Coupland, Sarah E

Fiorentzis, Miltiadis

Heimann, Heinrich

Thornton, Sophie

Clinical and Experimental Ophthalmology

Miltiadis Fiorentzis

Heinrich Heimann

Sophie Thornton

Sarah E Coupland

Crossref

Two different tumours in the same eye

University of Liverpool Repository

Letter to the EditorTwo different tumours in the sameeyeBenign and malignant intraocular pigmented lesionscan share similar clinical and diagnostic signs, posinga challenge for the clinician ophthalmologist.1 Wereport a case of a retinal pigment epithelium (RPE)adenoma imitating a malignant transformedmelanocytoma at the optic nerve, 10years after treat-ment of a peripheral choroidal melanoma in the sameeye. According to our knowledge, this is the ﬁrst re-port of a choroidal melanoma and an RPE adenomain the same eye.A 54-year-old woman was diagnosed with a pe-ripheral choroidal melanoma in the right eye andunderwent ruthenium plaque radiotherapy. At thattime, a presumed melanocytoma of the optic discwas documented in the same eye. The left eye wasunremarkable. Ten years after melanoma treatment,the patient complained about metamorphopsia andprogressive visual loss. On examination, best-corrected visual acuity was 6/38 oculus dexterQ2 (OD)and 6/6 oculus sinister (OSQ3 ). The intraocular pressurewas 18mmHg OD and 20mmHg OS. There was nosigniﬁcant change to the pigmented lesion at the rightoptic disc compared with previous ﬁndings (Fig.F1 1a).On ultrasonography, the tumour measured3.54×3.71mm with a thickness of 1.73mm. The pre-viously treated choroidal melanoma in the superiorperiphery had regressed completely. Six monthslater, however, the pigmented tumour at the opticnerve showed a slight increase in growth, measuring4.09×3.97mm with a thickness of 1.64mm. A vitrec-tomy with silicone oil tamponade and a transretinalbiopsy of the presumed melanocytoma with the 25-gauge vitreous cutter were conducted 8months laterbecause of an exudative retinal detachment. The cyto-logical examination suggested a pigmented tumour,predominantly of small plump cells with oval-shaped nucleus and with a discrete central nucleolus.The molecular diagnostics using microsatelliteanalysis revealed an allelic imbalance and loss of het-erozygosity for one of the four examined loci on chro-mosome 3p as well as for one locus on chromosome3q, suggestive (but not conclusively) of the diagnosisof a spindle cell choroidal melanoma.A further 2months later, the patient re-presentedwith a rhegmatogenous retinal re-detachment in theright eye. Best-corrected visual acuity was hand mo-tion OD and 6/6 OS. Both eyes were normotensive.On the grounds of signiﬁcantly reduced vision andthe suggested diagnosis of a malignant transforma-tion of the presumed melanocytoma into a mela-noma, enucleation of the right eye was decided onby the patient.The enucleation specimen revealed chorioretinalatrophy at the level of the equator, corresponding tothe area of the previously treated choroidal mela-noma. At the optic disc, a nodular proliferation ofRPE cells in the form of pseudoglands and trabeculaewas seen (Fig. 1b). Some of the RPE cells werepigmented Q4. The cells were small-to-medium in sizewith ovoid nuclei and prominent nucleoli. Mitoseswere not seen. The lesion was contiguous with theCompeting/conﬂicts of interest: None.Funding sources: None.Figure 1. Ophthalmoscopic image and histology of the right eye. (a) Ophthalmoscopic image demonstrating the black pigmented tu-mour at the optic disc and the area of plaque irradiation superiorly. Inset, magniﬁed view of the lesion of concern at the optic disc. (b)Enucleation specimen showing a chorioretinal atrophy following plaque brachytherapy and a nodular proliferation of the retinal pigmentepithelium (RPE) (arrow) at the optic disc (hematoxylin–eosin, original magniﬁcation × 1.5). Inset, magniﬁed view of the area in the cho-roidal and retinal atrophy (hematoxylin–eosin, original magniﬁcation × 10).Clinical and Experimental Ophthalmology 2016; ••: ••–•• doi: 10.1111/ceo.12830© 2016 Royal Australian and New Zealand College of OphthalmologistsJournal Code Article ID Dispatch: 06.09.16 CE:C E O 1 2 8 3 0 No. of Pages: 3 ME:123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960616263646566676869707172737475767778798081828384858687888990919293949596979899100101102103104105106107108109110111112113114115116117118119120121122123124adjacent RPE layer. On immunohistochemistry, thesecells were strongly positive for MelanA, Ki-67 andthe cytokeratin stain AE1/AE3 as well as forCAM5.2 (weak; Fig.F2 2b,c,d). Nuclear staining formicrophthalmia transcription factorQ5 was seen. Theywere negative for the cytokeratin markers CK5/6,CK7 and MNF-116, as well as for the melanocytemarkers SOX10 and HMB-45. These histologicalﬁndings led to the diagnosis of an RPE adenoma atthe optic nerve.We report a rare case of two different tumour enti-ties in the same eye. The coexistence of two or moreneoplasms in the same eye is very uncommon andcan be diagnostically challenging.2,3 To date, theoccurrence of an RPE adenoma and a choroidalmelanoma has not been described in the literature.There are some similarities among RPE adenomas,choroidal melanocytomas and melanomas; however,there are usually distinct clinical signs for differenti-ating these neoplasms.4 Despite this, in some cases,the differentiation between these entities can bedifﬁcult and requires pathological analysis.In the present case, it was clear that the peripheralchoroidal tumour was a melanoma and was treated assuch. The initial clinical diagnosis of an additionaloptic disc melanocytoma – a benign lesion, whichmay enlarge on follow-up examination but otherwiseseldom causes further ocular complications5 – wasbased on the tumour's location, size, shape, degreeof pigmentation and on ﬂuorescein angiographycharacteristics. The latter tends to demonstrate hypoﬂuorescence in these lesions. A late pooling of dyecan be seen if secondary optic disc oedema and/orsubretinal ﬂuid are present.5 Ultrasonography is oflow diagnostic value because of the small size ofmelanocytomas and the mean thickness of less than1mm.5 Only 1–2% of ocular melanocytomas willundergo transformation into melanoma.Similar to choroidal melanocytomas, RPE neo-plasms can present as dark brown or black lesions.4RPE tumours appear as abruptly elevated massesarising perpendicularly and usually lack the adjacentbase that is seen with most choroidal melanomas ormelanocytomas.4 It is reported that RPE adenomasrest upon Bruch's membrane and do not producethe characteristic mushroom conﬁguration of somemelanomas.4 However, RPE adenomas can induceyellow retinal or subretinal exudation and ultimatelyexudative retinal detachments.4 Tumours of the RPEshow prominent feeder vessels in arterial phase andtend to be hypoﬂuorescent in the ﬁlling stages. Thisis in contrast to choroidal melanomas, which showa dilated tortuous vein and an earlyhyperﬂuorescence and intense late staining.4 On ul-trasound, RPE adenomas show high internal reﬂec-tivity with A-scan and a dome-shaped mass withacoustic hollowness with B-scan compared with thelow internal reﬂectivity of the choroidal melanoma.4Figure 2. Immunohistochemical staining of the enucleated specimen. (a) Hematoxylin–eosin staining demonstrates the adenoma ofthe RPE, with the adjacent disorganised retina showing gliosis (asterix) and occasional silicone oil droplets (arrows) (original magniﬁca-tion ×20). (b) Immunostaining using AE1/AE3 indicates that the pigmented tumour has arisen from the RPE, which at the right has a reg-ular structure (original magniﬁcation ×20). (c) The RPE adenoma demonstrated patchy immunoreactivity for MelanA (originalmagniﬁcation ×40). (d) A very low Ki-67 growth fraction (arrow) (original magniﬁcation ×40).2 Letter to the Editor© 2016 Royal Australian and New Zealand College of Ophthalmologists123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960616263646566676869707172737475767778798081828384858687888990919293949596979899100101102103104105106107108109110111112113114115116117118119120121122123124Cytological analysis demonstrates deeply pigmented,plump, round cells with large melanosomes and raremitotic ﬁgures in RPE adenoma cases compared withthe spindle cells that characterize most melanomas.4,6Because of its rarity, the immunohistochemical char-acteristics of the RPE adenoma have not been exten-sively described. In contrast to melanoma, RPEadenoma is negative for HMB-45 and cytokeratin7.6 Instead, RPE may be positive for epithelial mem-brane antigen, S-100P, neurone-speciﬁc enolase,synaptophysin and vimentin.6 To date, the geneticchanges of RPE adenomas are not known.This case demonstrates the clinical complexity ofdifferentiating pigmented intraocular lesions as wellas the rarity of two different neoplastic entities inthe same eye. Further investigation of the molecularand immunohistochemical features of RPE adenomawould aid the diagnostic process in unclear casesand enhance the therapeutic approach for the affectedpatients.Q1 Miltiadis Fiorentzis MD,1,2,3 Heinrich Heimann MDFRCOphth,2 Sophie Thornton BSc1 andSarah E Coupland PhD FRCPath11Liverpool Ocular Oncology Research Group, Department ofClinical and Molecular Cancer Medicine, University ofLiverpool, 2Liverpool Ocular Oncology Centre, Liverpool, UKand 3Department of Ophthalmology, Saarland UniversityMedical Centre, Homburg, GermanyReceived 29 June 2016; accepted 26 August 2016.REFERENCES1. Shields JA, Augsburger JJ, Brown GC, Stephens RF.The differential diagnosis of posterior uveal melanoma.Ophthalmology 1980; 87: 518–22.2. Babu K, Murthy KR, Krishnakumar S. Two successiveocular malignancies in the same eye of a HIV-positivepatient: a case report. Ocul Immunol Inﬂamm 2010; 18:101–3.3. Călugăru M, Barsu M, Rotaru A, Ciuce C. Two differentprimary ophthalmic cancers in a 39-year-old femalepatient. Oftalmologia 1994; 38: 205–15.4. Shields JA, Shields CL, Gündüz K, Eagle RC Jr.Neoplasms of the retinal pigment epithelium: the 1998Albert Ruedemann, Sr, Memorial lecture, Part 2. ArchOphthalmol 1999; 117: 601–18.5. Shields JA, Demirci H, Mashayekhi A, Shields CL.Melanocytoma of optic disc in 115 cases: the 2004Samuel JohnsonMemorial Lecture, part 1. Ophthalmology2004; 111: 1739–46.6. Cupp DG, McCannel TA. Macular pucker in associationwith RPE adenoma: a report of a case and review of theliterature. Semin Ophthalmol 2014; 29: 199–201.Letter to the Editor 3© 2016 Royal Australian and New Zealand College of Ophthalmologists123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960616263646566676869707172737475767778798081828384858687888990919293949596979899100101102103104105106107108109110111112113114115116117118119120121122123124Author Query FormJournal: Clinical & Experimental OphthalmologyArticle: ceo_12830Dear Author,During the copyediting of your paper, the following queries arose. Please respond to these by annotating your proofs with thenecessary changes/additions. If you intend to annotate your proof electronically, please refer to the E-annotation guidelines. If you intend to annotate your proof by means of hard-copy mark-up, please use the standard proo ng marks. If manually writ-ing corrections on your proof and returning it by fax, do not write too close to the edge of the paper. Please remember thatillegible mark-ups may delay publication.Whether you opt for hard-copy or electronic annotation of your proofs, we recommend that you provide additional clari c tionof answers to queries by entering your answers on the query sheet, in addition to the text mark-up.Query No. Query RemarkQ1 AUTHOR: Please con rm that given names (red) and surnames/family names (green)have been identi ed correctly.Q2 AUTHOR:  oculus dexter was provided as the de nition for  OD. Please check andchange as necessary.Q3 AUTHOR:  oculus sinister was provided as the de nition for  OS. Please check andchange as necessary.Q4 AUTHOR: The sentence Some of the RPE cells were pigmented has been edited toavoid redundancy. Please check that the intended meaning was retained.Q5 AUTHOR:  microphthalmia transcription factor was provided as the de nition for MITF.  Please check and change as necessary.  Online Proofing System 1. 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Two different tumours in the same eye

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