Ординатура / Офтальмология / Английские материалы / Tumors of the Eye and Ocular Adnexa_Char_2001

240 TUMORS OF THE EYE AND OCULAR ADNEXA

loss by age 50 years at 35 percent. As would be expected, angiomas were rare in the posterior retina and more common in the supratemporal retina or on the optic disc.22

Our understanding of the molecular genetics of this syndrome continues to evolve. The gene for this disease is on chromosome 3 and seems to function as a tumor suppressor. Using a positional cloning strategy, it was located at 3p25-26.23–27 As we have noted in uveal melanoma, newer methods have shown several other genomic alterations in this condition.26,27 A study of 93 families all showed germline mutations.28 A compilation of the VHL mutations is available on the internet at www.ncicrf. gov/kidney. This tumor suppressor gene appears to negatively regulate the transcription of elongin.29,30 Studies of six intraocular angioma tissues demonstrated loss of heterozygosity of the gene in the vacuolated stromal cells but not the vascular or reactive endothelial cells. In addition, vascular endothelial growth factor was also found in these cells.31 Southern blot analysis, single stranded conformation and polymorphism (SSCP) analysis, and direct sequencing may be used to detect VHL gene mutations. The molecular genetic testing for VHL continues to evolve.32 Flourescent in situ hybridization (FISH) seems to be a reliable and relatively simple way of testing for deletion of the gene; however, potential complications with a pseudogene located on chromosome 1 may influence the results.33 FISH is used to delect deletions but does not detect VHL mutations, which are more common.

While for some other VHL lesions, either missense (pheochromocytoma) or nonsense correlations are correlative with systemic bondings, no specific type of genetic changes have correlated with the occular phenotypic expression or severity of eye findings.15,17,22 A cursory review of the molecular biology of VHL disease has recently been published.34

The clinical appearance of a retinal angioma, especially in endophytic tumors which protrude from the inner retina into the vitreous, is usually diagnostic.35 As shown in Figure 11–1A, endophytic lesions are usually pinkish, with an obvious arterial feeder vessel. Bilateral involvement is common in both isolated retinal angiomas and VHL syndrome. Usually, there are multiple lesions, often of different sizes. On

fluorescein angiography, there is rapid perfusion through the feeder vessels, with rapid filling and staining of the hemangioblastoma (Figure 11–2).36 Less commonly, an exophytic process presents as a pale gray lesion, without an obvious feeder vessel; the fluorescein angiogram identifies the lesion. Rarely, the VHL lesion can mimic a diabetic microaneurysm. A less common presentation includes an exudative detachment and a large pinkish red hemangioblastoma on the optic disc (Figure 11–3).37,38

Juxtapapillary exophytic capillary hemangiomas may be isolated or may be part of the VHL syndrome. As discussed below, results of treatment for peripapillary hemangioblastomas have been poor.5

Fluorescein angioscopy or angiography can detect lesions before they become clinically appar-

A

B

Figure 11–1. A, Endophytic von Hippel retinal angioma. B, Peripheral angioma with feeder vessels.

ent. Other retinal vascular malformations or tumors usually do not have obvious feeder vessels, although they occur occasionally in retinoblastomas and less commonly in melanomas. Figure 11–4 shows an apparent feeder vessel in a child initially misdiagnosed as having a possible retinal angioma that was histologically found to be a retinoblastoma.

Magnetic resonance imaging (MRI) with gadolinium has been shown to be more sensitive than computed tomography (CT) for detecting VHL lesions of the CNS.39,40 These and body scans should be obtained in any patient with a retinal angioma.41 MRI of the brain should be performed to establish whether or not there are CNS hemangioblastomas (Figures 11–5A and B); while these tumors are most common in the cerebellum, they can occur in the medulla, other areas of the brainstem, cerebrum, optic chiasm, optic nerve, or spinal cord.3,4,40,42,43 Abdominal MRI or ultrasonography should be performed to determine if there are angiomas, malignancies, or cysts (Figure 11–6).41,44,45

The choice of ocular therapy is dependent on the size and location of the retinal angioma and the presence or absence of overlying fibrosis and hemorrhage. Many small lesions (< 1.5 mm in diameter with minimal elevation) can be monitored and show little growth on serial evaluation.14,21 Lesions < 4.5 mm in diameter and 1.0 mm in elevation can usually be treated with argon laser or xenon arc photocoagulation; however, especially with thicker

lesions, adjunctive cryotherapy, using a double freeze-thaw technique, often is necessary. Usually, both the tumor and the vessels supplying the mass regress after successful therapy. Figures 11–7A to C show marked regression of the vessel caliber prior to obvious change of the peripheral tumor mass. Treatment complications are most common in lesions with an extensive overlying vitreous and fibrous reaction; the possibility of macular pucker and either exudative or rhegmatogenous detachment in these cases is significant.51,52 Small

Figure 11–4. Retinoblastoma simulating von Hippel lesion with enlarged “feeder vessels.”

lesions without these associated findings generally do well; large lesions, especially on the disc, have a poor visual prognosis. More recently, the use of indirect ophthalmoscopic lasers or dye yellow lasers have been used successfully for lesions < 4 mm in diameter.53 Vascular tumors on the disc are probably optimally managed with either a single high-dose fraction of Gamma-Knife irradiation (Figure 11–8) or approximately 20 Gy of proton radiation.54

Diathermy or eye wall resections have been used to treat very large tumors. In the author’s limited experience, it has been found that creating a partialthickness scleral flap decreases complications when diathermy is used.

New retinal angiomas can occur in the VHL syndrome. Consequently, patients require serial evaluations throughout life. Mortality in this syndrome is usually due to CNS or visceral malignancies. The use of radiosurgery for CNS hemangioblastomas has had excellent results. In one small study, 10 to 15 gray (Gy) resulted in excellent control in most patients without cysts.55 In another study of 29 tumors in 13 patients, only 3 progressed.56

MISCELLANEOUS RETINAL

VASCULAR LESIONS

Acquired retinal vascular abnormalities can simulate an isolated VHL lesion; however, they almost

Figure 11–6. Abdominal ultrasound demonstrating renal carcinoma in a patient with von Hippel-Lindau syndrome.

B

C

Figure 11–7. A, An equator-plus photograph of a large peripheral tumor in a case of von Hippel-Lindau syndrome. B, A 30° photograph shows expanded vessels. C, Two months after treatment, the tumor remains stationary in size, but vessels are markedly attenuated.

that arose in an area of intermediate uveitis after many years of inflammation. Figure 11–10 shows a spontaneous acquired hemangioma. Most of these tumefactions occur in the inferior temporal periphery. Shields and colleagues described 12 cases; usually, the lesions were peripheral and had an associated exudate and an intraretinal hemorrhage.57,58 Over 100 such cases have been described, occurring either as primary idiopathic vascular lesions or as complications of intermediate uveitis or retinitis pigmentosa.59 In a few cases, multiple or bilateral lesions were noted. The etiology remains obscure, although probably angiogenic cytokines are important in their pathophysiology.60

If these lesions remain stable, they do not require treatment.61 If the tumors progress or produce an exudative detachment, cryotherapy, or, if that fails, diathermy through a scleral flap is usually effective. The lesion shown in Figure 11–10A became symptomatic with exudative changes in the fovea, and vision decreased to 20/200. After double freezethaw cryotherapy, the lesion slowly regressed, with restoration of vision over a 6-week period to 20/20 (Figure 11–10B).

Retinal cavernous hemangiomas are unusual retinal vascular malformations that occur alone or in association with other CNS and systemic processes.62–64 Clinically, these lesions usually appear as multiple

244 TUMORS OF THE EYE AND OCULAR ADNEXA

sacculated aneurysms along the course of a retinal venule (Figure 11–11). Rarely, they can involve only the optic disc.65 These tumors do not grow and are not associated with subretinal fluid. As shown in Fig-

A

B

C

Figure 11–9. A, Acquired hemangiomas in patients with longstanding intermediate uveitis. Close up of pinkish lesion in area of scarring. B, Equator plus photograph of another small peripheral angioma. C, Quantitative echography demonstrated pattern similar to choroidal hemangioma.

ure 11–11, they occasionally demonstrate fibrotic changes overlying their surface and have been characterized as grape-like clusters with minimal elevation. In Figure 11–12, the angiogram shows the typical pattern with layering out of red cells due to the very slow perfusion through this area.

Most patients with retinal cavernous hemangiomas do not require ocular therapy. Approximately one-third of the patients have evidence of CNS vascular pathology. Approximately 55 cases have been reported, and those which were familial had an autosomal-dominant inheritance, with high penetrance.64,66

Racemose hemangioma, a subgroup that is part of the Wyburn-Mason syndrome, has a classic clinical appearance (Figure 11–13); these lesions can be associated with CNS disease but do not clinically simulate the appearance of retinal neoplasms.67–69

A

B

Figure 11–10. A, Acquired idiopathic hemangioma. B, Lesion shown in Figure 11–10A after cryotherapy.

Figure 11–11. Retinal cavernous hemangioma. These tumors have low flow and usually simulate a series of “grape like” microaneurysms along the course of a vein.

MISCELLANEOUS RETINAL LESIONS

Astrocytic hamartoma of the retina can occur as an isolated finding or as a part of tuberous sclerosis or neurofibromatosis.70-73 These lesions enlarge over time, without evidence of calcification, until late childhood.74 In one study, with an average follow-up of > 16 years, few of these lesions progressed.75 Figures 11–14A to C show a 3-month-old patient referred for a retinoblastoma, with several noncalcified astrocytic hamartomas. Fluorescein angiographic findings often demonstrate multiple vessels.

The youngest patient diagnosed with a retinal hamartoma in this syndrome was 7 days old.76 If a child has tuberous sclerosis, other systemic findings may include adenoma sebaceum, shagreen patches most often found in the lumbar area, cutaneous ashleaf lesions easily visible under Wood’s light, subunguial fibromas, and cardiac rhabdomyomas.77 Most patients with tuberous sclerosis are mentally retarded. The retinal mulberry pattern is very uncommon in young patients; calcification is not present until the child is at least 8 years old. Occasionally, a hypopigmented iris spot is also an early sign of tuberous sclerosis.78 A tuberous sclerosis fundus lesion in an older child is shown in Figures 11–15A and B. As discussed under retinoblastoma in Chapter 12, this calcification does not occur in the age group in which retinoblastoma is most prevalent. Occasionally, these retinal astrocytic hamartomas can be hard to diagnose. There is a case report of a fine-needle aspiration biopsy (FNAB) that showed benign spindle and stellate cells.79 Rarely, these tumefactions can grow to quite a large size and, less commonly, can appear in an otherwise normal adult.80,81

Massive gliosis of the retina is another condition which very rarely can mimic an intraocular neoplasm; in 72 cases reported from the Armed Forces Institute of Pathology, only 4 were thought to have a possible intraocular tumor. While calcification occurs as part of this syndrome, it is a late development.82

Figure 11–14. A, Three-month-old child with nine calcified astrocytic hamartomas. B, Tuberous sclerosis evident on axial MRI of brain. C, Skin lesion in 3-month-old, consistent with tuberous sclerosis.

Figure 11–15. A, Tuberous sclerosis in an older child. Calcification of these lesions is very unusual < 8 years. B, Ash-leaf sign is typical in this disease.

included in his description would encompass Leder’s miliary aneurysms, Reese’s telangiectasia, VHL disease, racemose aneurysms, and other malformations. Currently, most ophthalmologists restrict the diagnosis of Coats’ disease to those entities that have retinal vascular abnormalities with telangiectasia and exudation. Exudation from the vascular abnormalities produces a yellowish tumefaction which can simulate a neoplasm. Over 95 percent of cases are unilateral, and there is a strong male predominance; in one series, 25 of 28 patients were male. Coats’ syndrome is not hereditary.85

Two variants of Coats’ syndrome can simulate a tumor. In children under 3 years old, Coats’ syndrome can mimic an exophytic retinoblastoma; in teenage or older patients, the exudation associated with Coats’ syndrome can be confused with a metastatic uveal tumor or an amelanotic melanoma.86

In very young children, Coats’ syndrome usually presents as a total retinal detachment. The subretinal exudate is yellowish in color (Figure 11–16), in contrast to the white or pinkish color observed with retinoblastoma. Examination with scleral depression often reveals telangiectatic changes in the peripheral retina (see Figure 11–16). As discussed in more detail under retinoblastoma, high-resolution thin-section CT evaluation of Coats’ syndrome in a child under the age of 4 years never demonstrates intraocular calcifi-

Figure 11–16. Total detachment in Coats’ disease. Note the yellowish color of the subretinal exudate and the peripheral retinal telangiectasia.

cation.87 In contrast, intraocular calcification is almost uniformly present in retinoblastoma > 5 mm thick.88 Proton magnetic resonance spectroscopy (MRS) can also be used to differentiate Coats’ syndrome from retinoblastoma. There is hyperintensity on both T1- and T2-weighted images on MRS scans of Coats’ disease. In contrast, in retinoblastoma, they are often hyperintense on T1-weighted scans but hypointense on T2-weighted scans.89

There is great variation in the presentation patterns and clinical course of Coats’ syndrome. The majority of patients at presentation are either < 4 years or > 10 years old.87 Most untreated young children develop retinal detachment; Morales reported this complication in 17 of 22 cases.90 In addition, glaucoma occurred in some. Generally, patients < 3 years old had more complications, and the eyes of many of these patients were eventually removed.85,90,91

The choice of treatment in Coats’ syndrome depends on ocular status and patient age at diagnosis. We and others have used drainage and cryotherapy to treat total detachments, usually in patients < 3 years of age.91 Microscopic analysis of the subretinal fluid demonstrates lipid-laden macrophages (Figure 11–17). After subretinal fluid drainage, the peripheral retinal telangiectatic areas are treated with double freeze-thaw cryotherapy. Although there is basically no chance of retaining vision in these eyes, the retina remains attached after treatment, and cosmesis is better than if the eye were removed and a prosthesis implanted. In a recent publication, we noted that while we were able to achieve long-term (> 10 years) reattachment in 9 of 10 eyes with Coats’ syndrome presenting with possible retinoblastoma, the visual results were dismal.92

In older patients, the first symptom in Coats’ syndrome is usually decreased vision or visual distortion due to macular exudation with peripheral telangiectasia.93 These cases are managed with photocoagulation or cryotherapy of the peripheral retinal telangiectasia. In our experience, either ablative modality gives equally good results. The resorption of subretinal exudate is very slow, usually taking between 3 and 12 months following successful treatment. Rarely, after adequate treatment, new retinal telangiectases develop or become apparent in other areas of the peripheral fundus. Despite the rarity of

recurrence, frequent examinations are necessary, and we have observed disease reactivation as late as 5 years after successful treatment. As discussed elsewhere, isolated adult Coats’ syndrome in the macular area occurs but usually does not enter into the differential diagnosis of ocular oncologic problems. Occasionally, Coats’ syndrome occurs along with

Figure 11–18. Combined retinal-RPE hamartoma in a typical peripapillary location, showing surface contracture and minimum pigmentation.

other conditions, including retinitis pigmentosa or various systemic syndromes.93

RETINAL PIGMENTARY LESIONS

Retinal Pigmentary Hamartomas

Combined retinal-RPE hamartomas are quite rare. These lesions have a slight elevation with minimum pigmentation and show contraction of the retinal surface (see Figure 11–18).94 Their appearance thus produces a pattern consistent with a vascular retinopathy, and they usually do not simulate a neoplasm. Two recent cases of idiopathic reactive hyperplasias of the RPE have shown histologic features that simulate this combined hamartoma, and those authors speculated that this entity may be a reactive not a hamartomatous process.95

RPE hypertrophies and hyperplasias are discussed in Chapter 6. They usually are flat and jetblack; the former have rounded or scalloped margins, while the latter have irregular borders. Retinal pigment adenomas are also discussed in Chapter 6. Usually, there is a feeder vessel leading to the lesion as shown in Figures 6–16 and 6–17. Occasionally, RPE adenomas can be mistaken for a uveal melanoma.96

Figure 11–19. Cutaneous melanoma metastatic to the retina.

METASTATIC AND

PARANEOPLASTIC SYNDROMES

Approximately 40 cases of metastases to the retina have been reported; about one-half are from cutaneous melanomas and the others from a variety of metastatic carcinomas.97 The melanomas metastatic to the retina do not simulate a primary uveal melanoma. A case of a cutaneous melanoma metastatic to the retina is shown in Figure 11–19.

Several different carcinomas and melanomas have been shown to produce an autoimmune paraneoplastic syndrome with reactivity toward photoreceptors, other retinal cells, or the optic nerve.98–101 Usually, these patients have a history of malignancy and present with marked deterioration of their vision. In carcinomas, several antigens and antibodies have been described. The first antigen described in this syndrome was a 23-kDa retinal protein, labeled a cancer-associated retinopathy (CAR) antigen; many of these patients produce antibodies to this protein.101–103

Antibodies against recoverin, enolase, and other retinal proteins have also been described.101–104 The recoverin protein is involved in the activation and regulation of guanylate cyclase that helps to regulate rhodopsin.105,106 A rare presentation of paraneoplastic syndrome occurs along with retinal vasculitis.107 The patients with cutaneous melanoma may rarely develop night blindness.108 Twelve patients with what has been termed melanoma-associated

retinopathy have been described with diminished electroretinograms.109

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