This is secondary glaucoma caused by intraocular tumors obstructing aqueous outflow, leading to elevated intraocular pressure and optic nerve damage. It is mainly caused by primary or secondary intraocular tumors in the anterior segment 1). The main mechanisms include tumor cell infiltration into the trabecular meshwork, and trabecular blockage by tumor-related inflammation, debris, hemorrhage, or pigment dispersion. It may also present as secondary angle closure 1).
The prevalence of elevated intraocular pressure in eyes with intraocular tumors is about 5%. The prevalence of ocular metastasis from systemic tumors is estimated at about 4%, with the choroid being the most common site. Common primary sites include breast, lung, and kidney cancers.
The most common primary intraocular malignancy in adults is uveal melanoma, with glaucoma complicating 3–33% of cases. In children, retinoblastoma is the most common primary intraocular tumor. The glaucoma treatment guidelines also list tumors (benign/malignant, intraocular/orbital) as representative causes of secondary glaucoma due to acquired factors 5).
QDoes an intraocular tumor always lead to glaucoma?
A
The prevalence of elevated intraocular pressure is about 5%, so not all cases develop glaucoma. The risk varies depending on tumor type, location, size, and the degree of inflammation, necrosis, and hemorrhage. Tumors of the iris and ciliary body have a higher incidence; for iris melanoma, it can reach about one-third.
The symptoms experienced by patients vary depending on the type and location of the tumor and the extent of intraocular involvement. The main symptoms are as follows.
Blurred vision: The most common symptom
Eye pain: Associated with elevated intraocular pressure or inflammation
Redness: Reflects dilation of episcleral vessels
Floaters: Suggest involvement of the vitreous body
Some patients are asymptomatic. If atypical, unilateral, or markedly asymmetric glaucoma is observed, intraocular malignancy should be strongly suspected.
Glaucoma due to intraocular tumors is broadly classified into open-angle and angle-closure mechanisms1)4).
Open-angle mechanisms
Direct invasion: Tumor cells directly invade the anterior chamber angle and trabecular meshwork, mechanically obstructing aqueous outflow. This is the most common mechanism in anterior segment tumors.
Pigment dispersion: Large amounts of pigment from pigmented tumors obstruct the angle. This is the most common cause in ciliary body melanoma.
Melanomalytic: Macrophages that have phagocytosed tumor-derived pigment obstruct the trabecular meshwork.
Epithelialization: Sheet-like plaques of malignant cells cover the angle, mechanically obstructing the trabecular meshwork.
EVP elevation: Orbital tumors or extraocular extension increase episcleral venous pressure, reducing the pressure gradient.
Angle-closure mechanisms
Uveitic: Inflammation secondary to the tumor leads to peripheral anterior synechiae, closing the angle.
Neovascularization: Chronic retinal detachment or ischemia leads to neovascularization of the iris and angle, causing angle closure. It can also occur after radiation therapy.
Anterior displacement of the lens-iris diaphragm: A large tumor mass in the posterior pole pushes the iris and lens forward, causing pupillary block and angle closure.
Anterior displacement of the lens and iris due to a space-occupying tumor is a representative cause of secondary angle closure, and is clearly stated in glaucoma guidelines 5). Tumor-related inflammation, debris, hemorrhage, and pigment dispersion leading to trabecular obstruction are also important mechanisms 1).
Risk factors for elevated intraocular pressure:
Tumor located in the anterior uvea (iris or ciliary body)
Large tumor base
Tumor base located at the iris root
Flat tumor contour
Wide extent of angle seeding
QWhich mechanism is more common: open-angle or angle-closure?
A
It depends on the tumor type and location. For anterior segment tumors (e.g., iris melanoma), open-angle mechanisms due to direct invasion are more common. On the other hand, for large posterior segment tumors, angle closure due to anterior displacement of the lens-iris diaphragm is predominant. Both mechanisms have been reported in uveal melanoma.
Examination of the anterior and posterior segments of both eyes, and detailed gonioscopy of the angle, should be performed. Unless there is a risk of angle closure, a complete examination under mydriasis should be performed. Because tumors are frequently located posterior to the iris, routine slit-lamp microscopy and fundus examination may be insufficient.
B-scan ultrasonography: Useful for measuring posterior segment tumors in cases where mydriasis is not possible or media opacities are present. Can also detect concurrent retinal detachment or vitreous hemorrhage.
Ultrasound biomicroscopy (UBM): Useful for detailed evaluation of anterior segment tumors including the ciliary body. High-frequency allows accurate measurement and is particularly effective for differentiating iris cysts from solid tumors.
CT / MRI / PET: Often required for systemic evaluation to determine the extent of invasion and multi-organ involvement.
If the diagnosis remains uncertain after detailed examination, fine-needle aspiration biopsy (FNAB) using a 25-gauge needle or vitrector may be performed. Analysis with immunohistochemistry is conducted and is particularly useful for diagnosing leukemia and lymphoma. FNAB is contraindicated in retinoblastoma.
The differential diagnosis of intraocular tumors causing secondary glaucoma includes the following:
Leukemia: Ocular involvement occurs in about one-third of systemic leukemia cases. Characterized by angle closure due to leukemic cells and pseudohypopyon. ALL and AML are the most common causes of secondary glaucoma.
Lymphoma: CNS-NHL commonly involves the retina and vitreous. Elevated intraocular pressure due to tumor seeding into the trabecular meshwork is common.
Metastatic tumors: Commonly occur in the uvea. Breast and lung cancers are the most common primary sites. Anterior metastasis carries a high risk of elevated intraocular pressure.
Uveal melanoma: The most common primary intraocular malignancy in adults. Up to 25% have elevated intraocular pressure, via both open-angle and angle-closure mechanisms.
Retinoblastoma: The most common primary intraocular tumor in children. 17% have elevated intraocular pressure, mainly due to neovascularization.
Others: Medulloepithelioma (congenital ciliary body tumor, about half have elevated IOP), iris melanocytoma, multiple myeloma, juvenile xanthogranuloma.
In glaucoma secondary to intraocular tumors, elimination of viable tumor cells is the top priority, and intraocular pressure management is the secondary goal 1)4).
Depending on malignancy and residual visual function, laser therapy, anticancer drugs, or radiation therapy are selected. Collaboration with ocular oncologists and other specialists is important.
Drug treatment is performed according to the treatment of primary open-angle glaucoma.
Drug
Characteristics
Notes
Aqueous humor suppressants
First-line
Beta-blockers, alpha-agonists, CAIs
Oral CAIs
Second-line
When eye drops are insufficient
PGA
Controversial
Theoretical concern of metastasis promotion
Drug therapy is positioned as the first-line treatment until definitive therapy (tumor treatment) 1). In eyes with poor visual prognosis and high intraocular pressure, glaucoma treatment is performed only when pain is present.
Incisional glaucoma surgery: Filtering surgery and tube shunts are only indicated after tumor control1)4). There is a risk of promoting extraocular extension of the tumor.
En bloc resection: Resection of iris and ciliary body tumors combined with corneoscleral graft. Resection of 5 clock hours or more carries a risk of hypotony.
Steroid therapy is also an option for juvenile xanthogranuloma.
QCan prostaglandin analogs be used?
A
Strictly speaking, they are not contraindicated, but there is a theoretical concern that they may promote tumor metastasis by increasing uveoscleral outflow. Therefore, their use in patients with ocular tumors is controversial. Aqueous humor suppressants (beta-blockers, alpha-agonists, carbonic anhydrase inhibitors) are recommended as first-line therapy.
The most common mechanism in anterior segment tumors is direct infiltration of the anterior chamber angle and trabecular meshwork by tumor cells. Histopathological examination has confirmed infiltration of malignant melanoma and melanocytoma cells into the trabecular meshwork. In ring melanoma, aqueous outflow is circumferentially obstructed.
Trabecular meshwork infiltration by tumor cells floating in the aqueous humor has also been reported1). Obstruction of the trabecular meshwork by tumor-related inflammation, debris, hemorrhage, and pigment dispersion is also an important pathway1).
Pigment released from tumor cells is phagocytosed by macrophages, and pigment-laden macrophages obstruct the trabecular meshwork. This mechanism has been demonstrated by immunohistochemistry and electron microscopy.
Aqueous humor outflow depends on the pressure gradient between intraocular pressure and episcleral venous pressure. Orbital tumors or extraocular extension of intraocular tumors can directly compress and elevate episcleral venous pressure, reducing the pressure gradient.
The incidence of NVG as a primary finding in uveal melanoma has been decreasing due to early tumor detection. In recent years, NVG is more commonly observed as a secondary effect of radiation therapy 2).
Mechanisms of melanoma-related intraocular pressure elevation include direct invasion, infiltration/seeding into the aqueous outflow pathway, compressive angle closure, and anterior segment neovascularization2). Depending on pathophysiology, severity, and patient factors, treatment options include medication, laser peripheral iridotomy, laser trabeculoplasty, anti-VEGF therapy, and cyclodestructive procedures2).
Hyphema and long-standing residual blood in the vitreous can also cause intraocular pressure elevation 1). Normal red blood cells (hyphema), hemoglobin-laden macrophages and red blood cell debris (hemolytic glaucoma), and degenerated red blood cells (ghost cell glaucoma) cause trabecular meshwork dysfunction 1). Ghost cells are spherical, khaki-colored degenerated red blood cells that appear 1 to 4 weeks after vitreous hemorrhage1).
Tomkins-Netzer et al. (2024) comprehensively reviewed the mechanisms of blood-retinal barrier breakdown in intraocular tumors. They reported that tumor growth, cytokine production, and hypoxic conditions disrupt barrier homeostasis, and BRB damage can occur even at sites distant from the primary tumor 3).
Two major pathways are involved in BRB breakdown 3).
VEGF overexpression: Increased demand for angiogenesis with tumor progression enhances VEGF production, increasing vascular permeability. It is a major factor in vascular leakage in intraocular tumors.
Inflammatory cell infiltration: Leukocyte infiltration is a characteristic of intraocular malignancies and compromises BRB integrity. In tumor-bearing eyes, intraocular inflammation is enhanced compared to the contralateral eye, and flare values are elevated even at baseline before treatment.
Clinical consequences of BRB breakdown include aqueous flare, clinically significant subretinal fluid, and exudative retinal detachment3). This process is complex and multifactorial, and further research is needed to elucidate the exact pathophysiological mechanisms 3).
The interaction of cytokines, inflammatory cells, and structural factors leads to disruption of BRB homeostasis, but additional research is needed to elucidate the exact pathophysiological mechanisms 3). Inflammatory cells infiltrate the eye through vessel walls with increased permeability due to BRB damage, potentially destroying normal ocular tissue through release of cytotoxic mediators, proteases, and reactive oxygen species.
Elucidation of the mechanisms of BRB breakdown is expected to lead to the development of future therapeutic approaches 3).
The efficacy of anti-VEGF therapy has been reported in the management of NVG after radiotherapy 2). Combined management with cyclodestructive procedures is being considered.
Minimally invasive glaucoma surgery (MIGS) may play a role in intraocular pressure management in patients with intraocular tumors. However, the risk of tumor seeding remains, and safety and efficacy need to be verified.
Effects of Chemotherapeutic Agents on Intraocular Pressure
Systemic chemotherapeutic agents such as docetaxel, paclitaxel, and imatinib, as well as intravitreal rituximab/methotrexate, have been reported to cause elevated intraocular pressure. Attention from both tumor treatment and intraocular pressure management perspectives is required.
Tomkins-Netzer O, Niederer R, Greenwood J, et al. Mechanisms of blood-retinal barrier disruption related to intraocular inflammation and malignancy. Prog Retin Eye Res. 2024;99:101245.
European Glaucoma Society. European Glaucoma Society Terminology and Guidelines for Glaucoma, 5th Edition. Kugler Publications. 2020.
日本緑内障学会. 緑内障診療ガイドライン(第5版). 日眼会誌. 2022;126:85-177.
Copy the article text and paste it into your preferred AI assistant.
Article copied to clipboard
Open an AI assistant below and paste the copied text into the chat box.
