Neoplastic Diseases of the Retina




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.




13.01


Retinoblastoma.

A: Heterochromia irides, the presenting manifestation of retinoblastoma, in the right eye of this infant.

B–F: Large exophytic retinoblastoma. Note dilated tortuous retinal vessels that extend down into the substance of the tumor (B and C) and angiographic evidence of staining (D and E). Large blood vessels (arrows) were evident histopathologically near the surface of the tumor (F).

G–I: Multiple white tumor seeds were evident on the retinal surface posteriorly in this child with a peripherally located retinoblastoma. They showed no angiographic evidence of blood vessels (arrows, H). Note the necrotic center of the tumor seeds (arrow) evident histopathologically (I).

J–L: Small retinoblastoma or retinoma showing calcification (arrow, J) in a 4-year-old Indian child who had enucleation of his left eye 1 month before examination. Histopathologic examination of that eye revealed retinoblastoma with invasion of the optic nerve. He was referred for treatment of this solitary lesion noted in the right eye. He had a 6-year-old brother who had an enucleation of one eye at 6 months of age. His mother (Figure 13-04 A-E) had a retinoma. Fluorescein angiography revealed a fine capillary network within and immediately surrounding the tumor (K and L). There was extensive leakage of dye from these vessels. This patient died of widespread metastasis several months later. The clinical and angiographic appearance of this solitary nodule is quite similar to that of retinal astrocytic hamartomas and retinoma.


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 ).




13.02


Diffuse infiltrating retinoblastoma.

A–D: A 4½-year-old boy on a vision screening visit was found to have hand motion vision in the left eye. External appearance revealed leukocoria of the left eye at the time of initial screening (A). Ultrasonography revealed irregularly thickened retinal detachment with vitreous cells. Intraocular mass or intraocular calcification, features diagnostic of retinoblastoma were not present (B). Magnetic resonance imaging confirmed enhancing thickened retina (C). Gross examination of the enucleated globe confirmed findings of the imaging studies. Histopathology established the diagnosis of a diffuse infiltrating retinoblastoma (D). Poor prognostic factors for metastasis such as choroidal invasion, retrolaminar optic nerve extension, and extrascleral extension were absent.



13.03


Necrotic retinoblastoma.

A–D: A 13-month-old boy presented with left-sided orbital cellulitis. He did not have past medical or ocular history, and family history was negative for ocular tumor or other abnormalities. Examination of the left eye was difficult due to lid edema and conjunctival chemosis. Anterior examination of that eye revealed a diffusely hazy cornea, a fixed mid-dilated pupil, and brown-colored irides. Intraocular pressure in the left eye was 22 mmHg (A). The view of the posterior pole in the left eye was unobtainable. B-scan ultrasonography revealed a large intraocular mass extending from the optic disc with a maximal height of 11 mm (B). Multiple small hyperechogenic intensities were visible within the mass and were persistent at low gain, consistent with calcium deposition. Imaging with magnetic resonance imaging confirmed left orbit pre- and postseptal edema with an enhancing lesion along the posterior aspect of the left globe (C). The patient was started on topical prednisone and atropine, as well as oral prednisone. This treatment regimen led to partial improvement of the orbital inflammation. Examination under anesthesia confirmed that the right eye was normal. Examination of the left eye confirmed conjunctival chemosis, corneal edema, rubeosis, hyphema, and heterochromia. Additionally, fundus evaluation revealed vitreous hemorrhage with an ill-defined mass at the nasal quadrant. Despite the rubeosis, intraocular pressure was 13 mmHg in the left eye, likely indicating a prephthisical state. Given the clinical diagnosis of necrotic retinoblastoma, enucleation of the left eye was performed. Histopathology confirmed a retinovitreal vascular and inflammatory mass consisting of fibrin, inflammatory cells, detached and degenerating retina, prominent vasculature, and a small amount of necrosis, and calcification (D). Despite examination of several cuts of the globe, there was no evidence of retinoblastoma cells. It was assumed that the retinoblastoma had undergone infarction and was no longer detectable.

(From Sachdeva et al., with permission.)


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.




13.04


Retinoma/retinocytoma.

A–E: This asymptomatic 23-year-old mother of the patient illustrated in Figure 13.1J–L had three retinomas (A–C). The one in the right macula had club-shaped calcified opacities (arrow, A) within the zone of atrophic retina. Angiography showed perfusion of a network of retinal vessels and underlying large choroidal vessels in the area of the lesion (D). There was some staining of the periphery of the lesion (E).

F: Probable retinoma or astrocytic hamartoma in an asymptomatic 4-year-old child with no other ocular abnormalities and a negative family history.

G–I: Retinoma with calcification (arrow, G) in a 21-year-old asymptomatic mother who had a child with bilateral retinoblastomas. Note the “fish-flesh” tumor (G) and the rich vascular network and localized staining evident angiographically (H and I).

(F, courtesy of Dr. Bernard H. Doft.)



13.05


Retinoma/retinocytoma.

A–D: A 32-year-old Caucasian man was examined because his two children were diagnosed with bilateral multifocal retinoblastoma before the age of 1 (A). He reported a history of “amblyopia” in the right eye with a visual acuity of 20/40. Dilated fundoscopy showed two circumscribed chorioretinal atrophic lesions in the temporal region of the macula (B). Nonspecific retinal pigment epithelium (RPE) change of the margins and minimal intrinsic calcification were evident. Fluorescein angiogram showed transmission defects indicative of RPE and choroidal atrophy (C). Optical coherence tomography confirmed marked retinal atrophy within the lesions (D). No retinal tumor was identified.

The patient, his second daughter, and her biological mother underwent genetic testing. A heterozygous G to C substitution in the final base position of exon 19 of the RB1 gene (c.1960G→C (V654L)) was identified in the patient and his daughter on sequence analysis of peripheral blood. This mutation caused missplicing and out-of-frame skipping of exon 19 that resulted in a subsequent termination codon, and unstable mRNA with subsequent reduction of the retinoblastoma protein. The mother did not have the mutation.

Teratoma simulating retinoblastoma.

E–K:Two gray elevated tumors in the right fundus of this 2-month-old girl born at 32 weeks by cesarean section. Note the absence of large feeder vessels dipping into the tumor (E). Visual acuity was no light perception; the left eye was normal. Fluorescein angiography showed increased vascularity within the mass and late hyperfluorescence (F). The tumors grew in size over the next 2 months, and subsequently developed a total retinal detachment (G), neovascularization of the iris, and buphthalmos. Enucleation (H) and histology revealed cartilage, muscle, respiratory epithelium, glandular, and brain tissue consistent with a teratoma (I and J). The child had been delivered by elective cesarean section at 32 weeks for a sacral teratoma (K) that was operated upon soon after birth.

(E–K, courtesy of Dr. David Abramson; E and F, also from Yannuzzi, Lawrence J., The Retinal Atlas, Saunders 2010, 978-0-7020-3320-9, p.211.)


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.




13.06


Retinoblastoma treated with iodine episcleral plaque.

A 6-month-old girl with a familial unilateral retinoblastoma of the macular region. The tumor was 9×9 mm in basal dimension and was 4 mm in height.

A: Associated subretinal fluid and seeding (vitreous and subretinal were absent). The tumor was treated with iodine-125-notched episcleral plaque.

B: Fundus appearance 4 weeks later. The tumor has remained regressed over a period of 3 years.


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.




13.07


Retinoblastoma treated with systemic chemotherapy.

A: A 6-month-old girl presented with bilateral retinoblastoma (group D, right eye; group E, left eye). She was treated with chemoreduction and sub-Tenon carboplatin (cycles 2–4). She also received adjuvant focal therapy (cryotherapy and transpupillary thermotherapy).

B: Note dramatic reduction in tumor size. Subsequently, there was recurrence of the macular tumor, which failed to respond to iodine-125 plaque. The left eye was eventually enucleated.


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.




13.08


Intra-arterial chemotherapy for retinoblastoma.

A–J: This 10-month-old girl, one of a nonidentical set of twins with unilateral retinoblastoma, had a large mass with a total retinal detachment and a flat electroretinogram (ERG) (A and B). She received 1 cc of melphalan intra-arterially once a week for 3 weeks. The catheter that is 450 μm in diameter is threaded up the internal carotid artery into the ophthalmic artery (C–E). Melphalan is injected in a pulsed manner so as not to obstruct the blood flow through the artery. The retinal detachment disappeared, the tumor showed cottage-cheese type of regression, and 60% of her ERG amplitudes returned (F).

G–J: Another child with bilateral multiple tumors (G and H) shows complete regression (I and J).

Medulloepithelioma.

K: A 3-year-old white girl was evaluated for a white pupillary reflex in her right eye. Examination revealed a pigmented ciliary body mass with a fibrovascular membrane surrounding the lens. Following initial resection, the eye was enucleated because of tumor recurrence.

(A–J, courtesy of Dr. David Abramson; H, also from Abramson et al. © 2010, American Medical Association. All rights reserved. A, F, G, H, I, and J, also from Yannuzzi, Lawrence J., The Retinal Atlas, Saunders 2010, 978-0-7020-3320-9, p. 212; K, from Shields et al. © 2002 American Medical Association. All rights reserved.)


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 ).




13.09


Retinal astrocytic hamartoma associated with tuberous sclerosis.

A–C: Multiple astrocytic hamartomas of the optic nerve head and retina in a 35-year-old woman with tuberous sclerosis (A). She had a lifelong history of generalized seizures. She had five mentally retarded children. Examination revealed sebaceous adenoma and subungual fibromas of the fingers and toes (Figure 10.15B). Multiple endophytic astrocytic hamartomas of the retina were present in the left fundus. The lesions were elevated, globular, and semitranslucent. Retinal vessels could be seen within some of these tumors. Several of the tumefactions showed evidence of early calcification (arrow, A). Angiography revealed a capillary network within the hamartomas (B and C). These capillaries were permeable to fluorescein dye, and there was evidence of diffusion of the dye into the vitreous (C).

D–F: A partly calcified cystic astrocytic hamartoma in a 9-year-old girl with tuberous sclerosis. She had a history of seizures but was not mentally retarded. Note the mulberry-like areas of calcification within the large cystic lesions. Two smaller hamartomas were present within the optic nerve head (arrow) and inferior to the papillomacular bundle. Fluorescein angiography demonstrated dilation of the capillary network and staining within these tumors (E and F).

G–I: Large astrocytic hamartoma of the left macula of an 8-year-old boy with tuberous sclerosis. He had sebaceous adenoma and a large fibroma of the left lower lid (G).





13.10


Retinal astrocytic hamartoma associated with tuberous sclerosis.

A–D: Sebaceous adenoma of the nose and cheeks and a solitary hamartoma of the forehead (A). Subungual fibroma (arrow, B). Skull X-ray film of patient shown in (A) showed multiple calcified astrocytic hamartomas (arrows) characteristic of tuberous sclerosis (C). Enhanced computed tomography scan showed multiple astrocytic hamartomas in the paraventricular system of a patient with tuberous sclerosis (D). E and F: Photomicrograph of calcified astrocytic hamartoma of the optic disc and adjacent retina of a 17-year-old boy with sebaceous adenoma. The calcified central portion of the tumor was lost in sectioning (E). Endophytic noncalcified astrocytic hamartoma of the peripheral retina of the same patient in E (F).

Growth of astrocytic hamartoma

G–J: In 1978, this 9 year old male patient was evaluated at Wilmer with a calcified astrocytic hamartoma in the right eye (G) and 4 lesions in the left eye consisting of 2 atrophic patches above the ST arcade, 1 calcified and another non calcified hamartoma along the IT arcade (H). The optic nerve was swollen with blurred margins suggesting presence of abnormal tissue within its substance. He presented to Vanderbilt in 1997 with a vitreous hemorrhage in his left eye from a large partly calcified and partly fibrous hamartoma that had grown from the optic disc (J). Note the previously non calcified tumor inferior to the optic disc was now calcified (arrow). The calcified astrocytoma in the right eye was unchanged (I). The left eye needed a vitrectomy a year later for further vitreous hemorrhage.

Spontaneous regression of astrocytic hamartoma

K–N: This 11 year old boy with known history of tuberous sclerosis presented with an inferior scotoma in his right eye. He was found to have a circumscribed gelatinous appearing vascular lesion superonasal to the disc associated with lipid and blood (K). Fluorescein angiogram showed vascularity of the lesion without evidence of retinal nonperfusion elsewhere (L). The lesion began to regress spontaneously 2 months later with gradual resolution of the scotoma. By 4 months the lipid, blood and vascularity of the lesion had regressed considerably (M and N).

(E and F, from Zimmerman and Walsh. K-N, Dr. Affortit)



13.11


Retinal astrocytic hamartomas not associated with tuberous sclerosis.

A–C: Large calcified exophytic astrocytic hamartoma of the retina in a 15-year-old boy without other evidence of tuberous sclerosis (A). He gave an 8-year history of defective vision in the right eye first noted while firing a gun. The family history and past medical history were negative. Visual acuity in the affected eye was 20/300. Angiography (B and C) revealed an extensive capillary network that extended down into the tumor. There was leakage of dye from this network and pooling of dye within the cystic areas of the tumor (arrow, C).

D–F: Cystic astrocytic hamartoma of the retina in a 10-year-old girl without other evidence of tuberous sclerosis (D). This was an incidental finding, and her eye examination was otherwise normal. Note the white, finely polycystic tumor arising from the inner retinal layers just superior to the left macular region (D). Note that most of the retinal vessels are hidden within this cottony tumor. Fluorescein angiography revealed a network of retinal vessels within the tumor and late leakage of the dye (E and F).

G–I: Elevated, vascularized, partly calcified retinal mass in a healthy 17-year-old boy with no family history of tuberous sclerosis or retinoblastoma.

J–L: Nonpigmented, pedunculated, vascularized astrocytic hamartoma in the juxtapapillary region of a 41-year-old man with a 3-week history of blurred vision in the right eye (J and K). This was misinterpreted as a melanoma because of an increased phosphorus-32 uptake test (100%). Histopathologic examination of the enucleated eye revealed a retinal astrocytic hamartoma (L).

(J–L, from Ramsay et al. )



13.12


Lesions of uncertain etiology simulating retinal astrocytic hamartomas.

A–C: Endophytic retinal tumor in a 38-year-old woman with a 3-month history of blurred vision in her left eye (A). Her past history revealed convulsions unassociated with fever at 1 year of age. It was otherwise unremarkable. There were many dilated blood vessels present within the tumor, which was located in the retina inferior to the left macula (A). Angiography demonstrated an extensive vascular network within the tumor and late leakage of dye (B and C). Medical evaluation failed to reveal other evidence of tuberous sclerosis. The patient was re-examined 10 months later, and there was no change in the appearance of the lesion. Examination 3 years after her initial visit revealed that the lesion had disappeared, leaving only a minor disturbance in the retina in the area of the tumor. Because of its spontaneous disappearance, it is doubtful that it was an astrocytic hamartoma.

D–F: Sessile presumed astrocytic hamartoma in a healthy 42-year-old man with a recent history of blurred vision in the left eye. He had a small angioma and a pigmented nevus of the conjunctiva in the same eye. His visual acuity was 20/25, left eye, and 20/20, right eye. Note the ill-defined gray-whitening of the retina in the inferonasal macular area (arrowheads, D) and the cystoid macular edema (arrow, D). Angiography revealed evidence of a capillary network within the lesion and evidence of intraretinal edema (E and F). Two months following laser photocoagulation the vision had improved to 20/20. He had no other findings of tuberous sclerosis.

G–I: This 28-year-old woman complained of blurred vision in the left eye. Examination of the right eye was normal. In the left eye she had a gray, slightly elevated retinal tumor that straddled the major retinal vascular arcades in the superior macular area (G). Angiography showed evidence of the vascular nature of this lesion (H and I). There were no other stigmata of tuberous sclerosis. Several months later she had developed extensive exudative maculopathy. She was lost to follow-up.

J–L: An elevated, vascularized, and partly calcified tumor developed in this 17-year-old boy who when he was first examined at 10 years of age had the typical findings of bilateral pars planitis and no evidence of an intraocular mass. Stereo angiograms (H and I) revealed the highly vascular nature of this exophytic mass, which probably was the result of a reactive proliferation of the retinal vasculature and glial cells in response to the intraocular inflammatory disease.



13.13


Retinal astrocytoma treated with photodynamic therapy.

A–D: A 45-year-old Caucasian female with an unremarkable past medical history was referred for evaluation of a peripapillary tumor associated with a scotoma in the right eye (A). On initial evaluation, visual acuities (VA) were 20/20 in both eyes. An ill-defined, translucent, yellow-white superficial mass along the superotemporal margin of the optic disc and extending into the retina was observed (B). Prominent intrinsic vessels as well as dilated collateral vessels were present. The macula was flat; however, lipid exudates were present superonasal to the fovea, and a few retinal striae were noted in the papillomacular area. Based on morphological characteristics, the diagnosis of retinal astrocytoma was made with a decision to observe for progression. At a 6-month visit, VA remained 20/20; however, the lipid exudates were noted to be approaching the foveola (C). Four months after two sessions of standard-fluence photodynamic therapy (TAP; 1.5-mm spot covering the entire tumor up to the superotemporal edge of the optic disc), VA remained 20/15, the lipid exudates were diminished, and some gliosis of the tumor could be appreciated (D).


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.




13.14


Retinal achromic patch of tuberous sclerosis. A: Fundus photograph of a retinal achromic patch.

(From Turell et al., with permission.)


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.




13.15


Retinal cavernous hemangioma.

A–D: Large macular cavernous hemangioma of the retina was first observed in this 17-year-old female who presented at age 5 years because of left esotropia. Her visual acuity in the left eye was 20/30. Note the fluid level in some of the incompletely perfused aneurysms in C and D. Minimal change occurred in its appearance during this period of follow-up, but the visual acuity decreased to counting fingers only. She had no evidence of angiomas elsewhere.

E and F: Cavernous hemangioma in the left macula of a healthy 7-year-old boy (E). Note the delay in dye perfusion of this tumor (F). Five years later the tumor was unchanged.

G–I: Cavernous hemangioma of the retina in a 30-month-old girl who developed right esotropia at 6 months of age. Her general health and physical examination were normal except for the presence of a few spider angiomas on her hands and wrists. An identical twin sister was normal except for similar spider angiomas on the hands. There was an irregularly elevated vascular mass in the superotemporal quadrant of the right eye (G) that was composed of dilated, oval or rounded, thin-walled, saccular blood vessels that gave the appearance of a mass of grapes lying on the inner retinal surface and protruding into the vitreous. The tumor extended from the ora serrata almost into the macular area of the right eye. Fluorescein angiography showed slow and incomplete filling of the aneurysms making up the tumor (H and I). Note delay in venous drainage (arrow, H) from the area of the tumor. Approximately 30 minutes after dye injection there was still incomplete perfusion of the tumor. Note the level of dye in the large tumor cyst (arrow, I). The patient was lying on her left side in the operating room during the angiographic study.

J–L: Cavernous hemangioma of the optic nerve head in an asymptomatic 51-year-old woman. Visual acuity was 20/15. Angiography revealed slow perfusion, plasma–erythrocytic separation, and minimal staining (K and L).

(G–L, from Gass. )





13.16


Retinal cavernous hemangioma.

A–C: Cavernous hemangioma discovered in a 27-year-old woman who was hospitalized because of a generalized seizure. An electroencephalogram revealed low voltage in the left cerebral hemisphere. A skull roentgenogram and a carotid arteriogram were normal. Her father died at 49 years of age with status epilepticus. Autopsy of the father revealed a focal cavernous hemangioma in the midbrain, pons, and cerebellum (Figure 10.20F). The woman’s eye examination was normal except for the presence of a slightly elevated sessile cavernous hemangioma involving the inferonasal quadrant of the right eye (A). A small subretinal and deep retinal hemorrhage was present (arrow, A). Angiography revealed delayed and incomplete perfusion of the cavernous hemangioma (B and C). Note evidence of plasma layering (arrows) and minimal evidence of extravascular escape of dye. A general physical examination revealed a stellate angiomatous hamartoma of the right chin and several cherry angiomas of the thigh.

D and E: This 45-year-old otherwise healthy male suffered constant severe headache for 5 months associated with occasional dizziness and nausea. He had no visual complaints. Magnetic resonance imaging of his head to evaluate headache revealed more than 50 small vascular malformations in various parts of his brain (E). There was a family history of spine and neck lesions in his sister, a cousin with brain and abdominal tumors, an uncle with a brain lesion, and a son with epilepsy. His vision was 20/20 in each eye. He had 3–4 aneurysmal dilations in the far temporal periphery of his left fundus (D). The right eye was normal. Both he and his sister, who was evaluated at the Mayo Clinic, were positive for CCM1 gene at the 7q locus that codes for KRIT1 protein. He tested negative for the VHL gene.

F–K: This 13-year-old girl presented with floaters secondary to spontaneous vitreous hemorrhage from thin-walled saccular malformations in her left eye (F, H, J, and K). The lesions were extensive, involving the superior half of the fundus. Several of the aneurysmal walls were made up of glial tissue alone; these did not fill with fluorescein (arrows, F and G). Typical separation of blood cells and plasma was seen in some of them in the late angiograms (I). Of significance is the involvement of the larger vein walls with the malformation (arrow heads, F and G), which is unusual since these aneurysms are believed to occur at the capillary level (see Figure 13.16 L). She was kept under observation and the vitreous hemorrhage cleared over 5 months without treatment (K). She had an ipsilateral cavernous malformation of the corpus callosum. Gene testing is underway.

L: Diagram showing structural differences of: (1) normal retinal vessels; (2) diffuse and focal vascular dilation and permeability alteration in retinal telangiectasis; and (3) localized vascular malformation (hamartoma) arising from the capillary bed in cavernous hemangioma.

(A and B, from Gass ; F–K, courtesy of Dr. Stephen J. Kim.)


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).




13.17


Retinal cavernous hemangioma.

A and B: Histopathologic condition of cavernous hemangioma of the retina in a 2-year-old girl whose eye was enucleated with the mistaken diagnosis of retinoblastoma. The sessile retinal tumor was composed of multiple, thin-walled, dilated blood vessels that replaced the inner half of the retina (A). The arrow indicates pigment-laden macrophages in the subretinal space. The retinal detachment was artifactitious. A high-power view of the lesion revealed dilated, endothelium-lined aneurysms interconnected by narrow channels (arrows, B). These relatively isolated vascular saccules account for the sluggish circulation and plasma–erythrocytic separation demonstrated angiographically in these lesions.

C: Histologic condition of cavernous hemangioma of the optic nerve and adjacent retina.

D: Histopathologic condition of a retrobulbar cavernous hemangioma of the optic nerve head. This was an incidental finding in the optic nerve of a 3-month-old white girl who was born prematurely with a birth weight of 2 lb 14 oz (1.3 kg).

E: A slightly raised cutaneous cavernous hemangioma on the arm of a patient with a retinal cavernous hemangioma. This patient had generalized seizures. One son, who had multiple cutaneous angiomas on the face, leg, and foot, died soon after surgical excision of a cavernous hemangioma of the brain.

F: Cavernous hemangioma of the midbrain in the father of the patient illustrated in Figure 13.16 A-C.

(A, from Hogan and Zimmerman ; B, from Gass ; C, from Davies and Thumim ; D, from Spencer ; E, courtesy of Dr. L.L. Calkins; F, from Gass. )


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.




13.18


Retinal capillary hemangiomas.

A: Diagram showing sites of origin of retinal capillary angiomas. I, Endophytic angioma of the optic nerve head. II, Endophytic peripheral retinal angioma. III, Exophytic juxtapapillary angioma. IV, Exophytic peripheral retinal angioma. V, Intraneural angioma.

B–D: This 36-year-old woman noted blurred vision in the left eye caused by a juxtapapillary capillary hemangioma (arrow, A). She had no other stigmata of von Hippel–Lindau disease. Stereoscopic angiography revealed the sessile capillary angiomatous nature of the lesion (C and D).

E–J: Juxtapapillary (E) and peripheral capillary hemangioma (F) in a 10-year-old girl with no evidence of extraocular involvement with angiomatosis. Angiography revealed the capillary nature of the tumors (G and H), shunting of blood from the arterial to the venous side of the circulation in the region of the peripheral tumor (H), and late staining (I and J).

(A, from Gass. )



13.19


Retinal capillary hemangiomas.

A–F: Peripheral retinal capillary angiomas (A and B) and macular pucker (C) in a 23-year-old woman complaining of recent loss of central vision in the right eye. Her past medical history and family history were unremarkable. Visual acuity in the right eye was 20/70 and in the left eye was 20/15. In addition to the solitary angioma in the superotemporal fundus (A), there was a small angioma nasally (arrow, B). Fluorescein angiography demonstrated both lesions (D and E). The retinal tumors were treated with cryopexy and photocoagulation. Soon afterward the preretinal membrane spontaneously detached from the inner surface of the macula and remained attached to the optic nerve head (arrow, F). Her visual acuity improved to 20/25+3.

G–K: Exudative maculopathy (G) caused by an endophytic angioma nasal to the right optic disc (H and I) in this 23-year-old woman who presented with a 2-month history of blurred vision in the right eye. Her family history and past medical history were negative. Computed tomography scan of the brain was negative. Visual acuity was 20/70, right eye, and 20/20, left eye. Laser photocoagulation of the feeder artery and tumor resulted in a vitreous hemorrhage (J). Six years later her visual acuity was 20/40. Note the vitreoretinal traction, nasal displacement of the optic disc and foveal center (arrow, K), and resolution of the macular exudation.



13.20


Retinal capillary hemangioma.

A–E: Sessile juxtapapillary retinal angioma (A) misdiagnosed as papilledema in a 31-year-old woman with a 5-month history of intermittent headaches. She had recently been hospitalized for a thorough neurologic evaluation, which was negative. Her visual acuity in both eyes was 20/20. Angiography revealed a capillary angioma, largely confined to the outer two-thirds of the retina (B and C). She developed chronic serous detachment of the macula, and her visual acuity decreased to 20/50 in the right eye. She had two courses of argon laser grid pattern treatment (D) to the tumor that resulted in resolution of the intraretinal and subretinal exudate (E). At the time of her last photograph, made 9 years after her initial treatment, her visual acuity was 20/30.

F–L: This 19-year-old woman had a history of blurred vision and optic disc lesions first noted at age 15 years. She was asymptomatic in the right eye. Visual acuity was 20/30, right eye, and 20/400, left eye. There was exudative maculopathy associated with a juxtapapillary capillary angioma bilaterally (arrows, F and G). The angioma in the left eye was treated with argon green laser (H) and was retreated 4 months later. At that time the acuity in the right eye had decreased to 20/50 and the angioma (J) was treated with laser. One month later the angioma in the right eye (K) was retreated. Forty-two months later her visual acuity in the right eye was 20/40 and the left eye was 20/60. There was improvement in the exudation in both eyes (I and L). At the time of her initial examination magnetic resonance imaging of the brain revealed a left cerebellar hemangioblastoma that was successfully removed. There was no family history of angiomatosis.





13.21


Natural course of retinal capillary hemangiomas.

A–F: Exophytic capillary angioma in a 17-year-old boy complaining of blurred vision in the left eye (arrows, A and B). At that time there were no other lesions in either eye. Medical evaluation for extraocular evidence of angiomatosis was negative. Over the subsequent 10 years he had gradual enlargement of the angiomatous mass that grew through the center of his macula despite laser photocoagulation. During this time he developed a small angioma in the inferior fundus of the same eye and a small angioma on the right optic disc (arrow, C). This remained unchanged from 1979 until 1992, when he returned because he had noticed a paracentral scotoma in the right eye (D). Meanwhile he had developed total retinal detachment and had no light perception in the left eye. Laser treatment along the temporal margin of the tumor was advised and was refused. He returned in 1995 complaining of difficulty reading. His acuity was 20/15 but he had a large cecocentral scotoma associated with exudative retinal detachment and further enlargement of the angioma (E). In an effort to isolate the tumor from the center of the macula a row of krypton red laser burns was placed near the temporal margin of the tumor (arrow, F). Nine months later the exudate was gone and he was asymptomatic.

G–I: Gradual enlargement of juxtapapillary angioma occurred in this patient. G, March 1983. H, March 1985. I, September 1996. Several years later the patient had severe loss of central vision because of exudative retinal detachment. Use of a barrier-type laser treatment and direct treatment of the angioma early (G and H) may have prevented or delayed the loss of central vision.

J–L: A juxtapapillary angioma (arrows, K) developed 5 years later at the site of a choroidal rupture (arrow, J) in this 19-year-old woman with Stargardt’s disease. Her sister had Stargardt’s disease, but her family history was negative otherwise. This tumor may be a secondary angioma resulting from reactive glial vascular proliferation at the site of chorioretinal scarring.

(G–I, courtesy of Dr. Arnold Patz; J–L, from Retsas et al. )


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 ).




13.22


Histopathology of retinal capillary hemangioma.

A–D: Histopathologic condition of pre-exudative phase of retinal angioma in a 48-year-old man who complained of paresthesias of the arms and legs. His mother had died of a brain tumor at 40 years of age. His neurologic examination was normal. His cerebrospinal fluid protein was 300 mg/dl. A myelogram revealed a block at the first cervical vertebra, and a right brachial arteriogram revealed a large vascular tumor at the level of the brainstem. A cerebellar hemangioblastoma was found at the time of craniotomy. The patient died soon afterward. An autopsy revealed multiple cysts of the right kidney and pancreas. Gross examination of the right eye revealed two nodular retinal angiomas. The larger one (arrow, A) measured 1.5 mm. The retinal vessels leading to both angiomas were dilated. Histopathologic examination revealed dilated feeder vessels (arrow, B) supplying the capillary tumor, which replaced the normal retinal architecture and protruded into the vitreous cavity. A high-power view of the tumor showed that it was composed of capillary-sized blood vessels lined by flattened endothelial cells (C). Strands of fibroglial tissue and capillaries were present on the surface of the tumor and extended into the vitreous (arrow, D).

E and F: Clinicopathologic correlation of an exophytic capillary angioma of the optic nerve head and peripapillary retina simulating chronic papilledema in a 29-year-old man who first noted blurred vision in his right eye in 1959. He had similar swelling of both optic discs associated with exudative detachment of the surrounding retina (E). Over the subsequent 3 years he had progressive loss of vision in both eyes, and because of the uncertainty of the diagnosis the left eye was enucleated. His family history was positive for an angioblastic meningioma in his mother, a pheochromocytoma in a niece and a nephew, and bilateral optic nerve lesions similar to those in the patient in a nephew. Histopathologic examination revealed an exophytic capillary hemangioma involving the juxtapapillary retina and optic nerve head (arrows, F).

(A–D, from Nicholson et al. ; E and F, from Darr et al. © 1966, American Medical Association. All rights reserved.)


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 ).






13.23


Retinal capillary hemangioma treated with photodynamic therapy.

A–F: A 20-year-old man with solitary retinal capillary hemangioma with extensive exudation involving the macula (A and B). In addition to the hemangioma there are several small microaneurysms beyond the tumor suggesting associated retinal telangiectasia. In addition to the tumor vasculature filling up, fluorescein angiogram shows dilated capillary bed, peripheral nonperfusion and microaneurysms, suggesting associated Coats’-like vascular malformation (C). Family history, systemic evaluation, and genetic testing were negative for von Hippel–Lindau disease. Note shrinkage and gliosis with resolution of subretinal fluid and hard lipid exudation 3 months following treatment with a single session of standard-fluence photodynamic therapy (E and F).

G–M: A 76-year-old woman was observed for at least 10 years for a “retinal lesion.” Her vision decreased to 20/30– in this eye and a HVF showed paracentral scotoma. A strawberry-shaped capillary hemangioma was seen obscuring most of the optic disc (G and H). Angiogram showed that the vessels within the mass filled and leaked mildly, appearing like a smoke stack emanating from the superior pole of the tumor (I). There were lipid exudates inferior to the disc that extended to the fovea. Optical coherence tomography revealed cystic swelling of the inner retina in the vicinity of the tumor (J) and mild thickening of the fovea (K). She had no family history suggestive of von Hippel–Lindau and gene testing for von Hippel–Lindau returned negative. She underwent a reduced-fluence photodynamic therapy, which shrank the tumor considerably to reveal the underlying optic disc (L), lipid exudates gradually disappeared, and the foveal cysts resolved. Her vision remained at 20/30 eccentrically. However, the lesion regained some size at 13-month follow-up (M), and it has remained stable at 3 years. The vision returned to 20/20.


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.




Retinal Telangiectasis and Arteriovenous Aneurysm


Retinal telangiectasias, macrovessels, arteriovenous aneurysms, and arteriovenous communications are not true tumors and are discussed in Chapter 6.




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 ).




13.24


Vasoproliferative tumor.

A 15-year-old female with neurofibromatosis type-1 was referred for evaluation of painless floaters in her right eye of 1 month’s duration. Vision was absence of light perception in the left eye as a result of a left optic nerve glioma that had been treated with chemotherapy. In the right eye, visual acuity was 20/30 and intraocular pressure (IOP) was 12 mmHg. Anterior-segment examination revealed numerous Lisch nodules, florid neovascularization of the iris, and 360° neovascularization of the angle (A). Dilated fundus examination of the right eye revealed 1–2+ anterior vitreous cells and an inferiorly located pink, elevated vascular mass with areas of surrounding subretinal fluid and lipid accumulation (B). Dilated tortuous feeder vessels, as seen with retinal capillary hemangioma, were not observed. The patient had just completed a tapering course of oral steroids (starting dose 60 mg QD, tapered by 20 mg/week) that had been prescribed by the referring physician. Patient was treated with double freeze–thaw transconjunctival cryotherapy and simultaneous intravitreal injection of bevacizumab (1.25 mg in 0.05 ml).

One week later, the NVI was nearly completely resolved and the IOP was 13 mmHg. One month after treatment the retinal detachment overlying the vasoproliferative tumor had resolved and the tumor appeared less vascular with fibrotic changes. A second injection of intravitreal bevacizumab was given for persistent NVI. Over the course of the next 6 months the NVI resolved and the tumor underwent fibrotic changes with chorioretinal atrophy and hyperpigmentation at the posterior margin (C). At 36 months after initial treatment, clinical findings were stable, with vision of 20/30.

(From Hood et al., with permission.)




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.




13.25


Hemorrhagic retinopathy associated with acute leukemia.

A–E: This man with acute myelogenous leukemia developed bilateral loss of vision. Five months later after chemotherapy his vision had improved and there was marked improvement in the retinopathy.

F–H: This man with acute lymphatic leukemia experienced bilateral loss of vision. Note the white-centered hemorrhages and superficial retinal hematoma (arrow, G).

I and J: Before death this patient with chronic granulocytic leukemia had extensive perivascular infiltration and nodular white and hemorrhagic masses in the retina. Histopathologic examination of the eyes revealed massive perivascular leukemic infiltration and hemorrhagic nodular leukemic tumefactions lying beneath the internal limiting membrane (arrow).

(From Kuwabara et al. © 1964, American Medical Association. All rights reserved. )



13.26


Leukemic infiltration of the retina and optic nerve.

A–F: This 6-year-old girl developed lymphocytic leukemia in December 1966. She was treated with vincristine, prednisone, and methotrexate. Because of visual loss she was seen at the Bascom Palmer Eye Institute on November 8, 1967. Visual acuity in the right eye was finger counting and in the left eye was hand movements. The optic nerve head in both eyes was obscured by a massive cellular infiltration that extended into the retina in the peripapillary region (A and B). There was pronounced perivenous infiltration. By December 3, 1967, the degree of infiltration in the right eye had improved (C). There was further improvement by March 13, 1968 (D). On June 11, 1968, her visual acuity had returned to 20/20 in this eye. By November 14, 1968, the patient was quite well and was attending school. Her vision in the right eye was 20/20. Most of the perivascular infiltration had disappeared (E). The optic nerve head was pale, and its margins were blurred. The visual acuity in the left eye was 20/200, and there was still evidence of perivascular infiltration (F).

G–J: Leukemic infiltration of the retina. This 8-year-old girl with acute leukemia developed loss of central vision in the left eye. The optic nerve head was blurred, and there were scattered retinal hemorrhages in the macula and elsewhere in the fundus (G). In the periphery there was pronounced perivascular sheathing, presumed to be secondary to leukemic infiltration (H). Fluorescein angiography revealed dilation and microaneurysmal formation in the retinal capillary bed and widespread leakage of dye from the capillaries and veins (I and J).



13.27


Leukemic retinopathy.

A–F: This 16-year-old African American male woke up with sudden painless loss of vision in both eyes to hand motion. He had mild pulsating eye pain bilaterally. The anterior segment was quiet. The right eye revealed massive retinal, preretinal, and subretinal hemorrhages in the posterior pole (A–C). The mid-retina showed targetlike intraretinal hemorrhage with white center. Fluorescein angiogram revealed blockage of choroidal fluorescence from the blood (D). His laboratory investigations revealed hemoglobin of 3.4 with a hematocrit of 9.6, a platelet count of 4000, and a white blood cell count of 4000, suggesting severe pancytopenia. Computed tomography of the head was normal. Bone marrow biopsy confirmed acute lymphocytic leukemia of T-cell lineage. He was treated with intrathecal methotrexate weekly, vincristine, 6-thioguanine, and Bactrim and received several blood transfusions and platelet transfusions. The visual acuity improved to 20/50 in the right eye and 20/100 in the left eye. Two months later hemorrhages resolved with some pallor to the optic disc and residual pigmentary changes in the macula (E, F).

(Courtesy of Dr. William Mieler.)


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).


Mar 9, 2019 | Posted by in OPHTHALMOLOGY | Comments Off on Neoplastic Diseases of the Retina
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