CLINICAL SCIENCE

Iris Metastasis From Systemic Cancer in 104 Patients: The 2014 Jerry A. Shields Lecture Carol L. Shields, MD, Swathi Kaliki, MD, Gordon S. Crabtree, BA, Ani Peshtani, BS, Spenser Morton, BS, Ronan A. Anand, BA, Giulia Coco, MD, and Jerry A. Shields, MD

Purpose: To describe the clinical features, treatment, and outcome of patients with iris metastasis.

Methods: Retrospective case series of 160 tumors in 107 eyes of 104 patients with iris metastasis from systemic cancer. Results: The median age at presentation with iris metastasis was 60 years. Iris metastasis was more common in whites (n = 93, 89%) and women (n = 65, 62%). The primary tumor was located in the breast (n = 34, 33%), lung (n = 28, 27%), skin (melanoma) (n = 13, 12%), kidney (n = 7, 7%), esophagus (n = 3, 3%), and others (n = 19, 19%). The main symptoms were pain (n = 33, 32%) or blurred vision (n = 31, 30%). The main findings were corectopia (n = 38, 37%) and secondary glaucoma (n = 38, 37%). The metastasis was unifocal (n = 84, 78%) or multifocal (n = 23, 21%) for a total of 160 tumors. The main tumor was centered at the iris root (n = 72, 69%), midzone (n = 22, 21%), or pupillary margin (n = 10, 10%), with median tumor diameter of 5 mm. Coexistent conjunctival or ciliary body/choroidal metastases were found in 39 patients. Management of iris metastasis included systemic chemotherapy (n = 18, 22%), external beam radiotherapy (n = 34, 41%), plaque radiotherapy (n = 20, 24%), surgical excision (n = 4, 5%), enucleation (n = 3, 4%), or observation (n = 4, 5%). Following treatment, tumor control without recurrence was achieved in 95% cases. In 98 cases with adequate follow-up information, death occurred in 85 (87%) at median 10 months (range, ,1–239 months) from the date of iris metastasis.

Conclusions: Metastatic tumors to the iris generally originate from primary malignancies in the breast, lung, or skin (melanoma). Despite successful ocular treatment, life prognosis is poor. Received for publication June 27, 2014; revision received September 4, 2014; accepted September 5, 2014. Published online ahead of print October 23, 2014. From the Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, PA. Dr Kaliki is now with the Ocular Oncology Service, L. V. Prasad Eye Institute, Hyderabad, India. Supported by Eye Tumor Research Foundation, Philadelphia, PA (C.L.S.). The authors have no funding or conflicts of interest to disclose. Presented, in part, as the J. A. Shields Lecture at the Annual Meeting of the Asian Pacific Society of Ocular Oncology and Pathology; September 26, 2014; Hong Kong, China (C.L.S.), and at the American Academy of Ophthalmology Annual Meeting as a poster; October 17–21, 2014; Chicago, IL (C.L.S.). The funders had no role in the design and conduct of the study, in the collection, analysis and interpretation of the data, and in the preparation, review or approval of the manuscript. C. L. Shields has had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Reprints: Carol L. Shields, MD, Ocular Oncology Service, Suite 1440, Wills Eye Hospital, 840 Walnut St, Philadelphia, PA 19107 (e-mail: carol. [email protected]). Copyright © 2014 by Lippincott Williams & Wilkins

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Key Words: eye, tumor, iris, metastasis, cancer, carcinoma (Cornea 2015;34:42–48)

T

he American Cancer Society reported 1,660,290 new cancers (excluding cutaneous squamous cell carcinoma and basal cell carcinoma) in the United States during 2013.1 The most common cancers originated from the prostate (n = 238,590), breast (n = 234,580), lung and bronchus (n = 228,190), and colon (n = 102,480), as well as lymphoma (n = 79,030) and cutaneous melanoma (n = 76,690). The National Cancer Institute estimated that approximately 13.7 million living Americans in 2013 had a history of cancer, whether active or in remission. In 2013, approximately 580,350 Americans were estimated to die from cancer, which approximates to 1600 deaths per day.1 Cancer is the second most common cause of death in the United States, following death from heart disease. The huge impact of cancer on our daily lives is nearly imperceptible. Metastasis from systemic carcinoma to the eye is estimated to occur in 4% to 8% of cases, based on autopsy evaluation.2,3 From a clinical perspective, the rate of ocular metastases varies depending on the primary tumor site and degree of systemic control. In a cohort of patients with known breast carcinoma, 27% had symptomatic or asymptomatic choroidal metastasis.4 Most ocular metastasis from systemic cancer are found in the choroid. A survey of 950 metastatic foci in 520 eyes with uveal metastasis revealed involvement of the choroid in 88%, ciliary body in 2%, and iris in 9%.5 Metastatic tumors to the iris are relatively uncommon. Iris metastasis can manifest with a stromal nodule or illdefined iris thickening or with atypical features of pain, iridocyclitis, or hyphema. Nearly 20 years ago, Shields et al6 reviewed their 20-year clinical experience with 40 cases of iris metastasis. In this study, we review our 40-year experience with iris metastasis, providing information on clinical features, treatments, and outcomes.

METHODS This retrospective interventional case series included patients with iris metastasis managed on the Ocular Oncology Service at Wills Eye Hospital between September 1, 1974 and February 1, 2014. Approval from our institutional review board was obtained. Patient data were extracted from the medical records and included information on previous cancer with regard to Cornea  Volume 34, Number 1, January 2015

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TABLE 1. Iris Metastasis From Systemic Cancer in 107 Eyes of 104 Patients: Demographics Feature Age, mean (median, range), yr (N = 104 patients) Sex (N = 104 patients) Male Female Race (N = 104 patients) White African American Asian Hispanic Laterality (N = 104 patients) Right eye Left eye Both eyes

n (%) 58.5 (60, 0.1–88) 39 (38) 65 (62) 93 8 2 1

(89) (8) (2) (1)

52 (50) 49 (47) 3 (3)

date of detection and management. Details of primary systemic tumor, systemic metastasis, and treatment of the primary tumor were recorded. At presentation to the Ocular Oncology Service, data on demographic features included patient age, sex, and race. The presenting symptoms and visual acuity were recorded. The recorded ocular features

TABLE 2. Clinical Features of 160 Metastatic Tumors to the Iris From Systemic Cancer in 107 Eyes of 104 Patients Feature Presenting symptoms (N = 104 patients) Pain Blurred vision Mass Photophobia Foreign body sensation Asymptomatic Intraocular pressure, mean (median, range), mm Hg (n = 103 eyes) Clinical features* (n = 102 eyes) Feeder vessel to tumor Keratic precipitates Corectopia Ectropion uveae Iris neovascularization Hyphema Pseudohypopyon Secondary glaucoma Neovascular glaucoma Angle infiltration with tumor No tumors per eye (N = 107 eyes) 1 2 $3 Mean (median, range) Tumor features (N = 107 eyes) Intrinsic vasculature Tumor seeding

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n (%) 33 31 13 2 4 19 21

(32) (30) (12) (2) (4) (18) (18, 6–68)

37 26 38 10 28 11 9 38 8 30

(36) (25) (37) (10) (27) (11) (8) (37) (8) (29)

84 13 10 1.6

(78) (12) (9) (1, 1–15)

61 (57) 32 (30)

TABLE 2. (Continued ) Clinical Features of 160 Metastatic Tumors to the Iris From Systemic Cancer in 107 Eyes of 104 Patients Feature

n (%)

Tumor margin (n = 103 eyes) Well defined Poorly defined Configuration (n = 101 eyes) Flat Nodular Papillary Tumor color (n = 104 eyes) Yellow Brown Gray Red-orange White Main tumor epicenter (n = 105 eyes) Pupillary margin Midzone Root Diffuse Tumor quadrantic location of tumor (n = 103 eyes) Superior Nasal Inferior Temporal Diffuse Tumor size, mean (median, range), mm (N = 107) Diameter Thickness

44 (43) 59 (57) 27 (27) 68 (67) 6 (6) 69 15 2 13 5

(66) (14) (2) (12) (5)

10 22 72 1

(10) (21) (69) (1)

29 17 36 20 1

(28) (16) (35) (19) (1)

5.9 (5, 1–15) 2.0 (2, 1–8)

*Some patients had more than 1 feature.

included intraocular pressure (millimeters of mercury), anterior chamber inflammatory response, pseudohypopyon, hyphema, iris neovascularization, and tumor location and TABLE 3. Iris Metastasis in 107 Eyes of 104 Patients: Primary Tumor Site Primary Tumor Site (N = 104 Patients) Breast carcinoma Lung carcinoma Lung carcinoid Cutaneous melanoma Renal cell carcinoma Esophageal carcinoma Prostate carcinoma Endometrial carcinoma Bladder carcinoma Colon carcinoma Bone cancer Parotid gland carcinoma Pheochromocytoma Laryngeal carcinoma Ovarian carcinoma Leukemia/lymphoma Undetermined

Total, n (%) 34 26 2 13 7 3 2 2 2 2 1 1 1 1 1 3 3

(33) (25) (2) (12) (7) (3) (2) (2) (2) (2) (1) (1) (1) (1) (1) (3) (3)

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FIGURE 1. Iris metastasis from breast carcinoma. A, Large vascular iris metastasis in a woman who denied breast cancer but was found to have an erosive malignancy on breast examination. B, Soft white multinodular iris metastasis with hemorrhage. C, Soft white iris metastasis at the pupillary margin simulating iris granuloma. D, Dense white iris metastasis in the peripheral iris.

size [largest basal diameter and thickness (millimeters)]. Other features included tumor laterality (unilateral, bilateral), multiplicity (unifocal, multifocal), configuration (nodular, flat), color (white, yellow, brown), tumor intrinsic vascularity, sentinel vessels, and coexistent ocular (conjunctiva, contralateral iris, ciliary body, choroid) metastases. Included in this study are 40 patients reported previously.

All findings were documented with large color-coded anterior segment drawings and photography, anterior segment optical coherence tomography, ultrasonography, ultrasound biomicroscopy, and fluorescein angiography, when available. Fine-needle aspiration biopsy for cytological confirmation was recorded, when performed. Management of the iris tumor and outcomes of management were recorded at each examination.

FIGURE 2. Iris metastasis from lung carcinoma. A, Gray-brown nodular iris metastasis with prominent vessels. B, Soft, white irregular iris metastasis in iris temporally. C, Vascular iris metastasis with spontaneous hyphema. D, Gray-brown nodular iris metastasis with intralesional cystic appearance.

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FIGURE 3. Iris metastasis from miscellaneous tumors. A, Cutaneous melanoma metastasis to iris with prominent intrinsic vasculature. Note the second metastasis inferiorly. B, Esophageal carcinoma metastasis to iris with diffuse iris thickening and no visible mass. C, Renal cell carcinoma metastasis to iris with prominent intrinsic vasculature. D, Ovarian carcinoma with white dense appearance.

Patient systemic outcome (alive, alive with metastasis, death due to metastasis, death due to other causes) was noted. Treatment of iris metastasis [observation, systemic chemotherapy, iridectomy/partial lamellar iridocyclectomy, plaque radiotherapy, external beam radiotherapy (EBRT), or enucleation], treatment regression (complete/partial/absent) and systemic outcome (alive/dead) were recorded. If a patient had not followed up within the past year, we obtained records from the patient’s primary care physician or the referring physician for more information.

RESULTS Over a 40-year period, at an ocular oncology referral center, 107 eyes of 104 consecutive patients were identified with iris metastasis. By comparison, during this period, there were approximately 1972 patients with choroidal or ciliary body metastasis and 382 with orbital metastasis. Patient information is tabulated in Table 1. The mean patient age at presentation with iris metastasis was 58.5 years, 65 (62%) were women and 39 (38%) were men, and 93 (89%) were whites. Bilateral iris metastases were present in 3 patients (3%). The clinical features are described in Table 2. The most common presenting complaint was pain (n = 33, 32%) or blurred vision (n = 31, 30%). Secondary glaucoma was evident in 38 eyes (37%). The main tumor was located in the iris root in 72 (69%), midzone in 22 (21%), and at the pupillary margin in 10 (10%). The mean tumor diameter was 5.9 mm and mean tumor thickness was 2.0 mm. The primary tumor site is listed in Table 3. The most common malignancies originated in the breast (n = 34, 33%), lung (n = 28, 27%), or skin (melanoma) (n = 13, Ó 2014 Lippincott Williams & Wilkins

12%) (Figs. 1–3). Of those with iris metastasis from breast carcinoma, 26 had a single lesion and 8 had multiple lesions, whereas lung carcinoma/carcinoid showed single metastatic focus in 25 patients and multiple iris foci in 3 patients. The primary tumor was not determined in 3 cases. Confirmation TABLE 4. Iris Metastasis From Systemic Cancer in 107 Eyes of 104 Patients: Ocular Outcome Feature

n (%)

Treatment of iris metastasis (n = 83 patients)* Systemic chemotherapy EBRT Plaque radiotherapy Iridectomy/partial lamellar sclerouvectomy Enucleation Observation Response to treatment (n = 59 eyes) Complete regression Partial regression No change Tumor recurrence after treatment (n = 95 eyes) Coexistent ocular metastasis (n = 101 eyes) No Yes† Choroid ipsilateral Choroid contralateral Iris contralateral Ciliary body ipsilateral Conjunctiva ipsilateral

18 34 20 4 3 4

(22) (41) (24) (5) (4) (5)

38 18 3 5

(64) (31) (5) (5)

62 39 21 18 3 4 10

(61) (39) (21) (18) (3) (4) (10)

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*Details of treatment were available in 83 patients. †Some patients had more than one site of involvement.

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of metastasis was performed by cytology with fine-needle aspiration biopsy (n = 46, 45%), by histopathology with open biopsy (n = 9, 9%), or both (n = 7, 7%). The ocular outcomes are described in Table 4. In addition to the iris metastasis, coexistent metastases to other ocular sites were detected in 39 eyes (39%), including ipsilateral/contralateral choroid (n = 39, 39%) or ciliary body (n = 4, 4%). The iris metastases were most often treated with EBRT (n = 34, 41%), plaque radiotherapy (n = 20, 24%), or systemic chemotherapy (n = 18, 22%) (Fig. 4). Following treatment, tumor control was achieved with recurrence noted in 5 eyes (5%) at mean 17-month interval (median, 13; range, ,1–41 months). The systemic outcomes are described in Table 5. In 77 patients with adequate history, iris metastasis was discovered

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before or concomitant with systemic metastasis in 31 (40%). Adequate follow-up was available in 98 patients and death was noted in 85 (87%) at median time interval from iris metastasis to death of 10 months.

DISCUSSION In a comprehensive analysis of 3680 iris tumors managed at an ocular oncology center, the most common solid tumors (n = 2912) included melanocytic tumors such as nevus (n = 1534), melanoma (n = 645), melanocytoma (n = 68), melanocytosis (n = 64), Lisch nodules (n = 70), and nonmelanocytic tumors like metastatic tumors (n = 67), vascular tumors (n = 53), and solid epithelial tumors (n = 35).7 In

FIGURE 4. Treatment of iris metastasis. Iris metastasis from lung carcinoma before (A) and after (B) EBRT. Iris metastases with hyphema from lung carcinoma before (C) and after (D) plaque radiotherapy with regression of tumor and hyphema. Iris metastases from breast carcinoma before (E) and after (F) systemic chemotherapy. Iris metastasis from prostate carcinoma before (G) and after (H) tumor removal by iridectomy.

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TABLE 5. Iris Metastasis in 104 Patients: Systemic Outcomes Feature Primary tumor treatment (n = 99 patients)* Systemic chemotherapy Surgical excision EBRT Observation Detection of iris metastasis in relation to primary tumor (n = 102 patients) After primary tumor Interval, mean (median, range), mo Before primary tumor Interval, mean (median, range), mo Simultaneous detection with primary tumor Interval, mean (median, range), mo Detection of iris metastasis in relation to systemic metastasis (n = 77 patients) After systemic metastasis Before systemic metastasis Simultaneous detection with systemic metastasis Death, mean (median, range), (n = 85 patients) Time interval between detection of primary tumor and death, mo Time interval between detection of iris metastasis and death, mo

n (%) 63 55 47 5

(64) (56) (46) (5)

83 58 13 2 6

(81) (33, 1–299) (13) (1, ,1–5) (6) 0

46 (60) 23 (30) 8 (10) 68 (36, 1–420) 24 (10, ,1–239)

*Some patients had more than 1 treatment modality.

that clinic-based series, metastatic tumors were detected in older patients at median age of 60 years, compared with melanocytic and vascular tumors at ages 52 and 56 years, respectively. Uveal metastases are not uncommon in an ocular oncology practice, but occur far more often in the choroid than the iris. In 1997, Shields et al5 studied 950 uveal metastasis in 520 eyes and found the most common primary sites (per patient) to be breast (47%), lung (21%), gastrointestinal tract (4%), kidney (2%), skin (2%), prostate (2%), other sites (4%), and primary site undetected (17%). The metastatic site was found in the choroid (88%), ciliary body (2%), and iris (9%). It has been speculated that uveal metastases occur in the choroid more so than the iris due to the luxurious blood supply to the posterior choroid through the posterior ciliary arteries that allow greater volume of blood flow and higher chance for metastatic emboli compared with the fewer anterior ciliary vessels that supply the iris.8 In 1975, Ferry and Font9 provided a seminal analysis from the Armed Forces Institute of Pathology on 26 eyes with carcinoma metastatic to the anterior segment of the eye. They commented that this rare metastatic site had been recognized previously in the literature, but mostly by single case reports. In their series, the median patient age was 60 years and ocular findings included decreased visual acuity, visible mass, ocular redness, pain, iridocyclitis, glaucoma, and/or hyphema. The primary carcinoma originated in the lung (50%), breast (35%), kidney (8%), rectum (4%), and unknown (4%). The primary carcinoma detection preceded the iris metastasis in Ó 2014 Lippincott Williams & Wilkins

46%, followed the iris metastasis in 50%, or occurred simultaneously in 4%. In 1995, Shields et al6 provided a clinic-based analysis on iris metastases over a 20-year period from an ocular oncology center and found only 40 affected patients. In that series, the malignancies originated from breast (40%), lung (35%), skin melanoma (8%), colon (5%), esophagus, larynx, prostate, and kidney (2% each), and primary site not found (2%). This current publication includes retrievable charts from that previous series and has added an additional 20 years for a total of 40 years to increase cohort size and follow-up. In this current series of 107 eyes, we found primary tumor origin from breast (33%), lung (27%), skin (melanoma) (12%), kidney (7%), esophagus (3%), and others (Table 4). Pain and blurred vision were overwhelmingly the most common patient symptoms. The pain was presumably related to secondary glaucoma, iridocyclitis, or scleral invasion from tumor. Unlike the Ferry and Font9 series in which most iris metastasis were nasal or temporal, we found most to be inferior (35%) or superior (28%). Ocular outcome with iris metastasis was generally favorable with tumor control in 95%. Most commonly, in 65% of eyes, radiotherapy was used. Our preference is to use focal plaque radiotherapy because it requires only 4 days of treatment compared with EBRT that requires 20 days and chemotherapy that requires several months. When considering the overall poor prognosis of these patients with median time to death of 10 months, plaque radiotherapy occupies only 1% of their remaining days compared with EBRT at 7%. However, if multifocal sites in the globe are affected or there are active systemic metastases, then EBRT or systemic chemotherapy is used. Any form of radiotherapy can lead to side effects in the eye such as dry eye, cataract, glaucoma, and retinopathy. In this series, patient survival was generally poor and side effects were minimally experienced. However, with long-term follow-up on plaque radiotherapy for iris melanoma, using higher dose than is used for metastasis, corneal abnormalities occurred in 12% of cases at median interval of 34 months.10 In summary, iris metastatic tumors can have a variety of presenting signs and symptoms with pain, photophobia, blurred vision, or visible mass and it can manifest before the detection of the primary systemic malignancy.11 Occasionally, iris metastasis can masquerade as iridocyclitis with hypopyon or with intractable glaucoma.12–14 A high index of suspicion is warranted for unilateral nonresolving anterior uveitis or glaucoma because there could be an underlying malignancy. REFERENCES 1. American Cancer Society. Cancer Facts and Figures 2013. Atlanta, GA: American Cancer Society; 2013;1–62. 2. Bloch RS, Gartner S. The incidence of ocular metastatic carcinoma. Arch Ophthalmol. 1971;85:673–675. 3. 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;95:788–793. 4. Mewis L, Young SE. Breast carcinoma metastatic to the choroid. Analysis of 67 patients. Ophthalmology. 1982;89:147–151. 5. Shields CL, Shields JA, Gross NE, et al. Survey of 520 eyes with uveal metastases. Ophthalmology. 1997;104:1265–1276.

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6. Shields JA, Shields CL, Kiratli H, et al. Metastatic tumors to the iris in 40 patients. Am J Ophthalmol. 1995;119:422–430. 7. Shields CL, Kancherla S, Patel J, et al. Clinical survey of 3680 iris tumors based on patient age at presentation. Ophthalmology. 2012;119:407–414. 8. Ferry AP, Font RL. Carcinoma metastatic to the eye and orbit. I. A clinicopathologic study of 227 cases. Arch Ophthalmol. 1974;92:276–286. 9. Ferry AP, Font RL. Carcinoma metastatic to the eye and orbit II. A clinicopathological study of 26 patients with carcinoma metastatic to the anterior segment of the eye. Arch Ophthalmol. 1975;93:472–482. 10. Shields CL, Shah S, Bianciotto CG, et al. Iris melanoma management with Iodine-125 plaque radiotherapy in 144 patients: impact of

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11. 12. 13. 14.

melanoma-related glaucoma on outcomes. Ophthalmology. 2013;120: 55–61. Sen HN, Chan CC, Nussenblatt RB, et al. Occult primary carcinoma metastatic to the iris. Acta Ophthalmol Scand. 2004;82:746–747. Woog JJ, Chess J, Albert DM, et al. Metastatic carcinoma of the iris simulating iridocyclitis. Br J Ophthalmol. 1984;68:167–173. Kesen MR, Edward DP, Ulanski LJ, et al. Pulmonary metastasis masquerading as anterior uveitis. Arch Ophthalmol. 2008;126:572–574. Harvey BJ, Grossniklaus HE, Traynor MP, et al. Metastatic lung adenocarcinoma to the iris mimicking Cogan-Reese syndrome. J Glaucoma. 2012;21:567–569.

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Iris metastasis from systemic cancer in 104 patients: the 2014 Jerry A. Shields Lecture.

To describe the clinical features, treatment, and outcome of patients with iris metastasis...
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