Glaucoma Related to Ocular and Orbital Tumors

Secondary glaucoma due to ocular and orbital tumors can be a diagnostic challenge. It is an essential differential to consider in eyes with a known tumor as well as with unilateral, atypical, asymmetrical, or refractory glaucoma. Various intraocular neoplasms including iris and ciliary body tumors (melanoma, metastasis, lymphoma), choroidal tumors (melanoma, metastasis), vitreo-retinal tumors (retinoblastoma, medulloepithelioma, vitreoretinal lymphoma) and orbital tumors (extra-scleral extension of choroidal melanoma or retinoblastoma, primary orbital tumors) etc. can lead to raised intraocular pressure. The mechanisms for glaucoma include direct (tumor invasion or infiltration related outflow obstruction, trabecular meshwork seeding) or indirect (angle closure from neovascularization or anterior displacement or compression of iris) or elevated episcleral venous pressure secondary to orbital tumors. These forms of glaucoma need unique diagnostic techniques and customized treatment considerations as they often pose therapeutic dilemmas. This chapter will review and discuss the mechanisms, clinical presenta-tions and management of glaucoma related to ocular and orbital tumors.


Introduction
With the advent of constantly evolving and advancing ophthalmic imaging techniques as well as surgical modalities in the field of ophthalmic diseases, diagnostic accuracy, and treatment outcomes of ocular as well as orbital tumors have improved remarkably over the past few years. Raised intraocular pressure (IOP) is known to be one of the presenting features or associated finding for numerous ocular as well as orbital tumors. Ocular and orbital tumors can cause secondary glaucoma due to various mechanisms. They often pose a diagnostic challenge as well as a therapeutic dilemma owing to the complex pathophysiology involved. A thorough clinical evaluation, appropriate index of suspicion and optimum use of ancillary testing can lead to a proper diagnosis and management in such scenario.
Intraocular tumors that can lead to secondary glaucoma are malignancies like iris melanoma, iris metastasis, iris lymphoma, ciliochoroidal melanoma, retinoblastoma as well as benign pathologies like iris melanocytoma, benign ciliary body medulloepithelioma, diffuse choroidal hemangioma. [1] Indicators for a possible underlying intraocular tumor are, markedly elevated and often asymmetric level of IOP, acquired iris heterochromia, glaucoma non-responsive to optimum treatment or accompanying distinctive ocular features. [1,2] The mechanism by which these tumors can cause secondary glaucoma varies with tumor type, size, and extent of the main tumor as well as seeding, tumor location, growth pattern, ongoing treatment along with secondary features related to the tumor. [3] Iris and predominantly ciliary body tumors located in anterior segment can cause glaucoma by direct infiltration of anterior chamber angle or because of iris neovascularization; while large tumors originating in retina or choroid are likely to cause glaucoma following iris neovascularization because of long standing or total retinal detachment or secondary angle closure. [1,2] Orbital tumors which can be congenital, traumatic, inflammatory, vascular, or neoplastic in origin may cause secondary glaucoma due to mass effect or anatomical and vascular changes leading to raised IOP [4] Orbital tumors causing raised orbital pressure may directly increase the IOP by increasing hydrostatic pressure around the globe or indirectly by raising the episcleral venous pressure.
Management of secondary glaucoma due to ocular and orbital tumors depends on both tumor characteristics and glaucoma related factors. Treatment of primary tumor may lead to IOP control in some cases while for others, management options include medical management, laser trabeculoplasty, transscleral cyclophotocoagulation, anti-VEGF injections, minimally invasive glaucoma surgery (MIGS), filtering or shunting surgery or enucleation. Glaucoma surgery like filtering or shunting procedure can be performed with due caution in proven benign or completely regressed tumors post-treatment. Such surgeries in an eye with suspected but unproven benign/malignant ocular tumor must be avoided to prevent unintended iatrogenic tumor dispersion or seeding especially in cases with iridociliary tumors or retinoblastoma. (nodular or ring melanoma), iris lymphoma and iris metastasis. Direct invasion of the anterior chamber angle by infiltration followed by neovascularization and trabecular meshwork tumor seeding are the common etiologies of raised IOP in iris tumors; while pigment dispersion followed by direct angle invasion are the common etiologies for same in pigmented ciliary body tumors. [1,2,5,6] Iris melanocytoma, a variant of melanocytic iris nevus is a deeply pigmented benign tumor which is well circumscribed, often dark brown to black dome shaped lesion with cobblestone surface and feathery edges showing echogenic nodular thickening of iris on ultrasound biomicroscopy (UBM). (Figure 1A-C) [2,7] Melanocytoma can undergo spontaneous necrosis with pigment dispersion leading to pigment-laden melanophages seeding the angle causing secondary glaucoma. [8] ( Figure 1D) Secondary glaucoma has been reported in 11% of cases in a series of 47 iris melanocytoma where pigmented keratic precipitates and anterior chamber inflammation were identified as factors predictive of development of raised IOP emphasizing the role of macrophages in the anterior chamber angle. [7] Suspected melanocytoma can be observed cautiously. They are very rarely known to show malignant transformation. [9] Clear corneal approach fine needle aspiration biopsy, minimally invasive Finger Iridectomy technique (FIT), iridectomy or iridogoniocyclectomy can be utilized to obtain histopathological diagnosis in atypical iris nevi and suspected melanocytoma. [7,10] Secondary glaucoma demonstrating melanocytoma eyes can be treated medically, by transscleral photocoagulation, by sector iridectomy or with glaucoma filtration surgery. [7,8,11,12] However, a diagnostic confirmation of the lesion by prior biopsy and histopathology is mandated before planning a filtering surgery. Local surgical resection can be used to treat the secondary glaucoma caused by necrotic iris melanocytoma. [8,13] Enucleation is reserved for painful blind eyes or eyes with absolute glaucoma.

Mechanisms of glaucoma secondary to ocular and orbital tumors
Iris and iridociliary melanoma are the least common variant of uveal melanoma constituting only 2-3% of cases and have documented metastatic rate of 10.7-11%. [14][15][16]. Iris melanoma presents as a variably pigmented lesion (melanotic or amelanotic) which can be well circumscribed-nodular type, flat pigmented on iris surface-diffuse type and rarer predominantly trabecular meshwork involving type. (Figure 2) Secondary glaucoma has been reported in 33% of cases with iris melanoma while, with 100% of those with trabecular meshwork melanoma. [6,17] Mechanisms include direct angle invasion (infiltration), iris neovascularization and trabecular meshwork seeding (melanomalytic glaucoma). [2,3,6] Unilateral findings of markedly elevated IOP, heterochromia iridis along with pigment dispersion onto the corneal endothelium, anterior iris surface and into the angle point towards melanomalytic glaucoma. [2,18] Diffuse iris melanoma should be suspected in all cases of iris heterochromia and unilateral glaucoma. (Figure 2B and D) [2,19] Morphological features of iris melanoma such as diffuse tumor location (>1 quadrant), posterior tumor margin involving the angle, reduced median tumor thickness (flat configuration) and greater extent of tumor seeding on the iris stroma and angle have been statistically related to presence of glaucoma at presentation. [6] Patients with iris melanoma and secondary glaucoma are at significantly higher risk of systemic metastasis with a hazard ratio of 4.51 compared to iris melanoma without  glaucoma. [3,6] Possible explanation being-tumor location and its discohesive nature along with raised IOP that enables the egress of tumor cells into emissary veins leading to distant metastasis. [2,6,20].
Management of iris and iridociliary melanoma depends upon tumor size, location or extent, tumor seeding and presence of tumor related glaucoma. [15,20] Local resection (iridectomy, iridocyclectomy), plaque brachytherapy, proton beam radiotherapy and enucleation are available treatment options for both nodular as well as diffuse iris melanoma. [6,15,20,21] Secondary glaucoma in association with iris melanoma can be managed with medications, transscleral photocoagulation or laser trabeculoplasty. [22] Antivascular endothelial growth factor (anti-VEGF) injections can be tried in neovascular glaucoma. [23] Cases with refractory glaucoma resulting in blind painful eyes may warrant enucleation. [24] Filtering, shunting surgery or MIGS should be avoided in eyes with untreated tumor to prevent tumor spread outside of the globe. Diffuse iris melanoma or trabecular meshwork melanoma if misdiagnosed or missed prior to performing above named procedures can warrant enucleation for further tumor control. [3,19] Ring melanoma of the iris and ciliary body are a rare entity constituting only 0.3% of all uveal melanomas while having a poor prognosis owing to metastatic rate of up to 50%. [25]. The later could be likely due to delayed diagnosis as ring melanoma tend to grow circumferentially involving iris and entire ciliary body making them less obvious on ophthalmic examination. Prominent episcleral (sentinel) vessels, anterior chamber shallowing, multinodular tumor configuration, unilateral lens changes and occasional extra-scleral extension, light blockage on transillumination and ultrasonographic hollowness with intrinsic vascular pulsations are salient diagnostic features suggestive of ring melanoma. [25,26] They tend to initially manifest with low intraocular pressure and later develop secondary glaucoma and secondary retinal detachment. Secondary glaucoma has been reported in 35% of cases. [25] The mechanisms involved are direct angle infiltration, trabecular meshwork seeding, angle closure and neovascularization of iris. [2,3,[27][28][29] Plaque radiotherapy, proton beam radiotherapy or enucleation are available management options for the tumor. [25,26,30] Medical management, transscleral cyclophotocoagulation to uninvolved ciliary body or laser trabeculoplasty to uninvolved angle can be tried to control glaucoma in salvaged eyes. However, refractory cases require enucleation. [3] High index of suspicion is warranted when examining a case of unilateral refractory glaucoma with multinodular thickening of angle structures to avoid misdiagnosis as uveal effusion. Ultrasound biomicroscopy in such a case can help in identifying the tumor. Hurried shunting or filtering surgery for IOP control in tumor containing eyes can lead to tumor spread and further necessitate enucleation. [29,31] Iris and ciliary body metastasis constitute 8% and 2% of all cases of uveal metastasis respectively with breast and lung cancers being the most common primary tumors. [32] They tend to appear as solitary or multiple yellow, white, or pink stromal nodules with hyphema or pseudo hypopyon. They may present as ill-defined iris or ciliary body thickening in a setting of iridocyclitis. Ultrasound biomicroscopy (UBM) is useful in suspicious cases. (Figure 3A and B) Secondary glaucoma has been reported in about 37% of iris metastasis with angle invasion and iris neovascularization as mechanisms for raised IOP. [33] Treatment of primary, plaque brachytherapy, external beam radiotherapy (EBRT) or systemic chemotherapy are management options for iris and ciliary body metastasis. [2,3,33] Medical management, transscleral laser photocoagulation or laser trabeculoplasty can be useful for IOP control in these eyes. Anti VEGF injections may help in neovascular glaucoma. [3,[33][34][35] Iris lymphoma, localized or diffuse is a differential diagnosis of iris melanoma or metastasis. Unilateral or bilateral presentation of diffuse non-granulomatous uveitis with raised IOP in open angles, uveitis-glaucoma-hyphema syndrome (UGH) or steroid resistant pseudo-uveitis are documented clinical manifestations of intraocular lymphoma. [36][37][38] The mechanism for raised IOP include angle infiltration, angle closure, hyphema. [3,37] Plaque radiotherapy, EBRT, systemic chemotherapy have been used for management of iris lymphoma while, the raised IOP may respond to medical therapy, transscleral cyclophotocoagulation or laser trabeculoplasty. Enucleation is reserved for refractory cases. [2,3] Leukemic infiltration from acute lymphocytic leukemia (ALL) and acute myeloid leukemia (AML) in the anterior chamber, trabecular meshwork and Schlemm's canal can cause outflow obstruction and raised IOP. [2] ALL is the most common cause of both intraocular leukemia and secondary leukemia related glaucoma. Leukemia with central nervous system (CNS) involvement has been strongly associated with leukemic hypopyon and glaucoma. [2,39] Treatment with systemic chemotherapy or EBRT is recommended for these. EBRT is known to show rapid resolution of angle infiltration in cases with secondary glaucoma. [2] Other disorders like: Multiple myeloma, a malignant proliferation of plasma cells characterized by monoclonal production od immunoglobulins; Juvenile Xanthogranuloma, a benign histiocytic skin disorder can also affect anterior segment and lead to raised IOP. [2]

Choroidal tumors
Choroidal melanoma is the most common primary intraocular malignancy found in adults and the most common uveal melanoma encountered overall. Clinically it manifests as a dome shaped or mushroom shaped pigmented (melanotic) or non-pigmented (amelanotic) choroidal mass often associated with surrounding sub-retinal fluid, overlying orange pigmentation and exudative retinal detachment. (Figure 3C) The ultrasound B scan shows low to moderately reflective choroidal lesion with associated detached retina or occasional vitreous hemorrhage. (Figure 3D) Compared to anterior uveal melanomas, choroidal melanoma is less likely to cause secondary glaucoma (2%). [2,3] Secondary glaucoma has been reported in both known and previously undiagnosed cases of choroidal melanoma. [2,3] Secondary glaucoma has also been termed as the 'masquerading sign' for uveal melanomas in the literature. [40,41] The reported mechanisms for raised IOP include iris neovascularization, direct angle invasion, angle closure, hyphema and suprachoroidal hemorrhage. [1,3] Globe sparing episcleral plaque brachytherapy is commonly used modality of treatment followed by proton beam radiotherapy and local resection. Enucleation is warranted for large melanomas not amenable to radiotherapy or those causing absolute glaucoma. For control of IOP, medical management, transscleral cyclophotocoagulation or laser trabeculoplasty can be tried. In contrast to anterior uveal melanomas, for choroidal melanoma not involving ciliary body or iris root MIGS, filtering and shunting surgery can be considered in eyes where complete tumor regression has been achieved. [3] Contrary to traditional thinking, a recent study of analysis of glaucoma drainage device surgery for control of IOP in treated (totally regressed) uveal melanoma (both anterior as well as posterior) did not find a greater risk of local or extraocular recurrence after a median follow up of 2 years. [42] However, further analysis with larger sample size and longer follow up duration is warranted, and caution needs to be exercised while deciding regarding treatment options for control of IOP in such cases.
Choroidal metastasis represents around 90% of total uveal metastasis. Breast, lung, kidney, gastrointestinal tract, and cutaneous melanoma are the leading sites of primary malignancies. [32] (Figure 4A) Secondary glaucoma has been reported in 1% of cases with mechanism being angle closure and iris neovascularization. [24] Plaque brachytherapy, photodynamic therapy, EBRT, systemic chemotherapy or enucleation are available management options for choroidal metastasis. Secondary glaucoma can be managed like choroidal melanoma related secondary glaucoma described above.
Choroidal hemangioma is a benign vascular hamartoma presenting as an orange-red mass showing hyperreflectivity on ultrasound B scan. It can be solitary or 'circumscribed' or 'diffuse' . (Figure 4C) Circumscribed tumors cause secondary glaucoma in 1% of cases of due to angle closure and iris neovascularization due to total retinal detachment. [43] Diffuse choroidal hemangiomas appear as diffuse choroidal thickening and have been said to give 'tomato-catsup' fundus impression. They are known to be associated with Sturge-Weber syndrome (SWS). The raised IOP found in SWS has been found to be due to developmental anomalies of anterior chamber and raised episcleral venous pressure and often unrelated to diffuse choroidal hemangioma. Total retinal detachment and iris neovascularization can rarely cause secondary glaucoma in such eyes. [3] Management options include plaque brachytherapy (for circumscribed as well as to the nodular component if any, in the diffuse variant), photodynamic therapy or EBRT to halt tumor growth and control of subretinal fluid to achieve stabilization of visual acuity. [44,45] For control of IOP, medical management, transscleral cyclophotocoagulation, laser trabeculoplasty, MIGS, filtering or shunting surgeries can be performed.

Retinal tumors
Retinoblastoma is the most common primary intraocular malignancy found in pediatric population with estimated incidence of 1:16,000-18,000 live births. [46] White reflex or 'leukocoria' is the most common presenting feature of retinoblastoma. Presence of an intraocular mass with presence of intratumoral calcifications demonstrated on ultrasound B scan and/or computed tomography (CT) scan is pathognomic of the malignancy. Retinoblastoma can show endophytic, exophytic, diffuse or mixed growth pattern with presence of vitreous seeds. Secondary glaucoma is reported in 17% of cases due to iris neovascularization (5%), angle closure (1%), anterior tumor seeding (<1%) or related to hyphema (<1%). [24] Retinoblastoma is an important differential diagnosis to be considered in any pediatric uveitis or glaucoma. Delayed presentation and often misdiagnosis as either only intraocular inflammation or glaucoma can result in delay in retinoblastoma treatment and greater risk of metastasis with poor prognosis. [1,2] Neovascular glaucoma is the most common cause of retinoblastoma related raised IOP which is postulated to be mediated by vascular endothelial growth factor (VEGF) produced by necrotic and hypoxic tumor cells. [47] (Figure 5A and B) Other causes include pupillary block and tumor seeding in anterior chamber angle. Glaucoma in retinoblastoma has been reported to be associated with metastasis related to optic nerve invasion by tumor cells. [48] Presence of secondary glaucoma at presentation has also been identified as a predictor for high-risk histopathological features of retinoblastoma along with prolonged duration of symptoms. [49] Management options for retinoblastoma depend upon age at presentation, laterality as well as grouping and staging of the disease. Modalities used are systemic chemotherapy, intra-arterial chemotherapy, intravitreal chemotherapy, focal lasers, cryotherapy, plaque radiotherapy and Orbital radiotherapy. Non-salvageable and advanced tumor containing eyes need enucleation. The IOP can get controlled as tumor regression is achieved in some eyes precluding any need of separate management for the glaucoma. Medical management, laser trabeculoplasty or cyclophotocoagulation can be tried in selected eyes post-tumor treatment. Any filtering surgeries, shunting procedures, MIGS should be avoided in tumor containing eyes to avoid extra-scleral extension of tumor.

Glaucoma associated with management of ocular tumors
Radiotherapy associated glaucoma-Radiotherapy is increasingly being used for management of intraocular tumors as means of eye and vision salvage. The modalities in practice are plaque brachytherapy (Iodine1 25 , Palladium 103 , Ruthenium 106 ), proton beam radiotherapy, stereotactic radiotherapy, and external beam radiotherapy. Glaucoma has been reported as one of the common side effects of radiation. The common cause of radiation induced raised IOP is development of iris neovascularization and subsequent neovascular glaucoma (NVG). Pathogenesis of iris neovascularization is multifactorial, including increased release angiogenic factors, anterior and posterior segment ischemia, vascular occlusion, tumor hypoxia, radiation retinopathy ( Figure 4D) and optic neuropathy. [50] Secondary open angle glaucoma has also been noted in radiotherapy treated tumor eyes apart from NVG. After Iodine 125 plaque brachytherapy for uveal melanoma reported Kaplan-Meier estimated risk of secondary open angle glaucoma was 15% at 5 years with higher incidence in earlier postoperative period, whereas estimated incidence of NVG was 13% at 5 years. [51] The risk factors for development of radiation induced secondary glaucoma (both open angle and NVG) include larger tumor size, higher radiation dose, involvement of iris and ciliary body and presence of retinal detachment. [2,[51][52][53] Proton beam radiotherapy for uveal melanoma has reported NVG rate of 12-31% at 5 years with greater tumor height, older age at presentation and larger tumor diameter as identified risk factors. [54] Anti-VEGF injections as well as pan-retinal photocoagulation for treatment of ocular ischemia or radiation retinopathy might be useful to reduce rate of neovascular glaucoma induced by radiation retinopathy.
Tumor necrosis induced glaucoma-Hemolytic glaucoma (Ghost cell glaucoma) is known to occur in tumor containing eyes with vitreous hemorrhage following systemic chemotherapy or focal tumor treatments. It occurs due to obstruction of trabecular meshwork by red blood cells, their debris and macrophages filled with hemorrhagic components from phagocytosis of vitreous hemorrhage. It can be observed in retinoblastoma eyes showing tumor necrosis as well as vitreous hemorrhage post chemotherapy. (Figure 5C and D).

Special considerations
In instances where patient seeks attention with glaucoma as the presenting feature, a detailed work up involving slit lamp examination, dilated fundus examination, gonioscopy of anterior chamber angle, high frequency ultrasound microscopy (UBM) and ultrasound B scan of posterior segment will provide essential clues about diagnosis of possible intraocular tumor. Initial management with IOP lowering medications should be the first line treatment with simultaneous investigation for underlying cause. [2] When the tumor presents with atypical features or causes diagnostic uncertainty, a diagnostic biopsy is warranted in managing such case of secondary glaucoma.
[55] Systemic work up with the help of positron emission tomography (PET) CT scan can come in handy while evaluating a case of possible secondary ocular metastasis by highlighting an existing primary malignancy elsewhere.

Orbital tumor related glaucoma
The orbit is a pyramidal structure limited by bony walls except from anteriorly where it is limited by soft tissue i.e., orbital septum and eyelids. Thus, any instances of increased orbital volume may lead to increased hydrostatic pressure in the orbit. This increased orbital pressure can have a direct effect of IOP by raised hydrostatic pressure around the eye or indirect effect by compression of episcleral and orbital veins raising venous pressure. The episcleral venous system mainly empties into the anterior ciliary and superior ophthalmic veins and eventually draining into cavernous sinus. Thus, any disease process that might affect this drainage pathway due to structural, occlusive, compressive, or destructive pathophysiology can alter and raise IOP causing secondary glaucoma. [4] Focal mass effect due to tumors or swollen extraocular muscles may directly compress the eye globe leading to raised IOP while, vascular changes affecting venous pressure due to compression of episcleral veins or altered arterio-venous flow may also increase IOP indirectly. Table 1 summarizes the broad etiological classes of orbital tumors leading to rise in IOP and secondary glaucoma. Open angle glaucoma is more common in the listed diseases however, angle closure along with acute angle closure glaucoma has also been reported in variety of pathologies. IOP evaluation should be routinely performed when evaluating a case of suspected orbital tumor or pathology. Gonioscopic examination can provide essential information regarding the status of the anterior chamber angle as well as show evidence of blood in Schlemm's canal as the distinguishing feature of elevated venous pressure. The treatment of primary orbital pathology along with medical management of raised IOP is indicated for control of orbital tumor related secondary glaucoma.
In sum, glaucoma can be associated with various ocular as well as orbital tumors. It may constitute one of the many manifesting clinical features or be the sole presenting feature of these pathologies. Appropriate diagnosis and timely management of these tumors can help eye and vision salvage; however, a misdiagnosis or delayed diagnosis due to initial presentation as secondary glaucoma can lead to catastrophic sequel necessitating enucleation and can pose a greater risk to life. A thorough clinical evaluation, use of ancillary testing and stepwise management can help achieve optimum visual outcome and overall survival in cases with ocular or orbital tumors.

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