Glaucoma Secondary to Intraocular Tumors
Ocular tumors or systemic malignancies that spread to the eye can lead to intraocular pressure elevation through many different mechanisms. If not diagnosed early, the tumor’s effect on eye pressure or spread of the tumor itself can be sight or life threatening. In patients with highly asymmetric glaucoma or eye pressure elevation that is resistant to standard medical therapy a thorough history and ocular exam (including pertinent imaging) should be performed to rule out intraocular malignancies.
- 1 Disease
- 2 Etiology
- 3 Pathophysiology
- 3.1 Open Angle Glaucoma
- 3.2 Closed Angle Glaucoma
- 4 Diagnosis
- 5 Management
- 6 Additional Resources
- 7 References
Tumors within the globe can lead to elevation in intraocular pressure (IOP) and permanent damage to the ocular structures. In patients who present with atypical, unilateral or highly asymmetric glaucoma, suspicion for intraocular malignancies must be high.[1-2] The type of tumor, the location of the malignancy and the size of the mass affects the amount of pressure elevation within the globe. The pressure can be further increased depending on the amount of inflammation, necrosis or hemorrhage present.[1, 3-5] The prevalence of ocular metastasis from systemic tumors is estimated to be around 4%.
The majority of tumors that are found within ocular tissues are generally from distant sources that spread to the eye through the vascular/lymphatic system or rarely by direct invasion from surrounding tissues. Most systemic tumors affect the choroid with breast, lung and kidney being the most common primary sites.
Overall, in eyes which have intraocular tumors the prevalence of elevation in intraocular pressure is around 5%.8 The type as well as location of the intraocular malignancy affect the likelihood of causing elevation in intraocular pressure.3-4 In patients with metastasis or uveal melanoma an increase in intraocular pressure is much more common in tumors which affect the anterior uveal tract structures.[8-9] For iris metastasis or melanomas the rate of secondary glaucoma can be as high as one-third.[10-11]
Open Angle Glaucoma
Direct Invasion of Anterior Chamber Angle
In tumors located in the anterior segment of the eye the most common mechanism for secondary intraocular pressure elevation is direct invasion of the tumor cells into the anterior chamber angle. This mechanically blocks aqueous humor from leaving the eye, which directly causes a rise in pressure within the globe. This can been seen clinically on gonioscopy as well as at the cellular and molecular level using immunohistochemistry (ICH) and electron microscopy (EM) of tissue specimens.
For all anteriorly located metastatic tumors and iris melanomas, mechanical obstruction is the most common cause of secondary glaucoma. Ring melanoma, which involves most of the ciliary body and iris, blocks aqueous outflow as it spreads circumferentially.[9-10] Not every patient with seeding of the angle will develop glaucoma; patients with tumors with the following characteristics are more likely to develop elevated intraocular pressure: larger tumor base, iris root location of tumor base, flat contour of tumors and tumors with a large number of clock hours of angle seeding.[8, 11-12]
Secondary Pigmentary Glaucoma
Massive dispersion of pigment displaced from tumor cells (i.e.- melanoma and melanocytoma) can lead to obstruction of the anterior chamber angle and iris heterochromia.[7,17-18,53] In ciliary body melanomas this is the most common cause of secondary glaucoma.
Melanomalytic glaucoma is secondary to the release of pigment from tumor cells which subsequently get taken up by macrophages.[15-16] Based on studies using immunohistochemistry and electron microscopy, these pigment-laden macrophages cause blockage of the trabecular meshwork which leads to increased intraocular pressure.[7,15-17]
Anterior Chamber Angle Epithelialization
A sheet-like plaque of malignant tumor cells that spread over an open anterior chamber angle can cause mechanical obstruction if enough of the trabecular meshwork is blocked. This causes a secondary elevation of pressure within the eye and secondary glaucoma.
Increased Episcleral Venous Pressure
Aqueous humor outflow is dependent on the pressure gradient between intraocular pressure and episcleral venous pressure. Orbital tumors or extraocular extension of an intraocular tumor can cause an increase in episcleral venous pressure through direct compression.  Due to this pressure gradient reduction from the elevated episcleral pressure, there is a rise in intraocular pressure often causing a secondary glaucoma.
Closed Angle Glaucoma
Inflammation secondary to intraocular tumors can cause peripheral anterior synechiae, which can lead to closure of the angle and elevation in intraocular pressure. In patients with uveal melanomas and uveitis, secondary angle closure is common from peripheral anterior synechiae. Metastatic tumors also have been shown to have significant inflammation leading to peripheral anterior synechiae.
Patients with intraocular tumors can often develop neovascularization of the iris and angle, which can lead to angle closure glaucoma. This is commonly true in tumors which cause a chronic retinal detachment (especially choroidal melanomas) leading to ischemia of the tissue and resultant secondary neovascularization.[1,47] Metastatic cutaneous melanomas also are highly associated with neovascularization.20 Neovascularization can also present as a complication of tumor treatment (i.e.- after radiation).[5,29,44,46,48]
Anterior Displacement of Lens-Iris Diaphragm
The most common mechanism of angle closure in patients with intraocular tumor is forward displacement of the lens-iris diaphragm. The displacement is usually from a large mass in the posterior segment of the eye causing forward pressure of iris and lens structures leading to pupillary block, iris bombé and finally peripheral anterior synechiae closing the anterior chamber angle.[7,22,47]
The workup begins with a thorough history, which should be performed in all patients with elevated intraocular pressure from atypical cases of glaucoma. A thorough history includes all of the following:
- Complete history of present illness (including current and past symptoms)
- Past medical and ocular histories (focusing specifically on risk factors for cancer)
- Past surgical history (including radiation treatments)
- Medication list (including eye drops)
- Family history (especially cancer history)
- Complete review of systems
- Social history (including drugs, tobacco use, alcohol and occupation)
The symptoms that the patient experience depend greatly on the type and location of the malignancy as well as the amount of ocular involvement. The most frequently recorded symptoms are blurred vision, pain, redness and floaters. [8,11-12, 25] Some patients, however, will not complain of any symptoms.
Extraocular and slit lamp biomicroscopy exams of the anterior and posterior segments of each eye should be performed as well as a thorough gonioscopy of the angle. A complete dilated exam should be performed in all patients, as long as the anterior chamber angle is not too narrow. The following findings are essential to note for any patient suspected of having tumor induced secondary glaucoma. [1, 7-9,11-12,15,34,53]
Anterior Segment Exam Findings
- Pigment dispersion in anterior chamber or angle
- Dilated episcleral vessels
- Intraocular inflammation noting cell/flare, hypopyon or keratic precipitates
- Neovascularization of Iris or Angle
- Mass lesions of the iris/ciliary body/angle
- Transillumination of globe (tumors create shadows)
- Open versus closed angle
Posterior segment Findings:
- Retinal detachments
- Posterior segment masses
- Vitreous hemorrhage
B-Scan Ultrasonography (B-Scan)
In patients in whom dilation is not possible (closed angle patients) or if there is opacification of the media obstructing the examiner’s view, a B-scan ultrasound can be used to examine the posterior segment of the eye. Specifically, it is helpful in taking measurements of the posterior segment tumors like uveal melanomas and looking for concurrent retinal detachments, vitreous hemorrhage or vitritis.
Ultrasound Biomicroscopy (UBM)
To further characterize tumors in the anterior segment, ultrasound biomicroscopy can be performed. UBM uses a high frequency wavelength which allows for accurate measurements of anterior lesions which is helpful for diagnosis (solid versus cystic masses) and follow up.[1,22,36]
If there is still uncertainty with the diagnosis after a full history, physical exam and imaging then diagnostic sampling of the lesion can be performed for most tumors (it is contraindicated in retinoblastoma). The use of fine needle aspiration biopsy with either a 25-guage needle or vitrector can be performed with or without immunohistochemistry to help with diagnosis and has proven to be especially helpful in leukemia/lymphoma.[23-24,37-38]
Involvement of the eye can occur in just under one-third of cases of systemic leukemia. Secondary glaucoma is generally caused by anterior chamber angle obstruction from leukemic cells. Acute lymphoblastic (ALL) and acute myelogenous (AML) leukemias are the most common causes of secondary glaucoma in patients with leukemia.[1,6] On examination, due to layering of the leukemic cells, there may be a pseudohypopyon present in the anterior chamber. Secondary angle closure glaucoma has also been reported.
Non-Hodgkin lymphoma of the central nervous system (NHL-CNS) tend to more commonly affect the eye compared to non-CNS involving lymphoma.[1,6,8,33] NHL-CNS classically affects the retina and vitreous with patients complaining of floaters.[27,32-33] On anterior segment examination there can be signs of inflammation (cell/flare, keratic precipitates), hyphema, corneal edema and a pseudohypopyon (layered tumor cells). On posterior segment exam vitritis and subretinal infiltrates may be present.[27,32,35] Non-CNS intraocular lymphoma symptoms often metastasize through the choroidal circulation to the uveal tissue. Symptoms usually include pain, blurred vision and eye redness.[27,32-33]
Lymphoma with metastasis to the eye tends to occur at a lower rate compared to leukemia. Secondary elevation of intraocular pressure more commonly occurs from tumor seeding of the trabecular meshwork, but angle closure and iris neovascularization has also been reported.[8,32,35-37]
The most common type of intraocular tumor is metastases. These tumors most frequently are located in the uveal tract, with the most common primary sites being breast and lung.[3-4,7,10,21] Besides leukemia and lymphoma, carcinomas are by far more common than sarcomas in terms of metastasis to the eye.[6,38] These patients have symptoms of decreased vision and pain and may have exophthalmos, retinal detachment, mass lesions, uveitis and secondary glaucoma seen on exam.
Secondary intraocular pressure elevations is much more common in anteriorly located metastatic tumors.[3-4] The mechanism of elevation of pressure in the eye is generally from direct invasion of the anterior chamber angle but neovascularization has also been reported.[3,4,9] In one histopathological study of patients with metastatic carcinomas to the eye, high elevated pressure was present in 7.5%. Due to the general health and infrequent ophthalmic exams of these patients many of these metastatic tumors and secondary glaucomas likely go undetected.
The most common primary intraocular malignancy in adults is uveal melanoma with the majority located within the choroid.[1,2,8,28,30] Elevation of intraocular pressure has been reported in up to one-forth of patients with uveal melanoma through a variety of mechanisms causing both open and closed angle glaucomas.[2,8]
Open angle glaucoma in uveal melanoma patients can occur due to tumor seeding of the anterior chamber angle, direct invasion of the tumor into the angle and melanomalytic obstruction. [2,8,12,15,16,17,39] Ciliary body, iris and ring melanomas tend to cause elevation in intraocular pressure by invasion of the anterior chamber angle or pigment dispersion.[8,17]
Angle closure glaucoma is also common and can occur from a variety of mechanisms. It can be from neovascularization (usually with chronic retinal detachment), anterior displacement of the lens-iris diaphragm from large posterior segment tumors and peripheral anterior synechiae from inflammation.[1,2,8]
Retinoblastoma is the most common primary intraocular tumor in children and most commonly presents with strabismus and leukocoria. Patients also rarely can have a red, painful eye either from inflammation or elevated intraocular pressures.
In a large retrospective study it was shown that 17% of retinoblastoma patients had elevation of intraocular pressure.8 The majority of elevation in pressure is secondary to neovascularization followed by displacement of the iris-lens diaphragm.[8,40] Other less common causes of secondary glaucoma include tumor seeding of the anterior chamber angle, uveitis and vitreous hemorrhage.
- Medulloepithelioma. A congenital embryonal tumor of the ciliary body, causes intraocular pressure elevation in just under half of patients usually through direct tumor invasion of the angle or neovascularization.[8,42]
- Iris melanocytoma. Causes elevated intraocular pressure through pigmentary or melanomalytic glaucoma.[8,18,43]
- Multiple Myeloma. A malignant proliferation of plasma cells, has been reported to cause secondary glaucoma by anterior chamber angle invasion or secondary angle-closure.
- Juvenile Xanthogranuloma. A benign skin disorder that presents with cutaneous lesions, can have iris lesions, spontaneous hyphema, uveitis and secondary glaucoma.44 Cellular infiltration of the angle, hyphema, or peripheral anterior synechiae and angle closure lead to secondary glaucoma.
For intraocular tumors with secondary glaucoma elimination of the viable tumor cells is of primary importance. Control of intraocular pressure control is secondary and can be done either medically or surgically.
Treatment of the secondary glaucoma should begin with topical eye drops (alpha-agonists, beta-blockers and carbonic anhydrase inhibitors) which decrease aqueous humor production. If the pressure remains uncontrolled on topical medication then oral hypotensive agents like acetazolamide or methazolamide should be tried. It has been shown based on immunohistochemistry that prostaglandin analogues only increase the amount of melanin within the melanocytes and thus are unlikely to worsen the prognosis for melanomas. However, there is controversy over whether prostaglandin analogues should be given in tumor patients, as some argue that there is a theoretical concern of metastasis due to the increased uveoscleral outflow.
For metastases with multiple lesions in the eye, systemically chemotherapy can play a large role. In eyes that have poor visual potential and elevated pressure, treatment for the secondary glaucoma should only be given if pain is present.
Surgical intervention should only be considered if the patient failed more conservative treatment options. Successful en-bloc resections of the iris and ciliary body tumors have been reported with large tectonic corneoscleral grafts. These surgeries do carry a risk of hypotony if more than 5 clock hours are removed.51 Transscleral cyclophotocoagulation or cryotherapy to the ciliary body offer less invasive ways to control the intraocular pressure.[1,39,40]
Incisional glaucoma surgery, including filtration procedures and aqueous tube shunts, are generally contraindicated, except for cases of metastases, due to the potential risk of spreading viable tumor cells outside of the globe.[1,31,38,40, 42] Minimally invasive glaucoma procedures may also play a role. There are case reports on the successful sustained reduction in intraocular pressure using these procedures (trabectome trabeculotomy in lymphoma).
Sometimes treatment of the underlying tumors with plaque brachytherapy, external beam radiation, chemotherapy or radiation can improve the intraocular pressure. For certain tumors like large uveal melanomas, retinoblastoma or if the eye is painful with no visual potential then primary enucleation may be the appropriate option.
A significant number of patients will develop side effects from treatment of the original tumor with brachytherapy and proton beam radiation which can lead to neovascularization and secondary angle-closure glaucoma.[5,29,44,46,48] Other systemic medications including docetaxel, paclitaxel and imatinib as well as intravitreal rituximab/methotrexate have been reported to elevated intraocular pressure.[36,52,53]
The prognosis for the patient depends upon the type of tumor, the amount of involvement within the eye, as well as the treatment received. The primary goal for any treatment is to control the tumor first and then control the intraocular pressure. Management of any intraocular tumor must be done concurrently with an oncologist to account for systemic disease.
- American Academy of Ophthalmology. Glaucoma: Glaucoma associated with intraocular tumors Practicing Ophthalmologists Learning System, 2017 - 2019 San Francisco: American Academy of Ophthalmology, 2017.
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