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

Clearside Biomedical patent pending

National Cancer Institute research support

I have the following financial disclosures:

Financial Disclosure

• prehistologic• histologic• enucleation• irradiation/chemotherapy• molecular biology• targeted therapy• global health

Seven Eras of Retinoblastoma

1960 20191700s 1800s 1900s

200 years 60 years

James Wardrop 1782-1869

Prehistologic 1500s-1800s

fungus haematodes

Wintersteiner 1897 H&E

Histologic 1800s-present

Wintersteiner

Flexner

rosettes fleurettes

gross microscopic

Brenda Gallie

mother and grandmother of patient with retinoblastoma (courtesy B. Hubbard)

Curtis Margo

courtesy of C. Margo

fleurettes

retinocytoma

Endophytic retinoblastoma

Exophytic retinoblastoma

anterior diffuse retinoblastoma

Trilateral Retinoblastoma

Herman Knapp 1832-1911

Enucleation 1900s-present

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

Irradiation/chemotherapy 1950s-present

Konrad Röntgen Hyla Stallard Gerd Myer-Schwicherath

Carl KupferAlgernon Reese Robert Ellsworth

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

Reese and Ellsworth-bilateral EBRT

Alfred G. Knudson 1922-present

Molecular Biology 1980s-present

1st hit 2nd hitgermline developing retina

developing retina developing retina

heritable rb

non-heritable rb

early agemultiplebilateral

later agesingleunilateral

Ted Dryja

modified from Harbour IOVS 2006

choroid invasion

optic nerveinvasion

choroidinvasion

optic nerve

PO section

Retinoblastoma Optic Nerve and Choroidal Invasion

Molecular Pathology

mild

moderate severe

retinocytoma

retinoblastoma anaplasia vs survival

Severe Anaplasia

150X

Retinoblastoma

Moderate Anaplasia

150X

retinoblastoma anaplasia GEP

Photoreceptor and Nucleoporin Genes are ExpressedDifferentially in Severely Anaplastic Retinoblastoma

Cell free DNA (cfDNA) obtained from Aqueous in RB

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

Retinoblastoma International Classification

Group A Group B Group C

Group D Group E

pre-treatment post 3 cycles VEC

Retinoblastoma-chemoreduction

Targeted Therapy 1990s-present

David Abramson

IAC

Akihiro Kaneko

IAC before IAC after

Courtesy David Abramson MD

Vitreous Seeds Remain a Problem

Courtesy of Jasmine Francis MD

Francis Munier

Intravitreal chemotherapy

Intravitreal Chemotherapy

Carol Shields

A B

DC

E F

G H

intravitreousMelaphalanbefore

intravitreousMelaphalanafter

courtesyCarol Shields MD

rb

*

Rabbit Model of Retinoblastoma with Vitreous Seeds

J Biomed Biotech 2011; PMID 21253494

Intravitreal topotecan liposomes for vitreous seeds of retinoblastoma

Enucleation is a good option for Group D and Group E eyes

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

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

Pre-meeting Visits

Menelik TAPCCO

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

Ethiopia Retinoblastoma Symposium andNational RB Program Planning Meeting May 12-13, 2018

• retinoblastoma-ophthalmology success story

• ophthalmologists, ophthalmic pathologists, research scientists

• cure of fatal disease, preservation of eye and vision

• future challenges-global health

• prehistologic

• histologic

• enucleation

• irradiation/chemotherapy

• molecular biology

• targeted therapy

• global health

First 200 years

Last 60 years

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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