplastic translucent lesion with dilated vessels (Fig. 12.7C).

4 Melanocytoma is a rare, congenital, black, slowly-growing lesion which cannot be moved freely over the globe (Fig. 12.7D).

Fig. 12.7 Miscellaneous benign conjunctival tumours. (A) Haemangioma; (B) reactive pseudoepitheliomatous hyperplasia; (C) hereditary intraepithelial dyskeratosis; (D) melanocytoma

Malignant and premalignant epibulbar tumours

Primary acquired melanosis

Primary acquired melanosis (PAM) is a unilateral condition that typically affects white individuals with a fair complexion.

1 Histology shows one of the following:

a PAM without melanocytic cellular atypia is a benign intraepithelial proliferation of epithelial melanocytes with no risk of malignant transformation (Fig. 12.8A).

b PAM with melanocytic cellular atypia shows an increase in the number of intraepithelial melanocytes that exhibit pleomorphism. PAM with atypia, if severe, can be regarded as melanoma in situ that has a 50% chance of manifesting infiltration malignancy within 5 years.

2 Presentation is usually after the age of 45 years.

3 Signs cannot distinguish between the two histological types.

• Irregular, unifocal or multifocal areas of flat, golden brown-dark chocolate epithelial pigmentation which typically involve the limbus and interpalpebral region (Fig. 12.8B).

• Because any part of the conjunctiva may be affected, it is important to evert the eyelids (Fig. 12.8C).

• PAM may expand, shrink or remain stable for long periods of time. It may also lighten or darken focally.

• Malignant transformation to melanoma should be suspected by the sudden appearance of one or more nodules in otherwise flat lesions (see Fig. 12.9D).

4 Investigations involve biopsy with immunohistochemistry because the clinical features of PAM with and without atypia are the same.

5 Treatment of small lesions involves excision. Large widespread lesions should undergo incision biopsy from various sites. Lesions showing PAM with atypia are treated with cryotherapy or topical mitomycin C.

Page 482

6 Differential diagnosis includes conjunctival naevus, epithelial (racial) melanosis, congenital ocular melanocytosis and Addison disease.

Fig. 12.8 Primary acquired melanosis (PAM). (A) Histology shows an intraepithelial proliferation of conjunctival epithelial melanocytes; (B) large area of PAM; (C) small area of PAM associated with lentigo maligna of the lid margin

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

Fig. 12.9 Conjunctival melanoma. (A) Histology shows melanoma cells within the epithelium and subepithelial stroma; (B) pigmented melanoma; (C) amelanotic melanoma; (D) multifocal melanoma arising from PAM

(Courtesy of J Harry – fig. A)

Melanoma

Conjunctival melanoma accounts for about 2% of all ocular malignancies.

Diagnosis

1 Histology shows sheets of melanoma cells within the subepithelial stroma (Fig. 12.9A).

2 Classification

a Melanoma arising from a pre-existing naevus (junctional or compound) accounts for 20%.

b Primary melanoma (de novo) is the least common.

c Melanoma arising from PAM with atypia accounts for 75% of cases.

3 Presentation is in the 6th decade except in patients with the rare dysplastic naevus syndrome who develop multiple melanomas earlier.

4 Signs

• Melanoma arising de novo or from a pre-existing naevus appears as a black or grey vascularized nodule that may be fixed to the episclera.

• A common site is the limbus (Fig. 12.9B) although the tumour may arise anywhere in the conjunctiva.

• Amelanotic tumours are pink and have a characteristic smooth ‘fish-flesh’ appearance (Fig. 12.9C) that may give rise to diagnostic problems.

Page 483

• Multifocal lesions arise from PAM with atypia are characterized by areas of thickening and nodularity (Fig. 12.9D).

5 Differential diagnosis includes a large naevus, ciliary body melanoma with extraocular extension, melanocytoma (see Fig. 12.8D) and pigmented conjunctival carcinoma in a dark-skinned individual.

Treatment

• Circumscribed lesions are treated by excision with a wide margin and cryotherapy. If histology reveals tumour extension to the deep surface of the specimen, adjunctive radiotherapy can be administered.

• Diffuse melanoma associated with PAM is treated by excision of localized nodules and cryotherapy or mitomycin C to the diffuse component.

• Orbital recurrences (Fig. 12.8A) are treated by local resection and radiotherapy. Exenteration (Fig. 12.8B) does not improve the survival rate and is therefore reserved for patients with extensive and aggressive disease that cannot be controlled by other methods.

Prognosis

The overall mortality is 12% at 5 years and 25% at 10 years. The main sites for metastases are regional lymph nodes, lung, brain and liver. Poor prognostic indicators include:

• Multifocal tumours.

• Extralimbal tumours involving the caruncle, fornix or palpebral conjunctiva.

• Tumour thickness of 2 mm or more.

• Recurrence.

• Lymphatic or orbital spread.

Ocular surface squamous neoplasia

Definition

Ocular surface squamous neoplasia (OSSN) describes a spectrum of benign, pre-malignant and malignant unilateral slowly-progressive epithelial lesions of the conjunctiva and cornea. Risk factors include ultraviolet light exposure, human papilloma virus (type 16) infection, AIDS, xeroderma pigmentosum and stem cell therapy.

Diagnosis

1 Histology shows the following spectrum:

a Conjunctival epithelial dysplasia with dysplastic cells in the basal layers of the epithelium.

Page 484

b Carcinoma in-situ with dysplastic cells involving the full thickness of the epithelium (Fig. 12.10A).

c Squamous cell carcinoma is rare and is characterized by invasion of the underlying stroma (Fig. 12.10B).

2 Presentation is usually in late adult life with ocular irritation or a mass.

3 Signs are variable and clinical differentiation between the three histological types is unreliable. Most tend to occur within the interpalpebral fissure mostly at the limbus, although they may involve any part of the conjunctiva or cornea. The following appearances may be seen.

a Gelatinous mass with superficial vessels (Fig. 12.10C).

b White leukoplakic plaque that covers the lesion (Fig. 12.10D).

c Papillomatous lesion with corkscrew-like surface blood vessels (Fig. 12.10E).

d Squamous cell carcinoma is a fleshy, pink papillomatous mass with feeder vessels or occasionally it may exhibit diffuse growth and masquerade as ‘chronic conjunctivitis’. Corneal involvement may occur (Fig. 12.10F) but intraocular extension is uncommon and metastatic disease extremely rare.

Page 485

Page 486

4 Special investigations include ultrasonic biomicroscopy (UBM) to estimate the depth of invasion, exfoliative cytology and impression cytology.

Fig. 12.10 Ocular surface squamous neoplasia. (A) Histology of carcinoma in situ shows dysplastic changes throughout the thickened epithelium; (B) histology of squamous cell carcinoma shows downward proliferation of irregular, dysplastic, squamous epithelium with infiltration of subepithelial tissue; (C) gelatinous lesion with surface vessels; (D) leukoplakic lesion; (E) papillomatous lesion; (F) very extensive carcinoma with corneal involvement

(Courtesy of J Harry – figs A and B; R Bates – fig. E; B Damato – fig. F)

Treatment

Excision with 2–3 mm margins and assessment of surgical clearance with frozen sections is the traditional method. Measures aimed at reducing recurrences include adjunctive cryotherapy, brachytherapy or topical chemotherapy with mitomycin C, 5-fluorouracil and interferon-alpha 2b.

Lymphoproliferative lesions

Most conjunctival lymphoproliferative lesions are reactive lymphoid hyperplasia, a proliferation of B and T cells with germinal follicle formation (Fig. 12.11A). Conjunctival lymphoma may arise in three clinical settings. (a) de novo, (b) extension from orbital lymphoma and (c) occasionally associated with systemic involvement. Sometimes reactive lymphoid hyperplasia undergoes transformation to lymphoma. Most conjunctival lymphomas are B cell lymphomas and arise from MALT (mucosa-associated lymphoid tissue).

1 Presentation is usually in late adult life with irritation or painless swelling which may be bilateral.

2 Signs

• Slowly-growing, mobile, salmon-pink or flesh-coloured infiltrate on the epibulbar surface (Fig. 12.11B) or in the fornices (Fig. 12.11C).

• Rarely, a diffuse lesion (Fig. 12.11D) may mimic chronic conjunctivitis.

3 Treatment is most frequently with radiotherapy. Other options include chemotherapy, excision, cryotherapy and local injection of interferon alpha-2b.

Fig. 12.11 Conjunctival lymphoproliferative lesions. (A) Histology of reactive lymphoid hyperplasia shows a germinal lymphoid follicle consisting of immature lymphoid cells at the centre and mature cells at the periphery; (B) epibulbar lymphoma; (C) forniceal lymphoma; (D) diffuse lymphoma

(Courtesy of J Harry and G Misson, from Clinical Ophthalmic Pathology, Butterworth-Heinemann 2001 – fig. A.)

Kaposi sarcoma

Kaposi sarcoma is a slow-growing tumour which occurs in patients with AIDS.

1 Histology shows proliferation of spindle-shaped cells, vascular channels and inflammatory cells (Fig. 12.12A).

2 Presentation is in adult life with irritation or painless discoloration.

3 Signs. A flat bright-red lesion (Fig. 12.12B) that may mimic a subconjunctival haemorrhage.

4 Treatment is required for cosmetic reasons, bleeding or infection. Options include focal radiotherapy and excision with or without adjunctive cryotherapy.

Fig. 12.12 Conjunctival Kaposi sarcoma. (A) Histology shows proliferation of vascular endothelial cells, occasional mitotic figures, vascular channels and chronic inflammatory cells; (B) clinical appearance

(Courtesy of J Harry – fig. A)

Iris tumours

Iris naevus

1 Histology shows proliferation of melanocytes in the superficial iris stroma, consisting of predominantly spindle cells (Fig. 12.13A).

2 Signs

• Solitary pigmented, flat or slightly elevated, circumscribed lesion usually less than 3 mm in diameter typically located inferiorly.

• The normal iris architecture is disrupted and occasionally there may be mild distortion of the pupil and ectropion uveae (Fig. 12.13B). A freckle is smaller and never distorts the iris architecture.

• Extension into the trabecular meshwork may be present.

• Signs indicative of malignant transformation include prominent vascularity, rapid growth, diffuse spread and seeding.

3 Uncommon variants

a A diffuse naevus is flat and has indistinct margins and may be sectoral (Fig. 12.13C) or involve virtually the entire iris (Fig. 12.13D). It typically occurs in patients with congenital ocular melanocytosis and gives heterochromia iridis.

b Iris-naevus syndrome (Cogan–Reese syndrome – see Ch. 10), is characterized by a diffuse naevus that may be associated with numerous small pedunculated nodules (Fig. 12.13E).

c Lisch nodules are small bilateral iris naevi found after the age of 16 years in virtually all patients with NF1 (Fig. 12.13F).

Fig. 12.13 Iris naevus. (A) Histology shows localized proliferation of melanocytes on the anterior iris stroma; (B) multiple iris freckles and a large naevus causing mild ectropion uveae; (C) sectoral diffuse naevus; (D) total diffuse iris naevus; (E) Cogan-Reese syndrome; (F) Lisch nodules

(Courtesy of J Harry – fig. A; B Damato – fig. C; P Gili – fig. F)

Iris melanoma

Overview

In general, uveal melanomas are three times more common in patients with blue/grey than brown irides. They are extremely rare in blacks and there is no sexual predominance. Conditions associated with or predisposing to uveal melanomas are: (a) fair skin, (b) light iris colour, (c) numerous cutaneous naevi, (d) congenital ocular melanocytosis, (e) oculodermal melanocytosis (naevus of Ota), (f) uveal melanocytoma, (g) dysplastic cutaneous naevi, (h) familial cutaneous melanoma and (i) NF1. About 8% of uveal melanomas arise in the iris. The prognosis is very good and only about 5% of patients develop metastases within 10 years of treatment.

Diagnosis

1 Histology in the majority shows spindle cells (see below) that are of low-grade malignancy (Fig. 12.14A). A minority contain an epithelioid cell component and can be more aggressive.

2 Presentation is in the 5th–6th decades, a decade earlier than ciliary body and choroidal melanoma, usually with enlargement of a pre-existing iris lesion.

3 Signs

• A pigmented (Fig. 12.14B) or non-pigmented nodule (Fig. 12.14C) at least 3 mm in diameter and 1 mm thick, usually located in the inferior half of the iris and often associated with surface blood vessels.

• Pupillary distortion, ectropion uveae and occasionally localized cataract may be seen, although these can also occur with naevi.

Page 487

• The tumour usually grows very slowly along the iris surface and may invade the angle (Fig. 12.14D) and anterior ciliary body.

• Complications include hyphaema, cataract and glaucoma.

4 Rare variants

a Diffusely growing intrastromal melanoma may give rise to ipsilateral hyperchromic heterochromia (Fig. 12.14E).

b ’Tapioca melanoma’ is characterized by multiple surface nodules (Fig. 12.14F).

Fig. 12.14 Iris melanoma. (A) Histology shows infiltration of the entire thickness of the stroma; (B) highly pigmented tumour; (C) amelanotic tumour; (D) invasion of the angle; (E) extensive diffusely growing tumour; (F) ‘tapioca’ melanoma

(Courtesy of J Harry and G Misson, from Clinical Ophthalmic Pathology, Butterworth-Heinemann 2001 – fig. A; C Barry – fig. B; R Curtis fig. D; B Damato – fig. F)

Treatment

1 Observation of suspicious lesions involves documentation by slit-lamp examination, gonioscopy and photography. Follow-up should be life-long because growth may occur after several years of apparent inactivity.

2 Iridectomy for small tumours (with iris reconstruction to reduce postoperative photophobia), and iridocyclectomy for tumours invading the angle.

3 Radiotherapy with a radioactive plaque (brachytherapy) or external irradiation with a proton beam.

Page 488

4 Enucleation may be required for diffusely growing tumours, if radiotherapy is not possible.

Metastatic tumours

Metastasis to the iris is rare and is characterized by a fast-growing white, pink or yellow mass (Fig. 12.15A) which may be associated with anterior uveitis and occasionally hyphaema. Small multiple deposits may also be seen (Fig. 12.15B).

Fig. 12.15 Iris metastasis. (A) Metastasis from breast; (B) multiple small deposits

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

Miscellaneous tumours

1 Juvenile xanthogranuloma is a rare idiopathic granulomatous disease of early childhood that involves the skin, muscle, stomach, salivary glands and other organs. Iris involvement is characterized by a localized or diffuse yellow lesion (Fig. 12.16A) that may be associated with spontaneous hyphaema, or less commonly anterior uveitis and glaucoma. Treatment is with topical steroids.

2 Leiomyoma is an extremely rare benign tumour which arises from smooth muscle. The appearance is similar to that of an amelanotic melanoma, except that it does not have a predilection for the inferior half of the iris (Fig. 12.16B). Often the diagnosis can be established only histologically.

3 Melanocytoma is a deeply-pigmented nodular mass with a mossy, granular surface and no intrinsic vessels, most frequently occupying the peripheral iris (Fig. 12.16C). It may undergo spontaneous necrosis resulting in seeding of the iris stroma and chamber angle. Dispersion of melanophages may result in elevation of intraocular pressure.

Fig. 12.16 (A) Juvenile iris xanthogranuloma; (B) leiomyoma; (C) melanocytoma

(Courtesy of BJ Zitelli and HW Davis, from Atlas of Pediatric Physical Diagnosis, Mosby 2002 – fig. A; B Damato – fig. B)

Iris cysts

Primary

Primary iris cysts are rare lesions arising from the iris epithelium or, rarely, the stroma. Epithelial cysts lie between the two layers of the pigment epithelium (Fig. 12.17A).

1 Epithelial

• Unilateral or bilateral, solitary or multiple globular structures which may be brown or transparent, depending on whether they arise in the iris epithelium or iridociliary epithelium respectively.

• Location may be at the pupillary border (Fig. 12.17B), in the midzone or the iris root.

• Occasionally they become dislodged and float freely in the anterior chamber (Fig. 12.17C) or vitreous.

• The vast majority are asymptomatic and innocuous. Rarely large cysts may obstruct vision and require treatment with argon laser photocoagulation.

2 Stromal cysts present in the first years of life.

• Solitary and unilateral with a smooth translucent anterior wall.

• The cyst may remain dormant for many years or suddenly enlarge (Fig. 12.17D) and cause secondary glaucoma and corneal decompensation.

• Occasionally the cyst may break free from the iris and float in the anterior chamber or migrate to another location.

• Although spontaneous regression can occur, most require treatment by needle aspiration or surgical excision. Injection of ethanol into the cyst, removed after one minute, may avoid the need for excision of a recalcitrant cyst.

Fig. 12.17 Primary iris cysts. (A) Histology of epithelial cysts shows that they lie between the two layers of the pigment epithelium; (B) epithelial pupil margin cysts; (C) dislodged epithelial cyst in the angle; (D) enlarging stromal cyst

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

Secondary

Secondary iris cysts develop as a result of the following:

1 Implantation cysts are the most common. They originate by deposition of surface epithelial cells from the conjunctiva or cornea on the iris after penetrating or surgical trauma.

a Pearl cysts are white, solid lesions with opaque walls located in the stroma and are not connected to the wound (Fig. 12.18A).

b Serous cysts are translucent, filled with fluid and may be connected to the wound (Fig. 12.18B). They frequently enlarge, leading to corneal oedema, anterior uveitis and glaucoma. Ultrasound biomicroscopy (UBM) may be used to delineate the extent of a lesion when surgical excision is contemplated.

2 Prolonged use of long-acting miotics may be associated with usually bilateral small, multiple cysts located along the pupillary border (Fig. 12.18C). Their development can be prevented by the concomitant use of topical phenylephrine 2.5%.

3 Parasitic cysts are very rare (Fig. 12.18D).

Fig. 12.18 Secondary iris cysts. (A) Pearl cyst; (B) large serous cyst following penetrating keratoplasty; (C) small pupil border cysts due to miotics; (D) parasitic cyst

(Courtesy of R Bates – fig. C)

Ciliary body tumours

Ciliary body melanoma

Ciliary body melanomas comprise 12% of uveal melanomas.

Page 493

Signs

1 Presentation is usually in the 6th decade with visual symptoms although occasionally the tumour is discovered incidentally.

2 Signs depend on the size and location of the tumour.

• The tumour may be visualized on fundoscopy following dilatation of the pupil (Fig. 12.19A).

• Dilated episcleral blood vessels in the same quadrant as the tumour (sentinel vessels – Fig. 12.19B).

• Erosion through the iris root that may mimic an iris melanoma (Fig. 12.19C).

• Pressure on the lens may give rise to astigmatism, subluxation or cataract formation (Fig. 12.19D).

• Extraocular extension through the scleral emissary vessels may produce a dark epibulbar mass (Fig. 12.19E) which may be mistaken for a conjunctival melanoma.

• Exudative retinal detachment may be caused by posterior extension (Fig. 12.19F).

• Anterior uveitis, caused by tumour necrosis, is uncommon.

• Circumferential (annular) growth for 360° carries the worst prognosis because early diagnosis is difficult.

Fig. 12.19 Ciliary body melanoma. (A) Tumour seen on fundoscopy; (B) ‘sentinel’ vessels in the same quadrant as the tumour; (C) erosion of the tumour through the iris root; (D) pressure on the lens; (E) extraocular extension; (F) displacement of the lens and inferior retinal detachment

(Courtesy of B Damato – fig. B; R Curtis – fig. D)

Investigations

1 Three-mirror contact lens examination through a well-dilated pupil is essential and is particularly useful in detecting forward erosion through the iris root into the angle.

Page 494

Page 495

2 UBM is very useful in showing the dimensions and extent of the tumour.

3 Biopsy involving excisional, incisional or fine-needle aspiration techniques may be helpful in selected cases.

Treatment

1 Iridocyclectomy for small or medium-sized tumours involving no more than one-third of the angle. Complications include vitreous haemorrhage, cataract, lens subluxation, hypotony and incomplete resection.

2 Radiotherapy by brachytherapy or proton beam irradiation.

3 Enucleation for large tumours and those causing secondary glaucoma, resulting from extensive invasion of Schlemm canal.

Differential diagnosis

1 Uveal effusion syndrome may resemble circumferential ciliary body melanoma. However, the effusion is lobulated, transilluminates brightly and appears cystic on ultrasonography.

2 Congenital epithelial iridociliary cysts may also displace the lens but can be readily differentiated from melanomas by ultrasonography.

3 Other ciliary body tumours, which are extremely rare, include melanocytoma, medulloepithelioma, metastases, adenocarcinoma, adenoma neurolemmoma and leiomyoma. In most of these the correct diagnosis can be made only histologically.

Medulloepithelioma

Medulloepithelioma (previously known as diktyoma) is a rare embryonal neoplasm that arises from the inner layer of the optic cup and can be benign or malignant. The latter may be fatal as a result of intracranial spread or metastatic disease.

1 Histology

• Teratoid tumours contain heterotopic elements or tissue such as brain, cartilage and skeletal muscle (Fig. 12.20A).

• Non-teratoid tumours lack these elements.

• Both types may be benign or malignant.

2 Presentation is usually in the 1st decade with visual loss, pain, photophobia, leukocoria, or proptosis in advanced cases.

3 Signs

• Unilateral white, pink, yellow or brown ciliary body mass that may be solid or polycystic (Fig. 12.20B).

• An anterior chamber mass that may contain grey-white opacities consisting of cartilage (Fig. 12.20C).

• A sheet-like tumour growing behind the lens may resemble a cyclitic membrane.

4 Complications include glaucoma, cataract and retinal detachment.

5 Treatment is difficult and most patients require enucleation.

Fig. 12.20 Medulloepithelioma. (A) Histology of the teratoid type containing cartilage; (B) brown cystic ciliary body mass; (C) anterior segment mass

(Courtesy of J Harry – fig. A; R Curtis – fig. B)

Page 496

Tumours of the choroid

Choroidal naevus

Choroidal naevi are present in 5–10% of Caucasians but are very rare in dark-skinned races. They can be associated with NF1 and the dysplastic naevus syndrome. Although they are probably present at birth, growth occurs mainly during the pre-pubertal years and is extremely rare in adulthood. For this reason clinically detectable growth should arouse suspicion of malignancy.

Histology

The tumour is composed of a proliferation of spindle cell melanocytes (Fig. 12.21A).

Fig. 12.21 Choroidal naevus. (A) Histology shows proliferation of melanocytes in the choroid but sparing the choriocapillaris; (B) typical naevus; (C) naevus with surface drusen; (D) FA shows hypofluorescence of the naevus and hyperfluorescence of drusen; (E) ICGA shows hypofluorescence relative to the surrounding choroid; (F) B-scan shows slight elevation with high internal acoustic reflectivity

(Courtesy of J Harry – fig. A; M Karolczak-Kulesza – fig. F)

Signs

1 Presentation. The vast majority of naevi are asymptomatic and detected by routine examination. Rarely symptoms may be caused by involvement of the fovea by the tumour itself or by serous retinal detachment.

2 Signs of a typical naevus

• Usually post-equatorial, oval or circular, brown to slate-grey lesion with indistinct margins (Fig. 12.21B).

• Dimensions are <5 mm in basal diameter (i.e. 3 disc diameters) and <1 mm thickness.

• Surface drusen may be present, particularly in the central area of a larger lesion (Fig. 12.21C).

• Secondary choroidal neovascularization is uncommon.

• Typical naevi do not require follow-up because the risk of malignant transformation is extremely low.

Investigations

1 Photography as a baseline record is good practice.

2 FA findings depend on the amount of pigmentation within the naevus and associated changes in the overlying RPE. Most naevi are avascular and pigmented, giving rise to hypofluorescence caused by blockage of background choroidal fluorescence. If the lesion is associated with surface drusen and RPE detachment, this will result in areas of hyperfluorescence (Fig. 12.21D). FA is not helpful in distinguishing a small melanoma from a naevus although multiple pinpoint areas of hyperfluorescence may predict future growth.

3 ICGA shows hypofluorescence relative to the surrounding choroid (Fig. 12.21E).

4 Ultrasonography (US) shows a localized flat or slightly elevated lesion with high internal acoustic reflectivity (Fig. 12.21F).

Atypical naevus

• An amelanotic naevus (Fig. 12.22A).

• A ‘halo’ naevus which is surrounded by a pale zone resembling choroidal atrophy (Fig. 12.22B).

Fig. 12.22 Unusual choroidal naevi. (A) Presumed amelanotic naevus; (B) ‘halo’ naevus

(Courtesy of B Damato – fig. A)

Suspicious naevus

1 Clinical features. The following may suggest that a melanocytic lesion is not a naevus but a small melanoma.

• Documented growth.

• Symptoms such as blurred vision, metamorphopsia, field loss and photopsia.

• Dimensions >5 mm in diameter and >1 mm in thickness.

• Traces of surface orange pigment (lipofuscin).

• Absence of surface drusen on a thick lesion.

• Margin of the lesion at or near the optic disc.

• Serous retinal detachment either over the surface of the lesion or inferiorly.

The greater the number of these features, the higher the chance that the lesion is a melanoma.

2 Management involves baseline fundus photography and ultrasonography, and then indefinite follow-up. If growth has been documented, the lesion should be reclassified as a melanoma and managed accordingly.

Differential diagnosis

1 Congenital hypertrophy of the RPE is dark and flat, with a well defined outline.

2 Melanocytoma of the choroid is clinically indistinguishable from a large naevus.

3 Small melanoma is associated with serous retinal detachment and clumps of orange pigment.

Choroidal melanoma

Choroidal melanoma has an overall incidence of 5–7.5 per million per year in western hemisphere countries with no significant gender difference. It is the most common primary intraocular malignancy in adults and accounts for 80% of all uveal melanomas.

Pathology

1 Cell type

a Spindle cells are arranged in tight bundles; their cell membranes are indistinct and the cytoplasm is fibrillary or finely granular. Nuclei vary from slender to plump and nucleoli may or may not be distinct (Fig. 12.23A).

b Epithelioid cells are larger and more pleomorphic than spindle cells, often appearing polyhedral with abundant eosinophilic cytoplasm. The cell membranes are distinct and an extracellular space often separates adjacent cells. The nuclei are large with a coarse chromatin pattern and prominent nucleoli. Mitotic figures are more frequent than in spindle cells (Fig. 12.23B).

2 Classification of uveal melanomas.

a Spindle cell melanomas formed exclusively by spindle cells.

b Mixed cell melanomas in which there is a mixture of spindle and epithelioid cells.

3 Other histological features

a Fascicular pattern of cell growth which may be vasocentric in which the cells are arranged perpendicular to a central vessel (Fig. 12.23C), or ribbon-like.

Page 497

b Necrosis where the cell type may not be recognizable (Fig. 12.23D).

4 Pattern of tumour spread is as follows:

• Penetration of Bruch membrane and the RPE with herniation into the subretinal space, often with the development of a ‘collar-stud’ shape (Fig. 12.23E).

• Invasion of scleral channels for blood vessels and nerves resulting in orbital spread (Fig. 12.23F).

• Invasion of vortex veins.

• Metastatic haematogenous spread to the liver and occasionally to the lungs, bone, skin and brain.

• Optic nerve invasion is very rare, but may occur in eyes with large peripapillary melanomas.

Page 498

Fig. 12.23 Histology of choroidal melanoma. (A) Spindle cells – tightly arranged fusiform cells with indistinct cell membranes and slender or plump oval nuclei; (B) epithelioid cells – large pleomorphic cells with distinct cell membranes, large vesicular nuclei with prominent nucleoli, and abundant cytoplasm; (C) fascicular pattern – vasocentric; (D) necrotic tumour – cell type cannot be determined; (E) penetration of Bruch membrane in a ‘collar-stud’ fashion; (F) extraocular extension and an embolus of neoplastic cells within a blood vessel

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

Adverse prognostic factors

1 Histological features implying an adverse prognosis include large numbers of epithelioid cells, long and wide nuclei, multiple nucleoli, closed vascular loops within the tumour and lymphocytic infiltration.

2 Chromosomal abnormalities within the melanoma cells, particularly loss of chromosome 3 and gains in chromosome 8, are associated with a poor prognosis. Gains in the short arm of chromosome 6 carry a favourable prognosis.

3 Size. Large tumours have a worse prognosis than small tumours because of lead time bias (i.e. the tumour and any metastases being present for a longer time), and because they tend to show aggressive histological and cytogenetic features.

4 Extrascleral extension, because the tumour is more likely to be advanced and aggressive.

5 Location. Anterior tumours involving ciliary body have a worse prognosis, most likely because they are relatively more advanced by the time of presentation.

6 Local tumour recurrence after conservative treatment is associated with poor survival. This is probably because the recurrence is an indication that the original tumour was relatively aggressive.

Signs

1 Presentation peaks at around the age of 60 years and occurs in one of the following ways.

• An asymptomatic tumour, usually in the periphery, is detected by chance on routine fundus examination performed for other reasons.

• A symptomatic tumour causes decreased visual acuity, blurring, metamorphopsia, visual field loss, floaters or photopsia.

2 Signs

• A solitary elevated, subretinal, dome-shaped mass, which may be pigmented (Fig. 12.24A) or less commonly amelanotic (Fig. 12.24B); the former are usually grey or brown.

• About 60% of tumours are located within 3 mm of the optic disc or fovea.

• Clumps of orange pigment are frequently seen in the RPE overlying the tumour (Fig. 12.24C).

• If the tumour breaks through Bruch membrane it acquires a ‘collar-stud’ appearance, with visible blood vessels if the tumour is amelanotic (Fig. 12.24D).

• A diffuse tumour is rare and is characterized by an extensive flat or slightly raised morphology with grey or brown irregular discoloration (Fig. 12.24E).

• Exudative retinal detachment, initially confined to the surface of the tumour and which later shifts inferiorly and becomes bullous (Fig. 12.24F).

• Unlike rhegmatogenous retinal detachment, the subretinal fluid shifts with ocular movement and gravity (‘shifting fluid’). In addition, the retina does not show the fine, silvery rippling that occurs in the presence of a tear.

• Other signs include choroidal folds, intraocular inflammation, haemorrhage, rubeosis iridis, secondary glaucoma and cataract.

Fig. 12.24 Choroidal melanoma. (A) Highly pigmented melanoma; (B) amelanotic melanoma; (C) melanoma with surface orange pigment; (D) ‘collar-stud’ melanoma with intrinsic vessels; (E) diffuse melanoma; (F) large melanoma with subtotal retinal detachment

(Courtesy of B Damato – figs A, C and F); AD Singh, from Clinical Ophthalmic Pathology, Elsevier, 2007 – fig. E)

Special investigations

Although binocular indirect ophthalmoscopy combined with indirect slit-lamp biomicroscopy is sufficient for diagnosis in the vast majority of cases the following may be useful.

1 FA is of limited diagnostic value because there is no pathognomonic pattern. The most common findings are intrinsic tumour (‘dual’) circulation (Fig. 12.25A), mottled fluorescence during the arteriovenous phase and late diffuse leakage and staining. FA may, however, be useful in the differential diagnosis of simulating lesions such as choroidal haemangiomas and haemorrhagic lesions.

Page 499

2 US is useful in detecting tumours when the media are opaque and to show extraocular extension. It is also useful in measuring tumour dimensions. The characteristic findings are internal homogeneity, choroidal excavation and orbital shadowing (Fig. 12.25B); a collar-stud configuration is almost pathognomonic (Fig. 12.25C).

3 ICGA usually shows hypofluorescence throughout the study and provides more information than FA about the extent of the tumour, because there is less interference caused by RPE changes.

Page 500

Page 501

4 MR shows hyperintensity in T1-weighted images (Fig. 12.25D) and hypointensity in T2-weighted images, but these features are not pathognomonic. Enhancement with gadolinium improves image quality, demonstrating optic nerve and orbital invasion and facilitating differentiation from other tumours.

5 Colour-coded Doppler imaging may differentiate pigmented tumours from haemorrhage, particularly in eyes with opaque media.

6 Biopsy is useful when the diagnosis cannot be established by less invasive methods. It may be performed either with a fine needle or using the 25-gauge vitrectomy system, the latter providing a larger sample.

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 MR shows 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:

1 Excluding 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.

2 Detecting 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

Page 502

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.

1 Indications 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.

2 Technique

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

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

c Once it has been established that the template is correctly positioned, the sutures are loosened and used to secure the radioactive plaque.

d The 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.

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

4 Complications 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’).

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

Page 503

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.

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

2 Technique

a Radio-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.

c The patient directs gaze at an adjustable fixation target.

d Four fractions of radiotherapy are delivered over 4 consecutive days.

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

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

5 Survival 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 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.

1 Indications

• 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.

2 Technique

a Overlapping 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.

b A 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.

d The treatment is repeated if there is residual tumour after six months.

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

4 Complications 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

1 Indications 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.

2 Technique 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.

3 Complications 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:

1 Pigmented 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.

2 Non-pigmented lesions

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

Page 504

• 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).

2 Presentation 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.

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

3 Signs

• 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.

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

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

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

7 MR shows that the tumour is iso- or 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.

1 Photodynamic 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.

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

3 Radiotherapy 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.

4 Intravitreal anti-VEGF therapy shows promise.

Differential diagnosis

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

2 Choroidal 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.

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

4 Posterior 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).

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

2 Signs

• 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.

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

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

5 Treatment 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

Page 505

Page 506

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).

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

3 Signs

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

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

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

6 Treatment 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

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

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

3 Signs

• 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.

4 FA 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.

6 US 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).

Fig. 12.30 Choroidal osteoma. (A) Early juxtapapillary lesion; (B) long-standing tumour with overlying RPE changes; (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

1 Choroidal 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.

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

4 Sclerochoroidal 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

Page 507

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

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

2 Signs

• 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).

3 US 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.

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

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

Page 508

Page 509

Page 510

6 Biopsy 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.

2 Radiotherapy, either external beam or brachytherapy.

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

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

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

1 Histology. 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:

a Flexner–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).

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

c Fleurettes 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).

2 Patterns of tumour spread

a Growth 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.

d Metastatic 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 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.

1 Heritable (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.

2 Non-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.

Page 511

Page 512

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 tumour-induced 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.

Page 513

Fig. 12.33 Presentation of retinoblastoma. (A) Unilateral leukocoria; (B) secondary glaucoma and buphthalmos; (C) red eye due to uveitis; (D) iris nodules and pseudohypopyon; (E) orbital inflammation; (F) orbital invasion

(Courtesy of N Rogers – figs A and B; U Raina – fig. C)

Signs

Indirect ophthalmoscopy with scleral indentation must be performed on both eyes after full mydriasis. This is because without indentation pre-equatorial tumours may be missed (Fig. 12.34A) and one eye may harbour multiple tumours. The clinical signs depend on tumour size and growth pattern.

• An intraretinal tumour is a homogeneous, dome-shaped white lesion which becomes irregular, often with white flecks of calcification (Fig. 12.34B).

• An endophytic tumour projects into the vitreous as a white mass (Fig. 12.34C) that may ‘seed’ into the vitreous (Fig. 12.34D).

• An exophytic tumour forms subretinal, multilobular white masses (Fig. 12.34E) and causes overlying retinal detachment (Fig. 12.34F).

Fig. 12.34 Signs of retinoblastoma. (A) Small peripheral tumour; (B) intraretinal tumour; (C) endophytic tumour; (D) endophytic tumour with vitreous seeding; (E) exophytic tumour; (F) total retinal detachment

(Courtesy of B Dixon-Romanowska – figs C and D; L MacKeen – fig. E)

Investigations

1 Red reflex testing with a direct ophthalmoscope has been recommended as a screening test in the community. Any asymmetry indicates full eye examination with pupil dilatation and immediate referral to an ophthalmologist.

2 Examination under anaesthesia includes the following:

• General examination for congenital abnormalities of the face and hands.

• Tonometry.

• Measurement of the corneal diameter and, if glaucoma is present, the axial length of the eye.

• Anterior chamber examination with a hand-held slit-lamp.

• Ophthalmoscopy, documenting all findings with colour drawings or photography.

3 US is used mainly to assess tumour size. It also detects calcification within the tumour (Fig. 12.35A) and is helpful in the diagnosis of simulating lesions such as Coats disease.

4 CT also detects calcification (Fig. 12.35B) but entails a significant dose of radiation and is performed only rarely.

5 MR cannot detect calcification but it is superior to CT for optic nerve evaluation and detection of extraocular extension or pinealoblastoma (Fig. 12.35C), especially with contrast and fat suppression. MR may also be useful to differentiate retinoblastoma from simulating conditions.

6 Systemic assessment includes physical examination and MR scans of the orbit and skull, as a minimum in high-risk cases. If these indicate the presence of metastatic disease then bone scans, bone marrow aspiration and lumbar puncture are also performed.

7 Genetic studies require fresh tumour tissue from the enucleated eye and a blood sample for DNA analysis. Blood samples from the patient’s relatives and a sperm sample from the father may also be useful.

Fig. 12.35 Imaging of retinoblastoma. (A) B-scan with low gain shows echoes from calcification; (B) axial CT shows bilateral tumours and calcification; (C) sagittal MR shows a pinealoblastoma with secondary hydrocephalus

(Courtesy of K Nischal – fig. B; AD Singh, from Clinical Ophthalmic Pathology, Saunders Elsevier, 2007 – fig. C)

Treatment of small tumours

Tumours no more than 3 mm diameter and 2 mm thickness may be treated as follows:

1 Photocoagulation using low-energy 532 nm argon or 810 nm diode laser achieves focal consolidation after chemotherapy. At least three treatment sessions are needed.

2 Cryotherapy using the triple freeze-thaw technique is useful for pre-equatorial tumours without either deep invasion or vitreous seeding.

3 Chemotherapy without other treatment can be attempted for a macular tumour, to conserve as much vision as possible, but there is an increased risk of tumour recurrence.

Treatment of medium-size tumours

Tumours up to 12 mm wide and 6 mm thick may be treated as follows:

1 Brachytherapy using iodine-125 or ruthenium-106 is indicated for an anterior tumour if there is no vitreous seeding.

2 Primary chemotherapy with intravenous carboplatin etoposide and vincristine (CEV) is given in three to six cycles according to the grade of retinoblastoma. Single agent chemoreduction with carboplatin alone has recently been found to give similar results to multi-agent therapy. Systemic treatment can be supplemented with sub-Tenon carboplatin injections. This may be followed by local treatment with cryotherapy or TTT to consolidate tumour control.

3 External beam radiotherapy is avoided, if possible, in patients with heritable retinoblastoma because of the risk of inducing a second malignancy. Hypoplasia of the bony orbit can occur, especially if radiotherapy is administered in the first 6 months of life.

Treatment of large tumours

1 Chemotherapy to shrink the tumour (chemoreduction), facilitating subsequent local treatment, thereby avoiding enucleation or external beam radiotherapy. Chemotherapy will also have a beneficial effect if a smaller tumour is present in the fellow eye or if there is a pinealoblastoma.

2 Enucleation is indicated if there is rubeosis, vitreous haemorrhage or optic nerve invasion. It is also performed if chemoreduction fails or a normal fellow eye makes aggressive chemotherapy inappropriate and is also useful for diffuse retinoblastoma because of a poor visual prognosis and high risk of recurrence with other therapeutic modalities. Enucleation should be performed with minimal manipulation and it is imperative to obtain a long piece of optic nerve (12–15 mm). The orbital implant should be as large as possible. Tenon capsule and conjunctiva should be closed separately.

Treatment of extraocular extension

1 Adjuvant chemotherapy consisting of a 6-month course of CEV is given after enucleation by some centres if there is retrolaminar or massive choroidal spread.

2 External beam radiotherapy is indicated when there is tumour extension to the cut end of the optic nerve at enucleation, or extension through the sclera.

Page 514

Page 515

Follow-up

• After radiotherapy or chemotherapy, tumours regress to a ‘cottage-cheese’ calcified mass (Fig. 12.36B), a translucent ‘fish-flesh’ mass, a mixture of both, or a flat atrophic scar.

• New tumours can develop in patients with heritable retinoblastoma, especially those treated at a very young age.

• If retinoblastoma has been treated conservatively EUA is necessary every 2 to 8 weeks until the age of 3 years, after which time examination without anaesthesia is performed every 6 months until the age of about 5 years, then annually until the age of about 10 years.

Page 516

• Orbital MR is indicated in high risk cases for about 18 months. If the child has any risk of developing a second malignant neoplasm, the parents should be educated to be alert to features of pain, tenderness and swelling and to seek medical attention if there is no improvement in a week.

Fig. 12.36 Brachytherapy for retinoblastoma. (A) Before treatment; (B) ‘cottage-cheese’ appearance after treatment

(Courtesy of N Bornfeld)

Differential diagnosis

1 Persistent anterior fetal vasculature (persistent hyperplastic primary vitreous) is confined to the anterior segment and often involves the lens.

• Presentation is with leukocoria (Fig. 12.37A) due to a retrolental mass into which elongated ciliary processes are inserted (Fig. 12.37B and C).

• With time, the mass contracts and pulls the ciliary processes centrally so that they become visible through the pupil.

• Complications include cataract (Fig. 12.37D) formation due to a capsular dehiscence.

• Treatment involving vitreoretinal surgery may be successful in selected early cases in salvaging some vision.

2 Persistent posterior fetal vasculature is confined to the posterior segment and the lens is usually clear.

• Presentation is with leukocoria, strabismus or nystagmus.

• A dense fold of condensed vitreous and retina extends from the optic disc to the ora serrata and is associated with retinal detachment (Fig. 12.38).

• Treatment is not possible.

3 Coats disease is almost always unilateral, more common in boys and tends to present later than retinoblastoma (see Ch. 13).

4 Retinopathy of prematurity, if advanced, may cause retinal detachment and leukocoria. Diagnosis is usually straightforward because of the history of prematurity and low birth weight (see Ch. 13).

5 Toxocariasis. Chronic toxocara endophthalmitis may cause a cyclitic membrane and a white pupil. A granuloma at the posterior pole may resemble an endophytic retinoblastoma (see Ch. 14).

6 Uveitis may mimic the diffuse infiltrating type of retinoblastoma seen in older children. Conversely, retinoblastoma may be mistaken for uveitis, endophthalmitis or orbital cellulitis.

Page 517

7 Vitreoretinal dysplasia is caused by faulty differentiation of the retina and vitreous that results in a detached dysplastic retina (Fig. 12.39A) forming a retrolental mass with leukocoria (Fig. 12.39B). Other features include microphthalmos, shallow anterior chamber and elongated ciliary processes. Dysplasia may occur in isolation or in association with systemic abnormalities, most notably Norrie disease, incontinentia pigmenti (Bloch–Sulzberger syndrome) and Walker–Warburg syndrome.

a Norrie disease is an XL recessive disorder in which affected males are blind at birth or early infancy. It is caused by mutations in the NDP gene on chromosome Xp11. Systemic features include cochlear deafness and mental retardation.

b Incontinentia pigmenti is an XL dominant condition that is lethal in utero for boys. Mutations have been found in the NEMO gene on chromosome Xq28. It is characterized by a vesiculobullous rash on the trunk and extremities (Fig. 12.40A) which with time is replaced by linear pigmentation (Fig. 12.40B). Other features include malformation of teeth, hair, nails, bones and CNS.

c Walker–Warburg syndrome is an AR condition characterized by absence of cortical gyri and cerebellar malformations that may be associated with hydrocephalus and encephalocele. Neonatal death is common and survivors suffer severe developmental delay. Apart from vitreoretinal dysplasia other ocular features include Peters anomaly, cataract, uveal coloboma, microphthalmos and optic nerve hypoplasia.

8 Other tumours

a Retinoma (retinocytoma) is a benign variant of retinoblastoma. It is characterized by a smooth, dome-shaped lesion, which slowly involutes spontaneously to a calcified mass associated with RPE alteration and chorioretinal atrophy (Fig. 12.41). The final appearance is remarkably similar to that of a retinoblastoma following irradiation. Rarely, a retinoma can later transform into a rapidly growing retinoblastoma.

b Retinal astrocytoma, which may be multifocal and bilateral (see below).

Fig. 12.37 Persistent anterior fetal vasculature. (A) Leukocoria; (B) retrolental mass with inserted ciliary processes; (C) early involvement; (D) advanced case with cataract

(Courtesy of K Nischal)

Fig. 12.38 Persistent posterior fetal vasculature

Fig. 12.39 Vitreoretinal dysplasia. (A) Pathological specimen; (B) clinical appearance

(Courtesy of J Harry and G Misson, from Clinical Ophthalmic Pathology, Butterworth-Heinemann 2001 – fig. A)

Fig. 12.40 Incontinentia pigmenti. (A) Vesciculobullous rash; (B) linear cutaneous pigmentation in an older child

Fig. 12.41 Retinoma

(Courtesy of K Nischal)

Astrocytoma

Page 518

Astrocytoma of the retina and optic nerve head is a rare hamartoma, which does not usually threaten vision and does not require treatment. Most are endophytic, protruding into the vitreous, but exophytic subretinal tumours can occur. Astrocytomas may occasionally be encountered as incidental solitary lesions in normal individuals but are most frequently seen in tuberous sclerosis (see below) and occasionally in association with NF1 and retinitis pigmentosa. About 50% of patients with tuberous sclerosis have fundus astrocytomas which may be multiple and bilateral.

Diagnosis

1 Histology shows fibrillary astrocytes with small oval nuclei and cytoplasmic processes (Fig. 12.42A).

2 Presentation. Most tumours are asymptomatic and detected on screening for tuberous sclerosis.

3 Signs

• Yellowish, semitransparent round plaque or nodule (Fig. 12.42B).

• Large elevated mulberry-like lesion (Fig. 12.42C) that shows autofluorescence (Fig. 12.42D).

• Mixed type which is semitransparent in the periphery and calcified centrally.

• Most tumours are static, and long-standing lesions may become calcified (Fig. 12.42E).

4 FA shows a prominent superficial vascular network within the tumour in the arterial phase followed by late leakage and staining (Fig. 12.42F).

Fig. 12.42 Astrocytoma. (A) Histology shows proliferation of fibrous astrocytes with small oval nuclei and cytoplasmic processes; (B) small peripheral lesion; (C) juxtapapillary mulberry-like lesion; (D) red-free image shows autofluorescence; (E) two calcified lesions; (F) FA shows staining

(Courtesy of J Harry – fig. A; P Gili – figs C and D; J Donald M Gass, from Stereoscopic Atlas of Macular Diseases, Mosby 1997 – fig. F)

Tuberous sclerosis

Tuberous sclerosis (Bourneville disease) is an AD phacomatosis characterized by the development of hamartomas in multiple organ systems from all primary germ layers. The classic triad of (a) epilepsy, (b) mental retardation and (c) adenoma sebaceum is only present in a minority of patients, but is diagnostic. About 60% of cases are sporadic and 40% are AD.

1 Cutaneous signs

• Adenoma sebaceum, consisting of fibroangiomatous red papules with a butterfly distribution around the nose and cheeks, is universal (Fig. 12.43A).

• Ash leaf spots are hypopigmented macules on the trunk (Fig. 12.43B), limbs and scalp. In infants with sparse skin pigmentation they are best detected using ultraviolet light, under which they fluoresce (Wood lamp).

• Confetti skin lesions.

• Shagreen patches consist of diffuse thickening over the lumbar region.

• Fibrous plaques on the forehead.

• Skin tags (molluscum fibrosa pendulum).

• Café-au-lait spots.

• Subungual hamartomas (Fig. 12.43D).

2 Neurological features

• Intracranial paraventricular subependymal astrocytic nodules (Fig. 12.43D) and giant cell astrocytic hamartomas.

• Mental retardation.

• Seizures.

3 Visceral tumours

• Renal angiomyolipomas and cysts.

• Cardiac rhabdomyomas.

• Pulmonary lymphangiomatosis.

4 Ocular features, apart from fundus astrocytomas, include patchy iris hypopigmentation and atypical iris colobomas.

Fig. 12.43 Tuberous sclerosis. (A) Adenoma sebaceum; (B) ash leaf spot; (C) subungual hamartoma; (D) axial CT shows a periventricular astrocytic nodule

(Courtesy of K Nischal – fig. A; MA Mir, from Atlas of Clinical Diagnosis, Mosby 2003 – fig. B)

Vascular retinal tumours

Capillary haemangioma

Overview

Retinal capillary haemangioma is a rare sight-threatening tumour that may occasionally occur in isolation, although about 50% of patients with solitary lesions and virtually all patients with multiple lesions have von Hippel–Lindau disease (VHL – see below). The prevalence of retinal tumours in VHL is approximately 60%. Vascular endothelial growth factor (VEGF) is important in the development of retinal lesions.

Diagnosis

1 Histology. The tumour is composed of capillary-like vascular channels between large foamy cells that may represent histiocytes, endothelial cells or astrocytes (Fig. 12.44A).

2 Presentation. The median age at diagnosis in patients with VHL is earlier (median 18 years) than in those without VHL (median 31 years). Tumours may be detected by screening of those at risk or because of symptoms due to macular exudates or retinal detachment.

3 Signs

• An early tumour is a small, well-defined oval red lesion within the capillary bed between an arteriole and venule (Fig. 12.44B).

• A well-established tumour is a round orange-red mass usually located in the supero- or inferotemporal periphery with dilatation and tortuosity of the supplying artery and draining vein extending from the optic disc (Fig. 12.44C).

• In a juxtapapillary tumour the dilated vessels are absent or less evident (Fig. 12.44D).

• A sessile tumour is an ill-defined placoid juxtapapillary lesion (Fig. 12.44E).

4 FA shows early hyperfluorescence (Fig. 12.45A) and late leakage (Fig. 12.45B). There is also rapid filling and exit of dye.

5 Complications

• Exudate formation in the area surrounding the tumour and/or at the macula (Fig. 12.46).

• Bleeding and leakage resulting in macular oedema and exudative retinal detachment.

• Fibrotic bands, which can cause tractional or rhegmatogenous retinal detachment.

• Vitreous haemorrhage, secondary glaucoma and phthisis bulbi.

6 Differential diagnosis includes Coats disease, retinal macroaneurysm and vasoproliferative tumour.

Fig. 12.44 Retinal capillary haemangioma. (A) Histology shows capillary-like vascular channels between large foamy cells; (B) early tumour; (C) more advanced tumour associated with vascular dilatation and tortuosity; (D) optic nerve head lesion; (E) sessile lesion

(Courtesy of J Harry and G Misson, from Clinical Ophthalmic Pathology, Butterworth-Heinemann 2001 – fig. A; B Damato – fig. C; J Donald M Gass, from Stereoscopic Atlas of Macular Diseases, Mosby 1997 – fig. D; P Saine – fig. E)

Fig. 12.45 FA of retinal capillary haemangioma. (A) Early filling; (B) late leakage

(Courtesy of J Donald M Gass, from Stereoscopic Atlas of Macular Diseases, Mosby 1997)

Fig. 12.46 Severe exudation associated with a juxtapapillary capillary haemangioma

Treatment

1 Observation is advised for asymptomatic juxtapapillary haemangiomas without exudation, because these may remain inactive for many years and because of the high risk of iatrogenic visual loss. Early peripheral lesions are not usually left untreated because they are relatively easy to ablate.

2 Laser photocoagulation of small lesions. After closing the feeder vessels, the tumour is treated with low-energy, long duration burns. Multiple sessions may be needed.

3 Cryotherapy for larger peripheral lesions or those with exudative retinal detachment. Vigorous treatment of a large lesion may cause a temporary but extensive exudative retinal detachment.

4 Brachytherapy for lesions too large for cryotherapy.

5 Vitreoretinal surgery may be required for non-absorbing vitreous haemorrhage, epiretinal fibrosis or tractional retinal detachment. If appropriate, the tumour may be destroyed by endolaser photocoagulation or surgical removal.

6 Other modalities include PDT, which avoids damage to adjacent tissues, and anti-vascular endothelial growth factor (VEGF) agents. These are worth considering with juxtapapillary tumours, which are otherwise virtually untreatable without visual loss.

Von Hippel–Lindau syndrome

1 Inheritance is AD condition caused by a mutation of the VHL gene on chromosome 3p26-p25.

2 Clinical features

• CNS haemangioma involving the cerebellum (Fig. 12.47A), spinal cord, medulla or pons affects about 25% of patients with retinal tumours.

• Phaeochromocytoma.

• Renal carcinoma (Fig. 12.47B) and pancreatic islet cell carcinoma.

• Cysts of the testes, kidneys, ovaries, lungs, liver and pancreas.

Page 523

• Polycythaemia which may be the result of factors released by a cerebellar or renal tumour.

2 Screening is vital because it is impossible to predict which patients with retinal haemangiomas will harbour systemic lesions. The ophthalmologist must therefore refer all such patients for systemic and neurological evaluation. Relatives should also be screened because of the dominant inheritance pattern of the disease. The following screening protocol should be regularly performed in patients with established VHL and relatives at risk.

a Annual screening

• Physical examination.

• Annual ophthalmoscopy from age 5 years, increased to 6-monthly from 10 to 30 years.

• Renal ultrasonography from age 16 years.

• Twenty-four hour urine collection for estimation of vanillyl mandelic acid and catecholamine levels from age 10 years to detect phaeochromocytoma.

b Screening every 2 years involves abdominal and brain MR from the age of 15 years.

c Genetic tests are indicated in all patients with suspected disease and in first and second degree relatives. With modern techniques the sensitivity is almost 100%.

Fig. 12.47 Tumours in von Hippel–Lindau syndrome. (A) Axial MR shows a cerebellar haemangioma; (B) axial CT of the abdomen shows a renal carcinoma

(Courtesy of CD Forbes and WF Jackson, from Atlas and Text of Clinical Medicine, Mosby 2003 – fig. B)

Cavernous haemangioma

Cavernous haemangioma of the retina and optic nerve head is a rare, unilateral, congenital hamartoma. It is usually sporadic but occasionally can be inherited as AD with incomplete penetrance, in combination with lesions of the skin and CNS (‘neurooculocutaneous phacomatosis’ or ‘cavernoma multiplex’).

1 Histology shows multiple thin-walled dilated channels with surface gliosis.

2 Presentation may be with vitreous haemorrhage or, more frequently, as a chance finding.

3 Signs

• Sessile clusters of saccular aneurysms resembling a ‘bunch of grapes’ in the peripheral retina (Fig. 12.48A and B).

• Because of sluggish flow of blood, the red cells may sediment and separate from plasma, giving rise to ‘menisci’ or fluid levels within the lesion.

• The lesion occasionally involves the optic nerve head (Fig. 12.48C).

4 FA highlights the sedimentation of erythrocytes and shows delayed filling in the venous phase and lack of leakage (Fig. 12.48D).

5 Complications, which are uncommon, include haemorrhage and epiretinal membrane formation.

6 Treatment. Rarely vitrectomy may be necessary for non-absorbing vitreous haemorrhage but photocoagulation should be avoided as it may precipitate haemorrhage and enlargement of the tumour.

Fig. 12.48 Cavernous haemangioma. (A) Very small peripheral lesion; (B) larger peripheral lesion; (C) optic nerve involvement; (D) FA shows fluid levels due to separation of red cells (hypofluorescent) from plasma (hyperfluorescent)

(Courtesy of J Donald M Gass, from Stereoscopic Atlas of Macular Diseases, Mosby 1997 – fig. D)

Racemose haemangioma

Racemose haemangioma (also known as arteriovenous malformation) of the retina and optic nerve head is a rare, sporadic, usually unilateral, congenital malformation involving direct communication between the arteries and veins without an intervening capillary bed. Some patients have similar ipsilateral lesions involving the midbrain, basofrontal region and posterior fossa (an association referred to as Wyburn–Mason syndrome). Brain involvement may lead to spontaneous haemorrhage or epilepsy. Occasionally, malformations may involve the maxilla and mandible, predisposing the patient to haemorrhage after dental treatment. Facial skin lesions have also been reported.

1 Presentation is usually as a chance finding.

2 Signs

• Enlarged, tortuous blood vessels which are often more numerous than normal with the vein and artery appearing similar (Fig. 12.49A).

Page 524

• With time the vessels become more dilated and tortuous, and may become sclerotic (Fig. 12.49B).

3 FA shows hyperfluorescence but absence of leakage (Fig. 12.49C).

4 Treatment is not required.

Fig. 12.49 Racemose haemangioma. (A) Vascular dilatation and tortuosity; (B) more severe lesion in which some vessels show sclerosis; (C) FA shows hyperfluorescence but absence of leakage

(Courtesy of J Donald M Gass, from Stereoscopic Atlas of Macular Diseases, Mosby 1997 – fig. B)

Vasoproliferative tumour

Retinal vasoproliferative tumour is a rare gliovascular lesion which can be primary or secondary to conditions such as intermediate uveitis, ocular trauma and retinitis pigmentosa. Secondary lesions may be multiple and occasionally bilateral depending on the underlying aetiology.

1 Histology shows glial cells and a network of fine capillaries with some larger dilated vessels.

2 Presentation is usually in the 3rd–5th decades with blurring of vision due to macular exudation.

3 Signs

• A reddish-yellow globular vascular mass, most frequently located in the inferotemporal periphery (Fig. 12.50).

• Retinal vessels may be seen entering the lesion posteriorly.

4 Complications include subretinal exudation, exudative retinal detachment, macular oedema and fibrosis, and haemorrhage.

5 Treatment with cryotherapy or brachytherapy induces regression of the tumour and exudation but the visual prognosis is guarded if there is maculopathy.

Page 525

Fig. 12.50 Vasoproliferative tumour with retinal detachment

(Courtesy of B Damato)

Primary intraocular lymphoma

Overview

Lymphoma is a group of conditions characterized by neoplastic proliferation of cells of the immune system typified by lymphadenopathy, constitutional symptoms, and occasionally CNS involvement. The main classification and ocular manifestations are as follows:

1 Hodgkin disease may cause anterior uveitis, vitritis, and multifocal fundus lesions resembling chorioretinitis.

2 Non-Hodgkin lymphoma may cause conjunctival involvement, orbital involvement, Mikulicz syndrome and uveal infiltration.

3 CNS B-cell lymphoma may be associated with intermediate uveitis and sub-RPE infiltrates.

4 Primary intraocular lymphoma (PIOL) represents a subset of primary central nervous system lymphoma (PCNSL), which is a variant of extranodal non-Hodgkin lymphoma. The lymphoma cells are large, pleomorphic B lymphocytes with large multilobular nuclei, prominent nucleoli and scanty cytoplasm (Fig. 12.51A). The tumour arises from within the brain, spinal cord and leptomeninges, and has a very poor prognosis. About 20% of patients with PCNSL have ocular manifestations, which can precede or follow neurological involvement. Most patients with PIOL develop CNS symptoms after a mean delay of 29 months.

Fig. 12.51 Primary intraocular lymphoma. (A) Vitreous biopsy shows cells with irregular large nuclei and scanty cytoplasm; (B) multifocal subretinal infiltrates; (C) coalescent subretinal infiltrates; (D) shallow retinal detachment

(Courtesy of P Smith – fig. A; B Damato – figs B and C; A Turno-Krecicka – fig. D)

Ocular features

Page 526

1 Presentation is in the 6th–7th decades with unilateral floaters, blurred vision, red eye or photophobia, which frequently becomes bilateral after a variable interval.

2 Signs

• Mild anterior uveitis with cells, flare and keratic precipitates.

• Vitritis may impede visualization of the fundus.

• Large solid multifocal subretinal infiltrates (Fig. 12.51B).

• Occasionally coalescence of sub-RPE deposits may form a ring encircling the equator (Fig. 12.51C).

• Other features include retinal vasculitis, vascular occlusion, exudative retinal detachment (Fig. 12.51D) and optic atrophy.

• Lack of CMO is an important diagnostic clue, since in true uveitis significant vitritis is almost always accompanied by CMO.

Neurological features

• An intracranial mass may cause headache, nausea, personality change, focal deficit and seizures.

• Leptomeningeal disease may cause neuropathy.

• Spinal cord involvement may cause bilateral motor and sensory deficits.

• Abnormal clinical neurological examination, such as cranial nerve palsies, hemiparesis and ataxia.

• MR of head and spine with gadolinium, which can detect one or more intracranial tumours, diffuse meningeal or periventricular lesions, and/or localized intradural spinal masses.

• Lumbar puncture, which can demonstrate malignant cells in CSF in a minority of patients with abnormal MRI. A positive result avoids the need for brain or eye biopsy.

Page 527

Investigations

1 FA shows blockage with a granular characteristic, due to the presence of sub-RPE accumulation of lymphomatous cells (leopard skin spots).

2 US may show vitreous debris, elevated subretinal lesions, retinal detachment and thickening of the optic nerves.

3 Cytology of vitreous samples or subretinal nodules.

4 Immunohistochemistry based on cell-surface markers allows identification of the lymphocytic proliferation, which is of a B-cell type in most patients.

5 CNS screening by regular MR scans is indicated.

Treatment

1 Radiotherapy has long been the first-line treatment for PIOL, but recurrence is common and complications such as radiation retinopathy and cataract can occur.

2 Intravitreal methotrexate is useful for recurrent disease, but close monitoring is needed to detect ocular complications and any recurrence.

3 Systemic chemotherapy with a variety of regimes including methotrexate can prolong survival in patients with CNS disease. This can be given in combination with whole brain irradiation but neurotoxicity is a problem. A variety of methods have been developed to overcome the blood–brain barrier. Systemic treatment is usually effective for ocular disease and this is preferred to ocular radiotherapy in some centres because in addition to avoiding radiation-induced complications it may improve survival. Monotherapy for PIOL with ifosfamide or trofosfamide has also been successful.

4 Biologic agents involving specific anti-B cell monoclonal antibodies (such as rituximab), may represent a useful alternative, but probably need to be given locally because of poor penetration of the blood-brain barrier.

Tumours of the retinal pigment epithelium

Typical congenital hypertrophy of the RPE

Congenital hypertrophy of the retinal pigment epithelium (CHRPE) is a common benign lesion which may be (a) typical, either solitary or grouped, or (b) atypical. It is important to differentiate between the two types because the latter may have important systemic implications.

1 Solitary CHRPE

• A flat, dark-grey or black, round or oval lesion with well-defined margins usually located near the equator (Fig. 12.52A).

• Depigmented lacunae are common (Fig. 12.52B).

• Some lesions may become virtually totally depigmented (Fig. 12.52C).

• Juxtapapillary lesions are uncommon (Fig. 12.52D).

2 Grouped CHRPE

• Multiple lesions organized in a pattern simulating animal footprints (‘bear-track’ pigmentation) often confined to one sector or quadrant of the fundus with the smaller spots usually located more centrally (Fig. 12.53A).

• Rarely the lesions may be depigmented (‘polar bear tracks’) (Fig. 12.53B).

Fig. 12.52 Solitary CHRPE. (A) Completely pigmented lesion; (B) partly depigmented lesion; (C) largely depigmented lesion; (D) juxtapapillary lesion

Fig. 12.53 Grouped CHRPE. (A) ‘Bear-track’ lesions; (B) ‘polar bear track’ lesions

(Courtesy of J Donald M Gass, from Stereoscopic Atlas of Macular Diseases, Mosby 1997 –fig. B)

Atypical congenital hypertrophy of the RPE

Signs

• Bilateral, multiple, widely separated, frequently oval or spindle-shaped lesions of variable size associated with hypopigmentation at one margin (Fig. 12.54A and B).

• The lesions have a haphazard distribution and may be pigmented, depigmented or heterogeneous.

Fig. 12.54 (A) Atypical CHRPE; (B) magnification shows characteristic depigmentation at one margin; (C) adenomatous polyposis

Systemic associations

1 Familial adenomatous polyposis (FAP) is an AD condition characterized by adenomatous polyps throughout the rectum and colon which usually start to develop in adolescence (Fig. 12.54C). If untreated, virtually all patients with FAP develop carcinoma of the colorectal region by the age of 50 years. As a result of the dominant inheritance pattern, intensive survey of family members is imperative. Over 80% of patients with FAP have atypical CHRPE lesions, which are present at birth. A positive criterion for FAP is the presence of at least four lesions whatever their size, or at least two lesions of which one is large. Such fundus lesions in a family member should therefore arouse suspicion of FAP but the absence of CHRPE lesions does not exclude FAP.

2 Gardner syndrome is characterized by FAP, osteomas of the skull, mandible and long bones, and cutaneous soft tissue tumours such as epidermoid cysts, lipomas and fibromas.

3 Turcot syndrome is an AD or AR condition characterized by FAP and tumours of the CNS, particularly medulloblastoma and glioma.

Combined hamartoma of the retina and RPE

Page 528

Combined hamartoma of the retina and RPE is a rare, usually unilateral congenital malformation that predominantly affects males. It usually occurs sporadically in normal individuals and occasionally in patients with NF2 and Gorlin–Goltz syndrome.

1 Histology shows RPE, sensory retina, retinal blood vessels and vitreoretinal membranes to varying degrees.

2 Presentation is in late childhood or early adulthood with strabismus, blurred vision or metamorphopsia.

3 Signs

• Deep greyish pigmentation with superficial whitish gliosis resulting in retinal wrinkling and vascular tortuosity.

• The lesion is usually juxtapapillary (Fig. 12.55A), peripapillary (Fig. 12.55B) or at the posterior pole (Fig. 12.55C).

• Peripheral lesions are uncommon (Fig. 12.55D).

• Large lesions may cause ‘dragging’ of the disc or macula.

• Uncommon associated findings include hard exudate formation and occasionally choroidal neovascularization at the margins of the lesion.

• Occasional associations include disc pit, disc drusen and disc coloboma.

4 FA shows early hyperfluorescence of the vascular abnormalities and blockage by pigment (Fig. 12.55E); late phase shows intense hyperfluorescence due to leakage (Fig. 12.55F).

5 Treatment is not indicated.

Fig. 12.55 Combined hamartoma of the retina and retinal pigment epithelium. (A) Small juxtapapillary lesion; (B) large peripapillary lesion with peripheral hard exudates; (C) large posterior pole lesion with ‘dragging’ of the disc; (D) peripheral lesion; (E) FA early venous phase shows hyperfluorescence of vascular lesions and blockage by pigment; (F) late phase shows intense hyperfluorescence due to leakage

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

Congenital hamartoma of the RPE

Congenital hamartoma of the RPE is a rare entity, usually incidentally diagnosed in asymptomatic children and young adults.

1 Signs

• Small, jet-black, nodular lesion, with well-defined margins, which usually appears to involve the full-thickness of the retina and to spill onto the inner retinal surface in a mushroom configuration.

• The lesion is typically located immediately adjacent to the foveola and is 1.5 mm or less in base diameter (Fig. 12.56).

• Visual acuity is usually normal, but may occasionally be impaired as a result of surrounding foveal traction or central foveal involvement.

2 Treatment is not indicated.

Page 529

Fig. 12.56 Congenital hamartoma of the retinal pigment epithelium

Paraneoplastic syndromes

Paraneoplastic retinopathies are rare diseases that might be missed or misdiagnosed by the unwary observer. Many of the patients present with visual symptoms before the primary malignancy is diagnosed. It is therefore important for clinicians to be familiar with these syndromes to detect the underlying malignancy as early as possible.

Bilateral diffuse uveal melanocytic proliferation

Bilateral diffuse uveal melanocytic proliferation (BDUMP) is a very rare paraneoplastic syndrome occurring usually in patients with systemic, often occult, malignancy. It is characterized by proliferation of benign melanocytes in the outer choroid.

1 Signs

• Multiple naevus-like choroidal lesions (Fig. 12.57).

• Multiple red-grey subretinal patches which may have a reticular pattern.

• Exudative retinal detachment.

• Rapidly developing cataracts.

Page 530

Page 531

• Vitreous and anterior chamber cells.

• Anterior uveal cysts and tumours.

• Episcleral nodules.

2 US shows diffuse choroidal thickening and multiple tumours.

3 ERG is often reduced.

4 Treatment of BDUMP itself is not available. Detection of an occult primary malignancy might enable early treatment to enhance survival. Successful treatment of the underlying primary tumour may be followed by regression of the BDUMP but without improvement in vision.

Fig. 12.57 Naevus-like lesions in diffuse uveal melanocytic proliferation

(Courtesy of A Leys)

Cancer-associated retinopathy

Cancer-associated retinopathy (CAR) is most frequently associated with small cell bronchial carcinoma, followed by gynaecological and breast cancer.

1 Symptoms

• Subacute bilateral visual loss over 6–18 months.

• Visual symptoms precede the diagnosis of malignancy in half the cases, usually by several months.

• Positive visual phenomenon of shimmering or flickering lights.

• Progressive reduction of visual acuity, colour impairment, glare, photosensitivity and central scotoma attributed to cone dysfunction.

• Night blindness, impaired dark adaptation, ring scotoma and peripheral field loss due to rod dysfunction.

2 Signs

• Fundus often appears normal on presentation.

• Attenuated arterioles, optic disc pallor and mild RPE changes develop as the disease progresses.

3 Investigations

a ERG is severely attenuated under photopic and scotopic conditions; dark adaptation is abnormal.

b Lumbar puncture may show elevated cerebrospinal fluid protein and lymphocytosis.

c Search for an underlying malignancy.

4 Prognosis for both vision and life is poor.

Melanoma-associated retinopathy

The presentation of melanoma-associated retinopathy (MAR) differs from CAR because the visual symptoms usually arise after, rather than prior to, the diagnosis of cutaneous melanoma. There may be concurrent vitiligo. The specific antigen responsible has not been identified, but autoantibodies from MAR sera react against bipolar cells in human retina. Clinical and electrophysiological data also implicate the bipolar cells as the disease target abnormality in MAR.

1 Symptoms consist of shimmering or flickering lights and nyctalopia.

2 Signs

• Gradual central visual loss.

• Fundus appears normal initially, but optic disc pallor, retinal vascular attenuation and vitreous cells can develop.

3 ERG shows marked reduction of dark-adapted and light-adapted b-wave and preservation of a-wave (normal photoreceptor function). Both the amplitude and implicit time of the b-wave are abnormal. MAR is characterized by a ‘negative ERG’, similar to the pattern seen in congenital stationary night blindness.

4 Prognosis for vision is good.

Page 532