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Historical Review of Retinoblastoma
Hans E. Grossniklaus MDDirector, Ocular Oncology and Pathology ServiceDirector, L.F. Montgomery LaboratoryEmory University School of MedicineAtlanta, Georgia USA
European Society of Pathology 31st CongressNice, France
September 10, 2019
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Clearside Biomedical patent pending
National Cancer Institute research support
I have the following financial disclosures:
Financial Disclosure
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• prehistologic• histologic• enucleation• irradiation/chemotherapy• molecular biology• targeted therapy• global health
Seven Eras of Retinoblastoma
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1960 20191700s 1800s 1900s
200 years 60 years
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James Wardrop 1782-1869
Prehistologic 1500s-1800s
fungus haematodes
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Wintersteiner 1897 H&E
Histologic 1800s-present
Wintersteiner
Flexner
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rosettes fleurettes
gross microscopic
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Brenda Gallie
mother and grandmother of patient with retinoblastoma (courtesy B. Hubbard)
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Curtis Margo
courtesy of C. Margo
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fleurettes
retinocytoma
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Endophytic retinoblastoma
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Exophytic retinoblastoma
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anterior diffuse retinoblastoma
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Trilateral Retinoblastoma
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Herman Knapp 1832-1911
Enucleation 1900s-present
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1885 pre and post enucleation
• leeches
• poultices
• purgatives
• bland diet
• venesection
• antimony
• iodide
• vesicants
• chloroform as general anesthetic• ophthalmoscope for earlier diagnosis
prior to mid 1800s
after mid 1800s
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Irradiation/chemotherapy 1950s-present
Konrad Röntgen Hyla Stallard Gerd Myer-Schwicherath
Carl KupferAlgernon Reese Robert Ellsworth
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Reese-Ellsworth Classification of Retinoblastoma
Group A B
I (very favorable) solitary 4DD at/behind equatormultiple 4DD at/behind
equator
II (favorable)solitary 4-10 DD at/behind
equatormultiple 4-10DD at/behind
equator
III (doubtful) any lesion anterior to equatorsolitary tumor 10DD behind
equator
IV (unfavorable)multiple, some larger than
10DDany lesion anterior to ora
serrata
V (very unfavorable)
massive tumor half or more of retina
vitreous seeding
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Reese and Ellsworth-bilateral EBRT
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Alfred G. Knudson 1922-present
Molecular Biology 1980s-present
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1st hit 2nd hitgermline developing retina
developing retina developing retina
heritable rb
non-heritable rb
early agemultiplebilateral
later agesingleunilateral
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modified from Harbour IOVS 2006
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choroid invasion
optic nerveinvasion
choroidinvasion
optic nerve
PO section
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Retinoblastoma Optic Nerve and Choroidal Invasion
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Molecular Pathology
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mild
moderate severe
retinocytoma
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retinoblastoma anaplasia vs survival
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Severe Anaplasia
150X
Retinoblastoma
Moderate Anaplasia
150X
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retinoblastoma anaplasia GEP
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Photoreceptor and Nucleoporin Genes are ExpressedDifferentially in Severely Anaplastic Retinoblastoma
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Cell free DNA (cfDNA) obtained from Aqueous in RB
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International Classification of Retinoblastoma
Group General Specific Features
A Small tumor retinoblastoma ≤ 3mm in size
B Larger tumor retinoblastoma ˃ 3mm in size or
C Focal seeds seeds ≤3mm from retinoblastoma
D Diffuse seeds seeds ˃3mm from retinoblastoma
E Extensive retinoblastoma retinoblastoma occupying ˃50% globe
Murphree, Desjardins, Shields, Shields and others
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Retinoblastoma International Classification
Group A Group B Group C
Group D Group E
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pre-treatment post 3 cycles VEC
Retinoblastoma-chemoreduction
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Targeted Therapy 1990s-present
David Abramson
IAC
Akihiro Kaneko
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IAC before IAC after
Courtesy David Abramson MD
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Vitreous Seeds Remain a Problem
Courtesy of Jasmine Francis MD
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Francis Munier
Intravitreal chemotherapy
Intravitreal Chemotherapy
Carol Shields
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A B
DC
E F
G H
intravitreousMelaphalanbefore
intravitreousMelaphalanafter
courtesyCarol Shields MD
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rb
*
Rabbit Model of Retinoblastoma with Vitreous Seeds
J Biomed Biotech 2011; PMID 21253494
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Intravitreal topotecan liposomes for vitreous seeds of retinoblastoma
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Enucleation is a good option for Group D and Group E eyes
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Population (millions)
Esti
mat
ed A
nn
ual
Inci
den
ce o
f R
etin
ob
last
om
aGlobal Health 2000s-present
Courtesy of Tero Kivelä MD
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96,50%93%
79% 77%
40%
0,00%
20,00%
40,00%
60,00%
80,00%
100,00%
120,00%
5 Year Survival
USA Europe upper incomedeveloping
middle incomedeveloping
lower incomedeveloping
modified from Chanturk et al Br J Ophthalmol 2010
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Pre-meeting Visits
Menelik TAPCCO
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Stage at presentationICRB
Group
Classificati
on
Number,
n
Percent
Group A 0 0.0%
Group B 6 6.3%
Group C 0 0.0%
Group D 28 29.2%
Group E 62 64.6%
29 patients (30.2%) presented with fungating mass
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Ethiopia Retinoblastoma Symposium andNational RB Program Planning Meeting May 12-13, 2018
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• retinoblastoma-ophthalmology success story
• ophthalmologists, ophthalmic pathologists, research scientists
• cure of fatal disease, preservation of eye and vision
• future challenges-global health
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• prehistologic
• histologic
• enucleation
• irradiation/chemotherapy
• molecular biology
• targeted therapy
• global health
First 200 years
Last 60 years
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Grossniklaus labMax Griffin BSLauren Hudson MD, PhDShin Kang MD, PhDPia Mendoza MDThonnie Rose See MDGustav Stålhammar MD, PhDHua Yang MD, PhD
Emory CollaboratorsEldon Geisert PhDJohn Nickerson PhDSalma Ferdous BSJennifer Rha PhD
Bascom Palmer
Collaborator
J. William Harbour MD
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