tumors measuring less than 18 mm in base and less than 10 mm in thickness [52]. The benefit of plaque brachytherapy is the speed of treatment, as it only takes 2–4 days to deliver the dose. This is important for patients whose life expectancy is limited because it occupies less time of their remaining days than other methods of radiotherapy [52].

Following radiotherapy, choroidal metastases decrease in tumor thickness on ultrasonography, and secondary retinal detachment resolves, often with improved visual acuity. Rudoler and associates found that external beam radiotherapy provides globe preservation in 98% of patients, with visual improvement or vision better than 20/200 in 57% of patients [50, 51]. Ocular radiation complications were found in 12% of patients. Newer methods of radiotherapy such as gamma knife and cyberknife radiotherapy have been employed to successfully treat metastasis over a short time period.

Surgical Excision, Enucleation

In some instances, enucleation or local surgical excision of an intraocular metastasis may be justified. Uncontrollable, large tumors occasionally require enucleation for intractable pain caused by secondary glaucoma. However, chemotherapy or radiotherapy, rather than enucleation, should generally be considered first. Local excision of a tumor that has metastasized to the eyelid, conjunctiva, orbit, and occasionally the intraocular structures is justified in certain instances [53, 54]. This technique is useful for both diagnostic and therapeutic reasons.

Patient Prognosis

In general, the life prognosis is poor for patients with metastatic tumors to the ocular structures [11, 25]. Patients with breast carcinoma metastatic to the uvea have a mean survival of 18 months, which is better survival compared to patients with metastases from lung cancer (mean, 6 months) or cutaneous melanoma (mean,

1 month) [11]. Data collected from our department showed Kaplan-Meier survival estimates for patients with uveal metastasis from breast cancer to be 65% at 1 year, 34% at 3 years, and 24% at 5 years [25].

Controversies and Perspective

The main controversies regarding intraocular metastasis center around establishing the diagnosis and providing the best therapy to the patient with quality of life in mind. If a patient has known primary malignancy with multifocal metastasis systemically, then the diagnosis of a choroidal metastasis can be presumed by the history without the need for further intraocular biopsy. If the patient has known primary malignancy with no metastatic disease, then it is advisable to establish the diagnosis with systemic evaluation to look for other involved sites. If negative, then fine-needle aspiration biopsy of the mass should be performed. If the patient has no known primary cancer, then the ocular diagnosis should be established with fine-needle aspiration biopsy as simulating conditions like amelanotic melanoma and nevus, scleritis, and others can cloud the picture.

Regarding therapy, the clinician should choose the most effective method with the understanding that quality of life is perhaps the most important issue. The therapy should cure the ocular malignancy and provide the best visual acuity to allow good quality of life. Minimizing physician monitoring is also important. Our preference is to first treat the ocular metastasis with systemic therapy if the general oncologist agrees as there could be subclinical disease elsewhere. If, on the other hand, there is no need for systemic therapy, then we would use localized ocular therapy with external or plaque radiotherapy or even photodynamic therapy to the eye to control the cancer and regain visual acuity. We usually prefer plaque over external radiotherapy as plaque is faster and controls the disease over a 4-day period compared to external radiotherapy that takes 4 weeks. This is important when considering the guarded life prognosis.

Pearls

•Intraocular metastasis develops most commonly in the posterior choroid.

•Less commonly, intraocular metastasis is found in the retina, optic disk, and vitreous.

•The most important primary cancer sites include breast, lung, kidney, and gastrointestinal tract.

•The malignancy appears classically as a yellow choroidal mass producing serous retinal detachment.

•Diagnostic confirmation can be made with trans-pars plana fine-needle aspiration biopsy.

•Therapy generally involves systemic chemotherapy or local radiotherapy, and the globe is usually retained, often with intermediate or good visual acuity.

•Life prognosis is guarded with mean survival for some malignancies like lung cancer and skin melanoma at less than 1 year and breast cancer mean survival at 4 years or more.

References

1. Jemal A, Thun MJ, Ries LA, Howe HL, Weir HK, Center MM, Ward E, Wu XC, Eheman C, Anderson R, Ajani UA, Kohler B, Edwards BK. Annual report to the nation on the status of cancer, 1975–2005, featuring trends in lung cancer, tobacco use, and tobacco control. J Natl Cancer Inst. 2008;100:1672–94.

2. Shields CL, Shields JA, Gross NE, et al. Survey of 520 eyes with uveal metastases. Ophthalmology. 1997;104:1265–76.

3. Duke-Elder S. System of ophthalmology, Diseases of the uveal tract, vol. 9. St. Louis: CV Mosby; 1966. p. 917.

4. Hart WM. Metastatic carcinoma to the eye and orbit. Int Ophthalmol Clin. 1962;212:465–82.

5. Albert DM, Rubenstein RA, Scheie HG. Tumors metastasis to the eye. I. Incidence in 213 adult patients with generalized malignancy. Am J Ophthalmol. 1967;63:723–6.

6. Jensen OA. Metastatic tumors of the eye and orbit. A histopathological analysis of a Danish series. Acta Pathol Microbiol Scand Suppl. 1970;212:201–14.

7. Bloch RS, Gartner S. The incidence of ocular metastatic carcinoma. Arch Ophthalmol. 1971;85:673–5.

8. Ferry AP, Font RL. Carcinoma metastatic to the eye and orbit. I. A clinicopathologic study of 227 cases. Arch Ophthalmol. 1974;92:276–86.

9.Stephens RF, Shields JA. Diagnosis and management of cancer metastatic to the uvea: a study of 70 cases. Ophthalmology. 1979;86:1336–49.

10.Nelson CC, Hertzberg BS, Klintworth GK. A histopathologic study of 716 unselected eyes in patients with cancer at the time of death. Am J Ophthalmol. 1983;95:788–93.

11.Freedman MI, Folk JC. Metastatic tumors to the eye and orbit. Patient survival and clinical characteristics. Arch Ophthalmol. 1987;105:1215–9.

12.Eliassi-Rad B, Albert DM, Green WR. Frequency of ocular metastases in patients dying of cancer in eye bank populations. Br J Ophthalmol. 1996;80: 125–8.

13.Shields JA, Shields CL, Singh AD. Metastatic neoplasms in the optic disc: the 1999 Bjerrum Lecture: part 2. Arch Ophthalmol. 2000;118:217–24.

14.Bullock JD, Yanes B. Ophthalmic manifestations of metastatic breast cancer. Ophthalmology. 1980;87: 961–73.

15.Merrill CF, Kaufman DI, Dimitrov NV. Breast cancer metastatic to the eye is a common entity. Cancer. 1991;68:623–7.

16.Mewis L, Young SE. Breast carcinoma metastatic to the choroid. Analysis of 67 patients. Ophthalmology. 1982;89:147–51.

17.Demirci H, Shields CL, Chao A, Shields JA. Uveal metastasis from breast cancer in 264 patients. Am J Ophthalmol. 2003;136:264–71.

18. Amichetti M, Caffo O, Minatel E, et al. Ocular metastases from breast carcinoma: a multicentric retrospective study. Oncol Rep. 2000;7:761–5.

19.Wickremasinghe S, Dansingani KK, Tranos P, Liyanage S, Jones A, Davey C. Ocular presentations of breast cancer. Acta Ophthalmol Scand. 2007;85: 133–42.

20.Tamura M, Tada T, Tsuji H, Tamura M, Yoshimoto M, Takahashi K, Tada K, Tanabe M, Kutomi G, Sekine Y, Kasumi F. Clinical study on the metastasis to the eyes from breast cancer. Breast Cancer. 2004;11:65–8.

21.De Potter P, Shields CL, Shields JA, Tardio DJ. Uveal metastasis from prostate carcinoma. Cancer. 1993;71:2791–6.

22.Font RL, Naumann G, Zimmerman LE. Primary malignant melanoma of the skin metastatic to the eye and orbit. Report of ten cases and review of literature. Am J Ophthalmol. 1967;63:438–554.

23.Fishman ML, Tomaszewski MM, Kuwabara T. Malignant melanoma of the skin metastatic to the eye. Frequency in autopsy series. Arch Ophthalmol. 1976;94:1309–11.

24.Debustros S, Augsburger JJ, Shields JA, et al. Intraocular metastases from cutaneous malignant melanoma. Arch Ophthalmol. 1985;103:937–40.

25.Zografos L, Ducrey N, Beati D, Schalenbourg A, Spahn B, Balmer A, Othenin-Girard CB, Chamot L, Egger E. Metastatic melanoma in the eye and orbit. Ophthalmology. 2003;110:2245–56.

26.Harbour JW, De Potter P, Shields CL, Shields JA. Uveal metastasis from carcinoid tumor: clinical

observations in nine cases. Ophthalmology. 1994;101: 1084–90.

27.Shields JA, Shields CL. Metastatic tumors to the intraocular structures. Intraocular tumors: a text and atlas. Philadelphia: Saunders; 1992. p. 207–38.

28.Shields JA, Shields CL. Metastatic tumors to the uvea, retina, and optic disc. Intraocular tumors. An atlas and textbook. Philadelphia: Williams & Wilkins; 2008. p. 197–228.

29.Shields JA, Shields CL, Kiratli H, DePotter P.

Metastatic tumors to the iris in 40 patients. Am J Ophthalmol. 1995;119:422–40.

30.Kamby C, Ejlertsen B, Andersen J, et al. The pattern of metastases in human breast cancer. Influence of systemic adjuvant therapy and impact on survival. Acta Oncologica. 1988;27:715–9.

31.O’Brien J, Wieland M, Filer R. Breast cancer metastatic to the choroid in a male patient. Retina. 2000;2:214–6.

32.Lam A, Shields CL, Shields JA. Uveal metastases from breast cancer in three male patients. Ophthalmic Surg Lasers Imaging. 2006;37:320–3.

33.Soysal HG. Metastatic tumors of the uvea in 38 eyes. Can J Ophthalmol. 2007;42:832–5.

34.Shields JA, Shields CL. Posterior uveal melanoma: clinical and pathologic features. In: Intraocular tumors: a text and atlas. Philadelphia: Saunders; 1992. p. 117–36.

35.Michelson JB, Stephens RF, Shields JA. Clinical conditions mistaken for metastatic cancer to the choroid. Ann Ophthalmol. 1979;11:149–53.

36.Shields CL, Honavar SG, Shields JA, et al. Circumscribed choroidal hemangioma. Clinical manifestations and factors predictive of visual outcome in 200 consecutive cases. Ophthalmology. 2001;108: 2237–48.

37.Shields CL, Shields JA,Augsburger JJ. Review of choroidal osteomas. Surv Ophthalmology. 1988;33:17–27.

38.Gündüz K, Shields JA, Shields CL, Eagle Jr RC. Cutaneous melanoma metastatic to the vitreous cavity. Ophthalmology. 1998;105:600–5.

39.Lim JI. Paraneoplastic syndromes. O’Brien J, ed. Ophthalmol Clin North Am. 1999;12:213–224.

40.Shields CL, Shields CL, De Potter P. Patterns of indocyanine green angiography of choroidal tumors. Br J Ophthalmol. 1995;79:237–45.

41.Arevalo JF, Fernandez CF, Garcia RA. Optical coherence tomography characteristics of choroidal metastasis. Ophthalmology. 2005;112:1612–9.

42.De Potter P, Shields JA, Shields CL, et al. Metastatic carcinoma to the choroid and optic nerve: unusual magnetic resonance imaging findings. Int Ophthalmol. 1992;16:39–44.

43.Shields JA, Shields CL, Ehya H, et al. Fine needle aspiration biopsy of suspected intraocular tumors. The 1992 urwick lecture. Ophthalmology. 1993;100:1677–84.

44.Shields CL, Manquez ME, Ehya H, Mashayekhi A, Danzig CJ, Shields JA. Fine-needle aspiration biopsy of iris tumors in 100 consecutive cases: technique and complications. Ophthalmology. 2006;113:2080–6.

45.Char DH. Treatment of choroidal metastases. Arch Ophthalmol. 1991;18:333.

46.Kuo IC, Haller JA, Maffrand R, Sambuelli RH, Reviglio VE. Regression of a subfoveal choroidal metastasis of colorectal carcinoma after intravitreous bevacizumab treatment. Arch Ophthalmol. 2008;126: 1311–3.

47.Levinger S, Merin S, Seigal R, Pe’er J. Laser therapy in the management of choroidal breast tumor metastases. Ophthalmic Surg Lasers. 2001;32:294–9.

48.Harbour JW, Meredith TA, Thompson PA, Gordon ME. Transpupillary thermotherapy versus plaque radiotherapy for suspected choroidal melanomas. Ophthalmology. 2003;110:2207–14.

49.Vianna RN, Pena R, MuralhaA, Muralha L, Muranaka E. Transpupillary thermotherapy in the treatment of choroidal metastasis from breast carcinoma. Int Ophthalmol. 2004;25:23–6.

50.Rudoler SB, Corn BW, Shields CL, et al. External beam irradiation for choroid metastases: identification

of factors predisposing to long-term sequelae. Int J Radiat Oncol Biol Phys. 1997;1(38):251–6.

51.Rudoler SB, Shields CL, Corn BW, et al. Functional vision is improved in the majority of patients treated with external-beam radiotherapy for choroid metastases: a multivariate analysis of 188 patients. J Clin Oncol. 1997;15:1244–51.

52. Shields CL, Shields JA, De Potter P, et al. Plaque radiotherapy in the management of uveal metastasis. Arch Ophthalmol. 1997;115:203–9.

53.Shields JA, Shields CL, Shah P, Sivalingam V. Partial lamellar sclerouvectom y for ciliary body and choroidal tumors. Ophthalmology. 1991;98:971–83.

54.Rodriques M, Shields JA. Iris metastasis from a bronchial carcinoid tumor.Arch Ophthalmol. 1978;96: 77–83.

Introduction

Autoimmune retinopathy includes three main forms: cancer-associated retinopathy (CAR), mel- anoma-associated retinopathy (MAR), and non-

S. Yalamanchi, M.D. ( )

Uveitis and Intraocular Inflammation Service, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, 900 NW 17th Street, Miami,

FL 33136, USA

e-mail: syalamanchi@med.miami.edu

J.J. Miller, M.D.

Georgia Retina, 2867 Castlewood Drive, Atlanta, GA 30327, USA

e-mail: jjustusmiller@hotmail.com

J.L. Davis, M.D., M.A.

Anne Bates Leach Eye Hospital, Bascom Palmer Eye Institute, 900 NW 17th Street, Miami, FL 33136, USA e-mail: jdavis@med.miami.edu

neoplastic autoimmune-related retinopathy and optic neuropathy (ARRON). Autoimmune retinopathies encompass ophthalmic disorders in which autoantibodies are directed at various retinal components and lead to progressive vision loss. If evaluation reveals an underlying malignancy, it is considered a paraneoplastic syndrome. Although paraneoplastic syndromes occur in 10–15% of cancer patients [1], the incidence of paraneoplasiainduced antiretinal antibodies is considered rare. Without confirmed malignancy, patients with retinal dysfunction related to antiretinal antibodies are considered to have ARRON or nonneoplastic autoimmune retinopathy (npAIR). The differential for nonneoplastic cases of antiretinal autoantibodies usually includes inherited retinal degenerations [2, 3], as well as occult malignancies. This chapter will review and provide illustrative cases of CAR, MAR, and ARRON.

Paraneoplastic Retinopathy: Cancer-

Associated Retinopathy (CAR)

Cancer-associated retinopathy (CAR) is a paraneoplastic retinopathy in which autoantibodies are directed against retinal antigens causing retinal dysfunction and retinal cell death. CAR is believed to be the most common form of paraneoplastic retinopathy, although the exact prevalence has not been reported in the literature. Typically, older adults are affected, and the incidence is equal among men and women [4]. The malignancy most commonly associated with CAR is small cell lung cancer, followed by gynecologic and breast cancers [4]. Less commonly, cases have also been associated with non-small lung cancer, Hodgkin’s lymphoma, bladder, prostate, pancreatic, laryngeal, and colon cancers [4].

Malignancies associated with CAR:

•Small cell lung cancer

•Gynecologic malignancies: endometrial, uterine, and cervical

•Breast

•Lymphoma

•Colon

•Prostate

•Bladder

•Laryngeal

•Pancreatic

•Metastases of unknown primary

CAR was first described in 1976 by Sawyer et al. in three patients with small cell lung cancer with progressive vision loss and has since become an increasingly recognized clinical disorder [5].

A humoral immune reaction leading to photoreceptor destruction is the most likely underlying etiology for CAR. McGinnis et al. in 1995 proposed that CAR may be initiated with a p53 tumor suppressor gene mutation in the tumor cells [6]. This mutation subsequently turns on production of the recoverin protein with the cell line becoming cancerous due to loss of the tumor suppressor activity. The human gene for recoverin protein and the p53 gene have both been localized to chromosome 17 in proximity of one another [6]. Recoverin is a calcium-binding

protein located within retinal photoreceptor cells and bipolar cells and is highly immunogenic and leads to anti-recoverin antibody production [4, 7]. The anti-recoverin antibodies bind to recoverin molecules in the photoreceptor cells by penetrating the blood–retina barrier [1]. The inactivated form of retinal recoverin then causes closure of ion channels, depolarization of cells, and photoreceptor death. Specifically, antirecoverin antibody is likely incorporated into photoreceptor cells and modulates increased phosphorylation of rhodopsin, which increases the intracellular level of calcium and the activation of caspase-dependent apoptosis, ultimately leading to photoreceptor death [1, 4, 6]. Adamus et al. in 1998 demonstrated this concept with the injection of anti-recoverin antibodies intravitreally in rats, which caused flattening of both the a and b wave on ERG and triggered photoreceptor cell death [7].

In 1987, Thirkill et al. elucidated the autoimmune etiology of CAR by identifying antiretinal antibodies via immunofluorescence [1, 8]. These autoantibodies were demonstrated to be reactive with photoreceptor outer segments as well as retinal ganglion cells [1, 8]. The 23-kDa protein recoverin, which is a calcium-binding protein found in both rods and cones, is the most frequently identified antigen in CAR [1, 8]. The second most common autoimmune retinal antibody is a 46-kDa (anti-enolase) protein, followed by 45 and 60 kDa [4]. Antibodies against 65-kDa heat shock protein 70, 44, 43, and 63 kDa have also been identified [1]. Antibodies to TULP-1 (tubby-like protein 1) protein are directed against the inner segment of photoreceptor cells, which is in contrast to anti-recoverin antibodies that are directed against the outer segments of these cells [4]. The anti-TULP-1 protein has been identified in a CAR patient with endometrial cancer [4]. Antibodiesagainstthephotoreceptorcell–specific nuclear receptor (PNR) gene product have also been reported in a case of CAR secondary to lung cancer [4]. In addition, combined paraneoplastic retinopathy with vitreous cells and optic neuritis has been associated with CRMP-5-IgG antibody, which has a 77% association with small cell lung cancer [9].

Histopathologically, CAR demonstrates diffuse photoreceptor degeneration of both rods and cones with loss of nuclei from the outer nuclear layer [1, 4]. The retinal pigment epithelium and choriocapillaris are well preserved, and ganglion cells in the inner retina, optic nerve, and geniculocalcarine pathway are all spared [1, 4, 10]. In addition, there may also be a secondary cellular response with inflammatory infiltrates being sporadically reported in CAR [1, 4].

In terms of clinical symptoms, patients may present with progressive bilateral visual loss over weeks to months. Entoptic symptoms such as flashing or flickering lights, swirling vision, or other positive visual phenomenon are often prominent [1, 4]. Patients may also report transient dimming of vision [4]. CAR affects both rods and cones. Clinical problems associated with rod dysfunction include nyctalopia, prolonged dark adaptation, midperipheral ring scotomas, and peripheral visual field deficits [4]. Cone dysfunction can present with photosensitivity, reduced visual acuity, prolonged glare after light exposure, decreased color perception, and central scotomas [4]. Visual symptoms may precede diagnosis of a systemic malignancy in 50% of patients [1]. Early in the disease, fundus examination may appear normal [1]. However, characteristic changes may occur over time with disease progression and include attenuation of arterioles, thinning and mottling of the retinal pigment epithelium, and optic disk pallor [1, 4, 5, 11]. Anterior chamber and vitreous cells, periphlebitis, and arteriolar sheathing may also be present particularly late in the course of disease [1, 4, 5, 11].

Early diagnosis of CAR may be complicated due to subtle clinical findings, and maintaining a high index of clinical suspicion is warranted. Ancillary testing can include a Goldmann visual field test, which may indicate peripheral field or central deficits [1]. Optical coherence tomography (OCT) may demonstrate extensive photoreceptor loss, and fluorescein angiography can help exclude other clinical entities as potential causes of vision loss. Fluorescein findings are usually normal, but may demonstrate mild peripheral vascular leakage consistent with vasculitis in

occasional cases [12]. The most sensitive test in detecting retinal dysfunction associated with CAR is often electroretinography (ERG), in which findings are usually abnormal in the majority of cases [1]. Patients with a predominant rod or cone dysfunction show abnormal scotopic or photopic patterns, respectively [1]. In both scotopic and photopic conditions, a and b waves are depressed [1, 5, 13]. Along with ERG findings, a diagnosis of CAR can also be made by the demonstration of antiretinal antibodies using western blot analysis, immunofluorescent antibody assays, and enzyme-linked immunosorbent assay (ELISA) [1].

Results of ERG and antibody testing are not always definitive, and in patients suspected of CAR, an extensive evaluation for a malignancy should be initiated. A complete physical examination, including pelvic and breast examination for women, is recommended. A chest radiograph should initially be obtained. If normal, a chest CT scan should be performed for further evaluation [12]. Additional imaging studies for a possible malignancy include CT of the abdomen and pelvis, mammography, and total-body positron emission tomography (PET) [12]. Further evaluation for metastatic disease as the source of vision loss should also include contrast-enhanced MRI of the head and orbits and lumbar puncture for cytologic examination. Cerebrospinal fluid analysis in CAR often reveals a nonspecific finding of a mild lymphocytic pleocytosis and an increased concentration of protein [4].

The differential diagnosis in the setting of subacute unilateral or bilateral vision loss and the presence of retinal dysfunction includes paraneoplastic syndromes (CAR and MAR), npAIR (hereditary retinal degenerations and ARRON), and toxic retinopathy [12]. Etiologies for toxins include mellaril, chloroquine, and plaquenil. The time course of progression of visual symptoms is usually over years with hereditary retinopathies and weeks to months with acquired disease. Furthermore, the presence of antiretinal antibodies will also facilitate the diagnosis of autoimmune retinopathy, and evaluation for malignancy will distinguish between paraneoplastic conditions and npAIR. Specifically, npAIR can include