Introduction

Metastatic carcinoma of the eye is the most common malignant ocular neoplasm [1]. Among all cases, breast cancer is responsible for most of these metastases, making it a significant sequel [2]. Breast cancer as a cause is followed by lung carcinoma and carcinoma of an unknown primary. Gastrointestinal, genitourinary, and other carcinomas are infrequently responsible for ocular metastasis (Table 38.1) [3, 4]. Metastatic disease to the eye from the breast was first described by Johann Friedrich Horner in 1864 [5]. Since then, reports of ocular involvement have steadily increased in living patients as well as in histopathological studies on postmortem subjects. However, the true incidence of ocular metastases is underestimated because subclinical disease is frequently overlooked, especially in patients with metastatic disease in other life-threatening organs that affect the patient’s performance status [1].

Table 38.1 Primary sites for patients with ocular metastases [4]
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Because of differences in the diagnostic rate, the prevalence of ocular metastases in patients with breast carcinoma shows a large range between 10% and 38% [6, 7]. In a study of 250 patients with breast carcinoma, 38% of 152 patients with ocular symptoms and 9% of 98 asymptomatic patients had ocular metastases [7]. All asymptomatic patients had stage IV disease. Bilateral involvement is common and ranges between 20% and 40% [8]. Multifocal involvement of a single eye is also common, occurring in 20–28% of affected eyes [9, 10].

The globe itself is the anatomic structure that is the most frequently diagnosed site for ocular metastasis. In the globe, the uveal tract of the eye, which is composed of the iris, the ciliary body, and the choroidal layer with its rich vascular network, is involved in the large majority of ocular metastatic disease (Fig. 38.1) [3, 4].

Fig. 38.1
figure 1

Anatomic structures of the eye and anatomic locations of ocular metastases [4]

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The reasons for the propensity of breast carcinoma to cause ocular metastases rather than other tumors are unclear. Possible hypotheses include the ability of such cells to survive in relatively inhospitable microenvironments, the tendency to cause metastases many years after the diagnosis of the primary tumor, and the prolonged survival of many patients with metastatic disease [7, 10, 11].

Ocular metastasis from breast cancer usually occurs or is diagnosed after metastasis to other organs, primarily the lungs. At the time of ocular metastasis diagnosis, 85% of patients also have pulmonary involvement. The reported interval from breast cancer diagnosis to ocular metastasis is 2–5 years [10, 12], and the interval from the detection of non-ocular metastases to the detection of ocular metastasis is 10 months in most cases. In rare cases, ocular metastasis can be perceived as the first sign of metastatic spread in breast cancer [13] or may even be the initial symptom of breast carcinoma [14].

The expected median survival time of patients with ocular metastases is short and ranges between 4 and 12 months [15, 16]. As expected, breast cancer patients with ocular metastases survive significantly longer than patients with other primary tumors. This survival correlates with the results of modern multimodal therapy strategies for breast cancer [16, 17].

Given the increasing survival rates of cancer patients, the incidence of ocular metastasis is expected to increase. This point brings up the need for more focused attention on the importance of the patient quality of life.

Symptoms and Signs

The most common presenting symptom recorded in patients with ocular metastasis is blurred vision [18]. In contrast, either proptosis or visual loss frequently is the first complaint for most other ocular neoplasms [19]. However, this difference rarely assists the differential diagnosis.

More specific symptoms and signs may be present depending on the affected area. For example, choroidal involvement may induce blurry vision or vision field loss because these tumors cause retinal detachment, which leads to lens and iris displacement and secondary angle-closure glaucoma [20]. Optic disc metastases often produce rapid, profound visual loss. Iris metastases frequently cause secondary open-angle glaucoma when the trabecular meshwork becomes clogged with tumor cells [21]. Although some authors have stressed pain as a typical symptom for metastatic lesions, any primary malignancy that has perineural invasion and some benign processes will present with pain [22, 23].

The differential diagnosis with ocular melanoma or other ocular lesions can be made by clinical evaluation, including a previous cancer history. The standard workup includes direct ophthalmoscopy, Goldmann perimetry, and ultrasonography (USG) [3, 24]. Computed tomography (CT), magnetic resonance imaging (MRI), and single-photon emission computed tomography (SPECT) imaging are also utilized [25,26,27].

USG is useful for determining the extent of retinal detachment and outlining any underlying choroidal masses. MRI has several advantages. Most importantly, it may provide some indication regarding tissue specificity and, therefore, be helpful in distinguishing between benign and malignant lesions. MRI also provides additional information for small metastases or choroidal masses that are often missed by other modalities. Nevertheless, incorporating MRI or a CT scan of the brain as part of the initial evaluation is also essential because the risk of synchronous brain metastases for these patients is 25–30% [25, 26].

SPECT imaging with technetium-99 m-MIBI is another method that can be used if more conventional techniques fail to distinguish the nature of the lesions. It is a highly sensitive technique (92%) for detecting malignant ocular tumors [27].

The majority of intraocular tumors can be diagnosed based on clinical examination and radiographic features, which lessens the need for diagnostic ophthalmic fine-needle aspiration biopsy (FNAB). In general, the diagnostic precision of ophthalmic FNAB is high but still limited because cellularity can confound the results. Furthermore, surgical biopsy may cause a significant risk of visual loss or other ocular morbidity and presents a significant risk of seeding along the biopsy track [28].

Treatment

If ocular metastasis is detected early enough, it can be treated effectively to prevent vision loss and therefore to maintain quality of life [3]. The short-term prognosis for vision is usually good, but the systemic prognosis is poor. Treatment requires an individualized approach in which both the tumor and patient characteristics are considered. Tumor characteristics include the size, extent, and location of the tumor; the number of tumors; the laterality of involvement; and the effects on normal intraocular tissues. Patient characteristics involve the visual status of the affected eye or eyes, the visual status of the contralateral eye in unilateral cases, the extent of primary disease, and the age and general health of the patient [29].

Treatment requires a multidisciplinary approach with close communication between the patient’s ophthalmologist, medical oncologist, radiation oncologist, and neuroradiologist. Indications for treatment of uveal metastases include visual symptoms attributable to the lesion (e.g., blurred vision, scotoma, flashes, floaters, and dysmorphopsia), lesions close to the optic nerve or macula with signs of active disease, enlargement despite systemic chemotherapy, and painful lesions [30].

Since its first application in 1979, radiotherapy (RT) has become a well-established and widely available treatment for uveal metastases [31]. RT can be applied as a conventional external beam RT (EBRT), plaque brachytherapy, stereotactic body RT (SBRT), or proton beam. Other local therapies include intravitreal injection, laser therapy, and cryotherapy.

Though timely treatment with RT typically anticipates a higher probability for better vision and organ preservation, some patients with hormone-sensitive lesions may benefit from chemotherapy (CT) or hormone therapy (HT) [32]. Manquez et al. [33] found choroidal metastasis regression with aromatase inhibitor treatment in 10 of 17 patients with hormone receptor-positive breast cancer over a mean follow-up of 20 months.

In patients who are already on CT or HT when the metastatic carcinoma of the eye is detected, a regimen change may be recommended. An appropriate drug regimen often produces satisfactory regression of all tumors and preservation or recovery of useful vision in the affected eye or eyes [34].

Because the choroid is the most common site of ocular metastasis and has a vascular structure, anti-vascular endothelial growth factor (anti-VEGF) has been tested as part of the treatment in several case reports. Preliminary results support the use of anti-VEGF [35, 36], emphasizing the ease of administration and the minimal time commitment required. However, there are still many uncertainties, such as the optimal dose, the interval and number of injections, the indications for use, and maintenance therapy.

Surgical resection can be reserved for a minority of carefully chosen patients [34]. Resection may be indicated particularly when the metastases cause pain or proptosis and if RT, CT, or management approaches fail to relieve symptoms [37].

The optimal therapy for asymptomatic ocular metastases is controversial. Data in the literature regarding the treatment of asymptomatic metastasis are rare, and the best time for treatment initiation is arguable. A careful “watchful waiting” strategy and systemic CT in patients with breast cancer seem reasonable [22, 23, 38].

Radiotherapy Doses

RT is effective in relieving symptoms and controlling tumor growth. Though the reported series address the application of different techniques and doses, more current protocols suggest a total dose of 30–40 Gy, delivered in fractionated doses of 2–5 Gy [23, 39].

Doses of less than 30 Gy are less effective. Maor et al. reported that none of the nine patients in their study who received 30 Gy in ten fractions had tumor regrowth after therapy, but two of ten patients treated with 25 Gy in ten fractions had tumor regrowth [40]. In another series reported by Reddy et al. [41], 30% of tumors did not respond to treatment with doses of 21–30 Gy. Importantly, for most patients, the benefit in vision produced by RT lasted for the remainder of their lives.

Rudoler et al. [8] reported the results of the largest series of 188 patients with 233 ocular metastases over a 23-year time period. A wide range of doses, from 4 to 63 Gy, were used, but most (72%) patients were treated with 30–40 Gy total doses in 2–3 Gy fraction sizes. Their results showed an improvement or stabilization of visual acuity in 57% of all patients.

One of the most recent reports evaluating a more uniform treatment was presented by Wiegel et al. [22, 23]. They evaluated 65 eyes that were treated with a total dose of 40 Gy in 20 fractions that was applied with asymmetric fields, resulting in increased visual acuity for 36% of the patients. This was thought to correspond with the finding that doses higher than 30 Gy were strongly correlated with better or more stable visual acuity because almost 90% of the patients showed an increase or stabilization during their lifetime.

However, doses higher than 40 Gy are not used because of the possible increase in side effects.

A total of 15–20% of patients with unilateral metastasis develop symptomatic contralateral metastasis later. Additionally [22, 23, 42, 43], a unilateral field for unilateral choroidal metastasis without sparing the contralateral choroid is an effective technique in destroying possible contralateral micrometastasis and may lower the risk of late side effects compared with bilateral fields.

Radiotherapy Techniques

Most metastatic carcinomas are responsive to RT delivered by the external beam (EB) or plaque methods. These tumors generally show rapid regression after RT, and vision in the eye is frequently stabilized, if not improved [32].

EBRT is particularly applicable to patients with large tumors that involve the optic nerve or macula and either cause substantial visual disturbance or affect multiple areas in both eyes. Unilateral RT with a lateral electron portal of sufficient energy is adequate to treat most ocular metastases. The anterior border should be placed just behind the anterior chamber of the eye, and a posterior tilt should be utilized to avoid the lens. For bilateral metastases, posteriorly tilted opposing photon fields may be an option [44, 45].

Furthermore, single small-to-medium-sized tumors can occasionally be treated effectively by radioactive plaque therapy. This treatment consists of suturing a radioactive device (plaque) to the sclera directly overlying the intraocular tumor. The plaque is left in place for several days, generally until a radiation dose of 40–50 Gy has been delivered to the apex of the tumor, and then, the plaque is removed [46, 47].

Considering the risk of ocular toxicity, other techniques, such as stereotactic body radiotherapy (SBRT) [48] or proton beam therapy (PBT) [49], that promise less toxicity or shorter treatment times are applied to choroidal metastases.

Although SBRT has not been used to a great extent to treat choroidal metastases, evidence supporting its use is mounting. SBRT can deliver precisely targeted radiation in fewer high-dose treatments than conventional therapeutic techniques, thus preserving healthy tissue [48]. Reports have shown reduction of recurrence and high local control rates.

PBT, because of its physical characteristics, allows for more focused irradiation, with less scatter to nearby tissues (49) Tsina et al. showed regression of choroidal metastases in 84% and stability of the lesion in 14% of eyes treated with PBT over a mean follow-up period of 5 months. The average dosage administered was 28 Gy delivered over two treatments.

Side Effects

The rate of severe late side effects after EBRT is low. Approximately 30–50% of the patients died after 5–7 months; therefore, late side effects did not appear [50]. Referring to data from Wills Eye Hospital [32], patients who live significantly longer seem to have more late side effects, as expected. The small number of side effects, however, did not allow multivariate analysis of possible risk factors.

Radiation-induced ocular side effects have been well described. Thus far, cataracts, keratopathy, retinopathy, neovascularization of the iris, and optic neuropathy have been described [51]. Mild skin erythema and conjunctivitis occur frequently. Cataracts are particularly common in patients with irradiation of anterior segment metastases.

The retinal vasculature may also be damaged by RT [52]. Clinical manifestations are typically delayed in onset for a median of approximately 8 months after treatment and are progressive. The incidence of radiation-induced retinopathy and papillopathy is 8%. The severity of retinopathy does not correlate with the RT dose and may occur with doses as low as 50 cGy.

In particular, a significant influence of additional chemotherapy on retinopathy could not be demonstrated.

Course and Outcome

If untreated, most ocular metastases are progressive [22, 23]. They tend to grow faster when compared with primary malignant intraocular neoplasms. If the patient survives long enough, many of the untreated metastatic carcinomas ultimately yield to blindness and pain. Factors used to predict the potential for the preservation or recovery of vision in the affected eye or eyes include the number and size of tumors, their locations relative to the optic disc and fovea, the severity of their effects on the retina and other ocular tissues, and their response to treatment. Moreover, the treatment response is also dependent on the site of the primary tumor and its pathological features.

Ocular metastases do not affect overall survival because the eye is not a vital structure. The prognosis for a patient’s survival is dependent on the presence and extent of metastatic tumors in vital organs.

Conclusion

As the survival time of breast cancer patients increases, the incidence of ocular metastasis is expected to rise. With the new therapeutic regimes used in the modern treatment of breast cancer, the range of ocular and visual problems that may be observed will undoubtedly increase. Both ophthalmologists and oncologists should be aware of the range of disorders that may be directly or indirectly caused by breast cancer, not only for the palliation of symptoms but also because the first signs of breast cancer may present as eye symptoms in some cases. Early diagnosis may positively affect the long-term prognosis for patients.

Physicians who treat patients with breast cancer should maintain a high degree of suspicion of ocular metastases. Because patients with breast cancer often have prolonged survival after the diagnosis of ocular metastases, early diagnosis and treatment of this lesion is a primary concern to maximize their quality of life [10].