Retinal astrocytic hamartoma
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Retinal astrocytic hamartomas are benign glial cell tumors. They are often encountered as an asymptomatic lesion in screening of patients with tuberous sclerosis complex, but may be sporadic. Diagnosis is largely clinical and may be supported by ancillary tests. In tuberous sclerosis, retinal findings are significantly associated with concurrent neurological and renal disease. Growth or complications of RAH requiring treatment are rare.
Retinal astrocytic hamartomas (RAH) are benign retinal tumors composed of glial cells. They are typically encountered as an asymptomatic lesion in patients with tuberous sclerosis complex (TSC); however, may be isolated tumors or found in association with other ocular or systemic disease. Most RAH are thought to be congenital, but may not become clinically apparent until later in life.
RAH are not specifically recognised in the International Classification of Diseases (ICD) version 10 nomenclature.
- D31.2 Benign neoplasm: Retina
- Q85.1 Tuberous sclerosis
RAH were first recognised in 1921 by Van der Hoeve, in association with TSC. He termed the lesions ‘phakomas’ (from the Greek phakos meaning ‘spot’). RAH are found in one third to one half of patients with TSC. Approximately one third of these patients will have bilateral or multiple tumors.
The most frequent association of RAH is with TSC. Other associations have been reported, including:
- Neurofibromatosis (type 1)
- Retinitis pigmentosa
- Usher’s syndrome
- Stargardt’s disease / ABCR mutation
- Gyrate atrophy
A hamartoma (from the Greek hamartanein meaning ‘to err’) is a disorganised overgrowth of benign cells within their native tissue. RAH are hamartomas composed of elongated fibrous glial cells (mostly astrocytes), which have small uniform nuclei and interlacing cytoplasmic processes. Other histological features include foci of dystrophic calcification, and large pleomorphic gemistocytes.
TSC is caused by mutation of either TSC1 or TSC2, tumor suppressor genes that encode for the proteins hamartin and tuberin, respectively. Loss of function leads to dysregulation of cellular proliferation via the mTOR (mammalian target of rapamycin) pathway, resulting in hamartoma formation in multiple organs. Tumor formation relies on a second random mutation (Knudson’s ‘two hit’ hypothesis), accounting for the wide phenotypic variation.
TSC has an autosomal dominant inheritance pattern, with high penetrance but widely variable expressivity. Approximately 2/3 of cases are sporadic, but may then be inherited by subsequent generations.
RAH are diagnosed clinically based on characteristic ophthalmoscopic appearance. Ancillary testing may be of value in establishing a diagnosis in patients with atypical appearing lesions or those without tuberous sclerosis.
RAH are typically asymptomatic, and may be detected incidentally or on screening of patients with suspected phakomatoses. Macular or optic nerve tumors, or those complicated by hemorrhage or exudation, may cause visual disturbance (blur, floaters, or metamorphopsia).
- Type 1 (most common): relatively flat, smooth, semitransparent, grey-white lesions without calcification
- Type 2: raised, multinodular (‘mulberry-like’), opaque, calcified lesions
- Type 3: transitional lesion with features of Type 1 and Type 2
Lesions typically remain stable with age, and do not evolve between types.
Practically, tumors can be divided into calcified and non-calcified variants. The characteristic feature of calcified tumors is glistening yellow spherules of calcification. This differs from the chalky, dull calcification seen in retinoblastoma. RAH also lack a prominent feeding/draining vessel, in contrast to retinoblastoma or retinal capillary hemangioma.
In a large series of patients from a tuberous sclerosis program by Aronow et al., 36% had RAH. There was a significant prevalence of bilateral (43%) and multiple (40%) tumors. In this series, average basal tumor diameter was one disc diameter (range, 0.5-2.5 disc diameters), and the average number of RAH was four (range, 2-7).
Tuberous Sclerosis Complex
TSC is a phakomatosis, with widely variable manifestations depending on the severity and extent of involvement in various organ systems (eyes, brain, heart, lungs, kidneys, skin).
Other ocular signs associated with TSC include:
- ‘Punched out’ depigmented retinal pigment epithelial lesions
- Angiofibromas of the eyelids
- Iris or chorioretinal coloboma
- Sectoral iris heterochromia
TSC patients with retinal findings are more likely to have concurrent systemic disease compared to those with a normal ophthalmoscopic examination. Aronow et al. found that patients with retinal changes were three times more likely to have concurrent giant cell astrocytomas, and significantly more likely to describe cognitive impairment, epilepsy, and renal angiomyolipomas compared to those without.
Systemic signs associated with tuberous sclerosis complex include:
- Skin signs
- Ash leaf spots (depigmented macules – may require a ‘Wood’s lamp’ ultraviolet light in fair-skinned individuals)
- Shagreen patch (thick leathery dimpled patches)
- Adenoma sebaceum (cutaneous angiofibromas in malar distribution)
- Ungual fibromas
- Gingival fibromas
- Neurological signs
- Seizures / infantile spasms
- Intellectual disability
- Neuropsychiatric (developmental, behavioural, or psychosocial difficulties)
- Cortical tubers
- Giant cell astrocytoma (may cause obstructive hydrocephalus)
- Subependymal nodules (in the walls of ventricles)
- Other organ manifestations
- Cardiac rhabdomyoma (may cause cardiac arrhythmias)
- Renal angiomyolipoma (may cause significant renal hemorrhage and hematuria)
- Lymphangioleiomyomatosis (LAM, cystic replacement of the lung parenchyma)
TSC clinical diagnostic criteria have been defined by the International Tuberous Sclerosis Complex Consensus Group in 2012.
|Updated Diagnostic Criteria for Tuberous Sclerosis Complex, 2012
Courtesy of H. Northrup, D.A. Krueger on behalf of the International Tuberous Sclerosis Complex Consensus Group
|A. Genetic diagnostic criteria
|B. Clinical diagnostic criteria|
1. Hypomelanotic macules (≥3, at least 5mm diameter)
2. Angiofibromas (≥3) or fibrous cephalic plaque
3. Ungual fibromas (≥2)
4. Shagreen patch
5. Multiple retinal hamartomas
6. Cortical dysplasias*
7. Subependymal nodules
8. Subependymal giant cell astrocytoma
9. Cardiac rhabdomyoma
10. Lymphangioleiomyomatosis (LAM)
11. Angiomyolipomas** (≥2)
1. “Confetti” skin lesions
2. Dental enamel pits (>3)
3. Intraoral fibromas (≥2)
4. Retinal achromic patch
5. Multiple renal cysts
6. Nonrenal hamartomas
|Definite diagnosis: Two major features or one major feature with ≥2 minor features
Possible diagnosis: Either one major feature or ≥2 minor features
*Includes tubers and cerebral white matter radial migration lines.
**A combination of the two major clinical features (LAM and angiomyolipomas) without other features does not meet criteria for a definite diagnosis.
Ancillary (in clinic) testing may assist in diagnosis.
Optical Coherence Tomography
Spectral-domain (SD) optical coherence tomography (OCT) features of RAH are well described. Tumors are localized in the retinal nerve fiber layer, with dome-shaped thickening and hyperreflectivity present at the inner retina. Characteristic optically empty spaces (‘moth eaten’ areas) are present representing intralesional calcification or cavitation. Outer retinal layers may be compressed or disorganised by the tumor. Calcification and may cause posterior optical shadowing. OCT may also demonstrate CNVM.
An OCT classification system for RAH in TSC has been proposed, with four subtypes defined by OCT criteria. This study reported that thicker and calcified tumors are significantly more likely to have associated systemic disease.
Non-calcified RAH reduce the physiological background autofluorescence. Calcified tumors demonstrate hyperautofluorescence.
Fundus fluorescein angiography demonstrates early blockage of background choroidal fluorescence, a plexus of capillaries within the tumor, and late leak (hyperfluorescence, gradually increasing in intensity and extent). Angiography may demonstrate additional tumors that are not apparent clinically.
Indocyanine Green Angiography
Biopsy is rarely required and not typically recommended for RAH. Fine-needle aspiration for cytopathology can however be performed in atypical cases. Cytology demonstrates spindle cells, and immunohistochemistry staining is positive for glial cells (glial-fibrillary acidic protein stain).
TSC is a clinical diagnosis, but genetic testing for TSC1 and TSC2 mutations is available.
Differential diagnoses include:
- Solitary circumscribed retinal astrocytic proliferation
- Acquired retinal astrocytoma
- Solitary mass similar to RAH but lacking calcification, of adult onset in patients with no history of tuberous sclerosis
- Uveal melanoma
- May demonstrate cavitations, or rarely calcification
- Choroidal metastasis (in particular from carcinoid tumor)
- Combined hamartoma of the retina and retinal pigment epithelium
- Retinal pigment epithelial adenoma
- Retinal capillary hemangioma
- Optic nerve head drusen
- Anterior drusen typically demonstrate hyperautofluorescence
Complications are uncommon, but include:
- Retinal traction
- Choroidal neovascular membrane
- Cystoid macular edema
- Exudative retinal detachment
- Vitreous hemorrhage
- Subretinal hemorrhage
- Neovascular glaucoma
Most RAH are small and non-progressive, and periodic monitoring is typically all that is required. Serial ophthalmoscopic examination is necessary to detect those lesions showing aggressive growth behaviour or vision-threatening complications. TSC patients, particularly if young or cognitively impaired, may be less likely to report symptoms.
TSC patients may require treatment of subependymal giant cell astrocytomas with mTOR inhibitors (eg everolimus, sirolimus). mTOR inhibitors have been shown to cause regression of RAH, and have been used for aggressive ocular disease in a child.
Treatment may be required for the rare complications associated with RAH. Intravitreal ranibizumab has been reported to be effective for CNVM, achieving closure and resolution of fluid after a short course of injections. Laser photocoagulation may be effective for exudative retinal detachments that do not resolve spontaneously, but prognosis for improvement in vision is guarded. Low fluence, direct laser treatments are advocated to reduce the risk of exacerbating exudation.
RAH usually remain stable throughout life. Progressive growth and local complications (see above) are uncommon.
- TSC Alliance (USA)
- Tuberous Sclerosis Association (UK)
- Tuberous Sclerosis Australia (Aus)
- Tuberous Sclerosis – National Organization for Rare Disorders (NORD)
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