Hypertrophy With Hyperpigmentation of the Retinal Pigment Epithelium John J. Purcell, Jr, MD, Jerry A. Shields, MD
\s=b\ Fifty-two patients (one bilateral) exhibiting hypertrophy with hyperpigmentation of the retinal pigment epithelium (RPE) are described. Visual acuity was not affected, and the patients were asymptomatic. There was no correlation with systemic diseases, family history of
eye disease, associated fundus lesions, anterior segment abnormalities, or intraocular pressure. Field defects were rarely demonstrated using standard clinical techniques. There were three characteristic locations and four characteristic pigmentary variations that occurred alone or in any combination. The lesions were gray, black, or brown. The clinical characteristics and histopathology suggest that hypertrophy with hyperpigmentation of the RPE and congenital grouped pigmentation are different expressions of a similar condition, with the former being focal and the latter multifocal.
(Arch Ophthalmol 93:1122-1126, 1975) of benign lesions of the ocular fundus may clinical¬ resemble uveal malignant melano¬ mas, and such lesions have occasion¬ ally prompted enucleation because of their similarity to malignant mela¬
types Several ly
noma.1-2 With increasing diagnostic acumen, combined with the use of
clinical aids such as indirect ophthal¬ moscopy, fluorescein angiography, and radioactive phosphorus uptake studies, pigmented lesions such as choroidal nevi, hemorrhage beneath the retinal pigment epithelium (RPE), and hyperplasias of the RPE Submitted for publication May 31, 1974. From the Oncology Unit, Retina Service, Wills
Eye Hospital, Philadelphia. Read in part before the 26th Annual Conference, Wills Eye Hospital, Philadelphia, Feb 15, 1974.
Reprint requests to Oncology Unit, Retina Service, Wills Eye Hospital, 1601 Spring Garden St, Philadelphia, PA 19130 (Dr. Shields).
readily differentiated from malignant melanoma.1 Another con¬ dition that is perhaps less well-known are more
ophthalmologists is hypertrophy with hyperpigmentation of the RPE.4 This condition, which is probably con¬ genital, has certain characteristic features that distinguish it from malignant melanoma and other pig¬ mented lesions. During the last six years, a number of patients with this condition have been referred to the Retina Service of Wills Eye Hospital for evaluation with the diagnosis of possible choroidal malignant mela¬ noma. This report reviews fifty-two consecutive patients with hyper¬ trophy of the RPE and points out the variable clinical features of this condition. to
SUBJECTS AND METHODS The files of the Retina Service of Wills Eye Hospital from 1967-1973 were reviewed, and all fundus photo¬ graphs coded as choroidal nevus, melanocytoma, hyperplasia of the RPE, and hypertrophy of the RPE were examined. Only those cases meeting the criteria for the diagnosis of hypertrophy of the RPE were in¬ cluded. The diagnosis was established in each case by observing a well-de¬ lineated, flat, pigmented lesion at the level of the RPE. The margins of the lesions were smooth or scalloped, and the pigmentation within the lesion was variable. In some instances, the lesion was deeply pigmented and fairly round (Fig 1). In other cases it had a scalloped margin (Fig 2). Vari¬ able degrees of depigmentation were present in some lesions, so that the orange color of the choroid was visi¬ ble (Fig 3). Pigmented lesions that did not exhibit these characteristics, such as hemorrhage beneath the RPE, traumatic or inflammatory hyper-
Downloaded From: http://archopht.jamanetwork.com/ by a University of Michigan User on 06/20/2015
plasia of the RPE, choroidal nevi, and malignant melanomas were not in¬ cluded. A questionnaire was sent to the referring physician to determine the initial impression, visual acuity, intraocular pressure, condition of the anterior segment, refractive error, and any family history of ocular disease. The majority of patients included had been evaluated with fluorescein angiography. Selected pa¬ tients were recalled and studied in detail, and visual fields were per¬ formed. Two patients had radioactive phosphorus uptake studies (:l-P) and
electroretinography was performed on one patient. The peripherally lo¬ cated lesions were studied with scie¬ rai depression and transillumination. The clinical features of this condition were reviewed. RESULTS
Fifty-two patients with lesions meeting the criteria for the diagnosis of hypertrophy with hyperpigmen¬
tation of the RPE were selected. One patient had bilateral lesions. Thirtysix of the fifty-two questionnaires were received from the referring oph¬ thalmologists, and the data was ana¬ lyzed. The referring diagnoses were as follows:
Suspected malignant melanoma, 8
Choroidal nevus, 8 Unknown pigmented lesions, 12 Chorioretinal scar, 3 Retinal The the
detachment, 1 Hypertrophy of RPE, 4
diagnosis cases
diagnosis
was
correct in four of
(11%). The was
most frequent "rule out malignant "choroidal nevus." In
melanoma" or 12 cases the diagnosis was not speci¬ fied, but there was concern over a pig¬ mented lesion. Forty-five whites and seven blacks
Fig 1.—Fairly round, flat, deeply pigmented lesion pigment epithelium.
at level of
retinal
Fig 3—Lesion in superior fundus showing increased visibility of choroidal vasculature through hyperpigmented areas of RPE. included in the study. There 28 men and 24 women. The right eye was involved in 24 cases, the left eye in 27, and one case was bilateral. None of the patients had visual im¬ pairment attributable to the lesion. The intraocular pressure was normal bilaterally in all patients. No anterior were
were
segment abnormalities
were
present.
There was no correlation with iris color. The age at diagnosis ranged from 14 to 86 years, with a mean age of 51 years. There was no history of systemic or ocular disease, ocular trauma, or ab¬ normal birth history. One patient had bilateral xanthelasma, and another had a congenital brownish-purple pig¬ mentation of the nail of the middle finger. Two patients had a family his¬ tory of retinal detachment. Ten had
Fig 2.—Pigmented
lesion
showing scalloped
distinct
Fig 4.—Peripapillary hypertrophy of RPE extending gin with undeviated retinal vessels and focal areas mentation.
fundus changes such as paving stone or lattice degeneration. The lesion was found in any area of the fundus. In those patients who re¬ turned for examination, it was found temporally in 72.2% with an equal number of lesions (13) found supertemporally and infratemporally. Two were located superonasally, three inferonasally, four peripapillary, and one in the macula. The peripapillary cases extended to the disc margin (Fig 4). Those cases in the periphery of the fundus were
larger, more variably pigmented (Fig 5), and extended to and stopped at the ora serrata. The most frequent type encountered was a single iso¬ lated lesion between the posterior pole and the periphery. The lesions ranged from less than one to 14 disc
Downloaded From: http://archopht.jamanetwork.com/ by a University of Michigan User on 06/20/2015
margin.
to disc mar¬ of hypopig¬
diameters in
size, with larger lesions usually located more peripherally. Pigmentation variations fell into five categories. Eight of 53 of these
jet black or gray in ap¬ (Fig 1, 2, and 6). Fifteen ex¬ hibited a "peripheral mottling" with visualization of the underlying cho¬ roid (Fig 6). A marginal halo of de¬ pigmentation was seen in eight cases (Fig 3 and 7). In 17 cases, we observed areas of depigmentation within the lesion that superficially resembled the lipofuscin in pigmentation seen on the surface of some malignant choroi¬ dal melanomas5 (Fig 8). Thirty-two lesions
were
pearance
cases
demonstrated "swiss cheese"
mottling, characterized by variably sized, round to oval, yellow lacunae of depigmentation (Fig 9 and 10). There was frequently an overlapping of two
of
Fig 5.—Large peripheral area of hypertrophy of hypopigmentation and scalloped border.
Fig 7.—Marginal halo hypertrophy of RPE.
is
seen
around
areas
Fig 6.—Isolated area of hypertrophy of RPE ripheral mottling" inside margins of lesion.
with
area
of
"pe¬
periphery of infratemporal
Fig 8.—Diffuse orange mottling seen through hypopigmentation in large hypertrophy of RPE. of these variations in a single lesion. Fluorescein angiography revealed hypofluorescence of the pigmented portions of the lesions and hyper¬ fluorescence caused by transmission of choroidal fluorescence through the various pigmentary defects (Fig 11 and 12). Visual field studies by kinetic and static Goldmann perimetry and tan¬ gent screen examination showed an absolute isolated scotoma correspond¬ ing to the lesion in one case of 12 ex¬ amined, while in the others no rela¬ tive or absolute defect was verified. Radioactive phosphorus uptake or more
RPE with
focal
areas
of
studies were performed in two pa¬ tients in which a large peripheral le¬ sion was present. No increase in up¬ take of SSP was found. One patient had a family history of retinitis pigmentosa, but the elec¬ troretinogram was normal. COMMENT In nine
1956, Reese and Jones6 reported
of what they called "be¬ of the retinal pig¬ melanoma nign ment epithelium" in which the diag¬ nosis of malignant melanoma had been entertained clinically. These were described as unilateral, isolated, black, sharply demarcated, and flat. cases
Downloaded From: http://archopht.jamanetwork.com/ by a University of Michigan User on 06/20/2015
varied from one to three disc diameters in size. The normal retinal vascular pattern was undeviated and the pigmentation was uniformly gray to black except for occasional small nonpigmented areas with sharp bor¬ ders. The lesions were non-progres¬ sive and did not produce visual field defects. The eyes were otherwise normal. Kurz and Zimmerman4 described two similar cases and gave histo¬ pathologic documentation that this was a hypertrophy of the individual pigment granules and not a true hy¬ perplasia of the RPE. They also de¬ scribed the "marginal halo" in one
They
Fig 9.—"Swiss cheese lacunae" pigmented hypertrophy of RPE.
Fig 11.—Infratemporal
lesion
of
hypopigmentation
in
darkly
exhibiting undeviated retinal
vessels, swiss cheese lacunae, marginal halo, and orange mott¬
ling. case and showed histologically that this represented an area of hypopig¬ mentation of the RPE at the margins of the lesion. Buettner7 believed that the granules of pigment in the hypertrophic RPE cells may be lipofuscin or abnormal melanin granules, but they did not resemble normal melanin granules. Kurz and Zimmerman, how¬ ever, were of the opinion that they
Fig 10.—Similar "swiss cheese lacunae" in lesion.
lightly pigmented
Fig 12.—Fluorescein angiogram of Fig 11 in arterio-venous phase demonstrating hypofluorescence of pigmented portion of lesion and hyperfluorescence of hypopigmented areas.
represented melanin granules.4
In the past, this lesion has occasion¬ ally led to enucleation because it was misinterpreted as a malignant mela¬ noma.1-4 In a recent study by Shields and Zimmerman,2 however, no cases were enucleated as suspected malig¬ nant melanoma. This may indicate that ophthalmologists are beginning to recognize this lesion as benign, al-
Downloaded From: http://archopht.jamanetwork.com/ by a University of Michigan User on 06/20/2015
though they may not know the pre¬ cise diagnosis. Since only 11% of the referring ophthalmologists had the correct diagnosis, there must be an unfamiliarity with the lesion. Im¬ portantly, 16 of 36 cases were re¬ ferred because the lesion was sus¬ pected to be either a benign nevus or a malignant melanoma of the choroid, and in 12 other cases it was called an
"unknown pigmented lesion." The differential diagnosis includes malignant melanoma,'·' choroidal nevus," choroidal melanocytoma,1' hyperplasia of the RPE,10 sunburst lesion of sickle cell disease,11 hemor¬ rhage beneath the RPE, old chorio¬ retinitis (toxoplasmosis), paving stone degeneration, and enclosed oral bay. The characteristic configuration, lo¬ cation, and pigmentary variations, and the use of fluorescein angiogra¬ phy aid in differentiating this lesion from other pigmented fundus lesions. The most important lesion in the differential diagnosis is malignant melanoma of the choroid. This lesion may be differentiated ophthalmo¬ scopically from malignant melanoma by the lack of elevation, the unde¬ viated retinal vessels, sharp distinct margins, and the four characteristic pigmentary changes. In hypertrophy of the RPE, ultrasound and :l-P stud¬ ies are normal, and field defects are rarely found by Goldmann perimetry or tangent screen examination. Fluo¬ rescein angiography of malignant melanoma demonstrates early uptake and late staining. Choroidal nevi have less distinct margins and lie beneath the RPE. Hyperplasia of the RPE is associated with a history of inflammation or trauma, is irregular in outline, and may be associated with glial or fi¬ brous tissue. Melanocytomas are usu¬ ally seen on the optic nerve head, are elevated, and often leave an irregular margin. The sunburst lesion of sickle cell disease has irregular feathery borders, gliosis, and is seen with the characteristic hématologie findings. Hemorrhage beneath the RPE may be associated with ocular trauma or macular degeneration, and has a greenish hue with irregular margins. This hemorrhage clears with time, whereas there is no change in the pig¬ mentation of hypertrophy of the RPE. Inactive lesions of toxo¬ plasmosis have areas of bare sclera,
peripheral pigmentary hyperplasia, and frequently have satellite lesions.
The color of these lesions varies from brown to gray to black. The pig¬ mentary variations are quite dis¬ tinctive and frequently occur to¬ gether. The peripheral marginal halo,
orange
mottling, peripheral mottling,
and "swiss cheese" variations are probably areas of hypopigmentation in the retinal pigment epithelium. This has been verified histologically in the case of the "marginal halo,"4 and the fluorescein pattern of choroi¬ dal transmission in these areas rein¬ forces this assumption. The fluores¬ cein pattern and transillumination through the orange mottling differ¬ entiates this lesion from the orange
lipofuscin deposits
over
malignant
melanomas that block choroidal fluo¬ rescence early5 and do not permit transmission of light. In this study, the racial differential corresponds roughly to the distribu¬ tion of blacks to whites in this coun¬ try and in our clinics. The sex, age, eye, associated ocular findings, and history of ocular or systemic disease were not remarkable. The age at diagnosis probably reflects the age most people commonly have their first fundus examination. The histopathology of these areas of hypertrophy of the RPE has been described as a single layer of hyper¬ trophy of the RPE with an increase in the concentration of granules within the cells.4 The cause is unknown, but most observers agree that this is a congenital defect. Parsons'- described a similar histopathology of congeni¬ tal grouped pigmentation or "bear tracks," and more recently this was documented by Shields and Tso.13 Whether this pigment is lipofuscin or melanin has not been established. Lowenstein and Steel14 described a case of bilateral central grouped pigmentation with marginal haloes around each lesion similar to the mar¬ ginal haloes seen in these cases. Since both hypertrophy of the RPE and
congenital grouped pigmentation are flat pigmented lesions with variable degrees of pigmentation, undeviated retinal vessels, similar histopathol¬
ogy, and with no evidence of inflam¬ mation, it appears that these are different clinical expressions of the same condition with the former being focal and the latter multifocal. Although a field defect was docu¬ mented in one patient corresponding to the lesion, in 11 others no defect was found using kinetic and static
Downloaded From: http://archopht.jamanetwork.com/ by a University of Michigan User on 06/20/2015
Goldmann perimetry and tangent screen examination. This was most striking in the one macular case that was three disc diameters in size and had a normal visual acuity, normal Amsler grid recording, and absence of field defect on multiple examina¬ tions. This corresponds to the absence of field defects in Reese's cases" using normal clinical techniques, but dif¬ fers from the studies of Buettner, who demonstrated field defects with the more sophisticated Tubingen
perimetry.7
Terranee L. Tomer, Jean Douglas, and Ruth Reber assisted in this study. This investigation was supported in part by the Retina Research and Development Founda¬ tion, Philadelphia and by the Lions Club of
Pennsylvania.
References 1. Ferry AP: Lesions mistaken for malignant melanoma of the posterior uvea: A clinicopathologic analysis of 100 cases with ophthalmoscopically visible lesions. Arch Ophthalmol 72:463-469, 1964. 2. Shields JA, Zimmerman LE: Lesions simulating malignant melanoma of the posterior uvea. Arch Ophthalmol 89:466-471, 1973. 3. Shields JA, McDonald PR: Improvements in the diagnosis of posterior uveal melanomas. Arch Ophthalmol 91:259-264, 1974. 4. Kurz GH, Zimmerman LE: Vagaries of the retinal pigment epithelium. Int Ophthalmol Clin 2:441-464, 1962. 5. Smith LT, Irvine AR: Diagnostic significance of orange pigment accumulation over choroidal tumors. Am J Ophthalmol 76:212-216, 1973. 6. Reese AB, Jones IS: Benign melanomas of the retinal pigment epithelium. Am J Ophthalmol 42:207-212, 1956. 7. Buettner H: Retinal pigment epithelial hypertrophy. Am J Ophthalmol 79:177-189, 1975. 8. Nauman GOH, Hellmer K, Nauman LR: Pigmented nevi of the choroid: Clinical study of secondary changes in the overlying tissue. Trans Am Acad Ophthalmol Otolaryngol 75:110-123, 1971. 9. Shields JA, Font RL: Melanocytoma of the choroid clinically simulating a malignant melanoma. Arch Ophthalmol 87:396-400, 1972. 10. Frayer WC: Reactivity of the retinal pigment epithelium: An experimental and histopathologic study. Trans Am Ophthalmol Soc 64:586-643, 1966. 11. Welch RB, Goldberg MF: Sickle cell hemoglobin and its relation to fundus abnormality. Arch Ophthalmol 75:353-362, 1966. 12. Parsons JH: Some anomalies of pigmentation, in Dixi\l=e`\me Congr\l=e`\s International d'Ophtalmologie. Lausanne, G. Bridel, 1905, p 152. 13. Shields JA, Tso MOM: Congenital grouped pigmentation of the retina: Histopathologic description and report of a case. Arch Ophthalmol
93:1153-1155, 1975.
14. Lowenstein A, Steel J: Special case of melanosis fundi: Bilateral congenital group pigmentation of the central area. Br J Ophthalmol 25:417-423, 1941.
\s=b\ Fifty-two patients (one bilateral) exhibiting hypertrophy with hyperpigmentation of the retinal pigment epithelium (RPE) are described. Visual acuity was not affected, and the patients were asymptomatic. There was no correlation with systemic diseases, family history of
eye disease, associated fundus lesions, anterior segment abnormalities, or intraocular pressure. Field defects were rarely demonstrated using standard clinical techniques. There were three characteristic locations and four characteristic pigmentary variations that occurred alone or in any combination. The lesions were gray, black, or brown. The clinical characteristics and histopathology suggest that hypertrophy with hyperpigmentation of the RPE and congenital grouped pigmentation are different expressions of a similar condition, with the former being focal and the latter multifocal.
(Arch Ophthalmol 93:1122-1126, 1975) of benign lesions of the ocular fundus may clinical¬ resemble uveal malignant melano¬ mas, and such lesions have occasion¬ ally prompted enucleation because of their similarity to malignant mela¬
types Several ly
noma.1-2 With increasing diagnostic acumen, combined with the use of
clinical aids such as indirect ophthal¬ moscopy, fluorescein angiography, and radioactive phosphorus uptake studies, pigmented lesions such as choroidal nevi, hemorrhage beneath the retinal pigment epithelium (RPE), and hyperplasias of the RPE Submitted for publication May 31, 1974. From the Oncology Unit, Retina Service, Wills
Eye Hospital, Philadelphia. Read in part before the 26th Annual Conference, Wills Eye Hospital, Philadelphia, Feb 15, 1974.
Reprint requests to Oncology Unit, Retina Service, Wills Eye Hospital, 1601 Spring Garden St, Philadelphia, PA 19130 (Dr. Shields).
readily differentiated from malignant melanoma.1 Another con¬ dition that is perhaps less well-known are more
ophthalmologists is hypertrophy with hyperpigmentation of the RPE.4 This condition, which is probably con¬ genital, has certain characteristic features that distinguish it from malignant melanoma and other pig¬ mented lesions. During the last six years, a number of patients with this condition have been referred to the Retina Service of Wills Eye Hospital for evaluation with the diagnosis of possible choroidal malignant mela¬ noma. This report reviews fifty-two consecutive patients with hyper¬ trophy of the RPE and points out the variable clinical features of this condition. to
SUBJECTS AND METHODS The files of the Retina Service of Wills Eye Hospital from 1967-1973 were reviewed, and all fundus photo¬ graphs coded as choroidal nevus, melanocytoma, hyperplasia of the RPE, and hypertrophy of the RPE were examined. Only those cases meeting the criteria for the diagnosis of hypertrophy of the RPE were in¬ cluded. The diagnosis was established in each case by observing a well-de¬ lineated, flat, pigmented lesion at the level of the RPE. The margins of the lesions were smooth or scalloped, and the pigmentation within the lesion was variable. In some instances, the lesion was deeply pigmented and fairly round (Fig 1). In other cases it had a scalloped margin (Fig 2). Vari¬ able degrees of depigmentation were present in some lesions, so that the orange color of the choroid was visi¬ ble (Fig 3). Pigmented lesions that did not exhibit these characteristics, such as hemorrhage beneath the RPE, traumatic or inflammatory hyper-
Downloaded From: http://archopht.jamanetwork.com/ by a University of Michigan User on 06/20/2015
plasia of the RPE, choroidal nevi, and malignant melanomas were not in¬ cluded. A questionnaire was sent to the referring physician to determine the initial impression, visual acuity, intraocular pressure, condition of the anterior segment, refractive error, and any family history of ocular disease. The majority of patients included had been evaluated with fluorescein angiography. Selected pa¬ tients were recalled and studied in detail, and visual fields were per¬ formed. Two patients had radioactive phosphorus uptake studies (:l-P) and
electroretinography was performed on one patient. The peripherally lo¬ cated lesions were studied with scie¬ rai depression and transillumination. The clinical features of this condition were reviewed. RESULTS
Fifty-two patients with lesions meeting the criteria for the diagnosis of hypertrophy with hyperpigmen¬
tation of the RPE were selected. One patient had bilateral lesions. Thirtysix of the fifty-two questionnaires were received from the referring oph¬ thalmologists, and the data was ana¬ lyzed. The referring diagnoses were as follows:
Suspected malignant melanoma, 8
Choroidal nevus, 8 Unknown pigmented lesions, 12 Chorioretinal scar, 3 Retinal The the
detachment, 1 Hypertrophy of RPE, 4
diagnosis cases
diagnosis
was
correct in four of
(11%). The was
most frequent "rule out malignant "choroidal nevus." In
melanoma" or 12 cases the diagnosis was not speci¬ fied, but there was concern over a pig¬ mented lesion. Forty-five whites and seven blacks
Fig 1.—Fairly round, flat, deeply pigmented lesion pigment epithelium.
at level of
retinal
Fig 3—Lesion in superior fundus showing increased visibility of choroidal vasculature through hyperpigmented areas of RPE. included in the study. There 28 men and 24 women. The right eye was involved in 24 cases, the left eye in 27, and one case was bilateral. None of the patients had visual im¬ pairment attributable to the lesion. The intraocular pressure was normal bilaterally in all patients. No anterior were
were
segment abnormalities
were
present.
There was no correlation with iris color. The age at diagnosis ranged from 14 to 86 years, with a mean age of 51 years. There was no history of systemic or ocular disease, ocular trauma, or ab¬ normal birth history. One patient had bilateral xanthelasma, and another had a congenital brownish-purple pig¬ mentation of the nail of the middle finger. Two patients had a family his¬ tory of retinal detachment. Ten had
Fig 2.—Pigmented
lesion
showing scalloped
distinct
Fig 4.—Peripapillary hypertrophy of RPE extending gin with undeviated retinal vessels and focal areas mentation.
fundus changes such as paving stone or lattice degeneration. The lesion was found in any area of the fundus. In those patients who re¬ turned for examination, it was found temporally in 72.2% with an equal number of lesions (13) found supertemporally and infratemporally. Two were located superonasally, three inferonasally, four peripapillary, and one in the macula. The peripapillary cases extended to the disc margin (Fig 4). Those cases in the periphery of the fundus were
larger, more variably pigmented (Fig 5), and extended to and stopped at the ora serrata. The most frequent type encountered was a single iso¬ lated lesion between the posterior pole and the periphery. The lesions ranged from less than one to 14 disc
Downloaded From: http://archopht.jamanetwork.com/ by a University of Michigan User on 06/20/2015
margin.
to disc mar¬ of hypopig¬
diameters in
size, with larger lesions usually located more peripherally. Pigmentation variations fell into five categories. Eight of 53 of these
jet black or gray in ap¬ (Fig 1, 2, and 6). Fifteen ex¬ hibited a "peripheral mottling" with visualization of the underlying cho¬ roid (Fig 6). A marginal halo of de¬ pigmentation was seen in eight cases (Fig 3 and 7). In 17 cases, we observed areas of depigmentation within the lesion that superficially resembled the lipofuscin in pigmentation seen on the surface of some malignant choroi¬ dal melanomas5 (Fig 8). Thirty-two lesions
were
pearance
cases
demonstrated "swiss cheese"
mottling, characterized by variably sized, round to oval, yellow lacunae of depigmentation (Fig 9 and 10). There was frequently an overlapping of two
of
Fig 5.—Large peripheral area of hypertrophy of hypopigmentation and scalloped border.
Fig 7.—Marginal halo hypertrophy of RPE.
is
seen
around
areas
Fig 6.—Isolated area of hypertrophy of RPE ripheral mottling" inside margins of lesion.
with
area
of
"pe¬
periphery of infratemporal
Fig 8.—Diffuse orange mottling seen through hypopigmentation in large hypertrophy of RPE. of these variations in a single lesion. Fluorescein angiography revealed hypofluorescence of the pigmented portions of the lesions and hyper¬ fluorescence caused by transmission of choroidal fluorescence through the various pigmentary defects (Fig 11 and 12). Visual field studies by kinetic and static Goldmann perimetry and tan¬ gent screen examination showed an absolute isolated scotoma correspond¬ ing to the lesion in one case of 12 ex¬ amined, while in the others no rela¬ tive or absolute defect was verified. Radioactive phosphorus uptake or more
RPE with
focal
areas
of
studies were performed in two pa¬ tients in which a large peripheral le¬ sion was present. No increase in up¬ take of SSP was found. One patient had a family history of retinitis pigmentosa, but the elec¬ troretinogram was normal. COMMENT In nine
1956, Reese and Jones6 reported
of what they called "be¬ of the retinal pig¬ melanoma nign ment epithelium" in which the diag¬ nosis of malignant melanoma had been entertained clinically. These were described as unilateral, isolated, black, sharply demarcated, and flat. cases
Downloaded From: http://archopht.jamanetwork.com/ by a University of Michigan User on 06/20/2015
varied from one to three disc diameters in size. The normal retinal vascular pattern was undeviated and the pigmentation was uniformly gray to black except for occasional small nonpigmented areas with sharp bor¬ ders. The lesions were non-progres¬ sive and did not produce visual field defects. The eyes were otherwise normal. Kurz and Zimmerman4 described two similar cases and gave histo¬ pathologic documentation that this was a hypertrophy of the individual pigment granules and not a true hy¬ perplasia of the RPE. They also de¬ scribed the "marginal halo" in one
They
Fig 9.—"Swiss cheese lacunae" pigmented hypertrophy of RPE.
Fig 11.—Infratemporal
lesion
of
hypopigmentation
in
darkly
exhibiting undeviated retinal
vessels, swiss cheese lacunae, marginal halo, and orange mott¬
ling. case and showed histologically that this represented an area of hypopig¬ mentation of the RPE at the margins of the lesion. Buettner7 believed that the granules of pigment in the hypertrophic RPE cells may be lipofuscin or abnormal melanin granules, but they did not resemble normal melanin granules. Kurz and Zimmerman, how¬ ever, were of the opinion that they
Fig 10.—Similar "swiss cheese lacunae" in lesion.
lightly pigmented
Fig 12.—Fluorescein angiogram of Fig 11 in arterio-venous phase demonstrating hypofluorescence of pigmented portion of lesion and hyperfluorescence of hypopigmented areas.
represented melanin granules.4
In the past, this lesion has occasion¬ ally led to enucleation because it was misinterpreted as a malignant mela¬ noma.1-4 In a recent study by Shields and Zimmerman,2 however, no cases were enucleated as suspected malig¬ nant melanoma. This may indicate that ophthalmologists are beginning to recognize this lesion as benign, al-
Downloaded From: http://archopht.jamanetwork.com/ by a University of Michigan User on 06/20/2015
though they may not know the pre¬ cise diagnosis. Since only 11% of the referring ophthalmologists had the correct diagnosis, there must be an unfamiliarity with the lesion. Im¬ portantly, 16 of 36 cases were re¬ ferred because the lesion was sus¬ pected to be either a benign nevus or a malignant melanoma of the choroid, and in 12 other cases it was called an
"unknown pigmented lesion." The differential diagnosis includes malignant melanoma,'·' choroidal nevus," choroidal melanocytoma,1' hyperplasia of the RPE,10 sunburst lesion of sickle cell disease,11 hemor¬ rhage beneath the RPE, old chorio¬ retinitis (toxoplasmosis), paving stone degeneration, and enclosed oral bay. The characteristic configuration, lo¬ cation, and pigmentary variations, and the use of fluorescein angiogra¬ phy aid in differentiating this lesion from other pigmented fundus lesions. The most important lesion in the differential diagnosis is malignant melanoma of the choroid. This lesion may be differentiated ophthalmo¬ scopically from malignant melanoma by the lack of elevation, the unde¬ viated retinal vessels, sharp distinct margins, and the four characteristic pigmentary changes. In hypertrophy of the RPE, ultrasound and :l-P stud¬ ies are normal, and field defects are rarely found by Goldmann perimetry or tangent screen examination. Fluo¬ rescein angiography of malignant melanoma demonstrates early uptake and late staining. Choroidal nevi have less distinct margins and lie beneath the RPE. Hyperplasia of the RPE is associated with a history of inflammation or trauma, is irregular in outline, and may be associated with glial or fi¬ brous tissue. Melanocytomas are usu¬ ally seen on the optic nerve head, are elevated, and often leave an irregular margin. The sunburst lesion of sickle cell disease has irregular feathery borders, gliosis, and is seen with the characteristic hématologie findings. Hemorrhage beneath the RPE may be associated with ocular trauma or macular degeneration, and has a greenish hue with irregular margins. This hemorrhage clears with time, whereas there is no change in the pig¬ mentation of hypertrophy of the RPE. Inactive lesions of toxo¬ plasmosis have areas of bare sclera,
peripheral pigmentary hyperplasia, and frequently have satellite lesions.
The color of these lesions varies from brown to gray to black. The pig¬ mentary variations are quite dis¬ tinctive and frequently occur to¬ gether. The peripheral marginal halo,
orange
mottling, peripheral mottling,
and "swiss cheese" variations are probably areas of hypopigmentation in the retinal pigment epithelium. This has been verified histologically in the case of the "marginal halo,"4 and the fluorescein pattern of choroi¬ dal transmission in these areas rein¬ forces this assumption. The fluores¬ cein pattern and transillumination through the orange mottling differ¬ entiates this lesion from the orange
lipofuscin deposits
over
malignant
melanomas that block choroidal fluo¬ rescence early5 and do not permit transmission of light. In this study, the racial differential corresponds roughly to the distribu¬ tion of blacks to whites in this coun¬ try and in our clinics. The sex, age, eye, associated ocular findings, and history of ocular or systemic disease were not remarkable. The age at diagnosis probably reflects the age most people commonly have their first fundus examination. The histopathology of these areas of hypertrophy of the RPE has been described as a single layer of hyper¬ trophy of the RPE with an increase in the concentration of granules within the cells.4 The cause is unknown, but most observers agree that this is a congenital defect. Parsons'- described a similar histopathology of congeni¬ tal grouped pigmentation or "bear tracks," and more recently this was documented by Shields and Tso.13 Whether this pigment is lipofuscin or melanin has not been established. Lowenstein and Steel14 described a case of bilateral central grouped pigmentation with marginal haloes around each lesion similar to the mar¬ ginal haloes seen in these cases. Since both hypertrophy of the RPE and
congenital grouped pigmentation are flat pigmented lesions with variable degrees of pigmentation, undeviated retinal vessels, similar histopathol¬
ogy, and with no evidence of inflam¬ mation, it appears that these are different clinical expressions of the same condition with the former being focal and the latter multifocal. Although a field defect was docu¬ mented in one patient corresponding to the lesion, in 11 others no defect was found using kinetic and static
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Goldmann perimetry and tangent screen examination. This was most striking in the one macular case that was three disc diameters in size and had a normal visual acuity, normal Amsler grid recording, and absence of field defect on multiple examina¬ tions. This corresponds to the absence of field defects in Reese's cases" using normal clinical techniques, but dif¬ fers from the studies of Buettner, who demonstrated field defects with the more sophisticated Tubingen
perimetry.7
Terranee L. Tomer, Jean Douglas, and Ruth Reber assisted in this study. This investigation was supported in part by the Retina Research and Development Founda¬ tion, Philadelphia and by the Lions Club of
Pennsylvania.
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