History

• 69-year-old Caucasian female presented for yearly dilated fundus exam for diabetic screening
• Patient had no visual complaints
• PMH: Well controlled T2DM, Lasik OU few years prior
• ROS negative

Exam Findings

• BCVA 20/20 OD, 20/25 OS, IOP WNL and EOMI OU with no APD
• Anterior segment exam on slit lamp only notable for 1+ NSC of the lens OU
• DFE revealed choroidal lesion nasal and inferior to optic nerve OD, WNL OS

Differential Diagnosis

• Choroidal melanoma: most common primary intraocular tumor in adults
• Risk factors include:
• Ages 50-70 years
• Caucasian
• Sun exposure especially in fair skinned individuals
• Visual symptoms are variable with 30% of patients asymptomatic at diagnosis
• Choroidal Nevus (present in ~5% of Caucasians, by strict size definitions <1x5mm)
• High risk features for growth of nevus include:
• Thickness greater than 2 mm
• Subretinal fluid
• Visual symptoms
• Orange pigment
• Margin near the optic disc
• Ultrasonographic hollowness
• Absence of halo or drusen
• Peripheral exudative hemorrhagic chorioretinopathy (however, no fluid, no drusen, no anticoagulation or other risk factors)
• Congenital hypertrophy of the RPE (however, would not be a new finding; color of lesion is atypical)
• Circumscribed choroidal hemangioma (however, this lesion is the wrong color)
• Choroidal metastasis (however, generally amelanotic unless from melanoma)

Additional Investigations

• CT chest, abdomen, pelvis done for evaluation of metastatic disease and staging was negative

Diagnosis

• Choroidal melanoma

Pathophysiology

• Melanomas arise from the abnormal proliferation of melanocytes, which are melanin-producing cells derived embryologically from neural crest cells
• It is the most common primary intraocular tumor, although accounting for only 5% of all cases of melanoma with an incidence of 5.1 per million per year in the United States
• Genetic alterations such as monosomy of chromosome 3 or mutation/inactivation of BRCA associated protein 1 (BAP1) have been found to have a higher risk of metastasis

Treatment

• Depending on the tumor’s size, treatment options include:
• Plaque radiotherapy
• Proton beam therapy
• Stereotactic radio surgery
• Enucleation
• Given that the tumor dimensions were classified as medium-sized, iodine-125 radioactive episcleral plaque brachytherapy was pursued with the USC Eye Physics Plaque, developed at the University of Southern California. A CT orbits was done for 3D treatment planning.

• The plaque was placed in the right eye with an Rx of 85 Gy to the apex of the tumor and then removed one week later after the completion of brachytherapy
• The USC Ocular Oncology Service has described a novel method for plaque placement using a toric marker
• A surgical video of placement of the USC Eye Physics Plaques can be found online here (link: http://www.eyephysics.com/PS/PS6/UserGuide/EyePlaqueMovie.html) or on the USC Ocular Oncology Facebook page (link: https://www.facebook.com/usceyeonc/)
• A fine needle aspiration biopsy for gene expression profiling was offered to the patient, which she declined

Prognosis and Future Directions

• As described in COMS report No. 28, the risk of metastatic disease is similar whether patients undergo enucleation or brachytherapy for medium-size melanoma. This risk is 17-21% at 12 years.
• The most common site of metastasis is to the liver
• As reported by Berry et al, JAMA Ophthalmol 2013, the USC Eye Physics Plaques have compared favorably to the COMS plaques given its customization to the patient’s tumor characteristics (Table 1 below):

• Key findings illustrated in Table 1 are:
• Reduced tumor recurrence and enucleation rates at 5 years compared to the COMS plaques
• Reduced adverse radiation effects including radiation optic neuropathy, retinopathy and cataracts from USC Eye Physics Plaques, in a smaller cohort of patients

• Patient BCVA 20/20 OU with no adverse symptoms of optic neuropathy, radiation retinopathy, or accelerated cataracts noted, however she will be followed closely for adverse effects
• Patient undergoes liver ultrasound and liver function tests every six months, which have been negative to date
• While declined by this patient, many patients choose to have a biopsy for a PCR-based Gene expression profiling of 15 genes, which classifies tumors as Class 1A, 1B and 2. The risk of developing metastatic disease at five years, as reported by Castle Biosciences, is 2%, 21% and 72% respectively. Class 2 tumors have a much higher risk of metastatic disease and imaging surveillance can be appropriately targeted with this information
• Patient follows-up with the USC Ocular Oncology Service every three-to-four months to monitor for tumor regression, surveillance for recurrence, and adverse effects of radiation

References

• Berry JL, Dandapani SV, Stevanovic M, Lee TC, Astrahan M, Murphree AL, Kim JW. Outcomes of Choroidal Melanomas Treated with Eye Physics: A 20-Year Review. JAMA Ophthalmol. 2013; 131(11):1435-1442.
• Berry JL, Kim JW, Jenelle R, Astrahan M. Use of the Toric Surgical Marker to Aid in Intraoperative Plaque Placement for the USC Eye Physics Plaques to Treat Uveal Melanoma: A New Surgical Technique. Ophthalmic Surg Lasers Imaging Retina. 2015 Sep; 46(8):866-70.
• Chang AE, Karnell LH, Menck HR. The National Cancer Data Base report on cutaneous and noncutaneous melanoma: a summary of 84,836 cases from the past decade. The American College of Surgeons Commission on Cancer and the American Cancer Society. Cancer. 1998 Oct 15; 83(8):1664-78.
• The COMS randomized trial of iodine 125 brachytherapy for choroidal melanoma: V. Twelve-year mortality rates and prognostic factors: COMS report No. 28. Collaborative Ocular Melanoma Study Group. Arch Ophthalmol. 2006 Dec; 124(12):1684-93.
• Eskelin S, Pyrhönen S, Summanen P, Hahka-Kemppinen M, Kivelä T. Tumor doubling times in metastatic malignant melanoma of the uvea: tumor progression before and after treatment.Ophthalmology.2000 Aug; 107(8): 1443-9.
• 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.
• Weis E, Shah CP, Lajous M, Shields JA, Shields CL. The association between host susceptibility factors and uveal melanoma: a meta-analysis. Arch Ophthalmol. 2006 Jan; 124(1): 54-60.

Contact

• Jesse L. Berry, MD, Assistant Professor of Clinical Ophthalmology and Assistant Director of Ocular Oncology, jesse.berry@med.usc.edu
• Debarshi Mustafi, MD, PhD, PGY-2 Ophthalmology Resident, debarshi.mustafi@med.usc.edu

Section Editors

• Vivek Patel, MD, Associate Professor of Clinical Ophthalmology, Program Director, vivek.patel@med.usc.edu
• Jesse Berry, MD, Assistant Professor of Clinical Ophthalmology, Associate Program Director, jesse.berry@med.usc.edu

Produced by: Monica Chavez, John Daniel, Joseph Yim and Dr. Vivek Patel