Based on the incidence rates from the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute, the American Cancer Society estimated that approximately 2390 new cases of all types of primary ocular and orbital malignant tumors were diagnosed in the United States in 2008.¹ This demonstrates the rarity of ocular malignant tumors. Uveal melanoma is the single most common malignant tumor of the eye and orbit and makes up nearly 70% of all cancers of these tissues.¹ Irradiation is used in the management of many ocular and orbital cancers, as well as in the management of several benign ocular processes. Understanding the pathophysiologic processes of ocular cancers and the results of radiation treatment can guide treatment recommendations.

Complicating the assessment of ocular cancer treatment is the real possibility that therapy itself may result in loss of vision or loss of an eye. Understanding the radiation tolerances and sequelae from radiation is vital for estimating the vision-related quality of life following treatment.

Etiology and Epidemiology

Eyelid Skin Cancers

Basal and squamous cell carcinomas of the periorbital skin (nasal bridge, medial canthus, and eyelid) most frequently occur on the lower eyelid and medial canthus. Patients with sun exposure and those who are immunosuppressed have an increased incidence of these cancers.

Uveal melanoma is the most common primary malignant intraocular neoplasm.¹ It is thought to arise from melanocytes of the uveal tract and in the United States occurs in approximately 1500 patients per year.^1,² Uveal melanomas are more common in lightly pigmented persons and are infrequent in nonwhite races. The average age at the time of diagnosis is 60 years in most large series,²^–⁴ and the disease occurs with equal frequency in men and women. The tumors are rarely bilateral. Factors proposed as increasing the risk for the development of uveal melanoma are prolonged sustained sunlight exposure^5,⁶ and lighter-colored irises.^5,⁶ Certain diseases may predispose to melanoma, including xeroderma pigmentosum, which is an inherited disorder of DNA repair; oculodermal melanocytosis,⁷ in which the ocular surface and the uveal tract are hyperpigmented; and dysplastic nevus syndrome. There are some reports implying a possible rare genetic predisposition, although most melanomas occur as sporadic tumors.

Retinal Tumors

Retinoblastomas are discussed in Chapter 69.

Optic Nerve Tumors

Meningioma

Optic nerve sheath meningiomas arise from the meningothelial cap cells of arachnoid villi and can develop anywhere along the course of the optic nerve from the globe to the prechiasmal intracisternal optic nerve. They may be unilateral, bilateral, or multifocal. Patients with type 2 neurofibromatosis are predisposed to bilateral or multifocal lesions.⁸ Meningiomas from other locations can also extend to involve the optic nerve.

Optic nerve sheath meningiomas are more common in women. Dutton’s meta-analysis estimates a female preponderance of 61%.⁹ The typical age at presentation is 40 years. Bilateral cases appear to have an earlier age of onset.

Glioma

Optic nerve gliomas account for 1% to 5% of intracranial gliomas and 4% of orbital tumors. They occur most frequently in children, with 75% in the first decade and 90% in the first two decades of life.¹⁰ Approximately 25% of patients with optic gliomas also have type 1 neurofibromatosis. These tumors are increasingly being seen as markers of enhanced risk in patients and their families for the subsequent development of central nervous system tumors.¹¹

Orbital Tumors

In a recent report of 1264 consecutive patients with orbital masses, 33% of patients had malignant lesions. Rhabdomyosarcoma was the most common malignant tumor in children, representing 3% of all orbital masses, and lymphoma was the most common malignant tumor in older patients, representing 10% of cases.¹² In one large series, metastatic breast cancer comprised 4% of these lesions.

Rhabdomyosarcoma

Rhabdomyosarcomas are discussed in Chapter 66.

Lacrimal Gland Tumors

Lacrimal gland tumors are rare. The gender distributions are equal and patient age ranges from 10 to 73 years (mean of 46 years).¹³ Most of these lesions are malignant, with adenoid cystic carcinoma and mucoepidermoid cancer being the two most frequent ones. Benign pleomorphic adenomas also occur.

Lymphoma

Primary orbital lymphomas are rare and account for less than 1% of all lymphomas diagnosed.¹⁴ Lymphomas in the orbit can occur anteriorly in the conjunctival tissues or in the retrobulbar region. Patients with lymphoma at other sites can also present with eye involvement in the course of their disease.

Primary intraocular lymphoma may have malignant lymphoid cells involving the retina, vitreous, or optic nerve head, with or without concomitant central nervous system involvement. The incidence of primary intraocular lymphoma has been increasing over the past 15 years, in both immunocompetent and immunocompromised patients.¹⁵ The cause of this increased incidence is unknown. This is a disease of persons in their fifties and sixties, occurring more often in men than women.

Metastatic Tumors

The most common primary tumor to metastasize to the orbit is breast cancer.¹² Other orbital metastases have been reported to occur from neuroblastoma, lung cancer, renal cell cancer, and prostate cancer.

Benign Ocular Conditions

Pterygium

A pterygium is a benign growth of fibrovascular tissue on the cornea. These lesions may become red and inflamed, encroach on the visual axis, and be a cosmetic as well as a functional issue for patients.

Most pterygia are located nasally and occur in patients aged 20 to 50 years.¹⁷ They are more commonly encountered in warm, dry climates or in patients who are chronically exposed to outdoor elements or smoky and dusty environments. Ultraviolet light exposure appears to be the most significant factor in the development of pterygia. Heredity may also be a factor.

Pterygia represent a degeneration of the conjunctival stroma with replacement by thickened, tortuous elastotic fibers.¹⁸ Activated fibroblasts in the leading edge of the pterygium invade and fragment Bowman’s layer. Pterygium development resembles actinic degeneration of the skin.

Pseudotumor

Orbital pseudotumor, or idiopathic orbital inflammatory syndrome, is a nonspecific inflammatory process of unknown etiology that may mimic orbital lymphoma.¹⁹ Because the disease mimics infectious or neoplastic processes, these must be ruled out. Autoimmune disease, endocrinopathies, and granulomatous processes must be excluded, as well as local infection with secondary involvement of the orbit, such as sinusitis and subperiosteal abscess. The diagnosis of pseudotumor is vague and remains one of exclusion.

The cause is unknown, but several theories have been proposed. The response to steroids and immunosuppressive drugs suggests an autoimmune disorder. A fibroproliferative disorder has been suggested. Aberrant wound healing provoked by infection or autoimmune disease has also been postulated.

The term pseudolymphoma has been advocated for the diagnosis of reactive lymphoid hyperplasia. Unfortunately, the literature includes reports of patients with biopsied and unbiopsied lesions, as well as reactive lymphoid hyperplasia and the more nonspecific inflammatory lesions. For this reason, the term pseudotumor refers to any idiopathic inflammatory lesion of the orbit.

Graves’ Ophthalmopathy

The pathogenesis of Graves’ ophthalmopathy is thought to be an autoimmune one in which activated T lymphocytes invade the orbit and stimulate glycosaminoglycan production in fibroblasts, resulting in tissue edema, lymphocyte infiltration, and marked enlargement of the extraocular muscles.²⁰ Because lymphocytes and fibroblasts are sensitive to radiation, retrobulbar irradiation has been advocated as a treatment. The ophthalmopathy typically goes through three phases: progression, followed by stabilization, and perhaps some improvement. Residual signs of ophthalmopathy after the disease has reached a plateau are thought likely to be the result of fibrosis and other tissue changes rather than persistent inflammation.

Macular Degeneration

Age-related macular degeneration (AMD) is the leading cause of blindness in patients older than 65 years.²¹ The progressive loss of central vision is usually consequential to an atrophic process involving the retinal epithelium and choriocapillaries in the macula, which is classified as dry AMD. The wet form of AMD is an exudative process with subretinal neovascularization. Wet AMD generally progresses to destructive disciform scarring of the macula, with fibrovascular scars involving the choroid and sensory retina. Patients develop poor visual acuity.

Prevention and Early Detection

Because of the rarity of all ocular tumors, no prevention or early detection methods have been developed for most tumor types. However, in children born into a family with known retinoblastoma, early and careful ophthalmologic evaluation is warranted. Genetic counseling and evaluation of the siblings of patients with retinoblastoma is important, given the high hereditary likelihood.²² After the diagnosis of unilateral retinoblastoma, routine evaluation of the uninvolved eye is indicated because of the increased risk of contralateral disease (see Chapter 69).

Biologic Characteristics and Molecular Biology

Ocular Melanoma

Biologic characteristics that predict outcomes in patients with ocular melanoma include tumor cell type, tumor size, tumor location, and extension of the tumor outside the sclera.²³ Cell type is discussed in the pathology section of this chapter, with patients with spindle cell tumors having a better survival rate than those with epithelioid cell tumors. Recent data suggest that specific chromosomal aberrations within the tumor may be associated with the length of survival. Many tumors are treated by means other than enucleation, and because biopsy is rarely performed, the cell type is often unknown.

Survival rates are adversely affected by increased size of the uveal melanoma. Although the earlier literature had various size classifications, the Collaborative Ocular Melanoma Study (COMS) has established a standard size classification.²⁴^–²⁶ Small melanomas are 1 to 3 mm thick and less than 16 mm in largest dimension. Medium-sized melanomas are 3 to 8 mm thick and less than 16 mm in largest dimension, and large melanomas are more than 8 mm thick or more than 16 mm in largest dimension (Table 29-1).

TABLE 29-1 Various Other Definitions of Choroidal Melanoma Size

Size	Measurement
Small	1.5-2.4 mm height and 5-16 mm diameter
Medium	2.5-10 mm height and <16 mm diameter
Large	>10 mm height and >16 mm diameter

Prognosis is also affected by the location of the anterior tumor margin. Tumors located anterior to the equator of the eye in the anterior choroid or ciliary body have a worse prognosis than those located more posteriorly.²³ Extraocular extension of a uveal melanoma has poor prognostic implications.²⁴

Genetic studies of intraocular melanomas have indicated that the development of metastatic disease is highly correlated with chromosome 5 trisomy and monosomy for chromosome 3.

Orbital Lymphoma

The biology of these tumors varies with the histologic classification within the Revised European-American Lymphoma system or the Working Formulation.^27,²⁸ Stage and histologic type play the most significant roles in outcome for orbital lesions.

Primary intraocular lymphoma is believed to be a subset of primary central nervous system lymphoma. It is usually a diffuse large B-cell non-Hodgkin’s lymphoma, and, less commonly, it may be T-cell lymphoma. Because pathologic diagnosis can be difficult, flow cytometry is often done to demonstrate monoclonal populations of B lymphocytes. Immunohistochemical assessments have also been used to demonstrate expression of BCL-6 and MUM1.²⁹ These two markers have been revealed in systemic diffuse large B-cell lymphoma. Molecular analysis detecting immunoglobulin gene rearrangements and ocular cytokine levels showing elevated interleukin-10 (IL-10), with a ratio of IL-10 to IL-6 greater than 1, are helpful adjuncts for the diagnosis of intraocular lymphoma.^14,³⁰

Orbital Pseudotumor

The histopathologic type varies, and attempts to refine and subdivide patients have been advocated. The histopathologic spectrum of idiopathic orbital inflammation is typically nondiagnostic and diverse, ranging from the typical diffuse polymorphous infiltrate to the atypical granulomatous inflammation, tissue eosinophilia, and infiltrative sclerosis. One report suggested dividing this condition into three principal types: lymphoid, granulomatous, and sclerosing types.³¹ Several authors have endorsed the exclusion of reactive lymphoid hyperplasia and defined pseudotumor as a mixed inflammatory infiltrate with fibrosis of varying degrees.¹⁹

Immunologic cytochemical staining, polymerase chain reaction testing, and flow cytometry are all helpful for demonstrating surface membrane or cytoplasmic markers that correspond to a lymphoma. Polyclonal distributions are associated with pseudolymphoma.

Pathology and Pathways of Spread

Skin Cancers

Basal cell cancers are seen in 90% of patients, followed by squamous cell cancers in 10%. For patients with squamous cell cancer, involved regional lymph nodes have been reported in as many as 24% of patients.³² Lymph node involvement is more common for larger tumors, recurrent tumors, and those with perineural invasion. Patients with recurrent lesions or perineural invasion may have tumor cells spread more peripherally than is clinically apparent. This may require wider radiation fields. Tumors located in the embryologic fusion planes of the face have been found to be more deeply infiltrating. This area around the medial canthus may affect the depth of treatment necessary for a successful outcome.

Ocular Melanoma

Uveal melanomas arise from melanocytes that are of neuroectodermal origin. Melanoma cells have a large nuclear to cytoplasmic ratio, prominent or multiple nucleoli, and frequent mitotic figures. Tumors are generally classified as composed of either spindle cells or epithelioid cells.³³ Spindle cells have a fusiform shape and less pronounced atypia, whereas epithelioid cells are larger and more ovoid in shape and have more anaplastic characteristics. Uveal melanomas are classified as spindle cell melanomas if they are composed of only spindle cells, mixed cell melanomas if they contain both spindle cells and epithelioid cells, and epithelioid cell melanomas if they contain predominantly or exclusively epithelioid cells. Occasionally, the cells within the melanoma undergo necrosis, and these tumors are classified as necrotic melanomas.

The prognosis is more favorable in spindle cell melanoma, intermediate in mixed cell tumors, and poorest in epithelioid or necrotic melanoma. Other negative prognostic indicators include tumor dimension, thickness, and location of the anterior tumor margin.³³ Melanomas tend to be slow-growing tumors, but the rate of growth can be quite variable. More rapidly growing tumors, which have a worse prognosis, tend to be anaplastic and composed of epithelioid cells.

At the time of diagnosis, most posterior uveal melanomas are confined inside the sclera of the eye. Extraocular extension of the melanoma can occur through emissary canals, through which normal ocular structures such as vessels and nerves enter and exit the sclera, and generally not by atrophy or thinning of the sclera. Extraocular extension is classified as microscopic or gross (visible on gross inspection), occurs in 8% to 14% of eyes harboring a melanoma, and is associated with a worse prognosis.³⁴

Metastatic disease occurs in less than 3% of patients at the time of initial diagnosis. The most common sites of involvement include hematogenous spread to the liver and the lung. More unusual sites of spread include bone, skin and subcutaneous tissue, and brain and spinal cord tissue. Lymph node involvement was noted in 10% of patients dying from metastatic disease within the COMS.³⁵

Choroidal Metastasis

The most common pathologic type is adenocarcinoma from the breast or non–small cell lung cancer. Most patients have other sites of metastatic disease. Disease extent can be localized to the choroid. The average number of lesions seen in the choroid in one large series was two.¹⁶ In this situation, involvement of the opposite choroid can occur in as many as 50% of patients. Orbital metastases can occur and are typically unilateral.

Orbital and Ocular Lymphoma

A wide range of non-Hodgkin’s lymphomas have been described involving the orbit and globe. In patients with orbital lymphomas, most of the lesions are of B-cell origin and classified as low or intermediate grade by the Working Formulation.³⁶ The most common subtype of ocular adnexal lymphoma is a mucosa-associated lymphoid tissue (MALT) lymphoma. Intraocular lymphomas are usually of the aggressive, diffuse, large B-cell type.¹⁵

The pattern of spread in low-grade lymphomas is similar to that of its counterparts in the rest of the body, with a risk of distant sites of involvement. Intraocular lymphomas tend to disseminate into or be a component of disease within the central nervous system and therefore carry a more ominous prognosis.

Orbital Meningioma

Meningiomas spread along paths of least resistance, remaining confined to the subarachnoid or intradural space of the intraorbital optic nerve. The tumor may invade the dura, adjacent orbital tissue, muscle, bone, and globe. These tumors may traverse the optic canal and affect the intracranial segment of the optic nerve or adjacent structures. Orbital meningiomas have histologic features similar to those of intracranial meningiomas. Most lesions demonstrate concentric formations of spindle cells or ovoid meningothelial cells with sheets of polygonal cells separated by vascular trabeculae.³⁷

Lacrimal Gland Tumors

Pathologic findings are typically those of adenoid cystic cancer, followed by mucoepidermoid cancer and adenocarcinoma. Outcome seems to be related to the presence of necrosis, hemorrhage, perineural invasion, and high mitotic count.³⁸

Optic Nerve Glioma

In the pediatric form of the disease, the cell of origin for optic nerve gliomas is unknown. Optic nerve gliomas are classified as grade I astrocytomas (pilocytic astrocytomas) in the World Health Organization (WHO) classification of gliomas, are slow growing, and do not tend to metastasize.³⁹ Optic nerve gliomas develop in stages, from generalized hyperplasia of glial cells in the nerve to complete disorganization with loss of neural landmarks within the nerve and nerve sheath. A reactive meningeal hyperplasia may be incited, making it difficult to distinguish a glioma from a perioptic meningioma.

In pediatric patients with optic nerve glioma, 10% to 38% have type 1 neurofibromatosis, and 15% to 40% of children with neurofibromatosis 1 have an optic glioma.⁴⁰ When bilateral, the lesions are pathognomonic for neurofibromatosis 1.

In the adult form of the disease, the optic nerve gliomas are more likely to be diffusely infiltrative, including astrocytoma (WHO grade II), anaplastic astrocytoma (WHO grade III), or glioblastoma multiforme (WHO grade IV).⁴¹ Nuclear atypia, mitoses, endothelial proliferation, and necrosis are potential histologic features.

Clinical Manifestations, Patient Evaluation, and Staging

The diagnostic algorithm for ocular, orbital, and lid tumors is given in Figure 29-1.

Figure 29-1 Diagnostic algorithm for ocular, orbital, and lid tumors.

Skin Cancers

Patients should be evaluated for lymph node involvement with physical examination of the parotid, facial, and neck node areas. Symptoms of pain or sensory changes may indicate perineural invasion. Magnetic resonance imaging (MRI) of the skull base may detect enlargement of the affected nerves.

Ocular Melanoma

At the time of presentation, patients with uveal melanomas may be asymptomatic or complain of visual symptoms such as flashes of light, floaters, decreased visual acuity, or a visual field defect. Those who have visual symptoms typically have a more posteriorly located tumor, a large tumor, or an associated retinal detachment leading to a visual field deficit. Rarely, pain and redness are presenting symptoms, occurring in large or necrotic tumors that have associated inflammation.

The diagnosis of melanoma is based primarily on ophthalmoscopic appearance and ancillary testing. The tumor typically appears as a unilateral, solitary, elevated, dark brown or gray, variably pigmented, dome-shaped mass (Fig. 29-2). Orange pigment (lipofuscin) is often found on the surface of the tumor and is thought to represent increased metabolic activity.⁴² Retinal detachment may be present and is more likely in larger tumors.

Figure 29-2 Photograph of a melanoma in the cross section of a globe.

The initial ophthalmologic workup includes fundus photography, fluorescein angiography, and ultrasonography of the globe (Fig. 29-3). These tests facilitate making a correct diagnosis and are also useful in following the lesions for growth or regression after treatment. In a large prospective trial, 645 of 647 patients who underwent enucleation for melanoma were confirmed to be such at pathologic evaluation. Two of the patients had adenocarcinoma.²⁴ In eyes with opaque media secondary to cataract or vitreous hemorrhage, ultrasonography of the globe and MRI of the orbits can allow an accurate diagnosis. Biopsy of a lesion suspicious for an ocular melanoma is used only in cases of diagnostic uncertainty. In patients requiring biopsy, histopathologic and immunohistochemical assessments can be useful in confirming the diagnosis.

Figure 29-3 Ultrasound scan of a dome-shaped tumor.

To assess disease extent, obtain a general history and perform a physical examination with attention directed to skin lesions, weight loss, the lungs, and the liver. History of a prior cancer would indicate the possibility of a metastatic lesion in the eye rather than a primary melanoma. The most frequent site of metastasis is the liver, so the workup generally includes liver enzyme levels. Elevated levels will prompt evaluation with radiographic imaging. This approach was recently reported to have low sensitivity but high specificity and predictive value.⁴³ Other sites of metastatic disease include the lung, and imaging with chest computed tomography (CT) scanning is most accurate for early detection of disease. The COMS report of sites of metastasis from melanoma demonstrated that sites included liver (91%), lung (28%), and bone (18%).⁴³ Melanomas of the iris rarely metastasize. The brain is an infrequent site of metastasis; brain metastases were discovered in only 4% of patients at the time of death.⁴⁴

Ocular Metastasis

Patients with uveal metastasis from breast cancer presented to ophthalmologists with visual symptoms in 93% of cases. Of 264 patients with uveal metastasis, 225 (85%) had choroidal metastasis, 8 (3%) had iris metastasis, 2 (<1%) had ciliary body metastasis, and 29 (11%) had metastasis in multiple uveal sites. Asymptomatic metastases were detected in 56% of patients in the opposite eye.⁴⁵

Patients with orbital tumors more often present with diplopia, ocular motility disorder, and proptosis. Lesions are usually unilateral.⁴⁶ Metastatic disease may be detected in a high proportion of the patients who present with this entity.

Orbital Lymphoma

Orbital lymphoma can involve the soft tissues and present as a palpable mass. Proptosis, diplopia, and inflammation can also be present. Conjunctival lymphomas are erythematous and present as a visible and palpable mass that is sometimes referred to as salmon colored. Patients should be evaluated for systemic disease with routine staging for a lymphoma workup, including imaging of the chest, abdomen, and pelvis. Full nodal examination with assessment of symptoms including weight loss, fevers, and night sweats should be included. Bone marrow examination should be performed. CT scans of the orbit can be used to delineate the extent of retrobulbar and soft tissue involvement.

Primary intraocular lymphoma is one of the most challenging intraocular tumors to diagnose. Cytologic examination of vitreal aspirates remains the gold standard for exclusion of neoplastic disease in patients with idiopathic uveitis.¹⁴ Patients with primary vitreous involvement should also have cerebrospinal fluid (CSF) examination and MRI of the brain and meninges. Eighty percent of patients with primary vitreous involvement have bilateral involvement.

Staging is done using the Ann Arbor staging system.⁴⁷ A localized orbital lymphoma would be stage IeA.

Optic Nerve Meningioma

Patients typically present with visual loss, afferent papillary defect, color vision disturbance, visual field defect, proptosis, and optic disc edema. Ophthalmoscopic examination may reveal optic nerve head swelling, macular edema, nerve pallor, or choroidal folds. Optic disc swelling may also be observed. MRI is the procedure of choice for diagnosis of these lesions. Lesions appear slightly hypointense to brain and optic nerve tissue on T1-weighted images with fat suppression and gadolinium contrast. Thin CT scans may reveal regular or irregular thickening of the nerve sheath meninges. The nerve may appear normal in size or smaller as the result of circumferential compression or atrophy. Calcification has been described in 30% of patients and is associated with slower growth.⁴⁸ Differential diagnosis includes sarcoid, demyelinating optic neuritis, orbital inflammatory disease, schwannoma, lymphoma, hemangiopericytoma, and optic nerve metastasis.

Usually these lesions are described as slow growing. Visual loss will generally occur in untreated eyes over a period of 5 to 10 years.⁴⁹ Rapid growth has been observed during pregnancy, which may be mediated by hormone receptors.⁵⁰ Other tumors have demonstrated rapid visual loss even in the absence of radiographic enlargement.

Optic Nerve Gliomas

Of optic pathway gliomas, 10% to 20% are confined to the orbit, with the remainder involving the intracranial compartment.¹⁰ MRI is the preferred method for evaluation of optic pathway glioma. Both the intraorbital lesion and its intracranial extent can be effectively characterized on MRI. When evaluating the orbit, gadolinium-enhanced T1-weighted images with fat saturation are effective at defining the extent of adult optic glioma. In the intracranial region, MRI provides superior evaluation of the optic nerve, chiasm, tracts, and geniculate body and of optic irradiation compared with CT scanning.

Orbital Pseudotumors

Patients present with proptosis, decreased ocular motility, soft tissue edema, and pain. Decreased visual acuity is not unusual. The condition may be unilateral or bilateral.⁵¹ CT scanning may reveal a unilateral focal or more diffuse mass. One review documented infiltration of the retrobulbar fat in 76% of patients, enlargement of the extraocular muscles in 57%, thickening of the optic nerve/sheath complex in 38%, contrast enhancement in 95%, and proptosis in 71%.⁵² Intracranial extension is unusual but has been documented in up to 8.8% of patients.⁵³

Biopsy is recommended whenever possible to ensure accuracy of diagnosis. Lymphoma, metastatic carcinoma, and sarcomas may be ruled out by a biopsy.

Lacrimal Gland Tumors

Most patients present with an orbital mass and pain. A mass is frequently appreciated on examination. Biopsy can frequently be accomplished with fine-needle aspiration. CT scanning of the orbit should be performed to determine the extent of the mass.

Graves’ Ophthalmopathy

Signs and symptoms of Graves’ ophthalmopathy include bilateral exophthalmia, extraocular muscle dysfunction, diplopia, blurred vision, eyelid and periorbital edema, chemosis, lid lag and retraction, and compressive optic neuropathy. Imaging with CT scanning of the orbit will demonstrate changes consistent with enlargement of extraocular muscles, which are usually symmetric.⁵⁴

Primary and Adjuvant Therapy

Eyelid Skin Cancers

In general, surgical excision is the preferred treatment. A large report of patients treated with Mohs’ surgery for basal cell cancer revealed a 0% recurrence rate following treatment for a newly diagnosed basal cell cancer, but a 7% recurrence rate for those treated for recurrent basal cell cancer.⁵⁵ Another report of patients with squamous cell cancer demonstrated a recurrence rate of 3% at 5 years following Mohs’ surgery.⁵⁶

If surgery is not feasible because of associated functional and cosmetic problems, treatment with radiation has been very successful for patients with either histologic type.⁵⁷ In a series of more than 1000 patients with eyelid tumors treated with radiation, Fitzpatrick and colleagues⁵⁸ noted a 5-year local control rate of 95% (basal cell carcinoma, 1009 of 1062 [95%]; squamous cell carcinoma, 97 of 104 [93%]).

Ocular Melanoma

The primary therapy of posterior uveal melanomas depends on many factors. Ocular factors involved in the selection of the treatment modality include tumor size, location, the presence or absence of extraocular extension, visual function in the involved eye, and visual function in the patient’s fellow eye. Systemic factors important in management decisions include patient age, presence or absence of metastatic disease, and general health of the patient. The treatment algorithm is shown in Figure 29-4.

Figure 29-4 Treatment algorithm for ocular melanoma.

Observation without treatment is used for small melanomas with dormant characteristics. Patients managed by this strategy are often asymptomatic, and the lesion is discovered on routine ocular examination. Another subset of patients who may be managed by observation includes elderly patients with severe systemic health problems or with short life expectancy. In these situations, the treating physician and patient must weigh the risks of treatment (loss of vision and possible tumor dissemination) against the risks of withholding treatment with growth of the tumor and subsequent increased risk of metastatic disease. The COMS found that 21% of small melanomas managed initially by observation had grown by 2 years, with 31% having grown by 5 years.²⁶

Enucleation has been the standard of care for the treatment of choroidal melanoma since the nineteenth century. Enucleation requires disinsertion of the extraocular muscles from the sclera, with removal of the entire globe with a long segment of optic nerve. It is the treatment of choice for large tumors, for eyes that are blind and/or painful, or where the tumor has invaded or is contiguous with the optic nerve. An increase in the death rate at 2 years following enucleation has been reported, putatively supporting the hypothesis that enucleation may induce dissemination of tumor cells (Zimmerman-McLean hypothesis), but this hypothesis remains controversial, with no strong evidence to support it.⁵⁹ Although all eyes with uveal melanoma can be treated by enucleation, the obvious morbidity of immediate and permanent loss of the eye and of vision prompted the development of other techniques to treat these neoplasms.

Photocoagulation, transpupillary thermotherapy, and local resection have been used for treating selected patients.⁶⁰ Transpupillary thermotherapy is probably the most common management for small melanomas and has produced excellent control in selected patients. Local resection is used rarely and is most appropriate for anterior tumors involving the ciliary body. Appropriate use of these techniques in the treatment of choroidal melanomas remains investigational.

Radiotherapy Options

Radiation therapy in the management of uveal melanomas has revolutionized the treatment of this ocular cancer. The principal advantage of irradiation in the management of these tumors is that the globe is spared, salvaging the eye and useful vision in many patients. Two main modalities of treatment are used: episcleral plaque radiotherapy and charged particle therapy. In episcleral plaque therapy, tumors up to 18 mm in diameter and 8 to 10 mm thick may be treated, whereas with charged particle therapy tumors up to 24 mm in diameter and 12 mm in height have been treated.

A randomized multicenter trial (COMS) enrolled 1317 patients with medium-size melanomas to treatment with enucleation or with brachytherapy with ¹²⁵I plaques. This study demonstrated equivalent 5-year overall survival (OS) rates of 81% in both arms ²⁴ (Fig. 29-5). Visual acuity was found to decrease over time in a proportion of eyes treated with brachytherapy. Vision was 20/200 or worse in 43% of eyes. The risk of vision loss was associated with a history of diabetes, thick tumors, tumors close to or beneath the macula, tumors with secondary retinal detachments, and tumors that were not dome shaped. Five years after plaque therapy, enucleation was necessary in 10% of patients because of tumor growth and in 3% of patients secondary to complications such as radiation-induced ischemia.⁶¹ Complications leading to enucleation increased over time and consisted mainly of pain and/or loss of visual acuity⁶² (Fig. 29-6).

Figure 29-5 Cumulative proportion of patients who died by time after enrollment. The red dashed line indicates patients treated with primary enucleation, and the solid blue line represents patients treated by brachytherapy with ¹²⁵I plaques.

Figure 29-6 Cumulative proportion of all patients undergoing enucleation (solid blue line) and those with only local treatment failure (dashed red line) after ¹²⁵I brachytherapy.

Charged particle radiotherapy is a less common technique for treating uveal melanoma. With this technique, tantalum rings are sutured to the external sclera at the margins of the tumor for localization, and charged particles (either protons or helium ions) are delivered in four or five equivalent fractions over a 7-day period. The standard target dose is 50 to 70 Gy. An advantage of charged particle therapy is the relatively uniform dose of radiation delivered to the entire tumor and the sharp reduction in dose outside the treated area.⁶²

A systematic review published in 2009 found that as of 2007 there was one randomized control trial and 12 published case series using protons for eye melanoma.⁶³ The randomized controlled trial was a dose-seeking trial to determine whether 50 Gy had fewer complications than 70 Gy, and it was a negative trial. The case series suggested favorable survival rates with significant complication rates. More trials with better design in the future will help to elucidate the role of protons for this disease.

Newer techniques such as stereotactic radiosurgery are being used at some centers. However, no long-term data are available on efficacy or complication rates.

Ocular Metastasis

Choroidal metastases are very sensitive to radiation, but overall survival rates are poor. In one study, external beam radiotherapy (EBRT) was used in 137 patients with uveal metastasis (52%), providing tumor control in 116 patients (85%) at a mean follow-up of 21 months. Using Kaplan-Meier estimates, the overall survival rate of all patients with uveal metastasis from breast cancer was 65% at 1-year, 34% at 3-year, and 24% at 5-year follow-up.⁴⁵

In 1994, a prospective study of the German Cancer Society was initiated to examine the results of standardized EBRT for choroidal metastases with 40 Gy in 20 fractions.⁶⁴ With a median follow-up of 5.8 months (range, 1 to 44 months), 41 of 50 patients were dead. The median survival time of all patients was 7 months, and for patients with breast cancer, 10 months. Of the 50 symptomatic eyes, visual acuity increased two or more lines in 36% (18 of 50 eyes), was stabilized in 50% (25 of 50 eyes), and decreased in 14% (7 of 50 eyes). No patient with asymptomatic metastasis (n = 15 eyes) developed ocular symptoms during follow-up. No patient with unilateral tumor and unilateral irradiation developed contralateral metastasis. Severe side effects, possibly related to tumor progression, occurred in three eyes (5%).

Metastases to the orbit also carry a poor prognostic outcome, with metastatic lung cancer demonstrating a shorter survival rate than metastatic breast cancer. Patients should be assessed for systemic extent of disease. If the primary tumor is chemosensitive, the use of systemic therapy and localized EBRT may be indicated. Doses of radiation are typically 30 to 40 Gy in 2- to 2.5-Gy fractions. Consideration should be given to sparing the cornea and/or lens if possible.

Ocular Lymphoma

With systemic disease, chemotherapy is the primary therapy of choice. Patients with solitary low-grade lymphoma can be successfully treated with local irradiation to the orbit. Patients who have intermediate-grade lymphoma may be treated with a combination of systemic chemotherapy and irradiation. Radiation therapy should be considered if a less than complete response in the orbit is observed following chemotherapy. Doses to the orbit or conjunctiva range from 20 to 36 Gy with 1.8 to 2 Gy per fraction in most series, with 89% to 100% local control rates. Follicular lymphomas are controlled with doses in the mid 20-Gy range; data suggest that MALT lymphoma should receive 30 to 36 Gy with 1.8 to 2 Gy/fraction.⁶⁷ Complication rates are acceptably low with doses in the range of 20 to 30 Gy^65,66,67,68; however, cataract formation is common without lens shielding.⁶⁵ A recent publication suggested inferior results when only partial orbital irradiation was given compared with entire orbital irradiation with control rates of 66% and 100%, respectively.⁶⁹

Primary Intraocular Lymphoma

Currently, most primary intraocular lymphomas are treated with systemic high-dose methotrexate-based chemotherapy.⁷⁰ One report treated 10 patients with combined EBRT to the eye and chemotherapy. Complications of EBRT were high and included cataract in five patients (50%), dry eyes in four patients (40%), punctate keratopathy in two patients (20%), radiation retinopathy in two patients (20%), and optic atrophy in one patient (10%).⁷¹ Doses of EBRT in this report ranged from 20 to 60 Gy in 1.6- to 2-Gy fractions. Ocular recurrences are often treated with EBRT and increasingly with intraocular methotrexate.

Optic Nerve Meningioma

For most patients, fractionated EBRT is the technique most likely to achieve long-term preservation of visual function. Turbin and others ⁵⁰ studied 59 patients with visual loss at presentation. These patients were divided into four groups: observation, surgery, radiation therapy, or surgery and radiation therapy. Only the group treated with radiation alone did not have significant visual loss at the time of follow-up. Other series with shorter durations of follow-up have reported stable or improved vision in the majority of patients treated with more modern radiation therapy delivery techniques.⁷²^–⁷⁵ More precise delivery of EBRT to smaller volumes will reduce the amount of normal tissue exposed to radiation. These techniques require better immobilization for reproducibility of treatment, CT treatment planning for better tumor localization, and conformal beam arrangements for optimizing treatment planning.

Treatment is usually initiated as soon as a decline in visual acuity or fields is documented. Tumor enlargement without loss of vision is often considered an indication for radiation therapy. It is advisable to treat these lesions with tight margins. Dose per fraction should be no more than 1.8 to 2 Gy, with total doses of 50 to 54 Gy.⁷⁶ Complications can include radiation retinopathy, optic neuropathy, cataract formation, or dry eye, depending on the volume of normal tissue and dose gradients. Some authors have expressed concerns when treating a patient with diabetes because of potential vascular complications associated with irradiation.

Optic Nerve Glioma

The goals of treatment include survival improvement and stabilization of visual function. Children with isolated optic nerve tumors have a better prognosis than those whose lesions involve the chiasm or that extend along the visual pathway.⁷⁷^–⁷⁹ Children with neurofibromatosis also have a better prognosis, especially when the tumor is found in asymptomatic patients at the time of screening.⁷⁷ Observation is an option for patients with neurofibromatosis or slow-growing masses.^77,^78,⁸⁰ Spontaneous regressions have been reported.⁸¹ For children with isolated optic nerve lesions and progressive symptoms, complete surgical resection or local radiation therapy may result in prolonged progression-free survival (PFS).⁷⁶

One report of 24 patients detailed outcomes of patients treated with radiation therapy only if there was evidence of visual deterioration or other clinical or radiographic evidence of disease progression. Radiation doses ranged from 45 to 56.6 Gy (median, 54 Gy) in 1.8 Gy/fraction with up to a 17-year follow-up period (median, 6 years). The 6-year actuarial rates of freedom from disease progression and OS were 88% and 100%, respectively. Visual improvement or stabilization was seen in 21 patients (91%) after radiation therapy. A high incidence of endocrine abnormalities was reported, with 15 of the 18 patients evaluated after treatment showing growth hormone deficiency.⁸²

Treatment with chemotherapy has been used in order to avoid surgery or irradiation. One study treated 50 patients with progressive gliomas with carboplatin on a phase II Pediatric Oncology Group (POG) study. Objective responses were found in 30% of patients.⁸³

Orbital Pseudotumor

Treatment for this condition is usually recommended because of clinical symptoms and decreased visual function. Nonradiation options include the use of steroids with recommended doses of 60 to 100 mg of daily prednisone for at least 1 week. Surgical treatment has included local resection or orbital decompression. Immunosuppressive therapy with cyclophosphamide, azathioprine, or methotrexate has been advocated for aggressive or refractory lesions.

These lesions are radioresponsive. Irradiation is typically used for patients who fail to respond to medical management, patients who are intolerant of steroids, or those who have a rapidly aggressive course.

The EBRT treatment technique varies based on the anatomic extent of the lesion. Orbital imaging is important to verify the extent of involvement. Typical presentations include unilateral or bilateral anterior pseudotumor or unilateral or bilateral retrobulbar disease.

Patients with anterior lesions may be treated with an anterior direct electron beam that includes the lesion with a margin that is determined by the beam penumbra. Central lens shielding may be accomplished with either a lead-mounted contact lens or a hanging lens block. Low-energy electrons have significant skin sparing, and a bolus may be necessary to increase the surface dose. When pursuing this technique, particular attention must be paid to the scleral dose, and the recognition that if bolus material is used, the eyelids should be closed, to reduce trauma and irritation to the scleral surface. Even with closed eyelids, it is useful to instruct the patients to “look straight up” at a constant imaginary point, to minimize ocular motion and positional variability on a daily basis.

Patients with unilateral retrobulbar lesions are usually treated with a photon wedged-pair technique. Donaldson and colleagues ⁸⁴ suggested treatment with a central eye bar to shield the lens in each field. However, low-dose regions in the retrobulbar area do result from this technique.

Bilateral retrobulbar lesions are treated with opposed lateral fields with a half-beam block used to spare the anterior segment of the eye if it is uninvolved (Fig. 29-7).

Figure 29-7 Bilateral treatment plan for Graves’ disease.

Total EBRT doses are typically 20 Gy delivered in 2-Gy fractions. One report of nine patients treated with initial total doses of 3 Gy noted that five of these patients required further irradiation for durable control of orbital disease.⁸⁵ Local control rates range from 74% to 100% for doses of 3.8 to 36 Gy.^51,84–86

Lacrimal Gland Tumors

Primary therapy is surgical resection with adjuvant EBRT as needed for close surgical margins, perineural invasion, or adenoid cystic histology. Even with aggressive treatment, local recurrence rates were high following surgery and EBRT for adenoid cystic histologic types.⁸⁷

Graves’ Disease

Peterson and others ⁸⁸ reported results in 311 patients treated with orbital irradiation, with 80% showing improvement of soft tissue symptoms, 75% showing improvement in corneal signs, 61% and 52% having improved extraocular dysfunction and proptosis, and 41% to 71% having improved visual acuity. After irradiation, 76% were able to discontinue corticosteroid therapy.

An older randomized controlled double-blinded trial treated 42 patients with EBRT to one eye and sham therapy to the other eye.⁸⁹ Six months later, the therapies were reversed. There was no apparent benefit for the orbit that received initial irradiation. This study has been criticized because the patient characteristic included patients who had had onset of symptoms ranging from 0.2 to 16 years’ duration and may have included patients who had a more fibrotic reaction that would have been more stable compared with an inflammatory process.

A more recent controlled trial randomized 44 patients to orbital EBRT and 44 to sham irradiation. After 12 months, 52% of the irradiated patients had improvement compared with 27% of the sham-irradiated patients (p = .02).⁹⁰

Long-term follow-up suggests that orbital irradiation is safe, with a similar incidence of cataract formation to the corticosteroid group but with a possibly increased risk of retinopathy for diabetic patients.⁹¹ Orbital irradiation is typically used in the setting of symptomatic Graves’ ophthalmopathy that is difficult to control with steroids, for patients with poor tolerance to steroids, or for patients for whom surgical orbital decompression has failed.

Pterygia

Treatment for pterygia involves surgical excision with removal of the fibrous tissue down to the level of Tenon’s capsule. Free conjunctival flaps may be grafted over the bare sclera. Recurrence rates have varied, with rates of 20% to 68% with surgery alone.⁹²^–⁹⁴ Postoperative adjuvant therapy with irradiation, topical thiotepa, mitomycin, or other antimetabolic agents may diminish the chance of recurrence.

Multiple retrospective studies have been published that used irradiation with beta emitters started within 24 hours of surgery (Table 29-2). Doses range from 10 to 60 Gy given in one to six fractions.^{95,96,97–99} There does not appear to be a dose-response curve. Recurrence rates are more common for pterygia that are recurrent after initial surgery. Complication rates are low, but instances of scleral necrosis, cataract induction, corneal thinning, symblepharon, cataract, and corneal ulceration have been described. These are much more common in patients who have been reirradiated.⁹⁹ Treatment of multiple fields with possible dose overlap may be responsible for some of these complications.⁹⁹

TABLE 29-2 Radiation Treatment Following Resection of Pterygia

A randomized trial treated 96 patients with a single dose of 25 Gy using a strontium-90 (⁹⁰Sr) ophthalmic applicator or sham irradiation within 24 hours of surgery. Crude control rates of 93% versus 33% were observed and no serious complications were observed (p = .004).¹⁰⁰

Macular Degeneration

The advent over the past 5 years of intravitreal injection of antivegetative endothelial growth factor (VEGF) drugs for management of exudative macular degeneration has greatly improved the visual prognosis of these patients.

In the 1990s there was interest in investigating the effects of ionizing irradiation, which has the potential to destroy vascular tissue and prevent neovascularization. The rationale for using local irradiation for choroidal neovascular membrane is based on the radiosensitivity of proliferating endothelial cells, reduction in the inflammatory response, and possible occlusion of aberrant vessels. Various dose schedules have been given, ranging from 10 to 24 Gy, with 2- to 4-Gy fractions. Several small series suggested stabilization of vision and even improvement in vision.¹⁰¹^–¹⁰³ However, follow-up times were short. A randomized controlled trial from the Netherlands treated 34 patients with 24 Gy in four fractions compared with a control group. The time until vision decreased by at least three lines was prolonged.¹⁰³

Other studies did not validate these results. A prospective trial on 95 eyes treated with 10 to 36 Gy did not reveal an effect of dose, and decrease in visual acuity was not prevented.¹⁰⁴ Another group compared a historical group of patients treated with interferon with those who had been treated with radiation therapy. Irradiation did not prevent vision loss.¹⁰⁵ Another report of 69 patients followed for at least 1 year who received 16 Gy in eight fractions failed to show any influence on vision or reading ability.¹⁰⁶ A large prospective multicenter trial from Germany randomly assigned 205 patients to a dose of 16 Gy or sham irradiation. Radiation therapy did not prevent visual loss in this trial.¹⁰⁷ Another randomized controlled trial of 203 patients from the United Kingdom demonstrated that an irradiation dose of 12 Gy versus no irradiation did not statistically improve visual outcomes at 12 or 24 months.¹⁰⁸ Based on these data, there is little information at present that justifies radiation therapy for treatment of AMD outside of a clinical study.

Currently, studies are in progress to determine the efficacy of radiation therapy delivered at the time of surgical vitrectomy with a strontium applicator held over the macular area. Any therapy will need to demonstrate better efficacy than the currently used anti-VEGF agents ranibizumab and bevacizumab.

Locally Advanced Disease and Palliation

Ocular Melanoma

Patients with large choroidal melanoma are usually treated with enucleation. The COMS enrolled 1003 patients to a study that randomized them to either enucleation or enucleation preceded by EBRT (20 Gy).²⁵ Patients receiving preoperative radiation therapy had no significant difference in 5-year OS. The 5-year all-cause mortality rate for large melanomas was 40%. There was no difference in local control between the two groups.

Orbital Lymphoma

Irradiation to the orbit can provide effective palliation for patients with widespread systemic disease or locally advanced disease. Even in patients who have received prior radiation therapy, reirradiation for local disease progression that is resulting in progressive visual loss or symptoms can be considered.

Irradiation Techniques and Tolerance

Plaque Irradiation

Multiple different isotopes have been used for plaque therapy, including cobalt-60 (⁶⁰Co), gold-198 (¹⁹⁸Au), palladium-103 (¹⁰³Pd), ruthenium-106 (¹⁰⁶Ru), iodine-125 (¹²⁵I), and iridium-192 (¹⁹²Ir). The largest experience is with ¹²⁵I. This isotope carries the advantage of low-energy gamma rays and therefore decreased shielding and dose to distant structures. Ruthenium-106 is a beta emitter that has few shielding concerns, but it has a penetration of only a short distance, which may limit its application.

A variety of plaque applicators have been used for ocular melanomas, but the most commonly used ones are those developed for the COMS (Fig. 29-8). These plaques allow shielding of the posterior and lateral structures with a gold shield. A plaque that allows at least a 2-mm margin circumferentially around the tumor should be selected. Placement of the seeds within the applicator varies, depending on the height of the tumor. The prescription point should be the apex of the tumor or 5 mm, whichever is greater. A scleral thickness of 1 mm is added to the apical height. In the COMS, a total dose of 85 Gy was used and delivered to the apex of the tumor at a dose rate between 0.5 and 1.25 Gy/hour. The optimal dose of radiation therapy for treatment of choroidal melanoma is controversial. Equivalent local control, survival, and disease-free survival rates with less ocular morbidity and loss of vision have been reported with lower radiation therapy doses.¹⁰⁹

Figure 29-8 The plaque applicator was developed for the Collaborative Ocular Melanoma Study.

The plaque is placed by the ophthalmologist by marking the boundary of the tumor base with a surgical marking pencil or light cautery that can be seen when the tumor is transilluminated (Fig. 29-9). The plaque is then centered over the marks. Plaque placement may require detachment of the ocular rectus muscles. The plaque is then sutured to the sclera (Fig. 29-10). Good placement can be confirmed with ultrasonic evaluation of the eye. Occasionally, the melanoma is located adjacent to the optic nerve. The use of a notched plaque may allow better dosimetry and coverage of the tumor in this situation.

Figure 29-9 The ophthalmologist uses a surgical marking pen on the sclera, and the plaque is then centered over the marks.

Figure 29-10 The plaque is sutured to the sclera.

Principal complications of radiotherapy to the eye include cataract, radiation retinopathy, and optic neuropathy. Radiation effects on the retina and optic nerve can be potentiated by the presence of systemic vascular diseases such as hypertension and diabetes mellitus and often result in loss of useful vision. The proximity of the tumor to critical visual structures such as the optic nerve and macula is predictive of the long-term visual prognosis.

Skin Lesions

Treatment of skin lesions close to the eye can be difficult. The close proximity of normal structures must be balanced with the dosimetric constraints that are present with electrons. Most of the data supporting the use of radiation therapy came from series using kilovoltage x-ray beams. However, this type of x-ray equipment is no longer widely available. Electrons have a larger penumbra and area of beam constriction laterally, necessitating larger treatment fields than kilovoltage beams. One report demonstrated higher corneal doses with electrons compared with kilovoltage beams (doses were two to four times higher).¹¹⁰ Also, the 95% isodose area was 32% wider with kilovoltage beams than with 6-MeV electrons.¹¹⁰ Tungsten eye shields may provide better shielding of anterior eye structures than lead for 9-MeV electrons.¹¹¹

After the patient is immobilized, the tumor volume should be outlined, followed by design of the treatment field based on the margin felt necessary to encompass the tumor, beam penumbra, and setup uncertainties. Depth of treatment should be determined with attention to perineural invasion, location near an embryologic fusion plane, and size of the lesion.

Unilateral Eye Lesion

Treatment of one eye may be necessary for patients with choroidal or orbital metastasis or orbital lymphomas. This field arrangement is designed to limit the irradiation to the opposite eye. Typically, a wedged-pair technique is used if the entire orbit needs to be treated. CT planning can assist with location of the normal optic structures and the tumor volume that is to be included in the field (Fig. 29-11). Three-dimensional treatment planning may enable more treatment conformity around the structure to be treated and decrease normal tissue sequelae.

Figure 29-11 Unilateral orbit treatment plan.

Bilateral Eye Lesions

Treatment of both eyes is usually done with opposed lateral fields. If it is possible to spare the lens, the central axis of the beam can be placed at the location of the lens (5 mm behind the anterior globe). A split-beam technique is used to block the anterior structures if possible. Graves’ disease, bilateral choroidal metastasis, and bilateral lymphomas are treated in this manner (see Fig. 29-7).

Anterior Lesions

Involvement of the conjunctiva may require treatment of the anterior structures alone. This can be accomplished with electron fields directed en face to the globe. Central lens shielding can be accomplished with a hanging block at which the patient is instructed to look (Fig. 29-12). En face electrons can be used with a lead contact lens if electrons of not more than 6 MeV are used¹¹¹ (Fig. 29-13).

Figure 29-12 Apparatus used for the hanging block technique.

Figure 29-13 Electron cloud generated with the lead contact lens tech-nique.

Intensity-Modulated Radiation Therapy

Techniques using three-dimensional treatment planning and intensity-modulated radiation therapy (IMRT) may be advantageous for treating optic nerve meningiomas or gliomas. All critical structures of the eye should be identified and appropriate dose constraints applied. Patient immobilization is crucial, along with CT simulation (Fig. 29-14).

Figure 29-14 Unilateral treatment plan for an optic meningioma.

Tolerance Issues

Sequelae from radiation exposure to the eye vary by type of radiation therapy (photon, electron, or brachytherapy), total dose, radiotherapeutic fraction size, and part of the eye included in the radiation exposure. Unrelated medical conditions such as diabetes, hypertension, and collagen vascular diseases can affect the radiation tolerance of structures in the eye. Systemic chemotherapy or steroids can enhance radiation toxicity or contribute to additional symptoms.

The most sensitive structure in the eye is the lens, which is located directly behind the pupil. The germinal layer of the lens located at the equator is the layer most sensitive to radiation. These cells undergo mitotic division, elongate, lose their nuclei, and migrate posteriorly to the center of the lens. This posterior migration and proliferation of the lens epithelial cells reduce lens clarity, causing a cataract, and often some degree of visual loss. Therefore, a radiation cataract usually presents first as a posterior, central subcapsular opacification. The latency and frequency of lens opacities are a function of radiation therapy dose and fractionation.

In most human studies, total fractionated doses under 5 Gy have not produced visually significant lens opacities. Merriam and Focht ¹¹² reported cataract formation with EBRT fractions of 1.5 to 2 Gy, to a total dose of 12 Gy. When single-dose, total body irradiation was used, cataracts developed in 80% of survivors; the incidence decreased to 20% when fractionated EBRT was given to a total dose of 13 Gy.¹¹³ Reduction of dose to the lens may be possible with customized lens shields, pencil-beam lead blocks, or more complex treatment planning with IMRT. Lens extraction for cataract development can correct the vision in an otherwise functioning eye following irradiation.

Other anterior structures in the globe include the cornea and conjunctiva. The conjunctiva is a mucous membrane of nonkeratinized squamous epithelium with goblet cells overlying a thin substantia propria.¹¹⁴ It covers the inner surface of the eyelid and outer surface of the eye, extending to the peripheral cornea. The cornea is composed of nonkeratinized stratified squamous epithelium. Its outermost surface is composed of irregular microvilli made optically smooth by the precorneal tear film. The basal cells are attached to Bowman’s layer, which is made up of randomly dispersed collagen fibrils that may become opacified by scar tissue. The stroma, which makes up 90% of the total corneal thickness, is composed of fibroblasts and collagen lamellae.

Acute effects of fractionated radiotherapy include injection and erythema of the conjunctiva with irritation that is usually self-limited. Fractionated doses of radiation to a total dose above 40 to 50 Gy to the cornea can produce edema with punctate keratitis.¹¹⁵ Management consists of aggressive lubrication, patching, and antibiotic drops. Recurrent corneal erosions may progress to ulceration and infection leading, to either opacification or perforation. Ulcerations of the cornea have been reported with fractionated radiation therapy to doses above 40 Gy.^65,¹¹⁶ Similarly, ulceration, telangiectasias, and keratinization can develop in the conjunctiva.

The eyelid skin is the thinnest in the body. The lids contain sebaceous, serous, and apocrine glands, which contribute to the tear film. There are puncta on the medial lid margins that form the opening to the nasolacrimal drainage system. Transient effects of eyelash loss and erythema occur at 30 to 40 Gy with conventional fractionation, whereas permanent lash loss occurs at doses above 50 Gy.¹¹⁷ Scarring and fibrosis can develop at doses above 50 Gy, which can result in ectropion or entropion of the lid as well as stenosis of the eyelid puncta.

There are several structures necessary for adequate tear film production, which include the lacrimal gland, goblet cells, meibomian glands, and accessory lacrimal glands. Dry eye syndrome can result from injury to any component of the tear film. Symptoms include burning, decreased vision, excessive tearing, and a foreign body sensation. Examination reveals corneal changes ranging from keratitis to corneal scarring and opacification. One report described 19% of patients who received doses less than or equal to 45 Gy in 25 fractions developing a dry eye syndrome compared with 100% for doses above or equal to 57 Gy in 30 fractions.¹¹⁸ Severe keratitis sicca can lead to corneal ulceration and perforation of the globe. Prevention of lacrimal damage requires consideration of the location of the lacrimal gland when designing fields for radiation therapy delivery.¹¹⁹

The sclera covers the posterior 80% of the globe. It is largely avascular and consists of collagen fibrils, fibroblast, and ground substance. It is very resistant to radiation and can withstand doses of over 150 Gy that are delivered with plaque radiotherapy used to treat choroidal melanomas. Scleral thinning and ulceration are unusual complications of high doses of radiation therapy.¹²⁰

The retina consists of an extensive network of neural, glial, and vascular elements. The blood supply to the outer layers of the retina is via the choriocapillaries. The inner retinal layers are supplied by the branches of the central retinal artery, of which the largest branches are the temporal and nasal arcades. Pathology involving the region within the temporal arcades is more visually significant than that occurring elsewhere. Radiation retinopathy is caused by occlusive microangiopathy manifest by cotton wool spots, microaneurysms, telangiectasias, hemorrhages, macular edema, exudates, neovascularization, vitreous hemorrhage, and pigment changes. Visual symptoms secondary to radiation retinopathy depend on the area of the retina that is affected. A history of diabetes, collagen vascular disease, hypertension, and treatment with chemotherapy predisposes patients to radiation-induced injury.¹²¹ In one report, radiation retinopathy was not observed at doses below 45 Gy in 25 fractions but increased steadily above this dose.¹²¹ (Patients also seemed to be at increased risk if they were treated with doses per fraction greater than or equal to 1.9 Gy.¹²¹) The estimated tolerance for retinal damage is very steep, with a tolerance dose of 5% risk at 5 years (TD_5/5) of 45 Gy and TD_50/5 of 65 Gy.¹²²

Optic nerve injury occurs secondary to ischemia. Damage begins with perivascular lymphocyte cuffing, loss of endothelial cells, and hyalinization, with fibrosis, thrombosis, and infarction of neural tissue. Optic nerve injury presents with painless monocular loss of vision. Fractionation is quite important in the development of optic nerve injury. Of patients who were treated to a total dose of 45 to 50 Gy and received a daily fraction size of more than 2.5 Gy, 18% developed visually significant changes, whereas those patients who received fractions below 2.5 Gy did not develop optic neuropathy.¹²³ Stereotactic radiosurgery that delivers large fraction sizes can cause optic neuropathy with single doses of 8 Gy, although tiny volumes to high doses have been given without toxicity.¹²⁴ With conventional fractionation, the TD_5/5 of the optic nerve is considered to be 60 Gy.¹²⁵