Chapter 147 – Uveal Melanoma

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Chapter 147 – Uveal Melanoma











• Primary acquired malignant neoplasm of uveal melanocytes.



• Dark brown to golden tumor of choroid, ciliary body, or iris.

• Choroidal and ciliary body tumors are usually more than 7?mm in basal diameter and more than 2?mm thick at the time of diagnosis; iris tumors are much smaller at diagnosis.

• Unilateral, unifocal in almost all affected patients.

• Well-established tendency to metastasize, especially to liver.

• Much more common in lighter-skinned races.



• Nonrhegmatogenous retinal detachment with shifting subretinal fluid, frequently associated with choroidal and ciliary body melanomas.

• Prominent clumps of orange pigment lipofuscin commonly present on surface of choroidal tumors.

• Eruption of some choroidal tumors through Bruch’s membrane to achieve a mushroom-like shape.

• Extrascleral extension.





Uveal melanoma is a malignant neoplasm that arises from neuroectodermal melanocytes within the choroid, ciliary body, or iris. It is the most common primary malignant intraocular neoplasm of Caucasian adults. This neoplasm has a well-documented capacity to metastasize hematogenously and kill the patient. Its favored metastatic site is the liver. It can arise from any portion of the uveal tract, but choroidal involvement is by far the most common. Uveal melanomas confined to the iris appear to be substantially less malignant in terms of their potential to kill the host than are melanomas confined to the choroid and ciliary body. Furthermore, the extent of the tumor at the time of detection and the methods of management employed are substantially different for iris melanoma than for choroidal and ciliary body melanomas. For this reason, these two general forms of uveal melanoma are discussed separately in this chapter.


Uveal melanoma has a cumulative lifetime incidence of approximately 1 in 2000–2500 Caucasian individuals.[1] [2] It is between 15 and 50 times less common in African blacks and intermediate in frequency in other racial groups. The average annual incidence in Caucasians older than 30 years has been estimated to be approximately seven to eight new cases per million persons. The annual incidence increases with advancing age. Before age 30 years, the annual incidence is less than one new case per million. In contrast, by age 70 years, the annual incidence is approximately 50 new cases per million.

The average age at detection of melanomas of the choroid or ciliary body is about 55–60 years in most large series.[1] The average age at detection of melanomas of the iris is 10–20 years younger. As indicated earlier, uveal malignant melanoma is rare in persons younger than 30 years and increases in frequency with each decade of life. The cumulative lifetime incidence of primary uveal melanoma is slightly higher in men than in women.[2]

Patients who have a history of intense, sustained, recurrent sunlight exposure sometime during life appear to be more likely to develop a uveal melanoma than those without such exposure.[1] A generalized congenital ocular hyperpigmentation known as ocular melanocytosis appears to predispose patients to the development of uveal melanoma. The dermatological condition dysplastic nevus syndrome is also associated with an increased risk of uveal melanoma. However, reproductive factors, estrogen therapy, and cigarette smoking do not appear to increase the risk of uveal melanomas appreciably.

Although uveal malignant melanoma occurs in more than one member of a family more frequently than one would expect by chance alone, no strong familial inheritance pattern exists for this neoplasm. Several somatic cytogenetic abnormalities have been encountered rather frequently in uveal melanoma cells,[3] and these chromosomal abnormalities may be responsible in some way for the development of the malignancy. The most commonly encountered chromosomal abnormalities to date include monosomy of chromosome 3, a duplication of a portion of the long (q) arm of chromosome 8, partial deletion of the short (p) arm of chromosome 9, and complementary gains of material on chromosome 6p and loss of material from chromosome 6q.



The usual symptom of an iris melanoma is a visible spot on the iris or a discoloration of the iris in one eye. Many patients with an iris melanoma have no symptoms, and the lesion in these patients usually is detected on routine eye examination.

The typical iris melanoma is a localized, dark brown to tan iris tumor ( Fig. 147-1 ). Features of a tumor that help the ophthalmologist assess its malignant potential include size of the lesion, its apparent cohesiveness, its intrinsic vascularity, and its effects on the adjacent ocular tissues.[4] [5] As one would expect, the larger the lesion, the greater the concern about its potential malignancy. Thickness of the lesion greater than 0.5–1?mm is of particular concern in such cases. Prominent intralesional blood vessels frequently develop within iris melanomas ( Fig. 147-2 ). Such blood vessels are occasionally the source of spontaneous hyphema. Most iris melanomas appear well circumscribed and relatively cohesive, but others appear shaggy with dispersion of tumor cells, free pigment, or both onto the adjacent iris and trabecular meshwork. If tumor cells, liberated pigment, or macrophages clog the trabecular meshwork in such a case, a substantial rise in intraocular pressure can occur. Other features





Figure 147-1 Iris melanoma. Darkly melanotic iris tumor has a thick central nodule.



Figure 147-2 Iris melanoma. A melanotic iris tumor contains prominent intrinsic blood vessels. Note peaking of the pupil toward the tumor and focal ectropion iridis.

frequently associated with a melanocytic iris tumor include pupillary peaking (see Fig. 147-2 ), ectropion iridis, and iris splinting (failure to dilate fully in the zone of involvement); however, because all these features can also occur with benign nevi,[5] none of them should be regarded as a reliable indicator of malignancy.


Transpupillary or transconjunctival trans-scleral transillumination of the eye is a relatively simple method that can be used to assess the posterior extent of melanocytic iris tumors. If the tumor is confined to the iris, transillumination will project no shadow in the pars plicata region. In contrast, if the tumor involves both the iris and the ciliary body, transillumination will reveal a shadow that extends into the pars plicata or even pars plana region. Because darkly melanotic uveal tissue blocks light transmission, this technique is usually unsuccessful in darkly pigmented eyes, including those affected by ocular melanocytosis.

Anterior segment photography, including goniophotography, is frequently used to document the size, extent, color, surface texture, vascularity, and location of melanocytic iris lesions. Such photographs are most useful in patients who are followed for documentation of lesion enlargement or other signs of possible malignant behavior in lieu of biopsy or treatment. Fluorescein angiography is used occasionally to assess the intralesional vascularity and filling pattern of presumed melanocytic iris tumors. Although some authors suggest that the angiographic findings help distinguish between benign nevi and malignant melanomas, most experienced ocular tumor experts believe that angiograms provide little if any useful diagnostic or prognostic information in



Figure 147-3 Ultrasound biomicroscopy of iridociliary melanoma. Image shows the solid nature of the lesion and involvement of the ciliary body.

such cases. In some centers, indocyanine green angiography is now used as a diagnostic tool for iris tumors. There is no convincing evidence that this test provides any better diagnostic or prognostic information than does fluorescein angiography.

Ultrasound biomicroscopy enables clinicians to assess the size, cross-sectional shape, and internal characteristics of suspected iris melanomas ( Fig. 147-3 ).[6] It allows reliable differentiation between solid and cystic lesions of the iris and also provides a baseline for future assessment of lesion enlargement in the case of tumors that are observed rather than treated. In most cases, it shows clearly whether the tumor is confined to the iris or involves the ciliary body as well.

Biopsy can be performed on melanocytic iris lesions that are larger or more worrisome than typical benign nevi but are not convincingly malignant melanomas in terms of their clinical features. For such tumors, either incisional biopsy or fine-needle aspiration biopsy can be performed.[7] Advantages of incisional biopsy include the relatively large tumor specimen that can be obtained and the ability to process the obtained tissue by standard histopathological methods. Disadvantages of incisional biopsy include the need for a corneal or limbal incision that must be closed surgically and the possibility of hyphema, postoperative glare, and other less common problems. Advantages of fine-needle aspiration biopsy include the relative simplicity of the technique and the possibility that several portions of the tumor may be sampled. Disadvantages of fine-needle aspiration biopsy include the limited number of cells obtained and the inability to evaluate tissue architecture on fine-needle aspirates of the tumor. If biopsy is performed and malignant melanoma is confirmed pathologically, one can justifiably advise the patient to undergo excision of the lesion or other intervention and risk the visual consequences of that treatment.

Baseline Systemic Evaluation

Unless the tumor is relatively large, has a substantial ciliary body component, causes pronounced elevation of intraocular pressure, or shows clinical evidence of extrascleral tumor extension, an extremely limited likelihood exists of detection of any clinical metastatic disease at the time of ocular tumor diagnosis. Consequently, a systemic metastatic search before treatment is probably unwarranted in most patients who have an iris melanoma. In patients who have any or all of the higher-risk characteristics mentioned earlier, however, a baseline metastatic search similar to the type suggested for patients with a choroidal or ciliary body melanoma (see later) is probably appropriate.


A list of the pertinent lesions in the differential diagnosis of iris melanomas is presented in Box 147-1 .






Differential Diagnosis of Iris Melanomas

Nevus of iris


Cyst of iris pigment epithelium


Cyst of iris stroma


Metastatic carcinoma to iris


Iris lesions of iridocorneal endothelial (ICE) syndrome (essential iris atrophy and Cogan-Reese syndrome)


Leiomyoma of iris and ciliary body




Juvenile xanthogranuloma of iris


Other inflammatory granuloma


Intraocular foreign body


Adenoma or adenocarcinoma of iris pigment epithelium


Adenoma or adenocarcinoma of ciliary epithelium


Ectopic lacrimal gland in iris






Iris melanoma is composed of atypical melanocytic cells that occupy and replace normal iris stroma. These cells tend to have a larger nuclear-to-cytoplasmic ratio, more prominent nucleoli, a higher likelihood of multiple nucleoli, and more frequent mitotic figures than do nevus cells. Tumor cells that have a fusiform shape and relatively mild atypia are termed spindle melanoma cells, and those that have a more spherical shape and more pronounced anaplasia are called epithelioid melanoma cells. The majority of iris melanomas are composed either exclusively of spindle melanoma cells or of an admixture of spindle melanoma cells and benign nevus cells. [8] Most of the remaining iris melanomas consist of an admixture of spindle and epithelioid melanoma cells. Relatively few iris melanomas are composed exclusively of epithelioid melanoma cells. In comparison with choroidal and ciliary body melanomas, iris melanomas are more likely to be composed exclusively of spindle melanoma cells and to be smaller at the time of detection and treatment. Consequently, the survival prognosis of patients who have iris melanomas is generally substantially better than that of patients who have choroidal or ciliary body melanomas.[9]


Many suspected iris melanomas, especially those that are small, should be observed without intervention unless unequivocal enlargement occurs within a short time. Currently, no compelling evidence exists that prompt excision of small suspected iris melanomas improves the survival prognosis over that expected with observation alone.[5] Treatment of iris melanomas, when warranted, usually consists of excision of the tumor (iridectomy or iridocyclectomy; Box 147-2 ). Surgical techniques for such procedures have been described in detail by other authors.[10] Plaque radiotherapy and proton beam irradiation have been performed in a small number of cases and appear to be effective in short-term follow-up.[11] Enucleation is occasionally required for large iris melanomas that cannot be resected, diffuse iris melanomas associated with extensive seeding into the aqueous, iris melanomas extending trans-sclerally, and eyes rendered blind and painful by complications related to the tumor.[12]


The typical iris melanoma grows relatively slowly but eventually replaces a substantial proportion of the iris and ciliary body. It can cause secondary glaucoma by invading the peripheral iris and trabecular meshwork in a ring growth pattern or by clogging the trabecular meshwork with macrophages that contain phagocytosed cellular debris. Tumor cells can extend extrasclerally along the scleral vascular and neural foramina in the anterior ciliary



Treatment Options for Iris Melanomas



Excision (iridectomy or iridocyclectomy)


Plaque radiotherapy







body region. The eye can become blind and painful as a consequence of tumor progression.

Most patients who have an iris melanoma treated by excision of the primary tumor do well postoperatively and do not develop subsequent metastatic disease.[9] [13] After excision of an iris melanoma, the patient must be monitored on a regular basis for tumor recurrence in the adjacent iris or ciliary body and for development of satellite lesions caused by tumor cell dispersion before or during surgery. Ophthalmic follow-up evaluations are generally recommended at approximately 6-month intervals for the first 3–5 postexcision years and every year thereafter for life.

Important clinical prognostic factors for death from metastatic melanoma in patients who have primary iris melanoma and no evidence of metastatic disease at the time of diagnosis include the size of the tumor (the bigger the tumor, the worse the prognosis), the location of the tumor (tumors that involve the ciliary body are associated with a worse prognosis than are those confined to the iris), a diffuse or ring growth pattern, and extrascleral tumor extension.[5] [13]



Although some choroidal and ciliary body melanomas are detected on ophthalmic evaluations prompted by the development of visual symptoms (e.g., blurred vision, visual field defect, flashes, floaters), many patients who have such a tumor are asymptomatic at the time of detection of the lesion on routine ophthalmic examination. Pain is unusual, although some advanced cases are associated with severe ocular and periocular pain (usually due to secondary glaucoma or spontaneous tumor necrosis). Virtually all ciliary body melanomas stimulate the development of dilated episcleral sentinel blood vessels ( Fig. 147-4 , A), extend through the sclera to form a melanotic epibulbar nodule ( Fig. 147-4 , B), or both.

The typical choroidal melanoma appears as a dark brown to golden solid tumor and has a biconvex, lenticular cross-sectional shape ( Fig. 147-5 , A). About 20% of choroidal malignant melanomas eventually break through the overlying Bruch’s membrane and retinal pigment epithelium to form a nodular eruption beneath the retina. As this nodular eruption enlarges, the tumor commonly takes on a mushroom-like configuration ( Fig. 147-5 , B). This particular configuration is highly characteristic of choroidal melanoma.

Darkly melanotic choroidal melanomas commonly exhibit prominent clumps of orange lipofuscin pigment on their surface. These pigment clumps are not specific for choroidal melanomas and can be observed over some choroidal nevi and other benign choroidal tumors.[12] However, choroidal melanomas are much more likely to have prominent clumps of orange pigment on their surface than are benign simulating lesions.

Choroidal melanomas are commonly associated with secondary nonrhegmatogenous retinal detachment characterized by clear, serous, shifting subretinal fluid. In some cases, the fluid extends over and a short distance around the base of the lesion. In others, it accumulates to the extent that the retina is extensively







Figure 147-4 External indicators of underlying ciliary body melanoma. A, Sentinel blood vessels on the sclera overlying a ciliary body melanoma. B, Trans-scleral extension of an iridociliary melanoma. Note that the anterior margin of the intraocular tumor is in the peripheral iris.

or even totally detached. In some cases, the subretinal fluid is bloody, almost exclusively in eyes that have tumor eruption through Bruch’s membrane. In still other cases, vitreous hemorrhage is a presenting manifestation, sometimes precluding a clear view of the intraocular tumor. In most if not all such cases, the choroidal or ciliary body melanoma has not only erupted through Bruch’s membrane but also invaded the retina.

The typical ciliary body melanoma appears as a highly elevated, nodular, dark brown lesion in the peripheral fundus. Some of these tumors are thick enough to indent the lens in its equatorial region.


B-scan ultrasonography of a choroidal or ciliary body malignant melanoma usually reveals a solid, acoustically dark (relatively sonolucent) mass that has a biconvex cross-sectional shape ( Fig. 147-6 , A). Choroidal melanomas that have erupted through Bruch’s membrane show the more characteristic mushroom-like cross-sectional shape ( Fig. 147-6 , B). These tumors often have relative acoustic brightness in their caps but almost always show the characteristic relative internal sonolucency in their basal aspects.

Standardized A-scan ultrasonography of choroidal and ciliary body melanomas typically reveals low-amplitude internal reflectivity with a characteristic stepwise decremental reduction in echo spike amplitude from the front to the back of the lesion. Choroidal melanomas that have erupted through Bruch’s membrane typically show high-amplitude internal reflectivity corresponding to the apical cap but low-amplitude internal reflectivity corresponding to the basal region. In many tumors, A-scan also reveals fluctuations in the height of some of the intralesional echoes coincident with the pulse. These fluctuations are indicative of the presence of prominent intralesional blood vessels fed from choroidal or posterior ciliary arteries.





Figure 147-5 Typical shapes of choroidal melanomas. A, Dome-shaped choroidal melanoma. B, Mushroom-shaped choroidal melanoma.





Figure 147-6 Ultrasonography of choroidal melanoma. A, B-scan of dome-shaped choroidal melanoma. B, B-scan of mushroom-shaped choroidal melanoma.







Figure 147-7 Fluorescein angiography of dome-shaped choroidal melanoma. A, Early phase frame shows filling of both retinal and intratumoral arteries. B, Late phase frame shows nonuniform hyperfluorescent staining of tumor.

Fluorescein angiography of choroidal melanomas yields several distinct patterns that depend on the cross-sectional shape of the tumor, its intrinsic and overlying pigmentation, the presence or absence of healthy overlying retinal pigment epithelium, and the presence or absence of retinal invasion and retinal detachment. The typical dark brown choroidal melanoma that has not broken through Bruch’s membrane characteristically appears hypofluorescent throughout the early phases of the study ( Fig. 147-7 , A). A few large-caliber intralesional blood vessels can be detected in many cases in the early phase frames. Blood vessels of this type usually become ill defined and smudgy within a few seconds because of profuse fluorescein leakage into the extracellular space of the tumor. By the late frames of the study, the fluorescein that has leaked from the intralesional blood vessels stains the tumor intensely, along with any associated subretinal fluid ( Fig. 147-7 , B). Fluorescein also tends to accumulate in pinpoint foci at the retinal pigment epithelial level by the late phase of the study. Amelanotic melanomas show less lesional hypofluorescence and more prominent intralesional blood vessels than their melanotic counterparts but otherwise appear similar angiographically.

Fluorescein angiography of choroidal melanomas that have erupted through Bruch’s membrane typically reveals prominent apical intralesional blood vessels that fill slowly but intensely during the study ( Fig. 147-8 ). These vessels leak profusely and result in intense late staining of the tumor and any associated subretinal fluid. If a melanoma has invaded the overlying retina, the retinal blood vessels at the area of invasion can be masked





Figure 147-8 Fluorescein angiography of mushroom-shaped choroidal melanoma. A, Early laminar venous phase frame shows filling of intratumoral blood vessels. B, Late phase frame shows intense generalized staining of apical nodule and associated subretinal fluid.

by an overlying plaque of pigmented tumor cells. In such cases, the area of retinal invasion may appear completely nonfluorescent throughout the entire study. The small retinal blood vessels at the margins of an area of retinal invasion commonly leak fluorescein by the late phase of the study.

Indocyanine green angiography of choroidal melanomas shows most tumors to be quite hypofluorescent throughout the study.[14] However, large-caliber intralesional blood vessels usually are better defined on indocyanine green angiography than on fluorescein angiography, particularly if the study is performed using a scanning laser ophthalmoscope.

Computed tomography (CT) is capable of imaging most choroidal and ciliary body melanomas. Virtually all melanomas of the choroid and ciliary body (except for those that are totally necrotic) exhibit pronounced contrast enhancement. However, because almost all other viable intraocular tumors also show contrast enhancement, this feature is not usually of any differential diagnostic importance. Subretinal fluid associated with a choroidal or ciliary body melanoma appears almost isodense with the tumor on both nonenhanced and contrast-enhanced images.

Magnetic resonance imaging (MRI) is also used occasionally to image choroidal and ciliary body melanomas.[15] It appears to have greater differential diagnostic value than CT for differentiating melanomas from simulating lesions. The great majority of malignant melanomas of the choroid and ciliary body appear bright (hyperintense) relative to the dark vitreous on T1-weighted images and dark (hypointense) relative to the bright vitreous on T2-weighted






Differential Diagnosis of Choroidal and Ciliary Body Melanomas

Choroidal nevus (including melanocytoma of optic disc)


Metastatic carcinoma to choroid or ciliary body


Disciform lesion (central or peripheral)


Subretinal or subpigment epithelial hematoma


Localized suprachoroidal hematoma


Circumscribed choroidal hemangioma


Nodular posterior scleritis


Choroidal osteoma


Congenital hypertrophy of retinal pigment epithelium


Reactive hyperplasia of retinal pigment epithelium


Syndrome of bilateral diffuse uveal melanocytic proliferation associated with systemic carcinoma


Massive gliosis of retina


Ocular melanocytosis





images. Few intraocular tumors of other types have consistently shown this particular pattern. Unfortunately, some atypical choroidal and ciliary body melanomas, most notably ones that are almost completely amelanotic, do not yield this characteristic MRI pattern. Another important use of MRI is the detection of posterior extrascleral tumor extension.

Open surgical biopsy is not generally advised for suspected malignant melanomas of the choroid and ciliary body (unless the biopsy is intended to achieve complete tumor resection). Previous experience with incisional biopsy techniques for suspected choroidal and ciliary body melanomas showed unacceptably high rates of local tumor recurrence and death from metastatic disease after the biopsy.[16] In recent years, however, fine-needle aspiration biopsy methods have been used before treatment in selected choroidal and ciliary body melanomas.[17] Although implantation of a few melanoma cells along the scleral needle tract has been documented pathologically after fine-needle aspiration biopsy,[18] this type of biopsy has not been associated with any clinical tumor recurrence along the needle tract to date in eyes preserved by some modality after biopsy.

Baseline Systemic Evaluation

A standard baseline systemic assessment of the extent of disease generally consists of a complete physical examination; selected blood tests, which usually include at least a complete blood count and a serum liver enzyme panel; chest radiograph; and CT scan (with contrast), MRI, or ultrasound evaluation of the abdominal organs (especially the liver).[19] The great majority of patients (approximately 98%) who have a choroidal or ciliary body malignant melanoma have no detectable extraocular or metastatic disease at the time of detection and diagnosis of the ocular tumor.[20] Those who have concurrent clinically detectable metastatic uveal melanoma at baseline evaluation usually have a very large intraocular tumor and frequently have nodular extrascleral tumor extension.


The most important lesions in the differential diagnosis of choroidal and ciliary body melanomas are listed in Box 147-3 .


As mentioned earlier in the section on iris melanomas, all uveal melanomas are composed of anaplastic melanocytic cells that have a relatively large nuclear-to-cytoplasmic ratio and one or more prominent nucleoli.[21] Most tumors of this type also have relatively frequent mitotic figures. Tumor cells that have less pronounced anaplasia are termed spindle melanoma









Figure 147-9 Histopathology of posterior uveal melanoma. A, Spindle cell melanoma. B, Mixed-cell melanoma. C, Epithelioid cell melanoma. D, Vascular loops and networks that separate lobules of choroidal melanoma.

cells ( Fig. 147-9 , A), and those that exhibit more pronounced anaplasia are called epithelioid melanoma cells ( Fig. 147-9 , C). Precise morphological criteria for the two cell types have not been established. Uveal melanomas are generally classified as spindle cell melanomas if they contain only spindle cells (see Fig. 147-9 , A), mixed-cell melanomas if they are composed of an admixture of spindle cells and epithelioid cells without a preponderance of epithelioid cells (see Fig. 147-9 , B), and epithelioid cell melanomas if they are composed entirely or predominantly of epithelioid cells (see Fig. 147-9 , C). In many independent studies, spindle cell melanomas have



been shown to be associated with the most favorable survival prognosis, epithelioid cell melanomas with the least favorable survival prognosis, and mixed-cell melanomas with an intermediate survival prognosis.[21] Some choroidal and ciliary body melanomas contain only necrotic cells on histopathological study, and a cell type cannot be determined for such tumors.

In comparison with iris melanomas, choroidal and ciliary body melanomas are more likely to be composed of epithelioid melanoma cells and to be substantially larger at the time of detection and treatment. Consequently, the survival prognosis for patients who have choroidal or ciliary body melanomas is much worse than that for patients who have iris melanomas.[22]

Many pathological features other than melanoma cell type have prognostic value for melanoma-specific mortality. [21] [22] [23] Unfavorable pathological prognostic factors include larger tumor size, presence of fibrovascular loops and networks within the tumor (see Fig. 147-9 , D), larger calculated values of various cytomorphometric parameters of the tumor (mean nuclear diameter and area, standard deviation of nuclear area, mean nucleolar diameter and area, standard deviation of nucleolar area), presence of scleral invasion, presence of trans-scleral tumor extension, involvement of the ciliary body, higher mitotic index of the tumor, and greater level of pigmentation of tumor cells. Specific cytogenetic abnormalities (monosomy 3, partial duplication of chromosome 8, and others) have also been associated with increased risk of metastasis and metastatic death in patients with primary choroidal and ciliary body melanomas.[24] [25]


Many therapeutic options are available for choroidal and ciliary body melanomas ( Box 147-4 ). Factors that influence the therapeutic decision include the size and extent of the intraocular tumor, location of the tumor within the eye, presence or absence of extrascleral tumor extension, presence or absence of clinically detectable metastasis to other organs, visual status of the affected eye, visual status of the unaffected eye, age and general health of the patient, availability of the various treatments, and personal preferences and biases of the patient and physician.


At present, enucleation of the eye containing the tumor is still one of the more commonly employed therapeutic methods for patients who have choroidal or ciliary body melanomas. Enucleation is an aggressive local treatment designed to rid the body of the cancer. It has been in use longer than any of the alternative



Treatment Options for Choroidal and Ciliary Body Melanomas



Radiation therapy


• Plaque radiotherapy (iodine-125, ruthenium-106, palladium-103)

• Proton beam irradiation

• Gamma knife and stereotactic radiosurgery

• Microsurgical resection

• External trans-scleral resection

• Transvitreal endoresection

Photocoagulation and laser therapy


Photodynamic therapy






Observation (appropriate only for patients with small or dormant-appearing tumors or poor general health)




Chemotherapy (currently employed only as palliative therapy for metastatic disease)





treatments, and it is certainly the simplest of the available treatments. Surprisingly, there are no reliable natural history data on the outcomes of untreated patients with choroidal and ciliary body melanomas. Because of this, there is no convincing evidence that enucleation improves the survival prognosis of affected patients compared with no treatment at all. More disturbingly, a substantial body of evidence obtained from the analysis of survival distributions of patients undergoing enucleation suggests that enucleation may actually worsen rather than improve a patient’s survival prognosis.[26] The hypothesis that enucleation worsens the survival prognosis of patients who have choroidal or ciliary body melanomas (Zimmerman-McLean hypothesis) has been neither proved nor disproved.

Although all patients who have choroidal or ciliary body melanomas can be managed by enucleation, this method of treatment is most strongly indicated for those with tumors that cause the eye to be blind and painful, extremely large intraocular tumors, or tumors that surround or invade the optic disc. For such patients, especially those whose tumor has extended trans-sclerally into the orbit, pre-enucleation radiation therapy (20?Gy dose in five fractions of 4?Gy each over 5–7 days immediately before enucleation) is employed occasionally as adjuvant therapy. [27] Results from the Collaborative Ocular Melanoma Study and several nonrandomized comparative survival studies indicate that pre-enucleation radiation therapy does not improve survival appreciably compared with enucleation alone.[28] However, pre-enucleation radiation therapy may lessen the recurrence rate of melanoma in the anophthalmic orbit in such patients.[29]

As long as uveal melanoma cells have not metastasized via the bloodstream to distant organs before or at the time of removal of the eye, enucleation is curative; however, microscopic metastasis cannot be detected reliably by currently available methods. Consequently, failure of baseline medical tests to show metastatic disease before enucleation does not guarantee that metastasis will not develop in the future. Unfortunately, approximately half of all patients who have a choroidal or ciliary body melanoma treated by enucleation eventually die of metastatic melanoma. [22] Cosmetic results with an ocular prosthesis are quite satisfactory. Most patients adapt well to their monocular status within a few months.

Radiation Therapy

Radiation therapy is probably the most commonly employed method of management for choroidal and ciliary body melanomas today. Two principal methods of irradiation are currently in use for such tumors. In plaque radiotherapy, a radioactive device (plaque) is sutured to the episcleral surface of the eye directly exterior to the tumor. The radioisotopes used most commonly in episcleral plaques are ruthenium-l06 (mostly in Europe) and iodine-125 (in the United States). A plaque that is generally at least 3?mm larger in diameter than the measured maximal basal diameter of the tumor is selected for the treatment. Plaques are constructed in such a way that they typically deliver a radiation dose of 80–100?Gy to the apex of the tumor during a treatment interval of about 3–5 days. Implantation and removal of the radioactive plaque are generally performed under local anesthesia. Depending on national, regional, and local radiation safety guidelines, patients may have to remain in the hospital during the period of plaque treatment, but they can usually be discharged on the day the plaque is removed.

The second method of local tumor irradiation currently in use is proton beam irradiation. This treatment modality is much less widely available than plaque radiotherapy. Charged particle beam radiotherapy consists of surgical localization of the tumor base, suturing of radiopaque markers (tantalum rings) to the sclera around the tumor base, computer-assisted treatment simulation, and, finally, tumor treatment with the charged particle beam while the eye is maintained in a stable direction of gaze.



The treatment is generally given in four or five equivalent fractions over 4–7 days starting several days after the placement of the tantalum rings. The standard target dose is in the range of 50–70?Gy.

Plaque and charged particle beam radiation therapy appear to be most appropriate for patients who have relatively small tumors (preferably <15?mm at greatest diameter and <8?mm thick) located 3?mm or more from the optic disc and fovea. Older patients are more likely to be advised to undergo treatment by plaque or charged particle bea radiotherapy than are younger patients.

Plaque radiotherapy has been used extensively in Europe and the United States during the past 25 years. Charged particle beam radiotherapy has been used in a small number of centers since the mid-1970s. Both methods of local tumor radiotherapy cause substantial clinical regression of most treated tumors ( Fig. 147-10 ). Several nonrandomized comparative survival studies that included statistical adjustment for recognized differences in baseline prognostic clinical variables have shown that plaque and charged particle beam radiotherapy are essentially equivalent to enucleation in terms of their success in preventing death from metastatic disease. [31] [32] [33] [34] The recently published results of the randomized Collaborative Ocular Melanoma Study of enucleation versus iodine-125 plaque radiotherapy confirmed the equivalency of these two treatments.[35]

Vision in the treated eye usually remains the same as before treatment or even improves for several months to several years after uveal melanoma radiation therapy; however, many treated eyes eventually lose a substantial amount of vision as a consequence of radiation retinopathy, optic papillopathy, cataract, or neovascular glaucoma ( Fig. 147-11 ). [36] [37] Factors that influence how much vision will be lost and how soon the vision will deteriorate





Figure 147-10 Plaque radiotherapy of choroidal melanoma. A, Choroidal melanoma before treatment. B, Partially regressed lesion 24 months after iodine-125 plaque radiotherapy.

include the location of the posterior edge of the tumor relative to the optic disc and fovea, the visual acuity before treatment, the presence or absence of macular retinal detachment, and the thickness of the tumor. Some systemic factors, such as diabetes mellitus, may also worsen a patient’s prognosis for retention of useful vision in the treated eye. Some eyes treated by plaque or proton beam radiotherapy eventually become severely painful as a complication of the treatment, usually because of neovascular glaucoma. Furthermore, 10–15% of patients treated initially by plaque radiotherapy and 3–5% of those treated by charged particle irradiation experience local tumor relapse. [38] [39] [40] Patients who develop a blind, painful eye or local tumor relapse must undergo supplemental treatment, which usually consists of enucleation.[41] [42]

Gamma knife radiotherapy[43] and stereotactic radiosurgery[44] are alternative radiation therapies being used in several centers to treat selected patients with choroidal and ciliary body melanomas. No long-term results of these treatments are yet available.


At the other extreme of treatment from enucleation is observation (i.e., periodic re-evaluation of the tumor with appropriate documentation of its size and appearance to permit the detection of abrupt enlargement or other signs of malignant potential).[45] [46] Observation without intervention is probably an appropriate option for patients in whom the differentiation between nevus and melanoma cannot be made with reasonable certainty, and it is almost certainly advisable for those who have coexistent life-threatening medical conditions that preclude surgical intervention. However, observation is not deemed advisable





Figure 147-11 Ocular complications of plaque radiotherapy for uveal melanoma. A, Radiation retinopathy. B, Radiation-induced neovascular glaucoma with prominent rubeosis iridis.



by most ocular tumor experts for most patients who have an unequivocal malignant melanoma. The obvious concern about observation is that a patient whose tumor enlarges substantially during observation may have an increased risk of death from metastatic melanoma.[47]


Photocoagulation is a treatment that attempts to destroy a choroidal tumor with high-intensity light energy ( Fig. 147-12 ). It is applicable only to relatively small tumors (<3?mm thick and <7?mm in basal diameter). In this treatment, the clinician uses either a xenon arc photocoagulator or a laser to burn the tumor.[48] Treatment is usually provided first around the margin of the tumor to cause a strong chorioretinal adhesion. At subsequent sessions, the tumor itself is treated, usually in a concentric fashion from the periphery toward the center. Multiple photocoagulation sessions are required, typically at 2–4-week intervals, until the tumor is totally eradicated. Because relatively high power settings are required for such treatments, retrobulbar or periocular anesthesia is required before each treatment session. Sometimes an audible pop and the appearance of a small gas bubble accompany an intense burn, especially one created with a laser using a very short exposure time. If successful, photocoagulation causes total destruction not only of the tumor and its blood supply but also of the retina overlying the tumor. Consequently, this treatment produces a permanent scotoma or sectorial defect in the field of vision. If the tumor is located a substantial distance away from the macular region and optic disc, reasonably good visual acuity can be retained after successful photocoagulation. Conversely, if the tumor is located next to the optic disc or in the central macular region, vision in the affected eye is likely to be poor immediately after treatment.





Figure 147-12 Photocoagulation of choroidal melanoma. A, Pretreatment appearance of a small but growing choroidal melanoma. B, Regressed lesion 34 months after initial treatment.

Unfortunately, follow-up studies have shown relatively high rates of local treatment failure and delayed local tumor relapse following photocoagulation alone.[48]

Noncoagulative Laser Therapy

Laser therapy can be performed using various low-power, long-duration methods that are quite different from photocoagulation. In low-power, long-duration laser therapy, the tumor is heated to subcoagulative levels with transpupillary laser light.[49] [50] Because of this, some clinicians refer to this treatment as laser hyperthermia or transpupillary thermotherapy (TTT). A diode infrared laser (810?nm) is employed for deep penetration of the laser energy. The laser treatment is delivered using a slit lamp, operating microscope, or indirect ophthalmoscope delivery system. Relatively large spot sizes of 2–3?mm are commonly employed for this treatment. The duration of each exposure is generally at least 60 seconds. The appropriate endpoint of each spot is a dull white discoloration of the tumor without visible effects on the large, overlying retinal blood vessels. Overlapping spots are applied until the entire tumor has been treated. Although the temperature is not monitored during treatment, animal experiments have shown that low-power, long-duration laser therapy can produce sustained intralesional temperatures in the range of 45–60°C (113–140°F). Unfortunately, follow-up studies after TTT alone have shown relatively high rates of local tumor failure and late tumor relapse,[49] [50] including some instances of extrascleral tumor extension into the orbit.[51]

Microsurgical Resection

Microsurgical resection (surgical excision of the tumor) has been used for many years to treat selected patients who have choroidal or ciliary body melanomas. In the commonly employed trans-scleral resection technique,[52] the surgeon creates a partial-thickness scleral flap directly over the tumor; cuts the tumor out of the eye, along with some of the adjacent normal uveal tissue, using microscissors; and then closes the scleral opening with multiple interrupted sutures. If possible, the sensory retina is left intact. The surgery routinely requires 2–3 hours and is preferably performed under hypotensive general anesthesia to reduce the risk of major intraoperative intraocular bleeding. In the less common endoresection method,[53] the surgeon performs a complete pars plana vitrectomy, followed by internal tumor resection using vitreoretinal instruments. The retina that overlies the tumor can be resected along with the tumor (transretinal technique), or a retinotomy can be created some distance from the tumor, and the retina reflected away from the lesion before tumor resection (subretinal technique). The transretinal technique is usually employed in eyes that already have a firm, laser-induced chorioretinal adhesion surrounding the tumor or retinal invasion by the tumor. These techniques require considerable surgical skill and experience. Depending on case selection and the surgeon’s experience, these procedures may be associated with highly varied rates of operative and postoperative ocular complications, including massive intraocular bleeding, complicated retinal detachment, choroidal detachment, persistent hypotony, and phthisis bulbi. Such complications cause profound visual loss in the affected eye in approximately half the cases in most reported series.[52] [53] High rates of residual and recurrent local tumor also occur after such procedures. [54] [55] Because of this, some surgeons now perform supplemental plaque therapy immediately following external resection and advise plaque or proton beam radiotherapy prior to endoresection.[55] [56]

Trans-scleral resection appears to be most applicable for patients who are relatively young and systemically healthy and who have rather thick malignant melanomas of the ciliary body or peripheral choroid that are no more than 12–13?mm in basal dimension. Endoresection appears to be most applicable for patients who have relatively small choroidal melanomas adjacent



to or partly overlying the optic disc. In these patients, the best alternative would probably be enucleation of the eye rather than radiation therapy. For patients whose eyes tolerate the surgery well, there is an excellent chance for long-term stability of the postoperative visual acuity and field. The survival prognosis of patients who have similar tumors treated by primary enucleation versus local resection appears to be nearly equal.[57]


Exenteration of the orbit is occasionally performed for patients who have choroidal or ciliary body melanomas associated with massive extrascleral tumor extension or orbital recurrence after enucleation. However, survival data on such patients suggest that this radical surgery does not improve their survival chances compared with more conservative management approaches.[58] [59] In view of this, clinicians generally are advised not to perform a mutilating exenteration for limited extraocular melanoma extension or localized orbital recurrence. Many patients who have such limited orbital disease can be managed at least as effectively in terms of survival prognosis by enucleation of the eye or debulking of the orbital tumor, coupled with preoperative or postoperative orbital external beam radiation therapy (usually about 50?Gy in multiple fractions over 4–5 weeks).

Hyperthermia Therapy

Hyperthermia therapy entails treatment of a lesion by the application of local heat. When the temperature of a tumor is raised by several degrees Centigrade for even a few minutes, marked cellular damage and subsequent tumor regression usually result. The local heating is provided with a focused external ultrasonic beam[60] or a plaque that generates microwaves.[61] Very few patients with malignant melanoma of the choroid or ciliary body have been treated using hyperthermia, and most of those who have undergone hyperthermia treatment have done so in conjunction with plaque radiation therapy. True hyperthermia therapy employs a temperature-measuring instrument (thermocouple) to determine the temperature in (or at least on the surface of) a tumor during therapy. Some clinicians have suggested that tumor laser therapy using a relatively low power setting, long-duration exposures, and a laser of long-wavelength (infrared) light (i.e., TTT) is a form of hyperthermia treatment. Although some of the effect of this therapy is likely to be attributable to tumor heating, temperature is not monitored during this treatment. Consequently, it is inappropriate to regard TTT as true hyperthermia treatment.

Photodynamic Therapy

Photodynamic therapy employs a sensitizing drug and a subsequent low-power laser treatment to cause tumor destruction by means of a photochemical reaction.[62] Few patients worldwide have undergone this treatment for choroidal melanoma, and most ophthalmologists currently consider photodynamic therapy an unproven treatment for such tumors.


Cryotherapy has been used extensively to treat retinoblastomas but has not gained wide acceptance for the treatment of choroidal and ciliary body melanomas. However, several case reports have indicated that this treatment is effective against selected tumors of this type.[63]


Chemotherapy is not currently advocated as treatment for patients who have choroidal or ciliary body melanomas confined to the eye. This is because no currently available chemotherapy regimen has produced clinical regression of the intraocular tumor on a consistent basis. Patients who develop clinical metastatic disease are likely to be advised about various chemotherapy regimens and approaches that might be used in an attempt to control the disease.[64] Unfortunately, no chemotherapy regimen has been able to eradicate malignant melanoma once it has metastasized.

Multimodal Therapy

Several of the previously mentioned treatment methods are used in combination for choroidal and ciliary body melanomas. The most common multimodal therapies are combined plaque radiotherapy and laser treatment,[65] [66] combined plaque radiotherapy and hyperthermia treatment,[61] and combined microsurgical resection and plaque radiotherapy.[55] These combined treatments appear to increase the rate and extent of local tumor regression and decrease the rate of local tumor relapse compared with single-modality therapy. However, they also cause more early post-treatment visual impairment than do single-method treatments. At present, there is no evidence that such combined modalities significantly improve a patient’s survival prognosis compared with single-method treatment.

Randomized Clinical Trials

The Collaborative Ocular Melanoma Study was a multicenter study of uveal melanoma management sponsored by the National Eye Institute of the United States.[67] It recruited patients from 1986 through 1999. This study evaluated pre-enucleation radiation therapy versus enucleation alone for large choroidal melanomas and iodine-125 plaque radiotherapy versus enucleation for medium-sized choroidal melanomas. Neither trial showed any clinically important difference in survival.[2] [35] [48] Both clinical trials confirmed the results of previously published, nonrandomized clinical trials that included statistical adjustment for recognized intergroup differences in baseline clinical prognostic factors.[30] [33] [34] [68]


As surprising as it may seem, the natural history of untreated choroidal and ciliary body melanomas is not well documented. Relatively few patients with presumed choroidal or ciliary body melanomas have been followed for long periods without intervention when progressive tumor enlargement has occurred. Furthermore, relatively few untreated patients with choroidal or ciliary body melanomas have ever been documented to develop metastatic disease and die of metastatic melanoma.[20] Most of the patients with presumed choroidal or ciliary body melanomas who have been followed without treatment have had either small tumors (i.e., a large nevus versus a small melanoma) or clinically dormant tumors. These highly selected patients are not representative of the total spectrum of patients with choroidal and ciliary body melanomas, and their clinical course under observation without intervention cannot be extrapolated to the larger group of more typical patients who have larger and actively growing tumors.

Important clinical prognostic factors for death from metastatic melanoma in patients who have primary choroidal or ciliary body melanomas but no clinical evidence of metastatic disease at the time of diagnosis include the size of the tumor (the bigger the tumor, the worse the prognosis), the location of the tumor (tumors within the ciliary body are associated with a worse prognosis than are those confined to the choroid), the age of the patient at the time of diagnosis (the older the patient, the worse the short-term survival prognosis), and extrascleral tumor extension.[69] Choroidal and ciliary body melanomas are generally categorized on the basis of largest linear tumor dimension into small (10?mm in maximal linear dimension), medium (10–15?mm in maximal linear dimension), and large (>15?mm in maximal linear dimension) groups.





Figure 147-13 Survival curves of patients with primary choroidal or ciliary body melanoma as a function of initial treatment method. These curves are based on deaths from metastatic uveal melanoma only. The differences among the curves reflect baseline differences in susceptibility to uveal melanoma metastasis related to criteria used to select patients for each treatment; they are not intended to imply the relative effectiveness of the treatments for equivalent tumors. (Data from private practice of James J. Augsburger, M.D.)

Patients who have choroidal or ciliary body melanomas are routinely advised to undergo periodic physical examinations, blood tests for liver enzyme levels, and imaging studies such as chest radiographs and ultrasonography or MRI of the liver. The cost-benefit ratio of such testing for metastatic uveal melanoma, a condition for which there is currently no effective therapy, is high; consequently, the appropriateness of such testing is controversial.[19]

A patient’s prognosis for survival after detection and treatment of a primary choroidal or ciliary body melanoma is a function of many factors, including absence versus presence and extent of metastatic disease at the time of intraocular tumor detection, age at the time of treatment, size of the intraocular tumor, absence versus presence and extent of extrascleral tumor extension, absence versus presence of ciliary body involvement, and many histopathological and cytogenetic features of the tumor (which are not determinable unless the tumor is biopsied prior to treatment or treated by enucleation of the eye or en bloc tumor resection). At present, no compelling scientific evidence exists that one form of locally effective treatment is substantially better than any other in terms of preventing metastatic disease or prolonging survival. In spite of this, comparison of survival curves in patient subgroups treated by different methods reveals substantial differences ( Fig. 147-13 ); however, these differences are caused mainly by inequalities in baseline prognostic factors (such as tumor size and patient age) among the subgroups and not by differential effectiveness of the various forms of treatment. Fortunately, the vast majority of patients who have choroidal or ciliary body melanomas retain good vision in at least one eye for the remainder of their lives. Furthermore, most patients who undergo one of the conservative treatments mentioned earlier retain the affected eye, and at least some of these patients also retain good vision in the treated eye.





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