CYSTIC R E T I N O B L A S T O M A JOSEPH GINSBERG, M.D., ABBOT G. SPAULDING, M.D., AND TAYLOR ASBURY, M.D.
Cincinnati, Ohio Little information is available regarding cyst formation in retinoblastoma. The fre quency, pathogenesis, and clinical signifi cance of this phenomenon are virtually un known. We, however, have had the oppor tunity to study a patient with a retinoblas toma, clinically simulating uveitis, in which a macro- and microcystic pattern was promi nent. The unusual findings in our patient prompted us to investigate cystic changes in other cases of retinoblastoma.
grayish-green, slightly hemorrhagic fluid. Particulate matter and sheets of tumor occupied the vitreous remnant and partially surrounded the lens and ciliary body (Fig. 2).
CASE REPORT
An ^-year-old black boy developed persistent redness and irritation of the left eye after a hot water burn. Reinjury with a baseball V/2 months later resulted in severe pain and decreased vision. Two months after the initial trauma, examination revealed a fluffy, grayish-white exudate partially filling the anterior chamber and accompanied by rubeosis iridis. The fundus was obscured. Visual acuity was limited to inaccurate light projection. Ocular pressure was 64 mm Hg by Schiotz tonomFig. 1 (Ginsberg, Spaulding, and Asbury). etry. The diagnoses were traumatic iritis, hypopyon, Pseudohypopyon due to retinoblastoma in anterior and secondary glaucoma. The patient failed to improve with topical and segment. Suture (arrow) indicates site of diagnostic oral corticosteroids and cycloplegics. Cultures of iridectomy and aqueous aspiration. the iris and aqueous were negative. The cells in the aspirate were thought to be leukocytes. The anterior segment remained essentially un changed (Fig. 1), but a whitish mass became visible in the hazy vitreous body. Roentgenograms sug gested calcium deposits in the blind left eye. Ap proximately y/2 months after the initial trauma, enucleation was performed because of the possibility of retinoblastoma. The globe measured 25 mm in each of its three principal meridians; the optic nerve stump meas ured 4 mm. Flocculent, pinkish-gray material filled about one third of the anterior chamber. A hori zontal section revealed the retina to be totally de tached and diffusely thickened by a grayish-white neoplasm. The lesion was more prominent pos teriorly where it contained coalescent cysts (Fig. 2), the largest (4 to 5 mm) projecting toward the subretinal space which contained an abundance of From the University of Cincinnati College of Medicine, Cincinnati, Ohio. This study was sup ported in part by the Ohio Lions Eye Research Foundation. Fig. 2 (Ginsberg, Spaulding, and Asbury). Grossly Reprint requests to Joseph Ginsberg, M.D., Medi visible cysts (arrows) projecting toward the subcal Science Bldg., Department of Pathology, Cin retinal space. Retinoblastoma has spread to vitreous cinnati, OH 45267. and anterior segment. 930
VOL. 80, NO. 5
CYSTIC RETINOBLASTOMA
The eye was fixed in 10% formalin, embedded in paraffin, and sectioned at approximately 8 n ; stains were hematoxylin and eosin, PAS, and Alcian blue. Approximately 85% of the retina was infiltrated by a neoplasm extending to the lamina cribrosa and to all neuronal layers, but more or less sparing the periphery, macular, and disk areas. Except for a few, scattered foci showing what appeared to be photoreceptor differentiation, the tumor comprised relatively uniform, diffusely distributed cells with hyperchromatic nuclei and scant cytoplasm. Mitoses were frequent. Because of the characteristic cytol ogy, a diagnosis of retinoblastoma seemed justified. The cysts, grossly apparent within the tumor, extended into the subretinal space (Fig. 3). They contained deeply eosinophilic precipitate similar to that noted in the subretinal area. Cyst walls were thin, in some areas only one or two cell layers thick. In addition to the larger cysts, there were many ovoid, round, or irregular microcysts, some con fluent, and others partially separated by septa; a sinusoidal pattern prevailed (Fig. 3). Occasional free elements in the lumen resembled photoreceptors (Fig. 4). The precipitate in microcysts was sparse and mainly in the form of fine or coarse strands (Fig. 3). Lining cells appeared identical to those elsewhere in the tumor. Their nuclei were often com pressed, staining darker than adjacent cells, and tended to have a circumferential orientation.
931
There was an unusually prominent vasoproliferative component, especially on the medial aspect. This was characterized either by solid clumps of eridothelium or more mature vessels with walls seven to eight layers thick, lntracystic proliferation of endothelium appeared in about 10% of the smaller cysts (Fig. 5). Partially necrotic clusters of neoplastic cells lay in the anterior chamber, and a few leukocytes (mainly lymphocytes) appeared in the iris stroma that was deeply invaded by tumor. A fibrovascular membrane on the anterior iris surface resulted in ectropion uveae and peripheral synechiae. Three years after enucleation there was no re currence of the retinoblastoma. DISCUSSION
A cystic appearance in retinoblastoma is rarely described, 1 " 3 although cysts have been noted microscopically in several cases. W e reviewed the 44 retinoblastoma cases (35 patients) in our files and noted microcysts in 20 ( 4 5 % ) . These numbered from one to 20 per scanning lens field and averaged about 200 u, in diameter, the largest being
Fig. 3 (Ginsberg, Spaulding, and Asbury). Extensive distribution of cysts in a retinoblastoma. Micro cysts afford a sinusoidal appearence. Much proteinaceous precipitate appears in a macrocyst (arrow) projecting into the subretinal space (hematoxylin and eosin, X21).
932
AMERICAN JOURNAL OF OPHTHALMOLOGY
NOVEMBER, 1975
Fig. 4 (Ginsberg, Spaulding, and Asbury). Microcyst-containing cells (arrows) suggesting photoreceptor differentiation .(hematoxylin and eosin, X4S0).
3 mm. In only two or three cases did it appear that they could have been detected macroscopically. Cystic retinoblastoma has been recorded clinically, but rarely.4"7 The larger cysts in our patient might have been observed clini cally if the media had been clear. In a re cent report 8 the "cystic" retinoblastoma visualized by B-scan ultrasonography ap peared to be recognized by ophthalmoscopy with greater difficulty than the solid variety. Current knowledge and our own cases sug gest that clinically or grossly visible cysts may be evident in about 5% of retinoblastomas. The pathogenesis of cystic retinoblastoma is unclear and there appears to be no corre lation with the growth pattern, degree of differentiation or size of the neoplasm, or with its location. Ts'o, Zimmerman, and Fine 3 noted microcystic spaces in foci ex hibiting photoreceptor differentiation. On the other hand, most of the cysts in our pa
tient. and in those we reviewed, occurred in relation to undifferentiated neoplasm. We found no structural variation suggesting different mechanisms for the development of large or small cysts; the latter may ex pand or coalesce to form macrocysts. The nature of the vascularization in the tumor may be related to cyst formation. The degree is probably less significant than ab normalities of blood vessel development or capillary obliteration. In our patient and in 13 (65;%) of those we examined, incom pletely canalized or obliterated capillaries were contiguous with or within the lumen of about 10% of microcysts. This suggests that ischemia may be a factor in cyst forma tion, the fluid-filled cysts possibly represent ing a result of liquefactive necrosis. Coagulative necrosis is more frequent in retino blastoma, and both are probably related to vascular insufficiency. Calcification may also be associated with cyst formation; calcium was deposited adjacent to or within the
VOL. 80, NO. 5
CYSTIC RETINOBLASTOMA
lumen of larger cysts in four (20%) of our cases. The fluid in the cysts often resembled that in the subretinal region. In a few instances it stained weakly with PAS and Alcian blue; in the cases studied by Ts'o, Zimmer
933
man, and Fine,3 the fluid did not react to these stains. In our patient, the cells lining cysts were similar to those comprising the remainder of the tumor. There is no evi dence that retinoblastoma cells have a secre tory capacity. In our patient, possibly the
Fig. S (Ginsberg, Spaulding, and Asbury). Top, Capillary buds contiguous with microcysts. Bottom, Capillary growing in lumen of microcyst. Note incomplete canali zation or obliterated appearance (hematoxylin and eosin, X270).
934
AMERICAN JOURNAL OF OPHTHALMOLOGY
paracentesis and the two episodes of trauma were partially responsible for the produc tion of fluid in the cysts. Some of it may have seeped in from the subretinal space. The prognostic significance of the cystic phenomenon in retinoblastoma is unknown. In a recent case of spontaneous regression of bilateral retinoblastoma,7 an intraretinal cyst was noted in one of the affected eyes. Cystic and vascular alterations, similar to those in our case, are common in extraocular neoplasms including those of the cen tral nervous system.9 The growth pattern in the retinoblastoma in our patient did not conform with the three ^classical varieties, that is, exophytic, endophytic, or the planum types (diffuse infiltrating retinoblastoma). Apart from its grossly visible cysts, however, the tumor was comparatively flat and diffuse in its dis tribution, _thjis_jugg^stin|[_a_yanant of the diffusely infiltrating type. This is the least common form and tends to simulate^uveitis, usually with "hypopyon" and secondary glaucoma. This occurs even when there is no recognizable thickening of the retina.10'11 Optic nerve involvement was lacking in our case; nerve involvement has been reported in only one case.12 Most cases of diffuse infiltrating- retinoblastoma have occurred in boys between the ages" of 6 and l i years.1" like our patient. Retinoblastomas in children older than 4 yeaTs""oid have iim^nai Tmn^fffit•^tirTn'•" Delay in diagnosis and enucleation in our patient was the result of the "atypical" clini cal manifestations and a misinterpretation of the cells in the aqueous aspirate. A care ful evaluation of particulate matter in the anterior chamber is essential whenever retinoblastoma is suspected, using the Papanicolaou stain or electron microscopy, before a negative report is rendered.14
NOVEMBER, 1975
SUMMARY
A grossly cystic retinoblastoma, pre sumably a form of the diffuse infiltrating type, mimicked uveitis in an 8Yi -year-old boy. A review of 44 cases indicated that grossly (clinically) detectable cysts are rare in this neoplasm, although microcysts are relatively common. Lesions of this nature, especially if pre senting with a history of trauma, as in our patient, may lead the ophthalmologist to diagnose uveitis. The diagnosis of retino blastoma may thus be unduly delayed. REFERENCES
1. Samuels, B., and Fuchs, A.: Clinical Pathology of the Eye. New York, Hoeber, 1952, pp. 396-397. 2. Sovik, W. E.: Bilateral retinoblastoma in six siblings. Am. J. Ophthalmol. 35:1611, 1952. 3. Ts'o, M. O. M., Zimmerman, L. E., and Fine, B. S.: The nature of retinoblastoma. 1. Photoreceptor differentiation, a clinical and histopathologic study. Am. J. Ophthalmol. 69:339, 1970. 4. Theobald, G., in discussion, Bedell, A. J.: The diagnosis of retinoblastoma. Trans. Am. Ophthal mol. Soc. 45:282, 1947. 5. Heath, P.: Clinical pathological conference. Am. J. Ophthalmol. 38:222,1954. 6. Francois, J., in discussion, Bpniuk, M.: Ocular and Adnexal Tumors. St. Louis, C. V. Mosby, 1964, p. 198. 7. Morris, W. E., and La Piana, F. G.: Spontane ous regression of bilateral multi focal retinoblastoma with preservation of normal visual acuity. Ann. Ophthalmol. 6:1192, 1974. 8. Sterns, G. K., Coleman, D. J., and Ellsworth, R. M.: The ultrasonographic characteristics of ret inoblastoma. Am. J. Ophthalmol. 78:606, 1974. 9. Ackerman, L. V., and Rosai, J.: Surgical Pa thology. St. Louis, C. V. Mosby, 1974, pp. 12441252. 10. Schofield, P. B.: Diffuse infiltrating retino blastoma. Br. J. Ophthalmol. 44:35, 1960. 11. Blodi, F. C.: Tumors. In Sorsby, A.: Modern Ophthalmology, 2nd ed. Philadelphia, J. B. Lippincott, 1972, vol. 3, p. 355. 12. Weizenblatt, S. W.: Differential diagnostic difficulties in atypical retinoblastoma. Arch. Oph thalmol. 58:699, 1957. 13. Greer, C. H.: Ocular Pathology, 2nd ed. Lon don, Blackwell, 1972, p. 179. 14. Binder, P. S.: Unusual manifestations of retinoblastoma. Am. J. Ophthalmol. 77:674, 1974.
Cincinnati, Ohio Little information is available regarding cyst formation in retinoblastoma. The fre quency, pathogenesis, and clinical signifi cance of this phenomenon are virtually un known. We, however, have had the oppor tunity to study a patient with a retinoblas toma, clinically simulating uveitis, in which a macro- and microcystic pattern was promi nent. The unusual findings in our patient prompted us to investigate cystic changes in other cases of retinoblastoma.
grayish-green, slightly hemorrhagic fluid. Particulate matter and sheets of tumor occupied the vitreous remnant and partially surrounded the lens and ciliary body (Fig. 2).
CASE REPORT
An ^-year-old black boy developed persistent redness and irritation of the left eye after a hot water burn. Reinjury with a baseball V/2 months later resulted in severe pain and decreased vision. Two months after the initial trauma, examination revealed a fluffy, grayish-white exudate partially filling the anterior chamber and accompanied by rubeosis iridis. The fundus was obscured. Visual acuity was limited to inaccurate light projection. Ocular pressure was 64 mm Hg by Schiotz tonomFig. 1 (Ginsberg, Spaulding, and Asbury). etry. The diagnoses were traumatic iritis, hypopyon, Pseudohypopyon due to retinoblastoma in anterior and secondary glaucoma. The patient failed to improve with topical and segment. Suture (arrow) indicates site of diagnostic oral corticosteroids and cycloplegics. Cultures of iridectomy and aqueous aspiration. the iris and aqueous were negative. The cells in the aspirate were thought to be leukocytes. The anterior segment remained essentially un changed (Fig. 1), but a whitish mass became visible in the hazy vitreous body. Roentgenograms sug gested calcium deposits in the blind left eye. Ap proximately y/2 months after the initial trauma, enucleation was performed because of the possibility of retinoblastoma. The globe measured 25 mm in each of its three principal meridians; the optic nerve stump meas ured 4 mm. Flocculent, pinkish-gray material filled about one third of the anterior chamber. A hori zontal section revealed the retina to be totally de tached and diffusely thickened by a grayish-white neoplasm. The lesion was more prominent pos teriorly where it contained coalescent cysts (Fig. 2), the largest (4 to 5 mm) projecting toward the subretinal space which contained an abundance of From the University of Cincinnati College of Medicine, Cincinnati, Ohio. This study was sup ported in part by the Ohio Lions Eye Research Foundation. Fig. 2 (Ginsberg, Spaulding, and Asbury). Grossly Reprint requests to Joseph Ginsberg, M.D., Medi visible cysts (arrows) projecting toward the subcal Science Bldg., Department of Pathology, Cin retinal space. Retinoblastoma has spread to vitreous cinnati, OH 45267. and anterior segment. 930
VOL. 80, NO. 5
CYSTIC RETINOBLASTOMA
The eye was fixed in 10% formalin, embedded in paraffin, and sectioned at approximately 8 n ; stains were hematoxylin and eosin, PAS, and Alcian blue. Approximately 85% of the retina was infiltrated by a neoplasm extending to the lamina cribrosa and to all neuronal layers, but more or less sparing the periphery, macular, and disk areas. Except for a few, scattered foci showing what appeared to be photoreceptor differentiation, the tumor comprised relatively uniform, diffusely distributed cells with hyperchromatic nuclei and scant cytoplasm. Mitoses were frequent. Because of the characteristic cytol ogy, a diagnosis of retinoblastoma seemed justified. The cysts, grossly apparent within the tumor, extended into the subretinal space (Fig. 3). They contained deeply eosinophilic precipitate similar to that noted in the subretinal area. Cyst walls were thin, in some areas only one or two cell layers thick. In addition to the larger cysts, there were many ovoid, round, or irregular microcysts, some con fluent, and others partially separated by septa; a sinusoidal pattern prevailed (Fig. 3). Occasional free elements in the lumen resembled photoreceptors (Fig. 4). The precipitate in microcysts was sparse and mainly in the form of fine or coarse strands (Fig. 3). Lining cells appeared identical to those elsewhere in the tumor. Their nuclei were often com pressed, staining darker than adjacent cells, and tended to have a circumferential orientation.
931
There was an unusually prominent vasoproliferative component, especially on the medial aspect. This was characterized either by solid clumps of eridothelium or more mature vessels with walls seven to eight layers thick, lntracystic proliferation of endothelium appeared in about 10% of the smaller cysts (Fig. 5). Partially necrotic clusters of neoplastic cells lay in the anterior chamber, and a few leukocytes (mainly lymphocytes) appeared in the iris stroma that was deeply invaded by tumor. A fibrovascular membrane on the anterior iris surface resulted in ectropion uveae and peripheral synechiae. Three years after enucleation there was no re currence of the retinoblastoma. DISCUSSION
A cystic appearance in retinoblastoma is rarely described, 1 " 3 although cysts have been noted microscopically in several cases. W e reviewed the 44 retinoblastoma cases (35 patients) in our files and noted microcysts in 20 ( 4 5 % ) . These numbered from one to 20 per scanning lens field and averaged about 200 u, in diameter, the largest being
Fig. 3 (Ginsberg, Spaulding, and Asbury). Extensive distribution of cysts in a retinoblastoma. Micro cysts afford a sinusoidal appearence. Much proteinaceous precipitate appears in a macrocyst (arrow) projecting into the subretinal space (hematoxylin and eosin, X21).
932
AMERICAN JOURNAL OF OPHTHALMOLOGY
NOVEMBER, 1975
Fig. 4 (Ginsberg, Spaulding, and Asbury). Microcyst-containing cells (arrows) suggesting photoreceptor differentiation .(hematoxylin and eosin, X4S0).
3 mm. In only two or three cases did it appear that they could have been detected macroscopically. Cystic retinoblastoma has been recorded clinically, but rarely.4"7 The larger cysts in our patient might have been observed clini cally if the media had been clear. In a re cent report 8 the "cystic" retinoblastoma visualized by B-scan ultrasonography ap peared to be recognized by ophthalmoscopy with greater difficulty than the solid variety. Current knowledge and our own cases sug gest that clinically or grossly visible cysts may be evident in about 5% of retinoblastomas. The pathogenesis of cystic retinoblastoma is unclear and there appears to be no corre lation with the growth pattern, degree of differentiation or size of the neoplasm, or with its location. Ts'o, Zimmerman, and Fine 3 noted microcystic spaces in foci ex hibiting photoreceptor differentiation. On the other hand, most of the cysts in our pa
tient. and in those we reviewed, occurred in relation to undifferentiated neoplasm. We found no structural variation suggesting different mechanisms for the development of large or small cysts; the latter may ex pand or coalesce to form macrocysts. The nature of the vascularization in the tumor may be related to cyst formation. The degree is probably less significant than ab normalities of blood vessel development or capillary obliteration. In our patient and in 13 (65;%) of those we examined, incom pletely canalized or obliterated capillaries were contiguous with or within the lumen of about 10% of microcysts. This suggests that ischemia may be a factor in cyst forma tion, the fluid-filled cysts possibly represent ing a result of liquefactive necrosis. Coagulative necrosis is more frequent in retino blastoma, and both are probably related to vascular insufficiency. Calcification may also be associated with cyst formation; calcium was deposited adjacent to or within the
VOL. 80, NO. 5
CYSTIC RETINOBLASTOMA
lumen of larger cysts in four (20%) of our cases. The fluid in the cysts often resembled that in the subretinal region. In a few instances it stained weakly with PAS and Alcian blue; in the cases studied by Ts'o, Zimmer
933
man, and Fine,3 the fluid did not react to these stains. In our patient, the cells lining cysts were similar to those comprising the remainder of the tumor. There is no evi dence that retinoblastoma cells have a secre tory capacity. In our patient, possibly the
Fig. S (Ginsberg, Spaulding, and Asbury). Top, Capillary buds contiguous with microcysts. Bottom, Capillary growing in lumen of microcyst. Note incomplete canali zation or obliterated appearance (hematoxylin and eosin, X270).
934
AMERICAN JOURNAL OF OPHTHALMOLOGY
paracentesis and the two episodes of trauma were partially responsible for the produc tion of fluid in the cysts. Some of it may have seeped in from the subretinal space. The prognostic significance of the cystic phenomenon in retinoblastoma is unknown. In a recent case of spontaneous regression of bilateral retinoblastoma,7 an intraretinal cyst was noted in one of the affected eyes. Cystic and vascular alterations, similar to those in our case, are common in extraocular neoplasms including those of the cen tral nervous system.9 The growth pattern in the retinoblastoma in our patient did not conform with the three ^classical varieties, that is, exophytic, endophytic, or the planum types (diffuse infiltrating retinoblastoma). Apart from its grossly visible cysts, however, the tumor was comparatively flat and diffuse in its dis tribution, _thjis_jugg^stin|[_a_yanant of the diffusely infiltrating type. This is the least common form and tends to simulate^uveitis, usually with "hypopyon" and secondary glaucoma. This occurs even when there is no recognizable thickening of the retina.10'11 Optic nerve involvement was lacking in our case; nerve involvement has been reported in only one case.12 Most cases of diffuse infiltrating- retinoblastoma have occurred in boys between the ages" of 6 and l i years.1" like our patient. Retinoblastomas in children older than 4 yeaTs""oid have iim^nai Tmn^fffit•^tirTn'•" Delay in diagnosis and enucleation in our patient was the result of the "atypical" clini cal manifestations and a misinterpretation of the cells in the aqueous aspirate. A care ful evaluation of particulate matter in the anterior chamber is essential whenever retinoblastoma is suspected, using the Papanicolaou stain or electron microscopy, before a negative report is rendered.14
NOVEMBER, 1975
SUMMARY
A grossly cystic retinoblastoma, pre sumably a form of the diffuse infiltrating type, mimicked uveitis in an 8Yi -year-old boy. A review of 44 cases indicated that grossly (clinically) detectable cysts are rare in this neoplasm, although microcysts are relatively common. Lesions of this nature, especially if pre senting with a history of trauma, as in our patient, may lead the ophthalmologist to diagnose uveitis. The diagnosis of retino blastoma may thus be unduly delayed. REFERENCES
1. Samuels, B., and Fuchs, A.: Clinical Pathology of the Eye. New York, Hoeber, 1952, pp. 396-397. 2. Sovik, W. E.: Bilateral retinoblastoma in six siblings. Am. J. Ophthalmol. 35:1611, 1952. 3. Ts'o, M. O. M., Zimmerman, L. E., and Fine, B. S.: The nature of retinoblastoma. 1. Photoreceptor differentiation, a clinical and histopathologic study. Am. J. Ophthalmol. 69:339, 1970. 4. Theobald, G., in discussion, Bedell, A. J.: The diagnosis of retinoblastoma. Trans. Am. Ophthal mol. Soc. 45:282, 1947. 5. Heath, P.: Clinical pathological conference. Am. J. Ophthalmol. 38:222,1954. 6. Francois, J., in discussion, Bpniuk, M.: Ocular and Adnexal Tumors. St. Louis, C. V. Mosby, 1964, p. 198. 7. Morris, W. E., and La Piana, F. G.: Spontane ous regression of bilateral multi focal retinoblastoma with preservation of normal visual acuity. Ann. Ophthalmol. 6:1192, 1974. 8. Sterns, G. K., Coleman, D. J., and Ellsworth, R. M.: The ultrasonographic characteristics of ret inoblastoma. Am. J. Ophthalmol. 78:606, 1974. 9. Ackerman, L. V., and Rosai, J.: Surgical Pa thology. St. Louis, C. V. Mosby, 1974, pp. 12441252. 10. Schofield, P. B.: Diffuse infiltrating retino blastoma. Br. J. Ophthalmol. 44:35, 1960. 11. Blodi, F. C.: Tumors. In Sorsby, A.: Modern Ophthalmology, 2nd ed. Philadelphia, J. B. Lippincott, 1972, vol. 3, p. 355. 12. Weizenblatt, S. W.: Differential diagnostic difficulties in atypical retinoblastoma. Arch. Oph thalmol. 58:699, 1957. 13. Greer, C. H.: Ocular Pathology, 2nd ed. Lon don, Blackwell, 1972, p. 179. 14. Binder, P. S.: Unusual manifestations of retinoblastoma. Am. J. Ophthalmol. 77:674, 1974.
