Several benign and malignant ocular rumors occur in childhood. Tumors in the ocular region can lead to loss of vision, loss of the eye, and, in the case of malignant neoplasms, loss of life. Therefore, it is important for the pediatrician to recognize ocular tumors and to refer such patients for further diagnostic studies and appropriate treatment.
We review some general concepts of childhood eye tumors and discuss the clinical manifestations of selected tumors of the eyelid, conjunctiva, intraocular structures, and orbit. For more detailed information, the reader is encouraged to consult the general references cited at the end of this article.1"5
CLINICAL SIGNS OF CHILDHOOD OCULAR TUMORS
The clinical characteristics of a childhood ocular tumor vary according to whether the tumor is located in the eyelids, conjunctiva, intraocular tissues, or orbit.
Eyelids and Conjunctiva
Eyelid and conjunctival tumors are generally evident, prompting an early visit to a physician. Because most tumors in the ocular area have characteristic features, an accurate diagnosis can often be made with inspection alone.
Unlike tumors of the eyelids and conjunctiva, intraocular tumors are often not apparent on external ocular examination. However, there are several features that should alert the pediatrician to an intraocular tumor and prompt a timely referral.
Leukocoria. An important sign is leukocoria, or a white papillary reflex. Although characteristic of retinoblastoma (Fig. 1), there are other causes of leukocoria, including congenital cataract, retinal detachment due to retinopathy of prematurity, persistent hyperplastic primary vitreous, and congenital retinal telangiectasia with exudation (Coats' disease).6 Retinoblastoma is the most serious cause of leukocoria in children. A child with leukocoria should be referred promptly to an ophthalmologist.
Strabismus. Most children with strabismus do not have an intraocular tumor. However, approximately 30% of patients with retinoblastoma present initially with esotropia or exotropia, due to disruption of fixation caused by the location of the tumor in the macular area. A retinal examination should be performed on every child with strabismus to exclude an underlying tumor.
Visual Impairment. An older child with an intraocular tumor may complain of visual loss or may have poor sight on visual testing in school. This is usually caused by destruction of the retina by the tumor, or by vitreous hemorrhage, hyphema, or cataract.
Figure 1. Leukocoria secondary to retinoblastoma.
Orbital Tumors. Unlike tumors of the eyelid, conjunctiva, and ocular fundus, orbital tumors cannot be directly visualized. However, they often cause proptosis or displacement of the eye, pain, diplopia, or conjunctival edema. Computed tomography (CT) and magnetic resonance imaging (MRI) have revolutionized the diagnosis and treatment of orbital tumors.
Most ocular tumors in children have characteristic clinical features and can be diagnosed by a competent ophthalmologist or ocular oncologist.
Eyelid and Conjunctival Tumors. Many eyelid and conjunctival tumors are easily diagnosed by their typical clinical features, so special diagnostic studies are often unnecessary. Smaller tumors can be diagnosed following an excisional biopsy to completely remove the mass. Incisional biopsy for diagnostic reasons should be reserved for more extensive lesions where the resulting defect cannot be easily repaired.
Intraocular Tumors. Tumors of the iris can be recognized with external ocular examination or slitlamp biomicroscopy. Tumors of the retina and choroid can be visualized with ophthalmoscopy, which often reveals typical features depending on the type of tumor. Many small tumors are difficult to visualize and may be detected only by an ophthalmologist using indirect ophthalmoscopy. Ancillary studies such as fluorescein angiography, ultrasonography, and CT or MRI can help establish the diagnosis. Fine needle aspiration biopsy has been employed for selected intraocular tumors of children.1 Orbital Tumors. Some orbital tumors occur in an anterior location and can be recognized by their extension into the conjunctiva and the eyelid area.
This is particularly true of vascular tumors such as capillary hemangioma and lymphangioma. Others reside in deeper orbital tissues and are less accessible to inspection, palpation, or biopsy. Orbital ultrasonography, CT, and MRI are vital in the diagnosis of orbital tumors of childhood.
The treatment of an ocular tumor in a child also depends on the suspected diagnosis and the location and the size of the lesion.
Eyelid and Conjunctival Tumors. True neoplasms of the eyelids and conjunctiva can be removed surgically by a qualified ophthalmologist or ocular oncologist. Inflammatory lesions that simulate neoplasia can be managed with antibiotics or corticosteroids, depending on the diagnosis. Some malignant neoplasms, such as leukemias or lymphomas, are best managed with a limited diagnostic biopsy followed by irradiation, chemotherapy, or both.
Intraocular Tumors. Certain benign intraocular tumors that are asymptomatic are usually managed by serial observation. Benign tumors mat are symptomatic can be obliterated by laser or cryotherapy. Malignant tumors, such as retinoblastoma, often require enucleation. In recent years, however, there has been a trend away from enucleation for retinoblastoma, with the increasing use of more conservative methods of management, such as laser thermotherapy, cryotherapy, and various techniques of radiotherapy.7
Orbital Tumors. The treatment of an orbital tumor varies with the clinical or histopathologic diagnosis. Benign vascular tumors such as capillary hemangioma and lymphangioma can be managed by serial observation, patching treatment for associated amblyopia, or surgical excision. Circumscribed tumors in the anterior orbit may be managed by excisional biopsy. Many malignant tumors, such as rhabdomyosarcoma and granulocytic sarcoma (leukemia), may require subtotal biopsy followed by irradiation or chemotherapy.
Figure 2. Capillary hemangioma of the eyelid and orbit showing proptosis and a cutaneous vascular lesion.
There are many pediatric cutaneous tumors that can affect the skin of the eyelids. Only the more important ones are considered here.
Capillary hemangioma or strawberry hemangioma can occur on the eyelids as a diffuse or circumscribed reddish mass (Fig. 2). The main complications of this benign tumor are strabismus and amblyopia. The best management is refraction, eyeglasses for refractive error, patching of the opposite eye, and close follow-up. Intralesional injection of corticosteroids may hasten regression of the tumor in some cases. Surgical excision or radiotherapy is necessary only in exceptional cases because these tumors usually regress spontaneously during the first years of life.
Facial Nevus Flammeus
Facial nevus flammeus is a congenital cutaneous vascular lesion that occurs in the distribution of the fifth cranial nerve (Fig. 3). It may be an isolated entity or occur with variations of the Sturge-Weber syndrome. Infants with this lesion have a higher incidence of congenital glaucoma, diffuse choroidal hemangioma, and secondary retinal detachment. These are serious ocular conditions. Affected infants should be referred to an ophthalmologist as early as possible for diagnosis and treatment. Management of the cutaneous lesion includes observation, cosmetic make-up, or laser treatment.
With the emergence of acquired immunodeficiency syndrome (AIDS) in children, opportunistic neoplasms such as Kaposi's sarcoma have been diagnosed more frequently. Although the affected patient may have cutaneous lesions elsewhere, the eyelid can be the site of initial involvement. This lesion appears as a reddish-blue subcutaneous mass near the eyelid margin. It generally responds best to chemotherapy or radiotherapy.
Figure 3. Facial nevus flammeus
Basal Cell Carcinoma
Although basal cell carcinoma occurs mainly in adults, it is occasionally seen in younger patients, particularly if there is a positive family history. It generally occurs on the lower eyelid as a slowly progressive mass and frequently develops a central ulcer. Lesions at the eyelid margin often cause loss of eyelashes in the involved area. Treatment is local excision using frozen section control and eyelid reconstruction.
A melanocytic nevus can occur on the eyelid as a variably pigmented, well-circumscribed lesion, identical to nevi that occur elsewhere on the skin. The blue nevus is often apparent at birth, whereas the junctional or compound nevus may not become clinically apparent until puberty. Transformation into malignant melanoma is rare.
A neurofibroma can occur on the eyelid as a plexiform lesion and is commonly associated with von Recklinghausen's neurofibromatosis. It often produces a characteristic S-shaped curve in the upper lid. Larger lesions thicken the eyelid and often produce a secondary blepharoptosis. Because these diffuse tumors are difficult to resect, they should be managed by periodic observation or surgical debulking if they are a major cosmetic problem.
Figure 4. Limbal dermoid.
Figure 5. Conjunctival nevus.
The conjunctival dermoid is a congenital solid mass that occurs most commonly at the corneoscleral limbus inferotemporally (Fig. 4). This round, yellow-white tumor often has fine hairs on its surface. Histopathologically, it is a choristomatous mass lined by keratinizing stratified squamous epithelium and containing dermal elements. The conjunctival dermoid is often a part of Goldenhar's syndrome, a nonhereditary condition that also includes preauricular appendages, deafness, and vertebral anomalies.3
Epibulbat Osseous Choristoma
Epibulbar osseous choristoma is a malformation of mature bone on the sclera beneath the conjunctiva. It most often occurs superotemporally as a hard, fixed mass. It can be observed if it is asymptomatic or locally excised if it is symptomatic.
A complex choristoma is composed of a variety of ectopic tissues, such as cartilage, lacrimal gland adipose tissue, and smooth muscle. It may assume a variety of clinical appearances on the conjunctiva, but is generally a diffuse, fleshy thickening of the epibulbar tissues. A complex choristoma is sometimes seen in association with the nevus sebaceous of Jadassohn as part of the organoid nevus syndrome.8
Squamous papilloma can occur on the conjunctiva of young children as either a sessile vascular lesion or a fleshy papillomatous mass. It is believed to be induced by human papillomavirus. If a conjunctival papilloma is not responsive to topical corticosteroids, surgical excision and conjunctival cryotherapy are prudent. Oral Cimetidine may also be effective.9
A conjunctival nevus is a variably pigmented, multicystic mass that occurs on the bulbar conjunctiva, usually in the interpalpebral area (Fig. 5). It usually becomes clinically apparent as the child approaches puberty and remains stable throughout life. In rare instances, a conjunctival nevus undergoes malignant transformation to malignant melanoma. Lesions observed to have enlarged are best managed by local excision and supplemental cryotherapy.
Congenital Ocular Melanocytosls
Congenital ocular melanocytosis is a diffuse, patchy epibulbar pigmentation that is situated deep to the conjunctiva in the sclera (Fig. 6). Diffuse pigmentation of the ipsilateral iris usually causes heterochromia iridum. If the pigmentation extends onto the surrounding eyelid, it is called oculodermal melanocytosis, or nevus of Ota. Patients with congenital ocular melanocytosis have a greater incidence of uveal melanoma later in life. Thus, an ophthalmologist should perform a fundus examination every 1 or 2 years.
Figure 6. Congenital ocular meianocytosis.
Figure 7. Pyogenic granuloma of the inferior fornix.
Figure 8. Diffuse Kaposi's sarcoma of the conjunctiva.
Pyogenic granuloma is a fleshy pink mass that can occur anywhere on the conjunctiva (Fig. 7). It generally develops fairly rapidly following surgical or nonsurgical trauma. Topical corticosteroids or surgical resection can be used for treatment.
Kaposi's sarcoma, described earlier under eyelid tumors, can also occur in the conjunctiva of patients with AIDS. It appears as a diffuse red mass that may be mistaken for hemorrhagic conjunctivitis (Fig. 8).
Retinoblastoma is the most common intraocular malignancy of childhood.2,4 It occurs in hereditary and nonhereditary forms. The hereditary form is usually bilateral and multifocal. The nonhereditary form is unilateral and unifocal. The affected child presents with unilateral or bilateral leukocoria (Fig. 1), strabismus, or orbital cellulitis.10 Although usually diagnosed in children younger than 2 years, retinoblastoma can appear in older children.11 The diagnosis is best made by an ophthalmologist using slit-lamp biomicroscopy and indirect ophthalmoscopy. Small fundus tumors are gray-white and often show foci of chalky-colored calcification (Fig. 9). Ancillary studies that may provide diagnostic help are ultrasonography and CT. These may depict calcification within the mass (Fig. 10).
Treatment varies depending on the number of tumors and their size and location. Advanced tumors are managed by enucleation (Fig. 11). Less advanced tumors can be treated with external beam irradiation, plaque brachytherapy, or cryotherapy.4 Recently, methods of chemoreduction, chemothermotherapy, and other adjuvant therapies1216 have replaced enucleation and irradiation in selected cases.
There have been several recent developments related to the genetics of retinoblastoma.17 The genetic defect that leads to retinoblastoma is now recognized to be the deletion of a recessive suppressor gene on chromosome 13 at the 13ql4 segment. Some affected children have other systemic features of the 13q deletion syndrome. All family members of patients with retinoblastoma should be examined by an ophthalmologist.
Retinal Capillary Hemangioma
Retinal capillary hemangioma is a reddishpink retinal mass that can occur in the peripheral fundus or adjacent to the optic disc. Prominent dilated retinal blood vessels often supply and drain the lesion (Fig. 12). Untreated lesions can cause intraretinal exudation and retinal detachment. Patients with retinal capillary hemangioma should be evaluated for von Hippel-Lindau disease, a hereditary condition characterized by cerebellar hemangioblastoma, pheochromocytoma, hypernephroma, and other visceral tumors and cysts.
Figure 9. Fundus photograph of a small calcified retinoblastoma.
Figure 1 0. Axial computed tomography scan showing intraocular calcium in retinoblastoma.
Figure 11. Gross section of an enucleated eye showing retinoblastoma. The large, white intraocular mass accounts for the leukocoria seen clinically.
Figure 12, Fundus photograph of a retinal capillary hemangioma in a patient with von Hippel-Lindau disease.
Astrocytic Hamartoma of the Retina
Astrocytic hamartoma of the retina is a yellow-white inrrarerinal lesion that can also occur in the peripheral fundus or in the optic disc region. The lesion may be homogeneous or contain glistening foci of calcification (Fig. 13). Unlike retinal capillary hemangioma, astrocytic hamartoma of the retina does not generally produce significant exudation or retinal detachment. Patients with astrocytic hamartoma of the retina should be evaluated for tuberous sclerosis, which is also characterized by intracranial astrocytoma, cardiac rhabdomyoma, renal angiomyolipoma, pleural cysts, and other tumors and cysts.
Melanocytoma of the Optic Nerve
Melanocytoma of the optic nerve is a deeply pigmented congenital tumor that overlies a portion of the optic disc (Fig. 14). Unlike uveal melanoma, which occurs predominantly in whites, melanocytoma occurs equally in ail races. It must be differentiated from malignant melanoma.
Figure 1 3. Fundus photograph of a retinal astrocytic hamartoma in a child with tuberous sclerosis.
Figure 14. Fundus photograph of a melanocytoma of the optic disc.
Figure 15. Medulloepithelioma (diktyoma) of the ciliary body.
Medulloepithelioma is an embryonal tumor that arises from the primitive medullary epithelium or the inner layer of the optic cup. It generalIy becomes apparent in the first decade of life as a fleshy or cystic mass in the ciliary body (Fig. 15). Cataract and secondary glaucoma are frequent complications. Although more than 50% are cytologically malignant, intraocular medulloepithelioma tends to be invasive only locally and distant metastasis is exceedingly rare. Treatment is local excision by iridocyclectomy. Larger or recurrent tumors generally require enucleation.
Choroidal hemangioma is a benign vascular tumor that can occur as a circumscribed lesion in adults or a diffuse tumor in children. The diffuse choroidal hemangioma is usually associated with ipsilateral facial nevus flammeus (Fig. 3) or variations of Sturge-Weber syndrome. Ipsilateral congenital glaucoma and secondary retinal detachment are frequent complications. Affected children often have amblyopia in the involved eye.
Choroidal osteoma is a benign choroidal tumor that is probably congenital in origin. Although it has been recognized in infancy, choroidal osteoma is diagnosed more often in young adulthood and is more common in females. Choroidal osteoma consists of a plaque of mature bone that is generally adjacent to the optic disc. Slow enlargement is typical, and choroidal neovascularization with subretinal hemorrhage is a frequent complication. The pathogenesis is unknown. Serum calcium and phosphorus levels are normal.
Uveal nevus is a flat or minimally elevated, variably pigmented tumor that may occur in the iris (Fig. 16) or the choroid (Fig. 17). Although it is most likely congenital, uveal nevus is usually asymptomatic and thus not usually recognized until later in life. Although most uveal nevi are stationary and nonprogressive, malignant transformation into melanoma can occur in rare instances.
Figure 16. Congenital sector nevus of the iris.
Figure 1 7. Fundus photograph of a choroidal nevus adjacent to the optic disc.
Figure 18. Multiple Lisch nodules in a patient with neurofibromatosis.
An important variant of iris nevus is the presence of bilateral, multiple, slightly elevated melanocytic lesions of the iris, known as Lisch nodules (Fig. 18). These lesions become clinically apparent at approximately 5 years of age and are often the first sign of von Recklinghausen's neurofibromatosis.
Although uveal melanoma is generally a disease of adulthood, it is occasionally diagnosed in children.1819 A variably pigmented, elevated mass that shows slow progression is the usual presentation. If not treated early, uveal melanoma has a tendency to metastasize to the liver, the lungs, and other distant sites. Most advanced tumors are treated by enucleation. Radiotherapy and local tumor resection can be employed for less advanced tumors.
Congenital Hypertrophy of the Retinal Pigment Epithelium
Congenital hypertrophy of the retinal pigment epithelium is a well-circumscribed, flat, pigmented lesion (Fig. 19) that can occur anywhere in the fundus. Depigmented lacunae within the lesion and a surrounding pale halo are common signs. It can occur as a solitary lesion or be part of congenital grouped pigmentation. It has recently been recognized that some cases of congenital hypertrophy of the retinal pigment epithelium can give rise to a nodular neoplasm of the retinal pigment epithelium.20 Similar but distinct multifocal pigmented lesions may be a marker for familial adenomatous polyposis and Gardner's syndrome in which patients have a high likelihood of having colonic cancer.
Childhood leukemias can occasionally exhibit tumor infiltration of the retina, the optic disc, and the uveal tract. This is characterized by a swollen optic disc and thickening of the retina and choroid, often with hemorrhage and secondary retinal detachment. Intraocular leukemic infiltrates generally respond to irradiation and chemotherapy, but they usually portend a poor systemic prognosis.
Figure 1 9. Fundus photograph of congenital hypertrophy of the retinal pigment epithelium.
A variety of orbital neoplasms and related space-occupying lesions can affect the orbit. Orbital cellulitis secondary to sinusitis and inflammatory pseudotumors are more common than true neoplasms. Only approximately 5% of orbital lesions on which a biopsy is performed prove to be malignant.21 Cystic lesions are the most common group, followed by vascular lesions. This section covers orbital tumors and cysts, but does not discuss orbital inflammatory or infectious conditions.
Dermoid cyst is the most common noninflammatory, space-occupying orbital mass in children. It usually appears in the first decade of life as a fairly firm, fixed, subcutaneous mass at the superotemporal orbital rim near the zygomaticofrontal suture (Fig. 2O).22 Occasionally, a dermoid cyst may occur deeper in the orbit unattached to bone. Although its size is sometimes stable, the cyst has a tendency to slowly enlarge. It can occasionally rupture, inciting an intense inflammatory reaction. Management is either serial observation or surgical removal.
Figure 20. Dermoid cyst near the lateral orbital rim.
A teratoma is a cystic mass that contains elements of all three embryonic germ layers. An orbital teratoma causes proptosis, which is generally apparent at birth. Imaging studies often help make the diagnosis. Small teratomas can be removed intact without destroying the eye, but larger ones have caused blindness and thus may require orbital exenteration.
Capillary hemangioma is the most common orbital vascular tumor of childhood. It usually is clinically apparent at birth or within the first few weeks after birth. Capillary hemangioma tends to cause progressive proptosis during the first few months of life (Fig. 2) and then becomes stable and slowly regresses. Orbital imaging studies show a diffuse, poorly circumscribed orbital mass that is enhanced with contrast material. The best management is corrective refraction and treatment of any induced amblyopia with patching of the opposite eye. Local injection of corticosteroids or oral corticosteroids can hasten regression and minimize the complications.
Lymphangioma is the second most common vascular tumor of the orbit in children. It tends to become clinically apparent during the first decade of life. Abrupt proptosis may follow orbital trauma, secondary to hemorrhage into the lymphatic channels within the lesion. Such spontaneous hemorrhages, called "chocolate cysts," may require aspiration or surgical evacuation to prevent visual loss from compression of the eye.
Figure 21 . Juvenile pilocytic astrocytoma of the optic nerve. (A) Clinical appearance showing proptosis of the left eye. (B) Appearance on computed tomography.
Juvenile Pilocytic Astrocytoma
Juvenile pilocytic astrocytoma (optic nerve glioma) is the most common orbital neural tumor of childhood. It is a cytologic benign hamartoma that is generally stationary or very slowly progressive. The affected child has ipsilateral visual loss and slowly progressive axial proptosis (Fig. 21). Orbital imaging shows an elongated or oval mass that is well circumscribed because of the overlying dura mater. Patients with neurofibromatosis have an increased frequency of this tumor. Because surgical excision necessitates blindness, the best management is periodic observation and surgical removal if there is blindness and cosmetically unacceptable proptosis. Radiotherapy may be necessary for cases that extend to the optic chiasm and are surgically unresectable.
Rhabdomyosarcoma is the most important primary orbital malignant tumor of childhood.1-5 It usually occurs during the first decade of life, with a mean age of 8 years at diagnosis. Unlike retinoblastoma, it is not hereditary. Fairly rapid proptosis and displacement of the globe, usually without pain or major inflammatory signs, are characteristic (Fig. 22). Imaging studies show an irregular but fairly well-circumscribed mass, usually in the extraconal anterior orbit. Orbital exenteration was often employed in the past. However, more recent experience suggests that the best outcome is obtained by performing a generous biopsy to confirm the diagnosis and treating with combined irradiation and chemotherapy using vincristine, cyclophosphamide, and doxorubicin hydrochloride.
Granulocytic Sarcoma (Chloroma)
Granulocytic sarcoma is infiltration of soft tissue by myelogenous leukemia. Although leukemia usually appears first in the blood and the bone marrow, it may first become clinically apparent in the orbital soft tissues. The child presents with the fairly rapid onset of proptosis. Confirmation of the orbital lesion can be made by biopsy. Treatment is chemotherapy or low-dose irradiation.
The only important lymphoma to affect the orbit of children is Burkitt's lymphoma. Although this tumor was originally identified exclusively in African tribes, it is being seen more often in patients with AIDS.
Langerhans' Cell Histiocytosis
Eosinophilic granuloma can affect the orbital bones as an intraosseous bone-destructive inflammatory lesion. Although Langerhans' cell histiocytosis can occur anywhere in the orbit, the most common site is the anterior portion of the frontal and zygomatic bones. Recent ultrastructural studies have suggested that the stem cell of eosinophilic granuloma and certain other tumors in the histiocytic X group is the Langerhans' cell. Hence, the term Langerhans' cell histiocytosis is becoming preferable.
Figure 22. Orbital rhabdomyosarcoma. (A) Clinical appearance showing proptosis and downward displacement of the right eye. (B) Appearance on computed tomography showing a mass in the superomedial orbit.
Although orbital metastasis can occur secondary to Wilms' and Ewing's tumors in children, neuroblastoma is the most common metastatic orbital tumor of childhood. Most children with such orbital metastases have had a primary neoplasm in the adrenal gland diagnosed previously. However, the orbital metastasis can be diagnosed before the adrenal primary metastasis in approximately 3% of cases.
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