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  • 2020–2021 BCSC Basic and Clinical Science Course™

    Go to Academy Store Learn more and Purchase.

    4 Ophthalmic Pathology and Intraocular Tumors

    Part II: Intraocular Tumors: Clinical Aspects

    Chapter 20: Ocular Involvement in Systemic Malignancies

    Secondary Tumors of the Eye

    Metastatic Carcinoma

    Since the first report in 1872 of a metastatic tumor in the eye of a patient with carcinoma, ocular metastases have been described as the most common intraocular tumor in adults. However, they may not be the lesions that are most commonly seen by ophthalmologists, as much of the data regarding the incidence of these tumors are derived not from clinical studies but from evaluation of the eyes at the time of autopsy. As long-term survival rates for patients with primary systemic malignancies continue to improve and the incidence of intraocular and orbital metastatic disease increases, so will the need for prompt recognition and appropriate diagnostic and therapeutic management by the ophthalmologist.

    Metastases to the eye are being diagnosed with increasing frequency for various reasons, including

    • increased incidence of certain tumor types that metastasize to the eye (eg, breast, lung)

    • prolonged survival of patients with certain cancer types (eg, breast cancer)

    • increased awareness among medical oncologists and ophthalmologists of the pattern of metastatic disease

    • Ferry AP, Font RL. Carcinoma metastatic to the eye and orbit: I. A clinicopathologic study of 227 cases. Arch Ophthalmol. 1974;92(4):276–286.

    Mechanism of metastasis to the eye

    The most common mechanism of intraocular metastasis is the hematogenous dissemination of tumor cells. The anatomy of the arterial blood supply to the eye dictates the location of tumor cell deposits within the eye. The posterior choroid, with its rich vascular supply, is the most common site of intraocular metastases; it is affected 10–20 times as frequently as the iris or ciliary body. The retina and optic nerve head, which are supplied by the single central retinal artery, are rarely the sole site of involvement. Bilateral ocular involvement has been reported in approximately 25% of cases of metastatic disease, and multifocal involvement is frequently seen within an eye. Many patients with ocular metastases also have concurrent central nervous system (CNS) (Fig 20-1) and other metastases. Ocular metastatic lesions are sometimes found before a primary tumor is detected; this is most often seen with lung adenocarcinoma.

    Primary tumor sites

    The medical literature contains many reports of ocular metastases representing a wide variety of primary tumor types. Most metastatic solid tumors to the eye are carcinomas from various organs. In a survey of 520 eyes with uveal metastases, the most common primary tumors to metastasize to the eye were breast (47%), lung (21%), and gastrointestinal tract (4%). In females, the breast is the most common primary tumor site; in males, the lung. In contrast, cutaneous melanoma is rarely described as metastasizing to the eye. Table 20-1 shows the most common primary tumors that metastasize to the choroid.

    Clinical features and diagnosis

    The clinical features of intraocular metastases depend on the location within the eye and are discussed in the following sections. Metastatic tumors can be mistaken for other ocular lesions, including primary tumors. The steps involved in making an accurate diagnosis include taking a thorough medical history, performing a careful ocular examination, and using ancillary ophthalmic tests. The selection of ancillary ophthalmic testing is determined by the location of the tumor(s). Review of patient medical records, including previous pathology reports, may be necessary to determine the origin of metastatic tumors. In a minority of cases, biopsy of the lesion may be needed to make the diagnosis of metastatic tumor rather than primary intraocular tumor. When the ocular diagnosis is unclear, the clinician should consider referral to an ocular oncologist as this specialist has extensive experience in the diagnosis and management of ocular metastatic tumors.

    Figure 20-1 Axial T2-weighted magnetic resonance images of central nervous system (CNS) metastases. A, Metastatic intraocular tumor in the left eye (arrow).B, Concurrent left cerebellar mass with surrounding edema (arrow).

    (Courtesy of Dan S. Gombos, MD.)

    Table 20-1 Primary Solid Tumors That Metastasize to the Uveal Tract (in Decreasing Order of Frequency)

    Anterior segment: iris and ciliary body Metastases to the iris and ciliary body usually appear as gray-white to tan-pink gelatinous nodules (Figs 20-2, 20-3, 20-4). Metastases to the anterior uvea may include the following clinical features:

    • iridocyclitis (sometimes before the tumor becomes clinically evident)

    • secondary glaucoma

    • iris neovascularization (rubeosis iridis)

    • hyphema

    • irregular pupil

    • pseudohypopyon

    Anterior segment tumors are best evaluated with slit-lamp biomicroscopy coupled with gonioscopy. High-frequency ultrasonography (eg, ultrasound biomicroscopy) may quantify tumor size and anatomical relationships.

    Posterior segment: choroid, retina, and optic nerve With tumors in the posterior pole, patients commonly report painless loss of vision. Indirect ophthalmoscopy may reveal an exudative retinal detachment associated with a placoid or “lumpy bumpy” amelanotic tumor mass (Figs 20-5, 20-6, 20-7). These lesions are usually minimally elevated and ill defined, often amelanotic, gray, yellow, or off-white, with secondary alterations at the level of the retinal pigment epithelium (RPE) presenting as clumps of brown pigment (“leopard spots”; Fig 20-8).

    Figure 20-2 Metastatic tumor in the iris with associated hyphema (arrow).

    Figure 20-3 Metastasis from breast carcinoma to the iris. Note the 2 gray-white lesions on the iris surface.

    (Courtesy of Timothy G. Murray, MD.)

    Figure 20-4 Metastatic cutaneous melanoma to the iris. Note the 2 lesions located peripherally and lacking pigmentation.

    Figure 20-5 Multiple metastatic lesions in the choroid. Note the pale-yellow color, “lumpy bumpy” configuration, and shallow subretinal fluid (arrowheads).

    Figure 20-6 Choroidal metastases. A, Metastatic lesion to the choroid inferiorly, associated with bullous retinal detachment (asterisks).B, Subtle metastatic lesion to the choroid (arrows) in the macula, associated with serous effusion.

    The mushroom configuration seen in primary choroidal melanoma from invasion through Bruch membrane is rarely present in uveal metastases. The retina overlying the metastasis may appear opaque and often can detach because of the accumulation of subretinal fluid. Rapid tumor growth with necrosis and uveitis are occasionally seen. Dilated epibulbar vessels may be seen in the quadrant overlying the metastasis. For a differential diagnosis of choroidal metastasis, see Table 20-2.

    Although fluorescein angiography may be helpful in defining the margins of a metastatic tumor, it is typically less useful in differentiating a primary intraocular neoplasm from a metastasis. The double circulation pattern from an intrinsic intratumoral blood supply and prominent early choroidal filling often seen in choroidal melanomas are rarely found in metastatic tumors because of their rapid growth (ie, versus slow growth in choroidal melanomas, which allows for the development of an intratumoral vascular supply).

    Ultrasonography (echography) is diagnostically valuable in patients with choroidal lesions. In the setting of a metastatic tumor, B-scan ultrasonography shows an echogenic choroidal mass with an ill-defined, sometimes lobulated or lumpy bumpy outline (see Fig 20-7C). Overlying secondary exudative retinal detachment is commonly detected. A-scan ultrasonography demonstrates irregular and generally high reflectivity.

    Figure 20-7 Metastatic breast carcinoma to the choroid before and after external beam radiotherapy. A, Clinical photograph of metastatic breast carcinoma to the choroid. Note the yellowish choroidal lesion (between arrowheads) with focal retinal striae (arrow) and pigmentary change (asterisk).B, After radiation, note the yellowish focal drusenoid lesions (asterisks) and resolution of the retinal striae in the macular region. C, B-scan ultrasonography shows the choroidal mass demonstrated in part A with shallow exudative retinal detachment (arrow).D, B-scan ultrasonography shows reduction in the size of the choroidal mass after radiation therapy and resolution of the exudative retinal detachment corresponding to part B. Classically, metastatic lesions show high internal reflectivity on A-scan ultrasonography.

    (Courtesy of Dan S. Gombos, MD.)

    Enhanced depth imaging optical coherence tomography (EDI-OCT) may demonstrate a lumpy bumpy contour, choriocapillaris compression, and photoreceptor loss in the overlying retina.

    Metastases to the optic nerve may produce edema of the optic nerve head, decreased vision, and visual field defects. Because metastases may involve the parenchyma or the optic nerve sheath, magnetic resonance imaging (MRI) and ultrasonography may be valuable in detecting the presence of additional lesions and identifying their location.

    Metastases to the retina, which are quite rare, appear as white noncohesive lesions, often distributed in a perivascular location suggestive of cotton-wool spots (Fig 20-9). Because of secondary vitreous seeding of tumor cells, these metastases sometimes resemble retinitis rather than a tumor. Vitreous aspirates for cytologic studies may confirm the diagnosis (see Fig 20-9C).

    Figure 20-8 Clinical fundus photograph of metastatic breast carcinoma to the choroid. Note the amelanotic infiltrative choroidal mass with secondary overlying retinal pigment epithelial changes accounting for the characteristic leopard spots.

    (Courtesy of Matthew W. Wilson, MD.)

    Table 20-2 Differential Diagnosis of Choroidal Metastasis

    Other diagnostic factors

    One of the most important diagnostic factors in the evaluation of suspected ocular metastatic tumors is a history of systemic malignancy (see the section “Primary tumor sites”). At the time the ocular metastasis is diagnosed, most patients have a known systemic malignancy, although the interval between the diagnosis of the primary tumor and that of the ocular metastasis can be many years. For example, in a study of 264 patients with uveal metastases from breast cancer, greater than 90% of patients had a history of treatment before the development of ocular involvement. The ocular metastasis was the initial manifestation of the breast cancer in only 3% of patients, but the eye was the first site of metastatic disease in 16% of patients in this study, many of whom had been in remission for years.

    For some patients, however, often there is no history of systemic malignancy. Various studies have shown that in patients in whom an ocular metastatic lesion(s) was diagnosed, the ocular lesion was the first manifestation of cancer in about 30% of cases; that is, 30% of patients with an ocular metastatic lesion have an unknown primary tumor at the time of the ocular diagnosis. This is especially true of patients with ocular metastasis from lung cancer. A study of 194 patients with uveal metastases from lung carcinoma demonstrated that diagnosis of the uveal metastasis preceded the diagnosis of primary lung cancer in nearly half of the patients (44%). Thus, any patient with an amelanotic fundus mass suspected of being a metastatic focus should be referred for a thorough systemic evaluation, including imaging of the breast, chest, abdomen, and pelvis. Suspicious lesions identified on systemic evaluation often require biopsy before further management can be determined.

    Figure 20-9 Metastatic lung carcinoma to the retina. A, Metastatic lung carcinoma involving the macula. Vision was reduced to finger counting. B, Same eye, showing the characteristic perivascular distribution of metastases. C, Vitreous aspirate from the same eye, showing clumping of tumor cells that is characteristic of carcinoma.

    Fine-needle aspiration biopsy (FNAB) of the choroidal lesion may be helpful in rare cases when the diagnosis cannot be established by noninvasive procedures. Although metastatic tumors may recapitulate the histology of the primary tumor, they are often less differentiated. For this reason, special histochemical and immunohistochemical stains facilitate the diagnosis of metastatic tumors. It may not always be possible to narrow the differential to just one primary tumor type, but FNAB with appropriate special studies may reduce the list to a few likely primary sites. FNAB may be helpful even when the primary cancer is known. For example, breast cancer may demonstrate a change in receptor status during metastatic spread that warrants biopsy of new metastatic disease and often changes the therapeutic options for the patient. Communication between the patient’s ophthalmologist and medical oncologist is paramount throughout the diagnostic workup.

    • Demirci H, Shields CL, Chao AN, Shields JA. Uveal metastasis from breast cancer in 264 patients. Am J Ophthalmol. 2003;136(2):264–271.

    • Shah SU, Mashayekhi A, Shields CL, et al. Uveal metastasis from lung cancer: clinical features, treatment, and outcome in 194 patients. Ophthalmology. 2014;121(1):352–357.

    • Shields CL, Shields JA, Gross NE, Schwartz GP, Lally SE. Survey of 520 eyes with uveal metastases. Ophthalmology. 1997;104(8):1265–1276.

    Prognosis

    The diagnosis of an ocular metastasis is typically associated with a poor prognosis for survival because widespread dissemination of the primary tumor has usually occurred. In one report, survival time after the diagnosis of metastasis to the uvea ranged from 1 to 67 months, depending on the primary cancer type. Overall, the average survival of patients with ocular metastases is less than 1 year. Although the overall survival rate for women with breast cancer has improved, patients with breast carcinoma metastatic to the uvea have historically survived an average of 9–13 months after the metastasis was detected. The 5-year survival rate in patients with metastatic ocular disease in the setting of breast cancer is approximately 25% across studies. Shorter survival time is typically seen in patients with ocular metastases from lung carcinoma, with about half of patients deceased at 1 year.

    Treatment

    The goal in ophthalmologic management of ocular metastases is preservation or restoration of vision whenever possible and palliation of pain. Radical surgical procedures and treatments with risks that exceed the desired benefits should be carefully considered in the context of the patient’s overall health status. All treatment should be coordinated with the patient’s primary oncologists and should reflect the goals of the care plan.

    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 decision-making process. 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, confirmed after careful workup and systemic imaging, local therapeutic modalities may be sufficient, allowing conservation of visual function with minimal systemic morbidity.

    In patients with susceptible tumors, chemotherapy or hormonal therapy may induce a prompt response in the ocular lesion as well. In such patients, no additional ocular treatment may be indicated. However, when vision is endangered by choroidal metastases in spite of systemic therapy, additional forms of local therapy, such as external beam radiotherapy, brachytherapy, photodynamic therapy, or transpupillary thermotherapy, may be indicated. Radiotherapy is frequently associated with rapid improvement of the patient’s symptoms, along with 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; ocular surface irritation and dry eye are expected and should be aggressively treated, as they can cause significant discomfort. Sometimes, enucleation is performed because of severe, unrelenting pain.

    • Cohen VML. Ocular metastases. Eye (Lond). 2013;27(2):137–141.

    • Jardel P, Sauerwein W, Olivier T, et al. Management of choroidal metastases. Cancer Treat Rev. 2014;40(10):1119–1128.

    Excerpted from BCSC 2020-2021 series: Section 4 - Ophthalmic Pathology and Intraocular Tumors. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.

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