METASTATIC CHOROIDAL TUMORS

Signs and Symptoms

Metastatic tumors of the choroid may present with an assortment of signs and symptoms. Commonly, patients complain of visual symptoms such as blurred vision, scotoma or metamorphopsia.1 Patients may also report photopsia, floaters, visual field defects, red eye and even pain in some cases.1,2 Less commonly, patients may be entirely asymptomatic.1

Ophthalmoscopically, choroidal metastases appear as mild to moderately elevated placoid or oval lesions. They are typically creamy yellow in appearance with variable mottling, although the color may vary from white to orange depending upon the tumor’s origin.1,2 These lesions characteristically display irregular brown pigment deposits overlying the mass, which gives them a unique leopard skin appearance; the pigment spots have been shown histologically to represent macrophages containing lipofuscin.3 Choroidal metastases are often multilobular, multifocal and bilateral.1,2,4,5 These characteristics are in contradistinction to primary choroidal melanomas, which are almost invariably isolated and unilateral in presentation. Choroidal metastases have a predilection for the posterior pole, and frequently present with associated subretinal fluid and serous retinal detachment.1,4

Choroidal metastases may be en-coun-ter-ed at virtually any age, although the mean age at the time of diagnosis is 55.1 Patients with breast cancer tend to be diagnosed earlier (mean age of 48), while those with lung cancer are somewhat older (mean age of 61).1 There is no known racial predilection. The literature recognizes women to be more commonly affected than men.6 Patients typically have a concurrent history of cancer, although on occasion the diagnosis of ocular metastasis actually precedes the discovery of a systemic malignancy.4,7,8

Pathophysiology

Metastasis is the process by which malignant cells disseminate throughout the body from one organ system to another. It is a complex mechanism that occurs via vascular and lymphatic channels throughout the body. The choroid, which is particularly well vascularized, is the most common site of ocular metastasis.1,2,4 Embolic tumor cells reach the uvea by traveling through the internal carotid artery, the ophthalmic artery and the posterior ciliary arteries until they arrive at the choriocapillaris. The process of metastasis is not random; chemokines guide the tumor cells, targeting certain organ systems and tissues over others.9

A number of specific tumor types have been associated with choroidal spread. The most common of these by far is breast carcinoma, accounting for 40% to 47% of all uveal metastases.1,2,4,10 The second most common primary tumor site is the lung (21% to 29%), followed by the gastrointestinal tract (4%), kidney (2% to 4%), prostate (2%) and skin (2%).10 Metastasis to the eye has been reported for carcinomas of the pancreas, thyroid, testes, ovaries and urothelial tract, as well as carcinoid tumors.2,6,10,11 In roughly 17% of intraocular metastases, the primary tumor site remains unknown.6,10

Management

Differentiating choroidal metastases from other malignant and nonmalignant conditions is the first step of proper management. The most common differential diagnoses when considering metastasis include amelanotic choroidal melanoma or nevus, choroidal hemangioma, lymphoma, choroidal osteoma, disciform macular scarring, posterior scleritis, congenital hypertrophy of the retinal pigment epithelium (CHRPE) and rhegmatogenous retinal detachment.

While the majority of diagnoses are made by direct clinical inspection, ancillary testing is often helpful for confirmation. Historically, the most frequently used modalities have included fluorescein angiography and ultrasonography. Angiography of choroidal metastases characteristically demonstrates hypofluorescence during the arterial and early venous phases, with hyperfluorescence in the late venous phase, associated with persistent pinpoint leakage.1 This fluorescein pattern is not entirely diagnostic however, as other entities (e.g., choroidal hemangioma or melanoma) may demonstrate similar features.2,6 On ultrasound evaluation, choroidal metastases show medium to high internal reflectivity with A-scan and appear echo-dense on B-scan, with a significantly lower height-to-base ratio compared to melanomas.10 Ultrasonography can also help demonstrate shallow serous detachments which may not be discernable with ophthalmoscopy alone.

Newer methods of differentiating choroidal metastases include fundus autofluorescence (FAF) and optical coherence tomography (OCT). FAF shows hypoautofluorescence of the tumor, with overlying areas of bright hyperautofluorescence correlating to the deposits of lipofuscin; hyperautofluorescence of subretinal fluid can also be seen.10,12 OCT often demonstrates an “undulating” retinal surface overlying the mass, with areas of hyperintense irregularities in the photoreceptor layer.10 The RPE displays thickening, and overlying subretinal fluid may be evident.13 Additional diagnostic modalities may include indocyanine green angiography, magnetic resonance imaging and fine needle aspiration biopsy.2,10

Treatment for choroidal metastases depends on the degree of tumor activity, location and laterality of the tumor, extent of ocular or visual symptoms and the patient’s overall health status. For patients who are terminally ill with disseminated metastases and poor constitutional health, palliative therapy with observation is usually preferred.7,10 More aggressive treatment is indicated if the metastasis is threatening to vision or the overall health of the globe, or if the tumor continues to grow despite concomitant systemic chemotherapy.2,7

Therapeutic options for choroidal metastases are diverse; for multifocal or bilateral lesions, systemic chemotherapy, immunotherapy, hormone therapy or whole eye radiotherapy are recommended.10 For solitary lesions, external beam radiotherapy, proton beam radiotherapy and plaque brachytherapy are the most common first-line options.1,10,14,15

A variety of other treatments have been used and continue to be explored in the management of choroidal metastasis, including laser photocoagulation, transpupillary thermotherapy, gamma knife radiosurgery, photodynamic therapy and anti-VEGF injections.1,2,5-7,10,14-22 Enucleation, which is employed much more readily for a variety of other ocular malignancies, is generally reserved for those cases of choroidal metastasis associated with severe vision loss and intractable pain associated with secondary glaucoma.2,6,10,14

Despite numerous treatment options, ocular metastasis carries an exceedingly poor systemic prognosis. Life expectancy for these patients is generally less than five years; the mean survival time after diagnosis of metastatic breast carcinoma to the choroid is 21 months, while for lung carcinoma the mean survival time after diagnosis is 12 months.4,23,24 In general, patients with breast, lung, thyroid or carcinoid tumors seem to have a longer survival rate than those with metastases from the pancreas, kidney, gastrointestinal tract or cutaneous melanoma.6 However, survival times are quite variable. Given the unfortunate outlook, quality of life should be a key consideration when advising patients who are considering any invasive therapeutic options.

Clinical Pearls

Metastatic lesions are considered to be the most common type of intraocular malignant tumor in adults. Since these patients are frequently terminally ill and usually have concurrent metastases to other organ systems, the diagnosis is often made in an alternate setting, such as tertiary care centers, hospitals, nursing homes or even on autopsy studies.

While the choroid is the most common site of ocular metastasis, numerous other tissues can be involved, including the eyelids, iris, ciliary body, retina, optic nerve and even the vitreous. Anterior segment metastases account for less than 15% of reported cases.

Perhaps more important than treating the choroidal lesions associated with ocular metastasis is ensuring that the primary neoplasm is properly addressed, especially if the patient presents without a prior diagnosis of cancer.

An immediate referral to an ocular oncologist in all suspicious cases is warranted. Unfortunately, ocular oncologists are relatively few in number. The Eye Cancer Network (www.eyecancer.com) can assist in searching over 200 specialists in more than 50 countries around the world.

1. Jardel P, Sauerwein W, Olivier T, et al. Management of choroidal metastases. Cancer Treat Rev. 2014;40(10):1119-28.

2. Paul Chan RV, Young LH. Treatment options for metastatic tumors to the choroid. Semin Ophthalmol. 2005;20(4):207-16.

3. Stephens RF, Shields JA. Diagnosis and management of cancer metastatic to the uvea: a study of 70 cases. Ophthalmology. 1979;86(7):1336-49.

4. Demirci H, Shields CL, Chao AN, Shields JA. Uveal metastasis from breast cancer in 264 patients. Am J Ophthalmol. 2003;136(2):264-71.

5. Konstantinidis L, Rospond-Kubiak I, Zeolite I, et al. Management of patients with uveal metastases at the Liverpool Ocular Oncology Centre. Br J Ophthalmol. 2014;98(1):92-8.

6. Ou JI, Wheeler SM, O’Brien JM. Posterior pole tumor update. Ophthalmol Clin North Am. 2002;15(4):489-501.

7. Amer R, Pe’er J, Chowers I, Anteby I. Treatment options in the management of choroidal metastases. Ophthalmologica. 2004;218(6):372-7.

8. Salah S, Khader J, Yousef Y, et al. Choroidal metastases as the sole initial presentation of metastatic lung cancer: case report and review of literature. Nepal J Ophthalmol. 2012;4(2):339-42.

9. Ben-Baruch A. Organ selectivity in metastasis: regulation by chemokines and their receptors. Clin Exp Metastasis. 2008;25(4):345-56.

10. Arepalli S, Kaliki S, Shields CL. Choroidal metastases: Origin, features, and therapy. Indian J Ophthalmol. 2015;63(2):122-7.

11. Haddow J, Muthapati D, Arshad I, et al. Multiple bilateral choroidal metastasis from anal melanoma. Int J Clin Oncol. 2007;12(4):303-4.

12. Almeida A, Kaliki S, Shields CL. Autofluorescence of intraocular tumours. Curr Opin Ophthalmol. 2013;24(3):222-32.

13. Iuliano L, Scotti F, Gagliardi M, et al. SD-OCT patterns of the different stages of choroidal metastases. Ophthalmic Surg Lasers Imaging. 2012;43:e30-4.

14. Kanthan GL, Jayamohan J, Yip D, Conway RM. Management of metastatic carcinoma of the uveal tract: an evidence-based analysis. Clin Experiment Ophthalmol. 2007;35(6):553-65.

15. Tsina EK, Lane AM, Zacks DN, et al. Treatment of metastatic tumors of the choroid with proton beam irradiation. Ophthalmology. 2005;112(2):337-43.

16. Chen CJ, McCoy AN, Brahmer J, Handa JT. Emerging treatments for choroidal metastases. Surv Ophthalmol. 2011;56(6):511-21.

17. Lee SJ, Kim SY, Kim SD. A case of diode laser photocoagulation in the treatment of choroidal metastasis of breast carcinoma. Korean J Ophthalmol. 2008;22(3):187-9.

18. Romanowska-Dixon B, Kowal J, Pogrzebielski A, Markiewicz A. Transpupillary thermotherapy (TTT) for intraocular metastases in choroid. Klin Oczna. 2011;113(4-6):132-5.

19. Lally DR, Duker JS, Mignano JE, et al. Regression of choroidal metastasis from breast carcinoma treated with gamma knife radiosurgery. JAMA Ophthalmol. 2014;132(10):1248-9.

20. Kaliki S, Shields CL, Al-Dahmash SA, et al. Photodynamic therapy for choroidal metastasis in 8 cases. Ophthalmology. 2012;119(6):1218-22.

21. Augustine H, Munro M, Adatia F, et al. Treatment of ocular metastasis with anti-VEGF: a literature review and case report. Can J Ophthalmol. 2014;49(5):458-63.

22. Kim M, Kim CH, Koh HJ, et al. Intravitreal bevacizumab for the treatment of choroidal metastasis. Acta Ophthalmol. 2014;92(1):e80-2.

23. 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):352-7.

24. Wickremasinghe S, Dansingani KK, Tranos P, et al. Ocular presentations of breast cancer. Acta Ophthalmol Scand. 2007;85(2):133-42.