Zeynel A. Karcioglu,Barrett G. Haik
SUMMARY OF KEY POINTS
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Incidence
Etiology
Diagnosis
Treatment
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INTRODUCTION
In today's practice of oncology, the role of radiation therapy is vast. As with other oncologic subspecialties, the practice of ophthalmic oncology would be impossible without the use of radiation for imaging and therapeutic purposes.[1] A practical approach to a discussion of ophthalmic tumors—as with tumors of other anatomic regions—is to consider neoplastic conditions of the major structures with primary involvement: the globe, the conjunctiva and eyelids, and the orbit. Because the tumors and tumor-like conditions of these structures are exceedingly diverse, only the common entities that are encountered in daily practice are addressed in this chapter (Tables 71-1 to 71-4 [1] [2] [3] [4]).
Table 71-1 -- Malignant Intraocular Neoplasms
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PRIMARY MALIGNANT TUMORS OF THE GLOBE |
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Uveal melanoma[*] |
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Primary intraocular lymphoma (PIOL)[*] |
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Medulloepithelioma |
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Rhabdomyosarcoma |
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Leiomyosarcoma |
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Neuroepithelial adenocarcinoma |
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Retinoblastoma[*] |
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SECONDARY MALIGNANT TUMORS OF THE GLOBE |
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Conjunctival/skin carcinoma[*] |
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Orbital sarcoma |
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Lacrimal gland carcinoma |
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METASTATIC TUMORS OF THE GLOBE |
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Carcinoma[*] |
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Neuroblastoma |
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Melanoma |
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Carcinoid tumor |
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Leukemia/lymphoma[*] |
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* |
Relatively common tumor; discussed in text. |
Table 71-2 -- Malignant Conjunctival Neoplasms
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ATYPICAL REACTIVE LYMPHOID HYPERPLASIA INVOLVING CONJUNCTIVA |
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PREMALIGNANT LESIONS OF CONJUNCTIVA |
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Actinic keratosis[*] |
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Carcinomatous intraepithelial neoplasia |
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Primary acquired melanosis (PAM)[*] |
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PRIMARY MALIGNANT TUMORS OF CONJUNCTIVA |
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Squamous cell carcinoma[*] |
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Mucoepidermoid carcinoma[*] |
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Melanoma[*] |
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Sebaceous gland carcinoma[*] |
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Lymphoma[*] |
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Kaposi's sarcoma[*] |
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SECONDARY MALIGNANT TUMORS OF CONJUNCTIVA |
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Uveal melanoma |
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Orbital sarcomas |
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Eyelid malignancies[*] |
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Lacrimal drainage system malignancies |
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Retinoblastoma[*] |
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METASTATIC TUMORS OF CONJUNCTIVA |
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Distant carcinomas |
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Leukemia |
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* |
Relatively common tumor; discussed in text. |
Table 71-3 -- Malignant Eyelid Neoplasms
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PREMALIGNANT LESIONS OF EYELIDS |
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Actinic keratosis[*] |
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Lentigo maligna[*] |
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Juvenile xanthogranuloma[*] |
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PRIMARY MALIGNANT TUMORS OF EYELIDS |
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Basal cell carcinoma[*] |
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Bowen's disease[*] |
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Squamous cell carcinoma[*] |
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Melanoma[*] |
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Sebaceous gland carcinoma[*] |
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Kaposi's sarcoma |
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Malignant skin appendage tumors |
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Merkel cell carcinoma |
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SECONDARY MALIGNANT TUMORS OF EYELIDS |
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Uveal melanoma |
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Orbital sarcomas |
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METASTATIC TUMORS OF EYELIDS (exceptionally rare) |
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* |
Relatively common tumor; discussed in text. |
Table 71-4 -- Malignant Orbital Neoplasms
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LESIONS WITH CLINICALLY MALIGNANT BEHAVIOR |
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Langerhans cell tumors[*] |
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Non-Langerhans cell tumors[*] |
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Atypical lymphoid hyperplasia[*] |
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Meningioma of optic nerve[*] |
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PRIMARY MALIGNANT TUMORS OF ORBIT |
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Lymphoma[*] |
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Lacrimal gland carcinomas[*] |
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Rhabdomyosarcoma[*] |
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Primitive neuroectodermal tumors |
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Malignant peripheral nerve sheath tumor |
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Alveolar soft part sarcoma |
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Melanoma |
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Osteosarcoma |
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Fibrosarcoma |
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Leiomyosarcoma |
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Chondrosarcoma |
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Liposarcoma |
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Glioma of optic nerve[*] |
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SECONDARY MALIGNANT TUMORS OF ORBIT |
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Eyelid malignancies[*] |
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Conjunctival malignancies[*] |
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Uveal melanoma[*] |
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Retinoblastoma[*] |
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Lacrimal drainage system malignancies[*] |
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Paranasal sinus and nasal carcinoma[*] |
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Brain tumors |
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METASTATIC TUMORS OF ORBIT |
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Distant carcinomas (e.g., breast, lung, gastrointestinal tract)[*] |
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Neuroblastoma[*] |
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Leukemia (granulocytic sarcoma) |
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Carcinoid tumor |
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Metastatic melanoma |
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* |
Relatively common tumor; discussed in text. |
Retinoblastoma is a much more radiosensitive tumor than uveal melanoma; however, for both of these intraocular neoplasms, radiation treatment, in one form or another, is an indispensable management tool for today's ocular oncologist. Radiation also is used for the treatment of rarer types of intraocular tumors such as juvenile xanthogranuloma, ocular or central nervous system (CNS) lymphoma, multiple myeloma, leukemias, and some metastatic tumors.[2]
One large group of conjunctival, eyelid, and orbital tumors that respond to radiation therapy, alone or in combination with chemotherapy, are the lymphoproliferative neoplasms. In contrast with lymphoid lesions, epithelial tumors of the conjunctiva and the eyelids—including basal cell carcinoma, squamous cell carcinoma, and melanoma—are not very responsive to radiation, and severe ophthalmic complications may develop after radiation treatment. In this group of tumors, certain types of malignancies, such as sebaceous gland carcinoma, pose considerable therapeutic challenges in that although the tumor is radiation sensitive, the therapy results in substantial adverse effects in the eye. In most instances, ocular oncologists avoid this treatment modality. Accordingly, use of irradiation usually is limited to treatment for the advanced stages of these tumors, primarily for palliation.
In orbital tumors other than lymphoproliferative lesions, radiotherapy has been successfully used for rhabdomyosarcoma and, with less rewarding results, for other mesenchymal malignancies. Epithelial tumors of the lacrimal gland, sebaceous gland tumors, and histocytic tumors occasionally respond well to radiation treatment. Primary tumors of the optic nerve, including optic nerve glioma and meningioma, also benefit from radiation treatment. In the advanced stages of aggressive sarcomas, radiation treatment also may be used as an adjunct to surgery and chemotherapy.[3]
Finally, some of the idiopathic inflammatory conditions of the orbit, including Graves disease and pseudotumor of the orbit, also may be treated with radiation. [4] [5]
This chapter summarizes the specifics of radiation therapy and other recommended modalities for the management of the ophthalmic neoplasms commonly encountered in clinical practice (for discussion of other, rare ocular and periocular tumors, the reader is referred to ocular oncology textbooks and review references [6] [7] [8] [9] [10]). First, however, the effects of radiation on each of the major tissues and structures of the eye are reviewed.
RADIATION TOXICITY IN THE EYE
The eye is a complex organ composed of structures with widely variable radiation sensitivity. Its different components range from extremely radiosensitive tissues, such as the lens, to radioresistant tissues, such as the retina and the optic nerve.[11] The variations in radiation effect on the eye are dependent not only on tissue sensitivities but also on the methods of radiation delivery. Today, a majority of ophthalmic radiotherapy protocols involve the use of external beam radiation therapy (EBRT); indications for brachytherapy are fewer. With EBRT, radiation is delivered as photons (gamma rays or x-rays) or particles (e.g., protons and neutrons), primarily with linear accelerators. [12] [13] Newer techniques of radiation delivery improve the rates of ocular toxicity. For example, proton-photon accelerated fractionated radiation (AFR) allows the delivery of treatment doses to advanced tumors of the nasal cavity and paranasal sinus, with tolerable eye complication rates.[14] Modern EBRT techniques such as stereotactic fractionated radiation therapy (SFRT), photon EBRT, and carbon ion boost appear to allow safe delivery of high target doses to patients with locally advanced orbital malignancies. Although the ocular toxicity rates are reported to be reduced compared with the historical neutron therapy data, the follow-up periods are limited because of limited survival of these patients. [15] [16]
From the standpoint of radiation toxicity, the eye and periocular tissues can be divided into several zones: external eye (conjunctiva, cornea and the tear layer); anterior intraocular components (iris, anterior chamber angle, and lens), posterior intraocular components (retina, choroid, and optic disc), eyelid, orbital soft tissues, hypothalamus, and pituitary gland.
External Eye
Most of the tissues of the external eye, including the epithelium of the conjunctiva, cornea, glandular excretory ductules, and lacrimal drainage apparatus, have the same sensitivity as that of skin, because these structures are lined with epithelial cells, which are characterized as vegetative intermitotic cells (VICs). During the acute phase of radiation (within 6 months), fractional doses of 20 Gy cause erythema and edema of the eyelid skin and conjunctiva; if the dose is high enough, keratinization of the epithelium also takes place. The tear layer becomes thinner and irregular secondary to edema of the parenchyma of the lacrimal and meiobomian glands and goblet cells. Also, the damage to the epithelial cells of glandular ductules reduces the inflow of tears. Disruption of the tear layer is a serious matter, causing problems ranging from a scratchy sensation and mild visual distortion to severe external eye infections and cornea-sclera melt, which may even lead to perforation. Among its other functions, the tear layer possesses bactericidal properties because it contains immunoglobulins and lysozomes; it also flushes away foreign materials and bacterial debris from the external eye into the lacrimal drainage system. When the composition and the quantity of the tear layer are distorted by radiation-induced changes, both of these antibacterial properties are lost. As the orthovoltage dose approaches 40 to 50 Gy, a confluent mucositis appears. At this stage, lacrimal gland secretions are reduced and thickened, and the external eye may become infected. During this period, photophobia also may be noted.
In the subacute period, ranging from 6 to 24 months, telangiectasias may develop in the skin and the conjunctiva, and the dryness worsens. The cornea demonstrates few structural changes until fractionated doses are in the range of 50 Gy; at this point, superficial punctate keratitis may develop. The cause of corneal damage also is twofold: (1) the direct toxicity of ionizing radiation on its epithelial cells and stromal collagen and (2) drying of the ocular surface. Punctate keratitis, which develops during the acute stages owing to focal epithelial erosion and edema, becomes worse. Along with epithelial changes, the corneal sensation diminishes for weeks to months. During the subacute phase, scarring of the cornea may advance if deep keratitis was present during the acute period. Further scarring may lead to vascularization and thinning of the stroma, which in turn may lead to total opacification or perforation.[17] Medical and surgical management of radiation keratopathy may be difficult owing to poor wound healing.
It would be an error to underestimate the consequences of the dry eye syndrome and to send the patient home with artificial tears and antibiotic or steroid eyedrops or ointments. The management of dry eye should be directed by an ophthalmologist who is familiar with current treatments for radiation toxicity, which range from simple supplementation with artificial tears to complex surgical interventions. The scope of this chapter does not allow a detailed discussion of dry eye management; the reader is referred to recent reviews. [18] [19]
The sclera maintains the structural integrity of the anterior eye as well as that of the posterior eye. The sclera consists of thick, irregular collagen bundles, and it is less affected by ionizing radiation than the cornea.[20] No scleral radiation damage has been reported after EBRT at doses up to 60 Gy. High scleral brachytherapeutic doses (e.g., in excess of 600 Gy), however, can cause melting of the sclera.[21] In practice, strontium 90 (90Sr) and ruthenium 106 (106Ru) are more likely to deliver much higher scleral doses than is either iodine 125 (125I) or palladium 103 (103Pd) during plaque radiation therapy of intraocular tumors.[22]
Anterior Intraocular Components
The iris is located behind the cornea and in front of the lens and extends into the ciliary body. The iris and ciliary body are composed of fibroblasts, smooth muscle, vessels, and columnar pigmented and nonpigmented epithelial cells. Many of these cells are reverting postmitotic cells and therefore are quite resistant to radiation. Iritis has been reported with a single dose of 10 to 20 Gy, but severe anterior uveitis is not observed until higher doses of 30 to 40 Gy (in 10-Gy fractions) are given, and then appears only after 6 to 8 weeks. Radiation iritis may be followed by secondary glaucoma. Dry eye-related corneal ulceration also may exacerbate iritis and secondary iris neovascularization.[23] Localized iris atrophy has been noted after brachytherapy for iridociliary melanomas but not after EBRT for orbital tumors. [24] [25]
Among the anteriorly located intraocular tissues, the crystalline lens is uniquely susceptible to radiation injury. The lens is an avascular protein structure covered by an elastic tissue capsule. The anterior surface of the lens has a layer of epithelial cells that do not show much mitotic activity; these cells behave as reverting postmitotic cells. Near the equator of the lens, however, the epithelial cells divide regularly and thus behave as VICs. Formation of cataracts is the most frequently encountered delayed radiation effect in the mammalian eye. It is known that DNA damage and abnormal protein cross-linking lead to development of opacities within the lens protein; however, the exact mechanism of the DNA damage by radiation is not known.[26] Some practitioners postulate that cell membrane permeability changes are caused by radiation, whereas others hypothesize that radiation changes the activity of certain enzymes of the lens cortex.[27] The thermal damage also should be taken into account as a cataractogenic influence because heat cannot be dissipated effectively in the avascular lens tissue.
The best clinical description of radiogenic cataracts has been reported by Cogan and associates[28] ( Fig. 71-1 ). The development of radiation opacity begins in the posterior subcapsular zone when small granules turn into small vacuoles as they enlarge to 3 to 4 mm within months; a central clear area may be identified during development. If this opacity progresses, a hard, central, circular plaque of highly reflective material develops at the posterior pole. As the posterior opacity becomes denser, a faint anterior subcapsular cataract containing interspersed vacuoles and occasional fine striations may be seen. When the changes progress slowly over several years and the entire lens becomes opacified, it can no longer be distinguished from other types of mature cataract.
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Figure 71-1 A–C, Slit-lamp appearance of radiation cataracts. |
The development of radiation opacity is dose, time, and age dependent ( Fig. 71-2 ). Significant variation, however, is observed among persons who receive the same dose. The lenticular opacities do not always interfere with vision; clinically significant cataract development usually requires higher doses and longer postradiation times. The latent period for production of cataracts from the time of exposure is on average 2 to 3 years but may range from 6 months to 3 decades.
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Figure 71-2 Influence of radiation dose and exposure time on cataract formation in humans. (Data from Mettler FA, Moseley RD: Medical Effects of Ionizing Radiation. Orlando, FL, Grune & Stratton, 1985, p 138.) |
In Merriam and Focht's classic study, a large series of patients undergoing EBRT for ocular and orbital malignancies was studied from the standpoint of cataract formation.[29] The higher the absorbed dose, the shorter the latent period to cataract fomation. Single doses of 2 Gy or fractionated doses of 4 Gy result in the formation of posterior lens opacities but rarely in significant visual impairment. A dose of 7.5 Gy, however, invariably causes clinically significant cataract formation. A similar incidence has been noted with 14 to 21.5 Gy given over a period of 1 to 3 months. Merriam and Focht concluded that a given dose of radiation becomes less likely to produce a cataract when it is fractionated over a longer period. Fractionation of the radiation dose delays the onset and decreases the incidence of cataract development and slows its progression, as does the use of partial and total shielding of the equatorial areas of the lens.[30]
Because of treatment-related toxicity, studies increasingly focus on long-term complications secondary to hematopoietic stem cell transplantation in survivor populations. Gurney and coworkers recently reported an incidence of cataracts of 36% at 15 years after transplantation; cataracts developed only in those patients who received total-body irradiation as a conditioning regimen or head irradiation before transplantation.[31] Of 4000 cancer survivors, 4% had cataracts. Cataracts were a frequent occurrence in survivors of hematologic diseases (chronic leukemia, 17%; myeloma, 13%; acute leukemia, 9%; and lymphoma, 7%).[32] Cataracts that develop as a late effect following hematopoietic stem cell transplantation are related to either the transplantation process or the transplantation-preparative regimen. Problems related to the transplantation process include delayed recovery of the immune system and chronic graft-versus-host disease (GVHD). Chronic GVHD manifests between 3 and 14 months after transplantation in approximately 20% of matched sibling transplant recipients and in 40% of matched unrelated donor transplant recipients. Cataracts develop secondary to total-body irradiation or prolonged corticosteroid use. Cataracts developing after fractionated radiation do not impair the vision significantly enough to be removed.[33]
Another concern with radiation toxicity is the ocular exposure during modern imaging procedures. Although the great majority of CT scanners deliver lower than the threshold dose for development of cataracts, nevertheless the potential exists for delivery of higher doses.[34]
It has been reported that comprehensive imaging in patients with stroke may result in radiation exposure up to local doses of 490 mGy. Although critical doses for organ damage (e.g., cataract formation or hair loss) are not reached, physicians need to be aware of possible radiation-induced complications, particularly with repetitive examinations.[35] For decades, it has been known that in utero exposure to radiation, particularly during the first trimester, can result in cataract formation, as well as pigmentary degeneration of the retina or microphthalmia.[36] Bateman indicated that doses in the range of 3 to 5 Gy delivered during the first half of the pregnancy are quite damaging to the neurons of the developing retina, although as the neurons mature, they become much more radioresistant.[37] Long-term topical and systemic administration of corticosteroids is well known to induce formation of posterior subcapsular cataracts. In humans and experimental animals, even a low dose of radiation given with steroid treatment accelerates the development of lenticular opacities.[38]
Posterior Intraocular Components
The retina, choroid, and optic nerve are composed of relatively radioresistant tissues. At common therapeutic dose levels, acute effects of irradiation are rare; however, at doses higher than 50 Gy, acute retinal edema may occur, although this effect usually is transient ( Fig. 71-3 ).
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Figure 71-3 A, Acute radiation toxicity with focal intraretinal hemorrhages and cotton-wool spots. B and C, Chronic radiation toxicity of the fundus with hard exudates, edematous and necrotic retina, infarcted choroid, and vascular changes ranging from tortuosity and engorgement (B) to diffuse atrophy (“silver-wire vessels”) (C). D, Acute papillitis secondary to external beam irradiation for treatment of retinoblastoma. (A and B, Courtesy of Dr. Edward Chaum, Memphis, TN.) |
Chronic radiation damage to posterior ocular tissues usually is the result of disruptions in the vascular supply and is primarily a form of microangiopathy. Because of the radiation damage to vascular endothelial cells, abnormal vascular permeability occurs, and vascular lumina are narrowed or obliterated. Owing to vascular disruption, the nerve fiber layer becomes ischemic, with the potential for the development of infarcts, exudates, and hemorrhages. The retinal vascular changes include totally occluded “ghost” vessels, vascular sheathing, microaneurysm formation, increased tortuousity, retinal telangiectasis, and eventually neovascularization (see Fig. 71-3 ). The associated abnormal vascular permeability may impair vision secondary to macular exudates, often in a circinate pattern. Vascular occlusions of both the arterial and venous circulation may occur. Radiation retinopathy in the macula causes vision loss and blindness. Serious hemorrhagic complications may result from fragile vasculature and the neovascular tufts, leading to a hemorrhagic retinitis or a vitreous hemorrhage. Organized vitreous hemorrhage and associated fibrovascular proliferations may produce a traction retinal detachment followed by phthisis bulbi. Characteristic alterations also occur in the retinal pigment epithelium (RPE), leading to pigmentary mottling over large areas and extensive RPE cell atrophy. Occasionally, large areas of chorioretinal thinning are so pronounced that the sclera can be clearly visualized beneath this layer on ophthalmoscopic examination. Typically, onset of radiation retinochoroidal disease is between 6 months and 3 years after treatment; in some patients, however, the disease develops after much longer periods.[39] It has been reported that retinal damage may be produced by EBRT at doses as low as 15 Gy but is more common after EBRT at fractionated doses of 30 to 35 Gy. (At total fractionated doses of 70 to 80 Gy, retinopathy would occur in 85% of eyes.) Diabetes and chemotherapy, when combined with irradiation, seem to have an additive effect on progression of retinopathy. An associated papillitis often is seen with radiation retinopathy.
Both anterior ischemic optic neuropathy and posterior vascular occlusions can occur in the optic nerve, leading to visual loss (see Fig. 71-3 ). Radiation optic neuropathy can temporarily cause decreased vision, with later improvement over several months. This entity involves the anterior optic nerve and is characterized acutely by hyperemia and disc edema. Peripapillary hemorrhages and subretinal fluid also may be present. With EBRT, the mean total fractionated dose causing this effect is 55 Gy, with a range of 36 to 72 Gy. The mean latent period after radiotherapy is 19 months (5 to 36 months). Optic atrophy may be found secondary to ganglion cell degeneration or after a direct vascular insult. [40] [41]
In a long-term study of optic nerves that received a radiation dose greater than 60 Gy, the 15-year actuarial risk of optic neuropathy was 11% when fraction size was less than 1.9 Gy per day, compared with 47% for larger fractions.[42]
Eyelid and Orbital Tissues
Main eyelid changes associated with EBRT include acute erythema, depigmentation, atrophy, telangiectasias of the eyelid skin, and loss of eyelashes; ectropion and entropion also are seen. [43] [44]Radiation typically travels through the skin and other structures of the eyelids on its way to treat orbital tumors. Eyelid skin behaves like skin of other sites, but it is thinner. The first reaction is erythema (typically seen at 2 to 4 weeks after initiation of treatment), followed by dry and moist desquamation. Erythema, or reddening, usually is transient and subsides rapidly. Eyelid and periorbital skin erythema occurs if a single dose of 6 to 8 Gy is given and may not be identified until 1 to 2 days after irradiation. The higher the radiation dose, the more quickly the erythema develops. Erythema increases during the first week and usually fades during the second week. It then may return 2 to 3 weeks after the initial insult and last for 20 to 30 days. The early reddening presumably is due to release of vasoactive amines. The second phase of erythema is due to vessel damage; thermographic studies demonstrate increased blood flow during the first 2 to 3 months. Desquamation usually is healed by the time treatment has ended because compensatory regeneration occurs in the basal layer of the skin. Moist desquamation is more common after doses of 50 to 60 Gy (in 1.8- to 2.2-Gy daily fractions) given over 5 to 6 weeks, and also more common where superficial lesions break the skin. Healing typically is slow and may take up to 4 weeks. No radiation-related scar usually results unless an unusually high dosage is used or a complication such as secondary infection occurs.
Scarring can result in entropion or ectropion of the eyelids. Slowly progressive skin alterations may lead to depigmentation and telangiectasias.[1] The accessory glands around the eye (including Moll, meibomian, and lacrimal glands) contain reverting or fixed postmitotic cells; the ductal epithelium for some of these glands contains VICs as well. Thus, the excretory ducts, particularly in the meibomian glands, are relatively sensitive to direct effects of radiation, as are the equatorial regions of the optic lens and the basal cell layer of the cornea. Meibomian glands are of about the same radiosensitivity as that of hair follicles, but sweat glands are somewhat more resistant.
With EBRT, temporary loss of hair occurs in about 3 weeks with 3 to 5 Gy. Hair begins to return during the second month, and regrowth continues for up to 1 year. Single doses of 7 Gy may cause permanent epilation, with a latent period of less than 3 weeks. Not all body areas have the same radiation epilation sensitivity. The scalp and beard are most sensitive, with less sensitivity in the eyebrow and then the eyelashes. Eyelash loss may be incomplete or complete, depending on the dose and dose rate. It may occur with as little as 10 Gy but can be permanent with as little as 30 Gy. A radiation dose of 50 Gy has been used to achieve permanent epilation in patients with trichiasis and secondary corneal disease.
Doses in the range of 30 to 40 Gy can be delivered to the entire orbit without functional effect on the main lacrimal gland. On the other hand, evidence of histopathologic atrophy of the lacrimal gland has been reported with single doses of 20 Gy and after 50 to 60 Gy given over a 6-week period.[45] Although the mesenchymal tissues of the orbit including the extraocular muscles, fibroconnective tissue, and fat are rather resistant to radiation, orbital deformity leading to fascial asymmetry remains a major problem, particularly in children younger than 6 to 8 years of age who receive a tumor dose of approximately 50 Gy[46] ( Fig. 71-4 ).
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Figure 71-4 A patient who underwent orbital exenteration and external beam irradiation for unilateral retinoblastoma. Note the deformity of the left socket and ulceration of the skin posteriorly. |
Another very serious side effect of orbital EBRT is that it increases the incidence of multiple primary malignancies in patients with retinoblastoma and other childhood malignancies such as rhabdomyosarcoma, Ewing's sarcoma, Hodgkin's lymphoma, and Wilms’ tumor. [47] [48] [49] Acute leukemias also have been reported among the patients who survive retinoblastoma.[50] When the relative risk of death was calculated, it was found to exceed the expected rates for malignant tumors of bone and soft tissues by 300-fold, for melanoma by100-fold, and for brain tumors by about 25-fold.[51] At 40 years of follow-up, the cumulative mortality rate for all second primary malignancies was approximately 25% (expected 1.3%) for bilateral tumors and 1.5% (expected 1.1%) for unilateral disease. In the patients with bilateral retinoblastoma, radiotherapy further increases the risk of death. Early detection and management of these tumors are very difficult.
Hypothalamus and Pituitary Gland
Hypothalamic and pituitary dysfunction with growth hormone deficiency with height loss is commonly seen in children irradiated for optic nerve glioma. [52] [53]
INTRAOCULAR TUMORS
The most commonly encountered malignancies in adults and children—uveal melanoma, metastatic tumors to the eye including leukemia, intraocular lymphoma, and retinoblastoma—are reviewed in this section.
Uveal Melanoma
Uveal melanoma is the most common primary malignancy of the eye, but it comprises only 5% of all melanomas in the body.[54] Up to 85% of ocular melanomas are uveal (primarily choroidal) in origin. The annual incidence of this tumor is approximately 4 per million population in the United States; this incidence is similar to that reported from European countries. The most recently reported male-to-female ratio is 4.9:3.7.[55]
Pathogenesis
Approximately 98% of cases of uveal melanoma occur in the white population. This racial predisposition to uveal melanoma has been explained on the basis of susceptibility of the white persons to the oncogenic effects of sunlight. Although this hypothesis is convincing for skin melanoma, the evidence with regard to uveal melanoma is conflicting.[56] It is well known that intraocular melanoma develops as a result of the proliferation of uveal melanocytes, but the knowledge regarding this tumor's molecular pathogenesis is rather limited. It seems conceivable that these cells are intrinsically resistant to apoptosis because of constitutive Bcl2 expression. Hypothetically, the main event in the neoplastic conversion of the uveal melanocyte appears to be the inhibition of the Rb pathway. Genetic alterations that subvert the Rb and p53 pathways probably occur early, allowing the altered melanocytes to reenter the cell cycle and proliferate. The proliferation of the melanocytes may then become arrested by other tumor suppressor mechanisms, resulting in a dormant nevus; most of the nevi are permanently arrested at this stage. For further growth to occur, activation of a “malignant switch,” such as a reinhibition of the p53 pathway, may be necessary subsequent to another genetic shift.[57] Recently, a gene expression-based classification of uveal melanomas that predicts metastatic death has been reported, which may represent a breakthrough in current understanding of the molecular pathobiology of this neoplasm and may lead to major changes in management protocols for uveal melanoma. According to this scheme, class 1 tumors carry a low risk and class 2 tumors a high risk for metastatic death. [57] [58]
Clinical Features
Most patients remain asymptomatic unless the tumor involves the macula by means of direct extension, secondary retinal detachment, or macular edema. Large, anteriorly located tumors may induce lenticular astigmatism, cataract, or glaucoma. The typical posterior lesion is an elevated, brown, oval, dome-shaped choroidal mass ( Table 71-5 ). These tumors occasionally may be amelanotic. The presence of orange lipofuscin pigment at the level of the RPE is characteristic of choroidal melanoma ( Fig. 71-5 ). Mushroom-shaped eruption of the tumor through Bruch's membrane also is highly characteristic of melanoma.
Table 71-5 -- Classification of Uveal Melanomas by Size
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TUMOR SIZE |
||
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Dimension |
Small |
Medium |
Large |
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Diameter (mm) |
<10 |
10–15 |
>15 |
|
Height (mm) |
<2 |
2–5 |
>5 |
|
Figure 71-5 Funduscopic appearance of pigmented choroidal melanoma as a dome-shaped elevation; orange pigment partly covers its surface. Inset: Intravenous fluorescein angiography of the tumor depicts diffuse vascularity. |
Many conventional and newer imaging techniques, including fundus photography, Optomap (Optos, Marlborough, MS), intravenous angiography with or without indocyanine green, A- and B-scan ultrasonography, three-dimensional scan ultrasonography scanning, color Doppler imaging, ultrasound biomicroscopy (using higher-frequency ultrasound), optical coherence tomography (OCT), computed tomography (CT), and positron emission tomography (PET), may be used for diagnosis and treatment of choroidal melanoma. The most useful techniques are fundus photography, A- and B-scan ultrasonography, and intravenous fluorescein angiography (IVFA). Ultrasonography is the most important diagnostic modality in evaluation for suspected choroidal melanoma. Standardized A-scan ultrasonography can reliably differentiate the low-to-medium internal tumor reflectivity with a high initial scleral spike (positive angle kappa sign) of melanomas from medium-to-high internal tumor reflectivity of metastatic tumors and the high internal reflectivity of choroidal hemangiomas and osteomas ( Fig. 71-6 ).
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Figure 71-6 A, B-scan ultrasonographic appearance of choroidal melanoma with inferior retinal detachment (white arrow). B, The low-power histopathologic appearance of a choroidal melanoma with corresponding inferior retinal detachment (black arrow) is similar to that of the tumor in A. C and D, Histopathologic detail of a mixed, spindle and epithelioid cell choroidal melanoma in hematoxylin-eosin and Melan A stains, respectively. Numerous pleomorphic epithelioid tumor cells and mitotic figures are present (white arrow). |
Fine-needle aspiration and incisional biopsy occasionally may be valuable procedures for diagnosis of choroidal tumors of unknown origin. The relatively high frequency of postoperative complications and the potential risk of dissemination of tumor cells underline the importance of careful case selection. In the great majority of cases, the diagnosis of melanoma is based on clinical and imaging information.[59]
These tumors metastasize primarily to the liver. Usually within 15 years after the initial diagnosis of posterior uveal melanoma, metastasis develops in approximately 50% of the patients. Clinically evident metastatic disease at the time of initial presentation, however, is very rare, so if early metastasis is present, it is subclinical in most cases. The traditional means of metastasis detection has been screening with liver function tests and chest radiographs. Currently, however, the value of whole-body PET/CT in screening for metastatic choroidal melanoma has been emphasized. Liver enzyme levels can be normal in the presence of PET/CT abnormalities, but false-positive results on up to 5% of these assays also are possible.[60] The main disadvantages of PET/CT imaging are the high cost and the sometimes limited availability, but from the standpoint of sensitivity, this approach is superior to the conventional methods of screening for detection of metastatic disease.
Orbital extension of uveal melanoma is another major potential problem with these tumors.[61] Transscleral extension and invasion of the adjacent soft tissues usually occur with large choroidal melanomas composed of epithelioid cells, but occasionally medium-sized tumors of mixed cell type also may invade extraocular structures to a limited degree. Intraocular melanoma is known to leave the eye through emissarial channels, extend onto the scleral surface, and disseminate into the orbital soft tissues ( Fig. 71-7 ). It has been reported that approximately 10% of patients with ciliochoroidal melanomas have extrascleral extension at the time of enucleation.[62] In the early stages of the extrascleral extension, the tumor manifests as a nodular formation, but as it grows, it may be widespread and extend into the meninges, into the optic nerve, and to the lumina of the orbital vasculature (see Fig. 71-7 ).
|
Figure 71-7 Orbital extension of choroidal melanoma. A, The tumor (m) extends into the optic nerve as well as into the orbital soft tissues. Note that it is amelanotic in the orbit but densely pigmented in the optic nerve. B, The low-power histopathologic appearance of a juxtapapillary melanoma extending into orbital soft tissues (arrows). C, The orbital component of this melanoma (m) is as densely pigmented as the intraocular primary tumor. |
With continued growth, the mass effect of the retrobulbar melanoma will result in proptosis, extraocular motility disturbance, congestion, and chemosis. The eye and the periorbita may be painful and tender to palpation, masquerading as an inflammatory condition such as endophthalmitis.[63] Once extraocular extension is clinically suspected, the patient should be investigated with ultrasonography, CT scan, or MRI. Although the diagnosis of intraocular melanoma usually is made by indirect ophthalmoscopy, intravenous fluorescein angiography, and ultrasonography, in cases of suspected orbital extension, imaging with CT scan or MRI is more helpful. A particularly helpful feature of melanoma in MRI is based on the signal characteristics of the melanin. Melanin produces stable free radicals, which create a paramagnetic proton relaxation enhancement, which leads in turn to shortening of T1 and T2 relaxation times. The melanoma thus manifests with moderately high signal intensity on T1- weighted images and a moderately low signal intensity on T2-weighted images.[64]
It has been reported that secondary orbital melanoma originating from the choroid can be treated with brachytherapy with some success when the extraocular extension consists of a single nodule that is less than 3 mm in diameter.[63] In cases in which the melanoma nodule is greater than 3 mm in diameter, enucleation is performed to remove the melanoma nodule encased by normal-appearing orbital fat, and secondary EBRT is given. With larger and more invasive tumors, total or partial exenteration is done.[65] In general, extraocular extension, particularly orbital extension, is an indicator of poor prognosis, with a 5-year mortality rate of approximately 55%.
Differential Diagnosis
Other pigmented and nonpigmented mass lesions of the choroid may be clinically confused with choroidal melanoma. Such lesions include nevus, metastatic tumors, choroidal hemangioma, and other benign and malignant tumors; inflammatory lesions; and hemorrhages. [66] [67]
Management
The primary objective of any treatment for uveal melanoma is to prevent extraocular direct spread or metastases ( Box 71-1 ). Maintenance or recovery of good vision is rather secondary, for the reason that almost all forms of current therapy lead to vision-impairing complications. The choice among the wide range of therapeutic modalities is based on the patient's age and general health, tumor location and size, the extent of the tumor, the patient's preferences regarding vision and globe preservation, and the risk of metastases. The current belief is that patients in whom metastatic uveal melanoma develops already have micrometastases at the time their intraocular tumors are first detected. Detection of micrometastases is very important, because the outlook with existing therapies for detectable metastatic lesions is dismal; however, treatment of micrometastases promises to be more effective.[57]
Box 71-1
|
MANAGEMENT OF CHOROIDAL MELANOMA |
|||||||||||||||||||||||||||||||||||||||||||||
|
Observation
Surgical Excision (External Eyewall Resection)
Radiation Therapy
Enucleation/Exenteration Indications for this modality include the following:
|
At the initial presentation, approximately 30% the tumors are too large for treatment with current eye salvage techniques. Patients with these tumors are managed with primary enucleation. The remaining 70% of tumors are treated with radiation therapy delivered in different forms.[68] The proportion of cases treated by radiotherapy in the United States increased gradually from 2% to 28% over the last 25 years.[69] Brachytherapy frequently is used for tumors 3 to 8 mm in thickness or less than 16 mm in basal diameter[70] ( Table 71-6 ; Fig. 71-8 ). Irradiation of tumors greater than 10 mm in height or 16 mm in diameter usually leads to serious radiation-related toxicity of the retina and the optic disc. Tumors adjacent to or surrounding the optic nerve also can be treated with brachytherapy, but this strategy increases the chance of nerve and macular radiation toxicity.[71] 125I is the most frequently used radioactive source used in the United States because of its accessibility, relatively long half-life, good tissue penetration, and ease of shielding. The current treatment delivery design includes use of a lead or gold shield with radioactive seeds set within a silicone holder inside the plaque template.
Table 71-6 -- Radionuclides Commonly Used in Plaque Brachytherapy for Ocular Tumors
|
Radionuclide |
Half-life |
|
Cobalt 60 |
5 years |
|
Iodine 125 |
60 days |
|
Ruthenium 106 |
366 days |
|
Palladium 103 |
17 days |
|
Figure 71-8 A and B, Surgical insertion of the brachytherapy iodine-25 plaque. Inset with B: The gold plaque and silicone radioactive seed carrier. The histopathologic picture (C) depicts the partial response (asterisk) of choroidal melanoma to radiation; viable tumor (M) can be seen on the left. V, vitreous; S, sclera. |
The Collaborative Ocular Melanoma Study (COMS) trial has demonstrated that survival rates in patients with medium-sized melanomas treated with brachytherapy are not statistically different from those for patients whose eyes were enucleated. A mean local control rate of approximately 90% has been reported after approximately 4 years of follow-up. Complication rates and visual outcomes are associated with tumor dose, dose rate, and tumor location and size (patients with larger tumors have worse outcomes). Specifically, maculopathy and papillopathy are more likely to occur in patients with tumors that are near or adjacent to the optic disc or macula. The data from the COMS trial indicate that outcomes for eyes with medium-sized tumors treated with brachytherapy and with enucleation, as determined by Kaplan-Meier analysis, included 5-year rates of all-cause mortality of 18% and 19%, respectively. The 5-year rates of metastasis were 9% after brachytherapy and 11% after enucleation.[72] Studies of juxtapapillary tumors have demonstrated similar rates of metastatic disease.[73] In small choroidal melanomas, on the other hand, the 5-year melanoma-specific mortality rate after 125I plaque radiotherapy has been reported to be approximately 4%.[74]
The COMS trial also reported a 17% incidence of visual acuity of 20/200 or worse by 1 year, and 43% by 3 years after plaque therapy of medium-sized choroidal melanomas.[75] By the fifth year of follow-up, a 10% risk of treatment failure, defined as extrascleral extension, continued growth of the tumor, or recurrence of a tumor that initially responded to radiation, was noted. Although excellent tumor control was achieved in 90% of patients, the visual acuity in 63% of eyes had deteriorated to 20/200 or worse.[76]
Within 12 years after enrollment in the COMS, 45% of the patients were alive and clinically cancer free. Five, 10, and 12-year rates of death with histopathologically confirmed melanoma metastasis were 10%, 18%, and 21%, respectively, in the 125I brachytherapy group and 11%, 17%, and 17% in the enucleation group. Older age and larger maximum basal tumor diameter were the primary determinants correlating with melanoma metastasis and death.[77]
It has been reported that final visual acuity after brachytherapy is dependent on the patient's age, systemic medical problems, and initial visual acuity; tumor location and size; presence or absence of subretinal fluid; and the type of isotope used. Visual acuity was best preserved in eyes with small tumors and those with tumors located away from the optic disc and fovea.[78]
The other major radiation delivery system for the treatment of choroidal melanoma is proton beam radiation therapy (PBRT).[79] Although a theoretical advantage of PBRT is the capability focusing the radiation onto the lesion, the efficacy in terms of tumor control and complications is similar to that for brachytherapy.[80] With current PBRT techniques, an approximately 95% local control rate has been achieved. Long-term preservation of eyes is dependent on tumor size and thickness, as is the case with plaque therapy. In one report, approximately 84% of eyes were retained at 15 years. [80] [81]
A number of new radiation delivery systems for the treatment of choroidal melanoma are in the process of evolution.[82] The ideal new scheme should be noninvasive and should be less radiotoxic to the eye than PBRT and plaque radiotherapy, while ensuring therapeutic dose delivery as accurate as proton or plaque techniques. It also should allow fractionation of the dose as is used in proton treatment. New techniques, which include gamma knife radiosurgery, linear accelerator-based radiosurgery, and robot-controlled linear accelerator radiosurgery (CyberKnife, Accuray Inc., Sunnyvale, CA), thus farhave been found to be less effective than conventional delivery systems for the treatment of choroidal melanoma.[83]
Data from the COMS also have revealed that preoperative EBRT before the enucleation of the eyes containing large choroidal melanomas offers no protection against metastatic disease.[84] Other forms of treatment for uveal melanoma—surgical excision of the tumor and laser therapy—have limited applications.
Eye wall resection surgery is done to conserve the eye with as much useful vision as possible when radiotherapy is unlikely to give a satisfactory result, or if extensive retinal detachment develops after radiotherapy. Even in the best hands, however, this kind of surgery is associated with many vision-threatening complications. [85] [86] Laser therapy has always been considered to be an attractive potential treatment method for management of choroidal melanoma; however, its applications, even with modern technology, have been limited. At present, the most effective form of laser treatment for uveal melanoma is transpupillary thermal therapy (TTT). TTT is performed with an 810-nm-wavelength laser delivered through a slit-lamp biomicroscope or with an indirect ophthalmoscope. Usually, the eye is anesthetized with a retrobulbar block, and the beam is delivered with use of a lens. The depth of tumor necrosis created by the laser beam is directly correlated with elevations in temperature ranging from 45° to 60° C and exposure time varying from 1 to 10 minutes; but even in the best of circumstances, tumors thicker than 3 mm cannot be effectively treated with TTT. Despite the availability of the aforementioned different treatment modalities, the overall 5-year survival rate for this tumor is still high, ranging from approximately 75% to 85%.[87]
Metastatic Tumors to the Eye
Today, metastatic tumors to the uvea are considered to be the most common type of intraocular neoplasia ( Fig. 71-9 ). The vascular tissue of the posterior choroid is the most likely site for ocular metastasis. Presenting signs and symptoms include metamorphopsia, diminished central vision, and visual field defects. Serous retinal detachment represents the most frequent clinical presentation; pain typically is absent. The diagnostic workup for metastatic lesions is similar to that for choroidal melanoma, with particular use of ophthalmoscopy, IVFA, and ultrasonography. OCT also is useful in the evaluation of secondary RPE changes and in follow-up assessment of lesions after treatment.[88]
|
Figure 71-9 Funduscopic and B-scan ultrasonographic appearance of metastatic breast carcinoma to choroid. A, Elevated, nonpigmented mass (black arrow). B and D, Funduscopic and intravenous fluorescein angiography appearance of irregular, flat infiltrates of choroidal metastasis. C, The B-scans reveal flat metatastatic lesions and overlying retinal detachments (white arrows). |
Metastatic tumors may originate from a variety of different primary sites, with breast and lung carcinomas being the most common primary malignancies. Treatment options include systemic therapy, EBRT, plaque brachytherapy, PBRT, photodynamic therapy, TTT, and other types of laser photocoagulation[89] ( Box 71-2 ). The selection of the treatment modality depends on the size and location of the tumor, as well as on the life expectancy and preference of the patient. Overall prognosis for patients with metastatic tumors of the choroid is poor. Median survival is approximately 12 months. Palliative treatment for patients with metastatic tumors of the choroid has proved to be effective both in improving visual acuity and in maximizing quality of life.
Box 71-2
|
MANAGEMENT OF INTRAOCULAR METASTASES |
||||||||||||||||||
|
Diagnosis
Treatment
|
Another pathologic condition of the eye secondary to neoplasia elsewhere in the body is cancer-associated retinopathy (CAR), an uncommon paraneoplastic retinopathy, most commonly associated with small cell lung cancer, in which antibodies are directed against retinal antigens.[90] Clinical findings typically include bilateral visual loss and electroretinographic abnormalities in the absence of actual metastatic disease in the eye. Visual symptoms may precede diagnosis of the systemic malignancy or ocular metastases.
Ocular Leukemia
Ophthalmic infiltration by acute leukemia is rare.[91] With developing curative advances, the survival of patients with acute leukemia has been considerably prolonged. This has led to an increase in the variability of ocular presentations in the form of side effects of the treatment and the ways leukemic relapses are being first identified as an ocular presentation. Leukemia may involve many ocular and adnexal tissues, including the conjunctiva, cornea, sclera, anterior chamber, iris, lens, vitreous, retina, choroid, and optic nerve, either by direct infiltration or as a result of secondary toxicity due to chemotherapy and radiation therapy ( Fig. 71-10 ). Ocular involvement also may develop in the GVHD reaction seen in patients undergoing stem cell transplantation or occurring as the result of increased susceptibility to infections due to immunosuppression in patients with leukemia. [92] [93] Early diagnosis and treatment are essential to prevent visual deterioration. Chemotherapy and EBRT are the main modalities of treatment in ocular and orbital leukemia; irradiation may provide more prompt resolution of vision-threatening symptoms.[94]
|
Figure 71-10 A and B, The clinical appearance of orbital and iris involvement of acute myeloblastic leukemia (AML) before (A) and after (B) radiation treatment. Inset: Conjunctival “salmon patch” lesion of chronic lymphocytic leukemia (CLL). C, Pretreatment photograph of the iris with engorged tortuous blood and focal whitish infiltrates of leukemic cells within the stroma (white arrows). D, Scarred areas of iris (black arrows) after radiation treatment. |
Intraocular Lymphoma
Primary intraocular lymphoma (PIOL) is a rare subset of intraocular primary CNS lymphoma (PCNSL), in which lymphoma cells invade the eye. PCNSL is an aggressive form of non-Hodgkin's lymphoma typically associated with a worse prognosis than for other extranodal lymphomas with similar histologic characteristics. At least 95% of PCNSLs are of large B-cell histology, the most common subtype of non-Hodgkin's lymphoma. At the time of ocular diagnosis, CNS involvement may or may not be present. The incidence of this tumor has increased over the past several years in immunosuppressed as well as in immunocompetent patients.[95]
Pathogenesis
Some evidence indicates that chronic antigenic stimulation may result in the development of PIOL.[96] The immunophenotype of PIOL is CD79a+, CD20a+, PAX-5+, BCL-2+, and OCT2+; the only documented chromosomal translocation is t(14;18), with rearrangements being reported in 56% of the patients.[97]
Clinical Features
In most cases of PIOL, the patient presents with uveitis-like symptoms including pain, blurred vision, and vitritis ( Fig. 71-11 ). It is a common neoplastic masquerade syndrome involving the eye. Its protean ocular manifestations, plus in many cases the initial positive response to steroid therapy for presumed uveitis, may delay proper diagnosis and treatment. A high index of suspicion is essential; prompt tissue biopsy with cytologic and laboratory workup is indicated in any patient in whom PIOL is likely.
|
Figure 71-11 Intraocular lymphoma. A, Fundus appearance of hazy vitreous with the yellowish plaque-like lesions of intraocular lymphoma. B, Combined A- and B-scan showing the tumor infiltrate in vitreous (arrow). C, Atypical lymphocytes within the cellular debris retrieved by vitreous tap. |
Differential Diagnosis
Recent advances in the diagnosis of PIOL are due primarily to improved laboratory methods of processing vitreous specimens for cytologic studies and availability of immunocytologic investigation for lymphoid cells, flow cytometry, cytokine evaluation, and molecular analysis. Because PIOL has a nonspecific presentation, considerations in the differential diagnosis should include infectious and noninfectious causes manifesting with vitreitis or subepithelial infiltration, as well as paraneoplastic syndromes including CRMP-5 optic neuropathies. Because the treatment is prolonged and is associated with significant systemic and ocular complications, tissue diagnosis is important.[96]
Management
Treatment of PIOL may include EBRT and systemic chemotherapy with high-dose methotrexate-based regimens, as well as intraocular injections of methotrexate and rituximab (anti-CD20 antibody). In cases in which the vitreous cells persist after systemic chemotherapy, methotrexate may be given intravitreally thereafter; this is an effective, repeatable, and safe treatment.[98] Ocular remissions typically are sustained for years, but recurrence is possible. EBRT, which usually is delivered with high-energy photons, causes the production of free radicals, which target the DNA of the tumor cell. Today, EBRT to the eye and CNS is being used less often to treat this disease. Prognosis is poor owing to CNS involvement.
Retinoblastoma
Retinoblastoma, the most common intraocular neoplasm of childhood, is reported to have an incidence of approximately 6 in 100,000 live births, accounting for approximately 10% of cancers during the first year of life. Approximately 300 new cases are diagnosed annually in the United States. [99] [100] Approximately one third of cases of retinoblastoma are bilateral tumors.[101] This neoplasm, primarily a disease of early childhood, has been detected even in fetal life. [102] [103] It also may rarely occur in children older than 5 years of age and more rarely in young adults.[104]
Pathogenesis
Retinoblastoma is the prototypical model of hereditary neoplasms; it develops as a result of mutational inactivation of both alleles of the retinoblastoma gene (RB1).[105] This gene is mapped to chromosomal band 13q14. The RB-encoded protein (pRb) is a tumor suppressor that plays a pivotal role in negative control of the cell cycle and in tumor development. It has been shown that pRb is responsible for a major G1 checkpoint, blocking S-phase entry and cell growth. Loss of pRb functions may induce cell cycle deregulation and so lead to a malignant phenotype. Gene inactivation of pRB through chromosomal mutations is one of the principal reasons for retinoblastoma development.[106] Functional inactivation of pRb by viruses also is documented in many malignancies, including cervical cancer, mesothelioma, and Burkitt lymphoma.[107]
The two-mutation model of Knudson (the “two-hit” hypothesis) dictates that the development of retinoblastoma is caused by two corresponding chromosomal mutations. In hereditary retinoblastoma, the initial occurrence, or “hit,” is a germinal mutation that is inherited to be present in all the child's cells. The second hit occurs sometime during development and, if it occurs in a somatic cell such as the primitive photoreceptors, then the tumor develops. Therefore, in hereditary cases of retinoblastoma, all cells in the body are predisposed to neoplastic development, because germline mutation (the first hit) takes place in all cells of the body. This predisposition also may help to explain the high incidence of multiple nonocular tumors, such as sarcomas, lymphomas, and brain, seen in patients with hereditary retinoblastoma.
On the other hand, in most cases of unilateral sporadic retinoblastoma, the two hits occur during development of the retina, and both are somatic mutations. Theoretically, the rest of the body carries no higher risk for the development of other tumors, because affected persons have a normal chromosomal pattern in cells elsewhere in the body. It is well known that survivors of hereditary retinoblastoma have an increased risk for multiple malignant and benign neoplasms, especially soft-tissue sarcomas.[108] Some reports indicate a greater than 10-fold increase in overall mortality in patients with retinoblastoma compared with the general population, because of second malignancies.[109] For practical purposes, a child with retinoblastoma has approximately a 5% chance of developing another malignancy during the first 10 years of follow-up, 20% during the first 20 years, and 25% within 30 years. Survivors of hereditary retinoblastoma revealed a statistically significant increase of leiomyosarcoma and other soft-tissue sarcomas that persists decades after their initial diagnosis. These patients should undergo lifelong medical monitoring for sarcomas.[110] The 30-year cumulative incidence of nonocular tumor development is approximately 30% for those patients with retinoblastoma treated with EBRT, compared with approximately 10% for those patients who did not receive radiation. It has been reported that among patients with retinoblastoma treated with radiotherapy, an increased incidence of soft-tissue sarcomas, especially leiomyosarcomas, are found in the radiation field, as well as outside the field of radiation.[110]
Morphologically and clinically, hereditary and nonhereditary tumors generally are indistinguishable. The most important differences are that hereditary retinoblastoma usually occurs at a younger age and is more likely to be bilateral and multicentric. Although approximately one third of cases of retinoblastoma are inherited, only about 5% of patients in newly diagnosed cases present with a family history. Patients with bilateral tumors and those with a positive family history can be safely assumed to have a germinal mutation for the RB gene; for practical purposes, these patients are at a 50% risk of transmitting the RB gene to their offspring by autosomal dominant transmission. The gene is approximately 80% penetrant, so clinical expression will be seen in approximately 40% of these patients’ children; some offspring may be merely carriers of the gene, without development of clinical manifestations of the tumor. Approximately 15% of unilateral tumors develop by germinal mutations that, by chance, affect only one eye. The remaining 80% to 85% of unilateral tumors are due to somatic mutations that involve only the retina; in such cases, the disease is not passed on to future generations.
Clinical Features
Leukocoria, or cat's eye reflex (seen in 55% of cases), and strabismus (seen in 20%) are the most common presenting signs of retinoblastoma in children in Western countries [111] [112] ( Fig. 71-12 ). Retinoblastoma also may manifest with atypical features such as uveitis, vitreous hemorrhage, and orbital cellulitis, particularly in older children.[104] An important point is that invasive treatment and vitrectomy should be avoided in these children until the possibility of underlying retinoblastoma is excluded.[113]
|
Figure 71-12 Retinoblastoma. A, Leukocoria in the left eye. B, A- and B-scan appearance of preradiation (left) and postradiation (right) treatment of a large retinoblastoma mass. C, Postenucleation appearance of partially regressed retinoblastoma (asterisk). White arrowsshow multiple recurrent lesions. Black arrows show extensively calcified intraocular seeds after radiation treatment. |
The most dependable way of diagnosing retinoblastoma is by means of dilated indirect ophthalmoscopic examination performed with the patient under general anesthesia (EUA); tumor, if present, is recognized as a characteristic whitish gray mass within the eye[114] ( Fig. 71-13 ). Dilated fundus examination also permits identification of multifocal tumor or vitreous seeding. Currently this examination is made even more rewarding with the digital image capture and storage capability of the wide-angle fundus visualization systems, which include Retcam 120 (Massie Research Laboratories, Dublin, CA), Optomap (Optos, Marlborough, MS), and Panoret-1000 (CMT Medical Technologies Inc., Valley Stream, NY). The risk of general anesthesia is balanced by the benefit of improved survival of the patient and preservation or maximization of vision. The currently recommended schedule for surveillance among persons in whom a nongermline mutation is proved by genetic screening may perhaps be relaxed in the future, but in today's clinical practice, multiple EUAs within the first 5 years of life is the standard of care. Additional tests, although not always necessary, may be performed to confirm the diagnosis, but ocular biopsy in retinoblastoma is not done for histopathologic confirmation because of the fear of carrying tumor cells to extraocular tissues.[115]
|
Figure 71-13 A, Retinoblastoma with extensive intravitreous seeding. B, Totally calcified vitreous seeds after radiation treatment. C, Black arrows on the pathology specimen show partially regressed, calcified retinoblastoma after external beam irradiation. |
Ocular A- and B-scan ultrasonography or CT may demonstrate a solid intraocular tumor with characteristic calcifications. CT also may be required to exclude a concomitant primitive neuroectodermal tumor (PNET) in the midline (i.e., the so-called trilateral retinoblastoma, which consists of bilateral retinoblastomas and concomitant pineal PNET). [116] [117] [118]
Spontaneous regression of retinoblastoma is an exceptionally rare occurrence. If the tumor is not treated, it will rapidly enlarge to occupy the entire globe and extend into adjacent orbital, periorbital, and intracranial tissues[119] ( Fig. 71-14 ). The most common routes of extension are by direct infiltration of the optic nerve or sclera and spread via the choroid.[120] The risk of neural spread depends on the level of the invasion of tumor cells into the optic nerve. Mortality rates of up to 85% and 70% have been reported if tumor cells have reached the surgical transaction margin of the optic nerve and posterior to the lamina cribrosa, respectively. Additional routes of spread include dispersion of the tumor cells through the subarachnoid space into the CNS, lymphatic dissemination of the tumor anteriorly into the conjunctiva and eyelids, and hematogenous metastases to distant organs such as the bone, liver, and brain.
|
Figure 71-14 A, T1-weighted axial magnetic resonance image shows the extraocular extension of retinoblastoma into the orbit (black arrow). B, Contrasting histopathologic appearance of viable (asterisk) versus calcified tumor after external beam irradiation. C and D,Images reveal extension of the tumor into the optic nerve and then to the orbital soft tissues through scleral blood vessels (black arrow). |
MRI can be particularly helpful in those cases with possible extension into the optic nerve or choroid; fat suppression and gadolinium contrast techniques constitute the best imaging choice[121] (see Fig. 71-14 ). If imaging provides evidence of tumor outside the eye, a metastatic workup should be pursued.[122] Metastatic disease is rarely suspected at the time of initial presentation, and the usual tumor staging studies such as bone marrow biopsy, lumbar puncture, radionuclide bone scan, or PET usually are not performed. In the usual case of endophytic retinoblastoma in which the optic nerve can be seen, the morbidity associated with metastatic screening tests outweighs their likely value.[123] Symptoms and signs of metastatic disease may include weight loss, vomiting, headache, neurologic impairment, orbital mass, or enlarged neck nodes.[124] Preoperative bone scan is not justified in patients with intraocular disease even when it is advanced. Bone scan should be done only in patients with documented extraocular metastatic disease.[125]
The Reese-Ellsworth classification, still the most widely used retinoblastoma organization system, is based on intraocular tumor staging and globe salvage prediction after EBRT; survival is not taken into account in this categorization.[126] A newer proposed organization for the disease, the International Intraocular Retinoblastoma Classification (the “ABC classification”), is more suitable to current management senarios for this tumor. [127] [128] This classification stages intraocular tumors according to their prognosis after chemoreduction and adjuvant focal therapy. It consists of five groups—A, B, C, D, and E—in descending order of favorable prognosis ( Table 71-7 ).
Table 71-7 -- International Intraocular Retinoblastoma Classification
|
Group |
Quick Reference |
Specific Features |
|
A |
Small tumor |
Retinoblastoma ≤3 mm[*] |
|
B |
Larger tumor |
Retinoblastoma >3 mm or |
|
Macula |
Macular retinoblastoma location (≤3 mm to foveola) |
|
|
Juxtapupillary |
Juxtapupillary retinoblastoma location (≤1.5 mm to disc) |
|
|
Subretinal fluid |
Additional subretinal fluid (≤3 mm from margin) |
|
|
C |
Focal seeds |
Retinoblastoma with |
|
Subretinal seeds ≤3 mm from retinoblastoma |
||
|
Vitreous seeds ≤3 mm from retinoblastoma |
||
|
Both subretinal and vitreous seeds ≤3 mm from retinoblastoma |
||
|
D |
Diffuse seeds |
Retinoblastoma with |
|
Subretinal seeds >3 mm from retinoblastoma |
||
|
Vitreous seeds >3 mm from retinoblastoma |
||
|
Both subretinal and vitreous seeds 3 mm from retinoblastoma |
||
|
E |
Extensive retinoblastoma |
Extensive retinoblastoma occupying >50% globe or |
|
Neovascular glaucoma |
||
|
Opaque media from hemorrhage in anterior chamber, vitreous, or subretinal space |
||
|
Invasion of postlaminar optic nerve, choroid (>2 mm), sclera, orbit, anterior, chamber |
|
* |
Refers to 3 mm in basal dimension or thickness. |
Differential Diagnosis
Other causes of leukocoria such as Coats disease, persistent hyperplasic primary vitreous, retinopathy of prematurity, Toxocara endophthalmitis, large retinal detachments, and rarely unilateral congenital cataracts may be confused with retinoblastoma. [129] [130] Most of these pathologic conditions can be differentiated easily from retinoblastoma with today's advanced diagnostic technologies. Coats disease, however, may still be a problem when it presents in young children. MRI or IVFA can be helpful, particularly when Coats’ disease with retinal detachment is in the differential diagnosis. [131] [132]
Management
Retinoblastoma is now considered a “curable” tumor if it is diagnosed early. Early treatment of the disease is effective at a reasonable cost, saving both life and vision. Undertaken at a late stage, however, treatment is very costly, with poor outcome, particularly for vision. This underlines the call for early diagnosis and the importance of public and professional awareness of this deadly disease.[133] The hereditary form is associated with increased risk of second nonocular primary malignancies that are even more lethal than the retinoblastoma itself.[134]
Management of retinoblastoma should be tailored to the individual patient. All parameters should be taken into account, including the size, location, and laterality of the tumors; threat of metastases; risks for second malignancies; and projected visual prognosis. Today's treatment methods include chemotherapy (i.e., chemoreduction) with intravenous carboplatin, etoposide, and vincristine; subconjunctival carboplatin injection; TTT; cryotherapy; laser photocoagulation; plaque brachytherapy; EBRT; and enucleation or exenteration[135] ( Fig. 71-15 ). In general, eyes classified as group A are treated with cryotherapy or laser photocoagulation, or both. Eyes classified as group B or C typically receive chemoreduction; unilateral cases without seeding may be managed with plaque brachytherapy. Eyes with diffuse vitreous seeding (group D) are treated with either chemoreduction, EBRT, or enucleation, depending on the laterality of the disease. Chemoreduction usually reduces tumor volume by more than 50% within a few weeks and dries out most of the retinal detachment. The choice of antimetabolic agents, dosage, and the duration of treatment will vary from one hospital to another; however, most centers make use of vincristine, carboplatin, and an epipodophyllotoxin (etoposide or teniposide).[136] The tumor-related disadvantage of chemoreduction is the recurrence of vitreous or subretinal seeding or appearance of new crops of retinoblastomas elsewhere (in approximately one fourth of cases) in the eye after the discontinuation of therapy.[137] A permanent response is almost never achieved with chemoreduction alone, so the response to this treatment should be monitored closely and other focal therapies should be implemented before the recurrent tumor gets a chance to reach a large size. Also, chemoreduction is not without its systemic side effects, such as bone marrow suppression, loss of hair, and, possibly more serious, long-term complications such as development of second malignancies. Final data on chemoreduction are not yet available.
|
Figure 71-15 A and B, Prechemoreduction and postchemoreduction appearance of a large solitary retinoblastoma nodule. |
Plaque radiotherapy is a form of brachytherapy in which a radioactive seed carrier (i.e., plaque) is surgically sutured over the wall of the eye at the base of a tumor focus for transscleral irradiation (see Fig. 71-8 ). Placement of radioactive plaques (125I, 106Ru) is limited to tumors measuring approximately less than 15 mm in cord diameter and 8 mm in thickness and can be used for the primary treatment of medium-sized tumors. When a retinoblastoma focus reaches these sizes, however, it usually breaks down, with seeding into the vitreous and subretinal spaces. Therefore, the plaques more often are used as a secondary measure after other forms of treatment. Currently, the most widely used plaque is the 125I plaque, which delivers unidirectional low-energy gamma rays that can be shielded well. The old cobalt 60 plaques have been largely abandoned because their high-energy gamma rays cannot be shielded effectively. When plaque radiotherapy is given in cases with extensive subretinal or vitreous seeding, it has a high failure rate.[138] On the other hand, when this method is used as a primary treatment of RB, it provides long-term tumor control in almost 90% of cases. It also is very effective in those eyes in which a focus of RB recurs after chemoreduction. Of note, although plaque radiotherapy is much safer than EBRT in terms of local radiation toxicity, it may lead to localized radiation effects such as radiation vasculopathy, maculopathy, or papillopathy, depending on the location of the lesion.
EBRT is no longer considered to be first-line conservative treatment owing to its important long-term side effects. It may still be needed, however, in advanced bilateral disease or for control of recurrent tumors inaccessible to focal treatment methods. The customary total radiation dose is 40 to 50 Gy, delivered in fractions of 1.8 Gy through a lateral or anterior port. The use of other delivery techniques for external beam irradiation such as stereotactic conformal radiotherapy and accelerated proton beam irradiation are not commonly used in retinoblastoma.
The other form of treatment to be taken into account for retinoblastoma is enucleation. Although enucleation has become less common with early diagnosis and better alternative therapies for this tumor, it remains the treatment of choice for advanced disease in eyes with no visual potential or with high risk of metastasis. For unilateral tumors, enucleation is required in approximately two thirds of cases.[139]This stems from the fact that most cases of unilateral sporadic retinoblastoma are detected by the affected child's parents, who notice leukocoria or strabismus when the disease is advanced.[140] For those patients with less advanced unilateral disease, chemoreduction with focal consolidation of each focus of tumor with thermotherapy or cryotherapy or the use of plaque brachytherapy is helpful. The great majority of group E cases are managed by enucleation or more extensive surgical procedures such as exenteration with or without EBRT to the socket and adjuvant chemotherapy. Children with dissemination of retinoblastoma to the CNS or metastatic disease remain incurable and die of progressive disease despite the aggressive treatment. [124] [141]
CONJUNCTIVAL TUMORS
Conjunctival tumors comprise neoplasms originating from cells of all germ layers, including epithelial, melanocytic, glandular tissue, vascular, and other soft tissue elements, and other cells.[142] This section covers only the commonly encountered malignancies, including melanoma, squamous cell carcinoma, and Kaposi's sarcoma.
Conjunctival Squamous Cell Carcinoma
Squamous cell carcinoma is the most frequently encountered malignancy of the conjunctiva; the incidence of this tumor varies, ranging from 0.025 to 3.5 per 100,000 population, depending on the geographic location. [143] [144] The mean age of affected patients is approximately 60 years. Although this tumor is considered to be a low-grade malignancy, local extension into the globe and underlying eyelid structures may be seen. Regional and distant metastases are rare, but the tumor may show local aggressiveness.[145]
Pathogenesis
The etiology of conjunctival squamous cell carcinoma is multifactorial, involving such factors as age, fair pigmentation, ultraviolet light exposure, and exposure to human papillomavirus (HPV). Ultraviolet radiation is considered to be the most important cancerogenic factor for conjunctival squamous cell carcinoma.[146]
In the past, HPV infection and impairment of p53 function have been identified as frequent events in conjunctival squamous cell carcinoma.[147] Recent studies, however, indicate that the role of HPV in the pathogenesis of conjunctival and eyelid tumorigene-sis may be auxiliary. The p53 protein probably is involved in the development of conjunctival and eyelid carcinomas, owing to its frequent presence in both benign and malignant neoplasms of the eyelids. [148] [149]
It seems that human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) and other forms of immunosuppression-related conjunctival squamous cell carcinoma and virus-associated tumors are increasing in Africa and elsewhere in the world. Recent studies have described conjunctival tumors that behave more aggressively and are seen in younger patients. [150] [151]
Clinical Features
The most common presenting signs and symptoms of conjunctival squamous cell carcinoma are redness and irritation of the eye with or without foreign body sensation. The bulbar conjunctiva, particularly the limbus, is the frequent site for the occurrence of a slow-growing, elevated pinkish gray lesion with a pearly or gelatinous appearance with surrounding feeding vessels. Similar to squamous epithelial neoplasms elsewhere in the body, conjunctival tumors evolve through morphologic advances of dysplasia, to carcinoma in situ, to the invasive stage ( Fig. 71-16 ). The degree of dysplasia in these lesions cannot be determined by clinical examination; therefore, it is absolutely necessary that they be biopsied and examined histopathologically. [152] [153] Although most lesions manifest as a localized mass formation, atypical presentations of squamous cell carcinoma as a diffuse growth or a masquerade lesion mimicking scleral keratitis or scleromalacia also have been reported.[154] Both carcinoma in situ and the invasive form are considered to be low-grade malignancies that are locally invasive but rarely manifest with distant metastases. Once the neoplasm breaks through the basement membrane of the conjunctival epithelium and invades the subepithelial tissues and episclera, however, it behaves in a locally aggressive fashion.[155] Although squamous cell carcinomas are slowly growing tumors, under certain conditions they are known to extend into the underlying structures, including the globe and the orbit[156] (see Fig. 71-16 ).
|
Figure 71-16 A and B, Slit-lamp photograph and axial computed tomographic scan showing advanced-stage conjunctival squamous cell carcinoma originating from bulbar conjunctiva. Notice that the tumor extends into the orbital soft tissue laterally (white arrow in B). C,Squamous cell carcinoma originating from a conjunctival inverted papilloma of tarsal conjunctiva of the upper eyelid. |
Differential Diagnosis
Conjunctival squamous cell carcinoma should be differentiated from pingueculum or pterygium, foreign body granuloma, and other tumors of the conjunctiva such as lymphoma, melanoma, and metastatic tumors.
Management
The treatment of of conjunctival squamous cell carcinoma varies depending on the age and the extent of development. The management of superficial disease (carcinoma in situ, superficially invasive tumor) include surgical excision of the lesion with lamellar scleral keratoconjunctivectomy and cryotherapy. [157] [158] Although other treatments and immunotherapy with dinitrochlorobenzene and photodynamic therapy have been used, most of these regimens do not offer a very good prognosis.[159] Topical chemotherapy with mitomycin C and 5-fluorouracil has been reported to yield good results in superficial cases. A literature review reported that the use of mitomycin C, 5-fluorouracil, and interferon alfa-2b offers tumor regression rates for carcinoma in situ and squamous cell carcinoma ranging from 80% to 96%. Side effects of keratitis, redness, and irritation occurred most often with mitomycin C, followed by 5-fluorouracil and interferon alfa-2b. [160] [161] Radiation treatment with brachytherapy and EBRT may be considered in recurrent cases with or without globe invasion.[162] Current knowledge of the efficacy of EBRT is limited; however, proton beam therapy may be considered as a possible alternative to enucleation for the treatment of invasive conjunctival squamous cell carcinoma, although it has serious side effects.[163]
Conjunctival Melanoma
Conjunctival melanoma is a rare ocular malignancy, with an estimated incidence of 5 cases per 1 million population annually; the incidence of melanoma is much lower in the nonwhite population, but the tumor may be seen exceedingly rarely. [164] [165] Although conjunctival malignant melanoma is a rare disease, it is life-threatening, and complete tumor excision and other treatments are mandatory to prevent local recurrence and metastasis.
Pathogenesis
Conjunctival melanoma originates from dendritic melanocytes of the basal layer of the conjunctival epithelium. It is estimated that about 20% of conjunctival melanomas arise from pre-existing nevi, another 70% develops from primary acquired melanosis (PAM), and the rest is considered to develop de novo without a pre-existing lesion.
Conjunctival melanoma refers to the development of excessive melanocytic pigmentation as either an epithelial or a subepithelial lesion. Grayish blue subepithelial lesions occur congenitally and do not become malignant. PAM usually develops in the later decades of life and may be due to simple hyperplasia of conjunctival melanocytes, or to atypical melanocytic hyperplasia, which eventually progresses to malignant acquired melanosis and melanoma.
Clinical Features
Clinically, PAM areas form unilateral, tannish brown or black, flat, localized or patchy lesions ( Fig. 71-17 ). Clinical experience indicates that approximately one third of these lesions may eventually become melanomas, but the process is slow, usually taking several decades.[166] Malignant PAM lesions appear as darkly pigmented, irregularly thickened, nodular foci, arising within pre-existing flat lesions. The rapid growth, high vascularity, spontaneous bleeding, and fixation to underlying tissues of melanomas differentiate malignant transformation from benign PAM and cyst-containing nevi. Any long-standing conjunctival nevus that suddenly changes in size, color, or overall appearance should be excised for histopathologic examination.
|
Figure 71-17 Conjunctival pigmented lesions. A, Recurrent primary acquired melanosis (PAM) (arrows). Inset: The histopathologic appearance of the atypical melanoctes in hematoxylin-eosin and Melan-A stains. B, Transition of PAM to elevated but not pigmented lesions of conjunctival melanoma (arrows). C, Pigmented conjunctival melanoma at the limbus. |
In early stages, conjunctival melanoma lesions are not deeply invasive into the underlying tissues, and surgical excision is easy. With growth of the tumor, however, fixation to underlying structures may occur, and eventually the tumor invades the lacrimal drainage system, globe, or orbit.[167] Survival time after primary diagnosis of conjunctival melanoma averages approximately 6 years, with death ensuing from postregional metastasis within a median of approximately 12 months. Regional metastasis after treatment is associated with a poor prognosis. [168] [169]
Differential Diagnosis
The significant issues in the differential diagnosis lie in distinguishing between ordinary PAM and PAM with atypia, and between a nevus and conjunctival melanoma. Other masses such as conjunctival lymphoma, carcinoma, and granulomatous lesions also are seen occasionally. In most instances, the biopsy findings are conclusive. An anterior uveal melanoma with extrascleral extension may manifest as an epibulbar pigmented tumor mass; this should not be confused with conjunctival melanoma. If the clinical findings are suggestive, a high-resolution echographic examination with A and B scans or MRI will be helpful.
Management
Current management for early conjunctival melanoma is surgical excision under frozen section control whenever possible, followed by alcohol epitheliectomy and cryotherapy to the margins of excision. With larger tumors, the surgical technique should include wider and deeper excision for melanomas on the surface of the eye. Enucleation or exenteration should be considered for tumors with ocular or orbital invasion. In patients with large tumors, the regional lymph nodes should be biopsied for staging purposes. Some histopathologic features observed in the biopsy indicate the likelihood of recurrent and disseminated tumor. These include invasive melanoma thickness more than 0.8 mm, lack of inflammatory cell response at the invasive front, five or more mitotic tumor cells per 10 high-power fields (HPFs), and involvement of orbital soft tissues with melanoma and positive lateral and deep margins of the excisional biopsy. With one or more of these findings, the patient should undergo clinical evaluation every 2 to 3 months for 1 to 2 years to detect recurrent tumor. Recurrent cases should be evaluated for regional lymph node involvement and metastatic disease.
Once the tumor extends into the orbit, local resection of the lesion is no longer feasible and exenteration may be indicated. According to some physicians, exenteration should only performed for tumors involving the fornices or extending to the eyelid skin and for tumors which do not respond to EBRT. Recent investigation of regional lymph node metastasis in conjunctival melanoma performed with sentinel lymph node mapping and biopsy indicate that preauricular lymph nodes are most commonly involved. The sentinel lymph node biopsy may be used as a piece of information in decision making for exenteration. Other clinical features reported as predictive of orbital extension of conjunctival melanoma include visual acuity of 20/200 or worse, extralimbal location, amelanotic tumors, caruncular lesions, and tumors that manifest with histopathologic invasion deeper than 1 mm. Paridaens and coworkers reported mortality rates between 33% and 50% for melanomas thicker than 1-mm invasion despite exenteration.[170] The same investigators indicated that invasion of the lymphatics, blood vessels, and sclera, as well as the incomplete excision at the time of initial treatment, indicated very poor outcomes.
Topical mitomycin treatment also shows considerable promise, particularly in the treatment of diffuse PAM with atypia. Long-term data are lacking, however. [171] [172]
Although radiotherapy has been tried on conjunctival melanomas, these tumors are not very responsive to radiation, and EBRT may lead to various complications. Proton beam irradiation can serve as an alternative therapy to exenteration in cases of conjunctival melanoma with a large, diffuse, or multilocular growth pattern.[173] In extended tumors, ocular surface toxicity can result after therapy. Some physicians suggest that brachytherapy may offer better therapeutic outcomes with these tumors.[174]
Kaposi's Sarcoma of the Conjunctiva
With the advent of the HIV/AIDS epidemic, the incidence of conjunctival or eyelid Kaposi's sarcoma has increased, with development of these tumors in approximately 10% of HIV-infected male patients.[175] This rate varies among patient populations, however. An important point is that Kaposi's sarcoma is a multifocal disease, affecting, for example, the skin, mucous membranes, lung, and gastrointestinal tract; dissemination of the lesions carries significant morbidity and mortality.
Clinical Features
Conjunctival tumors appear as flat or slightly elevated, dark reddish plaques or larger, circumscribed nodular masses ( Fig. 71-18 ). These mass lesions can cause local irritation, chemosis and lid edema, trichiasis, ptosis, and visual problems.
|
Figure 71-18 Multiple foci of skin, eyelid, and conjunctival Kaposi's sarcoma in a patient with acquired immunodeficiency syndrome. |
Pathogenesis
Current evidence suggests that Kaposi's sarcoma is not a true tumor but rather represents a dysregulation of the inflammatory response. It is associated with viral infections, and the lesion's growth depends on numerous cytokines and growth factors, including the tat gene from the HIV genome.[176]
Differential Diagnosis
Conjunctival lesions may be confused clinically with pyogenic granuloma, hemangioma, subconjunctival hemorrhage, and inflamed pinguecula or bacillary angiomatosis from Bartonella henselae infection. Eyelid lesions may be confused with melanocytic tumors.
Management
Because of their apparent location, many lesions are discovered early and can be observed without treatment. Others can be surgically removed with 1- to 2-mm margins, but recurrence is common. Cryotherapy and local injections of antimetabolites and immunomodulators such as interferon-α and human chorionic gonadotropin have been reported to be effective in some patients. If the systemic antiretroviral therapy has favorably affected the course of HIV infection with normalized CD4+ levels, the associated Kaposi's sarcoma may regress.[176]
Radiotherapy also has been used effectively to treat ophthalmic Kaposi's sarcoma, but it is associated with numerous side effects and a high recurrence rate. It has been reported that a single dose of 800 cGy is a safe and effective palliative therapy for ophthalmic Kaposi's sarcoma.[177] Conjunctival and eyelid Kaposi's sarcomas seem to be more radiosensitive when compared with these tumors in other cutaneous sites, with a higher remission rate; an approximately 95% remission rate was reported with use of single doses ranging from 10 to 20 Gy.[178]
EYELID TUMORS
Eyelid tumors originate from many tissue components, including skin, glandular structures, vascular and other mesenchymal elements, lymphoid tissue, and other types of cells. This section covers the commonly encountered malignancies, including basal cell carcinoma, squamous cell carcinoma, sebaceous gland carcinoma, and melanoma.
Basal Cell Carcinoma of the Eyelid
Basal cell carcinoma accounts for greater than 90% of malignant eyelid tumors.[179] It rarely metastasizes, but may lead to significant morbidity and mortality by invading contiguous structures around the eye and the orbit. The mortality rate from basal cell carcinoma is approximately 10%, which is due mostly to intracranial extension. The typical patient is an elderly person who has been exposed to actinic radiation. Despite its prevalence in adults, it is extremely rare in children.[180]
Pathogenesis
The factors accounting for the development of basal cell carcinoma are complex and still not completely understood. Ultraviolet light (UV) exposure is a major influence, but its relationship to clinical phenotype is not yet clear. In addition, immunosuppression has been shown to be a significant risk factor.[181] UV radiation not only induces DNA damage in epidermal cells but also interferes with the pattern of the apoptosis process in the epidermis. Excessive UV exposure can mutate the p53 tumor suppressor gene, leading to the loss of its repair function and thus creating an apoptosis resistance. If the DNA damage is not repaired or the damaged cells are not eliminated by apoptosis, the result is uncontrolled proliferation and eventual formation of basal cell carcinoma. An additional pathway has also been identified for tumor formation.[182] A number of hereditary syndromes including basal cell nevus syndrome of Gorlin-Gotz,[183] linear unilateral basal cell nevus,[184] Rombo syndrome,[185] and Bazex syndrome[186] are associated with basal cell carcinoma.
Clinical Features
The most common sites for basal cell carcinomas on the eyelids are, in order of frequency, the lower eyelid, the medial canthus, the lateral canthus, and the upper eyelid. Four main subtypes of this tumor are recognized, each with a different clinicopathologic pattern and with distinct biologic behavior: nodular (“rodent ulcer”), sclerosing (morphea-like type), superficial, and basosquamous.
The nodular subtype accounts for 75% of all tumors. This lesion usually begins as a small translucent papule. As it gets larger, it forms a zone of central necrosis and ulceration as the tumor outgrows its blood supply. The periphery of the tumor is raised with pearly margins and the vessels course over the surface.
The morphea-like, or sclerosing, subtype is a plaque-like lesion that accounts for 15% of all basal cell carcinomas and is responsible for a majority of tumors invading the orbit. It may be difficult to diagnose and delineate, because the margins are clinically indistinct. Morphea-like basal cell carcinomas are characterized by deep invasion into the deeper tissues and loss of the eyelashes. The superficial subtype may appear as a scaly area that resembles chronic dermatitis, which may be difficult to differentiate from an inflammatory lesion.
The basosquamous subtype of basal cell carcinoma, which manifests with squamous differentiation, may not be clinically distinguishable from the nodular type. Biologically, however, it behaves in a more aggressive fashion, with perineural invasion and distant metastatic potential. Long-standing basal cell carcinomas may develop necrotic changes and manifest as cysts.[187]
Orbital invasion may develop with all subtypes of basal cell carcinoma, although it is more common in the diffuse morphea-like type. Delay in diagnosis and incomplete excision of the initial tumor are critical factors in the development of orbital invasion.[188] The most common presentation of orbital basal cell carcinoma is as a mass lesion and incomitant strabismus. Perineural spread, although more commonly reported with squamous cell carcinoma, can also occur in basal cell carcinoma and should be suspected if the patient complains of burning or stinging pain, numbness, or formication.
Differential Diagnosis
Basal cell carcinoma may mimic all other types of skin tumors and inflammatory conditions, including keratoacanthoma, sebaceous gland carcinoma, amelanotic malignant melanoma and metastatic tumors, and granulomas and fungal infections of the eyelids.
Management
Complete surgical excision monitored with frozen-section control of the margins of the lesion offers the lowest tumor recurrence rate.[189] Reports from tertiary care hospitals indicate approximately 25% of initially incomplete excisions lead to recurrent tumors in approximately 5% of patients.[190]
In many cases with orbital invasion, cure is possible only with exenteration. If the patients cannot undergo or refuse exenteration, other treatment modalities including EBRT may be offered. Radiotherapy is a useful measure, although in light of the significant recurrence rate, it is not to be recommended as an effective initial treatment. EBRT also causes significant complications in the eye and eyelids[191] (Fig. 71-19 ). Brachytherapy with 125I has been reported as an alternative to exenteration and EBRT for orbital invasion by the tumor.[192] Results appear to be better for untreated tumors than for incompletely excised tumors or tumors recurring after surgery.[193]
|
Figure 71-19 Eyelid and external eye complications after radiation treatment of basal cell carcinoma. Although the tumor was successfully eradicated, conjunctiva and cornea were scarred, with neovascularization. Radiation cataract also is seen through the pupil. The lower eyelid shows loss and misdirection of the cilia secondary to irradiation. Also, the eye was extremely dry. |
Squamous Cell Carcinoma of the Eyelid
Squamous cell carcinoma is the second most common form of skin cancer. It represents less than 2% of all eyelid malignancies. [194] [195] A majority of patients (75%) with squamous cell carcinoma are older than 60 years of age. The distinct male predominance (65% versus 35%) probably represents increased occupational sunlight exposure by men rather than a genetic predisposition. It tends to occur in fair-skinned persons with a history of exposure to UV light. The incidence of developing invasive squamous cell carcinoma increases with increasing proximity to the equator.
The incidence of squamous cell carcinoma has been on the rise for the last 3 to 4 decades. The annual incidence in the United States is approximately 100 per 100,000 population; Australia has the highest incidence of SCC in the world, with an annual incidence of approximately 200 per 100,000 population.[196]
The squamous proliferations of the eyelid and periorbital skin manifest with a spectrum of premalignant lesions, carcinoma in situ and invasive squamous cell carcinoma. Premalignant lesions are defined as dysplastic epidermal changes that harbor the potential for transformation into invasive squamous cell carcinoma. These lesions include actinic (solar) keratosis, epidermal dysplasia, radiation dermatoses, and xeroderma pigmentosum.
Pathogenesis
Squamous cell carcinoma may arise from a precancerous condition or de novo. The mechanism of UV-induced photocarcinogenesis appears to involve the inactivation of the p53 tumor suppressor gene, as with basal cell carcinoma. It is a potentially fatal neoplasm that can metastasize to regional lymph nodes and also exhibit aggressive local spread. Other predisposing factors for the development of squamous cell carcinoma are Bowen disease; solar keratosis; keratoses resulting from arsenic, tar, or irradiation[23]; xeroderma pigmentosum; therapeutic ultraviolet light treatments such as psoralen plus ultraviolet A (PUVA); fair skin; immunosuppression; and chronic inflammation. [197] [198]
Clinical Features
The lower lid is the most common site for squamous cell carcinoma, accounting for approximately 60% of lesions; the upper lid is the least common site.
Carcinoma in situ and actinic solar keratosis are similar clinically, although the average size of carcinoma in situ is larger than average actinic keratosis. Carcinoma in situ manifests as erythematous scaly patches or small placoid lesions, which may or may not show increased pigmentation.[199] Actinic keratosis may occasionally manifest as a nodular lesion. Left alone, all cases of carcinoma in situ develop into invasive squamous cell carcinoma, but the exact incidence of malignant transformation in actinic keratosis is not definitely known.
Once the epidermal neoplastic proliferation violates the epidermal-dermal interface and extends into the subepidermal tissues, the tumor is known as “invasive” squamous cell carcinoma, which may manifest as plaques, large ulcerated lesions, or papillomas. Squamous cell carcinoma is the second most common malignancy of the eyelid and periorbital skin. Invasive squamous cell carcinoma usually occurs in the sun-exposed skin areas of elderly persons with lightly pigmented skin. The most common histologic subtype of invasive tumors is the well-differentiated kind. High incidence rates of peripheral nerve involvement (25%) and orbital invasion (45%) have been reported.[200] Squamous cell carcinoma of the eyelid and periorbital skin is a malignant tumor with potential of invasion into the full thickness of the lid, underlying globe, and orbit. It also may spread into regional lymph nodes and to distant viscera. Regional lymph node metastasis is detected in approximately 5% of cases at initial examination. Some studies indicate that the overall rate of regional lymph node metastasis in patients with squamous cell carcinoma of the eyelid or periocular skin may be as high as 25%.[201]
Patients with squamous cell carcinoma require long-term follow-up because of the risk of new skin cancer formation. It has been reported that new foci of nonmelanotic skin cancer developed in about 60% of the patients every 3 years. The main risk factor for new cancer formation is the number of previous skin cancers that a patient had; those who had three or more cancers were at significantly greater risk than those with fewer than three.[202]
Differential Diagnosis
Periocular squamous cell carcinoma manifests with variable clinical features ranging from plaque-like scaly lesions to nodular growths.[203] Occasionally, the tumor may be totally or partially covered by pearly keratin or may show central or peripheral ulcerations.
The wide variation in clinical appearances of squamous cell carcinoma presents great difficulty in differentiating these lesions from basal cell carcinoma; approximately 30% are clinically diagnosed as basal cell lesions at presentation.[204] Other malignancies, such as sebaceous gland carcinoma and deep fungal infections, also should be considered in the differential diagnosis for squamous cell carcinoma.
Management
Before decisions regarding specific treatment, the patient with squamous cell carcinoma should undergo careful workup to assess for orbital and ocular invasion, as well as intrasinusoidal and intracranial extension of the tumor. Consultation with a medical oncologist is in order, to rule out distant metastasis. Orbital ultrasonography and cranial CT and MRI may be very useful to determine the extent of the tumor before any treatment preferences are selected. PET and radionuclide scans and microdissection of the sentinel lymph nodes also may be helpful to determine the extent of the disease.[205]
Some physicians firmly believe that all in situ and invasive squamous cell carcinomas should be treated with surgical excision. [206] [207] [208] If surgical treatment is not feasible, radiation therapy, carbon dioxide laser, or cryotherapy may be considered alternative treatment modalities. The essence of surgical treatment is to obtain tumor-free margins either with conventional frozen-section control or using the Mohs microsurgery technique ( Fig. 71-20 ). Although the Mohs technique has been very popular lately, the rates of tumor cure it offers are not distinctly different from those achieved with conventional frozen-section monitoring. [209] [210] Five-year survival rates greater than 95% have been reported with use of Mohs microsurgical excision for primary and recurrent squamous cell carcinoma.[211]
|
Figure 71-20 A, Preoperative appereance of squamous cell carcinoma of the lower eyelid. B, The appearance of the eyelid tissue defect at the end of excision under frozen section control. Note that although the tumor appears to be innocuous, the extent of the invasion is far greater than could be appreciated on clinical examination alone. |
These surgical techniques, however, are mostly reliable with surface tumors; once the tumors extend into the orbit, both methodologies become unreliable. If the tumor extends into the underlying soft tissues and bone, it is extremely difficult to remove surgically with tumor-free margins. Squamous cell carcinoma with bone involvement also responds poorly to radiotherapy.
Squamous cell carcinoma is responsible for approximately 10% of carcinomas involving the orbit, mainly as a result of direct spread from surrounding tissues. Like orbital invasion by basal cell carcinoma, invasion by squamous cell carcinoma tends to result from a delayed diagnosis, inadequate prior treatment with surgery or irradiation, and frequent recurrences. When perineural spread has extended to the orbit and beyond to the base of the skull or the cavernous sinus, the prognosis is extremely guarded. Radical surgery may be attempted to be followed by radiation but only after extensive consultation with the patient and the family.
On the other hand, some physicians believe that radiotherapy also offers high tumor regression with good cosmesis in squamous cell carcinoma as well as in basal cell carcinoma with local control rates of 75% and 91%, respectively. Recurrent tumors after other therapies are controlled by irradiation less effectively. [212] [213] The radiation treatment techniques employed to treat squamous cell carcinoma of the lids and the underlying structures include use of superficially penetrating orthovoltage x-rays, superficially penetrating electrons, or more deeply penetrating megavoltage x-rays and implantation of radioactive sources depending on the location and the extent of the tumor. The radiation is delivered over 1 to 7 weeks, depending on the site, size, and cosmetic requirements. Irradiated skin cancers may continue to regress for weeks after the end of therapy. Desquamation with erythema and peeling of the epidermis at the treatment site commonly develops, which may be more severe in the eyelids because of the thinness of the skin.[214]
The radiation fields usually include surrounding margins of normal-appearing skin to incorporate microscopic extension of tumor. It has been reported that the extent of microscopic extension of tumor beyond the grossly visible lesion averages approximately 5 mm, and a margin of 10 mm is required to provide a 95% chance of obtaining clear resection margins. The extent of the microscopic tumor correlates well with the size of the gross lesion.[215]
The advantages of radiation treatment include relative sparing of normal tissue with good cosmetic outcome, cure rates comparable to surgical treatment, and avoidance of hospitalization and surgery in elderly, debilitated, or anticoagulated patients or those in whom medical conditions make the tumor inoperable. The potential for complications and side effects such as alopecia and more serious ocular toxicity, particularly in upper lid lesions, and rarely occurring soft tissue and bone necrosis, also should be taken into account. The risk of complications is related to tumor size. Complications develop in approximately 5% of the patients with skin lesions smaller than 1 cm, but in up to 15% of patients who have lesions larger than 5 cm.[216]
Brachytherapy has also been recently advocated for fascial squamous cell carcinomas that pose problems of surgical reconstruction with a claim to provide a high level of local control and good cosmetic results. The results were particularly better for untreated tumors than for incompletely excised tumors or tumors recurring after surgery.[217] Topical and systemic chemotherapy and immunotherapy have limited applications in advanced cases.
Sebaceous Gland Carcinoma of the Eyelid
Sebaceous gland carcinoma is a relatively rare eyelid adenocarcinoma that originates from the meibomian or Zeis glands, or both, or from the sebaceous glands in the eyebrow or carbuncle.[218] Sebaceous gland carcinoma accounts for approximately 5% of all malignant eyelid tumors. It affects mainly elderly patients in the sixth to seventh decades of life and is encountered predominantly in women; no explanation is evident for its predilection for females. It is seen more often in the upper eyelid than in the lower, probably because meibomian glands are more abundant in the upper lid.[219]
Pathogenesis
Development of sebaceous gland carcinoma has been reported in patients who underwent irradiation for facial acne, hemangioma, or eczema, regardless of their age. Moreover, eyelid sebaceous carcinoma developed in children with hereditary retinoblastoma who received EBRT in their teenage years. It has been reported recently that sebaceous gland carcinoma also may be seen in younger age groups of immunosuppressed patients.[220]
Clinical Features
The tumor initially appears as a tarsal nodule in approximately 40% of the cases and as a diffuse thickening of the eyelids in 60%. The mean duration of symptoms or signs before diagnosis is approximately 2 years. The diffuse tumors usually simulate blepharoconjunctivitis. In patients who present with a chronic inflammatory condition, sebaceous gland carcinoma often exhibits “pagetoid” spread or conjunctival intraepithelial invasion. Of those with diffuse conjunctival involvement, the superior tarsal and conjunctiva and fornix are involved in almost all cases. Direct orbital invasion occurs in about 10% to 15% of the cases ( Fig. 71-21 ). Another point to keep in mind is that sebaceous gland carcinoma may be associated with Muir-Torre syndrome, which is a rare genodermatosis of autosomal dominant inheritance associated with mutations in mismatch repair proteins, which predispose affected patients to GI and genitourinary tract malignancies.[221] Almost half of the patients with sebaceous gland carcinoma have been reported to have additional visceral neoplasms.[222]
|
Figure 71-21 Sebaceous gland carcinoma. A and C, External photograph and axial computed tomographic scan showing massive growth of the tumor anteriorly and posteriorly into the orbital soft tissues and bone. B and D, Histopathologic appearance of the tumor, with infiltration of markedly pleomorphic tumor cells with mitotic figures. In better-differentiated areas of the tumor, positive staining with oil red O is seen (D). |
Differential Diagnosis
Known as a masquerader, sebaceous gland carcinoma may mimic other benign and malignant conditions such as chronic blepharoconjunctivitis or chalazion, as well as squamous cell carcinoma, oftenresulting in delayed diagnosis, which can lead to higher morbidity and mortality. [223] [224] Sebaceous gland carcinoma should be considered in any unilateral chronic inflammatory condition of the eyelids in the elderly.
Management
Treatment should be individualized on the basis of the extent of the tumor and the specific needs of the patient.[225] If the lesion is diffuse and without a nodular component, multiple mapping biopsy specimens should be obtained and submitted for histopathologic examination, with fixation of permanent slides. Currently, the mainstay of treatment of tumors without orbital involvement has been wide local excision, with monitoring of margins with both permanent and frozen sections.[226] In a majority (75%) of the cases, the initial treatment method is surgical excision with or without cryotherapy. In cases with orbital involvement, exenteration often is warranted.
Topical antimetabolites, brachytherapy, and EBRT also are used in some cases. EBRT with an appropriate delivery system is reported to be a curative treatment for eyelid sebaceous cell carcinoma when a radiation dose greater than 55 Gy is used.[227] Moreover, brachytherapy should be considered for patients seeking an alternative to surgical excision.[228] Some sebaceous gland carcinomas present a challenge to surgical excision because of the cosmetic and functional impairment. According to some experts, interstitial radiation with 19Ir may very well be an effective alternative treatment to surgical excision.[229] Treatment complications include symblepharon formation, irregular eyelid and conjunctival scarring, and eyelid malpositions as the result of multiple surgical procedures, cryotherapy, and radiation of the eyelids and conjunctiva.
TUMORS OF THE ORBIT
A variety of tumors and pseudotumors can involve the orbit. Approximately two thirds are benign and one third are malignant. The percentage of malignant tumors increases with age because of the higher incidence of lymphoma and metastasis in the elderly.[230]
Tumors that most commonly are treated with radiation are covered in this section; for more extensive literature coverage, the reader is referred to ophthalmic oncology and orbit textbooks. [2] [4] [5] [6] [7] [231] [232] [233]
Orbital Lymphoma
Lymphoproliferative tumors are the most common primary orbital neoplasms in adults yet constitute only approximately 2% of all lymphomas.[234] Lymphoid tumors constitute approximately 10% of all orbital tumors. A majority of orbital lymphomas are of the non-Hodgkin's type and are seen mostly in adults during the fifth and the seventh decades of life.
Pathogenesis
Malignant lymphoma is diagnosed when diffusely arranged populations of immature and mitotically active lymphocytes are found in the orbit. Monoclonal populations of B cells confirmed by immunohistochemical studies, with prominent nucleoli, chromatin margination, nuclear membrane irregularities, and cellular atypia are histologic hallmarks of this disease.[235]
Different theories regarding the pathogenesis of lymphomas have been proposed. Although no specific agents have yet been identified, new trends hypothesize an infectious etiology. A possible seasonal variation for a greater incidence of lymphomas also has been suggested.[236]
A higher risk of lymphoma has been noted in patients with rheumatoid arthritis or those on anti-inflammatory drug therapy.[237] The relationship between viruses and lymphomas, particularly Epstein-Barr virus (EBV) and Hodgkin's lymphoma, has been described.[238]
Clinical Features
Orbital lymphomas usually are unilateral, with a predilection for the superior and anterior orbits, but also may be seen in both orbits. The patient usually presents with a painless proptosis of insidious onset, downward displacement of the globe, a palpable nontender orbital mass, with or without exraocular motility problems, and ptosis. Imaging studies usually confirm the presence of a mass. On CT, lymphomas appear homogeneous in texture, are isodense to muscle, and show mild enhancement with contrast. A diffuse or well-defined orbital mass with molding to the globe, optic nerve, and orbital bones strongly suggests the diagnosis of orbital lymphoma; molding usually is associated with indolent histology, whereas bone destruction is associated with aggressive histology ( Fig. 71-22 ). MRI commonly reveals intermediate signal intensity on T1- and T2-weighted images and moderate signal intensity with gadolinium enhancement.[239]
|
Figure 71-22 Lymphoma. A and B, B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type depicted on T1- and T2-weighted axial magnetic resonance images. C, Intraoperative appearance of the well-encapsulated, firm tumor located in the lateral orbit. D,The “fish flesh” gross appearance of the cut surface of the tumor. |
In the orbit, the distinction between “primary” and “secondary” orbital lymphoma is to some extent arbitrary. Primary lymphomas are considered to be limited to the orbit. Thus, by definition, “primary” orbital lymphomas are stage I. In secondary orbital lymphomas, the orbit is considered as a secondary extranodal site of involvement. In these cases, the systemic disease is either known previously or it is diagnosed at the same time as the discovery of orbital lymphoma.[240] With application of the more advanced diagnostic tools such as PET, bone marrow biopsy, and monoclonal antibodies for detecting small foci of systemic lymphoma as part of the staging workup, it appears now that the incidence of truly “primary” orbital lymphoma is lower than was suggested in the past.[241]
Lacrimal gland lymphomas, which are considered in the category of orbital lymphomas, are B-cell tumors that develop in older adults. A majority of these tumors have mucosa-associated lymphoid tissue (MALT) characteristics and carry a favorable prognosis.[242]
Accurate histopathologic evaluation is the most critical diagnostic step in the management of orbital lymphomas.[243] Ideally, the biopsy tissue should be delivered to the laboratory fresh (without preservatives) and sterile. Current laboratory workup for lymphoma includes immunohistochemistry, flow cytometry, cytogenetics, and molecular studies.[241] Approximately 85% to 90% of orbital lymphomas are categorized as diffuse, low-grade proliferations of small, monoclonal B-cell lymphocytes. The remaining 10% to 15% have follicular or nodular characteristics. Lesions displaying high mitotic activity are most likely to be associated with extraorbital, systemic disease; follicular lesions with germinal centers are more likely to be indicative of localized disease.[244] The advances in the detection of monoclonal antibodies, which identify surface antigens on lymphoid cells, led to the classification of lymphomas based on their immunophenotype. In addition, the chromosomal and molecular characteristics of lymphomas are now studied routinely and correlated with their clinical behavior. The Revised European-American Classification of Lymphoid Neoplasms (REAL) is the most recently and widely used diagnostic classification system and is based on morphology, immunophenotype, genotype, and clinical features of the lymphoma[245] ( Table 71-8 ). In this classification, lymphomas are grouped as indolent, aggressive, and highly aggressive types.[246]
Table 71-8 -- Revised European-American Classification of Lymphoid Neoplasms
|
INDOLENT LYMPHOMAS |
|
Follicular lymphoma |
|
B-CLL/small lymphocytic lymphoma |
|
Lymphoplasmacytic lymphoma |
|
Marginal zone lymphoma (nodal and/or extranodal) |
|
T/NK large cell granular lymphocyte leukemia |
|
T-CLL |
|
AGGRESSIVE LYMPHOMAS |
|
Mantle cell lymphoma |
|
Diffuse large B-cell lymphoma |
|
Peripheral T-cell lymphoma (unspecified) |
|
Peripheral T-cell lymphoma (angioimmunoblastic, angiocentric) |
|
T/NK cell, hepatosplenic, intestinal T-cell lymphoma |
|
Anaplastic large cell lymphoma |
|
HIGHLY AGGRESSIVE LYMPHOMAS |
|
Precursor T- or B-cell lymphoblastic leukemia/lymphoma |
|
Burkitt and Burkitt-like lymphoma |
|
Adult T-cell leukemia/lymphoma |
A thorough staging workup with a complete history and physical examination, including gastrointestinal endoscopy, orbital and systemic imaging, barium studies of the gastrointestinal tract, and morphologic studies, is necessary for patients with orbital lymphoma in order to recognize systemic disease.[247] PET has replaced bone and gallium scans for detecting small foci of lymphoma throughout the body because of its high sensitivity.[248] PET/CT is another new and useful tool for the diagnosis and staging of orbital lymphoma.[249] Today, the Ann Arbor Staging System most commonly is used to assign a stage for lymphomas ( Table 71-9 ).
Table 71-9 -- Ann Arbor Staging System for Lymphoma
|
Stage |
Description |
|
I |
Single lymph node region or lymphoid structure (e.g., spleen or Waldeyer ring) |
|
II |
Two or more lymph node regions on the same side of the diaphragm OR localized involvement of an extranodal lymphoid structure AND of one or more lymph node regions on same side of diaphragm |
|
III |
Lymph nodes on both sides of diaphragm ± extranodal sites |
|
IV |
Two or more extranodal sites or liver or bone marrow |
Differential Diagnosis
So long as the orbital lymphoma is associated with a conjunctival component, which presents a salmon-colored “fish flesh” appearance, the differential diagnosis is not difficult. Pure orbital tumors, however, may mimic other localized or diffuse space-occupying masses in the orbit, including some inflammatory conditions such as Graves’ disease and idiopathic orbital inflammation.
Management
Current treatment of lymphoma is based on the use of EBRT or systemic chemotherapy, or both, for the treatment of primary orbital lymphomas. [250] [251]
The therapeutic approach should be individualized for each patient based on the histologic classification and staging of the disease. Lymphomas are radiosensitive; although EBRT at a 30-Gy dose may be successful in controlling local orbital disease in a majority of patients with low-grade indolent lymphoma, intermediate-grade lymphomas are more appropriately treated with higher doses of up to 40 Gy.[252] [253] Some reports have stated that with localized mucosa-associated lymphoid tissue (MALT)-type lymphomas, excellent control and prognosis can be achieved even after lower doses (15 to 25 Gy) of radiation.[254]
Distant relapse has been observed in approximately 25% of patients with low-grade lymphoma and 50% of those with higher grade lymphomas. For orbital lymphomas, the risk of distant relapse is significant with radiotherapy alone.[255] In patients with more aggressive orbital lymphoma for which widespread systemic involvement is likely, combining systemic chemotherapy with local radiation treatment is a safer approach[256] ( Fig. 71-23 ).
|
Figure 71-23 A, Large cell lymphoma of the orbit, with involvement of the skin, underlying soft tissues, and bone. B, The invasion of bone is not a typical feature of orbital lymphoma but may be seen in long-standing cases or in more malignant types of lymphoma. |
Low-dose external beam irradiation (at a dose of 20 Gy) also is used with good results in orbital pseudotumor (idiopathic orbital inflammatory disease) as well.[257] This regimen is recommended in patients with moderate to severe active orbital inflammation but contraindicated in young and diabetic patients because of the risk of secondary malignancies and aggravation of diabetic retinopathy.[258]
In most patients, radiotherapy for primary orbital lymphoma induces minimal acute ocular toxicity, but long-term follow-up can document the usual ocular side effects, including dry eye syndrome and occasionally cataracts.[259] A cumulative dose of 16.5 Gy or higher is likely to lead to formation of lens opacities. Adequate shielding can decrease the risk of cataract formation, but shielding usually does not prevent dry eye syndrome, which frequently occurs after EBRT for orbital lymphoma. Severe radiation vasculopathy of the retina and optic nerve does not commonly occur with the typical total dose used for orbital lymphoma.
Newer approaches in radiation delivery, such as conformal therapy, promise isodose delivery to tumors with minimal ocular radiation toxicity.[260]
Chemotherapy usually is indicated for the more aggressive histologic subtypes of orbital lymphoma and may have potential for subsequent or existent disseminated disease. Combined chemotherapy and radiation therapy may be an appropriate option for intermediate- to high-grade lymphomas. The rationale for combined-modality therapy originates from observations that systemic relapse is common after EBRT alone. Relapse-free 5-year survival rates of approximately 95% for stage I lymphomas and 75% for stage II disease have been reported.[261]
Low-grade lymphomas are very sensitive to both single-agent chemotherapy, such as cyclophosphamide, and combination chemotherapy, which usually is with a doxorubicin-containing regimen such as cyclophosphamide, doxorubicin (i.e., hydroxydaunomycin), vincristine, and prednisone (CHOP) or cyclophosphamide, vincristine, doxorubicin (Adriamycin), and dexamethasone (CVAD).
Recent reports have suggested that monoclonal antibody therapy also may be effective in the treatment of low-grade non-Hodgkin's lymphomas. The availability of active monoclonal antibodies has altered the treatment paradigms for patients with non-Hodgkin's lymphomas. Many patients do not respond, however, and almost all of those who do eventually relapse and require conventional treatment. [262] [263] [264] Thus the search for more effective treatment alternatives has led to the development of radioimmunotherapy (RIT). RIT entails the administration of a monoclonal antibody in combination with a radioactive ligand.[265] Beta particles emitted by commonly used radioisotopes are tumoricidal over a distance, allowing eradication of antigen-negative tumor cells by radioactive “crossfire” from neighboring antigen-positive antibody-coated cells. This additional mechanism for tumor lysis leads to more effective treatment than is possible using the nonradioactive antibody. Monoclonal antibodies labeled with radionuclides have become an important therapeutic tool in the treatment of patients with non-Hodgkin's lymphomas. RIT is an attractive option because of the inherent radiosensitivity of most NHLs. Yttrium 90 ibritumomab tiuxetan and 131I tositumomab are two radioimmunoconjugates currently available for clinical use. Toxicities primarily include myelosuppression, with a potential risk of treatment-associated myelodysplastic syndrome and acute myelogenous leukemia. Further development of RIT may be expected to lead to a prolongation of survival for patients with non-Hodgkin's lymphoma. [266] [267]
Lacrimal Gland Tumors
The lymphomas and pseudotumors of the lacrimal gland, which are two to three times more common than its epithelial neoplasms, are discussed earlier under “Orbital Lymphoma.” Although many carcinomas, including malignant mixed tumor, acinic cell carcinoma, mucoepidermoid carcinoma, and others, develop in the lacrimal fossa, the primary epithelial malignancy of the gland is adenoid cystic carcinoma, which accounts for approximately half of the epithelial malignancies. [268] [269]
The mean age at presentation in patients with adenoid cystic carcinoma is approximately 40 years, with a range of 7 to 80 years. A bimodal peak of distribution has been noted in the fourth and the sixth decades of life.
Pathogenesis
It has been proposed that allelic loss for microsatellite markers at 1p36 may be a common and an early event in formation of adenoid cystic carcinomas.[270]
Histopathologically, adenoid cystic carcinoma manifests in five different patterns: cribriform (“Swiss cheese”), basaloid, sclerosing, comedocarcinomatous, and ductal, in order of frequency. The Swiss cheese pattern has been associated with longer survival. The basaloid pattern may be seen more frequently in patients older than 40 years and is associated with a poor prognosis.[271] Perineural invasion of the peripheral nerves frequently is observed in exenteration specimens, accounting for the symptoms of pain and numbness.
Clinical Features
Lacrimal gland carcinomas typically manifest with upper eyelid fullness and rapidly developing downward and medial displacement of the globe with diplopia. In later stages of the disease, proptosis may be associated with pain and visual loss. Adenoid cystic carcinoma extends perineurally and into adjacent bone; therefore, periorbital pain and rarely numbness are associated with this tumor.[272]
On high-resolution CT, an elongated mass is seen to extend along the lateral orbital wall, with expansion of the lacrimal fossa with bone invasion. Calcifications more commonly are seen in malignant tumors. Immediate tumor biopsy is indicated in such cases. High-resolution CT typically shows a round or irregular mass lesion extending along the lateral orbital wall with expansion of the lacrimal fossa and bony invasion ( Fig. 71-24 ). Contrast enhancement helps to reveal involvement of the dura and intracranial extension.
|
Figure 71-24 Adenoid cystic carcinoma of the lacrimal gland. Mild proptosis of the right eye is present (A), but the destruction of the bony orbit seen on the computed tomographic scans is extensive (B and C). (Courtesy of Dr. Yoon-duck Kim, Republic of South Korea.) |
MRI will reveal the tumor as hypointense on the T1-weighted images and hyperintense on the T2-weighted images with contrast enhancement. This diagnostic modality also is useful for assessing invasion by tumor into the cavernous sinus and brain.
Differential Diagnosis
Acute onset of swelling, periorbital pain, chemosis, or an erythematous indurated lid indicates an inflammatory process. CT or MRI may reveal a diffuse glandular enlargement with irregular margins, frequently demonstrating contrast enhancement and no bone changes. Most cases of bacterial dacryoadenitis resolve rapidly with appropriate systemic antibiotics. Idiopathic acute inflammation can be treated with a short course of corticosteroids. Failure to respond to treatment over a few weeks should prompt incisional biopsy, because acute and subacute inflammatory episodes may be related to an underlying carcinoma.
As mentioned, orbital lymphoproliferative lesions are another common cause of glandular enlargement. It is characterized by an insidious and painless onset in a slightly older patient and often can be bilateral. Imaging shows that most lymphoid tumors mold themselves around existing orbital structures, such as the globe and the bony orbit, without eroding bone or enlarging the orbit.
When painless swelling in the upper lid without inflammatory symptoms and signs manifests more than 12 months, benign mixed tumor (pleomorphic adenoma) should be suspected. Most patients with malignant epithelial tumors present with painful swelling in the upper eyelid in less than 1 year. Imaging of pleomorphic adenomas usually shows a rounded, well-circumscribed mass with expansion of the lacrimal fossa without invasion of overlying bone. Biopsy of pleomorphic adenoma should be avoided. If biopsy is done before excision, the 5-year recurrence rate is estimated to be 30%, and many recurrent tumors undergo malignant transformation.
Management
Surgical tumor removal with postoperative radiotherapy constitutes the most common treatment for adenoid cystic carcinoma. The surgical techniques of tumor removal include local resection, en bloc removal, exenteration, and orbitectomy. Even with very radical surgical approaches, the survival rate with this tumor does not go beyond 20% at 10 years, and the median survival period is 5 years.[273]Patients usually die of intracranial spread. Orbitectomy with bone removal may help to achieve local control in advanced cases of adenoid cystic carcinoma of the lacrimal gland, but such surgery does not decrease the risk of distant metastases.[274] The use of brachytherapy has been tried in patients with adenoid cystic carcinoma, yielding reasonably good results.[275] The long-term results are unknown, however. The preliminary data suggest that intra-arterial cytoreductive chemotherapy (IACC) is potentially effective in improving local disease control and overall disease-free survival in lacrimal gland adenoid cystic carcinoma. Intracarotid cisplatin and intravenous doxorubicin were used before and after exenteration and irradiation, with long-term survival periods of 9.5 and 7.5 years, respectively.[276]Adenoid cystic carcinoma also is known to grow slowly and to exhibit recurrence and metastasis years after the initial treatment.
Orbital Rhabdomyosarcoma
Rhabdomyosarcoma makes up approximately 5% of all cancers in the pediatric population, but it is significant in ocular oncology as the most common malignant mesenchymal orbital tumor of childhood.[277]
Orbital tumors account for about 15% of the cases of rhabdomyosarcoma; males are more often affected than females, and the mean age at diagnosis is 8 years. A confirmed or unclear history of trauma frequently is associated with the clinical presentation of the tumor.[278]
Pathogenesis
Rhabdomyosarcoma, which is considered to originate from primitive mesenchymal cells, manifests in various histopathologic forms that usually differ among age groups. These lesions appear to be separate biologic entities as well as morphologic categories, with embryonal tumors manifesting genetic lesions related to loss of heterozygosity and aberrant parental imprinting, alveolar tumors containing fusions between PAX and forkhead genes, and pleomorphic tumors showing an accumulation of genetic lesions similar to those with other adult high-grade sarcomas. [279] [280] Infants and young children tend to have embryonal tumors, adolescents and young adults tend to have alveolar tumors, and older adults tend to have pleomorphic forms, although some overlap is recognized. A fusion-positive rhabdomyosarcoma has a distinct molecular signature, which may lead to successful genetic testing for diagnosis and staging in the near future.
Clinical Features
The most characteristic presenting feature of orbital rhabdomyosarcoma is its rapid onset and progression with proptosis and displacement of the globe.[281]
Rhabdomyosarcoma should always be suspected whenever the clinical presentation is that of a rapidly progressive unilateral exophthalmos in a child ( Fig. 71-25 ). Signs and symptoms depend on the site and histologic type of the tumor. With posterior tumors, rapid development of edema of the optic disc and loss of color vision, choroidal folds, and some degree of ophthalmoplegia are characteristic. When the tumor is situated in the inferior and anterior regions of the orbit, it often causes chemosis and edema of the eyelids and motility limitation.
|
Figure 71-25 A and B, Two children with superiorly (A) and inferiorly (B) located rhabdomyosarcomas in left and right orbits, respectively. |
The histopathologic types of rhabdomyosarcoma in the orbit consist primarily of embryonal and alveolar tumors. The embryonal type is the most common; the alveolar is less common and carries the worst prognosis. [282] [283] Tumor locations within the orbit usually correlate with histologic type: Embryonal and differentiated tumor types more commonly are located in the superior and superonasal regions, whereas the alveolar type originates from the mid- and posterior orbit. CT and MRI play important roles in the preoperative evaluation to determine the location and size of the tumor and also in evaluating residual or recurrent disease on follow-up examinations. [284] [285] Intracranial and sinonasal invasion are rather uncommon at presentation, whereas changes in the adjacent bone frequently have been reported.[284] CT depicts a moderately well-delineated, homogeneous orbital mass isodense to the extraocular muscles, which often shows enhancement after contrast administration ( Fig. 71-26 ). On MRI, on T1-weighted images, the tumor may appear isointense to hyperintense with respect to the extraocular muscles and hypointense with respect to orbital fat. Proton density and T2-weighted images are not very distinct. On T1-weighted, contrast-enhanced images, rhabdomyosarcoma exhibits moderate to marked enhancement, to a degree that its highly vascular internal architecture may resembles that of a capillary hemangioma.[286]
|
Figure 71-26 Large inferomedial rhabdomyosarcoma seen on magnetic resonance imaging. A, Axial T2-weighted image; B and C, coronal T1- and T2-weighted images. |
Differential Diagnosis
Considerations in the clinical differential diagnosis for rhabdomyosarcoma include most disorders that lead to rapidly developing proptosis in childhood, including orbital cellulitis, vascular tumors, Burkitt tumor, and metastatic tumors, particularly neuroblastoma in younger patients. The differential diagnosis has become simpler than in previous years because of the use of myogenic factors in immunohistochemistry studies, nevertheless, in some cases, it may still be challenging. Diagnosis and management of orbital rhabdomyosarcoma require close collaboration among the radiologist, the ophthalmologist, and the medical and radiation oncologists.[287]
Management
No matter how typical the clinical imaging features are, the ultimate diagnosis, staging, and the management plan are based on the histopathologic diagnosis. If the tumor is located within the posterior orbit, excision biopsy or open core biopsy should be performed; fine-needle aspiration biopsy usually does not yield enough information, and findings may be misleading.[288] After the biopsy, the tumor should be staged according to the schemes of the Intergroup Rhabdomyosarcoma Study (IRS) and American Joint Commission on Cancer (AJCC). [289] [290]
Simplification of the staging system by Shields and coworkers is a practical approach that can be applied to orbital rhabdomyosarcomas. Because most orbital tumors are biopsied without attempt at resection, gross residual disease is inevitable (group III); thus, most tumors will be stage I or group III; a minority will be stage I or group I or II, and rarely a primary orbital RMS will be found to be stage IV.[278]
Current treatment for rhabdomyosarcoma consists of surgery, chemotherapy, and EBRT, based on the recommendations of the IRS. [291] [292] Some surgeons limit the therapeutic role of surgery to excisional biopsy only; others, however, perform extensive surgery to remove or debulk the tumor. The surgical approach should be planned according to the clinical and imaging findings. We recommend that tumor excision be pursued if it can be done without damaging the vital structures of the orbit. It has been shown that 4000 cGy in fractionated doses provides satisfactory tumor control.
Children with orbital rhabdomyosarcoma treated on IRS protocols have had an extremely high cure rate. The 5-year survival rate for children with alveolar tumors was 74%; infants diagnosed with an alveolar rhabdomyosarcoma die very young. The 5-year survival rate for children with embryonal tumors, on the other hand, was approximately 95%.[293] Multiple malignant neoplasms in rhabdomyosarcoma survivors has become of increasing concern over the last 2 decades or so. These tumors, which occur in higher numbers after EBRT, may be benign or malignant and usually develop in a different site from that of the primary tumor several years after treatment. [47] [294] The ongoing IRS-V study uses actinomycin D and vincristine combined with a decreased dose of EBRT (4500 cGy compared with 5000 cGy) for patients with low-risk rhabdomyosarcoma, including group III orbital disease. Further reduction in radiation complications may result from the use of three-dimensional conformal radiation therapy techniques by minimizing the inclusion of normal tissues in the treated volume.
Ocular and Orbital Histiocytosis
Histiocytic cell dysfunctions and proliferations are important to the ophthalmic oncologist because these “pseudotumors” are encountered in many ophthalmic disorders of the eye and the orbit.[295]
Pathogenesis
Histiocytes are divided into two major types: macrophages and dendritic cells. Both types are nonlymphoid mononuclear cells involved in immune and nonimmune inflammatory responses. Macrophages, which derive from the bone marrow, are tissue phagocytes that serve both antigen processing and effector functions in T cell-mediated immunity. Dendritic cells are nonphagocytic immune accessory cells that also appear to originate from the stem cells of the bone marrow.[296] Dendritic cells are further divided into Langerhans cells (LCs) and non-Langerhans cells (nLCs). Both cell types express CD1 and CD45 antigens and S-100 protein and contain high levels of adenosine triphosphatase (ATPase). The distinct feature differentiating these two cell types is the presence of an intracytoplasmic organelle called a Birbeck granule in the LC but not in the nLC; Birbeck granules can be demonstrated only with electron microscopic examination.
Clinical Features
LC histiocytoses are class I histiocytoses (histiocytosis X in old terminology), including eosinophilic granuloma, Letterer-Siwe disease, Hand-Schüller-Christian disease, and Hashimoto-Pritzker disease.[297]
Current thinking is that LC histiocytosis is a clonal, “tumor-like” proliferation with variable biologic behavior that occurs most often in children aged 1 to 3 years, with a 2:1 male predominance; LC histiocytosis is rare in adults. An increased incidence of LC histiocytosis has been reported in patients with leukemia and solid tumors. Furthermore, these tumors, particularly acute lymphoblastic leukemia (ALL), commonly are reported in patients who received treatment for LC histiocytosis with chemotherapy and irradiation. Ophthalmic manifestations, which are seen in approximately 10% of cases, occur more often in eosinophilic granuloma and Hand-Schüller-Christian disease. The latter typically manifests with the triad of orbital lesions, diabetes insipidus, and bone lesions. Eosinophilic granuloma is the localized variant of LC histiocytosis, most often involving the orbit in the superior temporal area with lytic or sclerotic bone lesions. Solitary lesions of eosinophilic granuloma manifest only in the cranium. Multifocal LC histiocytosis manifests with multiple bone lesions scattered throughout the skeleton.
Necrobiotic xanthogranuloma is another non-LC disorder that manifests with destructive skin and soft tissue lesions of the periorbital region. In approximately 50% of the patients, other ophthalmic manifestations also develop, including proptosis due to orbital masses, ptosis, lid-apposition abnormalities, scleritis, and uveitis.[298] Necrobiotic xanthogranuloma frequently is associated with immunoglobulin G (IgG) monoclonal gammopathy, hepatosplenomegaly, plasma cell dyscrasias, and, less commonly, cryoglobulinemia and lymphoproliferative tumors.
Juvenile xanthogranuloma is an infantile disease with serious ophthalmologic consequences; it currently is considered to be a neoplasm of the non-LC. This disorder manifests with small papules of the skin in the head and neck region and tends to be self-limiting.[299] When the iris and anterior chamber are involved, which occurs in less than 1% of the cases, the intraocular histiocytic nodules easily break down, leading to hyphema, secondary glaucoma, cataracts, and corneal damage. Juvenile xanthogranuloma may occur on the external eye, on the eyelids, or in the orbit as a localized mass as well.[300]
Another type of non-LC proliferation is adult-onset xanthogranuloma, which occurs as a localized or systemic disease.[301] The localized form usually involves the eyelids and the orbit and consists of dense infiltrates of histiocytes intermingled with occasional multinucleated giant cells ( Fig. 71-27 ). These lesions show CD68 immunoreactivity. In its systemic form, known as Erdheim-Chester disease, the long bones, heart, lung, brain, and other organs may be involved, with histiocytic proliferations leading to serious, sometimes fatal symptoms.[302]
|
Figure 71-27 Two patients with bilateral orbital xanthogranuloma. The patient in A had diffuse xanthomas (yellow plaque lesions) of the eyelids, which responded well to bilateral external beam irradiation, without any recurrence. The patient in B failed to respond to any kind of treatment, including surgical excision, steroid injection, irradiation, and interferon alfa-2B treatment. Orbital, eyelid, and skin lesions recurred. |
Differential Diagnosis
The differential diagnosis is based on morphologic features. The histologic pattern in LC histiocytosis consists primarily of proliferation of large histiocytes surrounded by neutrophils, eosinophils, lymphocytes, and plasma cells. Specialized cells such as mast cells and multinucleated foreign body giant cells, called Touton cells, also may be seen. Definite characterization of the cell type should be done by identification of Birbeck granules with electron microscopy. Immunohistochemical identification is not dependable because non-LC disorders also may show positivity with markers such as CD-68, HAM-66, and CV1a.[303]
Management
Because these histiocytic lesions occur in a variety of ocular and adnexal locations, the details of treatment will depend on the anatomic site. In general, however, chemotherapy with adjuvant radiotherapy is the currently preferred modality of treatment.[304] Chemotherapy protocols consisting of systemic steroids, vinca alkaloids, antimetabolites, and antifols produce a variable response and have a high morbidity. The treatment of recurrent eosinophilic granuloma is challenging.[305] Necrobiotic xanthogranuloma does not respond well to medical, surgical, or radiation therapy; topical, regional, or oral corticosteroids are of no benefit. Minimal surgery consisting of gentle débridement is recommended.
Non-LC proliferations are treated with localized or systemic steroids, excisional surgery, radiation, or chemotherapy. Localized lesions respond well to treatment; diffuse or disseminated lesions, however, are difficult to control with any form of treatment. [306] [307]
Orbital Meningioma
Orbital meningiomas may develop primarily from the meninges of the optic nerve sheath or extend into the orbit secondarily from the intracranial cavity. [308] [309]
Meningiomas usually occur in middle-aged patients, with a female-to-male ratio of 3:1, and and whites are affected more often than blacks.[309] An increased incidence of this tumor is associated with neurofibromatosis types 1 and 2 (NF-1 and NF-2); multiple meningiomas and bilateral optic nerve sheath meningiomas (ONMs) may occur in these patients, particularly those with NF-2.[310]
Meningioma usually is a benign neoplasm; a malignant histologic pattern is very rare but is known to occur with metastatic potential. The most frequent sites of metastasis are the lung and bone. Histologic grading is the most important predictor of malignancy. Some physicians suggest that, in patients with a history of relapsed meningioma, a total-body CT scan should be performed in order to assess for other possible sites of disease. [311] [312]
Pathogenesis
Meningioma originates from the meningoendothelial cells of the meninges. Loss of the NF2 tumor suppressor gene in a biallelic fashion is believed to be central to the pathogenesis of NF-2-associated and sporadic meningiomas. The mechanism includes nonsense or missense mutation in the NF2 gene and loss of the other NF2 allele as a part of chromosomal losses on 22q.[313]
Clinical Features
The primary clinical manifestation of a meningioma affecting the anterior visual pathway is painless and gradually progressive loss of visual acuity or visual field. Patients with frontal or olfactory meningiomas may exhibit mental status changes. Ocular motility impairment, with or without diplopia, may occur with extraocular muscle, orbital, or cavernous sinus involvement. Other clinical findings include loss of color perception and ipsilateral afferent pupillary defect. Optic disc edema and optic atrophy may be seen on fundus examination; the disc, however, may look normal in early cases, particularly with posteriorly located lesions. Optociliary collateral (“shunt”) vessels may be present on the optic nerve head secondary to increased choroidal and retrobulbar venous pressure.[314]
Imaging of the orbit in general shows typical but not necessarily pathognomonic features of meningioma. MRI usually is superior to CT in the evaluation of patients with meningioma; however, a CT scan may show hyperostosis of adjacent bone or foci of calcification within the lesion, which are consistent with meningioma ( Fig. 71-28 ). MRI typically shows an isointense lesion on T1-weighted images with homogeneous gadolinium enhancement.[315] ONMs have a more diagnostic radiographic appearance and may display a classic “railroad track” appearance of enhancement of the optic nerve sheath.
|
Figure 71-28 Orbital meningioma. A, The patient had minimal proptosis of the left eye with diplopia at extreme left and upper gazes. The vision was severely diminished. B, The axial computed tomography reveals the apical location of the tumor with focal calcification. C,The sagittal T1-weighted magnetic resonance image depicts extension of the tumor into the optic canal. |
Differential Diagnosis
Metastatic tumors to the optic nerve are exceedingly rare and usually can be differentiated from ONM easily because of their rapid growth. However, occasional metastatic carcinomas are known to mimic ONM owing to their initial radiologic appearance and minimal growth on serial imaging.[316]
Imaging features considered characteristic of ONM, such as the “railroad track” sign or central optic nerve lucency seen on CT, also may be seen with metastases to the optic nerve.[317] Although typically more sensitive than CT, MRI also can be inconclusive because the appearances of these two pathologic conditions on ophthalmic imaging overlap considerably. Other rare lesions that may mimic an ONM include meningoceles and arachnoid cysts. [318] [319] Arachnoid cysts are cystic lesions filled with a cerebrospinal fluid-like content within the leptomeninges. Usually they represent congenital malformations.[320]
Management
The management of symptomatic intracranial meningiomas must be individualized. The tumor usually is benign but may compress adjacent vital structures. In general, total surgical resection is attempted if the patient is a good surgical candidate, and if the surgery is technically possible. If the meningioma encases vital structures, such as a cavernous sinus or internal carotid artery, a subtotal excision may be considered. Sequential neuro-ophthalmic evaluations and neuroimaging studies are recommended to detect postoperative recurrence or progression. Postoperative irradiation may be employed for malignant or aggressive pathologic processes or for residual, recurrent, or nonresectable meningiomas.
ONMs usually do not require biopsy for diagnosis if the typical clinical and radiographic features are present; tissue diagnosis may be needed in rapidly growing tumors to rule out an aggressivehistopathologic type. Observation for progression is a reasonable first step in management. Surgical excision of ONM usually produces irreversible visual loss and generally is reserved for eyes without visual potential or cosmetically unacceptable proptosis. In patients with severe disk edema and rapid vision loss, however, surgery may serve an adjuvant role to fractionated stereotactic radiation therapy.[321] Orbital decompression by transnasal endoscopic ethmoidectomy has been reported to delay the visual loss in sphenoid wing meningiomas for some years. Some patients require additional radiotherapy for progressive tumor growth.[322] Rare patients with acute visual deterioration also may benefit from optic nerve sheath fenestration.[323]
If no tumor growth is observed, an ideal monitoring protocol is repeated MRI of the head and orbits with gadolinium and fat suppression every 6 months for 2 years and then yearly. On the other hand, if visual acuity and visual field are lost, even in the absence of tumor enlargement, most physicians would consider radiation therapy to be the treatment of choice. [324] [325] Improved techniques for delivery of radiotherapy (e.g., conformal, three-dimensional, or intensity-modulated radiotherapy) may decrease the risks of radiation side effects. Stereotactic radiotherapy currently is the most effective method for treatment of primary ONM. It provides tumor control and visual preservation with low risk of complications. [325] [326] In some patients, the visual improvement may take place early, even before completion of a standard course of radiation therapy.[327]
Turbin and coworkers offered a comparison of treatment (observation, surgery only, radiotherapy only, or surgery and radiotherapy) outcomes in 64 patients with ONM after a minimum of 50 months of follow-up. Of 59 patients with vision better than no light perception at diagnosis, 13 patients were observed only, 12 had surgery only (4 biopsies or partial resections, 8 total resections), 18 received irradiation alone, and 16 had surgery and irradiation (14 biopsies or partial resections and irradiation, 2 total resections and irradiation). Irradiated patients received 4000 to 5500 cGy of conventional multiport or conformal external beam therapy, typically fractionated over 6 weeks. Visual acuity measurements at diagnosis were not different among the four groups. Visual acuity fell significantly for the observation-only, surgery-only, and surgery plus irradiation groups. Patients with ONM receiving radiation alone had the best visual outcome during the follow-up period. The investigators recommended that fractionated external beam irradiation (at a dose of 5000 to 5500 cGy) be considered for initial treatment in adults when preservation of visual function is the therapeutic goal.[328] Other workers also reported very promising CyberKnife radiosurgery results, with high rates of tumor control and preservation of visual function in patients with these tumors. In one study in which the radiation was delivered in two to five sessions to an average tumor volume of 7.7 cm3, with a cumulative average marginal dose of 20.3 Gy, 94% of the patients retained or improved pretreatment vision.[329]
Orbital Glioma
Optic pathway gliomas, which are tumors of childhood, account for approximately 1% of all CNS tumors.[330] No sex predilection has been noted, and although these tumors can manifest at any age, most patients are less than 10 years old. The presentation of this tumor in adulthood may suggest a more malignant behavior. [331] [332]
The incidence of optic gliomas in children with NF-1 is as high as 15%, with symptomatic visual loss in approximately 20% of affected patients.[333] Any part of the optic pathway may be occupied with tumor. In approximately 25% of the cases, one or both optic nerves alone are involved; in the remaining 75%, the optic chiasm or tract contains glioma.
Pathogenesis
A majority of optic pathway gliomas are low-grade astrocytomas. The astrocytic nature of the tumor can be confirmed using immunohistochemical techniques with antibodies against glial fibrillary acidic protein (GFAP; molecular weight of 15,000). Although this protein also may be present in some schwannomas, increased GFAP expression is typical for astrocytic tumors.
Clinical Features
Gliomas that develop in the orbit produce painless proptosis, ophthalmoplegia, and progressive visual loss.[332] Visual loss is noted at presentation in approximately 90% of the patients. Optic disc swelling (35%) or atrophy (60%) generally is present, and rarely optociliary shunts may be observed. In children with NF-1 and optic pathway gliomas, the likelihood of visual loss depends on the extent and location of the tumor as determined by MRI.[334]
Hypothalamic symptoms and endocrine abnormalities may occur with chiasmal-hypothalamic tumors.[335]
On CT, the glioma manifests as a fusiform enlarged, uncalcified optic nerve mass with frequent kinking and cystic areas. MRI with gadolinium is superior to CT to display the tumor and monitor intracranial extension. The imaging typically reveals intrinsic enlargement of the optic nerve with variable contrast enhancement. On T1-weighted images, the lesion usually is isointense to the cerebral gray matter. When the tumor is large, it may show marked enhancement centrally without peripheral enhancement; this appearance is consistent with ectactic or hyperplastic arachnoid around the nerve. On T2-weighted images, fusiform lesions reveal high signal intensity, whereas large, lobulated tumors tend to have a more heterogeneous signal. A double-intensity “tubular thickening,” with kinked and elongated optic nerves, suggests, but does not confirm, a diagnosis of glioma in patients with NF-1 ( Fig. 71-29 ). Enlargement of the chiasm or the optic tracts is a sign of intracranial involvement.[336]
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Figure 71-29 Optic nerve glioma. A, Barely noticeable proptosis of the right eye in a child with long-standing optic nerve glioma. Because of the very slow growth of these tumors, proptosis is subtle in a majority of affected children. This patient also has multiple skin neurofibromas of neurofibromatosis type 1. B, Optic nerve glioma seen on axial computed tomography (CT) scan. Although the tumor is clearly seen on the CT scan, magnetic resonance imaging is preferred to monitor for extension of tumor into brain. C, Histopathologic appearance of a low-grade astrocytoma of the optic nerve. |
Differential Diagnosis
Considerations in the differential diagnosis for optic nerve glioma include idiopathic optic neuritis, sarcoidosis, demyelinating disease, and other tumors and cysts of the optic nerve and its sheath, including metastatic tumors. [337] [338] [339]
Management
A period of observation for progression prior to initiation of therapy is recommended by most authorities, because gliomas often are static or slowly growing lesions.[340] Non-NF-1 patients usually have larger and more rapidly progressive tumors. Rapidly progressive chiasmatic tumors are best treated by radiotherapy and respond well by regression.[341]
EBRT generally is reserved for patients older than 5 years of age with progressive imaging findings or worsening clinical signs and symptoms.[342] The risks of radiation are substantial and include cerebral atrophy, cerebrovascular disease, moya moya disease, subnormal intelligence or learning disabilities, and secondary primary malignancies, cataracts, radiation damage to the retina and optic nerve, endocrinopathy, and hypothalamic dysfunction. These risks generally are higher in younger patients.[343] The usefulness of surgical therapy generally is limited. An optic nerve glioma in a patient with no useful vision or that demonstrates progression may be resected. However, chiasmal, hypothalamic, or optic tract gliomas cannot be completely resected because of unacceptable ocular and CNS morbidity.
Chemotherapy frequently fails in a majority of patients but serves to delay implementation of radiotherapy or surgery until the child has progressed neuropsychologically. In infants or children younger than 3 years of age, however, chemotherapy with carboplatin and vincristine is emerging as a possibly safer alternative to EBRT. Surgical debulking does not appear to enhance chemotherapy effectiveness.[344]The prognosis of optic pathway gliomas is quite variable and is primarily based upon location; the more anterior the location, the better the prognosis. The 10-year overall survival rate is between 85% and 100%. In approximately 80% of patients with gliomas, vision stabilizes after an initial period of visual loss.[345] The natural history of the optic pathway glioma usually is more indolent in patients with NF-1 than in the others, and regressions are observed.[346] The prognosis with these tumors also is dependent on the patient's age at presentation. Those tumors that manifest before the age of 6 years have a tendency to grow fast and must be followed closely.[347]
Metastatic and Secondary Tumors
Metastatic Tumors
Systemic malignancies may metastasize to the orbit, with a frequency ranging from 2% to 10% of all orbital tumors.[348] Although almost, any human neoplasm has been reported to metastasize to the orbit, the most frequent primary tumors in adults include breast, lung, prostate, and gastrointestinal tract carcinomas and cutaneous melanoma.[349] Most orbital metastases appear as solitary nodules, rather than infiltrating tumors, and approximately 10% are bilateral. Bilateral orbital and sino-orbital disease most frequently is seen with metastasis from breast carcinoma. Approximately 50% of orbital metastatic tumors were reported to have concurrent involvement of other metastatic sites, including the eye. Patients with metastatic orbital tumors most frequently present with rapidly developing unilateral motility disturbance, painful proptosis, and occasionally, a palpable mass.[350] Imaging studies with CT and MRI provide information regarding the location of the tumor and the pattern of orbital involvement ( Fig. 71-30 ); however, they rarely offer any clues in terms of the primary site. Fine-needle aspiration biopsy is an effective method for histopathologic confirmation of orbital metastasis.[351] Carcinoid tumors in the orbit may be primary or metastatic; the latter type is reported to be a slowly growing tumor associated with long survival after surgical treatment.[352]
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Figure 71-30 Multiple orbital and brain metastases from an abdominal neuroblastoma on an axial T1-weighted image. |
In approximately 10% of metastatic orbital tumors, the site of the primary lesion is unknown; this condition is known as occult primary malignancy.[353]
In children, metastatic neoplasms to the orbit are predominantly small, round, blue-cell tumors, including neuroblastoma, Ewing sarcoma, granulocytic sarcoma, and Wilms tumor. Neuroblastoma is the most common malignant tumor in infants, with an approximate incidence of 1 per 1000 live births, and it is the most common metastatic tumor of the orbit in this age group. Neuroblastoma, which originates from primitive neuroectodermal cells, most often is diagnosed during the first year of life. On histopathologic examination it is seen to be made of round or oval, small round cells with hyperchromatic nuclei and minimal cytoplasm containing numerous mitotic figures. Differentiating neuroblasts and ganglion cells, as well as rosette formations (Homer-Wright rosettes), may be seen in primary tumors. Approximately 75% of affected children excrete increased amounts of catacholamine byproducts, including vanillyl mandelic acid (VMA), norepinephrine, homovanillic acid (HVA), and dopamine, in the urine; assays for these substances are very helpful in diagnosis.
Secondary Tumors
Tumors extending into the orbit range from congenital malformations, hamartomatous and teratomatous lesions, and reactive proliferations to most malignant neoplasms such as retinoblastoma. Secondary orbital tumors may originate from the cranial bones and CNS tissues (meningioma, pituitary adenoma, craniopharyngioma), periorbital bones (osteoma and osteogenic sarcoma, giant cell-rich reactive lesions), paranasal sinuses and nasal cavity (squamous cell carcinoma), nasolacrimal drainage apparatus (squamous cell carcinoma), globe (uveal melanoma, retinoblastoma) and conjunctivae and the eyelids (squamous cell carcinoma, basal cell carcinoma, melanoma, and sebaceous gland carcinoma).
ACKNOWLEDGMENT
This chapter is partially supported by unrestricted funds from St. Giles Foundation and Research to Prevent Blindness, Inc.
Copyright © 2008 Elsevier Inc. All rights reserved. - www.mdconsult.com
Abeloff: Abeloff's Clinical Oncology, 4th ed.
Copyright © 2008 Churchill Livingstone, An Imprint of Elsevier
REFERENCES