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From OncoLog, January 2010, Vol. 55, No. 1

Ocular Cancer
Tumors of the eye threaten sight and often indicate the presence of extensive disease.

By Bryan Tutt

Photo: Dr. Dan S. Gombos

Photo: Retinoblastoma

Dr. Dan S. Gombos examines a pediatric patient with a RetCam II (Clarity Medical Systems, Inc., Pleasanton, CA). The high-resolution camera allows ocular tumors such as retinoblastoma (bottom) to be visualized. Ocular tumors may represent primary cancers, metastatic disease in the eye, or metastases elsewhere, and early assessment is crucial to treatment.

An ocular cancer may be an isolated tumor, a primary growth that originated in the eye and has metastasized distally, or a metastasis from another site. For each possibility, the therapeutic approach and prognosis can vary widely, and thus patients with eye tumors require a thorough evaluation following the diagnosis.

At The University of Texas MD Anderson Cancer Center, treatments for confined ocular cancer may include laser surgery and various types of radiation, with the goal of saving the patient’s life first and vision second. Thanks to such treatment options, the 5-year overall survival rate for patients with nonmetastatic ocular tumors is about 80%. Even in patients with metastatic disease, who have lower survival rates, it still may be possible to spare vision or at least the eye itself.

In adults, the most common primary tumor in the eye is uveal melanoma, followed by intraocular lymphoma. Retinoblastoma is the most common primary ocular tumor in children (see sidebar).

Uveal melanoma

In cases of primary uveal melanoma in which the tumor is limited to the eye, the prognosis depends largely on three factors: the largest diameter of the primary tumor, the location of the primary tumor, and extraocular invasion.

If the tumor’s largest diameter is more than 15 mm, the risk of systemic metastasis increases, as does the chance of local tumor recurrence. For this reason, lesions that are more than 15 mm in diameter are often treated with enucleation of the eye. “If they are less than 15 mm, then localized radiation therapy is effective for controlling the disease,” said Agop Y. Bedikian, M.D., a professor in The University of Texas MD Anderson Cancer Center’s Department of Melanoma Medical Oncology.

In patients with primary uveal melanoma, the location of the tumor often affects the onset of symptoms, which in turn can determine when the tumor is diagnosed. “Lesions located laterally and anteriorly—such as tumors of the iris or ciliary body—unfortunately are usually diagnosed later, so the chance of systemic metastasis is much higher,” Dr. Bedikian said. “These tumors are usually treated with enucleation.” If the tumor is located posteriorly (i.e., in the choroid), the patient is likely to become symptomatic early and thus be diagnosed when the tumor is very small, which can lead to a better prognosis. Tumors located in the posterior of the eye are likely to be treated with radiation.

Local extraocular involvement can indicate an increased risk of metastasis. “Once the tumor cells cross the sclera, they gain access to blood vessels and spread to other organs,” Dr. Bedikian said. Extraocular involvement also means a high chance of tumor recurrence in the eye socket, so enucleation of the eye will give better control of the disease locally. “Otherwise, if you treat with radiation and the tumor recurs in the eye socket, then you need to do more extensive surgery like exenteration of the tissues from the eye socket to prevent additional recurrences.”

Eye Care for Cancer Patients

Photo: Dr. Bita EsmaeliThe Section of Ophthalmology, part of the Department of Head and Neck Surgery at The University of Texas MD Anderson Cancer Center, provides treatment of ocular, orbital, and conjunctival and eyelid cancer, as well as comprehensive ophthalmic care for cancer patients.

Orbital and ocular adnexal tumors are more common than intraocular tumors, said Bita Esmaeli, M.D., a professor of ophthalmology who helped establish the Section of Ophthalmology in 1998. “Orbital tumors can be anything from lymphomas to sarcomas to meningiomas,” she said. Cutaneous cancers like basal cell carcinoma, squamous cell carcinoma, and melanoma can occur on the eyelid or on the ocular surface layer (conjunctiva)—as Dr. Esmaeli explained, “Every cancer that happens on the skin happens on the eyelid, too.” In addition to treating primary cancers of the eyelid and orbit, the Ophthalmology Section offers services in neuroophthalmology, corneal disease, cataract surgery, vitreoretinal surgery, and periocular reconstructive surgery.

The Ophthalmology Section is also actively involved in research. Studies initiated by doctors in the section include Dr. Esmaeli’s groundbreaking research on sentinel lymph node biopsies to detect early metastasis of eyelid and conjunctival tumors. The section also maintains a bank of uveal melanoma tissue and blood specimens.

Treatment of primary uveal melanoma largely depends on whether the tumor has already metastasized to other organs at the time of diagnosis. “Unfortunately, there is no effective treatment once it has metastasized,” Dr. Bedikian said. “The liver is involved in more than 85% of these cases, and the tumors do not respond well to systemic treatment.” Patients who have metastatic melanoma limited to the liver may benefit from regional therapy directed to the liver metastasis. These therapies, although not curative, are associated with tumor response more often than is systemic therapy. Dr. Bedikian, who has served as the principal investigator for several clinical trials involving metastatic melanoma, said studies have shown that dacarbazine and other chemotherapy agents that are effective against cutaneous melanoma are not effective for treating uveal melanoma or preventing metastasis.

“The biology that underpins uveal melanomas is distinct from that of cutaneous melanomas,” said Scott E. Woodman, M.D., Ph.D., a medical oncology fellow at MD Anderson whose research involves the role of genetic mutations in melanoma. He said this could explain why some of the therapies that have traditionally worked on other types of melanoma have not been effective against uveal melanoma. “We call them all melanomas, but they are different not only in their location anatomically—they are different molecularly, from what we can tell,” Dr. Woodman said. Up to 50% of uveal melanomas have a mutation of the GNAQ gene, a mutation not seen in any other form of melanoma to date. Also, some mutations found in cutaneous melanomas are not found in uveal melanomas.

“The drivers of these different types of melanomas are distinct; thus, the therapeutic targets that will evolve in the clinical trial area are going to be distinct,” he said.
Because current systemic chemotherapy agents are not effective against uveal melanoma, most patients are treated with either radiation therapy or enucleation. “In view of the fact that it may preserve the vision, obviously radiation is the preferred treatment over enucleation,” said Dr. Bedikian.

Dan S. Gombos, M.D., an associate professor in MD Anderson’s Section of Ophthalmology, Department of Head and Neck Surgery, estimated that about half the uveal melanoma patients he sees are candidates for radiation therapy. He said the most commonly used radiation treatment for uveal melanoma is plaque brachytherapy, in which a radioactive plaque is sewn onto the surface of the eye in the area of the tumor, minimizing the exposure of surrounding tissues to radiation. Dr. Gombos added that within the next year, MD Anderson is planning to install equipment for treating ocular tumors in adults with proton beams. MD Anderson currently uses proton beams to treat children with retinoblastoma and to treat primary tumors of orbit, but different equipment is required to treat uveal melanoma patients. “We’re looking to be one of the few centers that offer both plaques and protons, depending on the patient’s situation. Most centers offer one or the other,” he said. “I’m hopeful that with protons we will be able to offer more patients radiation.”

Metastases to the eye

Tumors presenting inside the eye have commonly metastasized from other sites, particularly the breast and lung. If an intraocular tumor is believed to be a metastasis, the primary tumor site and extent of the metastasis should be determined. “Because of the high association between intraocular disease and metastatic disease in the brain and central nervous system, whenever we see a diagnosis suggestive of intraocular metastasis, we also get imaging of the brain and central nervous system to make sure there is no involvement of those tissues,” said Dr. Gombos.

Photo: Uveal melanoma
A uveal melanoma (dark interior region).

Treatment for metastases to the eye usually involves radiation therapy, although systemic chemotherapy and laser surgery are used in some cases. Dr. Gombos said that external-beam radiation is the most common treatment option, but occasionally plaque brachytherapy is done. He added that because metastatic tumors in the eye often occur in patients with advanced metastatic disease, such tumors may go untreated or even undiagnosed.

“The location of the tumor in relation to other structures and the inherent radiation sensitivity of the tumor are critical to preserving vision,” said Dr. Gombos. “I once had a patient with very advanced metastatic breast cancer, and she had 15 tumors in her eyes. We were able to preserve 20/20 vision for the next 3 or 4 years until she ultimately died of her breast cancer.”

Diagnostic issues

Ocular cancer can be difficult to diagnose because there may be no symptoms, although patients sometimes have blurred vision or see flashing lights. Dr. Gombos said that if cancer is suspected, the patient should be referred to an ophthalmologist rather than an optometrist for an examination of the eye itself. “There are many things that can cause blurry vision, but in a cancer patient, metastatic disease is one,” he said. “If an ophthalmologist sees a metastatic lesion, we would strongly suggest that he or she refer the patient to a comprehensive cancer center as soon as possible,” he said. “Sometimes the ophthalmologist is the first doctor to diagnose recurrent or metastatic disease.”

Doctors can reassure their patients not to panic when ocular lesions are detected. “Among all the patients referred to me as having ocular melanoma, in about half I disagree with the initial diagnosis,” Dr. Gombos said. “These patients have indeterminant lesions or birthmarks. For most of those lesions, we don’t do anything; we closely and serially observe them. As long as they don’t grow, they don’t reflect a risk to the patient.” However, because the chances of preserving patients’ vision as well as their lives improve with early treatment, patients—especially those with a history of cancer—with lesions in the eyes should be referred to a cancer center.

Doctors Team Up to Battle Retinoblastoma

Although retinoblastoma is the most common primary intraocular tumor in children, only 300–350 children in the United States are diagnosed with the disease each year. “The irony is that there has been so much research on retinoblastoma on the basic science level, but most physicians rarely see a case,” said Dan S. Gombos, M.D., associate professor in the Department of Head and Neck Surgery, Section of Ophthalmology, at MD Anderson. Retinoblastoma usually occurs in children 1 or 2 years of age, and both eyes are involved in 30%–40% of patients.

To fight this serious but treatable cancer, the Children’s Cancer Hospital at The University of Texas MD Anderson Cancer Center has joined Texas Children’s Cancer Center, Baylor College of Medicine, and The Methodist Hospital Research Institute in a collaborative effort called the Retinoblastoma Center of Houston. “There’s been nothing like the collaboration between these four institutions. They’ve come together in a spectacular way,” said Dr. Gombos, one of the clinical co-directors of the Retinoblastoma Center.

The advantages of this alliance include a shared tumor board that reviews patients from MD Anderson and Texas Children’s Cancer Center (which serve as the two clinical sites) and a dedicated ocular pathologist who specializes in retinoblastoma. The Methodist Hos­pital houses a shared pathology and tissue bank, and Baylor College of Medicine and MD Anderson offer genetic testing and counseling for patients and their families.

“Retinoblastoma often requires the removal of one or both eyes, so our treatment priorities are saving the child’s life, saving the child’s eye, and saving the child’s vision,” Dr. Gombos said. Because radiation therapy confers a risk of developing a second tumor, chemotherapy is usually preferred as the first-line treatment for retinoblastoma and radiation therapy is used as a salvage approach. MD Anderson is one of the few centers in the United States that offer proton therapy for retinoblastoma, which exposes the child to less radiation than other radiation therapy modalities because the beam is much more focused.

Although only in its first year of existence, the Retinoblastoma Center is already conducting research and participating in clinical trials, including one involving gene therapy for retinoblastoma. “There are people in the Texas Medical Center who have dedicated their lives to fighting this disease,” Dr. Gombos said, “and this institution brings them together.”

For more information on MD Andersonís Ophthalmology Section, please call 713-792-6920. To refer a patient, call 713-745-5146.

Other articles in OncoLog, January 2010 issue:


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