Retinal astrocytic hamartoma (RAH) is a benign glial cell tumor that occurs in the retinal nerve fiber layer (RNFL). It is classified as a localized hyperplasia (hamartoma) of normal tissue components, not a neoplastic proliferation.
RAH is a characteristic ocular finding of tuberous sclerosis complex (TSC), observed in 36–50% of TSC patients. 4) Some reports indicate RAH in 87% of TSC patients. 1) TSC is caused by mutations in the TSC1 or TSC2 genes, with TSC2 mutations accounting for 75–80% of cases. 1) The prevalence is approximately 1 in 6,000 people. 1)3)
RAH also occurs in sporadic cases without TSC, with the proportion of sporadic RAH ranging from 29% to 81% depending on the report. 6) Sporadic RAH is known to be associated with neurofibromatosis type 1 (NF1).
RAH is a characteristic ocular finding of TSC, but sporadic cases without TSC also exist. The proportion of sporadic cases varies widely from 29% to 81% depending on the report, and an association with NF1 has also been suggested. 6) Even in the absence of a family history of TSC or systemic symptoms, if RAH is suspected, ophthalmological and neurological evaluation is recommended.
RAH is often asymptomatic. Subjective symptoms appear when the tumor occurs in the macula or when complications arise.
Complications of RAH include macular edema (approximately 20%), traction (approximately 27%), and epiretinal membrane (ERM). 5)Rarely, branch retinal vein occlusion (BRVO) may also occur. 1)
RAH is classified into three types based on fundus findings. Multiple types may coexist in the same eye (17.4%). 2)It is said to occur preferentially in the temporal retina. 2)
Type 1
Flat, semitransparent type: Most common, accounting for about 70%. 2)
Appearance: Smooth, semitransparent gray-white lesion. Observed as mild thickening of the nerve fiber layer.
Calcification: None to minimal. Common in children and young adults.
Type 2
Elevated, calcified type: Seen in about 55%. 2)
Appearance: Mulberry-shaped white elevated mass. Irregular surface with calcification.
Calcification: Prominent. More common in elderly and advanced stages.
Type 3
Mixed type: Found in about 9% (Chinese cohort). 2)
Appearance: Combines features of Type 1 and Type 2. Partially calcified, with surrounding translucent area.
OCT findings: Shows complex multilayered internal structure.
A method for classifying the internal structure of RAH into four stages using optical coherence tomography (OCT) has been proposed. 1)2)
Each stage begins with thickening of the RNFL and progresses to increased internal echogenicity, calcification, and posterior shadowing. SS-OCT (swept-source OCT) is superior for visualizing deeper structures and is useful for staging. 2)
Fundus autofluorescence (FAF) shows hyperfluorescence in calcified areas. 1) Fluorescein angiography (FA) shows blocked fluorescence in the early phase and leakage from tumor vessels in the late phase.
RAH originates from the RNFL (nerve fiber layer) and appears on OCT as a hyperreflective lesion localized to the inner side of the inner nuclear layer. In contrast, retinoblastoma originates from the inner nuclear layer and tends to show structural destruction across the full thickness of the retina. 6) OCT findings of sporadic RAH have been confirmed in infants as young as 3 months old, which is useful for early differentiation.
TSC is an autosomal dominant genetic disorder caused by loss-of-function mutations in the TSC1 gene (producing hamartin) or the TSC2 gene (producing tuberin). TSC2 mutations account for 75–80% of all mutations and generally lead to more severe disease than TSC1 mutations. 1)
The TSC1 and TSC2 gene products function as regulators of the mTOR (mammalian target of rapamycin) pathway. Mutations cause overactivation of the mTOR pathway, leading to increased cell proliferation and protein synthesis, resulting in the formation of hamartomatous lesions throughout the body. RAH is also thought to occur through this mechanism.
Sporadic RAH without TSC is known to be associated with neurofibromatosis type 1 (NF1). In sporadic RAH, initial presentation also requires differentiation from malignant tumors such as retinoblastoma. 6)
The diagnosis of RAH is based on a combination of fundus findings and various imaging tests. Particularly in infants and sporadic cases, differentiation from retinoblastoma (RB) is the most important issue.
The following shows the main imaging tests and their characteristics.
| Test | Main Findings | Usefulness |
|---|---|---|
| OCT (SD/SS) | Internal structure of RNFL origin, 4-stage evaluation | High (differential diagnosis, staging) |
| B-scan ultrasound | Calcification, tumor diameter measurement | Medium (initial screening) |
| Fundus autofluorescence | Hyperautofluorescence of calcified areas | Moderate (calcification assessment) |
| FA | Early blockage → late leakage | Moderate (vascular assessment) |
| MRI | Evaluation of intracranial lesions (e.g., SEGA) | High (systemic evaluation) |
In infants, a white fundus mass requires priority differentiation from RB. Batu Oto et al. (2022) reported a case of solitary RAH in a 3-month-old infant, showing that confirmation of RNFL origin by OCT and a well-defined homogeneous mass (3×3×2 mm) on B-scan are effective for differentiation. 6) No change was observed over 6 years of follow-up, confirming its benign nature.
Since most RAH cases are asymptomatic and stable, the basic policy is to follow up with regular fundus examinations. Treatment intervention is performed when complications occur or the tumor progresses.
Observation
Indications: Asymptomatic, stable cases (the majority).
Method: Regular fundus examination, OCT, and fundus autofluorescence. TSC patients should be examined at least once a year. 4)
Spontaneous regression: Dillon et al. (2025) reported a case where the tumor diameter spontaneously decreased from 1.04 mm to 0.75 mm over two years. 4)
Pharmacotherapy
mTOR inhibitor (everolimus): Used as a systemic treatment for TSC. Improvement of RAH and exudative retinal detachment was reported in a 13-month-old infant. 4)
Anti-VEGF drugs (bevacizumab): Used adjunctively for macular edema associated with branch retinal vein occlusion. 1)3)
Indications: Cases complicated by VEGF-related exudation or edema.
Surgery and Laser
Laser photocoagulation: Performed for abnormal blood vessels and exudative lesions around the tumor. 1)4)
Vitrectomy (PPV): Membrane peeling is performed for cases with epiretinal membrane (ERM). Cuadros et al. (2021) performed 23-gauge vitrectomy with membrane peeling for a sporadic RAH case with ERM, maintaining postoperative visual acuity of 20/20. 5)
Indications: Cases complicated by macular traction, epiretinal membrane, or rhegmatogenous retinal detachment.
Everolimus is a major systemic treatment for TSC, suppressing the mTOR pathway to shrink or stabilize tumors. Ophthalmologically, improvement in RAH and exudative retinal detachment (ERD) after everolimus administration has been reported in a 13-month-old TSC patient. 4)
RAH is essentially associated with VEGF, 1) and anti-VEGF agents such as bevacizumab are used for exudation from branch retinal vein occlusion or intratumoral vessels. 1)3) Patra S et al. (2024) reported a case of giant RAH treated with bevacizumab after PDT (photodynamic therapy). 3)
Cuadros Sánchez C et al. (2021) performed 23G vitrectomy and membrane peeling for a 37-year-old woman with sporadic RAH complicated by macular edema and epiretinal membrane. Postoperatively, visual acuity was maintained at 20/20, and this was the first report of an effective treatment for RAH with epiretinal membrane 5). Previous case series have reported macular edema and traction in some RAH cases, and a certain number of cases require surgical intervention 5).
Many RAH are asymptomatic and stable, and can be managed with observation alone. The 2021 revised TSC diagnostic criteria recommend annual ophthalmologic examination. 4) If complications such as macular edema or epiretinal membrane occur, active interventions such as anti-VEGF drugs or vitrectomy should be considered.
The gene products of TSC1 (hamartin) and TSC2 (tuberin) form a complex and function as upstream regulators of mTOR (mammalian target of rapamycin). The TSC1/TSC2 complex acts as a GAP (GTPase activating protein) for Rheb, suppressing mTORC1. When this suppression is released by mutations, mTORC1 becomes hyperactivated, leading to increased cell proliferation and protein synthesis, resulting in systemic hamartomatous lesions (cortical tubers, renal angiomyolipomas, pulmonary lymphangioleiomyomatosis, RAH, etc.).
The cellular components of RAH include Müller cells, gemistocytic astrocytes, and pleomorphic astrocytes, 3) and are histologically similar to SEGA. 3) There is no evidence that tumor cells undergo epithelial-mesenchymal transition (EMT), and they retain benign characteristics.
In sporadic RAH, it has been suggested that a germline mutation (first hit) in one allele of TSC1 or TSC2, followed by an acquired mutation (second hit) in the other allele, may lead to tumor formation (two-hit hypothesis). However, it has not been confirmed whether the same mechanism as in TSC always applies in sporadic cases.
The combination of retinal branch vein occlusion with RAH is thought to result from endothelial damage of abnormal blood vessels formed within the tumor. 1) Furthermore, RAH is essentially associated with VEGF, 1) and excessive VEGF secretion from intratumoral vessels may contribute to increased retinal vascular permeability and vascular occlusion. This provides the theoretical basis for anti-VEGF therapy.
A four-stage progression assessment of RAH using swept-source OCT (SS-OCT) is being established. 2)Dias PB et al. (2023) longitudinally classified internal structural changes of RAH using SS-OCT and reported that type 1 was the most common (70%), reaching 94% in a Chinese cohort, indicating ethnic differences. 2)SS-OCT can depict calcified areas in more detail and is considered superior to conventional SD-OCT for visualizing deep structures.
The effects of mTOR inhibitors such as everolimus on RAH have only been confirmed at the case report level. Dillon et al. (2025) reported a case of spontaneous tumor regression over two years in a 14-year-old female with TSC and type 1 diabetes (1.04→0.75 mm), 4)indicating the existence of cases that stabilize without mTOR inhibitors. Evidence prospectively evaluating the degree of RAH reduction by mTOR inhibitors from an ophthalmic perspective is still insufficient.
The effectiveness of vitrectomy for sporadic RAH complicated by epiretinal membrane is at the stage of initial reports. 5)
Cuadros Sánchez C et al. (2021) performed 23-gauge vitrectomy and membrane peeling in a 37-year-old woman with sporadic RAH complicated by macular edema and epiretinal membrane. Postoperative visual acuity of 20/20 was achieved, demonstrating for the first time the possibility of a surgical approach for RAH with epiretinal membrane. 5)
Shields reported that 20% of RAH patients have macular edema and 27% have traction, 5) and systematic evaluation of surgical candidates remains a future challenge.
In differentiating sporadic RAH from RB in infants, a multimodal approach combining OCT, B-scan, and fundus autofluorescence is attracting attention.
Batu Oto et al. (2022) reported a case of sporadic RAH in a 3-month-old infant. 6) B-scan ultrasound showed a homogeneous mass measuring 3×3×2 mm, and OCT confirmed internal structures originating from the RNFL, allowing noninvasive exclusion of RB. No changes were observed over 6 years of follow-up, demonstrating the utility of early multimodal evaluation.
In sporadic RAH, priority is given to excluding malignant tumors (especially retinoblastoma). Imaging evaluation with OCT, B-scan, and fundus autofluorescence is useful, and MRI may be performed if necessary. 3)6) Collaboration with neurology and dermatology should also be considered to rule out potential TSC complications (skin findings, intracranial lesions, renal lesions, etc.).
RAH is essentially a benign tumor, and reports of malignant transformation are extremely rare. However, complications such as macular edema and epiretinal membrane may impair visual function, so regular follow-up is recommended. Spontaneous regression has also been reported, 4) and it is important to confirm tumor stability.
