Retinoblastoma
Presenting signs of retinoblastoma include leukocoria (a white pupil), strabismus, hyphema (blood in the anterior chamber), vitreous hemorrhage, and, rarely, a red painful eye ( Figure 13.01 A). Parents are usually the first to note a “glazed look,” “wandering eye,” or “shiny” appearance of the pupil. A prolonged time to diagnosis, advanced disease, and extraocular involvement are more frequently observed in developing countries. The diagnosis of retinoblastoma is made in 90% of patients before 5 years of age. In cases with a family history of retinoblastoma, the diagnosis may be made in the first few days of life at a screening examination. Although most patients with retinoblastoma present as young children, retinoblastoma has been reported in patients as old as 60 years. Approximately 200 cases occur each year in the USA. Bilateral involvement occurs in 20–35% of cases. Second-eye involvement is delayed in approximately 20–25% of cases. The mean age of diagnosis is 13 months for those with bilateral retinoblastoma versus a mean age of 24 months in those with unilateral retinoblastoma. In a recently published study, the mean age-adjusted incidence rate of retinoblastoma in the USA was 11.8 cases per million children aged 0–4 years, similar to rates reported from European countries. Moreover, the age-adjusted incidence rate of retinoblastoma in the USA has remained stable for the last 30 years.
Retinoblastomas are typically globular, white, usually well-circumscribed tumors that may arise anywhere in the fundus ( Figure 13.01 B and C). They may grow inward toward the vitreous (endophytic) or outward (exophytic) into the subretinal space and may or may not be associated with ophthalmoscopic evidence of focal areas of calcification ( Figure 13.01 J). Varying degrees of vascularization of the tumor occur, and this is usually seen best with fluorescein angiography ( Figure 13.01 D, E, K, and L). Telangiectasis of the retinal vessels on the surface of exophytic tumors may occur. Biomicroscopic and angiographic evidence of communication of these dilated vessels with blood vessels extending into the depth of the tumor serves to differentiate retinoblastomas from primary retinal telangiectasis associated with underlying exudative detachment (Coats’ syndrome) ( Figure 13.01 A–E). Seeding of the tumor along the inner retinal surface and into the vitreous occurs frequently in advanced cases ( Figure 13.01 G–I). Extension of retinoblastoma into the anterior chamber may occur.
As many as 80% of eyes containing retinoblastoma have calcification demonstrable by ultrasonography or other imaging studies. Computed tomography (CT) is superior to magnetic resonance imaging (MRI) in detecting calcification. However, MRI is superior to CT scan in defining anatomic differences in pseudoglioma, particularly Coats’ disease, and in detecting extraocular extension of the tumor.
Diffuse infiltrating retinoblastoma is an unusual type of retinoblastoma (1.5% of cases). It may simulate uveitis, is unassociated with formation of a discrete mass, and may be accompanied by a pseudohypopyon ( Figure 13.02 ). CT and ultrasonography are of limited value in the diagnosis of diffuse retinoblastoma. Other features of this form of retinoblastoma are: older average age of presentation (6 years, compared to 13–24 months); slight male predominance (64%); all reported cases have been unilateral and none has been familial; and anterior-chamber paracentesis is helpful in making the diagnosis. A few patients with extensive involvement of the retina may develop orbital cellulitis that is not necessarily associated with extraocular extension of the tumor ( Figure 13.03 ).
The differential diagnosis in patients with localized white retinal tumors includes retinomas ( Figure 13.04 ), astrocytic hamartomas (see Figure 13.11 ), Toxocara canis granuloma (see Figure 10.26), intraocular teratoma and combined pigment epithelial and retinal hamartomas (see Figure 12.11). A rare intraocular teratoma is illustrated in Figure 13.05 E–K. Sacral teratomas are the most common newborn tumors (1/35 000); 75% occur in female infants. All teratomas seen at birth are benign, and 10% of those seen in older children are malignant. Teratomas arise from pluripotent cells from more than one germ layer. In patients with large tumors and leukocoria, the differential diagnosis includes retinal telangiectasis (Coats’ syndrome), Toxocara canis , retinopathy of prematurity, familial exudative vitreoretinopathy, persistent hyperplastic primary vitreous, retinal dysplasia, traumatic chorioretinopathy, calcified intraocular abscess, and incontinentia pigmenti. Clinical features that suggest a diagnosis of retinoblastoma are the absence of cataract and the relative lack of inflammation. Since surgery disseminates malignant cells outside the eye and worsens the prognosis for survival, intraocular surgery including biopsy should only be performed in exceptional cases when retinoblastoma cannot be ruled out by other methods.
Retinoma/Retinocytoma
Retinocytoma is a benign variant of retinoblastoma, previously referred to as retinoma, spontaneously regressed/arrested retinoblastoma, and retinoblastoma group 0 ( Figure 13.04 ). The diagnosis of retinocytoma is based upon its characteristic features of homogeneous translucent retinal mass, calcification, nonspecific retinal pigment epithelial (RPE) alteration, and chorioretinal atrophy. Nearly one-half of patients diagnosed with retinocytoma have a family history of retinoblastoma. Approximately 50% of their offspring will develop retinoblastoma. Malignant transformation of a retinoma has occurred. Fluorescein angiography reveals evidence of a vascular network within retinomas and some evidence of dye leakage ( Figure 13.04 D, E, H, and I). There is often evidence of RPE and choriocapillaris atrophy in the area of the retinoma ( Figure 13.04 D). Anastomosis between the retinal and choroidal vessels may occur. Histopathologically, in contrast to retinoblastoma, retinoma/retinocytoma is composed of well-differentiated, benign-appearing mature retinal cells without evidence of necrosis or mitotic activity. Ophthalmoscopically retinomas appear identical to so-called regressed retinoblastoma following irradiation treatment ( Figure 13.05 ). It has been suggested that this portion of the tumor remaining after treatment may be the result of a coexistent retinoma.
Retinoblastoma can be considered as familial or sporadic, bilateral or unilateral, and heritable or nonheritable. Thus, a case may be unilateral sporadic, bilateral sporadic, unilateral familial, or bilateral familial. About two-thirds of all cases are unilateral and one-third are bilateral. Approximately 10% of newly diagnosed retinoblastoma cases are familial and 90% are sporadic. All patients with familial retinoblastoma are at 50% risk of passing the predisposition for the development of the tumor to their offspring. From a genetic perspective, it is simpler to discuss retinoblastoma as heritable or nonheritable. Heritable cases (ones in which the predisposition to the tumor can be passed on to the next generation) result from a primary mutation in the germ cells (sperm or egg, hence all retinal cells in the individual have a first mutation) and second mutation(s) in retinal cells. Heritable cases include all bilateral cases, all multifocal cases, all familial cases, and all cases in which a second neoplasm developed. About 15% of sporadic unilateral cases (no family history) are also heritable.
In about 10% of families, reduced penetrance can be seen in individuals (absence of retinoblastoma) who are determined to be RB1 mutation carriers, either through molecular diagnosis or obligate carrier status in a family. Mechanisms of reduced penetrance and variable expressivity include mutations that lead to reduced expression of retinoblastoma protein expression or production of partially inactive protein.
The human retinoblastoma susceptibility gene ( RB1 ) was sequenced in 1993, allowing for development of molecular techniques for mutation detection and diagnosis. RB1 is located on chromosome 13 region q13–14. It is relatively large, with 180 kilobases and 27 exons. Analysis of a large number of germline mutations in patients with hereditary retinoblastoma has revealed that about 15% are large deletions, of which ~5–6% are cytogenetically detectable, 26% small-length alterations including small insertions and deletions, and 42% base substitutions. RB1 mutation analysis is appropriate in any case of retinoblastoma when the results will affect future treatment or surveillance. In patients with a known or suspected family history of retinoblastoma, RB1 analysis will detect a mutation in ~90% of families. If RB1 mutation has been identified in a family, then the individual is tested for the specific known family mutation. In this manner, unaffected at-risk children with a family history of hereditary retinoblastoma can undergo predictive testing. Prenatal and preimplantation genetic diagnoses are also available when an RB1 mutation is known in a parent or sibling. Bilateral tumors in the setting of a negative family history also indicate a high probability of a germline RB1 mutation (~90%) and therefore RB1 testing is recommended. In sporadic cases, it is recommended that both peripheral blood and tumor tissue (if available) should be analyzed. In all situations, a positive result clearly establishes a diagnosis of hereditary retinoblastoma but a negative result does not rule it out completely.
In recent years there has been a trend away from enucleation and from external-beam radiotherapy with the increasing use of alternative globe-conserving methods of treatment, including laser photocoagulation, cryotherapy, transpupillary thermotherapy, plaque radiotherapy, and chemotherapy. Laser photocoagulation or transpupillary thermotherapy is used to treat very small tumors located posterior to the equator. Cryotherapy is used to treat very small tumors located anterior to the equator. Transpupillary thermotherapy may be used for small tumors either primarily or in conjunction with chemotherapy. Plaque radiotherapy is highly effective in treating medium-sized tumors either as primary treatment or as secondary treatment for recurrent tumors ( Figure 13.06 ). External-beam radiotherapy is less frequently used for large and multiple tumors associated with vitreous seeding. Enucleation continues to be the main therapeutic option for advanced unilateral retinoblastoma.
Since the 1990s chemoreduction has been increasingly used for the management of retinoblastoma to avoid external-beam radiotherapy or enucleation. Chemotherapy is delivered intravenously to reduce the volume of intraocular retinoblastoma to make it amenable to focal therapy, such as cryotherapy, thermotherapy, or brachytherapy ( Figure 13.07 ). Six-cycle chemoreduction using three agents (vincristine, etoposide, and carboplatin) is generally prescribed. Based on the available (noncomparative series) data it can be concluded that chemoreduction combined with adjuvant focal therapy offers about 50–100% probability of avoiding enucleation or external-beam radiotherapy depending upon the severity of disease at initial presentation. It must be realized that chemoreduction is not without its problems. Recurrence of the neoplasm while on chemotherapy has been observed. Immediate complications related to transient bone marrow suppression requiring hospital admissions and intravenous antibiotics with consequent delay in examinations under anesthesia are frequent. Risk of late complications such as drug-induced leukemia cannot yet be excluded. It is recommended that chemoreduction therapy for retinoblastoma should only be offered at a specialist center.
International group classification of retinoblastoma, a newer system of classification of retinoblastoma, is most suited for the present-day management of retinoblastoma compared to the traditional Reese–Ellsworth classification. Eyes are classified according to the extent of disease and dissemination of intraocular tumor defined by the most advanced tumor in each eye. Moreover, the international group classification of retinoblastoma forms the basis of Children Oncology Group trials currently underway.
More recently, there is a trend towards superselective delivery of chemotherapy (melphalan) via cannulation of the ophthalmic artery. The aim of such an approach is to avoid the systemic complications and to achieve higher drug levels within the vitreous cavity. Although the initial results are encouraging, such treatments should only be conducted within a framework of a clinical trial in a specialized center ( Figure 13.08 ). The procedure involves three 1-weekly injections of 1 cc/5 mg melphalan (diluted in 30 ml of normal saline), an alkylating agent, directly into the ophthalmic artery via selective percutaneous catheterization via the femoral artery. An approximately 450-μm (1.5–1.7 French)-size catheter is used; an arteriogram is first performed by injecting contrast into the ophthalmic artery to ensure good blood supply to the eye, following which the medication is infused ( Figure 13.08 C–E). Since the drug is injected into the arterial supply of the tumor, a very small dose of one chemotherapeutic agent has proven sufficient. The procedure is done by skilled interventional neuroradiologists and has a learning curve. The drug is injected in a pulsatile fashion so as to deliver the drug uniformly. In bilateral cases ( Figure 13.08 G–J), after the chemotherapy is infused through one ophthalmic artery, the catheter is withdrawn into the aorta and threaded into the opposite internal carotid artery and on to the ophthalmic artery and delivered to the second eye. Complications outside the difficulties with catheterization include complete vascular obstruction of the arterial supply leading to total blindness if the catheter is wedged tightly into the lumen of the ophthalmic artery. The procedure is successfully performed at the Memorial Sloan Kettering by Dr. David Abramson and his team (USA) and in some centers in Europe.
About 8% of patients with heritable retinoblastoma may develop an associated pinealoblastoma, a tumor that is identical to retinoblastoma. This association of midline intracranial pineal tumors and suprasellar/parasellar neuroblastic tumors with bilateral retinoblastoma has been termed trilateral retinoblastoma. Unlike other second tumors mentioned below, pinealoblastoma usually occurs during the first 4 years of life. Prospective screening by periodic neuroimaging is generally recommended. The possibility of pinealoblastoma should be included in the genetic counseling of patients with hereditary retinoblastoma. Newer evidence suggests that recent treatment methods of systemic chemotherapy. A total of 95% of trilateral retinoblastoma patients have bilateral retinoblastomas and in most cases the disease is fatal. Most patients present with symptoms of increased intracranial pressure caused by obstructive hydrocephalus.
An important aspect concerns the development of unrelated cancers in survivors of bilateral or heritable retinoblastoma. The mean latency period for the appearance of the second malignant neoplasm (SMN) is approximately 13 years. There is a 5% chance of developing SMN during the first 10 years of follow-up, 18% during the first 20 years, and 26% within 30 years. The 30-year cumulative incidence of SMN is about 35% for those patients who receive radiation therapy (external-beam therapy) as compared to an incidence rate of 6% for those patients who do not. Osteogenic sarcoma, often involving the femur, is most common, but other tumors such as cutaneous malignant melanoma, spindle cell sarcoma, chondrosarcoma, rhabdomyosarcoma, neuroblastoma, glioma, leukemia, sebaceous cell carcinoma, squamous cell carcinoma, and lung and bladder carcinomas as SMN have also been recognized.
Several studies have evaluated histopathologic prognostic factors for metastasis, including choroidal, optic nerve, and extrascleral extension. Choroidal involvement by the retinoblastoma is a risk for metastasis, especially if it is associated with any degree of optic nerve involvement. Mortality increases with increasing extent of optic nerve involvement. However, it is generally agreed that prelaminar involvement of the optic nerve does not increase the risk of metastasis. The impact of laminar involvement on metastasis is debatable. Retrolaminar involvement is a poor prognostic factor and optic nerve involvement by retinoblastoma cells up to the line of transection predicts the worst prognosis.
It must be realized that retinoblastoma-related mortality could be due to one of three distinct causes: (1) metastases; (2) trilateral retinoblastoma; and (3) SMN. Metastases in retinoblastoma usually occur within 1 year of diagnosis. Metastatic retinoblastoma is observed infrequently in the USA and other developed nations. However, metastases continue to be a challenge in developing nations. Therefore, bone scans, lumbar puncture, and bone marrow aspirations at initial presentation are generally not performed in the USA. If there is no metastatic disease within 5 years of retinoblastoma diagnosis, the child is usually considered cured. Metastases usually involve the central nervous system (CNS), bones, and bone marrow. The prognosis of metastatic retinoblastoma is poor, with death usually occurring within 6 months. In the USA, over a period of 30 years (1975–2004), the 5-year observed actuarial survival rate increased from 92.3% (1975–1984) to 96.5% (1995–2004).
Medulloepithelioma
Intraocular medulloepithelioma is an embryonal neoplasm of the ciliary epithelium. It may contain cartilage, skeletal muscle, and brain tissue (teratoid medulloepithelioma). Medulloepithelioma typically presents during the first decade of life with poor vision, pain, leukocoria, and iris vascularization associated with a mass or cyst appearing behind the pupillary area ( Figure 13.08 K). Children with neovascularization of the iris of unknown cause should be evaluated to exclude underlying medulloepithelioma. Recently, an association with pleuropulmonary blastoma has been reported. Therapeutic options include local excision or enucleation depending upon the size, location, and secondary effects of the tumor.
Astrocytic Hamartomas
Retinal and optic disc astrocytic hamartomas may occur as a solitary finding in normal patients, in patients with dominantly inherited tuberous sclerosis complex (TSC) (Bourneville’s disease), or, rarely, in patients with neurofibromatosis (von Recklinghausen’s disease). The intraocular tumors are typically globular, white, well-circumscribed, elevated lesions arising from the inner surface of the retina or optic nerve head ( Figures 13.09–13.11 ). Multiple lesions are common in patients with TSC (Figure 13.09A–F). Early in life the tumors may be semitranslucent, free of calcification, and mistaken for retinoblastoma ( Figures 13.09 A and D, and 13.10 F). In infants and children they may occasionally arise where earlier no lesion was present. Later in life they assume a more densely white color and may develop multiple nodular areas of calcification, taking on a mulberry appearance ( Figures 13.09 A and D, 13.10E, and 13.11 A). Clear cystic spaces may be present within the tumor ( Figure 13.09 D). The tumors may show varying degrees of vascularization that are more evident angiographically than ophthalmoscopically ( Figures 13.09 B and C, and 13.11 E and F). The tumor’s blood vessels are usually permeable to fluorescein. In addition to nodular retinal tumors, flat or slightly elevated, white, circular or oval astrocytic hamartomas of the inner retinal layers are common ( Figure 13.09 D). These sessile tumors show less tendency to undergo calcific degeneration. In general, retinal astrocytic hamartomas show minimal evidence of growth and no treatment is indicated. Occasionally, however, particularly in younger individuals, progressive enlargement and calcification of these tumors may be demonstrated ( Figure 13.10G to J, 13.11 J–L). Visual loss may be caused by tumor growth, vitreous hemorrhage, or intraretinal and subretinal exudation ( Figure 13.12 D–F). The exudative complications of astrocytic hamartomas can be self-limited, and cases of spontaneous resolution within a few weeks have been observed (Fig. 13.10K to N) ; however, some cases are persistent, progressive, and vision-threatening, and for these cases various treatments have been attempted, including laser photocoagulation ( Figure 13.12 D–F), brachytherapy, transpupillary thermotherapy, and endoresection. More aggressive cases exhibiting progressive growth, tumor seeding, and neovascular glaucoma have been managed by enucleation. Recently, photodynamic therapy using the photosensitizing dye verteporfin (Visudyne) has been used in the treatment of a few cases of exudative astrocytic hamartomas, with encouraging results ( Figure 13.13 ).
In some, the rapid growth and necrosis may be mistaken for a nonpigmented melanoma ( Figure 13.11 J–L). In other patients the highly vascular component of the tumor may simulate a retinal angioma ( Figures 13.10G-J, 13.11 G–I and 13.12 A–C). In the case of spontaneous necrosis astrocytomas may simulate necrotizing retinochoroiditis. The fossilized mulberry tumors involving the optic nerve head should be distinguished from hyaline bodies of the optic nerve head. These latter are calcified masses of extracellular material unrelated to astrocytic hamartomas. When calcified astrocytic hamartomas of the optic disc are small, they may be difficult or impossible to distinguish from hyaline bodies. Demonstration of growth of these small lesions in patients with retinitis pigmentosa has suggested that these lesions in patients with retinitis pigmentosa are astrocytic hamartomas. Retinal telangiectasis, retinitis proliferans, and retinal exudation developed in one eye of a patient with familial TSC but no evidence of a retinal astrocytoma.
Histopathologically, these tumors are typically composed of spindle-shaped fibrous astrocytes, some of which are elongated and contain small oval nucleoli ( Figures 13.10 F and 13.11 L). Other tumors are composed of large, bizarre, pleomorphic astrocytic cells, that in at least one case showed ultrastructural and histochemical similarities to Müller cells. Cystic areas containing serous exudate and blood, as well as areas of calcified degeneration, may be present. Some of these tumors may be of Müller cell origin.
Retinal achromic patches have also been observed in published series, ranging from 8% to 39% of TSC patients. Some authors have described these lesions as diffusely hypopigmented, while others have noted them to be surrounded by some degree of pigment proliferation ( Figure 13.14 ). Clinically, these lesions bear a striking resemblance to the solitary-type hypomelanotic nevi described by Dr. Gass. While retinal achromic patches appear in increased frequency in individuals with TSC, the underlying mechanism explaining their existence is unknown.
A careful search should be made for the various manifestations of TSC in any patient with a white retinal tumor. These include the classic triad of seizures, mental deficiency, and sebaceous adenoma (fibroangiomas) as well as other manifestations, including white ash-leaf spots on the skin and iris, soft yellow-brown cutaneous fibromas ( Figures 13.09G and 13.10 A), subungual fibromas ( Figure 13.10 B), renal hamartomas, cardiac rhabdomyomas, calcified cerebral astrocytic hamartomas ( Figure 13.10 C and D), cystic lung disease, and bony changes, including cystic changes of the phalanges and cortical thickening of the metatarsal and metacarpal bones. In 1998, at the Tuberous Sclerosis Complex Consensus Conference, a revised set of clinical diagnostic criteria based upon major and minor features of the disease was firmly established.
CT and roentgenographic techniques are useful in the detection of intraocular tumors. In infants and children these tumors can appear identical to retinoblastoma or may mimic necrotizing retinochoroiditis. In older patients they may be confused with regressed retinoblastoma or retinoma ( Figure 13.11 G–I), capillary hemangiomas of the retina, or a localized retinal scar secondary to previous hemorrhage or inflammation.
More recently, genetic mutational analysis has uncovered two distinct variants of TSC resulting from mutations is the TSC1 gene located on chromosome 9q34 and the TSC2 gene on chromosome 16p13. These genes encode for hamartin and tuberin respectively, both of which are involved in regulation of the cellular growth cycle. TSC2 mutations are more frequent than TSC1 mutations in patients with atsrocytic hamartoma or retinal achromic patches.
Reactive Astrocytic Hyperplasia Simulating an Astrocytic Hamartoma
Dr. Gass had observed four healthy adult patients with focal vascularized retinal masses that appeared similar to astrocytic hamartomas. In two cases the lesions subsequently disappeared spontaneously ( Figure 13.12 A–C). In one boy with bilateral pars planitis an exophytic vascularized white retinal mass developed during observation ( Figure 13.12 J and K). It is probable that most of these lesions and some of those reported in the literature as sporadic astrocytomas are products of reactive proliferation of the retinal glial cells caused by focal retinitis, focal retinal vascular leakage, chorioretinitis, vitreoretinal traction, and, less often, subretinal neovascularization. (See discussion in Chapter 10, p. 812 and Figure 10.04I-L.)
Retinal Vascular Hamartomas
There are two distinct retinal vascular hamartomas, both of which may be associated with similar hamartomas elsewhere in the body.
Retinal Cavernous Hemangiomas
Retinal and optic disc cavernous hemangiomas are sessile tumors composed of clusters of thin-walled saccular aneurysms filled with dark venous blood that give the appearance of a cluster of grapes projecting from the inner retinal surface ( Figures 13.15A, B, E, G, and J, and 13.16A ). They can be clearly differentiated from other retinal vascular malformations, including retinal telangiectasis, retinal capillary angioma (angiomatosis retinae), and arteriovenous malformations. Small isolated clumps of aneurysms are often present around the tumor mass. Varying amounts of a gray fibrous membrane may partly cover the anterior tumor surface. Plasma–erythrocytic separation within the aneurysms is common. The caliber of the major retinal vessels is unaffected by the tumor. Exudation is rare. A small hemorrhage may occasionally be present on its surface. Evidence of bleeding into the vitreous has been reported in approximately 10% of cases but is usually minimal and unassociated with significant visual loss ( Figure 13.16 F–J). Vitreous traction on larger or gliotic aneurysms is the likely mechanism for bleeding. These lesions may be seen initially at any age, but the average age is 23 years. They are more common in females (female to male ratio of 3:2). Most patients have only a solitary lesion affecting one eye; however, multiple lesions may occur in one eye or occasionally in both eyes. The visual acuity is usually normal unless the macula is directly involved with the malformation ( Figure 13.15 A and E). Visual loss associated with macular pucker, macular traction, and amblyopia occurs infrequently ( Figure 13.15 G–I). The tumor is associated with a relative or an absolute scotoma that corresponds to the tumor size. Fluorescein angiography demonstrates that the vascular tumor is relatively isolated from the retinal circulation ( Figures 13.15C, D, F, H, I, K, and L, and 13.16B and C ). Perfusion of the hamartoma occurs but is delayed and appears incomplete. The plasma–erythrocytic layering within the saccular aneurysms is conspicuous in the later phases of fluorescein angiography ( Figure 13.15 I and L). Extravascular leakage of dye from the tumor vessels does not occur in most instances.
Whereas most retinal and optic nerve cavernous hemangiomas occur sporadically, there is evidence that some patients may have a dominantly inherited neurocutaneous syndrome that includes cavernous hemangiomas of the optic nerves, chiasm, optic tracts, the prerolandic area of the cerebral cortex, the midbrain, brainstem, and cerebellum ( Figure 13.17 F), as well as the skin ( Figure 13.17 E).
Familial cavernous hemangioma has been linked to three loci on chromosomes 3q, 7p, and 7q. Familial cases of cerebral cavernous malformation (FCCM) are associated with mutations in KRIT1 (CCM1), MGC4607 (CCM2), and PDCD10 (CCM3) genes. CCM1 is located at chromosome locus 7q11–q22 and was the first one identified with the familial form of CCMs. CCM1 mutation is involved in 40 – 53% of familial CCMs and nearly half these patients have neurological manifestations before 25 years of age. CCM2 is located at 7p15–13 and mutations in this gene are involved in up to 25-40% of familial CCMs. The numbers of lesions increase less rapidly with age in patients with CCM2 than with CCM1 disease. CCM3 is localized at 3q25.2–q27 and is the least common of mutations (10%), but has near 100% penetrance and patients are more likely to present with hemorrhage and become symptomatic before 15 years of age.
The angiomas of the brain may cause seizures or subarachnoid hemorrhages. Twin retinal vessels, defined as a pair of vessels, separated by less than one venule width, that run a parallel course for more than 1 disc diameter, located at least 2 disc areas distant from the optic disc, have been described in carriers as well as affected members of families with cavernous hemangiomas of the eye and brain, as well as in family members of patients with von Hippel–Lindau (VHL) disease. Cavernous hemangiomas do not increase in size. The amount of fibrous tissue on the anterior surface increases over a period of time and is associated with partial obliteration of the tumor.
Histopathologically, the tumor is composed of multiple thin-walled interconnecting aneurysms of variable size, occupying the inner half of the retina and in some patients the optic nerve ( Figure 13.17 A–D). The endothelial lining of the large vascular channels ultrastructurally appears normal. The gray membrane that overlies part of the angiomas in some cases is of glial origin.
Photocoagulation has been used to obliterate these lesions but is unnecessary as long as the patient shows no signs of developing vitreous hemorrhage. In one case of severe vitreous hemorrhage, the tumor was partly excised during a pars plana vitrectomy. Some of the cerebral cortical angiomas causing seizures or subarachnoid hemorrhage may be resectable.
In the past, retinal cavernous hemangioma was not recognized as a distinct retinal vascular hamartoma. The more sessile and smaller lesions ( Figure 13.16 A) were often misdiagnosed as congenital retinal telangiectasis. Figure 13.16 D diagrammatically indicates the basic structural difference between retinal telangiectasis, which is a congenital anomaly affecting the structure and integrity of the intrinsic retinal vasculature, and a retinal cavernous hemangioma, which is a localized vascular tumefaction composed of cavernous vascular channels that are partly isolated from normal retinal circulation. Some of the more globular retinal cavernous hemangiomas have been reported in the older literature as angiomatosis retinae.
It is uncertain whether the retinal vascular lesion reported in one patient with CNS symptoms and the dermatologic disorder angioma serpiginosum is related to retinal cavernous hemangioma. A lesion that angiographically was similar to a retinal cavernous hemangioma was observed in an infant with blue rubber bleb nevus syndrome. The fact that the lesion spontaneously disappeared over a 4-month period suggests that it may not have been a cavernous hemangioma.
Retinal Capillary Hemangioma
The terms “retinal and optic disc capillary hemangiomas,” “angiomatosis retinae,” and “von Hippel’s disease” are used synonymously to refer to congenital hereditary capillary angiomatous hamartomas of the retina and optic nerve head. When associated with CNS and other organ involvement the condition is referred to as von Hippel–Lindau disease VHL. VHL disease is a dominantly inherited systemic hamartia that includes not only capillary angiomas of the retina, cerebellum, brainstem, and spinal cord, but also angiomas, adenomas, and cysts affecting the kidney, liver, pancreas, epididymis, and mesosalpinx. The diagnosis of VHL is justified when either a retinal angioma or a CNS angioma occurs together with one or more visceral cysts or tumors in one patient or when a single lesion of the VHL complex is found in a relative at risk. Ocular manifestations of VHL are often the first to appear. Retinal angiomas and CNS angioma both eventually occur in approximately 50% of patients with VHL. Pheochromocytomas occur in approximately 10% of patients with VHL. Approximately 25% of patients with VHL develop clear cell renal carcinomas, typically during the late stages of the disease. Polycythemia occurs in approximately 15% of patients. Twin retinal vessels, a retinal sign of dominantly inherited retinal cavernous hemangioma (see previous discussion of retinal cavernous hemangioma), occur in approximately 70% of patients with familial VHL disease and in 50% of at-risk family members without ocular angiomas. Since most patients who present with a solitary retinal angioma and a negative family history suggesting VHL fail to show other evidence of the disease, the medical evaluation of these patients with sporadic tumors probably does not need to be as comprehensive as in patients with multiple ocular tumors or other evidence of familial involvement. Identification of the VHL gene on chromosome 3p25–26 has now made it possible for suspected individuals to undergo genetic testing with a high degree of accuracy.
Capillary hemangiomas are typically red or pink tumors that may arise from the superficial retina or optic nerve head and protrude inward (endophytic angiomas) ( Figures 13.18A-I, A-II, E, 13.19H, and 13.20G–I ). When located peripheral to the optic disc, these endophytic tumors are usually associated with arteriovenous shunting between a dilated tortuous feeding artery and a draining vein ( Figure 13.19 H and I). Capillary hemangiomas may also arise from the outer retinal layers (exophytic capillary hemangiomas) ( Figures 13.18B, 13.19A, A-III, A-IV, 13.20A, F, and G, and 13.21A and D–F ). These tumors are usually not associated with evidence of arteriovenous shunting, and there is a predilection for them to develop in the juxtapapillary area. When they arise in this area they are frequently sessile and may be misdiagnosed as papilledema or juxtapapillary choroidal neovascularization because of their predilection for causing juxtapapillary serous detachment of the retina and circinate exudation extending into the macular region ( Figures 13.18 B, 13.20 A, F, and G, and 13.21 A and E). Loss of central vision may occur secondary to the accumulation of yellow, lipid-rich exudate in the macula derived from peripheral retinal angiomas. The mechanism for this accumulation is similar to that in patients with peripheral retinal telangiectasia (see Chapter 6). Loss of vision may also be caused by an epiretinal membrane distorting the macula remote from the site of the angioma ( Figure 13.19 A–C). There is a striking predilection for these epiretinal membranes to peel spontaneously and for vision to return to near normal after treatment of the peripheral angioma ( Figure 13.19 A–F). For this reason, vitrectomy for excision of the epiretinal membrane should be considered only after a 4–6-month period of observation following treatment. Floaters and visual loss may also be caused by development of a retinal tear adjacent to an angioma and subsequent rhegmatogenous retinal detachment. Vitreous traction developing at the anterior surface of the retinal angioma and adjacent retina is responsible for the retinal tear. Vitreous traction may also be a factor in the development on the tumor surface of proliferative retinopathy, vitreous hemorrhage either spontaneously or following treatment of the tumor, and tractional retinal detachment. A retrobulbar capillary angioma ( Figure 13.18 A–E) should be considered in patients with angiomatosis and unexplained visual loss.
Stereoscopic fluorescein angiography is invaluable in detecting exophytic sessile juxtapapillary capillary hemangiomas ( Figures 13.18 B and 13.20 ). Because these tumors protrude into the subretinal space adjacent to the optic disc and because they frequently arise in the papillomacular bundle area in symptomatic patients, they are difficult to treat with photocoagulation ( Figure 13.20 A–F and G–L). Fluorescein angiography in peripheral endophytic lesions shows evidence of arteriovenous shunting ( Figures 13.18 J and 13.19 I). Angiography usually shows no evidence of fluorescein staining in the macular region in those patients with lipid-rich accumulations secondary to peripheral angiomas. Angiography is particularly useful in the detection of very small lesions that may be barely visible biomicroscopically ( Figure 13.19 B and E).
Light and electron microscopy reveals that these tumors are composed of a mass of retinal capillaries, many of which have a normal endothelium, basement membrane, and pericytes ( Figure 13.22 ).
In some cases, capillaries making up these tumors may show abnormal fenestrations. Stromal cells, which some have attributed to astrocytes, separate the vascular channels and frequently contain large lipid-filled vacuoles. It is now believed that the true neoplastic component (i.e., the cells with allelic deletion at the VHL gene locus) are the foamy stromal cells. The VHL protein (pVHL) targets hypoxia-inducible factors for degradation. In the absence of pVHL there is excessive production of vascular endothelial growth factor. New vessels may develop on the anterior surface of these tumors and extend into the vitreous ( Figure 13.22 D). Exophytic tumors may have vascular communication with the choroid in some cases.
Because of their capillary nature and predilection for the development of arteriovenous fistulas and exudation, these tumors are capable of reactive proliferation and continued growth even into adulthood. Progressive intraretinal and subretinal exudation and detachment are part of the natural course of the disease. Spontaneous fibrotic involution of angiomas, however, occasionally occurs. Identification of capillary angiomas ophthalmoscopically and by fluorescein angiography during the early stages is important because treatment with photocoagulation or cryotherapy at this stage of the disease is easier. Treatment of retinal capillary hemangioma is based upon tumor size, location, presence of subretinal fluid or retinal traction, and visual acuity. The sessile exophytic juxtapapillary hemangiomas associated with loss of macular vision are difficult to treat because of the frequency with which they are located in the papillomacular bundle and because laser treatment is ineffective in stopping the exudation derived from the outer portion of the tumor that protrudes into the subretinal space. The use of photocoagulation to create a barrier between juxtapapillary angiomas and the center of the macula before they cause macular detachment and exudation may prove to be of value ( Figure 13.21 D–I).
Treatment of the peripheral angiomas with photocoagulation or cryotherapy or both is generally effective in lesions whose diameter does exceed 1 disc diameter. Treatment of larger lesions is complicated by excessive subretinal exudation and a predilection for the development of retinitis proliferans on the surface of these tumors. Techniques for treating large retinal angiomas include repeated applications of laser to the feeding artery to reduce the tumor perfusion before treating the tumor directly, use of transscleral penetrating diathermy, and pars plana vitrectomy and direct diathermy to the tumor. The use of a transvitreal arterial clip together with diathermy and removal of the posterior vitreous may prove to be useful in the treatment of large angiomas. Surgical excision of these lesions has been reported.
Photodynamic therapy has been tried with moderate results to induce the occlusion of both juxtapapillary and peripheral retinal capillary hemangiomas ( Figure 13.23 ).
Most recently, systemic and intravitreal administration of inhibitors of vascular endothelial growth factor have demonstrated mixed treatment outcomes, suggesting that the general efficacy of antiangiogenic agents in VHL is uncertain.
The differential diagnosis for juxtapapillary capillary angiomas includes juxtapapillary choroidal neovascularization, hypopigmented combined retinal and RPE hamartoma, papilledema, juxtapapillary choroidal hemangiomas and osteomas, and reactive retinal glial and vascular proliferation (see discussion in the next section). Stereoscopic fluorescein angiography is the most important study in the differential diagnosis. The diagnosis of peripheral capillary hemangiomas is not difficult in the presence of a dilated, tortuous retinal artery and vein extending from the optic disc to the tumor. Vasoproliferative tumor can be mistaken for a peripheral retinal angioma.
Vasoproliferative Retinal Tumor (Reactive Retinal Vascular Proliferation)
There may be some difficulty in differentiating peripheral exophytic angiomas from retinal telangiectasis or pseudoangiomatous masses caused by reactive vascular proliferation in patients with retinopathy of prematurity, branch vein occlusion, diabetic retinopathy, familial exudative vitreoretinopathy, pars planitis, X-linked juvenile retinoschisis, chronic rhegmatogenous retinal detachment, and retinitis proliferans ( Figures 13.21J–L and 13.24 ).
Leukemic Retinopathy and Optic Neuropathy
Loss of central vision in patients with either acute or chronic leukemia may be caused either by direct leukemic invasion of the uveal tract, retina, vitreous, or optic nerve or by other associated hematologic abnormalities, including anemia and hyperviscosity or a combination of both. Previous studies have described an overall ocular involvement in 9–90% of cases based on clinical examination or autopsy findings. A figure of about 40% based on prospective clinical studies is more realistic. However, previously published reports have been biased towards acute leukemia, suggesting that ocular involvement in more common chronic leukemia is infrequent.
Leukemic Retinopathy
The most striking fundus pictures associated with leukemia involve the retina and they typically occur in patients with acute leukemia, frequently during a period of relapse and frequently associated with severe and coexisting anemia ( Figure 13.25 ). These patients may develop dilation, tortuosity, and beading of the retinal veins; retinal vascular sheathing; cotton-wool patches; superficial flame-shaped hemorrhages; deep, round hemorrhages; white-centered hemorrhages; and subhyaloid and subinternal limiting membrane hemorrhages ( Figure 13.25 ). These changes are similar to those seen in patients with severe anemia from any cause as well as dysproteinemias (see Figure 6.84A–F). Some patients may develop grayish-white nodular leukemic retinal infiltrations and perivascular retinal infiltration ( Figure 13.26 ). Patients, particularly with chronic myelogenous leukemia, may develop peripheral retinal microaneurysms, retinal vascular closure, and retinal and optic disc neovascularization. Increased blood viscosity and reduced blood flow associated with prolonged and marked leukocytosis and thrombocytosis are probably the cause of these latter changes. Fluorescein angiography is helpful in detecting these alterations. Leopard-spot RPE alterations seen in these patients, often during the stage of remission, are probably caused by choroidal infiltration ( Figure 13.27 G–I). Pigment epithelial and retinal degeneration may occur in one or both eyes and occasionally may be accompanied by development of a macular hole.
Leukemic Optic Neuropathy
Acute visual loss may be caused by leukemic invasion of the optic nerve, usually in children with acute lymphocytic leukemia ( Figures 13.26 A–F and 13.28 A and B). In some patients the infiltration may be confined to the retrobulbar area or may involve the optic nerve head. Visual loss in these latter patients may be minimal, and the swollen optic nerve may be mistaken for papilledema associated with increased intracranial pressure ( Figure 13.28 A). These patients show a dramatic response to antimetabolite, corticosteroid, or orbital irradiation therapy, which should be instituted promptly after a CT study and lumbar puncture to exclude papilledema. Infiltration of the optic nerve may be associated with occlusion of the central retinal artery ( Figure 13.28 C–H) and vein. Progressive visual loss and optic atrophy may occasionally occur coincident with a worsening of chronic lymphocytic leukemia or blast crisis in chronic myeloid leukemia ( Figure 13.28 I–K).
