Subtle signs, symptoms make recognition of ocular malignancies tricky but vital

Ocular tumors represent a dangerous, if often underappreciated, realm of ophthalmology. The limited incidence of tumors may suggest a lesser importance compared with other ocular pathologies, but the clinical course potentially threatens much more than a patient’s vision.

Precise figures on the incidence and prevalence of primary and metastatic tumors are difficult to come by, and even when epidemiologic studies are performed, the results are either alarming or in need of perspective.

For instance, Paul T. Finger, MD, FACS, and a team of researchers used data from the Surveillance, Epidemiology and End Results (SEER) Program — an effort by the National Cancer Institute to consolidate cancer-related statistics — reported in 2003 that the incidence of conjunctival melanoma increased 295% in white men over a 27-year period, particularly among individuals older than 65 years. The finding is apparently not isolated to the U.S. In a 2002 report, Finnish researchers noted a doubling of age-adjusted incidence between 1973 and 1999.

While the increasing incidence represents a startling rise, the rate of new conjunctival melanoma rose from 0.19 cases per million population between 1973 and 1979 to 0.33 per million from 1980 to 1989 and to 0.43 million in the 1990s, with 107 new cases in the last decade of surveillance. While the study found no such acceleration of incidence among white women, the rise mirrored, in part, a rise of cutaneous melanoma, suggesting a potentially shared etiology in sun exposure.

Carol L. Shields, MD, believes that for every millimeter increase in lesion size the risk of metastatic disease rises 5%. Image: Harmon S

The incidence of one subtype of cancer, though, may not reflect the overall impact of ocular malignancies. Conjunctival melanoma is less frequently reported than uveal melanoma involving the choroid, ciliary body or iris.

Although the incidence of uveal melanoma appears to be stable, associated mortality, even with the advent of new therapeutic modalities, is between 10% and 50% within 10 years of initial recognition, with risk of metastasis apparently playing a large role in melanoma-associated mortality.

In addition, although melanoma is the most commonly occurring primary tumor, ocular metastases from primary systemic cancers still constitute the most common malignancy in the eye. Factors such as better treatment and earlier detection have led to a decrease in cancer incidence in the past decade — down 1.3% between 1999 and 2007, according to SEER data — but incidence is still about 539 cases per 100,000 among men and 408 per 100,000 among women.

While an ophthalmologist may not frequently see a patient with a primary cancer — it is estimated that an ophthalmologist may see at least one patient every 10 years with an ocular malignancy — it is almost a certainty that the ophthalmologist will see patients who are at risk for something more serious than vision loss. And thus, it may be prudent for the practicing ophthalmologist to maintain a high index of suspicion for a disease state that is rare but potentially deadly.

“Cancer is common. Cancer in the human body is common. It is estimated that the average American carries a 35% chance of developing cancer in their body by age 65,” Carol L. Shields, MD, associate director of the Oncology Service at Wills Eye Institute, said. “Ophthalmologists are going to see patients in their practice every day that have a history of systemic cancer. The ophthalmologist should do a full exam to check the front and back of the eye just to be sure there is not a solid mass because these can metastasize to the eye or cause other problems.”

Masquerading presentations

Despite the potentially life-threatening nature of ocular malignancies, the rarity at which they occur complicates the recognition of their fine and sometimes subtle presentation. Furthermore, ocular malignancies often share similar signs and symptoms of more commonly occurring benign conditions that may appear in a patient’s differential.

“Because many of these conditions can present as a masquerade or can have relatively silent symptoms, the concern is to miss or delay the recognition of an intraocular malignancy or extraocular mass,” Timothy G. Murray, MD, MBA, FACS, an ocular oncologist at Bascom Palmer Eye Institute, said.

Timothy G. Murray

One example of shared symptomatology is choroidal nevi, which can either progress to melanoma or remain a benign finding on clinical exam. Another example is an inflammatory condition that may appear to be uveitis but in fact may be a masquerading presentation of lymphoma.

“We have seen a significant increase in the incidence of lymphoma at the Bascom Palmer Eye Institute over the past 10 years,” Dr. Murray said.

In some regards, following cutaneous nevi for potential progression to melanoma may be easier than in the case of ocular manifestations. Whereas a dermatologist may be able to tell a patient to return to the office if there is blood, pain or some other indication of progression, “we can’t tell patients to come in when you have a symptom because the majority of these lesions that go from nevi to melanoma do that with very little symptom presentation,” Dr. Murray said.

Biopsy is not a readily available option. The clinical value of ocular biopsy is a controversial subject, but according to Dr. Murray, even though it is often noncontributory, biopsy itself introduces a degree of risk.

As medicine enters the genetic age and molecular medicine gains wider acceptance, the role of biopsy might change. There is a genetic test for melanoma available in the U.S. to help tumor classification, but the size of a particular lesion may drive treatment decisions more so than lesion subtype.

The complexity in diagnosing ocular melanoma and distinguishing it from benign presentations may warrant caution about even seemingly innocuous lesions, especially when other risk determinants are present. For instance, a study by German researchers in women diagnosed with breast cancer who had systemic metastasis but no ocular symptoms found that 6% were carrying asymptomatic metastatic tumors in the eye.

“I tell my referring community, I’m never upset if they have a mass in the eye or if they have a concern for mass in the eye to have that patient referred and evaluated,” Dr. Murray said. “My perspective on this is you never, ever get in trouble by asking for a second opinion. If the generalist is looking at the patient, and there is the quandary if ‘should I refer the patient or not,’ I think 100% that you should.”

‘To Find Small Ocular Melanoma’

In some cases, diagnosing a patient with medium to large choroidal melanoma might be straightforward. However, in other cases, when the tumor is small, the challenge to differentiate melanoma from nevus can be difficult. According to Dr. Shields, certain signs, especially when the tumor is more than 3 mm in thickness, are worrisome. On the other hand, patients who present with overlying drusen or atrophy of the retinal pigment epithelium are more reassuringly a benign nevus, she said.

However, the more subtle presentation of choroidal lesions can be a diagnostic challenge, especially because early detection portends a better clinical outcome. For every millimeter of change in lesion size, Dr. Shields said, the risk of metastatic disease rises 5%.

Identification of risk factors known to suggest greater clinical significance may be instrumental in classifying malignancies. According to Dr. Shields, the mnemonic “To Find Small Ocular Melanoma” may be helpful in classifying patients at high risk for transformation of nevus into melanoma: The “T” stands for thickness more than 2 mm, “F” for fluid, “S” for symptoms, “O” for orange pigment and “M” for margin near the disc, referring to whether the lesion is within 3 mm of the optic disc.

“If the patient has two or three of these risk factors, then it would probably be wise for an ocular oncologist to take a look at this lesion because it could be a melanoma,” Dr. Shields said. “Most ophthalmologists are able to catch a big melanoma. We’re all trained to suspect melanoma when we visualize a large pigmented choroidal mass deep to the retina, but to be able to pick it up when it’s small is more difficult. To detect the melanoma early and allow the patient less of a risk for metastatic disease is important.”

Complicated etiology

Greater difficulty in identifying potentially cancerous presentations may occur in cases in which a pigmented lesion is not present. Specifically, nonpigmented choroidal lesions may represent a nevus or a calcified plaque, but they may also be metastatic disease or amelanotic melanoma.

“Probably doing an ultrasound would be a good first step because that will help sort out the granuloma and metastasis from the melanoma because the melanoma tends to be hollow and the others tend to be dense,” Dr. Shields said.

Diagnostic ultrasound may also be warranted in cases of vitreous hemorrhage and, if a mass is present, an MRI with gadolinium to confirm whether it is a solid mass.

“If it enhances on MRI, then you might be suspicious for a solid tumor like melanoma. If it doesn’t enhance on MRI, you are probably not dealing with a solid mass. You’re more likely dealing with subretinal or choroidal hemorrhage in the eye,” Dr. Shields said.

Subretinal hemorrhage is a common presenting symptom in ophthalmic practice and is potentially indicative of macular degeneration, polypoidal choroidopathy or trauma. But underlying malignancy may also be a concern, especially absent a history of trauma or in younger patients not prone to age-related macular changes.

Conjunctival tumors, although more visible and easier to examine than suspicious intraocular masses, are still a challenge because they can be benign, such as in racial melanoma; precancerous, such as in acquired melanosis; or deadly, such as in conjunctival melanoma. A bilateral and flat presentation may be a tip to benign melanosis, “but if it’s unilateral or asymmetric, you should probably have someone take a look, like a cornea specialist or an oncologist, just to make sure you are not dealing with the precancerous, primary acquired melanosis or a melanoma,” Dr. Shields said.

“Pigmented lesions of the conjunctiva should be taken seriously, and the bottom line is that most prove to be benign, but look at them carefully,” she said.

Paul T. Finger

Dr. Finger, director of The New York Eye Cancer Center, suggested taking slit lamp photographs of all conjunctival tumors to serve as a baseline for comparison if a physician chooses to observe the tumors for growth over time.

“Once referred, particularly after biopsy, initial photographs help the ophthalmic oncologist determine which subsequent treatment might be necessary,” he said. “If you don’t have a slit lamp camera, a portable high-megapixel camera on macro-mode can be adequate.”

Need for follow-up

Certain clinical presentations may also be a tip-off to a need for investigation, but further clinical workup may also be warranted when a patient is set to undergo surgery. On the more obvious end of the spectrum, proptosis is a strong indication that a tumor may be present within or around the orbital cavity.

Recalcitrant chalazion may also signal malignant involvement. A chalazion can often be drained on first occurrence without further complication, Dr. Shields said, but if it does not shrink in size or returns after draining, that might signify sebaceous carcinoma or basal cell carcinoma.

Unexplained vision loss is another case in which referral is a consideration, especially if ultrasound, fluorescein angiogram, optical coherence tomography and electroretinography are unremarkable.

“It’s not unusual for us to have a patient come in with unexplained vision loss and we find the patient has an underlying subtle choroidal tumor like a choroidal hemangioma or even a more serious condition like paraneoplastic retinopathy,” Dr. Shields said. “That condition is caused by systemic cancer stimulating auto-antibodies to the retina, eventually leading to gradual vision loss.”

Leukocoria and strabismus in pediatric patients are sometimes the early presenting signs of retinoblastoma. Although leukocoria may be secondary to retinal detachment, vitreous hemorrhage or cataract, it may also point toward something more serious.

Eliminating the potential for undiagnosed tumor, however, may not always follow from clinical signs or symptoms. According to Dr. Murray, any patient indicated for intraocular surgery deserves a thorough screening.

“I think that one of the greatest fears for any surgeon who is a comprehensive ophthalmologist is to operate on an eye that may harbor an unrecognized malignancy,” Dr. Murray said. “If you’re thinking about cataract surgery, I think the gold standard is to have complete evaluation of the fundus.”

According to Dr. Murray, the workup should include slit lamp evaluation of the anterior segment, examination of the posterior segment with a 90 D lens, and indirect ophthalmoscopy with a 20 D or 28 D lens to visualize the peripheral retina.

“But if there is a part of the eye that is incapable of examination or the cataract is too dense or the patient won’t let you depress them, then it’s those patients that should have diagnostic ultrasound,” Dr. Murray said.

Patient and host factors

Ocular malignancies occur rarely but carry a potentially sight- or life-threatening prognosis. Given that the clinical course is vastly improved by early detection, is more wide-scale screening warranted to rule out smaller, seemingly innocuous presenting lesions?

According to most experts, the rigors of even more careful screening may not make sense. But Dr. Finger noted that current practice may be insufficient to find most ocular malignancies while small.

“For example, if you want to catch every small choroidal melanoma, you would have to dilate the entire population every 4 to 6 months, which is just not practical,” Dr. Finger said. “There are [American Academy of Ophthalmology] recommendations for how often patients should be dilated, which are every 2 years until you are 40, then every year after. But I personally believe that most patients should be dilated every year. A lot can happen in 2 years.”

Using choroidal melanoma as an example, Dr. Finger said that most cases are asymptomatic at presentation and that yearly dilated eye exams are warranted.

“Clinical evidence suggests that certain factors can be used to shape the clinician’s index of suspicion for further investigation,” Dr. Finger said. For instance, retinoblastoma occurs most commonly before the age of 3 years with no preference for race. Thus, ophthalmic examinations are important because many such cases are missed by pediatricians, and smaller tumors are more amenable to life-, eye- and vision-sparing treatments. Also found in the pediatric population is rhabdomyosarcoma, a rare but potentially fatal tumor that can be rapidly progressive. For rhabdomyosarcoma, a prompt biopsy with subsequent treatment can be lifesaving.

In adults, patients with multi-organ metastatic cancer warrant close clinical scrutiny and periodic eye examinations.

“These patients need to be examined and treated early, before the tumor can extend beneath the fovea and cause irreversible vision loss,” Dr. Finger said. “I consider these cases ophthalmic urgencies. Most should be treated within a week or two, typically with external beam radiation therapy.”

Patients with a history of primary cancer, even absent diffuse metastatic involvement, warrant a higher index of clinical suspicion. In these cases, epidemiologic evidence may be helpful in differentiating which patients are at higher risk. For example, breast cancer is the most common cause of ocular metastasis in women, whereas lung cancer is the most common in men.

Patients with a history of prostate, thyroid or colon cancer can also develop a choroidal metastasis. However, in a recent review of cutaneous melanoma metastatic to the eye and orbit, Dr. Finger and Dr. Caroline Rosenberg found evidence that few cases of ocular metastasis occurred without other known sites of metastatic melanoma.

Age should also be considered. The Collaborative Ocular Melanoma Study found the average age of a patient with choroidal melanoma to be 60 years.

“Lastly, don’t forget that once the diagnosis of eye cancer, primary or metastatic, is made, one should look for evidence of diffuse metastatic disease,” Dr. Finger said. – by Bryan Bechtel

Should patients be routinely examined for potential ocular malignancy, and if so, how often?

References:

• Hu DN, Yu G, McCormick SA, Finger PT. Population-based incidence of conjunctival melanoma in various races and ethnic groups and comparison with other melanomas. Am J Ophthalmol. 2008;145(3):418-423.
• Hu DN, Yu GP, McCormick SA, Schneider S, Finger PT. Population-based incidence of uveal melanoma in various races and ethnic groups. Am J Ophthalmol. 2005;140(4):612-617.
• Krishna SM, Yu GP, Finger PT. The effect of race on the incidence of retinoblastoma. J Pediatr Ophthalmol Strabismus. 2009;46(5):288-293.
• Rosenberg C, Finger PT. Cutaneous malignant melanoma metastatic to the eye, lids, and orbit. Surv Ophthalmol. 2008;53(3):187-202.
• SEER Stat Fact Sheets. Surveillance, Epidemiology, and End Results website. http://seer.cancer.gov/statfacts/html/all.html. Accessed June 9, 2010.
• Shields CL, Furuta M, Thangappan A, et al. Metastasis of uveal melanoma millimeter-by-millimeter in 8033 consecutive eyes. Arch Ophthalmol. 2009;127(8):989-998.
• Shields CL, Shields JA. Conjunctival primary acquired melanosis and melanoma: tales, fairy tales, and facts. Ophthal Plast Reconstr Surg. 2009;25(3):167-172.
• Tuomaala S, Eskelin S, Tarkkanen A, Kivelä T. Population-based assessment of clinical characteristics predicting outcome of conjunctival melanoma in whites. Invest Ophthalmol Vis Sci. 2002;43(11):3399-3408.
• Yu GP, Hu DN, McCormick S, Finger PT. Conjunctival melanoma: is it increasing in the United States? Am J Ophthalmol. 2003;135(6):800-806.

• Paul T. Finger, MD, FACS, can be reached at The New York Eye Cancer Center, 115 East 61st St., New York, NY 10021; 212-832-8170; fax: 212-888-4030; e-mail: pfinger@eyecancer.com.
• Timothy G. Murray, MD, MBA, FACS, can be reached at Bascom Palmer Eye Institute, P.O. Box 016880, Miami, FL 33101-6880; 305-326-6166; fax: 305-326-6580; e-mail: tmurray@bpei.med.miami.edu.
• Carol L. Shields, MD, can be reached at Wills Eye Institute, Ocular Oncology Service, 900 Walnut St., Philadelphia, PA 19107; 215-928-3105; fax: 215-928-1140; e-mail: carol.shields@shieldsoncology.com.