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Differential Diagnosis of Retinoblastoma*
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A. HUGGERT AND E. SUNDMARK
Hoist, H. : The treatment of stenosis of the lacrimal canaliculi by the method of Huggert. Acta ophth. (Kbh.), 41:671-673, 1963. Huggert, A.: The treatment of stenosis of the lacrimal canaliculi. Acta ophth. (Kbh.), 37:355-358, 1959. Kaufman, H., and Chapman, R. : Modified probe for canaliculus surgery. Am. J. Ophth., 54 :461-462, 1962. Rosenthal, J. : A hook for polyethylene tubes. Am. J. Ophth., 54:1148, 1962. Sundmark, E. : Instruments for the temporary application of plastic tubes in the treatment of lacrimal obstruction. Acta ophth. (Kbh.), 42:528, 1964.
DIFFERENTIAL DIAGNOSIS O F
RETINOBLASTOMA*
A STATISTICAL SURVEY OF 5 0 0 CHILDREN I. R E L A T I V E FREQUENCY OF T H E LESIONS W H I C H S I M U L A T E RETINOBLASTOMA GEORGE M.
H O W A R D , M.D.,
A N D ROBERT M.
ELLSWORTH,
M.D.
New York The most common presenting sign in children with retinoblastoma is a white pupillary reflex, an abnormality for which the term "leukokoria" was introduced some years ago. 1 There are various other conditions, both congential and acquired, in which opaque tissue occurs behind the plane of the pupil, and which may simulate retinoblastoma. T h e aims of the present study were to investigate the frequency of the lesions which resemble retinoblastoma, and to study the factors relating to the diagnosis of retinoblastoma itself. Although the abnormal reflex in the pupil is described as "white" in this report, it may actually be pink-white or yellow-white in many instances. I n a clinicopathologic study, Treacher Collins (1893) applied the term "pseudoglioma" to a variety of pseudoneoplastic diseases of the posterior segment of the eye 2 and, since then, other similar studies have appeared. 3 " 9 Although the articles dealing with pseudoglioma constitute a group of ♦From the Tumor Clinic (Director: A. B. Reese, M.D.), Institute of Ophthalmology, Columbia-Presbyterian Medical Center. This work was supported by Special Fellowship NB1284-01 from the National Institute of Neurological Diseases and Blindness, Public Health Service (Dr. Howard). A summary of this work was read before the VII Congress of the Pan-American Association of Ophthalmology, Montreal, Canada, October 15, 1964.
vitally important pathologic studies, they do not contribute definitively to our clinical knowledge of the relative frequency of conditions simulating retinoblastoma. T h e reason for this is clear : many of the ocular diseases associated with a white reflex in the pupil prove to be benign, and no enucleation is performed. Hence, there seems to be an indication for a clinical study in which the diagnoses on all children with abnormal reflexes in the pupil are considered. T h e term "pseudoglioma" will be avoided in this article since the word "glioma" in current medical parlance refers to a tumor entirely different from retinoblastoma. T h e T u m o r Clinic at the Institute of Ophthalmology, New York, is organized so that 10 to 15 children are examined under anesthesia each week. D u r i n g the five-year period ending July, 1964, 500 new patients were seen consecutively who had been referred to this clinic, and in whom the diagnostic possibility of retinoblastoma had been raised. W i t h a few exceptions, these patients had leukokoria of one or both eyes. All examinations, except a few in the older children, were performed under anesthesia using halothane by the open-drop method. Binocular indirect ophthalmoscopy was employed, and scierai indentation was utilized to view the anterior portion of the retina. T h e diagnoses in the children who
611
DIFFERENTIAL DIAGNOSIS OF RETINOBLASTOMA did not have retinoblastoma were clinical in most instances, and were based upon the cumulative experience gained in this clinic during prior years. I n certain of the diagnostic categories, such as larval granulomatosis or Coats' disease, microscopic confirmation was obtained in some cases. T h e patients seen during the past five years were chosen for this study because of two considerations. T h e inclusion of children seen earlier would have prejudiced the statistical analysis in favor of retrolental fibroplasia, a disease which is not seen as frequently now as was the case 10 to 15 years ago. Also, increased appreciation of the entity of larval granulomatosis has allowed the diagnosis to be made with a reasonable degree of certainty during the past pentad. F R E Q U E N C Y OF LESIONS RETINOBLASTOMA
SIMULATING
(table
1)
Of the 500 children in whom retinoblastoma had been suspected, there were 265 in whom other diagnoses were made. Illustrations for most of the conditions will be found in the references cited and in Reese's Tumors of the Eye.51 A.
P E R S I S T E N T HYPERPLASTIC
PRIMARY
VITREOUS
This was the most frequent of the conditions other than retinoblastoma causing a white pupillary reflex, and accounted for 51 of the 265 diagnoses. There were 20 boys and 31 girls with a median age of four months at the time of diagnosis. T h e condition had been first noticed at, or shortly after, birth in all, and was unilateral except in two patients. All of the children were in apparent good health. Only one had been born prematurely. T h e diagnosis was suggested by some degree of unilateral microphthalmos, a shallow anterior chamber, prominent vessels on the iris, long ciliary processes, vascularized white retrolental tissue, and a progressive
TABLE 1
PATIENTS (265) WITH SUSPECTED RETINOBLASTOMA IN WHOM OTHER DIAGNOSES WERE MADE Diagnosis
No. Percent Cases of Total
1. Persistent hyperplastic primary vitreous 2. Retrolental fibroplasia 3. Posterior cataract 4. Coloboma of choroid or optic disc S. Uveitis 6. Larval granulomatosis 7. Congenital retinal fold 8. Coats' disease 9. Organizing vitreous hemorrhage 10. Retinal dysplasia 11. Tumor other than retinoblastomai 12. White-with-pressure sign 13. Juvenile xanthogranuloma 14. Retinoschisis IS. Tapetoretinal degeneration 16. Endophthalmitis 17. Persistent tunica vasculosa lends and pupillary membrane 18. Miscellaneous: a. Anteriorly dislocated lens with secondary glaucoma b. Congenital corneal opacity c. Incontinentia pigmenti (Bloch-Sulzberger Syndrome 70 ) with total funnelshaped retinal detachment d. Cyst in remnant of hyaloid artery e. Anomalous optic discs f. Hematoma under retinal pigment epithelium g. High myopia with advanced chorioretinal degeneration h. Medullation of nerve fiber layer i. Traumatic choroiditis TOTAL
51 36 36 30 27 18 13 10 9 7 4 3 3 3 2 2
19.0 13.5 13.5 11.5 10.0 6.5 5.0 4.0 3.5 2.5 1.5 1.0 1.0 1.0 1.0 1.0
2
1.0 3.5
1 1
1 1 1 1 1 1 1
265
100.0
posterior subcapsular cataract beginning at a point just nasal to the posterior lenticular pole where the fibrovascular tissue inserts. 1 0 · 1 1 In three of the children there were associated anomalies ; two of these had uveal colobomas and one had a persistence of the anterior portion of the tunica vasculosa lentis. Several of the children were seen in the stage of intumescence of the lens with secondary glaucoma. Brightly refractile crystals resembling those of cholesterol were visible in the retrolental space in two patients. Included in this classification were two children with only a Mittendorf dot and a prominent Bergmeister's papilla.
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GEORGE M. HOWARD AND ROBERT M. ELLSWORTH
B. RETROLENTAL FIBROPLASIA T h e incidence of this disease has declined sharply since the role of oxygénation was established. 12 " 20 However, a few cases are seen in this clinic each year, specifically, 36 during the past five years. Thirty-five of the patients in this group were seen in cicatricial stages. There were 19 boys and 17 girls. All except one were of low birth weight (less than 5.5 pounds) and had been in an incubator for a variable number of days or weeks. I n four of the 36 patients there was evidence of mental retardation or other anomalies of the central nervous system at the time of examination. I n addition to the information obtained by history, the factors suggesting this diagnosis are bilaterality, fibrovascular tissue originating near the temporal periphery of the retina and extending toward the retrolental region, dentate processes from the ciliary body to the retrolental tissue, and, when the fundus can be seen, traction upon the retina temporally leaving an atrophie peripapillary conus nasally. 21 " 29 In the advanced stages there is atrophy of the globe and orbital structures, posterior synechiae, and a shallow anterior chamber. There is a specific form of the cicatricial stage of this disease (Grade I I I ) which deserves particular mention because of its resemblance to congenital retinal fold. 28 I n this form, traction upon the retina produces a sharply demarcated, elevated, retinal septum which arches forward into the vitreous body, stretching from the disc to the extreme periphery of the fundus. C. POSTERIOR CATARACT
There were 36 patients (15 boys and 21 girls) of various ages who had localized posterior cataracts. T h e differential diagnosis of these lesions prior to referral had included a questionable retrolental mass. I n addition to the cataracts, two patients had aniridia, one had a congenital coloboma of the optic nerve in both eyes, and one a coloboma of the iris. There were six patients
who also had microphthalmos, and in three of these an adequate view of the fundus was not obtained; it is possible that the signs in these three patients were due to persistent hyperplastic primary vitreous. D.
COLOBOMA
T h e cells of the inner layer of the secondary optic vesicle retain their ability to develop into glial elements over the surface of the optic disc. W h e n colobomas of the optic nervehead occur these glial cells may proliferate to form varying amounts of elevated grayish tissue at the margin of the coloboma. I n addition, the coloboma itself may occasion a white reflex in the pupil. There were 10 patients with such an anomaly in this series, and in five the condition was bilateral. O n e of these patients had, in addition, an isolated cystic retinal detachment in the macular region. Central serous retinopathy has been reported several times in association with congenital pit, or craterlike hole, of the optic disc, 30 " 32 and it may be that the central serous retinal detachment noted in this case was of similar derivation. T w e n t y children had large choroidal colobomas. T h e lesions were bilateral in three cases. Most of the colobomas were "typical," that is, they occupied the lower portion of the fundus in the 6-o'clock meridian, extending upward a variable degree to involve the disc, the macula, or the upper portion of the fundus. T w o patients showed atypical, small, isolated colobomas, one of which was located in the macula and the other slightly below the disc. There were associated colobomas of the iris in six of the involved eyes, and in one eye there was a total retinal detachment. Altogether, there were 30 children with colobomas, 15 boys and 15 girls. E.
UVEITIS
Granulomatous choroidal infiltrates may attain proportions large enough to mimic a retinoblastoma. I n one boy, there was a solid, yellowish mass, infiltration of the vit-
DIFFERENTIAL DIAGNOSIS OF RETINOBLASTOMA
reous body with inflammatory cells, and a total retinal detachment. The eye was blind, chronically irritated, unsightly and was enucleated. Examination of the microscopic sections disclosed several pseudocysts of Toxoplasma gondii. In all, there were 27 patients with uveitis. Nine of these showed bilateral involvement of the macular areas and scattered punctate infiltrates elsewhere in the fundus considered to be compatible with ocular toxoplasmosis. The 27 patients ranged in age from two months to seven years ; the median age at the time of diagnosis in this clinic was two years, three months. Bilateral peripheral uveitis (pars planitis) occurred in four patients, and was characterized by caked yellow exudate along the ora serrata in the lower half of the fundus.33-35 Large, fluffy exudates were present posteriorly as well as anteriorly in the vitreous, and there was grayish opacification of the peripheral retina. This syndrome may closely resemble retinoblastoma. F. LARVAL GRANULOMATOSIS
Eighteen patients presented with elevated, globular or drop-shaped pinkish-yellow masses elevating the retina from which grayish-yellow vitreous veils, webs, or strands radiated. In such patients the diagnosis of larval granulomatosis was applied.36"43 There were 10 boys and eight girls, ranging in age from two years to eight and one-half years ; the median age when seen at this clinic was five years, two months. The vitreous was hazy in some active cases. In inactive cases, the vitreous was clear, the mass was more sharply demarcated and whitish in color. There was a narrow annulus showing disruption of the pigment epithelium surrounding the lesion. Several of the eyes showed a localized secondary retinal detachment, and in one eye the detachment was total. In five cases there was spotty calcification, thus promoting the sim-
613
ulation of retinoblastoma. In all patients in this group the disease was unilateral. In most of the cases (13) the lesions were located in the posterior pole. In three eyes, the granuloma was near the equator, in one it was in the macula, and in one it was directly on the pars plana. Microscopic confirmation of the diagnosis was obtained in five of the 18 patients. G. CONGENITAL RETINAL FOLD
This anomaly44"46 was diagnosed in 13 children, 11 boys and two girls. There was no history of oxygen therapy in any. Each had a history of normal birth weight and unremarkable development. The fold was unilateral in nine and bilateral in four. In unilateral cases the fellow eye was normal as far as could be determined. The fold in each case appeared to be elevated two to three mm and was about 30 degrees in width. It began at the margin of the disc and projected toward the ora serrata where it invariably fanned out into a fibrous extension about 90-degrees wide which occupied a position over the ciliary body just posterior to the equator of the lens. The lens itself was clear. The fold contained some retinal vessels, but the remainder of the retina was in situ. However, in one case, the entire retina appeared to be involved so that only choroidal vessels were seen elsewhere in the fundus. Most cases showed a pigmentary disturbance at the edge of the fold. There is a striking similarity between congenital retinal fold and Grade III cicatricial retrolental fibroplasia; some observers have considered them the same entity. However, there is reason to classify them separately. Retrolental fibroplasia nearly always occurs in infants of low birth weight who have been maintained in an incubator for a time. Such a history is not obtained in patients with congenital retinal fold. Microscopic examination of histologie sections provides another reason for segregating these two entities. The retina in congenital retinal fold is disposed in dysplastic ro-
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settes, whereas in retrolental fibroplasia, it is characterized by vascular proliferation leading to secondary gliosis. There is little possibility of confusing these two types of changes. The four patients who were diagnosed as having bilateral congenital retinal folds were quite puzzling, and did not fit easily into any known diagnostic category. Most descriptions of this anomaly characterize it as unilateral. It is conceivable that the ocular changes in these patients are manifestations of a chromosomal defect such as 13-15 trisomy. However, the four patients were in apparent good he; 1th, and there was no family history of ocular disease in any. Chromosomal studies are planned in the future for these and similar cases. H. COATS' DISEASE
This diagnosis was made in six boys and four girls ranging in age from two years to seven and one-half years, with an average age of four and one-half years. In two instances the diagnosis was confirmed by microscopic section. The condition was unilateral in all cases. The diagnosis depended upon the presence of a retinal detachment beginning in the lower portion of the fundus, dilated retinal blood vessels, and variable amounts of subretinal hemorrhage, exudate, and hematogenous pigmentation.47-52 In most of these cases circumscribed foci of capillary telangiectases of the retina were visible, and in three of them small miliary aneurysms were noted. In several of these cases yellow-white crystals resembling cholesterol were seen in the subretinal space. A clinicopathologic study of Coats' disease, in which all cases from this Institute will be reviewed, is now in progress.53 During the first few weeks of life, patients with retrolental fibroplasia frequently have dilated retinal blood vessels and an exudative detachment of the retina, ocular signs resembling those of Coats' disease. The factors of prematurity, oxygénation, bilaterality and the younger age of the pa-
tient, usually enable one to recognize the active stage of retrolental fibroplasia, and to differentiate it from Coats' disease. I. ORGANIZING VITREOUS HEMORRHAGE
The original red color of a vitreous hemorrhage gradually gives way to a yellow hue and finally is replaced by a grayish opacity or web which may wave to and fro when the patient moves his eye. There were nine patients in this series with a vitreous hemorrhage in various stages of organization. Four of these instances of hemorrhage occurred in infants with hemorrhagic disease of the newborn (hypoprothrombinemia). In two instances, the vitreous hemorrhage followed trauma. In one case it was associated with vasculitis of uncertain etiology, and in another it occurred with increased intracranial pressure following rupture of a congenital cerebral aneurysm. The vitreous hemorrhage in the remaining patient was of uncertain cause. J. RETINAL DYSPLASIA
In 1946, Krause reported 18 cases of a syndrome which he termed "congenital encephalo-ophthalmic dysplasia."54 Most of his patients were of low birth weight, and it is likely that many were afflicted with retrolental fibroplasia. There was a high incidence of mental retardation and central nervous system malformations. A similar syndrome was later described in the ophthalmic literature as "retinal dysplasia."1'55 The ocular anomalies in this syndrome now appear to be a manifestation of 13-15 trisomy in many instances,56"58 and are perhaps associated with 18 trisomy in some cases.59"61 Typical features of the disease include a family history of ocular defects and congenital deformities such as malformations of the central nervous system and cardiovascular system. There were seven patients in the present series in whom the diagnosis of retinal dysplasia was made. The ocular findings were bilateral microphthalmos, shallow anterior chambers, pupillary anomalies, and a
DIFFERENTIAL DIAGNOSIS OF RETINOBLASTOMA
pinkish-white retrolental mass. The lenses are usually clear in this syndrome, a finding which helps differentiate it from the rare case of bilateral persistent hyperplastic primary vitreous. It is quite possible to confuse retinal dysplasia with advanced retrolental fibroplasia in the examination of a given patient, but factors in the history will assist in distinguishing one disease from the other. The term "retinal dysplasia" is the ophthalmologists' appellation and does not connote the widespread congenital anomalies which occur in this syndrome ; it was applied by Reese and Straatsma 55 specifically to those cases showing congenital ocular anomalies, the microscopic examination of which revealed irregularly shaped rosettes, retinal detachment and persistent elements of the primary vitreous. K.
INTRAOCULAR
TUMORS
OTHER
THAN
RETINOBLASTOMA
In two girls (aged four and one-half and six and one-half years, respectively) the clinical diagnosis of a choroidal hemangioma was made. In the first of these, there was a broad, flat, translucent lesion in the posterior pole of the fundus which glowed brightly under observation with ultraviolet light after the intravenous administration of fluorescein. In the second, the neoplasm was flesh-colored and occurred as a manifestation of a Sturge-Weber syndrome. There was a total retinal detachment and secondary glaucoma. One girl (aged one and onehalf years) had an intraocular mass originating in the ciliary body which proved microscopically to be a dictyoma. The fourth patient in this group was a six and one-half year-old boy with intraocular extension of a meningioma of the optic nerve (demonstrated microscopically and previously reported 51 ). L. MISCELLANEOUS
There were several other diagnoses which were made three times or less in the present series, and which are listed in Table 1.
615
Some of these require a brief explanation. There were three infants with yellowish nodules on the iris and recurrent spontaneous hyphema in whom retinoblastoma seeds had originally been suspected. Examination under anesthesia disclosed unremarkable fundi and the diagnosis of juvenile xanthogranuloma was made. There were three children who were siblings of patients with known retinoblastoma in whom the white-with-pressure sign was noted in the periphery of the retina. Although these children did not show abnormal reflexes in the pupil, they are nevertheless included in this series because the diagnosis of retinoblastoma had been suspected in each. The confusion in these cases arose from the fact that there was a positive family history for the tumor, and a white lesion was present in the retinal periphery. Follow-up of one to two years in each of the three patients has demonstrated that these white-with-pressure plaques do not develop into retinoblastoma. The plaques were more marked in the upper temporal quadrant but in two of the three children they extended around the entire peripheral portion of the retina. One patient showed a grayish-white cyst about 1.5 disc diameters in size apparently suspended in the vitreous body about 0.5 mm anterior to the optic disc. In this patient the diagnosis of congenital cyst in a remnant of the hyaloid artery was made. 62 ' 63 Such lesions may be differentiated from the inactive granulomas caused by the larvae of Toxocara canis because of the absence of surrounding inflammatory changes, and because of their prepapillary location. COMMENT
In the older reports dealing with "pseudoglioma" the most common diagnosis demonstrated pathologically was metastatic endophthalmitis with vitreous abscess. For example, in the report of Treacher Collins,2 11 of 14 cases were ascribed to this cause. Prior to the days of antibiotic therapy, it
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G E O R G E M. H O W A R D A N D R O B E R T M.
was said that 7.5 percent of patients with epidemic cerebrospinal meningitis had metastatic endophthalmitis. 04 This condition is certainly less common today. In the present series, only two cases of endophthalmitis were recognized. It may be that some of the conditions formerly regarded as endophthalmitis would today be considered examples of larval granulomatosis. There are other entities described in the literature which might simulate retinoblastoma, but which were not encountered in the present series, such as Norrie's disease,C5"C7 colloid bodies of the disc and retina that may be a feature of tuberous sclerosis, 68 and various retinal anomalies described by Waardenburg. 0 9 Pathologic examination of enucleated globes does not always allow one to distinguish between the various types of intraocular disease which lead to opacification of the media. In some specimens there is atrophy of the globe, synechial closure of the angle, massive organization of the vitreous, and total detachment of the retina with advanced gliotic changes, without specific inflammatory or vascular characteristics.
ELLSWORTH
Such cases of vitreous organization may be due to far-advanced retrolental fibroplasia, recurrent vitreous hemorrhage due to persistent hyperplastic primary vitreous, old infection with larvae, or other entities. Prenatal histories of rubella infection early in pregnancy were noted in nine children in this series. Six of these patients had congenital cataracts, but only three were bilateral at the time of examination. T h r e e had an associated microphthalmos of the cataractous eye ; two had a unilateral congenital retinal fold, and one had persistent hyperplastic primary vitreous. In those eyes in which a view of the interior could be obtained, diffuse granular pigmentation was present in the fundus. SUMMARY
Five hundred children with suspected retinoblastoma were examined under anesthesia during the past five y e a r s ; 265 of them did not have the tumor. T h e diagnoses in this latter group are discussed, with a brief comment on the clinical characteristics of the lesions simulating this tumor. 635 West 165th Street (10032).
REFERENCES
1. Reese, A. B., and Blodi, F. C. : Retinal dysplasia. Am. J. Ophth., 33 :23, 1950. 2. Treacher Collins, E. : Pseudoglioma. Roy. Loud, ophth. Hosp. Rep., 13 :361, 1892. 3. Sanders, T. E. : Pseudogüoma : A clinicopathologic study of 15 cases: Part I. Introduction. Am. J. .Ophth., 35:61, 1952. 4. : Pseudoglioma: A clinicopathologic study of 15 cases: Part II. Pathologic classification. Am. J. Ophth., 35 :199, 1952. 5. : Pseudoglioma: A clinicopathologic study of 15 cases: Part III. Clinical considerations. Am. .1. Ophth., 35 :364, 1952. 6. Stokes, J. J. : Ocular lesions in children simulating retinoblastoma : A report of 14 cases of pseudoglioma. South. M. J., 46:63, 1953. 7. Duke, J. : Pseudoglioma in children: Aspects of clinical and pathological diagnosis. South. M. J., 51:754, 1958. 8. Kogan, L., and Boniuk, M. : Causes for enucleation in childhood with special reference to pseudogliomas and unsuspected retinoblastomas. Int. Ophth. Clin., 2:507, 1962. 9. Hamburg, A. : Pseudoglioma. Ophthalmologica, 146 :355, 1963. 10. Reese, A. B.: Persistence and hyperplasia of primary vitreous; retrolental fibroplasia—two entities. Arch. Ophth., 41:527, 1949. 11. : Persistent hyperplastic primary vitreous. Tr. Am. Acad. Ophth., 59:271, 1955; Am. J. Ophth., 40:317, 1955. 12. Michaelson, I. C. : The mode of development of the vascular system of the retina, with some observations on its significance for certain retinal diseases. Tr. Ophth. Soc. U.Kingdom, 68:137, 1948. 13. Campbell, K.: Intensive oxygen therapy as a possible cause of retrolental fibroplasia: A clinical approach. M. J. Aust., 2:48, 1951. 14. Campbell, F. W. : The influence of a low atmospheric pressure on the development of the retinal vessels in the rat. Tr. Ophth. Soc. U. Kingdom, 71:287, 1951.
DIFFERENTIAL DIAGNOSIS OF RETINOBLASTOMA
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15. Szewczyk, T. S. : Retrolental fibroplasia : Etiology and prophylaxis : A preliminary report. Am. J. Ophth., 34:1649, 1951. 16. Crosse, V. M., and Evans, P. J. : Prevention of retrolental fibroplasia. Arch. Ophth., 48 :83, 1952. 17. Gyllensten, L. J., and Hellstrom, B. E, : Retrolental fibroplasia—animal experiments : The effect of intermittingly administered oxygen on the postnatal development of the eyes of full-term mice : A preliminary report. Acta paediat. (Uppsala), 41:577, 1952. 18. Ingalls, T. H., Tedeschi, C. G., and Helpern, M. M. : Congenital malformations of the eye induced in mice by maternal anoxia : With particular reference to the problem of retrolental fibroplasia in man. Am. J. Ophth., 35 :311, 1952. 19. Ashton, N., Ward, B.. and Serpell, G. : Role of oxygen in the genesis of retrolental fibroplasia : A preliminary report. Brit. J. Ophth., 37:513, 1953. 20. Owens, W. C , Friedenwald, J. S., Silverman, W. A., Kinsey, V. E., Hemphill, F. M., Patz, A., Blodi, F. C , and Reese, A. B. : Symposium: Retrolental fibroplasia (retinopathy of prematurity). Tr. Am. Acad. Ophth., 59 :7, 1955. 21. Terry, T. L. : Extreme prematurity and fibroblastic overgrowth of persistent vascular sheath behind each crystalline lens : I. Preliminary report. Am. J. Ophth., 25:203, 1942. 22. Owens, W. C , and Owens, E. U. : Retrolental fibroplasia in premature infants. Am. J. Ophth., 32 : 1, 1949; Tr. Am. Acad. Ophth., 53 :18, 1948-1949. 23. King, M. J. : Retrolental fibroplasia: A clinical study of 238 cases. Arch. Ophth., 43:694, 1950. 24. Reese, A. B., and Blodi, F. C. : Retrolental fibroplasia. Acta X V I Cone. Ophth. (Britannia), 1950, p. 445. 25. Reese, A. B. : Retrolental fibroplasia. Am. J. Ophth., 34:1, 1951. 26. Friedenwald, J. S., Owens, W. C , and Owens, E. U. : Retrolental fibroplasia in premature infants: I I I . The pathology of the disease. Tr. Am. ophth. S o c , 49:207, 1951. 27. Reese, A. B., Blodi, F . C , and Locke, J. C. : T h e pathology of early retrolental fibroplasia—with an analysis of the histologie findings in the eyes of newborn and stillborn infants. Am. J. Ophth., 35 : 1407, 1952. 28. Reese. A. B., King, M. J., and Owens, W. C. : A classification of retrolental fibroplasia. Am. J. Ophth., 36:1333, 1953. 29. Reese, A. B., and Stepanik, J. : Cicatricial stage of retrolental fibroplasia. Am. J. Ophth., 38:308, 1954. 30. Kranenburg, E. W . : Craterlike holes in the optic disc and central serous retinopathy. Arch. Ophth. 64:912, 1960. 31. Sugar, H. S.: Congenital pits in the optic disc with acquired macular pathology. Am. J. Ophth., 53:307, 1962. 32. : An explanation : For the acquired macular pathology associated with congenital pits of the optic disc. Am. J. Ophth., 57 :833, 1964. 33. Brockhurst, R. J., Schepens, C. L., and Okamura, I. D. : Uveitis: II. Peripheral uveitis: Clinical description, complications and differential diagnosis. Am. J. Ophth., 49:1257, 1960. 34. Welch, R. B., Maumenee, A. E., and Wahlen, H. E. : Peripheral posterior segment inflammation; vitreous opacities ; and edema of the posterior pole : P a r s planitis. Arch. Ophth., 64 :540, 1960. 35. Brockhurst, R. J., Schepens, C. L., and Okamura, I. D.: Uveitis: I I I . Peripheral uveitis: pathogenesis, etiology and treatment. Am. J. Ophth., 51:19, 1961. 36. Wilder, H. C. : Nematode endophthalmitis. Tr. Am. Acad. Ophth., 55 :99, 1950. 37. Irvine, W. C , and Irvine, A. R., J r . : Nematode endophthalmitis: Toxocara canis : Report of one case. Am. J. Ophth., 47 :185, 1959. 38. Ashton, N. : Larval granulomatosis of the retina due to Toxocara. Brit. J. Ophth., 44:129, 1960. 39. Bourke, G. M., and Yeates, F. M. : Blindness due to household pets (Toxocara canis infestation). M . J . A u s t , 48:12, 1961. 40. Duguid, I. M. : Chronic endophthalmitis due to Toxocara. Brit. J. Ophth., 45:705, 1961. 41. : Features of ocular infestation by Toxocara. Brit. J. Ophth., 45:789, 1961. 42. Harris, W. : Pseudoglioma due to larval choroidoretinal granulomatosis. Brit. J. Ophth., 45:144, 1961. 43. Rey, A. : Nematode endophthalmitis due to Toxocara. Brit. J. Ophth., 46 :616, 1962. 44. Mann, I. C. : A case of congenital abnormality of the retina. Tr. Ophth. Soc. U.Kingdom, 48 :383, 1928. 45. Weve, H. : Ueber "Ablatio falciformis cong." Arch. Augenh., 109:371, 1936. 46. Mann, I. : Developmental Abnormalities of the Eye. Philadelphia, Lippincott, 1957, ed. 2. 47. Coats, G. : Forms of retinal disease with massive exudation. Roy. Lond. Ophth. Hosp. Rep., 17 : 440, 1907-1908. 48. Leber, T. : Ueber eine durch Vorkommen multipler miliaraneurysmen charakterisierte form von retinaldegeneration. Arch. f. Ophth., 81:1, 1912. 49. Elwyn, H. : T h e place of Coats' disease among the diseases of the retina. Arch. Ophth., 23 :507. 1940.
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50. Reese, A. B. : Telangiectasis of the retina and Coats' disease. Am. J. Ophth., 42:1, 1956. 51. : Tumors of the Eye. New York, Hoeber, 1963, ed. 2. 52. Woods, A. C, and Duke, J. R. : Coats' disease : I. Review of the literature, diagnostic criteria, clinical findings, and plasma lipid studies. Brit. J. Ophth., 47:385, 1963. 53. Gomez Morales, A.: Coats' disease: Natural history and results of treatment. In preparation. 54. Krause, A. C. : Congenital encephalo-ophthalmic dysplasia. Arch. Ophth., 36:387, 1946. 55. Reese, A. B., and Straatsma, B. R. : Retinal dysplasia. Am. J. Ophth., 45:199, 1958. 56. Patau, K., Smith, D. W., Therman, E., Inhorn, S. L., and Wagner, H. P. : Multiple congenital anomaly caused by an extra autosome. Lancet, 1:790, 1960. 57. Yanoff, M., Frayer, W. C, and Scheie, H. G. : Ocular findings in a patient with 13-15 Trisomy. Arch. Ophth., 70 :372, 1963. 58. Cogan, D. G., and Kuwabara, T.: Ocular pathology of the 13-15 Trisomy syndrome. Arch. Ophth., 72:246, 1964. 59. Smith, D. W., Patau, K., Therman, E., and Inhorn, S. L. : The No. 18 Trisomy syndrome. J. Pediat, 60 :S13, 1962. 60. Jesberg, D. O., and Owen, R. : Clinical manifestations of chromosomal Trisomy. Presented Western Section Research Ophth., 1963. 61. Francois, J.. and Matton-Van Leuven, M. T. : Chromosome abnormalities and ophthalmology. T. Pediat. Ophth., 1:1, 1964. 62. Lloyd, R. I. : Variations in the development and regression of Bergmeister's papilla and the hyaloid artery. Tr. Am. Ophth. Soc, 38:326, 1940. 63. Tower, P. : Congenital prepapillary cyst. Arch. Ophth., 48:433, 1952. 64. Lewis, P. M. : Eye changes in epidemic cerebrospinal meningitis : A clinical and pathologic study of 200 cases. Tr. Am. Ophth. Soc, 34:284, 1936. 65. Norrie, G. : Causes of blindness in children : 25 years' experience of Danish Institutes for the Blind. Acta Ophth. (Kbh.), 5 :357, 1927. 66. Andersen, R. S., and Warburg, M.: Norrie's disease: Congenital bilateral pseudotumor of the retina with recessive X-chromosomal inheritance: A preliminary report. Arch. Ophth., 66:614, 1961. 67. Warburg, M. : Norrie's disease (Atrofia bulborum hereditaria) : A report of 11 cases of hereditary bilateral pseudotumor of the retina, complicated by deafness and mental deficiency. Acta ophth. (Kbh.), 41:134, 1963. 68. Reese, A. B. : Problems encountered in an eye clinic for children. Am. J. Ophth., 43 :24, 1957. 69. Waardenburg, P. J. : Genetics and Ophthalmology : Vol. II. Neuro-ophthalmological Part. Assen, Netherlands, Royal Van Gorcum Ltd., 1963, chap. 21, 31. 70. Scott, J. G., Friedmann, A. I., Chitters, M., and Pepler, W. J. : Ocular changes in the BlochSulzberger syndrome (incontinentia pigmenti). Brit. J. Ophth., 39:276, 1955.
D I F F E R E N T I A L DIAGNOSIS O F RETINOBLASTOMA* A STATISTICAL SURVEY OF 5 0 0 CHILDREN II.
FACTORS RELATING TO T H E DIAGNOSIS OF RETINOBLASTOMA
GEORGE M.
H O W A R D , M.D.,
A N D ROBERT M.
ELLSWORTH,
M.D.
New York T h e initial portion of this report consisted of an analysis of the diagnoses in 265 of 500 patients in whom retinoblastoma had
been suspected, but who did not have the tumor. 1 T h e present and concluding section of the study deals with the remaining 235
* From the Tumor Clinic (Director : A. B. Reese, M.D.), Institute of Ophthalmology, Columbia-Presbyterian Medical Center. This work was supported by Special Fellowship NB1284-01 from the National Institute of Neurological Diseases and Blindness, Public Health Service (Dr. Howard). A summary of this work was read before the VII Congress of the Pan-American Association of Ophthalmology, Montreal, Canada, October 15, 1964.
patients who did have retinoblastoma. All patients were referred to the Tumor Clinic, Institute of Ophthalmology, for diagnostic evaluation during the five-year period ending July, 1964, and all were examined under general anesthesia, using binocular indirect ophthalmoscopy with scierai indentation. The diagnosis of retinoblastoma was
A. HUGGERT AND E. SUNDMARK
Hoist, H. : The treatment of stenosis of the lacrimal canaliculi by the method of Huggert. Acta ophth. (Kbh.), 41:671-673, 1963. Huggert, A.: The treatment of stenosis of the lacrimal canaliculi. Acta ophth. (Kbh.), 37:355-358, 1959. Kaufman, H., and Chapman, R. : Modified probe for canaliculus surgery. Am. J. Ophth., 54 :461-462, 1962. Rosenthal, J. : A hook for polyethylene tubes. Am. J. Ophth., 54:1148, 1962. Sundmark, E. : Instruments for the temporary application of plastic tubes in the treatment of lacrimal obstruction. Acta ophth. (Kbh.), 42:528, 1964.
DIFFERENTIAL DIAGNOSIS O F
RETINOBLASTOMA*
A STATISTICAL SURVEY OF 5 0 0 CHILDREN I. R E L A T I V E FREQUENCY OF T H E LESIONS W H I C H S I M U L A T E RETINOBLASTOMA GEORGE M.
H O W A R D , M.D.,
A N D ROBERT M.
ELLSWORTH,
M.D.
New York The most common presenting sign in children with retinoblastoma is a white pupillary reflex, an abnormality for which the term "leukokoria" was introduced some years ago. 1 There are various other conditions, both congential and acquired, in which opaque tissue occurs behind the plane of the pupil, and which may simulate retinoblastoma. T h e aims of the present study were to investigate the frequency of the lesions which resemble retinoblastoma, and to study the factors relating to the diagnosis of retinoblastoma itself. Although the abnormal reflex in the pupil is described as "white" in this report, it may actually be pink-white or yellow-white in many instances. I n a clinicopathologic study, Treacher Collins (1893) applied the term "pseudoglioma" to a variety of pseudoneoplastic diseases of the posterior segment of the eye 2 and, since then, other similar studies have appeared. 3 " 9 Although the articles dealing with pseudoglioma constitute a group of ♦From the Tumor Clinic (Director: A. B. Reese, M.D.), Institute of Ophthalmology, Columbia-Presbyterian Medical Center. This work was supported by Special Fellowship NB1284-01 from the National Institute of Neurological Diseases and Blindness, Public Health Service (Dr. Howard). A summary of this work was read before the VII Congress of the Pan-American Association of Ophthalmology, Montreal, Canada, October 15, 1964.
vitally important pathologic studies, they do not contribute definitively to our clinical knowledge of the relative frequency of conditions simulating retinoblastoma. T h e reason for this is clear : many of the ocular diseases associated with a white reflex in the pupil prove to be benign, and no enucleation is performed. Hence, there seems to be an indication for a clinical study in which the diagnoses on all children with abnormal reflexes in the pupil are considered. T h e term "pseudoglioma" will be avoided in this article since the word "glioma" in current medical parlance refers to a tumor entirely different from retinoblastoma. T h e T u m o r Clinic at the Institute of Ophthalmology, New York, is organized so that 10 to 15 children are examined under anesthesia each week. D u r i n g the five-year period ending July, 1964, 500 new patients were seen consecutively who had been referred to this clinic, and in whom the diagnostic possibility of retinoblastoma had been raised. W i t h a few exceptions, these patients had leukokoria of one or both eyes. All examinations, except a few in the older children, were performed under anesthesia using halothane by the open-drop method. Binocular indirect ophthalmoscopy was employed, and scierai indentation was utilized to view the anterior portion of the retina. T h e diagnoses in the children who
611
DIFFERENTIAL DIAGNOSIS OF RETINOBLASTOMA did not have retinoblastoma were clinical in most instances, and were based upon the cumulative experience gained in this clinic during prior years. I n certain of the diagnostic categories, such as larval granulomatosis or Coats' disease, microscopic confirmation was obtained in some cases. T h e patients seen during the past five years were chosen for this study because of two considerations. T h e inclusion of children seen earlier would have prejudiced the statistical analysis in favor of retrolental fibroplasia, a disease which is not seen as frequently now as was the case 10 to 15 years ago. Also, increased appreciation of the entity of larval granulomatosis has allowed the diagnosis to be made with a reasonable degree of certainty during the past pentad. F R E Q U E N C Y OF LESIONS RETINOBLASTOMA
SIMULATING
(table
1)
Of the 500 children in whom retinoblastoma had been suspected, there were 265 in whom other diagnoses were made. Illustrations for most of the conditions will be found in the references cited and in Reese's Tumors of the Eye.51 A.
P E R S I S T E N T HYPERPLASTIC
PRIMARY
VITREOUS
This was the most frequent of the conditions other than retinoblastoma causing a white pupillary reflex, and accounted for 51 of the 265 diagnoses. There were 20 boys and 31 girls with a median age of four months at the time of diagnosis. T h e condition had been first noticed at, or shortly after, birth in all, and was unilateral except in two patients. All of the children were in apparent good health. Only one had been born prematurely. T h e diagnosis was suggested by some degree of unilateral microphthalmos, a shallow anterior chamber, prominent vessels on the iris, long ciliary processes, vascularized white retrolental tissue, and a progressive
TABLE 1
PATIENTS (265) WITH SUSPECTED RETINOBLASTOMA IN WHOM OTHER DIAGNOSES WERE MADE Diagnosis
No. Percent Cases of Total
1. Persistent hyperplastic primary vitreous 2. Retrolental fibroplasia 3. Posterior cataract 4. Coloboma of choroid or optic disc S. Uveitis 6. Larval granulomatosis 7. Congenital retinal fold 8. Coats' disease 9. Organizing vitreous hemorrhage 10. Retinal dysplasia 11. Tumor other than retinoblastomai 12. White-with-pressure sign 13. Juvenile xanthogranuloma 14. Retinoschisis IS. Tapetoretinal degeneration 16. Endophthalmitis 17. Persistent tunica vasculosa lends and pupillary membrane 18. Miscellaneous: a. Anteriorly dislocated lens with secondary glaucoma b. Congenital corneal opacity c. Incontinentia pigmenti (Bloch-Sulzberger Syndrome 70 ) with total funnelshaped retinal detachment d. Cyst in remnant of hyaloid artery e. Anomalous optic discs f. Hematoma under retinal pigment epithelium g. High myopia with advanced chorioretinal degeneration h. Medullation of nerve fiber layer i. Traumatic choroiditis TOTAL
51 36 36 30 27 18 13 10 9 7 4 3 3 3 2 2
19.0 13.5 13.5 11.5 10.0 6.5 5.0 4.0 3.5 2.5 1.5 1.0 1.0 1.0 1.0 1.0
2
1.0 3.5
1 1
1 1 1 1 1 1 1
265
100.0
posterior subcapsular cataract beginning at a point just nasal to the posterior lenticular pole where the fibrovascular tissue inserts. 1 0 · 1 1 In three of the children there were associated anomalies ; two of these had uveal colobomas and one had a persistence of the anterior portion of the tunica vasculosa lentis. Several of the children were seen in the stage of intumescence of the lens with secondary glaucoma. Brightly refractile crystals resembling those of cholesterol were visible in the retrolental space in two patients. Included in this classification were two children with only a Mittendorf dot and a prominent Bergmeister's papilla.
612
GEORGE M. HOWARD AND ROBERT M. ELLSWORTH
B. RETROLENTAL FIBROPLASIA T h e incidence of this disease has declined sharply since the role of oxygénation was established. 12 " 20 However, a few cases are seen in this clinic each year, specifically, 36 during the past five years. Thirty-five of the patients in this group were seen in cicatricial stages. There were 19 boys and 17 girls. All except one were of low birth weight (less than 5.5 pounds) and had been in an incubator for a variable number of days or weeks. I n four of the 36 patients there was evidence of mental retardation or other anomalies of the central nervous system at the time of examination. I n addition to the information obtained by history, the factors suggesting this diagnosis are bilaterality, fibrovascular tissue originating near the temporal periphery of the retina and extending toward the retrolental region, dentate processes from the ciliary body to the retrolental tissue, and, when the fundus can be seen, traction upon the retina temporally leaving an atrophie peripapillary conus nasally. 21 " 29 In the advanced stages there is atrophy of the globe and orbital structures, posterior synechiae, and a shallow anterior chamber. There is a specific form of the cicatricial stage of this disease (Grade I I I ) which deserves particular mention because of its resemblance to congenital retinal fold. 28 I n this form, traction upon the retina produces a sharply demarcated, elevated, retinal septum which arches forward into the vitreous body, stretching from the disc to the extreme periphery of the fundus. C. POSTERIOR CATARACT
There were 36 patients (15 boys and 21 girls) of various ages who had localized posterior cataracts. T h e differential diagnosis of these lesions prior to referral had included a questionable retrolental mass. I n addition to the cataracts, two patients had aniridia, one had a congenital coloboma of the optic nerve in both eyes, and one a coloboma of the iris. There were six patients
who also had microphthalmos, and in three of these an adequate view of the fundus was not obtained; it is possible that the signs in these three patients were due to persistent hyperplastic primary vitreous. D.
COLOBOMA
T h e cells of the inner layer of the secondary optic vesicle retain their ability to develop into glial elements over the surface of the optic disc. W h e n colobomas of the optic nervehead occur these glial cells may proliferate to form varying amounts of elevated grayish tissue at the margin of the coloboma. I n addition, the coloboma itself may occasion a white reflex in the pupil. There were 10 patients with such an anomaly in this series, and in five the condition was bilateral. O n e of these patients had, in addition, an isolated cystic retinal detachment in the macular region. Central serous retinopathy has been reported several times in association with congenital pit, or craterlike hole, of the optic disc, 30 " 32 and it may be that the central serous retinal detachment noted in this case was of similar derivation. T w e n t y children had large choroidal colobomas. T h e lesions were bilateral in three cases. Most of the colobomas were "typical," that is, they occupied the lower portion of the fundus in the 6-o'clock meridian, extending upward a variable degree to involve the disc, the macula, or the upper portion of the fundus. T w o patients showed atypical, small, isolated colobomas, one of which was located in the macula and the other slightly below the disc. There were associated colobomas of the iris in six of the involved eyes, and in one eye there was a total retinal detachment. Altogether, there were 30 children with colobomas, 15 boys and 15 girls. E.
UVEITIS
Granulomatous choroidal infiltrates may attain proportions large enough to mimic a retinoblastoma. I n one boy, there was a solid, yellowish mass, infiltration of the vit-
DIFFERENTIAL DIAGNOSIS OF RETINOBLASTOMA
reous body with inflammatory cells, and a total retinal detachment. The eye was blind, chronically irritated, unsightly and was enucleated. Examination of the microscopic sections disclosed several pseudocysts of Toxoplasma gondii. In all, there were 27 patients with uveitis. Nine of these showed bilateral involvement of the macular areas and scattered punctate infiltrates elsewhere in the fundus considered to be compatible with ocular toxoplasmosis. The 27 patients ranged in age from two months to seven years ; the median age at the time of diagnosis in this clinic was two years, three months. Bilateral peripheral uveitis (pars planitis) occurred in four patients, and was characterized by caked yellow exudate along the ora serrata in the lower half of the fundus.33-35 Large, fluffy exudates were present posteriorly as well as anteriorly in the vitreous, and there was grayish opacification of the peripheral retina. This syndrome may closely resemble retinoblastoma. F. LARVAL GRANULOMATOSIS
Eighteen patients presented with elevated, globular or drop-shaped pinkish-yellow masses elevating the retina from which grayish-yellow vitreous veils, webs, or strands radiated. In such patients the diagnosis of larval granulomatosis was applied.36"43 There were 10 boys and eight girls, ranging in age from two years to eight and one-half years ; the median age when seen at this clinic was five years, two months. The vitreous was hazy in some active cases. In inactive cases, the vitreous was clear, the mass was more sharply demarcated and whitish in color. There was a narrow annulus showing disruption of the pigment epithelium surrounding the lesion. Several of the eyes showed a localized secondary retinal detachment, and in one eye the detachment was total. In five cases there was spotty calcification, thus promoting the sim-
613
ulation of retinoblastoma. In all patients in this group the disease was unilateral. In most of the cases (13) the lesions were located in the posterior pole. In three eyes, the granuloma was near the equator, in one it was in the macula, and in one it was directly on the pars plana. Microscopic confirmation of the diagnosis was obtained in five of the 18 patients. G. CONGENITAL RETINAL FOLD
This anomaly44"46 was diagnosed in 13 children, 11 boys and two girls. There was no history of oxygen therapy in any. Each had a history of normal birth weight and unremarkable development. The fold was unilateral in nine and bilateral in four. In unilateral cases the fellow eye was normal as far as could be determined. The fold in each case appeared to be elevated two to three mm and was about 30 degrees in width. It began at the margin of the disc and projected toward the ora serrata where it invariably fanned out into a fibrous extension about 90-degrees wide which occupied a position over the ciliary body just posterior to the equator of the lens. The lens itself was clear. The fold contained some retinal vessels, but the remainder of the retina was in situ. However, in one case, the entire retina appeared to be involved so that only choroidal vessels were seen elsewhere in the fundus. Most cases showed a pigmentary disturbance at the edge of the fold. There is a striking similarity between congenital retinal fold and Grade III cicatricial retrolental fibroplasia; some observers have considered them the same entity. However, there is reason to classify them separately. Retrolental fibroplasia nearly always occurs in infants of low birth weight who have been maintained in an incubator for a time. Such a history is not obtained in patients with congenital retinal fold. Microscopic examination of histologie sections provides another reason for segregating these two entities. The retina in congenital retinal fold is disposed in dysplastic ro-
614
GEORGE M. HOWARD AND ROBERT M. ELLSWORTH
settes, whereas in retrolental fibroplasia, it is characterized by vascular proliferation leading to secondary gliosis. There is little possibility of confusing these two types of changes. The four patients who were diagnosed as having bilateral congenital retinal folds were quite puzzling, and did not fit easily into any known diagnostic category. Most descriptions of this anomaly characterize it as unilateral. It is conceivable that the ocular changes in these patients are manifestations of a chromosomal defect such as 13-15 trisomy. However, the four patients were in apparent good he; 1th, and there was no family history of ocular disease in any. Chromosomal studies are planned in the future for these and similar cases. H. COATS' DISEASE
This diagnosis was made in six boys and four girls ranging in age from two years to seven and one-half years, with an average age of four and one-half years. In two instances the diagnosis was confirmed by microscopic section. The condition was unilateral in all cases. The diagnosis depended upon the presence of a retinal detachment beginning in the lower portion of the fundus, dilated retinal blood vessels, and variable amounts of subretinal hemorrhage, exudate, and hematogenous pigmentation.47-52 In most of these cases circumscribed foci of capillary telangiectases of the retina were visible, and in three of them small miliary aneurysms were noted. In several of these cases yellow-white crystals resembling cholesterol were seen in the subretinal space. A clinicopathologic study of Coats' disease, in which all cases from this Institute will be reviewed, is now in progress.53 During the first few weeks of life, patients with retrolental fibroplasia frequently have dilated retinal blood vessels and an exudative detachment of the retina, ocular signs resembling those of Coats' disease. The factors of prematurity, oxygénation, bilaterality and the younger age of the pa-
tient, usually enable one to recognize the active stage of retrolental fibroplasia, and to differentiate it from Coats' disease. I. ORGANIZING VITREOUS HEMORRHAGE
The original red color of a vitreous hemorrhage gradually gives way to a yellow hue and finally is replaced by a grayish opacity or web which may wave to and fro when the patient moves his eye. There were nine patients in this series with a vitreous hemorrhage in various stages of organization. Four of these instances of hemorrhage occurred in infants with hemorrhagic disease of the newborn (hypoprothrombinemia). In two instances, the vitreous hemorrhage followed trauma. In one case it was associated with vasculitis of uncertain etiology, and in another it occurred with increased intracranial pressure following rupture of a congenital cerebral aneurysm. The vitreous hemorrhage in the remaining patient was of uncertain cause. J. RETINAL DYSPLASIA
In 1946, Krause reported 18 cases of a syndrome which he termed "congenital encephalo-ophthalmic dysplasia."54 Most of his patients were of low birth weight, and it is likely that many were afflicted with retrolental fibroplasia. There was a high incidence of mental retardation and central nervous system malformations. A similar syndrome was later described in the ophthalmic literature as "retinal dysplasia."1'55 The ocular anomalies in this syndrome now appear to be a manifestation of 13-15 trisomy in many instances,56"58 and are perhaps associated with 18 trisomy in some cases.59"61 Typical features of the disease include a family history of ocular defects and congenital deformities such as malformations of the central nervous system and cardiovascular system. There were seven patients in the present series in whom the diagnosis of retinal dysplasia was made. The ocular findings were bilateral microphthalmos, shallow anterior chambers, pupillary anomalies, and a
DIFFERENTIAL DIAGNOSIS OF RETINOBLASTOMA
pinkish-white retrolental mass. The lenses are usually clear in this syndrome, a finding which helps differentiate it from the rare case of bilateral persistent hyperplastic primary vitreous. It is quite possible to confuse retinal dysplasia with advanced retrolental fibroplasia in the examination of a given patient, but factors in the history will assist in distinguishing one disease from the other. The term "retinal dysplasia" is the ophthalmologists' appellation and does not connote the widespread congenital anomalies which occur in this syndrome ; it was applied by Reese and Straatsma 55 specifically to those cases showing congenital ocular anomalies, the microscopic examination of which revealed irregularly shaped rosettes, retinal detachment and persistent elements of the primary vitreous. K.
INTRAOCULAR
TUMORS
OTHER
THAN
RETINOBLASTOMA
In two girls (aged four and one-half and six and one-half years, respectively) the clinical diagnosis of a choroidal hemangioma was made. In the first of these, there was a broad, flat, translucent lesion in the posterior pole of the fundus which glowed brightly under observation with ultraviolet light after the intravenous administration of fluorescein. In the second, the neoplasm was flesh-colored and occurred as a manifestation of a Sturge-Weber syndrome. There was a total retinal detachment and secondary glaucoma. One girl (aged one and onehalf years) had an intraocular mass originating in the ciliary body which proved microscopically to be a dictyoma. The fourth patient in this group was a six and one-half year-old boy with intraocular extension of a meningioma of the optic nerve (demonstrated microscopically and previously reported 51 ). L. MISCELLANEOUS
There were several other diagnoses which were made three times or less in the present series, and which are listed in Table 1.
615
Some of these require a brief explanation. There were three infants with yellowish nodules on the iris and recurrent spontaneous hyphema in whom retinoblastoma seeds had originally been suspected. Examination under anesthesia disclosed unremarkable fundi and the diagnosis of juvenile xanthogranuloma was made. There were three children who were siblings of patients with known retinoblastoma in whom the white-with-pressure sign was noted in the periphery of the retina. Although these children did not show abnormal reflexes in the pupil, they are nevertheless included in this series because the diagnosis of retinoblastoma had been suspected in each. The confusion in these cases arose from the fact that there was a positive family history for the tumor, and a white lesion was present in the retinal periphery. Follow-up of one to two years in each of the three patients has demonstrated that these white-with-pressure plaques do not develop into retinoblastoma. The plaques were more marked in the upper temporal quadrant but in two of the three children they extended around the entire peripheral portion of the retina. One patient showed a grayish-white cyst about 1.5 disc diameters in size apparently suspended in the vitreous body about 0.5 mm anterior to the optic disc. In this patient the diagnosis of congenital cyst in a remnant of the hyaloid artery was made. 62 ' 63 Such lesions may be differentiated from the inactive granulomas caused by the larvae of Toxocara canis because of the absence of surrounding inflammatory changes, and because of their prepapillary location. COMMENT
In the older reports dealing with "pseudoglioma" the most common diagnosis demonstrated pathologically was metastatic endophthalmitis with vitreous abscess. For example, in the report of Treacher Collins,2 11 of 14 cases were ascribed to this cause. Prior to the days of antibiotic therapy, it
616
G E O R G E M. H O W A R D A N D R O B E R T M.
was said that 7.5 percent of patients with epidemic cerebrospinal meningitis had metastatic endophthalmitis. 04 This condition is certainly less common today. In the present series, only two cases of endophthalmitis were recognized. It may be that some of the conditions formerly regarded as endophthalmitis would today be considered examples of larval granulomatosis. There are other entities described in the literature which might simulate retinoblastoma, but which were not encountered in the present series, such as Norrie's disease,C5"C7 colloid bodies of the disc and retina that may be a feature of tuberous sclerosis, 68 and various retinal anomalies described by Waardenburg. 0 9 Pathologic examination of enucleated globes does not always allow one to distinguish between the various types of intraocular disease which lead to opacification of the media. In some specimens there is atrophy of the globe, synechial closure of the angle, massive organization of the vitreous, and total detachment of the retina with advanced gliotic changes, without specific inflammatory or vascular characteristics.
ELLSWORTH
Such cases of vitreous organization may be due to far-advanced retrolental fibroplasia, recurrent vitreous hemorrhage due to persistent hyperplastic primary vitreous, old infection with larvae, or other entities. Prenatal histories of rubella infection early in pregnancy were noted in nine children in this series. Six of these patients had congenital cataracts, but only three were bilateral at the time of examination. T h r e e had an associated microphthalmos of the cataractous eye ; two had a unilateral congenital retinal fold, and one had persistent hyperplastic primary vitreous. In those eyes in which a view of the interior could be obtained, diffuse granular pigmentation was present in the fundus. SUMMARY
Five hundred children with suspected retinoblastoma were examined under anesthesia during the past five y e a r s ; 265 of them did not have the tumor. T h e diagnoses in this latter group are discussed, with a brief comment on the clinical characteristics of the lesions simulating this tumor. 635 West 165th Street (10032).
REFERENCES
1. Reese, A. B., and Blodi, F. C. : Retinal dysplasia. Am. J. Ophth., 33 :23, 1950. 2. Treacher Collins, E. : Pseudoglioma. Roy. Loud, ophth. Hosp. Rep., 13 :361, 1892. 3. Sanders, T. E. : Pseudogüoma : A clinicopathologic study of 15 cases: Part I. Introduction. Am. J. .Ophth., 35:61, 1952. 4. : Pseudoglioma: A clinicopathologic study of 15 cases: Part II. Pathologic classification. Am. J. Ophth., 35 :199, 1952. 5. : Pseudoglioma: A clinicopathologic study of 15 cases: Part III. Clinical considerations. Am. .1. Ophth., 35 :364, 1952. 6. Stokes, J. J. : Ocular lesions in children simulating retinoblastoma : A report of 14 cases of pseudoglioma. South. M. J., 46:63, 1953. 7. Duke, J. : Pseudoglioma in children: Aspects of clinical and pathological diagnosis. South. M. J., 51:754, 1958. 8. Kogan, L., and Boniuk, M. : Causes for enucleation in childhood with special reference to pseudogliomas and unsuspected retinoblastomas. Int. Ophth. Clin., 2:507, 1962. 9. Hamburg, A. : Pseudoglioma. Ophthalmologica, 146 :355, 1963. 10. Reese, A. B.: Persistence and hyperplasia of primary vitreous; retrolental fibroplasia—two entities. Arch. Ophth., 41:527, 1949. 11. : Persistent hyperplastic primary vitreous. Tr. Am. Acad. Ophth., 59:271, 1955; Am. J. Ophth., 40:317, 1955. 12. Michaelson, I. C. : The mode of development of the vascular system of the retina, with some observations on its significance for certain retinal diseases. Tr. Ophth. Soc. U.Kingdom, 68:137, 1948. 13. Campbell, K.: Intensive oxygen therapy as a possible cause of retrolental fibroplasia: A clinical approach. M. J. Aust., 2:48, 1951. 14. Campbell, F. W. : The influence of a low atmospheric pressure on the development of the retinal vessels in the rat. Tr. Ophth. Soc. U. Kingdom, 71:287, 1951.
DIFFERENTIAL DIAGNOSIS OF RETINOBLASTOMA
617
15. Szewczyk, T. S. : Retrolental fibroplasia : Etiology and prophylaxis : A preliminary report. Am. J. Ophth., 34:1649, 1951. 16. Crosse, V. M., and Evans, P. J. : Prevention of retrolental fibroplasia. Arch. Ophth., 48 :83, 1952. 17. Gyllensten, L. J., and Hellstrom, B. E, : Retrolental fibroplasia—animal experiments : The effect of intermittingly administered oxygen on the postnatal development of the eyes of full-term mice : A preliminary report. Acta paediat. (Uppsala), 41:577, 1952. 18. Ingalls, T. H., Tedeschi, C. G., and Helpern, M. M. : Congenital malformations of the eye induced in mice by maternal anoxia : With particular reference to the problem of retrolental fibroplasia in man. Am. J. Ophth., 35 :311, 1952. 19. Ashton, N., Ward, B.. and Serpell, G. : Role of oxygen in the genesis of retrolental fibroplasia : A preliminary report. Brit. J. Ophth., 37:513, 1953. 20. Owens, W. C , Friedenwald, J. S., Silverman, W. A., Kinsey, V. E., Hemphill, F. M., Patz, A., Blodi, F. C , and Reese, A. B. : Symposium: Retrolental fibroplasia (retinopathy of prematurity). Tr. Am. Acad. Ophth., 59 :7, 1955. 21. Terry, T. L. : Extreme prematurity and fibroblastic overgrowth of persistent vascular sheath behind each crystalline lens : I. Preliminary report. Am. J. Ophth., 25:203, 1942. 22. Owens, W. C , and Owens, E. U. : Retrolental fibroplasia in premature infants. Am. J. Ophth., 32 : 1, 1949; Tr. Am. Acad. Ophth., 53 :18, 1948-1949. 23. King, M. J. : Retrolental fibroplasia: A clinical study of 238 cases. Arch. Ophth., 43:694, 1950. 24. Reese, A. B., and Blodi, F. C. : Retrolental fibroplasia. Acta X V I Cone. Ophth. (Britannia), 1950, p. 445. 25. Reese, A. B. : Retrolental fibroplasia. Am. J. Ophth., 34:1, 1951. 26. Friedenwald, J. S., Owens, W. C , and Owens, E. U. : Retrolental fibroplasia in premature infants: I I I . The pathology of the disease. Tr. Am. ophth. S o c , 49:207, 1951. 27. Reese, A. B., Blodi, F . C , and Locke, J. C. : T h e pathology of early retrolental fibroplasia—with an analysis of the histologie findings in the eyes of newborn and stillborn infants. Am. J. Ophth., 35 : 1407, 1952. 28. Reese. A. B., King, M. J., and Owens, W. C. : A classification of retrolental fibroplasia. Am. J. Ophth., 36:1333, 1953. 29. Reese, A. B., and Stepanik, J. : Cicatricial stage of retrolental fibroplasia. Am. J. Ophth., 38:308, 1954. 30. Kranenburg, E. W . : Craterlike holes in the optic disc and central serous retinopathy. Arch. Ophth. 64:912, 1960. 31. Sugar, H. S.: Congenital pits in the optic disc with acquired macular pathology. Am. J. Ophth., 53:307, 1962. 32. : An explanation : For the acquired macular pathology associated with congenital pits of the optic disc. Am. J. Ophth., 57 :833, 1964. 33. Brockhurst, R. J., Schepens, C. L., and Okamura, I. D. : Uveitis: II. Peripheral uveitis: Clinical description, complications and differential diagnosis. Am. J. Ophth., 49:1257, 1960. 34. Welch, R. B., Maumenee, A. E., and Wahlen, H. E. : Peripheral posterior segment inflammation; vitreous opacities ; and edema of the posterior pole : P a r s planitis. Arch. Ophth., 64 :540, 1960. 35. Brockhurst, R. J., Schepens, C. L., and Okamura, I. D.: Uveitis: I I I . Peripheral uveitis: pathogenesis, etiology and treatment. Am. J. Ophth., 51:19, 1961. 36. Wilder, H. C. : Nematode endophthalmitis. Tr. Am. Acad. Ophth., 55 :99, 1950. 37. Irvine, W. C , and Irvine, A. R., J r . : Nematode endophthalmitis: Toxocara canis : Report of one case. Am. J. Ophth., 47 :185, 1959. 38. Ashton, N. : Larval granulomatosis of the retina due to Toxocara. Brit. J. Ophth., 44:129, 1960. 39. Bourke, G. M., and Yeates, F. M. : Blindness due to household pets (Toxocara canis infestation). M . J . A u s t , 48:12, 1961. 40. Duguid, I. M. : Chronic endophthalmitis due to Toxocara. Brit. J. Ophth., 45:705, 1961. 41. : Features of ocular infestation by Toxocara. Brit. J. Ophth., 45:789, 1961. 42. Harris, W. : Pseudoglioma due to larval choroidoretinal granulomatosis. Brit. J. Ophth., 45:144, 1961. 43. Rey, A. : Nematode endophthalmitis due to Toxocara. Brit. J. Ophth., 46 :616, 1962. 44. Mann, I. C. : A case of congenital abnormality of the retina. Tr. Ophth. Soc. U.Kingdom, 48 :383, 1928. 45. Weve, H. : Ueber "Ablatio falciformis cong." Arch. Augenh., 109:371, 1936. 46. Mann, I. : Developmental Abnormalities of the Eye. Philadelphia, Lippincott, 1957, ed. 2. 47. Coats, G. : Forms of retinal disease with massive exudation. Roy. Lond. Ophth. Hosp. Rep., 17 : 440, 1907-1908. 48. Leber, T. : Ueber eine durch Vorkommen multipler miliaraneurysmen charakterisierte form von retinaldegeneration. Arch. f. Ophth., 81:1, 1912. 49. Elwyn, H. : T h e place of Coats' disease among the diseases of the retina. Arch. Ophth., 23 :507. 1940.
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D I F F E R E N T I A L DIAGNOSIS O F RETINOBLASTOMA* A STATISTICAL SURVEY OF 5 0 0 CHILDREN II.
FACTORS RELATING TO T H E DIAGNOSIS OF RETINOBLASTOMA
GEORGE M.
H O W A R D , M.D.,
A N D ROBERT M.
ELLSWORTH,
M.D.
New York T h e initial portion of this report consisted of an analysis of the diagnoses in 265 of 500 patients in whom retinoblastoma had
been suspected, but who did not have the tumor. 1 T h e present and concluding section of the study deals with the remaining 235
* From the Tumor Clinic (Director : A. B. Reese, M.D.), Institute of Ophthalmology, Columbia-Presbyterian Medical Center. This work was supported by Special Fellowship NB1284-01 from the National Institute of Neurological Diseases and Blindness, Public Health Service (Dr. Howard). A summary of this work was read before the VII Congress of the Pan-American Association of Ophthalmology, Montreal, Canada, October 15, 1964.
patients who did have retinoblastoma. All patients were referred to the Tumor Clinic, Institute of Ophthalmology, for diagnostic evaluation during the five-year period ending July, 1964, and all were examined under general anesthesia, using binocular indirect ophthalmoscopy with scierai indentation. The diagnosis of retinoblastoma was