January 2019


Presentation spotlight
Advances in ocular oncology

by Stefanie Petrou Binder, MD, EyeWorld Contributing Writer

“Recognizing conjunctival tumors and understanding predisposing factors, biomarkers, and treatment strategies are vital to patient
outcomes. These are exciting
times in oncologic ophthalmology.”
—Carol Shields, MD

Oncology specialist elucidates the newest, most effective treatment methods for ophthalmic neoplasms

Ocular malignancies today have more sophisticated, nonsurgical treatments options than ever before. According to Carol Shields, MD, Ocular Oncology Service, Wills Eye Hospital, Philadelphia, who co-moderated a session on landmark advances in ophthalmology at the 2018 World Ophthalmology Congress, there have been tremendous advances in ocular cancer management.

Conjunctival tumors as completely resolvable

“According to a recent report on more than 5,000 conjunctival tumors in our practice, the most frequent conjunctival malignancies in an ocular oncology practice include ocular surface squamous neoplasias (14%), melanoma (12%), and lymphoma (7%),” Dr. Shields said. “We deal with these in our center on a day to day basis.”
Conjunctival squamous cell carcinoma, also known as ocular surface squamous neoplasia, is a gelatinous fleshy vascular mass that can be extensive in size and rarely invades the eye. It tends to occur at the limbus, can present with feeder vessels and leukoplakia, and is usually non-pigmented. These malignancies frequently present in immunosuppressed patients with HIV or after organ transplantation. Other predisposing factors are heavy smoking, xeroderma pigmentosum, and autoimmune disease. The tumors can be large, recurrent, bilateral, invasive, and need to be followed lifelong. Dr. Shields advises prophylactic interferon to prevent cancer from developing if the tumor recurs in high risk patients.
Treatment options for ocular surface squamous neoplasms are approached surgically and medically. Dr. Shields explained, “The nonsurgical approach has been used for about 20 years and has been impressive. There are several alternatives for the treatment of squamous cell carcinoma. In developed countries we prefer interferon. Although MMC is a good treatment usually given for a 1-month duration, it is toxic and can wipe out stem cells. 5-FU is the drug of choice in less developed nations because it is much more affordable, despite its toxicity to stem cells. In South America, it costs approximately $20 for a bottle of 5-FU compared to $200 for a bottle of interferon. Interferon is given from 3 to 6 months. It is nontoxic and has few complications.1 Photodynamic therapy (PDT) is used for patients who fail all of the above.”
In a study she performed, Dr. Shields found that interferon was able to resolve squamous neoplasms completely within a few weeks, even in more advanced tumors with extensive disease. Interferon when appropriately combined with surgical excision could provide complete control in 95% of cases.2


When treating retinoblastoma, it is vital to balance systemic safety, globe preservation, and visual potential. Dr. Shields distinguished between unilateral and bilateral treatments. For unilateral retinoblastoma, intra-arterial chemotherapy (IAC) is her treatment of choice, which has reduced the percentage of eye enucleations to between 3% and 5%. For bilateral tumors, she uses intravenous chemotherapy (IVC). Enucleation is reserved for children in which there is little hope, high risk, unreliable parents, or when chemotherapy is not available.
Although there is some agreement and disagreement on the best methods of treatment, IAC and IVC have completely replaced external beam radiotherapy and diminished enucleations by 90% without evidence of compromising patient survival.3 “What we did agree on is that we have made huge progress,” Dr. Shields said. “The death rate in the U.S. from retinoblastoma is less than 2%. This is the number one most successfully treated cancer in children. IAC should be performed at an experienced center to avoid major risks.”

Lymphoma and rituximab

Lymphoma is the fourth most common malignancy in the U.S., and its incidence is increasing by 4% every year. Lymphoma can be nodal (found in lymph nodes and the spleen) or extranodal elsewhere (found in conjunctiva, lid, orbit, uvea, vitreous, retina). In the eye, it typically presents as a salmon patch on the fornix bilaterally. Unilateral lymphoma has a 17% risk for systemic lymphoma, and bilateral lymphoma carries a 50% risk.
According to a large, retrospective observational case series, four important non-Hodgkin B cell subtypes were noted: extranodal marginal zone (68%), follicular (16%), diffuse large B cell (5%), and mantle cell (7%). While the first two are low grade with a 5-year survival of 97% and 82%, respectively, the latter two forms of non-Hodgkin lymphoma carry a 55% and 9% 5-year survival rate, respectively.4
Identifying the lymphoma type is important for effective treatment, as not all lymphomas are the same. “Surgical resection with radiotherapy is localized, but we will more often use chemotherapy and rituximab, my drug of choice,” Dr. Shields said. “Rituximab treats the eye and all the hidden pockets of lymphoma systemically. We had great results with this new, very targeted anti-CD20 medication. Often tumors resolve within 2 months. We achieved 80% tumor control using rituximab and a 2-day regimen of low dose external beam radiation therapy. Rituximab also has good effects on choroidal melanoma.”

Target the mutation

Choroidal melanoma is a serious malignancy with a high risk of metastasis and death. Thanks to advances in cytogenetics, physicians can now pinpoint the mutation in the melanoma and identify high/low risk patients for metastasis. Mutations in chromosome 3 and 8 are associated with a higher rate for metastatic disease. According to a study Dr. Shields headed,5 there is a correlation between larger tumor size category/higher number of mutations and a higher mutational profile by approximately 3- to 6-fold. “We put a needle in the tumor and get adequate DNA in 96% of cases, even in small/flat tumors. Using the DNA, we identify the mutation and give a quoted figure for what the risk for metastasis is. There are more than 50 genetic signatures with increasing risk for metastasis with uveal melanoma,” she explained.
Treatments for melanoma include systemic targeted drugs, vascularization blockade, and immunotherapy. A new, innovative therapy currently in trial in the U.S. called light-activated nanoparticle AU-011 is showing promise. This new class of therapy selectively targets tumor cells. The technology involves virus-like nanoparticles injected into the eye that binds the heparin sulfate matrix surrounding tumor cells. It is chromophore attached, laser light stimulated and causes precise tumor cell death. “This innovative therapy was tested in animal studies and has shown impressive response in rabbits,” Dr. Shields said. “We are in Phase 1b safety trials and efficacy trials are to begin soon. We have treated seven patients at Wills Eye Hospital. We might be able to treat smaller and smaller tumors with this modality. This is a new era of melanoma treatment and prevention.”
Melanoma metastasis are targeted with immune modulated T-cells against cancer. Dr. Shields elucidated, “We use this every week. It is a receptor that attaches itself to melanoma cells and attracts T-cells to it, causing necrosis of the melanocyte. We are learning to use this together with checkpoint inhibitors for better results for uveal melanoma.”

Tumor biomarkers

A biomarker is a measurable indicator of a biological condition or disease, used in the pharmacological industry to design targeted drugs. There are a number of known biomarkers in ocular oncology, just as the well known biomarkers that identify breast, ovarian, and colorectal cancers. “We test for all of the known biomarkers, but we do not have specific medications for all of them. Recognizing conjunctival tumors and understanding predisposing factors, biomarkers, and treatment strategies are vital to patient outcomes.6 These are exciting times in oncologic ophthalmology,” Dr. Shields said.


1. Karp CL, et al. Treatment of conjunctival and corneal intraepithelial neoplasia with topical interferon alpha-2b. Ophthalmology. 2001;108:1093–8.
2. Shields CL, et al. Interferon for ocular surface squamous neoplasia in 81 cases: outcomes based on the American Joint Committee on Cancer classification. Cornea. 2013;32:248–56.
3. Abramson DH, et al. Treatment of retinoblastoma in 2015: agreement and disagreement. JAMA Ophthalmol. 2015;133:1341–7.
4. Svendsen FH, et al. Lymphoma of the eyelid – an international multicenter retrospective study. Am J Ophthalmol. 2017;177:58–68.
5. Shields CL, et al. Personalized prognosis of uveal melanoma based on cytogenetic profile in 1059 patients over an 8-year period: the 2017 Harry S. Gradle Lecture. Ophthalmology. 2017;124:1523–1531.
6. Shields CL, et al. Conjunctival tumors: review of clinical features, risks, biomarkers, and outcomes – the 2017 J. Donald M. Gass Lecture. Asia Pac J Ophthalmol (Phila). 2017;6:109–120.

Editors’ note: Dr. Shields has financial interests with Aura Biosciences (Cambridge, Massachusetts).

Contact information

: carolshields@gmail.com

Advances in ocular oncology Advances in ocular oncology
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