Figure 17-13 Choroidal osteoma, clinical appearance. Note the yellow-orange color, well-defined pseudopod-like margins (arrows), and characteristic spotted pigmentation on the surface of this circumpapillary tumor.

Classification

Melanomas of the ciliary body and choroid have been categorized by size in a number of different ways. Although a size classification based on tumor volume is logical, no simple and reliable method for assessing tumor volume is available. The common practice of estimating tumor volume by multiplying maximal basal diameter, minimal basal diameter, and thickness yields a crude assessment of actual tumor size. The Collaborative Ocular Melanoma Study (COMS) classified posterior uveal melanomas as small, medium, or large based on thickness and basal diameter. Recently revised, evidence-based staging developed by the American Joint Committee on Cancer (AJCC) defines small (T1), medium-sized (T2), large (T3), and very large (T4) ciliochoroidal melanomas by tumor height, basal diameter, and extension to the ciliary body and extrasclerally. See the staging form for malignant melanoma of the uvea in the appendix.

Metastatic Evaluation

In a study by Kujala and colleagues, the incidence of metastatic uveal melanoma was observed to be as high as 50% at 25 years after treatment for choroidal melanoma. The COMS reported an incidence of metastatic disease of 25% at 5 years after initial treatment and 34% at 10 years. Nevertheless, clinically evident metastatic disease at the time of initial presentation can be detected in less than 2% of patients. Currently, it is hypothesized that many patients have undetectable micrometastatic disease at the time of their primary treatment. Despite the great accuracy that has been achieved in diagnosing uveal melanoma, mortality owing to this tumor has not changed significantly for many years. In general, survival with metastatic uveal melanoma is poor, with a median survival of less than 12 months, although early detection and prompt treatment of liver metastases can increase survival time significantly.

The liver is the predominant organ involved in metastatic uveal melanoma. Liver involvement also tends to be the first manifestation of metastatic disease. In the presence of liver involvement, lung, bone, and skin are other sites that may be affected. An assessment of metastatic disease patterns in the COMS revealed liver involvement in at least 90% of patients, lung involvement in 25%, bone involvement in nearly 20%, and skin and subcutaneous tissue involvement in approximately 10%. In cases that were autopsied, liver involvement was found in 100% and lung involvement in 50% of the patients with metastatic disease.

All patients require metastatic evaluation prior to definitive treatment of the intraocular melanoma (Table 17-3). The purpose of this evaluation is twofold:

1.To determine whether the patient has any other medical conditions that contraindicate surgical treatment or need to be ameliorated before surgery. For example, in one small series, 15% of the patients had a second malignancy at the time of presentation or during the course of a 10year follow-up; the COMS found preexisting independent primary cancers in approximately 10% of patients. If there is any question whether the lesion in the eye is a metastatic tumor, this possibility must be ruled out with a thorough medical evaluation directed at determining the site of primary malignancy.

2.To rule out the possibility of detectable metastatic melanoma from the eye. Only rarely is metastatic disease from uveal melanoma detectable at the time of initial presentation. If

metastatic disease is clinically present during the pretreatment evaluation of the eye tumor, enucleation is inappropriate unless the eye is painful.

Table 17-3

To detect metastatic disease of uveal melanoma at an early stage, metastatic evaluation should be performed on all patients on a yearly follow-up basis, and some centers will do so every 6 months. Metastatic evaluation should include a comprehensive physical examination. Liver imaging studies are probably the most important component of the metastatic evaluation. Ultrasonography of the abdomen is usually sufficient, but when a suspicion of metastatic disease is raised, triphasic CT, MRI, or PET-CT is usually recommended in order to evaluate the extent of the disease.

Liver function tests are usually performed; however, in recent years, they have become less reliable in the evaluation of liver metastases, because of the common use of cholesterol-lowering statins, which may alter liver enzyme levels. Chest x-ray is also usually performed, although its yield was found to be low. Recently, research has been performed in several centers investigating possible blood markers for early detection of metastatic uveal melanoma.

A liver or other organ site biopsy may be confirmatory of metastatic disease and is appropriate before the institution of any treatment for metastatic disease.

The interval between the diagnosis of primary uveal melanoma and its metastasis depends on various clinical, histopathologic, cytogenetic, and molecular genetic factors. It varies from 1–2 years to over 15–20 years. When metastatic disease is diagnosed early enough, before developing miliary spread, the options for treatment of the metastasis, mainly liver metastasis, include surgical resection; chemotherapy, including intra-arterial hepatic chemotherapy and chemoembolization; and immunotherapy.

Kaiserman I, Amer R, Pe’er J. Liver function tests in metastatic uveal melanoma. Am J Ophthalmol. 2004;137(2):236–243.

Treatment

Management of posterior uveal melanomas has long been the subject of considerable controversy. Two factors lie at the heart of this controversy:

1.the limited amount of data on the natural history of untreated patients with posterior uveal melanoma

2.the lack of groups of patients matched for known and for unknown risk factors and managed by different therapeutic techniques to assess the comparative effectiveness of those treatments

In 1882, Fuchs wrote that all intraocular melanomas were treated by enucleation and the only untreated cases were in the “older literature.” Currently, both surgical and radiotherapeutic management are used for intraocular melanoma. The COMS has reported randomized, prospectively administered treatment outcomes for patients with medium and large choroidal melanomas. The methods of patient management in use at this time depend on several factors:

size, location, and extent of the tumor

visual status of the affected eye and of the fellow eye age and general health of the patient

Observation

In certain instances, serial observation without treatment of an intraocular tumor is indicated. Most types of benign retinal and choroidal tumors, such as choroidal nevi, choroidal osteoma, and hyperplasia of the RPE, can be managed with observation. Growth of small melanocytic lesions of the posterior uvea that are 1 mm or less in thickness can be documented periodically by fundus photography and ultrasonography. Significant controversy persists regarding the management of small choroidal melanomas.

Lesions greater than 1 mm in thickness, with documented growth, should be considered for definitive treatment. Observation of active larger tumors may be appropriate in elderly and systemically ill patients who are not candidates for any sort of therapeutic intervention.

Enucleation

Historically, enucleation has been the gold standard in the treatment of malignant intraocular tumors. Although some authors in the past hypothesized that surgical manipulation of eyes containing melanoma leads to tumor dissemination and increased mortality, this hypothesis is no longer accepted, and enucleation remains appropriate for some medium-sized (T2), many large (T3), and most very large (T4) choroidal melanomas. The COMS compared the application of pre-enucleation external-beam radiation therapy followed by enucleation with enucleation alone for patients with large choroidal melanomas and found no statistically significant survival difference in 5-year mortality rates. Enucleation remains one of the most common primary treatments for choroidal melanoma.

Brachytherapy (radioactive plaque)

The application of a radioactive plaque to the sclera overlying an intraocular tumor is probably the most common method of treating uveal melanoma. It allows the delivery of a high dose of radiation to the tumor and a relatively low dose to the surrounding normal structures of the eye. The technique has been available since the 1950s. Although various isotopes have been used (eg, strontium 90, iridium 192, and palladium 103), the most common today are iodine 125 and ruthenium 106. Cobalt 60 plaques, which were the main source for brachytherapy in the past, are rarely used today. In the United States, 125I is the isotope most frequently used in the treatment of ciliary body and choroidal melanomas. Advances in intraoperative localization, especially the use of ultrasound, have increased local tumor control rates to as high as 95%. In most patients, the tumor decreases in size (Fig 17-14); in others, the result is total flattening of the tumor with scar formation or no change in tumor size, although clinical and ultrasound changes can be seen. Regrowth is diagnosed in only about 10% of the treated tumors. Late radiation complications, especially optic neuropathy and retinopathy, are visually limiting in as many as 50% of patients undergoing treatment. Radiation complications appear dose-dependent, and they increase for tumors involving, or adjacent to, the macula or optic nerve.

Charged-particle radiation

High-linear-energy transfer radiation with charged particles (protons and helium ions) has been used effectively in managing ciliary body and choroidal melanomas. The technique requires surgical attachment of tantalum clips to the sclera to mark the basal margins of the tumor prior to the first radiation fraction. The charged-particle beams deliver a more homogeneous dose of radiation energy to a tumor than does a radioactive plaque, and the lateral spread of radiation energy from such beams is less extensive (Bragg peak effect). Local tumor control rates of up to 98% have been reported. The

response is similar to that seen after brachytherapy.

Unfortunately, charged-particle radiation often delivers a higher dose to anterior segment structures. Radiation complications, most commonly anterior, lead to uncontrolled neovascular glaucoma in 10% of treated eyes and vision loss in approximately 50%.

Figure 17-14 Choroidal melanoma treated by radioactive brachytherapy. A, Mildly elevated remnants of melanoma surrounded by atrophic chorioretinal scarring, nasal to the optic nerve head. B, Flat remnants of melanoma pigmentation surrounded by chorioretinal scarring located temporal to the macula. (Courtesy of Jacob Pe’er, MD.)

External-beam radiation

Conventional external-beam radiation therapy is ineffective as a single-modality treatment for melanoma. Pre-enucleation external-beam radiotherapy combined with enucleation appears to limit orbital recurrence in large melanomas and showed a non–statistically significant reduction in 5-year and 10-year mortality in the COMS large-tumor trial. In recent years, several centers have used fractionated stereotactic radiotherapy and gamma knife radiosurgery, reporting results comparable to those of other irradiation methods.

Cataract may develop following all types of radiotherapy. Surgical removal of radiation-induced cataract is indicated if the intraocular tumor is nonviable and the patient appears to have visual limitations attributable to the cataract. No increase in mortality after cataract extraction has been documented.

Alternative treatments

Photoablation and hyperthermia Laser photocoagulation has played a limited role in the treatment of melanocytic tumors. Reports of focal/grid laser treatment to eradicate active subretinal fluid in choroidal melanoma have documented a propensity for accelerated tumor growth with rupture of the Bruch membrane. Advances in the delivery of hyperthermia (heat) using transpupillary thermotherapy (TTT) have been reported. Direct diode laser treatment using long duration, large spot size, and relatively low-energy laser has been associated with a reduction in tumor volume. Some reports have suggested that TTT is associated with an increased rate of local tumor recurrence