RUBEOSIS IRIDIS IN RETINOBLASTOMA AND PSEUDOGLIOMA* BY Abbot G. Spaulding, MD INTRODUCTION

IN THE COURSE OF EXAMINING ROUTINE OCULAR PATHOLOGIC

specimens over a period of several years, the author was impressed by the number of retinoblastoma specimens exhibiting rubeosis iridis. This association was not noted in classic textbook descriptions and was seldom recorded in the clinical descriptions accompanying the specimens. A study was therefore undertaken to determine whether these observations were accurate and whether the absence of references to rubeosis in the clinical descriptions was due to inadequate biomicroscopic study of the eyes during management. The investigation was extended in an attempt to discover the factors in retinoblastoma that might contribute to the development of rubeosis. While assembling the retinoblastoma specimens, it was noted that a substantial number of pseudoglioma specimens also displayed rubeosis. Rubeosis iridis had not heretofore been considered significant in the clinical differentiation between retinoblastoma and pseudoglioma of the retina. TERMINOLOGY AND GENERAL BACKGROUND

Rubeosis iridis is a familiar clinical term denoting the presence of newly grown blood vessels on the iris. The term "rubeosis iridis diabetica" was coined by Salus in 1928 to denote neovascularization of the iris in diabetic patients.' Prior to this time there were only sporadic references to such neovascularization in the ophthalmic literature as in an early paper by Nettleship published in 1882.2 *From the Eye Pathology Laboratory, Department of Ophthalmology, University of Cincinnati College of Medicine, 321 Bethesda Avenue, Cincinnati, Ohio 45229. These studies were supported in part by the Ohio Lions Eye Research Foundation and the Eugene Sanger Eye Research Fund. TR. AM. OPHTH. Soc., vol LXXVI, 1978

585 Rubeosis Iridis Over the years, however, the entity appears to have generally escaped notice. In recent times, more observers using new techniques have reported an increasing number of disease states associated with neovascularization of the iris. These can be grouped into four broad categories: retinal disease, inflammation, neoplasm, and vascular hypoxia.3 Diabetic retinopathy falls into the first category and, as noted, was first observed by Nettleship.2 Diabetes mellitus is also the sytemic disease most commonly associated with rubeosis iridis. Inflammatory disorders associated with rubeosis iridis are generally severe4 and prolonged.5 The vascular hypoxia group included central retinal artery and vein occlusion. The association of hypoxia with neovascularization of the iris has been appreciated for some time.6 Neoplastic diseases associated with the lesion are uveal melanoma7 and metastatic carcinoma of the uvea.8 Although this paper concerns itself with the association of rubeosis iridis and retinoblastoma, comparison with ocular melanoma will also be presented. The following facts about neovascularization of the iris are generally accepted today.9 Rubeosis is considered to be a noninflammatory new blood vessel formation usually associated with reduced retinal blood flow.10 It is characterized by the growth of a layer of fibroblasts and blood vessels on the anterior surface of the iris. The specific cause of this is not known. The most serious complications are hyphema and secondary glaucoma, both of which can destroy visual function. Spontaneous hyphema is due to fragility and engorgement of the new vessels, and may be precipitated by even minor trauma. The secondary glaucoma associated with rubeosis iridis is most often the result of occlusion of the anterior chamber angle by progressive peripheral anterior synechial formation. The newly developed vessels frequently become incorporated into the synechial growth. There appears to be no histologic difference between rubeosis iridis as it occurs in one or another- disease category. Clinically, florid cases of rubeosis iridis should be very striking and readily recognized; yet less than three decades ago, in a classic textbook on biomicroscopy of the eye, rubeosis iridis was said to result from chronic stasis or inflammation of pre-existing iris blood vessels thrown into prominence by loss of stroma. Newly formed vessels were mentioned as playing only a minor role. The complication of

586

Spaulding secondary glaucoma and the association of rubeosis with iris atrophy were, however, observed and noted at that time.-" Retinoblastoma, the most common ocular neoplasm of childhood, has been the subject of innumerable papers,'2 lectures,'3 and chapters in books,3 and the voluminous data that have accumulated about this disorder will not be recapitulated here. Two areas, however - clinical signs of retinoblastoma and tumor morphology are specifically pertinent to this paper. Howard and Ellsworth discuss clinical signs in retinoblastoma and in patients suspected of having retinoblastoma.'4 Of 500 children suspected of having retinoblastoma, only 235 actually had the neoplasm. The most common presenting sign (61%) in these patients was a white pupil. Strabismus appeared in 22% and decreased vision in 5%. In only 4% were signs noted in the anterior segment of the globe: heterochromia iridis, spontaneous hyphema, unilateral dilated pupil, and red, painful eye secondary to glaucoma. Among the 265 children without retinoblastoma, 122 exhibited one or another of the seven types of pseudoglioma discussed below.15 Howard and Ellsworth stressed that retinoblastoma may appear in an atypical or unfamiliar manner and that it can easily be confused with Coats' disease or larval granulomatosis. Five years after his first paper appeared in 1964, Ellsworth reiterated his observation that in 88% of children under 4 years of age with retinoblastoma the clinical manifestations consisted of leukokoria, strabismus, glaucoma, and reduction or loss of vision.16 Glaucoma, a definite sign of anterior segment disease, was beginning to receive long overdue recognition. Cogan, in discussing the diagnostic difficulties in the management of retinoblastoma, stated that a solid mass in the fundus with satellite tumors was a highly suggestive finding. He felt, however, that the most significant indicator was a normal-sized eye with normal or elevated intraocular tension; in most other conditions simulating retinoblastoma, the eyes tend to be small and the tension low.17 In 1973, Ramirez and de Buen, reviewing the clinical and pathologic manifestations of retinoblastoma, also found a high incidence of leukokoria (69.3%) as a presenting sign:'8 Glaucoma occurred in fewer than 4% of the eyes, but other anterior segment abnormalities reached a new high of 11%. In addition, the correct preoperative diagnosis was now made in 76% of the patients significantly higher than the less than 50% Howard and Ellsworth had recorded almost a decade earlier.

587 RuJbeosis Iridis Binder, in 1974, discussed unusual manifestations of retinoblastoma and listed several anterior segment features that might herald retinoblastoma. Included among iris abnormalities were neovascularization, atrophy, tumor deposits, heterochromia, anisocoria, and a fixed dilated pupil.19 He stressed, as had others before him, the importance of maintaining an alert for retinoblastoma when dealing with the ocular problems of childhood.20 Much has been written about the morphology of retinoblastoma.21 A contemporary description of the microscopic findings might well read as follows: the tumor is composed of densely packed, oval to round neoplastic cells with hypochromatic nuclei, scant cytoplasm, and abundant mitoses. A definite relationship between blood vessels and cellular alignment is usually noted, with viable cells arranged around the vessels and less viable cells being further removed. Widespread poorly staining foci of degenerated or necrotic cells are common. These foci may be demarcated or show a gradual transition. Retinoblastomas exhibit rapid growth and contain both the connective tissue stroma and the newly proliferated vessels necessary for growth. These newly formed vessels, however, tend to drain the precious few end arteries of the retina. In more rapidly growing lesions, the ability to grow new vascular channels and to deliver enough blood to fill them may be outstripped. This insufficiency results in characteristic focal necrosis. By contrast, necrosis is much less frequent in extensions of retinoblastoma into richly vascularized tissues, such as the choroid. Necrosis is a reflection of anoxia or hypoxia. There are studies indicating that anoxia provokes a vasoproliferative reaction in retinal blood vessels and may result in saccular dilations of the vessel walls. It is hypothesized that this is a partial attempt at retinal neovascularization.22 "Pseudoglioma", the term employed in the title and throughout this paper, is considered inappropriate by some.23 It was retained for two reasons: It is the traditional expression historically and is more euphonious than the more popular and less confusing term "pseudoretinoblastoma." Collins (1892) defined pseudoglioma as "any condition of the eye liable to be mistaken for a true glioma."24 A simpler or more straightforward definition could hardly be devised. Retinoblastoma was then popularly known as glioma following introduction of the term by Virchow in 1864.25 Collins did collect 14 cases of pseudoglioma and placed them into three classes: (1) cases in which there is persistence and thickening of the

588

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posterior part of the fetal fibrovascular sheath of the lens, or an atypical development of the anterior part of the vitreous with or without persistent hyaloid artery; (2) cases in which large masses of tubercle occur in the choroid; and (3) cases in which there has been inflammatory effusion into the vitreous, following retinitis and cyclitis, and in most cases accompanied by detachment of the retina. More than half a century passed before another series of pseudogliomas was reported. Sanders (1950) published a clinicopathologic study of 15 cases obtained in a review of 168 childhood ocular enucleations.26 Sixty-two eyes did contain retinoblastoma. Sanders established seven categories of pseudoglioma: Type I. Persistence and hyperplasia of the tunica vasculosa lentis Type II. Organization of a vitreous mass forming a cyclitic membrane. Type III. Chorioretinitis Type IV. Exudative retinitis Type V. Massive retinal fibrosis Type VI. Retrolental fibroplasia Type VII. Other tumors This was an attempt, following histologic examination, to classify pseudoglioma on the basis of site, nature, and probable pathogenesis of masses mimicking true ocular neoplasia. Only eight years later, Duke, utilizing Sanders' classification, reported 40 pseudogliomas among 201 enucleated eyes that also exhibited 60 retinoblastomas.27 In a 1962 study of 1000 enucleations in children by Koogan and Boniuk, there were 85 eyes with pseudoglioma, over half of which contained a congenital or a developmental lesion.m Among the more commonly observed entities were exudative retinitis, retinal dysplasia, retrolental fibroplasia, and persistent hyperplastic primary vitreous. In addition, nematode endophthalmitis was found in eight of 16 eyes thought to have had inflammatory pseudoglioma. Current journals and textbooks such as Duke-Elder's System of Ophthalmology still recognize the term "pseudoglioma," but Duke-Elder prefered the term "leukokoria."29 In this category, he included the following which require consideration in the differential diagnosis of retinoblastoma: (1) Inflammation, usually due to an active infective disease, tuberculosis, syphilis, or Toxocara.

Ruibeosis Iridis

589

(2) Intraocular hemorrhage (usually incurred at birth) which has become organized. (3) Retrolental fibroplasia occurring bilaterally in a premature infant. (4) Persistence of the vascular tunic of the lens (persistent hyperplastic primary vitreous, occurring in a full-term infant) unilaterally in a slightly microphthalmic eye. (5) Encephalo-ophthalmic dysplasia, affecting full-term infants bilaterally. (6) Retinal septum (falciform folds). (7) Congenital detachment of the retinal (rare); also retinoschisis. (8) Coats' syndrome, occurring unilaterally in males. (9) Angiomatosis of the retina (of von Hippel-Lindau). The pseudogliomas included in this study and to be reviewed later were selected because they were available in significant numbers. The author was indeed fortunate in obtaining sufficient numbers of specimens containing specific lesions traditionally and currently included in the differential diagnosis of retinoblastoma: retrolental fibroplasia, exudative retinitis, retinal dysplasia, nematode endophthalmitis, persistent hyperplastic primary vitreous, and angiomatosis retinae. CURRENT BACKGROUND

In 1967, Richard Schulze was the first to call attention to an association between rubeosis iridis and retinoblastoma.4 He made this observation after reviewing all enucleation specimens (870 eyes) received during a year period (1965) at the London Institute of Ophthalmology. In 105 eyes (12%), neovascularization of the iris was evident. In only three of these was there a retinoblastoma. Schulze also noted that in these eyes extensive separation of the retina was evident. In 1968, Walton and Grant found that rubeosis was most commonly associated with retinoblastoma in children five years of age or younger.30 The observation was made in the course of a histopathologic review of enucleated eyes in which there had been neither trauma nor irradiation. Thirty-nine (44%) of the 88 specimens containing retinoblastoma exhibited neovascularization of the iris. Some comparison with their data will follow later in the paper. A study at the University of Toronto (1971) revealed an

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overall incidence of rubeosis iridis in enucleated eyes similar to that observed by Schulze.31 Rubeosis iridis was present in 70 (15%) of 460 eyes, and in 48 percent of those containing retinoblastoma there was neovascularization on the iris. Both Schulze and the Toronto group, in their respective studies, carried out further studies of the pathogenesis in rubeosis iridis. Schulze developed an experimental method for producing angiogenesis on the iris surface in rabbits. He concluded that rubeosis was a response to proximal or remote ocular anoxia. The Toronto group, also working with rabbits subjected to variable degrees of anterior segment ischemia and subsequent necrosis, likewise noted the development of rubeosis iridis.32 Their findings, however, did not add substantially to the current understanding of the pathogenesis. The three main theories are (1) that hypoxic retina produces a metabolite (either vasoproliferative or vasoformative) capable of producing iris as well as retinal neovascularization, (2) that toxic products of tissue breakdown (disintegrating hemorrhage) diffuse forward and induce vascular proliferation and, (3) that a specific angiogenic factor is released from anoxic tissue. These are the same three etiologic possibilities postulated and developed at length by Ashton.33 The conclusion of the Toronto group was that rubeosis iridis had its origin in one or a combination of the three. In discussing pathogenesis, Schulze made one observation that seemed at variance with the clinical observations of others. He noted that in some eyes with rubeosis, such as eyes with iris melanoma, there had been no apparent anoxia in the posterior segment. The Toronto group remarked that all of their eyes exhibited a pathologic process in the posterior segment, thus enhancing the likelihood of posterior segment anoxia. Since no one has yet been able to produce rubeosis experimentally by creating anoxia in the posterior segment, the pathogenesis of rubeosis remains unclear. PART I: ANGIOGENIC ASPECTS

Part I of this study consists essentially of an attempt to explore and consider the physical properties of retinoblastoma that might contribute to neovascularization of the iris. Factors in tumor development, growth, and degeneration that might influence angiogenesis will be discussed.

Rubeosis Iridis

591

MATERIALS AND METHOD: PART I

Two factors considered were growth pattern and tumor size. In retinoblastoma, patterns are classicially both endophytic, with extension into the vitreous, either directly or by seeding; and exophytic, where extension is into the subretinal space, again directly or by seeding. Since the tumor is noted for its multicentricity, observations on this were recorded. Unfortunately, overall gross measurements of the eye and of the mass were not available in all specimens; therefore, in this study, size was recorded on the basis of two dimensions only and was always made in relation to overall eye size. Location of the lesion in relation to the equator of the eye was also recorded. Cytologic evaluation consisted of estimations of viability on microscopic examination, the degree of differentiation, mitotic activity, and the presence or absence of rosettes. The degree of necrosis, the extent of hemorrhage, and the amount of calcification were also tabulated. In addition, the existence of uveitis was noted, as were the direction, degree, and avenue of tumor extension. Three other factors considered important were iris atrophy, peripheral anterior synechias, and retinal detachment. A sequential group of 40 eyes with retinoblastoma was selected. Eight of the 40 were not acceptable because the anterior segment was lacking, the eye was severely altered by massive involvement, or necrosis was generalized. Among the remaining 32 eyes, 19 (59%) exhibited rubeosis iridis. RESULTS: PART I

Tables I, II, and III present the histologic features of eyes with retinoblastoma with and without rubeosis. A retinoblastomacontaining eye in which iris vascularization was noted, clinically or microscopically, would most likely present with a large posterior mass and show vitreous and subretinal seeding (Fig. 1). In addition, the tumor would be likely to exhibit necrosis and would have contributed to retinal detachment. Such an eye containing neovascularization would be three to four times more likely to show hemorrhage in or around the tumor and inflammation within the uveal tract than a tumor-containing eye in which rubeosis was not manifest. Approximately 50%o of globes containing retinoblastoma in which iris vascularization was lacking contained a medium-sized exophytic growth anterior to the equator (Fig. 2). Uveitis and hemorrhage were uncommon.

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p

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FIGURE 1~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~.........

A.. larg1poserio expyIc reiobatoaehiiin.eroi.hmrhaereia detachmentand subretinal seeding would very likely have rubeosis iridis~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~....

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45

Rubeosis Iridis

593

FIGURE 2

Retinoblastoma located anterior to the equator and of medium size was a frequent finding in eyes not involved with rubeosis iridis. The endophytic growth pattern shown here was not the common finding (hematoxylin and eosin, x4.5).

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DISCUSSION: PART I

In an earlier section we discussed tumor necrosis, posterior anoxia, and retinal aneurysmal dilatations. If the dilatations are acceptable as vasoproliferative manifestations of anoxia, it is an easy assumption that the same or a similar factor could produce vasoproliferative effects on the iris. Recent developments in the treatment of diabetic retinopathy by photocoagulation give strong support to this theory: Vasoproliferative factors derived from hypoxic retina cause new vessel formation on the iris. Similarly, in patients with central retinal vein occlusion, the development of rubeosis iridis and subsequent neovascular glaucoma could be avoided by utilizing panretinal photocoagulation.34 It has been found that such photocoagulation may have therapeutic value in eyes with established rubeosis iridis.5 Vessels in eyes so treated were noted to be smaller than normal or to disappear. Reviewing the data in Table I, it would seem reasonable to anticipate that necrosis would be an outstanding concomitant in retinoblastomatous eye with rubeosis. In 90%o of eyes with tumor and rubeosis, necrosis was manifest; among the eyes with tumor but no rubeosis, 100% also had conspicuous areas of necrosis. This disparity may be explained by comparing the relative sizes of the tumor masses that exhibited necrosis. In 78% of eyes with rubeosis, the tumor was large to massive; only 46% of the eyes without TABLE I. RESULTS - PART I RETINOBLASTOMA MORPHOLOGY (ALL VALUES ARE PERCENTAGES)

Growth Pattern: Multicentricity: Tumor Size:

Endophytic Exophytic Undeterminable Small Medium

Large Massive Location: Anterior to Equator Half Anterior/Half Posterior Posterior to Equator Cytology: Viable Undifferentiated & Differentiated Cells Less Viable Appearing Cells Least Viable Appearing (Faded) Cells True Rosette Formation:

(Flexner-Wintersteiner) (Obviously Dart of overall cvtoloyv)

Rubeosis Present 32% 42 26 37

Rubeosis Absent 15% 54 31 39

21 68 11 10 15 75

54 8 38 23 30 47

32 42

38 54

26 47

8 62

595

Rubeosis Iridis

rubeosis had tumors this large. Tumor growth is enhanced by a posterior location, since the blood supply here is more abundant than it is anterior to the equator.36 The superior vascular network posteriorly would tend to promote a more rapid neoplastic growth, producing a large mass which eventually and consequentially becomes more prone to degeneration and the production of factors promoting angiogenesis. In addition to these findings, cytologic study also suggests that hypoxic factors play more of a role in tumor-containing eyes with rubeosis. Considering the cells unaffected by necrosis, 25% of eyes with rubeosis exhibited a significant degree of degeneration. In eyes without rubeosis, cellular degeneration was far less frequent. In general, therefore, eyes without rubeosis iridis showed much less evidence of hypoxia or anoxia. The spontaneous development of neoplasm in more than one region in the same retina (multicentricity) occurred with about equal frequency whether or not rubeosis was present. It is well established that lesions containing significant numbers of Flexner-Wintersteiner rosettes imply a much better prognosis than those in which these structures are lacking. Cellular differentiation is also a feature of tumors that grow more slowly and are less aggressive. In eyes without rubeosis, the tumor tended to be of the more differentiated form. Table II shows little relationship between invasive qualities and the phenomenon of neovascularization except when deposits of neoplasm appear anteriorly, a feature suggesting more aggressive behavior. These tumors are large, and many are endophytic and expand forward into the vitreous. In eyes lacking rubeosis, there were 50% fewer with endophytic growth or vitreous seeding. Just TABLE II. RESULTS

-

PART I

RETINOBLASTOMA EXTENSION

(ALL VALUES ARE PERCENTAGES)

Anteriorly:

Seeding: Invasion:

Posteriorly: Extrascleral:

Vitreous Aqueous Iris

Ciliary Body

Subretinal Space Choroidal Invasion

Optic Nerve Invasion

Rubeosis Present

Rubeosis Absent

90% 32 21 26

54% 24 24 24

84 47 47 11

62 38 38 8

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as tumor progresses forward throughout the ocular elements, the theorized hypoxic factor could diffuse forward to stimulate angiogenesis. Table III shows that a significantly higher incidence of hemorrhage was encountered in eyes showing rubeosis than in eyes without rubeosis. This would seem to support the second theoretical explanation of rubeosis, that is, that toxic products derived from tissue breakdown diffuse forward and provoke neovascularization. Disintegrating blood products have often been considered a source of such substances. The theory, while attractive, is supported by no other evidence. Ocular disease associated with extensive necrosis is frequently accompanied by rubeosis. Therefore, it was not surprising to note that there was a significant difference in the number of eyes with rubeosis exhibiting uveitis compared to the few instances of uveitis in eyes without neovascularization. The data in Tables I, II, and III correlate well with the observations of Walton and Grant,30 whose figures are shown in parentheses in the text that follows: In both our study and that one, the percentages of eyes with retinoblastoma and rubeosis iridis showing tumor invasion of the optic nerve (45%), tumor invasion of the choroid (45%), and tumor seeding anteriorly (38%) were almost identical. This was the case also with respect to the incidence of necrosis (98%), calcification (75%) and rosette formation (60%). The only noteworthy difference occurred in relation to anterior synechial formation. Walton and Grant found an incidence of anterior synechias of 77% versus only a 47% incidence in our study. No explanation is offered for this discrepancy, although further data presented later in this paper tend to show that the higher incidence may be the true one. Furthermore, it was observed that approximately one-third of cases without rubeosis exhibited peripheral TABLE III. RESULTS - PART I RETINOBLASTOMA MISCELLANEOUS (ALL VALUES ARE PERCENTAGES)

Rubeosis Present

Necrosis:

Hemorrhage: Calcification: Uveitis: Iris Atrophy: Peripheral Anterior Synechias: Retinal Detachment:

90%o 42 63 37 66 47 84

Rubeosis Absent 100% 16 54 8 46 38 92

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anterior synechias. These eyes had marked anterior displacement of the lens-iris diaphragm or forward tumor extension altering the anterior chamber. Retinoblastoma, the most common ocular tumor in childhood, has a counterpart with respect to frequency in adult life: malignant melanoma. The relationships between ocular malnoma and vascularization of the iris have been recently explored by Cappin.37 Several of Cappin's conclusions are in accord with ours. The occurrence of rubeosis with melanoma correlated positively with tumor bulk, necrosis, uveitis, and retinal detachment. On the other hand, only 15% of eyes with melanoma exhibited rubeosis versus 44-55% in retinoblastoma. Significantly, too, in malignant melanoma, rubeosis was always associated with atrophy of the iris, a phenomenon said to be so in retinoblastoma by others but not substantiated in this study. Rubeosis has been found more commonly in eyes with melanoma involving the choroid anterior to the equator. Although melanoma characteristically arises in the uveal tract and retinoblastoma in the retina, the neovascularization is more common with posterior retinoblastoma. Finally, only in diffuse melanoma are peripheral anterior synechias observed in association with rubeosis whereas in cases of retinoblastoma over one-third of those free of rubeosis had synechias. The observation that the two most common primary intraocular tumors have a relationship with rubeosis raises another question, that is, whether a factor involved in malignant transformation or one necessary to sustain neoplastic growth might promote iris neovascularization. In 1971, Folkman showed that experimentally implanted human and animal solid tumors elaborated a substance that was mitogenic to capillary endothelial cells.38 The factor, composed of RNA and protein, causes the local capillary proliferation necessary to sustain growth.39 He called this substance tumor angiogenesis factor (TAF). In later studies following anterior chamber implantation, Folkman observed iris neovascularization at a distance from the implant.40 Later, he observed that central and peripheral corneal implantations were followed some weeks later by rubeosis iridis. The corneas, with poor vascular and lymphatic connections anatomically, showed no tumor or accidental performation of Descemet's membrane. He concluded from all his observations that a diffusible mediator of tumor-induced angiogenesis can produce a neovascular response at a distance from the tumor.

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He also noted that this could occur without significant tumor or host tissue necrosis. This most important clinical implication for ophthalmology would be the detection of TAF in the aqueous of an eye with rubeosis iridis where posterior tumor growth was suspected. The first part of the histopathologic study has shown an association and increased incidence of rubeosis iridis in eyes with retinoblastoma. The size and location of the tumor and the degree of necrosis foster the angiogenesis. Consideration of these observations contributes to a more clinically significant understanding of the development of retinoblastoma and the effect the presence of rubeosis has on prognosis and management. PART II: DIAGNOSTIC DIVIDEND

In Part II of this study, the determination of the importance the recognition of rubeosis iridis might have on the differential diagnosis of leukokoria is undertaken. Rubeosis is not a sequela of enucleation and must therefore be present prior to surgery and, if not noted before surgery, must have been either overlooked or ignored. This does not necessarily mean, however, that if rubeosis were to be assiduously searched for in any child with an obscure posterior lesion, it would help to establish the diagnosis. The question thus raised is whether rubeosis is of clinical value in distinguishing retinoblastoma from other intraocular diagnostic problems. MATERIALS AND METHOD: PART II

For this study, histologic sections from 528 eyes were examined; 241 were consecutive eyes with retinoblastoma and 287 were from randomly selected pseudoglioma. Among the retinoblastoma series, 49 were excluded for various inadequacies; in the pseudoglioma group, seven were eliminated. The pseudoglioma group comprised 76 examples of retrolental fibroplasia, 74 of exudative retinitis (Coats' disease), 48 of retinal dysplasia, 32 of nematode endophthalmitis, 28 of persi§tent hyperplastic primary vitreous, and 22 of angiomatosis retinae. The compiled data consisted of the percentage showing rubeosis, the microscopic pattern of the anterior chamber, the number of cases of rubeosis recognized clinically, the thickness of the fibrovascular membranes, and the diameters of newly formed vessels. Cross-sectional measurements and membrane thicknesses were determined using a calibrated micrometer reticle.4' This method, one

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of several means of measuring objects under a microscope, is both accurate and convenient and consists of a glass disk etched with a graduated scale. This disk is positioned within the ocular so that ruled lines appear in the microscopic field. Size is then determined by divisions of the etched scale. The value of each division varies with different magnifications or objectives and must be redetermined in each instance.42 A magnification of x 35 was purposely selected for the illustrations in this section since similar objectives are readily available on modern ophthalmic diagnostic instruments such as the biomicroscope. Detection of new blood vessels is much less difficult clinically since the lumens are blood-filled, the vessels are viewed over a greater length, and a greater number of vessels are visible in a single field of view. RESULTS: PART II

Table IV summarizes the results of the study. Rubeosis was recorded at clinical examination in 12 of 186 eyes, an incidence of only 6.4%. Five occurred among 100 eyes with retinoblastoma in which rubeosis existed and seven among 86 instances of pseudoglioma with rubeosis. The average thickness of the fibrovascular membrane was 12.3 microns; the range was 8.4-15.6 microns. The average internal diameter of newly formed vessels was 6.7 microns. Allowing approximately 1 micron (15%) for technical shrinkage of tissue, the actual value is probably 7.7 microns, quite close to the 8 micron figure usually given for a capillary.43 The range among new vessels was 5-9.4 microns. DISCUSSION: PART II

The high incidence of rubeosis iridis accompanying retinoblastoma was anticipated from published reports and from the data in the first part of this study. In the many cases reviewed, there were no unique histologic findings (Fig. 3). Although appearing in over 50%o of eyes, rubeosis was clinically noted in only 5%. All eyes in which rubeosis was recorded clinically when scrutinized microscopically were considered to be poor microscopic examples as compared to the typical or more florid examples that had been missed clinically. That exudative retinitis and angiomatosis retinae would have an equally high rate of occurrence was not anticipated (Fig. 4). In eyes with these two conditions, the disease had been or actually was an

Spaulding

600

TABLE IV. RESULTS

-

PART II

Rubeosis Iridis Disease

No Open

Closed

26

74

77

23

26

74

43

81

19

91

50

9 73 22

78

31

66

38

62

70

30

25

75

54

33

100

-

89

11

52 192

Exudative Retinitis

74

Angiomatosis Retinae

22

Retrolental

76

Retinal

48

Persistent Hyperplastic Primary Vitreous

28

Nematode

32

48 57

50 24

Fibroplasia

76*

17

Dysplasia

83 14

86** 9

Endophthalmitis * 2 infantile angles

Angle

No. Eyes % Present % Abent % Absent

Retinoblastoma

Anterior Chamber

91

27

** 3 infantile angles

active vasculopathy associated with exudation and retinal detachment. In exudative retinitis, telangiectatic retinal vessels leak fluid into and beneath the retina, resulting in an exudate-induced bullous detachment. In angiomatosis retinae, the growth and development of the hamartomatous hemangioblastoma causes hemorrhage and exudate followed by scarring and retinal detachment. In these two entities, clinical records showed a detection rate of l1o0. As with retinoblastoma, the cases identified microscopically as less florid were the ones noted clinically. Interesting observations and possibly distinguishing features made in half of the eyes with exudative retinitis were marked ectropion uvea, pronounced pupillary tag formation or complete pupillary membrane, and a membrane more fibrous than vascular. Clinically, the first two should be easily recognized but the fibrous membrane might require histologic study (Fig. 5).

*601

.

b:

.

I~~

.:. :.A

_~~~~~~~~~~~~~~~~~~~~~~~~~~~

FIGURE 3

Composite microphotographs showing rubeosis iridis in retinoblastoma. A thin but complete fibrovascular membrane (A), a membrane of moderate thickness (B), and a thick membrane (c) are shown. Corresponding areas are indicated by arrows (hematoxylin and eosin, x 100, top and x35, bottom).

.

:.

602

FIGURE 4

Composite microphotographs showing rubeosis iridis associated with exudative retinitis (A), angiomatosis retinae (B), and retrolental fibroplasia (c). Communications between iris stromal vessels and newly formed vessels are encircled in A and C. Corresponding areas are indicated by arrows (hematoxylin and eosin, x 100, top and x35, bottom).

~ ~ ~ ~ ~. . Rubeosis Iridis

603

. . . . .0 _

~~~~~~~~~~~~~~~~~~~~~.::.

:.

FIGURE 5

Ins Coats' disease, in addition to rubeosis iridis, pupillary membranes (A), fibrous membranes (B), and marked ectropion uvea (c) were frequently observed. Corresponding areas in composite A are indicated by arrows. The thickness of the fibrous membrane in B is also indicated by arrows (A: hematoxylin and eosin, x 100, top and x35, bottom. B and C: hematoxylin and eosin, x35, both).

Rubeosis was a feature in only 24% of the eyes showing retrolental fibroplasia, the essence of which is neovascularization of the retina and vitreous (Fig. 4C). In only one of the 18 eyes with rubeosis had it been recognized clinically. The salient features of the pathogenesis of retrolental fibroplasia are increased oxygen tension and prematurity of the retinal vessels. The lower incidence of occurrence may be explained by the embryonic differences in age of development of the vascular systems. By the seventh or eighth month of development, the vascular system of the iris shows a considerable degree of atrophy of vascular arcades established

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early in development at about the eighth to ninth weeks. In contrast, the retinal vascular tree at the seventh to eighth months is still developing and extends to the ora serrata nasally but only to the equator temporally. Also peculiar to retrolental fibroplasia was the higher incidence of closed angles when rubeosis iridis was absent. This discrepancy results from anterior displacement of the iris-lens diaphragm and the subsequent narrowing or closure of the anterior chamber angle caused by the contraction of detached gliotic retina in the retrolental area. The incidence of rubeosis was low in retinal dysplasia and persistent hyperplastic primary vitreous (Fig. 6A and B). The examples of retinal dysplasia were simply isolated ocular anomalies. In the histories of two patients with persistant hyperplastic primary vitreous, "abnormal vessels" had been noted on the iris. Although microscopic examination failed to demonstrate rubeosis, the possibility exists that the vessels noted may have been remnants of the anterior vascular tunic of the lens. The lowest incidence of the pseudoglioma group occurred in eyes with nematode endophthalmities (Fig. 6C). All of these eyes exhibited marked focal inflammatory reactions and large retinal detachments. A diffuse uveitis as noted in other eyes with rubeosis was lacking. Among all the eyes in the second part of this study, rubeosis iridis was present in one-third, and two-thirds of this latter group showed closure of the anterior chamber angle. In the absence of rubeosis, two-thirds of the eyes had wide-open angles. Thus, a total of 228 eyes examined microscopically had closed anterior chamber angles. In view of these numbers, it is quite surprising that there were so few indications, by history or examination, that glaucoma was present. In only three children was gonioscopic examination a part of the patient's clinical record. Several interesting observations were made about the microscopic appearance of iris neovascularization. In eyes with rubeosis and angle closure, the vascular membrane always participated in the synechia formation, although a cause and effect relationship could not be established. No consistent relationship was observed between the nature of the disease and the site where newly formed vessels communicated with pre-existing iris channels. Junctions appeared in such areas as the angle recess, the middle of the iris, and the pupillary margin (Fig. 4A and C). The vascular source of

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FIGURE 6

Rubeosis iridis in retinal dysplasia (A), persistent hyperplastic primary vitreous (B), and nematode endophthalmitis (c). The membrane in retinal dysplasia (A) is located in mid iris, at the pupillary margin in PHPV (B), and close to the chamber angle in nematode endophthalmitis (c). Corresponding areas are indicated by arrows (hematoxylin and eosin, x 100, top and x35, bottom).

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the vessels, whether arterial or venous capillaries or both, could not be determined. The differentiation into arterial and venous capillary may no longer be correct scientifically since electron-microscopic studies have shown that the iris blood vessels present the structural characteristics of capillaries - that is, a vessel wall one endothelial cell thick - even though the lumens are often quite large, 1-10 red blood cells in diameter.44 Electron-microscopic studies of rubeosis iridis have shown a rich and active proliferation of endothelial cells producing thin-walled vessels on the iris surface.45 No consistent relationship was noted between the underlying disease process and the apparent origin of the membrane (Fig. 6). Some appeared to arise in the angle recess, the pupillary margin, or from a union of fibrovascular tufts all along the iris surface. We should explain again that there is only slight clinical documentation recording the detection of rubeosis. Only 6% of the records accompanying these ocular specimens contained any notation regarding neovascularization. No doubt it was observed more often but was probably considered insignificant and not recorded. In some eyes, neovascularization was overlooked since clinical interest was directed at the major disorder affecting the posterior portion of the eye. This also undoubtedly accounted for the failure to recognize the existence and abundance of glaucoma. Intraocular pressure readings were not part of the record, and gonioscopic examination was reported in only three of 228 eyes with closed chamber angles. SUMMARY

The high incidence of rubeosis iridis accompanying retinoblastoma has been reaffirmed. Factors common to ocular tumors in general and retinoblastoma, as well as reactions to retinoblastoma that have some contributory effect upon vascularization of the iris have been studied and compiled. No single causative factor emerged, although tumor necrosis obviously played an important role. To a lesser extent, the site, location, and intraocular extension bore some relationship to neovascularization. That iris neovascularization carries a more grave prognosis, until now only a clinical impression, was definitely confirmed. Clinicians, therefore, studying patients with retinoblastoma would be well advised to pay more attention to the iris and anterior segment

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since recognition of changes leads to more timely and knowledgeable management. It was hoped that increased recognition of rubeosis would differentiate between eyes with retinoblastoma and those with pseudoglioma; however, an equally high incidence of neovascularization accompanied certain pseudogliomas. In both studies, as is often the case, numerous interesting observations were made; several with clinical implications. Finally, a frequently associated glaucoma, suggested by the anterior segment histologic features, went unrecognized and unrecorded in these patients. ACKNOWLEDGMENTS

Indebtedness for material to the Armed Forces Institute of Pathology; for review assistance Sidney Seltzer, MD; for technical assistance Margaret Crush; for editorial assistance Edward A. Gall, MD and James Ranson, PhD.; for secretarial and reference assistance Carolyn Alfano and Wendy Stewart; and for encouragement Taylor Asbury, MD. REFERENCES

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13. Dunphy EB: The story of retinoblastoma. Trans Am Acad Ophthalmol Otolaryngol 68:249, 1964. 14. Howard MG, Ellsworth R: Differential diagnosis of retinoblastoma I. Am J Ophthalmol 60:618, 1965. 15. Howard MG, Ellsworth R: Differential diagnosis of retinoblastoma II. Am J Ophthalmol 60:610, 1965. 16. Ellsworth MR: The practical management of retinoblastoma. Trans Am Ophthalmol Soc 67:462, 1969. 17. Cogan DG: Neurology of the Visual System. Springfield, Illinois. Charles C Thomas. 1966, p 116. 18. Ramirez LC, de Buen S: Clinical and pathologic findings in 100 retinoblastoma patients. J Ped Ophthalmol 10:12, 1973. 19. Binder PS: Unusual manifestations of retinoblastoma.AmJ Ophthalmol 77:674, 1974. 20. Spaulding AG, Naumann G: Unsuspected retinoblastoma. Arch Ophthalmol 76:575, 1966. 21. Reese AB: Tumors of the Eye. Hagerstown, Maryland, Harper & Row, 1976, pp 101-103. 22. Wolter JR: The blood vessels of retinoblastoma. Arch Ophthalmol 66:545, 1961. 23. Reese AB: Tumors of the Eye. New York, Harper & Row, 1963, p 112. 24. Collins ET: Pseudoglioma. Royal London Ophthalmol Hosp Rep 13:361, 18901892. 25. Virchow R: Die Krankhaften Geschwulste. Vol. 2, Berlin, Hirschwald, 1864-65, p 151. 26. Sanders TE: Pseudoglioma. Trans Am Ophthalmol Soc 48:575, 1950. 27. Duke J: Pseudoglioma in children. South Med J 51:754, 1958. 28. Kogan L, Boniuk M: Causes for enucleation in childhood with special references to pseudoglioma and unsuspected retinoblastoma. Int Ophthalmol Clin 2:507, 1962. 29. Duke-Elder S (ed) Systems of Ophthalmology. Vol. X, Diseases of the Retina. Stewart Duke-Elder, John H Dobree. St Louis, CV Mosby Co, 1967, p 712. 30. Walton DS, Grant WM: Retinoblastoma and iris neovascularization. Am J Ophthalmol 65:598, 1968. 31. Anderson DM, Morin JD, Hunter WS: Rubeosis iridis. CanJ Ophthalmol 6:183, 1971. 32. Anderson DM, Morin JD: Experimental anterior segment necrosis and rubeosis iridis. Can J Ophthalmol 6:196, 1971. 33. Ashton N: Neovascularization in ocular disease. Trans Ophthalmol Soc U K 81:145, 1961. 34. Callahan MA, Hilton GF: Photocoagulation and rubeosis iridis. Am J Ophthalmol 78:873:1974. 35. Zweng HC, Fahrenbruch RC, Little HL: Argon laser photocoagulation in the treatment of retinal vein occlusions. Mod Prob Ophthalmol 12:261, 1974. 36. Hogan MJ, Alvarado JA, Weddell JE: Histology of the Human Eye. Philadelphia, WB Saunders. 1971, p 517. 37. Cappin JM: Malignant melanoma and rubeosis iridis. BrJ Ophthalmol 57:815, 1973. 38. Folkman J, Merler E, Abernathy C, Williams G: Isolation of tumor factor responsible for angiogenesis. J Exp Med 133:275, 1971. 39. Folkman J: Tumor angiogenesis: Therapeutic implications. N Eng J Med 285:1182, 1971. 40. Gimbrone M, Leapman S, Rotran R, Folkman J; Tumor angiogenesis: Iris neovascularization at a distance from experimental intraocular tumors. J Natl Cancer Inst 50:219, 1973.

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