Glial tumors of the retina. The 2009 King Khaled Memorial Lecture

Abstract

Retinal glial tumors and pseudotumors can be classified into astrocytic hamartoma, acquired retinal astrocytoma, massive gliosis, and focal nodular gliosis. Each has different clinical manifestations. Astrocytic hamartoma is usually seen patients who have some manifestations of tuberous sclerosis complex (TSC). It can occur as a noncalcified or calcified variety, and often a combination of the two, and has fairly typical features with fluorescein angiography, ultrasonography, and optical coherence tomography. Although it is generally a stationary lesion, an aggressive variant seen in very young children with TSC can lead to exudative retinopathy, retinal detachment, and neovascular glaucoma. Acquired astrocytoma general occurs in somewhat older individuals who do not have TSC. Like the aggressive form of astrocytic hamartoma it can lead to exudative retinopathy and exudative retinal detachment. Pseudoneoplastic diffuse retinal gliosis can occur as massive glial proliferation in eyes with prior trauma, Coats disease, retinal angiomatosis and other conditions and often occurs in blind eyes. Pseudoneoplastic focal retinal gliosis is characterized by a very superficial, white, noncalcified lesion in otherwise normal eye in somewhat older individuals. Recognition of these glial lesions is important because they can resemble malignant tumors and have different clinical courses and complications.

1. Introduction

Like the central nervous system, the retina contains supportive glial cells known as astrocytes. These cells spawn several reactive processes that can assume clinical importance. The most common ones include surface wrinkling retinopathy, the gliosis that follows retinal hemorrhage, trauma, or tumors like combined retina hamartoma and retinal hemangioblastoma. In such cases the gliosis itself does not assume tumorous proportions and is not usually considered in the differential diagnosis of glial tumors. This review describes the clinical features of selected tumors and pseudotumors presumed to be of retinal glial cell origin. These include astrocytic hamartoma, acquired retinal astrocytoma, massive gliosis, and idiopathic focal pseudoneoplastic gliosis of the retina (Shields and Shields, 2009; Nyboer et al., 1976; Margo et al., 1993; Mullaney et al., 1997; Shields et al., 2004a,b, 2005, 1995, 1996; Zimmer-Galler and Robertson, 1995; Mennel et al., 2005; Jost and Olk, 1986; Drewe et al., 1985; Ulbright et al., 1984; Coppeto et al., 1982; Kroll et al., 1981; Reeser et al., 1978; Eagle et al., 2000; Gunduz et al., 1999; Cohen et al., 2008; Ramsay et al., 1979; Reeser et al., 1978; Bornfeld et al., 1987; Yanoff et al., 1971; Nowinski et al., 1984; Gelisken et al., 2004; Berger et al., 1979; Green, 1967; Ryan, 1954; Demirci et al., 2002; Khawly et al., 1999).

2. Retinal astrocytic hamartoma

Retinal astrocytic hamartoma is a benign tumor that is composed of a proliferation of well differentiated astrocytes (Shields and Shields, 2005, 2009; Nyboer et al., 1976; Margo et al., 1993; Mullaney et al., 1997; Shields et al., 2004a, 1996, 2005; Zimmer-Galler and Robertson, 1995; Mennel et al., 2005; Jost and Olk, 1986; Drewe et al., 1985; Ulbright et al., 1984; Coppeto et al., 1982; Kroll et al., 1981; Reeser et al., 1978; Eagle et al., 2000; Gunduz et al., 1999; Cohen et al., 2008). It is believed to be congenital in most cases but it can become clinically apparent sometime after birth. It is frequently associated with tuberous sclerosis complex (TSC), a syndrome that includes various combinations brain astrocytoma, cutaneous angiofibromas (“adenoma sebaceum”), cutaneous depigmented macules (ash-leaf sign), cardiac rhabdomyoma, renal angiomyolipoma, and other hamartomas (Shields and Shields, 2005, 2009; Nyboer et al., 1976). In those cases that are part of TSC, various genetic alterations have been identified on chromosomes 9 and 16. Some patients have only the retinal tumor without additional findings of TSC. It is still undetermined whether they represent a separate entity or a forme fruste, or partial expression, of TSC. An identical fundus tumor is occasionally seen in patients with neurofibromatosis type 1.

2.1. Clinical features

Ophthalmoscopically, retinal astrocytic hamartoma can show considerable variation from case to case. The two most common variations are the noncalcified tumor, the calcified tumor or, more commonly, a combination of the two. The noncalcified variant appears as a small gray-yellow, sessile of slightly elevated lesion in the inner aspect of the sensory retina. It can occasionally be transparent and fairly flat, sometimes suggesting reactive gliosis. Slightly larger lesions have a gray-yellow color and may cause adjacent retinal traction. The calcified variant may have minimal calcification or may be totally calcified. The characteristic feature is glistening yellow spherules of calcification.

In contrast to retinoblastoma, astrocytic hamartoma show glistening yellow calcification that differs from the more dull, chalky calcification that characterizes retinoblastoma. It does not usually develop prominent retinal feeding and draining blood vessels, and often causes retinal traction, a finding not usually seen with untreated retinoblastoma. Vitreous seeding of the tumor and hemorrhage can sometimes occur (Kroll et al., 1981; Cohen et al., 2008).

Although astrocytic hamartoma was historically considered to be a relatively stable lesion, there are recent reports of progressive growth and locally malignant behavior (Shields et al., 2005; Gunduz et al., 1999). These aggressive astrocytic hamartomas can cause exudative retinal detachment and neovascular glaucoma, ultimately requiring enucleation. Extraocular extension into the orbital and epibulbar tissues has been recognized in these cases (Shields et al., 2005; Gunduz et al., 1999).

2.2. Diagnostic approaches

Retinal astrocytic hamartoma, particularly the calcified variant, usually shows autofluorescence (Mennel et al., 2005). Fluorescein angiography of the typical lesion shows a characteristic network of small blood vessels in the venous phase with fairly intense late staining. In the case of a calcified lesion, ultrasonography shows a calcified plaque as might be seen with choroidal osteoma or calcified retinoblastoma. OCT can be used to document the retinal location and highly reflective features of retinal astrocytic hamartoma. It has very typical, although not pathognomonic, features (Shields et al., 2004a). Cytopathologic study of fine needle aspiration biopsy can be employed to make the diagnosis in atypical cases (Shields et al., 1996).

2.3. Pathology

Histopathologically, astrocytic hamartoma is usually composed of elongated fibrous astrocytes that have small uniform nuclei and interlacing cytoplasmic processes. Areas of calcification may be present, often in the form of calcospheres (Shields and Shields, 2009). Some larger tumors may be comprised of moderately pleomorphic gemistocytic astrocytes (Shields and Shields, 2009; Shields et al., 2005). The less common locally invasive variant is generally located on the optic disc and has large, poorly-differentiated cells similar to the subependymal astrocytomas that are seen in the brain in some patients with TSC (Shields et al., 2005).

2.4. Management

The majority of astrocytic hamartomas are small, extrafoveal, stationary lesions, with little or no tendency to grow or cause complications (Zimmer-Galler and Robertson, 1995). However, they should be followed periodically because some can show progressive growth, exudative retinal detachment, and neovascular glaucoma (Shields et al., 2005). When a lesion is growing and is suspected to have potential for such proliferation, then treatment is warranted. Depending of the circumstances, laser photocoagulation, cryotherapy, or vitrectomy and retinal detachment surgery may be necessary. Some cases of the giant cell variant have required enucleation because of severe neovascular glaucoma. However, we believe that if such a tumor is detected early, treatment with irradiation or other methods might possibly achieve tumor control and avoid enucleation.

3. Acquired retinal astrocytoma

Retinal astrocytic hamartoma accounts for the majority of true glial tumors of the sensory retina and in most instances it is associated with other signs of TSC. The typical case that is unassociated with clinically evident TSC may represent a forme fruste of tuberous sclerosis in which only the ocular features are manifest. Occasionally, however, the retina can spawn an acquired astrocytoma in somewhat older individuals who have no family history or clinical manifestations of TSC (Shields and Shields, 2009; Ramsay et al., 1979; Reeser et al., 1978; Bornfeld et al., 1987; Shields et al., 2004b). We choose to call this lesion an acquired retinal astrocytoma, as opposed to the congenital astrocytic hamartoma of TSC (Shields and Shields, 2009). Most such tumors appear to be different from a clinical standpoint. They may represent the retinal equivalent of a low grade astrocytoma.

3.1. Clinical features

Acquired retinal astrocytoma appears as a solitary mass that arises in the sensory retina. It typically is yellow and has abundant intrinsic vascularity that is best visualized with fluorescein angiography. Unlike the typical congenital astrocytic hamartoma, it generally lacks clinically evident calcification, is more likely to exhibit slowly progressive growth, and is not associated with TSC. Intraretinal exudation and secondary retinal detachment usually occur as the tumor enlarges (Shields and Shields, 2009; Ramsay et al., 1979; Reeser et al., 1978; Bornfeld et al., 1987; Shields et al., 2004b).

3.2. Diagnostic approaches

Fluorescein angiography characteristically shows small, well-defined fine blood vessels in the tumor in the vascular filling phases and diffuse late staining. Retinal feeder vessels can be apparent, but they are not dilated and tortuous like those seen with retinoblastoma and retinal hemangioblastoma. Ultrasonography usually discloses a noncalcified retinal mass with high internal reflectivity (Shields and Shields, 2009).

3.3. Pathology

Histopathologically, acquired retinal astrocytoma is composed of mature glial cells, similar to the astrocytic hamartoma. However, they do not tend to have the extensive calcification that characterizes many astrocytic hamartomas. Some tumors have large round cells with glassy eosinophilic cytoplasm (gemistocytes) similar to an equivalent tumor in the brain (Shields and Shields, 2009).

3.4. Management

In several reported cases, the affected eye has been enucleated because of growth and secondary glaucoma and/or because of suspicion that the lesion is a choroidal melanoma. Hence, no clear cut management is established. It is quite likely that if acquired retinal astrocytoma can be diagnosed earlier that laser photocoagulation, cryotherapy, or radiotherapy could control the tumor and prevent its complications.

4. Massive pseudoneoplastic gliosis of the retina

Massive retinal gliosis is a term used to define an extensive proliferation of glial cells that attains tumorous proportions. We prefer to not use the term massive gliosis for all such cases, since many are visible retinal nodules that are not massive. It occurs most often in eyes with chronic inflammation, prior ocular trauma, Coats’ disease, retinal hemangioblastoma, or congenital malformations. In some instances reactive gliosis can occur in an area of chronic retinal detachment or on a scleral buckle from retinal detachment surgery. Such lesions are very similar clinically to a secondary vasoproliferative tumor, which is listed under the rubric of retinal vascular tumors (Shields and Shields, 2009; Shields et al., 1995). In such instances, such extensive gliosis can show visible intraretinal and subretinal exudation. In others, it is not diagnosed clinically, but is recognized histopathologically after enucleation of a blind, uncomfortable eye (Nowinski et al., 1984).

Histopathologically, massive gliosis consists of a mass of closely arranged, well differentiated astrocytes similar to astrocytic hamartoma or acquired retinal astrocytoma. It is often markedly vascular, raising the possibility that some cases may represent a primary vascular tumor with secondary gliosis.

5. Focal pseudoneoplastic gliosis of the retina

We have seen a few unusual cases of focal presumed glial tumors in the inner retina in eyes with clear media and no prior ocular insults (Shields and Shields, 2009). It typically appears ophthalmoscopically as a solitary, white-yellow, superficial retinal lesion with no significant exudation or retinal traction. (Fig. 1) One similar lesion has been observed to spontaneously resolve and another has been observed to appear spontaneously and show rather rapid growth (Khawly et al., 1999). There are no specific findings with ancillary diagnostic studies like fluorescein angiography or ultrasonography. OCT shows an abruptly elevated retinal lesion.

Figure 1.

(A) Noncalcified astrocytic hamartoma. (B) Calcified astrocytic hamartoma. (C) Aggressive astrocytic hamartoma. (D) Gross appearance of sectioned globe of eye shown in figure 304-1, disclosing exophytic retinal mass and total retinal detachment. (E) Acquired retinal astrocytoma fundus. (F) Focal pseudoneoplastic gliosis of the retina.

6. Summary

Several interesting tumors and pseudotumors can arise from glial cells in the retina. They are generally benign and have no tendency to metastasize, but can sometimes exhibit aggressive local behavior. Glial tumors discussed herein include retinal astrocytic hamartoma seen with TSC, acquired astrocytoma, massive gliosis, and focal gliosis. The eye physician should be able to recognized such lesions and differentiate them from other benign and malignant fundus conditions.