One of the most challenging clinical scenarios an ophthalmologist can encounter is the management of glaucoma in eyes with cancer. These cases test the knowledge and understanding of glaucoma mechanisms as well as create unique treatment dilemmas. The worst possible outcome would be for the management of glaucoma to facilitate tumor spread beyond the eye, thus threatening the patient’s life. While there are such cases described in the literature, they are reportedly rare and likely difficult to quantify.1 This article will review how intraocular tumors commonly cause glaucoma and will compare treatment options when the eye has a history of intraocular malignancy.
Broadly speaking, intraocular tumors bring about glaucoma through 2 mechanisms. The tumor may directly interfere with aqueous outflow, or treatment of the tumor can create a situation within the eye favoring glaucoma. While the principal causes are primary tumor action and secondary outflow obstruction, the underlying processes vary. In terms of tumorigenic glaucoma, the usual scenario is when a tumor infiltrates the angle and replaces those structures with cancer cells, thus causing a deficiency in outflow function. A secondary open-angle mechanism can occur when a melanoma or melanocytoma disperses pigment into the angle.1 In other cases, tumor mass effect or tumor neovascularization may precipitate angle closure.2 Treatment-related glaucomas are most commonly associated with iris neovascularization due to radiation dose or ocular ischemia.3,4 Less commonly, steroid-induced glaucoma occurs after extensive topical, periocular, or intravitreal steroids are used to mitigate inflammation secondary to the neoplasm or irradiation. Moreover, although radiation-induced ischemic retinopathy is a regular cause of neovascular glaucoma, there is mounting evidence suggesting that multiple anti-VEGF injections can induce aqueous outflow dysfunction.5,6
Glaucoma Caused by Uveal Metastatic Tumors
Perhaps the most classic case of an intraocular tumor entering the angle is an infiltrative tumor caused by systemic cancer metastasizing to the anterior segment.7 These are often tan-colored, fleshy masses that may be found on gonioscopy or seen as a lesion on the peripheral iris.8 An ophthalmic oncology emergency, untreated metastatic tumors to the anterior segment can consume the trabecular meshwork, seed the outflow channels and induce an intractable, recalcitrant glaucoma. Prompt detection of the primary cancer (history, radiographic imaging) can obviate the need to make the diagnosis from the intraocular tumor.9 Then, prompt treatment (typically radiation therapy) offers the best method to preserve vision and the eye.10
Other common angle infiltration suspects include iris tumors and ciliary body tumors (Figures 1 and 2).1 Tumors in the angle can directly damage the trabecular meshwork and Schlemm’s canal, impairing aqueous outflow.1 Tumor-related angle closure is often due to a ciliary body or ring melanoma, where the tumor arises from the ciliary body and pushes the iris and/or lens forward.11 These glaucomas are more difficult to diagnose because the tumor is hidden behind the iris. Uveal melanomas, retinoblastomas, adenocarcinomas, and medulloepithelioma can force anterior displacement of the lens–iris diaphragm.12,13 Tumor-driven angle closure may be asymmetrically located in the angle, may not respond to laser iridotomy, and should be visualized by ultrasound biomicroscopy (Figure 3).1
Neovascular glaucoma is the most common type of treatment-related glaucoma, more frequently arising after proton beam radiotherapy and less frequently after plaque brachytherapy.4,14 While the primary goal of radiation is to destroy the tumor’s ability to metastasize, complications such as neovascular glaucoma could be reduced or avoided by pretreatment comparative dosimetry studies, reducing the dose to the iris and retina.15,16 Thus, eye cancer specialists could provide local tumor control while diminishing the chances of ischemic-drive–related intraocular VEGF production and radiation-induced neovascularization-related outflow obstruction.17
Approaching Tumor-Related Glaucoma
The pathophysiology of glaucomas secondary to intraocular tumors varies. However, the overall treatment goals can be uniform. Physicians’ priorities include (1) not endangering the patient’s life for the sake of regulating intraocular pressure (IOP); (2) preserving the eye when possible; and (3) limiting glaucoma-related vision loss (in cases where the tumor is unlikely to cause blindness or enucleation).1
When addressing eyes with cancer and glaucoma, one must first assess whether the patient has systemic disease and what the overall prognosis of the eye is. Excellent and ongoing communication with the patient’s cancer care team is critical. Patients who have had serious eye cancer diagnoses, such as choroidal melanoma, will frequently be under long-term surveillance for metastasis, including follow-up magnetic resonance imaging and positron emission tomography. The results of such testing can help determine the relative importance and intensity of glaucoma treatment.
Significant advances have been made to spare the neoplasia-laden eye from enucleation.15 Many patients, some even with large eye tumors, can maintain functional vision.2,17 These advances place a heavier burden on the glaucoma physician to protect the eye from vision loss. That said, it is equally important for the provider to understand when an eye has a poor prognosis, to communicate patient risks and benefits effectively, and know when to take a step back from aggressive glaucoma therapy.
The starting point for most glaucoma therapy is a prostaglandin analog.18 However, even this initial therapy can be controversial for patients with melanocytic iris neoplasia. There exist concerns related to increasing iris/tumor pigmentation and thus causing “pseudo-change.”19 For the majority of eye-cancer–related glaucomas, this will not be an issue.
Consider that prostaglandins likely do not interact with the tumor directly, for the clinical evidence suggests no link between latanoprost administration and malignant melanoma.20 Concerns have not been verified that increasing uveoscleral outflow with prostaglandins or increasing trabecular meshwork outflow with cholinergic agents may accelerate metastasis.21 However, in cases of pigmented anterior-segment tumors causing glaucoma, prostaglandins’ side effects can create a confusing diagnostic scenario. Iris melanocytomas and melanomas, which are known to elaborate pigment, offer a clinically relevant example. Increased pigmentation via the prostaglandin could mask or mimic the growth of such cancers, as has been reported in the literature.22 Still, prostaglandin analogs are the most potent and effectively dosed class of medication available to treat glaucoma. Pigment-spreading eye cancers are relatively rare, constituting only 12.4% of melanocytic iris tumors in one study.23 Thus, glaucoma specialists should feel comfortable using latanoprost and similar drugs for all but proven and suspected iris melanoma.
Beyond prostaglandin analogs, aqueous suppressants are important glaucoma therapies. In eyes with intraocular tumors, these agents include the carbonic anhydrase inhibitors, beta blockers, and alpha agonists.18 The authors could find no literature arguing against the use of such aqueous suppressant classes in the setting of ocular cancers.
However, readers should consider the mechanisms of action of every new drug prior to use for eye cancer patients. For example, Rho kinase inhibitors are the newest class of IOP-lowering medications. Their novel mechanism involves relaxing the cytoskeleton to help reduce outflow resistance in Schlemm’s canal.24 Hypothetically, a Rho kinase inhibitor could facilitate movement of tumor cells through a less occluded outflow tract. This theory uses the same reasoning that some use for criticism of prostaglandin analogs and cholinergic agents. However, there have not been clinical reports (as yet) on the effects of Rho kinase inhibitors in the context of eye cancer. The use of each medicine relies on a careful balance of the patient’s survival expectations, the likelihood of tumor spread compared to the risk of glaucoma-related vision loss, and what is best for the patient’s overall vision.
The literature contains various examples of eyes that underwent trabeculotomy prior to the diagnosis of eye cancer, allowing tumor egress through the surgically formed subconjunctival outflow pathway.25-27 The authors of this article have observed “black blebs.” There are also reports of undiagnosed ocular tumors seeding into the valve reservoirs of aqueous tube shunts.28,29 It is for this reason that glaucoma filtering procedures are classically contraindicated when untreated eye cancer is present. However, Baerveldt tube shunts have been implanted after proton beam therapy in 31 eyes with known eye cancer, with no subsequent metastases reported in over a year of average follow-up.30 No existing reports detail metastasis through a minimally invasive glaucoma surgery (MIGS) device. Nevertheless, multiple caveats exist for even considering MIGS (available from Glaukos [iStent], Allergan [XEN Gel Implant], Ivantis [Hydrus Microstent], Alcon [Cypass Micro-stent], Santen [PreserFlo MicroShunt], and MicroSurgical Technology [Trabectome]) or a tube shunt (New World Medical’s Ahmed Glaucoma Valve and Johnson & Johnson’s Baerveldt Glaucoma Implant) in eyes with cancer.
Local Tumor Control and Risks After Glaucoma Surgery
Glaucoma surgery decisions should be made in conjunction with the eye cancer specialist. The tumor must have been treated, noted to shrink, and remained stable for sufficient time as determined by the cancer specialist. A formal, documented, tumor-viability risk assessment should be performed prior to incisional surgery. Such assessments should include a discussion with the patient, revealing each center’s local control rates over time. Even after these criteria are met, it is wise to exhaust all other options before performing surgery. One case report described the metastasis of a ciliary body melanoma through a Baerveldt shunt that was placed after the patient had received plaque radiotherapy.31 Notably, the metastasis was identified 8 years after the tube shunt procedure. Some think that tube-shunt approaches are more appropriate for posterior than anterior choroidal melanomas. However, if successfully sterilized, intraocular tumor location should not be relevant. After the eye cancer physician and glaucoma physician have agreed on a tube shunt surgery, the patient should be guided through an informed consent that elaborates well upon the risks, benefits, and alternatives to such procedures.
Because traditional filtration surgery is generally avoided in eye-cancer–related glaucoma, laser therapy is a particularly appealing and efficacious treatment option. Selective laser trabeculoplasty (SLT; available in the United States from Ellex [Tango], Lumenis [Selecta II], Nidek [YC-200 S Plus], and Quantel Medical [Solutis and Optimis Fusion]) is a suitable therapeutic avenue in eyes with intact angle structures and open angles. It has been suggested that SLT may disperse cells into the chamber by striking the tumor directly and may enable outflow of the cancer cells.21 However, there are no case reports mentioning the metastasis of intraocular tumors after SLT. For a procedure that does not increase trabecular outflow at all, a diode laser may be used to reduce IOP. These nonincisional laser therapies should relatively diminish the risk of tumor spread. Diode laser procedures that may be performed include transscleral cyclophotocoagulation using a continuous wave laser (Oculight SLx; Iridex), endoscopic cyclophotocoagulation (Ophthalmic Laser Endoscopes; Endo Optiks), and the more recently available micropulse transscleral cyclophotocoagulation (MicroPulse P3 probe and Cyclo G6 glaucoma laser system; Iridex). In the personal experience of the second author of this article, nonincisional diode laser therapies have had good outcomes in eye-cancer–related glaucoma. Repeated treatments can be used to titrate any level of IOP control. Unfortunately, there is always the risk of phthisis bulbi, which one study reported as 2.9%, and rarely sympathetic ophthalmia after cyclodestructive procedures.32,33
The management of glaucoma in eyes with intraocular cancer increases the complexity of treatment algorithms typically employed by glaucoma physicians. Our task begins at diagnosis, where consideration that a tumor may be causing a glaucomatous presentation helps the eye specialist circumvent inadvertent metastases from inappropriate procedures. After diagnosis, the clinician must draw on all available information, from the patient’s overall prognosis to the prognosis of the eye.
Cooperation and communication with the eye cancer specialist and related physicians are paramount. Feedback from the tumor-treating physician allows the ophthalmologist to formulate a plan that accounts for the relative strengths and weaknesses of pharmacotherapy, laser therapy, and incisional surgery before committing the patient to a specific treatment path. However, when treatments are successfully initiated, these complex glaucomas may be controlled without jeopardizing overall health. Now, more than ever, we can avoid metastases, spare vision, and improve the quality of life for patients with eye-cancer–related glaucoma. GP
- Radcliffe NM, Finger PT. Eye cancer related glaucoma: current concepts. Surv Ophthalmol. 2009;54(1):47-73.
- Camp DA, Yadav P, Dalvin LA, Shields CL. Glaucoma secondary to intraocular tumors: mechanisms and management. Curr Opin Ophthalmol. 2019;30(2):71-81.
- Riechardt AI, Pilger D, Cordini D, et al. Neovascular glaucoma after proton beam therapy of choroidal melanoma: incidence and risk factors. Graefes Arch Clin Exp Ophthalmol. 2017;255(11):2263-2269.
- Summanen P, Immonen I, Kivela T, Tommila P, Heikkonen J, Tarkkanen A. Radiation related complications after ruthenium plaque radiotherapy of uveal melanoma. Br J Ophthalmol. 1996;80(8):732-739.
- Eadie BD, Etminan M, Carleton BC, Maberley DA, Mikelberg FS. Association of repeated intravitreous bevacizumab injections with risk for glaucoma surgery. JAMA Ophthalmol. 2017;135(4):363-368.
- Wingard JB, Delzell D, Houlihan NV, Lin J, Gieser JP. Incidence of glaucoma or ocular hypertension after repeated anti-vascular endothelial growth factor injections for macular degeneration. Clin Ophthalmol. 2019;13:2563-2572.
- Seidman CJ, Finger PT, Silverman JS, Oratz R. Intravitreal bevacizumab in the management of breast cancer iris metastasis. Retin Cases Brief Rep. 2017;11(1):47-50.
- Freeman TR, Friedman AH. Metastatic carcinoma of the iris. Am J Ophthalmol. 1975;80(5):947-952.
- Patel P, Finger PT. Whole-body 18F FDG positron emission tomography/computed tomography evaluation of patients with uveal metastasis. Am J Ophthalmol. 2012;153(4):661-668.
- Finger PT. Radiation therapy for orbital tumors: concepts, current use, and ophthalmic radiation side effects. Surv Ophthalmol. 2009;54(5):545-568.
- Demirci H, Shields CL, Shields JA, Honavar SG, Eagle RC Jr. Ring melanoma of the ciliary body: report on twenty-three patients. Retina. 2002;22(6):698-706.
- Shields CL, Shields JA, Shields MB, Augsburger JJ. Prevalence and mechanisms of secondary intraocular pressure elevation in eyes with intraocular tumors. Ophthalmology. 1987;94(7):839-846.
- Kaliki S, Shields CL, Eagle RC, et al. Ciliary body medulloepithelioma: analysis of 41 cases. Ophthalmology. 2013;120(12):2552-2559.
- Conway RM, Poothullil AM, Daftari IK, Weinberg V, Chung JE, O’Brien JM. Estimates of ocular and visual retention following treatment of extra-large uveal melanomas by proton beam radiotherapy. Arch Ophthalmol. 2006;124(6):838.
- Simpson ER, Gallie B, Laperrierre N, et al. The American Brachytherapy Society consensus guidelines for plaque brachytherapy of uveal melanoma and retinoblastoma. Brachytherapy. 2014;13(1):1-14.
- Finger PT, Chin KJ, Duvall G. Palladium-103 ophthalmic plaque radiation therapy for choroidal melanoma: 400 treated patients. Ophthalmology. 2009;116(4):790-796.e1.
- Finger PT, Chin KJ, Semenova EA. Intravitreal anti-VEGF therapy for macular radiation retinopathy: a 10-year study. Eur J Ophthalmol. 2016;26(1):60-66.
- Jonas JB, Aung T, Bourne RR, Bron AM, Ritch R, Panda-Jonas S. Glaucoma. Lancet. 2017;390(10108):2183-2193.
- Stjernschantz JW, Albert DM, Hu D-N, Drago F, Wistrand PJ. Mechanism and clinical significance of prostaglandin-induced iris pigmentation. Surv Ophthalmol. 2002;47:S162-S175.
- Tressler CS, Wiseman RL, Dombi TM, et al. Lack of evidence for a link between latanoprost use and malignant melanoma: an analysis of safety databases and a review of the literature. Br J Ophthalmol. 2011;95(11):1490-1495.
- Girkin CA, Goldberg I, Mansberger SL, Shields JA, Shields CL. Management of iris melanoma with secondary glaucoma. J Glaucoma. 2002;11(1):71-74.
- Skalicky SE, Giblin M, Conway RM. Diffuse iris melanoma: report of a case with review of the literature. Clin Ophthalmol. 2007;1(3):339-342.
- Harbour JW, Augsburger JJ, Eagle RC. Initial management and follow-up of melanocytic iris tumors. Ophthalmology. 1995;102(12):1987-1993.
- Tanna AP, Johnson M. Rho kinase inhibitors as a novel treatment for glaucoma and ocular hypertension. Ophthalmology. 2018;125(11):1741-1756.
- Grossniklaus HE, Brown RH, Stulting RD, Blasberg RD. Iris melanoma seeding through a trabeculectomy site. Arch Ophthalmol. 1990;108(9):1287.
- Pasternak S, Erwenne CM, Nicolela MT. Subconjunctival spread of ciliary body melanoma after glaucoma filtering surgery: a clinicopathological case report. Can J Ophthalmol. 2005;40(1):69-71.
- Ramaesh K, Marshall JWV, Wharton SB, Dhillon B. Intraocular metastases of cutaneous malignant melanoma: A case report and review of the literature. Eye. 1999;13(2):247-250.
- Kaliki S, Eagle RC, Grossniklaus HE, Campbell RJ, Shields CL, Shields JA. Inadvertent implantation of aqueous tube shunts in glaucomatous eyes with unrecognized intraocular neoplasms: report of 5 cases. JAMA Ophthalmol. 2013;131(7):925-928.
- Kiratli H, Koç I, Tarlan B. Orbital extension of an unsuspected choroidal melanoma presumably through an aqueous tube shunt. Ocul Oncol Pathol. 2016;2(3):144-147.
- Sharkawi E, Oleszczuk JD, Bergin C, Zografos L. Baerveldt shunts in the treatment of glaucoma secondary to anterior uveal melanoma and proton beam radiotherapy. Br J Ophthalmol. 2012;96(8):1104-1107.
- Sweeney AR, Keene CD, Klesert TR, Jian-Amadi A, Chen PP. Orbital extension of anterior uveal melanoma after Baerveldt tube shunt implantation. Can J Ophthalmol. 2014;49(6):e133-e135.
- Chen MF, Kim CH, Coleman AL. Cyclodestructive procedures for refractory glaucoma. Cochrane Database Syst Rev. 2019;3:CD012223.
- Tripathy K, Chawla R, Temkar S, et al. Phthisis bulbi—a clinicopathological perspective. Semin Ophthalmol. 2018;33(6):788-803.