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Necrosis of Malignant Melanoma of the Choroid
NECROSIS O F MALIGNANT MELANOMA O F T H E CHOROID ALGERNON B. REESE, M.D.,
EDUARDO ARENAS ARCHILA, M.D.,
AND W I L L I A M C. COOPER,
IRA S. JONES,
M.D.,
M.D
New York, New York In our study of necrosis of malignant choroidal melanoma, to be reported here, the objective was to determine the clinical sig nificance of the necrosis—how it confused the clinical picture and delayed the correct diagnosis. As the study progressed, our hori zons were broadened to include speculation about the cause of the necrosis and the possi bility that it is an immune response. The necrosis of uveal melanomas has been widely discussed in the literature. Two types are recognized : 1. Cellular—minimal recognizable changes From the Institute of Ophthalmology, ColumbiaPresbyterian Medical Center, New York. Pre sented in part at the meeting of the American Ophthalmological Society, Hot Springs, Virginia, May 26, 1969. Reprint requests to Algernon B. Reese, M.D., 635 West 165th Street, New York City 10032. Dr. Archila was the recipient of a fellowship from the Pan-American Association of Ophthalmology; present address: Calle 17, No. 4-80, Bogota, Co lombia.
associated with tumor-cell death, principally in the nuclei as pyknosis, karyorrhexis or karyolysis, or in the cytoplasm as swelling and hydropic degeneration (figs. 1 and 2 ) . 2. Lytic—an advanced stage characterized by areas of coalescing cystic spaces (fig. 3). A histopathologic survey of 100 consecu tive cases of malignant melanoma of the choroid at the Institute of Ophthalmology re vealed cellular and lytic necrosis in 22%. In addition, a type of coagulation or infarct necrosis was found in 5%. Since such an area is often observed in only one part of the tumor, the true incidence of infarct ne crosis may not be determined by statistics such as ours, based on random sections. Lymphocytic infiltration has been fre quently reported, not only in and around the necrosis of the uveal melanoma, but also throughout the uvea of the affected eye (fig. 4). This inflammatory reaction, associated with tumor necrosis, is usually attributed to
Fig. 1 (Reese, Archila, Jones, and Cooper). Spontaneous regression of a malignant choroidal melanoma, (A) dark solid mass in the lower nasal quadrant of the left eye of a 34-year-old woman shows some chorioretinal pigment changes around the base. (B) Regression of the tumor over the next two-anda-half years was manifested by a decrease in its size and an increase in chorioretinal scarring. 91
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Fig. 2 (Reese, Archila, Jones, and Cooper). Photomicrograph of a section of the enucleated globe shows hydropic necrosis of a malignant choroidal melanoma (hematoxylin-eosin, X400).
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Fig. 4 (Reese, Archila, Jones, and Cooper). Necrosis of a malignant melanoma of the choroid with an unusually large number of lymphocytes in the adjacent choroid (hematoxylin-eosin, XlOO).
cytotoxic agents of degenerating melanocytes. However, the necrosis of a uveal mel anoma produced by coagulation therapy causes no undue inflammatory reaction,1 suggesting that some factor other than ne crosis may be responsible. The size of the tumor appears to be unre lated to the incidence of necrosis (figs. 5 and 6). Since necrosis occurs in small or flat le sions, it cannot be attributed to hypotension in the vascular sinusoids of the tumor or to passive congestion. We have attempted to correlate (1) ne crosis observed in histologie sections with the
Fig. 3 (Reese, Archila, Jones, and Cooper). A malignant melanoma of the choroid with lytic ne crosis and chronic inflammation (hematoxylin-eosin, XlOO).
Fig. S (Reese, Archila, Jones, and Cooper). Is chémie necrosis of a small, flat, malignant choroi dal melanoma with inflammatory retinal edema and a macular star. ( A ) The drawing above shows dark, slightly elevated subretinal lesion below the disc with an extension toward the macula. The overlying retina, including the macula, was edematous, and hard white deposits radiated from the fovea. ( B ) Section shows infarct necrosis in the center of the lesion (hematoxylin-eosin, χ 2 5 ) .
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clinical findings, and (2) the uveal melano mas showing clinical signs of inflammation with the necrosis in histologie sections. The material falls into two groups which will be discussed. One is characterized by diffuse cellular and lytic necrosis and the other by sharply demarcated coagulation necrosis. GROUP
1:
MALIGNANT
CHOROIDAL
MELA
N O M A WITH DIFFUSE CELLULAR AND LYTIC NECROSIS
In this group (table 1), inflammation was clinically manifested in all 18 eyes (figs. 5-8). Choroiditis was present in 13, healed choroiditis in three, chorioretinal atrophy and serous detachment of the retina in one, and serous retinopathy with flat retinal de tachment in one. The presenting symptoms were blurred vision and, occasionally, pain. The final diagnosis of malignant choroidal melanoma was established only after periods ranging from four months to 17 years. Tumor sections showed varying degrees of cell necrosis ; the focal areas sometimes co alesced, forming cystic spaces (figs. 1, 2 and 3), or were replaced by scar tissue (fig. 9). Melanin liberated from the necrotic cells was dispersed as free melanin in the tumor sub stance, in the surrounding choroid, in the retina, and in the vitreous. Nests of macro-
Fig. 6 (Reese, Archila, Jones, and Cooper). Fundus shows inflammatory edema and a macular star due to a necrotic, flat, malignant choroidal melanoma. The presence of an indistinct, flat, subretinal mass suggested the diagnosis of a necrotic malignant choroidal melanoma, which was con firmed by histologie sections.
phages filled with liberated melanin were a prominent feature in some cases (fig. 10). We also found varying degrees of inflam matory reaction throughout the tumor. Many eyes showed chorioretinal adhesions and reti nal pigment proliferation over and around the tumor site (fig. 7). The adhesions simu lated those accompanying and following cho roiditis (figs. 7, 11, 12). The inflammatory
Fig. 7 (Reese, Archila, Jones, and Cooper). A regressing malignant choroidal melanoma, showing (A) flat, pigmented chorioretinal scar which became increasingly elevated over a period of eight months; (B) a section through the flat portion of the tumor showing regressive change with chorioretinal scarring (hematoxylin-eosin, XlOO).
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TABLE 1 MALIGNANT CHOROIDAL MELANOMA WITH DIFFUSE CELLULAR AND LYTIC NECROSIS
Early Diagnosis, Clinical Course
Case No., Sex, Age
Symptoms
1. F-45
Blurred vision
Choroiditis; inflammation treated with corticosteroids; vision improved from 20/50 to 20/20
9 months
Malignant melanoma with diffuse and focal lytic necrosis
2. M-17
Blurred vision
Juxtapapillary choroiditis; optic neuritis; inflammation of uvea improved with corticosteroids
9 months
Partially necrotic malig nant melanoma with scleritis, iridocyclitis, inflamma tory reaction in choroid and tumor
3. F-44
Blurred vision
Exacerbation of old chorioretinitis; inflammation of uvea; corticosteroids improved vision, symptoms
3 years, 3 months
Necrotic malignant choroi dal melanoma with inflam matory reaction in tumor, choroid, ciliary body and sciera
Period Before Enucleation
r
Pathologic Findings
4. F-14
Blurred vision
Angiospastic retinopathy; larval granuloma; inflammation of uvea treated with corticosteroids; vision im proved from 20/50 to 20/25.
3 years, 5 months
Partially necrotic malig nant choroidal melanoma with mild inflammation of choroid and sciera
5. M-4S
Blurred vision
Uveitis; inflammation treated with corticosteroids; vision improved from 20/200 to 20/40
3 years, 4 months
Malignant choroidal melanoma with lytic necrosis; inflammatory reaction in tumor, choroid, ciliary body and sciera
6. F-40
Blurred vision
Inflammation of uvea; some improvement with cortico steroids
4 months
Malignant choroidal mela noma with inflammatory reaction in tumor, choroid, ciliary body and, especially, sciera
7. F-S7
Blurred vision
Inflammation of uvea; improvement with corticosteroids
1 year, 6 months
Malignant choroidal mela noma with lytic necrosis; inflammatory reaction in tumor, choroid, ciliary body and sciera
8. M-54
Blurred vision
Old and active chorioretinitis; improvement in vision from 20/60 to 20/20 with cortico steroids
3 years
Malignant choroidal mela noma with inflammatory reaction in tumor, choroid, ciliary body and sciera
9. M-70
Blurred vision
Active uveitis; unusual migration of pigment into retina; improvement with cortico steroids
4 months
Malignant choroidal mela noma with lytic necrosis; inflammatory reaction in tumor, choroid, ciliary body and sciera
10. M-51
Poor vision
Uveitis; previous operation for detached retina. Improve ment in vision from counting of fingers to 20/50 with corticosteroids
9 years
Malignant choroidal mela noma with cellular necrosis; inflammatory reaction in tumor and uvea
11. M-50
Blurred vision
Serous retinopathy, then deep choroidal hemorrhage with flat retinal detachment; Steady decline of vision
2 years, 2 months
Flat, necrotic, malignant choroidal melanoma in macula, extending around disc and extraocularly
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TABLE 1—(Continued) MALIGNANT CHOROIDAL MELANOMA WITH DIFFUSE CELLULAR AND LYTIC NECROSIS
Case No., Sex, Age
c *. Symptoms
Period Before Enucleation
Early Diagnosis, Clinical Course
Pathologic Findings
12. F-79
Pain, poor vision
Secondary glaucoma, cataract, and finally rubeosis of iris and hyphema
2 years
Necrotic malignant choroidal melanoma
13. F-52
Pain
Secondary glaucoma; iridencleisis with control of tension for 3 years; enucleation because of painful blind eye with cataract
3 years
Necrotic malignant cho roidal melanoma with inflammatory reaction
14. M-51
Poor vision
Chorioretinal atrophy and then serous retinal detach ment. One dark, flat area suggestive of melanoma
4 years
Malignant choroidal mela noma with diffuse and focal lytic necrosis
15. M-53
Blurred vision
Patient had Hodgkin's disease; relatively unpigmented mass in fundus believed to be either granuloma or malignant melanoma
2 years
Malignant choroidal mela noma with diffuse and focal lytic necrosis
16. M-4S*
Blurred vision
Chorioretinitis or flat malignant choroidal melanoma
3 years
Malignant choroidal mela noma with lytic necrosis and increase in collagen
17. F-44f
Blurred vision
Chorioretinitis; healed for 16 years then repeated hemor rhages in vitreous with rapid development of mass; many pigment granules in vitreous
17 years
Malignant choroidal mela noma with lytic necrosis and sclerosis. Masses of pigment-laden macro phages
18. F-45Î
Blurred vision
Flat area of chorioretinal scarring in lower temporal quadrant of fundus; elevated arch in center
2 years
Malignant choroidal mela noma with lytic necrosis
* See Fig. 7. t See Fig. 10. j See Fig. 8. cells were small lymphocytes and plasma cells (fig. 4 ) . GROUP 2:
MALIGNANT CHOROIDAL MELA
NOMA WITH COAGULATION NECROSIS
The 17 eyes in this group (table 2) char acteristically produced a sudden onset of pain, blurred vision, swelling of the eyelids and the conjunctiva and occasionally proptosis. However, this abrupt onset was preceded by inflammation of the eye or its sequelae. The usual clinical picture was chemosis and congestion of the eyelids and the conjunc tiva (11 cases), associated with uveitis (five cases), localized siceritis (four cases), glau coma (six cases), and detachment of the ret ina (six cases). The inflammation often sub
sided sufficiently with steroid therapy to per mit diagnosis of the malignant choroidal melanoma. The delay in diagnosis was not as long in this group as in Group 1, ranging from a few days to nine years. Three patients had proptosis and immobil ity of the eye with orbital inflammation sim ulating panophthalmitis. One patient with proptosis had hypopyon and another had hyphema; in both, the tumor had diffusely infiltrated the orbit, extending into the antrum in one and into the sphenoidal and ethmoidal sinuses in the other. A sharply demarcated infarct or area of ischémie or coagulation necrosis was noted in sections of all the tumors (figs. 13-15). The line separating viable and necrotic
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TABLE 2 MALIGNANT CHOROIDAL MELANOMA WITH COAGULATION NECROSIS
Early Diagnosis, Clinical Course
Case No., Sex, Age
Symptoms
1. F-63
Sudden pain, blurred vision
Malignant melanoma, chemosis and congestion of conjunc tiva and eyelids, steamy cornea
3 days
Massive coagulation necro sis of malignant choroidal melanoma; keratitis, scler itis and necrosis of iris and ciliary body; collateral in flammatory tissue over sciera
2. F-23
Sudden pain, loss of vision, swelling of eye lid and conjunc tiva; chills and fever
Bacterial embolus. Proptosis, detached retina; symptoms cleared with corticosteroids: retinal reattachment per mitted visualization of subretinal gray mass
3 months
Coagulation necrosis of malignant choroidal mela noma with inflammation of iris, ciliary body, choroid and sciera
3. F-47*
Sudden pain, redness and swelling in both eyes
Malignant choroidal melanoma; chemosis of conjunc tiva and eyelids; indistinct grayish mass under retina
4. F-58
Intermittent pain
Malignant choroidal mêlanoma; localized scleritis and dilated episcleral vessels
S months
Coagulation necrosis of tumor
5. F-58
Pain, swelling, inflammation
Proptosis; biopsy from antrum revealed malignant melanoma
2 months
Necrotic malignant choroi dal melanoma invading orbital bones and sinuses
6. M-39f
Poor vision, pain
Malignant choroidal melanoma; localized chemosis and congestion of conjunctiva and sciera corresponding to site of retinal detachment
3 months
Necrotic and hemorrhagic malignant choroidal mela noma with marked inflam matory reaction in ad jacent sciera
7. F-48Î
Sudden pain, loss of vision
Absolute glaucoma (iridencleisis) ; previous episodes with spontaneous regression; chemosis of conjunctiva and eyelids complete detachment of retina, exophthalmos
10§ months
Coagulation necrosis of malignant choroidal mela noma surrounded by lym phocytes; extension to orbit
8. M-55§
Severe sudden pain, inflam mation
Malignant choroidal melanoma; chemosis of conjunc tiva, iridocyclitis, hemorrhage and pigment dispersement in subretinal mass
3 months
Flat tumor with coagula tion necrosis, marked inflammatory reaction and episcleral scar tissue from scleritis; extraocular extension of tumor
9. F-80
Sudden pain, loss ot vision
Absolute glaucoma
2 months
Massive coagulation necro sis of malignant choroidal melanoma with inflamma tory reaction throughout eye
10. F-30
Sudden pain, redness of eye
Malignant choroidal melanoma; conjunctival swelling and episcleral congestion over quadrant corresponding to indistinct mass in fundus
2 months
Coagulation necrosis of malignant choroidal mela noma; inflammatory re action in and around tumor and throughout uvea
* See t See t See § See
Fig. Fig. Fig. Fig.
13. IS. 14, 6.
Onset to Enucleation
Few days
Pathologic Findings
Coagulation necrosis of lesion with marked lymphocytic reaction which ex tended to adjacent choroid, sciera and episclera
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CHOROIDAL MELANOMA TABLE 2—(Continued) MALIGNANT CHOROIDAL MELANOMA WITH COAGULATION NECROSIS
C
Early Diagnosis, Clinical Course
«-s
Ä
Onset to Enucleation
Pathologic Findings
11. F-54
Pain, chemosis, glaucoma, loss of light per ception
Absolute glucoma; patient thought for S years to have inoperable detached retina from inflammation; not seen for 4 years when she developed sudden pain, chemosis and glaucoma
9 years
Coagulation necrosis of flat, malignant choroidal mela noma with extraocular extension
12. M-51
Recurrent pain
Uveitis; swollen eyelids and congested conjunctiva; iridocyclitis; detached retina with underlying indistinct mass; symptoms cleared with corticosteroids and retina reattached ; vision became nor mal but malignant choroidal melanoma was discernible
3 years
No necrosis or inflammation in tumor sections studied; old chorioretinal adhesions and cystic degeneration of retina probably from partially regressed tumor
13. M-69
Sudden severe pain, loss of vision
Inoperable serous detachment 17 months of retina diagnosed 17 months earlier; tension 4 + , hypopyon, globe fixed and proptosed
Coagulation necrosis of malignant choroidal mela noma with extension to orbit and sinuses; marked inflammatory reaction
14. F-40*
Blurred vision
Malignant choroidal melaFew weeks noma with focal necrosis; macular edema with white radiating striae around fovea; central scotoma; vision 20/40
Small, relatively flat tumor with central focus of coagulation necrosis
IS. F-69
Severe pain
Absolute glaucoma; edema of Few days bulbar conjunctiva and eye lids ; cornea too steamy to view f und us; T = 72 ; hemorrhage in anterior chamber
Extensive coagulation necrosis of malignant choroidal melanoma with inflammatory reaction of entire uvea and sciera
16. M-40f
Shadow before eye, micropsia
Malignant melanoma of Few weeks choroid diagnosed in 1963; malignant melanoma of skin of leg in 1955; radical resec tion of groin for recurrence in 1961
Small malignant choroidal melanoma with central infarct necrosis
17. M-54t
Poor vision, pain
Severe uveitis; marked imFew months provement with corticosteroid therapy
Focal area of sclerosis in flat, malignant choroidal melanoma interpreted as necrotic scar with evidence of scleritis and keratitis
* See Fig. 5. t See Fig. 16. X See Fig. 9. tumor tissues was often accentuated by a zone of lymphocytes. Inflammatory cells were present throughout the tumor as well as in the uvea, the sciera, and the cornea and even extended from the globe to the orbit. DISCUSSION
T h e clinical course in each group seemed to have a definite pattern: in Group 1 there
was inflammation and diffuse cellular ne crosis ; in Group 2 there was evidence of the Group 1 pattern and, in addition, an occlu sive vascular process which finally leads to ischémie necrosis. T h e inflammatory phase was followed by a chronic course masquerading as active or inactive choroiditis, scleritis, uveitis, secon dary glaucoma, or retinal detachment, until
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Fig. 8 (Reese, Archila, Jones, and Cooper). A regressing malignant choroidal melanoma, show ing a flat area of chorioretinal scarring from which arises a subretinal mass. The diagnosis of malig nant melanoma was confirmed by histologie sections which showed diffuse lytic necrosis. an infarct suddenly ushered in the acute phase. The regression of cancer is associated, clinically and experimentally, with necrosis, lymphocytic infiltration, hydropic degenera tion, and fibrosis. The cancer cells provoke a reaction from the immunocompetent cells of
Fig. 10 (Reese, Archila, Jones, and Cooper). A partially necrotic malignant choroidal melanoma with an area of pigment-laden macrophages (hematoxylin-eosin, XlOO). In 1951, three ophthal mologists diagnosed a healed chorioretinal scar in the left eye of a 44-year-old woman. By 19S8, the scar seemed elevated but no other change was observed until 1967, when her vision became blurred due to a vitreous hemorrhage. After it absorbed, her vision returned to normal. By March, 1968, the lesion had progressed considerably, and many pigment particles were noted in the vitreous.
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Fig. 9 (Reese, Archila, Jones, and Cooper). A malignant melanoma showing a postnecrotic scar (hematoxylin-eosin, χ 4 0 ) . After severe uveitis in the right eye had cleared, a subretinal mass could be visualized, with unusually heavy migration of pigment into the retina and vitreous. Histologie examination confirmed the diagnosis of malignant choroidal melanoma and revealed lymphocytic in filtration of the postnecrotic scar. the lymphocytic series: the lymphocyte and the plasma cell, by producing immunoglobulin, and the lymphocyte alone, by affecting the endothelium. The action of the endothelial cells paves the way for thrombosis and occlusive processes which produce necrosis and infarcts. Thus, immunity to cancer
Fig. 11 (Reese, Archila, Jones, and Cooper). Possible regressed malignant choroidal melanoma. A 76-year-old man had been advised by many ophthalmologists in past years that his left eye had a malignant choroidal melanoma and should be enucleated. Drawing shows a white elevated mass in the upper temporal quadrant of the left fundus and cataractous changes in the correspond ing sector surrounded by pigment changes. Below the disc was a benign choroidal melanoma. The corrected vision was 20/70. There was no history of injury and no intraocular foreign body was seen on x-ray films (case cited through the cour tesy of Dr. Richard Kanter).
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seems to be concerned more with cellular than with humoral factors. These histologie changes seem conspicu ous in the material from our series, of which one case seems particularly pertinent. CASE REPORT
A man, aged 45, had a malignant melanoma of the skin of the left leg in 1955. It was widely ex cised, but a similar lesion developed in the left groin six years later. After a radical dissection, he remained well until 1963 when he showed micropsia and a shadow before the right eye. On examination, a malignant choroidal melanoma was found with neovascularization, edema, and dis persed pigment in the central portion thought to be tumor necrosis. Since this tumor was consid ered primary, the eye was enucleated. The clinical course indicated marked host re sistance to the first malignant melanoma of the skin, reflected in the histopathology of the malig nant choroidal melanoma (fig. 16). S P O N T A N E O U S REGRESSION
The following sequence of events enabled us to observe malignant choroidal melano-
Fig. 12 (Reese, Archila, Jones, and Cooper). Possible regressed malignant choroidal melanoma. A woman, aged 63, had been told by many oph thalmologists during a 17-year period that her left eye should be removed because of cancer. Draw ing shows a flat, dirty-brown lesion with two nodular protrusions in the periphery of the fundus. The surrounding fundus showed marked pigmenta tion, and pigment granules were dispersed in and around the lesion. The patient had numerous nevi of the face, particularly on the left side (case cited through the courtesy of Dr. Solomon Liebowitz).
Fig. 13 (Reese, Archila, Jones, and Cooper). Inf arct necrosis of a small malignant choroidal mela noma.' A woman, aged 47, had a sudden painful in flammatory episode with edema of the eyelids and conjunctiva. Through cloudy media, a detached ret ina could be seen. There were dilated episcleral ves sels over the area corresponding to the detach ment. (A) Necrosis of the central portion of the melanoma with an inflammatory reaction extend ing to surrounding structures including the adjac ent sciera (hematoxylin-eosin, XlO). (B) Under higher power, portion outlined in (A) shows de marcation between necrotic and viable portions of the tumor (X40). mas during spontaneous regression to the point of a presumed cure. An unusual tume faction in the fundus of the eye in a woman of 30 years was attributed to massive hyperplasia of the pigment epithelium (fig. 17). Several ophthalmologists at different times in the past had diagnosed the lesion as a ma lignant tumor and advised enucleation, which the patient refused. At the time of our first examination, a bluish-black nodular lesion protruded abruptly into the vitreous and was surrounded by a flat zone of chorioretinal atrophy and pigmentation. The tumefaction regressed gradually over the next seven years, and only a small flat atrophie scar now remains after eight years.
Fig. 14 (Reese, Archila, Jones, and Cooper). Infarct necrosis of a malignant choroidal melanoma. Histologie examination following enucleation of the left eye revealed lymphocytic infiltration surrounding the necrosed and inflamed orbit to which the melanoma had spread. (A, left) Section of lesion shows coagulation necrosis (hematoxylin-eosin, χ ΐ θ ) . (Β) In a higher power view of the same area, the necrotic portion of the tumor is sharply demarcated from the viable portion with heavy lymphocytic infiltration (X40).
We have since tried to identify other such dark and nodular processes. If, as we be lieved, they represented hyperplasia of the pigment epithelium, they might well show
Fig. 15 (Reese, Archila, Jones, and Cooper). Infarct necrosis of a malignant choroidal me lanoma. A pigmented lesion in the fundus cor responded to the site of a retinal detachment. The necrotic and viable portions are clearly de marcated (hematoxylin-eosin, χ40).
spontaneous regression. A lesion thought to be of this type, in the fundus of a woman, aged 57, slowly regressed for a period of IS months, when the patient's vision suddenly dropped from 20/200 to the counting of fin gers, as the result of a vitreous hemorrhage (fig. 18). Since the lesion could not be ob served accurately through the cloudy media and it was feared that the hemorrhage might indicate active growth, the eye was enucle ated. Sections showed a malignant melanoma of the choroid with lytic necrosis. We now feel that such a hemorrhage does not neces sarily indicate active growth of a melanoma, but may be due to an occlusive vascular pro cess associated with its regression. Because of this finding, we did not pursue the same watchful course with another pa tient who had a similar lesion of the fundus (fig. i ) . It thus appeared impossible for us clini cally to identify hyperplasia of the pigment epithelium ; we concluded that it must be ex tremely rare in view of the dearth of histopathologic evidence of epithelial prolifera tion to the point of tumefaction. Our present conviction is that the lesion in Figure 17 was an unrecognized, partially regressed, malignant choroidal melanoma which was subsequently pronounced a
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"cure." This impression, and the apparent steady regression in the two cases cited above (figs. 1 and 18), led us to continue ob servations in another patient whose fundus lesion showed the steady regression pattern of a malignant choroidal melanoma. After seven years, we consider this a permanent spontaneous cure (fig. 19). In the absence of microscopic evidence, it is natural to question whether the clinical di agnosis was correct in the instances pre sented as spontaneous cures of malignant choroidal melanomas. We believe there is lit tle room for doubt based on the following: 1. Unanimous confirmation of the diagno sis by many ophthalmologists. 2. The fact that the two cases in question belonged in the large group (95%) of malig nant choroidal melanomas that can be clini cally diagnosed with certainty. In the other 5%, where diagnosis may be doubtful, the eyes have cloudy or opaque media, or a flat
Fig. 17 (Reese, Archila, Jones, and Cooper). A lesion thought to be a regressing malignant choroidal melanoma. A woman, aged 30, was seen because of a pigmented mass in the right fundus. The 4-disc diameter, solid-appearing lesion, which projected into the vitreous cavity, was above and temporal to the macula. The patient has now been followed for 13 years. Drawings show (A, left above) a mulberry-like lesion with pigment de posits disperesd in the vitreous and below the de pendent part of the tumor, which was interpreted as hyperplasia of the pigment epithelium; ( B , right above) relatively little change in the fundus seven months later; and (C, adjacent) dramatic shrinking of the tumor five years and three months after the first examination, when an atrophie base and increased pigment dispersion can be seen.
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Fig. 16 (Reese, Archila, Jones, and Cooper). Infarct necrosis of a primary malignant choroidal melanoma in a patient with an earlier primary malignant melanoma of the skin. ( A ) and ( B ) show occluded sclerosed vessels surrounded by lymphocytes in the region indicated by the rectan gle (hematoxylin-cosin, χ Ι Ο Ο ) ; (C) shows a par tially occluded vessel ( X 4 0 ) .
diffuse melanoma with detachment of the retina and/or necrosis.
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Fig. 18 (Reese, Archila, Jones, and Cooper). Spontaneous regression of a malignant melanoma of the choroid. A woman, aged 57, had had two hemorrhagic episodes involving the vitreous of the left eye. Drawing ( A ) made after the last hemorrhage had cleared shows a jet-black, mushroom-shaped mass with chorioretinal scarring around the base; ( B ) shows the tumor after it had steadily regressed for one year and three months.
If choroidal melanomas do undergo invo lution to a cure, why is the residuum not seen clinically? For one reason the eye is usually enucleated before the tumor has run its course, and for another the residuum may not be recognized. If the lesions shown in Figures 13 and 16 had been seen in the final stage of regression, their ancestry would very likely have been unsuspected, and they might have been interpreted as residua of a choroiditis. Since becoming interested in this subject, we have encountered several mysterious fundus lesions which we immediately suspected of being regressed malignant choroidal mel anomas. Two such cases are shown in Fig ures 18 and 19. Flat, malignant choroidal melanomas are particularly inclined to show inflammatory changes and necrosis ; in fact, Font, Spaulding and Zimmerman3 found postnecrotic scars in 40% of their cases. A flat melanoma with a localized tumefaction at one site is at times difficult to distinguish from the usual globular choroidal melanoma which has par tially regressed (figs. 18 and 19). The only reference to spontaneous regres
sion of uveal melanomas found in the litera ture is that of Fuchs 4 (1910), who stated that the flat lesions tend to cause iridocyclitis which may lead to phthisis bulbi. In their recent report on 103 patients with malignant melanoma, Lewis and associates5 stated that over one-third of the sera tested demonstrated antibodies to autologous mela noma cells. Two types of antibodies were recognized: one active against antigen(s) in the cell surface membrane, and the other reactive with cytoplasmic antigens which appeared to be present in most or all mela noma cells. Animal immunity to cancer has been es tablished beyond question, but in man there is the ever-present possibility that homolo gous and heterologous transplants will pro voke an antigenic response. Nevertheless, clinical and experimental evidence of an im munologie response to cancer in man pre sents a formidable case for host resistance. The excellent review articles by Southam8 in 1960, and by Fairley7 in 1969, document the following : 1. There are many cases of spontaneous cures of cancer.
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/-'.'Yl1.*'.
Fig. 19 (Reese, Archila, Jones, and Cooper). Complete spontaneous regression of a malignant choroidal melanoma. A woman, aged 30, presented with a pigmented mass in the right fundus. A number of ophthalmologists in different cities had diagnosed the lesion as a malignant choroidal melanoma. Around the base was a zone of atrophy and secondary pigmentation. The lesion was observed regularly over the next seven years during which time it steadily regressed. The patient is well more than eight years after her initial visit. Drawings of the fundus show the tumor (A) when first seen, (B) two and one half years later, (C) four years and two months later, and (D) seven years and two months after the first examination. The flat atrophie scar with surrounding pigment disturbance is considered an instance of spontaneous cure.
2. Métastases may be dormant for years. 3. Cancer cells are found more frequently in the peripheral blood, in pleural and perito neal fluids, and in operative wounds than the subsequent development of métastases would indicate. 4. Cancer may have periods of long quies cence, acute exacerbation, and remission. 5. Primary cancer sites may remain static, to be discovered during life or even found at necropsy. 6. Some cancers have a prolonged preclinical stage which, in the lung, may be many years. Prostatic cancer is found at necropsy five to 10 times more frequently than it is detected clinically. 7. The serum from a patient who has had a spontaneous cure of cancer with métas
tases may cause a regression in a patient with the same type of cancer. 8. The antitumor serum protein fraction may rise after irradiation and after intramus cular injection of whole-tumor antigen. 9. The incidence of cancer has increased with increasing use of immunosuppressive agents in graft surgery. CONCLUSIONS
An attempt has been made to show that inflammation and necrosis of choroidal mel anomas may confuse the clinical picture and delay the correct diagnosis, in turn leading to a poor prognosis. We have postulated that inflammation and necrosis may represent an immunologie response which causes the tumor to regress. We admit that evidence
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presented to support this premise is merely circumstantial—comparable in law to guilt by association. Investigation would seem worthwhile using some of the newer methods of analyz ing cell antigens in vitro and detecting spe cific serum antibodies and lymphocytic reac tivity ; specifically, immunofluorescence, mixed-cell agglutination techniques, and cytotoxicity studies. If the nature of the im mune factor could be established, the most important question would be whether it could produce active or passive immunity in man. SUMMARY
In a histopathologic study of malignant choroidal melanoma, an attempt has been made to show that inflammation and necrosis may confuse the clinical picture, delaying the correct diagnosis. It is believed that these findings may represent an immunologie re sponse which causes tumor regression. Sev eral cases are cited describing spontaneous regression of lesions interpreted as malig nant choroidal melanomas, in some instances to the point of presumed cure. ADDENDUM
An excellent article on 103 patients with malignant melanoma appeared recently8 in which the investigators reported that over one-third of the sera tested had antibodies to autologous melanoma cells. Two types of auto-antibodies were recogniezd: one active
JANUARY, 1970
against antigen(s) in the cell surface mem brane and the other reactive with cytoplasmic antigens which appeared to be present in most or all melanoma cells. ACKNOWLEDGMENTS
We thank the following colleagues for permis sion to cite certain patient material : Dr. A. E. Maumenee (Case 2, Table 2), Dr. A. G. DeVoe (Case 16, Table 1, presented before the Verhoeff Society), Dr. V. T. Curtin (Case 14, Table 2), and Dr. P. Ballen (Case 5, Table 1). REFERENCES
1. Hepler, R. S., Allen, R. A., and Straatsma, B. R.: Photocoagulation of choroidal melanoma: Early and late histopathologic consequences. Arch. Ophth. 79:177, 1968. 2. Reese, A. B. : Tumors of the Eye, 2nd ed. New York, McGraw-Hill, 1963. 3. Font, R. L., Spaulding, A. G., and Zimmer man, L. E. : Diffuse malignant melanoma of the uveal tract: A clinicopathologic report of 54 cases. Tr. Am. Acad. Ophth. Otol. 72:877, 1968. 4. Fuchs, E. : Über Sarkom der Adheraut nebst Bemerkungen über Nekrose der Uvea. Arch. f. Ophth. 77:304, 1910. 5. Lewis, M. G., Ikonopisov, R. L., Nairn, R. C, Phillips, T. M., Fairley, G. H., Bpdeham, D. C, and Alexander, P. : Tumour-specific antibodies in human malignant melanoma and their relationship to the extent of the disease Brit. Med. J., 2 :547, 1969. 6. Southam, C. M. : Relationships of immunol ogy to cancer: A review. Cancer Res. 20:271, 1960. 7. Fairley, G. H. : Immunity to malignant disease in man. Brit. Med. J. 2:467, 1969. 8. Lewis, M. G., Ikonopisov, R. L., Nairn, R. C, Phillips, T. M., Fairley, G. H., Bodenham, D. C, and Alexander, P.: Tumour-specific antibodies in human malignant melanoma and their relationship to the extent of the disease. Brit. Med. J. 3:547, 1969.
EDUARDO ARENAS ARCHILA, M.D.,
AND W I L L I A M C. COOPER,
IRA S. JONES,
M.D.,
M.D
New York, New York In our study of necrosis of malignant choroidal melanoma, to be reported here, the objective was to determine the clinical sig nificance of the necrosis—how it confused the clinical picture and delayed the correct diagnosis. As the study progressed, our hori zons were broadened to include speculation about the cause of the necrosis and the possi bility that it is an immune response. The necrosis of uveal melanomas has been widely discussed in the literature. Two types are recognized : 1. Cellular—minimal recognizable changes From the Institute of Ophthalmology, ColumbiaPresbyterian Medical Center, New York. Pre sented in part at the meeting of the American Ophthalmological Society, Hot Springs, Virginia, May 26, 1969. Reprint requests to Algernon B. Reese, M.D., 635 West 165th Street, New York City 10032. Dr. Archila was the recipient of a fellowship from the Pan-American Association of Ophthalmology; present address: Calle 17, No. 4-80, Bogota, Co lombia.
associated with tumor-cell death, principally in the nuclei as pyknosis, karyorrhexis or karyolysis, or in the cytoplasm as swelling and hydropic degeneration (figs. 1 and 2 ) . 2. Lytic—an advanced stage characterized by areas of coalescing cystic spaces (fig. 3). A histopathologic survey of 100 consecu tive cases of malignant melanoma of the choroid at the Institute of Ophthalmology re vealed cellular and lytic necrosis in 22%. In addition, a type of coagulation or infarct necrosis was found in 5%. Since such an area is often observed in only one part of the tumor, the true incidence of infarct ne crosis may not be determined by statistics such as ours, based on random sections. Lymphocytic infiltration has been fre quently reported, not only in and around the necrosis of the uveal melanoma, but also throughout the uvea of the affected eye (fig. 4). This inflammatory reaction, associated with tumor necrosis, is usually attributed to
Fig. 1 (Reese, Archila, Jones, and Cooper). Spontaneous regression of a malignant choroidal melanoma, (A) dark solid mass in the lower nasal quadrant of the left eye of a 34-year-old woman shows some chorioretinal pigment changes around the base. (B) Regression of the tumor over the next two-anda-half years was manifested by a decrease in its size and an increase in chorioretinal scarring. 91
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Fig. 2 (Reese, Archila, Jones, and Cooper). Photomicrograph of a section of the enucleated globe shows hydropic necrosis of a malignant choroidal melanoma (hematoxylin-eosin, X400).
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Fig. 4 (Reese, Archila, Jones, and Cooper). Necrosis of a malignant melanoma of the choroid with an unusually large number of lymphocytes in the adjacent choroid (hematoxylin-eosin, XlOO).
cytotoxic agents of degenerating melanocytes. However, the necrosis of a uveal mel anoma produced by coagulation therapy causes no undue inflammatory reaction,1 suggesting that some factor other than ne crosis may be responsible. The size of the tumor appears to be unre lated to the incidence of necrosis (figs. 5 and 6). Since necrosis occurs in small or flat le sions, it cannot be attributed to hypotension in the vascular sinusoids of the tumor or to passive congestion. We have attempted to correlate (1) ne crosis observed in histologie sections with the
Fig. 3 (Reese, Archila, Jones, and Cooper). A malignant melanoma of the choroid with lytic ne crosis and chronic inflammation (hematoxylin-eosin, XlOO).
Fig. S (Reese, Archila, Jones, and Cooper). Is chémie necrosis of a small, flat, malignant choroi dal melanoma with inflammatory retinal edema and a macular star. ( A ) The drawing above shows dark, slightly elevated subretinal lesion below the disc with an extension toward the macula. The overlying retina, including the macula, was edematous, and hard white deposits radiated from the fovea. ( B ) Section shows infarct necrosis in the center of the lesion (hematoxylin-eosin, χ 2 5 ) .
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clinical findings, and (2) the uveal melano mas showing clinical signs of inflammation with the necrosis in histologie sections. The material falls into two groups which will be discussed. One is characterized by diffuse cellular and lytic necrosis and the other by sharply demarcated coagulation necrosis. GROUP
1:
MALIGNANT
CHOROIDAL
MELA
N O M A WITH DIFFUSE CELLULAR AND LYTIC NECROSIS
In this group (table 1), inflammation was clinically manifested in all 18 eyes (figs. 5-8). Choroiditis was present in 13, healed choroiditis in three, chorioretinal atrophy and serous detachment of the retina in one, and serous retinopathy with flat retinal de tachment in one. The presenting symptoms were blurred vision and, occasionally, pain. The final diagnosis of malignant choroidal melanoma was established only after periods ranging from four months to 17 years. Tumor sections showed varying degrees of cell necrosis ; the focal areas sometimes co alesced, forming cystic spaces (figs. 1, 2 and 3), or were replaced by scar tissue (fig. 9). Melanin liberated from the necrotic cells was dispersed as free melanin in the tumor sub stance, in the surrounding choroid, in the retina, and in the vitreous. Nests of macro-
Fig. 6 (Reese, Archila, Jones, and Cooper). Fundus shows inflammatory edema and a macular star due to a necrotic, flat, malignant choroidal melanoma. The presence of an indistinct, flat, subretinal mass suggested the diagnosis of a necrotic malignant choroidal melanoma, which was con firmed by histologie sections.
phages filled with liberated melanin were a prominent feature in some cases (fig. 10). We also found varying degrees of inflam matory reaction throughout the tumor. Many eyes showed chorioretinal adhesions and reti nal pigment proliferation over and around the tumor site (fig. 7). The adhesions simu lated those accompanying and following cho roiditis (figs. 7, 11, 12). The inflammatory
Fig. 7 (Reese, Archila, Jones, and Cooper). A regressing malignant choroidal melanoma, showing (A) flat, pigmented chorioretinal scar which became increasingly elevated over a period of eight months; (B) a section through the flat portion of the tumor showing regressive change with chorioretinal scarring (hematoxylin-eosin, XlOO).
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TABLE 1 MALIGNANT CHOROIDAL MELANOMA WITH DIFFUSE CELLULAR AND LYTIC NECROSIS
Early Diagnosis, Clinical Course
Case No., Sex, Age
Symptoms
1. F-45
Blurred vision
Choroiditis; inflammation treated with corticosteroids; vision improved from 20/50 to 20/20
9 months
Malignant melanoma with diffuse and focal lytic necrosis
2. M-17
Blurred vision
Juxtapapillary choroiditis; optic neuritis; inflammation of uvea improved with corticosteroids
9 months
Partially necrotic malig nant melanoma with scleritis, iridocyclitis, inflamma tory reaction in choroid and tumor
3. F-44
Blurred vision
Exacerbation of old chorioretinitis; inflammation of uvea; corticosteroids improved vision, symptoms
3 years, 3 months
Necrotic malignant choroi dal melanoma with inflam matory reaction in tumor, choroid, ciliary body and sciera
Period Before Enucleation
r
Pathologic Findings
4. F-14
Blurred vision
Angiospastic retinopathy; larval granuloma; inflammation of uvea treated with corticosteroids; vision im proved from 20/50 to 20/25.
3 years, 5 months
Partially necrotic malig nant choroidal melanoma with mild inflammation of choroid and sciera
5. M-4S
Blurred vision
Uveitis; inflammation treated with corticosteroids; vision improved from 20/200 to 20/40
3 years, 4 months
Malignant choroidal melanoma with lytic necrosis; inflammatory reaction in tumor, choroid, ciliary body and sciera
6. F-40
Blurred vision
Inflammation of uvea; some improvement with cortico steroids
4 months
Malignant choroidal mela noma with inflammatory reaction in tumor, choroid, ciliary body and, especially, sciera
7. F-S7
Blurred vision
Inflammation of uvea; improvement with corticosteroids
1 year, 6 months
Malignant choroidal mela noma with lytic necrosis; inflammatory reaction in tumor, choroid, ciliary body and sciera
8. M-54
Blurred vision
Old and active chorioretinitis; improvement in vision from 20/60 to 20/20 with cortico steroids
3 years
Malignant choroidal mela noma with inflammatory reaction in tumor, choroid, ciliary body and sciera
9. M-70
Blurred vision
Active uveitis; unusual migration of pigment into retina; improvement with cortico steroids
4 months
Malignant choroidal mela noma with lytic necrosis; inflammatory reaction in tumor, choroid, ciliary body and sciera
10. M-51
Poor vision
Uveitis; previous operation for detached retina. Improve ment in vision from counting of fingers to 20/50 with corticosteroids
9 years
Malignant choroidal mela noma with cellular necrosis; inflammatory reaction in tumor and uvea
11. M-50
Blurred vision
Serous retinopathy, then deep choroidal hemorrhage with flat retinal detachment; Steady decline of vision
2 years, 2 months
Flat, necrotic, malignant choroidal melanoma in macula, extending around disc and extraocularly
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TABLE 1—(Continued) MALIGNANT CHOROIDAL MELANOMA WITH DIFFUSE CELLULAR AND LYTIC NECROSIS
Case No., Sex, Age
c *. Symptoms
Period Before Enucleation
Early Diagnosis, Clinical Course
Pathologic Findings
12. F-79
Pain, poor vision
Secondary glaucoma, cataract, and finally rubeosis of iris and hyphema
2 years
Necrotic malignant choroidal melanoma
13. F-52
Pain
Secondary glaucoma; iridencleisis with control of tension for 3 years; enucleation because of painful blind eye with cataract
3 years
Necrotic malignant cho roidal melanoma with inflammatory reaction
14. M-51
Poor vision
Chorioretinal atrophy and then serous retinal detach ment. One dark, flat area suggestive of melanoma
4 years
Malignant choroidal mela noma with diffuse and focal lytic necrosis
15. M-53
Blurred vision
Patient had Hodgkin's disease; relatively unpigmented mass in fundus believed to be either granuloma or malignant melanoma
2 years
Malignant choroidal mela noma with diffuse and focal lytic necrosis
16. M-4S*
Blurred vision
Chorioretinitis or flat malignant choroidal melanoma
3 years
Malignant choroidal mela noma with lytic necrosis and increase in collagen
17. F-44f
Blurred vision
Chorioretinitis; healed for 16 years then repeated hemor rhages in vitreous with rapid development of mass; many pigment granules in vitreous
17 years
Malignant choroidal mela noma with lytic necrosis and sclerosis. Masses of pigment-laden macro phages
18. F-45Î
Blurred vision
Flat area of chorioretinal scarring in lower temporal quadrant of fundus; elevated arch in center
2 years
Malignant choroidal mela noma with lytic necrosis
* See Fig. 7. t See Fig. 10. j See Fig. 8. cells were small lymphocytes and plasma cells (fig. 4 ) . GROUP 2:
MALIGNANT CHOROIDAL MELA
NOMA WITH COAGULATION NECROSIS
The 17 eyes in this group (table 2) char acteristically produced a sudden onset of pain, blurred vision, swelling of the eyelids and the conjunctiva and occasionally proptosis. However, this abrupt onset was preceded by inflammation of the eye or its sequelae. The usual clinical picture was chemosis and congestion of the eyelids and the conjunc tiva (11 cases), associated with uveitis (five cases), localized siceritis (four cases), glau coma (six cases), and detachment of the ret ina (six cases). The inflammation often sub
sided sufficiently with steroid therapy to per mit diagnosis of the malignant choroidal melanoma. The delay in diagnosis was not as long in this group as in Group 1, ranging from a few days to nine years. Three patients had proptosis and immobil ity of the eye with orbital inflammation sim ulating panophthalmitis. One patient with proptosis had hypopyon and another had hyphema; in both, the tumor had diffusely infiltrated the orbit, extending into the antrum in one and into the sphenoidal and ethmoidal sinuses in the other. A sharply demarcated infarct or area of ischémie or coagulation necrosis was noted in sections of all the tumors (figs. 13-15). The line separating viable and necrotic
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TABLE 2 MALIGNANT CHOROIDAL MELANOMA WITH COAGULATION NECROSIS
Early Diagnosis, Clinical Course
Case No., Sex, Age
Symptoms
1. F-63
Sudden pain, blurred vision
Malignant melanoma, chemosis and congestion of conjunc tiva and eyelids, steamy cornea
3 days
Massive coagulation necro sis of malignant choroidal melanoma; keratitis, scler itis and necrosis of iris and ciliary body; collateral in flammatory tissue over sciera
2. F-23
Sudden pain, loss of vision, swelling of eye lid and conjunc tiva; chills and fever
Bacterial embolus. Proptosis, detached retina; symptoms cleared with corticosteroids: retinal reattachment per mitted visualization of subretinal gray mass
3 months
Coagulation necrosis of malignant choroidal mela noma with inflammation of iris, ciliary body, choroid and sciera
3. F-47*
Sudden pain, redness and swelling in both eyes
Malignant choroidal melanoma; chemosis of conjunc tiva and eyelids; indistinct grayish mass under retina
4. F-58
Intermittent pain
Malignant choroidal mêlanoma; localized scleritis and dilated episcleral vessels
S months
Coagulation necrosis of tumor
5. F-58
Pain, swelling, inflammation
Proptosis; biopsy from antrum revealed malignant melanoma
2 months
Necrotic malignant choroi dal melanoma invading orbital bones and sinuses
6. M-39f
Poor vision, pain
Malignant choroidal melanoma; localized chemosis and congestion of conjunctiva and sciera corresponding to site of retinal detachment
3 months
Necrotic and hemorrhagic malignant choroidal mela noma with marked inflam matory reaction in ad jacent sciera
7. F-48Î
Sudden pain, loss of vision
Absolute glaucoma (iridencleisis) ; previous episodes with spontaneous regression; chemosis of conjunctiva and eyelids complete detachment of retina, exophthalmos
10§ months
Coagulation necrosis of malignant choroidal mela noma surrounded by lym phocytes; extension to orbit
8. M-55§
Severe sudden pain, inflam mation
Malignant choroidal melanoma; chemosis of conjunc tiva, iridocyclitis, hemorrhage and pigment dispersement in subretinal mass
3 months
Flat tumor with coagula tion necrosis, marked inflammatory reaction and episcleral scar tissue from scleritis; extraocular extension of tumor
9. F-80
Sudden pain, loss ot vision
Absolute glaucoma
2 months
Massive coagulation necro sis of malignant choroidal melanoma with inflamma tory reaction throughout eye
10. F-30
Sudden pain, redness of eye
Malignant choroidal melanoma; conjunctival swelling and episcleral congestion over quadrant corresponding to indistinct mass in fundus
2 months
Coagulation necrosis of malignant choroidal mela noma; inflammatory re action in and around tumor and throughout uvea
* See t See t See § See
Fig. Fig. Fig. Fig.
13. IS. 14, 6.
Onset to Enucleation
Few days
Pathologic Findings
Coagulation necrosis of lesion with marked lymphocytic reaction which ex tended to adjacent choroid, sciera and episclera
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CHOROIDAL MELANOMA TABLE 2—(Continued) MALIGNANT CHOROIDAL MELANOMA WITH COAGULATION NECROSIS
C
Early Diagnosis, Clinical Course
«-s
Ä
Onset to Enucleation
Pathologic Findings
11. F-54
Pain, chemosis, glaucoma, loss of light per ception
Absolute glucoma; patient thought for S years to have inoperable detached retina from inflammation; not seen for 4 years when she developed sudden pain, chemosis and glaucoma
9 years
Coagulation necrosis of flat, malignant choroidal mela noma with extraocular extension
12. M-51
Recurrent pain
Uveitis; swollen eyelids and congested conjunctiva; iridocyclitis; detached retina with underlying indistinct mass; symptoms cleared with corticosteroids and retina reattached ; vision became nor mal but malignant choroidal melanoma was discernible
3 years
No necrosis or inflammation in tumor sections studied; old chorioretinal adhesions and cystic degeneration of retina probably from partially regressed tumor
13. M-69
Sudden severe pain, loss of vision
Inoperable serous detachment 17 months of retina diagnosed 17 months earlier; tension 4 + , hypopyon, globe fixed and proptosed
Coagulation necrosis of malignant choroidal mela noma with extension to orbit and sinuses; marked inflammatory reaction
14. F-40*
Blurred vision
Malignant choroidal melaFew weeks noma with focal necrosis; macular edema with white radiating striae around fovea; central scotoma; vision 20/40
Small, relatively flat tumor with central focus of coagulation necrosis
IS. F-69
Severe pain
Absolute glaucoma; edema of Few days bulbar conjunctiva and eye lids ; cornea too steamy to view f und us; T = 72 ; hemorrhage in anterior chamber
Extensive coagulation necrosis of malignant choroidal melanoma with inflammatory reaction of entire uvea and sciera
16. M-40f
Shadow before eye, micropsia
Malignant melanoma of Few weeks choroid diagnosed in 1963; malignant melanoma of skin of leg in 1955; radical resec tion of groin for recurrence in 1961
Small malignant choroidal melanoma with central infarct necrosis
17. M-54t
Poor vision, pain
Severe uveitis; marked imFew months provement with corticosteroid therapy
Focal area of sclerosis in flat, malignant choroidal melanoma interpreted as necrotic scar with evidence of scleritis and keratitis
* See Fig. 5. t See Fig. 16. X See Fig. 9. tumor tissues was often accentuated by a zone of lymphocytes. Inflammatory cells were present throughout the tumor as well as in the uvea, the sciera, and the cornea and even extended from the globe to the orbit. DISCUSSION
T h e clinical course in each group seemed to have a definite pattern: in Group 1 there
was inflammation and diffuse cellular ne crosis ; in Group 2 there was evidence of the Group 1 pattern and, in addition, an occlu sive vascular process which finally leads to ischémie necrosis. T h e inflammatory phase was followed by a chronic course masquerading as active or inactive choroiditis, scleritis, uveitis, secon dary glaucoma, or retinal detachment, until
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Fig. 8 (Reese, Archila, Jones, and Cooper). A regressing malignant choroidal melanoma, show ing a flat area of chorioretinal scarring from which arises a subretinal mass. The diagnosis of malig nant melanoma was confirmed by histologie sections which showed diffuse lytic necrosis. an infarct suddenly ushered in the acute phase. The regression of cancer is associated, clinically and experimentally, with necrosis, lymphocytic infiltration, hydropic degenera tion, and fibrosis. The cancer cells provoke a reaction from the immunocompetent cells of
Fig. 10 (Reese, Archila, Jones, and Cooper). A partially necrotic malignant choroidal melanoma with an area of pigment-laden macrophages (hematoxylin-eosin, XlOO). In 1951, three ophthal mologists diagnosed a healed chorioretinal scar in the left eye of a 44-year-old woman. By 19S8, the scar seemed elevated but no other change was observed until 1967, when her vision became blurred due to a vitreous hemorrhage. After it absorbed, her vision returned to normal. By March, 1968, the lesion had progressed considerably, and many pigment particles were noted in the vitreous.
JANUARY, 1970
Fig. 9 (Reese, Archila, Jones, and Cooper). A malignant melanoma showing a postnecrotic scar (hematoxylin-eosin, χ 4 0 ) . After severe uveitis in the right eye had cleared, a subretinal mass could be visualized, with unusually heavy migration of pigment into the retina and vitreous. Histologie examination confirmed the diagnosis of malignant choroidal melanoma and revealed lymphocytic in filtration of the postnecrotic scar. the lymphocytic series: the lymphocyte and the plasma cell, by producing immunoglobulin, and the lymphocyte alone, by affecting the endothelium. The action of the endothelial cells paves the way for thrombosis and occlusive processes which produce necrosis and infarcts. Thus, immunity to cancer
Fig. 11 (Reese, Archila, Jones, and Cooper). Possible regressed malignant choroidal melanoma. A 76-year-old man had been advised by many ophthalmologists in past years that his left eye had a malignant choroidal melanoma and should be enucleated. Drawing shows a white elevated mass in the upper temporal quadrant of the left fundus and cataractous changes in the correspond ing sector surrounded by pigment changes. Below the disc was a benign choroidal melanoma. The corrected vision was 20/70. There was no history of injury and no intraocular foreign body was seen on x-ray films (case cited through the cour tesy of Dr. Richard Kanter).
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seems to be concerned more with cellular than with humoral factors. These histologie changes seem conspicu ous in the material from our series, of which one case seems particularly pertinent. CASE REPORT
A man, aged 45, had a malignant melanoma of the skin of the left leg in 1955. It was widely ex cised, but a similar lesion developed in the left groin six years later. After a radical dissection, he remained well until 1963 when he showed micropsia and a shadow before the right eye. On examination, a malignant choroidal melanoma was found with neovascularization, edema, and dis persed pigment in the central portion thought to be tumor necrosis. Since this tumor was consid ered primary, the eye was enucleated. The clinical course indicated marked host re sistance to the first malignant melanoma of the skin, reflected in the histopathology of the malig nant choroidal melanoma (fig. 16). S P O N T A N E O U S REGRESSION
The following sequence of events enabled us to observe malignant choroidal melano-
Fig. 12 (Reese, Archila, Jones, and Cooper). Possible regressed malignant choroidal melanoma. A woman, aged 63, had been told by many oph thalmologists during a 17-year period that her left eye should be removed because of cancer. Draw ing shows a flat, dirty-brown lesion with two nodular protrusions in the periphery of the fundus. The surrounding fundus showed marked pigmenta tion, and pigment granules were dispersed in and around the lesion. The patient had numerous nevi of the face, particularly on the left side (case cited through the courtesy of Dr. Solomon Liebowitz).
Fig. 13 (Reese, Archila, Jones, and Cooper). Inf arct necrosis of a small malignant choroidal mela noma.' A woman, aged 47, had a sudden painful in flammatory episode with edema of the eyelids and conjunctiva. Through cloudy media, a detached ret ina could be seen. There were dilated episcleral ves sels over the area corresponding to the detach ment. (A) Necrosis of the central portion of the melanoma with an inflammatory reaction extend ing to surrounding structures including the adjac ent sciera (hematoxylin-eosin, XlO). (B) Under higher power, portion outlined in (A) shows de marcation between necrotic and viable portions of the tumor (X40). mas during spontaneous regression to the point of a presumed cure. An unusual tume faction in the fundus of the eye in a woman of 30 years was attributed to massive hyperplasia of the pigment epithelium (fig. 17). Several ophthalmologists at different times in the past had diagnosed the lesion as a ma lignant tumor and advised enucleation, which the patient refused. At the time of our first examination, a bluish-black nodular lesion protruded abruptly into the vitreous and was surrounded by a flat zone of chorioretinal atrophy and pigmentation. The tumefaction regressed gradually over the next seven years, and only a small flat atrophie scar now remains after eight years.
Fig. 14 (Reese, Archila, Jones, and Cooper). Infarct necrosis of a malignant choroidal melanoma. Histologie examination following enucleation of the left eye revealed lymphocytic infiltration surrounding the necrosed and inflamed orbit to which the melanoma had spread. (A, left) Section of lesion shows coagulation necrosis (hematoxylin-eosin, χ ΐ θ ) . (Β) In a higher power view of the same area, the necrotic portion of the tumor is sharply demarcated from the viable portion with heavy lymphocytic infiltration (X40).
We have since tried to identify other such dark and nodular processes. If, as we be lieved, they represented hyperplasia of the pigment epithelium, they might well show
Fig. 15 (Reese, Archila, Jones, and Cooper). Infarct necrosis of a malignant choroidal me lanoma. A pigmented lesion in the fundus cor responded to the site of a retinal detachment. The necrotic and viable portions are clearly de marcated (hematoxylin-eosin, χ40).
spontaneous regression. A lesion thought to be of this type, in the fundus of a woman, aged 57, slowly regressed for a period of IS months, when the patient's vision suddenly dropped from 20/200 to the counting of fin gers, as the result of a vitreous hemorrhage (fig. 18). Since the lesion could not be ob served accurately through the cloudy media and it was feared that the hemorrhage might indicate active growth, the eye was enucle ated. Sections showed a malignant melanoma of the choroid with lytic necrosis. We now feel that such a hemorrhage does not neces sarily indicate active growth of a melanoma, but may be due to an occlusive vascular pro cess associated with its regression. Because of this finding, we did not pursue the same watchful course with another pa tient who had a similar lesion of the fundus (fig. i ) . It thus appeared impossible for us clini cally to identify hyperplasia of the pigment epithelium ; we concluded that it must be ex tremely rare in view of the dearth of histopathologic evidence of epithelial prolifera tion to the point of tumefaction. Our present conviction is that the lesion in Figure 17 was an unrecognized, partially regressed, malignant choroidal melanoma which was subsequently pronounced a
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"cure." This impression, and the apparent steady regression in the two cases cited above (figs. 1 and 18), led us to continue ob servations in another patient whose fundus lesion showed the steady regression pattern of a malignant choroidal melanoma. After seven years, we consider this a permanent spontaneous cure (fig. 19). In the absence of microscopic evidence, it is natural to question whether the clinical di agnosis was correct in the instances pre sented as spontaneous cures of malignant choroidal melanomas. We believe there is lit tle room for doubt based on the following: 1. Unanimous confirmation of the diagno sis by many ophthalmologists. 2. The fact that the two cases in question belonged in the large group (95%) of malig nant choroidal melanomas that can be clini cally diagnosed with certainty. In the other 5%, where diagnosis may be doubtful, the eyes have cloudy or opaque media, or a flat
Fig. 17 (Reese, Archila, Jones, and Cooper). A lesion thought to be a regressing malignant choroidal melanoma. A woman, aged 30, was seen because of a pigmented mass in the right fundus. The 4-disc diameter, solid-appearing lesion, which projected into the vitreous cavity, was above and temporal to the macula. The patient has now been followed for 13 years. Drawings show (A, left above) a mulberry-like lesion with pigment de posits disperesd in the vitreous and below the de pendent part of the tumor, which was interpreted as hyperplasia of the pigment epithelium; ( B , right above) relatively little change in the fundus seven months later; and (C, adjacent) dramatic shrinking of the tumor five years and three months after the first examination, when an atrophie base and increased pigment dispersion can be seen.
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Fig. 16 (Reese, Archila, Jones, and Cooper). Infarct necrosis of a primary malignant choroidal melanoma in a patient with an earlier primary malignant melanoma of the skin. ( A ) and ( B ) show occluded sclerosed vessels surrounded by lymphocytes in the region indicated by the rectan gle (hematoxylin-cosin, χ Ι Ο Ο ) ; (C) shows a par tially occluded vessel ( X 4 0 ) .
diffuse melanoma with detachment of the retina and/or necrosis.
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Fig. 18 (Reese, Archila, Jones, and Cooper). Spontaneous regression of a malignant melanoma of the choroid. A woman, aged 57, had had two hemorrhagic episodes involving the vitreous of the left eye. Drawing ( A ) made after the last hemorrhage had cleared shows a jet-black, mushroom-shaped mass with chorioretinal scarring around the base; ( B ) shows the tumor after it had steadily regressed for one year and three months.
If choroidal melanomas do undergo invo lution to a cure, why is the residuum not seen clinically? For one reason the eye is usually enucleated before the tumor has run its course, and for another the residuum may not be recognized. If the lesions shown in Figures 13 and 16 had been seen in the final stage of regression, their ancestry would very likely have been unsuspected, and they might have been interpreted as residua of a choroiditis. Since becoming interested in this subject, we have encountered several mysterious fundus lesions which we immediately suspected of being regressed malignant choroidal mel anomas. Two such cases are shown in Fig ures 18 and 19. Flat, malignant choroidal melanomas are particularly inclined to show inflammatory changes and necrosis ; in fact, Font, Spaulding and Zimmerman3 found postnecrotic scars in 40% of their cases. A flat melanoma with a localized tumefaction at one site is at times difficult to distinguish from the usual globular choroidal melanoma which has par tially regressed (figs. 18 and 19). The only reference to spontaneous regres
sion of uveal melanomas found in the litera ture is that of Fuchs 4 (1910), who stated that the flat lesions tend to cause iridocyclitis which may lead to phthisis bulbi. In their recent report on 103 patients with malignant melanoma, Lewis and associates5 stated that over one-third of the sera tested demonstrated antibodies to autologous mela noma cells. Two types of antibodies were recognized: one active against antigen(s) in the cell surface membrane, and the other reactive with cytoplasmic antigens which appeared to be present in most or all mela noma cells. Animal immunity to cancer has been es tablished beyond question, but in man there is the ever-present possibility that homolo gous and heterologous transplants will pro voke an antigenic response. Nevertheless, clinical and experimental evidence of an im munologie response to cancer in man pre sents a formidable case for host resistance. The excellent review articles by Southam8 in 1960, and by Fairley7 in 1969, document the following : 1. There are many cases of spontaneous cures of cancer.
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Fig. 19 (Reese, Archila, Jones, and Cooper). Complete spontaneous regression of a malignant choroidal melanoma. A woman, aged 30, presented with a pigmented mass in the right fundus. A number of ophthalmologists in different cities had diagnosed the lesion as a malignant choroidal melanoma. Around the base was a zone of atrophy and secondary pigmentation. The lesion was observed regularly over the next seven years during which time it steadily regressed. The patient is well more than eight years after her initial visit. Drawings of the fundus show the tumor (A) when first seen, (B) two and one half years later, (C) four years and two months later, and (D) seven years and two months after the first examination. The flat atrophie scar with surrounding pigment disturbance is considered an instance of spontaneous cure.
2. Métastases may be dormant for years. 3. Cancer cells are found more frequently in the peripheral blood, in pleural and perito neal fluids, and in operative wounds than the subsequent development of métastases would indicate. 4. Cancer may have periods of long quies cence, acute exacerbation, and remission. 5. Primary cancer sites may remain static, to be discovered during life or even found at necropsy. 6. Some cancers have a prolonged preclinical stage which, in the lung, may be many years. Prostatic cancer is found at necropsy five to 10 times more frequently than it is detected clinically. 7. The serum from a patient who has had a spontaneous cure of cancer with métas
tases may cause a regression in a patient with the same type of cancer. 8. The antitumor serum protein fraction may rise after irradiation and after intramus cular injection of whole-tumor antigen. 9. The incidence of cancer has increased with increasing use of immunosuppressive agents in graft surgery. CONCLUSIONS
An attempt has been made to show that inflammation and necrosis of choroidal mel anomas may confuse the clinical picture and delay the correct diagnosis, in turn leading to a poor prognosis. We have postulated that inflammation and necrosis may represent an immunologie response which causes the tumor to regress. We admit that evidence
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presented to support this premise is merely circumstantial—comparable in law to guilt by association. Investigation would seem worthwhile using some of the newer methods of analyz ing cell antigens in vitro and detecting spe cific serum antibodies and lymphocytic reac tivity ; specifically, immunofluorescence, mixed-cell agglutination techniques, and cytotoxicity studies. If the nature of the im mune factor could be established, the most important question would be whether it could produce active or passive immunity in man. SUMMARY
In a histopathologic study of malignant choroidal melanoma, an attempt has been made to show that inflammation and necrosis may confuse the clinical picture, delaying the correct diagnosis. It is believed that these findings may represent an immunologie re sponse which causes tumor regression. Sev eral cases are cited describing spontaneous regression of lesions interpreted as malig nant choroidal melanomas, in some instances to the point of presumed cure. ADDENDUM
An excellent article on 103 patients with malignant melanoma appeared recently8 in which the investigators reported that over one-third of the sera tested had antibodies to autologous melanoma cells. Two types of auto-antibodies were recogniezd: one active
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against antigen(s) in the cell surface mem brane and the other reactive with cytoplasmic antigens which appeared to be present in most or all melanoma cells. ACKNOWLEDGMENTS
We thank the following colleagues for permis sion to cite certain patient material : Dr. A. E. Maumenee (Case 2, Table 2), Dr. A. G. DeVoe (Case 16, Table 1, presented before the Verhoeff Society), Dr. V. T. Curtin (Case 14, Table 2), and Dr. P. Ballen (Case 5, Table 1). REFERENCES
1. Hepler, R. S., Allen, R. A., and Straatsma, B. R.: Photocoagulation of choroidal melanoma: Early and late histopathologic consequences. Arch. Ophth. 79:177, 1968. 2. Reese, A. B. : Tumors of the Eye, 2nd ed. New York, McGraw-Hill, 1963. 3. Font, R. L., Spaulding, A. G., and Zimmer man, L. E. : Diffuse malignant melanoma of the uveal tract: A clinicopathologic report of 54 cases. Tr. Am. Acad. Ophth. Otol. 72:877, 1968. 4. Fuchs, E. : Über Sarkom der Adheraut nebst Bemerkungen über Nekrose der Uvea. Arch. f. Ophth. 77:304, 1910. 5. Lewis, M. G., Ikonopisov, R. L., Nairn, R. C, Phillips, T. M., Fairley, G. H., Bpdeham, D. C, and Alexander, P. : Tumour-specific antibodies in human malignant melanoma and their relationship to the extent of the disease Brit. Med. J., 2 :547, 1969. 6. Southam, C. M. : Relationships of immunol ogy to cancer: A review. Cancer Res. 20:271, 1960. 7. Fairley, G. H. : Immunity to malignant disease in man. Brit. Med. J. 2:467, 1969. 8. Lewis, M. G., Ikonopisov, R. L., Nairn, R. C, Phillips, T. M., Fairley, G. H., Bodenham, D. C, and Alexander, P.: Tumour-specific antibodies in human malignant melanoma and their relationship to the extent of the disease. Brit. Med. J. 3:547, 1969.