Glaucoma Secondary to Intraocular Tumors
Sumit P. Shah, MD, FACS and Jay S. Duker, MD
The association between unilaterally elevated intraocular pressure (IOP) and intraocular tumor has been appreciated for many years.1 Because intraocular neoplasms are far from common, this occurrence is rarely encountered in general ophthalmologic practice. However, when present, it is critically important to recognize. The presence of intraocular cancer represents one of the few situations in ophthalmology in which delay in diagnosis and/or inappropriate surgical intervention (eg, filtering surgery) can not only threaten vision but life as well.
In determining the proper treatment for elevated IOP in an eye with a tumor, the histopathologic cell type and therefore the risk of tumor growth and/or metastasis greatly impacts the treatment decisions. In such cases, definitive histologic diagnosis may be required. Contrary to widespread thought, the mere presence of elevated IOP associated with an intraocular neoplasm does not necessarily indicate that the underlying tumor is malignant.
In a study published almost 125 years ago, elevated IOP was documented in more than 50% of eyes enucleated with intraocular tumors.1 Because of increased familiarity with intraocular tumors, modern improvements in diagnostic techniques, including indirect ophthalmoscopy and ultrasonography, as well as earlier therapeutic interventions, at the present time, only 5% of eyes harboring intra ocular tumors will have elevated IOP at the time of diagnosis.2 In the setting of melanoma of the uveal tract (iris, ciliary body, and choroid), location of the tumor is key in determining the risk of IOP elevation. Elevated IOP is much more common with ciliary body melanomas (17%) than with iris melanomas (7%) or choroidal melanoma (2%).2 With anterior, pigmented tumors, tumor invasion of the angle followed by pigment dispersion are the most common causes of elevated IOP. For posterior tumors, iris neovascularization with secondary angle closure is the usual cause.
INSIGHTS INTO MECHANISMS OF ELEVATED INTRAOCULAR PRESSURE
Nine well-recognized mechanisms (Table 42-1) by which an intraocular tumor can abnormally elevate IOP2,3 include the following:
- Direct tumor invasion and/or seeding of the angle structures
- Pigmentary dispersion mechanically obstructing the outflow apparatus
- Melanophagic, in which macrophages with ingested melanin mechanically obstruct the outflow apparatus (melanophagic or melanomalytic)
- Hemolytic as a result of bleeding from neovascular vessels, inherent tumor vessels, tumor necrosis, or invasion of the tumor into normal vessels
- Uveitic from secondary inflammatory cells mechanically obstructing the outflow apparatus
- Iris neovascularization with secondary angle closure (neovascular glaucoma)
- Angle closure from choroidal detachment with anterior displacement of the lens-iris diaphragm
- Angle closure from massive suprachoroidal hemorrhage with anterior displacement of the lens-iris diaphragm
- Angle closure from anterior displacement of the lens-iris diaphragm due to mass effect by extremely large posterior tumors or ring melanomas
TABLE 42-1. MECHANISMS OF ELEVATED INTRAOCULAR PRESSURE
Tumor invasion of the angle structures |
Pigmentary dispersion |
Melanophagic or melanomalytic |
Hemolytic |
Uveitic |
Neovascular |
Angle closure due to:
|
As in any case of elevated IOP, gonioscopy is the critical diagnostic procedure to determine the mechanism. Whenever a diagnosis of unilateral glaucoma secondary to one of these mechanisms is made, the clinician must rule out the presence of an intraocular neoplasm with further appropriate studies. In the setting of acutely elevated IOP, clinicians must not forget to fully evaluate the mechanism of elevated IOP after the acute episode is resolved.
Ancillary testing helps greatly in determining the location, size, site of origin, and growth characteristics of intra ocular masses. Depending on the clinical situation, dilated examination with indirect ophthalmoscopy, B-scan ultrasonography, ultrasound biomicroscopy (UBM), transillumination, computed tomography (CT) scanning, magnetic resonance imaging (MRI) scanning, diagnostic paracentesis, fine-needle aspiration biopsy, incisional biopsy, and excisional biopsy may all be considered.4,5
STEPS IN MANAGEMENT
Previously Undiagnosed and Untreated Intraocular Tumor
The first critical step in managing patients with glaucoma secondary to an intraocular tumor is to recognize the presence of the tumor. Depending on the location of the tumor, cell type, size, and growth characteristics, this may be either an exercise in the obvious or an arduous undertaking punctuated by multiple follow-up examinations and ancillary tests. In the setting of grossly elevated IOP, immediate medical management is usually indicated to forestall rapid optic disc damage or a retinal vascular obstruction. Further management of the glaucoma, however, will be intimately inter twined with the future management of the underlying tumor.
Based on patient history, clinical characteristics of the tumor, and the results of ancillary testing, a systemic search for either a primary malignancy or secondary metastases from the intraocular primary lesion may be indicated. If this search yields evidence of systemic malignancy and/or metastases, then the systemic prognosis will impact further future interventions with respect to the glaucoma.
Eyes that may harbor malignant tumors should not undergo partial resection of the tumor through a full-thickness scleral incision as this may predispose to local seeding through the incision site (extrascleral extension). If biopsy is necessary, several options exist:
- Complete excision for diagnosis and therapy, preferably through a trap-door lamellar scleral incision or, if anterior, a limbal or clear corneal incision
- Incisional biopsy with frozen section histopathologic evaluation followed by immediate enucleation if the tumor proves to be malignant
- Fine-needle aspiration biopsy through the clear cornea or trans-pars plana
In eyes with elevated IOP on the basis of pigment dispersion or melanophagic glaucoma, complete excision of the tumor can result in clearing of the pigment and/or macrophages from the trabecular meshwork with accompanying normalization of the IOP.6,7 Alternatively, radiation therapy of the underlying tumor has been noted to yield similar results in selected cases.
As a general rule, treatment of the tumor should supersede treatment of the glaucoma. When enucleation is indicated to manage the tumor, glaucoma therapy is no longer a concern. In eyes that retain useful vision, however, medical management of the elevated IOP be comes the mainstay. Eyes with benign tumors such as nevi and adenomas have no contraindication to filtering surgery. Eyes that may harbor actively growing malignant tumors, especially melanomas, should not undergo filtering surgery as this may lead to orbital and eventually systemic dissemination of tumor cells. Alternatively, in eyes with unresponsive glaucoma secondary to a malignant tumor, enucleation may be the only therapeutic option, even if therapy of the primary tumor does not require it.
Treated Intraocular Tumors
Radiation therapy (Figure 42-1) has become the mainstay of treatment for uveal melanomas as it can salvage the eye and preserve vision while maintaining a survival rate comparable to enucleation.8 But, this paradigm shift has made the possibility of secondary mixed mechanism glaucoma more likely as a long-term sequelae. Surgical intervention for glaucoma, whether laser cyclophotocoagulation or incisional, should be avoided if at all possible in the setting of a previous intraocular malignancy.
Figure 42-1. (A) Iridociliary melanoma with pigment dispersion anteriorly and extraocular extension treated with plaque radiotherapy (B) to the entire anterior segment and ciliary body. (Reprinted with permission from Drs. Carol and Jerry Shields.)
Exceptions may exist. For instance, under certain circumstances, a choroidal melanoma successfully treated with radiation therapy but complicated by secondary angle closure from neovascular glaucoma could be considered for filtering surgery depending on the potential visual outcome, timing of the treatment, and location of the tumor.
Likewise, there is a single case report in the literature of a patient who developed intractable vitreous hemorrhage and secondary hemorrhagic glaucoma arising 7 years after plaque brachytherapy for a choroidal melanoma. The patient continued to rebleed with secondary glaucoma despite undergoing 3 pars plana vitrectomies and a trabeculectomy with mitomycin C. Endoresection of the irradiated choroidal melanoma was done to treat the refractory vitreous hemorrhage and glaucoma. The patient maintained 20/200 vision at 1 year with no reported local recurrence or metastasis.9
If indicated, ciliary body destructive procedures can be safely and effectively performed in eyes with intraocular tumors; however, ciliary body destructive procedures do lead to a breakdown in the blood-aqueous barrier. It is not currently known whether this breakdown might predispose to cellular elements (eg, viable tumor cells), gaining access to the systemic circulation. No definite data implying an increased risk of metastases with ciliary destructive procedures exist, but common sense and caution should be used in such circumstances.
Ultimately, in these refractory secondary glaucoma cases involving radiation-treated intraocular malignant tumors, therapeutic intervention should be tailored on a case-by-case basis. The patient and ophthalmologist must carefully review the risks and benefits of the various treatment options before embarking upon a management plan.
The Role of Vascular Endothelial Growth Factor
Recent immunohistochemical evidence suggests ocular melanoma angiogenesis may be vascular endothelial growth factor (VEGF) dependent.10 Bevacizumab is a recombinant humanized anti-VEGF IgG1 monoclonal antibody that has been approved as an antiangiogenic agent for the treatment of metastatic colorectal cancer. In addition, it has been shown to be effective in reducing anterior and posterior segment neovascularization of varying etiologies.
Although, with limited experience, it has not shown any evidence for efficacy as a primary treatment for uveal melanoma. There may be an adjunctive role of bevacizumab in addition to brachytherapy in ocular melanomas associated with neovascular glaucoma (Figure 42-2).11,12 Furthermore, radiation therapy is known to cause retinal and choroidal ischemia manifested as neovascularization of the iris, neovascular glaucoma, and exudative retinal detachment (Figure 42-3). These late complications may also be amenable to anti-VEGF therapy.12
LOCATION: IRIS
Tumor Type: Primary
In most instances, iris tumors are easily detected at the slit lamp. Differentiation between benign and malignant lesions may not be quite as straightforward. If definite differentiation is required by the clinical circumstances, an invasive procedure like anterior chamber paracentesis, fine-needle aspiration biopsy, or excisional biopsy will be required.
Benign iris melanocytic lesions (iris nevi) rarely cause elevated IOP. When they do, pigment dispersion is the most likely mechanism. Iris nevi are usually solitary, while malignant iris melanocytic lesions are classified as either solitary or diffuse melanomas. Diffuse iris nevus has been reported to cause elevated IOP.13 Iris nevi tend to be stable over time and can safely be observed.
Melanocytoma is a type of nevus that most commonly occurs in the posterior segment of the eye. Rarely, they occur as solitary iris lesions that are dark brown or jet black in color. Melanocytomas have a strong tendency to undergo necrosis leading to pigment dispersion and secondarily elevated IOP.2
An iris pigment epithelial adenoma is a rare, benign tumor arising from the posterior pigment epithelial layer. They are typically dark brown or black in color and may elevate IOP via pigment dispersion. Complete surgical excision is often possible if the tumor involves less than half the iris.
Figure 42-2. (A, B) Ring melanoma causing elevated IOP secondary to significant involvement of the trabecular meshwork seen on histologic specimen (C) after enucleation. (Reprinted with permission from Drs. Carol and Jerry Shields.)
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