Ocular Melanoma

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Ocular Melanoma

• J. William Harbour, MD
• Washington University St. Louis

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Uveal tract
IRIS
CHOROID
CILIARY BODY
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Uveal melanoma

• Can involve iris, ciliary body and choroid

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Uveal melanocytic tumors
17 of Caucasians
Nevus
99.5
Atypical nevus
.45
0.05
About 80,000 individuals in the U.S. with an
atypical nevus or melanoma
Melanoma
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Demographics

• Mean age 50-60
• Caucasians at highest risk
• Weak link to UV
• Weak link with skin melanoma

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Diagnostic evaluation
Ultrasound
Angiography
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Fine needle biopsy
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Treatment

• Enucleation
• Plaque radiotherapy
• Laser hyperthermia
• Surgical excision
• Proton beam radiotherapy

Radiation plaque
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Pathology

• Callender classification (1931)
• Prognostic significance
• Wilder and Paul (1951)

Spindle
Epithelioid
22 mortality
62 mortality
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Pathology

• Folberg (1993)
• Extracellular matrix patterns

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Prognosis

• 50 risk of metastatic death despite successful
  primary treatment

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Metastasis occurs prior to primary treatment
Ophthalmology 2000 1071443-9
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Gene expression profiling
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Gene expression signature predicts metastatic
death
Plt0.0001
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Gene expression signatures
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Class 2 loss of melanocytic features and gain
of epithelial features
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Class 2 tumors are enriched for epitheliod cells
Class 1
Class 2
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Class 2 tumors exhibit epithelial features
Beta-Catenin
Class 1 melanoma
Class 2 melanoma
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Class 2 tumors exhibit epithelial features
E-cadherin
Class 1 melanoma
Class 2 melanoma
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Class 2 tumors exhibit epithelial features
Extracellular matrix deposition
Class 2 melanoma
Class 1 melanoma
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Extracellular matrix deposition
Mesenchymal
Epithelial
Brugge et al., Nat Cell Biol, Vol. 3, Sept. 2001
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Class 2 tumors express stem cell markers
Nibrin
Class 2 Class 1
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Bifurcation in melanoma progression
100 survival
Class 1
Melanocyte
Class 1 early neoplasm
lt25 survival
Class 2
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Id2 can regulate this bifurcation
100 survival
Class 1
Id2
Melanocyte
Class 1 early neoplasm
lt25 survival
Class 2
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Class 1 Class 2 (Id2
siRNA) (Id2 exp vector)
Class 1 melanoma cells
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(No Transcript)
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Dye-excluding side population
Mel202 primary uveal melanoma cells
(-) reserpine ()
reserpine
Hoechst 33258 dye
Control
c-Kit
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Class 2 cells grow in spheres
Class 1
Class 2
Class 2 E-cadherin blocking antibody
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Stem cell phenotype may allow cells to survive
away from the primary tumor
Class 1 melanomas do not survive in the
bloodstream
Class 2 melanomas form epithelial-like clusters
that may survive during embolization in the
bloodstream
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Molecular testing can be performed on biopsy
samples
Class 1
Class 2
Onken, J Molec Diagn 2007
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Individualized patient management
Class 1
Class 2
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Individualized patient care
Low Intensity Screening
Class 1
Molecular testing
High Intensity Screening
Class 2
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Individualized patient care
Observation
Class 1
Molecular testing
Systemic treatment
Class 2
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Individualized patient care
Exclusion
Class 1
Molecular testing
Inclusion
Class 2
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Acknowledgements

• Mike Onken, PhD
• Lori Worley, BS
• Olga Agapova, PhD
• Rachel Delston, BS
• Katie Golder, BS
• Justis Ehlers, MD
• Holly Chang, MD
• Matt Council, MD
• Kam Ramaiya, MD
• Young Sun, MD, PhD
• Erica Person, MD
• Amy Loercher, PhD

• NCI
• NEI
• BJH Foundation
• Research to Prevent Blindness
• Knights Templar
• Macula Society
• Tumori Foundation