Ocular Oncology

From the 59th Annual Post-Graduate Review Course in Ophthalmology, presented by the State University of New York, Upstate Medical University

Jerry A. Shields, MD, Professor of Ophthalmology, Jefferson Medical College of Thomas Jefferson University,

and Director, Oncology Service, Wills Eye Institute, Philadelphia, PA

Update on Management of Uveal Melanoma

Controversy in borderline melanocytic lesions: case examples  —  9 patients in whom lesions treated when slight growth occurred all died of metastatic melanoma; early diagnosis and prompt treatment has led to improved prognosis for colon cancer, breast cancer, cutaneous melanoma, and other ocular cancers (eg, retinoblastoma, orbital rhabdomyosarcoma, se­baceous carcinoma of eyelid); lack of improved survival among patients with uveal melanoma suggests need to treat small lesions earlier

Treatment of choroidal nevi: lesions potentially malignant and metastatic; valid arguments against treating all such lesions include high prevalence (5%-6% of population), rare growth and metastasis, and possibility that treatment may destroy vision

Risk factors predicting growth and metastasis: mnemonic to find small ocular melanoma (TFSOM) stands for thickness >2 mm, fluid (subretinal), symptoms, orange pigment, and margin touching disc; >3 risk factors associ­ated with >50% chance of growth within 5 yr; study of 1329 lesions <3 mm thick found 3% metastasized; risk fac­tors included thickness >2 mm, symptoms, proximity to optic disc, and documented growth; with no risk factors, rate of metastasis <1%; with 4 risk factors, rate increased to 20%; rule of 5s  —  presence of each risk factor in­creases risk by 5%

Transpupillary thermotherapy (TTT): case example  — patient had melanoma measuring 8 mm x 7 mm x 3 mm, impending break through Bruch’s membrane, and subretinal fluid involving fovea; after treatment with TTT, tumor flattened, subretinal fluid resolved, and vision improved; TTT appropriate for properly selected, less advanced cases

Plaque radiotherapy (PR): most common treatment; involves radioactive iodine-125 placed over tumor; Collabora­tive Melanoma Study (COMS)  —  found no difference in long-term prognosis between PR and enucleation; most physicians enucleate juxtapapillary, ciliary body, diffuse iris, large melanomas, and melanomas with extraocular extension; however, speaker’s study showed equal survival with enucleation and PR of tumors that touched or overhung optic disc; observed trend toward better survival in patients >50 yr of age who received PR; notched plaque used for treatment of many melanomas; also suitable for ciliary body melanomas, diffuse iris melanoma too large for iridectomy, large tumors, and tumors with extraocular extension

Adverse effects: include radiation retinopathy, acute or chronic papillopathy, cataract, inflammation with posterior synechiae, and scleral melt; all manageable

Genetic studies: large size of lesion, location in ciliary body, diffuse growth pattern, and epithelioid cell type associ­ated with poorer prognosis; recent studies showed tumors with abnormality or monosomy in chromosome 3 associ­ated with 50% 5-yr mortality; normal disomy of chromosome 3 associated with only 5% 5-yr mortality; important to obtain tumor cells for genetic analysis; if enucleation performed, use corneal trephine opening of 8 mm to re­move fresh tumor tissue for fluorescence in situ hybridization (FISH) or microarray analysis; if PR used, perform needle biopsy of tumor before placing plaque; consider more detailed follow-up for patients with monosomy of chromosome 3 and prophylactic treatment for subclinical liver melanoma cells with, eg, sunitinib (Sutent) via intra­hepatic catheterization; routine follow-up appropriate for patients with disomy of chromosome 3

Enucleation: treatment of choice for patients with large (diameter >18 mm) melanoma because radiotherapy of these lesions associated with increased morbidity; most patients receive coated Bio-Eye hydroxyapatite implant

Intraocular leiomyoma: most common in young women; located in ciliary body, transmit light, and some located between sclera and uvea (resect by opening sclera and leaving choroid intact)

Update on Management of Retinal and
Retinal Pigment Epithelium (RPE) Tumors

Retinoblastoma (RB)

Background: most common primary intraocular malignancy of childhood (»1 in 15,000 births); presents with unilat­eral or bilateral leukocoria; early stages small and difficult to detect; later, dilated feeding artery and draining vein apparent; pattern of growth either endophytic (tumor seeds from retina into vitreous and simulates endophthalmitis) or exophytic (tumor grows from retina into subretinal space and simulates Coats disease or traumatic retinal de­tachment)

Diagnosis: perform initial examination in office to differentiate from less urgent disorders, eg, pseudo-RB, persistent hyperplastic primary vitreous (PHPV), or Coats disease

Management: chemoreduction and chemothermotherapy now used more than enucleation and external beam irradia­tion; enucleation  —  appropriate for eye filled with tumor; important to excise long section of optic nerve to pre­vent extension of tumor to central nervous system; purely intraocular RBs rarely metastasize; with enucleation, RB tissue sample should be obtained according to established protocol and submitted for genetic and other spe­cial studies

Chemoreduction: triple-agent chemotherapy; goal to reduce size of tumor; allows treatment with conservative methods (eg, TTT, cryotherapy, plaque brachytherapy), rather than enucleation or external beam radiation ther­apy; even advanced cases highly sensitive to chemotherapy; currently >95% survival rate for patients with RB in United States; however, mortality often due to second tumor (eg, osteosarcoma) which develops from same mu­tation; new international classification system  —  tumors categorized as A through E; group C has localized seed­ing; study of 158 eyes found chemoreduction allowed salvage of eye in 100% of patients in group A (small tumors), 91% in group B, and 68% in group C; only 11% salvageable in advanced cases with total detachment and glaucoma

Intra-arterial chemotherapy: recently introduced in United States; involves cannulation of carotid and ophthalmic arteries and injection of chemotherapeutic agent; in advanced cases, enucleation preferable (98% survival rate), unless patient has had enucleation of first eye

Astrocytic hamartomas in tuberous sclerosis complex (TSC)

Case examples: child had total detachment, large mass, and hazy view; ultrasonography showed dome-shaped mass with internal calcium; after enucleation, neovascular glaucoma observed; diagnosis giant cell astrocytoma of ret­ina, rather than RB, due to findings of astrocytes and calcispheres (not found in RB); identical to brain tumors in TSC; 3 other similar cases presented with neovascular glaucoma; one retinal tumor extended extrasclerally through cornea; not all astrocytomas stable; some may require enucleation

Differentiating from RB: most patients have TSC skin lesions, and tumors produce extensive yellow exudation

Vascular tumors: include hemangioblastoma (capillary hemangioma), cavernous hemangioma, racemose hemangi­oma, and acquired vasoproliferative tumors of fundus; each has different features, complications, and systemic associations

Retinal hemangioblastoma: types include peripheral with dilated feeder vessels and yellow exudation, and juxta­papillary; associated with von Hippel-Lindau (VHL) syndrome; treat smaller lesions with surrounding photoco­agulation; treat larger lesions at equator with cryotherapy; speaker has found that tumors do not respond to antivascular endothelial growth factor (anti-VEGF; more investigation needed)

New developments: melanocytomas  —  benign; important to differentiate from melanoma; growth observed in 15%; series of 115 cases showed malignant transformation occurred in 1% to 2%; check annually; congenital hypertro­phy of retinal pigment epithelium (CHRPE)  —  studies showed growth occurs in 78% to 83%; generally have depig­mented lacunae and well-defined margins; can develop nodules that grow, produce yellow exudate, and become adenocarcinoma; can give rise to adenocarcinoma of RPE that resembles malignant melanoma; 2% of CHRPE le­sions spawn nodular tumors (initially slow-growing, but can progress to total exudative retinopathy and detach­ment); pigmented epithelial tumors “almost identical” to melanoma; differentiate from melanoma on basis of dilated vessels and yellow exudate

Update on Conjunctival Tumors

Dermoid: solid white tumor; choristoma; usually found at limbus inferotemporally; present at birth; possibly associ­ated with Goldenhar syndrome; patients may have dermolipoma and auricular and vertebral anomalies; no known hereditary basis; superotemporal dermolipomas relatively common and often overlooked in Goldenhar syndrome

Epibulbar osseous choristoma: patients born with ectopic bone on surface of sclera; simple form appears as lump on surface of eye, with density of bone on computed tomography; complex choristoma shows thickening of con­junctiva; when seen in children with nevus sebaceous of Jadassohn, alopecia, and pigmented lesion within area of alopecia on face, referred to as organoid nevus syndrome; 20% of patients develop basal cell carcinoma in area of alopecia; organoid nevus syndrome  —sporadic nonfamilial condition; no recognized genetic abnormalities; classi­fied as oculoneurocutaneous syndrome (similar to other phakomatoses)

Squamous cell carcinoma (SCC): may resemble inflammatory conditions; sometimes pedunculated; may have leu­koplakia on conjunctiva and cornea; rarely metastasizes, except in immunosuppressed patients; can be locally inva­sive

Melanocytic lesions: compound nevus most common; appear before 10 yr of age; usually brown, with characteristic clear cysts within (sometimes amelanotic and misdiagnosed as episcleritis)

Primary acquired melanosis (PAM): occurs in middle age; diffuse patchy flat appearance without cysts; almost al­ways pigmented; one study showed patients with PAM had 32% overall chance of developing melanoma; second study found 4% chance, based on clinical and pathologic criteria; Armed Forces Institute of Pathology (AFIP) ad­vises biopsy for all cases of PAM, but not feasible, as PAM occurs in 35% of white population (according to less stringent criteria); speaker found that only 3% developed melanoma if atypia present (possibly because his patients undergo earlier extensive surgery)

Melanoma: relatively rare, but incidence increasing; treat early; lesions can arise from preexisting nevus or de novo; PAM can also give rise to melanoma; adjacent skin involvement called lentigo maligna; can metastasize

Management of circumscribed melanoma or SCC: use retrobulbar (not subconjunctival) anesthesia; remove tumor with partial lamellar sclerokeratoconjunctivectomy followed by double freeze-thaw cryotherapy with “no touch” approach; procedure  —  make drawing of anterior segment and surgical plan; use cellulose ophthalmic sponge (eg, Weck-Cel) to apply alcohol to corneal portion with epithelial involvement; scroll off denatured epithelium and lay on surface of tumor; insert blade under tumor while holding sclera or Tenon’s and remove entire tumor by smooth dissection; if attached to sclera, also remove small piece of sclera up to termination of Bowman’s membrane; place specimen flat on paper for pathology; place cryoprobe under conjunctiva and freeze outward (cryotherapy of sclera or ciliary body not necessary for superficial lesions)

Management of PAM: make drawing that shows all patches of PAM (even in tarsal conjunctiva) and create more complex surgical plan; surgery indicated if elevation, nodules, large size, vascularity, or involvement of palpebral conjunctiva present; important to completely remove any amelanotic lesions (definitely melanoma despite lack of pigmentation); study of PAM in 311 eyes showed extent (in clock hours) represented important factor in pre­dicting progression to melanoma; if only 1 clock hour involved, patient did well with or without surgery; with 2 clock hours, risk for progression increased 3.4-fold; with 10 clock hours, risk increased 17-fold

Ancillary management: topical chemotherapy with mitomycin C or 5-fluorouracil; topical or injected interferon for melanoma and SCC most effective for conjunctival intraepithelial neoplasia (CIN), somewhat less effective for PAM; not useful for deeper lesions; after surgery, use amniotic membrane if large area of conjunctiva removed; for extensive and recurring melanoma and SCC, apply PR to conjunctiva

Pyogenic granuloma: actually proliferation of fibrovascular tissue; appears as fleshy red-pink lesion in area of previ­ously ruptured chalazion or after surgery for strabismus or enucleation

Lymphangioma: appears as numerous bleeding red vessels in conjunctiva and orbit that produce characteristic oily cysts (chocolate cysts)

Kaposi’s sarcoma: occurs more frequently in patients with AIDS; red lesions simulate hemorrhage; manage with ir­radiation or chemotherapy

Lymphoid tumors: range from benign lymphoid hyperplasia to malignant lymphoma; »20% of patients with “salmon patch” lesion develop systemic lymphoma within 5 yr; most classified as extranodal marginal B cell lymphomas of mucosal-associated lymphoid tissue (MALT) type; similar to gastric lymphomas; Helicobacter pylori possibly involved in etiology; almost always CD20-positive

Management: if small (<1 cm), remove entire lesion; incisional biopsy better if lesion larger; use oral antibiotics, ie, doxycycline or amoxicillin/clarithromycin/lansoprazole (Prevpac), or subconjunctival injections of interferon; use rituximab (Rituxan) for lesions positive for CD20; usual treatment radiation therapy

Caruncular tumors and cysts: tissues of caruncle similar to skin and conjunctiva, and can spawn neoplasms related to both; papilloma and nevus most common (benign) caruncular lesions; others include pyogenic granuloma (9%), inclusion cysts, and oncocytoma; only 5% malignant (eg, melanoma, SCC, sebaceous carcinoma)

Suggested Reading

Bianciotto C et al: Metastatic tumors to the eyelid: report of 20 cases and review of the literature. Arch Ophthalmol 127:999, 2009; Brodie SE et al: Persistence of retinal function after selective ophthalmic artery chemotherapy infusion for retinoblastoma. Doc Oph­thalmol 119:13, 2009; Damato B, Coupland SE: A reappraisal of the significance of largest basal diameter of posterior uveal mela­noma. Eye (Lond) Oct 30, 2009 [Epub ahead of print]; Damato B, Coupland SE: Conjunctival melanoma and melanosis: a reappraisal of terminology, classification, and staging. Clin Experiment Ophthalmol 26:786, 2008; Lin P, O’Brien JM: Frontiers in the management of retinoblastoma. Am J Ophthalmol 148:192, 2009; Maki JL et al: Diagnosis of retinoblastoma: how good are re­ferring physicians? Ophthalmic Genet 30:199, 2009; Mehta M, Fay A: Squamous cell carcinoma of the eyelid and conjunctiva. Int Ophthalmol Clin 49:111, 2009; Ossowski L, Aguirre-Ghiso JA: Dormancy of metastatic melanoma. Pigment Cell Melanoma Res Oct 19, 2009 [Epub ahead of print]; Pilotto E et al: Long-term choroidal vascular changes after iodine brachytherapy versus transpu­pillary thermotherapy for choroidal melanoma. Eur J Ophthalmol 19:646, 2009; Radhakrishnan A et al: Analysis of chromosomal aberration (1, 3, and 8) and association of microRNAs in uveal melanoma. Mol Vis 15:2146, 2009; Sastre X et al: Proceedings of the consensus meetings from the International Retinoblastoma Staging working Group on the pathology guidelines for the examination of enucleated eyes and evaluation of prognostic risk factors in retinoblastoma. Arch Pathol Lab Med 133:1199, 2009; Sato T et al: The biology and management of uveal melanoma. Curr Oncol Rep 10:431, 2008; Schild SE: Role of radiation therapy in the treat­ment of melanoma. Expert Rev Anticancer Ther 9:583, 2009; Shields CL et al: Choroidal nevus transformation into melanoma: anal­ysis of 2514 consecutive cases. Arch Ophthalmol 127:981, 2009; Shields CL, Shields JA: Ocular melanoma: relatively rare but requiring respect. Clin Dermatol 27:122, 2009; Shields CL, Shields JA: Conjunctival primary acquired melanosis and melanoma: tales, fairy tales, and facts. Ophthal Plast Reconstr Surg 25:167, 2009; Shome D, Esmaeli B: Targeted monoclonal antibody therapy and radioimmunotherapy for lymphoproliferative disorders of the ocular adnexa. Curr Opin Ophthalmol 19:414, 2009; Singh AD et al: Primary transpupillary thermotherapy of “small” choroidal melanoma: is it safe? Br J Ophthalmol 92:727, 2009; Suesskind D et al: Circulating melanoma cells in peripheral blood of patients with uveal melanoma before and after different therapies and associa­tion with prognostic parameters: a pilot study. Acta Ophthalmol Sep 11, 2009 [Epub ahead of print]; Yarovoy AA et al: Which cho­roidal melanoma should be treated with primary transpupillary thermotherapy? Our experience from 78 patients. Eur J Ophthalmol Jul 7, 2009 [Epub ahead of print]; You QS et al: Change of choroidal nevi during five years follow-up. The Beijing Eye Study. Br J Ophthalmol Oct 12, 2009 [Epub ahead of print].