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Malignant Melanoma: A Fifteen-Year Review
90
RALPH G. JANES AND JAMES F. STILES
4. de Berardinis, E., and Bonavolonta, G.: Ricerche sperimentali sul passaggio e sulla concentrazione del cortisone nell'umore acqueo e nel vitreo, Rass. ital. ottal., 22:151-167 (Mar.-Apr.) 19S3. 5. Hamashige, S., and Potts, A. M.: The penetration of cortisone and hydrocortisone into ocular structures. Am. J. Ophth., 40:211-215 (Nov. Pt. II) 1955. 6. Bush, I. E.: Methods of paper chromatography of steroids applicable to study of steroids in mam malian blood and tissues. Biochem. J., 50:370-378 (Jan.) 1952. 7. Ellis, P. P.: The dangers of ophthalmic corticosteroids. J. Iowa State M. Soc, 48:355-357 (July) 1958. 8. Vogel, A. W., Leopold, I. H., and Nichols, A.: Neomycin: Ocular tissue tolerance and penetration when locally applied in the rabbit eye. Am. J. Ophth., 34:1357-1362 (Oct.) 1951. 9. Scheie, H. G., and Leopold, I. H.: Penetration of sulfathiazole into the eye: Further studies. AMA Arch. Ophth., 27:997-1004 (May) 1942. 10. Hellman, L., Bradlow, H. L., Adesman, J., Fukushima, D. K., Kulp, J. L., and Gallagher, T. F.: The fate of hydrocortisone-4-CM in man. J. Clin. Invest., 33:1106-1115 (Aug.) 1954.
MALIGNANT MELANOMA: A F I F T E E N - Y E A R R E V I E W HERBERT N. FITTERMAN, M.D.,
AND J. A. M C L E A N ,
M.D.
Vancouver, British Columbia MELANOMAS OF THE UVEAL TRACT
A melanoma arising from the uveal tract has as its cellular origin, one, possibly two, cell types. It is generally considered that the first type of cellular origin is from the Schwann cell. Reese believes that, in addi tion to the Schwann cell, the stromal mela noblast or chromatophore may also give rise to these tumors. In general, those tumors arising from the Schwann cell are composed of elongated spindle cells, with palisading of the nuclei. Those of stromal origin are iden tified as having syncytial processes, with the shape of the cell varying from the spindle type to those polyhedral in shape. The latter variations are determined by the degree of pigment and by the anaplastic nature which the tumor might assume. PHYSIOLOGIC CHEMISTRY
1. The pigment found has been termed melanin. It is a nonspecific pigment, having absorbable properties for light, which is pro duced by the melanoblasts. It is first seen in the uvea during the fifth prenatal month. The precursor of this pigment is premelanin or leukomelanine. An enzymatic oxidation oc curs within the melanoblast which oxidizes 2,3,dioxyphenylalanine (DOPA) to melanin. It has been reported (Black) that the mar
ginal cells of a malignant melanoma contain a greater concentration of the oxidase than the more centrally located cells. Thus, the melanosis of the adjacent tissues may be ex plained by the elaboration of this enzyme by the tumor cells. Also, since this oxidative reaction is reversible, the amount of pigment present may vary. 2. Occasionally, a malignant melanoma may be associated with general melanosis, in which the pigment is formed within the cells of the reticulo-endothelial system, the vascu lar endothelium, the renal tissue and other tissue systems. 3. Sex hormones have been implicated be cause of three observed factors : a. Malignant melanomas do not occur prior to puberty. b. The degree of malignancy may be en hanced during pregnancy. c. The adrenocortical hormones are known to influence melanin metabolism. 4. There is no evidence to point to a hered itary association. ORIGIN
According to Reese, the following are the cell types which may give rise to malignant melanomas: (1) Schwann cell, (2) nevus cell, (3) basal cell, (4) uveal stromal cell,
MALIGNANT MELANOMA
■ *'%f'?%i$>$$%·
91
"^S"
Plate 1 (Fitterman and McLean). (1) Spindle type with fascicular structure. (2) Spindle B tumor. (3) Mixed type, spindle B and epithelioid. (4) Mixed but mainly epithelioid. (S) Mixed with marked septa formation. (6) Epithelioid type with mitoses. (5) pigmented epithelial cells from the ret ina, ciliary body or the iris and (6 leptomeninges. At this time, only those cell types which are pertinent to the present study will be briefly discussed. In favor of the Schwann cell as the cell of origin of these tumors, it has been ob served that, if the body and the sensory ter minations of a nerve, are pathologically af fected, a malignant melanoma may form. Therefore, the uveal cells of neural origin may be the responsible cells because: (1) nevus cells may wholly make up the tumor, (2) adjacent ciliary nerves may exhibit pro liferation of the cells in the sheath of
Schwann, (3) occasionally a case will occur with corneal anesthesia or with alteration in the pupillary size and/or reaction, (4) the tumor may have a palisading, fascicular structure and (5) there have been at least two cases in which there has been an associ ation of von Recklinghausen's disease with malignant melanoma of the uvea (Strachan and Gartner). Those who argue in favor of the nevus cell as the origin for these tumors are di vided into two schools. The neurogenic the ory states that this cell is intermediate be tween the Schwann cell and the cell of the end-organ. According to Massow, this is the
92
HERBERT N. FITTERMAN AND J. A. McLEAN
pigmented cell of Merkel-Ranvier. The epi dermal theory (Allan) considers that the cell of origin arises from the cells of a junctional nevus. Agreeing with Reese, Wagener, Wellbank and Knight regard the malignant melanoma of the uvea as epithelial in origin, arising from the stromal cells. Wolff feels that these tumors may arise from nevus cells, epithelial cells or from stromal melanoblasts. The lat ter cell is what Reese refers to as the branch ing melanoblast, and he feels that this cell is the origin of a more anaplastic type tumor. PATHOLOGY
1. The tumor begins in the pigmented tis sue of the choroid following which it breaks
through into the lamina vitrea to take up a subretinal position. 2. Three definite cell types are recognized : (a) spindle-A (non-nucleolated), (b) spindle-B (nucleolated) and (c) epithelioid (multinucleated with nucleoli and an acidophilic cytoplasm). 3. An organized arrangement may be as sumed by the growing tumor: (a) fasicular (whorls and sheets of cells), (b) tubular (cells tend to form tubules), (c) funicular (cells are in solid cords) and (d) alveolar (glandlike arrangement). 4. The amount of pigment may vary, and is usually in greatest concentration around the necrotic areas of the tumor. It is ob served within the tumor cells proper, within
Plate 2 (Fitterman and McLean). (7) Epithelioid type with pigmentation. (8) General fascicular tumor structure. (9) Spindle cells with whorls and pigment. (10) Epithelioid with alveolarlike arrange ment. (11) Spindle B with marked pigmentation. (12) Primary pigmented focus in choroid.
MALIGNANT MELANOMA
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93
a«.
Plate 3 (Fitterman and McLean). (13) Early scierai invasion. (14) Advanced scierai invasion. (IS) Elevation of retina by tumor. (16) Nerve invasion. (17) Vascular invasion. (18) Replacement of endothelial tissue by tumor cells.
HERBERT N. FITTERMAN AND J. A. McLEAN
94
Age (yr.)
TABLE 1
TABLE 2
AGE
LATERALITY
Male 25
30
Under SO
8
8
Under 40
4
3
Over SO
Average
56.8 yr.
61.7 yr.
TOTAL
46.7%
53.3%
phagocytes, or else free in the interstices of the tumor. 5. The growth may be either localized or diffuse, the latter possibly complicating the diagnosis because of earlier scierai invasion, secondary glaucoma or retinal detachment. 6. Due to poor blood supply, areas of ne crosis are seen in approximately 80 percent of these tumors. 7. Inflammation may arise as a result of necrosis of the tumor, absolute glaucoma, panophthalmitis, endophthalmitis or phthisis bulbi, and, due to the production of cytotoxins, these possibilities may make the diagno sis very difficult. The cytotoxins may cause corneal clouding, hemorrhage, scierai necro sis, cataracts, glaucoma or rubeosis irides. 8. Hemorrhage occurs in approximately 50 percent of cases (Verhoeff). 9. Complications resulting from the neo plasm are: (a) retinal detachment, (b) sec ondary glaucoma from large tumors pushing the iris-lens diaphragm forward, obstruction of the vortex lakes, necrosis, lens swelling or hemorrhage, (c) sympathetic ophthalmia, (d) extraocular extension (15-30 percent) via the emissary vessels, by direct extension through the sciera or by invasion of the optic nerve, and (e) distant métastases via blood spread. CYTOLOGIC CLASSIFICATION
1. 2. 3. 4.
Spindle A Spindle B Mixed Epithelioid
O.D.
O.S.
Male
14(42.4%)
19(57.6%)
Female
16(43.3%)
21(56.7%)
TOTAL
30(42.9%)
40(57.1%)
Female
(Callender)
PRESENT STUDY
This study is based on those patients seen at the Vancouver General Hospital and the British Columbia Cancer Institute during the years 1946-1960. During this period, a total of 71 cases of malignant melanoma of the uvea were seen. The youngest age in the entire series was 32 years while the oldest was 86 years (table 1). Table 2 illustrates the laterality and sex relationship. None of the cases seen ex hibited any bilaterality. (Only three such cases have been reported in the literature— Shine, Cordes, Reese.) Tables 3 and 4 list the symptoms and the signs in decreasing order of frequency. Due to not having a standard method of record ing such detail, it was not possible to deter mine the incidence with any degree of ac curacy. Many of the cases studied exhibited detachment of the retina. There was only one case in which a staphyloma occurred, while scierai perforation occurred in two of the cases. Treatment at the two institutions con cerned in the study was by one of three methods: (1) Enucleation, (2) enucleation TABLE 3 SYMPTOMS
1. 2. 3. 4. 5. 6. 7. 8. 9. 10.
Blurred vision Subjective loss of field Ocular pain Total amaurosis Photopsia "Film" over the eye Macropsia Strabismus Diplopia Xanthopsia
95
MALIGNANT MELANOMA
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.
TABLE 4
TABLE 6
SIGNS
QUADRANTS
Retinal detachment Observable mass Visible small nevi Intraocular hemorrhage Abnormal pupil response Secondary glaucoma Absolute glaucoma Phthisis bulbi Conjunctival injection Hypopyon Staphyloma Scierai perforation Bulging of the iris root Pyramidal signs Iridodialysis Subluxation of the lens
combined with the implantation of a 5.5-mg. radium needle into the orbit for 24 hours, (3) enucleation followed by X-ray irradia tion. Table 5 shows the number of patients treated by each of these methods. The following three cases were not treated: 1. The patient was admitted to the hospital with abdominal distress. Laparotomy showed gross métastases. The primary tumor was later found in the eye. 2. Surgery was deferred because of poor cardiac status. 3. The patient died of cardiac arrest while on the operating table. The results of therapy will be discussed later. CLINICAL PATHOLOGY
A. Gross examination of the globes fol lowing enucleation showed evidence of exTABLE S TREATMENT
Treatment
No. Treated
Quadrant
Nasal
Temporal
Upper Lower Combined
4 13 5
2 12 6
trabulbar spread in only three cases (4.3 percent). One of these exhibited a staphylo ma of the sciera, while the other two showed evidence of scierai perforation. Because Frie denwald reported a frequency of these tumors in the lower nasal quadrant of the globe, an attempt was made to ascertain the position of the tumor in the globes sectioned here. This was not possible in all the cases; Table 6 is based on a total of 42 cases. All that can be inferred from Table 6 is that the lower quadrants were most commonly involved. B. Microscopically, the tumors were classi fied according to Callender's classification. The only addition made is of an unclassified group, from which, if the cellular structure were known, the majority would probably be put into the mixed group of tumors (table 7)· The numbers in the brackets represent the series reported from the Armed Forces In stitute. The large disparity between the mixed groups from both series is explained: 1. By the large unknown group in the present series, the majority of which would probably fall into the mixed classification. 2. The larger figure from the Armed Forces Institute also represents fascicular and necrotic types of growth, which are not cell classifications but rather classifications of general structure. In regard to local tumor invasion, that is,
Enucleation
49
Enucleation—Radium
14
TABLE 7
Enucleation—X-ray
4
CLASSIFICATION
Not treated
3
Not known
1
TOTAL
71
Spindle A Spindle B Mixed Epithelioid Unclassified
22.5% IS.5% 21.1% 9.8% 20.9%
(7.0%) (23.4%) (66.8%) (2.8%)
HERBERT N. FITTERMAN AND J. A. McLEAN
96
TABLE 8 LOCAL SPREAD
3 9 7 1 1 1
Socket Sciera Vascular Lymphatic Nerve Iris/ciliary
22(30.9%)
TOTAL
globe and orbit, 21 cases showed further spread from the primary focus within the eye (table 8). There was definite correlation between the degree of malignancy (or cell type) and the final prognosis of the patient. In other words, the cell type was used as a means to deter mine the possible outcome of the case. Table 9 illustrates the results achieved according to cell type, as compared to the results which have been reported by Wilder and Paul in a five-year study. The latter figures are in the brackets. The highest mortality rate, 42.8 percent, occurred in the epithelioid group. It is un fortunate that some of the cases were un classified, as undoubtedly some would have fallen into the epithelioid grouping. Table 10 is a comparison of the treatment received and the end-result: Table 11 shows the survival rates, accord ing to the treatment received over a stated period of time. Combining all these methods, the five-year survival rate has been 23.9 percent. How ever, it is most probable that these figures will be modified in terms of greater longevity when the next study is made, as many of those patients having lived, at the present
time, for under five years will have longer periods of life. The average five-year survival rate as given by Reese, Von Hippel and Von Poplzy is 45 percent, and this decreases over a 10-year period. Although it is only specula tion, if the status of those in the unknown group were known, the survival rate in the present series would probably approach the same percentage. In this series, there were three cases with orbital recurrence, all of which had exenteration of the orbit. These patients have since died, the average survival being 29 months. Reese reported eight such cases with a mor tality rate of 100 percent and with an aver age survival of 14 months. There were no cases of involvement of the optic nerve in this series. Clinically, it would seem easy to mistake other intraocular conditions for malignant melanoma. In this series, there have been two such cases. The first was one of a capillary hemangioma in a pregnant woman. The di agnosis in the second case was chromatophore hyperplasia. This compares to a mis taken diagnosis in 25 out of 1,600 cases listed in the Ophthalmic Registry. In addition, in the series studied here, there was only one case in which a malignant melanoma was found following enucleation for absolute glaucoma. This compares to 18 such cases in the Ophthalmic Registry. The average time of survival for the pa tients treated in this center has been 48.3 months, as compared to 45 months in Reese's series. Two of the deaths were due to cardiac arrest and myocardial infarction, while the
TABLE 9 CELL TYPE OUTCOME
Cell Type
Status?
Living
Spindle A Spindle B Mixed Epithelioid Unclassified
2 2 3
11 6 7 4 3
3
Dead 3 3 5 3 13
Total
% Dead
16 11 IS 7 19
18.7(11) 27.3(22) 33.3(63) 42.8(66) 81.2
MALIGNANT MELANOMA
97
TABLE 10 TREATMENT/RESULT
Enucleation Enucl./Radium Enucl./X-ray
Total
Alive
Dead
Status?
49/70% 14/20% 4/5.7%
23/46.9% 6/42.8% 1/35.0%
15/30.6% 7/50% 3/75.0%
11/22.5% 1/7.2%
The numerator represents the total number of cases, while the denominator represents the percentage of the total. TABLE 11 TREATMENT/SURVIVAL
Alive after Five Years Enucleation Enucl./Ra Enucl./X-ray TOTAL
ψ™
™££
10(20.4%) 5(35.7%) 1(25.9%)
15 3 1
16(23.9%)
19(28.3%)
rest were due to blood-borne métastases. Fol lowing is a list of the tissues in which sec ondary growths were found: (1) Liver, (2) lymph nodes, (3) stomach, (4) pancreas, (5) ovaries, (6) heart, (7) lung, (S) brain, (9) suprarenals and (10) breast. The liver was the most common site for métastases. Not only does this list illustrate the impor tance of vascular invasion but it also shows that these tumor cells can even replace the endothelium of the blood vessels themselves.
Dead under Five Years
Status?
8 5 1 14(20.9%)
16 1 1 18
SUMMARY
A review of 72 cases of intraocular ma lignant melanoma seen at the Vancouver General Hospital and the British Columbia Cancer Institute has been presented. In ad dition, the basic chemistry and pathology of these tumors have also been reviewed. 2096 West 41st Avenue (13). ACKNOWLEDGMENT
I wish to thank Miss M. Kendall for the excellent microphotographs.
REFERENCES
Friedenwald, J. S.: Textbook of Ophthalmic Pathology. Philadelphia, Saunders, 1957. Reese, A. B.: Tumors of the Eye. New York, Hoeber, 1951.
OPHTHALMIC MINIATURE
Then he came through into the light of the lamp and the purple, crumpled strawberry mark stretching from above the cheek-bone down to the point of the chin was almost like a mark of distinction.—I had maligned him, he could have no satisfaction in looking at that. Graham Greene, The End of the Affair, Penguin Press.
RALPH G. JANES AND JAMES F. STILES
4. de Berardinis, E., and Bonavolonta, G.: Ricerche sperimentali sul passaggio e sulla concentrazione del cortisone nell'umore acqueo e nel vitreo, Rass. ital. ottal., 22:151-167 (Mar.-Apr.) 19S3. 5. Hamashige, S., and Potts, A. M.: The penetration of cortisone and hydrocortisone into ocular structures. Am. J. Ophth., 40:211-215 (Nov. Pt. II) 1955. 6. Bush, I. E.: Methods of paper chromatography of steroids applicable to study of steroids in mam malian blood and tissues. Biochem. J., 50:370-378 (Jan.) 1952. 7. Ellis, P. P.: The dangers of ophthalmic corticosteroids. J. Iowa State M. Soc, 48:355-357 (July) 1958. 8. Vogel, A. W., Leopold, I. H., and Nichols, A.: Neomycin: Ocular tissue tolerance and penetration when locally applied in the rabbit eye. Am. J. Ophth., 34:1357-1362 (Oct.) 1951. 9. Scheie, H. G., and Leopold, I. H.: Penetration of sulfathiazole into the eye: Further studies. AMA Arch. Ophth., 27:997-1004 (May) 1942. 10. Hellman, L., Bradlow, H. L., Adesman, J., Fukushima, D. K., Kulp, J. L., and Gallagher, T. F.: The fate of hydrocortisone-4-CM in man. J. Clin. Invest., 33:1106-1115 (Aug.) 1954.
MALIGNANT MELANOMA: A F I F T E E N - Y E A R R E V I E W HERBERT N. FITTERMAN, M.D.,
AND J. A. M C L E A N ,
M.D.
Vancouver, British Columbia MELANOMAS OF THE UVEAL TRACT
A melanoma arising from the uveal tract has as its cellular origin, one, possibly two, cell types. It is generally considered that the first type of cellular origin is from the Schwann cell. Reese believes that, in addi tion to the Schwann cell, the stromal mela noblast or chromatophore may also give rise to these tumors. In general, those tumors arising from the Schwann cell are composed of elongated spindle cells, with palisading of the nuclei. Those of stromal origin are iden tified as having syncytial processes, with the shape of the cell varying from the spindle type to those polyhedral in shape. The latter variations are determined by the degree of pigment and by the anaplastic nature which the tumor might assume. PHYSIOLOGIC CHEMISTRY
1. The pigment found has been termed melanin. It is a nonspecific pigment, having absorbable properties for light, which is pro duced by the melanoblasts. It is first seen in the uvea during the fifth prenatal month. The precursor of this pigment is premelanin or leukomelanine. An enzymatic oxidation oc curs within the melanoblast which oxidizes 2,3,dioxyphenylalanine (DOPA) to melanin. It has been reported (Black) that the mar
ginal cells of a malignant melanoma contain a greater concentration of the oxidase than the more centrally located cells. Thus, the melanosis of the adjacent tissues may be ex plained by the elaboration of this enzyme by the tumor cells. Also, since this oxidative reaction is reversible, the amount of pigment present may vary. 2. Occasionally, a malignant melanoma may be associated with general melanosis, in which the pigment is formed within the cells of the reticulo-endothelial system, the vascu lar endothelium, the renal tissue and other tissue systems. 3. Sex hormones have been implicated be cause of three observed factors : a. Malignant melanomas do not occur prior to puberty. b. The degree of malignancy may be en hanced during pregnancy. c. The adrenocortical hormones are known to influence melanin metabolism. 4. There is no evidence to point to a hered itary association. ORIGIN
According to Reese, the following are the cell types which may give rise to malignant melanomas: (1) Schwann cell, (2) nevus cell, (3) basal cell, (4) uveal stromal cell,
MALIGNANT MELANOMA
■ *'%f'?%i$>$$%·
91
"^S"
Plate 1 (Fitterman and McLean). (1) Spindle type with fascicular structure. (2) Spindle B tumor. (3) Mixed type, spindle B and epithelioid. (4) Mixed but mainly epithelioid. (S) Mixed with marked septa formation. (6) Epithelioid type with mitoses. (5) pigmented epithelial cells from the ret ina, ciliary body or the iris and (6 leptomeninges. At this time, only those cell types which are pertinent to the present study will be briefly discussed. In favor of the Schwann cell as the cell of origin of these tumors, it has been ob served that, if the body and the sensory ter minations of a nerve, are pathologically af fected, a malignant melanoma may form. Therefore, the uveal cells of neural origin may be the responsible cells because: (1) nevus cells may wholly make up the tumor, (2) adjacent ciliary nerves may exhibit pro liferation of the cells in the sheath of
Schwann, (3) occasionally a case will occur with corneal anesthesia or with alteration in the pupillary size and/or reaction, (4) the tumor may have a palisading, fascicular structure and (5) there have been at least two cases in which there has been an associ ation of von Recklinghausen's disease with malignant melanoma of the uvea (Strachan and Gartner). Those who argue in favor of the nevus cell as the origin for these tumors are di vided into two schools. The neurogenic the ory states that this cell is intermediate be tween the Schwann cell and the cell of the end-organ. According to Massow, this is the
92
HERBERT N. FITTERMAN AND J. A. McLEAN
pigmented cell of Merkel-Ranvier. The epi dermal theory (Allan) considers that the cell of origin arises from the cells of a junctional nevus. Agreeing with Reese, Wagener, Wellbank and Knight regard the malignant melanoma of the uvea as epithelial in origin, arising from the stromal cells. Wolff feels that these tumors may arise from nevus cells, epithelial cells or from stromal melanoblasts. The lat ter cell is what Reese refers to as the branch ing melanoblast, and he feels that this cell is the origin of a more anaplastic type tumor. PATHOLOGY
1. The tumor begins in the pigmented tis sue of the choroid following which it breaks
through into the lamina vitrea to take up a subretinal position. 2. Three definite cell types are recognized : (a) spindle-A (non-nucleolated), (b) spindle-B (nucleolated) and (c) epithelioid (multinucleated with nucleoli and an acidophilic cytoplasm). 3. An organized arrangement may be as sumed by the growing tumor: (a) fasicular (whorls and sheets of cells), (b) tubular (cells tend to form tubules), (c) funicular (cells are in solid cords) and (d) alveolar (glandlike arrangement). 4. The amount of pigment may vary, and is usually in greatest concentration around the necrotic areas of the tumor. It is ob served within the tumor cells proper, within
Plate 2 (Fitterman and McLean). (7) Epithelioid type with pigmentation. (8) General fascicular tumor structure. (9) Spindle cells with whorls and pigment. (10) Epithelioid with alveolarlike arrange ment. (11) Spindle B with marked pigmentation. (12) Primary pigmented focus in choroid.
MALIGNANT MELANOMA
OFT"''·-
93
a«.
Plate 3 (Fitterman and McLean). (13) Early scierai invasion. (14) Advanced scierai invasion. (IS) Elevation of retina by tumor. (16) Nerve invasion. (17) Vascular invasion. (18) Replacement of endothelial tissue by tumor cells.
HERBERT N. FITTERMAN AND J. A. McLEAN
94
Age (yr.)
TABLE 1
TABLE 2
AGE
LATERALITY
Male 25
30
Under SO
8
8
Under 40
4
3
Over SO
Average
56.8 yr.
61.7 yr.
TOTAL
46.7%
53.3%
phagocytes, or else free in the interstices of the tumor. 5. The growth may be either localized or diffuse, the latter possibly complicating the diagnosis because of earlier scierai invasion, secondary glaucoma or retinal detachment. 6. Due to poor blood supply, areas of ne crosis are seen in approximately 80 percent of these tumors. 7. Inflammation may arise as a result of necrosis of the tumor, absolute glaucoma, panophthalmitis, endophthalmitis or phthisis bulbi, and, due to the production of cytotoxins, these possibilities may make the diagno sis very difficult. The cytotoxins may cause corneal clouding, hemorrhage, scierai necro sis, cataracts, glaucoma or rubeosis irides. 8. Hemorrhage occurs in approximately 50 percent of cases (Verhoeff). 9. Complications resulting from the neo plasm are: (a) retinal detachment, (b) sec ondary glaucoma from large tumors pushing the iris-lens diaphragm forward, obstruction of the vortex lakes, necrosis, lens swelling or hemorrhage, (c) sympathetic ophthalmia, (d) extraocular extension (15-30 percent) via the emissary vessels, by direct extension through the sciera or by invasion of the optic nerve, and (e) distant métastases via blood spread. CYTOLOGIC CLASSIFICATION
1. 2. 3. 4.
Spindle A Spindle B Mixed Epithelioid
O.D.
O.S.
Male
14(42.4%)
19(57.6%)
Female
16(43.3%)
21(56.7%)
TOTAL
30(42.9%)
40(57.1%)
Female
(Callender)
PRESENT STUDY
This study is based on those patients seen at the Vancouver General Hospital and the British Columbia Cancer Institute during the years 1946-1960. During this period, a total of 71 cases of malignant melanoma of the uvea were seen. The youngest age in the entire series was 32 years while the oldest was 86 years (table 1). Table 2 illustrates the laterality and sex relationship. None of the cases seen ex hibited any bilaterality. (Only three such cases have been reported in the literature— Shine, Cordes, Reese.) Tables 3 and 4 list the symptoms and the signs in decreasing order of frequency. Due to not having a standard method of record ing such detail, it was not possible to deter mine the incidence with any degree of ac curacy. Many of the cases studied exhibited detachment of the retina. There was only one case in which a staphyloma occurred, while scierai perforation occurred in two of the cases. Treatment at the two institutions con cerned in the study was by one of three methods: (1) Enucleation, (2) enucleation TABLE 3 SYMPTOMS
1. 2. 3. 4. 5. 6. 7. 8. 9. 10.
Blurred vision Subjective loss of field Ocular pain Total amaurosis Photopsia "Film" over the eye Macropsia Strabismus Diplopia Xanthopsia
95
MALIGNANT MELANOMA
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.
TABLE 4
TABLE 6
SIGNS
QUADRANTS
Retinal detachment Observable mass Visible small nevi Intraocular hemorrhage Abnormal pupil response Secondary glaucoma Absolute glaucoma Phthisis bulbi Conjunctival injection Hypopyon Staphyloma Scierai perforation Bulging of the iris root Pyramidal signs Iridodialysis Subluxation of the lens
combined with the implantation of a 5.5-mg. radium needle into the orbit for 24 hours, (3) enucleation followed by X-ray irradia tion. Table 5 shows the number of patients treated by each of these methods. The following three cases were not treated: 1. The patient was admitted to the hospital with abdominal distress. Laparotomy showed gross métastases. The primary tumor was later found in the eye. 2. Surgery was deferred because of poor cardiac status. 3. The patient died of cardiac arrest while on the operating table. The results of therapy will be discussed later. CLINICAL PATHOLOGY
A. Gross examination of the globes fol lowing enucleation showed evidence of exTABLE S TREATMENT
Treatment
No. Treated
Quadrant
Nasal
Temporal
Upper Lower Combined
4 13 5
2 12 6
trabulbar spread in only three cases (4.3 percent). One of these exhibited a staphylo ma of the sciera, while the other two showed evidence of scierai perforation. Because Frie denwald reported a frequency of these tumors in the lower nasal quadrant of the globe, an attempt was made to ascertain the position of the tumor in the globes sectioned here. This was not possible in all the cases; Table 6 is based on a total of 42 cases. All that can be inferred from Table 6 is that the lower quadrants were most commonly involved. B. Microscopically, the tumors were classi fied according to Callender's classification. The only addition made is of an unclassified group, from which, if the cellular structure were known, the majority would probably be put into the mixed group of tumors (table 7)· The numbers in the brackets represent the series reported from the Armed Forces In stitute. The large disparity between the mixed groups from both series is explained: 1. By the large unknown group in the present series, the majority of which would probably fall into the mixed classification. 2. The larger figure from the Armed Forces Institute also represents fascicular and necrotic types of growth, which are not cell classifications but rather classifications of general structure. In regard to local tumor invasion, that is,
Enucleation
49
Enucleation—Radium
14
TABLE 7
Enucleation—X-ray
4
CLASSIFICATION
Not treated
3
Not known
1
TOTAL
71
Spindle A Spindle B Mixed Epithelioid Unclassified
22.5% IS.5% 21.1% 9.8% 20.9%
(7.0%) (23.4%) (66.8%) (2.8%)
HERBERT N. FITTERMAN AND J. A. McLEAN
96
TABLE 8 LOCAL SPREAD
3 9 7 1 1 1
Socket Sciera Vascular Lymphatic Nerve Iris/ciliary
22(30.9%)
TOTAL
globe and orbit, 21 cases showed further spread from the primary focus within the eye (table 8). There was definite correlation between the degree of malignancy (or cell type) and the final prognosis of the patient. In other words, the cell type was used as a means to deter mine the possible outcome of the case. Table 9 illustrates the results achieved according to cell type, as compared to the results which have been reported by Wilder and Paul in a five-year study. The latter figures are in the brackets. The highest mortality rate, 42.8 percent, occurred in the epithelioid group. It is un fortunate that some of the cases were un classified, as undoubtedly some would have fallen into the epithelioid grouping. Table 10 is a comparison of the treatment received and the end-result: Table 11 shows the survival rates, accord ing to the treatment received over a stated period of time. Combining all these methods, the five-year survival rate has been 23.9 percent. How ever, it is most probable that these figures will be modified in terms of greater longevity when the next study is made, as many of those patients having lived, at the present
time, for under five years will have longer periods of life. The average five-year survival rate as given by Reese, Von Hippel and Von Poplzy is 45 percent, and this decreases over a 10-year period. Although it is only specula tion, if the status of those in the unknown group were known, the survival rate in the present series would probably approach the same percentage. In this series, there were three cases with orbital recurrence, all of which had exenteration of the orbit. These patients have since died, the average survival being 29 months. Reese reported eight such cases with a mor tality rate of 100 percent and with an aver age survival of 14 months. There were no cases of involvement of the optic nerve in this series. Clinically, it would seem easy to mistake other intraocular conditions for malignant melanoma. In this series, there have been two such cases. The first was one of a capillary hemangioma in a pregnant woman. The di agnosis in the second case was chromatophore hyperplasia. This compares to a mis taken diagnosis in 25 out of 1,600 cases listed in the Ophthalmic Registry. In addition, in the series studied here, there was only one case in which a malignant melanoma was found following enucleation for absolute glaucoma. This compares to 18 such cases in the Ophthalmic Registry. The average time of survival for the pa tients treated in this center has been 48.3 months, as compared to 45 months in Reese's series. Two of the deaths were due to cardiac arrest and myocardial infarction, while the
TABLE 9 CELL TYPE OUTCOME
Cell Type
Status?
Living
Spindle A Spindle B Mixed Epithelioid Unclassified
2 2 3
11 6 7 4 3
3
Dead 3 3 5 3 13
Total
% Dead
16 11 IS 7 19
18.7(11) 27.3(22) 33.3(63) 42.8(66) 81.2
MALIGNANT MELANOMA
97
TABLE 10 TREATMENT/RESULT
Enucleation Enucl./Radium Enucl./X-ray
Total
Alive
Dead
Status?
49/70% 14/20% 4/5.7%
23/46.9% 6/42.8% 1/35.0%
15/30.6% 7/50% 3/75.0%
11/22.5% 1/7.2%
The numerator represents the total number of cases, while the denominator represents the percentage of the total. TABLE 11 TREATMENT/SURVIVAL
Alive after Five Years Enucleation Enucl./Ra Enucl./X-ray TOTAL
ψ™
™££
10(20.4%) 5(35.7%) 1(25.9%)
15 3 1
16(23.9%)
19(28.3%)
rest were due to blood-borne métastases. Fol lowing is a list of the tissues in which sec ondary growths were found: (1) Liver, (2) lymph nodes, (3) stomach, (4) pancreas, (5) ovaries, (6) heart, (7) lung, (S) brain, (9) suprarenals and (10) breast. The liver was the most common site for métastases. Not only does this list illustrate the impor tance of vascular invasion but it also shows that these tumor cells can even replace the endothelium of the blood vessels themselves.
Dead under Five Years
Status?
8 5 1 14(20.9%)
16 1 1 18
SUMMARY
A review of 72 cases of intraocular ma lignant melanoma seen at the Vancouver General Hospital and the British Columbia Cancer Institute has been presented. In ad dition, the basic chemistry and pathology of these tumors have also been reviewed. 2096 West 41st Avenue (13). ACKNOWLEDGMENT
I wish to thank Miss M. Kendall for the excellent microphotographs.
REFERENCES
Friedenwald, J. S.: Textbook of Ophthalmic Pathology. Philadelphia, Saunders, 1957. Reese, A. B.: Tumors of the Eye. New York, Hoeber, 1951.
OPHTHALMIC MINIATURE
Then he came through into the light of the lamp and the purple, crumpled strawberry mark stretching from above the cheek-bone down to the point of the chin was almost like a mark of distinction.—I had maligned him, he could have no satisfaction in looking at that. Graham Greene, The End of the Affair, Penguin Press.