Uveal Melanoma

Educational Objectives

The goal of this lecture is to improve the management of posterior segment diseases. After hearing and assimilating this lecture, the clinician will be better able to:

1. Predict the likelihood of metastatic progression based on uveal melanoma size.
2. Differentiate between uveal melanoma and choroidal nevus.

Summary

“Size matters”: study evaluating metastasis of uveal melanoma in >8000 eyes found that each millimeter increase in thickness adds 5% risk for metastasis at 10 yr (2-mm thickness associated with 10% risk for metastasis by 10 yr; 10 mm, with 50% risk for metastasis by 10 yr); early detection may save lives

Prognostication by size: with 0 to 1 mm in thickness, risk ≈5%; with 1 to 2 mm, risk 10%; with 2 to 3 mm, risk ≈15%

Metastatic disease: Kivela and Eskelin — estimated that, at time of micrometastasis, size of average melanoma 7 mm3 (3 mm by 3 mm by 1.5 mm); smaller melanoma unlikely to have metastasized; detecting melanoma at this size or earlier “could improve prognosis”; overall risk for metastasis 25% to 50%

American Joint Committee on Cancer (AJCC) classification: divides melanoma into 4 groups (T1, T2, T3, and T4) based on size (most are T1); at 10 yr, risk for metastatic disease with T4 melanoma 10 times greater than risk with T1; AJCC classification not intuitive but does confirm importance of tumor size

Genetics: use sampling to look for abnormality of chromosome 3 or 8 in DNA, and to classify RNA (class ≥2 raises risk for metastasis); mutations — GNAQ and GNA11 lead to induction of melanoma; EIF1AX is protective (reduces risk for metastasis); SF3B1 implies late onset of metastasis; BAP1 and PRAM associated with early onset of metastasis; findings of genetic profiles — among 500 consecutive cases of uveal melanoma, rate of chromosome 3 abnormalities low in smaller (0-3 mm) melanomas and higher among larger melanomas; chromosome 3 abnormality correlated with high risk for metastatic disease by 3 yr; profiles allow personalization of prognosis

Technique for tumor sampling: perform needle biopsy through pars plana and into tumor using indirect ophthalmoscopy guidance; aspirate cells, then withdraw; drop of blood at side of biopsy heals; rhegmatogenous detachment very rare even though retina perforated

Large melanomas: cause subluxation of lens; prognosis very poor (no effective treatment available); detection before significant growth occurs is crucial; speaker recommends once- or twice-yearly eye examination to ensure early detection

Choroidal nevus: prevalence >5% in US adults; may be related to hormones, obesity, and vitamin C deficiency; with extrapolation to whole fundus, rate could be ≤20%; ratio of occurrence in whites to blacks is 10:1

National Health and Nutrition Examination Survey: hormonal factors — risk increased 5-fold in women >40 yr of age who had short childbearing period; postmenopausal obesity increases risk 2-fold; hypothesized to have correlation with total lifetime exposure to unopposed estrogen; obesity — elevated body mass index confers 1.4-fold increase in relative risk; vitamin C deficiency — increases relative risk 2-fold

Transformation to melanoma: 5 to 8 risk factors found among 2514 patients with choroidal nevus; mnemonic (TFSOM UHHD) — thickness >2 mm; fluid; symptoms of flashing, floaters, or vision loss; orange pigment margin at disk; ultrasonographic hollow; no halo or drusen

Optical coherence tomography angiography (OCTA): melanoma increases level of vascular endothelial growth factor and causes mild macular ischemia on OCTA; 3 parameters — central macular thickness (CMT), macular capillary density, and foveal avascular zone (FAZ) size

Five key OCTA reports: in affected eyes, CMT significantly thickened at 312 μ (control eyes 266 μ); capillary density reduced in affected eyes; eyes with melanoma tend to have enlarged FAZ; eyes with nevi show no difference in CMT, superficial capillary density, or deep capillary density; nevi do not create microischemic environment; OCTA allows early detection of radiation retinopathy (graded from 0 [no OCTA features] to 5 [OCTA unreadable]); irradiated melanoma — OCTA shows enlargement of FAZ and reduction in capillary density; after plaque irradiation, CMT enlarged even in those with radiation maculopathy; capillary density reduced; FAZ enlarged, especially in those with visible radiation maculopathy; OCTA in eyes with no radiation retinopathy and completely normal macular features on fundus evaluation shows significant decrease in parafoveal capillary density

Prognostication: genetic testing shows abnormalities of chromosomes 3 and 8 increase risk for metastatic disease 37-fold; disomy of chromosome 3 absent in small melanoma; monosomy 3 is found in 17% of small melanoma, 37% of medium melanoma, and 15% of large melanoma; as thickness increases, risk for cytogenetic abnormalities increases; hazard ratio — partial monosomy 3 in uveal melanoma increases risk for metastatic disease 2.8-fold (6.7-fold with complete monosomy); 8p losses and 8q gains associated with highest risk (risk increased by factor of 21 with 8p loss); slow growth of nevus — reduces risk for cytogenetic abnormalities

New treatments: GNAQ vaccine; MEK inhibitors; sunitinib (Sutent) for prevention; despite success in skin melanoma, checkpoint inhibitors have not been highly effective for uveal melanoma; immune modulation T cells against cancer (IMTAG) — “educates” patient’s own T cells to fight metastasis of melanoma; nanoparticle therapy — selectively binds to heparin sulfate on surface of melanoma cells; coupled with photosensitive dye; when treated with laser, “cooks” small tumors

Readings

Eskelin S et al: Tumor doubling times in metastatic malignant melanoma of the uvea: tumor progression before and after treatment. Ophthalmology 2000 Aug;107(8):1443-9; Dogrusoz M et al: Uveal melanoma treatment and prognostication. Asia Pac J Ophthalmol (Phila) 2017 Mar-Apr;6(2):186-96; Qui M et al: Choroidal nevus in the United States adult population: Racial disparities and associated factors in the National Health and Nutrition Examination Study. Ophthalmology 2015 Oct;122(10):2071-83; Rishi P et al: Using risk factors for detection and prognostication of uveal melanoma. Indian J Ophthalmol 2015 Feb;63(2):110-6; Shields CL et al: Choroidal nevus transformation into melanoma: analysis of 2514 consecutive cases. Arch Ophthalmol 2009 Aug;127(8):981-7.

Disclosures

For this program, the following has been disclosed: Dr. Shields is on the advisory panel for Aura Biosciences. The planning committee reported nothing to disclose.

Acknowledgements

Dr. Shields spoke at the 2016 Posterior Segment Summit, presented by the Ocular Immunology and Uveitis Foundation, and held on November 12, 2016, in Waltham, MA. For information on upcoming CME activities presented by the Ocular Immunology and Uveitis Foundation, please visit www.uveitis.org. The Audio Digest Foundation thanks the speakers and the Ocular Immunology and Uveitis Foundation for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0 CE contact hours.

Lecture ID:

OP551303

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.