Melanoma, Intraocular (Eye)

Introduction

Intraocular tumors are rare causes of glaucoma. In cases of unexplained glaucoma, the possibility of an ocular tumor must be considered because of the dire consequences of a missed diagnosis. The epidemiology, prognosis, and mechanism of action depend on the specific tumor type. The tumor may not be directly visible in many instances, and different methods of indirect visualization may need to be used.

Pathophysiology

There are a number of different mechanisms by which ocular tumors can cause glaucoma: (1) direct invasion, (2) pigment dispersion, (3) melanophagic, (4) hemolytic, (5) uveitic, (6) secondary angle closure, (7) iris neovascularization, (8) choroidal detachment, (9) suprachoroidal hemorrhage, and (10) anterior displacement of lens-iris diaphragm.

Mechanisms of elevated intraocular pressure in intraocular malignant melanoma, which is the most common intraocular tumor causing secondary glaucoma, include the following:

Melanoma arising within the iris

• Direct growth of the tumor into the angle
• Tumor seeding into the angle
• Pigment release into the anterior chamber and into the angle

Melanoma arising within the ciliary body

• Pigment dispersion
• Direct invasion

Melanoma arising within the choroid

• Neovascularization of the angle
• Anterior displacement of lens-iris diaphragm with angle closure
• Hemorrhage with volume effect or angle closure
• Spontaneous necrosis causing uveitis and secondary glaucoma

Frequency United States

Although individual rates vary, Shields showed a 5% incidence of increased intraocular pressure due to intraocular tumors in a series of 2597 patients with ocular tumors.This is in contrast to 50% incidence of increased intraocular pressure in eyes enucleated for tumors. Incidence of increased intraocular pressure also is dependent on location. Reports indicate a 17% incidence of glaucoma in ciliary body melanoma, 7% in iris melanoma, and 2% in choroidal melanoma. Given the relative infrequency of intraocular tumors, this condition is a rare event.

Early detection of this rare tumor is important because it may increase mortality.

Symptoms vary depending on the location of the ocular tumor.

• Glaucoma symptoms are dependent on the speed at which the pressure rises. With acute glaucoma from angle closure, decreased vision, halos around lights, ocular pain, and nausea may be present. With chronic glaucoma with progressive angle closure or open angles, no ocular symptoms may be present.
• With iris melanoma, a hyperchromic heterochromia may be present.
• With a ciliary body melanoma, a distorted pupil or vision change from lenticular astigmatism may occur.
• With choroid melanoma, the visual symptoms may be decreased vision or a change in the peripheral vision, depending on the location of the tumor.
• Melanocytoma of the optic disk is usually asymptomatic.

Physical

• Diagnosis is assisted by gonioscopy, indirect ophthalmoscopy, and ultrasonography. Clinical scenarios depend on tumor location. Hyperchromic heterochromia with glaucoma may help to diagnose ipsilateral iris melanoma, whereas anterior displacement of the iris-lens diaphragm may be present in ciliary body melanoma.
  • Iris melanoma can occur as either diffuse or well-circumscribed forms, with the former being less common and more malignant.
  • Ciliary body melanomas tend to be larger at presentation due to their obscure location and usual lack of visual symptoms. They may present as a ring melanoma, which completely encircles the ciliary body. Proportion of epithelioid cells is higher in ciliary body melanoma. Shields reports that 50% of patients seen at Wills Eye Hospital with ciliary body melanoma died within 2 years due to metastases.1
  • Choroidal tumors associated with glaucoma typically have broken through the Bruch membrane and are mushroom shaped.
• Diagnosis of melanocytoma is through direct visualization using slit lamp, gonioscopy, or indirect ophthalmoscopy.
  • Melanocytomas can occur anywhere along the uveal tract, although the optic nerve is the most common site.
  • These appear as darkly pigmented, isolated lesions, which have a strong tendency to undergo necrosis and fragmentation, leading to pigment release. Consequently, trabecular meshwork becomes obstructed, leading to intraocular pressure elevation.
  • Treatment of melanocytoma consists of observation with photographic documentation in smaller lesions. Glaucoma management starts with medical therapy.
  • Benign iris melanocytic lesions (iris nevi) are difficult to grossly distinguish from malignant lesions of the iris.
  • These occur as small, discrete, flat, or slightly raised nodules with variable pigmentation.
  • Jakobiec, in a study of 189 lesions of the anterior uvea, notes that 80% of clinically diagnosed melanoma of the iris cases were reclassified at pathological examination as nevi of several cell types.2
  • Another study identified 5 factors associated with higher risk of malignancy, as follows: (1) diameter greater than 3 mm, (2) pigment dispersion, (3) prominent tumor vascularity, (4) increased intraocular pressure, and (5) tumor-related ocular symptoms.
  • Although iris nevi rarely cause a pathologic process, diffuse growth can cause elevated intraocular pressure by direct extension into the trabecular meshwork.
  • The treatment of an iris nevus is the same as the treatment of a melanocytoma.
• Tumors of the nonpigmented ciliary epithelium
  • Medulloepithelioma, previously known as diktyoma, is an embryonic tumor that manifests in the first few years of life. These are solid or cystic lesions of the nonpigmented ciliary epithelium, which can extend into the anterior chamber and present with glaucoma, hyphema, and leukocoria.
  • In a large series from the Armed Forces Institute of Pathology, 46% of these patients had glaucoma. Glaucoma results from iris neovascularization, direct invasion of the angle structures, hyphema, or tumor-induced angle closure.
  • Adenomas and adenocarcinomas of the ciliary epithelium rarely are associated with glaucoma. However, in such rare instances, the presentation and management are similar to ciliary body melanoma.
• Tumors of the retina (retinoblastoma)
  • The tumor may assume an endophytic or exophytic configuration. In the former configuration, tumor cells may invade into the vitreous and anterior chambers.
  • In the Wills Eye Hospital series, 17% of 303 patients were associated with glaucoma and iris neovascularization. In another series, glaucoma secondary to retinoblastoma ranged from 2-22%.
  • Neovascularization is associated with angiogenic factor production from the tumor or ischemia due to large retinal vasculature involvement. Subsequent neovascularization of the iris with angle closure accounts for 73% of glaucoma. Pupillary block leading to angle closure from large tumors and infiltration of the trabecular meshwork account for the remaining cases.

Causes

• Intraocular tumors that may cause elevated intraocular pressure
  • Iris
    • Nevus
    • Melanocytoma
    • Iris pigment epithelium adenoma
    • Malignant melanoma
    • Metastatic
  • Ciliary body
    • Medulloepithelioma
    • Melanocytoma
    • Malignant melanoma
    • Metastatic
  • Choroid
    • Malignant melanoma
    • Metastatic
  • Optic nerve
    • Melanocytoma
    • Metastatic
  • Retina - Retinoblastoma (most common malignant intraocular tumor in children)
  • Metastatic
    • Carcinoma
    • Cutaneous melanoma
    • Breast
    • Lung
    • Kidneys
    • Testicles
    • Prostrate
    • Pancreas
    • Colon
    • Gastrointestinal
  • Others
    • Leukemia
    • Lymphoma
    • Phakomatoses
    • Multiple myelomas
    • Juvenile xanthogranuloma
• Metastatic
  • The 2 most common sites of primary tumor metastatic to the eye are breast and lung cancers. In 2 large studies, 6% of lung cancers and up to 37% of breast cancers metastasized to the eye.
  • The posterior uvea is the most common site of metastases, but glaucoma more often is associated with anterior metastases.
  • In a series of 227 cases of metastatic carcinoma, glaucoma was detected in 7.5% of the total group and 56% of those with anterior segment metastases.
  • Mechanism of glaucoma includes direct invasion of the trabecular meshwork by tumor cells, secondary angle closure by anterior displacement of the lens-iris diaphragm, and neovascularization of anterior chamber angle.
  • Squamous cell carcinoma may produce a sheet of tumor cells.
  • Glaucoma may be the initial presentation in some patients.
  • Management includes paracentesis with aqueous aspiration for cytologic examination or flow cytometry for diagnosis. Medical management of intraocular pressure coupled with radiation or chemotherapy may be useful. Enucleation is reserved for blind, painful eyes.
• Phakomatoses
  • Phakomatoses are a group of hamartomatous disorders in which abnormal proliferation of tissues occurs in their normal locations. These tumors primarily affect the eye, skin, and nervous system, although other systems may be affected to a lesser degree.
  • Sturge-Weber syndrome (encephalotrigeminal angiomatosis) involves hamartomatous, vascular tissues and produces a characteristic port-wine hemangioma of the skin along the trigeminal distribution and ipsilateral angioma of the meninges and the brain.
    • Estimates vary, but one study showed the presence of glaucoma in up to 50% of cases in which the port-wine stain involves the ophthalmic and maxillary divisions of the trigeminal nerve. Glaucoma develops before age 2 years in 60% of patients, with the remainder developing by early adulthood.
    • Ipsilateral conjunctival and episcleral vascular dilation may signal arteriovenous malformation, leading to elevated episcleral venous pressure.
    • In the same study, 69% of 51 patients had conjunctival or episcleral hemangiomas, and glaucoma was present in 71% of these patients.
    • Various other studies have shown anterior chamber angle anomalies, including angle neovascularization. The major mechanism may involve increased episcleral venous pressure, causing delay in the aqueous outflow.
    • Management consists of combining medical, laser, and surgical options for late-onset glaucoma and primarily surgical intervention in infants.
    • In one study, the median period of control was determined as the following: goniotomy (12 mo), trabeculotomy (21 mo), trabeculectomy (21 mo), argon laser trabeculopexy (ALT) (25 mo), and medications (57 mo). However, trabeculectomy was associated with a high incidence of choroidal effusions and expulsive hemorrhage.
  • Neurofibromatosis is a common autosomal dominant systemic disorder divided into types 1 and 2 whose ocular and systemic findings are well documented. See Neurofibromatosis-1.
    • Ocular findings include enlargement of the eye and cornea, heterochromia, ectropion uveae, and Lisch nodules.
    • Glaucoma usually is unilateral and associated with eyelid thickening and contour abnormalities.
    • Different mechanisms for elevated intraocular pressure have been proposed, as follows: (1) direct infiltration of the angle tissue, (2) secondary angle closure due to ciliary body and choroid thickening, (3) fibrovascular membrane formation over the angle, and (4) anterior chamber dysgenesis.
    • Extensive medical therapy is tried before the surgical approach, which must be tailored to the cause and often is unsatisfactory. Goniosurgery, filtration surgery with or without cytotoxic agents, and cyclodestructive surgeries have been tried without significant success.
• Miscellaneous tumors
  • The eye may become involved in acute and chronic lymphocytic leukemia and affect the anterior and posterior segment.
    • Despite a relative high incidence of ocular involvement in leukemia, ranging up to 80%, glaucoma is rare, according to Jakobiec.
    • Elevated intraocular pressure results from outflow obstruction secondary to iritis, hyphema, pseudohypopyon, or leukemic infiltration of the trabecular meshwork and Schlemm canal, as well as episcleral tissue, which may involve aqueous veins.
    • Management is primarily through medical means to control intraocular pressure and to address the underlying leukemia through appropriate means.
    • Multiple myeloma may cause ciliary body cysts, which may lead to secondary glaucoma arising from lens dislocation or anterior displacement of the iris root. Treatment involves a combination of medical therapy, lens removal, and laser iridectomy/laser cyst puncture.
    • Large cell lymphoma may mimic uveitis and may infiltrate the uveal tract, leading to secondary angle closure. The tumor is treated with radiation therapy, and glaucoma is managed medically.
    • Juvenile xanthogranuloma is a benign histiocytic tumor affecting the skin and eye in young children. A salmon colored iris tumor is associated with spontaneous hyphema in children. Glaucoma results from direct obstruction of the outflow tract by histiocytes or outflow obstruction secondary to hyphema. Radiation therapy to the iris tissue has helped to resolve the iris tumor and glaucoma.
• All 3 of the following conditions may be associated with elevated intraocular pressure secondary to pigment release.
  • Melanosis iridis is characterized by verrucous elevation of the iris stroma, usually in a unilateral and sectorial distribution.
  • Melanosis oculi involves the episclera and/or choroid.
  • Oculodermal melanocytosis involves the periocular skin.

Treatment Medical Care

• Glaucoma management itself begins with medical therapy, concurrent with treatment of the intraocular tumor through surgery, radiation, chemotherapy, or a combination of these treatments.
• Standard methods of intraocular pressure control should be used, although success rates with these topical medications will necessarily be low.
• Anti-vascular endothelial growth factor (anti-VEGF) therapy may be helpful in those cases where neovascularization plays a role in the pathogenesis of the glaucoma.

Surgical Care

• Surgical options to control intraocular pressure must be tempered by the need for preventing extraocular tumor spread.
  • For smaller tumors, observation is warranted until growth is documented.
  • Iridectomy or iridocyclectomy also are options for removing smaller tumors.
  • For anterior tumors, argon laser trabeculopexy to tumor-free areas is an option.
  • More posterior tumors may require local resection, photocoagulation, or episcleral radioplaque therapy. Enucleation or exenteration also is an option.
• For melanocytoma, laser or surgical excision of the lesion may decrease the pigment load and decrease the intraocular pressure.
• Glaucoma usually is associated with advanced stages of retinoblastoma, and enucleation may need to be discussed. Other therapeutic options include radiotherapy, cryotherapy, and photocoagulation. Any intervention must be tempered by the risk of extraocular spread.

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