points causes features therapy collaborative ocular melanoma study prognosis Choroid Nevus

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1 The Game of Uveal Melanoma Carol Shields MD Oncology Service Wills Eye Hospital Philadelphia PA USA Oncology Service Wills Eye Institute points causes features therapy collaborative ocular melanoma study prognosis Causes of uveal melanoma host factors nevus melanocytosis light eye color fair skin color inability to tan environmental factors arc welding chronic sunlight exposure few reports white population 7% features pigmented 90% thickness <2mm drusen RPE atrophy questions answers do the features change over time can nevus affect vision can nevus enlarge rate of transformation into melanoma 1/8000 Clinical Spectrum of Choroidal Nevi Based on Age at Presentation in 3422 Consecutive Eyes Carol L. Shields, MD, Minoru Furuta, MD, Arman Mashayekhi, MD, Edwina L. Berman, MBBS, Jonathan D. Zahler, DO, Daniel M. Hoberman, BS, Diep H. Dinh, BS, Jerry A. Shields, MD Purpose: To evaluate the clinical features of choroidal nevi based on patient age at presentation and to investigate features of the nevi that are predictive of patient symptoms. Design: Observational case series. Participants: Three thousand four hundred twenty-two consecutive eyes of 3187 patients. Methods: Retrospective clinic-based study of clinical features at referral. Cox proportional hazards regressions were used for evaluation of factors predictive of patient symptoms. Main Outcome Measures: Nevus features as related to patient age group at diagnosis (young [ 20 years], mid-adult [21 50 years], older adult [ 50 years]) and factors predictive of patient symptoms secondary to the nevus. Results: Of the 3422 eyes with choroidal nevus, 63 (2%) were in young patients, 795 (23%) in mid-adults, and 2564 (75%) in older adults. The following factors showed no substantial increase or decrease by age category (young, mid-adult, older adult) at presentation: symptoms (14%, 12%, 13%), mean nevus base (5.6, 4.7, 5.2 mm), intrinsic nevus pigmentation (89%, 74%, 77%), related subretinal fluid (SRF) (11%, 15%, 9%), overlying orange pigment (6%, 10%, 6%), retinal pigment epithelial hyperplasia (0%, 9%, 7%), and retinal pigment epithelial atrophy (2%, 13%, 10%). The following factors statistically increased with age category: multiple nevi per eye (2%, 8%, 10%) (P ), mean nevus thickness (1.2, 1.5, 1.6 mm) (P ), and overlying drusen (11%, 40%, 58%) (P ). Using multivariate analysis of the entire group, factors predictive of any symptom included nonpigmented nevus (P 0.001), location 3 mm to foveola (P 0.001), subfoveolar fluid (P 0.002), any SRF (P 0.02), and subfoveolar nevus (P 0.027). Conclusions: Choroidal nevi show similar clinical features regardless of age of presentation, with the exception of increasing number of nevi per eye, slightly increasing thickness, and increasing drusen in adults versus younger patients. Symptomatic nevi are more likely to be nonpigmented, beneath the foveola, and with subfoveolar fluid. Ophthalmology 2008;115: by the American Academy of Ophthalmology. groups young 0-20 yrs mid adult yrs older adult >50 yrs thick >1per eye drusen 1.2 2% 11% 1.5 8% 40% % 58% Young Mid Adult p<0.0001

2 groups Older Adult subfoveal extrafoveal initial final 20/20 20/30 20/20 20/25 vision loss @20 yrs 15% 20% 26% <1% 1% 2% questions answers do the features change over time can nevus affect vision can nevus enlarge rate of transformation into melanoma 1/8000 questions answers do the features change over time can nevus affect vision can nevus enlarge rate of transformation into melanoma 1/8000 CLINICAL SCIENCES Visual Acuity in 3422 Consecutive Eyes With Choroidal Nevus Carol L. Shields, MD; Minoru Furuta, MD; Arman Mashayekhi, MD; Edwina L. Berman, MBBS; Jonathan D. Zahler, DO; Daniel M. Hoberman, BS; Diep H. Dinh, BS; Jerry A. Shields, MD Objective: To evaluate visual acuity in eyes with choroidal nevus. Design: This was an observational case series. Of 3422 consecutive eyes with choroidal nevus, vision loss at 15 years occurred in 2% of eyes with extrafoveolar nevus and in 26% of eyes with subfoveolar nevus, particularly those with overlying retinal pigment epithelial detachment and foveal edema. A retrospective medical record review was conducted, with evaluation of visual acuity at presentation and at final examination. The main outcome measure was visual acuity. Results: The median visual acuity at presentation was 20/20 for eyes with either extrafoveolar or subfoveolar choroidal nevus. Using Kaplan-Meier estimates, vision loss of 3 or more logarithm of the minimum angle of resolution (logmar) lines at 5, 10, and 15 years occurred in less than 1%, 1%, and 2% of eyes with extrafoveolar nevus compared with 15%, 20%, and C26% of eyes with subfoveolar choroidal nevus, respectively. By multivariate analysis, factors predictive of visual loss of 3 or more log- MAR lines included subfoveolar nevus location (relative risk [RR], 15.52), juxtapapillary nevus location (RR, 4.52), initial visual acuity of 20/50 or worse (RR, 15.40), overlying retinal pigment epithelial detachment (RR, 22.16), and foveal edema (RR, 9.02). Factors predictive of poor final visual acuity of 20/200 or worse included subfoveolar nevus location (RR, 11.32), overlying orange pigment (RR, 3.68), overlying retinal pigment epithelial detachment (RR, 12.80), and foveal edema (RR, 18.72). Conclusion: Mild vision loss over many years should be anticipated in patients with subfoveolar choroidal nevus, particularly those with overlying retinal pigment epithelial detachment, orange pigment, and foveal edema. Arch Ophthalmol. 2007;125(11): why does subfoveal nevus have vision loss? growth is a presumed indicator of malignant potential Slow Enlargement of Choroidal Nevi: A Long-Term Follow-Up Study Enlargement growth is not an unequivocal indicator of malignancy Arman Mashayekhi, MD, Sophia Siu, BS, Carol L. Shields, MD, Jerry A. Shields, MD Purpose: Choroidal nevi are generally considered to be stable lesions, and growth of a choroidal nevus is usually believed to be a sign of malignant transformation. We performed this study to determine whether choroidal nevi enlarge over a long period of follow-up without undergoing malignant transformation. Design: Retrospective observational case series. Participants: A total of 278 patients with 284 nevi who had at least 7 years of photographic follow-up without clinical signs of transformation into melanoma were included in the study. Methods: Data on demographic and clinical information were extracted from patients charts. Detailed fundus drawings and color fundus photographs were reviewed and compared for evidence of enlargement. Main Outcome Measures: Nevus enlargement without clinical evidence of transformation into melanoma. Results: Of the 278 patients, 69% were female and more than 99% were White with a median age at presentation of 57 years (range, 4 87 years). The largest nevus basal diameter was a median of 5 mm (range, mm), and the median thickness was 1.5 mm (range, mm). Only 14 nevi (5%) had subretinal fluid outside the nevus, and 6% showed overlying orange pigment. Overlying retinal pigment epithelial alterations included drusen (61%), atrophy (6%), hyperplasia (10%), and fibrous metaplasia (6%). Of 284 nevi, 31% showed slight enlargement over a mean follow-up of 15 years. The median increase in diameter was 1 mm (mean, 0.9 mm; range, mm), and the median rate of enlargement was 0.06 mm/yr (mean, 0.06 mm/yr; range, mm/yr). None of the lesions that enlarged developed new risk factors that are generally associated with malignant transformation. Frequency of enlargement was 54% in patients aged less than 40 years and 19% in patients aged more than 60 years. On multivariate analysis, younger patient age was the only factor predictive of nevus enlargement (P 0.001). Conclusions: With long-term follow up, 31% of choroidal nevi showed slight enlargement without clinical evidence of transformation into melanoma. The frequency of enlargement was inversely related to patient age. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Ophthalmology 2011;118: by the American Academy of Ophthalmology. 16 yowm enlargement over 10 years

3 Enlargement Enlargement Melanoma questions answers do the features change over time can nevus affect vision can nevus enlarge rate of transformation into melanoma 1/8000 enlargement over 10 years 3 mm growth in 2 years Nevus Growth to Melanoma Nevus Growth to Melanoma Mathematical estimates Ganley 1/4500 Singh et al 1/8845 annual rate cumulative rate Kivela et al 1/ if we live to 80 yrs Population based study - Blue Mtn Eye Study Clinic based study - Shields et al Nevus Growth to Melanoma Risk factors low risk high risk Nevus Growth to Melanoma most important paper from our practice published 1995 published 2009 Nevus Growth to Melanoma Th > 2 mm Fluid Symptoms Orange pigment Margin at disc To Find Small Ocular Melanoma Using Helpful Hints Daily US Hollow Halo absent Drusen absent Nevus Growth to Melanoma Th > 2 mm Fluid - Each factor adds relative risk of ~ x greater risk Symptoms Orange pigment Margin at disc US Hollow Halo absent Drusen absent

4 Tests OCT EDI OCT Autofluorescence pigmented lesion no transmission poor posterior border compression of choroidal vessels Ultrasound Fluorescein Angiography Nevus vs Melanoma Nevus vs Melanoma thicker subretinal fluid shaggy photoreceptors p=0.001 important difference is shaggy photoreceptors edi oct of choroidal nevus versus melanomaimportant difference is shaggy photoreceptors - elongated shaggy photoreceptors Autofluorescence Autofluorescence nevus nevus melanoma melanoma Causes of uveal melanoma host factors nevus melanocytosis light eye color fair skin color inability to tan environmental factors arc welding chronic sunlight exposure

5 Melanocytosis! 1/400 risk Causes for uveal melanoma Melanocytosis! 1/400 risk Causes for uveal melanoma at risk for melanoma at risk for melanoma at risk for melanoma points causes features therapy collaborative ocular melanoma study prognosis color melanotic 85% amelanotic 15% size base 11 mm thickness 5.5 mm

6 Quadrant uveal melanoma in 8033 eyes Nasal 21% Superior 22% Macula 4% Temporal 28%! 2.6 mm!! 4.3 mm!! 7.0 mm points causes features therapy collaborative ocular melanoma study prognosis Diffuse 3% Inferior 22% Treatment Uveal Melanoma Observation Laser Thermotherapy Plaque radiotherapy Charged particle radiotherapy Resection Enucleation Exenteration Systemic therapies Treatment Uveal Melanoma Depends Tumor size Tumor location Status of opposite eye Patient age Patient health Patient desires and fears Basically Small Medium Large Treatment Uveal Melanoma 0-3mm 3-8mm >8mm TTT Radiotherapy Radiotherapy Resection Enucleation Radiotherapy Enucleation Plaque Radiotherapy Melanoma Plaque Radiotherapy Melanoma Radiation parameters Apex 8000 cgy Base cgy custom curvilinear standard custom notch custom round

7 Radiation Team Radiation Lead Container Radiation oncologist Radiation physicist Plaque transportation Prevent exposure Ocular Oncologists All personnel Radiation Device Surgical placement of radiation plaque Every person in the room wears radiation badge Exposure measurement Dummy plaque Radioactive plaque Radioactive Plaque Radioactive Plaque Radioactive Plaque Stored on hospital tray Betadiene Sterile metal container face down Rinsed Rinsed Seed count Sutures already in sclera Tie down Precisely localize intraocular tumor with transillumination or scleral depression Rotate eye with muscle sutures Long sutures to find plaque for removal

8 Radioactive Plaque Conjunctival closure with 7-0 vicryl Maxitrol and Atropine ointments Tarsorrhaphy suture Patch Plaque Radiotherapy Choroid Melanoma Plaque Radiotherapy Iris Melanoma Plaque Radiotherapy Follow up Eye Maxitrol tid 3-6 wks Atropine qhs 3-6 wks Recheck and measure 4 months Eye exam q 4 months then q 6 months for life Systemic Twice yearly Physical examination (liver and lung) Liver function tests Once yearly Chest xray MRI abdomen Plaque Small Melanoma Plaque Small Melanoma Plaque TTT small melanoma before!! after 3.0 mm!! 1.3 mm Plaque Medium Melanoma thickness 5 mm!!!!! 2 mm Plaque Large Melanoma thickness 9 mm!!!!! 2 mm Plaque Large Melanoma thickness 10 mm!!!!! 2 mm Oncology Service Wills Eye Institute

9 Juxtapapillary choroidal melanoma Magnitude of this problem of >10,000 uveal melanoma treated over 30 years n=650 juxtapapillary melanoma 7% of all uveal melanoma Juxtapapillary choroidal melanoma Requirements include knowledge and precision in Tumor measurement Plaque design Plaque placement 8 x 6 x 2.9 mm require 12 mm radiation field situate on 15 mm notched plaque post distribution precision in placement Juxtapapillary choroidal melanoma Plaque radiotherapy Juxtapapillary n=650 Epipapillary! Circumpapillary Plaque Radiotherapy for Juxtapapillary Choroidal Melanoma Tumor Control in 650 Consecutive Cases Mandeep S. Sagoo, MB, PhD, 1 Carol L. Shields, MD, 1 Arman Mashayekhi, MD, 1 Jorge Freire, MD, 2 Jacqueline Emrich, PhD, 2 Jay Reiff, PhD, 2 Lydia Komarnicky, MD, 2 Jerry A. Shields, MD 1 Purpose: To evaluate treatment of juxtapapillary choroidal melanoma with plaque radiotherapy and to investigate the role of supplemental transpupillary thermotherapy (TTT). Design: Retrospective, comparative case series. Participants: We included 650 consecutive eyes with juxtapapillary choroidal melanoma within 1 mm of the optic disc. Methods: Eyes with juxtapapillary choroidal melanoma receiving plaque radiotherapy over a 31-year period from October 1974 to November 2005 were included in the study. The TTT and no TTT groups were analyzed separately and compared. Main Outcome Measures: Local tumor control, metastasis, and tumor-related mortality. Results: The median basal tumor diameter was 10 mm (range, ) and median thickness was 3.5 mm (range, ). In 481 eyes (74%), the tumor was directly adjacent to the optic disc and in 169 eyes (26%) the posterior tumor margin was between 0.1 and 1.0 mm from the optic disc. The circumpapillary extent of the tumor was 4 clock-hours in 321 eyes (50%), 4 8 clock-hours in 250 eyes (38%), and 8 clock-hours in 79 eyes (12%). Plaque radiotherapy using iodine-125 in 616 eyes (95%), cobalt-60 in 19 eyes (3%), iridium-192 in 12 eyes (2%), and ruthenium-106 in 3 eyes ( 1%) delivered a median radiation dose of 8000 cgy (range, ) to the tumor apex and adjunctive TTT was used in 307 eyes (56%). Kaplan-Meier estimates for tumor recurrence, metastasis, and death were 14%, 11%, and 4% at 5 years and 21%, 24%, and 9% at 10 years, respectively. Eyes treated with additional TTT showed slight (statistically nonsignificant) reduction in recurrence and metastasis. Using multivariable analysis, factors predictive of tumor recurrence included foveolar tumor requiring TTT (hazard ratio, 5.07; P 0.001) and greater tumor thickness (hazard ratio, 1.29 per mm increase; P 0.001). Factors predictive of metastasis included greater tumor base (hazard ratio, 1.21 per mm increase; P 0.001) and increasing intraocular pressure (hazard ratio, 1.11 per mmhg increase; P 0.020). Conclusions: Plaque radiotherapy for juxtapapillary melanoma provides local tumor control in approximately 80% of eyes at 10 years. In subjects who received TTT, there was slight but nonsignificant improved local tumor control and lower metastatic rate. Financial Disclosure(s): The authors have no proprietary or commercial interest in any of the materials discussed in this article. Ophthalmology 2011;118: by the American Academy of Ophthalmology. points causes features therapy collaborative ocular melanoma study prognosis Collaborative Ocular Melanoma Study Collaborative Ocular Melanoma Study what should you remember? 1. medium melanoma 3-8 mm thickness plaque provides same prognosis as enucleation 2. large melanoma >8 mm thickness no need to irradiate eye before enucleation neither proved that therapy prevents metastasis early detection may be the best way to minimize metastasis points causes features therapy collaborative ocular melanoma study prognosis Prognosis of Uveal Melanoma melanoma is a deadly eye cancer

10 (REPRINTED) ARCH OPHTHALMOL / VOL 127 (NO. 8), AUG Prognosis of Uveal Melanoma old literature several reports on prognosis factors related to prognosis clinical histopathology cytology genetic Prognosis of Uveal Melanoma 2003 Kujala, Makitie, Kivela Metastasis n=289 5 yrs yrs yrs yrs 52% Prognosis of Uveal Melanoma 2003 Kujala, Makitie, Kivela If death from melanoma 62% by 5 yrs 90% by 10 yrs 98% by 25 yrs 100% by 35 yrs if metastasis, most picked up by 15 years following eye diagnosis Prognosis of Uveal Melanoma 2009 Shields CL, Furuta, Thangappan, et al. n=8033 Metastasis Practical millimeter by millimeter basis CLINICAL SCIENCES Metastasis of Uveal Melanoma Millimeter-by-Millimeter in 8033 Consecutive Eyes Carol L. Shields, MD; Minoru Furuta, MD; Archana Thangappan, MD; Saya Nagori, MD; Arman Mashayekhi, MD; David R. Lally, MD; Cecilia C. Kelly, MD; Danielle S. Rudich, MD; Anand V. Nagori, MD; Oojwala A. Wakade, MD; Sonul Mehta, MD; Lauren Forte, BS; Andrew Long, BS; Elaina F. Dellacava, MD; Bonnie Kaplan, MD; Jerry A. Shields, MD Objective: To determine the rate of metastasis of uveal melanoma on the basis of tumor thickness in millimeters. Methods: Retrospective medical record review. Results: The mean (median) patient age was 58 (59) years. A total of 8033 eyes were examined. Of the 285 eyes with iris melanoma, the mean tumor thickness was 2.7 mm and metastasis occurred in 0.5%, 4%, and 7% at 3, 5, and 10 years, respectively. Of the 492 eyes with ciliary body melanoma, the mean tumor thickness was 6.6 mm and metastasis occurred in 12%, 19%, and 33% at 3, 5, and 10 years, respectively. Of the 7256 eyes with choroidal melanoma, the mean tumor thickness was 5.5 mm and metastasis occurred in 8%, 15%, and 25% at 3, 5, and 10 years, respectively. For all uveal melanoma, metastasis at 5, 10, and 20 years was 6%, 12%, and 20% for small melanoma (0-3.0 mm thickness), 14%, 26%, and Author Affiliations: Ocular Oncology Service, Wills Eye Institute, Thomas Jefferson University, Philadelphia, Pennsylvania. 37% for medium melanoma ( mm), and 35%, 49%, and 67% for large melanoma ( 8.0 mm). More specifically, metastasis per millimeter increment at 10 years was 6% (0-1.0 mm thickness), 12% ( mm), 12% ( mm), 16% ( mm), 27% ( mm), 28% ( mm), 29% ( mm), 41% ( mm), 50% ( mm), 44% ( mm), and 51% ( 10.0 mm). Clinical factors predictive of metastasis by multivariate analysis included increasing patient age, ciliary body location, increasing tumor diameter, increasing tumor thickness, having a brown tumor, and the presence of subretinal fluid, intraocular hemorrhage, or extraocular extension. Conclusion: Increasing millimeter thickness of uveal melanoma is associated with increasing risk for metastasis. Arch Ophthalmol. 2009;127(8): IN 1962, PAUL ET AL 1 FROM THE Armed Forces Institute of Pathology reported the demographic data and prognosis of 3852 patients with uveal melanoma, the largest collection of patients with intraocular melanoma then. Their data revealed the following information: mean age at diagnosis of 55 years, approximately 54% male, and less than 1% African American. On the basis of the follow-up of 2652 cases, mortality rate by actuarial method was 29% at 5 years, 40% at 10 years, and 46% at 15 years, with a median survival of 15 years. Ten-year mortality was lower in younger patients (aged years) at 26% vs older patients (aged 70 years) at 51%. In 1992, Diener-West et al 2 provided a meta-analysis of 8 published articles that further refined our understanding of uveal melanoma prognosis by general tumor size. The combined weighted estimate of 5-year mortality was 16% for small tumors, 32% for medium tumors, and 53% for large tumors. Later, the Collaborative Ocular Melanoma Study disclosed melanoma-related mortality at 10 years to be 17% to 18% for medium melanoma and 40% to 45% for large melanoma. 3-6 Uveal melanoma prognosis has been shown to be dependent on several clinical factors including tumor location in the ciliary body, large tumor size, diffuse (flat) configuration, and extraocular extension as well as histopathologic and cytogenetic factors including epithelioid cell type, increased mitotic activity, infiltrating lymphocytes, tumor vascular networks, and chromosomal mutations including monosomy 3 and 8q addition. 7,8 In several articles, tumor size has been identified as one of the key clinical features predictive of metastasis. 9,10 Furthermore, increasing tumor thickness, from small to medium to large, has been correlated with increasing risk for metastasis, but the exact relationship per millimeter of tumor thickness has not been previously addressed, to our knowledge. In this analysis, we evaluate a large cohort of 8033 patients observed long-term for melanoma-related Practical method for estimating metastatic risk Downloaded from at Thomas Jefferson University, on August 13, American Medical Association. All rights reserved. Melanoma Prognosis tumor thickness ajcc classification age melanocytosis configuration genetics - most powerful Prognosis of Uveal Melanoma doctor, what is my prognosis? individualize prognosis based on data in office at first visit CLINICAL SCIENCES Metastasis of Uveal Melanoma Millimeter-by-Millimeter in 8033 Consecutive Eyes Carol L. Shields, MD; Minoru Furuta, MD; Archana Thangappan, MD; Saya Nagori, MD; Arman Mashayekhi, MD; David R. Lally, MD; Cecilia C. Kelly, MD; Danielle S. Rudich, MD; Anand 8033 V. Nagori, MD; eyes Oojwala A. Wakade, MD; Sonul Mehta, MD; Lauren Forte, BS; Andrew Long, BS; Elaina F. Dellacava, MD; Bonnie Kaplan, MD; Jerry A. Shields, MD each mm adds 5% risk for mets 2 mm emphasize (x5%) = early 10% detection 4 mm small (x5%) melanoma = 20% 8 mm reduce (x5%) risk = for 40% mets Objective: To determine the rate of metastasis of uveal melanoma on the basis of tumor thickness in millimeters. Methods: Retrospective medical record review. Results: The mean (median) patient age was 58 (59) years. A total of 8033 eyes were examined. Of the 285 eyes 10mm with iris melanoma, (x5%) the mean tumor = thickness 50% was 2.7 mm and metastasis occurred in 0.5%, 4%, and 7% at 3, 5, and 10 years, respectively. Of the 492 eyes with ciliary body melanoma, the mean tumor thickness was 6.6 mm and metastasis occurred in 12%, 19%, and 33% at 3, 5, and 10 years, respectively. Of the 7256 eyes with choroidal melanoma, the mean tumor thickness was 5.5 mm and metastasis occurred in 8%, 15%, and 25% at 3, 5, and 10 years, respectively. For all uveal melanoma, metastasis at 5, 10, and 20 years was 6%, 12%, and 20% for small melanoma (0-3.0 mm thickness), 14%, 26%, and IN 1962, PAUL ET AL 1 FROM THE Armed Forces Institute of Pathology reported the demographic 37% for medium melanoma ( mm), and 35%, 49%, and 67% for large melanoma ( 8.0 mm). More specifically, metastasis per millimeter increment at 10 years was 6% (0-1.0 mm thickness), 12% ( mm), 12% ( mm), 16% ( mm), 27% ( mm), 28% ( mm), 29% ( mm), 41% ( mm), 50% ( mm), 44% ( mm), and 51% ( 10.0 mm). Clinical factors predictive of metastasis by multivariate analysis included increasing patient age, ciliary body location, increasing tumor diameter, increasing tumor thickness, having a brown tumor, and the presence of subretinal fluid, intraocular hemorrhage, or extraocular extension. Conclusion: Increasing millimeter thickness of uveal melanoma is associated with increasing risk for metastasis. Arch Ophthalmol. 2009;127(8): closed melanoma-related mortality at 10 years to be 17% to 18% for medium melanoma and 40% to 45% for large mela- Choroid Melanoma > >50

11 Melanoma Prognosis >50 tumor thickness ajcc classification age melanocytosis configuration genetics - most powerful AJCC defined by base and thickness Melanoma Prognosis tumor thickness ajcc classification age melanocytosis configuration genetics - most powerful Melanoma Prognosis Choroid melanoma in ocular melanocytosis children have slightly better pronosis than adults tumor thickness ajcc classification age melanocytosis configuration genetics - most powerful melanoma arising from ocular melanocytosis has 2x higher risk for metastasis than those without

12 Melanoma Prognosis tumor thickness ajcc classification age melanocytosis configuration genetics - most powerful AJCC defined by base and thickness diffuse melanoma flat 18x18x Diffuse Melanoma special variant of flat melanoma <3 mm thickness thin melanoma is better thin (flat) melanoma could be worse diffuse melanoma carries 2x risk for metastasis compared to non-diffuse if <3 mm: flat (diffuse) melanoma has 2x higher risk for metastasis than non-diffuse Melanoma Prognosis tumor thickness ajcc classification age melanocytosis configuration genetics - most powerful Oncology Service Wills Eye Prognosis of Uveal Melanoma in 500 Cases Using Genetic Testing of Fine-Needle Aspiration Biopsy Specimens Carol L. Shields, MD, 1 Arupa Ganguly, PhD, 2 Carlos G. Bianciotto, MD, 1 Kiran Turaka, MD, 1 Ali Tavallali, MD, 1 Jerry A. Shields, MD 1 questions Purpose: To determine the relationship between monosomy 3 and incidence of metastasis after genetic testing of uveal melanoma using fine-needle aspiration biopsy (FNAB). Design: how Noncomparative do we retrospective do case itseries. Participants: Five hundred patients. Methods: Fine-needle aspiration biopsy was performed intraoperatively immediately before plaque radiotherapy. what The specimenare underwenthe geneticresults analysis using DNA amplification and microsatellite assay. Systemic follow-up was obtained regarding melanoma-related metastasis. Main Outcome Measures: Presence of chromosome 3 monosomy (loss of heterozygosity) and occurrence of melanoma metastasis. Results: Disomy 3 was found in 241 melanomas (48%), partial monosomy 3 was found in 133 melanomas (27%), and complete monosomy 3 was found in 126 melanomas (25%). The cumulative probability for metastasis by 3 years was 2.6% for disomy 3, 5.3% for partial monosomy 3 (equivocal monosomy 3), and 24.0% for complete monosomy 3. At 3 years, for tumors with disomy 3, the cumulative probability of metastasis was 0% for small (0 3 mm thickness), 1.4% for medium (3.1 8 mm thickness), and 23.1% for large ( 8 mm thickness) melanomas. At 3 years, for tumors with partial monosomy 3, the cumulative probability of metastasis was 4.5% for small, 6.9% for medium, and [insufficient numbers] for large melanomas. At 3 years, for tumors with complete monosomy 3, the cumulative probability of metastasis was 0% for small, 24.4% for medium, and 57.5% for large melanomas. The most important factors predictive of partial or complete monosomy 3 included increasing tumor thickness (P 0.001) and increasing distance to optic disc (P 0.002). Conclusions: According to FNAB results, patients with uveal melanoma demonstrating complete monosomy 3 have substantially poorer prognosis at 3 years than those with partial monosomy 3 or disomy 3. Patients with partial monosomy 3 do not significantly differ in outcome from those with disomy 3. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Ophthalmology 2011;118: by the American Academy of Ophthalmology.

13 after FNAB plaque applied microarray analysis monosomy 3 correlated with increasing thickness peripheral location monosomy 3 small mm 25% med mm 30% large mm 50% MLPA analysis Mortality at 10 years disomy 3 0% monosomy 3 55% monosomy 3, 8q gain 71% GEP gene expression profiling 2 classes correlate with survival at 8 years class 1 95% class 2 31% points causes features therapy collaborative ocular melanoma study prognosis The Game of Uveal Melanoma Carol Shields MD Oncology Service Wills Eye Hospital Philadelphia PA USA Oncology Service Wills Eye Institute