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Ocular Oncology
and Pathology 2016
Breezing Along in
Ocular Oncology and
Pathology in the Windy City
Program Directors
Patricia Chevez-Barrios MD and Carol L Shields MD
In conjunction with the American Association
of Ophthalmic Oncologists and Pathologists
McCormick Place
Chicago, Illinois
Saturday, Oct. 15, 2016
Presented by:
The American Academy of Ophthalmology
2016 Ocular Oncology and Pathology
Planning Group
Patricia Chevez-Barrios MD
Program Director
Carol L Shields MD
Program Director
2014 Program Directors
Hans E Grossniklaus MD
Arun D Singh MD
Subspecialty Day Advisory Committee
Daniel S Durrie MD
Associate Secretary
Julia A Haller MD
Francis S Mah MD
R Michael Siatkowski MD
Kuldev Singh MD MPH
Nicolas J Volpe MD
Jonathan B Rubenstein MD
Secretary for Annual Meeting
Staff
Ann L’Estrange, Scientific Meetings
Specialist
Melanie R Rafaty CMP DES, Director,
Scientific Meetings
Lisa Romero, Presenter Coordinator
Debra Rosencrance CMP CAE, Vice
President, Meetings & Exhibits
Patricia Heinicke Jr, Copy Editor
Mark Ong, Designer
Gina Comaduran, Cover Design
©2016 American Academy of Ophthalmology. All rights reserved. No portion may be reproduced without express written consent of the American Academy of Ophthalmology.
ii
Planning Group
2016 Subspecialty Day | Ocular Oncology & Pathology
2016 Ocular Oncology and Pathology Planning Group
On behalf of the American Academy of Ophthalmology and the American Association of Ophthalmic Oncologists
and Pathologists, it is our pleasure to welcome you to Chicago and Ocular Oncology and Pathology 2016:
Breezing Along in Ocular Oncology and Pathology in the Windy City.
Patricia Chevez-Barrios MD
Carol L Shields MD
None
Aura BioScience: C
Program Director
2016 Subspecialty Day
Advisory Committee
Daniel S Durrie MD, Chair
(Refractive Surgery)
Abbott Medical Optics: L,S
AcuFocus Inc.: C,L,O,S
Alcon Laboratories Inc.: S
Allergan: S | Alphaeon: C,L,O
Avedro: L,O,S
Hoopes Durrie Rivera Research
Center: C
Strathspey Crown LLC: C,L,O
Wavetec: O
Julia A Haller MD (Retina)
Celgene: O | Janssen: C
KalVista: C | Merck & Co. Inc.: C
ThromboGenics Inc.: S
Francis S Mah MD (Cornea)
Abbott Medical Optics Inc.: S,L,C
Aerie: C
Alcon Laboratories Inc.: L,S,C
Allergan: S,L,C
Bausch+Lomb: C,L
CoDa: C | ForeSight: C
NovaBay: C | Ocular Science: O,C
Ocular Therapeutix: C,S
PolyActiva: C | Shire: C
Slack Publishing: C | Sun Pharma: C
Sydnexis: C | TearLab: C
Program Director
R Michael Siatkowski MD
(Pediatric Ophthalmology)
National Eye Institute: S
Kuldev Singh MD MPH
(Glaucoma)
Abbott Medical Optics Inc.: C
Aerie: C
Alcon Laboratories Inc.: C
Allergan: C
Carl Zeiss Meditec: C
ForSight Vision 5: C
InnFocus: C | Ivantis: C
Mynosys: C
National Eye Institute: S
National Space Biomedical Research
Institute: C
Santen Inc.: C | Shire: C
Thieme Medical Publishers: C
Transcend: C
U.S. Food and Drug
Administration: C
Nicholas J Volpe MD
(Neuro-Ophthalmology)
Opticent Inc.: O
AAO Staff
Ann L’Estrange
None
Melanie Rafaty
None
Lisa Romero
None
Debra Rosencrance
None
Beth Wilson
None
2016 Subspecialty Day | Ocular Oncology & Pathology
Contents
Ocular Oncology and Pathology 2016 Contents
Program Planning Group ii
CME iv
Faculty Listing vi
Program Schedule xii
Section I:
Sunrise Over Lake Michigan—Top 5 Advancements Over the Past Decade 1
Section II:
Blustery Debates in the Management of Intraocular Tumors 13
Advocating for Patients 32
Section III: Forecasting the Future 34
Section IV: Frosty Opinions in Ocular Oncology 52
Section V: Weathering the Storm 67
Faculty Financial Disclosure 73
Presenter Index 76
iii
iv
CME Credit
2016 Subspecialty Day | Ocular Oncology & Pathology
CME Credit
Academy’s CME Mission Statement
The purpose of the American Academy of Ophthalmology’s
Continuing Medical Education (CME) program is to present
ophthalmologists with the highest quality lifelong learning
opportunities that promote improvement and change in physician practices, performance, or competence, thus enabling such
physicians to maintain or improve the competence and professional performance needed to provide the best possible eye care
for their patients.
2016 Ocular Oncology and Pathology Subspecialty
Day Meeting Learning Objectives
Upon completion of this activity, participants should be able to:
■
■
■
■
Identify clinical and pathologic features of certain tumors
such as ocular melanoma, retinoblastoma, conjunctival
tumors, and orbital tumors
Identify and manage treatment complications such as
radiation retinopathy
Recognize advances in biologic markers for ocular
pathology
Determine when a patient should be referred to an ocular
oncology center
2016 Ocular Oncology and Pathology Subspecialty
Day Meeting Target Audience
The intended target audience for this program is practicing ophthalmologists, residents in training, and fellows.
2016 Ocular Oncology and Pathology Subspecialty
Day CME Credit
The American Academy of Ophthalmology is accredited by
the Accreditation Council for Continuing Medical Education
(ACCME) to provide continuing medical education for physicians.
The American Academy of Ophthalmology designates this
live activity for a maximum of 7 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate
with the extent of their participation in the activity.
Self-Assessment Credit
This activity meets the Self-Assessment CME requirements
defined by the American Board of Ophthalmology (ABO).
Please be advised that the ABO is not an accrediting body for
purposes of any CME program. The ABO does not sponsor this
or any outside activity, and the ABO does not endorse any particular CME activity. Complete information regarding the ABO
Self-Assessment CME Maintenance of Certification requirements is available at http://abop.org/maintain-certification/
part-2-lifelong-learning-self-assessment/sacme/.
NOTE: Credit designated as “self-assessment” is AMA PRA
Category 1 Credit™ and is also preapproved by the ABO for
the Maintenance of Certification (MOC) Part II CME requirements.
Teaching at a Live Activity
Teaching instruction courses or delivering a scientific paper or
poster is not an AMA PRA Category 1 Credit™ activity and
should not be included when calculating your total AMA PRA
Category 1 Credits™. Presenters may claim AMA PRA Category 1 Credits™ through the American Medical Association.
To obtain an application form please contact the AMA at
www.ama-assn.org.
Scientific Integrity and Disclosure of Financial
Interest
The American Academy of Ophthalmology is committed to
ensuring that all CME information is based on the application
of research findings and the implementation of evidence-based
medicine. It seeks to promote balance, objectivity, and absence
of commercial bias in its content. All persons in a position to
control the content of this activity must disclose any and all
financial interests. The Academy has mechanisms in place to
resolve all conflicts of interest prior to an educational activity
being delivered to the learners.
The Academy requires all presenters to disclose on their first
slide whether they have any financial interests from the past 12
months. Presenters are required to verbally disclose any financial interests that specifically pertain to their presentation.
Control of Content
The Academy considers presenting authors, not co-authors, to
be in control of the educational content. It is Academy policy
and traditional scientific publishing and professional courtesy
to acknowledge all people contributing to the research, regardless of CME control of the live presentation of that content. This
acknowledgement is made in a similar way in other Academy
CME activities. Though they are acknowledged, co-authors do
not have control of the CME content and their disclosures are
not published or resolved.
Attendance Verification for CME Reporting
Before processing your requests for CME credit, the Academy
must verify your attendance at Subspecialty Day and/or AAO
2016. In order to be verified for CME or auditing purposes, you
must either:
■
Register in advance, receive materials in the mail, and
turn in the Subspecialty Day Syllabi exchange voucher(s)
onsite;
CME Credit
2016 Subspecialty Day | Ocular Oncology & Pathology
■
■
■
Register in advance and pick up your badge onsite if
materials did not arrive before you traveled to the meeting;
Register onsite; or
Scan the barcode on your badge as you enter an AAO
2016 course or session room.
v
The Academy transcript cannot list individual course attendance. It will list only the overall credits spent in educational
activities at Subspecialty Day and/or AAO 2016.
Nonmembers: The Academy will provide nonmembers with
verification of credits earned and reported for a single Academy-sponsored CME activity.
CME Credit Reporting
Proof of Attendance
Academy Resource Center, Booth 508, and South Level 2.5
Attendees whose attendance has been verified (see above) at
AAO 2016 can claim their CME credit online during the meeting. Registrants will receive an email during the meeting with
the link and instructions on how to claim credit.
Onsite, you may report credits earned during Subspecialty
Day and/or AAO 2016 at the CME Credit Reporting booth.
Academy Members: The CME credit reporting receipt is not
a CME transcript. CME transcripts that include AAO 2016
credits entered onsite will be available to Academy members on
the Academy’s website beginning Nov. 10, 2016.
After AAO 2016, credits can be claimed at www.aao.org/
cme.
The following types of attendance verification will be available
during AAO 2016 and Subspecialty Day for those who need it
for reimbursement or hospital privileges, or for nonmembers
who need it to report CME credit:
■
■
■
CME credit reporting/proof-of-attendance letters
Onsite registration receipt
Instruction course and session verification
Visit www.aao.org/cme for detailed CME reporting information.
vi
Faculty Listing
2016 Subspecialty Day | Ocular Oncology & Pathology
Faculty
No photo
available
David H Abramson MD FACS
Mary E Aronow MD
Patricia Chevez-Barrios MD
New York, NY
Chief, Ophthalmic Oncology Service
Memorial Sloan Kettering Cancer
Center
Professor of Ophthalmology
Weill Cornell University
Ellicott City, MD
Assistant Professor
Wilmer Eye Institute
Johns Hopkins School of Medicine
Houston, TX
Professor of Pathology & Laboratory
Medicine and Ophthalmology
Weill Cornell Medical College
Director, Ophthalmic Pathology
Houston Methodist Hospital
No photo
available
No photo
available
Kenneth V Cahill MD FACS
Daniel M Albert MD FACS
Madison, WI
Founding Director
University of Wisconsin McPherson Eye
Research Institute
F A Davis Professor
Department of Ophthalmology &
Visual Sciences
University of Wisconsin School of
Medicine & Public Health
Columbus, OH
Clinical Professor of Ophthalmology
The Ohio State University
Clinical Professor of Ophthalmology
Nationwide Children’s Hospital
Murali Chintagumpala MD
Houston, TX
Professor of Pediatrics
Baylor College of Medicine
Director, Solid Tumor Program
Texas Children’s Cancer Center
Colleen M Cebulla MD PhD
Columbus, OH
Associate Professor
Havener Eye Institute
The Ohio State University
Richard C Allen MD PhD
Houston, TX
Professor, MD Anderson Cancer Center
Victoria M Cohen FRCOphth
Cambridgeshire, United Kingdom
Director of Ocular Oncology Service
Moorfields Eye Hospital
Consultant Ocular Oncologist
Moorfields Eye Hospital / NHS
Foundation Trust and Barts Health
Faculty Listing
2016 Subspecialty Day | Ocular Oncology & Pathology
Zelia M Correa MD
Ralph Eagle MD
Paul T Finger MD
Cincinnati, OH
Professor of Ophthalmology
Director of the Ocular Oncology Service
Department of Ophthalmology
University of Cincinnati College of
Medicine
Philadelphia, PA
Director, Department of Pathology
The Noel T and Sara L Simmonds
Professor of Ophthalmic Pathology
Wills Eye Hospital
New York, NY
Director, The New York Eye Cancer
Center
Clinical Professor of Ophthalmology
New York University School of
Medicine
No photo
available
Hakan Demirci MD
Ann Arbor, MI
Associate Professor and Director
Ocular Oncology
W K Kellogg Eye Center
University of Michigan
Victor M Elner PhD MD
Ann Arbor, MI
Ravitz Foundation Professor of
Ophthalmology
Professor of Pathology
University of Michigan
Jasmine H Francis MD
New York, NY
No photo
available
James A Garrity MD
Sander Dubovy MD
Miami, FL
Professor of Ophthalmology and
Pathology
Bascom Palmer Eye Institute
University of Miami
Bita Esmaeli MD FACS
Houston, TX
Professor of Ophthalmology
Director, Ophthalmic Plastic &
Reconstructive Surgery Fellowship
Program
MD Anderson Cancer Center
Rochester, MN
Professor of Ophthalmology
Mayo Clinic
vii
viii
Faculty Listing
2016 Subspecialty Day | Ocular Oncology & Pathology
Dan S Gombos MD
J William Harbour MD
Carol L Karp MD
Houston, TX
Professor & Chief, Section of
Ophthalmology
MD Anderson Cancer Center
Clinical Codirector
Retinoblastoma Center of Houston
MD Anderson / Texas Children’s
Hospital / Baylor / Methodist
Miami, FL
Professor, Vice Chairman, and Dr.
Mark J Daily Endowed Chair
Bascom Palmer Eye Institute
Associate Director for Basic Research
Sylvester Comprehensive Cancer Center
Miami, FL
Professor of Ophthalmology
Bascom Palmer Eye Institute
University of Miami Miller School of
Medicine
No photo
available
Santosh G Honavar MD
Evangelos S Gragoudas MD
Boston, MA
Professor of Ophthalmology
Harvard Medical School
Director of Retina Service
Massachusetts Eye and Ear Infirmary
Hans E Grossniklaus MD
Atlanta, GA
Vice Chairman
Professor of Ophthalmology and
Pathology
Department of Ophthalmology
Emory University School of Medicine
Ivana K Kim MD
Hyderabad, India
Director, Ophthalmic Plastic Surgery
and Ocular Oncology
Centre for Sight
Boston, MA
Associate Professor of Ophthalmology
Harvard Medical School
Retina Service
Massachusetts Eye and Ear
G Baker Hubbard MD
Jonathan W Kim MD
Atlanta, GA
Professor of Ophthalmology
Emory University School of Medicine
Glendale, CA
Associate Professor of Ophthalmology
USC Roski Eye Institute
Director of Ocular Oncology
Children’s Hospital Los Angeles
Faculty Listing
2016 Subspecialty Day | Ocular Oncology & Pathology
Tero T Kivela MD
Brian P Marr MD
Tatyana Milman MD
Espoo, Finland
Professor and Chair
Department of Ophthalmology
University of Helsinki
New York, NY
Associate Attending
Memorial Sloan Kettering Cancer
Center
Princeton Junction, NJ
Pathology Resident
University of Pennsylvania
ix
No photo
available
Sara E Lally MD
Miguel A Materin MD
Wallingford, PA
Staff, Wills Eye Hospital
Associate Professor
Thomas Jefferson University
New Haven, CT
Director, Ophthalmic Oncology
Smilow Cancer Hospital
Yale New Haven Health
Prithvi Mruthyunjaya MD
Durham, NC
Timothy G Murray MD MBA
Nora V Laver MD
Tara A McCannel MD
Boston, MA
Director, Ocular Pathology Laboratory
Tufts Medical Center and New England
Medical Center
Ocular Pathology Consultant
Boston University Medical Center
Los Angeles, CA
Associate Professor of Ophthalmology
University of California, Los Angeles
Director of Ophthalmic Oncology
Stein Eye and Doheny Eye Institutes
South Miami, FL
Founding Director
Ocular Oncology and Retina (MOOR)
Professor Emeritus of Ophthalmology
and Radiation Oncology
Bascom Palmer Eye Institute
x
Faculty Listing
No photo
available
Mary A O’Hara MD
Sacramento, CA
Professor, Departments of
Ophthalmology and Strabismus
University of California, Davis
Associate Professor
Department of Surgery
Uniformed Services University of the
Health Sciences
2016 Subspecialty Day | Ocular Oncology & Pathology
No photo
available
Fairooz Puthiyapurayil
Manjandavida MD
Bangalore, India
Consultant, Oculoplasty, Orbit and
Ocular Oncology
Narayana Nethralaya Superspecialty
Eye Hospitals
Diva R Salomao MD
Rochester, MN
Surgical Pathologist
Ophthalmic Pathologist
Mayo Clinic
No photo
available
Emil Anthony T Say MD
Ann Arbor, MI
Philadelphia, PA
Clinical Instructor
Wills Eye Hospital
Mandeep S Sagoo MBBChir PhD
Amy C Schefler MD
London, United Kingdom
Consultant Ophthalmic Surgeon
Moorfields Eye Hospital
Senior Lecturer
Institute of Ophthalmology
University College London
Houston, TX
Clinical Assistant Professor
Weill Cornell Medicine
Associate Partner
Retinal Consultants of Houston
Rajesh C Rao MD
Heather A D Potter MD
Madison, WI
No photo
available
Jose S Pulido MD MS
Rochester, MN
Professor of Ophthalmology and
Molecular Medicine
The Mayo Clinic
Faculty Listing
2016 Subspecialty Day | Ocular Oncology & Pathology
Stefan Seregard MD
Arun D Singh MD
David J Wilson MD
Stockholm, Sweden
Professor, St Eriks Eye Hospital
Karolinska Institutet
Cleveland, OH
Director, Ophthalmic Oncology
Cole Eye Institute
Professor of Ophthalmology
Cleveland Clinic
Portland, OR
Director, Chair, and Professor
Casey Eye Institute
Oregon Health & Science University
No photo
available
Carol L Shields MD
Philadelphia, PA
Codirector, Ocular Oncology Service
Wills Eye Hospital
Professor of Ophthalmology
Thomas Jefferson University Hospital
Alison H Skalet MD PhD
Portland, OR
Assistant Professor
Casey Eye Institute
Oregon Health & Science University
No photo
available
Jerry A Shields MD
Philadelphia, PA
Director, Oncology Service
Wills Eye Hospital
Professor of Ophthalmology
Thomas Jefferson University
Jill R Wells MD
Atlanta, GA
Assistant Professor of Ophthalmology
Emory University
Matthew W Wilson MD
Memphis, TN
Professor of Ophthalmology
Hamilton Eye Institute / University of
Tennessee Health Science Center
Department of Surgery, Chief of
Ophthalmology
St Jude Children’s Research Hospital
xi
xii
Program Schedule
2016 Subspecialty Day | Ocular Oncology & Pathology
Ocular Oncology and Pathology 2016:
Breezing Along in Ocular Oncology and Pathology
in the Windy City
In conjunction With the American Association of
Ophthalmic Oncologists and Pathologists
Saturday, Oct. 15
7:00 AM
CONTINENTAL BREAKFAST
8:00 AM
Welcome, Introductions, and Audience Interaction
Patricia Chevez-Barrios MD
Section I: Sunrise Over Lake Michigan—Top 5 Advancements Over the Past Decade
Moderators: Carol L Shields MD*, Amy C Schefler MD*
8:05 AM
Top 5 Advancements Over the Past Decade With Retinoblastoma
Jonathan W Kim MD*
1
8:12 AM
Top 5 Advancements Over the Past Decade With Choroidal Melanoma
Mary E Aronow MD
3
8:19 AM
Top 5 Advancements Over the Past Decade With Choroidal Hemangioma
Amy C Schefler MD*
4
8:26 AM
Top 5 Advancements With Other Intraocular Tumors: What Should I Know?
Carol L Shields MD*
5
8:33 AM
Top 5 Current Approaches in Ophthalmic Pathology
Patricia Chevez-Barrios MD 7
8:40 AM
Can OCT Help in Diagnosis and Management?
David J Wilson MD
8
8:47 AM
Is Intravenous Fluorescein Angiography or OCT Angiography Better for Imaging Tumors?
Emil Anthony T Say MD
9
8:54 AM
How Well Does OCT Correlate With Histopathology?
Sander Dubovy MD
11
9:01 AM
Next Generation Sequencing of Vitreoretinal Lymphomas:
New Routes to Targeted Therapies through Precision Medicine
Rajesh C Rao MD
12
9:08 AM
REFRESHMENT BREAK and AAO 2016 EXHIBITS
Section II: Blustery Debates in the Management of Intraocular Tumors
Moderators: Tara A McCannel MD*, Jose S Pulido MD MS
9:50 AM
Introduction and Audience Interaction
Patricia Chevez-Barrios MD
9:55 AM
Fine Needle Aspiration Biopsy for Genetic Information: Pro
Tara A McCannel MD*
13
10:00 AM
Fine Needle Aspiration Biopsy for Genetic Information: Con
Jose S Pulido MD MS
14
10:05 AM
Fine Needle Aspiration Biopsy for Genetic Information: Emotional Distress
Arun D Singh MD
15
10:10 AM
Cancer of Unknown Primary: From Immunohistochemistry to Gene Expression Profiling
Nora V Laver MD
16
10:17 AM
Bevacizumab for Prevention of Radiation Retinopathy: The Evidence
Timothy G Murray MD MBA* 19
10:22 AM
Bevacizumab for Prevention of Radiation Retinopathy: Hogwash
Brian P Marr MD*
20
10:27 AM
Sector Panretinal Photocoagulation for Prevention of Radiation Retinopathy: The Evidence
Miguel A Materin MD*
21
10:32 AM
How We Manage Radiation Retinopathy in the UK
Victoria M Cohen FRCOphth 22
10:37 AM
Retinoblastoma: Intra-arterial Chemotherapy All the Way
Jasmine H Francis MD
* Indicates that the presenter has financial interest.
No asterisk indicates that the presenter has no financial interest.
23
2016 Subspecialty Day | Ocular Oncology & Pathology
Program Schedule
xiii
10:42 AM
Retinoblastoma: Intra-arterial Chemotherapy in Selected Cases
Mandeep S Sagoo MBBChir PhD
24
10:47 AM
Retinoblastoma: Intra-arterial Chemotherapy—Never
Matthew W Wilson MD
26
10:52 AM
Retinoblastoma: Children’s Oncology Group Update on Intra-arterial Chemotherapy
Murali Chintagumpala MD
28
10:57 AM
Retinoblastoma: Documented Toxicities of Intra-arterial Chemotherapy
Dan S Gombos MD*
29
11:02 AM
Pathology: Evisceration and Enucleation Disasters
Ralph Eagle MD*
31
11:09 AM
Advocating for Patients
Zelia M Correa MD*
32
11:14 AM LUNCH and AAO 2016 EXHIBITS
Section III: Forecasting the Future
Moderators: Prithvi Mruthyunjaya MD*, Diva R Salomao MD*
12:40 PM
Introduction and Audience Interaction
Carol L Shields MD
12:45 PM
Sildenafil Citrate (Viagra) for Lymphatic Malformations
Mary A O’Hara MD
34
12:52 PM
Sclerosing Therapy for Lymphatic Malformations
Kenneth V Cahill MD FACS
35
12:59 PM
Coats Disease: What Works
G Baker Hubbard MD
36
1:06 PM
mTOR Inhibitors for Retinal Astrocytic Hamartomas
Prithvi Mruthyunjaya MD*
38
1:13 PM
Vismodegib for Basal Cell Carcinoma: Current Status and Future Promise
Bita Esmaeli MD FACS*
39
1:20 PM
Update on Orbital Xanthogranuloma Diseases: Role of BRAF Inhibition
Hakan Demirci MD
40
1:27 PM
What Pathology Biomarkers Should We Use for Conjunctival Tumors?
Victor M Elner PhD MD*
42
1:34 PM
What Pathology Biomarkers Should We Use for Skin and Orbital Tumors?
Tatyana Milman MD
43
1:41 PM
VEGF Receptors on Orbital Vascular Tumors
Diva R Salomão MD
44
1:48 PM
Is IgG4 Orbitopathy for Real?
James A Garrity MD
45
1:55 PM
Orbital Fine Needle Aspiration Biopsy: What Works
Richard C Allen MD PhD
47
2:02 PM
How Can We Improve Ocular Oncology Care in Developing Nations?
Fairooz Puthiyapurayil Manjandavida MD
49
2:09 PM
Day by Day Ocular Oncology in India
Santosh G Honavar MD
50
2:16 PM
The First Eye Cancer Working Day in Paris: Outcomes
Paul T Finger MD*
51
2:23 PM
REFRESHMENT BREAK and AAO 2016 EXHIBITS
Section IV: Frosty Opinions in Ocular Oncology
Moderators: G Baker Hubbard MD, Ivana K Kim MD*
3:07 PM
Introduction and Audience Interaction
Carol L Shields MD
3:12 PM
Conjunctival Melanoma: How to Beat This Disease
Jill R Wells MD
3:19 PM
Conjunctival Squamous Cell Carcinoma: Which Topical Therapy and Why Carol L Karp MD
54
3:26 PM
Conjunctival Lymphoma: What Works
Sara E Lally MD
56
3:33 PM
Vitreoretinal Lymphoma: How Can We Improve Outcomes?
Tero T Kivela MD
57
3:40 PM
BAP-1 Cancer Predisposition Syndrome
Colleen M Cebulla MD PhD
58
3:47 PM
Future Applications of Uveal Melanoma Genetic Testing
J William Harbour MD*
60
3:54 PM
Systemic Melanoma Therapies That Work
Ivana K Kim MD*
61
4:01 PM
Do I Use the American Joint Commission on Cancer Classification?
Alison H Skalet MD PhD
62
* Indicates that the presenter has financial interest.
No asterisk indicates that the presenter has no financial interest.
52
xiv
Program Schedule
2016 Subspecialty Day | Ocular Oncology & Pathology
4:08 PM
Why You Should Use the American Joint Commission on Cancer Classification
Stefan Seregard MD
63
4:15 PM
Online Forum and Social Media: Communication Between Oncologist and Pathologist
Heather A D Potter MD
64
4:22 PM
Telemedicine in Ocular Oncology and Pathology: What Works
Hans E Grossniklaus MD*
65
67
Section V: Weathering the Storm
Moderators: G Baker Hubbard MD, Ivana K Kim MD*
4:29 PM
Comparative Eye Pathology: The Third Dimension in Eye Pathology
Daniel M Albert MD FACS
4:36 PM
Ocular Oncology: What I Like and Don’t Like
David H Abramson MD FACS 68
4:43 PM
Forty Years in Practice: I Will Tell You 5 Secrets
Evangelos S Gragoudas MD*
69
4:50 PM
Running an Ocular Oncology Practice: My Top 5 Lessons Learned
Jerry A Shields MD
71
4:57 PM
Closing Remarks
Carol L Shields MD*
* Indicates that the presenter has financial interest.
No asterisk indicates that the presenter has no financial interest.
2016 Subspecialty Day | Ocular Oncology & Pathology
Section I: Top 5 Advancements Over the Past Decade
1
Top 5 Advancements Over the Past Decade With
Retinoblastoma
Jonathan W Kim MD
Top 5 Advancements 2006-2016
E. Cryotherapy is applied as the needle is withdrawn.
F. The eye is then shaken to distribute the chemotherapy.
1.
2.
3.
4.
5.
Intra-arterial chemotherapy
Intravitreal chemotherapy
Gene testing for retinoblastoma
Optical coherence tomography
Treatment for extraocular retinoblastoma
I. Intra-arterial Chemotherapy (IAC), 2006-2007:
Abramson, et al. Ophthalmology 2008.
A.Protocol
A. 10 published studies on IVC for RB
B. 295 patients, 1287 injections, mean follow-up: 74
months
C. 38 patients with ocular side effects
1. Microcatheter at ophthalmic artery (500 μm)
1. 17 major (2 with retinal detachment)
2. Melphalan 3-7.5 mg diluted in 30 cc, infused
over 30 minutes
2. 21 minor (IOP, cataract)
B. Clinical results
1. First 9 patients treated (mean follow-up 9
months)
2. 7 of 9 eyes with advanced retinoblastoma (RB)
salvaged
3. 2 eyes enucleated (no active tumor seen)
IV. Review of IVC Complications: Smith SJ, Br J
Ophthalmol. 2014.
D. 1 patient with extraocular spread in Japan
E. 395 injections in 71 patients outside Japan with no
extraocular spread
V. Overview of Clinical Results in Published Series of
IVC
C. Systemic toxicity: No vascular complications
II. Clinical Experience at Memorial Sloan-Kettering
Cancer Center (MSKCC)
A. 4-year experience at MSKCC (2011)
1. 95 eyes in 78 patients, 289 infusions
2. Median: 3 infusions per patient (1-7), 2-7.5 mg
(mean: 4 mg)
3. Catheterization successful in 98.5%
1. Treatment naïve: 85%
2. < 6 months of age: 85%
3. Secondary treatment: 72%
C. No catheterization complications
D. Grade 3 neutropenia: 29% (> 0.5 mg/kg)
E. No deaths
B. Paracentesis (0.1 cc of aqueous humor)
C. An injection is done with a 32-gauge needle in a
quadrant of the eye free of tumor.
D. The needle is visualized behind the lens.
2. Weekly injections, total of 3-7 per eye (average:
4.5)
3. 87% globe salvage
4. Median follow-up: 13.5 months
B. Abramson, 2014
1. 107 eyes: 30 μg, median 6.5 injections per eye
2. Decreased ERG responses at 30 μg (5.8 uV per
injection)
C. Shields, 2015
1. 12 eyes, 8-50 μg, 83% salvage rate
VI. Next-Generation Sequencing (NGS) for RB
A. Mark the injection site 3.25-3.5 mm posterior the
limbus.
1. 23 eyes, 122 injections, 20-30 μg
III. Intravitreal Melphalan: Munier Technique
B. Results in Group D eyes (MSKCC 2015):
A. Munier, 2012
Ion semiconductor sequencing
A. Sequences the entire RB1 gene including promoter,
exons, and introns with an average coverage above
500x, MYCN copy number
B. Mutations confirmed by Sanger sequencing
C. Mosaicism detected to 5% level
D. Cannot detect RB1 promoter hypermethylation
VII. MCYN and Retinoblastoma
A. 2.7% of unilateral RB tumors demonstrate no
RB1 mutations. 50% of these tumors demonstrate
MCYN oncogene amplification (28-121 copies),
functional RB protein.
2
Section I: Top 5 Advancements Over the Past Decade
B. MCYN: encodes N-Myc, transcription factor that
controls expression of cell cycle genes that promote
proliferation. Often amplified in neuroblastoma,
retinoblastoma, glioblastoma, medulloblastoma,
rhabdomyosarcoma.
C. Subset of unilateral RB patients who have wild type
RB1 gene and functional RB protein. Median age:
4.5 months, aggressive histology.
2016 Subspecialty Day | Ocular Oncology & Pathology
IX. Top 5 Advancements 2006-2016: Summary
A. IAC rivals systemic chemoreduction as a primary
modality for retinoblastoma in 2016.
B. IVC has replaced external beam radiation as a salvage therapy for vitreous seeding.
C. Gene testing for RB is becoming faster, cheaper,
and more widely used in clinical practice.
D. Up to 18% of unilateral RB < 6 months of age may
be due to MYCN.
D. OCT is currently an important diagnostic tool to
detect early RB lesions.
E. Enucleation recommended
E. Treatment for extraocular RB: Radiation and
surgery are becoming less important in treatment
regimens, as survival rates improve.
VIII. OCT and RB
A. Identify retinal anatomy adjacent tumor/seeding
B. Monitor treatment (distinguish scar vs. tumor)
C. Identify small tumors
D. Elucidating tumorigenesis
2016 Subspecialty Day | Ocular Oncology & Pathology
Section I: Top 5 Advancements Over the Past Decade
3
Top 5 Advancements Over the Past Decade With
Choroidal Melanoma
Mary E Aronow MD
I.Introduction
Uveal melanoma is the most common primary intraocular malignancy in adults. The incidence, which
has remained stable over the past several decades,
is estimated to be 5.1 per million population in the
United States. Approximately half of individuals with
uveal melanoma ultimately develop metastatic disease.
While present therapies for metastatic uveal melanoma are minimally effective, recent discoveries are
changing the landscape of ophthalmic oncology. This
presentation focuses on several of the most influential
areas of progress.
II.Advancements
A. Improvements in ancillary imaging technology
1.OCT
2. Color fundus photography (ultrawide-field systems)
3.Angiography
B. Universal language for tumor staging; tumor-nodemetastasis staging system
C. Tumor prognostication: DNA- and RNA-based
techniques
D. Adjuvant treatments; multiple clinical trials worldwide
E.Collaboration
III.Summary
Recent developments have furthered our ability to
characterize and document uveal melanoma, to
classify these tumors, to understand the underlying
mechanisms governing metastatic behavior, and to
explore potential adjuvant therapies. These advances,
combined with a collaborative effort, create an ideal
environment for study of emerging therapies.
Selected Readings
1. Singh AD, Turell ME, Topham AK. Uveal melanoma: trends
in incidence, treatment, and survival. Ophthalmology 2011;
118(9):1881-1885.
2. Torres VL, Brugnoni N, Kaiser PK, Singh AD. Optical coherence
tomography enhanced depth imaging of choroidal tumors. Am J
Ophthalmol. 2011; 151(4):586-593.
3. Field MG, Harbour JW. Recent developments in prognostic and
predictive testing in uveal melanoma. Curr Opin Ophthalmol.
2014; 25(3):234-239.
4. ClinicalTrials.gov website: http://www.clinicaltrials.gov.
4
Section I: Top 5 Advancements Over the Past Decade
2016 Subspecialty Day | Ocular Oncology & Pathology
Top 5 Advancements Over the Past Decade With
Choroidal Hemangioma
Amy C Schefler MD
I.Introduction
II. Choroidal Hemangioma: Anatomy and Recently
Described Clinical Associations
A.Circumscribed
B.Diffuse
III. Choroidal Hemangioma: New Diagnostics and
Clinical Observations
A. Spectral domain OCT
B. Swept source OCT
C. OCT angiography
D. 20 MHz ultrasound
IV. Reviews of New Treatment Strategies
A. Photodynamic therapy / other forms of laser
B. Anti-VEGF and steroid injections
C. Beta blockers
D. Radiation: plaques, intensity modulated radiation
therapy, proton beam
V.Conclusions
2016 Subspecialty Day | Ocular Oncology & Pathology
Section I: Top 5 Advancements Over the Past Decade
Top 5 Advancements With Other Intraocular Tumors:
What Should I Know?
Carol L Shields MD
I. Choroid Nevus
A. Prevalence of nevus in two 45-degree fundus
photographs from National Health and Nutrition
Examination Survey (NHANES); see Table 1.
B. Risk for transformation to melanoma: 1/8845 but
varies with age
C. Risk factors predictive of growth to melanoma (see
Table 2)
Table 1. Prevalence of Choroidal Nevus in NHANES: Stratified by Age, Gender, and Race
Age, years
Gender
Race
Female
n = 2790
P-value
Total
40-50
n = 1483
5.0%
4.4%
0.7
4.7%
50-60
n = 1322
3.3%
2.9%
0.7
3.1%
60-70
n = 1384
6.5%
4.4%
0.2
5.4%
70-80
n = 915
6.8%
6.5%
0.9
6.6%
80+
n = 471
7.5%
7.5%
0.9
7.5%
0.07
0.1
n/a
n/a
P-value
Male
n = 2785
White
n = 3012
6.2%
5.2%
0.4
5.6%
Black
n = 1133
1.0%
0.2%
0.07
0.6%
Hispanic
n = 1249
2.8%
2.5%
0.8
2.7%
Other
n = 181
0.5%
3.5%
0.02
2.1%
P-Value
< 0.0001
0.0001
n/a
n/a
Total
5.0%
4.4%
n/a
4.7%
Table information adapted from Qiu M, Shields CL. Choroidal nevus in the United States adult population: racial disparities and associated factors in the national
health and nutrition examination survey. Ophthalmology 2015; 122(10):2071-2083.
Table 2.
Nevus Growth Into
Melanoma if Feature
Present (%)
Nevus Growth Into
Melanoma if Feature
Absent (%)
Initials
Mnemonic
Features
Hazard
Ratio
T
To
Thickness > 2 mm
2
19%
5%
F
Find
Fluid
3
27%
5%
S
Small
Symptoms
2
23%
5%
O
Ocular
Orange pigment
3
30%
5%
M
Melanoma
Margin ≤ 3 mm to disc
2
13%
4%
UH
Using Helpful
Ultrasound hollow
3
25%
4%
H
Hints
Halo absent
6
7%
2%
D
Daily
Drusen absent
na
na
na
na: The risk factor of drusen absent was identified in other studies to be significant so it was included in this mnemonic for risk factors.
Table information adapted from Shields CL, Furuta M, Berman EL, et al. Choroidal nevus transformation into melanoma: analysis of 2514 consecutive cases. Arch
Ophthalmol. 2009; 127(8); 981-987.
5
6
Section I: Top 5 Advancements Over the Past Decade
2016 Subspecialty Day | Ocular Oncology & Pathology
Table 3. Systemic Outcome in 59 Patients With Choroidal Lymphoma
Total Number (%)
Primary Number (%)
Secondary Number (%)
Alive, no systemic lymphoma
33 (65)
33 (100)
0 (0)
Alive, regressed systemic lymphoma
6 (12)
0 (0)
6 (33)
Alive, under treatment for systemic lymphoma
4 (8)
0 (0)
4 (22)
Dead, from systemic lymphoma
6 (12)
0 (0)
6 (33)
Dead, from other causes
2 (4)
0 (0)
2 (11)
Information adapted from Mashayekhi A, Shukla SY, Shields JA, Shields CL. Choroidal lymphoma: clinical features and association with systemic lymphoma. Ophthalmology 2014; 121:342-351.
II. Choroid Lymphoma
A. Clinical features: Patchy orange-yellow choroidal
infiltration
B. Systemic outcome: Depends on whether lymphoma
is primary or secondary (see Table 3)
III. Retinal Astrocytic Hamartoma
A. Clinical features: Yellow-white inner retinal tumor
with/without intrinsic calcification
B. Systemic implications: If a patient with tuberous
sclerosis complex has astrocytic hamartoma, risk
for:
1. Subependymal giant cell astrocytoma: 37%
2. Renal angiomyolipoma: 60%
3. Cognitive impairment: 77%
4. Seizure: 91%
C. Imaging: OCT has documented astrocytic hamartoma is in the nerve fiber layer in all cases and
many show optically empty “moth-eaten” cavities,
representing calcification or cavitation.
IV. Retinal Hemangioblastoma
A. Clinical features: Red-orange retinal tumor with
surrounding exudation and subretinal fluid
B. Visual outcomes: Depends on number and location
of tumors. Risk for poor vision of 20/160 or worse:
1. Juxtapapillary tumor (vs. peripheral tumor[s]
only): odds ratio (OR) = 2.88
2. Juxtapapillary and peripheral tumors (vs.
peripheral tumor(s) only): OR = 6.38
3. ≥ 3 (vs. < 3) peripheral tumors: OR = 4.18
4. ≥ 5 (vs. < 5) peripheral tumors: OR = 8.27
5. ≥ 1 (vs. < 1) quadrant of peripheral involvement:
OR = 26.58
V. Sclerochoroidal Calcification
A. Clinical features: Yellow-white mass deep to choroid, generally superotemporally and calcified
B. Relationship with serum metabolic abnormalities:
1. Calcium high 21%
2. Potassium low 7%
3. Magnesium low 24%
4. Parathyroid hormone high 27%
5. Parathyroid adenoma 15%
C. Imaging with OCT shows mountain-like topography with rocky, rolling, or table mountain configuration.
References & Selected Readings
1. Qiu M, Shields CL. Choroidal nevus in the United States adult
population: racial disparities and associated factors in the
National Health and Nutrition Examination Survey. Ophthalmology 2015; 122(10):2071-2083.
2. Shields CL, Furuta M, Berman EL, et al. Choroidal nevus transformation into melanoma: analysis of 2514 consecutive cases.
Arch Ophthalmol. 2009; 127(8); 981-987.
3. Mashayekhi A, Shukla SY, Shields JA, Shields CL. Choroidal lymphoma: clinical features and association with systemic lymphoma.
Ophthalmology 2014; 121:342-351.
4. Shields CL, Arepalli S, Pellegrini M, Mashayekhi A, Shields JA.
Choroidal lymphoma appears with calm, rippled, or undulating
topography on enhanced depth imaging optical coherence tomography in 14 cases. Retina 2014; 34:1347-1353.
5. Aronow MR, Nakagawa JA, Gupta A, et al. Tuberous sclerosis
complex: genotype phenotype correlation of retinal findings.
Ophthalmology 2012; 119:1917-1923.
6. Shields CL, Say EAT, Fuller T, Arora S, Samara WA, Shields
JA. Retinal astrocytic hamartoma arises in nerve fiber layer and
shows “moth-eaten” optically empty spaces on optical coherence tomography: analysis of 47 eyes. Ophthalmology 2016;
123(8):1809-1816.
7. Wang WT, Agron E, Coleman HR, et al. Clinical characterization
of retinal capillary hemangioblastomas in a large population of
patients with von Hippel Lindau disease. Ophthalmology 2008;
115:181-188.
8. Shields CL, Hasanreisoglu M, Saktanasate J, Shields PW, Seibel
I, Shields JA. Sclerochoroidal calcification: clinical features,
outcomes and relationship with hypercalcemia and parathyroid
adenoma in 179 eyes. Retina 2015; 35:547-554.
9. Hasanreisoglu M, Saktanasate J, Shields PW, Shields CL. Classification of sclerochoroidal calcification based on enhanced depth
imaging optical coherence tomography “mountain-like” features.
Retina 2015; 35:1407-1414.
2016 Subspecialty Day | Ocular Oncology & Pathology
Section I: Top 5 Advancements Over the Past Decade
7
Top 5 Current Approaches in Ophthalmic Pathology
Patricia Chévez-Barrios MD
Advancements in ophthalmic pathology are tied to technological advancements, as many tests depend on faster and more
precise ways of detecting proteins, antigens, and molecular messages. The following are 5 current approaches used in ophthalmic pathology that exemplify these advancements.
I. Retinoblastoma Assessment of Genetics and
Prognostic Factors
A. Gene expression profile
B. Monosomy of chromosome 3 assessment
C. Assessment of other chromosomes by other molecular techniques
1. Fresh retrieval of tumor (opening with blade
vs. trephine or by needle aspiration biopsy
[FNABx])
D. Cytopathology for confirmation of diagnosis
2. Assessment of genetics: Recognition of small
cohort of patients with N-MYC amplification
with different histopathologic and clinical features
1. With or without adequacy check
2. Immunohistochemistry (double stain – melanoma marker + proliferation rate marker)
E. Biomarkers for skin, conjunctiva, and uveal melanomas (BRAF, BAP1)
3. Adequate fixation and sampling of optic nerve
margin
III. Infectious Ocular Diseases (Atypical Keratitis, Uveitis
and Retinitis)
4. Entire eye submitted for examination: Pupil
optic nerve (PO) and calottes (in anterior posterior segments for maximum choroidal examination) sections
Aqueous and vitreous and corneal scrapings, tap /
biopsy
FNABx prior to plaque implantation for uveal melanoma to obtain material for molecular analysis
A. Guidelines for handling eyes with retinoblastoma
II. Ocular Melanoma Diagnosis and Assessment of
Metastatic Potential
5. Adequate sampling of each block with histologic examination of complete optic nerve in
the PO section (central vessels present in lamina
cribrosa and optic nerve head)
A. Polymerase chain reaction single or multiplex to
detect most common viral pathogens
B. Whole genome sequencing of nonhuman message
C. Cultures and cytology
6. Definition of massive choroidal invasion (equal
or more than 3 mm in any diameter) and focal
choroidal invasion (less than 3 mm)
IV. Lymphoma, Conjunctiva, Orbit, and Intraocular
A. Flow cytometry
B.Molecular
B. New staging for retinoblastoma: American Joint
Commission on Cancer, 8th edition, incorporating
“H” for hereditary and assessing a stage
C. Use of “liquid biopsy” for assessment of recurrence
of disease at extraocular sites using blood and CSF
(ie, cone-rod homeobox [CRX] mRNA as a marker
for retinoblastoma)
1. Gene rearrangement
2. Other markers
C.Immunohistochemistry
V. Other Tumors and Lesions With Biomarkers and
Specific Antigen Expression
A. Rhabdomyosarcoma: Mutations for alveolar vs.
embryonal
B. Sebaceous gland adenoma / carcinoma
1. Microsatellite instability associated with MuirTorre syndrome (association with internal
malignancies)
2. Androgen receptor
C. Other orbital tumors
8
Section I: Top 5 Advancements Over the Past Decade
2016 Subspecialty Day | Ocular Oncology & Pathology
Can OCT Help in Diagnosis and Management of
Ocular Neoplasia?
David J Wilson MD
I. Ocular Surface Disease
III. Posterior Segment
A.Diagnosis
A.Melanoma
1. Thickened epithelium
1. Detection of subretinal fluid
2. Abrupt transition between normal and abnormal epithelium
2. Differential diagnosis
3. Distinction from benign surface disease
B. Monitoring treatment
II. Anterior Intraocular Tumors
A. OCT vs. ultrasound biomicroscopy
B. OCT angiography of iris tumors
B.Retinoblastoma
1. Defining foveal anatomy
2. Optic nerve evaluation
C. Lymphoma: Monitoring subclinical disease
IV. Enhanced Depth OCT
A. Metastatic lesions
B. Choroidal nevi
V. OCT Angiography for Radiation Retinopathy
A. Early detection
B. Quantitative evaluation
2016 Subspecialty Day | Ocular Oncology & Pathology
Section I: Top 5 Advancements Over the Past Decade
9
Is Intravenous Fluorescein Angiography or OCT
Angiography Better for Imaging Tumors?
Emil Anthony T Say MD
I. Background on Angiography Use in Ophthalmology
A. Intravenous fluorescein angiography (IVFA)
1. Real-time perfusion through intravenous dye
injection
2. Dependent on actual flow of blood
3. Detects patterns of flow (leakage, staining,
pooling) and areas of nonperfusion
4. Detects microvascular anomalies based on leakage (CNV and neovascularization of the disc
[NVD] and elsewhere [NVE])
C. Assess peripheral vascular abnormalities
1. Assessment of peripheral vascular anomalies
required for assessment of treatment complications (after intra-arterial chemotherapy or
radiation) and diagnosis (Coats disease, familial
exudative vitreoretinopathy), particularly in
children
2. IVFA: Field of view up to 200° in both nonsteering and steering machines
3. OCT-A: Nonsteerable 3-, 6-, and 8-mm en face
views with current machines and loss of detail
with increasing scan lengths
4. Advantage: IVFA
5. Takes 15-20 minutes
B. OCT angiography (OCT-A)
1. Analyzes relative perfusion noninvasively
2. Dependent on movement of red blood cells
3. Cannot detect patterns of flow but can detect
areas of nonperfusion
4. Takes less than 10 seconds
D. Check for neovascularization
1. CNV is sometimes associated with treatment
(laser scars) or associated with tumors (choroidal osteoma and choroidal nevus).
2. Surface neovascularization (NVD and NVE) is
sometimes associated with radiation and rarely
seen in treatment-naïve tumors.
3. IVFA: Poorly delineates neovascularization but
detects all NV regardless of velocity of flow (not
flow limited)
4. OCT-A: Excellent delineation of neovascularization but is flow limited
5. Advantage: IVFA = OCT-A
II. Clinical Use of Angiography in Ocular Oncology
A. Differentiate tumors from pseudotumors
1. Check for patterns associated with tumors or
pseudotumors, such as smoke stack (central
serous chorioretinopathy) and double circulation (choroidal melanoma)
2. IVFA: Wide-field and increased depth of field
allow visualization of all regions of interest.
3. OCT-A: Limited field of view and limited depth
of field do not allow visualization of the entire
tumor due to artifacts (cut edge, mirror, etc.).
4. Advantage: IVFA
B. Assess etiology of vision loss
E. Laser treatment planning
1. Focal/grid laser and photodynamic therapy
require visualization of areas with active leakage, such as focal leaks in choroidal nevi with
subretinal fluid.
2. Panretinal photocoagulation requires visualization of all areas of nonperfusion for complete
therapy.
3. IVFA: Detects actual flow and can analyze leakage; wide-field allows visualization of all areas
of nonperfusion.
4. OCT-A: Cannot determine leakage or lesion
activity with correlation with IVFA and OCT;
limited field of view to check for all areas of
nonperfusion
5. Advantage: IVFA
1. Macular etiologies of vision loss
a. Macular nonperfusion
b. Foveal avascular zone (FAZ) enlargement
and irregularity
c. Loss of capillary density
2. IVFA: Detects nonperfusion and FAZ at the
superficial plexus only, cannot analyze capillary
density due to limited axial resolution
3. OCT-A: Detects all possible macular etiologies
of vision loss, at both the superficial and deep
plexus in less than 10 seconds
4. Advantage: OCT-A
10
Section I: Top 5 Advancements Over the Past Decade
III.Conclusion
A. Intravenous fluorescein angiography
1. Can differentiate tumors from pseudotumors
2. Assesses peripheral vascular abnormalities
3. Laser treatment planning
4. Assesses neovascular activity for diagnosis and
treatment planning
B. OCT angiography
1. Assesses etiology of vision loss efficiently
2. Assesses size of neovascular tissue for treatment
monitoring
2016 Subspecialty Day | Ocular Oncology & Pathology
2016 Subspecialty Day | Ocular Oncology & Pathology
Section I: Top 5 Advancements Over the Past Decade
11
How Well Does OCT Correlate With Histopathology?
Sander Dubovy MD
N OTE S
12
Section I: Top 5 Advancements Over the Past Decade
2016 Subspecialty Day | Ocular Oncology & Pathology
Next Generation Sequencing of Vitreoretinal
Lymphomas: New Routes to Targeted Therapies
through Precision Medicine
Rajesh C Rao MD
N OTE S
2016 Subspecialty Day | Ocular Oncology & Pathology
Section II: The Management of Intraocular Tumors
13
Fine Needle Aspiration Biopsy for Genetic
Information—Pro
Tara A McCannel MD
In 2016, the modern approach to the treatment of a patient with
choroidal melanoma includes determining metastatic risk with
fine needle aspiration biopsy for molecular prognosis at time of
brachytherapy. Although we are highly successful at treating the
primary tumor, choroidal melanoma has at least a 50% risk of
developing metastatic disease and death due to liver metastases.
People want to receive all possible information regarding their
cancer, including metastatic prognosis, whether or not it will
alter their present medical therapy.1,2 Knowledge of metastatic
risk may empower patients and reduce anxiety caused by uncertainty. Since 1993, monosomy 3, or loss of one copy of chromosome 3 in the tumor tissue, was demonstrated to be highly associated with the development of metastases.3 It wasn’t until 2006
that the first publication demonstrating the feasibility of in vivo
fine needle aspiration biopsy for molecular prognostication in
North American was reported.4 Since then a number of publications have demonstrated feasibility, success rates, and safety
of performing in vivo fine needle biopsy during brachytherapy
treatment of the primary tumor.5-8 Major ophthalmic oncology
centers have demonstrated that needle biopsy does not alter the
risk of metastasis and that this technique is safe in experienced
hands. Furthermore, evolving techniques for fine needle biopsy,
such as transvitreal and vitrectomy-assisted methods, have
allowed clinicians to obtain tissue from patients with very small
tumors in whom future targeted therapies may benefit most.9
Finally, fine needle aspiration biopsy of choroidal melanoma
is critical to obtain tissue for research to better understand the
biology of choroidal melanoma so that new targeted treatments
for metastasis can be developed.10-12
References
3. Horsman DE, White VA. Cytogenetic analysis of uveal melanoma: consistent occurrence of monosomy 3 and trisomy 8q.
Cancer 1993; 71(3):811-819.
4. Young TA [McCannel TA], Rao NP, Glasgow BJ, Moral JN,
Straatsma BR. Fluorescent in situ hybridization for monosomy 3
via 30-gauge fine-needle aspiration biopsy of choroidal melanoma
in vivo. Ophthalmology 2007; 114(1):142-146.
5. McCannel TA, Chang MY, Burgess BL. Multi-year follow-up of
fine-needle aspiration biopsy in choroidal melanoma. Ophthalmology 2012; 119(3):606-610.
6. Shields CL, Ganguly A, Materin MA, et al. Chromosome 3 analysis of uveal melanoma using fine-needle aspiration biopsy at the
time of plaque radiotherapy in 140 consecutive cases: the Deborah
Iverson, MD, Lectureship. Arch Ophthalmol. 2007; 125(8):10171024.
7. Shields CL, Ganguly A, Bianciotto CG, Turaka K, Tavallali
A, Shields JA. Prognosis of uveal melanoma in 500 cases using
genetic testing of fine-needle aspiration biopsy specimens. Ophthalmology 2011; 118(2):396-401.
8. Sellam A, Desjardins L, Barnhill R, et al. Fine needle aspiration
biopsy in uveal melanoma: technique, complications, and outcomes. Am J Ophthalmol. 2016; 162:28-34.e1.
9. Chang MY, McCannel TA. Comparison of uveal melanoma
cytopathologic sample retrieval in trans-scleral versus vitrectomyassisted transvitreal fine needle aspiration biopsy. Br J Ophthalmol. 2014; 98(12):1654-1658.
10. McCannel TA, Burgess BL, Rao NP, Nelson SF, Straatsma BR.
Identification of candidate tumor oncogenes by integrative molecular analysis of choroidal melanoma fine-needle aspiration biopsy
specimens. Arch Ophthalmol. 2010; 128(9):1170-1177.
1. Beran TM, McCannel TA, Stanton AL, Straatsma BR, Burgess
BL. Reactions to and desire for prognostic testing in choroidal
melanoma patients. J Genet Couns. 2009; 18(3):265-274.
11. Burgess BL, Rao NP, Eskin A, Nelson SF, McCannel TA. Characterization of three cell lines derived from fine needle biopsy of
choroidal melanoma with metastatic outcome. Mol Vis. 2011;
17:607-615.
2. Cook SA, Damato B, Marshall E, Salmon P. Psychological aspects
of cytogenetic testing of uveal melanoma: preliminary findings
and directions for future research. Eye (Lond). 2009; 23(3):581585.
12. McCannel TA, Burgess BL, Nelson SF, Eskin A, Straatsma BR.
Genomic identification of significant targets in ciliochoroidal
melanoma. Invest Ophthalmol Vis Sci. 2011; 52(6):3018-3022.
14
Section II: The Management of Intraocular Tumors
2016 Subspecialty Day | Ocular Oncology & Pathology
Fine Needle Aspiration Biopsy for Genetic
Information: Con
Evolution of Decisions, Species, Tumors, and Tests
Jose S Pulido MD MS
I. Evolution of Decisions
A. Decision making: science showed that decisions
are formed by a surprisingly rapid combination of
emotion (“gut,” “instinct”) and reason (“facts,”
“rationality,” “science”).
B. Some patients are dead-set on having a biopsy.
C. Some of you are dead-set on doing biopsies.
D. I will still have the talk.
E. Descartes’ Error: Emotion, Reason, and the
Human Brain
II. Cancer Selection vs. Darwinian Selection
III. Evolution of a Test
IV. Original: Nice Binary! Failure Rate 3%
V. Next Iteration: Report Sent, 3 Classes
VI. Most Recent Publication: 4 Classes
XII. So how is discordance/heterogeneity handled?
A. So some are suggesting biopsying more than 1 site.
B. But we know that for other melanomas, incisional
biopsies are associated with a worse prognosis.
C. Do uveal melanomas have exceptionalism in this
regard? Or should we take care, and if we do a
biopsy limit ourselves to 1 site?
XIII. Other Concerns That We Do Not Have Time to
­Discuss
A. 20% incidence of regret following biopsy
B. No prophylactic therapy, and if prophylactic therapy will be tried, it should be in a clinical trial.
C. No data that early treatment makes a difference in
the vast majority of cases
XIV. Final Questions
A. So should one biopsy a melanoma <12 mm lbd
since if it is Class 2, the prognosis is about the same
as Class 1 tumors?
B. For those >12 mm, if it is Class 2 the patient needs
to be aware that 20% will have regret after doing
the biopsy.
C. In addition, if it is Class 1, there is still a 16%
chance that it is Class 2.
VII. Class 2 <12 mm vs. Website Class 1a (98%) and 1b
(79%)
Results: better to be Class 2 (90%)
VIII. Comparing size equivalent to size equivalent, it’s still
better to be class 2!
IX. Truly an Evolution From the Original Binary Result
X. Evolution of Tumors: Clonality
XI. Is there heterogeneity in uveal melanomas like other
tumors?
16% discordance if biopsied at 2 sites, and discordant
cases have a greater chance of mortality similar to
class 2.
2016 Subspecialty Day | Ocular Oncology & Pathology
Section II: The Management of Intraocular Tumors
Fine Needle Aspiration Biopsy for Genetic
Information: Emotional Distress
Arun D Singh MD
Given that prognostication fine needle aspiration biopsy is routinely performed as management of uveal melanoma and would
be eventually used to identify patients eligible for enrollment
into adjuvant treatment trials, psychosocial assessment, including anxiety, depression, and decision regret, should be integrated into clinical trials, ideally prior to any testing. Decline
in depression, anxiety, and decision regret appears to lessen
or dissipate with time; study on larger numbers of patients is
necessary to elucidate factors that may be addressed to mitigate
decision regret.
15
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Section II: The Management of Intraocular Tumors
2016 Subspecialty Day | Ocular Oncology & Pathology
Cancer of Unknown Primary: From
Immunohistochemistry to Gene Expression Profiling
Nora V Laver MD
Introduction
Carcinoma of unknown primary (CUP), although uncommon,
is usually a challenging clinical problem. Approximately 15% of
all cancers first present with metastasis; in approximately twothirds of those cases the primary is found early in the course
of the disease. However, in up to one-third of the cases the
primary remains unknown or is found out over a longer period
of time. The use of sophisticated imaging, immunohistochemical testing, and molecular-profiling tools has influenced the
approach to CUP diagnosis. In most patients with CUP, pathological findings supersede the interpretations of radiologic testing. Adequate tissue sampling is essential, as is communication
between the treating oncologist and the pathologist. Diagnostic
biopsies classify tumors based on anatomic location and tumor
morphology to guide patient care. Immunohistochemistry panels aid in establishing cancer type, subtype, and site of origin.
Molecular tissue profiling can aid not only in determining the
tumor origin in CUP but also in uncovering therapeutic targets
and key mutational signatures of certain cancers. A growing
number now believe that CUP may retain the signature of the
primary origin and that extending the management of known
cancers to subtypes of unknown primary cancer can contribute
to advancements in therapies for this disease.
Background Observations
Since the 1990s immunohistochemistry (IHC) has revolutionized the way we make diagnoses, with large numbers of
validated panels available for pathology interpretation. IHC
antibodies are used singly or in panels, and the results depend
on the tissue fixation, staining technique, and microscopic
interpretation. Table 1 presents the usual algorithm used to
make a histological diagnosis and lists the common immunohistochemical markers to determine tumor type, subtype, and
site of origin. Although individual immunohistochemical tests
have modest specificity and sensitivity, their predictive value
may improve with grouping and recognition of patterns that
are strongly indicative of specific tumors. Diagnostic dilemmas
arise when few specific immunohistochemical markers stain or
when the staining is hard to interpret due to insufficient tissue,
necrosis, or poor staining or when the results conflict with the
morphology or clinical scenario.
Molecular tissue differentiation is based on the differences in
gene expression profiles. The human genome contains approximately 25,000 protein encoding genes; of these, 12,000 genes
are active and expressed at the mRNA and protein levels in tissues. Of the 12,000 active genes, 8000 are expressed widely and
are involved in basic cellular functions. A subset of active genes
is specific to one or a few tissue types related to its differentiation. Tissue-specific or -restrictive genes are often regulatory
genes or protein products. Regulatory genes include transcription factors, like thyroid transcription factor in lung and thyroid
tissues. Protein products may be secreted or expressed in the
cell—for example, cytokeratins in carcinomas. Tissues tend to
resemble morphologically the tissue of origin and also express
some tissue-specific genes, not only in primary cancers but also
in metastasis.
Tissue-of-origin molecular profiling assays large numbers of
genes from known cancers examined with tools such as DNA
microarray and quantitative real-time polymerase chain reaction (rt-PCR) assay, using formalin-fixed tissue samples. Both
techniques exploit the preferential binding or “base pairing” of
complementary nucleic acid sequences. Metastatic CUP tumors
have molecular signatures that match their primary origin
(see Table 2). The performance of tissue-of-origin molecularprofiling assays in known cancers has been validated with the
use of independent, blinded evaluation of sets of tumor samples,
with an accuracy of approximately 90%. Molecular profiling
performs well in already worked-up, poorly differentiated metastatic tumors, including CUP, with sensitivities of 72%-95%.
For CUP patients, molecular profiling may change the diagnosis
in around 50% of cases, and it affects management in most
cases. There are numerous commercially available molecular
profile panels (see Table 3). The use of IHC and molecular profiling in CUP is gradually aiding in finding the unknown tumor
primary and will continue to improve with advances in treatments for patients with CUP.
2016 Subspecialty Day | Ocular Oncology & Pathology
Section II: The Management of Intraocular Tumors
17
Table 1. Diagnostic Pathology Approaches Using Immunohistochemical Stains
CUP Morphologic Workup
Useful Immunohistochemical Panels
1. Identify cancer type
Carcinoma
Pancytokeratin AE1/3, EMA, CK7, CK20, CK5 (and other), p16, p63, HPV, etc.
Melanoma
Melan-A, S100, HMB45, TIFT-1
Lymphoma/leukemia
LCA, CD20, CD3, CD138, CD30, CD5, CD10, kappa, lambda, EBV, etc.
Sarcoma
Vimentin, desmin, actin, c-kit, S100, myogenin-D
Neuro-glial tumors
GFAP, EMA, CD34, CD99, synaptophysin, HMB-45, S100, vimentin, pancytokeratin
2. Identify subtype (for example if carcinoma)
Adenocarcinoma
CK7, CK20, PSA, etc.
Squamous cell carcinoma
CK5, p63, p16, HPV
Neuroendocrine carcinoma
Chromogranin, synaptophysin, CD56, TTF-1
Transitional cell carcinoma
TCC, CK7, urothelin
Renal carcinoma
RCC, CD10, PAX8, Napsin A
Hepatocellular carcinoma
Hepar-1, glypican 3, CD10
Thyroid carcinoma
TTF-1, thyroglobulin, PAX8
Adrenal carcinoma
Melan-A, inhibin
Germ cell tumor
OCT4, PLAP, HCC, AFP
Mesothelioma
Calretinin, mesothelin, WTI, D2-40
3. Identify possible primary site
Lung
TTF-1, Napsin A, CK7
Breast
GCDFP-15, mammaglobin, CK7, ER, PR
Colon
CDX2, CK7
Pancreas
CK7, CA125, CDX2
Stomach
CK7, CK20, CDX2
Prostate
PSA, NKX3.1
Ovary
Serous
PAX8, WT1,ER, CA125, CK7
Mucinous
PAX8, WT1,ER, CA125, CK7, CDX2
Table 2. Example of Genetic Panels Used in the Diagnosis of CUP
Solid Tumors Panel
Breast Cancer Panel
AKT1, ALK, BRAF, CTNNB1, DDR2, EGFR, EPHA2, ERBB2,
ESR1, FGFR1, FGFR2, FGFR3, GNA11, GNAQ, HRAS, IDH1,
IDH2, IDHS, KIT, KRAS, MAP2K1, MET, MTOR, NOTCH1,
NRAS, PDGFRA, PIK3CA, PTEN, RAC1, RET, ROS1, TP53
Ki67, STK15, Survivin, CCNB1, MYTBL2, ACTB, GAPDH, RPLPO,
MMP11, GUS, CTL2, TFRC, GRB2, Her2, ER, PGB, BCL2, SCUBE2
Melanoma Panel
Lung Cancer Panel
BRAF, CTNNB1, GNA11, GNAQ, KIT, MAP2K1, NRAS
AKT1, ALK, BRAF, DDR2, EFGR, EPHA2, ERBB2, FGRF1, FGFR2,
FGFR3, KRAS, MARP2k1, MET, NRAS, PIK3CA, RET, ROS1, TR53
18
Section II: The Management of Intraocular Tumors
2016 Subspecialty Day | Ocular Oncology & Pathology
Table 3. Commercially Available Molecular Profile Panels
Company Name
City
Foundation One (Foundation Medicine)
Molecular
Intelligence™
GeneTrails®
Service or Target
Cambridge, MA
now™
Molecular Profiling Service (Caris Life Sciences)
Solid Tumor Panel (Knight Diagnostic Lab)
Irving , TX
Portland, OR
GeneKey (GeneKey Corp.)
Boston, MA
Guardant 360 ® Panel (Guardant Health)
Redwood City, CA
OncInsights™
(Intervention Insights)
Grand Rapids, MI
OnkoMatch™
(GenPath Diagnostics)
Elmwood Park, NJ
Pathwork Tissue of Origin – Cancer Genetics Incorporated-Gentrics
Raleigh NC; Hyberadad, India
BioTheranostics Cancer Type ID (CTID)
San Diego, CA
MiRview mets2 – Rosetta, Precision Therapeutics
Redwood, CA
Selected Readings
1. Varadhachary GR, Raber MN. Carcinoma of unknown primary
site. N Engl J Med. 2014; 371:757-765.
2. Oien KA, Dennis JL. Diagnostic work-up of carcinoma of
unknown primary: from immunohistochemistry to molecular
profiling. Ann Oncol. 2012; 23(10): 271-277.
3. Teruya-Feldstein J. The immunohistochemistry laboratory: looking at molecules and preparing for tomorrow. Arch Pathol Lab
Med. 2010; 134:1659-1665.
2016 Subspecialty Day | Ocular Oncology & Pathology
Section II: The Management of Intraocular Tumors
19
Bevacizumab for Prevention of Radiation Retinopathy:
The Evidence
Timothy G Murray MD MBA
Introduction
Radiation therapy for uveal melanoma, either brachytherapy or
proton beam therapy, is the current “gold standard” for treatment. The largest prospective randomized clinical trial, the
Collaborative Ocular Melanoma Study (COMS), has shown
excellent survival outcomes that are influenced by tumor size.
Recently, understanding of tumor biology and access to tumor
genetics has shifted treatment away from enucleation and, in
many instances, toward earlier treatments to minimize or avoid
radiation treatment complications. In the COMS, approximately 12.5% of iodine-125 brachytherapy-treated mediumsized uveal melanoma patients were enucleated within the first
5 years after treatment. Radiation treatment complications,
either radiation maculopathy, optic neuropathy, or secondary
neovascular glaucoma, limited BCVA in the remaining eyes to
approximately 20/200, occurring in 43% of eyes, while 49%
of eyes lost greater than 6 lines of VA, all occurring within the
first 36 months of treatment. Foundational work by Finger
et al, Mieler et al, Shields et al, and others utilized treatment
approaches to minimize radiation complications while maximizing visual acuity outcomes utilizing anti-VEGF, steroid,
and/or laser therapies. Multiple investigators have now documented significant short- and long-term benefits of anti-VEGF
treatments in decreasing enucleation rates, stabilizing IOP,
enhancing macular anatomy, and ultimately improving visual
acuity and function.
Data Review
Anti-VEGF treatment strategies evolved around the recognition
of vascular damage secondary to direct, and indirect, vascular
damage. Documentation of elevated VEGF levels in primary
uveal melanoma along with significantly elevated post–radiation therapy levels led many investigators to utilize anti-VEGF
therapies in clinical practice and in small clinical studies. A confluence of understanding of tumor biology, advances in imaging technologies (spectral domain OCT [SD-OCT]/ widefield
fluorescein angiography / indocyanine green angiography), and
intravitreal pharmacotherapies, including multiple anti-VEGF
agents / steroids, enabled clinicians to enhance the early detection of radiation retinopathy, establish grading schemas, and
personalize treatment approaches targeted at reducing retinal
edema and improving VA.
Finger et al first reported anti-VEGF use for radiation
maculopathy. Shields et al then developed an SD-OCT targeted
grading schema for radiation maculopathy. Since 2008, over
70 peer-reviewed articles have discussed the use of anti-VEGF
in the treatment of radiation complications associated with
treated uveal melanoma. In 2012, Shah et al reported serial SDOCT follow-up for detection and targeted treatment of radia-
tion maculopathy. In this series of 159 patients, the mean VA
at 36 months was 20/50 (compared to COMS VA at 20/200).
Additionally, targeted use of anti-VEGF was found to decrease
enucleation rates at 5 years from 12.5% in the COMS to < 1%.
A subset of eyes showed severe radiation maculopathy and were
subsequently treated with combination anti-VEGF and triamcinolone acetonide. Several recent long-term follow-up studies
by Murray et al and Finger et al have documented the ability
to preserve VA and anatomic function over treatment periods
greater than 10 years.
Key take-home points for enhanced VA and anatomic outcomes include:
1. Early detection and treatment, with typical onset of radiation retinopathy at 9 months following radiation therapy
2. Need for close follow-up and targeted treatment often
requiring anti-VEGF treatment at 4-6 week intervals
3. The benefit of early recognition of peripheral ischemia
and tractional changes of the retina that may be amenable
to surgical intervention via laser and/or vitrectomy.
Recently, next-generation anti-VEGF agents have been investigated in the treatment of radiation maculopathy. In a prospective, randomized treatment cohort reported at the ASRS 2016,
aflibercept was delivered for complications of radiation maculopathy using an every 6-week vs. treat-and-extend approach
that documented improvement in radiation maculopathy grading classification, decreasing SD-OCT retinal thickness (CPT),
lowered IOP, and improved VA.
Conclusions
Radiation complications are the most common treatmentrelated morbidity for patients with uveal melanoma. Currently,
anti-VEGF treatments using SD-OCT targeted therapy and
employing active short-interval screening are associated with
marked improvements in all outcome measures, including VA,
macular thickening, vitreous hemorrhage, and neovascular
glaucoma. The use of anti-VEGF with iodine-125 brachytherapy has virtually eliminated the need for post-brachytherapy
enucleation. These existing studies clearly document the impact
of anti-VEGF therapy in managing the complications of radiation treatment for uveal melanoma. Ongoing and future studies will further identify eyes that may benefit from strategies
incorporating anti-VEGF treatment to impact the development
of radiation maculopathy, to evaluate combined therapies with
ocular steroids, particularly sustained-release modalities, and
to describe the impact of surgical management targeted to
decrease tumor treatment–related ischemia and traction-related
complications.
20
Section II: The Management of Intraocular Tumors
2016 Subspecialty Day | Ocular Oncology & Pathology
Bevacizumab for Prevention of Radiation Retinopathy:
Hogwash
Brian Marr MD
Radiation has been used in the field of oncology for more than
8 decades as a means to cause irreversible damage to DNA in
tumor cells to prevent replication. Unfortunately, healthy cells
in the treatment field receive the same damage and can suffer
the same fate, depending on the dose they receive and type of
cell or rate of replication of that cell. Such damage in the retina,
which we term “radiation retinopathy,” can be seen months to
many years after treatment. This results in progressive visual
loss.
Treatment with bevacizumab (Avastin) following radiation
does not reverse the DNA damage to cells and thus cannot
reverse the radiation effects. Treatment may delay the clinical
appearance of radiation retinopathy but does not prevent it long
term.
Selected Readings
1. Archambeau JO, Mao XW, McMillan PJ, et al. Dose response of
rat retinal microvessels to proton dose schedules used clinically: a
pilot study. Int J Radiat Oncol Biol Phys. 2000; 48:1155-1166.
2. Collaborative Ocular Melanoma Study (COMS) Group. The
COMS randomized trial of iodine 125 brachytherapy for medium
choroidal melanoma: I. Visual acuity after 3 years: COMS report
No. 16. Ophthalmology 2001; 108:348-366.
3. Shields CL, Shields JA, Cater J, et al. Plaque radiotherapy for
uveal melanoma: long-term visual outcome in 1106 consecutive
patients. Arch Ophthalmol. 2000; 118:1219-1228.
4. Finger PT. Radiation retinopathy is treatable with anti-vascular
endothelial growth factor bevacizumab (Avastin). Int J Radiat
Oncol Biol Phys. 2008; 70:974-977.
5. Horgan N, Shields CL, Mashayekhi A, Shields JA. Classification
and treatment of radiation maculopathy. Curr Opin Ophthalmol.
2010; 21:233-238.
6. Mason JO 3rd, Albert MA Jr, Persaud TO, Vail RS. Intravitreal
bevacizumab treatment for radiation macular edema after plaque
radiotherapy for choroidal melanoma. Retina 2007; 27:903-907.
2016 Subspecialty Day | Ocular Oncology & Pathology
Section II: The Management of Intraocular Tumors
21
Sector Panretinal Photocoagulation for Prevention of
Radiation Retinopathy: The Evidence
Miguel A Materin MD
Radiation retinopathy represents the most common ocular
side effect after brachytherapy for uveal melanoma. Different options of treatment have been used for this condition,
including intraocular injections of anti-VGEF medications or
corticosteroids, periocular injections of corticosteroids, sector retinal photocoagulation, and others, with variable results.
Early microvascular damage has been demonstrated by OCT
angiography.
The current treatments might improve the radiation retinopathy (cystoid macular edema) with a variable improvement
in visual acuity loss.
Selected Readings
1. Finger PT, Kurli M. Laser photocoagulation for radiation retinopathy after ophthalmic plaque radiation therapy. Br J Ophthalmol.
2005; 89;730-738.
2. Horgan N, Shields CL, Mashayekhi A, et al. Periocular triamcinolone for prevention of macular edema after iodine 125 plaque
radiotherapy of uveal melanoma. Retina 2008; 28(7):987-995.
3. Materin MA, Bianciotto CG, Wu C, Shields CL. Sector laser photocoagulation for the prevention of macular edema after plaque
radiotherapy for uveal melanoma: a pilot study. Retina 2012;
32(8):1601-1607.
4. Say EA, Samara WA, Khoo CT, et al. Parafoveal capillary density
after plaque radiotherapy for choroidal melanoma: analysis of
eyes without radiation maculopathy. Retina. Epub ahead of print
2016 May 25.
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Section II: The Management of Intraocular Tumors
2016 Subspecialty Day | Ocular Oncology & Pathology
How We Manage Radiation Retinopathy in the UK
Victoria M L Cohen FRCOphth
Introduction
Most uveal melanomas are treated by radiotherapy, which
can consist of various forms of brachytherapy, proton beam
radiotherapy, and stereotactic radiotherapy. The therapeutic
effects and the ocular morbidity differ according to the choice
of radiotherapy treatment. The benefits of administering an
effective tumoricidal dose must be balanced against the possible
consequences of ocular morbidity from radiation retinopathy,
radiation maculopathy, optic neuropathy, cataract, neovascular
glaucoma, and scleral necrosis.
Prevention is better than cure.
Strategies to minimize the radiation dose to the macula have
included reducing the overall tumor treatment dose, the use of
collimating and “custom-designed” plaques, and the eccentric
placement of plaques and delivery of a notched proton beam.
We now use intravitreal anti-VEGF injections prior to brachytherapy and after proton beam therapy to reduce subretinal
fluid and risk of the retinal ischemia that precipitates radiation
retinopathy.
Treatment of Radiation Retinopathy
Different treatment modalities have been used to treat radiation
retinopathy. These include laser photocoagulation, photodynamic therapy, corticosteroids, and anti-VEGF agents. Vitrectomy, endolaser, and argon laser photocoagulation are still used
to treat retinal neovascularization. However, due to the limited
success experienced with grid argon laser photocoagulation
for radiation-induced macular edema,1 this complication has
changed.
In London, laser and intravitreal steroid injection for macular edema have been superseded by the use of off-license intravitreal bevacizumab. Several studies have reported promising
results with the use of anti-VEGF agents in the treatment of
radiation-induced macular edema. Mason et al2 evaluated the
effect of a single intravitreal injection of bevacizumab in 10 consecutive patients. The mean visual acuity improved from 20/100
to 20/86 at 6 weeks and to 20/95 at 4 months. The mean foveal
thickness was 482 μm before injection, 284 μm at 6 weeks, and
449 μm at 4 months after injection. Finger3 reported the results
of intravitreal injections of bevacizumab (1.25 mg in 0.05 mL)
repeated every 6-12 weeks in 21 patients with radiation retinopathy. They noted reduction in retinal hemorrhage and exudation, while visual acuity was maintained in 86% of patients
and 14% gained vision. Gupta and Muecke4 suggested that
following ruthenium plaque brachytherapy, younger patients
with shorter duration of macular edema benefit the most after
intravitreal injections of bevacizumab.
In summary, most published studies suggest that anti-VEGF
agents reduce radiation-induced macular edema and retinal
neovascularization, although not all studies demonstrate
improvement in visual acuity.5 The optimal treatment regime
has yet to be defined.
References
1. Hykin PG, Shields CL, Shields JA, Arevalo JF. The efficacy of
focal laser therapy in radiation-induced macular edema. Ophthalmology 1998; 105(8):1425-1429.
2. Mason JO, Albert MA, Persaud TO, Vail RS. Intravitreal bevacizumab treatment for radiation macular edema after plaque radiotherapy for choroidal melanoma. Retina 2007; 27(7):903-907.
3. Finger PT, Chin KJ. Intravitreous ranibizumab (Lucentis) for
radiation maculopathy. Arch Ophthalmol. 2010; 128(2):249-252.
4. Gupta A, Muecke JS. Treatment of radiation maculopathy with
intravitreal injection of bevacizumab (Avastin). Retina 2008;
28(7):964-968.
5. Giuliari GP, Sadaka A, Hinkle DM, Simpson ER. Current treatments for radiation retinopathy. Acta Oncologica (Stockholm)
2011; 50(1):6-13.
2016 Subspecialty Day | Ocular Oncology & Pathology
Section II: The Management of Intraocular Tumors
Retinoblastoma: Intra-arterial Chemotherapy
All the Way
Jasmine H Francis MD
In many centers worldwide, intra-arterial chemotherapy has
become first-line treatment for retinoblastoma. Reportedly,
three-quarters of retinoblastoma centers worldwide use intraarterial chemotherapy as first-line treatment for advanced unilateral disease. Intra-arterial chemotherapy can also be useful
for cases beyond those that are advanced unilateral disease,
including bilateral, less advanced, and very advanced disease.
With first-line use of intra-arterial chemotherapy and a decade
of follow-up, our group demonstrates ocular survival rates that
exceed all historical data without compromising patient survival.
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Section II: The Management of Intraocular Tumors
2016 Subspecialty Day | Ocular Oncology & Pathology
Retinoblastoma: Intra-arterial Chemotherapy in
Selected Cases
Mandeep S Sagoo MBBChir PhD
I. Range of Options for Treating Intraocular
Retinoblastoma (Rb)
A. Depends on the International Classification of
Retinoblastoma (ICRB) group
a. Diode thermotherapy laser (TTT)
b.Cryotherapy
c. Plaque brachytherapy
a. Systemic chemotherapy
i. Vincristine, etoposide, and carboplatin
ii. 6 cycles, given intravenously
iii. Some centers vary this regimen.
iv. Cyclosporine added by some centers
v. Primary treatment
7. Parental wishes
A.Advantages
1. Controls Rb according to ICRB group
2. Resolves retinal detachment
3. Prevents new tumors
4. Prevents pineoblastoma
5. Preserves visual acuity
B.Disadvantages
1. Recurrences or treatment failure
2. Failure related to tumor, vitreous, or subretinal
seeds
3. Most recurrences year
4.Toxicities
b. Intra-ophthalmic artery chemotherapy
i. Initial reports with melphalan
ii. Many centers now add in topotecan.
iii. 2-6 cycles
iv. Primary or secondary treatment
II. The Pros and Cons of Systemic Chemotherapy
2.Chemotherapy
6. Risk / benefit ratio
1. Local treatments
c. Intravitreal chemotherapy
i. Specific technique to avoid seeding
ii. Melphalan ± topotecan
iii. Main indication is vitreous disease.
3.Radiotherapy
a. Plaque brachytherapy
b. Proton beam radiotherapy
c. External beam radiotherapy: Now considered equal to conservative treatment failure
2. Age of patient
3. Status of fellow eye
4. Treatment availability and expertise of the multidisciplinary team
5. Complication profile
b. Long term: hearing loss, kidney failure, leukemia
A.Advantages
1. Selective local treatment
2. Controls Rb
B.Disadvantages
1. Highly specialized team to deliver IAC
2.Risks
B. Specialist Rb centers choose treatment according
to:
1. ICRB group
a. Short term: cytopenia, infection, fever
III. The Pros and Cons of Intra-arterial Chemotherapy
(IAC)
4. Surgery: Enucleation with orbital implant insertion
a. Severe visual loss: 42%
i. Retinal detachment
ii. Choroidal ischemia involving the foveola
b. Third cranial nerve palsy: 40%
c. Orbital edema: 20%
d. Vitreous hemorrhage: 27%
e. Retinal pigment epithelium changes: 47%
3. Failure related to vitreous seeds or anterior segment involvement
4. Toxicity – vagal response possible
5. Metastatic Rb reported
2016 Subspecialty Day | Ocular Oncology & Pathology
IV. Selected Cases for IAC
A. Relapse after primary systemic chemotherapy as a
salvage treatment
1. Burden of disease is retinal or subretinal.
2. Multiple relapse in 1 eye
3. Relapse has failed other local therapy.
4. Area of relapse is too broad for other local
therapy.
5. Replaces external beam radiotherapy for salvage
6. Poor for control of vitreous disease
B. Primary treatment
1. ICRB Group C
2. Possible role in ICRB Group D, but hard to predict cases with high-risk histopathology features
from clinical presentation
3. Unilateral vs. bilateral
Section II: The Management of Intraocular Tumors
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Section II: The Management of Intraocular Tumors
2016 Subspecialty Day | Ocular Oncology & Pathology
Retinoblastoma: Intra-arterial Chemotherapy—Never
Super-Selective Intra-arterial Chemotherapy (SSIOAC) or Chemosurgery
Matthew W Wilson MD
I.Why?
A. Targeted local delivery of drug
B. Minimize total dose exposure of chemotherapy
C. Great results
1. Ocular salvage
2. Electroretinography data
II. Why Not?
1. Different delivery site
2. Different dilution of drug
3. Same amount of drug 5-mg melphalan
B. Preclinical modeling with vascular toxicity
C. Clinical vascular complications
1.Ocular
2.Cerebral
D. Systemic dosing through the ophthalmic artery:
Neutropenia
E. SSIOAC does not provide patient-centric care.
A. SSIOAC is an evolution of Kaneko’s intracarotid
chemotherapy.
1. High-risk eyes have high-risk pathology.
2. Undertreating the entire patient poses risk of
metastases.
3. Neoadjuvant therapies alter pathology going
forward.
F. No prospective clinical trial; Children’s Oncology
Group trial ongoing
III. What Is the Value of the Eye Being Saved?
Selected Readings
1. Abramson DH, Dunkel IJ, Brodie SE, et al. A Phase I/II study of
direct intraarterial (ophthalmic artery) chemotherapy with melphalan for intraocular retinoblastoma: initial results. Ophthalmology 2008; 115:1398-1404.
2. Munier FL, Beck-Popovic M, Balmer A, et al. Occurrence of
sectoral choroidal occlusive vasculopathy and retinal arteriolar
embolization after ophthalmic artery chemotherapy for advanced
intraocular retinoblastoma. Retina 2011; 31:566-573.
5. Shields CL, Bianciotto CG, Jabbour P, et al. Intra-arterial chemotherapy for retinoblastoma: report no. 2, treatment complications.
Arch Ophthalmol. 2011; 129:1407-1415.
6. Gobin YP, Dunkel IJ, Marr BP, et al. Intra-arterial chemotherapy
for the management of retinoblastoma: four-year experience. Arch
Ophthalmol. 2011; 129:732-737.
7. Muen WJ, Kingston JE, Robertson F, et al. Efficacy and complications of super-selective intra-ophthalmic artery melphalan for the
treatment of refractory retinoblastoma. Ophthalmology 2012;
119:611-616.
8. Wilson MW, Jackson JS, Phillips BX, et al. Real-time ophthalmoscopic findings of superselective intraophthalmic artery chemotherapy in a nonhuman primate model. Arch Ophthalmol. 2011;
129:1458-1465.
9. Tse BC, Steinle JJ, Johnson D, et al. Superselective intraophthalmic artery chemotherapy non-human primate model: histopathology. JAMA Ophthalmol. 2013; 131:903-911.
10. Vajzovic LM, Murray TG, Aziz-Sultan MA, et al. Clinicopathologic review of enucleated eyes after intra-arterial chemotherapy
with melphalan for advanced retinoblastoma. Arch Ophthalmol.
2010; 128:1619-1623.
11. Graeber CP, Gobin YP, Marr BP, et al. Histopathologic findings
of eyes enucleated after treatment with chemosurgery for retinoblastoma. Open Ophthalmol J. 2011; 5:1-5.
12. Kim J, Do H, Egbert P. Enucleated eyes after failed intra-arterial
infusion of chemotherapy for unilateral retinoblastoma: histopathologic evaluation of vitreous seeding. Clin Ophthalmol. 2011;
5:1655-1658.
13. Eagle RC, Shields CL, Bianciotto C, et al. Histopathologic observations after intra-arterial chemotherapy for retinoblastoma. Arch
Ophthalmol. 2011; 129:1416-1421.
14. Pannicke T, Iandiev I, Uckermann O, et al. A potassium channellinked mechanism of glial cell swelling in the postischemic retina.
Mol Cell Neurosci. 2004; 26:493-502.
15. Pannicke T, Uckermann O, Iandiev I, et al. Ocular inflammation
alters swelling and membrane characteristics of rat Muller glial
cells. J Neuroimmunol. 2005; 161:145-154.
16. Ruiz-Moreno JM, Flores-Moreno I, Lugo F, et al. Macular choroidal thickness in normal pediatric population measured by sweptsource optical coherence tomography. Invest Ophthalmol Vis Sci.
2013; 54:353-359.
17. Park KA, Oh SY. Choroidal thickness in healthy children. Retina
2013; 33:1971-1976.
18. Mapelli C, Dell’Arti L, Barteselli G, et al. Choroidal volume
variations during childhood. Invest Ophthalmol Vis Sci. 2013;
54:6841-6845.
3. Shields CL, Shields JA. Retinoblastoma management: advances in
enucleation, intravenous chemoreduction, and intra-arterial chemotherapy. Curr Opin Ophthalmol. 2010; 21:203-212.
19. Wilson MW, Haik BG, Dyer MA. Superselective intraophthalmic
artery chemotherapy: what we do not know. Arch Ophthalmol.
2011; 129:1490-1491.
4. Vajzovic LM, Murray TG, Aziz-Sultan MA. Supraselective intraarterial chemotherapy: evaluation of treatment related complications in advanced retinoblastoma. Clin Ophthalmol. 2011; 5:171176.
20. Ditta LC, Choudhri AF, Tse BC, et al. Validating a nonhuman
primate model of super-selective intra-ophthalmic artery chemotherapy: comparing ophthalmic artery diameters. Invest Ophthal
Vis Sci. 2012; 53:7791-7794.
2016 Subspecialty Day | Ocular Oncology & Pathology
21. Steinle JJ, Zhang Q, Thompson KE, et al. Intra-ophthalmic artery
chemotherapy triggers vascular toxicity through endothelial cell
inflammation and leukostasis. Invest Ophthalmol Vis Sci. 2012;
53:2439-2445.
22. Silva RA, Dubovy SR, Hess D, et al. Hemorrhage as sign of treatment failure after intra-arterial chemotherapy in retinoblastoma.
J AAPOS. 2015; 19:268-270.
23. Matthew AA, Sachdev N, Stafferi SE, et al. Superselective intraarterial chemotherapy for advanced retinoblastoma complicated
by metastatic disease. J AAPOS. 2015; 19:72-74.
24. Huerta I, Selder MI, Hetts SW, Damato BE. Delayed cerebral
infarction following intra-arterial chemotherapy for retinoblastoma. JAMA Ophthalmol. 2016; 134(6):712-714.
25. Dunkel IJ, Shi W, Salvaggio K et al. Risk factors for severe neutropenia following intra-arterial chemotherapy for intra-ocular
retinoblastoma. PLoS ONE 2014; 9(10): e108692.
Section II: The Management of Intraocular Tumors
27
28
Section II: The Management of Intraocular Tumors
2016 Subspecialty Day | Ocular Oncology & Pathology
Retinoblastoma: Children’s Oncology Group Update
on Intra-arterial Chemotherapy
Murali Chintagumpala MD
Introduction
COG Study
Systemic chemotherapy in combination with local ophthalmic
therapies is successful in salvaging globes and avoiding radiation therapy. However, this approach is associated with systemic toxicity, sometimes requiring hospitalizations, decreased
success in eyes with advanced disease, and the treatment course
uniformly lasting approximately 6 months or longer. In an
effort to overcome these limitations, efforts are under way to
deliver chemotherapy directly to the tumor via the ophthalmic
artery (intra-arterial chemotherapy) or into the vitreous.
The primary objective of this study is to study the feasibility
of delivering melphalan directly into the ophthalmic artery in
children with newly diagnosed unilateral Group D retinoblastoma, who would otherwise be considered for enucleation. The
secondary objectives are (1) to estimate the ocular salvage rate
after treatment with intra-arterial melphalan in children with
newly diagnosed unilateral retinoblastoma with Group D disease, (2) to evaluate the toxicities and adverse events associated
with delivering multiple doses of intra-arterial chemotherapy,
(3) to evaluate vision outcomes in children treated with intraarterial chemotherapy, and (4) to monitor the rate of the development of metastatic disease while on protocol therapy.
Central review panels were established to confirm the diagnosis of “D” disease before study entry and confirm progression
while on therapy, and to confirm the validity of the intra-arterial procedure. A patient will be considered to have experienced
intra-arterial therapy feasibility failure if (1) the interventional
radiologist is not able to access the ophthalmic artery for chemotherapy administrations during the first 3 cycles of therapy,
(2) the patient develops central retinal artery occlusion after the
first or second cycle that does not reopen by the time the next
injection is due, or (3) the patient cannot receive all 3 treatments
with intra-arterial therapy because of CTC adverse event complications Grade III or IV that are considered possibly, probably,
or likely related to treatment.
This is the first attempt to conduct a multi-institutional
study using intra-arterial therapy for retinoblastoma with wellestablished guidelines for the conduct of the study.
Background
Single-institution experiences showed promising results with
chemotherapy delivered through the ophthalmic artery of the
affected eye. However, the data from these experiences were
difficult to interpret in the absence of protocol-driven guidelines
for treatment, number and course of chemotherapy agents, and
the monitoring and grading of toxicities, either short term or
cumulative. Evaluating the feasibility and efficacy of this procedure in the context of a multi-institutional study is a critical
next step toward the goal of establishing guidelines for the safe
implementation of the intra-arterial technique across Children’s
Oncology Group (COG) sites.
2016 Subspecialty Day | Ocular Oncology & Pathology
Section II: The Management of Intraocular Tumors
29
Retinoblastoma: Documented Toxicities of
Intra-arterial Chemotherapy
Dan S Gombos MD
Introduction
The management of retinoblastoma is not limited in modalities associated with excellent tumor control. The malignancy is
associated with a 98%-99% cure rate in developed countries.
Surgery (enucleation), external beam radiation therapy, systemic chemotherapy, and local chemotherapy (intra-arterial
and intravitreal chemotherapy) differ primarily in their toxicity
profile. The side-effects associated with external beam radiation
therapy and intravenous chemotherapy have played a significant
role in advocating for local treatment strategies. A full understanding of the toxicity profile associated with intra-arterial
chemotherapy (IAC) is critical as the acceptance and utilization
of this modality increase among centers worldwide.
As with any new therapy, the learning curve associated
with its application has the potential to impact reported and
observed complication rates. Retrospective studies have been
limited in their ability to report specific complication rates.
Nonetheless, excellent review articles have attempted to collate and estimate the toxicity profile associated with IAC in the
management of retinoblastoma.
Overall, the toxicities associated with this modality are best
classified as local (globe and periocular structures) versus systemic (CNS and distant) effects.
Local Toxicity
Ocular (globe) toxicity
Vascular complications, including vascular occlusion and choroidal ischemia, are among the most common findings in eyes
treated with IAC. Optic atrophy and vitreous hemorrhage have
also been described. Careful attention by the interventional
radiologist to avoid wedge flow and to ensure uniform pulsatile administration of chemotherapy is thought to reduce these
complications. The presence of birefringent material in enucleated specimens is a new pathologic feature not seen prior to
application of IAC. There is debate among experts whether this
represents cotton fibers or crystalline deposits of the administered agents. Regardless, filtering the drugs and administering
them in a timely fashion after compounding appears to mitigate
this toxicity. Retinal detachment and phthisis are serious complications with increased likelihood of poor visual outcome and
secondary enucleation. One group has suggested reduced axial
length in eyes treated with IAC. Animal primate models have
also demonstrated toxicity to the vascular endothelium following the administration of melphalan. The long-term implications of these findings in children remains unclear. Of note, few
studies have looked at long-term visual outcomes and secondary
related risks of amblyopia and strabismus.
Periocular/orbital toxicity
Significant periocular edema and cellulitis can occur following
IAC administration. These cases can be treated with steroids.
Some centers use periocular vasoconstrictors to reduce this risk.
Secondary lash loss, ptosis, and motility abnormalities have all
been described as well. Accessory lacrimal vasculature is likely
to play a role in the amount of chemotherapy administered to
the periocular structures, including the orbit and lid. Specific
chemotherapeutic agents (such as high-dose carboplatin) may
have a greater likelihood of causing these complications.
Distant (Non-ocular) Toxicity
CNS toxicity
Vasospasm is a common occurrence and one that should be
anticipated by the interventional radiologist. Strokes and transient neurologic deficits have now been described by multiple
centers and are fortunately a rare occurrence. Some experts
have advocated screening patients at high risk for embolic
phenomena, including sickle cell and hypercoagulable states.
At present it is unclear how transient hypoxia associated with
vasospasm or downstream administration of chemotherapy to
the CNS impacts these patients neuro-developmentally.
IAC necessitates the use of fluoroscopy and thereby exposes
all children to radiation. Although studies suggest that the
amount of radiation exposure is low, patients with atypical
vasculature requiring nontraditional approaches are more likely
to be exposed to longer fluoroscopy times and increased radiation doses. It is unclear how even low-dose radiation will impact
second tumor risk in this cohort, particularly children less than
1 year of age. Historically, most experts advocated against any
radiation exposure during this critical developmental period,
including avoidance of CT scans.
Systemic and distant toxicity
Although IAC is locally administered, it is well recognized that
this approach is associated with fever and neutropenia in a
small but considerable cohort. These findings demonstrate that
despite local administration these agents are absorbed systemically and impact the bone marrow. Melphalan in particular is
a highly toxic drug with significant impact on bone marrow
myelosuppression.
While not a toxicity per se, many experts have raised the
concern that locally administered chemotherapy does not provide systemic prophylaxis against metastasis to patients with
eyes harboring high-risk histopathologic features. Data from
limited studies demonstrate that a small number of children
treated with IAC developed distant metastases, some of whom
were cured with high-dose chemotherapy.
Conclusions
IAC is increasingly recognized as an effective modality in treating various stages of retinoblastoma. One of the main drivers in
advancing this technique was to avoid enucleation and minimize
toxicities associated with other treatment strategies. A thorough
understanding of the toxicities and complications associated
with this approach is critical if we are to integrate this treatment
strategy with others that are long established. As with external
30
Section II: The Management of Intraocular Tumors
2016 Subspecialty Day | Ocular Oncology & Pathology
beam radiation and intravenous chemotherapy, long-term toxicity, particularly in high-risk cohorts, will ultimately impact the
continued use of this technique in the future.
4. Shields CL, Manjandavida FP, Lally SE, et al. Intra-arterial chemotherapy for retinoblastoma in 70 eyes: outcomes based on the
international classification of retinoblastoma. Ophthalmology
2014; 121(7):1453-1460.
Selected Readings
5. Suzuki S, Yamane T, Mohri M, Kaneko A. Selective ophthalmic
arterial injection therapy for intraocular retinoblastoma: the longterm prognosis. Ophthalmology 2011; 118(10):2081-2087.
1. Gobin YP, Dunkel IJ, Marr BP, et al. Intra-arterial chemotherapy
for the management of retinoblastoma: four-year experience. Arch
Ophthalmol. 2011; 129(6):732-737.
2. Monroy JE, Orbach DB, VanderVeen D. Complications of intraarterial chemotherapy for retinoblastoma. Semin Ophthalmol.
2014; 29(5-6):429-433.
3. Munier FL, Beck-Popovic M, Balmer A, et al. Occurrence of
sectoral choroidal occlusive vasculopathy and retinal arteriolar
embolization after superselective ophthalmic artery chemotherapy
for advanced intraocular retinoblastoma. Retina 2011; 31(3):566573.
6. Yousef YA, Soliman SE, Astudillo PP, et al. Intra-arterial chemotherapy for retinoblastoma: a systematic review. JAMA Ophthalmol. Epub ahead of print 2016 Mar 17. doi: 10.1001/jamaophthalmol.2016.0244.
2016 Subspecialty Day | Ocular Oncology & Pathology
Section II: The Management of Intraocular Tumors
31
Pathology: Evisceration and Enucleation Disasters
Ralph C Eagle Jr MD
Inadvertent Evisceration of Eyes With Unrecognized
Intraocular Tumors
Today, an increasing number of blind painful eyes are being
eviscerated instead of enucleated. Major reasons for this therapeutic modification include better cosmesis after evisceration
and a reassessment of the risk of a sympathetic uveitis after
evisceration. In many instances, patients with blind painful eyes
are referred to oculoplastic surgeons who may perform evisceration without working-up the patient to exclude an occult
tumor. It must be remembered that prior to the availability of
modern imaging techniques, pathologic examination disclosed
intraocular tumors, usually malignant melanomas, in approximately 10% of enucleated blind painful eyes with opaque
media. This incidence has remarkably decreased in recent years,
but neoplastic surprises are still encountered. Admittedly, most
ophthalmic pathologists have never seen a case of sympathetic
uveitis following evisceration, but many have seen one or more
eyes with unsuspected uveal melanomas that have been inadvertently eviscerated.
Necrosis-related inflammation can confound the clinical
diagnosis of occult lesions; patients with necrotic tumors have
been misdiagnosed as having endophthalmitis, orbital cellulitis,
or orbital pseudotumor. The failure of largely necrotic tumors
to enhance on imaging studies may be a factor in misdiagnosis. The presence of a malignant intraocular neoplasm should
be excluded prior to evisceration of a blind or blind painful
eye. B-scan ultrasonography is recommended for screening.
Evisceration of an eye with retinoblastoma usually has fatal
consequences, but the effect on the prognosis of patients with
melanoma is less clear since many cases are thought to have
metastasized before they are evaluated by ophthalmologists.
Despite this, physicians who inadvertently eviscerate an eye
containing a uveal melanoma, a neoplasm that carries a 50%
lifetime risk of metastasis, are at risk to be found liable medicolegally for failure to diagnose or offer effective treatment
options if the patient subsequently develops metastasis.
Inadvertent Implantation of Tube Shunts in
Glaucomatous Eyes With Unrecognized Intraocular
Tumors
Intraocular tumors are well-recognized causes of secondary
glaucoma. Common mechanisms of tumor-related glaucoma
include infiltration and blockage of aqueous outflow pathways
by tumor cells, neovascular glaucoma, anterior displacement of
the lens-iris diaphragm in eyes with total retinal detachments,
and blockage of the trabecular meshwork by macrophages that
have ingested necrotic tumor. Cases of inadvertent tube shunt
implantation in glaucomatous eyes with occult neoplasms have
been reported in adults with ciliochoroidal or diffuse iris melanomas and children with unsuspected ciliary body medulloepitheliomas who developed neovascular glaucoma. In some
instances, tumor cells were found in the tube shunt’s extraocular reservoir.
The possibility of an intraocular tumor should always be
considered in an eye with unilateral glaucoma. Such glaucomatous eyes should be carefully evaluated for an occult intraocular
tumor, particularly medulloepithelioma or uveal melanoma,
before proceeding with tube shunt surgery. In suspicious cases,
surgery may be deferred until an ocular oncology consultation
is obtained and an intraocular tumor is excluded. Aqueous tube
shunts can provide an avenue for extraocular tumor extension.
A child with neovascular glaucoma has an intraocular tumor
until proven otherwise. The incidence of neovascular glaucoma
in eyes with ciliary body medulloepitheliomas and retinoblastoma are 47% and 26%, respectively.
Selected Readings
1. Eagle RC Jr, Grossniklaus HE, Syed N, et al. Inadvertent evisceration of eyes containing uveal melanoma. Arch Ophthalmol. 2009;
127(2):141-145.
2. Kaliki S, Eagle RC, Grossniklaus HE, et al. Inadvertent implantation of aqueous tube shunts in glaucomatous eyes with unrecognized intraocular neoplasms: report of 5 cases. JAMA Ophthalmol. 2013; 131(7):925-928.
32
Advocating for Patients
2016 Subspecialty Day | Ocular Oncology & Pathology
2016 Advocating for Patients
Zelia M Correa MD PhD
Ophthalmology’s goal to protect sight and empower lives
requires active participation with and commitment to advocacy
efforts. Contributions to the following three critical funds by all
ophthalmologists is part of that commitment:
1.OPHTHPAC® Fund
2. Surgical Scope Fund (SSF)
3. State Eye PAC
Your ophthalmologist colleagues serving on Academy committees—the Surgical Scope Fund Committee, the Secretariat
for State Affairs, and the OPHTHPAC Committee—are dedicating significant time to advocating for patients and the profession. The OPHTHPAC Committee is identifying congressional
advocates in each state to maintain close relationships with federal legislators in order to advance ophthalmology and patient
causes. The Secretariat for State Affairs is collaborating closely
with state ophthalmology society leaders to protect Surgery by
Surgeons at the state level. Both groups require robust funds
from both the Surgical Scope Fund and the OPHTHPAC Fund
in order to protect quality patient care.
These committed ophthalmologists serving on your behalf
have a simple message to convey: “It takes the entire community of ophthalmologists” to be effective.
■
■
■
We need each member of the ophthalmology community
to contribute to each of these 3 funds.
We need each member of the ophthalmology community
to establish relationships with state and federal legislators.
We need each member of the ophthalmology community
to make a commitment to protect quality patient eye care
and the profession.
OPHTHPAC® Fund
OPHTHPAC is a crucial part of the Academy’s strategy to
protect and advance ophthalmology’s interests in key areas,
including physician payments from Medicare as well as protecting ophthalmology from federal scope of practice threats.
Established in 1985, OPHTHPAC is one of the oldest, largest,
and most successful political action committees in the physician
community. We are very successful in representing your profession to the U.S. Congress. As one election cycle ends, a new one
starts. OPHTHPAC is always under financial pressure to support our incumbent friends as well as to make new friends with
candidates. These relationships allow us to have a seat at the
table and legislators willing to work on issues important to us
and our patients.
For the past year, the media and the country have focused
on the U.S. presidential primaries. But the races most important
to ophthalmology involve seats in Congress. The entire House
of Representatives and one-third of the Senate is up for election. Several physicians need our help—and we have many new
friends to make.
In order for ophthalmology to remain seated at the table, we
need to be heavily invested in this year’s election. That takes
investment by each member of the ophthalmology community,
whether with time or money. Currently, only a minority of
ophthalmologists have realized the vital importance of contributing to OPHTHPAC and the other funds. Right now, major
transformations are taking place in health care and we need
participation from the majority of ophthalmologists so that we
have the resources to better our profession and ensure quality
eye care for our patients.
Among the significant impacts made by OPHTHPAC are the
following:
■
■
■
■
■
■
■
Repealed the flawed Sustainable Growth Rate (SGR)
formula
Blocked the unbundling of Medicare global surgery payments
Removed a provision in Medicare fraud and abuse legislation that targeted eyelid surgery
Working to reduce the burdens from Medicare’s existing
quality improvement programs, such as the EHR Meaningful Use program
Working in collaboration with subspecialty societies to
preserve access to compounded and repackaged drugs
such as Avastin
Working to get the Centers for Medicare and Medicaid
Services to revisit drastic Medicare fee cuts to glaucoma
and retinal detachment surgeries
Working to protect your ability to perform in-office ancillary services in your office
Contributions to OPHTHPAC can be made here at AAO
2016 or online at www.aao.org/ophthpac.
Leaders of the American Association of Ophthalmic
Oncologists (AAOOP) are part of the American Academy of
Ophthalmology’s Ophthalmic Advocacy Leadership Group
(OALG), which has met for the past nine years in January in the
Washington, DC, area to provide critical input and to discuss
and collaborate on the Academy’s advocacy agenda. The topics
discussed in the 2016 OALG agenda included the impact of the
Medicare Access and the CHIP Reauthorization Act (MACRA);
the IRISTM Registry and quality reporting under Medicare;
data transparency and public reporting, and a roundtable to
discuss challenges for surgical specialties. At Mid-Year Forum
2016, the Academy and AAOOP ensured a strong presence of
ophthalmic oncologists and pathologists to support our priorities, and a record number of ophthalmologists visited members
of Congress and their key health staff to discuss ophthalmology
priorities as part of Congressional Advocacy Day. The AAOOP
remains a crucial partner with the Academy in its ongoing federal and state advocacy initiatives.
Surgical Scope Fund (SSF)
The Surgical Scope Fund (SSF) provides grants to state ophthalmology societies to support their legislative, regulatory, and
public education efforts to derail optometric surgery proposals
that pose a threat to patient safety, quality of surgical care, and
surgical standards. Since its inception, the Surgery by Surgeons
campaign—in partnership with state ophthalmology societies
Advocating for Patients
2016 Subspecialty Day | Ocular Oncology & Pathology
Surgical Scope Fund
OPHTHPAC® Fund
State EyePAC
To derail optometric surgical scope of practice
initiatives that threaten patient eye safety and
quality of surgical care
Ophthalmology’s interests at the federal level /
support for candidates for U.S. Congress
Support for candidates for State House and
Senate
Political grassroots activities, lobbyists, and
media; no funds may be used for candidates
or PACs.
Campaign contributions, legislative education
Campaign contributions, legislative education
Contributions: Unlimited
Contributions: Limited to $5,000
Contribution limits vary based on state regulations.
Contributions above $200 are on the public
record.
Contributions are on the public record
depending upon state statutes.
Individual, practice, and organization
Contributions are 100% confidential.
and with support from the SSF—has helped 32 state / territorial ophthalmology societies reject optometric scope of practice
expansion into surgery.
In 2016, thanks to Surgical Scope Fund support by Academy
members and tireless advocacy by state ophthalmology society
leaders, ophthalmology continues to champion surgical safety
at state capitols across the country. State ophthalmological societies and the Academy’s Secretariat for State Affairs faced eight
concurrent Surgery by Surgeons battles, in Alaska, California,
Delaware, Illinois, Iowa, Massachusetts, Pennsylvania, and
Puerto Rico.
In each of these legislative battles, the benefits from Surgical
Scope Fund distributions are crystal clear. The fund has allowed
for successful implementation of patient safety advocacy campaigns, which result in defeating attempts by optometry to
expand their scope of practice to include surgery.
The Academy relies not only on the financial contributions
to the Surgical Scope Fund from individual ophthalmologists
and their practices, but also on the contributions made by ophthalmic state, subspecialty, and specialized interest societies.
The Academy counts on AAOOP’s contribution in 2016.
Contributions to the SSF can be made here at AAO 2016 or
online at www.aao.org/ssf.
Please respond to your Academy colleagues and be part of
the community that contributes to OPHTHPAC, the Surgical
Scope Fund, and your State Eye PAC. Please be part of the community advocating for your patients now.
*OPHTHPAC Committee
Donald J Cinotti MD (NJ) – Chair
Janet A Betchkal MD (FL)
William S Clifford MD (KS)
Sidney K Gicheru MD (TX)
Michael L Gilbert MD (WA)
Gary S Hirshfield MD (NY)
David W Johnson MD (CO)
Jeff Maltzman MD (AZ)
Lisa Nijm MD JD (IL)
John D Roarty MD (MI)
Diana R Shiba MD (CA)
Woodford S Van Meter MD (KY)
John (“Jack”) A Wells III MD (SC)
Charles M Zacks MD (ME)
State Eye PAC
It is also important for all ophthalmologists to support their
respective State Eye PACs because PAC contributions to legislators at the state level must come from individual ophthalmologists and cannot come from the Academy, OPHTHPAC, or the
Surgical Scope Fund. The presence of a strong State Eye PAC,
providing financial support for campaign contributions and
legislative education to elect ophthalmology-friendly candidates
to the state legislature, is critical as scope of practice battles and
many regulatory issues are all fought on the state level.
Action Requested: ADVOCATE FOR YOUR PATIENTS
Academy Surgical Scope Fund contributions are used to support the infrastructure necessary in state legislative / regulatory
battles and for public education. PAC contributions are necessary at the state and federal level to help elect officials who will
support the interests of our patients. Contributions to each of
these three funds are necessary and help us protect sight and
empower lives. Surgical Scope Fund contributions are completely confidential and may be made with corporate checks or
credit cards, unlike PAC contributions, which must be made by
individuals and are subject to reporting requirements.
33
Ex Officio Members
Daniel J Briceland MD (AZ)
David W Parke II MD (CA)
Michael X Repka MD (MD)
William L Rich III MD FACS (VA)
George A Williams MD (MI)
**Surgical Scope Fund Committee
Kenneth P Cheng MD (PA) – Chair
Matthew F Appenzeller MD (NC)
Ronald A Braswell MD (MS)
John P Holds MD (MO)
Cecily A Lesko MD FACS (NJ)
C Blake Myers MD (SC)
William (“Chip”) W Richardson II MD (KY)
David E Vollman MD MBA (MO)
Ex Officio Members:
Daniel J Briceland MD (AZ)
Kurt F Heitman MD (SC)
34
Section III: Forecasting the Future
2016 Subspecialty Day | Ocular Oncology & Pathology
Sildenafil Citrate (Viagra) for Lymphatic
Malformations
Mary O’Hara MD
I Types of Lymphatic Malformations (LM)
A.Macrocystic
B.Microcystic
C.Mixed
II. Proposed Mechanism of Action of Sildenafil on LM
Phosphodiesterase E selective inhibitor
A. Smooth muscle relaxation
B. Cyst decompression
III. Treatment Results to Date
A. Not uniformly effective
B. More effective on mixed or macrocystic LM
C. Effect may be related to duration of treatment.
D. Treatment with other interventions such as
sclerotherapy does not diminish effect.
IV. Presentation of Long-term Follow-up on 2 Orbital LM
Treated With Viagra
Selected Readings
1. Swetman GL, Berk DR. Sildenafil for severe lymphatic
malformations. N Engl J Med. 2012; 366(4):384-386.
2. Danial C, Tichy AL, Tariq U, et al. An open-label study to
evaluate sildenafil for the treatment of lymphatic malformations.
J Am Acad Dermatol. 2014; 70(6):1050-1057.
3. Gandhi NG, Lin LK, O’Hara M. Sildenafil for pediatric orbital
lymphangioma. JAMA Ophthalmol. 2013; 131(9):1228-1230.
4. Koshy JC, Eisemann BS, Agrawal N, et al. Sildenafil for
microcystic lymphatic malformations of the head and neck: a
prospective study. Int J Ped Otolaryngol. 2015; 79:980-982.
5. Quddus AI, Nizami N, Dilawar S, et al. Sildenafil in cystic
hygroma. J Coll Physicians Surg Pak. 2015; 25(suppl 2):S117-S118.
6. Bagrodia N, Defnet AM, Kandel JJ. Management of lymphatic
malformations in children. Curr Opin Pediatr. 2015; 27:356-363.
7. Defnet AM, Bagrodia N, Hernandez SL, et al. Pediatric lymphatic
malformations: evolving understanding and therapeutic options.
Pediatr Surg Int. 2016; 32:425-433.
8. Rankin H, Zwicker K, Trenor CC. Caution is recommended prior
to sildenafil use in vascular anomalies. Pediatr Blood Cancer.
2015; 62:2015-2017.
2016 Subspecialty Day | Ocular Oncology & Pathology
Section III: Forecasting the Future
35
Sclerosing Therapy for Lymphatic Malformations
Kenneth Cahill MD FACS, James Murakami MD, William Shiels DO (1954–2015),
Jill Foster MD, Cameron Nabavi MD, Daniel Straka MD
This paper is presented regarding an institutional review entity–
approved study of intralesional treatment of venolymphatic
malformations at Nationwide Children’s Hospital in Columbus,
Ohio.
The diagnosis of venolymphatic malformations is usually
based upon clinical and radiological characteristics. Histopathology is only infrequently obtained. Affected patients usually
have the onset of symptoms before the age of 20 years. There
is typically an acute expansion(s). In this presentation, we are
particularly interested in the periocular involvement of eyelids,
conjunctiva, orbit, and face. CNS and other body parts can also
be affected. Radiologically, there are typically thin-walled fluidfilled cysts ranging from micro (4 mm) to macro (> 1 cm) in size.
They can be solitary or numerous. Frequently , they will exhibit
layers associated with blood degradation products. Thick
fibrotic tissue can occur, especially with chronic lesions.
The treatment can consist of observation or emergent aspiration when vision and/or the cornea are at risk. Intralesional
sclerotherapy has been shown to be effective. Some systemic
medications show promise and are being actively studied.
For sclerotherapy, there is no single agent or single treatment
protocol that works for all lesions. Bleomycin in concentrations
of 1-2 mg/mL is the most frequently used sclerosing agent. Of
the agents that we use, it seems to cause the least amount of
swelling and inflammation. When used in relatively low doses,
its risks of pulmonary fibrosis and skin hyperpigmentation are
diminished. It is used as a foam prepared with 25% human
serum albumin (HAS) and administered with real-time ultrasound. Direct observation is used for the conjunctival lesions.
This is not used for macrocysts.
Doxycycline can be used in concentrations of 10 mg/mL
mixed with 25% HAS. More concentrated doses are not used
because of the increased tissue inflammation. Despite this,
doxycycline still causes more inflammation and swelling than
bleomycin. For this reason, it is typically not chosen for deeper
orbital lesions or subconjunctival cysts. It is primarily used for
small to medium-sized cysts in the eyelids, especially if bleomycin has not been effective. Doxycycline has been shown to
disrupt the VEGF pathway.
Dehydrated ethanol is used following the instillation of
sodium tetradecyl sulfate (STS). The ethanol is very caustic,
so we use it only in macrocysts in which an indwelling flexible
pigtail catheter can be placed to facilitate steps of the treatment
and to provide post-treatment drainage of the effusion fluids for
48 hours. Due to the potential for severe tissue damage caused
by ethanol, the procedure is performed under fluoroscopy to
make sure that no leakage occurs.
The review of our first 20 patients showed efficacy, low incidence of complications, frequent need for multiple treatments
to minimize treatment swelling and to maximize the obliteration of cysts, and an apparent decrease in the risk of recurrent “rebleeds.” We are now reviewing our first 80 treated
patients, who all have follow-up over 1 year, up to 13 years.
Systemic treatment with sildenafil and sirolimus as systemic
or as medical treatments is being studied. Both of these medications do have side effects and need to be monitored. Their beneficial effect may be partially lost upon discontinuation. Hopefully, treatment trials of these medications will result in more
treatment options, either as independent agents or as adjunct to
sclerotherapy. Hopefully, these trials will also enable us to learn
more about the nature of lymphangioma s so that future treatments can more specifically control their specific properties.
Selected Readings
1. Shiels W, Kenney B, Caniano D, Besner G. Definitive percutaneous treatment of lymphatic malformation of the trunk and
extremities. J Pediatr Surg. 2008; 43(1):136-139.
2. Hill R, Shiels W, Foster J, et al. Percutaneous drainage and ablation as first line therapy for macrocystic and microcystic orbital
lymphatic malformations. Ophthal Plast Reconstr Surg. 2012;
28(2):119-125.
3. Paramasivam S, Fay A, Fifi J, Berenstein A. 0-015 image guided
bleomycin sclerotherapy for orbital lymphatic malformation.
J Neurointerv Surg. 2014; 6(suppl 1):A8-9.
4. Nosher J, Murillo P, Liszewski M, Gendel V, Gribbin C. Vascular anomalies: a pictorial review of nomenclature, diagnosis and
treatment. World J Radiol. 2014; 6(9):677-692.
5. Stacy A, Gemmete J, Kahana A. Management of orbital and periocular vascular anomalies. Ophthal Plast Reconstr Surg. 2015;
31(6):427-436.
6. Katz S, Rootman J, Vangveeravong S, Graeb D. Combined venous
lymphatic malformations of the orbit (so-called lymphangiomas):
association with noncontiguous intracranial vascular anomalies.
Ophthalmology 1998; 105(1):176-184.
7. Swetman G, Berk D, Vasanawala S, Bruckner A. Sildenafil for
severe lymphatic malformations. N Engl J Med. 2012; 366:384386.
8. Lackner H, Karastaneva A, Schwinger W, et al. Sirolimus for the
treatment of children with various complicated vascular anomalies. Eur J Pediatr. 2015; 174(12):1579-1584.
9. Adams D, Trenor C 3rd, Hammill A, et al. Efficacy and safety
of sirolimus in the treatment of complicated vascular anomalies.
Pediatrics 2016; l37(2):1-10.
36
Section III: Forecasting the Future
2016 Subspecialty Day | Ocular Oncology & Pathology
Coats Disease: What Works
G Baker Hubbard MD
Coats disease is an idiopathic retinal vascular disease that typically affects young males. Characteristic retinal lesions include
vascular telangiectasias and dilated aneurysmal vessels along
with patches of avascular retina. These lesions are visible with
indirect ophthalmoscopy, but the full extent of vascular abnormality is best seen by wide-angle fluorescein angiography (FA).1
The vascular lesions cause exudation that leads to progressive
accumulation of yellow deposits, exudative retinal detachment,
and fibrosis, which in turn cause vision loss or blindness. The
goal of treatment is to reduce leakage by ablating the retinal
vascular lesions or by pharmacologically modulating leakage
from these lesions. Various techniques and agents have been
described to achieve this goal.
Cryotherapy has been used for decades as an effective means
of ablating the retinal vascular lesions of Coats disease.2 Cryotherapy has the advantage of being effective even when there is
shallow subretinal fluid under the vascular lesions because the
ice ball from the cryo probe can traverse shallow fluid and still
freeze the vascular lesions. After a double freeze-thaw, vascular
lesions reliably respond and stop leaking over a period of 1-2
months.
There are 2 main disadvantages of cryotherapy. One is that
sometimes the vascular lesions are not accessible with a cryo
probe. This is true when there is bullous subretinal fluid present or when the vascular lesions are located on top of subretinal
fibrosis or thick accumulations of exudate. A second disadvantage is that the requisite heavy freezing can be inflammatory
and can cause significant discomfort. As a result of the inflammatory effects, temporary worsening of exudation immediately
after cryotherapy is common.
Laser has also been used to ablate retinal vascular lesions
in Coats, and laser indirect ophthalmoscopes (LIOs) are now
widely available in operating rooms.3 Wavelength of laser matters for Coats disease. Infrared 810-nm lasers commonly used
to treat retinoblastoma and ROP in pediatric operating rooms
are not effective for Coats because there is virtually no uptake
of infrared energy by vascular lesions. The lack of uptake by
vascularized structures is a major advantage for infrared lasers
in treating ROP because there is no uptake by the perfused
tunica vasculosa lentis and the risk of cataract is minimized. For
Coats, however, uptake in the vascular lesions is the goal. Optimum uptake in vascular tissue is achieved with wavelengths in
the yellow spectrum and yellow wavelength 577-nm LIOs are
now available.
Intravitreal injections of steroids and more recently antiVEGF agents have been reported to pharmacologically modulate the leakage associated with Coats disease. The rationale
has been to reduce leakage to facilitate ablative treatment with
cryotherapy or laser. Extensive experience with other exudative
retinal vascular diseases (AMD, branch and central retinal vein
occlusion, diabetic macular edema) has proven these agents to
be effective. In Coats, however, results are mixed in comparison to the other diseases. Intravitreal steroids when used with
cryotherapy may induce a “crunch” phenomenon with resulting rhegmatogenous detachment. Anti-VEGF results in Coats
have been generally good but not as strikingly beneficial as with
other retinal vascular diseases.
Advanced vitreoretinal techniques have been reported for
Coats disease to drain subretinal fluid and to alleviate traction
caused by organized vitreous and subretinal fibrosis. Techniques have included scleral buckling, vitrectomy, membrane
peeling, internal or external drainage, and tamponade using
oil or gas. Some have advocated for multimodal treatment
using anti-VEGF, laser ablation, and vitreoretinal surgery for
advanced cases.
We recently reported good results of treating Coats disease
with FA-guided yellow (577-nm) LIO as monotherapy. Our
protocol uses yellow LIO to “paint” all visible telangiectasias.
Uptake with yellow laser can be achieved in the vascular lesion
even when bullously detached. After resolution of exudative
retinal detachment, we treat areas of nonperfusion with scatter
laser treatment. The procedure is repeated every 3-4 months
until all vascular lesions are ablated. Mild cases are treated in
1-2 sessions, and severe cases are treated in 3-4 sessions. In our
series, even patients with bullous retinal detachment and highly
detached vascular lesions were successfully treated with laser
alone. Similar results have also been achieved with green 532nm laser for Coats.4
Laser monotherapy offers several advantages over treatment
protocols that employ multiple treatment modalities. One,
fewer examinations under anesthesia (EUAs) are required, and
the patient is thereby spared of additional risk and expense
associated with the EUAs required to deliver monthly injections
of anti-VEGF in young children. Two, the technique is noninvasive, and risk of inadvertent injection or incision in a patient
who may harbor occult retinoblastoma is avoided. Three, the
noninvasive nature of the treatment is also preferable because
of the limited visual potential for most eyes with Coats. The
majority of eyes with advanced Coats, for which invasive vitreoretinal surgical techniques may be considered, have dense
amblyopia that would severely limit vision even if normal
anatomy could be promptly restored. Such cases generally have
long-standing exudative retinal detachment with substantial
accumulation of yellow exudate or fibrosis in the macula. As a
result, the recovery time, expense, risk, and emotional investment of family members associated with major vitreoretinal
surgery are not likely to be rewarded with outcomes that match
expectation in most cases. This is especially true when there is a
noninvasive treatment option available that can yield equivalent
results.
To summarize, multiple modalities have been described to
treat Coats disease. Advanced cases with bullous retinal detachment have a limited prognosis for good vision regardless of
treatment. Our approach of laser monotherapy has achieved
excellent results even with bullous retinal detachment. Laser
monotherapy offers a noninvasive, low-risk, and cost-effective
option for most cases of Coats disease. Rare cases may benefit
from anti-VEGF injections or intervention with advanced vitreoretinal techniques.
2016 Subspecialty Day | Ocular Oncology & Pathology
References
1. Suzani M, Moore AT. Intraoperative fluorescein angiographyguided treatment in children with early Coats’ disease. Ophthalmology 2015; 122(6):1195-1202.
2. Shields JA, Shields CL, Honavar SG, Demirci H, Cater J. Classification and management of Coats disease: the 2000 Proctor
Lecture. Am J Ophthalmol. 2001; 131(5):572-583.
3. Levinson JD, Hubbard GB 3rd. 577-Nm Yellow laser photocoagulation for Coats disease. Retina 2016; 36(7):1388-1394.
4. Shapiro MJ, Chow CC, Karth PA, Kiernan DF, Blair MP. Effects
of green diode laser in the treatment of pediatric Coats disease.
Am J Ophthalmol. 2011; 151(4):725-731 e722.
Section III: Forecasting the Future
37
38
Section III: Forecasting the Future
2016 Subspecialty Day | Ocular Oncology & Pathology
mTOR Inhibitors for Retinal Astrocytic Hamartomas
Prithvi Mruthyunjaya MD
Tuberous sclerosis complex (TSC) is an autosomal dominant
disorder characterized by hamartomas in multiple organ systems caused by mutations in the TSC1 or TSC2 genes.1 The
TSC1 and TSC2 genes are involved in integration of growth
signals and nutrient inputs to downregulate mammalian target
of rapamycin (mTOR), which controls cell growth and cell survival.2
Aside from debilitating systemic manifestations (commonly
in the CNS, kidney, heart, and lung), retinal astrocytic hamartomas (RAHs) are the most commonly noted ocular findings
in TSC, occurring in approximately 50% of patients with TSC.
When seen in association with TSC, RAHs are typically relatively stationary.
Treatments have been directed toward reducing growth
and fluid exudation in RAH with numerous local therapies
including photodynamic therapy, transpupillary thermotherapy
(TTT), intravitreal anti-VEGF medications, and intravitreal
steroids. However, a subset of patients with TSC has been
described in whom aggressive behavior of RAHs leads to
severe ocular complications, including vitreous tumor seeding,
macular edema, exudative retinal detachment, and neovascular
glaucoma. These patients tend to be young children, with onset
often before the age of 5 years, ultimately requiring enucleation
for a blind, painful eye.3
TSC presents a unique opportunity to apply targeted drug
therapies to a complex systemic disease. The TSC1 and TSC2
gene products form a complex, sensing the presence of nutrients, growth factors, and energy. The TSC1 / TSC2 complex
down-regulates mTOR complex activation (mTORC1 and
mTORC2) through the intermediary RHEB (Ras homolog
enriched in brain). In the absence of TSC1 / TSC2 complex
function, constitutive activation of mTORC1 occurs, leading to
increased protein synthesis and decreased catabolic processes,
such as autophagy. This imbalance of anabolic and catabolic
processes results in a cell-growth advantage over surrounding
cells, leading to development of hamartomatous lesions.
Further understanding of TOR-driven development of hamartomatous lesions in TSC has led to the study of rapamycin
(sirolimus) and its analogs (everolimus, temsirolimus, and ridaforolimus) for the systemic treatment of TSC. Everolimus use
has meaningfully reduced subependymal giant-cell astrocytoma
volume in children with TSC in the Phase 3 EXIST-1 trial with
secondary modification of other disease sites.4
It may be inferred that systemic mTOR inhibition may
impact ocular manifestations of TSC, including RAH. Zhang
et al from Peking Union Medical College Hospital studied the
impact of systemic oral sirolimus on RAH in a cohort of 7 TSC
patients already being treated for systemic complications of the
disease. All lesions improved in thickness, and there was no
increase in lesion size. There was an average reduction of 13.9%
after a mean treatment duration of 7.9 months.5
An interventional case report presentation will outline
impact of systemic mTOR inhibition with everolimus on an
aggressive RAH and future therapeutic directions in this disease.
References
1. Northrup H, Krueger DA; International Tuberous Sclerosis Complex Consensus G. Tuberous sclerosis complex diagnostic criteria
update: recommendations of the 2012 International Tuberous
Sclerosis Complex Consensus Conference. Pediatr Neurol. 2013;
49(4):243-254.
2. MacKeigan JP, Krueger DA. Differentiating the mTOR inhibitors
everolimus and sirolimus in the treatment of tuberous sclerosis
complex. Neuro Oncol. 2015; 17(12):1550-1559.
3. Shields JA, Eagle RC Jr, Shields CL, Marr BP. Aggressive retinal
astrocytomas in four patients with tuberous sclerosis complex.
Trans Am Ophthalmol Soc. 2004; 102:139-147; discussion 147138.
4. Franz DN, Belousova E, Sparagana S, et al. Efficacy and safety
of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre,
randomised, placebo-controlled phase 3 trial. Lancet 2013;
381(9861):125-132.
5. Zhang ZQ, Shen C, Long Q, et al. Sirolimus for retinal astrocytic
hamartoma associated with tuberous sclerosis complex. Ophthalmology 2015; 122(9):1947-1949.
2016 Subspecialty Day | Ocular Oncology & Pathology
Section III: Forecasting the Future
Vismodegib for Basal Cell Carcinoma:
Current Status and Future Promise
Bita Esmaeli MD FACS
Vismodegib is sonic hedgehog pathway inhibitor that was first
studied in humans in 2008 and was approved by the U.S. Food
and Drug Administration (FDA) for treatment of metastatic and
locally advanced basal cell carcinoma in January 2012. Since
the identification of vismodegib, multiple small molecule inhibitors of the hedgehog pathway have been developed, and one
additional drug, sonidegib, has also been approved by the FDA
with indications similar to those of vismodegib.
Several small series have demonstrated promising results
with the use of vismodegib in patients with large tumors of the
orbit and periorbital region. Of particular interest is the use of
vismodegib as a method of chemoreduction in the neoadjuvant
setting prior to surgical resection, although this latter indication is considered off-label use. Several recent cases of locally
advanced periorbital and orbital lesions not amenable to eyepreserving surgery or radiation that have been successfully
managed with sonic hedgehog pathway inhibition using vismodegib will be highlighted in this presentation. The usual sideeffect profile, as well as timing of surgery and typical duration
of treatment prior to surgery, will also be discussed through
illustrative cases and review of published literature.
39
40
Section III: Forecasting the Future
2016 Subspecialty Day | Ocular Oncology & Pathology
Update on Orbital Xanthogranuloma Diseases:
Role of BRAF Inhibition
Hakan Demirci MD
This heterogeneous group of rare orbital and ocular adnexal
disorders are classified as class II non-Langerhans histiocytic
proliferations.
Classified into 4 subtypes:
1. Adult-onset xanthogranuloma: Any age from 17 to 85
years
●● No gender preference
●● Bilateral, yellow-orange, elevated, indurated, and
nonulcerated xanthomatous eyelids and anterior orbit
lesions
●● Good prognosis without systemic findings
2. Necrobiotic xanthogranuloma: Any age from 20 to 85
years
●● No gender preference
●● Indurated papule, nodule, or plaque that is violaceous,
red-orange, or xanthogranulomatous in color
●● Involves periocular region (bilateral or unilateral),
with other parts of the face, trunk, and extremities
3. Erdheim-Chester disease: Any age from 7 to 84 years
●● Male to female: 2:1
●● Xanthoma-like lesions of eyelids, orbital disease with
exophthalmos, involvement of internal organs, including heart, lungs, retroperitoneum, and bone
●● Bone pain and associated systemic symptoms including fever, weakness, weight loss, and night sweats
4. Adult-onset asthma and periocular xanthogranuloma:
Any age from 22 to 74 years
●● No gender preference
●● Bilateral, yellow-orange, elevated, indurated eyelid
and orbital lesions
●● Associated asthma in patients with sinus histiocytosis
and massive lymphadenopathy
Systemic Associations
■
■
■
Necrobiotic xanthogranuloma is associated with plasma
cell dyscrasias (paraproteinemia, monoclonal gammopathy, Walderstrom macroglobulenemia, plasmacytoma,
multiple myeloma).
In Erdheim-Chester disease, bony lesions including bilateral symmetric osteosclerosis involving metaphyseal and
diaphyseal regions, with sparing epiphyses, are pathognomonic. Obstructive renal impairment, neurologic
manifestations due to CNS involvement, and cardiac,
pulmonary, liver, spleen, and skin involvement are the
other signs.
Adult-onset asthma and periocular xanthogranuloma are
frequently associated with lymphadenopathy, paraprotenemia, and rarely hematologic malignancies including
chronic lymphocytic leukemia, multiple myeloma, and
small lymphocytic lymphoma.
Ethiopathogenesis
The ethiopathogenesis of xanthogranulomatous disorders is
unknown. In the literature, 2 cases with juvenile xanthogranuloma have been reported to be associated with cytomegalovirus.
Reported chromosomal instabilities in juvenile xanthogranuloma suggest a basic genetic defect or evidence of a cellular
response to an environmental agent such as cytomegalovirus.
Similarly, the association of necrobiotic xanthogranuloma and
paraprotenemia suggests that paraprotenemia could be the primary inciting factor or a cofactor that facilitates in eliciting the
characteristic giant cell granulomatous reaction.
Recent studies uncovered a complex network of cytokines
that are involved in the disease process of Erdheim-Chester
disease. A unique inflammatory cytokine signature is characterized by elevated levels of interferon-α, interleukin-12, and
monocyte chemotactic protein-1 and decreased levels of interleukin-4 and interleukin-7. Interleukin-1 and interleukin-6 were
also strongly expressed in biopsies obtained from patients with
Erdheim-Chester disease. It is proposed that the production
of cytokines by histiocytes and associated lymphoid infiltrate
contribute to an inflammatory milieu with resultant tissue
damage and organ dysfunction. The question of whether the
Erdheim-Chester disease process is clonally driven or a reactive
phenomenon was previously debated. In a study from France,
13 of 24 Erdheim-Chester disease patients (57%) showed the
pathogenic gain-of-function V600E mutation in the BRAF
proto-oncogene. The V600E mutation ratio varies from 13% to
100% of patients in different series. As the sensitive techniques
are applied, BRAF V600E mutation is constantly detected in
biopsies and in circulating monoctyes from Erdheim-Chester
disease, demonstrating that Erdheim-Chester disease is a clonal
disease. BRAF V600E mutation has been associated with oncogene-induced senescence, a major protective mechanism against
oncogenic events. In oncogene-induced senescence, the activating mutation of a specific oncogene without additional cooperating mutations leads to cell cycle arrest and induction of proinflammatory molecules. Oncogene-induced senescence has been
linked to the induction of the senescence-associated secretory
phenotype, a proinflammatory pattern characterized by the
same chemokines and cytokines expressed by Erdheim-Chester
disease histiocytes. So, oncogene-induced senescence seems to
play a central role in Erdheim-Chester pathogenesis, as it is able
to integrate the oncogene mutation and the observed inflammatory activation. However, this mutation was not observed in
the other xanthogranulomas. V600E mutations in BRAF protooncogene was observed in 40% of patients with Langerhans cell
histiocytosis, suggesting a common origin of these diseases.
Treatment
In adult-onset xanthogranulomatosis, systemic corticosteroid
can be started with 1 mg/kg per day with tapering as the lesions
abate. Local steroid injections have been used successfully for
eyelid and orbital lesions. Methotrexate was used as corticosteroid-sparing therapy; however, it is not certain that it can be a
Section III: Forecasting the Future
2016 Subspecialty Day | Ocular Oncology & Pathology
first-line therapy. The role of low-dose radiotherapy in the treatment of xanthogranulomatous disorder is controversial.
In Erdheim-Chester disease, systemic corticosteroid, lowdose radiotherapy, and chemotherapy, including cyclophosphamide, doxorubicin, and vincristine, and autologous hematopoietic stem cells were treatment choices used with limited
clinical efficacy. Since the first report of its efficacy in 2005,
interferon-α became the first line during the management of
Erdheim-Chester disease. Depending on the severity of the disease, a dose of 3 million units to 9 million units 3 times/week
was used with a significant overall survival compared to the
other therapies. The optimal dose and schedule have not been
established yet. After the identification of a complex chemokine-cytokine network, IL-1R antagonist anakinra, infliximab,
an anti-TNFα monoclonal antibody, and monoclonal antibody
against the IL-6 receptor has been used. With the recent discovery of BRAF V600E mutation, BRAF inhibitor vemurafenib has
been used in the management of Erdheim-Chester disease. So
far, all patients have had an extremely positive and persistent
response. The duration of therapy and the long-term outcome
are still unclear.
41
References
1. Pearce ZD, Hassan AS. Orbital xanthogranulomatous diseases.
In Demirci H, ed. Orbital Inflammatory Diseases and Their Differential Diagnosis. Berlin: Springer; 2015:61-66.
2. Kerstetter J, Wang J. Adult orbital xanthogranulomatous disease:
a review with emphasis on etiology, systemic associations, diagnostic tools and treatment. Dermatol Clin. 2015; 32:457-463.
3. Campochiaro C, Tomelleri A, Cavlli G, Berti A, Dagna L. Erdheim-Chester disease. Eur J Int Med. 2015; 26:223-229.
4. Haroche J, Charlotte F, Arnaud L, et al. High prevalence of BRAF
V600E mutations in Erdheim-Chester disease but not in other
non-Langerhans cell histiocytoses. Blood 2012; 120:2700-2703.
42
Section III: Forecasting the Future
2016 Subspecialty Day | Ocular Oncology & Pathology
What Pathology Biomarkers Should We Use for
Conjunctival Tumors?
Victor M Elner PhD MD
N OTE S
Section III: Forecasting the Future
2016 Subspecialty Day | Ocular Oncology & Pathology
43
What Pathology Biomarkers Should We Use for
Skin and Orbital Tumors?
Tatyana Milman MD
I. Vascular and Lymphatic Lesions
A. Infantile hemangioma, cavernous hemangioma
(encapsulated cavernous venous lesion, cavernous
venous malformation), lymphangioma (lymphatic
venous malformation), and other vascular malformations
II. Fibrocytic Lesions
A. Solitary fibrous tumor: the role of STAT-6
B. Nodular fasciitis: the role of USP6
C. Dermatofibrosarcoma protuberans: the role of
COL1A/PDGFB rearrangement studies
III. Tumors With Muscle Differentiation
A. Rhabdomyosarcoma: the role of desmin, myogenin, and t(2;13)(q35;q14): PAX3-FOXO1, PAX7FOXO1
A. Spindle cell/pleomorphic lipoma: the role of CD34
and RB1
B. Liposarcoma: the role of MDM2 and CDK4
B. The role of GLUT-1, ERG, CD31, FXIII, and
D2-40
IV. Tumors With Adipocytic Differentiation
V. Epithelial Tumors of Lacrimal Gland
A. Pleomorphic adenoma / adenocarcinoma ex pleomorphic adenoma: the role of 8q12 / PLAG1 studies
B. Adenoid cystic carcinoma: the role of MYB-NFIB
studies
C. Mucoepidermoid carcinoma: the role of MECTMAML studies
VI. Lymphoproliferative Orbital Lesions
A. DLBCL: The role of MYD88, MYC, EBER, and
CD30
VII.Metastases
A. The role of GATA-3, PSMA, NKX3.1, and napsin
A in metastatic carcinomas
44
Section III: Forecasting the Future
2016 Subspecialty Day | Ocular Oncology & Pathology
VEGF Receptors on Orbital Vascular Tumors
Expression of Vascular Endothelial Growth Factors in
Benign Vascular Lesions of the Orbit
Diva Regina Salomão MD, Elizabeth A Atchison MD, and James A Garrity MD
Introduction
Conclusions
Benign vascular lesions comprise a large number of mass-forming lesions in the orbit, varying from 9.5% to 24% of all orbital
masses in large published case series. Although these lesions
have no malignant potential, they can cause significant morbidity through compression and infiltration of crucial structures
and interference with functional anatomy. Treatment has been
usually observation or surgical excision. In this presentation, I
will discuss the expression of the various vascular endothelial
growth factor (VEGF) receptors in a series of these lesions, and
the potential use of anti-VEGF agents as a nonsurgical alternative treatment for such lesions.
Most benign vascular lesions in the orbit in this series expressed
VEGF receptors, particularly VEGFR2, suggesting that there
may be a role for treatment of these lesions with anti-VEGF
agents. Future prospective studies including larger numbers
of cases are necessary to define the effectiveness of anti-VEGF
agents in such patients.
Results
A total of 55 specimens from 52 patients (38 female and 14
male; average age 40 years; range: 75 days – 90 years), all
resected by a single surgeon, were included in our study. The
lesions consisted of venous malformation (38), lymphatic
malformation (7), lymphaticovenous malformation (6), and
capillary hemangioma (4). Immunohistochemical stains were
performed in all specimens for VEGF receptor (VEGFR; nonspecific), VEGFR-1, VEGFR-2, and VEGFR-3. All lesions
expressed VEGFR (27% focal and 73% diffuse). The majority of the lesions (94%) showed diffuse VEGFR-2 expression.
Most lesions expressed VEGFR-3 (20% focal and 76% diffuse).
However, the expression of VEGFR-1 was quite variable, with
45% of all lesions lacking expression for this receptor.
Selected Readings
1. Rootman J, Heran MK, Graeb DA. Vascular malformations of
the orbit: classification and the role of imaging in diagnosis and
treatment strategies. Ophthal Plast Reconstr Surg. 2014; 30:91104.
2. Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its
receptors. Nat Med. 2003; 9:669-676.
3. Shibuya M. Vascular endothelial growth factor and its receptor
system: physiological functions in angiogenesis and pathological
roles in various diseases. J Biochem. 2013; 153:13-19.
Section III: Forecasting the Future
2016 Subspecialty Day | Ocular Oncology & Pathology
45
Is IgG4 Orbitopathy for Real?
James A Garrity MD
IgG4-related sclerosing disease is a recently recognized fibroinflammatory disease syndrome characterized by lymphocytoplasmic mass forming lesions in one or more tissues (usually
exocrine organs), raised serum IgG4 levels, and increased
IgG4 positive plasma cells in the involved tissues. The pancreas (autoimmune sclerosing pancreatitis) was the index
organ described, but since then other sites including biliary
tract, liver, lungs, retroperitoneum / mediastinum, kidney,
breast, thyroid, prostate, lymph nodes, salivary gland, and lacrimal gland have all been reported. Histologically, a chronic
inflammatory lymphocytoplasmic infiltrate includes numerous
IgG4-positive plasma cells associated with CD4- or CD8positive T-lymphocytes producing atrophy of normal tissue
and sclerosis. Reactive lymphoid follicles are frequently present, and lymphomas have been seen. An obliterative phlebitis
may also be present. A more recent consensus statement on the
pathology of IgG4-related sclerosing disease emphasized that
there are organ-specific diagnostic criteria in which histology
is a key component. The two critical diagnostic features are
a characteristic histopathological appearance (dense lymphocytoplasmic infiltrate, fibrosis often arranged in a storiform
pattern, and obliterative fibrosis [not seen commonly in ophthalmic specimens]), along with an elevated number of IgG4
staining cells in the tissue, in terms of both absolute numbers
and ratio of IgG4 to IgG staining cells.
The first reports of ocular adnexal involvement described
lacrimal gland enlargement (dacryoadenitis), and one paper
noted an association with lymphoma. Since then numerous
reports have appeared in the literature with ocular adnexal
disease. The clinical presentation typically resembles that of a
lymphoma—namely, few symptoms and signs other than that
of swelling or protrusion. Pain or an inflammatory presentation is unusual. Associated asthma is common. Radiographic
features of 27 biopsy-proven cases revealed that extraocular
muscle enlargement was the most frequent feature (24/27),
which was typically bilateral (21/24), most commonly involved
the lateral rectus muscle (41/54 orbits), and spared the tendon
(26/27). The next most common feature was lacrimal gland
enlargement, which was seen in 19/27 patients and was bilateral in 11/19. Enlargement of a lacrimal gland plus an extraocular muscle was seen in 16/27 patients. Orbital infiltrates
were present in 12/27; infraorbital nerve enlargement, in 8/27;
and 3/27 had intracranial (cavernous sinus) disease. Paranasal
sinus disease was present in 24/27 patients. One important
finding in patients with enlarged infraorbital nerves is retention of function in contradistinction to infraorbital nerves
infiltrated with lymphoma or carcinoma that do lose their
function. Biopsy specimens of the infraorbital nerve show
infiltration of the peri- and epineuron with sparing of the
endoneuron. Orbital biopsies are often reported as “reactive
lymphoid hyperplasia” with fibrosis as described above. IgG4
staining in and of itself is not diagnostic, as other conditions
are associated with IgG4 tissue staining, such as Castleman
disease, granulomatosis with polyangiitis (formerly Wegener
disease), and eosinophilic granulomatosis with polyangiitis
(Churg-Strauss), to name just a few. This emphasizes the critical appearance of the histologic picture as more important
than the IgG4 staining of the tissue. Our evaluation of any
patient with IgG4 disease includes an examination by a hematologist with imaging of the chest / abdomen / pelvis. Serum
IgG4 levels are checked and are helpful if elevated but not
diagnostic. Further investigation is directed by results of this
evaluation.
In general, for any medical condition, treatment should
be influenced by the natural history, which in IgG4-related
disease is not known. Treatment is directed by the organs
involved and the extent to which they are involved, with a goal
of retaining function of the involved organ before it is replaced
by fibrosis. Corticosteroids are first-line therapy, but relapses
with dosage reductions or steroid dependency are common.
Azathrioprine and mycophenolate mofetil are effective steroidsparing agents, but lymphocyte depletion with rituximab has
been shown to be effective when other treatments fail. Asthma
responds favorably to treatment with rituximab.
In summary, IgG-4 related disease is a real phenomenon,
but questions remain about its etiology, pathogenesis, and ultimate prognosis. What does this mean?
Selected Readings
1. Hamano H, Kawa S, Horiuchi A, et al. High serum IgG4 concentrations in patients with sclerosing pancreatitis. N Engl J Med.
2001; 344:732-738.
2. Kamisawa T, Egawa N, Nakajima H. Autoimmune pancreatitis
is a systemic autoimmune disease. Am J Gastoenterol. 2003;
98:2811-2812.
3. Deshpande V, Zen Y, Chan JKC, et al. Consensus statement
on the pathology of IgG4-related disease. Mod Pathol. 2012;
25:1181-1192.
4. Cheuk W, Yuen HKL, Chan ACL, et al. Ocular adnexal lymphoma associated with IgG4+ chronic sclerosing dacryoadenitis:
a previously undescribed complication of IgG4-related sclerosing
disease. Am J Surg Pathol. 2008; 32:1159-1167.
5. Cheuk W, Yuen HKL, Chan JKC. Chronic sclerosing dacryoadenitis: part of the spectrum of IgG4-related sclerosing disease?
Am J Surg Pathol. 2007; 31:643-645.
6. Plaza JA, Garrity JA, Dogan A, Ananthamurphy A, Witzig TE,
Salomao DR. Orbital inflammation with IgG4-positive plasma
cells: manifestations of IgG4 systemic disease. Arch Ophthalmol.
2011; 129:421-428.
7. Takahira M, Kawano M, Zen Y, Minato H, Yamada K, Sugiyama K. IgG4-related chronic sclerosing dacryoadenitis. Arch
Ophthalmol. 2007; 125:1575-1578.
8. Tiegs-Heiden CA, Eckel LJ, Hunt CH, et al. Immunoglobulin
G4-related disease of the orbit: imaging features in 27 patients.
AJNR Am J Neuroradiol. 2014; 35:1393-1397.
46
Section III: Forecasting the Future
9. Chang SY, Keogh KA, Lewis JE, et al. IgG4-positive plasma cells
in granulomatosis with polyangiitis (Wegener’s): a clinicopathologic and immunohistochemical study on 43 granulomatosis with
polyangiitis and 20 control cases. Hum Pathol. 2013; 44:24322437.
10. Stone JH, Zen Y, Deshpande V. IgG4-related disease. N Engl J
Med. 2012; 366:539-551.
11. Khosroshani A, Carruthers MN, Deshpande V, Unizony S, Bloch
DB, Stone JH. Rituximab for the treatment of IgG4-related disease: lessons from 10 consecutive patients. Medicine 2012; 91:5766.
2016 Subspecialty Day | Ocular Oncology & Pathology
Section III: Forecasting the Future
2016 Subspecialty Day | Ocular Oncology & Pathology
47
Fine-Needle Aspiration Biopsy of the Orbit:
What Works?
Richard C Allen MD PhD
I. History of Fine-Needle Aspiration Biopsy (FNAB) of
the Orbit
1. Kennerdell et al, 1979
2. Dubois et al, 1979
3. Tarkkanen et al, 1982
4. Dresner et al, 1983
B. Disparaging reports in the mid-80s
4. In patients who underwent additional biopsy,
the FNA diagnosis and excisional / incisional
biopsy diagnosis corresponded in 87%.
5. Complications, none of which were significant,
occurred in 6 patients.
B. Lymphoproliferative lesions: 23% underwent additional biopsy to aid in classification.
1. Krohel et al, 1985. Inaccuracy of fine-needle
aspiration biopsy
C. Inflammatory lesions: 48% underwent additional
biopsy to aid in diagnosis.
2. Liu, 1985. Complications of fine-needle aspiration biopsy of the orbit
D. Recommendations from the study
C. Enthusiasm persists in Europe and Asia
1. Zajdela et al, 1990
2. Tijl and Koornneef, 1991
3. Zeppa et al, 1997
4. Rastogi and Jain, 2001
5. 75%-88% diagnostic accuracy reported.
1. Patients with anterior lesions that are thought to
be inflammatory or lymphoproliferative should
undergo an incisional biopsy with the patient
awake.
2. If the lesion is radiographically suggestive of a
lesion that would best be treated with complete
excision, FNA does not need to be performed.
3. If the lesion is the in the posterior third of the
orbit, FNA should not be done.
4. All other lesions should be considered for FNA.
Patients with suspected posterior inflammatory or lymphoproliferative lesions may need an
additional biopsy.
5. If the FNA gives normal cytology, an open
biopsy should be considered.
D. FNAB in Stockholm
1. Seregard and Tani
2. Up to 99% successful diagnosis with the use of
immunohistochemistry and flow cytometry
II.Concerns
A. Lymphoproliferative lesions
B. Inflammatory lesions
C. Cavernous hemangioma
D.Meningioma
E. Needle tract seeding
III.Advantage
Less invasive
IV.Disadvantages
A. Less material
B. Need for an experience cytopathologist
3. Successful diagnosis is not dependent on the
size, quadrant, or imaging appearance of the
lesion.
A. Enthusiasm in the 1970s and early 80s
V. Recent Study From Stockholm
A. 210 orbits from 2005 to 2013
1. Diagnosis obtained in 176/210 orbits.
2. FNA is more successful in anterior and palpable
lesions.
References
1. Kennerdell JS, et al. Fine-needle aspiration biopsy: its use in
orbital tumors. Arch Ophthalmol. 1979; 97:1315-1317.
2. Dubois PJ, et al. Computed tomographic localization for fine needle aspiration biopsy of orbital tumors. Radiology 1979; 131:149152.
3. Tarkkanen A, et al. Fine-needle aspiration biopsy in the diagnosis
of orbital tumors. Graefes Arch Clin Exp Ophthalmol. 1982;
219:165-170.
4. Dresner SC, et al. Fine needle aspiration biopsy of metastatic
orbital tumors. Surv Ophthalmol. 1983; 27:397-398.
5. Krohel GB, et al. Inaccuracy of fine needle aspiration biopsy.
Ophthalmology 1985; 92:666-670.
6. Liu D. Complications of fine needle aspiration biopsy of the orbit.
Ophthalmology 1985; 92:1768-1771.
7. Zajdela A, et al. Fine-needle cytology of 292 palpable orbital and
eyelid tumors. Am J Clin Pathol. 1990; 93:100-104.
8. Tijl JW, Koornneef L. Fine needle aspiration biopsy in orbital
tumors. Br J Ophthalmol. 1991; 75:491-492.
48
Section III: Forecasting the Future
9. Zeppa P, et al. Fine needle aspiration (FNA) biopsy of orbital
mass: a critical review of 51 cases. Cytopathology 1997; 8:366372.
10. Rastogi A, Jain S. Fine needle aspiration biopsy in orbital lesions.
Orbit 2001; 20:11-23.
11. Tani E, et al. Fine-needle aspiration cytology and immunocytochemistry of orbital masses. Diagn Cytopathol. 2006; 34:1-5.
12. Wiktorin AC, et al. Fine-needle aspiration biopsy in orbital
lesions: a retrospective study of 225 cases. Am J Ophthalmol.
2016; 166:37-42.
2016 Subspecialty Day | Ocular Oncology & Pathology
Section III: Forecasting the Future
2016 Subspecialty Day | Ocular Oncology & Pathology
How Can We Improve Ocular Oncology Care in
Developing Nations?
Fairooz Puthiyapurayil Manjandavida MD
N OTE S
49
50
Section III: Forecasting the Future
2016 Subspecialty Day | Ocular Oncology & Pathology
Day by Day Ocular Oncology in India
Santosh G Honavar MD
Introduction
The practice of ocular oncology involves diagnosis and management of tumors of the eyelid, ocular surface, intraocular structures, and orbit. The spectrum of clinical cases and the severity
(and thus prognosis) varies from one geographic region to
another. While basal cell carcinoma is the most common malignant eyelid tumor and melanoma is the predominant ocular
surface and intraocular tumor in the West, these are relatively
rare in the East. While Group D and E retinoblastoma comprise
20%-30% of new cases in the developed countries, over 75% of
retinoblastoma in India present at an advanced stage. This presentation aims to highlight the clinical spectrum of cases that
one encounters in India.
Observations
Among malignant tumors of the eyelid, sebaceous gland carcinoma is most common (50%-70%), followed by squamous cell
carcinoma and basal cell carcinoma, and very rarely melanoma.
Prognosis is excellent with excision with 4-mm clinically clear
margins, intraoperative frozen section margin control, and
conjunctival map biopsy when indicated. Sebaceous gland carcinoma often presents at an advanced stage, with primary orbital
invasion and regional lymph node metastasis. We use chemoreduction in such situations to reduce the tumor bulk, following
which local tumor excision often becomes feasible in cases that
otherwise would have needed primary orbital exenteration.
Ocular surface squamous neoplasia is the most common
malignant conjunctival tumor in India. Standard management
includes surgical excision with 4-mm clinically clear margins
with alcohol-assisted keratoepitheliectomy for the corneal epithelial component and excision edge cryotherapy. The use of
topical chemotherapy (mitomycin C) and topical or injectable
immunotherapy (interferon alpha-2b) has now replaced surgery
in several patients or has resulted in minimally invasive surgery
for the residual tumor following optimal chemoreduction. The
use of anterior segment imaging to evaluate the tumor base and
plaque brachytherapy for tumors with scleral infiltration has
helped improve the prognosis for eye salvage.
Retinoblastoma is the most common primary malignant
intraocular tumor in India. A majority of patients present at
an advanced stage, thus precluding the use of standard intravenous chemotherapy. We extensively use high-dose intravenous
chemotherapy, intra-arterial chemotherapy, periocular chemotherapy, and intravitreal chemotherapy to optimize eye and
vision salvage. Standardized enucleation with a long optic nerve
stump, assessment of histopathological high-risk features, and
adjuvant therapy as appropriate has become the standard of
care. Successful use of multimodal treatment for orbital retinoblastoma has brought in a paradigm change. With these recent
advances, we are able to save over 90% of the eyes overall, and
to salvage life in 95% of children with retinoblastoma using
cost-effective treatment protocols.
The prognosis has improved in certain difficult malignant
tumors of the orbit, such as rhabdomyosarcoma and adenoid
cystic carcinoma of the lacrimal gland, with the use of multimodal treatment protocol.
Day-by-day practice of ocular oncology in India is challenging yet interesting and provides scope for lateral thinking and
customization of treatment modalities to improve life, eye, and
vision salvage.
Section III: Forecasting the Future
2016 Subspecialty Day | Ocular Oncology & Pathology
51
The First Eye Cancer Working Day in Paris: Outcomes
Paul T Finger MD for the Ophthalmic Oncology Task Force
I. Multicenter Tumor Registries
A. Toronto: Uveal melanoma, retinoblastoma, vitreoretinal lymphoma, and conjunctival melanoma
B. Houston: eyelid, orbital carcinoma
C. Copenhagen: ocular adnexal lymphoma
D. Mainstream ophthalmic oncology: American Joint
Commission on Cancer (AJCC) / Union for International Cancer Control (UICC) staging
E. Evidence-Based medicine, recurrence-based mortality. What is TNMH!
II. Retinoblastoma Specialists for Unserved Countries
A. The Eye Cancer Foundation
B. Princess Margaret Cancer Center
C. Children’s Eye Cancer Foundation Germany KAKS
D. International Council of Ophthalmology
E. IRB World
III. Doctor-Reported Outcomes
A. Literature-based self-reporting
B. Web-based self-reporting
C. Clinical guidelines
D. EMR crawlers
E. E-Cancer Care
IV. Open Access Surgical Textbook
A. Best practice recommendations for:
1. Generalists providing oncology care
2. Specialists without access
B. Opens dialog for sharing techniques that are not
typically published
V. The Second International Working Day at the ISOO
2017
A. Organizing Committee
B.Outline
C. What we need to do!
Selected Readings
1. Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A;
Ophthalmic Oncology Task Force. Ophthalmic sites. Part X of
The AJCC Cancer Staging Manual, 7th ed. (New York: Springer;
2009, 8 chapters).
2. Ophthalmic Oncology Task Force. Ophthalmic sites. Part X of
The AJCC Cancer Staging Manual, 8th ed. In press.
3. AJCC Ophthalmic Oncology Task Force; Simpson ER, Gallie BL,
Saakyan S, et al. International validation of the American Joint
Committee on Cancer’s 7th edition classification of uveal melanoma. JAMA Ophthalmol. 2015; 133(4):376-383.
4. AJCC Ophthalmic Oncology Task Force; Gallie BL, Simpson ER,
Saakyan S, et al. Local recurrence significantly increases the risk
of metastatic uveal melanoma. Ophthalmology 2016; 123:86-91.
5. Kirkegaard MM, Rasmusssen PK, Coupland SE, et al. Conjunctival lymphoma: an international multicenter retrospective study.
JAMA Ophthalmol. 2016; 134(4):406-414.
6. Much-Peterson HD, Rasmussen PK, Coupland SE, et al. Ocular
adnexal diffuse large B-cell lymphoma: a multicenter international study. JAMA Ophthalmol. 2015; 133(2):165-173.
7. Rasmussen PK, Coupland SE, Finger PT, et al. Ocular adnexal
follicular lymphoma: a multicenter international study. JAMA
Ophthalmol. 2014; 132(7):851-858.
8. American Brachytherapy Society – Ophthalmic Oncology Task
Force. The American Brachytherapy Society consensus guidelines
for plaque brachytherapy of uveal melanoma and retinoblastoma.
Brachytherapy 2014; 13:1-14.
9. Nassar QJ, Roth KG, Warneke CL, Yin VT, El Sawy T, Esmaeli
B. Impact of AJCC “T” designation on risk of regional lymph
node metastasis in patients with squamous carcinoma of the eyelid. Br J Ophthalmol. 2014; 98(4):498-501.
10. Finger PT. The 7th edition AJCC staging system for eye cancer: an
international language for ophthalmic oncology. Arch Pathol Lab
Med. 2009; 133(8):1197-1198.
52
Section IV: Frosty Opinions in Ocular Oncology
2016 Subspecialty Day | Ocular Oncology & Pathology
Conjunctival Melanoma: How to Beat This Disease
Jill Razor Wells MD
I.Epidemiology
III. Clinical Features
A. Incidence is between 0.24 to 0.8 per million.
A. Typically unilateral
B. Represents 2%-4% of ocular melanomas
C. More common in fourth to seventh decades of life
B. Thickened, raised, smooth pigmented lesion with
dilated feeder vessels and surrounding areas of pigment (see Figure 2)
D. White to black ratio: 13.6 : 1
C. May be amelanotic (see Figure 3)
D. Most develop in the bulbar conjunctiva at the
limbus but can be found in caruncle, plica, and palpebral conjunctiva. Worse prognosis if not on the
bulbar conjunctiva.
II. Risk Factors and Associated Diseases
A. No clear evidence that ultraviolet radiation is a
causative factor
B. Two main precursors to melanoma are nevus and
primary acquired melanosis (PAM) with atypia
1. 17% of conjunctival melanomas associated with
conjunctival nevus
2. 71% of conjunctival melanomas associated with
PAM with atypia
a. Up to 50% of PAM with atypia cases can
progress to melanoma, so this condition
must be treated (see Figure 1).
b. PAM without atypia is unlikely to progress
to melanoma.
3. Racial- or complexion-associated melanosis has
no malignant potential.
Figure 2.
Figure 1.
Figure 3.
2016 Subspecialty Day | Ocular Oncology & Pathology
Section IV: Frosty Opinions in Ocular Oncology
IV.Diagnosis
A. Definitive diagnosis is made by histopathologic
examination.
2. Mean interval between treatment and recurrence is 2.5 years.
3. Risk factors for recurrence include treatment
with excision alone and no adjuvant therapy,
location other than limbus, positive surgical
margins, and multifocal disease.
B. If conjunctival melanoma is suspected, do not perform an incisional biopsy.
V.Treatment
A. Standard of care is surgical excision with wide margins (at least 3 mm) using a “no touch” technique.
1. Double freeze thaw cryotherapy to the margins
and base at the time of surgery
2. When deep limbal or scleral involvement is
suspected, partial sclerectomy should be considered.
C. Adjuvant therapy after excision
1. Mitomycin C typically used by ocular oncologists for melanoma
a. Never use as primary treatment
b. Occlude punctum prior to starting drops
c. Can cause limbal stem cell deficiency
2. Interferon alpha-2b
a. Drops are tolerated well.
b. Only few reports in the literature
3. Sentinel lymph node biopsy to detect metastases
and provide opportunity to treat systemic disease
a. Controversial with no consensus
b. May be indicated for patients with ≥ 2 highrisk clinical and/or pathological features for
nodal metastasis, including tumor thickness
> 2 mm, nonlimbal location, histopathologic
ulceration, and presence of > 1 mitotic figure
4. Possibility of new biological therapies
a. Genetic mutations identified in conjunctival
melanoma include BRAF, KIT, and NRAS.
b. Clinical studies may help identify medications targeting these pathways.
VI.Prognosis
A. Local recurrence
B. Metastatic disease and mortality
1. Systemic metastases following surgical excision
range from 11%-16% to 18-26% at 5 and 10
years.
2. Metastatic disease can be found in the liver,
lung, brain, and skin.
3. According to the American Joint Commission
on Cancer classification of conjunctival melanoma, 5- and 10-year estimates of melanomarelated death were 5%-23% and 14%-20%,
respectively.
4. Risk factors for mortality include thickness
greater than 2 mm, de novo origin, nodular
growth pattern, caruncular involvement, recurrence, and involvement of nonbulbar conjunctiva.
3. If corneal involvement, alcohol epitheliectomy
should be performed.
B. PAM must be treated with excision and/or cryo as
it can be the origin of recurrent melanoma.
1. Reported in 56%-65% of cases
53
Selected Readings
1. Wong JR, Nanji AA, Galor A, Karp CL. Management of conjunctival malignant melanoma: a review and update. Expert Rev
Ophthalmol. 2014; 9(3):185-204.
2. Shields JA, Shields CL, dePotter P. Surgical management of conjunctival tumors: the 1994 Lynn B McMahan Lecture. Arch Ophthalmol. 1997; 115:808-815.
3. Shields CL, Markowitz JS, Belinsky I, et al. Conjunctival melanoma: outcomes based on tumor origin in 382 consecutive cases.
Ophthalmology 2011; 118(2):389-395.
4. Damato B, Coupland SE. Conjunctival melanoma and melanosis: a reappraisal of terminology, classification and staging. Clin
Experiment Ophthalmol. 2008; 36(8):786-795.
5. Shields CL, Kaliki S, Al-Dahmash SA, Lally SE, Shields JA. American Joint Committee on Cancer (AJCC) clinical classification predicts conjunctival melanoma outcomes. Ophthal Plast Reconstr
Surg. 2012; 28(5):313-323.
6. Aziz HA, Gastman BR, Singh AD. Management of conjunctival
melanoma: critical assessment of sentinel lymph node biopsy.
Ocul Oncol Pathol. 2015; 1(4):266-273.
7. Larcen AC, Dahmcke CM, Dahl C, et al. A retrospective review
of conjunctival melanoma presentation, treatment, and outcome
and an investigation of features associated with BRAF mutations.
JAMA Ophthalmol. 2015; 133(11):1295-1303.
8. Kao A, Afshar A, Bloomer M, Damato B. Management of primary acquired melanosis, nevus, and conjunctival melanoma.
Cancer Control. 2016; 23(2):117-125.
54
Section IV: Frosty Opinions in Ocular Oncology
2016 Subspecialty Day | Ocular Oncology & Pathology
Conjunctival Squamous Cell Carcinoma:
Which Topical Therapy and Why?
Carol L Karp MD
Adapted/excerpted from Nanji AA, Moon CS, Galor A, Sein J,
Oellers P, Karp CL. Surgical versus medical treatment of ocular surface squamous neoplasia: a comparison of recurrences
and complications. Ophthalmology 2014; 121(5):994-1000.
Ocular surface squamous neoplasia (OSSN) encompasses a
spectrum of epithelial squamous malignancies, ranging from
dysplasia to invasive carcinoma. It represents the most common
nonpigmented tumor of the ocular surface. Risk factors for this
disease include human immunodeficiency virus (HIV),1,2 ultraviolet light exposure,3,4 exposure to petroleum products,5 heavy
cigarette smoking,5 age,6 and male gender.6 Human papilloma
virus (HPV) has also been implicated in the pathogenesis of
OSSN, although its role remains controversial.7-11
Traditional treatment for OSSN involves excision alone
with a no-touch technique, described by Shields.12 Despite the
surgeon’s best efforts, there is likely microscopic disease beyond
the edge of the clinically identified lesion, and the frequency of
recurrence with excision alone has been reported to be as high
as 56%.13 Even with clear margins on pathology specimens,
recurrences of up to 33% have been reported.13 As a result,
adjuvant therapies are often performed with excision, including cryotherapy or topical chemotherapy, with reduction in the
rates of recurrence.14-16
Extensive tumor excision can carry risks of limbal stem cell
deficiency and symblephara formation. In order to potentially
avoid these risks and treat the entire ocular surface, medical
treatment alone has increased in popularity.17 This has allowed
for treatment of the entire ocular surface, treating subclinical
tumor load.
Chemotherapeutic agents used for treatment of OSSN
include mitomycin C, 5-fluorouracil, and interferon-alpha-2b
(IFNα2b), all of which have been shown to be effective.16-26
Our discussion today will evaluate the pros and cons of surgery vs. interferon, 5-fluorouracil, and mitomycin as therapy for
OSSN.
References
1. Guech-Ongey M, Engels EA, Goedert JJ, et al. Elevated risk for
squamous cell carcinoma of the conjunctiva among adults with
AIDS in the United States. Int J Cancer. 2008; 122:2590-2593.
2. Nagaiah G, Stotler C, Orem J, et al. Ocular surface squamous
neoplasia in patients with HIV infection in sub-Saharan Africa.
Curr Opin Oncol. 2010; 22:437-442.
3. Lee GA, Hirst LW. Incidence of ocular surface epithelial dysplasia
in metropolitan Brisbane: a 10-year survey. Arch Ophthalmol.
1992; 110:525-527.
4. Waddell K, Kwehangana J, Johnston WT, et al. A case-control
study of ocular surface squamous neoplasia (OSSN) in Uganda.
Int J Cancer. 2010; 127:427-432.
5. Napora C, Cohen EJ, Genvert GI, et al. Factors associated with
conjunctival intraepithelial neoplasia: a case control study. Ophthalmic Surg. 1990; 21:27-30.
6. Lee GA, Hirst LW. Retrospective study of ocular surface squamous neoplasia. Aust N Z J Ophthalmol. 1997; 25:269-276.
7. Scott IU, Karp CL, Nuovo GJ. Human papillomavirus 16 and 18
expression in conjunctival intraepithelial neoplasia. Ophthalmology 2002; 109:542-547.
8. Eng HL, Lin TM, Chen SY, et al. Failure to detect human papillomavirus DNA in malignant epithelial neoplasms of conjunctiva by
polymerase chain reaction. Am J Clin Pathol. 2002; 117:429-436.
9. Tulvatana W, Bhattarakosol P, Sansopha L, et al. Risk factors
for conjunctival squamous cell neoplasia: a matched case-control
study. Br J Ophthalmol. 2003; 87:396-398.
10. Guthoff R, Marx A, Stroebel P. No evidence for a pathogenic role
of human papillomavirus infection in ocular surface squamous
neoplasia in Germany. Curr Eye Res. 2009; 34:666-671.
11. Manderwad GP, Kannabiran C, Honavar SG, Vemuganti GK.
Lack of association of high-risk human papillomavirus in ocular
surface squamous neoplasia in India. Arch Pathol Lab Med. 2009;
133:1246-1250.
12. Shields JA, Shields CL, De Potter P. Surgical management of
conjunctival tumors: the 1994 Lynn B. McMahan Lecture. Arch
Ophthalmol. 1997; 115:808-815.
13. Tabin G, Levin S, Snibson G, et al. Late recurrences and the necessity for long-term follow-up in corneal and conjunctival intraepithelial neoplasia. Ophthalmology 1997; 104:485-492.
14. Peksayar G, Altan-Yaycioglu R, Onal S. Excision and cryosurgery
in the treatment of conjunctival malignant epithelial tumours. Eye
(Lond). 2003; 17:228-232.
15. Siganos CS, Kozobolis VP, Christodoulakis EV. The intraoperative use of mitomycin-C in excision of ocular surface neoplasia
with or without limbal autograft transplantation. Cornea 2002;
21:12-16.
16. Midena E, Angeli CD, Valenti M, et al. Treatment of conjunctival
squamous cell carcinoma with topical 5-fluorouracil. Br J Ophthalmol. 2000; 84:268-272.
17. Adler E, Turner JR, Stone DU. Ocular surface squamous neoplasia: a survey of changes in the standard of care from 2003 to
2012. Cornea 2013; 32(12):1558-1561.
18. Ballalai PL, Erwenne CM, Martins MC, et al. Long-term results
of topical mitomycin C 0.02% for primary and recurrent conjunctival-corneal intraepithelial neoplasia. Ophthal Plast Reconstr
Surg. 2009; 25:296-299.
19. Frucht-Pery J, Sugar J, Baum J, et al. Mitomycin C treatment for
conjunctival-corneal intraepithelial neoplasia: a multicenter experience. Ophthalmology 1997; 104:2085-2093.
20. Galor A, Karp CL, Chhabra S, et al. Topical interferon alpha 2b
eye-drops for treatment of ocular surface squamous neoplasia: a
dose comparison study. Br J Ophthalmol. 2010; 94:551-554.
21. Karp CL, Galor A, Chhabra S, et al. Subconjunctival / perilesional
recombinant interferon alpha2b for ocular surface squamous neoplasia: a 10-year review. Ophthalmology 2010; 117:2241-2246.
2016 Subspecialty Day | Ocular Oncology & Pathology
22. Karp CL, Galor A, Lee Y, Yoo SH. Pegylated interferon alpha 2b
for treatment of ocular surface squamous neoplasia: a pilot study.
Ocul Immunol Inflamm. 2010; 18:254-260.
23. Yeatts RP, Engelbrecht NE, Curry CD, et al. 5-Fluorouracil for
the treatment of intraepithelial neoplasia of the conjunctiva and
cornea. Ophthalmology 2000; 107:2190-2195.
24. Joag MG, Sise A, Murillo JC, Sayed-Ahmed IO, Wong JR, Mercado C, Galor A, Karp CL. Topical 5-fluorouracil 1% as primary
treatment for ocular surface squamous neoplasia. Ophthalmology. 2016; 123(7):1442-1448.
25. Schechter BA, Koreishi AF, Karp CL, Feuer W. Long-term followup of conjunctival and corneal intraepithelial neoplasia treated
with topical interferon alfa-2b. Ophthalmology 2008; 115:12911296, 6 e1.
26. Sturges A, Butt AL, Lai JE, Chodosh J. Topical interferon or
surgical excision for the management of primary ocular surface
squamous neoplasia. Ophthalmology 2008; 115:1297-1302, 302
e1.
Section IV: Frosty Opinions in Ocular Oncology
55
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Section IV: Frosty Opinions in Ocular Oncology
2016 Subspecialty Day | Ocular Oncology & Pathology
Conjunctival Lymphoma: What Works
Sara E Lally MD
I. Lymphoid Tumors
A. Range from benign reactive lymphoid hyperplasia
to malignant lymphoma
B. Difficult to differentiate them clinically
C. Can occur in intraocular and periocular structures
D. Conjunctiva is the area most commonly involved.
VII.Treatment
A. Observation: Why not?
B. Oral antibiotics: Does it work?
C. Cryotherapy: Viable option?
D. Complete excision: If possible?
E.Radiation
II.Etiology
A.Infectious
B.Autoimmune
“Salmon patch”: pink fleshy mass
A. Likes to hide out in the fornices, must look carefully
B. Incidence on the rise
A.Incisional
B.Excisional
V. Pathology: How to Send Specimen and What Study
A. Mucosa-associated lymphoid tissue (MALT)
B.Follicular
C.Diffuse
VI.Workup
A. American Joint Commission on Cancer classification / staging
B. Systemic monitoring: unilateral vs. bilateral
involvement
2.Doses
F. Systemic therapy
1. Immunotherapy: cd20 antibody
2.Chemotherapy
IV. Diagnosing: Biopsy
1.Types
III. Clinical Features
G. Intralesional injection
1. Interferon alpha-2b
2.Rituximab
VIII.Pseudolymphoma
A. Benign reactive lymphoid hyperplasia
B.Amyloidosis
C. Follicular conjunctivitis
D. Drug induced
E.Others
2016 Subspecialty Day | Ocular Oncology & Pathology
Section IV: Frosty Opinions in Ocular Oncology
Vitreoretinal Lymphoma:
How Can We Improve Outcomes?
Tero T Kivela MD
N OTE S
57
58
Section IV: Frosty Opinions in Ocular Oncology
2016 Subspecialty Day | Ocular Oncology & Pathology
BAP-1 Cancer Predisposition Syndrome
Colleen M Cebulla MD PhD
I.
BAP1 Germline Mutation / BAP1-TPDS (OMIM
614327)
IX. Proposed Counseling Recommendations
Consider genetics referral / germline testing for BAP1
in patients who are or have:
A. 2010: Uveal melanoma somatic mutation
1. One germline case reported
A. Family members of germline mutation carriers
2. Harbour, et al. (Science, 2010)
B. 2 or more BAP1 tumors in the patient / family
C. Exception for 2 cases of cutaneous melanoma—
high-frequency gen population
B. 2011: Hereditary predisposition syndrome
1. Uveal melanoma (UM) and other cancers:
Abdel-Rahman, et al. (J Med Genet.)
2. Cutaneous melanoma and atypical spitz tumors:
Wiesner, et al. (Nat Genet.)
X. Our Recommendations for GERMLINE BAP1Positive Individuals and Families
A. Annual eye examination: age, 11 years (5 years
younger than the earliest reported case of UM
(Hoiom, et al., 2013)
B. Referral pigmented ocular lesions to an ocular
oncologist
C. Annual dermatological examination: age, 20 years
(5 years younger than the earliest reported CM in
BAP1 families; see Abdel-Rahman et al., 2011)
D. Consider VHL renal protocol imaging (MRI q2y)
for renal disease and mesothelioma.
3. Mesothelioma: Testa, et al. (Nat Genet.)
C.2013
1. Renal carcinoma: Popova, et al. (Am J Human
Genet.)
II.Purpose
To provide an update on the hereditary BAP1-TPDS
(OMIM 614327)
III.Comprehensive BAP1-TPDS Review
A. 57 families with 174 individuals with germline
BAP1 mutation
B. Autosomal dominant with high penetrance
(148/174, 88%)
C. 67 male (39%), 95 female (55%), 12 not reported
D. Younger median age cancer diagnosis; UM most
common cancer
XI.Conclusions
A. Important hereditary cancer syndrome
B. Risk of UM and other tumors/cancers
C. Need for ocular oncology monitoring
XII. OSU Uveal Melanoma Genetics Study
IV. Other Possible Cancers
V. 8 Major Cancer BAP1 Families
A. 56/57 families presented with 1 or more of 4 main
cancers.
B. 1/57 with atypical spitz nevi and another cancer
1. Phone: 614.293.7774
[email protected]
B. Dr. Cebulla: [email protected]
XIII. Uveal Melanoma Team at OSU
A. Ocular Oncology
VI. Tumor Aggressiveness
1. Colleen Cebulla
A. Increased for:
2. Frederick Davidorf
A. Rob Pilarski: study coordinator
B. Radiation Oncology
1. Uveal melanoma
2. Cutaneous melanoma
1. Doug Martin
3. Renal carcinoma
2. Karl Haglund
3. Allison Quick
B. Decreased for: Mesothelioma
VII.Germline BAP1 in Young Patients with UM
VIII.Germline BAP1 in Familial UM
C.Pathology
1. Lynn Schoenfield
2016 Subspecialty Day | Ocular Oncology & Pathology
D. Cancer Genetics
Section IV: Frosty Opinions in Ocular Oncology
XIV.Acknowledgments
1. Robert Pilarski
A. Melanoma Know More Foundation
2. Mohamed Abdel-Rahman
B. American Cancer Society, IRG-67-003-47
3. Karan Rai
C. National Eye Institute, K08EY022672
D. National Cancer Institute, R21CA191943
E. Medical Oncology
1. Thomas Olencki
E. Ohio Lions Eye Research Foundation
2. Kari Kendra
F. Patti Blow Research Fund in Ophthalmology
3. Joanne Jeter
G. Ocular Melanoma Foundation
F. Surgical Oncology
1. Hepatic perfusion/resection: Carl Schmidt
2. Neurosurgery / Spine, skull base: Brad Elder
59
60
Section IV: Frosty Opinions in Ocular Oncology
2016 Subspecialty Day | Ocular Oncology & Pathology
Future Applications of Uveal Melanoma
Genetic Testing
J William Harbour MD
N OTE S
Section IV: Frosty Opinions in Ocular Oncology
2016 Subspecialty Day | Ocular Oncology & Pathology
61
Systemic Melanoma Therapies that Work
Ivana K Kim MD
I. Unique Molecular Biology of Uveal Melanoma1,2
1. MAP kinase pathway
2. PI3K / AKT / mTOR pathway
3. YAP pathway
B. Few other recurring mutations
1.BAP1
2.SF3B1
3.EIF1AX
A. MEK inhibition
1.Selumetinib
a. Phase 2 study: selumetinib vs. chemotherapy3
i. Longer progression-free survival in selumetinib group (15.9 weeks vs. 7 weeks,
HR = 0.46, P < .001)
ii. No benefit for overall survival (11.8
months vs. 9.1 months, HR = 0.66, P = .09)
b. Phase 3 study (SUMIT): selumetinib + dacarbazine vs. placebo + dacarbazine4
i. No benefit in progression-free survival
(2.8 months vs. 1.8 months, HR = 0.78,
P = .32)
2.Others
B. Other targets: PKC, PI3K, MET, mTOR, HDAC
C. Combination strategies
III.Immunotherapies
A. Checkpoint blockade
1.CTLA-4
a.Ipilmumab5
i. Median progression-free survival: 2.8-3.6
months
ii. Median overall survival: 5.2-10.3 months
iii. Responses + stable disease: 46% at 12
weeks, 28% at 23 weeks6
b.Tremelimumab7
i. Median progression-free survival: 2.9
months
ii. Median overall survival: 12.8 months
iii. No responses
a.Pembrolizumab8
i. Single report: 8/10 patients evaluated for
response; all patients previously treated
with ipilimumab
ii. Median progression-free survival: 18
weeks
iii. Reponses + stable disease: 50%
B. Dendritic cell vaccination9
II. Targeted Therapies
2.PD-1
A. Frequent mutations in GNAQ and GNA11; resulting activation of downstream signaling pathways
1. 14 patients
2. Median overall survival: 19.2 months
3. Stable disease in 10/14 at 3 months, 3/14 at 6
months
IV. Adjuvant Therapy
A. No proven agent
B. Both targeted agents and immunotherapy under
investigation
References
1. Chattopadhyay C, Kim DW, Gombos DS, et al. Uveal melanoma:
from diagnosis to treatment and the science in between. Cancer
2016; 122(15):2299-2312.
2. Luke JJ, Triozzi PL, McKenna KC, et al. Biology of advanced
uveal melanoma and next steps for clinical therapeutics. Pigment
Cell Melanoma Res. 2014; 28(2):135-147.
3. Carvajal RD, Sosman JA, Quevedo JF, et al. Effect of selumetinib
vs chemotherapy on progression-free survival in uveal melanoma:
a randomized clinical trial. JAMA 2014; 311(23):2397-2405.
4. Komatsubara KM, Manson DK, Carvajal RD. Selumetinib for the
treatment of metastatic uveal melanoma: past and future perspectives. Future Oncol. 2016; 12(11):1331-1344.
5. Zimmer L, Vaubel J, Mohr P, et al. Phase II DeCOG-study of ipilimumab in pretreated and treatment-naïve patients with metastatic
uveal melanoma. PLoS ONE 2015; 10(3):e0118564.
6. Luke JJ, Callahan MK, Postow MA, et al. Clinical activity of ipilimumab for metastatic uveal melanoma: a retrospective review of
the Dana-Farber Cancer Institute, Massachusetts General Hospital, Memorial Sloan-Kettering Cancer Center, and University Hospital of Lausanne experience. Cancer 2013; 119(20):3687-3695.
7. Joshua AM, Monzon JG, Mihalcioiu C, Hogg D, Smylie M,
Cheng T. A Phase 2 study of tremelimumab in patients with
advanced uveal melanoma. Melanoma Res. 2015; 25(4):342-347.
8. Kottschade LA, McWilliams RR, Markovic SN, et al. The use of
pembrolizumab for the treatment of metastatic uveal melanoma.
Melanoma Res. 2016; 26(3):300-303.
9. Bol KF, Mensink HW, Aarntzen EHJG, et al. Long overall survival after dendritic cell vaccination in metastatic uveal melanoma
patients. Am J Ophthalmol. 2014; 158(5):939-947.
62
Section IV: Frosty Opinions in Ocular Oncology
2016 Subspecialty Day | Ocular Oncology & Pathology
Do I Use the American Joint Committee on
Cancer Classification?
Alison Skalet MD PhD
The short answer: No, not routinely for clinical care. But I do
think staging is important.
Staging is a basic tenet of cancer care designed to serve several purposes:
1. Document the extent of disease and facilitate clinical
communication
2. Assist in determining appropriate treatment
3. Provide a measurement tool for gauging therapeutic
response
4. Provide prognostic information
5. Facilitate exchange of data / research
Currently, staging using the American Joint Committee on
Cancer (AJCC) system rarely dictates clinical care for uveal
melanoma patients. The AJCC system is defined by the primary
tumor (T), lymph node (N), and distant metastasis (M). Based
upon these factors, a disease stage (0-IV) is determined. For
uveal melanoma, tumor classification is based upon tumor size,
location, and presence of extrascleral extension. Nodal involvement is exceedingly rare in uveal melanoma, and the vast majority of patients do not have overt metastatic disease at the time of
diagnosis. Therefore, stratification for uveal melanoma patients
based upon the seventh edition AJCC system is limited primarily to tumor features, but the system does not include information pertinent to ocular morbidity and ophthalmic treatment
decisions. Similarly, therapeutic response to local treatment
is not easily documented using the AJCC system. While presence of metastatic disease (stage IV) necessarily changes care,
more aggressive therapy is not typically offered to patients
with higher stage disease (ie, stage III). This may change in the
future, with better therapeutic options and emerging adjuvant
therapies.
Prognostication is an important consideration. The AJCC
system has been validated in a large multicenter study to have
prognostic value for metastasis-free survival.1 However, my
preference is to use molecular prognostication when possible.
For patients who decline biopsy but desire prognostic information, I do discuss the AJCC Ocular Oncology Task Force data.
The most compelling reason to use a standardized staging
system is to facilitate research. While the AJCC system is not
perfect, it does provide a language to efficiently communicate
the information most pertinent to survival outcomes, with the
exception of molecular prognostic testing. With the promise of
novel therapeutics on the horizon, staging will become more
relevant. Improvements in coding specificity as well as disease
staging, together with more widespread adoption of a staging
system, will allow us to better study uveal melanoma and will
provide a foundation for the type of collaborative research necessary for improving survival and vision outcomes.
Reference
1. AJCC Ophthalmic Oncology Task Force. International validation
of the American Joint Committee on Cancer’s 7th Edition Classification of Uveal Melanoma. JAMA Ophthalmol. 2015; 133:376383.
2016 Subspecialty Day | Ocular Oncology & Pathology
Section IV: Frosty Opinions in Ocular Oncology
63
Why You Should Use the American Joint Commission
on Cancer Classification
Stefan Seregard MD
The key issue for the development of all cancer treatment is to
be able to compare, and the appropriate comparison is made
prospectively in the setting of a clinical trial. For this we need to
make sure we compare cancers with a similar prognosis.
Cancer is a heterogeneous group of diseases, with any entity
typically arranged in groups defined by their prognosis—socalled staging. This makes comparison easier and less prone to
bias. Anatomy, like size, location, and histopathologic features,
and presence or absence of metastases are important in assessing prognosis, but we are increasingly aware that a number of
other factors, so-called biomarkers, also come into play. In the
future, such biomarkers will increasingly be incorporated into
cancer staging.
The American Joint Commission on Cancer (AJCC) classification was first published in 1977, and for many years there
has been a collaborative effort with the International Union for
Cancer Control (UICC). The present AJCC classification is the
result of the combined efforts of workers from many countries
and as such is a product of the ocular oncology community. The
present AJCC classification is certainly not perfect; in fact, as
more knowledge is gained there will always be a need to further
refine the classification. Work is in progress to replace the current seventh edition with an updated version.
The editors of most ophthalmic journals now require that
cancer data published in any one of their journals are presented
uniformly according to the AJCC classification. Therefore, if
cancer data are not classified according to AJCC, you are less
likely to get your work published. Ocular cancer is rare, and
improvement in treatment requires multicenter collaboration.
Such collaboration should be based on the common ground provided by the AJCC classification. There is no alternative classification of a similar international standing.
In conclusion, the only reason for you not to use the seventh
edition AJCC would be that the eighth edition has already
become available.
64
Section IV: Frosty Opinions in Ocular Oncology
2016 Subspecialty Day | Ocular Oncology & Pathology
Online Forum and Social Media: Communication
Between Oncologist and Pathologist
Heather A D Potter MD
The need for a forum in which to collaborate comes from 4
main features common to ophthalmic pathology and oncology.
1.
2.
3.
4.
Small total number and widely spread geographically
Absence of local colleagues
Case complexity
Innovative specialty
Currently we have regional and national meetings, we have
excellent journals, and we have friends and colleagues with
whom we can consult.
And we have a forum built by the Academy. The forum is a
HIPPA-compliant way to communicate with each other regarding:
■
■
■
■
■
Complex cases where help / input would be appreciated
Interesting cases for teaching medical students, residents,
and fellows
Polls of existing labs with regard to new technology /
techniques
New changes to technology / reimbursement
Updates to our educational materials
One email is sent when there is an update to the forum, and
this contains a link to take the user there. The current use of
and membership to our forum will be discussed, and individuals will be present to help American Association of Ophthalmic
Oncologists and Pathologists members subscribe to the forum.
Section IV: Frosty Opinions in Ocular Oncology
2016 Subspecialty Day | Ocular Oncology & Pathology
65
Telemedicine in Ocular Oncology and Pathology:
What Works
Hans E Grossniklaus MD
Table 1.
I.Telemedicine
A. Branch of telehealth
Date
Historical Milestones
B. Remote transfer of clinical information via electronic communication
1968
Black-and-white photos sent via video
1980
Remote telepathology broadcasting
1986
Video robotic telepathology
1989
Norway nationwide telepathology
1990
Published VA experience
1994
Hardware becomes available
1995
AFIP static image consult service
A. Models: face to face, oral medications, chemo­
therapy infusion, multidisciplinary teams
(MDTs)
2000
WSI comes to market
2001
Dynamic telepathology U.S. Army Telemedicine Program
2005
U.S. Army converts to WSI platform
B. Examples: Townsville Teleoncology Network
(TTN), Kansas Telemedicine Network
2009
FDA panel meeting
C. Existing model: Medical oncologists consult to
rural doctors and/or nurses
2011
WSI dynamic robotic / static imaging systems
2013
Telepathology guidelines Royal College of Pathologists
D.MDTs
2014
Updated guidelines ATA
E. Concerns: physical examination, remote supervision of chemotherapy
Abbreviations: AFIP indicates Armed Forces Institute of Pathology; WSI, whole
slide imaging; ATA, American Telemedicine Association.
F. Patient satisfaction: 80% to 90%
Table 2.
G. Physicians less satisfied
Advantages
Disadvantages
Rapid diagnosis
Some cases difficult to handle
C. Internet, video conferencing, store & forward
imaging, streaming media, wireless communication, teleconferencing
D. Subdivided: teleoncology, telepathology, teleophthalmology, etc.
II.Teleoncology
III.Telepathology
A. Historical milestones: See Table 1
Cost-effective
Deferral to glass slide in some cases
B. Advantages/disadvantages: See Table 2
Remote sites
May take longer than slide review
C. Types of telepathology: See Table 3
Remote frozen sections
Technology errors and down time
FNAB
System maintenance required
Potential to improve care
State limited licensure
Abbreviation: FNAB indicates fine needle aspiration biopsy.
Table 3.
Technology
Method
Image System
Remote
Control
Images
per Case
Image
Selection
Bandwidth
Needed
Cost
Static
Still
No
Limited
Host
Low
Low
Dynamic
Live
Yes
Unlimited
Telepathologist
High
High
Whole slide imaging
Still
Yes
Unlimited
Telepathologist
High
High
Hybrid
Still and live
Yes
Unlimited
Telepathologist
High
High
66
Section IV: Frosty Opinions in Ocular Oncology
D. Eye pathology examples
1. Internet Based Eye Pathology Teaching Initiative
(IBETI)
2. American Association of Ophthalmic Oncologists and Pathologists Virtual Eye Path Slides
2016 Subspecialty Day | Ocular Oncology & Pathology
V. What Works?
A. Static images for teaching and clinical impressions
B. Equipment for static images inexpensive and available
C. Dynamic images for teaching and more in-depth
pathology assessment
D. Equipment for dynamic images (Aperio, etc.)
expensive; institutional purchase
IV.Teleophthalmology
A. Widely accepted
B. Worldwide adoption: UK, Canada, India
C. Care extenders
1. Store & forward
2. Live contact
D.Examples
1. PHOTO ED (nonmydriatic emergency department fundus photos)
2. TECS (Technology-based Eye Care Services)
3. Proposed: Uveal Nevus Teleimaging Project
Selected Readings
1. Sabesan S. Medical models of teleoncology: current status and
future directions. Asia-Pacific J Clin Oncol. 2014; 10:200-204.
2. Farahani N, Pantanowitz L. Overview of telepathology. Clin Lab
Med. 2016; 36:101-112.
3. Lynch MG, Maa AY. The use of telemedicine to extend ophthalmology care. JAMA Ophthalmol. 2016; 134:543-544.
2016 Subspecialty Day | Ocular Oncology & Pathology
Section V: Weathering the Storm
67
Comparative Eye Pathology:
The Third Dimension in Eye Pathology
Daniel M Albert MD MS
I.Background
A. Comparative pathology: An old discipline (Hammurabi, 2100 BC; Aristotle, 350 BC)
B. Specimens collected at Armed Forces Institute of
Pathology since 1862
II. My Introduction to the Subject
A. Whale eye specimen
B. Elk eye episode
C. Melanocytoma and snake eyes
III. Differences Exist
Dog melanomas and asteroid hyalosis
IV. Lens Tumors: Humans vs. Animals
A. Ida Mann’s dictum
B. Trout lens tumors
C. Induced lens tumors in hamsters
D. Spontaneous lens tumors in cats and other animals
E. No occurrence in humans
F. Hypothesis and ongoing research
Selected Readings
1. von Sallmann L, et al. Thioacetamide-induced cataract with invasive proliferation of the lens epithelium in rainbow trout. Cancer
Res. 1966; 26(8):1819-1825.
2. Albert DM, et al. Neoplastic transformation in vitro of hamster
lens epithelium by simian virus 40. Science 1969; 164(3883):10771078.
3. Woog J, Albert DM, et al. Osteosarcoma in a phthisical feline eye.
Vet Pathol. 1983; 20(2):209-214.
4. Dubielzig RR. Ocular sarcoma following trauma in three cats.
J Am Vet Med Assoc. 1984; 184(5):578-581.
5. Dubielzig RR, Albert DM, et al. Clinical and morphologic features of post-traumatic ocular sarcomas in cats. Vet Pathol. 1990;
27(1):62-65.
68
Section V: Weathering the Storm
2016 Subspecialty Day | Ocular Oncology & Pathology
Ocular Oncology: What I Like and Don’t Like
David H Abramson MD FACS
■
■
Assigned topic: What I like and don’t like
My topic: Mistaken ideas, hypotheses, and misinterpretation of results in ocular oncology that led to major
advances in the field
I. Gerd Myer-Schwickerath MD1
A. Hypothesis: Photocoagulation of macula holes
would prevent peripheral retinal detachment.
B. 103 cases of macula hole photocoagulated in macula (and no retinal detachments)
C. Misinterpretation: Untreated macula holes rarely
(?never) lead to rhegmatogenous detachments.
VI. Carol Shields MD
A. Hypothesis: Systemic chemotherapy decreases the
incidence of pineal tumors in children with bilateral retinoblastoma.
B. Based on two papers: First on 1 patient, second on
4 patients. Published conclusion says “no statistical
evidence… but I still believe it.”
C. Based on incorrect assumption for incidence of
pineal. Subsequent meticulous meta-analysis
showed incidence of trilateral to be not 10% but
closer to 2%.6
D. Led to successful development of photocoagulation
of ocular tumors (benign and malignant)
II. Algernon B Reese MD2
A. Hypothesis: Adding systemic chemotherapy to
external beam radiation allowed him to reduce the
dose of 15,000 rads to 7500 rads and still be successful.
VII. Ophthalmic Community
A. CCSG (Children’s Cancer Study Group) protocol
961
B. Randomized trial of systemic chemotherapy for
unilateral retinoblastoma enucleated. Result: Excellent and equal survival in both chemotherapy group
and no chemotherapy group. Recommendation: no
systemic chemotherapy for unilateral retinoblastoma unless outside the eye.
C. But many centers still expose children to systemic
chemotherapy for so called “high-risk factors.”
Survival excellent and similar to centers that use no
systemic chemotherapy.
B. Misinterpretation: Chemotherapy not needed to
decrease the dose: Success with only 7500 rads
would have been attained without chemotherapy.
III. Robert M Ellsworth MD
A. Hypothesis: Late metastases of retinoblastoma may
occur (even 30 years later).
B. Sent me to the Armed Forces Institute of Pathology
C. Recognition that bilateral patients had a cancer
predilection and that this predilection was altered
by exposure to external beam irradiation3
IV. David H Abramson MD
A. Hypothesis: Periocular chemotherapy can cure retinoblastoma.4
B. Pharmacokinetics / importance of dose
C. Recognition that retinoblastoma can be cured with
chemotherapy alone, but doses with periocular
delivery are not high enough; doses attained with
intra-arterial or intravitreal are curative.
V. Lorenz E Zimmerman MD
A. Hypothesis: Enucleation causes release of cells and
explains peak of metastases in uveal melanoma
within 2.5 years after procedure.5
B. Mathematical modeling demonstrating metastases
within 2.5 years after enucleation.
C. Led to recognition that uveal melanoma is more
than one disease. One such group (class II tumors)
present with metastases within a few years of diagnosis or treatment by any means.
References
1. Meyer-Schwickerath G. The preservation of vision by treatment
of intraocular tumors with light coagulation. Arch Ophthalmol.
1961; 66:458-466.
2. Reese AB, Hyman GA, Tapley ND, Forrest AW. The treatment
of retinoblastoma by x-ray and triethylene melamine. AMA Arch
Ophthalmol. 1958; 60(5):897-906.
3. Abramson DH, Ellsworth RM, Zimmerman LE. Nonocular cancer in retinoblastoma survivors. Trans Sect Ophthalmol Am Acad
Ophthalmol Otolaryngol. 1976; 81(3 pt 1):454-457.
4. Abramson DH, Frank CM, Dunkel IJ. A Phase I/II study of subconjunctival carboplatin for intraocular retinoblastoma. Ophthalmology 1999; 106(10):1947-1950.
5. Zimmerman LE, McLean IW, Foster WD. Statistical analysis of
follow-up data concerning uveal melanomas, and the influence of
enucleation. Ophthalmology 1980; 87(6):557-564.
6. de Jong MC, Kors WA, de Graaf P, Castelijns JA, Kivelä T, Moll
AC. Trilateral retinoblastoma: a systematic review and metaanalysis. Lancet Oncol. 2014; 15(10):1157-1167.
2016 Subspecialty Day | Ocular Oncology & Pathology
Section V: Weathering the Storm
69
Forty Years in Practice: I Will Tell You 5 Secrets
Evangelos S Gragoudas MD
Introduction
Forty years ago almost all eyes with malignant melanoma were
enucleated. The management of uveal melanoma (UM) has
changed, and most eyes are treated with conservative therapies.
Some unanswered questions still exist. I will share “secrets”
about 5 issues that remain controversial.
1. Management of Suspicious Lesions
Rates of malignant transformation depend on the presence of
several risk factors.1 Presence of orange pigment, subretinal
fluid, and symptoms are some of the predictors. Growth of the
lesion is the most reliable but not the most certain predictor.
Rates of growth vary between 4% and 56%, depending on the
number of risk factors present.
In my experience, follow-up of these lesions before definite
and significant growth does not increase the risk of dying from
UM and avoids treatments that are associated with morbidity
in many patients. Of 334 suspicious lesions followed at Massachusetts Eye and Ear (MEE), 39 showed signs of tumor growth
or other changes and were subsequently treated with proton
irradiation. Two of these patients, treated 10 and 20 months
after initial presentation at MEE, developed metastasis and died
from UM 4.7 years and 10.3 years after receiving treatment.2
There is no evidence to indicate that earlier treatment of these
cases would have prevented metastasis.
2. Management of Iris Melanomas
The natural history of iris “melanomas” is different than that
of choroidal melanomas, raising the question of their malignant
potential. In one study of iris and iridociliary melanomas, 87%
were reclassified as benign lesions after pathological evaluation.3 Iris melanoma dimensions are usually small, and these
tumors rarely metastasize. Treatment should be restricted to
“large” iris melanomas that show definitive and significant
growth.
3. Treatment of Tumor Recurrences
The management of recurrences after conservative treatment
has not been established. Reasonable results after proton irradiation of patients with recurrences have been demonstrated in
our group and suggest that enucleation is unnecessary in many
cases. In a recent review of 51 patients with tumor recurrences
treated with proton beam irradiation at MEE, median visual
acuity at last follow-up examination was 20/800, with 39.5%
of patients retaining vision of at least 20/200. Four patients
underwent enucleation due to complications. Approximately
one-third of patients (n = 18) developed metastasis. In another
study4 of treatment for recurrences, 32% who had proton irradiation died of UM, compared to 59% who underwent enucleation.
4. Treatment of Collaborative Ocular Melanoma
Study (COMS) Ineligible Tumors
Conservative treatments can be used to treat patients with large
tumors (largest tumor diameter > 16 mm or height > 10 mm)
and tumors near the optic nerve (≤ 1 disc diameter) that were
excluded from the COMS. Reasonably good results can be
achieved in patients with these tumors using proton beam irradiation: vision loss is not inevitable, particularly for patients
with small–medium tumors near the optic nerve, and long-term
eye conservation is possible. Visual acuity of 20/200 or better
was observed in 54.9% of patients at 2 years after irradiation,
but this diminished to 20.3% by 5 years after irradiation.5
5. Metastatic Surveillance
The optimal timing and battery of tests to use for diagnosis of
metastasis remains unclear. The COMS found no differences in
survival between patients who received treatment for metastatic
disease and those who did not.6 In a Finnish registry, patients
diagnosed with metastatic melanoma at an annual examination
experienced longer survival than those diagnosed after developing symptoms (8.9 months vs. 4.3 months; P = .08), but there
was no difference in survival from the time of initial tumor
diagnosis (P = .25) to death.7
At MEE, we evaluated the incidence of metastasis in asymptomatic (early diagnosis) vs. symptomatic (late diagnosis)
patients8 and found the following:
a. Longer median survival time from diagnosis of metastasis
to death was observed in asymptomatic patients.
b. Similar median survival time from diagnosis of primary
tumor to death was observed in asymptomatic patients
and symptomatic patients.
These data suggest lead-time bias. (See Figure 1.)
Regardless of the surveillance protocols that are followed,
until effective treatments for hepatic metastasis are found, the
benefit of surveillance is limited. Our data demonstrate that no
progress has been made during the last 2 decades in improving
survival after diagnosis of metastasis. The 1-year survival rate
in 614 patients with metastasis was 20%, and after 3 years, only
4% of patients were alive. Over half of these patients (n = 323)
received treatment, which included chemotherapy (44%) and
treatment with more than one modality—eg, radiation, surgery
(35%). Median survival was 6 months for patients who received
treatment compared to 1.5 months for patients who did not
receive treatment. Consistent with our findings, a meta-analysis
of 25 clinical trials9 provided no evidence that any treatments
for liver metastases prolong life. More recently, in a randomized Phase 2 clinical trial of selumetinib vs. chemotherapy
for patients with metastatic uveal melanoma, no improvement in overall survival and a high rate of adverse events were
observed.10
70
Section V: Weathering the Storm
2016 Subspecialty Day | Ocular Oncology & Pathology
Early Dx of Mets
Dx of tumor
Death
TM=31.4
T0
TD=40.6
Late Dx of Mets
Dx of tumor
T0
0
TM=40.3
3
6
9
12
15 18
21
24 27
30 33
36 39
Death
TD=45.1
42 45
48
Months after Initial Diagnosis of Tumor
Figure 1. Median time to metastasis and death.
References
1. Shields CL, Cater J, Shields JA, Singh AD, Santos MC, Carvalho
C. Combination of clinical factors predictive of growth of small
choroidal melanocytic tumors. Arch Ophthalmol. 2000; 118:360364.
2. Lane AM, Egan KM, Kim IK, Gragoudas ES. Mortality after
diagnosis of small melanocytic lesions of the choroid. Arch Ophthalmol. 2010; 128:996-1000.
3. Jakobiec FA, Silbert G. Are most iris “melanomas” really nevi? A
clinicopathologic study of 189 lesions. Arch Ophthalmol. 1981;
99:2117-2132.
4. Marucci L, Ancukiewicz M, Lane AM, Collier JM, Gragoudas
ES, Munzenrider JE. Uveal melanoma recurrence after fractionated proton beam therapy: comparison of survival in patients
treated with reirradiation or with enucleation. Int J Radiat Oncol
Biol Phys. 2011; 79:842-846.
5. Lane AM, Kim IK, Gragoudas ES. Proton irradiation for peripapillary and parapapillary melanomas. Arch Ophthalmol. 2011;
129:1127-1130.
6. Diener-West M, Reynolds SM, Agugliaro DJ, et al. Development
of metastatic disease after enrollment in the COMS trials for
treatment of choroidal melanoma: Collaborative Ocular Melanoma Study Group Report No. 26. Arch Ophthalmol. 2005;
123:1639-1643.
7. Eskelin S, Pyrhönen S, Hahka-Kemppinen M, Tuomaala S, Kivelä
T. A prognostic model and staging for metastatic uveal melanoma.
Cancer 2003; 97:465-475.
8. Kim IK, Lane AM, Gragoudas ES. Survival in patients with presymptomatic diagnosis of metastatic uveal melanoma. Arch Ophthalmol. 2010; 128:871-875.
9. Augsburger JJ, Corrêa ZM, Shaikh AH. Effectiveness of treatments for metastatic uveal melanoma. Am J Ophthalmol. 2009;
148:119-127.
10. Carvajal RD, Sosman JA, Quevedo JF, et al. Effect of selumetinib
vs chemotherapy on progression-free survival in uveal melanoma:
a randomized clinical trial. JAMA. 2014; 311:2397-2405.
2016 Subspecialty Day | Ocular Oncology & Pathology
Section V: Weathering the Storm
Running an Ocular Oncology Practice:
My Top 5 Lessons Learned
Jerry A Shields MD
1. Patients come first.
2. Take care of your office staff.
3. Teach your colleagues and students.
4. Try to be academic.
a. Be organized.
b. Keep track of good cases.
c. Set up coding system so that you can retrieve large
series of disease.
d. Document with excellent images and know your
technology.
5. Learn the business of running a business.
71
Financial Disclosure
2016 Subspecialty Day | Ocular Oncology & Pathology
73
Financial Disclosure
The Academy has a profound duty to its members, the larger
medical community and the public to ensure the integrity of
all of its scientific, educational, advocacy and consumer information activities and materials. Thus each Academy Trustee,
Secretary, committee Chair, committee member, taskforce
chair, taskforce member, councilor, and representative to other
organizations (“Academy Leader”), as well as the Academy
staff and those responsible for organizing and presenting CME
activities must disclose interactions with Companies and manage conflicts of interest or the appearance of conflicts of interest that affect this integrity. Where such conflicts or perceived
conflicts exist, they must be appropriately and fully disclosed
and resolved.
All contributors to Academy educational and leadership
activities must disclose all financial relationships (defined
below) to the Academy annually. The ACCME requires the
Academy to disclose the following to participants prior to the
activity:
■
■
All financial relationships with Commercial Companies
that contributors and their immediate family have had
within the previous 12 months. A commercial company is
any entity producing, marketing, re-selling or distributing
health care goods or services consumed by, or used on,
patients.
Meeting presenters, authors, contributors or reviewers
who report they have no known financial relationships to
disclose.
The Academy will request disclosure information from
meeting presenters, authors, contributors or reviewers, committee members, Board of Trustees, and others involved in
Academy leadership activities (“Contributors”) annually.
Disclosure information will be kept on file and used during
the calendar year in which it was collected for all Academy
activities. Updates to the disclosure information file should be
made whenever there is a change. At the time of submission of a
Journal article or materials for an educational activity or nomination to a leadership position, each Contributor should specifically review his/her statement on file and notify the Academy of
any changes to his/her financial disclosures. These requirements
apply to relationships that are in place at the time of or were in
place 12 months preceding the presentation, publication submission, or nomination to a leadership position. Any financial
relationship that may constitute a conflict of interest will be
resolved prior to the delivery of the activity.
Visit www.aao.org/about/policies for the Academy’s policy
on identifying and resolving conflicts of interest.
Financial Relationship Disclosure
For purposes of this disclosure, a known financial relationship
is defined as any financial gain or expectancy of financial gain
brought to the Contributor or the Contributor’s immediate family (defined as spouse, domestic partner, parent, child or spouse
of child, or sibling or spouse of sibling of the Contributor) by:
■
■
■
■
■
Direct or indirect compensation;
Ownership of stock in the producing company;
Stock options and/or warrants in the producing company,
even if they have not been exercised or they are not currently exercisable;
Financial support or funding to the investigator, including research support from government agencies (e.g.,
NIH), device manufacturers, and/or pharmaceutical
companies; or
Involvement with any for-profit corporation that is likely
to become involved in activities directly impacting the
Academy where the Contributor or the Contributor’s
family is a director or recipient
Description of Financial Interests
Category Code Description
Consultant / Advisor
C
Consultant fee, paid advisory
boards or fees for attending a
meeting
Employee E
Employed by a commercial
company
Lecture Fees L
Lecture and speakers bureau
fees (honoraria), travel fees or
reimbursements when speaking
at the invitation of a commercial company
Equity Owner
O
Equity ownership/stock options
(publicly or privately traded
firms, excluding mutual funds)
Patents / Royalty
P
Patents and/or royalties that
might be viewed as creating a
potential conflict of interest
Grant Support
S
Grant support from all sources
74
Financial Disclosure
2016 Subspecialty Day | Ocular Oncology & Pathology
Faculty Financial Disclosure
Control of Content
The Academy considers presenting authors, not co-authors, to be in control of the educational content. It is Academy policy and
traditional scientific publishing and professional courtesy to acknowledge all people contributing to the research, regardless of
CME control of the live presentation of that content. This acknowledgement is made in a similar way in other Academy CME activities. Though they are acknowledged, co-authors do not have control of the CME content and their disclosures are not published or
resolved.
David H Abramson MD FACS
Bita Esmaeli MD FACS
Ivana K Kim MD
None
Genentech: C
Daniel M Albert MD FACS
Paul T Finger MD
None
LV Liberty Vision: O
Richard C Allen MD PhD
Jasmine H Francis MD
Alcon Laboratories Inc.: C
Allergan: C
Biophytis: C
Genentech: S
Iconic Therapeutics: C
None
None
Mary E Aronow MD
James A Garrity MD
None
None
Kenneth V Cahill MD FACS
Dan S Gombos MD
None
Aura: C
Castle: C
Children’s Oncology Group: S
Iconic Therapeutics: C
Lois Kuss Fund for Glaucoma
Research: S
The Houseman/Wilkins
Ophthalmological Foundation: S
Sara E Lally MD
Evangelos S Gragoudas MD
Miguel A Materin MD
Aura Biosciences: C
Iconic Therapeutics: C
Ocata Therapeutics: C
Valeant Pharmaceuticals: P
Castle Bioscience: C
Colleen M Cebulla MD PhD
None
Patricia Chevez-Barrios MD
None
Murali Chintagumpala MD
None
Victoria M Cohen FRCOphth
None
Zelia M Correa MD
Jonathan W Kim MD
None
Tero T Kivela MD
None
None
Nora V Laver MD
None
Brian P Marr MD
Arua Bioscience: C
Tara A McCannel MD
Impact Genetics: C
Novartis Pharmaceuticals Corp.: C
Castle Biosciences: C
Hans E Grossniklaus MD
Hakan Demirci MD
Tatyana Milman MD
None
Aura Biosciences: S
Clearside Biomedical: P
National Cancer Institute: S
Sander Dubovy MD
J William Harbour MD
Santen Inc.: C
None
Castle Biosciences Inc.: P,C
Ralph Eagle MD
Santosh G Honavar MD
Merck & Co. Inc.: O
None
Victor M Elner PhD MD
G Baker Hubbard MD
OcuSciences: O,P
Takeda: C
None
Carol L Karp MD
None
Disclosures current as of 9/23/2016
Check the Mobile Meeting Guide / Online Program for the most up-to-date financial disclosures.
None
Prithvi Mruthyunjaya MD
Timothy G Murray MD MBA
Alcon Laboratories Inc.: C
Mary A O’Hara MD
None
Heather A D Potter MD
None
Financial Disclosure
2016 Subspecialty Day | Ocular Oncology & Pathology
Jose S Pulido MD MS
Emil Anthony T Say MD
Arun D Singh MD
None
None
None
Fairooz Puthiyapurayil
Manjandavida MD
Amy C Schefler MD
Alison H Skalet MD PhD
Genentech: S
None
Stefan Seregard MD
Jill R Wells MD
None
None
Carol L Shields MD
David J Wilson MD
Aura Bioscience: C
None
Jerry A Shields MD
Matthew W Wilson MD
None
None
None
Rajesh C Rao MD
NIH: S
Mandeep S Sagoo MBBChir PhD
None
Diva R Salomão MD
None
Disclosures current as of 9/23/2016
Check the Mobile Meeting Guide / Online Program for the most up-to-date financial disclosures.
75
76
Presenter Index
2016 Subspecialty Day | Ocular Oncology & Pathology
Presenter Index
Abramson, David 68
Albert, Daniel M 67
Allen, Richard C 47
Aronow, Mary E 3
Cahill, Kenneth V 35
Cebulla, Colleen M 58
Chevez-Barrios, Patricia 7
Chintagumpala, Murali 28
Cohen, Victoria M 22
Correa*, Zelia M 32
Demirci, Hakan 40
Dubovy, Sander 11
Eagle*, Ralph 31
Elner*, Victor M 42
Esmaeli*, Bita 39
Finger*, Paul 51
Francis, Jasmine H 23
Garrity, James A 45
Gombos*, Dan S 29
Gragoudas*, Evangelos S 69
Grossniklaus*, Hans E 65
Harbour*, J William 60
Honavar, Santosh G 50
Hubbard, G Baker 36
Karp, Carol L 54
Kim*, Ivana K 61
Kim, Jonathan W 1
* Indicates that the presenter has financial interest.
No asterisk indicates that the presenter has no financial interest.
Kivela, Tero T 57
Lally, Sara E 56
Laver, Nora V 16
Marr*, Brian P 20
Materin*, Miguel A 21
McCannel*, Tara A 13
Milman, Tatyana 43
Mruthyunjaya*, Prithvi 38
Murray*, Timothy G 19
O’Hara, Mary A 34
Potter, Heather A D 64
Pulido, Jose S 14
Puthiyapurayil Manjandavida, Fairooz 49
Rao*, Rajesh C 12
Sagoo, Mandeep S 24
Salomao, Diva R 44
Say, Emil Anthony T 9
Schefler*, Amy C 4
Seregard, Stefan 63
Shields*, Carol L 5
Shields, Jerry A 71
Singh, Arun D 15
Skalet, Alison H 62
Wells, Jill R 52
Wilson, David J 8
Wilson, Matthew W 26