Ocular Melanoma Task Force Report

MEETINGS, CONFERENCES, SYMPOSIA EDITED BY THOMAS CHALKLEY,

OCULAR MELANOMA TASK FORCE REPORT

M.D.

EPIDEMIOLOGY

Uveal melanomas (choroidal, ciliary body, and iris) are the most common priIn response to a resolution passed by the National Advisory Eye Council, the mary intraocular malignancies in adults National Eye Institute convened a task and constitute over 80% of all eye maligforce to evaluate the published reports on nancies. In the United States, the annual ocular melanoma and to recommend what incidence rate is six cases per one million research is needed to solve problems population, that is, approximately 1,500 associated with this disease. The stimuli new cases each year. Limited data are for this action were conflicting conclu- available on the risk factors associated sions and recommendations appearing in with uveal melanomas. White populapublished reports about the management tions are at a higher risk than members of of ocular melanoma and a controversy other races: ocular melanomas occur stemming from the interpretation of eight times more frequently among white mortality data on patients with uveal than among black Americans. The risk of melanomas who underwent enucleation uveal melanoma increases greatly with compared with those who remained un- age: the median age at diagnosis is approximately 55 years and the peak incitreated. Four months before the task force dence is between 60 and 69 years. Intermeeting, the participants were sent more national data on incidence and mortality than 700 abstracts from which to select rates for all ocular tumors show higher relevant articles on the epidemiology, rates for males than for females. diagnosis, treatment, natural (untreated) Most clinical studies of uveal melanocourse, and biology of ocular and cutane- ma present comprehensive data on ocular ous melanoma. Approximately 150 arti- findings, yet data on possible risk factors cles were chosen for critical review. The other than age, sex, and race are seldom participants were asked to analyze the recorded. Additionally, practically all articles in terms of three questions: studies lack adequate control groups, What do we know? thus limiting the interpretation of deWhat do we need to know? scriptive data on uveal melanoma paHow do we find out? tients. To increase our understanding of The task force met April 17 and 18, 1980, the epidemiology of uveal melanomas we at the National Institutes of Health, Be- need to know: thesda, Maryland, to discuss its findings. What are the risk factors for uveal Its recommendations are summarized in melanoma? For example, eye, skin, the following sections. and hair color; nevi and other cutaneous findings; sunlight exposure; laterality of tumor by sex; previous ocular conditions; hormonal factors; Complete transcripts of the meeting and the bibliography reviewed by the task force participants sociodemographic factors; occupamay be obtained by writing to Bettie J. Graham, tional or other exposure to chemical Ph. D., Room 6A-52, Building 31, National Eye and family history. carcinogens; Institute, National Institutes of Health, Bethesda, MD 20205. What are the patterns of occurrence of 728

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uveal melanoma over time, and in different geographic areas, especially where the risk of ocular tumors is known to be high? Is there a correlation between the incidence of cutaneous and uveal melanomas? Do they share the same risk factors? At least two types of epidemiological studies would address some of the questions posed. Analytic epidemiologic studies of the case-control type are needed to determine whether certain factors are associated with an increased risk of uveal melanoma. Such studies would also estimate the magnitude of risk involved. Descriptive epidemiologic studies would evaluate past and present patterns of incidence and mortality and provide baseline data for monitoring future trends. By analyzing existing data on ocular tumors and separating melanomas from all other histologic types, a trend in occurrence might be determined. DIAGNOSIS

Clinical diagnosis of ocular melanoma is remarkably accurate, considering that it is usually performed without the benefit of histopathologic material. Errors in diagnosis in ocular melanoma have become increasingly rare in eye centers where experienced physicians and ancillary diagnostic testing are available. Currently, the mainstay of diagnosis in ocular melanoma remains clinical examination including pupillary dilation and indirect ophthalmoscopy. Ancillary diagnostic tests, while nonspecific, can be extremely helpful in confirming the clinical diagnosis. Ultrasound-Examination of the eye by ultrasound may improve the accuracy of diagnosis in eyes with opaque media and can add significantly to diagnostic accuracy in eyes with clear media. The combined use of A- and B-scan techniques is ideal, and A-scan techniques can often provide size data

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for serial measurements. Ultrasonography is extremely helpful in distinguishing between melanomas and some lesions which simulate melanomas, especially choroidal hemorrhage or hemangioma. Serial fundus photography-This technique is useful in evaluating lesions which are located posteriorly and can be included in a single field of the fundus camera. Problems in reproducibility must be considered when evaluating serial photographs. Stereoscopic fundus photographs are useful in evaluating changes in small lesions, where minimal degrees of elevation are present. Newer wide-angle fundus cameras will greatly expand the utility of photography in following the course of the tumor. Fluorescein angiography-This technique can help differentiate between melanomas and lesions which simulate melanomas, especially choroidal hemorrhage and hemangioma. Damage to the retinal pigment epithelium and neovascularization along the plane of Bruch's membrane, detectable by angiography, may be a guide to growth in choroidal tumors. Radiologic examination-Standard X-ray and computed axial tomography have limited use in the diagnosis of most ocular melanomas, but can confirm the presence of osseous choristoma or help to assess extraocular or optic nerve extension of the tumor. Radioactive phosphorus (S2P) uptake test-This is another ancillary test which is utilized by some clinicians and may not always be necessary in routine cases where diagnosis of ocular melanoma can be made with less complicated procedures. Complete evaluation of the patient's health status is essential and provides baseline information for monitoring treatment or progression of disease. Patients with ocular melanoma should have a

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complete physical examination and clinical laboratory studies, including routine blood work, chest X-ray, liver enzyme measurements, and, probably, radioisotope liver and spleen scans. These tests should be supervised and evaluated by physicians who are experts in the diagnosis and treatment of tumors. At present, clinical observation and documentation of growth remain the most reliable ways to differentiate between benign nevi and melanomas. The diagnostic tool most needed in evaluating ocular melanoma is one which would differentiate between a nevus and a small melanoma and reliably measure tumor growth, in addition to being noninvasive. Techniques which are relatively new in ophthalmology, such as immunologic tests, are exciting areas for future development. PATHOLOGY

Histologic examinations of ocular tumors can be useful to the clinician when the relationship between the histopathologic features of the tumor can be correlated with the natural course of the disease or the prognosis. In order to achieve this goal it is necessary to: Develop standard terminology to describe and compare such aspects of ocular tumors as uveal nevus, uveal melanoma, tumor size, and necrosis. Develop uniform methods of preparing tumor-bearing eyes for histologic, ultrastructural, and biochemical studies. Define how events in the natural course of the tumor are reflected in the histopathology of the tumor and how such findings correlate with prognosis. Improve the cellular criteria for categorizing tumors by the Callender classification and expand the Callender classification to an ultrastructural level to relate morphologic findings with tumor behavior and prognosis.

NOVEMBER, 1980

The above tasks can be accomplished by convening a panel of experienced ophthalmic pathologists and oncologic pathologists who could formulate terms and definitions that would be accepted and Widely utilized by the ophthalmic community. The same or a similar panel, in a masked study, could review retrospective cases with defined histories in an attempt to relate significant histologic features to prognosis. As a control, eyes from patients with nonmetastasizing lesions should also be included in the survey. These studies should be complemented by correlating ultrastructural changes in tumor cells with malignant potential. NATURAL COURSE

Knowledge of the natural course of uveal melanomas is critical for designing treatment regimens, and such information also serves as the control for their evaluation. Most of our present information on ocular melanoma is inadequate and is derived from retrospective studies done after treatment, usually enucleation. While small tumors probably evolve into large tumors given sufficient time, and in so doing become more likely to produce metastatic disease, this concept is based on few actual observations. Since most melanomas are enucleated promptly, especially if they show signs of growth, very limited data are available regarding outcome without treatment. Additionally, very few cases have been followed with quantitative measurements over a sufficient number of years to provide any prospective data on the importance of growth rate to prognosis, and virtually nothing is known about the frequency of spontaneous regression in ocular melanoma, although it occurs in skin melanomas. The data needed to define the natural history of ocular melanomas include: Determing the natural course in large numbers of patients with lesions of varying size.

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Determining which of the following clinically measurable factors are important in determining metastasizing potential and prognosis of uveal melanoma: size, location, degree of pigmentation, transillumination, surface alterations such as yellow pigment, drusen, retinal pigment, epithelial damage, neovascularization, collar-button extension, retinal detachment, vitreous or choroidal hemorrhage, secondary glaucoma, and visual field changes. How does tumor growth rate and size correlate with prognosis? Do nevi represent the only recognizable precursor lesions for choroidal melanomas or do some melanomas develop de novo? Can the hormonal status of the individual or other factors influence the growth rate of uveal melanomas? What is the frequency of spontaneous regression in ocular tumors? How does the patient's immune state relate to prognosis? Are there skin changes that correlate with prognosis in ocular melanoma, for example, vitiligo, or growth or change in pigmentation of skin nevi? Melanomas of the ciliary body and iris, as well as malignant melanomas of the conjunctiva and eyelid, appear to be clinically different from choroidal melanomas; therefore, the natural course of each of these tumors should be evaluated separately. A prospective study done before treatment of patients with uveal melanoma would provide needed information on the natural course of this disease. The study protocol and standardized data collection would be developed in collaboration with ophthalmologists, oncologists, and epidemiologists. Patients entering the study would receive a comprehensive evaluation to determine risk factors as well as local and systemic factors which might influence possible prognosis. After the initial evaluation, patients would be ex-

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amined at regular intervals and complete follow-up data obtained. Considering the present variation in management, many patients with small-to-medium-sized lesions would probably be observed for a long period before treatment. In many cases, it would be possible to collect data on the epidemiology and natural course simultaneously. THERAPY

Effective intervention should alter the natural course of the primary lesion, or prevent metastases, or delay recurrence. The prognosis for local intraocular melanomas depends upon cell type, lesion size, stage of the disease, age, location in the uvea, mitotic activity, and, possibly, sex. The relative effectiveness of radiation therapy, such as rhodium 106 and proton beam, is not known, and the benefits of cryosurgery have not been properly evaluated. However, retrospective studies of patients with small melanomas treated by enucleation confirm their relatively favorable prognosis. The prognosis of patients with uveal melanoma with extrascleral extension is poor, and the cure rate is less than 50%. Exenteration of the orbit is probably the most commonly used procedure, although the precise technique (partial vs complete) varies among ophthalmic surgeons. In evaluating the data, it is often unclear whether cases of extrascleral extension have residual tumor in the orbit or extend near or to the line of transection. The pattern of metastatic disease in ocular melanoma is similar to that of cutaneous melanoma, with a single obvious exception: the lack of lymphatic drainage of the eye precludes the presence oflymph-borne metastases. Hepatic metastases tend to predominate in uveal melanoma, but the disease is capable of widespread metastatic dissemination and this complication should be suspected and explored in every patient. In any case, the disease is probably incurable at this stage. For tumors no longer confined

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to the orbit, surgery, perhaps in combination with other therapy, is only palliative. The interpretation of available data on the prognosis and efficacy of enucleation of medium and large tumors remains controversial. The recognition of metastasis before enucleation is very infrequent (1% to 3%) but no valid data exist. Additionally, the high mortality from metastases after surgery is not unique to uveal melanomas, but is characteristic of many other neoplasms. Proper management of uveal melanomas requires knowledge about appropriate clinical technology and the basic biology of the tumor. Questions about appropriate clinical technology include: Is there a subgroup of primary ocular melanomas, based on size and rate of growth, for which observation alone is the optimal management choice? What is the effect of enucleation on the natural course of primary ocular melanoma? Can preoperative or postoperative radiation improve results when combined with enucleation? Can adjunctive therapy with immunotherapeutic agents such as thymosin, interferon, or transfer factor improve the outcome of treatment? Is there an optimal surgical procedure for orbital exenteration? Is antipigmentary therapy of any value in treating ocular melanoma? A rigorous test of the efficacy of treatment on disease outcome is best accomplished by a randomized, controlled clinical trial. The feasibility of a clinical trial in this disease is greatly limited by insufficient information on the natural course of the disease; this is especially true for small melanomas without extraocular extension. However, since the prognosis of large melanomas or melanomas with extrascleral extensions is poor, patients with tumors in these two categories and their ophthalmic surgeons might ethically consider participating in a randomized controlled clinical study.

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BIOLOGY OF OCULAR MELANOMAS

Understanding the biological and biochemical properties of uveal melanoma cells is a key to effective diagnosis and treatment. Our knowledge of ocular melanomas has been hampered by lack of cell lines or strains of human uveal melanomas and appropriate animal models. Some of the questions that need to be addressed include the following: What are the causative agents in .ocular melanoma, for example, viruses, chemicals, environment? Are there receptors for hormones and vitamin A on melanoma tumor cells? Do melanoma tumor cells have specific enzyme requirements which explain their high incidence of liver metastasis? Can early ocular melanomas be induced to differentiate into nevi? Are some histopathologic types of tumor cells more hormonally sensitive or dependent than others? Are growth factors present within the melanoma tumors? Since there are variations within melanin pigments, are there specific pigments associated with melanomas? Are there tumor-specific antigens associated with the different cell types? If so, can monoclonal antibodies be produced against these antigens for immunodiagnostic purposes? Do patients develop cell-mediated or humoral antibodies to melanoma tumor cells? If so, how does the host's immune competency affect the behavior of the tumor and the development of metastasis? To study the biology of tumor cells at the cellular and molecular level will require the establishment of tumor cell lines and strains, and the availability of properly prepared fresh human donor materials (eyes and sera). The development of appropriate animal models is also essential. Additionally, the latest technology should be used in solving problems associated with ocular melanoma.

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In conclusion, the task force agreed that one of the first steps in achieving the desired goal of determining how to manage ocular melanomas properly is to pursue epidemiologic and natural course studies. This does not rule out a randomized controlled clinical trial of carefully chosen treatment(s) using a select group of patients with poor prognoses. Since the number of patients with ocular melanoma is relatively small, a collaborative effort between ophthalmologists caring TASK FORCE PARTICIPANTS THOMAS D. DUANE, M.D. Chairman of Task Force Wills Eye Hospital Philadelphia, Pennsylvania DANIEL M. ALBERT, M.D. Howe Laboratory of Ophthalmology Massachusetts Eye and Ear Infirmary Boston, Massachusetts WALLACE H. CLARK, M.D. Department of Dermatology University of Pennsylvania Philadelphia, Pennsylvania M. CRISTINA LESKE, M. D. School of Medicine,

THREE INTERNATIONAL MEETINGS ON SPECULAR MICROSCOPY Three international meetings on specular microscopy of the human corneal endothelium occurred in the spring of 1980: the Workshop on Specular Microscopy of the Corneal Endothelium, hosted by F. Bigar in Zurich, Switzerland, on April 14 and 15; the Round Table on Specular Microscopy, chaired by R. Buckley at the VI European Congress of Ophthalmology in Brighton, England, on April 25; and the 1980 Specular Microscopy Symposium, organized by P. Binder preceding the Association for Research in Vision and Ophthalmology meeting in Orlando, Florida, on May 4. These meetings provided information on the current state and future direction of specular microscopy. Optical problems-In a historical sur-

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for melanoma patients and scientists involved in ocular melanoma research is needed. Underlying these recommendations was the task force's belief in the need to share resources, the need for greater cooperation among ophthalmologists, and the need for increased communication among ophthalmologists, epidemiologists, and medical oncologists.

J.

BETTIE GRAHAM THOMAS D. DUANE

Department of Community and Preventive Medicine State University of New York Stony Brook, New York DONALD S. MINCKLER, M.D. Pathology Laboratory Estelle Doheny Eye Foundation Los Angeles, California LARRy NATHANSON, M. D. Medical Oncology New England Medical Center Boston, Massachusetts BETTIE J. GRAHAM, PH.D. National Eye Institute National Institutes of Health Bethesda, Maryland

vey, F. Bigar (Zurich) emphasized that A. Vogt's remarkably accurate drawings contained details now being observed with specular photomicrography. R. Laing (Boston) pointed out that the specular image is formed by light reflecting from each optical interface in the cornea combined with the light scattered back from the various tissue layers. The wider the slit used, the more cells can be photographed; the wider slit, however, increases the overlap of the reflected and scattered light, reducing the image contrast. A. Thaer (Zurich) sought to improve image contrast by reducing the light scatter with a narrow slit and reducing the reflections from the corneal surface with an objective lens or contact solution that has an index of refraction similar to that of the cornea. C. Koester (New York) stated that, since the endothelial specular image reflected only about 0.02% of the incident light, there