Retinal Metastases

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Chapter 133 Retinal Metastases

Sunil K. Srivastava, Chris Bergstrom

Introduction

Retinal metastases represent a small percentage of intraocular malignancy secondary to systemic cancers, even though 10% of patients who die of cancer have been found to have intraocular metastases.¹^–⁴ While relatively rare, the diagnosis of retinal metastases can be challenging, as its presentation can mimic other etiologies. High clinical suspicion and use of appropriate diagnostic techniques are vital in order to successfully diagnose and manage these challenging cases. This chapter provides a review of the literature of this rare clinical entity and management recommendations.

Metastatic cascade

Metastases are responsible for most cancer deaths.⁵ The understanding of metastases is limited due to the “hidden” nature of this process, as it occurs inside the body and is difficult to observe.⁵ Although many tumor cells are shed daily into the bloodstream or lymphatic system in those with cancer, the evidence is unclear on the fate of these tumor cells.^6,⁷ Some models suggest that the majority do not survive in the circulation, while others suggest that most can survive and extravasate.^5,^6,⁸^–¹⁰ For tumor metastasis to develop, a series of biological steps must be completed for a tumor cell to grow at a different site.^5,^6,¹⁰^–¹⁵

Dissociation, invasion, and intravasation

For tumor cells to invade the circulation, they must dissociate from the primary tumor.^5,^6,¹⁰^–¹⁴ On a molecular level, the dissociation is initiated by an array of motility factors^11,¹² and requires modulation of the expression of cadherins and integrins.^5,^6,¹³^–¹⁶ Degradation of the extracellular matrix by proteolytic enzymes (primarily matrix metalloproteases and the plasminogen activator system) facilitates invasion of the surrounding connective tissue components.^5,^6,^13,^15,¹⁷^–²³ Metalloproteases also modulate cell adhesion in their local environment and help release growth factors from their stores.^18,^19,²¹ Then, tumor cells must penetrate the basement membranes of endothelial cells to enter the blood and lymphatic circulation.^5,^6,¹⁵ This step again requires well-coordinated proteolysis, as well as mechanical deformation and locomotion of the tumor cells.^5,^6,^14,¹⁵ If this complex interaction is regulated successfully, certain populations of cells can break through the matrix and endothelium to reach the blood stream.

Hematogenous dissemination

Because intraocular structures have no lymphatic supply, metastatic cancer cells can gain access to the eye only by hematogenous routes. From the aorta, tumor cells enter the internal carotid artery directly on the left and indirectly through the innominate artery on the right. After passing through the internal carotid artery, tumor cells reach the eye through the ophthalmic artery. The ophthalmic artery gives rise to 10–20 short posterior ciliary arteries supplying the posterior uvea, two long ciliary arteries supplying the anterior uvea, and the central retinal artery supplying the inner half of the retina and the optic disc.

The destination within the eye of circulating tumor cells may depend on several factors. Tumor size, vascular circulatory patterns and organ-specific factors which encourage tumor growth (so-called seed and soil factors) all may play a role in the location of metastases.^5,^6,¹⁵ Reese emphasized that, although tumor emboli are more prominent in the uvea, more than 90% of infectious emboli involve the retina.²⁴ Because large emboli (e.g., tumor emboli) travel along the vessel wall in the slower-moving part of the blood stream, they are more likely to enter vessel branches, such as the short ciliary arteries. Small emboli (e.g., bacterial emboli) travel in the central, faster-moving part of the blood stream towards the terminal vessels, such as the central retinal artery.²⁵ The marked vascularity of the posterior choroid relative to that of the retina (as noted above) could also contribute to more frequent choroidal involvement as metastatic tumors to the retina and optic disc, supplied by the central retinal artery, are rare.^3,⁴

Extravasation and angiogenesis

Although circulation patterns and tumor size may play a role in implantation, metastatic growth may require organ-specific factors which facilitate tumor cell survival.^5,^15,^16,²⁶^–²⁸ Animal models of metastases support the role of both vascular flow patterns and organ compatibility factors in the development of metastases.^5,²⁹^–³¹ Tumor cell anchorage at a target organ site depends on shear-resistant attachment to local endothelium. Various integrins and selectins have been identified which appear to mediate such specialized tumor cell adhesion under dynamic flow conditions.^5,^16,^32,³³

The delivery of the tumor cell to the site of metastasis depends on mechanical flow, but the growth or survival can depend on organ specific molecular interactions. These interactions can encourage tumor cell growth via expression of growth factors, and altering the gene expression of tumor cells.^5,^6,³⁴^–³⁷ Expression of specific chemokine receptors by tumor cells may also target tumor cells to specific organs which express the specific ligands for these receptors.^5,^15,³⁸^–⁴¹ This match could lead to chemokine signal activation of genes which would encourage tumor cell growth.^5,¹⁵ Specific interactions unique to retinal metastasis to this point have not been identified.

After the colony at the secondary site is established, angiogenesis will again play a key role in the continued growth of the tumor. The onset of angiogenesis involves an alteration in the balance between positive and negative regulators. In vivo experiments with human tumor cell lines have shown that both vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (FGF) have direct roles in tumor-associated angiogenesis,⁴² and FGF-2 also are the two major angiogenic factors in the retina and increased expression of both has been identified in retinal tumors.⁴³^–⁴⁷ VEGF not only regulates tumor-associated angiogenesis in response to local hypoxia and various cytokines, but may regulate breakdown of the blood–ocular barrier in ocular melanoma and other tumors.^43,⁴⁷^–⁵⁰ FGF-2 is a potent mitogen of choriocapillary endothelial cells, and FGF acts synergistically with VEGF to stimulate tumor angiogenesis.^44,⁵¹^–⁵³

Review of case reports

As noted above, retinal metastasis represents a small percentage of intraocular metastasis. Thus, no large single-center review has been published detailing outcomes associated with retinal metastasis. Publications in the literature have been limited to case reports.⁵⁴^–⁸⁸ The first was published in 1934 and was diagnosed at autopsy.⁵⁴ Until 1979, the diagnosis of retinal metastasis was made either by enucleation or at autopsy. Since 1979, diagnosis of retinal metastasis has been made via biopsy including vitreous, chorioretinal, retinal biopsies, clinical inspection or surgical removal.⁶³ Although the case reports reviewed provide detail in presentation and treatment of retinal metastases, follow-up is limited for many of the publications. The clinical appearance, symptoms and outcomes from published case reports will be reviewed below and are displayed in Table 133.1.

Table 133.1 Retinal metastases: case reports

Demographics

A total of 37 cases of isolated retinal metastasis have been reported (with or without vitreous involvement). Of those 37 cases, there were 23 females and 14 males. The average age at diagnosis of retinal metastases was 52 years (range 26–81). The primary tumor sites included 16 cases of cutaneous melanoma, eight cases from the gastrointestinal tract, seven cases of lung carcinoma, five cases of breast carcinoma, one case from the genitourinary tract, and two cases of unknown primary malignancy.

Clinical findings

Symptoms

The most common visual complaint among those with retinal metastases is decreased or blurred vision (Table 133.1). Floaters are also a common complaint. Other symptoms include pain, diplopia, and red eye. Some cases presented without any specific visual symptoms.^54,^58,⁶⁵ The underlying primary source of the metastases did not have a bearing on the type of visual symptom reported by the patient.

Signs

The clinical appearance of retinal metastases can vary based on the primary tumor and level of invasion of the tumor. Metastatic melanoma typically presents as a pigmented lesion within the retina with irregular borders and flat appearance (Fig. 133.1). Carcinomas tend to be non-pigmented, white or yellow in appearance and vary in size (Fig. 133.2). Some metastatic carcinomas can appear with significant mass and an elevated appearance with surrounding subretinal fluid.

Fig. 133.1 Cutaneous melanoma metastatic to the retina. Note the extensive exudates and scattered hemorrhages that accompany the gray-white retinal lesion.

(Reproduced with permission from de Bustros S, Augsburger JJ, Shields JA, et al. Intraocular metastases from cutaneous malignant melanoma. Arch Ophthalmol 1985;103:937–40. ©1985 American Medical Association. All rights reserved.)

Fig. 133.2 Small cell lung carcinoma metastatic to the retina. (A) At the macula, perivascular retina infiltrates are seen. (B) Nasal to the nerve, multiple retinal lesions are seen of varying size. Scattered intraretinal hemorrhages are also seen.

(Courtesy of Daniel F. Martin, Rishi P. Singh, and Careen Y. Lowder.)

Intraretinal hemorrhage and exudates have been described in association with these lesions (Figs. 133.3, 133.4). Subretinal hemorrhage has also been described as a presenting feature of metastatic carcinoma.⁸⁵ Perivascular infiltrates can also be seen in some cases (Fig. 133.2). Retinal hemorrhages and exudates are thought to occur secondary to damage to the retinal microvasculature. Additionally, subretinal fluid has been described in several cases of retinal metastases. The appearance of subretinal fluid or exudative retinal detachment warrants an evaluation for a choroidal lesion.