Ординатура / Офтальмология / Английские материалы / Retinal Vascular Disease_Joussen, Gardner, Kirchhof_2007

References

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Core Messages

Vascular tumors of the retina are rare, benign lesions that may be associated with systemic disease, or may be an isolated finding

Although decreases in visual acuity may be associated with certain types of lesions, initial observation is usually advocated

It is important to distinguish these benign pro-

cesses from malignant tumors such as melanoma and metastatic tumors

Characteristic fluorescein angiographic or echographic findings may be useful in securing the diagnosis

Treatment may consist of laser photocoagulation, cryotherapy, radiotherapy, vitrectomy, or a combination of these

28.1.1 Cavernous Hemangioma

Essentials

Benign, unilateral, congenital

Cluster of slow-filling, vascular globules Vascular channels have normal walls and non-fenestrated endothelium and do not leak

These congenital, non-progressive lesions are benign, and often solitary and unilateral. Patients are usually asymptomatic, although some may experience decreased vision and neurologic symptoms, such as seizures and cranial nerve palsies [15, 87]. Cutaneous or cerebral hemangiomas may also be found, especially in cases of inherited lesions [2, 4, 15, 22, 23, 58]. Pedigree analysis suggests that this neurooculocutaneous syndrome may be inherited in an autosomal dominant pattern, with incomplete penetrance or variable expressivity [23, 58].

Ophthalmoscopy reveals a cluster of saccular aneurysms filled with venous blood one to two disk diameters in size, found in the mid-peripheral or peripheral retina. Occasional cases of posterior pole or peripapillary lesions have been reported [30, 42, 50, 60] (Fig. 28.1.1a). Overlying retinal hemorrhage or grayish-white preretinal membrane may be seen. No feeder vessels are present. The vascular globules have normal vascular permeability, and only rarely

lead to hard exudation. Fluorescein angiography (FA) reveals a normal arterial supply and slow, incomplete filling of the saccules, with characteristic layering of the erythrocytes in the inferior aspect of the saccules, and plasma in the superior aspect (Fig. 28.1.1b). The erythrocytes appear hypofluorescent, while the overlying plasma is hyperfluorescent. No leakage is seen.

Visual acuity may be impaired if the lesion is located near the macula, if a preretinal membrane overlies the lesion, or if vitreous hemorrhage from retinal traction occurs. Amblyopia has been reported in children with vitreous hemorrhage from cavernous hemangiomas [85]. It is relatively easy to distinguish cavernous hemangiomas from other retinal telangiectases due to Coats’ disease, branch retinal vein occlusion, capillary hemangioma, and racemose hemangioma. However, they may be confused with Leber’s miliary aneurysms. Cavernous hemangiomas tend to stay stable in size while Leber’s is progressive and involves intrinsic retinal vasculature [22].

Histopathology of cavernous hemangioma

Histopathologically, the retina is thickened by multiple, large vascular channels with normal walls and non-fenestrated endothelium arising from the inner half of the retina [25] (Fig. 28.1.2a). In the area of the saccular aneurysms, the inner retinal layers are discontinuous. Thin stromal tissue separates the aneurysms. Vitreous condensates overlying the lesion may lead to hemorrhage from retinal traction in the case of a posterior vitreous detachment (Fig. 28.1.2b).

Since most cavernous hemangiomas remain stable in size and rarely lead to severe vitreous hemorrhage or lipid exudate, observation is the mainstay of therapy. Cryotherapy, laser photocoagulation, or even vitrectomy may be performed in cases of severe vitreous hemorrhage [26].

28.1.2 Capillary Hemangioma

Essentials

Benign, congenital, may be bilateral or multifocal

May be associated with von Hippel-Lindau disease

Dilated afferent and efferent vessels Abnormal capillary-like vasculature may have fenestrated endothelium and leak Lipidized fibrous astrocytes are present between vascular channels, and appear as vacuolated interstitial cells

Capillary hemangiomas are benign, congenital hamartomas which are typically found in the 2nd or 3rd decade of life, and have no gender or racial predilection. In up to 50 % of cases, these tumors may be bilateral or multifocal [10]. The tumors are most commonly endophytic, involving the inner retinal layers, but may be exophytic, involving the outer layers of the retina. Both types may be seen in a peripheral or juxtapapillary location, though peripheral angiomas are more common [36, 49, 83]. Juxtapapillary hemangiomas tend to have worse visual prognosis, but are less likely to progress [54].

Both juxtapapillary and peripheral retinal capillary hemangiomas may be isolated findings, or may be associated with von Hippel-Lindau disease in about 20 % of patients [48]. Von Hippel-Lindau disease is an autosomal dominant disorder linked to mutations in the VHL tumor suppressor gene on the short arm of chromosome 3 [64]. Along with retinal capillary hemangiomas, which are the most common and earliest manifestation in many cases, cerebellar and spinal cord hemangioblastomas, pheo-

chromocytoma, and renal cell carcinomas are found. A suggestive family history warrants a thorough evaluation for other manifestations of von HippelLindau disease, including magnetic resonance imaging of the brain and spinal cord, abdominal computed tomography, and urinary catecholamine studies [12]. In addition, genetic testing for von Hippel-Lin- dau disease, which is 99 % sensitive, is available [73].

Early lesions may not have abnormal afferent and efferent vessels, and appear as a small red or gray nodule. With enlargement of the lesion, a more clusterlike appearance develops, and feeder vessels enlarge. The characteristic ophthalmoscopic appearance is that of a reddish or gray, round retinal lesion with prominent afferent and efferent vessels (Figs. 28.1.3, 28.1.4). Preretinal membranes or fibrovascular proliferation may be present on the surface of larger hemangiomas. Fluorescein angiography classically shows dilated feeder vessels, hyperfluorescence of the vascular lesion, and late continuous leakage.

Decreased vision may occur secondary to macular lipid exudation, vitreous hemorrhage, or exudative

Fig. 28.1.3. Small capillary hemangioma in von Hippel-Lindau disease with dilated feeder vessels

Fig. 28.1.4. Trypsin digest preparation of a small retinal hemangioma illustrates the feeder artery and efferent vein. H&E, periodic acid-Schiff, original magnification × 45

Histopathology of capillary hemangioma

Histopathologically, the tumor is composed of tortuous, cap- illary-like vessels lined by endothelium and delicate reticulum (Fig. 28.1.5), with larger feeding and draining vessels [36, 56] (Fig. 28.1.4). Pericytes, endothelial cells, and rare multilaminar pericytes with smooth muscle differentiation can be seen on electron microscopy [33]. In larger lesions, the abnormal capillary-like vessels may have fenestrated endothelium, and have a propensity to leak, leading to exudation that may lead to disciform scarring or exudative retinal detachment [33]. Cystic degeneration of surrounding retina may be present.

Collagenous fibrous tissue and vacuolated interstitial cells, representing lipidized fibrous astrocytes, are usually present between the vascular channels [33, 56] (Figs. 28.1.6, 28.1.7). The lipid in these cells is likely derived from leakage of plasma from the intravascular space. A study of patients with a history of von Hippel-Lindau (VHL) disease and retina angiomas found expression of vascular endothelial growth factor and loss of heterozygosity of the VHL gene in these vacuolated stromal cells [11]. Interestingly, this loss of heterozygosity was not found in vascular cells or glial tissue, suggesting that the vacuolated stromal cells may be the true neoplastic component of retinal angiomas.

Endophytic juxtapapillary tumors have minimal interstitial tissue, whereas exophytic tumors are more dispersed within retinal tissue, and have more prominent interstitium [56]. Fusiform thickening of the retina occurs in the areas of tumor. In some cases, the tumor may extend through a defect in the internal limiting membrane with overlying vitreous condensation; vitreous traction may then lead to hemorrhage [25] (Fig. 28.1.5).

Initially, most retinal capillary hemangiomas less than 500 μm in size may be carefully observed. Treatment should be considered for lesions which are larger than 500 μm, located in a vision threatening area, or associated with subretinal fluid or exudates. Laser photocoagulation is effective for lesions smaller than 1,500 μm, located in the posterior pole. Treatment is applied to the surface of the lesion and on the feeding artery to reduce blood flow through the tumor. For larger, more anterior tumors, cryotherapy may be required, and is generally applied until the lesion is completely enclosed by the ice ball [68]. Proton beam [57] and plaque radiotherapy [39, 68] have been used for capillary hemangiomas larger than 4 mm, since those lesions are poorly responsive to laser photocoagulation and cryotherapy. However, experience with radiotherapy has been limited to small numbers of patients. Transpupillary thermotherapy has been used for juxtapapillary tumors with mixed results [59, 68]. Capillary hemangiomas associated with exudative and tractional detachments often require vitrectomy and diathermy or endolaser, but outcomes are often poor [35, 47].

28.1.3 Retinal Vasoproliferative Tumors

Essentials

Peripheral vascular tumors similar to capillary hemangiomas but with normal feeding and draining vessels

Not associated with von Hippel-Lindau disease

May be secondary to other ocular conditions

Reactive retinal gliosis and hyalinization of vessel walls is common

These tumors were previously described as “retinal angiomas” [9], “angioma-like lesions” [21], “peripheral retinal telangiectasis” [46], and “retinal angiomatous masses” [24]. Retinal vasoproliferative tumor is a term coined by Shields et al. in 1995 [65] to describe peripheral vascular tumors without systemic or familial associations that are distinguished from capillary hemangiomas associated with von Hippel-Lindau disease [65]. Primary tumors are idiopathic, small, solitary, reddish-yellow lesions with normal feeding and draining vessels, found most

a

history, and possibly multiple tumors. Choroidal melanomas and metastases are usually confined to the choroidal space, but should also be included in the differential, as these can involve the retina in later stages and can be associated with enlarged retinal vasculature mimicking feeder and draining vessels. Peripheral exudative hemorrhagic chorioretinopathy may also mimic retinal vasoproliferative tumors, with hemorrhage and exudates in subretinal, retinal, and vitreous spaces [3]. However, peripheral exudative hemorrhagic chorioretinopathy is usually subretinal in location, bilateral, associated with macular degeneration, and darkly pigmented [3].

Histopathology of retinal vasoproliferative tumors

Shields et al. hypothesized that these tumors develop secondary to underlying disease processes that stimulate reactive gliosis and vascular and pigment epithelial proliferation [65]. Histopathologic studies of vasoproliferative tumors have demonstrated marked spindle cell gliosis of the retina with cystic changes. These irregularly arranged, spindle-shaped cells stain positively with glial fibrillary acid protein [32, 34], and have no cellular atypia or mitotic figures. The vessels may be dilated or small and fibrotic, but hyalinization and lack of smooth muscle in vessel walls is usually found. In some vessels, thrombosis and intraluminal endothelial cell proliferation is present. In some instances, the lesion develops from choroidal neovascularization and the vascular complex is fed by an artery from the choroid (Fig. 28.1.8). Lipid, serous, and fibrinous exudates may be present in the connective tissue surrounding the abnormal vasculature [32]. Basal deposits on the inner surface of Bruch membrane, retinal pigment epithelium (RPE) proliferation and metaplasia leading to fibrosis, preretinal neovascularization, and associated retinal hemorrhage and exudate have also been described [28, 32, 65, 71].

Fig. 28.1.8. Peripheral retinal vasoproliferative tumor.

a Cavernous-like vascular channels (arrowheads) and hemorrhage (asterisk) are surrounded by fibrous connective tissue. A well-devel- oped artery and vein traverse into the tumor through a defect in the ciliary epithelium (arrow). H&E, original magnification × 35.

Fig. 28.1.8. b Higher magnification shows the artery (arrow) and vein (arrowhead) extend from the choroid and into the tumor at the ora serrata. H&E, original magnification × 125. (From [25])

III 28

b

Most of these lesions can be observed, unless visionthreatening subretinal fluid or exudates, macular edema or epiretinal membrane is present. Laser photocoagulation, cryotherapy, plaque radiotherapy, and vitrectomy with endolaser and/or membranectomy are useful modalities that have been used in a limited number of patients [28, 34, 43, 65]. For patients in whom a malignant process cannot be excluded clinically, transscleral resection may prevent unnecessary enucleation by giving a tissue diagnosis [32, 71].

28.1.4Combined Hamartoma

of the Retinal Pigment Epithelium and Retina

Essentials

Congenital, unilateral, solitary

Elevated, often pigmented lesions most commonly found at optic nerve head

Proliferation of retinal pigment epithelium around blood vessels

Fluorescein angiography shows a spidery vascular pattern

These benign tumors containing vascular, glial, and retinal pigment epithelial components may be mistaken for choroidal melanoma or other malignant intraocular tumors. They are most likely congenital, as the diagnosis has been made in patients in the first

few months of life [20, 62]. However, some cases have occurred following intraocular inflammation [13, 77], and may be acquired. Patients are usually diagnosed in the 2nd decade, but have presented as late as the 7th decade [20, 62]. There is no clear gender predilection, though it appears that Caucasians are more likely to be affected [20, 62]. Most cases are isolated ocular findings, though an association with neurofibromatosis types 1 and 2 has been found [6, 38, 69, 79, 81], especially for those with bilateral lesions.

Lesions are usually unilateral and solitary. Most involve the optic nerve head or juxtapapillary area, though macular lesions are also common. Midperipheral lesions have been noted, but comprise only 5 % of cases [62]. Clinically, lesions of the posterior pole tend to be slightly elevated, black or charcoal gray, and have features of vascular, glial, and retinal pigment epithelial tissue, though one type usually predominates. If retinal pigment epithelial tissue is not prominent, the lesion may not be pigmented (Fig. 28.1.9a). Intralesional vascular tortuosity, contraction of the tumor’s inner surface with juxtalesional tractional retinal distortion, vitreoretinal interface changes, and epiretinal membrane formation are common. The choroid is not involved. With fol- low-up examination, growth may be demonstrated. On early phases of fluorescein angiography, the lesion appears hypofluorescent. Vascular tortuosity and telangiectasis in a spidery configuration within the lesion, and traction of retinal vessels at the periphery of the hamartoma, are commonly detected