Acquired Tumors Arising from Congenital Hypertrophy of the Retinal Pigment Epithelium

CLINICAL SCIENCES Acquired Tumors Arising From Congenital Hypertrophy of the Retinal Pigment Epithelium

Jerry A. Shields, MD; Carol L. Shields, MD; Arun D. Singh, MD

Background: Congenital hypertrophy of the retinal lacunae in all 5 patients. The CHRPE ranged in basal di- pigment epithelium (CHRPE) is widely recognized to ameter from 3ϫ3mmto13ϫ11 mm. The size of the el- be a flat, stationary condition. Although it can show evated lesion ranged from 2ϫ2ϫ2mmto8ϫ8ϫ4 mm. minimal increase in diameter, it has not been known to The nodular component in all cases was supplied and spawn nodular tumor that is evident ophthalmoscopi- drained by slightly prominent, nontortuous retinal blood cally. vessels. Yellow retinal exudation occurred adjacent to the nodule in all 5 patients and 1 patient developed a second- Objectives: To report 5 cases of CHRPE that gave rise ary retinal detachment. Two tumors that showed progres- to an elevated lesion and to describe the clinical features sive enlargement, increasing exudation, and progressive of these unusual nodules. visual loss were treated with iodine 125–labeled plaque brachytherapy, resulting in deceased tumor size but no im- Methods: Retrospective medical record review. provement in the visual acuity.

Results: Of 5 patients with a nodular lesion arising from Conclusions: Congenital hypertrophy of the retinal pig- CHRPE, there were 4 women and 1 man, 4 whites and 1 ment epithelium can spawn a nodular growth that slowly black. Three patients were followed up for typical CHRPE enlarges, attains a retinal blood supply, and causes exuda- for longer than 10 years before the tumor developed; 2 pa- tiveretinopathyandchroniccystoidmacularedema.Although tients were recognized to have CHRPE and the elevated no histopathologic evidence is yet available, we believe that tumor concurrently. Visual acuity was decreased in 3 pa- the tumor probably represents either an acquired adenoma tients, mainly due to cystoid macular edema. The tumor or a reactive proliferation of the retinal pigment epithelium. was located between the equator and ora serrata in all 5 The best treatment of these lesions is not yet established. patients. There was no predilection for quadrant of the fundus. The flat part of the lesion was black and had visible Arch Ophthalmol. 2000;118:637-641

ONGENITAL hypertrophy evated lesion developed from solitary of the retinal pigment epi- CHRPE. thelium (CHRPE) is a well-known fundus con- REPORT OF CASES dition that generally ap- pearsC as an asymptomatic flat lesion at the CASE 1 level of the retinal pigment epithelium (RPE).1-5 It can occur as a solitary lesion A 24-year-old white woman was found on or as multifocal lesions known as congen- routine ophthalmic examination in 1970 ital grouped pigmentation or “bear to have a flat, sharply demarcated, pig- tracks.”1,2 In contrast with the similar bi- mented lesion at the temporal equator of lateral, multiple, irregular lesions that are the right eye, consistent with CHRPE. The associated with familial adenomatous pol- lesion was stable until October 1988 when yposis and Gardner syndrome, the typi- a nodule was noted arising from the flat cal solitary and multifocal forms of CHRPE lesion. On ophthalmic examination then, are not associated with those diseases.6 the oval CHRPE measured about 6ϫ4mm Both the solitary and the multifocal forms in basal dimensions and had typical de- are generally believed to be stationary le- pigmented lacunae and a marginal light sions. There have been reports of in- halo. In its center was a round nodule that crease in diameter of solitary CHRPE, but measured 1ϫ1ϫ1mm(Figure 1). Our 7-10 From the Oncology Service, the change is usually minimal. To our diagnosis was solitary CHRPE with pos- Wills Eye Hospital, Thomas knowledge, CHRPE has not been docu- sible adenoma of the RPE. By November Jefferson University, mented to spawn an elevated intraocular 1998, the CHRPE was stable in basal di- Philadelphia, Pa. nodule. We report 5 cases in which an el- mensions, but the nodule was larger, mea-

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We performed a review of all patients seen by the Ocu- lar Oncology Service, Wills Eye Hospital, Philadel- phia, Pa, who had been coded as having CHRPE and who developed a solid, elevated nodule that arose from the flat component of the lesion. All patients pro- vided informed consent for inclusion in this study. We determined the age, race, sex, visual acuity, lo- cation and color of the lesion, associated macular changes, size of the CHRPE, size of the associated nodular tumor, presence of retinal feeder blood vessels and exudation, and follow-up data.

Figure 1. Case 1. Oval congenital hypertrophy of the retinal pigment epithelium, measuring 6 ϫ4 mm in basal dimensions, with typical depigmented lacunae and a marginal light halo. A distinct, round nodular suring 2ϫ2ϫ2 mm at ultrasonography. The patient con- tumor has developed in an area that was previously flat. tinues to have yearly ophthalmic examinations.

CASE 2

A 54-year-old black woman was found in April 1995 to have a pigmented lesion at the equator superonasally in the left eye measuring 5ϫ4 mm in diameter. Most of the lesion was flat with a well-defined border, depigmented lacunae, and marginal light halo, compatible with CHRPE. Arising from the anterior edge of the flat component of the lesion was a black nodule that measured 2ϫ2mm in basal dimensions and 2 mm in thickness. Minimally dilated retinal blood vessels appeared to feed and drain the nodule and circinate exudation was present around the base of the nodule (Figure 2). By April 1998, the flat component of the lesion was unchanged, but the elevated nodule had enlarged slightly and there was more Figure 2. Case 2. Pigmented lesion located at the equator superonasally in yellow intraretinal exudation. the left eye, measuring 5 ϫ4 mm. There is a posterior component compatible with congenital hypertrophy of the retinal pigment and an CASE 3 anterior round nodule with retinal feeder and drainer vessels. The black nodule is surrounded by yellow intraretinal exudation. In 1984, a 47-year-old white woman was found to have a pigmented equatorial lesion inferonasally, consistent with Near the equator inferonasally was a black mass with a well- CHRPE. In 1988, a black nodule, measuring 2ϫ2ϫ2mm defined flat portion measuring 6ϫ6 mm and a dome- was noted on the anterior margin of the flat lesion shaped portion that measured 3ϫ3ϫ3 mm arising from (Figure 3, A). The nodule had retinal feeding and drain- the anterior margin of the flat lesion (Figure 4). Our di- ing blood vessels, yellow intraretinal exudation, and over- agnosis was presumed adenoma of the RPE arising from lying vitreous inflammatory cells and erythrocytes along CHRPE. Because the cystoid macular edema and visual loss its anterior border. By June 1991, the elevated lesion were most likely secondary to the tumor, the patient was measured 6ϫ5ϫ4 mm (Figure 3, B). B-scan ultrasonog- treated with 125I-plaque brachytherapy. In August 1995, raphy showed an elevated lesion with acoustic solidity, visual acuity was light perception in the right eye and se- no choroidal excavation, and a secondary retinal detach- vere cystoid macular edema was still present. ment (Figure 3, C). Because of tumor enlargement, exudation, retinal detachment, and hemorrhage, the patient CASE 5 was treated with 125I-plaque brachytherapy in July 1992. In May 1997, her visual acuity was 3/400 OS and tumor A 63-year-old white woman with a history of branch reti- thickness had decreased to 1.9 mm at ultrasonography. nal vein obstruction in the right eye was found in January The cystoid macular edema and exudation persisted. 1997 to have a 13ϫ11-mm, well-defined CHRPE lesion in the superior equatorial region of the same eye, with an CASE 4 8ϫ8ϫ4-mm light brown mass arising from its anterior aspect (Figure 5). The foveal area showed mottling of A 42-year-old white man was found in October 1994 to the RPE, mild preretinal vitreous fibrosis, and slight cys- have finger counting vision and a tumor in his right eye. toid macular edema. The nodule was supplied by mini-

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©2000 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 Figure 4. Case 4. Pigmented lesion located near the equator inferonasally, showing a well-defined flat component posteriorly with depigmented lacunae and a dome-shaped nodule overriding the anterior margin of the lesion. The subtle exudation seen clinically around the black nodule is not apparent in the photograph.

Figure 5. Case 5. Flesh-colored, light brown nodule arising from typical congenital hypertrophy of the retinal pigment epithelium. There is slight retinal exudation around the base of the nodule.

elevated tumor was 50 years (age range, 42-63 years). Two of the patients (cases 1 and 3) had been recognized to have typical flat solitary CHRPE before the elevated nodule (4 Figure 3. Case 3. A, Lesion as seen in 1988 showing typical congenital and 18 years, respectively). The other 3 patients (cases 2, hypertrophy of the retinal pigment epithelium. On the anterior border of the 4, and 5) had simultaneous diagnosis of the flat CHRPE flat lesion is a distinct black nodule with adjacent accumulation of yellow intraretinal exudation and overlying vitreous inflammatory cells and and the elevated lesion. The right eye was affected in 3 pa- erythrocytes. B, Appearance of lesion in June 1991, showing enlargement of tients and the left eye in 2 patients. The meridional loca- the lesion, increased exudation, and more overlying vitreous haze. C, B-scan tion of the fundus lesion was superior in 1 patient, su- ultrasonogram showing acoustically solid nodule with secondary retinal detachment. peronasal in 1 patient, inferonasal in 2 patients, and temporal in 1 patient. The initial visual acuity in the affected eye ranged from 6/6 to finger counting. The nodu- mally dilated retinal blood vessels. In April 1999, the le- lar component of the lesion was black in 4 patients (cases sion was slightly larger, measuring 4.3 mm in thickness. 1 through 4) and light brown in 1 patient (case 5). The 3 patients with worse than 6/6 visual acuity all had cystoid RESULTS macular edema and 2 patients had surface wrinkling retinopathy. The size of the flat CHRPE component ranged A tabulation of the most pertinent information on these 5 from 5ϫ4mmto13ϫ11 in basal dimensions. patients is listed in the Table. There were 4 women and There were several important associated retinal find- 1 man, 4 white and 1 black patient. The mean age at the ings. As mentioned previously, 3 patients had cystoid time of diagnosis of the CHRPE was 46 years (age range, macular edema and 2 patients had surface wrinkling reti- 24-63 years). The mean age at the time of diagnosis of the nopathy. All of these changes were remote from the main

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©2000 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 Data on Patients With Nodular Lesions Arising From Congenital Hypertrophy of the Retinal Pigment Epithelium (CHRPE)*

Age of Patient at Diagnosis, y Visual Acuity Size, mm Patient Status Presence of Duration of No. Of CHRPE Of Nodule Initial Finalof Macula Of CHRPE Of Nodule RFV/Exudation Follow-up, y 1 24 42 6/6 6/6 Normal 6 ϫ 42ϫ2ϫ2 Yes/yes 29 2 54 54 6/6 6/6 Normal 5 ϫ 42ϫ2ϫ2 Yes/yes 4 3 47 51 6/18 CF CME 8 ϫ 76ϫ5ϫ4 Yes/yes 15 4 42 42 CF LP CME and SWR 6 ϫ 63ϫ3ϫ3 Yes/yes 4 5 63 63 6/15 6/18 CME and SWR 13 ϫ 11 8 ϫ 8 ϫ 4 Yes/yes 2

*RFV indicates retinal feed vessels; CF, counting fingers; LP, light perception; CME, cystoid macular edema; and SWR, surface wrinking retinopathy.

pigmented lesion, but there were no other evident causes Another consistent finding with this fundus condition for the macular changes. Minimally dilated, nontortu- is the development of a slightly prominent, nontortuous reti- ous feeder and drainer blood vessels were identified en- nal artery and vein that supply and drain the nodular por- tering and exiting the tumor in all 5 patients. Some amount tion of the lesion, supporting the observation that the lesion of yellow intraretinal exudation was also seen adjacent has extended to involve the sensory retina. The occurrence to the nodule in all 5 cases. One patient (case 3) had a of yellow intraretinal exudation around the nodule suggests secondary localized exudative retinal detachment. that it contains hyperpermeable blood vessels, presumably Ultrasonography, performed in all 5 patients, showed derivedfromthesensoryretina.Ourrecentstudyonacquired an abruptly elevated, round mass in all cases with high neoplasms of the RPE, which did not include the cases re- internal reflectivity with A-scan and acoustic solidity with- ported here, revealed that those RPE tumors can assume a out choroidal excavation with B-scan (Figure 3, C). Spon- retinal blood supply and produce exudative retinopathy.11 taneous vascular pulsations were not clearly seen in any A presumed adenoma arising from CHRPE should be added of the tumors. to the list of lesions that can cause exudative retinopathy. The CHRPE in these cases was located at or ante- COMMENT rior to the equator in all 5 of our patients and the nodular growth usually occurred near the anterior margin of Congenital hypertrophy of the retinal pigment epithe- the CHRPE. This made it difficult to obtain clear fundus lium, once considered to be a stationary lesion, has re- photographs of the lesions. cently been documented to show an increase in basal di- The microscopic features of the tumors described mensions.7-10 Although such growth was previously in this article are still unknown. Possibilities include ac- considered rare, Chamot et al10 demonstrated slight en- quired adenoma of the RPE, reactive hyperplasia of the largement of the lesion in 26 (74%) of 35 patients. How- affected RPE, secondary form of retinal vasoprolifera- ever, a clinically evident, elevated nodule associated with tive tumor, and choroidal melanoma. CHRPE has not, to our knowledge, been previously rec- An acquired neoplasm of the RPE (adenoma) gen- ognized. The fact that we have seen 5 such cases sug- erally occurs in otherwise normal eyes of patients who gests that it may not be rare. It is likely that some of these have not had prior ocular trauma or inflammation.11 It peripheral lesions are never detected clinically because appears clinically as a dome-shaped pigmented mass that the asymptomatic patient does not have an ocular ex- often assumes a retinal blood supply and induces in- amination. In other cases, the CHRPE may be detected traretinal exudation. In that sense, reported cases of ad- but periodic follow-up is not recommended because of enoma and adenocarcinoma of the RPE have been simi- its benign nature. lar to the lesions described here, with the exception that The fundus changes associated with the nodular they have not had typical CHRPE at their base.11 It is pos- tumors arising from CHRPE are noteworthy. The 3 sible that some reported cases of adenoma of the RPE ac- patients with visual impairment (cases 3 through 5) all tually arose from CHRPE, which eventually became ob- had cystoid macular edema and 2 of them (cases 4 and scured by the overlying neoplasm. 5) also had surface wrinkling retinopathy. There was no Reactive hyperplasia of the RPE is best known to de- other apparent cause for their visual loss. We have velop in traumatized or inflamed eyes. Usually there is a observed such remote macular changes associated with history or clinical findings of such prior insults. None other peripheral tumors such as uveal melanoma, of our patients had a history or ocular findings to sug- adenoma of the RPE, adenoma of the nonpigmented cili- gest inflammation or trauma. It is possible that CHRPE, ary epithelium, retinal capillary hemangioma, and vaso- which was clearly evident in our patients, could spawn proliferative tumor. The mechanism of development of reactive hyperplasia of the RPE. In a histopathologic study cystoid macular edema and surface wrinkling retinopa- of a case of flat CHRPE, Wirz et al12 noted a small focus thy in association with peripheral fundus lesions is not of associated hyperplasia of the RPE. However, it had not well understood. A nodular tumor arising from CHRPE assumed tumorous proportions. should be added to the list of entities known to be asso- The presumed acquired retinal hemangioma,13 more ciated with cystoid macular edema and with surface recently called “vasoproliferative tumor of the fundus,”14 is wrinkling retinopathy. a recently described entity that can occur as a primary or sec-

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©2000 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 ondary form. The secondary form develops in association scribed, is characteristically slowly progressive, assumes with intermediate uveitis, retinitis pigmentosa, Coats’ dis- a blood supply from the sensory retina, causes localized ease, chronic retinal detachment, and a variety of other ocu- exudative retinopathy, cystoid macular edema, and sur- lar insults. It is feasible that such a vasoproliferative process face wrinkling retinopathy. Although histopathologic evi- could occur secondary to solitary CHRPE. The vasoprolif- dence is yet unavailable, we speculate that the mass is erative tumor typically is a fleshy red-pink, whereas lesions either an acquired adenoma of the RPE or a reactive pro- in our patient were deeply pigmented. The only exception liferation of the RPE. Clinicians should be aware of this was our patient 5 in whom the nodule was a light brown. lesion and periodically follow up patients with solitary However, the tumor in that case clearly arose from solitary CHRPE for its development. Asymptomatic patients can CHRPE. The light color of the lesion in that patient does not be observed without treatment. The best management for exclude adenoma of the RPE, since we have observed cases those that produce visual loss is not clearly established. of histologically documented neoplasms of the RPE in which the tumor had a fleshy color clinically.11,15 Accepted for publication November 29, 1999. We speculate that the tumors observed in these pa- This investigation was supported by the Eye Tumor Re- tients probably are examples of acquired adenoma of the search Foundation, Philadelphia, Pa; the Award of Merit in RPE that arose from solitary CHRPE. However, it is pos- Retina Research, Houston, Tex (Dr J. A. Shields); and the sible that they represent a reactive proliferation of the RPE. Macula Foundation, New York, NY (Dr C. L. Shields). Attempting to differentiate acquired adenoma from re- Presented as part of the 2000 Lu Esther T. Mertz Lec- active hyperplasia may be superfluous because both are ture, New York, NY, March 15, 2000. benign conditions that have similar clinical courses.1,2 We gratefully acknowledge John J. Coyle, MD, An- There have been several reports of CHRPE in which drew P. Schachat, MD, Jose Sabina, MD, Neal Hall, MD, histopathologic studies have been done,3-5,12,16-18 but none and Steven Cohen, MD,who referred the 5 patients. have shown a solid nodule similar to the ones observed clini- Corresponding author: Jerry A. Shields, MD, Ocular cally in our patients. The case of Reese and Jones16 showed Oncology Service, Wills Eye Hospital, 900 Walnut St, Phila- reduplication of the RPE, but no distinct nodule was ob- delphia, PA 19107. served clinically or histopathologically. The case of Duke 17 and Maumenee was reported as a flat lesion but histopatho- REFERENCES logically it showed irregular pigment in the overlying sensory retina. However, the pigment epithelial component of 1. Shields JA, Shields CL. Tumors and related lesions of the pigment epithelium. their lesion was flat, whereas in our patients there was a dis- In: Shields JA, Shields CL, eds. Intraocular Tumors: A Text and Atlas. Philadel- tinct nodule, confirmed clinically and ultrasonographically. phia, Pa: WB Saunders Co; 1992:438-444. 18 2. Shields JA, Shields CL. Tumors of the retinal pigment epithelium. In: Shields JA, Likewise, the case reported by Kurz and Zimmerman was Shields CL, eds. Atlas of Intraocular Tumors. Philadelphia, Pa: Lippincott Wil- flat, with no nodular component. Kasner et al19 reported liams &Wilkins; 1999:288-292. histopathologic studies of the multiple pigment epithelial 3. Buettner H. Congenital hypertrophy of the retinal pigment epithelium. Am J Oph- thalmol. 1975;79;177-189. lesions that occurred in a patient with familial adenoma- 4. Purcell JJ, Shields JA. Hypertrophy with hyperpigmentation of the retinal pig- tous polyposis. Although their patient had been examined ment epithelium. Arch Ophthalmol. 1975;93:1122-1126. 5. Lloyd WC III, Eagle RC Jr, Shields JA, Kwa DM, Arbizo VV. Congenital hypertro- clinically, none of the lesions formed a distinct nodule as phy of the retinal pigment epithelium: electron microscopic and morphometric seen in our patients. The RPE lesions seen in familial ad- observations. Ophthalmology. 1990;97:1052-1060. enomatous polyposis are different clinically from the soli- 6. Shields JA, Shields CL, Shah P, Pastore D, Imperiale SM Jr. Lack of association between typical congenital hypertrophy of the retinal pigment epithelium and Gard- tary lesions described in this article, although it is possible ner’s syndrome. Ophthalmology. 1992;99:1705-1713. that the lesions in our patients could have a similar histo- 7. Norris JL, Cleasby GW. An unusual case of congenital hypertrophy of the retinal pathologic pattern. pigment epithelium. Arch Ophthalmol. 1976;94;1910-1911. 8. Boldrey EE, Schwartz A. Enlargement of congenital hypertrophy of the retinal pig- Concerning management of these lesions, it seems ment epithelium. Am J Ophthalmol. 1982;94:64-66. advisable to observe them periodically if the patient is 9. van der Torren K , Luyton GP. Progression of papillomacular congenital hypertrophy of the retinal pigment epithelium associated with impaired visual func- asymptomatic and there is no apparent visual threat from tion. Arch Ophthalmol. 1998;116:256-257. cystoid macular edema or progressive exudation. Four 10. Chamot L, Zografos L, Klainguti G. Fundus changes associated with congenital hy- of our 5 patients experienced visual loss secondary to pertrophy of the retinal pigment epithelium. Am J Ophthalmol. 1993;115:154-161. 11. Shields JA, Shields CL, Gu¨ndu¨z K, Eagle RC Jr. Neoplasms of the retinal pig- macular changes, presumably related to the peripheral ment epithelium: The 1998 Albert Ruedemann Sr Memorial Lecture, part 2. Arch mass. Management options for those causing visual loss Ophthalmol. 1999;117:601-608. include treating the macular edema medically or with grid 12. Wirz K, Lee WR, Coaker T. Progressive changes in congenital hypertrophy of the retinal pigment epithelium. Graefes Arch Clin Exp Ophthalmol. 1982;219:214-221. laser photocoagulation or treating the tumor with laser 13. Shields JA, Decker WL, Sanborn GE, Augsburger JJ, Goldberg RE. Presumed photocoagulation, cryotherapy, or 125I-plaque brachy- acquired retinal hemangiomas. Ophthalmology. 1983;90:1292-1300. 14. Shields CL, Shields JA, Barrett J, De Potter P. Vasoproliferative tumors of the therapy, or local resection. The 2 tumors that were treated ocular fundus: classification and clinical manifestations in 103 patients. Arch Oph- 125 with I-plaque brachytherapy showed a moderately thalmol. 1995;113:615-623. favorable response but the cystoid macular edema and 15. Shields JA, Eagle RC Jr, Barr CC, Shields CL, Jones DE. Adenocarcinoma of the retinal pigment epithelium arising from a juxtapapillary histoplasmosis scar. Arch exudation persisted. Ophthalmol. 1994;112:650-653. 16. Reese AB, Jones IS. Benign melanomas of the retinal pigment epithelium. Am J Ophthalmol. 1956;44:207-212. CONCLUSION 17. Duke JR, Maumenee AE. An unusual tumor of the retinal pigment epithelium. Am J Ophthalmol. 1959;47:31-17 We have described 5 patients who developed an el- 18. Kurz GH, Zimmerman LE. Vagaries of the retinal pigment epithelium. Int Oph- thalmol Clin. 1962;2:441-464. evated nodule that arose from solitary CHRPE. This 19. Kasner L, Traboulsi EI, Delacruz Z, Green WR. A histopathologic study of the pig- tumor, which we believe has not been previously de- mented fundus lesions in familial adenomatous polyposis. Retina. 1992:12:35-42.

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