T his chapter discusses some of the nonvascular hamartomas and choristomas of the retina, retinal pigment epithelium (RPE), and choroid that may be seen in the pediatric population.

Nonvascular Hamartomas

Chittaranjan V. Reddy and Arlene V. Drack

T his chapter discusses some of the nonvascular hamartomas and choristomas of the retina, retinal pigment epithelium (RPE), and choroid that may be seen in the pediatric population.

Although many of the lesions discussed in this chapter are present in childhood, they are frequently discovered later in life during routine examination or when late visual symptoms develop.

CHOROIDAL NEVUS

Choroidal nevi are tumors consisting of benign uveal melanocytes that are derived embryologically from the neural crest. Choroidal nevi are believed to be developmental tumors;

they are rarely seen at birth or during infancy but increase in frequency around puberty.

The pathogenesis of choroidal nevi is poorly understood, but they are similar to nevi involving other parts of the uveal tract. Clinically evident choroidal nevi are estimated to occur in 1% to 2% of the general population, but they are found in 6.5% of autopsied eyes.

There is no known sexual predilection, but whites have these lesions more com- monly than blacks.

Ophthalmoscopically, choroidal nevi usually appear as brown to slate gray lesions with fairly distinct margins (Fig.

8-1). However, lesions may be amelanotic or show variable pig- mentation.Choroidal nevi vary from 0.5 to 10 mm in diameter, but they are usually approximately one disc area in size.

Choroidal nevi are usually flat but may be elevated 1 to 3 mm.

Most choroidal nevi are located posterior to the equator. In con- trast, choroidal freckles, also frequently seen, are fairly indis-

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tinct, flat lesions. Choroidal freckles simply represent localized increased choroidal pigmentation.

Over several years, the clinical appearance of a choroidal nevus may change secondary to degeneration within the tumor or in the overlying tissue. Changes include the appearance of drusen, RPE atrophy, and pigment migration into the retina that can appear as bone spicules at the edge of the lesion. Clumps and patches of orange pigmentation can also be seen overlying the nevus (Fig. 8-2). Orange pseudohypopyon with metamorphopsia, which resolved without treatment, has been reported.

Serous detachment of the retina, RPE detachments, and choroidal neo- vascular membranes (CNVM) can occur in association with choroidal nevi. Laser photocoagulation has been helpful in some cases.

The visual prognosis is dependent on the secondary changes and on the location of the choroidal nevus. Macular lesions have the worst prognosis. For most nevi, the visual prog- nosis is quite good.

Choroidal nevi may undergo malignant transformation

into melanomas. Over a 10-year period, approximately 1 in

500 patients with choroidal nevi develop choroidal melanoma.

Thus, most patients with choroidal nevi do not develop

melanoma. It is not clear what percentage of melanomas arise

de novo and what percentage arise from preexisting choroidal

nevi. Features that are associated with an increased risk of malignant transformation include largest diameter greater than 3 mm, elevation greater than 1 to 2 mm, and overlying orange pigmentary changes.

Suspicious lesions require examination and photography every 6 to 12 months to look for evidence of growth.

The diagnosis of a choroidal nevus is usually based on the ophthalmoscopic appearance. Echography is of little help in dif- ferentiating nevi from small melanomas. Histologically, nevi are comprised of four benign cell types (occurring in decreasing fre- quency): polyhedral cells, spindle cells, fusiform or dendritic cells, and balloon cells. Individual nevus cells may be pigmented or nonpigmented.

The mnemonic TFSOM (To Find Small Ocular Melanoma) has been suggested by Shields and Shields

to help differenti- ate between nevi and malignancies. Thickness ⬎2mm, Fluid subretinally, Symptoms, Orange pigment, and Margin touching the disc are all risk factors. Tumors with no factors have a 3%

chance for growth at 5 years, those with one factor have a 38% chance and those with two or more factors have a 50%

chance and often require treatment as they are actually small melanomas.

FIGURE 8-2. Choroidal nevus with pigmentary changes and overlying drusen suggesting chronicity.

MELANOCYTOMA

(MAGNOCELLULAR NEVUS)

The term melanocytoma refers to a dark brown or black variant of a choroidal nevus composed histopathologically of highly pig- mented, plump, round to oval nevus cells. Melanocytomas can be seen anywhere in the uveal tract, but most are seen near the optic nerve head (Fig. 8-3). Although most are well circumscribed, diffuse forms of the lesion exist. It is difficult to determine the exact incidence of this unusual tumor because some may be con- fused with typical choroidal nevi. Melanocytomas are probably present at birth, but the diagnosis is usually made at a later age.

Although there is no significant sexual predilection, there is a strong racial predisposition to melanocytomas. Approximately one-third to one-half of melanocytomas occur in blacks, in strong contrast to malignant melanomas, of which less than 1% occur in blacks. When melanocytomas occur in whites, they are usually seen in those of Hispanic or Italian descent.

A melanocytoma of the optic nerve head is usually an inci- dental finding. If the lesion is fairly large, the patient may com- plain of slight blurring of vision. Additionally, an afferent pupillary defect and visual field abnormalities may be seen. In approximately half the cases, a typical choroidal nevus is con-

FIGURE 8-3. Typical melanocytoma of the optic nerve head with an adja- cent choroidal nevus. (Courtesy of Dr. F.C. Blodi.)

tiguous with the melanocytoma at the optic nerve head. Extra- papillary melanocytomas are quite similar to other uveal nevi but tend to be much more pigmented.

In about 15% of cases, a subtle growth of the tumor at the optic nerve head is seen. Some larger melanocytomas may also undergo necrosis and liberate pigmentary debris into the vitreous cavity. Retinal vascular occlusion at the optic nerve head can occur with melanocytomas. In extremely rare cases, malignant transformation to melanomas has been described.

Diagnosis is usually made by ophthalmoscopy alone.

Fundus photography, fluorescein angiography, and visual field testing may be helpful for comparison on follow-up visits.

Echography is not necessary in most cases.

CONGENITAL HYPERTROPHY OF THE RETINAL PIGMENT EPITHELIUM

Congenital hypertrophy of the retinal pigment epithelium (CHRPE) is fairly commonly seen on routine ophthalmoscopy and usually does not cause any symptoms. There are two rec- ognized clinical forms: solitary lesions and multifocal grouped pigmentation of the RPE, also known as bear tracks. The lesions seen in these two variants are similar histologically and proba- bly have a similar pathogenesis. The lesions are typically hyper- pigmented although amelanotic lesions are seen as well.

CHRPE has no racial predilection, in contrast to choroidal nevi, choroidal melanomas, and melanocytomas, which may be related to the fact that the other tumors are derived from uveal melanocytes rather than the RPE. The diagnosis of CHRPE lesions is typically made on the basis of the clinical appearance of the lesion. Visual field testing has demonstrated defects in older individuals that are secondary to degeneration of the overlying photoreceptors. Therefore, lesions in the macula may cause visual loss with time.

Solitary CHRPE lesions are usually hyperpigmented with a sharply demarcated border that may be smooth or scalloped (Fig.

8-4). The lesions are usually flat, vary from 1 to 6 mm in diam- eter, and are more commonly found in the temporal fundus.

CHRPE lesions may show central lacunae or peripheral depig-

mentation (Fig. 8-5). Overlying retinal vessels may be attenu-

ated, but there is typically no invasion into the retina. Some

solitary CHRPE lesions may be completely nonpigmented.

FIGURE 8-4. Congenital hypertrophy of the retinal pigment epithelium (CHRPE). Note the fairly distinct border of the lesion.

FIGURE 8-5. CHRPE lesion with several hypopigmented lacunae and a surrounding halo.

There may be one to three lesions per eye, but bilateral involve- ment occurs only in 1% to 2% of cases.

Although growth of these lesions may occur, there is no known potential for malig- nant transformation.

The multifocal variant of CHRPE, similar to the solitary form, does not usually cause symptoms. Ophthalmoscopically, multifocal CHRPE lesions are usually grouped in one sector of the fundus (Fig. 8-6). Several small, variably sized lesions are arranged such that they resemble animal footprints (bear tracks).

They do not typically have the lacunae or halos of depigmenta- tion that are noted in the solitary form of CHRPE. Occasionally lesions may be amelanotic and are sometimes referred to as

CHRPE AND INHERITED

GASTROINTESTINAL POLYPOSIS

CHRPE lesions have been associated with familial adenomatous polyposis, Gardner’s syndrome, and Turcot’s syndrome.

These autosomal dominant syndromes are associated with a very high risk of developing adenocarcinoma of the colon by age 50 years.

Polyps may develop in early childhood. These patients may also

have skeletal hamartomas and various other soft tissue tumors.

The identification of typical CHRPE lesions may provide very useful diagnostic information to potentially affected offspring whose intestinal manifestations develop at a later age. Mutations of the APC gene are causative in some patients.

The presence of four or more CHRPE lesions not restricted to one sector of the fundus or bilateral involvement should make one suspicious of a familial polyposis syndrome. In addition, the CHRPE lesions seen in these patients have a characteristic appearance (Fig. 8-7). They tend to be oval in shape, oriented hor- izontally, and typically have a hypopigmented area that gives them a fishtail or comet-like appearance. There is no known histopathological difference between the CHRPE lesions associ- ated with familial polyposis and those that are not.

Histopathologically, CHRPE lesions consist of focal areas of taller retinal pigment epithelial cells densely packed with pigment granules that are also larger than those found in the normal surrounding RPE. Within the lesions, areas of decreased density of the pigment granules have been noted and probably

FIGURE 8-7. Macular CHRPE lesion in a patient with intestinal poly- posis. Note the horizontal orientation of the “fishtail” lesion. (Courtesy of Dr. T.A. Weingeist. Previously published in Ophthalmology 1991;98:

113, used with permission.)

correspond to the depigmented lacunae seen clinically. The overlying Bruch’s membrane may be thickened, and the pho- toreceptors are usually very sparse or absent.

CONGENITAL HYPERPLASIA OF THE RETINAL PIGMENT

EPITHELIUM

Congenital hyperplasia of the retinal pigment epithelium (RPE) (Figs. 8-8, 8-9) is far less common than CHRPE. Asymptomatic children and adults have been diagnosed with this condi- tion following ophthalmoscopic examination. Unlike typical CHRPE lesions, these hamartomas are composed of hyperplas- tic RPE cells that extend anteriorly into the overlying retina.

Histopathologically, these lesions are probably characterized by sheets of increased numbers of fairly normal sized RPE cells.

There has been no demonstrated malignant transformation of these lesions.

FIGURE 8-8. Congenital hyperplasia of the retinal pigment epithelium (RPE). (Courtesy of Dr. S. Pautler.)

COMBINED HAMARTOMA OF THE RETINAL PIGMENT EPITHELIUM AND RETINA

The clinical entity of a combined hamartoma of the retinal pigment epithelium and sensory retina was first clearly defined by Gass.

These tumors are quite rare. Clinically, the lesions may be found at any age including early childhood and infancy.

The previous clinical history is often noncontributory, and the patient’s visual complaints are dependent on the location of the tumors.

Ophthalmoscopically, the tumors may be located in a jux-

tapapillary (Figs. 8-10, 8-11) or peripheral distribution. Patients

with juxtapapillary tumors are more commonly seen in young

adulthood because of decreased or distorted vision. The tumors

tend to be poorly-defined, elevated, variably pigmented, and

involve part of the optic nerve and the adjacent retina. Tortuos-

ity of the large retinal vessels emanating from the optic nerve

head, a prominent feature, may be worsened by contraction of

the fibroglial tissue. Additionally, the tumors may have a

FIGURE 8-10. Juxtapapillary combined hamartoma of the RPE and retina.

FIGURE 8-11. Fluorescein angiogram of the lesion shown in Figure 8-10. Note the vascularity of the lesion and the distortion of the sur- rounding retinal vessels.

prominent capillary network that can lead to macular exuda- tion. Retinoschisis, intraretinal and subretinal lipid deposition, and retinal hole formation have been described.

Rarely, retinal hemorrhage, vitreous hemorrhage, or choroidal neovascular membranes occur. When located peripherally, dragging of the retinal vessels is a prominent feature. Regardless of location, the tumors have a variable composition of glial tissue and RPE.

The visual prognosis is dependent on the location of the tumor. Most peripheral lesions are asymptomatic and tend to be associated with good vision. Visual acuity in juxtapapillary lesions is dependent on the extent of macular distortion or optic nerve involvement. Overall, approximately 40% of patients main- tain vision of 20/40 or better and approximately 30% of patients have vision that is 20/200 or worse.

Vitrectomy to relieve trac- tion caused by epiretinal membrane formation usually does not improve vision.

The diagnosis of combined hamartomas is based on the clin- ical appearance of the lesions. Fluorescein angiography may provide useful information regarding the vascular abnormalities associated with the tumor. Echography is of little value.

The pathogenesis of these lesions is not fully understood, but they may be developmental or arise secondary to inflam- mation. Evidence to support the notion that these are devel- opmental tumors comes from cases in which the combined hamartomas are associated with neurofibromatosis, congenital anomalies of the optic disc, incontinentia pigmenti, X-linked retinoschisis, and facial hemangiomas.

Histopathologically, disorganization of retinal architecture is noted. Sheets of pro- liferating RPE are seen along with increased numbers of blood vessels. Fibroglial tissue on the inner surface of the retina and vitreous condensations are a prominent feature in some cases.

CHOROIDAL OSTEOMA

Choroidal osteomas are benign tumors of the choroid consisting

of mature bone that are usually found in a juxtapapillary or a

macular location (Fig. 8-12). They are typically discovered in

women in their teens and twenties. Occasionally, they may be

seen in men and adults older than 30.The symptoms at the time

of diagnosis are dependent on the location of the osteoma as well

as the presence or absence of an associated serous or hemor-

rhagic detachment of the retina. The lesions may be bilateral in

20% to 25% of cases. There is no known predilection for race.

The exact incidence of choroidal osteoma is not known.

Ophthalmoscopically, a choroidal osteoma typically appears as a slightly elevated, yellow to orange subretinal lesion. At the time of diagnosis, mottling of the overlying retinal pigment epithelium is frequently present. Multicentric lesions may occur, but solitary lesions are the norm. A pathognomonic feature of choroidal osteoma is the appearance of small vascular tufts that emerge on the anterior surface of the tumor. These tufts are particularly evident with fluorescein angiography and represent feeder vessels exiting from the spaces between the can- cellous bone that make up the tumor. These blood vessels do not cause exudation or hemorrhage.

The presence of subretinal fluid or hemorrhage are signs of choroidal neovascular mem- brane development. Laser photocoagulation should be consid- ered if the choroidal neovascular membrane appears to be vision threatening. Several treatment sessions may be required to erad- icate the new blood vessels.

The visual prognosis of a choroidal osteoma is dependent

on its location. Subfoveal lesions tend to have the worst prog-

nosis, with gradual visual loss secondary to progressive degen- eration of the overlying retina or serous detachment. Most patients with juxtapapillary osteomas tend to have a better prognosis.

Diagnosis of choroidal osteomas is best made by ophthal- moscopic examination and fluorescein angiography. Echography may be useful in differentiating choroidal osteomas from similar lesions. A-scan ultrasound typically shows a sharp high- intensity echo spike from the anterior surface of the tumor, along with high internal reflectivity (Fig. 8-13). A CT scan may show the characteristic appearance of a radioopaque lesion at the level of the choroid.

The exact pathogenesis of choroidal osteomas is unknown.

Intraocular calcification has been noted in association with trauma, inflammation, congenital malformations, and long- standing retinal detachment, as well as abnormalities of calcium and phosphorus metabolism. Choroidal osteomas have similarly been described following a history of trauma or intraocular inflammation but most are seen in the absence of any associ- ated ophthalmic problems. Female hormones probably play a role in the pathogenesis of choroidal osteomas given its prepon- derance in women. Familial occurrence of choroidal osteomas has also been reported.

Two conditions that may be confused with typical choro-

idal osteomas are sclerochoroidal calcification and the nevus

cally seen along the superotemporal arcade and are more fre-

quently multifocal. In older patients, they may occur in the

absence of any abnormalities of calcium or phosphorus metab-

olism and probably represent calcification at the site of

insertion of the superior oblique muscle.

The linear nevus

sebaceous syndrome (of Jadassohn) consists of midline facial

skin lesions, seizures, mental retardation, and ophthalmologic

abnormalities. The ophthalmic abnormalities include conjunc-

tival lipodermoids, colobomata of the lids, iris, choroid, and disc,

angiomas of the orbit, osseous choristomas of the choroid

(similar to typical choroidal osteomas), and subretinal neovas-

cularization.

FIGURE 8-13. Echography of a typical choroidal osteoma. The b-scan shows the highly reflective tumor (small arrow) with shadowing posteri- orly (large arrows). The a-scan shows a sharp peak (arrow) that represents the anterior surface of the tumor with decreasing echoes posteriorly.

(Courtesy of Dr. K. Ossonig.)

TUBEROUS SCLEROSIS

Tuberous sclerosis, first described by Bourneville in 1880, con- sists of the triad of adenoma sebaceum, seizures, and variable mental retardation. There are many other cutaneous, CNS, and systemic features, discussed elsewhere in this volume.

The most characteristic fundus lesion seen in tuberous scle- rosis is an astrocytic hamartoma of the optic nerve head or the retina; these are estimated to occur in approximately 50% of the patients with tuberous sclerosis. Astrocytic hamartomas are not a pathognomonic feature of tuberous sclerosis, as they may occur in neurofibromatosis as well. Moreover, it is unclear what percentage of astrocytic hamartomas is associated with tuber- ous sclerosis. Most patients with astrocytic hamartomas are asymptomatic, but gradual visual loss may be related to tumors at the optic nerve head or in the macula. These tumors can occur in the pediatric population.

Ophthalmoscopically, one or more elevated, white, fairly well circumscribed lesions arising from the inner retinal surface or the optic nerve are seen (Fig. 8-14). In younger patients, the lesions may be smaller, less opaque, and have poorly defined

FIGURE 8-14. Typical “gelatinous” retinal astrocytoma in a patient with tuberous sclerosis. (Courtesy of Dr. F. Judisch.)

margins; these may be mistakenly diagnosed as retinoblastoma.

Another striking feature of astrocytic hamartomas is the char- acteristic nodular calcification that may give a mulberry appear- ance that has also been likened to fish eggs or tapioca (Fig. 8-15).

The calcification seen in retinoblastoma is usually dull and chalky white as opposed to the more glistening yellow, nodular calcification that is seen with astrocytic hamartomas. Dilated, tortuous retinal feeder vessels are a more common feature of retinoblastomas than of astrocytic hamartomas.

Diagnosis of astrocytic hamartomas is usually made on the basis of the ophthalmoscopic appearance and associated findings of tuberous sclerosis. Fluorescein angiography reveals varying degrees of vascularity within and on the surface of the tumor.

There is an invariable leakage of dye from the tumor vessels late in the angiogram, which may pool within the cystic areas of the tumor. Echography is helpful for larger tumors but is of little value with smaller tumors.

Histopathologically, the tumors are composed of well- differentiated, spindle-shaped fibrous astrocytes with round or oval nuclei and abundant eosinophilic cytoplasm. Some authors have stressed the importance of the vascular component of these lesions, which may suggest a link between these typically glial

FIGURE 8-15. Retinal astrocytoma with calcifications appearing like

“tapioca.”

tumors and the retinal capillary hemangiomas seen in von Hippel–Lindau syndrome.

The calcification seen clinically has been verified histopathologically. The most common retinal finding in tuberous sclerosis is usually reported to be a flat, hypopigmented macule which appears similar to ash leaf spots on the skin, however a large British study found this punched- out lesion in only 39% of patients, compared to a flat translu- cent hamartoma in 70%. “Mulberry” lesions were found in 55%.

Mutations of the TSC1 and TSC2 genes cause tuberous sclerosis.

NEUROFIBROMATOSIS

Neurofibromatosis is a syndrome with skin, neurological, and ophthalmic manifestations and is discussed more fully elsewhere in this volume. The most common ocular features are the iris Lisch nodules (probably nevi), neurofibromas of the eyelids, large corneal nerves, and optic nerve gliomas and meningiomas.

The most frequent retinal lesion seen with neurofibro- matosis is an astrocytic hamartoma, although these occur less frequently than in patients with tuberous sclerosis. The astro- cytic hamartomas seen in both phakomatoses are identical clinically and histologically. Additional retinal findings include myelinated nerve fibers. Multifocal congenital hypertrophy of the RPE (bear tracks) probably occurs more frequently in asso- ciation with neurofibromatosis than in the general population.

Additionally combined hamartomas of the RPE and retina have been described in patients with neurofibromatosis, lending support to the idea that the combined hamartomas may be developmental in origin.

Choroidal lesions similar to iris Lisch nodules have been described. Histopathologically, these hamartomas are probably nevi. Malignant melanomas are also more common in patients with neurofibromatosis and may be related to the greater number of nevi.

Additionally, some patients have thickened long ciliary nerves (neurilemoma) or may have diffuse thicken- ing of the uveal tract (neurofibroma), which is probably caused by proliferation of neurons and Schwann cells of the ciliary nerves. Choroidal neurofibromas and neurilemomas occur more frequently in neurofibromatosis than in the general population, with the former tumor occurring in approximately 35% to 50%

of patients.

Acknowledgments. Revision of this chapter was supported in

part by the Georgia Lions Children’s Eyecare Center.

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