Acta Ofihthalmologica . Sufifilementum 76

From the Department of Ophthalmology, Medical College of Virginia, Richmond, Virginia

LIGHT COAGULATION AND INTRAOCULAR MALIGNANT TUMORS:

A N EXPERIMENTAL STUDY

BY

Guy Chan, M. D., DuPont Guerry, 111, M . D., and Walter J . Geeraets, M . D.

The purpose of this study is to review briefly different methods and results of treatment of choroidal melanoma and retinoblastoma and to evaluate the effect of light coagulation on experimentally implanted pigmented and non- pigmented tumor cells in the suprachoroidal space.

Melanoma: In the past, patients with intraocular malignant melanoma have been treated by enucleation or diathermy. More recently, light coagulation has been employed in treating small intraocular tumors, 'particularly in those patients with only one eye. Treatment by enucleation of the affected eye has been shown to reduce the mortality rate, but a death rate of over 50 percent with ten years follow-up was noted in the series of AFIP (1951) ( l ) , Wester- veld-Brandon Zeeman (1957) (2) (Table 1) . Weve (1939) (3) reported no deaths after 20 years of follow-up in his series of 20 cases treated by means of elec- trodiathermy. However, the exact nature of the intraocular tumors treated with diathermy remain unverified since there was no histopathological in- formation available. Meyer-Schwickerath ( 1 96 1) (4) has reported six cases of melanoblastoma treated wi,th light coagulation. After a mean observation period of three to four years, his series showed a mortality rate of 5 percent.

Retinoblastoma: The response of retinoblastoma to treatment is generally recognized as being more favorable than that of melanoma. In a series of patients treated by enucleation the mortality rate was relatively high (AFIP, 1939) ( 1 ) (Table 2). Dunphy (1958) (5) reported a mortality rate of 25 percent

This study was supported in part by the American Cancer Society and by the National Society for the Prevention of Blindness.

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Table I. Mortality rate corresponding to types of treatment of intraocular malignant melanomas.

Malignant melanoma (pigmented)

Methods of treatment Series Per cent Years Cases dead follow-up

66 AFIP (1951) 200 Enucleation

Light coagulation & Enucleation

10+

Meyer- 3+ Schwickerath 61 1 5 1 (3.4 longest) (1961) (1.6 shortest)

Enucleation

Diathermy

in cases where only diathermy was used. In addi,tion to enucleation and dia- thermy, retinoblastoma has been attacked by radiotherapy alone and in com- bination with TEM (triethylenemelamine). The last named combination of x-ray and TEM was found to give a striking response (Reese, 1955) (6, 7), (Hyman, 1956) (8). Of the three methods of administration, oral, intracarotid, and intramuscular, the latter gives the lowest mortality rate (10 O/o) as com- pared with oral application (30 'O//O) and intracarotid application (40 O/o). Meyer- Schwickerath (1961) (4) reported his results of treating 33 cases of retino- blastoma with light coagulation alone and in combination with x-ray and chlorambucil. The mortality rate in his series was 12 percent within an observation period ranging from 1.6 to 3.4 years.

The use of light coagulation for the treatment of small intraocular tumors is still controversial. Its proponents contend that it has the advantage of pro- ducing minimal damage to the normal ocular tissue particularly when a lesion of the posterior pole is treated. Furthermore, when employed in treating a small tumor in the remaining eye of a one-eyed patient, less normal tissue is destroyed than would be the case if diathermy were used and a useful eye remains. This is in contrast to the picture of total blindness resulting from enucleation. In the treatment of intraocular tumors, two distinct steps have been advocated. First, small tumors which are not supplied by large retinal vessels are encompassed by a ring of light coagulation placed in normal re- tina (Fig. 1). Then, as a second step, the tumor itself is treated by multiple direct exposures (Fig. 2).

Westerveld- Brandon Zeeman (1957)

Weve (1948)

66 l o + 103

0 20 20

6

LIGHT - BEAM

Methods of treatment

RETINA PIGMENT EPITHELIUM

CHOROID (vascular)

SCLERA (avascular)

Per cent Years dead follow-up Series Cases

LI Y

Fig. 1. Schematic diagram of double light coagulation barrage encircling an

intraocular neoplasm.

Enucleation 1 121 I 41 . 1 AFIP

Diathermy Dunphy I 8 I 25 1 2 -16

X-ray 1 195 I 50 I 10< Reese

X-ray I 23 I 40 I 10< artery

Intramuscular & TEM (Triethylene Melanine

artery (1956)

Intramuscular 29 17

Light coagulation alone or in combination with

X-ray and Chlorambucil

Schwickerath 1.7 (av.) Meyer- (5 years (1961) longest)

PIGMENT

RETl NA EPlTH E LI U M

CHOROI D (vascular)

SCLERA (avascular)

Fig. 2. Schematic diagram showing direct light coagulation of an intraocular tumor.

The first step was suggested as a means of cutting off the blood supply to the tumor, and hence the supply of oxygen and nutrition as well as to prevent metastasis of tumor cells at a rapid rate through the blood stream. The second step was for the direct destruction of the tumor itself.

The question arises, >>How effective is light coagulation in achieving the goal of tumor destruction without increasing the mortality rate?* Both clinical and experimental evaluation of this therapy are hindered by a number of

Fig. 3. Method of implanting tumor cells in the suprachoroidal space, (a) before,

and (b) after implantation of tumor cells.

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a b C

Fig. 4. Fundus photographs showing the posterior pole before (a) and after (b) implantation

as well as after multiple exposures with the light coagulator (c).

Fig. 5. Satisfactory complete blockage of choroidal blood vessels by double line of coagulated spots. The blood vessels within the encircled area are free of blood as evident by

the lack of latex paint injected via the internal carotid artery.

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factors. Clinically, the few cases reported in the literature have not stood the classical test of time. Moreover, eyes with intraocular tumors available for histological examination after light coagulation are few in number. Experi- mentally, animal eyes with intraocular tumors that are suitable for such eva- luation are not available. There are reports on experimentally induced intra- ocular tumors (Patz, 1959 (9) and Burns, 1961 (10); however, the production of these tumors thus far has been successful only in mice and hamsters. But the small eyes of these animals are not suitable for experimental light coagu- lation.

A special technique was therefore devised for implantation of tumor cells of choice into the suprachoroidal space at the posterior pole of the rabbit eye (Fig. 3). These implanted cells could then be localized visually, light coagulated with known light intensities, and examined histologically after treatment (Fig. 4).

The experiment was studied in two parts corresponding to the two steps recommended clinically in the treatment of intraocular tumors. The results of Part I, the effect of blockage of choroidal circulation by encircling barrage has been reported in previous communications (11, 12) but may be summarized here. Blockage of choroidal circulation could be achieved only if a double line

Fig. 6. Incomplete blockage of choroidal blood due to leakage of blood between gaps

of coagulated spots.

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Fig. 7. Recanalization or new tortuous vessel formation within the encircled area occurred

from ten to fourteen days following light coagulation.

of coagulations were employed (Figure 5) . Such double barrages were effectful only if there were no gaps separating single coagulation spots since otherwise choroidal vessels penetrated the barrage in those areas (Figure 6). The barrage was without effect when short ciliary arteries penetrated the sclera within the walled-off area. The required light energy for obtaining temporary complete blockage of choroidal vessels was found to be extremely high, approaching levels which are close to intensities that will produce explosion-like disruptions of retina and choroid. Recanalization and neovascularization of the encircled chorioretinal area occurred in from ten to fourteen days following coagulation (Figure 7).

The second part concerns the histological evaluation of implanted intra- ocular tumor cells after direct multiple exposures to light coagulation (Figure 2). For this part, two types of tumor cells were selected for implantation. The black pigmented melanoma carried in strain C57BL/6J mouse" and the non- pigmented mammary adenocarcinoma cells carried in C3H/He J strain". The non-pigmented cells were selected to represent the non-pigmented human retinoblastoma which does not exist in mice and is very rare in other species.

* Roscoe B. Jackson Memorial Laboratory, Bar Harbor, Maine.

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METHOD

Ninety chinchilla rabbit eyes were used in this study and were divided into three groups. The pupils were dilated with neosynephrine 1 0 ~ l o and atropine solution 1 percent. The first group was used as a pilot study in which liver cells were implanted since they were easily available. A specially designed stylet was used for implantation of the tissue (Figure 3). The stylets measured 2 cm in length and were made from glass tubes. The rough end of the glass tube was fire polished to reduce the incidence of rupturing the globe during implantation into the suprachoroidal space. The plunger for the stylet was made of plastic. Tumor cells were obtained with the stylet similar to clinical needle biopsy. A 2 mm column of cells was used for each implantation. The conjunctiva was incised above, exposing the sclera and the optic nerve which could be easily located by rotation of the globe downward. A 2 mm scleral incision was then made through to the suprachoroidal space about 2 mm nasal to the optic nerve. The stylet was introduced and the tissue placed by means of the plastic plunger.

After the technique of implantation of the tissue was perfected, the two types of tumor cells mentioned above were implanted into both eyes of the remaining two groups of rabbits. One eye was used as control, the other was light coagulated with multiple exposures to the implanted tumor itself. The exposure time was 0.3 sec, ,the applied retinal dose measured 10 to 12 caUcm2. Direct visualization was possible at all steps of the experiment. The eyes were removed after light coagulation and processed for histological evaluation.

RESULTS

In group 1, in which the liver cells were implanted and light coagulated, the histological sections revealed definite cellular changes in the implanted tissue. There was disruption and fragmentation of the cellular structure in the light coagulated area. The nuclei were poorly stained, pyknotic and indistinct in outline (Figure 8 a through d).

In group 2, in which non-pigmented breast adenocarcinoma was implanted, there were similar histological changes (Figure 9 a - d). The remaining ap- parent viable cells suggest incomplete tumor destruction. In clinical treatment the preliminary encircling double barrage may help to immobilize these re- maining cells and deprive them of their nutritional supply by blocking the blood circulation. The trapped toxic cellular debris might add to the de- struction of these cells.

In group 3, in which the pigmented melanoma was implanted, the cellular disintegration affeoted by light coagulation was most striking. Providing that the implanted tumor mass did not exceed 0.5 to 1 mm in thickness, there was complete disintegration of the cellular structure with mere fibrous framework

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left (Figure 10 a - d). The difference in response between the non-pigmented breast carcinoma and the pigmented melanoma is quite obviously due to the difference in pigmentation since the light absorbed by the pigment generates the heat necessary for coagulation.

C O M M E N T

Observations made in this study on non-pigmented tumors must be interpreted with extreme cau'tion. While chical ly the non-pigmented retinoblastoma is located in the retina, the experimentally induced non-pigmented tumor was located in the suprachoroidal space. This, however, means that in clinical retinoblastoma the white surface of the tumor reduces the effect of incident light by reflection and scattering, while in the implanted tumor the pigment epithelium and choroid located in front of the tumor will absorb part of the incident light with resulting heat generattion, thus secondarily affecting the implanted tumor (Figure 1 I).

On the other hand, clinically, pigmented melanoma is located behind the pigment epithelium within the choroid. The incident light thus affects the tumor in two ways: 1) Directly by its own absorption because of its own

Fig. 11. Relationship of clinical and experimental tumors. Arrows indicate direction

of incident light.

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a b

Fig.

12.

a)

Loc

atio

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oma

in e

nucl

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. b)

Loc

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pigment content; 2) Indirectly, because of conducted heat f rom absorption in the pigment epithelium and choroid lying i n f ront (Figure 11).

Experimentally, the topography of t h e implanted pigmented melanoma is almost identical to the normal occurrence of this tumor and hence i t is af- fected much the same way as this (Fig. 12 a a n d b).

SUMMARY

Black pigmented mouse melanoma and non-pigmented breast carcinoma of the mouse were implanted into the suprachoroidal space of chinchilla gray rabbit eyes. Light coagulation was performed to study the histological effect of high intensity light on the tumor cells.

W h i l e the melanoma could be destroyed completely, providing the tumor thickness d id not exceed 0.5 to 1 mm, the effect on the non-pigmented tumor was not a s marked. Even with a retinal dose of 10 to 12 cal/cm2, employed over 0.3 sec, histologically normal appearing non-pigmented tumor cells re- mained.

The usefulness of an encircling barrage surrounding the tumor before light coagulation of the tumor itself is discussed.

BIBLIOGRAPHY

1) Reese, A. B.: Tumors of the Eye, New York, Paul B. Hoeber, Inc., 1951. 2) Westeveld-Brandon Zeeman, E. R. and Zeeman, W. P.: The Prognosis of Melano-

blastoma of the Choroid, Ophthalmologica, 134: 20, 1957. 3) Weve, H. J. M.: Derde geval van melanosarcoma, genezen door ,diathermische

behandeling, Nederl. tijdschr. v. geneesh., p. 3472, 1948. 4) Meyer-Schwickerath, G.: The Preservation of Vision by Treatment of Intraocular

Tumors with Light Coagulation, Arch. Ophth. 66: 458-466, 1961. 5) Dunphy, E. B.: Report on the Diathermy Treatment of Retinoblastoma, Am. J. O.,

45: 95, 1958. 6) Reese, A. B., Hyman, G. A., Merriam, G. R., Jr., Forrest, A. W., and Kligerwan.

M. M.: Treatment of Retinoblastoma by Radiation and Triethylene Melamine, AMA Arch. Ophth., 53: 505-513, 1955.

7) Reese, A. B., Hyman, G. A., Tapley, N., Forrest, A. W.: The Treatment of Retino- blastoma by X-Ray and Triethylene Melamine (VIII), Concilium Ophthalmo- logicum, 1958, Belgica, Acta V 11, XVIII 2: 1370, 1958.

8) Hyman, G. A. and Reese, A. B.: Combination Therapy of Retinablastoma with Triethylene Melamine and Radiotherapy, J. A. M. A., 162: 1368, Dec., 1956.

9) Patz, A., Wulff, L., Rogers, S.: Experimental Production of Epithelial Invasion of the Anterior Chamber, A. J. O., 47: 6, 815, 1959.

10) Burns, R. P. and Fraunfelder, F. T.: Experimental Intraocular Malignant Mela- noma in the Syrian Golden Hamster, A. J. O., 51: 977, 1961.

11) Geeraets, W. J.: Research Data Applicable to Clinical Lightcoagulation, Ophthal- mology Clinics, I, 4, Dec., 1961, Little, Brown and Company.

12) Geeraets, W. J., Ghosh, J. M., Guerry, D., 111: The Effect of High Intensity Light on Choroidal Circulation, A. J. O., 54: 2, 278, 1962.

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