28 Other Retinal, Retinal Pigment Epithelial, and Choroidal Tumors
Several benign and malignant neoplasms can occur in the retina and choroid. The most important malignancies, retinoblastoma and choroidal melanoma, have been covered in other chapters. Herein, we review the clinical features, pathologic characteristics, diagnostic approaches, and management of other selected tumors of the retina and choroid.
28.2 Retinal Tumors
There are several benign and malignant neoplasms that can arise in the retina and retinal pigment epithelium (RPE). Tumors can arise from the neural elements (retinoblastoma), vascular elements (hemangioma/hemangioblastoma), and glial elements (astrocytic hamartoma/astrocytoma) of the retina. The most important of these tumors is retinoblastoma, a malignant neoplasm of childhood that arises from the neurons of the sensory retina. There are several distinct types of retinal vascular tumors and glial tumors that can arise in the sensory retina, some of which are associated with the oculoneurocutaneous syndromes, or phakomatoses. Therefore, the finding of a vascular or glial tumor should prompt the clinician to perform an appropriate systemic evaluation, looking for evidence of these syndromes. The RPE can spawn a number of tumors and pseudotumors, most of which are benign and should be differentiated from malignant choroidal melanoma.
It is important for the clinician to have a basic knowledge of the ophthalmoscopic features of retinal and RPE lesions to be able to advise the patient regarding the best approach to management or refer the patient to an ocular oncologist who manages ocular tumors routinely. We will review the more important tumors of the sensory retina and the RPE. When pertinent, the results of ancillary techniques, such as fluorescein angiography, ultrasonography, optical coherence tomography (OCT), and other studies, are described.
Retinoblastoma is a malignant tumor that arises in the sensory retina in children. This malignancy is discussed in detail in ¦Chapter 27¦.
28.2.2 Retinal Hemangioblastoma (Retinal Capillary Hemangioma)
Several benign vascular tumors can arise in the sensory retina. It is important to differentiate the various retinal vascular tumors as each has distinct ophthalmologic features, fluorescein angiographic characteristics, complications, associated systemic findings, and management.
Retinal hemangioblastoma is a vascular hamartoma that usually has its clinical onset in the first two decades of life. In the past, this tumor was termed “retinal capillary hemangioma,” but currently it is termed “retinal hemangioblastoma.” Unilateral solitary lesions can occur due to sporadic mutations and have no systemic associations, whereas bilateral or multiple lesions are more likely to be associated with the von Hippel–Lindau (VHL) syndrome (Table 28-1).
Bilateral or multiple retinal hemangioblastomas are associated with VHL syndrome and patients should be evaluated for this condition with brain and renal imaging. Solitary retinal hemangioblastoma may or may not be associated with VHL syndrome. Genetic testing is advised.
Retinal hemangioblastoma appears ophthalmoscopically as a reddish orange mass, located in the peripheral retina or near the macula or optic disc 1 , 2 , 3 , 4 , 5 (Fig. 28-1 and Fig. 28-2). This tumor appears as a red-orange retinal mass with dilated retinal vessels that feed and drain the tumor. As the tumor enlarges, the vessels become more dilated and tortuous. This tumor may be associated with subretinal and intraretinal exudation, subretinal fluid, and vitreoretinal fibrosis. The exudation has a tendency to accumulate selectively in the macular area. When retinal hemangioblastoma is located at the optic disc, the dilated retinal vessels are often not visible. Regardless of tumor location, accumulation of subretinal fluid with exudation can lead to profound visual acuity loss.
Genetics and Pathogenesis
In the VHL syndrome, the stromal cells have a mutation on chromosome 3p25–26, which leads to dysfunctional VHL protein. 6 , 7 These cells cannot degrade hypoxia-inducible factor 1a, so it accumulates and causes production of vascular endothelial growth factor (VEGF), platelet-derived growth factor, erythropoietin, and transforming growth factor alpha, all of which lead to proliferation and vascularization of the tumor. 7
There are three types of mutations in the VHL gene: (1) type 1 with a deletion or nonsense mutation and manifesting mainly hemangioblastomas only; (2) type 2 with a missense mutation predisposing to hemangioblastomas and pheochromocytomas (type 2A), or also renal cell carcinoma (type 2B), or only pheochromocytoma (type 2C); and (3) type 3, which predisposes to polycythemia. 8
Retinal hemangioblastoma may be diagnosed with fluorescein angiography. This test characteristically shows rapid filling of the vascular tumor with fluorescein through the feeding artery into the tumor; fluorescein then exits rapidly through the draining vein. Larger tumors show leakage of fluorescein dye from the mass into the adjacent retina and vitreous cavity.
Ultrasonography can depict the intraocular mass as an acoustically solid mass and can also demonstrate surrounding subretinal fluid. OCT can show the intraretinal tumor occupying full-thickness retina as a dense mass, with related subretinal fluid, intraretinal edema, and epiretinal membrane. 9 OCT is very helpful in judging treatment response.
Magnetic resonance imaging (MRI) or computed tomography (CT) can provide some help for diagnosis as each will show an enhancing mass in the retina, often with overlying retinal detachment. MRI or CT is helpful to look for associated central nervous system and abdominal neoplasms.
Management and Course
Management of retinal hemangioblastoma consists of both a systemic and an ocular evaluation. The systemic evaluation includes testing for tumors associated with the VHL syndrome, such as cerebellar hemangioblastoma, pheochromocytoma, renal cell carcinoma, and other associated neoplasms and cysts. Brain and abdominal MRI or CT should be performed periodically in affected patients. In addition, close ophthalmic follow-up is important to detect early retinal tumors. If a small retinal capillary hemangioma is detected, early treatment is advisable, often using laser photocoagulation or thermotherapy.
The treatment of a retinal hemangioblastoma varies with the clinical situation. 4 , 10 , 11 , 12 , 13 Tumors associated with the VHL syndrome tend to be more aggressive; thus, all hemangioblastomas associated with this syndrome are considered for treatment. Laser photocoagulation or photodynamic therapy can be used for small tumors (<3 mm), but photodynamic therapy or cryotherapy should be used for medium tumors (3–6 mm) (Fig. 28-2). Large tumors may require plaque radiotherapy or internal resection via pars plana vitrectomy.
For retinal hemangioblastomas unassociated with the VHL syndrome, small asymptomatic lesions without subretinal fluid can be observed carefully, particularly if they are in the perimacular or juxtapapillary region where treatment could be detrimental to vision. If leakage ensues, then treatment is warranted. However, most retinal hemangioblastomas require treatment to prevent subretinal fluid or macular complications. Laser photocoagulation or photodynamic therapy is useful for tumors located posterior to the equator and cryotherapy is employed for those anterior to the equator. Plaque radiotherapy is reserved for larger tumors. Surgical repair of secondary retinal detachment or epiretinal membrane is often necessary. In the case of an aggressive tumor that does not respond to conventional treatment, external beam radiotherapy or plaque radiotherapy can be employed.
There have been anecdotal cases that have responded to oral propranolol, oral acetazolamide, and oral prednisone, but large studies have not been performed. Oral and intravitreal anti-VEGF have not been successful in inducing tumor regression, but intravitreal anti-VEGF can be useful for reduction of macular edema and occasionally subretinal fluid. Wong and Chew reviewed the role of anti-VEGF and emerging therapies for retinal hemangioblastoma. 4
The management of retinal hemangioblastoma is controversial as there are no singular excellent therapies. Most patients respond to cryotherapy if the tumor is peripheral or to laser photocoagulation if the tumor is small and posterior to the equator. For larger postequatorial tumors, photodynamic therapy can be effective.
Histopathologically, retinal hemangioblastoma consists of a proliferation of retinal capillaries that usually replace full-thickness neurosensory retina. With light microscopy, there appears to be a benign proliferation of endothelial cells, pericytes, and stromal cells. In the end stage, total retinal detachment with massive retinal gliosis, cataract, and phthisis bulbi ensue.
28.2.3 Retinal Cavernous Hemangioma
Retinal cavernous hemangioma has clinical features, systemic implications, and complications that are distinctly different from those of other retinal vascular tumors, such as retinal hemangioblastoma, racemose hemangioma, and the vasoproliferative tumor. This vascular tumor is often associated with similar skin and central nervous system lesions and, therefore, should be classified with the oculoneurocutaneous syndromes, or phakomatoses.
Ophthalmoscopically, retinal cavernous hemangioma usually appears as a cluster of dark intraretinal venous aneurysms, sometimes referred to as a “bunch of concord grapes” 1 , 2 , 14 , 15 , 16 , 17 , 18 , 19 , 20 (Fig. 28-3). This tumor can be asymptomatic or associated with moderate or severe visual impairment resulting from macular scarring, secondary retinal traction, or vitreous hemorrhage. Unlike retinal hemangioblastoma, cavernous hemangioma does not have a feeding artery and is typically located along the course of a retinal vein, but can be on the optic disc. Rarely is there exudation, but commonly there is overlying white fibroglial tissue on the tumor surface, suggesting previous vitreous or preretinal hemorrhage. Retinal cavernous hemangioma is usually nonprogressive but on rare occasions can show minimal enlargement over time. The main complication of retinal cavernous hemangioma is vitreous hemorrhage.
Retinal cavernous hemangioma is typically located along a retinal vein and can produce vitreous hemorrhage.
Retinal cavernous hemangioma can occur with cerebral cavernous malformations as a sporadic or familial autosomal dominant disorder with incomplete penetrance. There are three cerebral cavernous malformation (CCM) genes, including CCM/KRIT1, CCM2/MGC4607, and CCM3/PDCD10. 18 CCM3 is associated with a higher risk for cerebral hemorrhage in childhood.
In most instances, retinal cavernous hemangioma has a typical ophthalmoscopic appearance. The most helpful diagnostic ancillary test is fluorescein angiography, which produces nearly pathognomonic findings. During the arterial phase, the vascular channels are hypofluorescent; fluorescein enters slowly in the late phase of the angiogram. The fluorescein is contained within the venous aneurysms and occupies the superior portion of each cavernous space, while the red blood cells collect in the inferior portion of each aneurysm and there is no leakage of dye. This produces a “fluorescein–erythrocyte interface” in the late angiogram, a characteristic feature of cavernous hemangioma.
With large retinal cavernous hemangiomas, extensive vitreous hemorrhage can occur, obscuring the tumor which is then detectable by ultrasonography. With A-scan ultrasonography, there is a high initial spike and high internal reflectivity. With B-scan ultrasonography, the lesion shows an irregular but well-defined surface, acoustic solidity, and no choroidal excavation.
OCT demonstrates the numerous cavernous spaces within the retina which cause a markedly irregular retinal surface. In general, the retinal anatomy is disorganized from tumor compression.
Management and Course
Most cases of retinal cavernous hemangioma require no treatment. These tumors rarely progress or produce visual symptoms. Vitreous hemorrhage can occur and is managed with observation or vitrectomy. For repetitive hemorrhage, the tumor can be sclerosed with plaque radiotherapy, photodynamic therapy, or cryotherapy. It is important to perform brain MRI to evaluate for related cerebral cavernomas, and genetic testing for the CCM genes is advised, especially if there is a family history of cavernomas or the patient shows multiple cavernomas.
Histopathologically, retinal cavernous hemangioma appears as a mass of large-caliber vascular spaces in the inner retina, but potentially involving all layers of the retina. This tumor consists of endothelial-lined venous aneurysms interconnected by narrow channels. 20 There can be extensive cystic and fibrous degeneration of the retina.
28.2.4 Retinal Racemose Hemangioma
The retinal racemose hemangioma is not a true neoplasm but rather a simple or complex arteriovenous communication. 1 , 2 It can occur as a solitary unilateral lesion or it can be part of the Wyburn–Mason syndrome (also called Bonnet–Dechaume–Blanc syndrome), which is more anatomically termed retinoencephalofacial angiomatosis. This arteriovenous malformation can affect the retina, visual pathways, midbrain, and facial bones including the mandible and maxilla. There is no hereditary tendency.
Ophthalmoscopically, the retinal racemose hemangioma is characterized by a large, dilated, tortuous retinal artery that passes from the optic disc for a variable distance into the fundus, where it then communicates directly with a similarly dilated retinal vein that passes back to the optic disc. In some cases, the vascular anomaly displays a complex array of blood vessels. This retinal malformation does not usually produce exudation or hemorrhage, unless branch retinal vein obstruction occurs. This retinal condition is classified by the Archer classification according to size and location of the malformation 21 , 22 , 23 , 24 , 25 , 26 (Table 28-2).
There is evidence that genetic or developmental factors early in gestation lead to dysgenesis of the embryologic vascular plexus. 26 The time of insult determines the location and extent of manifestations.
The retinal racemose hemangioma is established with ophthalmoscopy and confirmed with fluorescein angiography, which shows rapid filling of the affected dilated artery and vein, usually with no intervening capillary channels and typically without leakage into surrounding tissues (Fig. 28-4).
Management and Course
The management of a patient with a retinal racemose hemangioma consists of systemic and ophthalmic monitoring. The patient should be evaluated for the Wyburn–Mason syndrome with imaging studies investigating for the presence of vascular abnormalities in the brain and facial bones. The retinal lesion usually remains stable and treatment is rarely indicated.
Little histopathologic information is available on retinal racemose hemangioma. The large, dilated retinal vessels appear to have an acellular adventitial covering. The retina is thin and may show extensive degeneration.
28.2.5 Acquired Vasoproliferative Tumor
The acquired vasoproliferative tumor of the ocular fundus is a vascular mass that can occur as a primary or secondary condition, from predisposing intermediate uveitis, retinitis pigmentosa, Coats’ disease, or chronic retinal detachment 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 (Table 28-3). There are generally no systemic associations, but some patients have underlying hypertension or hyperlipidemia.
Ophthalmoscopically, the acquired vasoproliferative tumor appears as an elevated sessile or dome-shaped mass that is usually located in the equatorial inferotemporal region (Fig. 28-5 and Fig. 28-6). This mass can be circumscribed or ill-defined. An associated retinal feeding artery and draining vein can be minimally dilated, but not as markedly dilated or tortuous as seen with retinal hemangioblastoma. The tumor may be associated with complications including intraretinal and subretinal exudation, subretinal fluid, remote epiretinal membrane, cystoid macular edema, retinal hemorrhage, and vitreous hemorrhage. The retinal exudation generally begins at the tumor margin and gradually accumulates posteriorly into the macula, with ensuing visual loss.
There are no genetic abnormalities associated with this condition, but for those tumors that are secondary, evaluation for underlying retinitis pigmentosa or other mutations can be performed.
Fluorescein angiography demonstrates filling of the mass through a feeding, slightly dilated and minimally tortuous retinal artery and draining vein. There is frequently leakage from the vasoproliferative tumor into the surrounding retina and vitreous cavity. Remote macular edema is seen on fluorescein angiography and confirmed on OCT.
Management and Course
Small peripheral tumors may be observed carefully if there is no leakage. Those with active leakage require therapy including laser photocoagulation, thermotherapy, indocyanine green–enhanced thermoablation, photodynamic therapy, or plaque radiotherapy. 28 , 29 , 30 , 31 , 32 , 33 Intravitreal anti-VEGF therapy can assist in reducing remote macular edema, and sub-Tenon’s fascia triamcinolone can minimize the inflammatory response associated with treatment.
Histopathology of the acquired vasoproliferative tumor in the early phases, when the tumor is mostly vascular, has not been clearly established. It is believed to represent a proliferation of blood vessels, glial tissue, and RPE, often in response to previous insults. Later, as the tumor becomes clinically fibrotic, a more reactive astrocytic appearance is documented. 34
28.2.6 Astrocytic Hamartoma
Although reactive gliosis can occur in the retina after trauma or inflammation, true tumors arising from the glial elements of the retina are relatively uncommon. The most important retinal glial tumors are astrocytic hamartoma and acquired astrocytoma. 1 , 2 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 Although these two lesions appear different in most cases, there are some instances in which the clinical features overlap.
Astrocytic hamartoma of the retina (and optic disc) is a benign glial tumor that can occur as a manifestation of tuberous sclerosis. The general systemic manifestations of tuberous sclerosis include cutaneous sebaceous adenoma, cardiac rhabdomyoma, renal angiomyolipoma, and others. Detection of a retinal astrocytic hamartoma should alert the clinician to the possibility of tuberous sclerosis or, less commonly, neurofibromatosis.
Small retinal astrocytic hamartoma can be subtle, appearing as an ill-defined translucent thickening of the nerve fiber layer, sometimes with slight retinal traction (Fig. 28-7). Larger tumors assume a more opaque appearance but typically remain sessile and yellow-white, located in the nerve fiber layer and overlying the retinal vessels. There are usually no dilated vessels leading to this tumor, but mild retinal traction may be observed. Astrocytic hamartoma can manifest intrinsic calcification that appears round, refractile, and yellow, resembling fish eggs, tapioca, or a yellow mulberry. 35 , 36 , 37 , 38 , 39 , 40 This tumor is generally stable and without complications, but vitreous or subretinal hemorrhage and retinal detachment can occur. Rarely does this tumor show uncontrolled growth. If related to tuberous sclerosis complex (TSC), there might be depigmented “punched-out” spots in the RPE. 38
An isolated, solitary astrocytic hamartoma may or may not be associated with TSC. Patients with multiple astrocytic hamartomas likely have TSC. TSC is a multisystem disorder that can occur in multiple tissues but primarily the skin, brain, and eye. This autosomal dominant condition displays two genetic loci, including 9q34 (TSC1) and 16p13 (TSC2). These two sites control products of hamartin (TSC1) and tuberin (TSC2) that act synergistically to regulate cellular growth and differentiation. 40 , 41 Deregulation of these products leads to hamartomatous tumors.
There are diagnostic criteria for TSC that were established by the Tuberous Sclerosis Consensus Conference in 1998 41 , 42 (Table 28-4). A definite diagnosis of TSC is established by the presence of two major or one major plus two minor features. Probable TSC requires one major and one minor feature, and possible TSC requires either one major or two or more minor features.
The diagnosis of retinal astrocytic hamartoma is usually made with indirect ophthalmoscopy and subsequent physical evaluation for signs of tuberous sclerosis or neurofibromatosis. Ancillary studies can be confirmatory, including fluorescein angiography, ultrasonography, and OCT. On fluorescein angiography, the tumor shows slow and incomplete filling in the late arterial or midvenous phases. There is a classic corkscrew or “hairpin” looping to the intrinsic vessels, suggestive of the diagnosis. These fine blood vessels can leak in the late phases.
Ultrasonography is of some diagnostic value to document the intrinsic calcification. With B-scan, medium and large astrocytic hamartomas appear as well-demarcated, oval masses with a sharp anterior border, acoustic solidity, and acoustic shadowing of the orbital fat posterior to the tumors. Persistent focal echoes at reduced sensitivities suggest calcification within the mass. A-scan ultrasonography shows a sharp anterior border, high internal reflectivity, and attenuation of orbital echoes posterior to the tumor.
OCT demonstrates the tumor, with sharp borders, arising in the nerve fiber layer or full-thickness retina. The intrinsic calcification can give a “moth-eaten” lucent appearance with posterior shadowing. 43 Fine-needle aspiration biopsy is rarely necessary.
Management and Course
Most retinal astrocytic hamartomas are asymptomatic and nonprogressive and, thus, do not require treatment. Ocular examination should be performed yearly. If there is associated serous retinal detachment, then photodynamic therapy may be employed. All patients with retinal astrocytic hamartoma should be evaluated for TSC, particularly if they display multiple lesions.
Histopathologically, the typical noncalcified retinal astrocytic hamartoma is a lightly eosinophilic lesion arising from the nerve fiber layer of the retina. It is composed of well-differentiated elongated fibrous astrocytes with lightly eosinophilic cytoplasm and round to oval nuclei. Mitotic figures are extremely rare. The more calcified tumors show fossilization and round, basophilic, laminated structures resembling corpora arenacea. 34
28.2.7 Acquired Retinal Astrocytoma
The acquired retinal astrocytoma is a rare tumor, unrelated to TSC and showing features different from astrocytic hamartoma. Unlike astrocytic hamartoma that is usually found in children, the acquired astrocytoma develops at any age, demonstrates growth and exudative retinopathy, and is unassociated with systemic syndromes.
The acquired retinal astrocytoma occurs as a solitary, pink-yellow retinal mass, usually in the posterior retina near the optic disc. 1 , 2 , 44 The retinal blood vessels can be slightly dilated and ramify over and into the lesion. Unlike the congenital astrocytic hamartoma, the acquired astrocytoma can show progressive growth and produce a secondary serous/exudative retinal detachment. A large, elevated astrocytoma can be pedunculated and have numerous superficial blood vessels, resembling an amelanotic choroidal melanoma. In contrast to a similar-sized melanoma, however, the astrocytoma is more likely to involve the sensory retina and be associated with retinal exudation, retinal detachment, and vitreous hemorrhage.