A Moratorium on Enucleation for Choroidal Melanoma?

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R. S., and Thomas, A. H.: No-touch technique for intraocular malignant melanomas. Arch. Ophthalmol. 95:1616, 1977. 4. Fraunfelder, F. T., and Wilson, R. S.: A new approach for intraocular malignancy. The "notouch" enucleation. In Jakobiec, F. A. (ed.): Ocular and Adnexal Tumors. Birmingham, Aesculapius Publishing Co., 1978, pp. 39-45. 5. Boniuk, M., and Cohen, J. S.: Combined use of radiation plaques and photocoagulation in the treat­ ment of choroidal melanomas. In Jakobiec, F. A. (ed.): Ocular and Adnexal Tumors. Birmingham, Aesculapius Publishing Co, 1978, pp. 80-86.

A MORATORIUM ON ENUCLEATION FOR CHOROIDAL MELANOMA? In their magisterial review of the role of enucleation in the management of cho­ roidal and ciliary body melanomas, Zim­ merman and McLean have concluded that an imposing body of data exists, much of it disconcertingly circumstantial and anecdotal, that enucleation is ineffec­ tive in saving lives. They believe that posterior uveal melanomas metastasize late when left alone, but that an increased rate of fatality in the second postoperative year is in part attributable to events (sur­ gical or immunologic, or both) surround­ ing the act of enucleation. In my view they have made the most cogent argument they can with the imper­ fect clinical and statistical information on the biologic behavior of choroidal mela­ noma presently available. To test my own reaction to their construction of the case against enucleation, I asked a group of six professional peers, all but one outside of the mainstream of clinical ophthalmolo­ gy, to offer a critique of the paper: an experienced clinician with an orientation toward ophthalmic pathology (Paul Henkind); an ocular immunologist (Julian Manski); a general surgeon with experi­ ence in performing "no-touch" abdomi­ nal tumor surgery (Frederick Herter); a dermatopathologist with an interest in cutaneous melanoma (David Silvers); a

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general surgical pathologist (Karl Perzin); and a cellular pathologist (Gabriel Godman). They all found the essential clinical features of Zimmerman and McLean's thesis to be compelling, although they expressed reservations about some of the explanations for the clinical observations. Despite the seductive plausibility of Zimmerman and McLean's argument—a virtuoso performance demonstrating the bias of perspective that enters into the handling of any set of moldable data—a nagging concern remains that their con­ clusion has not been proved beyond a reasonable doubt. Have they fallen prey to the logical fallacy of post hoc, ergo propter hoc, the error of arguing from a temporal sequence to a causal relation­ ship? Is it possible that when a choroidal melanoma has reached a size necessitat­ ing its removal its biological character has also undergone a radical transformation with the concomitant production of oc­ cult metastases undetectable by current methods of noninvasive investigation? One could take as time zero the surgical removal of any gastrointestinal or renal tumor, and say: "The tumor was removed and the patient died two years later—just look at what your surgery has done." Although the previous example may be facetious, the parallelism between cuta­ neous melanoma and choroidal mela­ noma is both awkward and worrisome. Wallace Clark and Matthew Harris, two well know specialists in cutaneous mela­ noma, have seen only a few patients with untreated primary cutaneous melanomas (apart from neglected fungating tumors, which would be the cutaneous counter­ part of an intraocular melanoma with proptosis) who had clinically dissemin­ ated disease at the time they were first seen. Of those patients who have a fatal cutaneous melanoma, 40% will be dead within two years after the excision of their tumors. These features are remarkably reminiscent of what happens in the clini-

VOL. 87, NO. 6 cal course of enucleated choroidal mela­ nomas, yet no dermatologist believes that the excision of skin tumors causes metastases. A dermatologic report 1 shows that an incisional biopsy through a cutaneous melanoma, during which malignant cells have to be dislocated into vascular or lymphatic channels, does not worsen the prognosis. The intellectual and clinical melee that will follow in the wake of the article by Zimmerman and McLean should not ob­ scure the reality that a uveal melanoma showing progressive growth, if left un­ treated, will cause death after a variably prolonged period. Of Raivio's five pa­ tients and Sobanski's ten patients who refused enucleation for their choroidal melanomas, 14 died from their disease, eight of these one to three years after the clinical diagnosis of their tumors. If routine enucleation is deleterious to the survival of patients harboring "large" choroidal tumors, Zimmerman and Mc­ Lean are willing to concede that enuclea­ tion probably does not adversely affect the outcome of "small" melanomas (tu­ mors measuring 10 mm or less in greatest diameter and 2 mm or less in height). With our improved clinical and patholog­ ic knowledge regarding the indistinct zone of classification between nevi and small melanomas, it may well be that the comparatively favorable outcome of many of these tumors after enucleation reflects their benign condition at the time of enucleation. Alternatively, some of these small tumors may be biologically malignant (small choroidal tumors occa­ sionally contain epithelioid cells), but enucleation aborts their continued growth toward a fatal "critical mass." In cutaneous melanomas, the removal of a tumor with a thickness of 1.5 mm or less results in an 80% cure rate; if untreated, the majority of these tumors will inexora­ bly grow to a thickness of 3.0 mm, which results in a 75% death rate. 2

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Experimental evidence in support of Zimmerman and McLean's interpretation that enucleation dislodges metastasizable clumps of tumor cells into the circulation ("intravasation") shows that, the larger the size of the tumor cell emboli, the more likely the cells are to implant successfully in the new micro-environment. 3 Although a few individual tumor cells are probably constantly seeding the bloodstream from the primary site, such small numbers of cells are usually destroyed by the host's defense mechanisms. In an animal study, only 1% of intravenously injected tumor cells survived after 24 hours, whereas less than 0.1% of cells had survived by the 14th day. 4 Enucleation probably creates larger cellular aggregates with enhanced capacity to survive in metastasis; none­ theless, the presence of cells in the blood should not be equated with the produc­ tion of metastases. While marshalling evidence to prove that enucleation is a culprit in promoting metastases from large intraocular melano­ mas, Zimmerman and McLean also indi­ cate that such tumors are apt to contain more malignant cell types (particularly epithelioid cells). Regrettably cytomorphology is a weak reflector of the biologic properties of tumor cells, because tumors of identical histologic appearance may well be composed of cells with signifi­ cantly different membrane components and other properties conducive to metas­ tasis. For example, there are benign cuta­ neous nevi composed at times almost ex­ clusively of epithelioid cells; if such a lesion were transposed to the uvea it would precipitate a malignant diagnosis. Indeed, benign epithelioid cell nevi of the iris have recently been identified. 5 Although Zimmerman and McLean point out that there is a dearth of clinical infor­ mation on what happens to small choroidal melanomas after long-term fol­ low up, we have almost no information available on the clonal composition of

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these melanomas undergoing evolution and evading immunological defenses. The emphasis on the mechanical factor in Zimmerman and McLean's study, therefore, sidesteps an even more impor­ tant aspect of the metastatic phenomenon, that is, the intrinsic biologic properties of the tumor cells. What are the stages by which a metastasis is produced? With respect to intraocular melanomas, the tumor cells must invade blood cells (there are no intraocular lymphatic channels), and detach into the bloodstream. Thinwalled venules are the presumed pathway into the circulation for most solid tumors; as Zimmerman and McLean have pointed out, large intraocular melanomas abound in delicate dilated vascular spaces into which tumor cells can be pushed during an enucleation, that is, through surgical manipulations that are the ocular equiva­ lent of a Valsalva maneuver. In the blood­ stream tumor cells may aggregate togeth­ er, reaching a sufficiently large size to metastasize successfully by becoming " h u n g - u p " in the microcirculation. After extending outside of the capillaries, the ability of the microemboli to survive in the metastatic extravascular environment is brought about by a tumor angiogenesis factor. This substance, which is elabo­ rated by the tumor cells, promotes the proliferation of adjacent endothelial cells causing vascularization of the tumor seedlet. The precondition for metastasis is that the tumor cells have the requisite biologic properties to survive in distant sites. Exhypothesi, if the cells of a benign spindle cell nevus are trypsinized and directly injected into the veins of a "human vol­ unteer" none of the cells should survive in the form of a metastasis. Conversely, if the cells of a malignant melanoma are trypsinized and injected intravenously, one would discover that some of the cells do produce metastases, depending on the immune status of the host.

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The best available experimental animal data suggest that there are heterogeneous subpopulations of tumor cells in the pri­ mary lesion, and that the ability of tumor cells to metastasize is a pre-existent prop­ erty resident in limited tumor cell lines, rather than being representative of a ran­ dom adaptation of tumor cells to survive once ensconced in a favorable milieu. 6 Extrapolating these findings to the growth of a uveal melanoma, clones of tumor cells that escape immunologic survellance may emerge with the ability to metastasize. Enucleation would therefore accelerate the formation of metastases by the early dislodgement into the blood­ stream of metastasizable subpopulations of cells within the tumor, but these cells would probably have invaded the blood­ stream on their own at a later date, if indeed they had not already done so be­ fore enucleation. The in vivo immunologic backdrop of the choroidal melanoma story is also more intimidatingly complex than limned by Zimmerman and McLean. By the time uveal melanoma cells have become ma­ lignantly transformed with acquisition of intrinsic cellular properties for metasta­ sis, they have also acquired a set of cell surface neo-antigens that should be capa­ ble of inciting immunocompetent cells to reject them. Unfortunately, the immune system may paradoxically react in some instances to enhance tumor cell growth. Antigens shed by the tumor cells, block­ ing antibodies, antibody fragments, a n d immune complexes can all apparently in­ terfere with the cancer immunosurveillance system. We are now confronted with an immune system that functions differently from person to person, de­ pending on their variable histocompatibility and genetic patterns, and that in­ volves the idiosyncratic orchestration of B-lymphocytes, helper T-cells, killer Tcell^, blocking antibodies, cytophilic an­ tibodies, opsonizing antibodies, primed

VOL. 87, NO. 6 macrophages, and suppressor T-lymphocytes, inter alia, all acting in concert upon the peculiar features of the neo­ plasm. The suppressor T-cell function is par­ ticularly fascinating. 7 A subset of T-lymphocytes called suppressor cells works to turn off immunoreactions by directly in­ teracting with other T- or B-cells to pre­ vent excessive responses and autoim­ mune processes. In some cancerous con­ ditions, much of the host's inability to cope with a tumor may be traceable to the disadvantageous effects of suppressor Tcells on other lymphoid elements, which could eradicate the tumor if not interfered with. In some animal tumor models, sup­ pressor T-cells have been selectively de­ pleted by total body irradiation, splenectomy, or thymectomy which enables the remaining killer T-lymphocytes to attack and retard progression of the tumor. Drugs such as cyclophosphamide, colchicine, indomethacin, and cortisone also have the desirable effect of selectively depleting suppressor T-cells to the rela­ tive advantage of the effector cytotoxic T-lymphocytes. Immunotherapy with BCG has not been successful in the treatment of cuta­ neous melanoma and other malignancies, and immunization of patients with prepa­ rations from their own tumors has some­ times shortened survival, which may result because nonselective immunostimulation activates as many or more sup­ pressor T-lymphocytes as effector killer T-lymphocytes. In whatever manner the immune system plays upon the growth and modifies the metastatic potential of choroidal melanomas, enucleation itself must be an epiphenomenon to the "war of the cells." One cannot dismiss the arguments pre­ sented by Zimmerman and McLean be­ cause of cavils over the manifest defects of some of the data they use; the same data are equally frail in justifying tradi­

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tional enucleation. If they are wrong in alleging the enucleation causes metastases, they have nonetheless disabused us of our complacent attitude that enuclea­ tion as presently performed is an effective form of life saving therapy. Fortunately, guidelines are emerging for the manage­ ment of choroidal melanomas. A consen­ sus has been reached that small stationary tumors need not be enucleated. Slowly enlarging, asymptomatic tumors can probably also be prudently observed, but at shorter intervals. A dilemma arises when the tumor approaches a size where conservative local therapies (iridocyclectomy, eye-wall resection, cobalt plaque, proton beam irradiation, photocoagulation, or cryotherapy) may no longer be serviceable. It is in this uncertain area between doing nothing and doing some­ thing less drastic than enucleation that better indications will have to be devel­ oped. In this regard, the results of studies on survival after enucleation may not be valid with respect to subtotal ocular re­ sections, because reported survivals have been excellent to date (possibly the result of interrupting the trajectory of smaller tumors toward malignant clones). 8 - 9 Fi­ nally, what is to be done for tumors that can be removed only by enucleation if they are to be treated at all? For young patients enucleation is probably still mandatory, whereas for older patients enucleation may be optional depending on the patient's overall health. Improved methods of enucleation (no-touch cou­ pled with isolation of the vortex veins, tumor freezing, or hypotensive surgery, or all three) or enucleation combined with preoperative or postoperative radio­ therapy or chemotherapy, or both, or newer immunotherapy, may avert the now ominous specter of promoting metastases. Only properly designed and ethical prospective studies will lead us out of our present impasse and clinical uncertainty by assembling the necessary

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"control groups" of untreated patients and of those managed by modalities other than straight-forward enucleation. Regardless of the ultimate resolution of the enucleation controversy, we are all indebted to Zimmerman and McLean for sharpening the issues and making us less dependent on conventional wisdom. Not only should the method of enucleation be refined, but a demarche should develop in our thinking and in our research efforts toward a better understanding of the bio­ logic properties of uveal melanomas and the countervailing (or enhancing?) immunologic response to their growth. F R E D E R I C K A. JAKOBIEC

REFERENCES 1. Epstein, E., Bragg, K., and Linden, G.: Biopsy and prognosis of malignant melanoma. J.A.M.A. 208:1369, 1969. 2. Kopf, A. W., Bart, R. S., and Rodriguez-Sains, R. S.: Malignant melanoma. A review. J. Dermatol. Surg. Oncol. 3:41, 1977. 3. Fidler, I.: The relationship of emboli homogenity, number, size, and viability to the incidence of experimental metastasis. Europ. J. Cancer 9:223, 1973. 4. : Metastasis. Quantitative analysis of dis­ tribution and fate of tumor emboli labelled with 125 l-5-iodo-2-deoxyuridine. J. Natl. Cancer Inst. 45:733, 1970. 5. Jakobiec, F . A., Moorman, L., and Jones, I. S.: Benign epithelioid cell nevi of the iris. Arch. Ophthalmol. In press. 6. Fidler, I.: Tumor heterogenity and the biology of cancer invasion and metastasis. Cancer Res. 38: 265, 1978. 7. Broder, S., and Waldman, T.: The suppressorcell network in cancer. N. Engl. J. Med. 299:1335, 1978. 8. Forrest, A. W.: Iridocyclectomy for ciliary body tumors. Criteria for operative success. In Jakobiec, F.A. (ed.): Ocular and Adnexal Tumors. Birming­ ham, Aesculapius, 1978, pp. 46-60. 9. Peyman, G. A., and Raichand, N.: Resection of choroidal melanoma. In Jakobiec, F . A. (ed.): Ocular and Adnexal Tumors. Birmingham, Aesculapius, 1978, p p . 61-69.

AN EVALUATION O F ENUCLEATION IN T H E MANAGEMENT O F UVEAL MELANOMAS Zimmerman and McLean have chal­ lenged the value of enucleation in eyes

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1979

with choroidal melanoma and have pre­ sented data suggesting that the procedure may actually disseminate the tumor. Their paper may well prove to be a classic that will change our concepts and man­ agement of melanomas of the choroid. What is the clinician to do until the many questions raised by this exciting presentation are answered? Ideally, one would like to design a study in which randomly selected matched cases would be observed for five, ten, and 15 years while other cases were being enucleated and observed for the same time spans. The extensive education of the public to the necessity of early detection and thera­ py for cancer precludes such a study even if one were scientifically convinced of its necessity. I believe, however, that management can be broken down into two general categories. First, that of small tumors (that is, those of less than 10 x 10 x 2mm). This is a subject in which I have long been interested, for at my suggestion, Flocks, 1 reviewed the cases of choroidal melanoma in which histologic specimens were available at the Armed Forces Insti­ tute of Pathology. In 1955, he reported that small melanomas had a better prog­ nosis than large melanomas. On the basis of slightly different criteria, this has been confirmed by Jensen 2 ; Davidorf and Lang 3 ; Shammas and Rlodi 4 ; and Thom­ as, Green, and Maumenee. 5 Therefore, because lesions of this size have frequent­ ly been found to be either benign or of low-grade malignancy on both histologic and clinical follow-up it seems justifiable to observe these cases after photography and ultrasound examination for definite evidence of growth, especially elevation, before proceeding with invasive therapy. In these cases I am dubious about the necessity or effectiveness of radioactive isotope studies, photocoagulation, or local excision if there is no evidence of growth. The decsion to treat larger lesions be-