Bilateral Diffuse Uveal
Melanocytic Proliferation
in Patients With Occult Carcinoma J. Donald M.
Gass, MD; Richard G. Gieser, MD; C. P. Wilkinson, MD; Donald
\s=b\ The development of multiple, round or oval, subtle, red patches at the level of the pigment epithelium in the posterior ocular fundus and their striking early hyperfluorescence angiographically are character-
istic features of the bilateral diffuse uveal
melanocytic proliferation syndrome. They may be accompanied by severe visual loss and may antedate the appearance of mul-
tiple melanocytic tumors, retinal detachment, and cataract in these patients with occult systemic carcinomas. These hyperfluorescent patches are caused by focal damage to the pigment epithelium overlying an intact choriocapillaris and diffuse benign nonpigmented uveal melanocytic infiltration of the outer choroid. We suggest that outer retinal damage may not be primarily caused by melanocytic proliferation, but rather by toxic and immune factors generated by interaction between a systemic carcinoma and congenital melanocytosis of the uveal tract. We report the longest survivor of this disorder to date (102 months).
(Arch Ophthalmol. 1990;108:527-533)
"Dilaterai diffuse uveal melanocytic
JJ
proliferation (BDUMP) is a bi¬ paraneoplastic ocular syndrome occurring in patients with systemic, often occult carcinoma, which typi¬ cally causes death within 12 to 24 months. Five cardinal ocular signs zarre
that accompany visual loss in these patients are the following: (1) multi¬ ple, round or oval, subtle, red patches at the level of the retinal pigment ep-
Accepted for publication December 29, 1989. From the Departments of Ophthalmology, Bascom Palmer Eye Institute, University of Miami, Fla (Dr Gass); Loyola University of Chicago Stritch School of Medicine, Maywood, Ill (Dr Gieser); Dean A. McGee Eye Institute, Oklahoma City, Okla (Dr Wilkinson); University of Kansas, Kansas City (Dr Beahm); and University of South Florida, Tampa (Dr Pautler). Reprints not available.
E.
Beahm, MD; Scott
ithelium in the
posterior fundus; (2) a striking pattern of multifocal areas of early hyperfluorescence corresponding with these patches; (3) development of multiple, slightly elevated, pigmented and nonpigmented uveal melanocytic tumors,
as
well
as
evidence of diffuse
thickening of the uveal tract; (4) exu¬ dative retinal detachment; and (5) rapid progression of cataracts.1 " Pre¬ vious reports have emphasized the lat¬ ter three signs. The purposes of this report are (1) to present four patients to stress the importance of the first two signs, both of which may antedate the other three, and both of which are highly suggestive of the correct diag¬ nosis; (2) to demonstrate clinicopathologic correlations pertaining to these two signs; (3) to discuss the implica¬ tions of these findings in regard to the pathogenesis of visual loss; and (4) to present the first patient with longterm survival.
REPORT OF CASES Case 1.—An apparently healthy
68-year-
old woman noted rapid loss of vision in both eyes. Her visual acuity was counting fingers at 4 ft in each eye. The conjunctivae were moderately hyperemic. The anterior cham¬ bers and lenses were clear. The ophthalmoscopic examination revealed faint, oval and round, fiat, reddish patches at the level of the pigment epithelium throughout the posterior fundi (Fig 1, left). These con¬ trasted only slightly with the normal, or¬ ange-red appearance of the surrounding fundus. In the right eye there was a shallow serous detachment of the retina posteri¬ orly, and a shallow choroidal detachment inferiorly. Early retinal arteriovenousphase fluorescein angiography revealed a striking unexpected pattern of multifocal areas of early hyperfluorescence that cor¬ responded with the reddish subretinal le¬ sions (Fig 1, center). This hyperfluores¬ cence persisted into the late phases of angiography and was accompanied by the development of multifocal areas of pinpoint staining at the level of the pigment epithe-
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E.
Pautler,
MD
lium (Fig 1, right). A medical evaluation, including chest roentgenography and scans of the liver and spleen, produced results that were within normal limits. A single sub-Tenon's injec¬ tion of methylprednisolone acetate and oral prednisone, 60 mg/d for 2 weeks, produced no change in the retinal detachment or vi¬ sual acuity. Three months later, the pa¬ tient's visual acuity improved to 20/100 OD and 20/80 OS. Multiple, slightly elevated, pigmented, choroidal lesions resembling choroidal nevi developed in both eyes. Within several weeks, rapid development of cataracts occurred bilaterally. A diagnosis of BDUMP was made. The patient was hos¬ pitalized for cataract extraction and under¬ went further medical evaluation to look for an occult carcinoma. A carcinoma of the cervix with extension to the pelvic walls was found. Within 1 year from the onset of visual symptoms, the patient died of metastatic carcinoma. No autopsy was done. Case 2.—A 77-year-old woman was in apparently good health when she rapidly developed loss of vision in both eyes. When seen by her local physician in August 1976, her visual acuity was 20/300 OD and 20/100 OS. The physician noted bilateral cataracts and fluorescein angiographie changes that he interpreted as senile macular degenera¬ tion (Fig 2, left). No pigmented lesions were noted. Angiography revealed multifocal ar¬ eas of hyperfluorescence that were inter¬ preted as probably being caused by large drusen. When the patient was seen by us in November 1976, her visual acuity in the right eye was counting fingers only and was unchanged in the left eye. There was dila¬ tion of the episcleral vessels bilaterally. Pigmented keratitic precipitates and pig¬ mented cells were present in the anterior chamber and vitreous of both eyes. There was a posterior synechia in the left eye.
Multiple, slightly elevated, subretinal, pig¬ mented lesions of variable size were barely visible through media compatible with vis¬ ual acuity of 20/100 OU. These were vari¬ ously interpreted by several physicians as multiple subretinal hematomas, multiple choroidal nevi, and metastatic melanoma to the choroid. Results of an extensive medical evaluation were normal.
Fig 1.—Case 1. Left eye. Left, Note the round patches (arrows) that were red. Center, Early-phase angiogram showing focal hyperfluorescence (arrows) corresponding with the red patches (left). Right, Late pin¬ point areas of staining in macular area."
Fig 2.—Case 2. Left eye. Left, August 1976; right, January 1977. Arrowheads indicate the reticular pattern of pigment epithelium (nonfluorescent areas [left] and light-colored areas [right]) surrounding the zones of pigment epithelial atrophy (hyperfluorescent areas [left] and dark areas [right]).
During a 2-week period, there was rapid progression of the patient's cataracts. Vis¬ ual acuity was counting fingers only in both
eyes and cataract extraction was done in the left eye. Postoperatively, multiple, pig¬
mented, choroidal lesions were easily visu¬ alized. There were large, multiple, conflu¬ ent, round and oval, red and gray patches outlined by a triradiate pattern of orange pigment epithelium that was most promi¬ nent in the
papillary
peripheral macular and peri(Fig 2, right). In spite of
areas
clear media and the absence of retinal detachment, visual acuity was counting
lingers only.
Within 4 months, visual acuity in both eyes decreased to hand movements only and
there was exudative retinal detachment in¬ teriorly. The patient developed malaise and weight loss, and 10 months later a medical
evaluation, including roentgenographic
studies of the gastrointestinal tract, re¬ vealed evidence suggesting a pancreatic carcinoma. The patient died 23 months af-
ter the onset of visual
symptoms, and an autopsy revealed metastatic ovarian carci¬ noma. The eyes were obtained at autopsy
and the findings have been previously reported.' They included diffuse infiltration of the entire uveal tract with benign-ap¬ pearing, nonpigmented, uveal melanocytes and multifocal areas of choroidal thicken¬
ing by benign-appearing, partly necrotic, pigmented, uveal melanocytes. Important changes were the extensive destructive changes in the overlying pigment epithe¬ lium and outer retina despite the relative sparing of the choriocapillaries by the uveal infiltrate (Fig 3, left) and the presence of extensive necrosis within the focal pig¬ mented tumors (Fig 3, right). Case 3.—In November 1982, a 65-year-old woman developed blurred vision in both eyes. Two months previously her visual acuity was 20/20 OU. Two years previously she underwent an incomplete excision of an ovarian papillary serous cystadenocarcinoma, which was followed by chemotherapy.
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Her son had bilateral testicular tumors, and her daughter had cervical cancer. The patient's visual acuity was 20/200 OD and 20/50 OS. An ophthalmoscopic examina¬ tion revealed multiple, widely scattered, slightly elevated, pigmented choroidal le¬ sions in both fundi. In the posterior fundi that were relatively free of pigmented le¬ sions, there were multiple, round and oval, red, subretinal patches that were barely evident against the normal background or¬ ange-red of the fundi (Fig 4, left). Fluorescein angiography showed hyperfluores¬ cence of these lesions in both eyes (Fig 4, right). The medical evaluation failed to show evidence of ovarian or other metastatic carcinoma. Within several months the patient devel¬ oped a pigmented tumor on the iris of the right eye, rapidly progressing cataracts in both eyes, and bullous retinal detachment in both eyes. Optic disc swelling and sur¬ rounding retinal hemorrhages were pres¬ ent in the left eye where the pigmented tu-
Fig 3.—Case 2. Left eye. Left, Photomicrograph showing diffuse choroidal infiltration with small hypopigmented benign melanocytes, relative sparing of the choriocapillaris (arrow), and depigmentation and degeneration of the pigment epithelium (hematoxylin-eosin, original magnification X175). Right, Photomi¬ crograph showing focal, partly necrotic (arrows), pigmented, choroidal tumor and extensive degeneration of the pigment epithelium and retinal receptor cells (hematoxylin-eosin, original magnification X70).
Fig 4.—Case 3. Right eye. Left, Note the faintly visible patches (small arrows) that were red in the posterior fundus and a pigmented choroidal tumor (large arrow). Right, Angiogram showing focal hyperfluorescence (arrows) corresponding with the red patches (left)." mors extended to the disc margin. The pa¬ tient underwent a combined cataract extraction and a biopsy of the iris tumor. The biopsy specimen showed melanocytic proliferation that was interpreted as be¬ nign by some observers and malignant by others. The patient experienced progressive visual loss in both eyes that failed to im¬ prove after being treated with 40 Gy of ex¬ ternal beam cobalt 60 radiation in each eye. Multiple extensive medical investigations failed to reveal evidence of metastatic dis¬ ease. The results of lymphocyte analysis and assays for -glutamyl transpeptidase membrane marker enzyme and carcinoembryogenic antigen were normal. Within 2 years after the onset of visual symptoms, the patient was blind. Soon thereafter, she developed absolute glau¬ coma and evidence of continued growth of the uveal lesions. The right eye was enucle¬ ated in 1984 and the left eye in 1986. Both eyes showed evidente of diffuse uveal mei-
anocytic proliferation (Fig 5) by a mixture of cells showing both nevoid (Fig 6, left) and, in some areas, epithelioid cell differ¬ entiation (Fig 6, right). There was minimal evidence of mitotic activity. There was rel¬ ative sparing of the choriocapillaris and extensive degeneration of the pigment epi¬ thelium and receptor cells (Fig 6, left). In May 1989, 8V2 years after treatment for ovarian carcinoma and 6V2 years after the onset of visual symptoms, the patient de¬ veloped signs and symptoms of presenile dementia, but had no evidence of metastatic disease. Case 4.—A 61-year-old man complained of an abrupt loss of central vision in his right eye 1 week previously and mild blur¬ ring of vision in the left eye for 1 year. His visual acuity was normal 5 years previously when last examined by an ophthalmologist. He had a 27-year history of diabetes mellitus, obstructive pulmonary disease, and chronic osteomyelitis. The patient had no
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other medical problems and no history of cancer. The family medical history was negative. The patient's visual acuity was 20/200 OU. Amsler grid testing revealed bilateral central scotomata. The intraocu¬ lar pressures were 10 and 8 mm Hg in the right and left eyes, respectively. The ante¬ rior segments were unremarkable. The pa¬ tient had mild nuclear cataracts; his optic discs were normal. The retinal arterioles were minimally attenuated and there were rare retinal microaneurysms. Posteriorly, in the extramacular area of both eyes, there were multiple, round and oval, slightly ele¬ vated, pigmented choroidal lesions measur¬ ing 0.5 to 2 disc diameters in size. Through¬ out the posterior fundi there were multiple, round and oval, reddish patches separated by a reticular pattern of yellow-orange pig¬ ment clumping (Fig 7, left). There was a shallow retinal detachment in the right macula. When examined 2 weeks later, the pa-
tient's visual acuity was 20/400 OD and 20/ 200 OS. His examination results were un¬ changed except for the presence of subret¬ inal fluid in the macula and the inferior periphery of the left eye. Fluorescein an¬ giography revealed a reticular pattern of nonfluorescence on a background of marked hyperfluorescence during the early arteriovenous-phase angiograms (Fig 7, right) and late pinpoint areas of staining. Electroretinography revealed normal photopic responses in both eyes and severely abnor¬ mal scotopic responses in the left eye. Electro-oculography was borderline normal in both eyes (the light/dark ratio was 1.63% in the right eye and 1.57% in the left eye). During the next 2 months, six new pig¬ mented choroidal lesions developed in the periphery of the right eye and two new similar lesions developed in the periphery of the left eye. Three lesions in the left macula enlarged and coalesced. There was
Fig 5.—Case 3. Right eye. Photomicrograph showing diffuse and focal thickening of the uveal tract by melanocytic cells (hematoxylineosin, original magnification X6).
bullous and neurosensory retinal detach¬ ment in both eyes. This was associated with shifting of the subretinal fluid. A medical
evaluation, including a general physical ex¬ amination, chest roentgenography, lung and abdominal computed tomographic scanning, sigmoidoscopy, and bronchos-
washings, revealed no evidence of malignancy in either the lungs or the retroperitoneal space. An otolaryngological copy with
examination revealed melanosis of the trachea! mucous membranes. Antiretinal
antibody
assays
were
negative.'2
COMMENT
The ocular manifestations of BDUMP usually antedate signs and symptoms of the systemic carcinoma (10 of the 16 reported cases) by 3 to 12 months. Of the five cardinal ocular features of the syndrome, the multifo¬ cal, faintly visible, round or oval, red, subretinal patches, which are promi¬ nently hyperfluorescent during the early phases of angiography, are usu¬ ally the first to appear and are usually still visible after the development of the other three signs. Other biomicroscopic signs that may be present in¬ clude anterior chamber cells, vitreous cells, and signs of ciliary body enlarge¬ ment, including dilated episcleral vessels,' shallow anterior chamber,6 ciliary body cysts,4·6 and iridodonesis.5 The subtle red patches and their strik¬ ing tendency to fluoresce are charac¬ teristic of this syndrome and are not usually seen in patients with other disorders characterized by either mul¬ tifocal or diffuse cellular infiltrate of the choroid by either inflammatory or neoplastic cells. Thus, recognition of these two signs is of great importance in the early diagnosis of this syn¬ drome.
The precise correspondence of the focal areas of early hyperfluorescence and the subretinal patches suggest that they are fenestrations of the pig¬ ment epithelium caused by its depigmentation and focal destruction in the absence of infiltration and obstruction of the underlying choriocapillaris (Fig 8). Histopathologically, this interpre¬ tation is supported by the remarkable predilection for the uveal melanocytic proliferation to spare the choriocapil¬ laris, and by the widespread areas of necrosis and degeneration of the pig¬ ment epithelium and outer retina, even in large areas where only minimal melanocytic proliferation is present (Fig 3, left, and Fig 6, left). These are consistent features that one of us (J.D.M.G.) has seen in eyes removed from four patients with this syndrome. The diffuse redness of the patches (or their dark gray color in the case of pa¬ tients with brunette fundi) that is only barely discernible biomicroscopically from the normal reddish orange of the surrounding retinal pigment epithe¬ lium is probably caused by the hypopigmented diffuse melanocytic infil¬ tration that hides from view details of the underlying large choroidal vessels and sclera (Fig 3, left, Fig 6, left, and Fig 8). These patches of depigmented or fenestrated pigment epithelium progressively enlarge and become con¬ fluent to produce a triradiate or retic¬ ular pattern of orange pigment epithe¬ lium that angiographically appears nonfluorescent on a background of marked choroidal hyperfluorescence (Figs 1,4,7, and 9). This was strikingly demonstrated in the case reported by Margo et al.10
Fig 6.—Case 3. Right eye. Left, Benign melanocytic proliferation of the choroid with relative sparing of the choriocapillaris (arrow). Note the multifocal areas of pigment epithelial destruction and clumping (hematox¬ ylin-eosin, original magnification X440). Right, A focal area of epithelioid cell proliferation (white arrow) ad¬ jacent to the benign melanocytic infiltration of the choroid (black arrow) (hematoxylin-eosin, original mag¬ nification X175).
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Fig 7.—Case 4. Left eye." Left, Note the faintly visible reticular pattern of retinal pigment epithelium (RPE) was yellow-orange surrounding the multiple, round and oval, dark RPE fenestrations that were reddish (arrowheads). Right, Angiogram showing marked hyperfluorescence corresponding to the fenestrated ar¬ eas of RPE damage. that
The mechanism causing the acute multifocal areas of depigmentation or destruction of the RPE is uncertain. The angiographie and histopathologic evidence of an intact choriocapillaris suggests that ischemia may not be an important factor. Clinically and histopathologically, the marked pigment epithelial damage and outer retinal damage in large areas of only minimal outer choroidal melanocytic infiltra¬ tion is far greater than that in many patients with greater infiltration of full-thickness choroid by carcinoma and melanoma. It is likely that other local toxic or immune reactions are re¬ sponsible for the damage to the retinal pigment epithelium, as well as to the overlying retinal receptor cells. For example, we observed in patients 2 and 3 that the visual function was profoundly affected before the devel¬ opment of secondary retinal detach¬ ment. The pathogenesis of retinal damage in these patients may be similar to that in patients who, in association with an occult carcinoma, develop rapid loss of vision, nyctalop¬ ia, and a fundus picture simulating retinitis pigmentosa sine pigmenti.1215 In these latter patients the retinal pigment epithelium is typically less affected than the retinal receptor cells. Patient 4 had a negative assay for antibodies to a retinal cancer-associ¬ ated antigen.12 A similar paraneoplastic acute night blinding disorder
associated with rapidly developing vitíligo of the skin and uveal tract depigmentation may occur in patients with metastatic cutaneous mela¬ noma.16·" The histopathologic picture in most of the 23 eyes of 12 patients examined to date has been remarkably similar. It includes diffuse infiltration of the uveal tract, including the scierai emis¬ sary canals, with predominantly small nevoid hypopigmented melanocytic cells. The choroidal thickening is typ¬ ically minimal in comparison with that of the ciliary body, and the cho¬ riocapillaris is relatively spared. Mul¬ tiple focal areas of increased thicken¬ ing of the choroid by heavily pig¬ mented melanocytes typical of melanocytomas have been present in most eyes. In at least four eyes there has been focal necrosis within these pig¬ mented tumors.3 Although the mel¬ anocytic infiltration is predominantly benign in appearance, most eyes have shown foci of spindle and epithelioid cellular differentiation.-'·5·6·9·10 This, however, has been accompanied by lit¬ tle or no evidence of mitotic activity. Since the mean survival time after the initial symptom appeared in these pa¬ tients is approximately 16 months, there has been only limited opportu¬ nity to observe evidence of progression of the uveal melanocytic proliferation. The appearance and enlargement of the focal pigmented and, less often,
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tumors of the choroid and iris have been observed in two of our patients and by others.1·3 Only in one of our patients (case 3) who has survived 8V2 years has there been doc¬ umentation of considerable increase in the diffuse infiltration of the uveal
nonpigmented
tract.
The pathogenesis of the melanocytic infiltration in BDUMP is uncertain. Two types of melanocytes are found in the normal uveal tract: the normal melanocyte and, in many patients, ne¬ vus cells. Normal melanocytes are nonreactive cells that rarely, if ever, pro¬ liferate. Nevus cells that are present, either focally or diffusely (melanocytosis), do have the capability of prolif¬ eration that, in part, is subject to hor¬ monal control and that normally is limited to the prepubertal and early adult years. Suggestions for the patho¬ genesis of BDUMP have included the following: (1) de novo development of uveal melanocytic proliferation and the systemic carcinoma in response to a common oncogenic stimulus3; (2) de novo development of uveal melano¬ cytic proliferation in response to a hormone-secreting visceral carcin¬ oma3; and (3) coincidental develop¬ ment of bilateral low-grade diffuse uveal melanomas and a systemic car¬ cinoma in patients genetically predis¬
to neoplasia.5 regard to the first two sugges¬ tions, it is unlikely that normal mei-
posed In
Fig 8.
Diagram of the anatomy of the red subretinal patches occurring in bilateral diffuse uveal melanocytic proliferation. Arrows indicate the fenestrated area of depigmentation and degeneration of the retinal pig¬ ment epithelium (RPE) overlying the intact choriocapillaris (cc) and in¬ filtration of the outer choroid (ch) by benign melanocytic cells. The di¬ agram below illustrates perfusion of the choroid with fluorescein (dots) during the early arteriovenous phase, causing hyperfluorescence of the fenestrated area. —
Differential Diagnosis in Patients With Diffuse Bilateral Uveal
Fig 9.—Frontal view diagram showing round fenestrations in the retinal pigment epithelium (left) that enlarge, become confluent, and produce a reticular pattern of retinal pigment epithelium (right).
Melanocytic Proliferation
development of multifocal pigmented choroidal tumors Idiopathic uveal effusion syndrome Large-cell lymphoma, metastatic carcinoma, leukemia Acute polymorphous vitelliform maculopathy'8 Multifocal or diffuse choroiditis, acute posterior multifocal placoid pigment epitheliopathy, pathetic uveitis, sarcoidosis Benign reactive lymphocytic hyperplasia of the uveal tract
Prior to 1.
2. 3. 4. 5.
sym¬
6. Posterior scleritis 7. 8. After 1. 2. 3. 4.
Rhegmatogenous retinal detachment Harada's disease of multifocal pigmented choroidal tumors Metastatic melanoma Multifocal subretinal hematomas Multiple choroidal nevi Multifocal hypertrophy of the pigment epithelium (Gardner's
development
anocytes, regardless of the stimulus, would be likely to proliferate since there is no precedent for this to occur. In regard to the third suggestion, it is equally difficult to accept the concept of a malignant transformation occur¬ ring throughout the uveal tract bilat¬ erally. Diffuse bilateral uveal mela¬ noma outside the context of BDUMP is unreported. We believe, as suggested by Ryll et al,2 that these patients prob¬ ably have bilateral diffuse congenital uveal melanocytic nevi, which, because most of the constituent cells are hypopigmented, are relatively unapparent clinically. In response to certain hormone-producing visceral carcino¬ mas, particularly those of the repro¬ ductive organs in women (six of the eight reported cases) and those of the retroperitoneal areas and lungs in men (six of seven reported cases), these ne¬ vus cells may exhibit limited growth and melanin production, which, in
some
syndrome)
cases, may be associated with
melanocytic necrosis.
We suggest, however, that the acute
damage to the pigment epithelium, the outer retina, and the lens that results in the rapid development of retinal de¬
tachment and cataract formation is not adequately explained by the lim¬ ited melanocytic proliferation that oc¬ curs in these patients. Much of this damage probably is caused by a toxic or immune reaction that is either a by-product of the carcinoma-uveal melanocytic interaction or the direct result of hormonal interaction be¬ tween the carcinoma and the pigment epithelium and retinal receptors. The development of BDUMP in one patient with congenital oculodermal melanocytosis (nevus of Ota) reported by Prause et al6 lends some support to this concept that most of the cellular infil¬ tration of the uveal tract that spares the choriocapillaris in these patients is
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developmental in origin, and is not primarily the result of recent cellular proliferation in response to the carci¬ noma. It is of interest that patient 4 had melanosis of the upper airway. We have recently seen BDUMP develop
within several months after the exci¬ sion of a malignant intestinal polyp in a patient who developed melanotic oral macules typical of the Peutz-Jeghers syndrome. This concept of limited hormonally induced multiplication and hyperpigmentation of nevus cells may explain the frequently observed foci of
cytologie atypia, which, although sug¬ gesting melanoma differentiation in BDUMP, is accompanied by a paucity of mitotic activity and an apparent in¬ ability of the tumor to metastasize. The long-term survival of our pa¬ tient 3 and the continued slow growth of the uveal tumors long after the ap¬ parent eradication of her systemic car¬
cinoma suggests that the continued existence of the carcinoma is not al¬ ways necessary for the stimulation of melanocytic proliferation. It is too early, however, to exclude the possi¬ bility that this patient has subclinical carcinoma. Except for her and patient 4, all of the other 14 patients with this syndrome died of the carcinoma a mean 16 months (range, 4 to 25 months) after first developing symp¬ toms of this syndrome. The Table lists the differential diag¬ nostic possibilities in patients with BDUMP. The small round or oval red fenestrations that develop in the pig¬ ment epithelium early in BDUMP, the later triradiate pattern of preserved
pigment epithelium that results from their confluence, and the angiographie evidence of preserved choriocapillaris in the
of these fenestrations are infrequently duplicated by other dis¬ eases. We have seen the early round or oval fenestrated stage of BDUMP du¬ plicated only by one other disorder. This occurred in two young adults who presented with headache, acute bilat¬ eral visual loss, and serious macular detachment. Both had multiple, round, grayish, subretinal patches that showed early hyperfluorescence simi¬ lar to BDUMP. Both patients showed prompt visual improvement, disap¬ pearance of retinal detachment, and development of large polymorphous vitelliform submacular lesions after systemic corticosteroid therapy.18 The triradiate pattern of pigment epithelium, which develops after con¬ fluence of the lesions in BDUMP, may be simulated by several other disor¬ ders. Patients with the idiopathic uveal effusion syndrome are typically middle-aged males who initially present with exudative retinal and ciliochoroidal detachment. They may, af¬ ter prolonged or recurrent retinal de¬ areas
tachment, develop a leopard-spot or triradiate pattern of pigment epithe¬ lial clumping similar to BDUMP.19 There is no sex predilection for BDUMP, and it usually occurs in older
individuals (mean age, 67 years; range, 34 to 89 years). A similar pattern of
pigment epithelial derangement may occur binocularly in patients receiving systemic treatment with the cortico¬ steroids azathioprine and cyclosporine, because of renal or heart-lung transplants,20 and in patients with sys¬ temic large-cell lymphomas.21 The pathogenesis of the pigment epithelial changes in all of these disorders is poorly understood. Visual loss caused by bilateral dif¬ fuse infiltration of the uveal tract by neoplastic cells (metastatic carci¬ noma, leukemia, or melanoma) occurs infrequently, and when it occurs, it is usually associated with angiographie evidence of irregular disruption of the pigment epithelium, delayed fluores¬ cence because of choriocapillaris infil¬ tration, and late pinpoint or irregular areas of staining at the level of the pigment epithelium. One patient who was presented with bilateral diffuse
and multifocal metastatic carcinoma probably had the BDUMP syndrome.4 Likewise, patients with a diffuse in¬ flammatory cell infiltration of the choroid, eg, Harada's disease, typically show similar angiographie changes. After the appearance of multifocal pigmented choroidal tumors in addi¬ tion to the red subretinal patches, the diagnosis of BDUMP becomes certain.
In the absence of these red patches, metastatic melanoma to the choroid, multiple choroidal nevi, multifocal extramacular subretinal pigment epithe¬ lial hematomas, or multifocal areas of
congenital pigment epithelial hyper¬ trophy (Gardner's syndrome) would be more likely diagnostic possibilities. Although several patients with BDUMP have shown
a
transient im¬
provement in the amount of retinal
detachment in response to systemic corticosteroid and radiation treat¬ ment,8 no treatment has succeeded in arresting the progressive course of vi¬ sual loss. Even cataract extraction may have limited beneficial effects be¬ cause of the diffuse retinal damage that may occur prior to the develop¬ ment of exudative detachment. Ag¬ gressive treatment and eradication of the systemic carcinoma offers the best hope for the patient's survival, but even that may not prevent progressive visual loss. Attempts at identifying an ectopie hormone by assaying a fresh sample of the carcinoma, as well as obtaining samples of the patient's urine and serum, might prove fruitful in devising an antihormonal-type ap¬
proach
to
therapy.
Antiretinal antibody assays were performed C. E. Thirkill, PhD.
by
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16. Gass JDM. Acute Vogt-Koyanagi-Harada\x=req-\ like syndrome occurring in a patient with metastatic cutaneous melanoma. In: Saari KH, ed. Uveitis Update: Proceedings of the International Symposium on Uveitis. Amsterdam, Holland: Elsevier Science Publishers; 1984:407-408. 17. Berson EL. Paraneoplastic night blindness with malignant melanoma. Am J Ophthalmol.
1988;106:307-311. 18. Gass JDM, Chuang EL, Granek H. Acute exudative polymorphous vitelliform maculopathy. Trans Am Ophthalmol Soc. 1988;86:354-366. 19. Gass JDM. Uveal effusion syndrome: a new hypothesis concerning pathogenesis and technique of surgical treatment. Trans Am Ophthalmol Soc. 1983;81:246-260.
20. Gass JDM. Bilateral exudative retinal detachment occurring in patients receiving hemodialysis and after organ transplantation. Presented at Club Jules Gonin XVI meeting; September 8, 1988, Bruges, the Netherlands. 21. Gass JDM, Weleber RG, Johnson DR. Non\x=req-\ Hodgkin's lymphoma causing fundus picture simulating fundus flavimaculatus. Retina. 1987;7:209\x=req-\ 214.
Melanocytic Proliferation
in Patients With Occult Carcinoma J. Donald M.
Gass, MD; Richard G. Gieser, MD; C. P. Wilkinson, MD; Donald
\s=b\ The development of multiple, round or oval, subtle, red patches at the level of the pigment epithelium in the posterior ocular fundus and their striking early hyperfluorescence angiographically are character-
istic features of the bilateral diffuse uveal
melanocytic proliferation syndrome. They may be accompanied by severe visual loss and may antedate the appearance of mul-
tiple melanocytic tumors, retinal detachment, and cataract in these patients with occult systemic carcinomas. These hyperfluorescent patches are caused by focal damage to the pigment epithelium overlying an intact choriocapillaris and diffuse benign nonpigmented uveal melanocytic infiltration of the outer choroid. We suggest that outer retinal damage may not be primarily caused by melanocytic proliferation, but rather by toxic and immune factors generated by interaction between a systemic carcinoma and congenital melanocytosis of the uveal tract. We report the longest survivor of this disorder to date (102 months).
(Arch Ophthalmol. 1990;108:527-533)
"Dilaterai diffuse uveal melanocytic
JJ
proliferation (BDUMP) is a bi¬ paraneoplastic ocular syndrome occurring in patients with systemic, often occult carcinoma, which typi¬ cally causes death within 12 to 24 months. Five cardinal ocular signs zarre
that accompany visual loss in these patients are the following: (1) multi¬ ple, round or oval, subtle, red patches at the level of the retinal pigment ep-
Accepted for publication December 29, 1989. From the Departments of Ophthalmology, Bascom Palmer Eye Institute, University of Miami, Fla (Dr Gass); Loyola University of Chicago Stritch School of Medicine, Maywood, Ill (Dr Gieser); Dean A. McGee Eye Institute, Oklahoma City, Okla (Dr Wilkinson); University of Kansas, Kansas City (Dr Beahm); and University of South Florida, Tampa (Dr Pautler). Reprints not available.
E.
Beahm, MD; Scott
ithelium in the
posterior fundus; (2) a striking pattern of multifocal areas of early hyperfluorescence corresponding with these patches; (3) development of multiple, slightly elevated, pigmented and nonpigmented uveal melanocytic tumors,
as
well
as
evidence of diffuse
thickening of the uveal tract; (4) exu¬ dative retinal detachment; and (5) rapid progression of cataracts.1 " Pre¬ vious reports have emphasized the lat¬ ter three signs. The purposes of this report are (1) to present four patients to stress the importance of the first two signs, both of which may antedate the other three, and both of which are highly suggestive of the correct diag¬ nosis; (2) to demonstrate clinicopathologic correlations pertaining to these two signs; (3) to discuss the implica¬ tions of these findings in regard to the pathogenesis of visual loss; and (4) to present the first patient with longterm survival.
REPORT OF CASES Case 1.—An apparently healthy
68-year-
old woman noted rapid loss of vision in both eyes. Her visual acuity was counting fingers at 4 ft in each eye. The conjunctivae were moderately hyperemic. The anterior cham¬ bers and lenses were clear. The ophthalmoscopic examination revealed faint, oval and round, fiat, reddish patches at the level of the pigment epithelium throughout the posterior fundi (Fig 1, left). These con¬ trasted only slightly with the normal, or¬ ange-red appearance of the surrounding fundus. In the right eye there was a shallow serous detachment of the retina posteri¬ orly, and a shallow choroidal detachment inferiorly. Early retinal arteriovenousphase fluorescein angiography revealed a striking unexpected pattern of multifocal areas of early hyperfluorescence that cor¬ responded with the reddish subretinal le¬ sions (Fig 1, center). This hyperfluores¬ cence persisted into the late phases of angiography and was accompanied by the development of multifocal areas of pinpoint staining at the level of the pigment epithe-
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E.
Pautler,
MD
lium (Fig 1, right). A medical evaluation, including chest roentgenography and scans of the liver and spleen, produced results that were within normal limits. A single sub-Tenon's injec¬ tion of methylprednisolone acetate and oral prednisone, 60 mg/d for 2 weeks, produced no change in the retinal detachment or vi¬ sual acuity. Three months later, the pa¬ tient's visual acuity improved to 20/100 OD and 20/80 OS. Multiple, slightly elevated, pigmented, choroidal lesions resembling choroidal nevi developed in both eyes. Within several weeks, rapid development of cataracts occurred bilaterally. A diagnosis of BDUMP was made. The patient was hos¬ pitalized for cataract extraction and under¬ went further medical evaluation to look for an occult carcinoma. A carcinoma of the cervix with extension to the pelvic walls was found. Within 1 year from the onset of visual symptoms, the patient died of metastatic carcinoma. No autopsy was done. Case 2.—A 77-year-old woman was in apparently good health when she rapidly developed loss of vision in both eyes. When seen by her local physician in August 1976, her visual acuity was 20/300 OD and 20/100 OS. The physician noted bilateral cataracts and fluorescein angiographie changes that he interpreted as senile macular degenera¬ tion (Fig 2, left). No pigmented lesions were noted. Angiography revealed multifocal ar¬ eas of hyperfluorescence that were inter¬ preted as probably being caused by large drusen. When the patient was seen by us in November 1976, her visual acuity in the right eye was counting fingers only and was unchanged in the left eye. There was dila¬ tion of the episcleral vessels bilaterally. Pigmented keratitic precipitates and pig¬ mented cells were present in the anterior chamber and vitreous of both eyes. There was a posterior synechia in the left eye.
Multiple, slightly elevated, subretinal, pig¬ mented lesions of variable size were barely visible through media compatible with vis¬ ual acuity of 20/100 OU. These were vari¬ ously interpreted by several physicians as multiple subretinal hematomas, multiple choroidal nevi, and metastatic melanoma to the choroid. Results of an extensive medical evaluation were normal.
Fig 1.—Case 1. Left eye. Left, Note the round patches (arrows) that were red. Center, Early-phase angiogram showing focal hyperfluorescence (arrows) corresponding with the red patches (left). Right, Late pin¬ point areas of staining in macular area."
Fig 2.—Case 2. Left eye. Left, August 1976; right, January 1977. Arrowheads indicate the reticular pattern of pigment epithelium (nonfluorescent areas [left] and light-colored areas [right]) surrounding the zones of pigment epithelial atrophy (hyperfluorescent areas [left] and dark areas [right]).
During a 2-week period, there was rapid progression of the patient's cataracts. Vis¬ ual acuity was counting fingers only in both
eyes and cataract extraction was done in the left eye. Postoperatively, multiple, pig¬
mented, choroidal lesions were easily visu¬ alized. There were large, multiple, conflu¬ ent, round and oval, red and gray patches outlined by a triradiate pattern of orange pigment epithelium that was most promi¬ nent in the
papillary
peripheral macular and peri(Fig 2, right). In spite of
areas
clear media and the absence of retinal detachment, visual acuity was counting
lingers only.
Within 4 months, visual acuity in both eyes decreased to hand movements only and
there was exudative retinal detachment in¬ teriorly. The patient developed malaise and weight loss, and 10 months later a medical
evaluation, including roentgenographic
studies of the gastrointestinal tract, re¬ vealed evidence suggesting a pancreatic carcinoma. The patient died 23 months af-
ter the onset of visual
symptoms, and an autopsy revealed metastatic ovarian carci¬ noma. The eyes were obtained at autopsy
and the findings have been previously reported.' They included diffuse infiltration of the entire uveal tract with benign-ap¬ pearing, nonpigmented, uveal melanocytes and multifocal areas of choroidal thicken¬
ing by benign-appearing, partly necrotic, pigmented, uveal melanocytes. Important changes were the extensive destructive changes in the overlying pigment epithe¬ lium and outer retina despite the relative sparing of the choriocapillaries by the uveal infiltrate (Fig 3, left) and the presence of extensive necrosis within the focal pig¬ mented tumors (Fig 3, right). Case 3.—In November 1982, a 65-year-old woman developed blurred vision in both eyes. Two months previously her visual acuity was 20/20 OU. Two years previously she underwent an incomplete excision of an ovarian papillary serous cystadenocarcinoma, which was followed by chemotherapy.
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Her son had bilateral testicular tumors, and her daughter had cervical cancer. The patient's visual acuity was 20/200 OD and 20/50 OS. An ophthalmoscopic examina¬ tion revealed multiple, widely scattered, slightly elevated, pigmented choroidal le¬ sions in both fundi. In the posterior fundi that were relatively free of pigmented le¬ sions, there were multiple, round and oval, red, subretinal patches that were barely evident against the normal background or¬ ange-red of the fundi (Fig 4, left). Fluorescein angiography showed hyperfluores¬ cence of these lesions in both eyes (Fig 4, right). The medical evaluation failed to show evidence of ovarian or other metastatic carcinoma. Within several months the patient devel¬ oped a pigmented tumor on the iris of the right eye, rapidly progressing cataracts in both eyes, and bullous retinal detachment in both eyes. Optic disc swelling and sur¬ rounding retinal hemorrhages were pres¬ ent in the left eye where the pigmented tu-
Fig 3.—Case 2. Left eye. Left, Photomicrograph showing diffuse choroidal infiltration with small hypopigmented benign melanocytes, relative sparing of the choriocapillaris (arrow), and depigmentation and degeneration of the pigment epithelium (hematoxylin-eosin, original magnification X175). Right, Photomi¬ crograph showing focal, partly necrotic (arrows), pigmented, choroidal tumor and extensive degeneration of the pigment epithelium and retinal receptor cells (hematoxylin-eosin, original magnification X70).
Fig 4.—Case 3. Right eye. Left, Note the faintly visible patches (small arrows) that were red in the posterior fundus and a pigmented choroidal tumor (large arrow). Right, Angiogram showing focal hyperfluorescence (arrows) corresponding with the red patches (left)." mors extended to the disc margin. The pa¬ tient underwent a combined cataract extraction and a biopsy of the iris tumor. The biopsy specimen showed melanocytic proliferation that was interpreted as be¬ nign by some observers and malignant by others. The patient experienced progressive visual loss in both eyes that failed to im¬ prove after being treated with 40 Gy of ex¬ ternal beam cobalt 60 radiation in each eye. Multiple extensive medical investigations failed to reveal evidence of metastatic dis¬ ease. The results of lymphocyte analysis and assays for -glutamyl transpeptidase membrane marker enzyme and carcinoembryogenic antigen were normal. Within 2 years after the onset of visual symptoms, the patient was blind. Soon thereafter, she developed absolute glau¬ coma and evidence of continued growth of the uveal lesions. The right eye was enucle¬ ated in 1984 and the left eye in 1986. Both eyes showed evidente of diffuse uveal mei-
anocytic proliferation (Fig 5) by a mixture of cells showing both nevoid (Fig 6, left) and, in some areas, epithelioid cell differ¬ entiation (Fig 6, right). There was minimal evidence of mitotic activity. There was rel¬ ative sparing of the choriocapillaris and extensive degeneration of the pigment epi¬ thelium and receptor cells (Fig 6, left). In May 1989, 8V2 years after treatment for ovarian carcinoma and 6V2 years after the onset of visual symptoms, the patient de¬ veloped signs and symptoms of presenile dementia, but had no evidence of metastatic disease. Case 4.—A 61-year-old man complained of an abrupt loss of central vision in his right eye 1 week previously and mild blur¬ ring of vision in the left eye for 1 year. His visual acuity was normal 5 years previously when last examined by an ophthalmologist. He had a 27-year history of diabetes mellitus, obstructive pulmonary disease, and chronic osteomyelitis. The patient had no
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other medical problems and no history of cancer. The family medical history was negative. The patient's visual acuity was 20/200 OU. Amsler grid testing revealed bilateral central scotomata. The intraocu¬ lar pressures were 10 and 8 mm Hg in the right and left eyes, respectively. The ante¬ rior segments were unremarkable. The pa¬ tient had mild nuclear cataracts; his optic discs were normal. The retinal arterioles were minimally attenuated and there were rare retinal microaneurysms. Posteriorly, in the extramacular area of both eyes, there were multiple, round and oval, slightly ele¬ vated, pigmented choroidal lesions measur¬ ing 0.5 to 2 disc diameters in size. Through¬ out the posterior fundi there were multiple, round and oval, reddish patches separated by a reticular pattern of yellow-orange pig¬ ment clumping (Fig 7, left). There was a shallow retinal detachment in the right macula. When examined 2 weeks later, the pa-
tient's visual acuity was 20/400 OD and 20/ 200 OS. His examination results were un¬ changed except for the presence of subret¬ inal fluid in the macula and the inferior periphery of the left eye. Fluorescein an¬ giography revealed a reticular pattern of nonfluorescence on a background of marked hyperfluorescence during the early arteriovenous-phase angiograms (Fig 7, right) and late pinpoint areas of staining. Electroretinography revealed normal photopic responses in both eyes and severely abnor¬ mal scotopic responses in the left eye. Electro-oculography was borderline normal in both eyes (the light/dark ratio was 1.63% in the right eye and 1.57% in the left eye). During the next 2 months, six new pig¬ mented choroidal lesions developed in the periphery of the right eye and two new similar lesions developed in the periphery of the left eye. Three lesions in the left macula enlarged and coalesced. There was
Fig 5.—Case 3. Right eye. Photomicrograph showing diffuse and focal thickening of the uveal tract by melanocytic cells (hematoxylineosin, original magnification X6).
bullous and neurosensory retinal detach¬ ment in both eyes. This was associated with shifting of the subretinal fluid. A medical
evaluation, including a general physical ex¬ amination, chest roentgenography, lung and abdominal computed tomographic scanning, sigmoidoscopy, and bronchos-
washings, revealed no evidence of malignancy in either the lungs or the retroperitoneal space. An otolaryngological copy with
examination revealed melanosis of the trachea! mucous membranes. Antiretinal
antibody
assays
were
negative.'2
COMMENT
The ocular manifestations of BDUMP usually antedate signs and symptoms of the systemic carcinoma (10 of the 16 reported cases) by 3 to 12 months. Of the five cardinal ocular features of the syndrome, the multifo¬ cal, faintly visible, round or oval, red, subretinal patches, which are promi¬ nently hyperfluorescent during the early phases of angiography, are usu¬ ally the first to appear and are usually still visible after the development of the other three signs. Other biomicroscopic signs that may be present in¬ clude anterior chamber cells, vitreous cells, and signs of ciliary body enlarge¬ ment, including dilated episcleral vessels,' shallow anterior chamber,6 ciliary body cysts,4·6 and iridodonesis.5 The subtle red patches and their strik¬ ing tendency to fluoresce are charac¬ teristic of this syndrome and are not usually seen in patients with other disorders characterized by either mul¬ tifocal or diffuse cellular infiltrate of the choroid by either inflammatory or neoplastic cells. Thus, recognition of these two signs is of great importance in the early diagnosis of this syn¬ drome.
The precise correspondence of the focal areas of early hyperfluorescence and the subretinal patches suggest that they are fenestrations of the pig¬ ment epithelium caused by its depigmentation and focal destruction in the absence of infiltration and obstruction of the underlying choriocapillaris (Fig 8). Histopathologically, this interpre¬ tation is supported by the remarkable predilection for the uveal melanocytic proliferation to spare the choriocapil¬ laris, and by the widespread areas of necrosis and degeneration of the pig¬ ment epithelium and outer retina, even in large areas where only minimal melanocytic proliferation is present (Fig 3, left, and Fig 6, left). These are consistent features that one of us (J.D.M.G.) has seen in eyes removed from four patients with this syndrome. The diffuse redness of the patches (or their dark gray color in the case of pa¬ tients with brunette fundi) that is only barely discernible biomicroscopically from the normal reddish orange of the surrounding retinal pigment epithe¬ lium is probably caused by the hypopigmented diffuse melanocytic infil¬ tration that hides from view details of the underlying large choroidal vessels and sclera (Fig 3, left, Fig 6, left, and Fig 8). These patches of depigmented or fenestrated pigment epithelium progressively enlarge and become con¬ fluent to produce a triradiate or retic¬ ular pattern of orange pigment epithe¬ lium that angiographically appears nonfluorescent on a background of marked choroidal hyperfluorescence (Figs 1,4,7, and 9). This was strikingly demonstrated in the case reported by Margo et al.10
Fig 6.—Case 3. Right eye. Left, Benign melanocytic proliferation of the choroid with relative sparing of the choriocapillaris (arrow). Note the multifocal areas of pigment epithelial destruction and clumping (hematox¬ ylin-eosin, original magnification X440). Right, A focal area of epithelioid cell proliferation (white arrow) ad¬ jacent to the benign melanocytic infiltration of the choroid (black arrow) (hematoxylin-eosin, original mag¬ nification X175).
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Fig 7.—Case 4. Left eye." Left, Note the faintly visible reticular pattern of retinal pigment epithelium (RPE) was yellow-orange surrounding the multiple, round and oval, dark RPE fenestrations that were reddish (arrowheads). Right, Angiogram showing marked hyperfluorescence corresponding to the fenestrated ar¬ eas of RPE damage. that
The mechanism causing the acute multifocal areas of depigmentation or destruction of the RPE is uncertain. The angiographie and histopathologic evidence of an intact choriocapillaris suggests that ischemia may not be an important factor. Clinically and histopathologically, the marked pigment epithelial damage and outer retinal damage in large areas of only minimal outer choroidal melanocytic infiltra¬ tion is far greater than that in many patients with greater infiltration of full-thickness choroid by carcinoma and melanoma. It is likely that other local toxic or immune reactions are re¬ sponsible for the damage to the retinal pigment epithelium, as well as to the overlying retinal receptor cells. For example, we observed in patients 2 and 3 that the visual function was profoundly affected before the devel¬ opment of secondary retinal detach¬ ment. The pathogenesis of retinal damage in these patients may be similar to that in patients who, in association with an occult carcinoma, develop rapid loss of vision, nyctalop¬ ia, and a fundus picture simulating retinitis pigmentosa sine pigmenti.1215 In these latter patients the retinal pigment epithelium is typically less affected than the retinal receptor cells. Patient 4 had a negative assay for antibodies to a retinal cancer-associ¬ ated antigen.12 A similar paraneoplastic acute night blinding disorder
associated with rapidly developing vitíligo of the skin and uveal tract depigmentation may occur in patients with metastatic cutaneous mela¬ noma.16·" The histopathologic picture in most of the 23 eyes of 12 patients examined to date has been remarkably similar. It includes diffuse infiltration of the uveal tract, including the scierai emis¬ sary canals, with predominantly small nevoid hypopigmented melanocytic cells. The choroidal thickening is typ¬ ically minimal in comparison with that of the ciliary body, and the cho¬ riocapillaris is relatively spared. Mul¬ tiple focal areas of increased thicken¬ ing of the choroid by heavily pig¬ mented melanocytes typical of melanocytomas have been present in most eyes. In at least four eyes there has been focal necrosis within these pig¬ mented tumors.3 Although the mel¬ anocytic infiltration is predominantly benign in appearance, most eyes have shown foci of spindle and epithelioid cellular differentiation.-'·5·6·9·10 This, however, has been accompanied by lit¬ tle or no evidence of mitotic activity. Since the mean survival time after the initial symptom appeared in these pa¬ tients is approximately 16 months, there has been only limited opportu¬ nity to observe evidence of progression of the uveal melanocytic proliferation. The appearance and enlargement of the focal pigmented and, less often,
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tumors of the choroid and iris have been observed in two of our patients and by others.1·3 Only in one of our patients (case 3) who has survived 8V2 years has there been doc¬ umentation of considerable increase in the diffuse infiltration of the uveal
nonpigmented
tract.
The pathogenesis of the melanocytic infiltration in BDUMP is uncertain. Two types of melanocytes are found in the normal uveal tract: the normal melanocyte and, in many patients, ne¬ vus cells. Normal melanocytes are nonreactive cells that rarely, if ever, pro¬ liferate. Nevus cells that are present, either focally or diffusely (melanocytosis), do have the capability of prolif¬ eration that, in part, is subject to hor¬ monal control and that normally is limited to the prepubertal and early adult years. Suggestions for the patho¬ genesis of BDUMP have included the following: (1) de novo development of uveal melanocytic proliferation and the systemic carcinoma in response to a common oncogenic stimulus3; (2) de novo development of uveal melano¬ cytic proliferation in response to a hormone-secreting visceral carcin¬ oma3; and (3) coincidental develop¬ ment of bilateral low-grade diffuse uveal melanomas and a systemic car¬ cinoma in patients genetically predis¬
to neoplasia.5 regard to the first two sugges¬ tions, it is unlikely that normal mei-
posed In
Fig 8.
Diagram of the anatomy of the red subretinal patches occurring in bilateral diffuse uveal melanocytic proliferation. Arrows indicate the fenestrated area of depigmentation and degeneration of the retinal pig¬ ment epithelium (RPE) overlying the intact choriocapillaris (cc) and in¬ filtration of the outer choroid (ch) by benign melanocytic cells. The di¬ agram below illustrates perfusion of the choroid with fluorescein (dots) during the early arteriovenous phase, causing hyperfluorescence of the fenestrated area. —
Differential Diagnosis in Patients With Diffuse Bilateral Uveal
Fig 9.—Frontal view diagram showing round fenestrations in the retinal pigment epithelium (left) that enlarge, become confluent, and produce a reticular pattern of retinal pigment epithelium (right).
Melanocytic Proliferation
development of multifocal pigmented choroidal tumors Idiopathic uveal effusion syndrome Large-cell lymphoma, metastatic carcinoma, leukemia Acute polymorphous vitelliform maculopathy'8 Multifocal or diffuse choroiditis, acute posterior multifocal placoid pigment epitheliopathy, pathetic uveitis, sarcoidosis Benign reactive lymphocytic hyperplasia of the uveal tract
Prior to 1.
2. 3. 4. 5.
sym¬
6. Posterior scleritis 7. 8. After 1. 2. 3. 4.
Rhegmatogenous retinal detachment Harada's disease of multifocal pigmented choroidal tumors Metastatic melanoma Multifocal subretinal hematomas Multiple choroidal nevi Multifocal hypertrophy of the pigment epithelium (Gardner's
development
anocytes, regardless of the stimulus, would be likely to proliferate since there is no precedent for this to occur. In regard to the third suggestion, it is equally difficult to accept the concept of a malignant transformation occur¬ ring throughout the uveal tract bilat¬ erally. Diffuse bilateral uveal mela¬ noma outside the context of BDUMP is unreported. We believe, as suggested by Ryll et al,2 that these patients prob¬ ably have bilateral diffuse congenital uveal melanocytic nevi, which, because most of the constituent cells are hypopigmented, are relatively unapparent clinically. In response to certain hormone-producing visceral carcino¬ mas, particularly those of the repro¬ ductive organs in women (six of the eight reported cases) and those of the retroperitoneal areas and lungs in men (six of seven reported cases), these ne¬ vus cells may exhibit limited growth and melanin production, which, in
some
syndrome)
cases, may be associated with
melanocytic necrosis.
We suggest, however, that the acute
damage to the pigment epithelium, the outer retina, and the lens that results in the rapid development of retinal de¬
tachment and cataract formation is not adequately explained by the lim¬ ited melanocytic proliferation that oc¬ curs in these patients. Much of this damage probably is caused by a toxic or immune reaction that is either a by-product of the carcinoma-uveal melanocytic interaction or the direct result of hormonal interaction be¬ tween the carcinoma and the pigment epithelium and retinal receptors. The development of BDUMP in one patient with congenital oculodermal melanocytosis (nevus of Ota) reported by Prause et al6 lends some support to this concept that most of the cellular infil¬ tration of the uveal tract that spares the choriocapillaris in these patients is
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developmental in origin, and is not primarily the result of recent cellular proliferation in response to the carci¬ noma. It is of interest that patient 4 had melanosis of the upper airway. We have recently seen BDUMP develop
within several months after the exci¬ sion of a malignant intestinal polyp in a patient who developed melanotic oral macules typical of the Peutz-Jeghers syndrome. This concept of limited hormonally induced multiplication and hyperpigmentation of nevus cells may explain the frequently observed foci of
cytologie atypia, which, although sug¬ gesting melanoma differentiation in BDUMP, is accompanied by a paucity of mitotic activity and an apparent in¬ ability of the tumor to metastasize. The long-term survival of our pa¬ tient 3 and the continued slow growth of the uveal tumors long after the ap¬ parent eradication of her systemic car¬
cinoma suggests that the continued existence of the carcinoma is not al¬ ways necessary for the stimulation of melanocytic proliferation. It is too early, however, to exclude the possi¬ bility that this patient has subclinical carcinoma. Except for her and patient 4, all of the other 14 patients with this syndrome died of the carcinoma a mean 16 months (range, 4 to 25 months) after first developing symp¬ toms of this syndrome. The Table lists the differential diag¬ nostic possibilities in patients with BDUMP. The small round or oval red fenestrations that develop in the pig¬ ment epithelium early in BDUMP, the later triradiate pattern of preserved
pigment epithelium that results from their confluence, and the angiographie evidence of preserved choriocapillaris in the
of these fenestrations are infrequently duplicated by other dis¬ eases. We have seen the early round or oval fenestrated stage of BDUMP du¬ plicated only by one other disorder. This occurred in two young adults who presented with headache, acute bilat¬ eral visual loss, and serious macular detachment. Both had multiple, round, grayish, subretinal patches that showed early hyperfluorescence simi¬ lar to BDUMP. Both patients showed prompt visual improvement, disap¬ pearance of retinal detachment, and development of large polymorphous vitelliform submacular lesions after systemic corticosteroid therapy.18 The triradiate pattern of pigment epithelium, which develops after con¬ fluence of the lesions in BDUMP, may be simulated by several other disor¬ ders. Patients with the idiopathic uveal effusion syndrome are typically middle-aged males who initially present with exudative retinal and ciliochoroidal detachment. They may, af¬ ter prolonged or recurrent retinal de¬ areas
tachment, develop a leopard-spot or triradiate pattern of pigment epithe¬ lial clumping similar to BDUMP.19 There is no sex predilection for BDUMP, and it usually occurs in older
individuals (mean age, 67 years; range, 34 to 89 years). A similar pattern of
pigment epithelial derangement may occur binocularly in patients receiving systemic treatment with the cortico¬ steroids azathioprine and cyclosporine, because of renal or heart-lung transplants,20 and in patients with sys¬ temic large-cell lymphomas.21 The pathogenesis of the pigment epithelial changes in all of these disorders is poorly understood. Visual loss caused by bilateral dif¬ fuse infiltration of the uveal tract by neoplastic cells (metastatic carci¬ noma, leukemia, or melanoma) occurs infrequently, and when it occurs, it is usually associated with angiographie evidence of irregular disruption of the pigment epithelium, delayed fluores¬ cence because of choriocapillaris infil¬ tration, and late pinpoint or irregular areas of staining at the level of the pigment epithelium. One patient who was presented with bilateral diffuse
and multifocal metastatic carcinoma probably had the BDUMP syndrome.4 Likewise, patients with a diffuse in¬ flammatory cell infiltration of the choroid, eg, Harada's disease, typically show similar angiographie changes. After the appearance of multifocal pigmented choroidal tumors in addi¬ tion to the red subretinal patches, the diagnosis of BDUMP becomes certain.
In the absence of these red patches, metastatic melanoma to the choroid, multiple choroidal nevi, multifocal extramacular subretinal pigment epithe¬ lial hematomas, or multifocal areas of
congenital pigment epithelial hyper¬ trophy (Gardner's syndrome) would be more likely diagnostic possibilities. Although several patients with BDUMP have shown
a
transient im¬
provement in the amount of retinal
detachment in response to systemic corticosteroid and radiation treat¬ ment,8 no treatment has succeeded in arresting the progressive course of vi¬ sual loss. Even cataract extraction may have limited beneficial effects be¬ cause of the diffuse retinal damage that may occur prior to the develop¬ ment of exudative detachment. Ag¬ gressive treatment and eradication of the systemic carcinoma offers the best hope for the patient's survival, but even that may not prevent progressive visual loss. Attempts at identifying an ectopie hormone by assaying a fresh sample of the carcinoma, as well as obtaining samples of the patient's urine and serum, might prove fruitful in devising an antihormonal-type ap¬
proach
to
therapy.
Antiretinal antibody assays were performed C. E. Thirkill, PhD.
by
References 1. Machemer R. Zur Pathogenese des flachenhaften malignen Melanoms. Klin Monatsbl Au-
genheilkd. 1966;149:641-652. 2. Ryll DL, Campbell RJ,
Robertson DM, Brubaker SJ. Pseudometastatic lesions of the choroid. Ophthalmology. 1980;87:1181-1186. 3. Barr CC, Zimmerman LE, Curtin VT, Font RL. Bilateral diffuse melanocytic uveal tumors associated with systemic malignant neoplasms. Arch Ophthalmol. 1982;100:249-255. 4. Prusiner PE, Butler A, Yavitz EQ, Stern WH. Metastatic adenocarcinoma presenting as bilateral blindness. Ann Ophthalmol. 1983;15:653\x=req-\ 656. 5. Mullaney J, O'Connor MM, McDonald GSA. Bilateral ovarian carcinoma with bilateral uveal melanoma. Br J Ophthalmol. 1984;68:261-267. 6. Prause JU, Jensen OA, Eisgart F, Hansen U, Kieffer M. Bilateral diffuse malignant melanoma of the uvea associated with large cell carcinoma, giant cell type, of the lung. Ophthalmologica
(Basel). 1984;189:221-228.
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