Etiologic classification of orbital tumors causing secondary glaucoma.
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 presentations and management of glaucoma related to ocular and orbital tumors.
- ocular tumors
- secondary glaucoma
- orbital tumors
- angle infiltration
- neovascular glaucoma
- neoplastic glaucoma
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.  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.  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  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.
2. Mechanisms of glaucoma secondary to ocular and orbital tumors
Solid tumor invasion- related outflow obstruction
Infiltrative tumor -related outflow obstruction
Trabecular meshwork seeding
Angle closure from neovascularization
Angle closure (compressive and rotational)
Ghost cell- Hemolytic
Elevated episcleral venous pressure
3. Ocular tumor related glaucoma
3.1 Anterior segment tumors
Anterior uveal tumors known to cause secondary glaucoma are iris/ciliary body melanocytoma, iris melanoma (nodular or diffuse), ciliary body melanoma (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]
Suspected melanocytoma can be observed cautiously. They are very rarely known to show malignant transformation.  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.
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.  Antivascular endothelial growth factor (anti-VEGF) injections can be tried in neovascular glaucoma.  Cases with refractory glaucoma resulting in blind painful eyes may warrant enucleation.  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]
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. 
3.2 Posterior segment tumors
3.2.1 Choroidal tumors
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.  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.
3.2.2 Retinal tumors
4. Glaucoma associated with management of ocular tumors
4.1 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.  When the tumor presents with atypical features or causes diagnostic uncertainty, a diagnostic biopsy is warranted in managing such case of secondary glaucoma.  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.
4.2 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.  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.
|1||Inflammatory||Non-specific Orbital Inflammatory Disease (NSOID)|
Thyroid eye disease
Orbital granulomatous disease
Orbital Foreign Body granuloma
Juvenile Xanthogranuloma (orbital histiocytosis)
|2||Vascular||Carotid-cavernous fistula (Direct or Indirect)|
Optic nerve glioma
Optic nerve meningioma
Lacrimal gland tumors
Primary orbital melanoma
|4||Secondary||Orbital metastasis (from breast, lung carcinoma)|
Orbital chloroma (Acute myeloid leukemia)
Invasive (secondary) ocular melanoma
Extra-scleral (orbital) extension of retinoblastoma
Invasive (secondary) squamous cell carcinoma
Phakomatosis (Neurocutaneous syndromes)
Collagen tissue disorders (Lupus erythematosus, Wegener granulomatosis)
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.
The author acknowledges contributions from Dr. Paul T Finger MD, FACS, Director- The New York Eye Cancer Center, New York, USA and Dr. Santosh G Honavar MD, FACS, Director- Ocular Oncology Services, Centre For Sight Hospital, Hyderabad, India for select clinical images used in this chapter.