The goal in ophthalmic management of ocular metastases is preservation or restoration of vision and palliation of pain. Radical surgical procedures and treatments with risks greater than the desired benefits should be avoided.
Treatment
Indications for treatment include decreased vision, pain, diplopia, and severe ocular proptosis. The patient’s age and health status and the condition of the fellow eye are also critical in the decisionmaking process. The treatment modality in patients with metastatic ocular disease should be individually tailored. When ocular metastases are concurrent with widespread metastatic disease, systemic chemotherapy alone or in combination with local therapy is reasonable. In patients manifesting metastases in the eye alone, local therapy modalities may be sufficient, allowing conservation of visual function with minimal systemic morbidity.
Chemotherapy or hormonal therapy for sensitive tumors (eg, breast cancer) may induce a prompt response. In such patients, no additional ocular treatment may be indicated. However, when vision is endangered by choroidal metastases in spite of chemotherapy, additional modalities of local therapy such as external-beam radiation, brachytherapy, laser photocoagulation, or transpupillary thermotherapy may be necessary. Radiotherapy is frequently associated with rapid improvement of the patient’s symptoms, along with rapid resolution of exudative retinal detachment and, often, direct reduction in tumor size. Possible adverse effects of the radiation include cataract, radiation retinopathy, and radiation optic neuropathy. Rarely, enucleation is performed because of severe, unrelenting pain.
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Shields CL, Shields JA, Gross NE, Schwartz GP, Lally SE. Survey of 520 eyes with uveal metastases. Ophthalmology. 1997;104(8):1265–1276.
Shields JA, Shields CL, Brotman HK, Carvalho C, Perez N, Eagle RC Jr. Cancer metastatic to the orbit: the 2000 Robert M. Curts lecture. Ophthal Plast Reconstr Surg. 2001;17(5):346–354.
Direct Intraocular Extension
Direct extension of extraocular tumors into the eye is rare. Intraocular extension occurs most commonly with conjunctival squamous cell carcinoma and less frequently with conjunctival melanoma and basal cell carcinoma of the eyelid. The sclera is usually an effective barrier against intraocular invasion. Only a small minority of carcinomas of the conjunctiva ever successfully penetrate the globe, but those that do are often variants of squamous cell carcinoma: mucoepidermoid carcinoma or spindle cell variant. These more aggressive neoplasms usually recur several times after local excision before they invade the eye.
Lymphomatous Tumors
Intraocular lymphomas may arise in different parts of the eye, expressing various clinical manifestations. Primary intraocular lymphoma (also known as large cell lymphoma, vitreoretinal lymphoma, or retinal lymphoma), is the most common and most aggressive type of lymphoma involving the eye and is usually associated with primary central nervous system lymphoma (PCNSL). In these cases, the vitreous and retina are involved. Less frequently, the eye can be involved in
systemic/visceral/nodal lymphoma. In these cases, the uveal tract is more commonly involved, usually in a pattern of metastatic disease. In advanced cases, the intraocular findings of the 2 types may overlap. In recent decades, the incidence of PCNSL has increased significantly in both immunocompetent and immunocompromised persons.
Primary Intraocular Lymphoma
Clinical evaluation
Ocular signs and symptoms may occur before CNS findings. In such cases, the disease may masquerade as a nonspecific uveitis. The onset of bilateral posterior uveitis in patients older than 50 years is suggestive of large cell lymphoma, as is “chronic” uveitis in patients in their fifth to seventh decades. Although 30% of patients present with unilateral involvement, delayed involvement of the second eye occurs in approximately 85% of patients.
Diffuse vitreous cells may be associated with deep subretinal yellow-white infiltrates (Fig 20-9). Often, fine details of the retina are obscured by the density of the vitritis (“headlight in the fog”). Retinal vasculitis and/or vascular occlusion may be observed. The RPE may reveal characteristic clumping overlying the subretinal/sub-RPE infiltrates (see Fig 10-14 and the discussion of histologic findings in Chapter 10). Anterior chamber reaction may be minimal.
Photographic and fluorescein angiographic studies document baseline clinical findings but are rarely helpful in defining a differential diagnosis. Ultrasonographic examination may reveal discrete nodular or placoid infiltration of the subretinal space, associated retinal detachment, and vitreous syneresis with increased reflectivity. Clinical history and neurologic evaluation may reveal neurologic deficits in up to 10% of patients, and 60% of patients show concomitant CNS involvement at the time of presentation. If the diagnosis is suspected, neurologic consultation coupled with CT or MRI studies and lumbar puncture should be coordinated with diagnostic vitrectomy.
Figure 20-9 Fundus picture of a patient with vitreoretinal lymphoma. Note the vitreous haze, optic disc involvement, and peripapillary subretinal infiltrates. (Courtesy of Jacob Pe’er, MD.)
Pathologic studies
Diagnostic confirmation of ocular involvement requires sampling of the vitreous and, when appropriate, the subretinal space. Coordinated planning with the ophthalmic pathologist prior to surgery regarding sample handling is important. The ophthalmic pathologist should be skilled in the handling of small-volume intraocular specimens and experienced in the evaluation of vitreous samples.
The best approach to pathologic evaluation of the specimen remains controversial. Diagnostic pars plana vitrectomy is indicated to obtain an undiluted or diluted vitreous specimen. If a subretinal nodule is accessible in a region of the retina unlikely to compromise visual function, subretinal
aspiration of the lesion can be performed. A single-vitrectomy biopsy may not be adequate, and a second biopsy may be required. Evaluation of the vitreous and subretinal specimen may be performed using cytopathology (see Chapter 10, Fig 10-15), including immunohistochemical studies for subclassification of the cells, flow cytometry, and polymerase chain reaction/fluorescence in situ hybridization (PCR/FISH) analysis for gene rearrangements and the ratio of interleukin-10 (IL-10) to IL-6 (see Chapters 3, 4, and 10).
Preferably, a pathologist familiar with the diagnosis of intraocular large cell lymphoma should evaluate the specimen. If an adequate specimen is obtained, multiple pathologic approaches may be employed. Cytologic evaluation is essential in establishing the diagnosis, with flow cytometry, PCR, and cytokine levels (IL-10/IL-6) serving as ancillary studies. Specimens that reveal malignant lymphocytic cells establish the diagnosis (Fig 20-10), and evaluation of cell surface markers may allow for subclassification of the tumor.
Treatment
Because the blood–ocular barriers may limit penetration of chemotherapeutic agents into the eye, irradiation of the affected eye using fractionated external-beam radiation has remained popular in some centers for treatment of intraocular lymphoma. However, although radiotherapy may induce an ocular remission, the tumor invariably recurs, and further irradiation places the patient at high risk for irreversible vision loss caused by radiation retinopathy. Radiotherapy to the eye is often given with systemic or intrathecal chemotherapy. Some centers use systemic chemotherapy alone, mainly high-dose methotrexate, for the treatment of vitreoretinal lymphoma. However, studies have shown that drug penetration into the retina and vitreous is limited with systemic administration, and recurrence is common. Because of concern about the disadvantages of ocular irradiation and systemic chemotherapy, several groups use intraocular chemotherapy, injecting methotrexate into the vitreous, with very good responses and low recurrence rates. Recently, intravitreal injections of rituximab have been used experimentally. Parallel to the treatment of the intraocular disease, the CNS and/or systemic lymphoma should be treated by a medical oncologist.