AMERICAN JOURNAL OF OPHTHALMOLOGY VOLUME 79
FEBRUARY, 1975
NUMBER 2
CONGENITAL H Y P E R T R O P H Y O F T H E R E T I N A L PIGMENT E P I T H E L I U M HELMUT BUETTNER,
M.D.
Miami, Florida
The flat, round, hyperpigmented fundus lesion now designated congenital hyper trophy of the retinal pigment epithelium ( R P E ) was previously described1"5 by the terms "benign melanoma"1'4 and "congenital hyperplasia of the retinal pigment epi thelium."2 Recent work,3 however, demon strated the hypertrophie nature of the retinal pigment epithelium in this condition and the absence of any signs of pigment epithelial hyperplasia. Although a histopathologic study showing photoreceptor cell degeneration overlying the hypertrophied retinal pigment epithelium was reported,8 clinical studies suggested that visual fields are normal in patients with this lesion.1·3 In view of this discrepancy, patients with such lesions were examined with special emphasis on visual field testing. SUBJECTS AND METHODS
Ten patients (Table) between the ages of 10 and 72 years with congenital hyper trophy of the R P E underwent complete ocular examination, including electro-oculography ( E O G ) , electroretinography ( E R G ) , color fundus photography, and fluorescein angiography. Visual field examinations were performed with the Tübinger perimeter in all ten patients. When dynamic field testing revealed a scotoma to a certain isopter,
static visual field testing was performed along the meridian passing through the cen ter of the scotoma. Light and electron microscopic studies were performed on two specimens of con genital hypertrophy of the RPE, recovered from unused donor eyes of the Florida Lions Eye Bank. CLINICAL FINDINGS
Ophthalmoscopic appearance—The typical fundus lesion termed "congenital hyper trophy of the RPE" 3 was usually solitary, round, flat, hyperpigmented, and well de marcated (Figs. 1-3). The color of the le sion ranged from light grayish-brown (Fig. 2) to black (Fig. 3) regardless of the pa tient's race. It was often surrounded by a narrow, hypopigmented halo (Figs. 4 and 5), which accounted for the occasionally used term "halo nevus." Punched-out hypopig mented or depigmented lacunae were found
From the Bascom Palmer Eye Institute, Depart ment of Ophthalmology, University of Miami School of Medicine, Miami, Florida. This investiga tion was supported in part by the Florida Lions Eye Bank, Inc. Reprint requests to Helmut Buettner, MD., P.O. Box 875, Biscayne Annex, Miami, FL 331S2. 177
TABLE SUMMARY OF PATIENT DATA
Patient 1 2 3 4 5 6 7 8 9 10
D^
e
^
10, W, F 14, W, M 18, W, F 27, B, M 39, W, M 40, W, M 45, B, M 55, W, M 60, W, F 72, W, F
Scotoma
Location of Lesion
lOasb Midperipheral 32asb Midperipheral lOasb Midperipheral 1,000 asb Midperipheral 16 asb Midperipheral 1,000 asb Midperipheral 1,000 asb Peripapillary 1,000 asb Midperipheral 1,000 asb Midperipheral 1,000 asb Midperipheral
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lasb
100
1000
Fig. 1 (Buettner). Patient 7. Peripapillary congenital hypertrophy of RPE in a 45-year-old black man (A). The hypopigmented lacunae within the lesion allow the observation of a normal choriocapillaris flush in the early fluorescein angiogram (B) and transmit scierai staining in the late angiogram. Note the normalcy of the retinal vasculature (B) and the absence of leakage of dye from either part of the lesion (C). Dynamic perimetry (upper right portion) reveals an enlarged blind spot surrounded by a relative scotoma to a target brightness of 10 apostilbs. The static profile obtained along the interrupted line in the dynamic field is shown in the lower right portion. in the lesions (Figs. 1-5). The overlying retina and retinal vasculature appeared clini cally normal (Figs. 1 and 2), except for occasional discrete areas of intraretinal pig mentation more evident near the margin of the lesion and usually only apparent by biomicroscopy. The size of the lesion varied considerably and appeared to be independent of its location in the fundus. In this study, the smallest lesion was approximately the
size of the optic disk, while the largest was approximately 10 disk diameters in size. Ten patients had solitary unilateral lesions. The abnormality was found in the fundus pe riphery in nine of ten cases. One lesion was peripapillary (Table). There was no appar ent predilection for location in any particu lar quadrant. Fluorescein angiographie appearance— Fluorescein angiography demonstrated nor-
Fig. 2 (Buettner). Peripapillary con genital hypertrophy of the RPE with large depigmented lacunae (same lesion as shown in Figure 1).
Fig. 3 (Buettner). Three-disk-diameter large congenital hypertrophy of the RPE with a small depigmented lacuna, found in the mid-periphery of the fundus in a 27-year-old black man (Patient 4).
Fig. 5 (Buettner). Gross photograph of congenital hypertrophy of the RPE (about 5 mm in diameter) in a 23-yearo l d white man with confluent de p i g m e n t e d lacunae and a discrete hypopigmented halo surrounding the lesion. The retinal fold overlying the inferior portion of this lesion developed artifactitiously during processing of the specimen. (Histopathology of this speci men shown in Figure 7.)
Fig. 9 (Buettner). Probable peripapillary melanocytoma of the choroid. Although this lesion can be differentiated with certainty from a choroidal nevus only by histopathology, the dark pigmenta tion indicates a melanocytoma rather than a nevus. Note the ill-defined de marcation from the surrounding cho roid, a clinical feature common to both melanocytomas and nevi of the choroid.
Fig. 10 ( B u e t t n e r ) . Grouped Pigmentations or bear tracks.
Fig. 11 (Buettner), Congenital hyper trophy of the RPE in a 14-year-old white boy (Patient 2). This lesion showed no change in size or shape dur ing the past five years. Note the irregu lar, lobulated shape of this lesion, which more closely resembles grouped pig mentations or bear tracks than the soli tary lesions depicted in Figures 2 , 3 , and 5.
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mal retina and retinal vasculature overlying 6). Patient 8 had anisometropic hyperopia and these lesions (Fig. 1, B ) . The hypertrophied amblyopia in the eye containing the hyperR P E totally blocked the normal background trophic R P E lesion. None of the patients had choroidal fluorescence. However, through the a history of previous ocular trauma or inflam the hypopigmented or depigmented lacunae mation. In Patient 10, congenital hypertrophy present in some cases, a normal chorio- of the R P E was associated with a small cho capillaris flush was observed (Fig. 1, B ) . roidal nevus in the same eye. External, slitChoroidal fluorescence was also seen through lamp, and tonometric examinations were nor the hypopigmented halo that surrounded mal in all ten patients. some of the lesions. There was no leakage EOG—All ten patients had normal EOGs of fluorescein from any part of the lesion with a light rise of more than 16Q% as com during any phase of the angiogram. The pared to the dark-trough value. R P E and choroid adjacent to the area of ERG—All ten patients had normal phohypertrophied R P E exhibited a normal fluo topic, scotopic, and flicker ERGs. rescein angiographie pattern (Fig. 1, B Visual fields—All ten patients examined and C). with the Tübinger perimeter had visual General ocular examination—Nine of ten field defects corresponding to the location patients had normal near and distance vi and size of the fundus abnormality (Table). sion. Only one of these patients had a signifi- The three youngest patients, aged 10, 14, and can refractive error (severe myopia in Patient 18 years, had only shallow or relative sco-
losb
looo Fig. 4 (Buettner). Patient S. Congenital hypertrophy of the RPE in a 39-year-old white man demon strating the hypopigmented and apigmented lacunae, which may enlarge or increase in number with time, while the size of the lesion itself does not change. Dynamic and static fields with relative scotoma are shown on the right.
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Fig. 6 (Buettner). Gross photograph of congenital hypertrophy of RPE incidentally found in the post mortem eye of a 62-year-old white man (A). The histologie specimen (B) demonstrates absence of photoreceptor cells exactly overlying an area of thickened and darker appearing RPE (arrows). The margin of this lesion (C) shows abrupt transition from normal to abnormal RPE and retina (arrow). There are only a few photoreceptor remnants present (single arrow in D) in a space filled with slightly PAS-positive amorphous material (double arrow in D). A bleached section (E) reveals the monocellular nature of this hypertrophied RPE and a marked thickening of Bruch's membrane (B, x20; C-E, X200).
tomas (Table), while the patients aged 27 to 72 years, with the exception of Patient 5, had absolute scotomas in the visual fields corre sponding to the fundus lesions (Fig. 1; Table). Follow-up—In Patient 5 (Fig. 4), a threeyear, photographically documented follow-up showed no change in the overall size of the fundus lesion. However, enlargement of pre existing lacunae and appearance of new depigmented lacunae in the lesion were ob served (Fig. 4 ) . Two other patients (Nos. 2 and 3) were followed photographically over a period of five years without change in the size of the fundus lesions. HlSTOLOGIC FINDINGS
Light microscopy—Congenital hypertro phy of the R P E was found in two unused donor eyes. As the eyes were enucleated
some time after death, they were not per fectly preserved. The gross photograph of one lesion found in the eye of a 62-year-old man (Fig. 6, A) showed a 2-disk-diameter, round, flat, hyperpigmented lesion at the equator, surrounded by a lighter pigmented halo. On histologie section, there was a 3-mm-wide area of darker and thickened R P E ; the overlying photoreceptor cell layer appeared to be absent. Retina and R P E were normal on both sides of this defect (Fig. 6, B ) . Higher magnification of the margin of the lesion showed the abrupt transition between nor mal and abnormal pigment epithelium associ ated with an abrupt, strongly PAS-positive thickening of Bruch's membrane underneath the single layer of hypertrophie pigment epi thelial cells (Fig. 6, C), more clearly dem onstrated in a bleached section (Fig. 6, E ) .
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The photoreceptor cell layer disappeared abruptly where the hypertrophied R P E be gan, leaving an almost empty space contain ing amorphous, PAS-positive material and a few remnants of photoreceptor cells (Fig. 6, D ) . The inner retinal layers were essen tially normal, considering the peripheral lo cation of this lesion, the patient's age, and the state of preservation of the specimen. The second specimen of congenital R P E hypertrophy was recovered from the donor eye of a 23-year-old white man. The gross examination (Fig. S) showed the lesion (about 5 mm in diameter) in the midperiphery of the fundus. Large confluent depig mented lacunae (cf. Figs. 1 and 4) were present within the lesion, which was sur rounded by a hypopigmented halo. Phase contrast microscopy (Fig. 7, A) demonstrated an abrupt change from normal to hypertrophie RPE. Overlying the latter, the photoreceptor cells' inner and outer seg ments showed marked degeneration, which were not as advanced as that overlying the same lesion in the previous specimen (Fig. 6). The outermost margin of the area of hypertrophie R P E was formed by less densely pigmented hypertrophie R P E cells (Fig. 7, A ) , corresponding to the hypopig mented halo seen in the gross photograph (Fig. 5). Bruch's membrane was not thick ened underneath the hypertrophie RPE, in contrast to the findings in the previously described lesion, and the choriocapillaris appeared to be normal (Fig. 7, A ) . Toward the center of the lesion, the hypertrophic RPE, as well as the degenerated photoreceotor cells, ended abruptly (Fig. 7, B). The remaining inner retinal layers, which were as normal as those overlying the R P E hypertrophy, were firmly attached to Bruch's membrane by horizontally oriented glial tissue (Fig. 7, B ) . This area corre sponded to the depigmented lacuna seen in the gross photograph (Fig. 5). Electron microscopy—On electron micro scopic examination, the pigment epithelium on both sides of the lesion depicted in Fig
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ure 6 exhibited normal cell shape and con tained the usual football-shaped melanin granules (Fig. 8, A ) . The R P E cells were in contact with photoreceptor outer segments, both of which showed autolytic changes due to the poor preservation of the specimen. Basement membrane, Bruch's membrane, and choriocapillaris were normal. In the area of hypertrophy (Fig. 8, B), the R P E cells were about twice normal dimensions and contained numerous large, round pigment granules. No football-shaped melanin granules were found in these cells. Anterior to the hypertrophied R P E cells, no photoreceptor outer segments were seen. The thickening of Bruch's mem brane seen with light microscopy (Fig. 6, E ) resulted from tremendous thickening of the basement membrane of the hypertrophied R P E cells (Fig. 8, B ) . The outer layers of Bruch's membrane were morphologically normal. The choriocapillaris appeared nor mal and contained numerous intact erythrocytes (Fig. 8, B ) . Electron microscopy of the lesion of con genital hypertrophy of the R P E found in the second specimen (Fig. 5) showed practically the same cellular features in the hypertrophie cells as just mentioned, except for less marked thickening of their basement mem branes (Fig. 7, C). In the area of the depig mented lacuna (Fig. 5), the hypertrophie R P E cells disappeared, leaving only base ment membrane behind. There were glial cells interposed between the retina and the choriocapillaris. These cells possessed cell junctions and were in the process of laying down new basement membranes (Fig. 7, D ) . DISCUSSION
Clinical findings—Congenita.] hypertrophy of the R P E is usually found incidentally during routine fundus examinations. Pa tients generally do not complain of any symptoms related to this lesion, except when it possibly involves the macula. Normal ERGs and EOGs in this condition are not surprising, since both tests measure only mass responses and do not allow de-
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Fig. 7 (Buettner). Phase contrast and electron microscopic photographs of specimen from the post mortem eye of a 23-year-old white man. At the margin of the lesion (A), there is a narrow zone of slightly hypopigmented, hypertrophie RPE cells (arrows) between the normal (n) and hypertrophie, hyperpigmented (h) RPE cells. These hypopigmented cells correspond with the halo surrounding the lesion, as seen in Figure 5. Pho'-oreceptor inner and outer segments are normal overlying the normal RPE (n), but show progressive degeneration as one approaches the hypertrophie RPE (h). Artifactitious detachment required photomontage (dotted line). Electron rnicrograph (C) demonstrates the same large granules in the hypertrophie RPE cells as found in the other specimen (Fig. 8, B). At the border between hypertrophie RPE and a depigmented lacuna (B) (see Fig. 5), the hypertrophie RPE, as well as the degenerated photoreceptor cells, end suddenly (arrow in B), and the remaining normal inner retinal layers are fused to Bruch's membrane by horizontally oriented glial cells. Electron microscopy (D) demon strates formation of new basement membrane (single arrow) on the remaining basement membrane of the disintegrated RPE cells, as well as cell junctions between glial cells (double arrows) (A and B, X200 ; C, x 18,000 ;D, x 13,000).
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tection of localized abnormalities of photoreceptors or pigment epithelium.6-8 The ophthalmoscopic criteria of congenital hypertrophy of the R P E have been out lined above and previously reported by others.1"5 The diagnosis is facilitated by stereoscopic fundus photography and fluorescein angiography, which show uniform blockage of choroidal fluorescence by the lesion and normal retina and retinal vasculature overlying it. The fact that the hyperpigmented areas do not exhibit any fluorescein leakage or staining can be interpreted to indicate that the cellular integrity of the R P E is preserved. The integrity of these cells is clearly demonstrated electron micro scopically (Fig. 7, C). The absence of fluorescein leakage from the area of the depigmented lacunae (Fig. 1) demonstrates the fact that not only R P E cells but also other cells, i.e., glial cells (Fig. 7, D ) , can pre vent diffusion of fluorescein dye from the choriocapillaris into the retina or subretinal space. Differential diagnosis—Although the
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proper diagnosis in congenital hypertrophy of the R P E can readily be made using mod ern examination techniques, confusing no menclature found in earlier reports sug gests that this lesion has been misdiagnosed frequently. Review of histopathologic ma terial indicates that this lesion has often been mistaken for a malignant melanoma of the choroid.1'9 Reese and Jones 1 found nine such lesions among 151 enucleated eyes thought to harbor a malignant melanoma, while Ferry 10 found two such lesions in a series of 100 eyes enucleated with a misdiagnosis of malignant melanoma of the choroid or ciliary body. Choroidal mela nomas are almost always clearly elevated, and they are almost never as uniformly and darkly pigmented or as sharply demarcated as are lesions in congenital hypertrophy of the RPE. Furthermore, the lack of progres sion in congenital hypertrophy, as demon strated in this study, clearly distinguishes this lesion from malignant melanoma of the choroid. Congenital hypertrophy of the R P E might
Fig. 8 (Buettner). Electron micrograph of normal RPE (A) immediately adjacent to lesion shown in Figure 6, A and B. Note the typical wedge-shaped melanin granules. B, At the same magnification, hypertrophied RPE cells within the lesion. The difference in size and appearance of pigment granules as compared to A is quite evident, as well as the tremendous thickening of the basement membrane (bm) of the RPE cells. Note further the normalcy of the choriocapillaris, containing numerous erythrocytes (X6,600).
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also be misdiagnosed as choroidal nevus. One may avoid this error by recognizing the ill-defined border in the vicinity of larger choroidal vessels of nevi, their lighter pig mentation, and their location below the RPE. Drusen often overly a choroidal nevus. These may superficially resemble depigmented lacunae in congenital hypertrophy. However, the flat, sharply demarcated and punched-out character of these lacunae (through which choroidal vessels can often be seen) contrasts with the elevated opaque appearance of drusen. Melanocytomas of the choroid, although usually darker than choroidal nevi, share many of their morphologic characteristics. Therefore, they cannot be differentiated clinically from choroidal nevi in many in stances.9 Melanocytomas of the choroid may also be confused with congenital hypertro phy of the RPE. Although melanocytomas are typically situated in the optic nerve head, they may also be found in a peripapillary location (Fig. 9) or elsewhere in the uveal tract.9 Congenital hypertrophy of the R P E is, at least terminologically,2'4,5 confused occasion ally with true benign hyperplasia of the RPE. 9 ' 17 True hyperplasia is characterized by diffuse proliferation of the R P E with local invasion and infiltration of the retina, usually in a juxtapapillary location, but also occurring in the periphery.12 This abnor mality is often slowly progressive, and asso ciated visual loss is often present. These factors appear to be responsible for the fre quently made diagnosis of malignant mela noma, as indicated by the relatively large number of histopathologic reports avail able.11·15"17 Other lesions to be considered in the dif ferential diagnosis of congenital hypertrophy of the R P E are inflammatory pigmented fundus lesions, pigmented colobomas,18·19 and rare adenomas and carcinomas of the RPE. 20 The value of visual fields in the differ ential diagnosis of pigmented fundus lesions
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had. been emphasized repeatedly in the past.21'22 However, the postulation that le sions with a visual field defect represent neoplasms or malignancies does not hold true. Choroidal nevi, for instance, are fre quently associated with visual field defects,23-26 as are areas of hyperplasia of the RPE.11"17 The field defects in congenital hypertrophy of the R P E are clearly demon strated in this study. Pathology—The morphologic basis of the visual field defects in congenital hyper trophy of the R P E is selective degeneration of photoreceptor cells overlying the area of hypertrophie R P E cells. The extent of these degenerative changes appears to de pend on the patient's age. Kurz and Zim merman3 observed only mild changes in the photoreceptors overlying an area of congen ital hypertrophy of the R P E in the eye of a 19-year-old woman, similar to those found in such a lesion in the postmortem eye of a 23-year-old white man (Fig. 7). However, in the postmortem eye of a 62-year-old man, almost total degeneration of the photorecep tor cells was found overlying the area of hypertrophy of the R P E (Fig. 6). This in dication of progressive degeneration of photoreceptors is well supported clinically by visual field findings of only shallow scotomas early in life and deep scotomas later in life. The cause of the photoreceptor degenera tion seems to be the abnormal nature of the retinal pigment epithelium. The markedly enlarged R P E cells are almost entirely filled with large round pigment granules that re semble lipofuscin inclusions, rather than melanin granules. Whether this is the cause or the result of malfunction of the R P E is speculative. According to Feeney, Grieshaber, and Hogan,27 lipofuscin is the degradation product of outer segment material that breaks off constantly at the outer segments' distal ends and is engulfed by R P E cells. In congenital hypertrophy of the RPE, the accumulation of these lipofuscin-like inclu sions could indicate that the cells cannot
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eliminate this material in the usual ( a s yet unknown) way. T h e marked thickening of the basement membrane of the R P E cells then may be interpreted as an unsuccessful attempt of these cells to eliminate some of this material. Parsons 2 8 observed the thick ening of the basement membrane. However, he noted hyaline material resembling "col loid bodies" in grouped pigmentations or "bear tracks" on the fundus ( F i g . 10), a condition which is pathologically 28 ' 29 and clinically 19 · 30 " 32 similar to congenital hyper trophy of the R P E (Figs. 2, 3, 5, and 11). Hoeg 8 1 found subtle visual field defects cor responding to grouped pigmentations of the fundus. Congenital hypertrophy of the R P E can be regarded as a solitary form of grouped pigmentations of the fundus 3 3 on the basis of clinical, histologie, and etiologic similarity. T h e normal appearance of the outer layers of Bruch's membrane and the choriocapillaris essentially rules out the pos sibility that this lesion results from a patho logic process originating in the choroid. T h e depigmented lacunae, which were not seen in young patients, are caused by the disap pearance of hypertrophie R P E , as demon strated in follow-up photographs (Fig. 4 ) . The photoreceptor cells disappear, together with the hypertrophie R P E . Glial cells pro liferate into this space and form a compact layer between the remainder of the retina and the unaltered Bruch's membrane. Know ing that there a r e no photoreceptors over lying the depigmented lacunae, the visual field findings in Patient 5 (Fig. 4) have to be regarded as faulty. T h e r e should be an absolute scotoma corresponding to the fun dus lesion, not only on the basis of the patient's age of 39 years, but also because of the presence of numerous depigmented areas within the lesion. Etiology and pathogenesis—According to Ida Mann, 1 8 congenital hypertrophy of the R P E represents an area where cells of the inner layer of the optic cup, for example, the sensory retina, underwent aberrant differenti ation and formed a cluster of pigment cells.
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H o g a n and Zimmerman, 4 however, postu lated that the R P E proliferated in areas in which there has been a failure of rods and cones to develop. The clinical and histologie findings of this investigation contradict both these theories. Shallow scotomas only in the visual fields of young patients with con genital hypertrophy strongly suggest that the retina develops relatively well, or even normally, in these areas. This assumption is supported by the histopathologic findings of K u r z and Zimmerman 3 of only mild photo receptor degeneration overlying an area of congenital hypertrophy of the R P E in a 19-year-old patient. With age, the photore ceptors seem to degenerate progressively, as indicated by clinical findings of absolute scotomas in older patients, and by the almost total degeneration of photoreceptors over lying such a lesion found in a 62-year-old patient. T h e congenital abnormality probably con sists of aberrant differentiation of a localized patch of R P E cells. Overlying this area of abnormal R P E , the retina apparently de velops relatively normally. However, the aberrant, hypertrophie R P E cells are not fully able to maintain the integrity of the photoreceptor cell layer, 34 resulting in pro gressive photoreceptor degeneration during life. Clinical significance—Congenital hyper trophy of the R P E is a well-defined clinical and pathologic entity presenting either as grouped pigmentations or as a solitary form, as described herein. Using the abovementioned criteria, it should be possible to differentiate congenital hypertrophy of the R P E from inflammatory lesions, pigmented colobomas, choroidal nevi, melanocytoma, and malignant melanomas of the choroid. This lesion should always be followed clini cally and should never be cause for enucleation of the eye. SUMMARY
T h e flat, circumscribed, and hyperpigmented lesion of the retinal pigment epi-
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thelium ( R P E ) without clinically apparent involvement of the overlying retina, desig nated as congenital hypertrophy, was found to be associated with corresponding scotomas in the visual field. The depth of the scotoma increased with the age of the patient. These lesions did not grow. They could be readily differentiated from other pigmented fundus lesions on the basis of their typical clinical appearance. Histopathology revealed a single layer of hypertrophied cells, containing numerous large pigment granules, and degeneration of photoreceptor cells overlying the area of abnormal R P E . The clinical as well as the histologie find ings suggested that the retinal abnormality overlying the hypertrophied R P E was due to secondary degeneration rather than primary maldevelopment of photoreceptor cells. ACKNOWLEDGMENTS
I thank Mrs. S. McKenney for performing the visual field examinations ; Mrs. I. Holmes for electrophysiological testing; Mrs. N. Hechlinski, Mrs. B. French, and Mr. D. Clark for photographic assistance ; Mrs. B. Monterò and Mr. M. Solis for histologie assistance ; and Mr. B. Davis helped with electron microscopy. Drs. J. D. M. Goss and E. Fineberg recovered the histologie specimen. Mrs. R. Hurles, Drs. E. W. D. Norton, J. D. M. Gass, and R. L. Jack provided editorial assistance. REFERENCES
1. Reese, A. B., and Jones, I. S.: Benign mela nomas of the retinal pigment epithelium. Am. J. Ophthalmol. 42:207, 1956. 2. Reese, A. B.: Tumors of the Eye, 2nd ed. New York, Harper and Row, 1963. 3. Kurz, G. H., and Zimmerman, L. E. : Vagaries of the retinal pigment epithelium. Int. Ophthalmol. Clin. 2:441, 1962. 4. Hogan, M., and Zimmerman, L. E. (eds.) : Ophthalmic Pathology. An Atlas and Textbook, 2nd ed. Philadelphia, W. B. Saunders, 1962, p. 477. 5. Reese, A. B.: The role of the pigment epi thelium in ocular pathology. Am. J. Ophthalmol. 50:1066,1960. 6. Arden, G. B., and Kelsey, J. H. : New clinical test of retinal function based upon the standing potential. Br. J. Ophthalmol. 46:449, 1962. 7. Jacobson, J. H., Najac, H. T., Stephens, G., Kara, G. B., and Gestring, G. F.: The role of the macula in the electroretinogram of monkey and man. Am. J. Ophthalmol. 50:889, 1960.
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8. Jacobson, J. H.: Clinical Electroretinography. Springfield, Charles C Thomas, 1961. 9. Zimmerman, L. E. : Melanocytes, tnelanocytic nevi and melanocytomas. Invest. Ophthalmol. 4:11, 1965. 10. Ferry, A. P. : Lesions mistaken for malignant melanomas of the posterior uvea. Arch. Ophthalmol. 72:463,1964. 11. Theobald, G. D., Floyd, G., and Kirk, H. G. : Hyperplasia of the retinal pigment epithelium. Sim ulating a malignant melanoma. Report of two cases. Am. J. Ophthalmol. 45:235, 1958. 12. Duke, J. R., and Maumenee, A. E.: An unusual tumor of the retinal pigment epithelium. Am. J. Ophthalmol. 47:311, 1959. 13. Rein, G.: Ueber Melanoblastome der Papille und Tumoren des retinalen Pigmentepithels. Graefe's Arch. Ophthalmol. 161:519, 1960. 14. Cardell, B. S., and Starbuck, M. J.: Juxtapapillary hamartoma of retina. Br. J. Ophthalmol 45:672, 1961. 15. Spiers, F., and Jensen, O. A. : Pseudo-epitheliomatous hyperplasia of the retinal pigment epithelium. Acta Ophthalmol. 41:722, 1963. 16. Machemer, R. : Die primaere retinale Pigmentepithelhyperplasie. Graefe's Arch. Ophthalmol. 167:284, 1964. 17. Vogel, M. H., Zimmerman, L. E., and Gass, J. D. M. : Proliferation of the juxtapapillary retinal pigment epithelium simulating malignant melanoma. Doc. Ophthalmol. 26:461, 1969. 18. Mann, I.: Developmental Abnormalities of the Eye, 2nd ed. Philadelphia, T. B. Lippincott, 1957, p. 140. 19. Sorsby, A. : Congenital coloboma of the macula. Br. J. Ophthalmol. 19:65, 1935. 20. Garner, A.: Tumors of the retinal pigment epithelium. Br. J. Ophthalmol. 54:715, 1970. 21. Duke-Elder, S., and Perkins, E. S.: Diseases of the Uveal Tract. In Duke-Elder, S. (ed.) : Sys tem of Ophthalmology, vol. 9. London, Kimpton, 1966. 22. Bettman, J. W., and Fellows, V.: The differ ential diagnosis of dark lesion of the posterior fundus. Am. J. Ophthalmol. 41:975, 1956. 23. Tamler, E., and Maumenee,·A. E. : A clinical study of choroidal nevi. Arch. Ophthalmol. 62:196, 1959. 24. Naumann, G., Zimmerman, L. E., and Yanoff, M.: Visual field defect associated with choroidal nevus. Am. J. Ophthalmol. 62:914, 1966. 25. Karickhoff, J. R.: Loss of visual function and visual cells in 600 cases of malignant melanoma. Am. T. Ophthalmol. 64:268, 1967. 26. Flindall, R. J., and Drance, S. M. : Visual field studies of benign choroidal melanomata. Arch. Ophthalmol. 81:41,1969. 27. Feeney, L., Grieshaber, A., and Hogan, M. J.: Studies on human ocular pigment, In Rohen, J. W. (ed.) : The Structure of the Eye. Stuttgart, Schattauer-Verlag, 1965, p. 535. 28. Parsons, J. H. : Some anomalies of pigmenta tion. Xe Congrès d'ophtalmologie, Lucerne, vol. 10,B, 1904, p. 152.
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29. Legrand, J., Hervouet, A., Ginguené, A., and Lenoir, A. : Pigmentation groupée de la rétine. Bull. Soc. Ophtalmol. Fr. 64:313,1964. 30. Stephenson, S.: A peculiar form of retinal pigmentation. Trans. Ophthalmol. Soc. U.K. 11:77, 1891. 31. Höeg, N.: Die gruppierte Pigmentation des Augengrundes. Klin. Monatsbl. Augenheilkd. 49:49, 1911. 32. Morse, P. H.: Fluorescein angiography of
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grouped pigmentation of the retina. Ann. Ophthal mol. 5:27, 1973. 33. Fraver, W. C. : Neoplasms and related lesions of the retinal pigment epithelium. Int. Ophthalmol. Clin. 12:63,1972. 34. Buettner, H., Machemer, R., Charles, S., and Anderson, D. R. : Experimental deprivation of choroidal blood flow. Retinal morphology, early receptor potential, and ëlectroretinogram. Am. J. Ophthalmol. 75:917, 1973.
OPHTHALMIC MINIATURE
Scientific writers are rarely literate. If a colleague tells a scientist that His latest article is difficult to understand, the writer is more likely to assume that his colleague is unintelligent than that his article is un intelligible. Such writers believe that discussions about style, choice of words, length of sentences, active and passive voices, subjunctives, and the like, are for non-scientific second-rate minds with nothing original to say, and are irrelevant for serious scientific workers. Unfortunately, this argument can be supported by reference to published accounts of important work, many of which are badly written. No editor will reject first-class research because it is in poor English, and few journals have enough staff to rewrite all the articles they publish. So why does style matter? Simplicity and clarity are the features of good scientific writing. Clear thought can be expressed clearly; and a man with something of value to say has no need to pad out his account. Watson and Crick's account of the double-helix structure of DNA was communicated as a 900-word letter to-"Nature." Charles Thorne, Better Medical Writing London, Pitman, 1970
FEBRUARY, 1975
NUMBER 2
CONGENITAL H Y P E R T R O P H Y O F T H E R E T I N A L PIGMENT E P I T H E L I U M HELMUT BUETTNER,
M.D.
Miami, Florida
The flat, round, hyperpigmented fundus lesion now designated congenital hyper trophy of the retinal pigment epithelium ( R P E ) was previously described1"5 by the terms "benign melanoma"1'4 and "congenital hyperplasia of the retinal pigment epi thelium."2 Recent work,3 however, demon strated the hypertrophie nature of the retinal pigment epithelium in this condition and the absence of any signs of pigment epithelial hyperplasia. Although a histopathologic study showing photoreceptor cell degeneration overlying the hypertrophied retinal pigment epithelium was reported,8 clinical studies suggested that visual fields are normal in patients with this lesion.1·3 In view of this discrepancy, patients with such lesions were examined with special emphasis on visual field testing. SUBJECTS AND METHODS
Ten patients (Table) between the ages of 10 and 72 years with congenital hyper trophy of the R P E underwent complete ocular examination, including electro-oculography ( E O G ) , electroretinography ( E R G ) , color fundus photography, and fluorescein angiography. Visual field examinations were performed with the Tübinger perimeter in all ten patients. When dynamic field testing revealed a scotoma to a certain isopter,
static visual field testing was performed along the meridian passing through the cen ter of the scotoma. Light and electron microscopic studies were performed on two specimens of con genital hypertrophy of the RPE, recovered from unused donor eyes of the Florida Lions Eye Bank. CLINICAL FINDINGS
Ophthalmoscopic appearance—The typical fundus lesion termed "congenital hyper trophy of the RPE" 3 was usually solitary, round, flat, hyperpigmented, and well de marcated (Figs. 1-3). The color of the le sion ranged from light grayish-brown (Fig. 2) to black (Fig. 3) regardless of the pa tient's race. It was often surrounded by a narrow, hypopigmented halo (Figs. 4 and 5), which accounted for the occasionally used term "halo nevus." Punched-out hypopig mented or depigmented lacunae were found
From the Bascom Palmer Eye Institute, Depart ment of Ophthalmology, University of Miami School of Medicine, Miami, Florida. This investiga tion was supported in part by the Florida Lions Eye Bank, Inc. Reprint requests to Helmut Buettner, MD., P.O. Box 875, Biscayne Annex, Miami, FL 331S2. 177
TABLE SUMMARY OF PATIENT DATA
Patient 1 2 3 4 5 6 7 8 9 10
D^
e
^
10, W, F 14, W, M 18, W, F 27, B, M 39, W, M 40, W, M 45, B, M 55, W, M 60, W, F 72, W, F
Scotoma
Location of Lesion
lOasb Midperipheral 32asb Midperipheral lOasb Midperipheral 1,000 asb Midperipheral 16 asb Midperipheral 1,000 asb Midperipheral 1,000 asb Peripapillary 1,000 asb Midperipheral 1,000 asb Midperipheral 1,000 asb Midperipheral
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lasb
100
1000
Fig. 1 (Buettner). Patient 7. Peripapillary congenital hypertrophy of RPE in a 45-year-old black man (A). The hypopigmented lacunae within the lesion allow the observation of a normal choriocapillaris flush in the early fluorescein angiogram (B) and transmit scierai staining in the late angiogram. Note the normalcy of the retinal vasculature (B) and the absence of leakage of dye from either part of the lesion (C). Dynamic perimetry (upper right portion) reveals an enlarged blind spot surrounded by a relative scotoma to a target brightness of 10 apostilbs. The static profile obtained along the interrupted line in the dynamic field is shown in the lower right portion. in the lesions (Figs. 1-5). The overlying retina and retinal vasculature appeared clini cally normal (Figs. 1 and 2), except for occasional discrete areas of intraretinal pig mentation more evident near the margin of the lesion and usually only apparent by biomicroscopy. The size of the lesion varied considerably and appeared to be independent of its location in the fundus. In this study, the smallest lesion was approximately the
size of the optic disk, while the largest was approximately 10 disk diameters in size. Ten patients had solitary unilateral lesions. The abnormality was found in the fundus pe riphery in nine of ten cases. One lesion was peripapillary (Table). There was no appar ent predilection for location in any particu lar quadrant. Fluorescein angiographie appearance— Fluorescein angiography demonstrated nor-
Fig. 2 (Buettner). Peripapillary con genital hypertrophy of the RPE with large depigmented lacunae (same lesion as shown in Figure 1).
Fig. 3 (Buettner). Three-disk-diameter large congenital hypertrophy of the RPE with a small depigmented lacuna, found in the mid-periphery of the fundus in a 27-year-old black man (Patient 4).
Fig. 5 (Buettner). Gross photograph of congenital hypertrophy of the RPE (about 5 mm in diameter) in a 23-yearo l d white man with confluent de p i g m e n t e d lacunae and a discrete hypopigmented halo surrounding the lesion. The retinal fold overlying the inferior portion of this lesion developed artifactitiously during processing of the specimen. (Histopathology of this speci men shown in Figure 7.)
Fig. 9 (Buettner). Probable peripapillary melanocytoma of the choroid. Although this lesion can be differentiated with certainty from a choroidal nevus only by histopathology, the dark pigmenta tion indicates a melanocytoma rather than a nevus. Note the ill-defined de marcation from the surrounding cho roid, a clinical feature common to both melanocytomas and nevi of the choroid.
Fig. 10 ( B u e t t n e r ) . Grouped Pigmentations or bear tracks.
Fig. 11 (Buettner), Congenital hyper trophy of the RPE in a 14-year-old white boy (Patient 2). This lesion showed no change in size or shape dur ing the past five years. Note the irregu lar, lobulated shape of this lesion, which more closely resembles grouped pig mentations or bear tracks than the soli tary lesions depicted in Figures 2 , 3 , and 5.
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mal retina and retinal vasculature overlying 6). Patient 8 had anisometropic hyperopia and these lesions (Fig. 1, B ) . The hypertrophied amblyopia in the eye containing the hyperR P E totally blocked the normal background trophic R P E lesion. None of the patients had choroidal fluorescence. However, through the a history of previous ocular trauma or inflam the hypopigmented or depigmented lacunae mation. In Patient 10, congenital hypertrophy present in some cases, a normal chorio- of the R P E was associated with a small cho capillaris flush was observed (Fig. 1, B ) . roidal nevus in the same eye. External, slitChoroidal fluorescence was also seen through lamp, and tonometric examinations were nor the hypopigmented halo that surrounded mal in all ten patients. some of the lesions. There was no leakage EOG—All ten patients had normal EOGs of fluorescein from any part of the lesion with a light rise of more than 16Q% as com during any phase of the angiogram. The pared to the dark-trough value. R P E and choroid adjacent to the area of ERG—All ten patients had normal phohypertrophied R P E exhibited a normal fluo topic, scotopic, and flicker ERGs. rescein angiographie pattern (Fig. 1, B Visual fields—All ten patients examined and C). with the Tübinger perimeter had visual General ocular examination—Nine of ten field defects corresponding to the location patients had normal near and distance vi and size of the fundus abnormality (Table). sion. Only one of these patients had a signifi- The three youngest patients, aged 10, 14, and can refractive error (severe myopia in Patient 18 years, had only shallow or relative sco-
losb
looo Fig. 4 (Buettner). Patient S. Congenital hypertrophy of the RPE in a 39-year-old white man demon strating the hypopigmented and apigmented lacunae, which may enlarge or increase in number with time, while the size of the lesion itself does not change. Dynamic and static fields with relative scotoma are shown on the right.
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Fig. 6 (Buettner). Gross photograph of congenital hypertrophy of RPE incidentally found in the post mortem eye of a 62-year-old white man (A). The histologie specimen (B) demonstrates absence of photoreceptor cells exactly overlying an area of thickened and darker appearing RPE (arrows). The margin of this lesion (C) shows abrupt transition from normal to abnormal RPE and retina (arrow). There are only a few photoreceptor remnants present (single arrow in D) in a space filled with slightly PAS-positive amorphous material (double arrow in D). A bleached section (E) reveals the monocellular nature of this hypertrophied RPE and a marked thickening of Bruch's membrane (B, x20; C-E, X200).
tomas (Table), while the patients aged 27 to 72 years, with the exception of Patient 5, had absolute scotomas in the visual fields corre sponding to the fundus lesions (Fig. 1; Table). Follow-up—In Patient 5 (Fig. 4), a threeyear, photographically documented follow-up showed no change in the overall size of the fundus lesion. However, enlargement of pre existing lacunae and appearance of new depigmented lacunae in the lesion were ob served (Fig. 4 ) . Two other patients (Nos. 2 and 3) were followed photographically over a period of five years without change in the size of the fundus lesions. HlSTOLOGIC FINDINGS
Light microscopy—Congenital hypertro phy of the R P E was found in two unused donor eyes. As the eyes were enucleated
some time after death, they were not per fectly preserved. The gross photograph of one lesion found in the eye of a 62-year-old man (Fig. 6, A) showed a 2-disk-diameter, round, flat, hyperpigmented lesion at the equator, surrounded by a lighter pigmented halo. On histologie section, there was a 3-mm-wide area of darker and thickened R P E ; the overlying photoreceptor cell layer appeared to be absent. Retina and R P E were normal on both sides of this defect (Fig. 6, B ) . Higher magnification of the margin of the lesion showed the abrupt transition between nor mal and abnormal pigment epithelium associ ated with an abrupt, strongly PAS-positive thickening of Bruch's membrane underneath the single layer of hypertrophie pigment epi thelial cells (Fig. 6, C), more clearly dem onstrated in a bleached section (Fig. 6, E ) .
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The photoreceptor cell layer disappeared abruptly where the hypertrophied R P E be gan, leaving an almost empty space contain ing amorphous, PAS-positive material and a few remnants of photoreceptor cells (Fig. 6, D ) . The inner retinal layers were essen tially normal, considering the peripheral lo cation of this lesion, the patient's age, and the state of preservation of the specimen. The second specimen of congenital R P E hypertrophy was recovered from the donor eye of a 23-year-old white man. The gross examination (Fig. S) showed the lesion (about 5 mm in diameter) in the midperiphery of the fundus. Large confluent depig mented lacunae (cf. Figs. 1 and 4) were present within the lesion, which was sur rounded by a hypopigmented halo. Phase contrast microscopy (Fig. 7, A) demonstrated an abrupt change from normal to hypertrophie RPE. Overlying the latter, the photoreceptor cells' inner and outer seg ments showed marked degeneration, which were not as advanced as that overlying the same lesion in the previous specimen (Fig. 6). The outermost margin of the area of hypertrophie R P E was formed by less densely pigmented hypertrophie R P E cells (Fig. 7, A ) , corresponding to the hypopig mented halo seen in the gross photograph (Fig. 5). Bruch's membrane was not thick ened underneath the hypertrophie RPE, in contrast to the findings in the previously described lesion, and the choriocapillaris appeared to be normal (Fig. 7, A ) . Toward the center of the lesion, the hypertrophic RPE, as well as the degenerated photoreceotor cells, ended abruptly (Fig. 7, B). The remaining inner retinal layers, which were as normal as those overlying the R P E hypertrophy, were firmly attached to Bruch's membrane by horizontally oriented glial tissue (Fig. 7, B ) . This area corre sponded to the depigmented lacuna seen in the gross photograph (Fig. 5). Electron microscopy—On electron micro scopic examination, the pigment epithelium on both sides of the lesion depicted in Fig
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ure 6 exhibited normal cell shape and con tained the usual football-shaped melanin granules (Fig. 8, A ) . The R P E cells were in contact with photoreceptor outer segments, both of which showed autolytic changes due to the poor preservation of the specimen. Basement membrane, Bruch's membrane, and choriocapillaris were normal. In the area of hypertrophy (Fig. 8, B), the R P E cells were about twice normal dimensions and contained numerous large, round pigment granules. No football-shaped melanin granules were found in these cells. Anterior to the hypertrophied R P E cells, no photoreceptor outer segments were seen. The thickening of Bruch's mem brane seen with light microscopy (Fig. 6, E ) resulted from tremendous thickening of the basement membrane of the hypertrophied R P E cells (Fig. 8, B ) . The outer layers of Bruch's membrane were morphologically normal. The choriocapillaris appeared nor mal and contained numerous intact erythrocytes (Fig. 8, B ) . Electron microscopy of the lesion of con genital hypertrophy of the R P E found in the second specimen (Fig. 5) showed practically the same cellular features in the hypertrophie cells as just mentioned, except for less marked thickening of their basement mem branes (Fig. 7, C). In the area of the depig mented lacuna (Fig. 5), the hypertrophie R P E cells disappeared, leaving only base ment membrane behind. There were glial cells interposed between the retina and the choriocapillaris. These cells possessed cell junctions and were in the process of laying down new basement membranes (Fig. 7, D ) . DISCUSSION
Clinical findings—Congenita.] hypertrophy of the R P E is usually found incidentally during routine fundus examinations. Pa tients generally do not complain of any symptoms related to this lesion, except when it possibly involves the macula. Normal ERGs and EOGs in this condition are not surprising, since both tests measure only mass responses and do not allow de-
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Fig. 7 (Buettner). Phase contrast and electron microscopic photographs of specimen from the post mortem eye of a 23-year-old white man. At the margin of the lesion (A), there is a narrow zone of slightly hypopigmented, hypertrophie RPE cells (arrows) between the normal (n) and hypertrophie, hyperpigmented (h) RPE cells. These hypopigmented cells correspond with the halo surrounding the lesion, as seen in Figure 5. Pho'-oreceptor inner and outer segments are normal overlying the normal RPE (n), but show progressive degeneration as one approaches the hypertrophie RPE (h). Artifactitious detachment required photomontage (dotted line). Electron rnicrograph (C) demonstrates the same large granules in the hypertrophie RPE cells as found in the other specimen (Fig. 8, B). At the border between hypertrophie RPE and a depigmented lacuna (B) (see Fig. 5), the hypertrophie RPE, as well as the degenerated photoreceptor cells, end suddenly (arrow in B), and the remaining normal inner retinal layers are fused to Bruch's membrane by horizontally oriented glial cells. Electron microscopy (D) demon strates formation of new basement membrane (single arrow) on the remaining basement membrane of the disintegrated RPE cells, as well as cell junctions between glial cells (double arrows) (A and B, X200 ; C, x 18,000 ;D, x 13,000).
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tection of localized abnormalities of photoreceptors or pigment epithelium.6-8 The ophthalmoscopic criteria of congenital hypertrophy of the R P E have been out lined above and previously reported by others.1"5 The diagnosis is facilitated by stereoscopic fundus photography and fluorescein angiography, which show uniform blockage of choroidal fluorescence by the lesion and normal retina and retinal vasculature overlying it. The fact that the hyperpigmented areas do not exhibit any fluorescein leakage or staining can be interpreted to indicate that the cellular integrity of the R P E is preserved. The integrity of these cells is clearly demonstrated electron micro scopically (Fig. 7, C). The absence of fluorescein leakage from the area of the depigmented lacunae (Fig. 1) demonstrates the fact that not only R P E cells but also other cells, i.e., glial cells (Fig. 7, D ) , can pre vent diffusion of fluorescein dye from the choriocapillaris into the retina or subretinal space. Differential diagnosis—Although the
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proper diagnosis in congenital hypertrophy of the R P E can readily be made using mod ern examination techniques, confusing no menclature found in earlier reports sug gests that this lesion has been misdiagnosed frequently. Review of histopathologic ma terial indicates that this lesion has often been mistaken for a malignant melanoma of the choroid.1'9 Reese and Jones 1 found nine such lesions among 151 enucleated eyes thought to harbor a malignant melanoma, while Ferry 10 found two such lesions in a series of 100 eyes enucleated with a misdiagnosis of malignant melanoma of the choroid or ciliary body. Choroidal mela nomas are almost always clearly elevated, and they are almost never as uniformly and darkly pigmented or as sharply demarcated as are lesions in congenital hypertrophy of the RPE. Furthermore, the lack of progres sion in congenital hypertrophy, as demon strated in this study, clearly distinguishes this lesion from malignant melanoma of the choroid. Congenital hypertrophy of the R P E might
Fig. 8 (Buettner). Electron micrograph of normal RPE (A) immediately adjacent to lesion shown in Figure 6, A and B. Note the typical wedge-shaped melanin granules. B, At the same magnification, hypertrophied RPE cells within the lesion. The difference in size and appearance of pigment granules as compared to A is quite evident, as well as the tremendous thickening of the basement membrane (bm) of the RPE cells. Note further the normalcy of the choriocapillaris, containing numerous erythrocytes (X6,600).
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also be misdiagnosed as choroidal nevus. One may avoid this error by recognizing the ill-defined border in the vicinity of larger choroidal vessels of nevi, their lighter pig mentation, and their location below the RPE. Drusen often overly a choroidal nevus. These may superficially resemble depigmented lacunae in congenital hypertrophy. However, the flat, sharply demarcated and punched-out character of these lacunae (through which choroidal vessels can often be seen) contrasts with the elevated opaque appearance of drusen. Melanocytomas of the choroid, although usually darker than choroidal nevi, share many of their morphologic characteristics. Therefore, they cannot be differentiated clinically from choroidal nevi in many in stances.9 Melanocytomas of the choroid may also be confused with congenital hypertro phy of the RPE. Although melanocytomas are typically situated in the optic nerve head, they may also be found in a peripapillary location (Fig. 9) or elsewhere in the uveal tract.9 Congenital hypertrophy of the R P E is, at least terminologically,2'4,5 confused occasion ally with true benign hyperplasia of the RPE. 9 ' 17 True hyperplasia is characterized by diffuse proliferation of the R P E with local invasion and infiltration of the retina, usually in a juxtapapillary location, but also occurring in the periphery.12 This abnor mality is often slowly progressive, and asso ciated visual loss is often present. These factors appear to be responsible for the fre quently made diagnosis of malignant mela noma, as indicated by the relatively large number of histopathologic reports avail able.11·15"17 Other lesions to be considered in the dif ferential diagnosis of congenital hypertrophy of the R P E are inflammatory pigmented fundus lesions, pigmented colobomas,18·19 and rare adenomas and carcinomas of the RPE. 20 The value of visual fields in the differ ential diagnosis of pigmented fundus lesions
FEBRUARY, 1975
had. been emphasized repeatedly in the past.21'22 However, the postulation that le sions with a visual field defect represent neoplasms or malignancies does not hold true. Choroidal nevi, for instance, are fre quently associated with visual field defects,23-26 as are areas of hyperplasia of the RPE.11"17 The field defects in congenital hypertrophy of the R P E are clearly demon strated in this study. Pathology—The morphologic basis of the visual field defects in congenital hyper trophy of the R P E is selective degeneration of photoreceptor cells overlying the area of hypertrophie R P E cells. The extent of these degenerative changes appears to de pend on the patient's age. Kurz and Zim merman3 observed only mild changes in the photoreceptors overlying an area of congen ital hypertrophy of the R P E in the eye of a 19-year-old woman, similar to those found in such a lesion in the postmortem eye of a 23-year-old white man (Fig. 7). However, in the postmortem eye of a 62-year-old man, almost total degeneration of the photorecep tor cells was found overlying the area of hypertrophy of the R P E (Fig. 6). This in dication of progressive degeneration of photoreceptors is well supported clinically by visual field findings of only shallow scotomas early in life and deep scotomas later in life. The cause of the photoreceptor degenera tion seems to be the abnormal nature of the retinal pigment epithelium. The markedly enlarged R P E cells are almost entirely filled with large round pigment granules that re semble lipofuscin inclusions, rather than melanin granules. Whether this is the cause or the result of malfunction of the R P E is speculative. According to Feeney, Grieshaber, and Hogan,27 lipofuscin is the degradation product of outer segment material that breaks off constantly at the outer segments' distal ends and is engulfed by R P E cells. In congenital hypertrophy of the RPE, the accumulation of these lipofuscin-like inclu sions could indicate that the cells cannot
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eliminate this material in the usual ( a s yet unknown) way. T h e marked thickening of the basement membrane of the R P E cells then may be interpreted as an unsuccessful attempt of these cells to eliminate some of this material. Parsons 2 8 observed the thick ening of the basement membrane. However, he noted hyaline material resembling "col loid bodies" in grouped pigmentations or "bear tracks" on the fundus ( F i g . 10), a condition which is pathologically 28 ' 29 and clinically 19 · 30 " 32 similar to congenital hyper trophy of the R P E (Figs. 2, 3, 5, and 11). Hoeg 8 1 found subtle visual field defects cor responding to grouped pigmentations of the fundus. Congenital hypertrophy of the R P E can be regarded as a solitary form of grouped pigmentations of the fundus 3 3 on the basis of clinical, histologie, and etiologic similarity. T h e normal appearance of the outer layers of Bruch's membrane and the choriocapillaris essentially rules out the pos sibility that this lesion results from a patho logic process originating in the choroid. T h e depigmented lacunae, which were not seen in young patients, are caused by the disap pearance of hypertrophie R P E , as demon strated in follow-up photographs (Fig. 4 ) . The photoreceptor cells disappear, together with the hypertrophie R P E . Glial cells pro liferate into this space and form a compact layer between the remainder of the retina and the unaltered Bruch's membrane. Know ing that there a r e no photoreceptors over lying the depigmented lacunae, the visual field findings in Patient 5 (Fig. 4) have to be regarded as faulty. T h e r e should be an absolute scotoma corresponding to the fun dus lesion, not only on the basis of the patient's age of 39 years, but also because of the presence of numerous depigmented areas within the lesion. Etiology and pathogenesis—According to Ida Mann, 1 8 congenital hypertrophy of the R P E represents an area where cells of the inner layer of the optic cup, for example, the sensory retina, underwent aberrant differenti ation and formed a cluster of pigment cells.
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H o g a n and Zimmerman, 4 however, postu lated that the R P E proliferated in areas in which there has been a failure of rods and cones to develop. The clinical and histologie findings of this investigation contradict both these theories. Shallow scotomas only in the visual fields of young patients with con genital hypertrophy strongly suggest that the retina develops relatively well, or even normally, in these areas. This assumption is supported by the histopathologic findings of K u r z and Zimmerman 3 of only mild photo receptor degeneration overlying an area of congenital hypertrophy of the R P E in a 19-year-old patient. With age, the photore ceptors seem to degenerate progressively, as indicated by clinical findings of absolute scotomas in older patients, and by the almost total degeneration of photoreceptors over lying such a lesion found in a 62-year-old patient. T h e congenital abnormality probably con sists of aberrant differentiation of a localized patch of R P E cells. Overlying this area of abnormal R P E , the retina apparently de velops relatively normally. However, the aberrant, hypertrophie R P E cells are not fully able to maintain the integrity of the photoreceptor cell layer, 34 resulting in pro gressive photoreceptor degeneration during life. Clinical significance—Congenital hyper trophy of the R P E is a well-defined clinical and pathologic entity presenting either as grouped pigmentations or as a solitary form, as described herein. Using the abovementioned criteria, it should be possible to differentiate congenital hypertrophy of the R P E from inflammatory lesions, pigmented colobomas, choroidal nevi, melanocytoma, and malignant melanomas of the choroid. This lesion should always be followed clini cally and should never be cause for enucleation of the eye. SUMMARY
T h e flat, circumscribed, and hyperpigmented lesion of the retinal pigment epi-
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thelium ( R P E ) without clinically apparent involvement of the overlying retina, desig nated as congenital hypertrophy, was found to be associated with corresponding scotomas in the visual field. The depth of the scotoma increased with the age of the patient. These lesions did not grow. They could be readily differentiated from other pigmented fundus lesions on the basis of their typical clinical appearance. Histopathology revealed a single layer of hypertrophied cells, containing numerous large pigment granules, and degeneration of photoreceptor cells overlying the area of abnormal R P E . The clinical as well as the histologie find ings suggested that the retinal abnormality overlying the hypertrophied R P E was due to secondary degeneration rather than primary maldevelopment of photoreceptor cells. ACKNOWLEDGMENTS
I thank Mrs. S. McKenney for performing the visual field examinations ; Mrs. I. Holmes for electrophysiological testing; Mrs. N. Hechlinski, Mrs. B. French, and Mr. D. Clark for photographic assistance ; Mrs. B. Monterò and Mr. M. Solis for histologie assistance ; and Mr. B. Davis helped with electron microscopy. Drs. J. D. M. Goss and E. Fineberg recovered the histologie specimen. Mrs. R. Hurles, Drs. E. W. D. Norton, J. D. M. Gass, and R. L. Jack provided editorial assistance. REFERENCES
1. Reese, A. B., and Jones, I. S.: Benign mela nomas of the retinal pigment epithelium. Am. J. Ophthalmol. 42:207, 1956. 2. Reese, A. B.: Tumors of the Eye, 2nd ed. New York, Harper and Row, 1963. 3. Kurz, G. H., and Zimmerman, L. E. : Vagaries of the retinal pigment epithelium. Int. Ophthalmol. Clin. 2:441, 1962. 4. Hogan, M., and Zimmerman, L. E. (eds.) : Ophthalmic Pathology. An Atlas and Textbook, 2nd ed. Philadelphia, W. B. Saunders, 1962, p. 477. 5. Reese, A. B.: The role of the pigment epi thelium in ocular pathology. Am. J. Ophthalmol. 50:1066,1960. 6. Arden, G. B., and Kelsey, J. H. : New clinical test of retinal function based upon the standing potential. Br. J. Ophthalmol. 46:449, 1962. 7. Jacobson, J. H., Najac, H. T., Stephens, G., Kara, G. B., and Gestring, G. F.: The role of the macula in the electroretinogram of monkey and man. Am. J. Ophthalmol. 50:889, 1960.
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8. Jacobson, J. H.: Clinical Electroretinography. Springfield, Charles C Thomas, 1961. 9. Zimmerman, L. E. : Melanocytes, tnelanocytic nevi and melanocytomas. Invest. Ophthalmol. 4:11, 1965. 10. Ferry, A. P. : Lesions mistaken for malignant melanomas of the posterior uvea. Arch. Ophthalmol. 72:463,1964. 11. Theobald, G. D., Floyd, G., and Kirk, H. G. : Hyperplasia of the retinal pigment epithelium. Sim ulating a malignant melanoma. Report of two cases. Am. J. Ophthalmol. 45:235, 1958. 12. Duke, J. R., and Maumenee, A. E.: An unusual tumor of the retinal pigment epithelium. Am. J. Ophthalmol. 47:311, 1959. 13. Rein, G.: Ueber Melanoblastome der Papille und Tumoren des retinalen Pigmentepithels. Graefe's Arch. Ophthalmol. 161:519, 1960. 14. Cardell, B. S., and Starbuck, M. J.: Juxtapapillary hamartoma of retina. Br. J. Ophthalmol 45:672, 1961. 15. Spiers, F., and Jensen, O. A. : Pseudo-epitheliomatous hyperplasia of the retinal pigment epithelium. Acta Ophthalmol. 41:722, 1963. 16. Machemer, R. : Die primaere retinale Pigmentepithelhyperplasie. Graefe's Arch. Ophthalmol. 167:284, 1964. 17. Vogel, M. H., Zimmerman, L. E., and Gass, J. D. M. : Proliferation of the juxtapapillary retinal pigment epithelium simulating malignant melanoma. Doc. Ophthalmol. 26:461, 1969. 18. Mann, I.: Developmental Abnormalities of the Eye, 2nd ed. Philadelphia, T. B. Lippincott, 1957, p. 140. 19. Sorsby, A. : Congenital coloboma of the macula. Br. J. Ophthalmol. 19:65, 1935. 20. Garner, A.: Tumors of the retinal pigment epithelium. Br. J. Ophthalmol. 54:715, 1970. 21. Duke-Elder, S., and Perkins, E. S.: Diseases of the Uveal Tract. In Duke-Elder, S. (ed.) : Sys tem of Ophthalmology, vol. 9. London, Kimpton, 1966. 22. Bettman, J. W., and Fellows, V.: The differ ential diagnosis of dark lesion of the posterior fundus. Am. J. Ophthalmol. 41:975, 1956. 23. Tamler, E., and Maumenee,·A. E. : A clinical study of choroidal nevi. Arch. Ophthalmol. 62:196, 1959. 24. Naumann, G., Zimmerman, L. E., and Yanoff, M.: Visual field defect associated with choroidal nevus. Am. J. Ophthalmol. 62:914, 1966. 25. Karickhoff, J. R.: Loss of visual function and visual cells in 600 cases of malignant melanoma. Am. T. Ophthalmol. 64:268, 1967. 26. Flindall, R. J., and Drance, S. M. : Visual field studies of benign choroidal melanomata. Arch. Ophthalmol. 81:41,1969. 27. Feeney, L., Grieshaber, A., and Hogan, M. J.: Studies on human ocular pigment, In Rohen, J. W. (ed.) : The Structure of the Eye. Stuttgart, Schattauer-Verlag, 1965, p. 535. 28. Parsons, J. H. : Some anomalies of pigmenta tion. Xe Congrès d'ophtalmologie, Lucerne, vol. 10,B, 1904, p. 152.
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29. Legrand, J., Hervouet, A., Ginguené, A., and Lenoir, A. : Pigmentation groupée de la rétine. Bull. Soc. Ophtalmol. Fr. 64:313,1964. 30. Stephenson, S.: A peculiar form of retinal pigmentation. Trans. Ophthalmol. Soc. U.K. 11:77, 1891. 31. Höeg, N.: Die gruppierte Pigmentation des Augengrundes. Klin. Monatsbl. Augenheilkd. 49:49, 1911. 32. Morse, P. H.: Fluorescein angiography of
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OPHTHALMIC MINIATURE
Scientific writers are rarely literate. If a colleague tells a scientist that His latest article is difficult to understand, the writer is more likely to assume that his colleague is unintelligent than that his article is un intelligible. Such writers believe that discussions about style, choice of words, length of sentences, active and passive voices, subjunctives, and the like, are for non-scientific second-rate minds with nothing original to say, and are irrelevant for serious scientific workers. Unfortunately, this argument can be supported by reference to published accounts of important work, many of which are badly written. No editor will reject first-class research because it is in poor English, and few journals have enough staff to rewrite all the articles they publish. So why does style matter? Simplicity and clarity are the features of good scientific writing. Clear thought can be expressed clearly; and a man with something of value to say has no need to pad out his account. Watson and Crick's account of the double-helix structure of DNA was communicated as a 900-word letter to-"Nature." Charles Thorne, Better Medical Writing London, Pitman, 1970
