Ординатура / Офтальмология / Английские материалы / Handbook of Pediatric Retinal Disease_Wright, Spiegel, Thompson_2006

would be “primary systemic chemotherapy followed by local consolidation.”

During the slightly more than one decade that primary systemic chemotherapy has been employed as the preferred treatment for intraocular retinoblastoma, there is an increasing body of evidence that supports care of these patients is best delivered in ocular oncology centers. There is no such animal as a “simple enucleation for retinoblastoma.” Harvesting of fresh tumor is an essential part of the management of unilateral retinoblastoma under 2 years of age. Genetic counseling can only be done adequately if tumor DNA and peripheral white cell DNA are available for comparison. Once the eye with retinoblastoma is in formalin, the ability to carry out adequate genetic counseling has probably been lost.

Ideally, ophthalmologists with oncology training should be treating retinoblastoma. Because it is a rare tumor, even most pediatric oncologists do not have much experience treating this tumor. They know the drugscarboplatin,— etoposide, and vincristinebut— require close collaboration with an experienced ocular oncologist for treatment planning.

Because the pediatric ophthalmologist may be aware that chemotherapy is being used in the treatment of this tumor, lack of experience by both ophthalmologist and oncologist can lead to grossly inappropriate therapy. For example, there is rarely, if ever, an indication to treat advanced unilateral retinoblastoma with systemic chemotherapy for the intraocular disease. Parents with a child newly diagnosed with retinoblastoma will have searched the Internet. They are aware of the chemotherapy option and often push for attempts to salvage the eye through the use of systemic chemotherapy. This approach is, in most cases, not advised.

Another not uncommon mistake made by pediatric ophthalmologists during surveillance exam under anesthesia (EUAs) on the fellow normal eye following enucleation of unilateral retinoblastoma is to treat a small peripheral white dot in the retina because of the possibility that it could be retinoblastoma. Small white dots are relatively common as part of the “bay complex.” If they are treated before there is clear definite evidence of growth, the child will forever be labeled as having bilateral retinoblastoma. The consequences of that label are so devastating and far-reaching that an experienced ocular oncologist would make absolutely certain that the child did have an expanding mass before instituting treatment. The confidence to

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know that a 3-week delay in treating a lesion of this size would not have an adverse effect on the ability to control the tumor is essential to avoid the impulse to treat immediately.

The Children’s Oncology Group (COG) has formed a Retinoblastoma Steering Committee to generate clinical trials in retinoblastoma. Questions under development at this time concern whether etoposide can be eliminated in the systemic regimen for the treatment of intraocular retinoblastoma that has not developed vitreous or subretinal seeding. At least four known cases of leukemia were induced by this drug when large doses were used to treat unilateral retinoblastoma. The value of local, sub-Tenon carboplatin as an adjunct to systemic chemotherapy in eyes with vitreous and/or subretinal seeding will also be evaluated. Finally, the role that intensity-modulated radiotherapy (IMRT), a technique that allows the radiotherapist to spread the entry dose over multiple sites, giving tighter isodose curves, will also be evaluated for efficacy as consolidation treatment in a protocol for bilateral advanced disease.

Once the COG protocols are in place pediatric ophthalmologists with an interest in retinoblastoma will be able to make application to COG as treating ophthalmologists on COGapproved protocols at their institutions. An ongoing part of such protocols will be Internet review of RetCam images for appropriateness of protocol entry and local treatment.

Consideration of a cyclosporine trial by the American College of Surgeons Oncology Group has been discontinued. A decision has been made by that group that any chemotherapybased therapy would more appropriately be managed through the COG Intergroup mechanism. The data that high doses of cyclosporine significantly add to the efficacy of systemic chemotherapy by the proposed mechanism of blocking multiple drug resistance (p-glycoprotein) are awaiting confirmation.

UVEAL MELANOMA

Uveal melanoma is rare, but can occur, in children. The youngest reported case is an Australian infant who underwent enucleation at 5 days of age for a choroidal melanoma.18 Only 1% of choroidal melanoma patients are less than 20 years of age and the majority of these patients are in their late teens.3,4,34,66 An 11-year experience at the Wills Eye Institute was reported in 1975.34 Among 378 patients with uveal melanoma, only 5 were

less than 20 years of age. More recently, the Wills experience has been rereported. Of 3706 consecutive patients with intraocular melanoma, only 40 were patients less than 20 years of age.57 Barr et al. reviewed uveal melanomas at the AFIP registry.4 Of 6358 patients with the disease, 101 were less than 20 years of age. Choroidal melanoma in a child has been reported in association with dysplastic nevus syndrome.26 In a few older teenagers and one 5-year-old child, choroidal mela-noma has been associated with ocular melanocytosis.49,65 Although diffuse uveal melanomas comprise 4.5% to 5.0% of melanomas reported in adults, only one diffuse tumor has been reported in patients under 20 years of age, and this was in a 5-year-old child.50

The prevalence of uveal melanoma among male and female children appears to be equal in most series. Caucasian patients predominate, but there are at least four cases reported with choroidal and/or ciliary body melanomas in young black patients.23 In the AFIP series of uveal melanoma, 78 of the 101 cases found in patients less than 20 years of age met the criteria of adequate historical information and at least 5 years followup.4 Of these, 42 cases were of choroidal or ciliary body origin. Of the remaining tumors, 27 involved the iris and 9 additional iris lesions were reclassified as nevi. The relative incidence of iris melanomas in this series of young patients is higher than that generally reported for adults. In the recent Wills series of young patients, 12% of intraocular melanomas occurred exclusively in the iris.57

Presenting signs and symptoms of choroidal melanoma in children and adolescents are variable. Five of 42 patients in Barr’s series came to ophthalmologic attention because of antecedent trauma.4 Retinal reattachment or glaucoma surgery was performed in 6 of 42 patients before the correct diagnosis was made. A review of case reports of 6 children under age 6 years revealed that 3 presented with red eyes,12,26,46 1 with strabismus,55 1 with blurred vision,23 and 1 with ocular enlargement.18 Frequently, young patients have retinal detachment at the time of diagnosis.

The differential diagnosis of pigmented intraocular tumors in children includes choroidal nevus, melanocytoma, pigmented neurofibroma, juvenile xanthogranuloma (JXG), and RPE hamartoma. A diffuse choroidal melanocytoma mimicking a diffuse choroidal melanoma has been reported,20 but both lesions are extremely rare in young patients. Patients with melanocytomas are usually over age 30. Moreover, these tumors usually arise

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adjacent to the optic disc. Intraocular neurofibromas may involve the iris and ciliary body and may be pigmented. Occasionally, a diktyoma is pigmented, but this is rarely confused with melanoma.

The diagnosis of uveal melanoma is made in the same manner as in adults. However, in children, retinal detachment and an inadequate view of the tumor may be more common.4 Ultrasound is essential. Choroidal melanoma is rarely calcified on CT scan although eyes with long-standing disorganization may develop calcification. An index of suspicion regarding intraocular masses should be maintained as these tumors do occur in young people.

Malignant melanomas in children were once thought to have a more benign course than their adult counterparts. However, the review of Barr et al. demonstrated that the mortality at 5 years is similar to the adult population.4 Of the 42 patients with choroidal or ciliary body tumors, 13 died of metastatic disease. Features that correlated with a poor outcome were a red painful eye at presentation, extraocular extension, basal tumor diameter greater than 10 mm, increased mitotic activity, and tumor necrosis. Their follow-up ranged from a minimum of 5 to a maximum of 47 years. In the recent Wills series, 23 cases of choroidal tumors had a basal diameter greater than 10 mm, and 1 patient had extraocular extension. Of the 27 patients with malignant iris tumors, 4 succumbed to metastatic disease. Fatal outcome in this group correlated with glaucoma, tumor invasion of the ciliary body and angle and scleral invasion, diffuse growth, and increased mitotic activity.

Uveal melanoma in children and adolescents, albeit rare, may be similar in behavior to the disease in adults.3,4,34 However, children rarely complain of visual loss and, as a result, choroidal tumors may present at a more advanced stage. Treatment plans frequently include enucleation if the disease is advanced and the eye is blind. Modern diagnostic methods may permit earlier diagnosis and intervention with fewer diagnostic errors. Patient care in referral centers may also significantly improve survival rates. The COMS study, a 15-year multicenter trial comparing enucleation with Iodine 125 brachytherapy for medium choroidal melanomas in adults, found no difference in survival (approximately 80%) between the two groups.9a Pre-radiation of large melanomas before enucleation did not enhance survival.9b After plaque brachytherapy, 68% have poor acuity in one tenyear followup study.59a

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FIGURE 9-15. Enucleated eye showing medulloepithelioma filling the eye. (Courtesy of Dr. K.W. Wright, Los Angeles, CA)

Medulloepitheliomas usually appear as a grayish-white mass, often cystic, which arises from the iris or ciliary body. The tumor can be solid, fleshy pink, and occasionally pigmented (Fig. 9-15). In several case reports, the tumor consisted of almost flat, nondescript sheets over the iris. Thus, the differential may include JXG, iris melanoma, and leiomyoma. In the Broughton and Zimmerman series of 56 patients at the AFIP, 9 patients had undergone enucleation for blind and/or painful eyes.6 In these 9 cases, the existence of intraocular tumor was not suspected preoperatively. In only 7 of these 56 cases was the diagnosis of medulloepithelioma made correctly preoperatively.

Rarely, these tumors can arise from the optic nerve and retina and simulate retinoblastoma.22 In one case, the tumor involved the retrobulbar portion of the optic nerve and mimicked an optic nerve glioma.17 A case report exists of an infant presenting with a medulloepithelioma that mimicked PHPV.58 The presenting signs were leukocoria, a shallow anterior chamber, mild cataract, and retrolental fibrovascular tissue.

Delay of diagnosis of as much as 1 year from the onset of signs and symptoms is common.6 CT and ultrasound may or may not be helpful. Frequently, the tumor is very anterior and may not have much mass effect. The diagnosis should be suspected in any blind or distorted eye in a child. Several case

reports had an anecdotal history of trauma as a “red herring.” The diagnosis should be considered particularly with ciliary body and iris lesions. In several cases, an anterior chamber (AC) tap has led to the correct diagnosis.44 However, it is often contraindicated to enter the eye of a child with a needle, especially if the eye may harbor an active retinoblastoma.

Enucleation has been the preferred method of treatment in the majority of cases. In a few cases, iridocyclectomy has been curative.6,8 In one report, however, a patient developed two recurrences following local excision that looked increasingly malignant histopathologically. Highly malignant histopathological features developed, and the eye was subsequently enucleated.29

The survival rate from this tumor is excellent. It is slow growing and only locally invasive. In the series of Canning et al., all 15 patients who were included survived.8 From the AFIP series, 4 of 56 patients died of metastatic disease. The most important prognostic factor identified in their series was the presence of extraocular extension. All 4 tumor deaths were preceded by orbital spread.

LEUKEMIA

Leukemia is classified as acute or chronic, and in children acute leukemia predominates. The cell type most common among the acute leukemias in childhood is lymphoblastic (ALL). All ocular structures may be affected by the leukemia in these children.28 Ocular tissue may be involved by direct infiltration of leukemic cells, hemorrhage, or infection.

In a series of 117 consecutive patients with acute leukemia reported by Guyer et al., 44 of the patients were pediatric.19 Among the children in this series, 16 had some form of leukemic retinopathy at the time of diagnosis. Several authors have noted a much higher incidence of ocular involvement if the entire course of the disease is considered.48

Clinically, the retina is most commonly involved in leukemia, whereas histopathologically the choroid is most frequently infiltrated.28 Leukemic retinopathy is more common in acute leukemia and is more common at diagnosis in adults than in children.19 The retinopathy may be characterized by tortuous dilated veins, vascular sheathing, cotton wool spots, and exudates. Retinal hemorrhage is the most common feature of the retinopathy and usually occurs in the posterior pole. The hem-

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orrhages may be white centered. In children, cotton wool spots are rare.19,28,51 Guyer et al.19 found an association between the presence of intraretinal hemorrhages and thrombocytopenia, as well as relatively lower hematocrit levels.

Leukemia may also manifest in the eye as conjunctival thickening, perilimbal infiltrate, ring corneal ulcers, hypopyon, iris infiltrate, nodular retinal infiltrate, vitreous invasion, optic nerve or peripheral neovascularization, exudative retinal detachment, RPE detachment, microaneurysms, and preor postlaminar optic nerve involvement.1,10,24,52,54,61,67

Ocular involvement is rarely the presenting sign of the underlying disease, but with longer-term survival, ocular disease is being reported in association with or following CNS relapse.7 There are increasing numbers of case reports of ocular disease (hypopyon, iris infiltration, choroidal relapse, optic nerve leukemia) as isolated sites of extramedullary relapse in patients who are in remission and who have not had any antecedent or concurrent evidence of CNS or hematological relapse.1,7,43,56

Opportunistic infections are common in the immunocompromised host. Rarely, a leukemic retinal or choroidal infiltrate or leukemic hypopyon may be difficult to distinguish from infectious processes. In certain cases, an anterior chamber tap, posterior chamber aspirate, or biopsy of the choroid and retina may be necessary to distinguish direct leukemic infiltrate from an infectious process.56,64

There are many clinical ocular signs of the disease, but a significant number do not require treatment. The signs are often noted by the oncologist and not referred to the ophthalmologist. A red eye associated with pain can be an indication of opportunistic infection or direct conjunctival or anterior chamber infiltrate by leukemia. An infiltrative conjunctival process, a leukemic hypopyon, or preor postlaminar optic nerve disease can certainly result in visual loss. In the case of conjunctival, anterior chamber, or iris involvement, after cytological diagnosis external beam radiation has been very effective in eliminating the infiltrative process (400–2000 cGy over 2 weeks).28 A mild anterior chamber reaction in a leukemic patient may represent active ocular leukemia. There are case reports of this type of active disease responding temporarily to topical steroids when treated as a “uveitis.”1

Prelaminar optic nerve infiltrations are most common in children with ALL and must be distinguished from papilledema secondary to CNS relapse.51 Postlaminar nerve invasion more

frequently results in significant visual loss and also may have concurrent disc edema.

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