A C T A O P H T H A L M O L O G I C A V O L . 5 0 1 9 7 2

From Ulleva"1 Hospital, Departments of Ophthalmology and Pathology, (Heads: Professor dr. med. / a n Ytteborg and

Professor dr. med. Kristen Arnesen) University of Oslo, Norway

LATE RECURRENCE OF RETINOBLASTOMA

BY

JAN YTTEBORG and KRISTEN ARNESEN

A case is presented with recurrence of retinoblastoma in a 14-year-old girl 12 years after irradiation treatment. The first eye had been enucleat- ed for the same diagnosis at the age of 12 months. In the differential diagnosis between an inflammatory and a neoplastic condition in the eye, cytologic examination of material aspirated from the anterior chamber appeared useful.

Key word: retinoblastoma.

A case is presented of bilateral retinoblastoma with intraocular recurrence in the conservatively treated eye af ter 12 years. The case aIso demonstrates the usefulness of diagnostic cytology in ophthalmology.

Case History

The patient is a girl, born in April 1955. No family history of retinoblastoma. In 1956, when 12 months old, the child was admitted to the University Eye Clinic, Rikshospi- talet, with the diagnosis of bilateral retinoblastoma. The right eye was observed to be filled with tumour masses and was enucleated. Histopathological examination verified the diagnosis.

Received March 13, 1972.

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/an Ytteborg and Kristen Arnesen

Fig. 1. Retinoblastoma cells in smear of aqueous aspirate. Papanicolaou stain. X 1920.

In the left eye a tumour was found 2-3 disc diameters above the disc, prominating 5-6 D and 2-3 disc diameters wide. X-ray treatment was given in a total dose of b250 rad from the left temporal region and 5550 rad from the right orbit. The tumour showed signs of regression, but one year later, in 1957, the patient was readmitted to the hospital with findings indicating active tumour growth at the same site in the eye ground. She was again treated with deep X-ray on the same two fields as pre- viously with a total dose of 3100 rad on each. At this time obvious signs of irradiation damage of the skin occurred, and according to the radiologists’ opinion no further, deep X-ray treatment was possible. The tumour now showed little evidence of re- gression, and three months later, in December 1957, the patient was treated in London by implantation of a @JCo disc (Mr. Stallard). Following this treatment a typical, flat, white, post-irradiation scar appeared corresponding to the tumour site. Two years later, in 1959, a small recurrence at the border of the scar was suspected, and this area was light-coagulated by Mr. Stallard.

During the following years there were no signs of recurrence. Some small, punctate haemorrhages were seen in the posterior pole, and 5 years after the last treatment a circinate retinopathy developed close to the macular region. These findings were considered to represent late complications of the therapy given, probably caused by the irradiation damage to the choroidal and retinal vessels. In addition a posterior, cor- tical cataract developed. The patient had a visual acuity of about 5/20, and she attended ordinary school without any difficulty.

In April 1969, when she was 14 years old, and 10 years after the light coagulation, the girl was admitted to the Eye Department, Ullevdl Hospital. After a long, cross-country skiing trip the eye had become red, and she had noticed failing vision. On admission there were signs of an uveitis with ciliary injection, flare and cells in the anterior chamber. The vitreous was so hazy that the eye-ground could not be inspected. The disc and the white scar above it could hardly be seen. Ophthalmoscopy gave no suspicion of tumour growth, and there was no shadow by trans-scleral illumination. The condition deteriorated during the following days, and the cells in the anterior chamber took on an appearance of a more clotted, fluffy material. The tension rose considerably, probably caused by a blocking of the trabecular meshwork by the exudate, which gonioscopically was seen to cover the meshwork around the whole cir- cumference.

A puncture of the anterior chamber was made and a smear prepared, which was

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Late Recurrence of Retinoblastoma

fixed and stained according to the Papanicolaou method and studied in the Depart- ment of Pathology. The finding of malignant cells was reported.

During the following days the inflammatory signs and tension increased, the patient had considerable pain in the eye, and the function was rapidly failing. Consequently the eye was enucleated April 14, 1969 and sent to the pathologists for examination.

Exfoliative Cytology

The smear from the anterior chamber showed clusters of cells, the majority of which were not well preserved, some of them being necrotic. A certain number of relatively well-preserved cells was present, however. They were slightly larger than mature lymphocytes. The cytoplasm was scanty, and most of the nuclei appeared naked. They were round to oval, varying slightly in size, with a punctate chromatin structure and usually a well-defined nuclear mem- brane (Fig. 1) . Nucleoli were usually indistinct. The nuclear structure clearly differed from that of lymphocytes. In addition, groups of neutrophile granulo- cytes were present.

The predominating cells in the smear were interpreted as malignant, neo- plastic cells, which were well compatible with retinoblastoma. The possibility of a purely inflammatory exudate was rejected.

Histopathology

The enucIeated specimen was fixed in 4 010 unbuffered formaldehyde solution. The globe measured 22 X 23 mm. A cloudy exudate was seen in the anterior chamber. The upper and lower cups were cut off. In the upper section plane, no definite tumour could be recognized macroscopically, but the retina showed some variation in thickness. In the lower section plane the retina was irregu-

Fig. 2. The enucleated left eye cut horizontally below the optic nerve and limbus. 1:l.

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J a n Yttcborg and Kristen Arnesen

Fig. 3. Retina above the papilla with atrophy, gliosis and serous exudation. Haematoxylin and

eosin. X 135.

larly thickened, especially on the nasal side all the way from the ora serrata to the papilla of the optic nerve (Fig. 2).

Horizontal sections from different levels were studied after staining with haematoxylin and eosin.

Sections above the papilla showed no tumour, but an atrophic retina with gliosis and exudative changes was seen (Fig. 3).

Fig. 4. Retinoblastoma a t the edge of the optic papilla. Haematoxylin and eosin. X 105.

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Lute Recurrence of Retinoblastoma

Fig. 5. Retinoblastoma in the retina and subretinal space. Haematoxylin and eosin. X 105.

Sections through the papilla demonstrated partial atrophy of the retina, especially on the temporal side. Between the layer of rods and cones and the pigment epithelium, islands of tumour tissue were seen from the ora serrata to the edge of the papilla on both sides (Fig. 4).

Below the papilla there was diffuse or focal growth of retinoblastoma in the retina and in the subretinal space (Fig. 5 ) .

Fig. 6. Clusters of retinoblastoma cells in the anterior chamber. Haematoxylin and eosin.

X 105.

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Jan Ytteborg and Kristen Arnesen

In all levels studied, freely floating clusters of tumour cells appeared in the posterior and anterior chamber (Fig. 6), partly attached to the surface of the iris, cornea or trabecular meshwork.

The tumour was poorly differentiated with only few rosette-like structures, many mitoses and large areas of necrosis with many neutrophile granulocytes. The vitreous was protein-rich and contained a limited number of erythrocytes and leucocytes.

The lens was cataractous.

Discussion

In this case the effect of the W o applicator was convincing following two series of rather extensive, deep X-ray treatment which had failed to eradicate the tumour. The degenerative changes which developed in the eye-ground after several years indicate that X-ray treatment should be kept at a minimum.

At the late recurrence the inflammatory signs dominated the clinical picture. This has recently been discussed by Richards (1968) and Stafford, Yanoff & Parnell (1969). Among 618 histologically verified cases of retinoblastoma, the latter authors found that 6.6 O/O were primarily misdiagnosed as inflammatory conditions. By histopathologic examination of 81 retinoblastoma eyes Jensen (1965) found inflammatory changes in 23.

A recurrence of retinoblastoma as late as 12 years after the last irradiation treatment is most unusual. Paterson & Charteris (1965) report a case with re- currence 9 years after treatment with radon,seeds. Reese (1963, p. 146) had seen three cases with recurrence several years after X-ray treatment. In the first of these cases the remaining eye was enucleated because of glaucoma 9 years after treatment for bilateral retinoblastoma. After another 5 years, the tumour had spread to the nose and paranasal sinuses. The two other patients showed extraocular tumour growth 6 and 8 years after treatment.

Activation of retinoblastoma many years after apparently successful radio- logical treatment may be explained by some of the tumour cells having re- mained in a state of suspended viability, perhaps caused by the irradiation, as indicated by a case reported by Calhoun & Reese (1942). They obtained an eye for histopathologic study, which had been treated 8 years previously for retinoblastoma, and where clinical follow-up had indicated arrested growth. On microscopic examination the eye contained tumour cells which did not look necrotic, but had apparently lost their power to proliferate. Another pos- sible explanation is that these cases of late recurrence represent a new growth of tumour.

The multifocal nature of retinoblastoma is well known, and there are several

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reports of tumour in the second eye appearing many years after treatment of the first eye, e. g. 81/2 years (Stallard 1962), and 121/2 years (Skeggs & Wil- liams 1966). The histopathologic study of the present case could give no clue to this problem, except for the fact that a large area of the retina showed atrophy and gliosis without any trace of tumour tissue, probably resulting from the irradiation performed many years previously, whereas active tumour growth took place rather diffusely outside this field.

This case represents our first and only experience regarding the value of exfoliative cytology in the diagnosis of retinoblastoma, or rather in the dif- ferentiation between a neoplastic and an inflammatory condition within the eye.

The cytologic diagnosis of material aspirated from the anterior chamber of the eye has been discussed by several authors (Verrey 1954, Ashton 1958, Schofield 1960, Naib, Clepper & Elliott 1967, Richards 1968). Naib et al. (1967) seem to have the most extensive Cxperience in the cytologic diagnosis of retinob1.astoma in aqueous aspirate. They give a clear description of the characteristic findings, which correspond closely to our own observations. The importance of this method in the examination of eyes demonstrating clinical signs of inflammation with hypopyon or pseudohypopyon is stressed by Scho- field (1960) and Richards (1968).

The finding of neutrophile granulocytes in the aspirate, as in our case, does not disfavour the diagnosis of a primary, neoplastic condition, especially when the latter is prone to undergo necrosis, such as a retinoblastoma. The finding of granulocytes in a sterile aspirate rather favours the diagnosis of neoplasia.

Retinoblastoma cells in the aqheous can show some resemblance to lymph- ocytes. If the cells are reasonably well preserved, the chromatin structure of the nuclei is fairly characteristic, and differentiation from lymphocytes should be easy.

Addendum

March 1972, almost 3 years after the enucleation of the last eye, there are no signs of metastasis.

References ’

Ashton, N. (1958) Cited by Schofield, 1960. Calhoun, F. P. & Reese, A. B. (1942) Rhabdomyosarcoma of the orbit. Arch. Ophthal.

27, 558-578.

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J a n Ytteborg and Kristen Arnesen

Jensen, 0. A. (1965) Retinoblastoma in Denmark. Acta ophthal. (Kbh.) 43, 821-840. Naib, Z. M., Clepper, A. S. & Elliott, S. R. (1967) Exfoliative cytology as an aid in the

Paterson, M. W. & Charteris, A. A. (1965) Retinoblastoma. Report of 19 patients

Reese, A. B. (1963) Tumors of the Eye. 2nd. ed. Harper & Row. New York, Evanston

Richards, W. W. (1968) Retinoblastoma simulating uveitis. Amer. /. Ophthal. 65, 427-

Schofield, P. B. (1960) Diffuse infiltrating retinoblastoma. Brit. /. Ophthal. 44, 35-41. Skeggs, D. & Williams, J. (1966) The treatment of advanced retinoblastoma by means

Stafford, W. R., Yanoff, M. & Parnell, B. L. (1969) Retinoblastomas initially mis-

Stallard, H. B. (1962) The conservative treatment of retinoblastoma. Trans. Ophthal.

Verrey, F. (1954) Clinique de I'Humeur Aqzieuse Pathologique. Delachaux SC Niestl6

diagnosis of ophthalmic lesions. Acta Cytol. 11, 295-303.

treated with radiotherapy. Brit. J. Ophthal. 49, 347-358.

and London.

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of external irradiation combined with chemotherapy. Clin. Radial. 17, 169-1 72.

diagnosed as primary ocular inflammations. Arch. Ophthal. 82, 771-773.

SOC. U.K. 82, 473-534.

S.A., Neuchatel, Paris.

Author's address: Professor Kristen Arnesen, Department of Pathology, Ulleviil Hospital, Oslo, Norway.

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