Malignant Melanoma of the Uvea*

594

F. C. RODGER

Soliman, K. N.: Brit. vet. J., 109:148, 1953. Stoll, N. R.: J. Parasit., 33:1, 1947. Strong, R. P.: New England J. Med., 204:916,1931. : Onchocerciasis. Cambridge, Harvard Univ. Press, 1934, Part VIII, p. 78. Sulzberger, M. B. : J. Allergy, 21:85,1950. —T—

Toulant, P.: WHO unpublished report, 1953. Toulant, P., Robineau, G., and Puyuelo, R.: Bull. Soc. Path, exot., 43:615, 1950. Toulant, P., and Boithias, R.: Bull. Acad. nat. Med., 136:378, 1952. : Arch. Ophth., 14:567, 1954. —U—V— Van den Berghe, L.: Ann. Soc. Belge Med. Trop., 21:261, 1941. Vogel, H.: Med. Wolt, 25:876, 1931. —W—

Waddy, B. B. : Onchocerciasis and Blindness. D.M.S. Rep., Gold Coast, 1951, p. 36. Wald, G, and Hubbard, R.: J. gen. Physiol., 32:367, 1949. Wald, G., Brown, P. K., and Smith, P. H.: Fed. Proc, 11:304, 1952. Wilson, J. F.: Blindness in British African and Middle East Territories. London, Pub. H.M Sla tionery Office, 1948. Wolff, E.: Anatomy of the Eye and Orbit. London, Lewis, 1954, ed. 4, p. 56. —X—Y—Z—

MALIGNANT MELANOMA O F T H E UVEA* JAMES H.

SCRUGGS,

M.D.

Waco, Texas Malignant melanoma of the uvea is a rela­ tively rare but very important condition with which the ophthalmologist must deal. The intent of this paper is to review some of the literature, pointing out the salient features of the disease, and then to report four cases illustrating some of these points. Duke-Elder states that the disease occurs in from two to six times in each 10,000 eye patients seen. Based on the records of Moorfields Hospital from 1871 to 1925, this in­ cidence remained rather constant during that period.1 Various studies have shown a slightly higher occurrence in one sex but no statis­ tically significant difference has been sug­ gested in any large series, and some studies have shown more in males and others more in females. The average age incidence is about 50 years ; 45 percent of cases occur in the fifth ♦Read before Texas Society of Ophthalmology and Otolaryngology, Houston, Texas, December, 1958.

and sixth decades of life. Patients under 30 and above 80 years of age are rare. 1 Malignant melanoma is rare in the Negro race. In 1,600 cases reported by the Armed Forces Institute of Pathology in 1942 only eight occurred in Negroes. Bilateral cases of malignant melanoma are very rare. Shine3 reported the first patho­ logically proved case occurring in both eyes in 1930. The second eye showed the tumor three years after the first. The iris of one eye and the choroid of the other was in­ volved. He also collected seven other cases in the literature, though these had not been proved pathologically. Cordes and Cook4 re­ ported a case in 1948 with a malignant mela­ noma involving the choroid of one eye and the iris of the other. Reese2 reported a proved case of malignant melanoma of the choroid of both eyes, the tumor becoming manifest in the second eye eight years after the first. Heredity is seldom a factor in the occur­ rence of these tumors. Occasionally a pedi-

MALIGNANT MELANOMA OF THE UVEA gree will show a Duke-Elder 1 cites by Nelleship, in showed malignant four generations.

definite family tendency. one family, first reported which seven individuals melanoma of the uvea in ORIGIN

For many years these tumors were con­ sidered to be of mesodermal origin and were called sarcomas. Theobald,5 in 1937, pre­ sented evidence that the tumors arose from the Schwann cell. Only a few years before this report was published, several workers had presented evidence that melanomas of the skin were of neurogenic origin. The nevus cell is a modified Schwann cell. The occurrence of true nevi in the uvea was shown by Wilder 6 in 1946. Reese formerly felt that the more malignant melanomas con­ taining epithelioid cells arose from stromal melanoblasts. However, in a more recent study of tissue cultures of uveal melanomas, he concludes that they all arise from Schwann cells, and that the fascicular cells are better differentiated because they are slower growing.7 LOCATION

The majority of the malignant melanomas occur in the choroid. Reese2 reports that, in 271 eyes enucleated for malignant melanoma at the Institute of Ophthalmology (New York) since 1933, there were 224 of the choroid, 24 of the ciliary body, and 23 of the iris. Of the 224 occurring in the choroid, 205 were localized, 18 extended into the ciliary body, and one into the ciliary body and iris. Of the 24 occurring in the ciliary body 15 were localized and nine extended into the iris. Of the 23 occurring in the iris 20 were localized and three extended into the ciliary body. These numbers are in close agreement, being within two percentage points, on each count, with the statistics orig­ inally reported by Fuchs in 18821 in which he found 85 percent in the choroid, nine per­ cent in the ciliary body, and six percent in the iris. Most of the choroidal lesions occur on the temporal side posteriorly.

595

HISTOLOGY

Many cell types are seen, frequently in the same tumor. In spindle cells the nucleus is long and oval and the ends of the cells terminate in long fibers. Callender8 divided these into subtypes A and B. The spindle A has a delicate reticulum and poorly defined nucleolus. Spindle B has a coarser, deeper staining nuclear network and a dense round central nucleolus. These cells are arranged in closely packed bundles running parallel or in whorls, or they may be quite irregular. Fascicular cells are elongated oval or spindleshaped and are arranged in columns, or fasciculi, around a central lymphatic or cap­ illary. Epithelioid, cells are larger and may be rounded or polygonal in shape, with an oval nucleus. They occur in a well-differentiated reticular stroma. Callender classified these tumors according to cell type as: (1) spindle A and B, (2) fascicular, (3) epithelioid, (4) mixed. The prognosis becomes increas­ ingly worse with each type in the order listed. Existing benign melanomas may become malignant. Reese2 reports one case involv­ ing the iris and another involving the ciliary body. Other authors have reported cases in which a presumably benign lesion was ob­ served for a number of years and then began growing. After enucleation, microscopic sec­ tions proved the lesion to be malignant. Asbury and Vail9 reported such a case that was kept under observation for three years be­ fore the tumor appeared to be growing. Albers10 observed a case for eight years before the lesion appeared to be growing ac­ tively and the eye was enucleated. Reese states that there is histologie, as well as clini­ cal, evidence for this. He states that around the base of a malignant melanoma of the uvea there is a flatter zone of tumor tissue extending into the adjacent uvea which is usually more pigmented and composed of more mature cells. He further states that in microscopic sections very small malignant melanomas are seen to arise in the outer layers of the choroid, or in the supracho-

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JAMES H. SCRUGGS

roidea, and that this is the location of benign melanomas. Benign melanomas may spontaneously be­ come malignant or this change may be pre­ cipitated by long-standing irritation or in­ flammation. Thus, the incidence of malig­ nant melanoma in pthisical eyes is greater than in eyes without inflammation. All pthisical eyes showing malignant melanomas are not of this category for, indeed, the proc­ ess may work in reverse ; that is, a malignant melanoma may show necrotic areas which are quite toxic and thus initiate the inflam­ matory process from which the eye may eventually become pthisical. Duke-Elder 1 quotes from an original German article by Leber and Krahnstover (1898) in which were collected 34 cases of malignant mela­ nomas the authors felt were secondary to a long-standing inflammatory process; in 22 cases they felt the pthisical eyes were caused by toxicity of necrotic malignant melanoma. In any event all pthisical eyes should be viewed with the suspicion that they may har­ bor a malignant melanoma. Reese2 states "the occurrence, therefore, of malignant melanoma in eyes which have been blind for a long time is encountered sufficiently often to be in itself a reason for enucleating these useless and disfiguring eyes." COURSE

The course of a malignant melanoma is quite varied so that it is unwise to expect a certain chain of events. Thus, the classical description of Knapp that there are four stages—(1) symptomless, (2) glaucoma, (3) extraocular extension, and (4) metasta­ sis—may apply to many tumors but by no means all. Metastasis may occur at any stage and may be widespread before any trouble in the eye is even suspected. As has been mentioned, growth begins in the outer layers of the choroid or even in the suprachoroidea. In the majority of cases, growth progresses as a circumscribed tumor but in some it may be diffuse. The circumscribed tumor is at first flat­

tened somewhat by the resistance of the sciera on one side and Bruch's membrane on the other. Later it breaks through Bruch's membrane and grows in a globular fashion into the subretinal space. The resistance of Bruch's membrane keeps the tumor con­ stricted more in this region so that a mush­ room shape is usually assumed. At this stage the retina usually becomes detached. It rests on the tumor and the surrounding retina is separated by exudate. This richly albuminous exudate is formed partly by venous obstruction and partly by irritative or toxic reaction from the tumor. 1 If the tumor is in the superior por­ tion of the eye, this fluid may gravitate inferiorly, forming a detachment that is en­ tirely separated from the tumor itself. Iridocyclitis and glaucoma, or both, may super­ vene at any time. More rarely a definite hy­ potension may exist. The course of growth may be modified if the tumor gains early access through the sciera to a. neural or vas­ cular channel. In such event, the tumor may invade or penetrate the sciera along the channel without appreciably elevating the retina.11 Diffuse malignant melanomas of the cho­ roid spread through the uvea without form­ ing a circumscribed tumor. They are usually slower growing and may not affect vision or give other objective signs for a long time. Since the sciera may be diffusely infiltrated, extraocular extensions may be more fre­ quent. Métastases may occur before ocular signs are evident. Toxic effects are not usually present because necrotic areas do not occur as in the circumscribed growth. DukeElder states that these neoplasms are rela­ tively avascular and therefore more depend­ ent on preformed vessels for their growth as well as early metastasis. Juxtapapillary tumors also take a different course. Beginning in the choroid near the disc the tumor grows around the termination of Bruch's membrane and spreads over the disc, appearing clinically to arise from the disc itself. Many such cases have been re-

MALIGNANT MELANOMA OF THE UVEA ported in the literature and some authors have reported malignant melanomas of the optic disc. De Veer12 reported a juxtapapillary tumor that clinically appeared to arise from the disc. He cites reported cases of malignant melanoma being primary in the disc and challenges all of these reports, stat­ ing that the pathologic evidence presented is inadequate and that he believes all of these reported cases were actually juxtapapillary in origin. As noted earlier, malignant melanomas of the ciliary body represent only nine to ten percent of those involving the uvea. The course of growth is similar to that in the choroid. If it begins in the posterior part of the ciliary body, it forms a globular mass into the vitreous and forward into the pos­ terior chamber. If it begins anteriorly, it invades the posterior chamber early and pushes the iris forward, then invades it and the angle of the anterior chamber. DukeElder states that extraocular extension along the perforating scierai canals is usually early in such cases.1 There is a tendency for the tumor to form a ring growth in the ciliary body, spreading around the globe within the ciliary body. Reese2 states that there are two reasons for this: (a) the tumor extends around the major arterial circle because of good blood supply and because the potential perivascular space offers little resistance, and (b) the ciliary body acts as a confined space due to tissue cleavages. Desquamated tumor cells may be carried by the aqueous to other sites to produce implanation growths in the trabeculae, on the iris, or in the angle. Malignant melanomas of the iris are still more rare. Many authors have reported be­ nign melanomas that underwent malignant changes while under observation. Coats13 (1902) reported 26 cases of benign melano­ mas of the iris, and seven of these became malignant while under observation. DukeElder 1 states that this is probably the usual origin of malignant melanoma of the iris. The malignant tumor may be a localized mass or a diffuse growth throughout the iris

597

stroma. The cells may desquamate, be car­ ried by the aqueous, and form implantation growths, as in the case of malignant mela­ nomas of the ciliary body. Ring melanomas may be formed. The average age of the pa­ tient with iris malignant melanoma is younger than those with the tumor in the ciliary body or choroid. In Reese's series the average age was 46 years. This is prob­ ably partly due to the fact that, as a group, these patients are diagnosed earlier than those with tumors occurring in the ciliary body or choroid. Cytologically more iris tumors contain nevus cells and some are en­ tirely composed of nevus cells. Glaucoma, which may develop rather early, is present in a larger percentage of melanomas of the iris, due to obliteration of the angle. DIAGNOSIS

As in any other malignancy early diagno­ sis is of paramount importance if treatment is to be successful. Terry and Johns 14 re­ ported in their first series of 94 malignant melanomas of the uvea that 44.6 percent were unsuspected clinically. Objectively the ophthalmologist may visu­ alize a pigmented lesion of the choroid. The size and amount of elevation may be helpful in deciding whether or not it is malignant. If it can be determined that there is a fairly large globular pigmented solid growth pres­ ent, little problem in clinical diagnosis exists. Many tumors will not present this typical appearance. Terry and Johns1* reported retinal detach­ ment to be present in 85 of 94 melanomas of the choroid in their series. They stated that the retina over the tumor was usually smooth and free of undulations. Pigment deposits may be present and newly formed blood vessels may be seen. The area of detachment is usually rather sharply defined. An accompanying serous detachment may make the margins less sharply defined but a difference can usually be seen in the appearance of the elevated retina with the solid tumor behind it and the

598

JAMES H. SCRUGGS

serous portion. There is less scattering of the ophthalmoscope light beam on the area of retina overlying the tumor and it has a thicker and whiter look, in addition to being free of undulations that may be present in the area of serous detachment. The absence of holes in the retina is also suggestive. Most spontaneous detachments begin peripherally, though many of the tumors begin more pos­ teriorly and normal retina may be seen pe­ ripheral to them. While these signs in a reti­ nal detachment are suggestive, their absence does not rule out the possibility of a malig­ nant melanoma. Rones and Linger 15 studied slides of 117 malignant melanomas occurring in the pos­ terior pole with no anterior pathology to impede ophthalmoscopic study. Their pri­ mary purpose was to try to determine any factors that might lead to an earlier and more accurate diagnosis clinically. They di­ vided these cases into three groups. In Group I there was no bulging of the lamina vitrea, in Group II there was bulging, and in Group III the lamina vitrea had been broken through by the tumor. Group I was composed of 18 cases in which there was no bulging of the lamina vitrea. Clinically these appeared as gray le­ sions with slight retinal elevation; five ap­ peared as slate-colored retinal detachments. The commonest symptom was blurring of vision. Pathologically, they found that, even in these early tumors, there was cystoid de­ generation of the overlying retina in 10 of the 18 tumors and in these 10 there were adhesions of varying degree between tumor and retina. In the remaining eight cases the tumor and retina were separated by serous exudate. They found pigmentation to be of no significance in these cases. Although the authors do not comment on field changes it would seem that measurable field loss should be present in the area of cystoid degenera­ tion and in those cases with serous separa­ tion. Their Group II was comprised of 48 cases in which the lamina vitrea was bulging, but

not broken through. Subretinal serous exuda­ tion was present in all but two of these cases but the amount of exudation bore no relation­ ship to the size of the tumor. There was marked hyperplasia of the retinal pigment epithelium in 31 cases ; 22 cases showed defi­ nite cystoid degenerative changes. Gliosis of the overlying retina occurred in 18 cases ; in six of these it was associated with cystoid degenerative changes. Group III was composed of 51 cases in which the tumor had broken through the lamina vitrea. These were selected cases that were felt still to present a diagnostic prob­ lem ophthalmoscopically in that the anterior segment was uninvolved. In nine of these the overlying retina showed gliosis or cystoid degeneration. In 26 the overlying retina was thinned and atrophie as a result of pressure from the tumor, and in 16 cases the tumor had completely broken through the retina. The authors felt that in these posterior le­ sions the primary clinical evidence for diag­ nosis was loss of vision and interpretation of the retinal detachment, differentiating it from other causes. They felt that pigment disturbance was of no diagnostic value. Reese2 does not agree with the idea that pigment disturbance is of no value. He states that, when the retina adheres to the surface of the tumor and contains pigmentary changes secondary to proliferation of the pigment epithelium, the detachment's ap­ pearance is that of an old chorioretinitis. In addition to these pigmentary changes drusen sometimes appear around the base of the lesion. Subjective manifestations will depend on the site of the tumor to some extent. In the posterior pole increasing hyperopia may be the first finding, later to give way to blurred vision which is not correctible with lenses. If the tumor lies more peripheral, a large field defect may be present before the pa­ tient notices it. Hemorrhage into the vitre­ ous may occur, with resulting loss of vision which is noticed by the patient. Uveitis may occur and cause the patient to seek help. As

MALIGNANT MELANOMA OF THE UVEA a very rare occurrence a severe panophthalmitis associated with exophthalmos resulting from tumor necrosis may develop.2 When it is difficult to determine the nature of a detachment, bedrest with binocular bandage may be helpful. If the retina flattens down entirely, or lies in folds, it is probably only a serous detachment. On the other hand if a tumor is present the retina may remain globular, or the serous element subside enough to allow detection of the underlying mass. The slitlamp may be of value in helping to differentiate a serous from a solid detach­ ment. The serous detachment shows a translucency caused by the light's penetration of the subretinal fluid. When a solid tumor is lying immediately under the retina, the light is obstructed by the tumor and the translu­ cent appearance is absent.16 Transillumination is a diagnostic aid that may be useful. However, in my experience the results are often difficult to interpret and may be misleading. Unless the growth is large and the point source of light small and of low intensity the lesion may be missed. Blood interferes with transillumination so that subchoroidal hemorrhage may be mis­ taken for a malignant melanoma. Transillu­ mination is usually carried out by placing a small source of light external to the sciera and observing through a dilated pupil in a darkened room for any interference with the transmission of the light. The transilluminator of Lancaster is very satisfactory. In more posterior lesions an incision must be made in conjunctiva and bulbar fascia to introduce the instrument posteriorly. A vari­ ation of this is the method of Lindahl in which the fundus is observed with an oph­ thalmoscope, without its light being turned on, while a transillumination light is moved external to the sciera. Another variation for anterior lesions is to place a brighter source of light over the sciera opposite the lesion, observing to see whether or not there is any interference with transmission of light at the site of the lesion.

599

In his book, Tumors of the Eye (1951), Reese felt that transillumination was a use­ ful adjunct to diagnosis of malignant mela­ noma of the eye. Since then he has modified his views and stated that he depends on it very little.17 He described a technique of "retroillumination" with the ophthalmoscope and believes this to be a useful adjunct when one has become familiar with the technique. This is carried out by using a direct ophthal­ moscope. The light is directed on the lesion and moved over it and the surrounding ret­ ina. If a malignant melanoma is present, there is less scattering of the edges of the ophthalmoscope light because it is absorbed more completely by the tumor.17 Study of the visual field may be an aid in diagnosis. Malignant melanoma usually gives a dense scotoma. If there is a sur­ rounding area of retinal detachment, this will also affect the field, but the loss here may be present only for smaller isopters, with a complete loss in the area occupied by the tumor. The question of doing some type of biopsy has been discussed by many investigators. Needle biopsy, aspiration of subretinal fluid, and incision of sciera and biopsy with for­ ceps have been reported on and discussed. Diagnosis from subretinal fluid studies have not proved feasible from the standpoint of accuracy of diagnosis. Reese2 states that he believes it to be impossible to be certain whether cells present are those of malignant melanoma or macrophages containing pig­ ment. Christensen and Rowen 18 undertook a rather extensive study of the cells in sub­ retinal fluid. They too experienced difficulty in differentiating between malignant cells and macrophages, though they felt that this could sometimes be done. In 83 eyes that had been enucleated for malignant melanoma, they demonstrated tumor cells in the sub­ retinal fluid of 45. Four eyes were examined prior to enucleation and tumor cells identi­ fied in three of these. Pathologic study of the eyes proved all four to have malignant mela­ noma. In three of these the tumor was ex-

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tending through the diathermy punctures made at the operation to obtain the subretinal fluid; in one of these this occurred in 13 days. They concluded that, because of tech­ nical difficulties and the obvious danger of extraocular extension, this procedure should not be done. Kauffman10 reported a case in which he did a needle biopsy of the tumor and made diagnosis of malignant melanoma. The eye was enucleated and examination proved the diagnosis correct. The patient died nine months later of a cerebral vascular accident without evidence of metastasis. At the same time this report was given, Zentmayer19 re­ ported a similar aspiration biopsy with or­ bital recurrence of the tumor in a few months following enucleation. Another study that may be an aid to diag­ nosis is the injection of radioactive isotopes with study of the uptake by the suspected lesion. Radioactive phosphorus is used in­ stead of other isotopes because it emits beta radiation. Thus the penetration is shallow and there is not any effect from remote tis­ sues. A suspected lesion in the anterior por­ tion of the eye can be studied without inter­ ference with the normal uptake by the choroid. In a study by Terner, Leopold, and Eisenberg20 the highest normal eye had a 28-percent uptake count. They consider an uptake of 30-percent or more as significant ; this has been generally accepted by other writers. They feel that one count is not sig­ nificant unless it remains up or increases, and do not make a positive diagnosis on a 30-percent count unless the count done 24 hours later is higher. Vascular tumors will show an increased uptake but this will fall on the 24-hour count, whereas malignant tissue will show an increase. The technique of doing the counts is quite important and the application of the counter tip must be made very carefully and control areas on the other eye studied. Shapiro 21 re­ ports on 80 countings. Twenty-four of these were followed pathologically. Of these 24 there were three false negatives. He stresses the importance of individualizing the count­

ing and control areas in each patient, and of doing several counts so that an unquestioned trend may be noted. He relies chiefly on the 48-hour count. Griffey, Whalen, and Allen22 reported on a smaller series of 25 patients. Six of these showed an uptake of more than 30-percent. Two of the six refused surgery: one of these died two months later of metastasis, the fate of the other is unknown. Four of the six had enucleations and three of these four had malignant melanoma and the other had a hemangioma. On this false positive no 24hour count had been done. In two of the 24 patients who were not considered to have a significant uptake of P 32 , the eyes were enucleated and proved to have malignant melanoma. Thus we see that, while this test may be a valuable adjunct to diagnosis, it is sub­ ject to error in giving both false negatives and false positives. In cases in which the diagnosis is reasonably certain from clinical evidence P 32 studies should probably not be done because the test itself is not without some risk. In studying posterior lesions an incision has to be made through conjunctiva and bulbar fascia of both the affected and the normal eye and this incision has to be re­ opened at least once. However, it would seem that in doubtful cases these studies would be worthwhile and much safer than any type of biopsy. DIFFERENTIAL DIAGNOSIS

In deciding whether or not a lesion of the choroid is a malignant melanoma the follow­ ing conditions should be considered: Serous detachment of the retina. This has already been discussed in detail. In a serous detachment the retina appears more translu­ cent. It may be seen to move in a tremulous manner when the eye is rotated. Retinal folds may be present. The presence of a reti­ nal hole speaks strongly for a serous detach­ ment but failure to find one does not rule it out. Transillumination is good unless subretinal hemorrhage is present. Intraocular hemorrhage. This is perhaps

MALIGNANT MELANOMA OF THE UVEA

601

the most difficult thing to differentiate. sumptive of this diagnosis in the eye, though Choroidal hemorrhage may cause retinal ele­ the eye lesion may manifest itself before the 2 vation, simulate the appearance of a mela­ primary site is known. noma, and transilluminate poorly. Hemor­ Cyst of the retina. A large solitary cyst rhage into the vitreous may obscure a clear may occur with hemorrhage and resemble a view to the extent that the fundus cannot be malignant melanoma. carefully studied at all. If the hemorrhage In the differential diagnosis of those le­ is due to diabetes, hypertension, arterio­ sions involving the ciliary body the follow­ sclerosis, or blood dyscrasia these changes ing must be considered: can probably be seen in the fellow eye. It Intraepithelial cysts of the ciliary body. must be borne in mind that a malignant Most of these are small but they may become melanoma undergoing necrotic changes can large enough to push the iris forward to cause hemorrhage. obliterate part of the angle, or forward to In Kuhnt-Junius disease, or disciform de­ the cornea. When the cyst extends along the generation of the macula, the lesion is posterior surface of the iris it may resemble usually elevated and of dark color and may a melanoma. It is dark in color and the pig­ closely resemble a malignant melanoma in ment epithelium comprising the cyst wall in­ this region. Important points are the pres­ terferes some with transillumination. If the ence of exudates or hemorrhages around the cyst arises from the corona ciliaris it translesion and a similar process present or be­ illuminates light. Another method of study is to observe the posterior chamber gonioginning in the fellow eye. Detachment of the choroid. This usually scopically with dilated pupil ; with this direct follows soon after surgery and these cases observation it may be easy to tell that the should not be easily confused with malig­ lesion is a cyst. nant melanoma. However, choroidal detach­ Malignant epithelioma may arise from the ment may follow injury or inflammation of ciliary epithelium and be difficult to differen­ the choroid or sciera, or the onset may be tiate. Since treatment would be the same for delayed following surgery. In addition to the either case, the clinical differentiation makes importance of the history, there is no inter­ little difference. ference with transillumination. Granulomatous lesions may occur in the The lesions produced by tuberculosis, ciliary body. Diagnosis of the systemic dis­ syphilis, or sarcoid may resemble a tumor. ease would be of help in making the diag­ General examination by an internist should nosis. help to establish the presence of the disease. Leiomyoma and diktyoma are rare lesions Inflammatory signs may be present in the that may occur in the ciliary body and re­ eye, though this is not pathognomonic be­ semble malignant melanoma. cause toxic reaction from the melanoma may In the differential diagnosis of iris lesions cause a similar picture. the conditions to be considered are much the Hemangioma of the choroid may closely same as those of the ciliary body. Iris cysts resemble a melanoma. Transillumination is are the most common lesion. These may be of no help. In a recently reported series on implantation cysts of epithelium that has the use of P 32 , one eye with a positive uptake been implanted in the iris by perforating was removed and contained hemangioma. wounds. Intraepithelial cysts may be formed The presence of other hemangiomas in the by the separation of pigment epithelium eye or about the face would be strongly sug­ from underlying smooth muscle. This usu­ gestive. ally occurs in the pupillary area. Such a Metastatic carcinoma may resemble malig­ cyst may also occur at the base of the iris or nant melanoma but is usually lighter in color, in the ciliary body, pushing the iris forward Diagnosis of the primary site would be pre­ as previously described. Leiomyoma may oc-

JAMES H. SCRUGGS

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cur in the iris. It is poorly demarcated and contains little or no pigment and does not show implantation growths. Metastatic le­ sions, primary carcinoma, granuloma, lymphosarcoma, and encysted foreign bodies are other conditions to be considered. TREATMENT

Reese sharply disagrees, and the following is a direct quotation from him: "Irradiation in any form is without benefit in arresting the primary growth, in controlling residual or recurrent tumor in the orbit, in prevent­ ing metastasis, and in prolonging life. More­ over, it is of no value as a postoperative pro­ phylactic measure. Not only is the tumor tissue entirely radioresistant but also there is some evidence to indicate that the tumor growth may be stimulated by irradiation." 2

Once the diagnosis of malignant mela­ noma is established with reasonable cer­ tainty the treatment is usually enucleation. Enucleation should be done in all cases of PROGNOSIS malignant melanoma of the choroid and ciliary body unless it is felt that extraocular The most complete statistical study on extension has occurred, in which case the follow-up was that reported by Callender, orbit should be exenterated. In doing the Wilder, and Ash 23 in which they studied enucleation, care should be taken not to dis­ 1,600 cases on file in the Armed Forces In­ sect into any encapsulated extraocular ex­ stitute. In 500 of these there was at least a tension. A long section of optic nerve should five-year follow-up. The mortality on these be obtained routinely, though it is rare for 500 cases after five years was 48 percent. A a melanoma to spread by this route. Exami­ 10-year follow-up was obtained in 200 cases nation of the globe should be made carefully and the mortality rate increased to 66 per­ and if unencapsulated extraocular extension cent. is found, or if an encapsulated extension has Certain histologie characteristics are of been dissected into, exenteration of the orbit definite prognostic significance. The authors should be done.2 Before doing an enuclea­ studied these 500 cases from several stand­ tion it is well to check the liver for enlarge­ points and their results were: The different ment and have a chest X-ray film to deter­ cell types comprising the tumor had a very mine whether or not metastasis already ex­ different rate of metastasis. Least malignant ists. If there is definite evidence of metasta­ was spindle A, the mortality rate being six sis, there is little point in removing the eye percent in five years. These cases comprised a total of 35. Tables 1 and 2 were taken from unless it is painful. their report. Circumscribed tumors of the iris may be The authors also studied the 500 eyes removed by iridectomy rather than by enu­ cleation. This should be done only when the from the standpoint of pigment content, and lesion is well circumscribed and gonioscopic reported their findings as in Table 3. Though there appears to be an increased mortality examination shows the angle to be clear. Treatment other than surgical removal with increased pigment content, the authors should be strictly a second choice. Several did not feel that this one series justified def­ authors have reported on treatment with sur­ inite conclusions in this respect. face diathermy in the case of malignant TABLE 1 melanoma of the patient's only eye. The very OUTCOME ACCORDING TO CELL TYPE early results in some of these cases seem Living Dead Total % Fatal promising, but the literature does not contain adequate follow-up to draw any valid con­ 2 33 35 Spindle A 6 clusions. 25 88 29 117 Spindle B 38 8 S 13 Fascicular Radiation has been used. Duke-Elder 49 23 22 45 Necrotic 62 105 171 276 Mixed states that it is of no value as a primary 71 4 10 14 Epithelioid treatment but is worthwhile postoperatively.1

MALIGNANT MELANOMA OF T H E UVEA TABLE 2 OUTCOME ACCORDING TO ARGYROPHIL-FIBER CONTENT

Heavy Marked Medium Light Absent

Living

Dead

Total

% Fatal

17 58 80 101 S

2 32 63 122 20

19 90 143 223 25

10 36 44 55 80

The mortality according to cell type is in accord with that of neoplasms in general, in that the more anaplastic the cell the more malignant is the tumor. The spindle cell is the least anaplastic and the epithelioid the most. Reticulum is one of the intercellular elements that can be stained alone with the Wilder silver stain, thus the name argyrophil fiber. The more anaplastic epithelioid cell lays down the least reticulum and the slowergrowing spindle cell the most, so that these tables run roughly parallel. Another factor of significance in the mor­ tality in cases of these tumors is the time elapsed between onset of the tumor and the enucleation. No· such study is possible be­ cause in most cases the time of onset is not known. Unless the tumor occurs in the pos­ terior pole, causing some blurring or dis­ tortion of vision, the patient may not suspect it for a long time. Terry and Johns 14 re­ ported in their first series that 44.6 percent were unsuspected clinically. Reese2 reports figures of mortality originally reported by von Hippel and von Papolczy in which the mortality in cases of eyes enucleated in the first stage of the disease is 33 percent, in the second stage 45 percent, and in the third stage 90 percent. These figures do not show the time of onset but certainly support the idea that the earlier enucleation is done the better is the prognosis. TABLE 3 OUTCOME ACCORDING TO PIGMENT CONTENT

Light Medium Marked Heavy

Living

Dead

Total

% Fatal

93 114 50 4

48 121 61 9

141 235 111 13

34 51 55 69

603

The host's resistance to malignancy is an­ other unknown factor of which there is no measure. Thus in some individuals the ma­ lignant cell lies dormant for many years after the eye is enucleated before it metastasizes; in others the time is much shorter. Death from metastasis may occur as late as 20 or 25 years after the eye has been enucle­ ated. It does not seem unreasonable to assume that the same thing occurs in the case of the primary growth; that is, that the same type tumor histologically may take longer to grow in one patient than in another. Extraocular extension causes an increase in fatalities. In the Armed Forces Institute series, six percent had extraocular extension and the five-year fatality in this group was 67 percent, this being 19 percent greater than the average without extraocular exten­ sion. Duke-Elder 1 cites patients reported by Spicer (1912) and Denecke (1936) who were alive without evidence of metastasis 13 years after enucleation, though they had evi­ dent extraocular extension at the time. Recurrence in the orbit carries a more serious prognosis. Reese2 reports eight such cases in his personal experience. The mor­ tality rate in these was 100 percent and the average time of death 15 months after the orbital recurrence. Callender, Wilder, and Ash 23 reported three deaths in 32 malignant melanomas of the iris for a mortality rate of 9.4 percent. Three of the living patients had only an iridectomy. It was felt that earlier diagnosis was probably a large factor in the lower mortality from these tumors. Chisholm24 restudied Terry and Johns' series of 94 cases, first reported in 1935, from the standpoint of longer follow-up. He found that of those patients dying from spindle-A and spindle-B tumors the average time between enucleation and death was 10.5 years. The patients with fascicular, epithe­ lioid, and mixed tumors died in 3.8 years. Compared with malignant melanoma else­ where in the body the prognosis is better in the eye. Pack and Scharnagel,25 in reporting on 575 cases of nonocular malignant mela-

604

JAMES H. SCRUGGS

noma, showed a five-year cure of 21.4 per­ cent. This varied according to location. Ten cases of anorectal lesions had no survivals. Oronasal had 9.1 percent five-year survival, trunk 13.7 percent, sublingual 38.9 percent and palm 97.5 percent. The authors felt that two factors were responsible for this, early diagnosis in some sites and accessibility of wide excision. Seventy-three percent of this group were considered operable when first seen and immediate surgery cured 39.9 per­ cent. Delay of more than one month in sur­ gery gave 17 percent less cure. As has been reported earlier in this paper, the cell type of the intraocular melanoma is of definite prognostic significance. It would seem that another factor of definite importance is the location of the tumor inside the eye. The density of the encasing sciera is a limiting factor in the tumor's growth as well as help­ ing to insure its complete removal, except in a small number of cases in which extraocular extension has occurred. It would seem that this must play some part in the lowered mortality of intraocular malignant mela­ noma. In the group of nonocular malignant melanomas reported by Pack and Scharnagel,23 there was a marked difference in mortality, ranging from 12.5 percent, fatali­ ties from those lesions on the palm to 100 percent from those in the anorectal region. No mention is made of any difference in cell type. The authors felt the difference to be due to early detection and accessibility of wide excision. As previously stated it was felt that delay of more than one month in surgical removal increased mortality 17 per­ cent. In the eye most of the tumors probably go a good many months before detection, some of the slower-growing ones perhaps for years. Probably the time of removal from the eye is not so important to the prognosis as removal elsewhere in the body because the encasing sciera may limit its growth. The factor of "accessibility of wide excision" is greatly eliminated by the tumor usually being contained within the sciera.

It would seem then that both the cell type of the tumor and the structure of the eye itself, as compared to the body elsewhere, are factors that give a better prognosis to intraocular melanoma. C A S E REPORTS CASE 1

Mrs. E. W. was 83 years of age when first seen on August 28, 1952. She complained of pain in the right eye and blindness for three months. Vision, O.D., was no light perception; O.S., 20/40. Intra­ ocular pressure (Schätz); O.D., 64; O.S., 17 mm. Hg. The right eye was injected and the cornea edematous. Enucleation was advised and refused. A retrobulbar injection of alcohol was done and this relieved the pain. On September 14, 1953, the eye was again painful and a dark elevated mass could be seen on the globe behind the limbus su­ periorly. It was felt that this might be a melanoma. Surgery was again refused. Another year passed and the globe eroded in this area with some drain­ age of dark material; a smear of this showed it to be a malignant melanoma. Her internist found no clinical evidence of metastasis at this time; X-ray studies were not done. The patient died in Janu­ ary, 1955, at the age of 86 years. Post-mortem studies were not done. Death was attributed to cardiac failure. CASE 2

Mr. J. R. B., a 72-year-old man was seen on March 9, 1956, with complaint of loss of vision in the left eye. History revealed some light flashes in the lower field about five months previously, vision had been noticeably reduced for two months. Vision : O.D., 20/20; O.S., finger counting. A large dark mass was visible superiorly. Examination by an in­ ternist revealed an enlarged liver, chest X-ray films were negative. It was decided to have a liver biopsy and to proceed with enucleation at the same time if this was negative for melanoma. However, biopsy revealed extensive liver metastasis and the enuclea­ tion was not done. The patient died April 14, 1956. The eye was not obtained. The liver biopsy showed many epithelioid cells. CASE 3

Mr. F. D., a 68-year-old man, was seen first March 26, 1954, because of some irritation and pain in his left eye. History was given of having surgery for glaucoma, O.S., in 1950 with some vision re­ tained for six months. Then several intraocular hemorrhages had occurred. Schätz tension: O.D., 15 ; O.S., 42 mm. Hg. There was some ciliary in­ jection, O.S., and blood staining of the cornea. The right anterior chamber was of normal depth, fundus and field normal. Enucleation was done April 5, 1954. Microscopic sections showed a spindle-cell malignant melanoma in the anterior segment. The patient was last seen in January, 1957, without evi­ dence of recurrence, metastasis, or glaucoma in the right eye.

M A L I G N A N T M E L A N O M A OF T H E U V E A CASE 4

Mr. O. L. This 50-year-old man was first seen July, 1953, with the complaint of blurred vision in his left eye. His glasses had been changed three months before and vision Iiad been good at that time. Vision, O.S., 20/60, improved to 20/25 with the addition of a -1- 1.25D. sph. There was a slightly elevated faint gray lesion seen in the macula about 0.5 disc diameter in size. The patient was told that it might be a hemorrhage and might be a tumor and to return in six weeks for follow-up. He did not keep this appointment and was next heard from a year later (December, 1956) through another ophthalmologist who had enucleated his eye two months earlier for malignant melanoma. He was apparently in good health. COMMENT

Case 1 presents a unilateral glaucoma without evidence of glaucoma in the fellow eye. Melanoma was probably present at that time, though the fundus could not be visual­ ized. The patient lived two and a half more years without evidence of metastasis, though the tumor eroded the ruptured globe. Case 2 presents quite a contrast. First symptoms were five months prior to the pa­

60S

tient being seen, and metastasis was already well established in the liver; the patient died a month later. Case 3 presents another case of unilateral glaucoma without any evidence of glaucoma in the fellow eye. Again the fundus could not be visualized but enucleation revealed a malignant melanoma. Case 4 represents a case in which the symptoms of blurred vision were noticeable very early because the tumor was in the pos­ terior pole. Its growth was relatively slow. Both Cases 3 and 4 present the problem of patients failing to return for adequate follow-up observation and eventually chang­ ing doctors, one patient leaving another doc­ tor and coming to me, and another leaving me and going to another doctor. In each case, the second doctor was not consulted in order to obtain a second opinion but was seen only after considerable time had elapsed and symptoms had increased. 2225 Austin Avenue.

REFERENCES 1. Duke-Elder, W. S.: Text Book of Ophthalmology. St. Louis, Mosby, 1940, v. 3, pp. 2477-2518. 2. Reese, A. B.: Tumors of the Eye. New York, Hoeber, 1951, pp. 221-316. 3. Shine, F. W.: Report of a case of bilateral sarcoma of the uveal tract. New York Eye & Ear Inf. Clinic Rep., 1:31, 1930. 4. Cordes, F. C , and Cook, R. D.: Tr. Am. Ophth. Soc, 47:80, 1949. 5. Theobald, G. D.: Neurogenic origin of choroidal sarcoma. Arch. Ophth., 18:971, 1937. 6. Wilder, H. C : Intraocular tumors in soldiers of World War II. Military Surgeon, 99:459, 1946. 7. Reese, A. B.: The culture of uveal melanomas. Am. J. Ophth., 46:163 (Oct. Pt. I I ) , 1958. 8. Callender, G. R.: Malignant melanoma of the eye: A study of histologic types in 111 cases. Tr. Am. Acad. Ophth., 1931, p. 131. 9. Albers, E. C : Benign melanomas of the choroid and their malignant transformation. Am. J. Ophth., 23:779, 1940. 10. Asbury, M. K., and Vail, D . : Multiple primary malignant neoplasms. Am. J. Ophth., 26:688, 1943. 11. Goulden and Stallard: Tr. Ophth. Soc. U. Kingdom, 52 : 481,1932. 12. De Veer, J. Α.: Arch. Ophth., 51:147, 1954. 13. Coats: Tr. Ophth. Soc. U. Kingdom, 32:165,1902. 14. Terry, T. L., and Johns, J. P.: Uveal sarcoma. Am. J. Ophth., 18:903, 1935. 15. Rones, B., and Linger, H. T.: Early malignant melanoma of the choroid. Am. J. Ophth., 38:163, 1954. 16. Pischel, D. K.: Discussion of Prof. Verdaguer. Am. J. Ophth., 32:68, 1949. 17. Reese, A. B.: Paper given at Univ. of Florida Midwinter Seminar, 1957. 18. Christensen, L., and Rowen, G.: Arch, of Ophth., 54:477, 1954. 19. Kauflfman, L., and Zentmayer, W . : Arch. Ophth., 47:541, 1952. 20. Terner, I. S., Leopold, I. H., and Eisenber, I. J.: Arch. Ophth., 55:52, 1956. 21. Shapiro, I.: Arch. Ophth. 57:14, 1957. 22. Griffey, E. W., Whalen, H., and Allen, H.: Report given at Texas M. A. meeting. May, 1957. 23. Callender, G. R., Wilder, H. C , and Ash, J. E.: Five hundred malignant melanomas of choroid and ciliary body followed five years or longer. Tr. Am. Acad. Ophth., 1941-42, p. 223. 24. Chisholm, J. F., Jr.: A long-term follow-up on malignant melanoma of the choroid: based on the Terry and Johns' Series. Am. J. Ophth., 36:61, 1954. 25. Pack, G. T., Gerber, D. M., and Scharnagel, I. M.: Ann. Surg., 136:905, 1952.